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	Ashwin Kishtagari, MD Vanderbilt University Nashville, TN, USA LinkedIn

16 regimens on this page 19 variants on this page

Note: these regimens are primarily culled from literature that describes them as part of a comprehensive treatment regimen. If that is the case, the original regimens can be found on the following pages:

CNS prophylaxis, local therapy

IT Cytarabine & Methotrexate

Regimen variant #1, 16 doses

Study	Dates of enrollment	Evidence
Thomas et al. 2006	2000-02 to 2005-01	Pilot, fewer than 20 pts

CNS therapy, prophylaxis

Methotrexate (MTX) by the following route-based criteria:
- LP: 12 mg IT once on day 2
- Ommaya reservoir: 6 mg IT once on day 2
Cytarabine (Ara-C) 100 mg IT once on day 7

Given each cycle for a total of 16 intrathecal treatments

Regimen variant #2, 6 to 8 doses

Study	Dates of enrollment	Evidence
Thomas et al. 1999	1992-09 to 1997-06	Phase 2
Thomas et al. 2003	2001-04 to 2003-03	Phase 2
Ravandi et al. 2010 (MDACC 2006-0478)	2006-09-28 to 2009-07-15	Phase 2

Note: Total number of doses depends on risk for CNS relapse based on serum lactate dehydrogenase (LDH) greater than 1400 IU/L and/or proliferative index percentage of S + G2M greater than or equal to 14%.

CNS therapy, prophylaxis

Methotrexate (MTX) by the following route-based criteria:
- LP: 12 mg IT once on day 2
- Ommaya reservoir: 6 mg IT once on day 2
Cytarabine (Ara-C) 100 mg IT once on either day 7 or 8

Given each cycle (approximately every 3 weeks) for a total of 6 or 8 intrathecal treatments

References

Thomas DA, Cortes J, O'Brien S, Pierce S, Faderl S, Albitar M, Hagemeister FB, Cabanillas FF, Murphy S, Keating MJ, Kantarjian H. Hyper-CVAD program in Burkitt's-type adult acute lymphoblastic leukemia. J Clin Oncol. 1999 Aug;17(8):2461-70. link to original article contains dosing details in manuscript PubMed
Thomas DA, Faderl S, Cortes J, O'Brien S, Giles FJ, Kornblau SM, Garcia-Manero G, Keating MJ, Andreeff M, Jeha S, Beran M, Verstovsek S, Pierce S, Letvak L, Salvado A, Champlin R, Talpaz M, Kantarjian H. Treatment of Philadelphia chromosome-positive acute lymphocytic leukemia with hyper-CVAD and imatinib mesylate. Blood. 2004 Jun 15;103(12):4396-407. Epub 2003 Oct 9. link to original article contains dosing details in manuscript PubMed
1. Update: Daver N, Thomas D, Ravandi F, Cortes J, Garris R, Jabbour E, Garcia-Manero G, Borthakur G, Kadia T, Rytting M, Konopleva M, Kantarjian H, O' Brien S. Final report of a phase II study of imatinib mesylate with hyper-CVAD for the frontline treatment of adult patients with Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia. Haematologica. 2015 May;100(5):653-61. Epub 2015 Feb 14. link to original article link to PMC article PubMed
Thomas DA, Faderl S, O'Brien S, Bueso-Ramos C, Cortes J, Garcia-Manero G, Giles FJ, Verstovsek S, Wierda WG, Pierce SA, Shan J, Brandt M, Hagemeister FB, Keating MJ, Cabanillas F, Kantarjian H. Chemoimmunotherapy with hyper-CVAD plus rituximab for the treatment of adult Burkitt and Burkitt-type lymphoma or acute lymphoblastic leukemia. Cancer. 2006 Apr 1;106(7):1569-80. link to original article contains dosing details in manuscript PubMed
1. Update: Fayad L, Thomas D, Romaguera J. Update of the MD Anderson Cancer Center experience with hyper-CVAD and rituximab for the treatment of mantle cell and Burkitt-type lymphomas. Clin Lymphoma Myeloma. 2007 Dec;8 Suppl 2:S57-62. link to original article PubMed
MDACC 2006-0478: Ravandi F, O'Brien S, Thomas D, Faderl S, Jones D, Garris R, Dara S, Jorgensen J, Kebriaei P, Champlin R, Borthakur G, Burger J, Ferrajoli A, Garcia-Manero G, Wierda W, Cortes J, Kantarjian H. First report of phase 2 study of dasatinib with hyper-CVAD for the frontline treatment of patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia. Blood. 2010 Sep 23;116(12):2070-7. Epub 2010 May 13. link to original article contains dosing details in manuscript--parts of the protocol were not explicitly listed in this reference, which instead referred to Thomas et al. 2004 and Kantarjian et al. 2004 link to PMC article PubMed NCT00390793
1. Update: Ravandi F, O'Brien SM, Cortes JE, Thomas DM, Garris R, Faderl S, Burger JA, Rytting ME, Ferrajoli A, Wierda WG, Verstovsek S, Champlin R, Kebriaei P, McCue DA, Huang X, Jabbour E, Garcia-Manero G, Estrov Z, Kantarjian HM. Long-term follow-up of a phase 2 study of chemotherapy plus dasatinib for the initial treatment of patients with Philadelphia chromosome-positive acute lymphoblastic leukemia. Cancer. 2015 Dec 1;121(23):4158-64. Epub 2015 Aug 26. link to original article link to PMC article PubMed

IT Cytarabine, Methotrexate, Methylprednisolone

Regimen

Study	Dates of enrollment	Evidence
Huguet et al. 2009 (GRAALL-2003)	2003-2005	Phase 2

Note: Intrathecal treatments are given on days 1 & 8 of induction, day 29 of each series of consolidation blocks, and day 1 of late intensification -- 6 doses total.

CNS therapy, prophylaxis

Cytarabine (Ara-C) 40 mg IT mixed with methotrexate and methylprednisolone
Methotrexate (MTX) 15 mg IT mixed with cytarabine and methylprednisolone
Methylprednisolone (Solumedrol) 40 mg IT mixed with cytarabine and methotrexate

6 doses (see note)

References

GRAALL-2003: Huguet F, Leguay T, Raffoux E, Thomas X, Beldjord K, Delabesse E, Chevallier P, Buzyn A, Delannoy A, Chalandon Y, Vernant JP, Lafage-Pochitaloff M, Chassevent A, Lhéritier V, Macintyre E, Béné MC, Ifrah N, Dombret H. Pediatric-inspired therapy in adults with Philadelphia chromosome-negative acute lymphoblastic leukemia: the GRAALL-2003 study. J Clin Oncol. 2009 Feb 20;27(6):911-8. Epub 2009 Jan 5. Erratum in: J Clin Oncol. 2009 May 20;27(15):2574. Dosage error in article text. link to original article contains dosing details in manuscript PubMed NCT00222027

IT Cytarabine, Methotrexate, Prednisone

Regimen

Study	Dates of enrollment	Evidence
Tsukasaki et al. 2007 (JCOG 9801)	1998-2003	Non-randomized part of phase 3 RCT
Ishida et al. 2015 (Kyowa 0761-003)	2010-2011	Non-randomized part of phase 2 RCT

Note: Treatments were given after cycles 1, 3, and 5 after platelets greater than 70 x 10⁹/L and within 2 days before the next cycle.

CNS therapy, prophylaxis

Cytarabine (Ara-C) 40 mg IT mixed with methotrexate and prednisone
Methotrexate (MTX) 15 mg IT mixed with cytarabine and prednisone
Prednisone (Sterapred) 10 mg IT mixed with cytarabine and methotrexate

3 doses (see note)

References

JCOG 9801: Tsukasaki K, Utsunomiya A, Fukuda H, Shibata T, Fukushima T, Takatsuka Y, Ikeda S, Masuda M, Nagoshi H, Ueda R, Tamura K, Sano M, Momita S, Yamaguchi K, Kawano F, Hanada S, Tobinai K, Shimoyama M, Hotta T, Tomonaga M; JCOG. VCAP-AMP-VECP compared with biweekly CHOP for adult T-cell leukemia-lymphoma: Japan Clinical Oncology Group Study JCOG9801. J Clin Oncol. 2007 Dec 1;25(34):5458-64. Epub 2007 Oct 29. link to original article contains dosing details in manuscript PubMed NCT00145002
Kyowa 0761-003: Ishida T, Jo T, Takemoto S, Suzushima H, Uozumi K, Yamamoto K, Uike N, Saburi Y, Nosaka K, Utsunomiya A, Tobinai K, Fujiwara H, Ishitsuka K, Yoshida S, Taira N, Moriuchi Y, Imada K, Miyamoto T, Akinaga S, Tomonaga M, Ueda R. Dose-intensified chemotherapy alone or in combination with mogamulizumab in newly diagnosed aggressive adult T-cell leukaemia-lymphoma: a randomized phase II study. Br J Haematol. 2015 Jun;169(5):672-82. Epub 2015 Mar 2. link to original article link to PMC article PubMed NCT01173887

IT Cytarabine & WBRT

Cytarabine & WBRT: Cytarabine & Whole Brain Radiation Therapy

Regimen

Study	Dates of enrollment	Evidence
Rowe et al. 2005 (MRC UKALL XII/ECOG E2993)	1993-2003	Non-randomized part of phase 3 RCT

Note: while this is not chemoradiation in the traditional sense, the delivery of chemotherapy and radiation overlap so may have synergistic effects.

CNS therapy, prophylaxis

Cytarabine (Ara-C) as follows:
- Consolidation & Maintenance: 50 mg IT once per week for 4 weeks, then once per quarter for 4 doses (8 doses, total)

Radiotherapy

Whole-brain irradiation to 2400 cGy, given during consolidation

References

MRC UKALL XII/ECOG E2993: Rowe JM, Buck G, Burnett AK, Chopra R, Wiernik PH, Richards SM, Lazarus HM, Franklin IM, Litzow MR, Ciobanu N, Prentice HG, Durrant J, Tallman MS, Goldstone AH; ECOG; MRC/NCRI Adult Leukemia Working Party. Induction therapy for adults with acute lymphoblastic leukemia: results of more than 1500 patients from the international ALL trial: MRC UKALL XII/ECOG E2993. Blood. 2005 Dec 1;106(12):3760-7. Epub 2005 Aug 16. link to original article contains dosing details in manuscript PubMed NCT00002514
1. Update: Goldstone AH, Richards SM, Lazarus HM, Tallman MS, Buck G, Fielding AK, Burnett AK, Chopra R, Wiernik PH, Foroni L, Paietta E, Litzow MR, Marks DI, Durrant J, McMillan A, Franklin IM, Luger S, Ciobanu N, Rowe JM. In adults with standard-risk acute lymphoblastic leukemia, the greatest benefit is achieved from a matched sibling allogeneic transplantation in first complete remission, and an autologous transplantation is less effective than conventional consolidation/maintenance chemotherapy in all patients: final results of the International ALL Trial (MRC UKALL XII/ECOG E2993). Blood. 2008 Feb 15;111(4):1827-33. Epub 2007 Nov 29. link to original article PubMed
2. Update: Fielding AK, Rowe JM, Richards SM, Buck G, Moorman AV, Durrant IJ, Marks DI, McMillan AK, Litzow MR, Lazarus HM, Foroni L, Dewald G, Franklin IM, Luger SM, Paietta E, Wiernik PH, Tallman MS, Goldstone AH. Prospective outcome data on 267 unselected adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia confirms superiority of allogeneic transplantation over chemotherapy in the pre-imatinib era: results from the International ALL Trial MRC UKALLXII/ECOG2993. Blood. 2009 May 7;113(19):4489-96. Epub 2009 Feb 24. link to original article link to PMC article PubMed
3. Update: Fielding AK, Rowe JM, Buck G, Foroni L, Gerrard G, Litzow MR, Lazarus H, Luger SM, Marks DI, McMillan AK, Moorman AV, Patel B, Paietta E, Tallman MS, Goldstone AH. UKALLXII/ECOG2993: addition of imatinib to a standard treatment regimen enhances long-term outcomes in Philadelphia positive acute lymphoblastic leukemia. Blood. 2014 Feb 6;123(6):843-50. Epub 2013 Nov 25. link to original article contains dosing details in manuscript link to PMC article PubMed

IT Methotrexate monotherapy

Regimen

Study	Dates of enrollment	Evidence
Rowe et al. 2005 (MRC UKALL XII/ECOG E2993)	1993-2003	Non-randomized part of phase 3 RCT

CNS therapy, prophylaxis

Methotrexate (MTX) as follows:
- Phase 1: 12 mg IT once on day 15
- Phase 2: 12 mg IT once per day on days 1, 8, 15, 22

References

MRC UKALL XII/ECOG E2993: Rowe JM, Buck G, Burnett AK, Chopra R, Wiernik PH, Richards SM, Lazarus HM, Franklin IM, Litzow MR, Ciobanu N, Prentice HG, Durrant J, Tallman MS, Goldstone AH; ECOG; MRC/NCRI Adult Leukemia Working Party. Induction therapy for adults with acute lymphoblastic leukemia: results of more than 1500 patients from the international ALL trial: MRC UKALL XII/ECOG E2993. Blood. 2005 Dec 1;106(12):3760-7. Epub 2005 Aug 16. link to original article contains dosing details in manuscript PubMed NCT00002514
1. Update: Goldstone AH, Richards SM, Lazarus HM, Tallman MS, Buck G, Fielding AK, Burnett AK, Chopra R, Wiernik PH, Foroni L, Paietta E, Litzow MR, Marks DI, Durrant J, McMillan A, Franklin IM, Luger S, Ciobanu N, Rowe JM. In adults with standard-risk acute lymphoblastic leukemia, the greatest benefit is achieved from a matched sibling allogeneic transplantation in first complete remission, and an autologous transplantation is less effective than conventional consolidation/maintenance chemotherapy in all patients: final results of the International ALL Trial (MRC UKALL XII/ECOG E2993). Blood. 2008 Feb 15;111(4):1827-33. Epub 2007 Nov 29. link to original article PubMed
2. Update: Fielding AK, Rowe JM, Richards SM, Buck G, Moorman AV, Durrant IJ, Marks DI, McMillan AK, Litzow MR, Lazarus HM, Foroni L, Dewald G, Franklin IM, Luger SM, Paietta E, Wiernik PH, Tallman MS, Goldstone AH. Prospective outcome data on 267 unselected adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia confirms superiority of allogeneic transplantation over chemotherapy in the pre-imatinib era: results from the International ALL Trial MRC UKALLXII/ECOG2993. Blood. 2009 May 7;113(19):4489-96. Epub 2009 Feb 24. link to original article link to PMC article PubMed
3. Update: Fielding AK, Rowe JM, Buck G, Foroni L, Gerrard G, Litzow MR, Lazarus H, Luger SM, Marks DI, McMillan AK, Moorman AV, Patel B, Paietta E, Tallman MS, Goldstone AH. UKALLXII/ECOG2993: addition of imatinib to a standard treatment regimen enhances long-term outcomes in Philadelphia positive acute lymphoblastic leukemia. Blood. 2014 Feb 6;123(6):843-50. Epub 2013 Nov 25. link to original article contains dosing details in manuscript link to PMC article PubMed

IT Methotrexate & Hydrocortisone

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Sullivan et al. 1977	1971-1973	Phase 3 (C)	IT MTX, Ara-C, HC	Did not meet primary endpoint of DOR
Kim et al. 2015 (AMC-UUCM-2008-0310)	2009-2012	Phase 2

Note: Treatment can be started during or after induction.

