Difference between revisions of "B-cell acute lymphoblastic leukemia"

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===References===
 
===References===
 
# 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. [http://onlinelibrary.wiley.com/doi/10.1002/cncr.21776/full link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/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. [http://onlinelibrary.wiley.com/doi/10.1002/cncr.21776/full link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/16502413 PubMed]
 +
# '''Update:''' Fayad L, Thomas D, Romaguera J. Update of the M. D. 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. [http://www.ncbi.nlm.nih.gov/pubmed/18284717 PubMed]
  
 
=Induction therapy, Ph-positive=
 
=Induction therapy, Ph-positive=

Revision as of 20:48, 29 May 2014

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Is there a regimen missing from this list? Would you like to share a different dosage/schedule or an additional reference for a regimen? Have you noticed an error? Do you have an idea that will help the site grow to better meet your needs and the needs of many others? You are invited to contribute to the site.


Please note, mature B-cell ALL (L3) is now classified as Burkitt lymphoma/leukemia. Regimens for this variant are available here

Induction therapy, Ph-negative

Hyper-CVAD (induction)

Hyper-CVAD: Hyperfractionated Cyclophosphamide, Vincristine, Adriamycin, Dexamethasone

Regimen

Phase II

Part A (cycles 1, 3, 5, 7):

Supportive care:

Next cycle to start as soon as absolute neutrophil count is > 1 x 10^9/L at least 24 hours off of G-CSF and platelet count > 60 x 10^9/L

Part B (cycles 2, 4, 6, 8):

  • Methotrexate (MTX) 200 mg/m2 IV over 2 hours, then 800 mg/m2 IV over 22 hours on day 1
  • Cytarabine (Cytosar) 3000 mg/m2 (1000 mg/m2 for patients ≥60 years old) IV over 2 hours Q12H on days 2 & 3 (4 total doses)

Supportive care:

Next cycle to start as soon as absolute neutrophil count is > 1 x 10^9/L at least 24 hours off of G-CSF and platelet count > 60 x 10^9/L

CNS prophylaxis

Given each cycle for a total of 6 or 8 intrathecal treatments (i.e. 3 each of methotrexate and cytarabine or 4 each of methotrexate and cytarabine), depending on risk for CNS relapse based serum lactate dehydrogenase (LDH) >1400 IU/L and/or proliferative index percentage of S + G2M ≥14%

For known CNS disease

  • Methotrexate (MTX) 12 mg (6 mg if given via Ommaya reservoir) IT alternating with Cytarabine (Cytosar) 100 mg IT, with both given every week until cell count in CSF normalizes and cytology is negative for malignancy
  • Then Methotrexate (MTX) 12 mg (6 mg if given via Ommaya reservoir) IT given weeks 1 & 3 and Cytarabine (Cytosar) 100 mg IT, given weeks 2 & 4
  • Once those 4 weeks are complete, then intrathecal treatment is given similar to the prophylactic schedule, with each drug given once during every remaining cycle of induction therapy:

Certain patient populations (see Kantarjian et al. 2004) received additional Hyper-CVAD maintenance therapy.

References

  1. Cortes J, O'Brien SM, Pierce S, Keating MJ, Freireich EJ, Kantarjian HM. The value of high-dose systemic chemotherapy and intrathecal therapy for central nervous system prophylaxis in different risk groups of adult acute lymphoblastic leukemia. Blood. 1995 Sep 15;86(6):2091-7. link to original article PubMed
  2. 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 verified protocol PubMed
  3. Kantarjian HM, O'Brien S, Smith TL, Cortes J, Giles FJ, Beran M, Pierce S, Huh Y, Andreeff M, Koller C, Ha CS, Keating MJ, Murphy S, Freireich EJ. Results of treatment with hyper-CVAD, a dose-intensive regimen, in adult acute lymphocytic leukemia. J Clin Oncol. 2000 Feb;18(3):547-61. link to original article PubMed
  4. Thomas DA, O'Brien S, Cortes J, Giles FJ, Faderl S, Verstovsek S, Ferrajoli A, Koller C, Beran M, Pierce S, Ha CS, Cabanillas F, Keating MJ, Kantarjian H. Outcome with the hyper-CVAD regimens in lymphoblastic lymphoma. Blood. 2004 Sep 15;104(6):1624-30. Epub 2004 Jun 3. link to original article contains verified protocol PubMed
  5. Update: Kantarjian H, Thomas D, O'Brien S, Cortes J, Giles F, Jeha S, Bueso-Ramos CE, Pierce S, Shan J, Koller C, Beran M, Keating M, Freireich EJ. Long-term follow-up results of hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (Hyper-CVAD), a dose-intensive regimen, in adult acute lymphocytic leukemia. Cancer. 2004 Dec 15;101(12):2788-801. link to original article contains verified protocol PubMed