CNS therapy, prophylaxis

Methotrexate (MTX) 15 mg IT (schedule not specified), admixed with hydrocortisone
Hydrocortisone (Cortef) 50 mg IT (schedule not specified), admixed with methotrexate

Up to 10 doses

References

Sullivan MP, Moon TE, Trueworthy R, Vietti TJ, Humphrey GB, Komp D. Combination intrathecal therapy for meningeal leukemia: two versus three drugs. Blood. 1977 Sep;50(3):471-9. link to original article PubMed
AMC-UUCM-2008-0310: Kim DY, Joo YD, Lim SN, Kim SD, Lee JH, Lee JH, Kim DH, Kim K, Jung CW, Kim I, Yoon SS, Park S, Ahn JS, Yang DH, Lee JJ, Lee HS, Kim YS, Mun YC, Kim H, Park JH, Moon JH, Sohn SK, Lee SM, Lee WS, Kim KH, Won JH, Hyun MS, Park J, Lee JH, Shin HJ, Chung JS, Lee H, Eom HS, Lee GW, Cho YU, Jang S, Park CJ, Chi HS, Lee KH; Adult Acute Lymphoblastic Leukemia Working Party of the Korean Society of Hematology. Nilotinib combined with multiagent chemotherapy for newly diagnosed Philadelphia-positive acute lymphoblastic leukemia. Blood. 2015 Aug 6;126(6):746-56. Epub 2015 Jun 11. link to original article contains dosing details in manuscript PubMed NCT00844298

IT Methotrexate & Methylprednisolone

Regimen

Study	Dates of enrollment	Evidence
Lo-Coco et al. 2010 (GIMEMA AIDA-2000)	2000-2006	Non-randomized

Note: It is not explicitly stated but presumably these are admixed and given together.

CNS therapy, prophylaxis

Methotrexate (MTX) 12 mg IT once prior to each consolidation cycle
Methylprednisolone (Solumedrol) 40 mg IT once prior to each consolidation cycle

Total of 3 doses

References

GIMEMA AIDA-2000: Lo-Coco F, Avvisati G, Vignetti M, Breccia M, Gallo E, Rambaldi A, Paoloni F, Fioritoni G, Ferrara F, Specchia G, Cimino G, Diverio D, Borlenghi E, Martinelli G, Di Raimondo F, Di Bona E, Fazi P, Peta A, Bosi A, Carella AM, Fabbiano F, Pogliani EM, Petti MC, Amadori S, Mandelli F; GIMEMA. Front-line treatment of acute promyelocytic leukemia with AIDA induction followed by risk-adapted consolidation for adults younger than 61 years: results of the AIDA-2000 trial of the GIMEMA Group. Blood. 2010 Oct 8;116(17):3171-9. Epub 2010 Jul 19. link to original article contains dosing details in manuscript PubMed NCT01064570

IT Methotrexate & WBRT

IT Methotrexate & WBRT: IntraThecal Methotrexate & Whole Brain Radiation Therapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Linker et al. 1987	1980-1986	Phase 2
Nachman et al. 1998 (CCG 1882)	1989-1995	Phase 3 (C)	IT MTX; intensified	Did not meet primary endpoint of EFS

Note: Treatment is started within 1 week of achieving complete remission. Details are from Linker et al. 1987

CNS therapy, prophylaxis

Methotrexate (MTX) 12 mg IT once per week x 6 doses concurrent with radiation

Radiotherapy

Whole-brain irradiation, 1800 cGy total given in 10 fractions over 12 to 14 days

References

Linker CA, Levitt LJ, O'Donnell M, Ries CA, Link MP, Forman SJ, Farbstein MJ. Improved results of treatment of adult acute lymphoblastic leukemia. Blood. 1987 Apr;69(4):1242-8. link to original article contains dosing details in manuscript PubMed
1. Update: Linker CA, Levitt LJ, O'Donnell M, Forman SJ, Ries CA. Treatment of adult acute lymphoblastic leukemia with intensive cyclical chemotherapy: a follow-up report. Blood. 1991 Dec 1;78(11):2814-22. link to original article contains dosing details in manuscript PubMed
CCG 1882: Nachman J, Sather HN, Cherlow JM, Sensel MG, Gaynon PS, Lukens JN, Wolff L, Trigg ME. Response of children with high-risk acute lymphoblastic leukemia treated with and without cranial irradiation: a report from the Children's Cancer Group. J Clin Oncol. 1998 Mar;16(3):920-30. link to original article PubMed

WBRT

WBRT: Whole Brain Radiation Therapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Nesbit et al. 1981	1972-1975	Phase 3 (C)	WBRT; lower-dose	Did not meet endpoint of OS
Freeman et al. 1983 (CALGB 7611)	1976-1979	Phase 3 (C)	Intermediate-dose MTX	Mixed results
Pui et al. 2009 (Total Therapy XV)	2000-2007	Phase 3 (C)	Observation	Did not meet co-primary endpoints of EFS/OS

Note: in Total Therapy XV, this is the control arm of a de-escalation study.

Radiotherapy

Whole-brain irradiation

One course

References

Nesbit ME Jr, Sather HN, Robison LL, Ortega J, Littman PS, D'Angio GJ, Hammond GD; Children's Cancer Group. Presymptomatic central nervous system therapy in previously untreated childhood acute lymphoblastic leukaemia: comparison of 1800 rad and 2400 rad: a report for Children's Cancer Study Group. Lancet. 1981 Feb 28;1(8218):461-6. link to original article PubMed
CALGB 7611: Freeman AI, Weinberg V, Brecher ML, Jones B, Glicksman AS, Sinks LF, Weil M, Pleuss H, Hananian J, Burgert EO Jr, Gilchrist GS, Necheles T, Harris M, Kung F, Patterson RB, Maurer H, Leventhal B, Chevalier L, Forman E, Holland JF. Comparison of intermediate-dose methotrexate with cranial irradiation for the post-induction treatment of acute lymphocytic leukemia in children. N Engl J Med. 1983 Mar 3;308(9):477-84. link to original article PubMed
1. Update: Freeman AI, Boyett JM, Glicksman AS, Brecher ML, Leventhal BG, Sinks LF, Holland JF. Intermediate-dose methotrexate versus cranial irradiation in childhood acute lymphoblastic leukemia: a ten-year follow-up. Med Pediatr Oncol. 1997 Feb;28(2):98-107. link to original article PubMed
Total Therapy XV: Pui CH, Campana D, Pei D, Bowman WP, Sandlund JT, Kaste SC, Ribeiro RC, Rubnitz JE, Raimondi SC, Onciu M, Coustan-Smith E, Kun LE, Jeha S, Cheng C, Howard SC, Simmons V, Bayles A, Metzger ML, Boyett JM, Leung W, Handgretinger R, Downing JR, Evans WE, Relling MV. Treating childhood acute lymphoblastic leukemia without cranial irradiation. N Engl J Med. 2009 Jun 25;360(26):2730-41. link to original article link to PMC article PubMed NCT00137111

CNS prophylaxis, systemic therapy

Mercaptopurine & WBRT

Mercaptopurine & WBRT: Mercaptopurine & Whole Brain Radiation Therapy

Regimen

Study	Dates of enrollment	Evidence
Huguet et al. 2009 (GRAALL-2003)	2003-2005	Phase 2

Note: Chemoradiation is given before maintenance therapy.

Chemotherapy

Mercaptopurine (6-MP) 60 mg/m²/day PO during irradiation

Radiotherapy

Whole-brain irradiation to 1800 cGy (details not provided)

One course

References

GRAALL-2003: Huguet F, Leguay T, Raffoux E, Thomas X, Beldjord K, Delabesse E, Chevallier P, Buzyn A, Delannoy A, Chalandon Y, Vernant JP, Lafage-Pochitaloff M, Chassevent A, Lhéritier V, Macintyre E, Béné MC, Ifrah N, Dombret H. Pediatric-inspired therapy in adults with Philadelphia chromosome-negative acute lymphoblastic leukemia: the GRAALL-2003 study. J Clin Oncol. 2009 Feb 20;27(6):911-8. Epub 2009 Jan 5. Erratum in: J Clin Oncol. 2009 May 20;27(15):2574. Dosage error in article text. link to original article contains dosing details in manuscript PubMed NCT00222027

CNS treatment, local therapy

IT Cytarabine & Methotrexate

Regimen variant #1, LP

Study	Dates of enrollment	Evidence
Thomas et al. 1999	1992-09 to 1997-06	Phase 2

Note: while there is measurable CNS disease, both drugs are given every week, alternating, usually separated by at least 48 hours (e.g., on Mondays & Thursdays).

CNS therapy, treatment

Methotrexate (MTX) as follows:
- Measurable CNS disease: 12 mg IT once per week
- First 4 weeks after cell count & cytology are negative: 12 mg IT once per week on weeks 1 & 3
- Remainder of induction: 12 mg IT once on day 2
Cytarabine (Ara-C) as follows:
- Measurable CNS disease: 100 mg IT once per week
- First 4 weeks after cell count & cytology are negative: 100 mg IT once per week on weeks 2 & 4
- Remainder of induction: 100 mg IT once on day 7 or 8

Regimen variant #2, Ommaya reservoir

Study	Dates of enrollment	Evidence
Thomas et al. 1999	1992-09 to 1997-06	Phase 2

Note: while there is measurable CNS disease, both drugs are given every week, alternating, usually separated by at least 48 hours (e.g., on Mondays & Thursdays).

CNS therapy, treatment

Methotrexate (MTX) as follows:
- Measurable CNS disease: 6 mg IT once per week
- First 4 weeks after cell count & cytology are negative: 6 mg IT once per week on weeks 1 & 3
- Remainder of induction: 6 mg IT once on day 2
Cytarabine (Ara-C) as follows:
- Measurable CNS disease: 100 mg IT once per week
- First 4 weeks after cell count & cytology are negative: 100 mg IT once per week on weeks 2 & 4
- Remainder of induction: 100 mg IT once on day 7 or 8

References

Thomas DA, Cortes J, O'Brien S, Pierce S, Faderl S, Albitar M, Hagemeister FB, Cabanillas FF, Murphy S, Keating MJ, Kantarjian H. Hyper-CVAD program in Burkitt's-type adult acute lymphoblastic leukemia. J Clin Oncol. 1999 Aug;17(8):2461-70. link to original article contains dosing details in manuscript PubMed

IT Cytarabine, Methotrexate, Methylprednisolone

Regimen

Study	Dates of enrollment	Evidence
Huguet et al. 2009 (GRAALL-2003)	2003-2005	Phase 2

Note: Intrathecal treatments are given as follows: eight between days -7 and 21 of induction, four during the first two consolidation blocks, and one at day 29 of consolidation blocks 3 and 6 -- 14 total doses.

CNS therapy, treatment

Cytarabine (Ara-C) 40 mg IT mixed with methotrexate and methylprednisolone
Methotrexate (MTX) 15 mg IT mixed with cytarabine and methylprednisolone
Methylprednisolone (Solumedrol) 40 mg IT mixed with cytarabine and methotrexate

14 doses (see note)

References

GRAALL-2003: Huguet F, Leguay T, Raffoux E, Thomas X, Beldjord K, Delabesse E, Chevallier P, Buzyn A, Delannoy A, Chalandon Y, Vernant JP, Lafage-Pochitaloff M, Chassevent A, Lhéritier V, Macintyre E, Béné MC, Ifrah N, Dombret H. Pediatric-inspired therapy in adults with Philadelphia chromosome-negative acute lymphoblastic leukemia: the GRAALL-2003 study. J Clin Oncol. 2009 Feb 20;27(6):911-8. Epub 2009 Jan 5. Erratum in: J Clin Oncol. 2009 May 20;27(15):2574. Dosage error in article text. link to original article contains dosing details in manuscript PubMed NCT00222027

IT Cytarabine, Methotrexate, WBRT

Cytarabine, Methotrexate, WBRT: Cytarabine, Methotrexate, Whole Brain Radiation Therapy

Regimen variant #1, LP

Study	Dates of enrollment	Evidence
Thomas et al. 2003	2001-04 to 2003-03	Phase 2
Ravandi et al. 2010 (MDACC 2006-0478)	2006-09-28 to 2009-07-15	Phase 2

Note: while there is measurable CNS disease, both drugs are given every week, alternating, usually separated by at least 48 hours (e.g., on Mondays & Thursdays).

CNS therapy, treatment

Methotrexate (MTX) as follows:
- Measurable CNS disease: 12 mg IT once per week
- First 4 weeks after cell count & cytology are negative: 12 mg IT once per week on weeks 1 & 3
- Remainder of induction: 12 mg IT once on day 2
Cytarabine (Ara-C) as follows:
- Measurable CNS disease: 100 mg IT once per week
- First 4 weeks after cell count & cytology are negative: 100 mg IT once per week on weeks 2 & 4
- Remainder of induction: 100 mg IT once on day 7 or 8

Radiotherapy

Therapeutic whole-brain irradiation is given to patients with CNS disease at presentation

Regimen variant #2, Ommaya reservoir

Study	Dates of enrollment	Evidence
Thomas et al. 2003	2001-04 to 2003-03	Phase 2
Ravandi et al. 2010 (MDACC 2006-0478)	2006-09-28 to 2009-07-15	Phase 2

Note: while there is measurable CNS disease, both drugs are given every week, alternating, usually separated by at least 48 hours (e.g., on Mondays & Thursdays).

CNS therapy, treatment

Methotrexate (MTX) as follows:
- Measurable CNS disease: 6 mg IT once per week
- First 4 weeks after cell count & cytology are negative: 6 mg IT once per week on weeks 1 & 3
- Remainder of induction: 6 mg IT once on day 2
Cytarabine (Ara-C) as follows:
- Measurable CNS disease: 100 mg IT once per week
- First 4 weeks after cell count & cytology are negative: 100 mg IT once per week on weeks 2 & 4
- Remainder of induction: 100 mg IT once on day 7 or 8

Radiotherapy

Therapeutic whole-brain irradiation is given to patients with CNS disease at presentation

References

Thomas DA, Faderl S, Cortes J, O'Brien S, Giles FJ, Kornblau SM, Garcia-Manero G, Keating MJ, Andreeff M, Jeha S, Beran M, Verstovsek S, Pierce S, Letvak L, Salvado A, Champlin R, Talpaz M, Kantarjian H. Treatment of Philadelphia chromosome-positive acute lymphocytic leukemia with hyper-CVAD and imatinib mesylate. Blood. 2004 Jun 15;103(12):4396-407. Epub 2003 Oct 9. link to original article contains dosing details in manuscript PubMed
1. Update: Daver N, Thomas D, Ravandi F, Cortes J, Garris R, Jabbour E, Garcia-Manero G, Borthakur G, Kadia T, Rytting M, Konopleva M, Kantarjian H, O' Brien S. Final report of a phase II study of imatinib mesylate with hyper-CVAD for the frontline treatment of adult patients with Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia. Haematologica. 2015 May;100(5):653-61. Epub 2015 Feb 14. link to original article link to PMC article PubMed
MDACC 2006-0478: Ravandi F, O'Brien S, Thomas D, Faderl S, Jones D, Garris R, Dara S, Jorgensen J, Kebriaei P, Champlin R, Borthakur G, Burger J, Ferrajoli A, Garcia-Manero G, Wierda W, Cortes J, Kantarjian H. First report of phase 2 study of dasatinib with hyper-CVAD for the frontline treatment of patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia. Blood. 2010 Sep 23;116(12):2070-7. Epub 2010 May 13. link to original article contains dosing details in manuscript--parts of the protocol were not explicitly listed in this reference, which instead referred to Thomas et al. 2004 and Kantarjian et al. 2004 link to PMC article PubMed NCT00390793
1. Update: Ravandi F, O'Brien SM, Cortes JE, Thomas DM, Garris R, Faderl S, Burger JA, Rytting ME, Ferrajoli A, Wierda WG, Verstovsek S, Champlin R, Kebriaei P, McCue DA, Huang X, Jabbour E, Garcia-Manero G, Estrov Z, Kantarjian HM. Long-term follow-up of a phase 2 study of chemotherapy plus dasatinib for the initial treatment of patients with Philadelphia chromosome-positive acute lymphoblastic leukemia. Cancer. 2015 Dec 1;121(23):4158-64. Epub 2015 Aug 26. link to original article link to PMC article PubMed

IT Methotrexate monotherapy

Regimen

Study	Dates of enrollment	Evidence
Shanbrom et al. 1961	1957-1960	Pilot
Huguet et al. 2009 (GRAALL-2003)	2003-2005	Phase 2

CNS therapy, treatment

Methotrexate (MTX) as follows:
- Pre-phase: 15 mg IT once at some point between days -7 and -4

References

Shanbrom E, Miller S, Fairbanks VF. Intrathecal administration of amethopterin in leukemic encephalopathy of young adults. N Engl J Med. 1961 Jul 27;265:169-71. link to original article PubMed
GRAALL-2003: Huguet F, Leguay T, Raffoux E, Thomas X, Beldjord K, Delabesse E, Chevallier P, Buzyn A, Delannoy A, Chalandon Y, Vernant JP, Lafage-Pochitaloff M, Chassevent A, Lhéritier V, Macintyre E, Béné MC, Ifrah N, Dombret H. Pediatric-inspired therapy in adults with Philadelphia chromosome-negative acute lymphoblastic leukemia: the GRAALL-2003 study. J Clin Oncol. 2009 Feb 20;27(6):911-8. Epub 2009 Jan 5. Erratum in: J Clin Oncol. 2009 May 20;27(15):2574. Dosage error in article text. link to original article contains dosing details in manuscript PubMed NCT00222027

IT Methotrexate & WBRT

IT Methotrexate & WBRT: IntraThecal Methotrexate & Whole Brain Radiation Therapy

Regimen

Study	Dates of enrollment	Evidence
Linker et al. 1987	1980-1986	Phase 2

Note: Treatment starts while patient is receiving induction therapy.