International ALL Trial (MRC UKALL XII/ECOG E2993)

Regimen

Phase II

To our knowledge, this is the largest induction trial in adult ALL, N=1,646. CR rate was 90%. There are many local variants of this protocol, including substitution of peg-asparaginase for L-asparaginase.

Phase I, weeks 1 to 4

CNS prophylaxis

Phase II, weeks 5 to 8

CNS prophylaxis

Ph+ patients

Two variants have been tested: from 2003 to 2005, imatinib was added after induction; from 2005 onward, imatinib was added during induction. Various durations are proposed, see Fielding et al. 2013 for more details.

  • Imatinib (Gleevec) 400 mg PO once per day, increased to 600 mg PO once per day "wherever possible"

To be followed by consolidation portion of the protocol.

References

  1. 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 verified protocol PubMed
  2. 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
  3. 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 PubMed
  4. 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. 2013 Nov 25. [Epub ahead of print] link to original article contains verified protocol PubMed

Larson/CALGB 8811 regimen (induction)

Regimen

Phase II

Course I (induction):
For patients <60 years old:

For patients ≥60 years old:

To be followed by Larson/CALGB 8811 regimen courses II to IV (maintenance).

References

  1. Larson RA, Dodge RK, Burns CP, Lee EJ, Stone RM, Schulman P, Duggan D, Davey FR, Sobol RE, Frankel SR et al. A five-drug remission induction regimen with intensive consolidation for adults with acute lymphoblastic leukemia: cancer and leukemia group B study 8811. Blood. 1995 Apr 15;85(8):2025-37. link to original article contains verified protocol PubMed

Linker regimen

Regimen

Phase II

If bone marrow on day 14 has residual leukemia:

If bone marrow on day 28 has residual leukemia:

Central nervous system (CNS) prophylaxis for patients without CNS involvement at diagnosis is started within 1 week of achieving complete remission:

  • Cranial radiation, 18 Gy total given in 10 fractions over 12-14 days
  • Methotrexate (MTX) 12 mg IT weekly x 6 doses concurrent with radiation

Central nervous system (CNS) treatment for patients with CNS involvement at diagnosis:

  • Cranial radiation, 28 Gy total given
  • Methotrexate (MTX) 12 mg IT weekly x 10 doses that starts while they are receiving induction therapy, then given monthly during the first year of therapy

To be followed by Linker regimen consolidation therapy.

References

  1. 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 verified protocol PubMed
  2. 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 verified protocol PubMed

R-Hyper-CVAD

R-Hyper-CVAD: Rituximab, Hyperfractionated Cyclophosphamide, Vincristine, Adriamycin, Dexamethasone

Regimen

Pilot, <20 patients reported

Part A (cycles 1, 3, 5, 7):

Supportive care:

Next cycle to start no sooner than 14 days or as soon as "unmaintained" WBC count is > 3 x 10^9/L and platelet count > 50 x 10^9/L

Part B (cycles 2, 4, 6, 8):

Supportive care:

Next cycle to start no sooner than 14 days or as soon as "unmaintained" WBC count is > 3 x 10^9/L and platelet count > 50 x 10^9/L

CNS prophylaxis:

Given each cycle for a total of 16 intrathecal treatments. If CNS disease present, therapy augmented to twice-weekly alternating (MTX, ara-C) treatments until CSF cell count normalizes and cytology is negative, then continues for 4 more alternating weekly treatments; prophylaxis course then resumes.

Dose modifications:

  • Cytarabine (Cytosar) reduced to 1000 mg/m2 for patients ≥60 years old, creatinine ≥1.5 mg/dL or 0 hour MTX level ≥ 20 μmol/L
  • Vincristine (Oncovin) reduced to 1 mg for bilirubin > 2 mg/dL or NCI common toxicity criteria Grade 2+ peripheral neuropathy, omitted for bilirubin > 3 mg/dL or for ileus
  • Doxorubicin (Adriamycin) reduced by 50% for bilirubin 2 to 3 mg/dL, by 75% for bilirubin 3 to 5 mg/dL (eliminated for bilirubin > 5 mg/dL or for gastric/small-bowel involvement with Course 1 to reduce duration of myelosuppression given risk of perforation)
  • Methotrexate (MTX) reduced by 50% for creatinine clearance 10 to 50 mL/min (eliminated for < 10 mL/min), by 25% to 75% for delayed excretion and/or nephrotoxicity with prior course (dependent on severity) or by 50% for pleural effusions/ascites with drainage of fluid as feasible.