CNS therapy, treatment

Methotrexate (MTX) as follows:
- Induction: 12 mg IT once per week x 10 doses
- Remainder of first year of therapy: 12 mg IT once per month

Radiotherapy

Whole-brain irradiation, 2800 cGy total given (no details provided)

References

Linker CA, Levitt LJ, O'Donnell M, Ries CA, Link MP, Forman SJ, Farbstein MJ. Improved results of treatment of adult acute lymphoblastic leukemia. Blood. 1987 Apr;69(4):1242-8. link to original article contains dosing details in manuscript PubMed
1. Update: Linker CA, Levitt LJ, O'Donnell M, Forman SJ, Ries CA. Treatment of adult acute lymphoblastic leukemia with intensive cyclical chemotherapy: a follow-up report. Blood. 1991 Dec 1;78(11):2814-22. link to original article contains dosing details in manuscript PubMed

CNS treatment, systemic therapy

Mercaptopurine & WBRT

Mercaptopurine & WBRT: Mercaptopurine & Whole Brain Radiation Therapy

Regimen variant #1

Study	Dates of enrollment	Evidence
Huguet et al. 2009 (GRAALL-2003)	2003-2005	Phase 2

Note: Treatment administered before HSCT or maintenence initiation.

Chemotherapy

Mercaptopurine (6-MP) 60 mg/m²/day PO during irradiation

Radiotherapy

Whole-brain irradiation 1500 cGy before HCT (details not provided)

One course

Regimen variant #2

Study	Dates of enrollment	Evidence
Huguet et al. 2009 (GRAALL-2003)	2003-2005	Phase 2

Note: Treatment was administered before HSCT or maintenance initiation.

Chemotherapy

Mercaptopurine (6-MP) 60 mg/m²/day PO during irradiation

Radiotherapy

Whole-brain irradiation 2400 cGy before maintenance therapy initiation (details not provided)

One course

References

GRAALL-2003: Huguet F, Leguay T, Raffoux E, Thomas X, Beldjord K, Delabesse E, Chevallier P, Buzyn A, Delannoy A, Chalandon Y, Vernant JP, Lafage-Pochitaloff M, Chassevent A, Lhéritier V, Macintyre E, Béné MC, Ifrah N, Dombret H. Pediatric-inspired therapy in adults with Philadelphia chromosome-negative acute lymphoblastic leukemia: the GRAALL-2003 study. J Clin Oncol. 2009 Feb 20;27(6):911-8. Epub 2009 Jan 5. Erratum in: J Clin Oncol. 2009 May 20;27(15):2574. Dosage error in article text. link to original article contains dosing details in manuscript PubMed NCT00222027

@@ Line 1: / Line 1: @@
-{| class="wikitable" style="text-align:center; width:50%;"
+<span id="BackToTop"></span>
-! colspan="2" align="center" style="color:white; font-size:125%; background-color:#de2d26" |'''Section editor'''
+<div class="noprint" style="background-color:LightGray; position:fixed; bottom:2%; right:0.25%; padding-left:5px; padding-right:5px; margin: 15px; opacity:0.8; border-style: solid; border-color:DarkGray; border-width: 1px">
-|-
+[[#top|Back to Top]]
-| style="background-color:#F0F0F0; width:15%" |[[File:MartinSchoen.jpg|frameless|upright=0.3|center]]
+</div>
-| style="width:35%" |<big>[[User:Marteens|Martin W. Schoen, MD, MPH]]<br>Saint Louis University<br>St. Louis, MO</big><br>[[File:Social-twitter-icon.png|frameless|upright=0.1]][https://twitter.com/mwschoen mwschoen]
+{{#lst:Editorial board transclusions|leuk}}
-|-
-|}
 {| class="wikitable" style="float:right; margin-right: 5px;"
 |-
@@ Line 12: / Line 10: @@
 |}
 {{TOC limit|limit=3}}
 ''Note: these regimens are primarily culled from literature that describes them as part of a comprehensive treatment regimen. If that is the case, the original regimens can be found on the following pages:''
 *[[Acute promyelocytic leukemia]]
@@ Line 18: / Line 15: @@
 *[[B-cell acute lymphoblastic leukemia]]
 *[[T-cell acute lymphoblastic leukemia]]
 =CNS prophylaxis, local therapy=
 ==IT Cytarabine & Methotrexate {{#subobject:c47af4|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
+<div class="toccolours" style="background-color:#eeeeee">
-|-
-|[[#top|back to top]]
-|}
 ===Regimen variant #1, 16 doses {{#subobject:8be879|Variant=1}}===
-{| class="wikitable" style="width: 50%; text-align:center;"
+{| class="wikitable sortable" style="width: 60%; text-align:center;"
-!style="width: 25%"|Study
+!style="width: 33%"|Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 33%"|Dates of enrollment
+!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|[https://onlinelibrary.wiley.com/doi/10.1002/cncr.21776/full Thomas et al. 2006]
+|[https://doi.org/10.1002/cncr.21776 Thomas et al. 2006]
-|style="background-color:#ffffbe"|Pilot, <20 pts
+|2000-02 to 2005-01
+|style="background-color:#ffffbe"|Pilot, fewer than 20 pts
 |-
 |}
-====Chemotherapy, CNS====
+<div class="toccolours" style="background-color:#b3e2cd">
-*[[Methotrexate (MTX)]] as follows:
+====CNS therapy, prophylaxis====
+*[[Methotrexate (MTX)]] by the following route-based criteria:
 **LP: 12 mg IT once on day 2
 **Ommaya reservoir: 6 mg IT once on day 2
 *[[Cytarabine (Ara-C)]] 100 mg IT once on day 7
 '''Given each cycle for a total of 16 intrathecal treatments'''
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
 ===Regimen variant #2, 6 to 8 doses {{#subobject:f842e7|Variant=1}}===
-{| class="wikitable" style="width: 50%; text-align:center;"
+{| class="wikitable sortable" style="width: 60%; text-align:center;"
-!style="width: 25%"|Study
+!style="width: 33%"|Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 33%"|Dates of enrollment
+!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|[http://jco.ascopubs.org/content/17/8/2461.long Thomas et al. 1999]
+|[https://doi.org/10.1200/jco.1999.17.8.2461 Thomas et al. 1999]
-|style="background-color:#91cf61"|Phase II
+|1992-09 to 1997-06
+|style="background-color:#91cf61"|Phase 2
 |-
-|[http://www.bloodjournal.org/content/103/12/4396.long Thomas et al. 2003]
+|[https://doi.org/10.1182/blood-2003-08-2958 Thomas et al. 2003]
-|style="background-color:#91cf61"|Phase II
+|2001-04 to 2003-03
+|style="background-color:#91cf61"|Phase 2
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4081177/ Ravandi et al. 2010]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4081177/ Ravandi et al. 2010 (MDACC 2006-0478)]
-|style="background-color:#91cf61"|Phase II
+|2006-09-28 to 2009-07-15
+|style="background-color:#91cf61"|Phase 2
 |-
 |}
-''Total number of doses depends on risk for CNS relapse based on serum lactate dehydrogenase (LDH) greater than 1400 IU/L and/or proliferative index percentage of S + G2M greater than or equal to 14%.''
+''Note: Total number of doses depends on risk for CNS relapse based on serum lactate dehydrogenase (LDH) greater than 1400 IU/L and/or proliferative index percentage of S + G2M greater than or equal to 14%.''
-====Chemotherapy, CNS====
+<div class="toccolours" style="background-color:#b3e2cd">
-*[[Methotrexate (MTX)]] as follows:
+====CNS therapy, prophylaxis====
+*[[Methotrexate (MTX)]] by the following route-based criteria:
 **LP: 12 mg IT once on day 2
 **Ommaya reservoir: 6 mg IT once on day 2
 *[[Cytarabine (Ara-C)]] 100 mg IT once on either day 7 or 8
 '''Given each cycle (approximately every 3 weeks) for a total of 6 or 8 intrathecal treatments'''
+</div></div>
 ===References===
-# Thomas DA, Cortes J, O'Brien S, Pierce S, Faderl S, Albitar M, Hagemeister FB, Cabanillas FF, Murphy S, Keating MJ, Kantarjian H. Hyper-CVAD program in Burkitt's-type adult acute lymphoblastic leukemia. J Clin Oncol. 1999 Aug;17(8):2461-70. [http://jco.ascopubs.org/content/17/8/2461.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/10561310 PubMed]
+# Thomas DA, Cortes J, O'Brien S, Pierce S, Faderl S, Albitar M, Hagemeister FB, Cabanillas FF, Murphy S, Keating MJ, Kantarjian H. Hyper-CVAD program in Burkitt's-type adult acute lymphoblastic leukemia. J Clin Oncol. 1999 Aug;17(8):2461-70. [https://doi.org/10.1200/jco.1999.17.8.2461 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/10561310/ PubMed]
-# Thomas DA, Faderl S, Cortes J, O'Brien S, Giles FJ, Kornblau SM, Garcia-Manero G, Keating MJ, Andreeff M, Jeha S, Beran M, Verstovsek S, Pierce S, Letvak L, Salvado A, Champlin R, Talpaz M, Kantarjian H. Treatment of Philadelphia chromosome-positive acute lymphocytic leukemia with hyper-CVAD and imatinib mesylate. Blood. 2004 Jun 15;103(12):4396-407. Epub 2003 Oct 9. [http://www.bloodjournal.org/content/103/12/4396.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/14551133 PubMed]
+# Thomas DA, Faderl S, Cortes J, O'Brien S, Giles FJ, Kornblau SM, Garcia-Manero G, Keating MJ, Andreeff M, Jeha S, Beran M, Verstovsek S, Pierce S, Letvak L, Salvado A, Champlin R, Talpaz M, Kantarjian H. Treatment of Philadelphia chromosome-positive acute lymphocytic leukemia with hyper-CVAD and imatinib mesylate. Blood. 2004 Jun 15;103(12):4396-407. Epub 2003 Oct 9. [https://doi.org/10.1182/blood-2003-08-2958 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/14551133/ PubMed]
-## '''Update:''' Daver N, Thomas D, Ravandi F, Cortes J, Garris R, Jabbour E, Garcia-Manero G, Borthakur G, Kadia T, Rytting M, Konopleva M, Kantarjian H, O' Brien S. Final report of a phase II study of imatinib mesylate with hyper-CVAD for the frontline treatment of adult patients with Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia. Haematologica. 2015 May;100(5):653-61. Epub 2015 Feb 14. [http://www.haematologica.org/content/100/5/653 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4420214/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25682595 PubMed]
+## '''Update:''' Daver N, Thomas D, Ravandi F, Cortes J, Garris R, Jabbour E, Garcia-Manero G, Borthakur G, Kadia T, Rytting M, Konopleva M, Kantarjian H, O' Brien S. Final report of a phase II study of imatinib mesylate with hyper-CVAD for the frontline treatment of adult patients with Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia. Haematologica. 2015 May;100(5):653-61. Epub 2015 Feb 14. [https://doi.org/10.3324/haematol.2014.118588 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4420214/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25682595/ PubMed]
-# Thomas DA, Faderl S, O'Brien S, Bueso-Ramos C, Cortes J, Garcia-Manero G, Giles FJ, Verstovsek S, Wierda WG, Pierce SA, Shan J, Brandt M, Hagemeister FB, Keating MJ, Cabanillas F, Kantarjian H. Chemoimmunotherapy with hyper-CVAD plus rituximab for the treatment of adult Burkitt and Burkitt-type lymphoma or acute lymphoblastic leukemia. Cancer. 2006 Apr 1;106(7):1569-80. [https://onlinelibrary.wiley.com/doi/10.1002/cncr.21776/full link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/16502413 PubMed]
+# Thomas DA, Faderl S, O'Brien S, Bueso-Ramos C, Cortes J, Garcia-Manero G, Giles FJ, Verstovsek S, Wierda WG, Pierce SA, Shan J, Brandt M, Hagemeister FB, Keating MJ, Cabanillas F, Kantarjian H. Chemoimmunotherapy with hyper-CVAD plus rituximab for the treatment of adult Burkitt and Burkitt-type lymphoma or acute lymphoblastic leukemia. Cancer. 2006 Apr 1;106(7):1569-80. [https://doi.org/10.1002/cncr.21776 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/16502413/ PubMed]
-## '''Update:''' Fayad L, Thomas D, Romaguera J. Update of the MD Anderson Cancer Center experience with hyper-CVAD and rituximab for the treatment of mantle cell and Burkitt-type lymphomas. Clin Lymphoma Myeloma. 2007 Dec;8 Suppl 2:S57-62. [https://pubmed.ncbi.nlm.nih.gov/18284717 PubMed]
+## '''Update:''' Fayad L, Thomas D, Romaguera J. Update of the MD Anderson Cancer Center experience with hyper-CVAD and rituximab for the treatment of mantle cell and Burkitt-type lymphomas. Clin Lymphoma Myeloma. 2007 Dec;8 Suppl 2:S57-62. [https://doi.org/10.3816/clm.2007.s.034 link to original article] [https://pubmed.ncbi.nlm.nih.gov/18284717/ PubMed]
-# Ravandi F, O'Brien S, Thomas D, Faderl S, Jones D, Garris R, Dara S, Jorgensen J, Kebriaei P, Champlin R, Borthakur G, Burger J, Ferrajoli A, Garcia-Manero G, Wierda W, Cortes J, Kantarjian H. First report of phase 2 study of dasatinib with hyper-CVAD for the frontline treatment of patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia. Blood. 2010 Sep 23;116(12):2070-7. Epub 2010 May 13. [http://www.bloodjournal.org/content/116/12/2070.long link to original article] '''contains verified protocol'''--parts of the protocol were not explicitly listed in this reference, which instead referred to [[#Hyper-CVAD_.26_Imatinib_.28Gleevec.29_.28induction_.26_maintenance.29|Thomas et al. 2004]] and [[#Hyper-CVAD_.28induction.29|Kantarjian et al. 2004]] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4081177/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/20466853 PubMed]
+# '''MDACC 2006-0478:''' Ravandi F, O'Brien S, Thomas D, Faderl S, Jones D, Garris R, Dara S, Jorgensen J, Kebriaei P, Champlin R, Borthakur G, Burger J, Ferrajoli A, Garcia-Manero G, Wierda W, Cortes J, Kantarjian H. First report of phase 2 study of dasatinib with hyper-CVAD for the frontline treatment of patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia. Blood. 2010 Sep 23;116(12):2070-7. Epub 2010 May 13. [https://doi.org/10.1182/blood-2009-12-261586 link to original article] '''contains dosing details in manuscript'''--parts of the protocol were not explicitly listed in this reference, which instead referred to [[#Hyper-CVAD_.26_Imatinib_.28Gleevec.29_.28induction_.26_maintenance.29|Thomas et al. 2004]] and [[#Hyper-CVAD_.28induction.29|Kantarjian et al. 2004]] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4081177/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/20466853/ PubMed] [https://clinicaltrials.gov/study/NCT00390793 NCT00390793]
-## '''Update:''' Ravandi F, O'Brien SM, Cortes JE, Thomas DM, Garris R, Faderl S, Burger JA, Rytting ME, Ferrajoli A, Wierda WG, Verstovsek S, Champlin R, Kebriaei P, McCue DA, Huang X, Jabbour E, Garcia-Manero G, Estrov Z, Kantarjian HM. Long-term follow-up of a phase 2 study of chemotherapy plus dasatinib for the initial treatment of patients with Philadelphia chromosome-positive acute lymphoblastic leukemia. Cancer. 2015 Dec 1;121(23):4158-64. Epub 2015 Aug 26. [https://onlinelibrary.wiley.com/doi/10.1002/cncr.29646/full link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4666803/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26308885 PubMed]
+## '''Update:''' Ravandi F, O'Brien SM, Cortes JE, Thomas DM, Garris R, Faderl S, Burger JA, Rytting ME, Ferrajoli A, Wierda WG, Verstovsek S, Champlin R, Kebriaei P, McCue DA, Huang X, Jabbour E, Garcia-Manero G, Estrov Z, Kantarjian HM. Long-term follow-up of a phase 2 study of chemotherapy plus dasatinib for the initial treatment of patients with Philadelphia chromosome-positive acute lymphoblastic leukemia. Cancer. 2015 Dec 1;121(23):4158-64. Epub 2015 Aug 26. [https://doi.org/10.1002/cncr.29646 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4666803/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26308885/ PubMed]
 ==IT Cytarabine, Methotrexate, Methylprednisolone {{#subobject:eb3e09|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
+<div class="toccolours" style="background-color:#eeeeee">
-|-
-|[[#top|back to top]]
-|}
 ===Regimen {{#subobject:daa284|Variant=1}}===
-{| class="wikitable" style="width: 50%; text-align:center;"
+{| class="wikitable sortable" style="width: 60%; text-align:center;"
-!style="width: 25%"|Study
+!style="width: 33%"|Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 33%"|Dates of enrollment
+!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|[https://doi.org/10.1200/JCO.2015.61.5385 Huguet et al. 2009 (GRAALL-2003)]
+|[https://doi.org/10.1200/JCO.2008.18.6916 Huguet et al. 2009 (GRAALL-2003)]
-|style="background-color:#91cf61"|Phase II
+|2003-2005
+|style="background-color:#91cf61"|Phase 2
 |-
 |}
-''Intrathecal treatments are given on days 1 & 8 of induction, day 29 of each series of consolidation blocks, and day 1 of late intensification -- 6 doses total.''
+''Note: Intrathecal treatments are given on days 1 & 8 of induction, day 29 of each series of consolidation blocks, and day 1 of late intensification -- 6 doses total.''
-====Chemotherapy, CNS====
+<div class="toccolours" style="background-color:#b3e2cd">
+====CNS therapy, prophylaxis====
 *[[Cytarabine (Ara-C)]] 40 mg IT mixed with methotrexate and methylprednisolone
 *[[Methotrexate (MTX)]] 15 mg IT mixed with cytarabine and methylprednisolone
 *[[Methylprednisolone (Solumedrol)]] 40 mg IT mixed with cytarabine and methotrexate
+'''6 doses (see note)'''
-'''6 doses'''
+</div></div>
 ===References===
-# '''GRAALL-2003:''' Huguet F, Leguay T, Raffoux E, Thomas X, Beldjord K, Delabesse E, Chevallier P, Buzyn A, Delannoy A, Chalandon Y, Vernant JP, Lafage-Pochitaloff M, Chassevent A, Lhéritier V, Macintyre E, Béné MC, Ifrah N, Dombret H. Pediatric-inspired therapy in adults with Philadelphia chromosome-negative acute lymphoblastic leukemia: the GRAALL-2003 study. J Clin Oncol. 2009 Feb 20;27(6):911-8. Epub 2009 Jan 5. Erratum in: J Clin Oncol. 2009 May 20;27(15):2574. Dosage error in article text. [https://doi.org/10.1200/JCO.2015.61.5385 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/19124805 PubMed]
+# '''GRAALL-2003:''' Huguet F, Leguay T, Raffoux E, Thomas X, Beldjord K, Delabesse E, Chevallier P, Buzyn A, Delannoy A, Chalandon Y, Vernant JP, Lafage-Pochitaloff M, Chassevent A, Lhéritier V, Macintyre E, Béné MC, Ifrah N, Dombret H. Pediatric-inspired therapy in adults with Philadelphia chromosome-negative acute lymphoblastic leukemia: the GRAALL-2003 study. J Clin Oncol. 2009 Feb 20;27(6):911-8. Epub 2009 Jan 5. Erratum in: J Clin Oncol. 2009 May 20;27(15):2574. Dosage error in article text. [https://doi.org/10.1200/JCO.2008.18.6916 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/19124805/ PubMed] [https://clinicaltrials.gov/study/NCT00222027 NCT00222027]
 ==IT Cytarabine, Methotrexate, Prednisone {{#subobject:d81b63|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
+<div class="toccolours" style="background-color:#eeeeee">
-|-
-|[[#top|back to top]]
-|}
 ===Regimen {{#subobject:6f33ca|Variant=1}}===
-{| class="wikitable" style="width: 50%; text-align:center;"
+{| class="wikitable sortable" style="width: 60%; text-align:center;"
-!style="width: 25%"|Study
+!style="width: 33%"|Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 33%"|Dates of enrollment
+!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|[http://jco.ascopubs.org/content/25/34/5458.long Tsukasaki et al. 2007 (JCOG 9801)]
+|[https://doi.org/10.1200/jco.2007.11.9958 Tsukasaki et al. 2007 (JCOG 9801)]
-|style="background-color:#91cf61"|Non-randomized
+|1998-2003
+|style="background-color:#91cf61"|Non-randomized part of phase 3 RCT
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5024033/ Ishida et al. 2015]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5024033/ Ishida et al. 2015 (Kyowa 0761-003)]
-|style="background-color:#91cf61"|Non-randomized
+|2010-2011
+|style="background-color:#91cf61"|Non-randomized part of phase 2 RCT
 |-
 |}
-''Treatments were given after cycles 1, 3, and 5 after platelets greater than 70 × 10<sup>9</sup>/L and within 2 days before the next cycle.''
+''Note: Treatments were given after cycles 1, 3, and 5 after platelets greater than 70 x 10<sup>9</sup>/L and within 2 days before the next cycle.''
-====Chemotherapy, CNS====
+<div class="toccolours" style="background-color:#b3e2cd">
+====CNS therapy, prophylaxis====
 *[[Cytarabine (Ara-C)]] 40 mg IT mixed with methotrexate and prednisone
 *[[Methotrexate (MTX)]] 15 mg IT mixed with cytarabine and prednisone
 *[[Prednisone (Sterapred)]] 10 mg IT mixed with cytarabine and methotrexate
+'''3 doses (see note)'''
-'''3 doses'''
+</div></div>
 ===References===
 <!-- Presented in part at the 47th Annual Meeting of the American Society of Hematology, December 10-13, 2005, Atlanta, GA. -->
-# Tsukasaki K, Utsunomiya A, Fukuda H, Shibata T, Fukushima T, Takatsuka Y, Ikeda S, Masuda M, Nagoshi H, Ueda R, Tamura K, Sano M, Momita S, Yamaguchi K, Kawano F, Hanada S, Tobinai K, Shimoyama M, Hotta T, Tomonaga M; Japan Clinical Oncology Group Study JCOG9801. VCAP-AMP-VECP compared with biweekly CHOP for adult T-cell leukemia-lymphoma: Japan Clinical Oncology Group Study JCOG9801. J Clin Oncol. 2007 Dec 1;25(34):5458-64. Epub 2007 Oct 29. [http://jco.ascopubs.org/content/25/34/5458.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17968021 PubMed]
+# '''JCOG 9801:''' Tsukasaki K, Utsunomiya A, Fukuda H, Shibata T, Fukushima T, Takatsuka Y, Ikeda S, Masuda M, Nagoshi H, Ueda R, Tamura K, Sano M, Momita S, Yamaguchi K, Kawano F, Hanada S, Tobinai K, Shimoyama M, Hotta T, Tomonaga M; [[Study_Groups#JCOG|JCOG]]. VCAP-AMP-VECP compared with biweekly CHOP for adult T-cell leukemia-lymphoma: Japan Clinical Oncology Group Study JCOG9801. J Clin Oncol. 2007 Dec 1;25(34):5458-64. Epub 2007 Oct 29. [https://doi.org/10.1200/jco.2007.11.9958 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17968021/ PubMed] [https://clinicaltrials.gov/study/NCT00145002 NCT00145002]
-# Ishida T, Jo T, Takemoto S, Suzushima H, Uozumi K, Yamamoto K, Uike N, Saburi Y, Nosaka K, Utsunomiya A, Tobinai K, Fujiwara H, Ishitsuka K, Yoshida S, Taira N, Moriuchi Y, Imada K, Miyamoto T, Akinaga S, Tomonaga M, Ueda R. Dose-intensified chemotherapy alone or in combination with mogamulizumab in newly diagnosed aggressive adult T-cell leukaemia-lymphoma: a randomized phase II study. Br J Haematol. 2015 Jun;169(5):672-82. Epub 2015 Mar 2. [https://onlinelibrary.wiley.com/doi/10.1111/bjh.13338/full link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5024033/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25733162 PubMed]