References

  1. 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 verified protocol PubMed
  2. Update: Fayad L, Thomas D, Romaguera J. Update of the M. D. 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. PubMed

Induction therapy, Ph-positive

Hyper-CVAD & Dasatinib (Sprycel)

Hyper-CVAD: Hyperfractionated Cyclophosphamide, Vincristine, Adriamycin, Dexamethasone

Regimen

Phase II

Part A (cycles 1, 3, 5, 7)

Supportive care:

Next cycle to start after count recovery. No definite criteria listed by the reference, but other Hyper-CVAD regimens used absolute neutrophil count > 1 x 10^9/L at least 24 hours off of G-CSF and platelet count > 60 x 10^9/L

Part B (cycles 2, 4, 6, 8)

Supportive medications:

Next cycle to start after count recovery. No definite criteria listed by the reference, but other Hyper-CVAD regimens used absolute neutrophil count > 1 x 10^9/L at least 24 hours off of G-CSF and platelet count > 60 x 10^9/L

CNS prophylaxis

Given each cycle for a total of 6 or 8 intrathecal treatments (i.e. 3 each of methotrexate and cytarabine or 4 each of methotrexate and cytarabine), depending on risk for CNS relapse based serum lactate dehydrogenase (LDH) >1400 IU/L and/or proliferative index percentage of S + G2M of at least 14%

For known CNS disease

  • Methotrexate (MTX) 12 mg (6 mg if given via Ommaya reservoir) IT alternating with Cytarabine (Cytosar) 100 mg IT, with both given every week until cell count in CSF normalizes and cytology is negative for malignancy
  • Then Methotrexate (MTX) 12 mg (6 mg if given via Ommaya reservoir) IT given weeks 1 & 3 and Cytarabine (Cytosar) 100 mg IT, given weeks 2 & 4
  • Once those 4 weeks are complete, then intrathecal treatment is given similar to the prophylactic schedule, with each drug given once during every remaining cycle of induction therapy:
  • Therapeutic external radiation is given to patients with CNS disease at presentation

References

  1. 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 verified protocol--parts of the protocol were not explicitly listed in this reference, which instead referred to Thomas et al. 2004 and Kantarjian et al. 2004 PubMed

Hyper-CVAD & Imatinib (Gleevec) (induction & maintenance)

Hyper-CVAD: Hyperfractionated Cyclophosphamide, Vincristine, Adriamycin, Dexamethasone

Regimen

Phase II

Part A (cycles 1, 3, 5, 7)

Supportive care:

Next cycle to start after count recovery. No definite criteria listed by the reference, but other Hyper-CVAD regimens used absolute neutrophil count > 1 x 10^9/L at least 24 hours off of G-CSF and platelet count > 60 x 10^9/L

Part B (cycles 2, 4, 6, 8)

Supportive medications:

Next cycle to start after count recovery. No definite criteria listed by the reference, but other Hyper-CVAD regimens used absolute neutrophil count > 1 x 10^9/L at least 24 hours off of G-CSF and platelet count > 60 x 10^9/L

CNS prophylaxis

Given each cycle for a total of 6 or 8 intrathecal treatments (i.e. 3 each of methotrexate and cytarabine or 4 each of methotrexate and cytarabine), depending on risk for CNS relapse based serum lactate dehydrogenase (LDH) >1400 IU/L and/or proliferative index percentage of S + G2M of at least 14%

For known CNS disease

  • Methotrexate (MTX) 12 mg (6 mg if given via Ommaya reservoir) IT alternating with Cytarabine (Cytosar) 100 mg IT, with both given every week until cell count in CSF normalizes and cytology is negative for malignancy
  • Then Methotrexate (MTX) 12 mg (6 mg if given via Ommaya reservoir) IT given weeks 1 & 3 and Cytarabine (Cytosar) 100 mg IT, given weeks 2 & 4
  • Once those 4 weeks are complete, then intrathecal treatment is given similar to the prophylactic schedule, with each drug given once during every remaining cycle of induction therapy:
  • Therapeutic external radiation is given to patients with CNS disease at presentation