+# '''Kyowa 0761-003:''' Ishida T, Jo T, Takemoto S, Suzushima H, Uozumi K, Yamamoto K, Uike N, Saburi Y, Nosaka K, Utsunomiya A, Tobinai K, Fujiwara H, Ishitsuka K, Yoshida S, Taira N, Moriuchi Y, Imada K, Miyamoto T, Akinaga S, Tomonaga M, Ueda R. Dose-intensified chemotherapy alone or in combination with mogamulizumab in newly diagnosed aggressive adult T-cell leukaemia-lymphoma: a randomized phase II study. Br J Haematol. 2015 Jun;169(5):672-82. Epub 2015 Mar 2. [https://doi.org/10.1111/bjh.13338 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5024033/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25733162/ PubMed] [https://clinicaltrials.gov/study/NCT01173887 NCT01173887]
 ==IT Cytarabine & WBRT {{#subobject:d62e53|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
 Cytarabine & WBRT: Cytarabine & '''<u>W</u>'''hole '''<u>B</u>'''rain '''<u>R</u>'''adiation '''<u>T</u>'''herapy
+<div class="toccolours" style="background-color:#eeeeee">
 ===Regimen {{#subobject:b3f29d|Variant=1}}===
-{| class="wikitable" style="width: 50%; text-align:center;"
+{| class="wikitable sortable" style="width: 60%; text-align:center;"
-!style="width: 25%"|Study
+!style="width: 33%"|Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 33%"|Dates of enrollment
+!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|[http://www.bloodjournal.org/content/106/12/3760.long Rowe et al. 2005 (MRC UKALL XII/ECOG E2993)]
+|[https://doi.org/10.1182/blood-2005-04-1623 Rowe et al. 2005 (MRC UKALL XII/ECOG E2993)]
-|style="background-color:#91cf61"|Non-randomized portion of RCT
+|1993-2003
+|style="background-color:#91cf61"|Non-randomized part of phase 3 RCT
 |-
 |}
 ''Note: while this is not chemoradiation in the traditional sense, the delivery of chemotherapy and radiation overlap so may have synergistic effects.''
-====Chemotherapy, CNS====
+<div class="toccolours" style="background-color:#b3e2cd">
+====CNS therapy, prophylaxis====
 *[[Cytarabine (Ara-C)]] as follows:
 **Consolidation & Maintenance: 50 mg IT once per week for 4 weeks, then once per quarter for 4 doses (8 doses, total)
 ====Radiotherapy====
 *[[External_beam_radiotherapy|Whole-brain irradiation]] to 2400 cGy, given during consolidation
+</div></div>
 ===References===
-# Rowe JM, Buck G, Burnett AK, Chopra R, Wiernik PH, Richards SM, Lazarus HM, Franklin IM, Litzow MR, Ciobanu N, Prentice HG, Durrant J, Tallman MS, Goldstone AH; ECOG; MRC/NCRI Adult Leukemia Working Party. Induction therapy for adults with acute lymphoblastic leukemia: results of more than 1500 patients from the international ALL trial: MRC UKALL XII/ECOG E2993. Blood. 2005 Dec 1;106(12):3760-7. Epub 2005 Aug 16. [http://www.bloodjournal.org/content/106/12/3760.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/16105981 PubMed]
+# '''MRC UKALL XII/ECOG E2993:''' Rowe JM, Buck G, Burnett AK, Chopra R, Wiernik PH, Richards SM, Lazarus HM, Franklin IM, Litzow MR, Ciobanu N, Prentice HG, Durrant J, Tallman MS, Goldstone AH; ECOG; MRC/NCRI Adult Leukemia Working Party. Induction therapy for adults with acute lymphoblastic leukemia: results of more than 1500 patients from the international ALL trial: MRC UKALL XII/ECOG E2993. Blood. 2005 Dec 1;106(12):3760-7. Epub 2005 Aug 16. [https://doi.org/10.1182/blood-2005-04-1623 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/16105981/ PubMed] [https://clinicaltrials.gov/study/NCT00002514 NCT00002514]
-## '''Update:''' Goldstone AH, Richards SM, Lazarus HM, Tallman MS, Buck G, Fielding AK, Burnett AK, Chopra R, Wiernik PH, Foroni L, Paietta E, Litzow MR, Marks DI, Durrant J, McMillan A, Franklin IM, Luger S, Ciobanu N, Rowe JM. In adults with standard-risk acute lymphoblastic leukemia, the greatest benefit is achieved from a matched sibling allogeneic transplantation in first complete remission, and an autologous transplantation is less effective than conventional consolidation/maintenance chemotherapy in all patients: final results of the International ALL Trial (MRC UKALL XII/ECOG E2993). Blood. 2008 Feb 15;111(4):1827-33. Epub 2007 Nov 29. [http://www.bloodjournal.org/content/111/4/1827.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/18048644 PubMed]
+## '''Update:''' Goldstone AH, Richards SM, Lazarus HM, Tallman MS, Buck G, Fielding AK, Burnett AK, Chopra R, Wiernik PH, Foroni L, Paietta E, Litzow MR, Marks DI, Durrant J, McMillan A, Franklin IM, Luger S, Ciobanu N, Rowe JM. In adults with standard-risk acute lymphoblastic leukemia, the greatest benefit is achieved from a matched sibling allogeneic transplantation in first complete remission, and an autologous transplantation is less effective than conventional consolidation/maintenance chemotherapy in all patients: final results of the International ALL Trial (MRC UKALL XII/ECOG E2993). Blood. 2008 Feb 15;111(4):1827-33. Epub 2007 Nov 29. [https://doi.org/10.1182/blood-2007-10-116582 link to original article] [https://pubmed.ncbi.nlm.nih.gov/18048644/ PubMed]
-## '''Update:''' Fielding AK, Rowe JM, Richards SM, Buck G, Moorman AV, Durrant IJ, Marks DI, McMillan AK, Litzow MR, Lazarus HM, Foroni L, Dewald G, Franklin IM, Luger SM, Paietta E, Wiernik PH, Tallman MS, Goldstone AH. Prospective outcome data on 267 unselected adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia confirms superiority of allogeneic transplantation over chemotherapy in the pre-imatinib era: results from the International ALL Trial MRC UKALLXII/ECOG2993. Blood. 2009 May 7;113(19):4489-96. Epub 2009 Feb 24. [http://www.bloodjournal.org/content/113/19/4489.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4188540/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19244158 PubMed]
+## '''Update:''' Fielding AK, Rowe JM, Richards SM, Buck G, Moorman AV, Durrant IJ, Marks DI, McMillan AK, Litzow MR, Lazarus HM, Foroni L, Dewald G, Franklin IM, Luger SM, Paietta E, Wiernik PH, Tallman MS, Goldstone AH. Prospective outcome data on 267 unselected adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia confirms superiority of allogeneic transplantation over chemotherapy in the pre-imatinib era: results from the International ALL Trial MRC UKALLXII/ECOG2993. Blood. 2009 May 7;113(19):4489-96. Epub 2009 Feb 24. [https://doi.org/10.1182/blood-2009-01-199380 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4188540/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19244158/ PubMed]
-## '''Update:''' Fielding AK, Rowe JM, Buck G, Foroni L, Gerrard G, Litzow MR, Lazarus H, Luger SM, Marks DI, McMillan AK, Moorman AV, Patel B, Paietta E, Tallman MS, Goldstone AH. UKALLXII/ECOG2993: addition of imatinib to a standard treatment regimen enhances long-term outcomes in Philadelphia positive acute lymphoblastic leukemia. Blood. 2014 Feb 6;123(6):843-50. Epub 2013 Nov 25. [http://www.bloodjournal.org/content/123/6/843.full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3916877/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24277073 PubMed]
+## '''Update:''' Fielding AK, Rowe JM, Buck G, Foroni L, Gerrard G, Litzow MR, Lazarus H, Luger SM, Marks DI, McMillan AK, Moorman AV, Patel B, Paietta E, Tallman MS, Goldstone AH. UKALLXII/ECOG2993: addition of imatinib to a standard treatment regimen enhances long-term outcomes in Philadelphia positive acute lymphoblastic leukemia. Blood. 2014 Feb 6;123(6):843-50. Epub 2013 Nov 25. [https://doi.org/10.1182/blood-2013-09-529008 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3916877/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24277073/ PubMed]
 ==IT Methotrexate monotherapy {{#subobject:98fb82|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
+<div class="toccolours" style="background-color:#eeeeee">
-|-
-|[[#top|back to top]]
-|}
 ===Regimen {{#subobject:0f3d6e|Variant=1}}===
-{| class="wikitable" style="width: 50%; text-align:center;"
+{| class="wikitable sortable" style="width: 60%; text-align:center;"
-!style="width: 25%"|Study
+!style="width: 33%"|Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 33%"|Dates of enrollment
+!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|[http://www.bloodjournal.org/content/106/12/3760.long Rowe et al. 2005 (MRC UKALL XII/ECOG E2993)]
+|[https://doi.org/10.1182/blood-2005-04-1623 Rowe et al. 2005 (MRC UKALL XII/ECOG E2993)]
-|style="background-color:#91cf61"|Non-randomized portion of RCT
+|1993-2003
+|style="background-color:#91cf61"|Non-randomized part of phase 3 RCT
 |-
 |}
-====Chemotherapy, CNS====
+<div class="toccolours" style="background-color:#b3e2cd">
+====CNS therapy, prophylaxis====
 *[[Methotrexate (MTX)]] as follows:
 **Phase 1: 12 mg IT once on day 15
 **Phase 2: 12 mg IT once per day on days 1, 8, 15, 22
+</div></div>
 ===References===
-# Rowe JM, Buck G, Burnett AK, Chopra R, Wiernik PH, Richards SM, Lazarus HM, Franklin IM, Litzow MR, Ciobanu N, Prentice HG, Durrant J, Tallman MS, Goldstone AH; ECOG; MRC/NCRI Adult Leukemia Working Party. Induction therapy for adults with acute lymphoblastic leukemia: results of more than 1500 patients from the international ALL trial: MRC UKALL XII/ECOG E2993. Blood. 2005 Dec 1;106(12):3760-7. Epub 2005 Aug 16. [http://www.bloodjournal.org/content/106/12/3760.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/16105981 PubMed]
+# '''MRC UKALL XII/ECOG E2993:''' Rowe JM, Buck G, Burnett AK, Chopra R, Wiernik PH, Richards SM, Lazarus HM, Franklin IM, Litzow MR, Ciobanu N, Prentice HG, Durrant J, Tallman MS, Goldstone AH; ECOG; MRC/NCRI Adult Leukemia Working Party. Induction therapy for adults with acute lymphoblastic leukemia: results of more than 1500 patients from the international ALL trial: MRC UKALL XII/ECOG E2993. Blood. 2005 Dec 1;106(12):3760-7. Epub 2005 Aug 16. [https://doi.org/10.1182/blood-2005-04-1623 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/16105981/ PubMed] [https://clinicaltrials.gov/study/NCT00002514 NCT00002514]
-## '''Update:''' Goldstone AH, Richards SM, Lazarus HM, Tallman MS, Buck G, Fielding AK, Burnett AK, Chopra R, Wiernik PH, Foroni L, Paietta E, Litzow MR, Marks DI, Durrant J, McMillan A, Franklin IM, Luger S, Ciobanu N, Rowe JM. In adults with standard-risk acute lymphoblastic leukemia, the greatest benefit is achieved from a matched sibling allogeneic transplantation in first complete remission, and an autologous transplantation is less effective than conventional consolidation/maintenance chemotherapy in all patients: final results of the International ALL Trial (MRC UKALL XII/ECOG E2993). Blood. 2008 Feb 15;111(4):1827-33. Epub 2007 Nov 29. [http://www.bloodjournal.org/content/111/4/1827.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/18048644 PubMed]
+## '''Update:''' Goldstone AH, Richards SM, Lazarus HM, Tallman MS, Buck G, Fielding AK, Burnett AK, Chopra R, Wiernik PH, Foroni L, Paietta E, Litzow MR, Marks DI, Durrant J, McMillan A, Franklin IM, Luger S, Ciobanu N, Rowe JM. In adults with standard-risk acute lymphoblastic leukemia, the greatest benefit is achieved from a matched sibling allogeneic transplantation in first complete remission, and an autologous transplantation is less effective than conventional consolidation/maintenance chemotherapy in all patients: final results of the International ALL Trial (MRC UKALL XII/ECOG E2993). Blood. 2008 Feb 15;111(4):1827-33. Epub 2007 Nov 29. [https://doi.org/10.1182/blood-2007-10-116582 link to original article] [https://pubmed.ncbi.nlm.nih.gov/18048644/ PubMed]
-## '''Update:''' Fielding AK, Rowe JM, Richards SM, Buck G, Moorman AV, Durrant IJ, Marks DI, McMillan AK, Litzow MR, Lazarus HM, Foroni L, Dewald G, Franklin IM, Luger SM, Paietta E, Wiernik PH, Tallman MS, Goldstone AH. Prospective outcome data on 267 unselected adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia confirms superiority of allogeneic transplantation over chemotherapy in the pre-imatinib era: results from the International ALL Trial MRC UKALLXII/ECOG2993. Blood. 2009 May 7;113(19):4489-96. Epub 2009 Feb 24. [http://www.bloodjournal.org/content/113/19/4489.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4188540/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19244158 PubMed]
+## '''Update:''' Fielding AK, Rowe JM, Richards SM, Buck G, Moorman AV, Durrant IJ, Marks DI, McMillan AK, Litzow MR, Lazarus HM, Foroni L, Dewald G, Franklin IM, Luger SM, Paietta E, Wiernik PH, Tallman MS, Goldstone AH. Prospective outcome data on 267 unselected adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia confirms superiority of allogeneic transplantation over chemotherapy in the pre-imatinib era: results from the International ALL Trial MRC UKALLXII/ECOG2993. Blood. 2009 May 7;113(19):4489-96. Epub 2009 Feb 24. [https://doi.org/10.1182/blood-2009-01-199380 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4188540/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19244158/ PubMed]
-## '''Update:''' Fielding AK, Rowe JM, Buck G, Foroni L, Gerrard G, Litzow MR, Lazarus H, Luger SM, Marks DI, McMillan AK, Moorman AV, Patel B, Paietta E, Tallman MS, Goldstone AH. UKALLXII/ECOG2993: addition of imatinib to a standard treatment regimen enhances long-term outcomes in Philadelphia positive acute lymphoblastic leukemia. Blood. 2014 Feb 6;123(6):843-50. Epub 2013 Nov 25. [http://www.bloodjournal.org/content/123/6/843.full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3916877/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24277073 PubMed]
+## '''Update:''' Fielding AK, Rowe JM, Buck G, Foroni L, Gerrard G, Litzow MR, Lazarus H, Luger SM, Marks DI, McMillan AK, Moorman AV, Patel B, Paietta E, Tallman MS, Goldstone AH. UKALLXII/ECOG2993: addition of imatinib to a standard treatment regimen enhances long-term outcomes in Philadelphia positive acute lymphoblastic leukemia. Blood. 2014 Feb 6;123(6):843-50. Epub 2013 Nov 25. [https://doi.org/10.1182/blood-2013-09-529008 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3916877/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24277073/ PubMed]
 ==IT Methotrexate & Hydrocortisone {{#subobject:d0d04e|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
+<div class="toccolours" style="background-color:#eeeeee">
-|-
-|[[#top|back to top]]
-|}
 ===Regimen {{#subobject:edc35f|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
+!style="width: 20%"|Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Dates of enrollment
-!style="width: 25%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[http://www.bloodjournal.org/content/50/3/471.long Sullivan et al. 1977]
+|[https://doi.org/10.1182/blood.V50.3.471.471 Sullivan et al. 1977]
-| style="background-color:#1a9851" |Phase III (C)
+|1971-1973
+| style="background-color:#1a9851" |Phase 3 (C)
 |IT MTX, Ara-C, HC
-| style="background-color:#ffffbf" |Seems not superior
+| style="background-color:#ffffbf" |Did not meet primary endpoint of DOR
 |-
-|[http://www.bloodjournal.org/content/126/6/746.long Kim et al. 2015 (AMC-UUCM-2008-0310)]
+|[https://doi.org/10.1182/blood-2015-03-636548 Kim et al. 2015 (AMC-UUCM-2008-0310)]
-|style="background-color:#91cf61"|Phase II
+|2009-2012
+|style="background-color:#91cf61"|Phase 2
 | style="background-color:#d3d3d3" |
 | style="background-color:#d3d3d3" |
 |-
 |}
-''Treatment can be started during or after induction.''
+''Note: Treatment can be started during or after induction.''
-====Chemotherapy, CNS====
+<div class="toccolours" style="background-color:#b3e2cd">
+====CNS therapy, prophylaxis====
 *[[Methotrexate (MTX)]] 15 mg IT (schedule not specified), admixed with hydrocortisone
 *[[Hydrocortisone (Cortef)]] 50 mg IT (schedule not specified), admixed with methotrexate
 '''Up to 10 doses'''
+</div></div>
 ===References===
-# Sullivan MP, Moon TE, Trueworthy R, Vietti TJ, Humphrey GB, Komp D. Combination intrathecal therapy for meningeal leukemia: two versus three drugs. Blood. 1977 Sep;50(3):471-9. [http://www.bloodjournal.org/content/50/3/471.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/577889 PubMed]
+# Sullivan MP, Moon TE, Trueworthy R, Vietti TJ, Humphrey GB, Komp D. Combination intrathecal therapy for meningeal leukemia: two versus three drugs. Blood. 1977 Sep;50(3):471-9. [https://doi.org/10.1182/blood.V50.3.471.471 link to original article] [https://pubmed.ncbi.nlm.nih.gov/577889/ PubMed]
-# '''AMC-UUCM-2008-0310:''' Kim DY, Joo YD, Lim SN, Kim SD, Lee JH, Lee JH, Kim DH, Kim K, Jung CW, Kim I, Yoon SS, Park S, Ahn JS, Yang DH, Lee JJ, Lee HS, Kim YS, Mun YC, Kim H, Park JH, Moon JH, Sohn SK, Lee SM, Lee WS, Kim KH, Won JH, Hyun MS, Park J, Lee JH, Shin HJ, Chung JS, Lee H, Eom HS, Lee GW, Cho YU, Jang S, Park CJ, Chi HS, Lee KH; Adult Acute Lymphoblastic Leukemia Working Party of the Korean Society of Hematology. Nilotinib combined with multiagent chemotherapy for newly diagnosed Philadelphia-positive acute lymphoblastic leukemia. Blood. 2015 Aug 6;126(6):746-56. Epub 2015 Jun 11. [http://www.bloodjournal.org/content/126/6/746.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/26065651 PubMed]
+# '''AMC-UUCM-2008-0310:''' Kim DY, Joo YD, Lim SN, Kim SD, Lee JH, Lee JH, Kim DH, Kim K, Jung CW, Kim I, Yoon SS, Park S, Ahn JS, Yang DH, Lee JJ, Lee HS, Kim YS, Mun YC, Kim H, Park JH, Moon JH, Sohn SK, Lee SM, Lee WS, Kim KH, Won JH, Hyun MS, Park J, Lee JH, Shin HJ, Chung JS, Lee H, Eom HS, Lee GW, Cho YU, Jang S, Park CJ, Chi HS, Lee KH; Adult Acute Lymphoblastic Leukemia Working Party of the Korean Society of Hematology. Nilotinib combined with multiagent chemotherapy for newly diagnosed Philadelphia-positive acute lymphoblastic leukemia. Blood. 2015 Aug 6;126(6):746-56. Epub 2015 Jun 11. [https://doi.org/10.1182/blood-2015-03-636548 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/26065651/ PubMed] [https://clinicaltrials.gov/study/NCT00844298 NCT00844298]
 ==IT Methotrexate & Methylprednisolone {{#subobject:6a4bad|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
+<div class="toccolours" style="background-color:#eeeeee">
-|-
-|[[#top|back to top]]
-|}
 ===Regimen {{#subobject:358389|Variant=1}}===
-{| class="wikitable" style="width: 50%; text-align:center;"
+{| class="wikitable sortable" style="width: 60%; text-align:center;"
-!style="width: 25%"|Study
+!style="width: 33%"|Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 33%"|Dates of enrollment
+!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|[http://www.bloodjournal.org/content/116/17/3171.long Lo-Coco et al. 2010 (GIMEMA AIDA-2000)]
+|[https://doi.org/10.1182/blood-2010-03-276196 Lo-Coco et al. 2010 (GIMEMA AIDA-2000)]
+|2000-2006
 |style="background-color:#91cf61"|Non-randomized
 |-
 |}
-''It is not explicitly stated but presumably these are admixed and given together.''
+''Note: It is not explicitly stated but presumably these are admixed and given together.''
-====Chemotherapy, CNS====
+<div class="toccolours" style="background-color:#b3e2cd">
+====CNS therapy, prophylaxis====
 *[[Methotrexate (MTX)]] 12 mg IT once prior to each consolidation cycle
 *[[Methylprednisolone (Solumedrol)]] 40 mg IT once prior to each consolidation cycle
 '''Total of 3 doses'''
+</div></div>
 ===References===
-# '''GIMEMA AIDA-2000:''' Lo-Coco F, Avvisati G, Vignetti M, Breccia M, Gallo E, Rambaldi A, Paoloni F, Fioritoni G, Ferrara F, Specchia G, Cimino G, Diverio D, Borlenghi E, Martinelli G, Di Raimondo F, Di Bona E, Fazi P, Peta A, Bosi A, Carella AM, Fabbiano F, Pogliani EM, Petti MC, Amadori S, Mandelli F; Italian GIMEMA Cooperative Group. Front-line treatment of acute promyelocytic leukemia with AIDA induction followed by risk-adapted consolidation for adults younger than 61 years: results of the AIDA-2000 trial of the GIMEMA Group. Blood. 2010 Oct 8;116(17):3171-9. Epub 2010 Jul 19. [http://www.bloodjournal.org/content/116/17/3171.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/20644121 PubMed]
+# '''GIMEMA AIDA-2000:''' Lo-Coco F, Avvisati G, Vignetti M, Breccia M, Gallo E, Rambaldi A, Paoloni F, Fioritoni G, Ferrara F, Specchia G, Cimino G, Diverio D, Borlenghi E, Martinelli G, Di Raimondo F, Di Bona E, Fazi P, Peta A, Bosi A, Carella AM, Fabbiano F, Pogliani EM, Petti MC, Amadori S, Mandelli F; GIMEMA. Front-line treatment of acute promyelocytic leukemia with AIDA induction followed by risk-adapted consolidation for adults younger than 61 years: results of the AIDA-2000 trial of the GIMEMA Group. Blood. 2010 Oct 8;116(17):3171-9. Epub 2010 Jul 19. [https://doi.org/10.1182/blood-2010-03-276196 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/20644121/ PubMed] [https://clinicaltrials.gov/study/NCT01064570 NCT01064570]
 ==IT Methotrexate & WBRT {{#subobject:4b9a67|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
 IT Methotrexate & WBRT: '''<u>I</u>'''ntra'''<u>T</u>'''hecal Methotrexate & '''<u>W</u>'''hole '''<u>B</u>'''rain '''<u>R</u>'''adiation '''<u>T</u>'''herapy
+<div class="toccolours" style="background-color:#eeeeee">
 ===Regimen {{#subobject:b1f086|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
+!style="width: 20%"|Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Dates of enrollment
-!style="width: 25%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[http://www.bloodjournal.org/content/69/4/1242.full.pdf+html Linker et al. 1987]
+|[https://doi.org/10.1182/blood.V69.4.1242.1242 Linker et al. 1987]
-|style="background-color:#91cf61"|Phase II
+|1980-1986
+|style="background-color:#91cf61"|Phase 2
 | style="background-color:#d3d3d3" |
 | style="background-color:#d3d3d3" |
 |-
 |[https://doi.org/10.1200/JCO.1998.16.3.920 Nachman et al. 1998 (CCG 1882)]
-| style="background-color:#1a9851" |Phase III (C)
+|1989-1995
-|[[#IT_Methotrexate_monotherapy|Intensified IT MTX]]
+| style="background-color:#1a9851" |Phase 3 (C)
-| style="background-color:#ffffbf" |Seems not superior
+|[[#IT_Methotrexate_monotherapy|IT MTX]]; intensified
+| style="background-color:#ffffbf" |Did not meet primary endpoint of EFS
 |-
 |}
-''Treatment is started within 1 week of achieving complete remission. Details are from Linker et al. 1987''
+''Note: Treatment is started within 1 week of achieving complete remission. Details are from Linker et al. 1987''
-====Chemotherapy, CNS====
+<div class="toccolours" style="background-color:#b3e2cd">
+====CNS therapy, prophylaxis====
 *[[Methotrexate (MTX)]] 12 mg IT once per week x 6 doses concurrent with radiation
 ====Radiotherapy====
-*[[External_beam_radiotherapy|Whole-brain irradiation]], 18 Gy total given in 10 fractions over 12 to 14 days
+*[[External_beam_radiotherapy|Whole-brain irradiation]], 1800 cGy total given in 10 fractions over 12 to 14 days
+</div></div>
 ===References===
-# Linker CA, Levitt LJ, O'Donnell M, Ries CA, Link MP, Forman SJ, Farbstein MJ. Improved results of treatment of adult acute lymphoblastic leukemia. Blood. 1987 Apr;69(4):1242-8. [http://www.bloodjournal.org/content/69/4/1242.full.pdf+html link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/3470055 PubMed]
+# Linker CA, Levitt LJ, O'Donnell M, Ries CA, Link MP, Forman SJ, Farbstein MJ. Improved results of treatment of adult acute lymphoblastic leukemia. Blood. 1987 Apr;69(4):1242-8. [https://doi.org/10.1182/blood.V69.4.1242.1242 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/3470055/ PubMed]
-## '''Update:''' Linker CA, Levitt LJ, O'Donnell M, Forman SJ, Ries CA. Treatment of adult acute lymphoblastic leukemia with intensive cyclical chemotherapy: a follow-up report. Blood. 1991 Dec 1;78(11):2814-22. [http://www.bloodjournal.org/content/78/11/2814.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/1835410 PubMed]
+## '''Update:''' Linker CA, Levitt LJ, O'Donnell M, Forman SJ, Ries CA. Treatment of adult acute lymphoblastic leukemia with intensive cyclical chemotherapy: a follow-up report. Blood. 1991 Dec 1;78(11):2814-22. [https://doi.org/10.1182/blood.V78.11.2814.2814 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/1835410/ PubMed]
-# '''CCG 1882:''' Nachman J, Sather HN, Cherlow JM, Sensel MG, Gaynon PS, Lukens JN, Wolff L, Trigg ME. Response of children with high-risk acute lymphoblastic leukemia treated with and without cranial irradiation: a report from the Children's Cancer Group. J Clin Oncol. 1998 Mar;16(3):920-30. [https://doi.org/10.1200/JCO.1998.16.3.920 link to original article] [https://pubmed.ncbi.nlm.nih.gov/9508174 PubMed]
+# '''CCG 1882:''' Nachman J, Sather HN, Cherlow JM, Sensel MG, Gaynon PS, Lukens JN, Wolff L, Trigg ME. Response of children with high-risk acute lymphoblastic leukemia treated with and without cranial irradiation: a report from the Children's Cancer Group. J Clin Oncol. 1998 Mar;16(3):920-30. [https://doi.org/10.1200/JCO.1998.16.3.920 link to original article] [https://pubmed.ncbi.nlm.nih.gov/9508174/ PubMed]
 ==WBRT {{#subobject:4c3d39|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
 WBRT: '''<u>W</u>'''hole '''<u>B</u>'''rain '''<u>R</u>'''adiation '''<u>T</u>'''herapy
+<div class="toccolours" style="background-color:#eeeeee">
 ===Regimen {{#subobject:bcb463|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
+!style="width: 20%"|Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Dates of enrollment
-!style="width: 25%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
 |[https://doi.org/10.1016/s0140-6736(81)91849-3 Nesbit et al. 1981]
-| style="background-color:#1a9851" |Phase III (C)
+|1972-1975
+| style="background-color:#1a9851" |Phase 3 (C)
 |[[#WBRT|WBRT]]; lower-dose
-| style="background-color:#ffffbf" |Seems not superior
+| style="background-color:#ffffbf" |Did not meet endpoint of OS
 |-
-|[https://www.nejm.org/doi/full/10.1056/NEJM198303033080902 Freeman et al. 1983 (CALGB 7611)]
+|[https://doi.org/10.1056/NEJM198303033080902 Freeman et al. 1983 (CALGB 7611)]
-| style="background-color:#1a9851" |Phase III (C)
+|1976-1979
+| style="background-color:#1a9851" |Phase 3 (C)
 |Intermediate-dose MTX
 | style="background-color:#ffffbf" |Mixed results
 |-
 |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2754320/ Pui et al. 2009 (Total Therapy XV)]
-| style="background-color:#1a9851" |Phase III (C)
+|2000-2007
+| style="background-color:#1a9851" |Phase 3 (C)
 |Observation
-| style="background-color:#ffffbf" |Seems not superior
+| style="background-color:#ffffbf" |Did not meet co-primary endpoints of EFS/OS
 |-
 |}
 ''Note: in Total Therapy XV, this is the control arm of a de-escalation study.''
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Radiotherapy====
 *[[External_beam_radiotherapy|Whole-brain irradiation]]
 '''One course'''
+</div></div>
 ===References===
-# Nesbit ME Jr, Sather HN, Robison LL, Ortega J, Littman PS, D'Angio GJ, Hammond GD. Presymptomatic central nervous system therapy in previously untreated childhood acute lymphoblastic leukaemia: comparison of 1800 rad and 2400 rad: a report for Children's Cancer Study Group. Lancet. 1981 Feb 28;1(8218):461-6. [https://doi.org/10.1016/s0140-6736(81)91849-3 link to original article] [https://pubmed.ncbi.nlm.nih.gov/6110090 PubMed]
+# Nesbit ME Jr, Sather HN, Robison LL, Ortega J, Littman PS, D'Angio GJ, Hammond GD; Children's Cancer Group. Presymptomatic central nervous system therapy in previously untreated childhood acute lymphoblastic leukaemia: comparison of 1800 rad and 2400 rad: a report for Children's Cancer Study Group. Lancet. 1981 Feb 28;1(8218):461-6. [https://doi.org/10.1016/s0140-6736(81)91849-3 link to original article] [https://pubmed.ncbi.nlm.nih.gov/6110090/ PubMed]
-# '''CALGB 7611:''' Freeman AI, Weinberg V, Brecher ML, Jones B, Glicksman AS, Sinks LF, Weil M, Pleuss H, Hananian J, Burgert EO Jr, Gilchrist GS, Necheles T, Harris M, Kung F, Patterson RB, Maurer H, Leventhal B, Chevalier L, Forman E, Holland JF. Comparison of intermediate-dose methotrexate with cranial irradiation for the post-induction treatment of acute lymphocytic leukemia in children. N Engl J Med. 1983 Mar 3;308(9):477-84. [https://www.nejm.org/doi/full/10.1056/NEJM198303033080902 link to original article] [https://pubmed.ncbi.nlm.nih.gov/6571946 PubMed]
+# '''CALGB 7611:''' Freeman AI, Weinberg V, Brecher ML, Jones B, Glicksman AS, Sinks LF, Weil M, Pleuss H, Hananian J, Burgert EO Jr, Gilchrist GS, Necheles T, Harris M, Kung F, Patterson RB, Maurer H, Leventhal B, Chevalier L, Forman E, Holland JF. Comparison of intermediate-dose methotrexate with cranial irradiation for the post-induction treatment of acute lymphocytic leukemia in children. N Engl J Med. 1983 Mar 3;308(9):477-84. [https://doi.org/10.1056/NEJM198303033080902 link to original article] [https://pubmed.ncbi.nlm.nih.gov/6571946/ PubMed]
-## '''Update:''' Freeman AI, Boyett JM, Glicksman AS, Brecher ML, Leventhal BG, Sinks LF, Holland JF. Intermediate-dose methotrexate versus cranial irradiation in childhood acute lymphoblastic leukemia: a ten-year follow-up. Med Pediatr Oncol. 1997 Feb;28(2):98-107. [https://onlinelibrary.wiley.com/doi/abs/10.1002/(SICI)1096-911X(199702)28:2%3C98::AID-MPO3%3E3.0.CO;2-N link to original article] [https://pubmed.ncbi.nlm.nih.gov/8986145 PubMed]
+## '''Update:''' Freeman AI, Boyett JM, Glicksman AS, Brecher ML, Leventhal BG, Sinks LF, Holland JF. Intermediate-dose methotrexate versus cranial irradiation in childhood acute lymphoblastic leukemia: a ten-year follow-up. Med Pediatr Oncol. 1997 Feb;28(2):98-107. [https://doi.org/10.1002/(SICI)1096-911X(199702)28:2%3C98::AID-MPO3%3E3.0.CO;2-N link to original article] [https://pubmed.ncbi.nlm.nih.gov/8986145/ PubMed]
-# '''Total Therapy XV:''' Pui CH, Campana D, Pei D, Bowman WP, Sandlund JT, Kaste SC, Ribeiro RC, Rubnitz JE, Raimondi SC, Onciu M, Coustan-Smith E, Kun LE, Jeha S, Cheng C, Howard SC, Simmons V, Bayles A, Metzger ML, Boyett JM, Leung W, Handgretinger R, Downing JR, Evans WE, Relling MV. Treating childhood acute lymphoblastic leukemia without cranial irradiation. N Engl J Med. 2009 Jun 25;360(26):2730-41. [https://www.nejm.org/doi/full/10.1056/NEJMoa0900386 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2754320/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19553647 PubMed]
+# '''Total Therapy XV:''' Pui CH, Campana D, Pei D, Bowman WP, Sandlund JT, Kaste SC, Ribeiro RC, Rubnitz JE, Raimondi SC, Onciu M, Coustan-Smith E, Kun LE, Jeha S, Cheng C, Howard SC, Simmons V, Bayles A, Metzger ML, Boyett JM, Leung W, Handgretinger R, Downing JR, Evans WE, Relling MV. Treating childhood acute lymphoblastic leukemia without cranial irradiation. N Engl J Med. 2009 Jun 25;360(26):2730-41. [https://doi.org/10.1056/NEJMoa0900386 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2754320/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19553647/ PubMed] [https://clinicaltrials.gov/study/NCT00137111 NCT00137111]
 =CNS prophylaxis, systemic therapy=
 ==Mercaptopurine & WBRT {{#subobject:fab960|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
 Mercaptopurine & WBRT: Mercaptopurine & '''<u>W</u>'''hole '''<u>B</u>'''rain '''<u>R</u>'''adiation '''<u>T</u>'''herapy
+<div class="toccolours" style="background-color:#eeeeee">
 ===Regimen {{#subobject:846b99|Variant=1}}===
-{| class="wikitable" style="width: 50%; text-align:center;"
+{| class="wikitable sortable" style="width: 60%; text-align:center;"
-!style="width: 25%"|Study
+!style="width: 33%"|Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 33%"|Dates of enrollment
+!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|[https://doi.org/10.1200/JCO.2015.61.5385 Huguet et al. 2009 (GRAALL-2003)]
+|[https://doi.org/10.1200/JCO.2008.18.6916 Huguet et al. 2009 (GRAALL-2003)]
-|style="background-color:#91cf61"|Phase II
+|2003-2005
+|style="background-color:#91cf61"|Phase 2
 |-
 |}
-''Chemoradiation is given before maintenance therapy.''
+''Note: Chemoradiation is given before maintenance therapy.''
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
 *[[Mercaptopurine (6-MP)]] 60 mg/m<sup>2</sup>/day PO during irradiation
 ====Radiotherapy====
-*[[External_beam_radiotherapy|Whole-brain irradiation]] to 18 Gy (details not provided)
+*[[External_beam_radiotherapy|Whole-brain irradiation]] to 1800 cGy (details not provided)
 '''One course'''
+</div></div>
 ===References===
-# '''GRAALL-2003:''' Huguet F, Leguay T, Raffoux E, Thomas X, Beldjord K, Delabesse E, Chevallier P, Buzyn A, Delannoy A, Chalandon Y, Vernant JP, Lafage-Pochitaloff M, Chassevent A, Lhéritier V, Macintyre E, Béné MC, Ifrah N, Dombret H. Pediatric-inspired therapy in adults with Philadelphia chromosome-negative acute lymphoblastic leukemia: the GRAALL-2003 study. J Clin Oncol. 2009 Feb 20;27(6):911-8. Epub 2009 Jan 5. Erratum in: J Clin Oncol. 2009 May 20;27(15):2574. Dosage error in article text. [https://doi.org/10.1200/JCO.2015.61.5385 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/19124805 PubMed]
+# '''GRAALL-2003:''' Huguet F, Leguay T, Raffoux E, Thomas X, Beldjord K, Delabesse E, Chevallier P, Buzyn A, Delannoy A, Chalandon Y, Vernant JP, Lafage-Pochitaloff M, Chassevent A, Lhéritier V, Macintyre E, Béné MC, Ifrah N, Dombret H. Pediatric-inspired therapy in adults with Philadelphia chromosome-negative acute lymphoblastic leukemia: the GRAALL-2003 study. J Clin Oncol. 2009 Feb 20;27(6):911-8. Epub 2009 Jan 5. Erratum in: J Clin Oncol. 2009 May 20;27(15):2574. Dosage error in article text. [https://doi.org/10.1200/JCO.2008.18.6916 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/19124805/ PubMed] [https://clinicaltrials.gov/study/NCT00222027 NCT00222027]
 =CNS treatment, local therapy=
 ==IT Cytarabine & Methotrexate {{#subobject:7536ce|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
+<div class="toccolours" style="background-color:#eeeeee">
-|-
-|[[#top|back to top]]
-|}
 ===Regimen variant #1, LP {{#subobject:c0aa53|Variant=1}}===
-{| class="wikitable" style="width: 50%; text-align:center;"
+{| class="wikitable sortable" style="width: 60%; text-align:center;"
-!style="width: 25%"|Study
+!style="width: 33%"|Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 33%"|Dates of enrollment
+!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|[http://jco.ascopubs.org/content/17/8/2461.long Thomas et al. 1999]
+|[https://doi.org/10.1200/jco.1999.17.8.2461 Thomas et al. 1999]
-|style="background-color:#91cf61"|Phase II
+|1992-09 to 1997-06
+|style="background-color:#91cf61"|Phase 2
 |-
 |}
 ''Note: while there is measurable CNS disease, both drugs are given every week, alternating, usually separated by at least 48 hours (e.g., on Mondays & Thursdays).''
-====Chemotherapy, CNS====
+<div class="toccolours" style="background-color:#b3e2cd">
+====CNS therapy, treatment====
 *[[Methotrexate (MTX)]] as follows:
 **Measurable CNS disease: 12 mg IT once per week
@@ Line 371: / Line 361: @@
 **First 4 weeks after cell count & cytology are negative: 100 mg IT once per week on weeks 2 & 4
 **Remainder of induction: 100 mg IT once on day 7 or 8
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
 ===Regimen variant #2, Ommaya reservoir {{#subobject:c0aa53|Variant=1}}===
-{| class="wikitable" style="width: 50%; text-align:center;"
+{| class="wikitable sortable" style="width: 60%; text-align:center;"
-!style="width: 25%"|Study
+!style="width: 33%"|Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 33%"|Dates of enrollment
+!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|[http://jco.ascopubs.org/content/17/8/2461.long Thomas et al. 1999]
+|[https://doi.org/10.1200/jco.1999.17.8.2461 Thomas et al. 1999]
-|style="background-color:#91cf61"|Phase II
+|1992-09 to 1997-06
+|style="background-color:#91cf61"|Phase 2
 |-
 |}
 ''Note: while there is measurable CNS disease, both drugs are given every week, alternating, usually separated by at least 48 hours (e.g., on Mondays & Thursdays).''
-====Chemotherapy, CNS====
+<div class="toccolours" style="background-color:#b3e2cd">
+====CNS therapy, treatment====
 *[[Methotrexate (MTX)]] as follows:
 **Measurable CNS disease: 6 mg IT once per week
@@ Line 391: / Line 385: @@
 **First 4 weeks after cell count & cytology are negative: 100 mg IT once per week on weeks 2 & 4
 **Remainder of induction: 100 mg IT once on day 7 or 8
+</div></div>
 ===References===
-# Thomas DA, Cortes J, O'Brien S, Pierce S, Faderl S, Albitar M, Hagemeister FB, Cabanillas FF, Murphy S, Keating MJ, Kantarjian H. Hyper-CVAD program in Burkitt's-type adult acute lymphoblastic leukemia. J Clin Oncol. 1999 Aug;17(8):2461-70. [http://jco.ascopubs.org/content/17/8/2461.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/10561310 PubMed]
+# Thomas DA, Cortes J, O'Brien S, Pierce S, Faderl S, Albitar M, Hagemeister FB, Cabanillas FF, Murphy S, Keating MJ, Kantarjian H. Hyper-CVAD program in Burkitt's-type adult acute lymphoblastic leukemia. J Clin Oncol. 1999 Aug;17(8):2461-70. [https://doi.org/10.1200/jco.1999.17.8.2461 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/10561310/ PubMed]
 ==IT Cytarabine, Methotrexate, Methylprednisolone {{#subobject:833d98|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
+<div class="toccolours" style="background-color:#eeeeee">
-|-
-|[[#top|back to top]]
-|}
 ===Regimen {{#subobject:0ded48|Variant=1}}===
-{| class="wikitable" style="width: 50%; text-align:center;"
+{| class="wikitable sortable" style="width: 60%; text-align:center;"
-!style="width: 25%"|Study
+!style="width: 33%"|Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 33%"|Dates of enrollment
+!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|[https://doi.org/10.1200/JCO.2015.61.5385 Huguet et al. 2009 (GRAALL-2003)]
+|[https://doi.org/10.1200/JCO.2008.18.6916 Huguet et al. 2009 (GRAALL-2003)]
-|style="background-color:#91cf61"|Phase II
+|2003-2005
+|style="background-color:#91cf61"|Phase 2
 |-
 |}
-''Intrathecal treatments are given as follows: eight between days -7 and 21 of induction, four during the first two consolidation blocks, and one at day 29 of consolidation blocks 3 and 6 -- 14 total doses.''
+''Note: Intrathecal treatments are given as follows: eight between days -7 and 21 of induction, four during the first two consolidation blocks, and one at day 29 of consolidation blocks 3 and 6 -- 14 total doses.''
-====Chemotherapy, CNS====
+<div class="toccolours" style="background-color:#b3e2cd">
+====CNS therapy, treatment====
 *[[Cytarabine (Ara-C)]] 40 mg IT mixed with methotrexate and methylprednisolone
 *[[Methotrexate (MTX)]] 15 mg IT mixed with cytarabine and methylprednisolone
 *[[Methylprednisolone (Solumedrol)]] 40 mg IT mixed with cytarabine and methotrexate
+'''14 doses (see note)'''
-'''14 doses'''
+</div></div>
 ===References===
-# '''GRAALL-2003:''' Huguet F, Leguay T, Raffoux E, Thomas X, Beldjord K, Delabesse E, Chevallier P, Buzyn A, Delannoy A, Chalandon Y, Vernant JP, Lafage-Pochitaloff M, Chassevent A, Lhéritier V, Macintyre E, Béné MC, Ifrah N, Dombret H. Pediatric-inspired therapy in adults with Philadelphia chromosome-negative acute lymphoblastic leukemia: the GRAALL-2003 study. J Clin Oncol. 2009 Feb 20;27(6):911-8. Epub 2009 Jan 5. Erratum in: J Clin Oncol. 2009 May 20;27(15):2574. Dosage error in article text. [https://doi.org/10.1200/JCO.2015.61.5385 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/19124805 PubMed]