Maintenance therapy after completing 8 cycles of the intensive Part A and Part B chemotherapy:

28-day cycles x 5 cycles; then, in month 6, Hyper-CVAD Part A x 1 cycle as described above; then resume maintenance therapy, 28-day cycles x 6 cycles; then, in month 13, Hyper-CVAD Part A x 1 cycle as described above

References

  1. 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 verified protocol PubMed

International ALL Trial (MRC UKALL XII/ECOG E2993)

Regimen

Phase II

To our knowledge, this is the largest induction trial in adult ALL, N=1,646. CR rate was 90%. There are many local variants of this protocol, including substitution of peg-asparaginase for L-asparaginase.

Phase I, weeks 1 to 4

CNS prophylaxis

Phase II, weeks 5 to 8

CNS prophylaxis

Ph+ patients

Two variants have been tested: from 2003 to 2005, imatinib was added after induction; from 2005 onward, imatinib was added during induction. Various durations are proposed, see Fielding et al. 2013 for more details.

  • Imatinib (Gleevec) 400 mg PO once per day, increased to 600 mg PO once per day "wherever possible"

To be followed by consolidation portion of the protocol.

References

  1. 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 verified protocol PubMed
  2. 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
  3. 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 PubMed
  4. 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. 2013 Nov 25. [Epub ahead of print] link to original article contains verified protocol PubMed


Consolidation therapy

International ALL Trial (MRC UKALL XII/ECOG E2993)

Regimen

Phase II

To our knowledge, this is the largest induction trial in adult ALL, N=1,646. CR rate was 90%. There are many local variants of this protocol, including substitution of peg-asparaginase for L-asparaginase, and omission of cranial irradiation.

Preceded by induction portion of the protocol.

Phase III, "Intensification"

Supportive medications:

3 cycles (length of cycle not specified in original reference)

For patients randomized to transplantation (autologous or allogeneic), no further therapy was specified, except that Ph+ patients were given interferon for another 15 months.

Phase IV, "Consolidation"

Cycle 1
Cycle 2

To start 4 weeks after Cycle 1

Cycle 3

To start 4 weeks after Cycle 2

Cycle 4

To start 8 weeks after Cycle 3

CNS Prophylaxis

  • Cytarabine (Cytosar) 50 mg IT weekly x 4 weeks, then quarterly x 4 doses (8 doses, total)
  • Cranial irradiation to 2400 cGy

To be followed by maintenance portion of the protocol.

References

  1. 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 verified protocol PubMed

Larson/CALGB 8811 regimen (consolidation)

Preceded by Larson/CALGB 8811 regimen course I (induction).

Regimen

Phase II

Course II (early intensification):

28-day cycles x 2 cycles

Course III (CNS prophylaxis and interim maintenance):

12-week course

Course IV (late intensification):

8-week course

To be followed by Larson/CALGB 8811 regimen course V (maintenance).

References

  1. Larson RA, Dodge RK, Burns CP, Lee EJ, Stone RM, Schulman P, Duggan D, Davey FR, Sobol RE, Frankel SR et al. A five-drug remission induction regimen with intensive consolidation for adults with acute lymphoblastic leukemia: cancer and leukemia group B study 8811. Blood. 1995 Apr 15;85(8):2025-37. link to original article contains verified protocol PubMed

Linker regimen (consolidation)

Preceded by Linker regimen induction therapy.

Regimen

Phase II

Treatment A (cycles 1, 3, 5, 7)

Treatment B (cycles 2, 4, 6, 8)

Treatment C (cycle 9)

Supportive medications:

Central nervous system (CNS) prophylaxis for patients without CNS involvement at diagnosis is started within 1 week of achieving complete remission:

  • Cranial radiation, 18 Gy total given in 10 fractions over 12-14 days
  • Methotrexate (MTX) 12 mg IT weekly x 6 doses concurrent with radiation

To be followed by Linker regimen maintenance therapy.

References

  1. 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 verified protocol PubMed content property of HemOnc.org
  2. 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 verified protocol PubMed

Maintenance therapy

Hyper-CVAD (maintenance) - POMP

Preceded by Hyper-CVAD (induction).