+# '''GRAALL-2003:''' Huguet F, Leguay T, Raffoux E, Thomas X, Beldjord K, Delabesse E, Chevallier P, Buzyn A, Delannoy A, Chalandon Y, Vernant JP, Lafage-Pochitaloff M, Chassevent A, Lhéritier V, Macintyre E, Béné MC, Ifrah N, Dombret H. Pediatric-inspired therapy in adults with Philadelphia chromosome-negative acute lymphoblastic leukemia: the GRAALL-2003 study. J Clin Oncol. 2009 Feb 20;27(6):911-8. Epub 2009 Jan 5. Erratum in: J Clin Oncol. 2009 May 20;27(15):2574. Dosage error in article text. [https://doi.org/10.1200/JCO.2008.18.6916 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/19124805/ PubMed] [https://clinicaltrials.gov/study/NCT00222027 NCT00222027]
 ==IT Cytarabine, Methotrexate, WBRT {{#subobject:2457a6|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
 Cytarabine, Methotrexate, WBRT: Cytarabine, Methotrexate, '''<u>W</u>'''hole '''<u>B</u>'''rain '''<u>R</u>'''adiation '''<u>T</u>'''herapy
+<div class="toccolours" style="background-color:#eeeeee">
 ===Regimen variant #1, LP {{#subobject:b3fdae|Variant=1}}===
-{| class="wikitable" style="width: 50%; text-align:center;"
+{| class="wikitable sortable" style="width: 60%; text-align:center;"
-!style="width: 25%"|Study
+!style="width: 33%"|Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 33%"|Dates of enrollment
+!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|[http://www.bloodjournal.org/content/103/12/4396.long Thomas et al. 2003]
+|[https://doi.org/10.1182/blood-2003-08-2958 Thomas et al. 2003]
-|style="background-color:#91cf61"|Phase II
+|2001-04 to 2003-03
+|style="background-color:#91cf61"|Phase 2
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4081177/ Ravandi et al. 2010]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4081177/ Ravandi et al. 2010 (MDACC 2006-0478)]
-|style="background-color:#91cf61"|Phase II
+|2006-09-28 to 2009-07-15
+|style="background-color:#91cf61"|Phase 2
 |-
 |}
 ''Note: while there is measurable CNS disease, both drugs are given every week, alternating, usually separated by at least 48 hours (e.g., on Mondays & Thursdays).''
-====Chemotherapy, CNS====
+<div class="toccolours" style="background-color:#b3e2cd">
+====CNS therapy, treatment====
 *[[Methotrexate (MTX)]] as follows:
 **Measurable CNS disease: 12 mg IT once per week
@@ Line 450: / Line 443: @@
 ====Radiotherapy====
 *Therapeutic [[External_beam_radiotherapy|whole-brain irradiation]] is given to patients with CNS disease at presentation
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
 ===Regimen variant #2, Ommaya reservoir {{#subobject:b3fadu|Variant=1}}===
-{| class="wikitable" style="width: 50%; text-align:center;"
+{| class="wikitable sortable" style="width: 60%; text-align:center;"
-!style="width: 25%"|Study
+!style="width: 33%"|Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 33%"|Dates of enrollment
+!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|[http://www.bloodjournal.org/content/103/12/4396.long Thomas et al. 2003]
+|[https://doi.org/10.1182/blood-2003-08-2958 Thomas et al. 2003]
-|style="background-color:#91cf61"|Phase II
+|2001-04 to 2003-03
+|style="background-color:#91cf61"|Phase 2
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4081177/ Ravandi et al. 2010]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4081177/ Ravandi et al. 2010 (MDACC 2006-0478)]
-|style="background-color:#91cf61"|Phase II
+|2006-09-28 to 2009-07-15
+|style="background-color:#91cf61"|Phase 2
 |-
 |}
 ''Note: while there is measurable CNS disease, both drugs are given every week, alternating, usually separated by at least 48 hours (e.g., on Mondays & Thursdays).''
-====Chemotherapy, CNS====
+<div class="toccolours" style="background-color:#b3e2cd">
+====CNS therapy, treatment====
 *[[Methotrexate (MTX)]] as follows:
 **Measurable CNS disease: 6 mg IT once per week
@@ Line 475: / Line 473: @@
 ====Radiotherapy====
 *Therapeutic [[External_beam_radiotherapy|whole-brain irradiation]] is given to patients with CNS disease at presentation
+</div></div>
 ===References===
-# Thomas DA, Faderl S, Cortes J, O'Brien S, Giles FJ, Kornblau SM, Garcia-Manero G, Keating MJ, Andreeff M, Jeha S, Beran M, Verstovsek S, Pierce S, Letvak L, Salvado A, Champlin R, Talpaz M, Kantarjian H. Treatment of Philadelphia chromosome-positive acute lymphocytic leukemia with hyper-CVAD and imatinib mesylate. Blood. 2004 Jun 15;103(12):4396-407. Epub 2003 Oct 9. [http://www.bloodjournal.org/content/103/12/4396.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/14551133 PubMed]
+# Thomas DA, Faderl S, Cortes J, O'Brien S, Giles FJ, Kornblau SM, Garcia-Manero G, Keating MJ, Andreeff M, Jeha S, Beran M, Verstovsek S, Pierce S, Letvak L, Salvado A, Champlin R, Talpaz M, Kantarjian H. Treatment of Philadelphia chromosome-positive acute lymphocytic leukemia with hyper-CVAD and imatinib mesylate. Blood. 2004 Jun 15;103(12):4396-407. Epub 2003 Oct 9. [https://doi.org/10.1182/blood-2003-08-2958 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/14551133/ PubMed]
-## '''Update:''' Daver N, Thomas D, Ravandi F, Cortes J, Garris R, Jabbour E, Garcia-Manero G, Borthakur G, Kadia T, Rytting M, Konopleva M, Kantarjian H, O' Brien S. Final report of a phase II study of imatinib mesylate with hyper-CVAD for the frontline treatment of adult patients with Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia. Haematologica. 2015 May;100(5):653-61. Epub 2015 Feb 14. [http://www.haematologica.org/content/100/5/653 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4420214/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25682595 PubMed]
+## '''Update:''' Daver N, Thomas D, Ravandi F, Cortes J, Garris R, Jabbour E, Garcia-Manero G, Borthakur G, Kadia T, Rytting M, Konopleva M, Kantarjian H, O' Brien S. Final report of a phase II study of imatinib mesylate with hyper-CVAD for the frontline treatment of adult patients with Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia. Haematologica. 2015 May;100(5):653-61. Epub 2015 Feb 14. [https://doi.org/10.3324/haematol.2014.118588 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4420214/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25682595/ PubMed]
-# Ravandi F, O'Brien S, Thomas D, Faderl S, Jones D, Garris R, Dara S, Jorgensen J, Kebriaei P, Champlin R, Borthakur G, Burger J, Ferrajoli A, Garcia-Manero G, Wierda W, Cortes J, Kantarjian H. First report of phase 2 study of dasatinib with hyper-CVAD for the frontline treatment of patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia. Blood. 2010 Sep 23;116(12):2070-7. Epub 2010 May 13. [http://www.bloodjournal.org/content/116/12/2070.long link to original article] '''contains verified protocol'''--parts of the protocol were not explicitly listed in this reference, which instead referred to [[#Hyper-CVAD_.26_Imatinib_.28Gleevec.29_.28induction_.26_maintenance.29|Thomas et al. 2004]] and [[#Hyper-CVAD_.28induction.29|Kantarjian et al. 2004]] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4081177/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/20466853 PubMed]
+# '''MDACC 2006-0478:''' Ravandi F, O'Brien S, Thomas D, Faderl S, Jones D, Garris R, Dara S, Jorgensen J, Kebriaei P, Champlin R, Borthakur G, Burger J, Ferrajoli A, Garcia-Manero G, Wierda W, Cortes J, Kantarjian H. First report of phase 2 study of dasatinib with hyper-CVAD for the frontline treatment of patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia. Blood. 2010 Sep 23;116(12):2070-7. Epub 2010 May 13. [https://doi.org/10.1182/blood-2009-12-261586 link to original article] '''contains dosing details in manuscript'''--parts of the protocol were not explicitly listed in this reference, which instead referred to [[#Hyper-CVAD_.26_Imatinib_.28Gleevec.29_.28induction_.26_maintenance.29|Thomas et al. 2004]] and [[#Hyper-CVAD_.28induction.29|Kantarjian et al. 2004]] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4081177/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/20466853/ PubMed] [https://clinicaltrials.gov/study/NCT00390793 NCT00390793]
-## '''Update:''' Ravandi F, O'Brien SM, Cortes JE, Thomas DM, Garris R, Faderl S, Burger JA, Rytting ME, Ferrajoli A, Wierda WG, Verstovsek S, Champlin R, Kebriaei P, McCue DA, Huang X, Jabbour E, Garcia-Manero G, Estrov Z, Kantarjian HM. Long-term follow-up of a phase 2 study of chemotherapy plus dasatinib for the initial treatment of patients with Philadelphia chromosome-positive acute lymphoblastic leukemia. Cancer. 2015 Dec 1;121(23):4158-64. Epub 2015 Aug 26. [https://onlinelibrary.wiley.com/doi/10.1002/cncr.29646/full link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4666803/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26308885 PubMed]
+## '''Update:''' Ravandi F, O'Brien SM, Cortes JE, Thomas DM, Garris R, Faderl S, Burger JA, Rytting ME, Ferrajoli A, Wierda WG, Verstovsek S, Champlin R, Kebriaei P, McCue DA, Huang X, Jabbour E, Garcia-Manero G, Estrov Z, Kantarjian HM. Long-term follow-up of a phase 2 study of chemotherapy plus dasatinib for the initial treatment of patients with Philadelphia chromosome-positive acute lymphoblastic leukemia. Cancer. 2015 Dec 1;121(23):4158-64. Epub 2015 Aug 26. [https://doi.org/10.1002/cncr.29646 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4666803/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26308885/ PubMed]
 ==IT Methotrexate monotherapy {{#subobject:d4a3c5|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
+<div class="toccolours" style="background-color:#eeeeee">
-|-
-|[[#top|back to top]]
-|}
 ===Regimen {{#subobject:183c87|Variant=1}}===
-{| class="wikitable" style="width: 50%; text-align:center;"
+{| class="wikitable sortable" style="width: 60%; text-align:center;"
-!style="width: 25%"|Study
+!style="width: 33%"|Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 33%"|Dates of enrollment
+!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|[https://www.nejm.org/doi/full/10.1056/NEJM196107272650404 Shanbrom et al. 1961]
+|[https://doi.org/10.1056/NEJM196107272650404 Shanbrom et al. 1961]
+|1957-1960
 | style="background-color:#ffffbe" |Pilot
 |-
-|[https://doi.org/10.1200/JCO.2015.61.5385 Huguet et al. 2009 (GRAALL-2003)]
+|[https://doi.org/10.1200/JCO.2008.18.6916 Huguet et al. 2009 (GRAALL-2003)]
-|style="background-color:#91cf61"|Phase II
+|2003-2005
+|style="background-color:#91cf61"|Phase 2
 |-
 |}
-====Chemotherapy, CNS====
+<div class="toccolours" style="background-color:#b3e2cd">
+====CNS therapy, treatment====
 *[[Methotrexate (MTX)]] as follows:
-**Prephase: 15 mg IT once at some point between days -7 and -4
+**Pre-phase: 15 mg IT once at some point between days -7 and -4
+</div></div>
 ===References===
-# Shanbrom E, Miller S, Fairbanks VF. Intrathecal administration of amethopterin in leukemic encephalopathy of young adults. N Engl J Med. 1961 Jul 27;265:169-71. [https://www.nejm.org/doi/full/10.1056/NEJM196107272650404 link to original article] [https://pubmed.ncbi.nlm.nih.gov/13750662 PubMed]
+# Shanbrom E, Miller S, Fairbanks VF. Intrathecal administration of amethopterin in leukemic encephalopathy of young adults. N Engl J Med. 1961 Jul 27;265:169-71. [https://doi.org/10.1056/NEJM196107272650404 link to original article] [https://pubmed.ncbi.nlm.nih.gov/13750662/ PubMed]
-# '''GRAALL-2003:''' Huguet F, Leguay T, Raffoux E, Thomas X, Beldjord K, Delabesse E, Chevallier P, Buzyn A, Delannoy A, Chalandon Y, Vernant JP, Lafage-Pochitaloff M, Chassevent A, Lhéritier V, Macintyre E, Béné MC, Ifrah N, Dombret H. Pediatric-inspired therapy in adults with Philadelphia chromosome-negative acute lymphoblastic leukemia: the GRAALL-2003 study. J Clin Oncol. 2009 Feb 20;27(6):911-8. Epub 2009 Jan 5. Erratum in: J Clin Oncol. 2009 May 20;27(15):2574. Dosage error in article text. [https://doi.org/10.1200/JCO.2015.61.5385 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/19124805 PubMed]
+# '''GRAALL-2003:''' Huguet F, Leguay T, Raffoux E, Thomas X, Beldjord K, Delabesse E, Chevallier P, Buzyn A, Delannoy A, Chalandon Y, Vernant JP, Lafage-Pochitaloff M, Chassevent A, Lhéritier V, Macintyre E, Béné MC, Ifrah N, Dombret H. Pediatric-inspired therapy in adults with Philadelphia chromosome-negative acute lymphoblastic leukemia: the GRAALL-2003 study. J Clin Oncol. 2009 Feb 20;27(6):911-8. Epub 2009 Jan 5. Erratum in: J Clin Oncol. 2009 May 20;27(15):2574. Dosage error in article text. [https://doi.org/10.1200/JCO.2008.18.6916 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/19124805/ PubMed] [https://clinicaltrials.gov/study/NCT00222027 NCT00222027]
 ==IT Methotrexate & WBRT {{#subobject:d129ea|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
 IT Methotrexate & WBRT: '''<u>I</u>'''ntra'''<u>T</u>'''hecal Methotrexate & '''<u>W</u>'''hole '''<u>B</u>'''rain '''<u>R</u>'''adiation '''<u>T</u>'''herapy
+<div class="toccolours" style="background-color:#eeeeee">
 ===Regimen {{#subobject:f7b824|Variant=1}}===
-{| class="wikitable" style="width: 50%; text-align:center;"
+{| class="wikitable sortable" style="width: 60%; text-align:center;"
-!style="width: 25%"|Study
+!style="width: 33%"|Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 33%"|Dates of enrollment
+!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|[http://www.bloodjournal.org/content/69/4/1242.full.pdf+html Linker et al. 1987]
+|[https://doi.org/10.1182/blood.V69.4.1242.1242 Linker et al. 1987]
-|style="background-color:#91cf61"|Phase II
+|1980-1986
+|style="background-color:#91cf61"|Phase 2
 |-
 |}
-''Treatment starts while patient is receiving induction therapy.''
+''Note: Treatment starts while patient is receiving induction therapy.''
-====Chemotherapy, CNS====
+<div class="toccolours" style="background-color:#b3e2cd">
+====CNS therapy, treatment====
 *[[Methotrexate (MTX)]] as follows:
 **Induction: 12 mg IT once per week x 10 doses
 **Remainder of first year of therapy: 12 mg IT once per month
 ====Radiotherapy====
-*[[External_beam_radiotherapy|Whole-brain irradiation]], 28 Gy total given (no details provided)
+*[[External_beam_radiotherapy|Whole-brain irradiation]], 2800 cGy total given (no details provided)
+</div></div>
 ===References===
-# Linker CA, Levitt LJ, O'Donnell M, Ries CA, Link MP, Forman SJ, Farbstein MJ. Improved results of treatment of adult acute lymphoblastic leukemia. Blood. 1987 Apr;69(4):1242-8. [http://www.bloodjournal.org/content/69/4/1242.full.pdf+html link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/3470055 PubMed]
+# Linker CA, Levitt LJ, O'Donnell M, Ries CA, Link MP, Forman SJ, Farbstein MJ. Improved results of treatment of adult acute lymphoblastic leukemia. Blood. 1987 Apr;69(4):1242-8. [https://doi.org/10.1182/blood.V69.4.1242.1242 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/3470055/ PubMed]
-## '''Update:''' Linker CA, Levitt LJ, O'Donnell M, Forman SJ, Ries CA. Treatment of adult acute lymphoblastic leukemia with intensive cyclical chemotherapy: a follow-up report. Blood. 1991 Dec 1;78(11):2814-22. [http://www.bloodjournal.org/content/78/11/2814.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/1835410 PubMed]
+## '''Update:''' Linker CA, Levitt LJ, O'Donnell M, Forman SJ, Ries CA. Treatment of adult acute lymphoblastic leukemia with intensive cyclical chemotherapy: a follow-up report. Blood. 1991 Dec 1;78(11):2814-22. [https://doi.org/10.1182/blood.V78.11.2814.2814 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/1835410/ PubMed]
 =CNS treatment, systemic therapy=
 ==Mercaptopurine & WBRT {{#subobject:d6ba9e|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
+Mercaptopurine & WBRT: Mercaptopurine & '''<u>W</u>'''hole '''<u>B</u>'''rain '''<u>R</u>'''adiation '''<u>T</u>'''herapy
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #1 {{#subobject:cd21c7|Variant=1}}===
+{| class="wikitable sortable" style="width: 60%; text-align:center;"
+!style="width: 33%"|Study
+!style="width: 33%"|Dates of enrollment
+!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
+|-
+|[https://doi.org/10.1200/JCO.2008.18.6916 Huguet et al. 2009 (GRAALL-2003)]
+|2003-2005
+|style="background-color:#91cf61"|Phase 2
 |-
-|[[#top|back to top]]
 |}
-Mercaptopurine & WBRT: Mercaptopurine & '''<u>W</u>'''hole '''<u>B</u>'''rain '''<u>R</u>'''adiation '''<u>T</u>'''herapy
+''Note: Treatment administered before HSCT or maintenence initiation.''
-===Regimen {{#subobject:cd21c7|Variant=1}}===
+<div class="toccolours" style="background-color:#b3e2cd">
-{| class="wikitable" style="width: 50%; text-align:center;"
+====Chemotherapy====
-!style="width: 25%"|Study
+*[[Mercaptopurine (6-MP)]] 60 mg/m<sup>2</sup>/day PO during irradiation
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+====Radiotherapy====
+*[[External_beam_radiotherapy|Whole-brain irradiation]] 1500 cGy before HCT (details not provided)
+'''One course'''
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #2 {{#subobject:cd75g7|Variant=1}}===
+{| class="wikitable sortable" style="width: 60%; text-align:center;"
+!style="width: 33%"|Study
+!style="width: 33%"|Dates of enrollment
+!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|[https://doi.org/10.1200/JCO.2015.61.5385 Huguet et al. 2009 (GRAALL-2003)]
+|[https://doi.org/10.1200/JCO.2008.18.6916 Huguet et al. 2009 (GRAALL-2003)]
-|style="background-color:#91cf61"|Phase II
+|2003-2005
+|style="background-color:#91cf61"|Phase 2
 |-
 |}
-''Treatment administered before HSCT or maintanence initiation.''
+''Note: Treatment was administered before HSCT or maintenance initiation.''
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
 *[[Mercaptopurine (6-MP)]] 60 mg/m<sup>2</sup>/day PO during irradiation
 ====Radiotherapy====
-*[[External_beam_radiotherapy|Whole-brain irradiation]] as follows:
+*[[External_beam_radiotherapy|Whole-brain irradiation]] 2400 cGy before maintenance therapy initiation (details not provided)
-**15 Gy before HCT (details not provided), or
-**24 Gy before maintenance therapy initiation (details not provided)
 '''One course'''
+</div></div>
 ===References===
-# '''GRAALL-2003:''' Huguet F, Leguay T, Raffoux E, Thomas X, Beldjord K, Delabesse E, Chevallier P, Buzyn A, Delannoy A, Chalandon Y, Vernant JP, Lafage-Pochitaloff M, Chassevent A, Lhéritier V, Macintyre E, Béné MC, Ifrah N, Dombret H. Pediatric-inspired therapy in adults with Philadelphia chromosome-negative acute lymphoblastic leukemia: the GRAALL-2003 study. J Clin Oncol. 2009 Feb 20;27(6):911-8. Epub 2009 Jan 5. Erratum in: J Clin Oncol. 2009 May 20;27(15):2574. Dosage error in article text. [https://doi.org/10.1200/JCO.2015.61.5385 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/19124805 PubMed]
+# '''GRAALL-2003:''' Huguet F, Leguay T, Raffoux E, Thomas X, Beldjord K, Delabesse E, Chevallier P, Buzyn A, Delannoy A, Chalandon Y, Vernant JP, Lafage-Pochitaloff M, Chassevent A, Lhéritier V, Macintyre E, Béné MC, Ifrah N, Dombret H. Pediatric-inspired therapy in adults with Philadelphia chromosome-negative acute lymphoblastic leukemia: the GRAALL-2003 study. J Clin Oncol. 2009 Feb 20;27(6):911-8. Epub 2009 Jan 5. Erratum in: J Clin Oncol. 2009 May 20;27(15):2574. Dosage error in article text. [https://doi.org/10.1200/JCO.2008.18.6916 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/19124805/ PubMed] [https://clinicaltrials.gov/study/NCT00222027 NCT00222027]
 [[Category:CNS leukemia regimens]]
 [[Category:Disease-specific pages]]
-[[Category:CNS cancers]]
+[[Category:Acute leukemias]]