POMP: 6-MP, Oncovin, Methotrexate, Prednisone

Regimen

Phase II

Kantarjian et al. 2004 said how many days each drug is given per month, but did not specifically say, for example, that certain drugs are taken on days 1 to 5 of the cycle.

Supportive medications:

1-month cycles

References

  1. Kantarjian H, Thomas D, O'Brien S, Cortes J, Giles F, Jeha S, Bueso-Ramos CE, Pierce S, Shan J, Koller C, Beran M, Keating M, Freireich EJ. Long-term follow-up results of hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (Hyper-CVAD), a dose-intensive regimen, in adult acute lymphocytic leukemia. Cancer. 2004 Dec 15;101(12):2788-801. link to original article contains verified protocol PubMed

Hyper-CVAD & Dasatinib (Sprycel)

Hyper-CVAD: Hyperfractionated Cyclophosphamide, Vincristine, Adriamycin, Dexamethasone

Regimen

Phase II

For patients with Philadelphia chromosome (Ph+) disease

Maintenance therapy for 2 years after completing 8 cycles of the intensive Part A and Part B chemotherapy:

28-day cycles x 2 years; maintenance therapy could be interrupted by provider's choice--typically only given to people with at least minimal residual disease (MRD) or more--in month 6 and 13 to give Hyper-CVAD Part A x 1 cycle

Then, after 2 years of maintenance therapy:

References

  1. 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 verified protocol--parts of the protocol were not explicitly listed in this reference, which instead referred to Thomas et al. 2004 and Kantarjian et al. 2004 PubMed

International ALL Trial (MRC UKALL XII/ECOG E2993)

Regimen

Phase II

To our knowledge, this is the largest induction trial in adult ALL, N=1,646. CR rate was 90%. There are many local variants of this protocol, including substitution of peg-asparaginase for L-asparaginase, and omission of cranial irradiation.

Preceded by consolidation portion of the protocol.

Continue for a total of 2.5 years from the start of phase III.

References

  1. 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 verified protocol PubMed

Larson/CALGB 8811 regimen (maintenance)

Preceded by Larson/CALGB 8811 regimen courses II to IV (consolidation).

Regimen

Phase II

Course V (prolonged maintenance):

28-day cycles, continue until 24 months from diagnosis

References

  1. Larson RA, Dodge RK, Burns CP, Lee EJ, Stone RM, Schulman P, Duggan D, Davey FR, Sobol RE, Frankel SR et al. A five-drug remission induction regimen with intensive consolidation for adults with acute lymphoblastic leukemia: cancer and leukemia group B study 8811. Blood. 1995 Apr 15;85(8):2025-37. link to original article contains verified protocol PubMed

Linker regimen (maintenance)

Preceded by Linker regimen consolidation therapy.

Regimen

Phase II

References

  1. 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 verified protocol PubMed
  2. 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 verified protocol PubMed

Relapsed/refractory, Ph-negative

CCE

CCE: Clofarabine, Cyclophosphamide, Etoposide

Regimen, Locatelli et al. 2009

Non-randomized, 25 patients

Patients in Locatelli et al. 2009 were pediatric: ≤15 years old at diagnosis and ≤21 years old at time of treatment.

  • Clofarabine (Clolar) 40 mg/m2 IV over 2 hours once per day on days 1 to 5, given first
  • Cyclophosphamide (Cytoxan) 400 mg/m2 IV over 1 hour once per day on days 1 to 5
  • Etoposide (Vepesid) 150 mg/m2 IV over 2 hours once per day on days 1 to 5
  • No patients in Locatelli et al. 2009 had CNS disease at time of treatment, and no patients received CNS prophylaxis.

5-day course. 2 out of 25 patients in Locatelli et al. 2009 received a second course of CCE as consolidation therapy. "Responding patients were given allogeneic HSCT if a suitable donor was immediately available or were given consolidation courses of chemotherapy including multiple agents active against ALL cells, chosen according to the treating physician's preference."

Supportive medications:

  • Prophylactic steroids used for patients with >30 x 109 blasts/L in the peripheral blood prior to treatment

References

  1. Locatelli F, Testi AM, Bernardo ME, Rizzari C, Bertaina A, Merli P, Pession A, Giraldi E, Parasole R, Barberi W, Zecca M. Clofarabine, cyclophosphamide and etoposide as single-course re-induction therapy for children with refractory/multiple relapsed acute lymphoblastic leukaemia. Br J Haematol. 2009 Nov;147(3):371-8. Epub 2009 Aug 29. link to original article contains verified protocol PubMed

Clofarabine (Clolar)

Currently, no positive prospective trials using clofarabine have been published in adults. The retrospective series below reports a variety of regimens used in off-label fashion, based on pediatric regimens.