Difference between revisions of "CNS leukemia"

Latest revision as of 21:10, 25 June 2024

CNS prophylaxis, local therapy

IT Cytarabine & Methotrexate

Regimen variant #1, 16 doses

CNS therapy, prophylaxis

Regimen variant #2, 6 to 8 doses

CNS therapy, prophylaxis

References

IT Cytarabine, Methotrexate, Methylprednisolone

Regimen

CNS therapy, prophylaxis

References

IT Cytarabine, Methotrexate, Prednisone

Regimen

CNS therapy, prophylaxis

References

IT Cytarabine & WBRT

Regimen

CNS therapy, prophylaxis

Radiotherapy

References

IT Methotrexate monotherapy

Regimen

CNS therapy, prophylaxis

References

IT Methotrexate & Hydrocortisone

Regimen

CNS therapy, prophylaxis

References

IT Methotrexate & Methylprednisolone

Regimen

CNS therapy, prophylaxis

References

IT Methotrexate & WBRT

Regimen

CNS therapy, prophylaxis

Radiotherapy

References

WBRT

Regimen

Radiotherapy

References

CNS prophylaxis, systemic therapy

Mercaptopurine & WBRT

Regimen

Chemotherapy

Radiotherapy

References

CNS treatment, local therapy

IT Cytarabine & Methotrexate

Regimen variant #1, LP

CNS therapy, treatment

Regimen variant #2, Ommaya reservoir

CNS therapy, treatment

References

IT Cytarabine, Methotrexate, Methylprednisolone

Regimen

CNS therapy, treatment

References

IT Cytarabine, Methotrexate, WBRT

Regimen variant #1, LP

CNS therapy, treatment

Radiotherapy

Regimen variant #2, Ommaya reservoir

CNS therapy, treatment

Radiotherapy

References

IT Methotrexate monotherapy

Regimen

CNS therapy, treatment

References

IT Methotrexate & WBRT

Regimen

CNS therapy, treatment

Radiotherapy

References

CNS treatment, systemic therapy

Mercaptopurine & WBRT

Regimen variant #1