Regimen

Retrospective

References

  1. Retrospective: Barba P, Sampol A, Calbacho M, Gonzalez J, Serrano J, Martínez-Sánchez P, Fernández P, García-Boyero R, Bueno J, Ribera JM. Clofarabine-based chemotherapy for relapsed/refractory adult acute lymphoblastic leukemia and lymphoblastic lymphoma. The Spanish experience. Am J Hematol. 2012 Jun;87(6):631-4. Epub 2012 Mar 19. link to original article PubMed

Vincristine liposomal (Marqibo)

Regimen, O'Brien et al. 2012 (RALLY)

Phase II

28-day cycles, continued until "response achievement, leukemia progression, toxicity, or decision to pursue other therapy"

References

  1. O'Brien S, Schiller G, Lister J, Damon L, Goldberg S, Aulitzky W, Ben-Yehuda D, Stock W, Coutre S, Douer D, Heffner LT, Larson M, Seiter K, Smith S, Assouline S, Kuriakose P, Maness L, Nagler A, Rowe J, Schaich M, Shpilberg O, Yee K, Schmieder G, Silverman JA, Thomas D, Deitcher SR, Kantarjian H. High-dose vincristine sulfate liposome injection for advanced, relapsed, and refractory adult Philadelphia chromosome-negative acute lymphoblastic leukemia. J Clin Oncol. 2013 Feb 20;31(6):676-83. Epub 2012 Nov 19. link to original article contains verified protocol PubMed

Relapsed/refractory, Ph-positive

Bosutinib (Bosulif)

Regimen

Phase II

Note: the dosing described is that reported for the phase 2 portion of the phase 1/2 study.

  • Bosutinib (Bosulif) 500 mg PO once per day, take with food
    • If no grade 3 or higher drug-related toxicity occurs, dose of Bosutinib (Bosulif) can be escalated to 600 mg PO once per day if response is suboptimal. Suboptimal response defined as no complete hematologic response (CHR) by week 8 or complete cytogenetic response (CCyR) by week 12.

Given until progression of disease or unacceptable toxicity

References

  1. Cortes JE, Kantarjian HM, Brümmendorf TH, Kim DW, Turkina AG, Shen ZX, Pasquini R, Khoury HJ, Arkin S, Volkert A, Besson N, Abbas R, Wang J, Leip E, Gambacorti-Passerini C. Safety and efficacy of bosutinib (SKI-606) in chronic phase Philadelphia chromosome-positive chronic myeloid leukemia patients with resistance or intolerance to imatinib. Blood. 2011 Oct 27;118(17):4567-76. Epub 2011 Aug 24. link to original article contains verified protocol PubMed
  2. Khoury HJ, Cortes JE, Kantarjian HM, Gambacorti-Passerini C, Baccarani M, Kim DW, Zaritskey A, Countouriotis A, Besson N, Leip E, Kelly V, Brümmendorf TH. Bosutinib is active in chronic phase chronic myeloid leukemia after imatinib and dasatinib and/or nilotinib therapy failure. Blood. 2012 Apr 12;119(15):3403-12. Epub 2012 Feb 27. link to original article contains verified protocol PubMed
  3. Update: Kantarjian HM, Cortes JE, Kim DW, Khoury HJ, Brümmendorf TH, Porkka K, Martinelli G, Durrant S, Leip E, Kelly V, Turnbull K, Besson N, Gambacorti-Passerini C. Bosutinib safety and management of toxicity in leukemia patients with resistance or intolerance to imatinib and other tyrosine kinase inhibitors. Blood. 2014 Feb 27;123(9):1309-18. Epub 2013 Dec 17. link to original article contains verified protocol PubMed

Dasatinib (Sprycel)

Regimen, Ottmann et al. 2007 (START-L); Lilly et al. 2010

Phase II

Lilly et al. found that the once daily regimen was similar in toxicity and efficacy to the twice daily regimen.

given until progression of disease or unacceptable toxicity

References

  1. Ottmann O, Dombret H, Martinelli G, Simonsson B, Guilhot F, Larson RA, Rege-Cambrin G, Radich J, Hochhaus A, Apanovitch AM, Gollerkeri A, Coutre S. Dasatinib induces rapid hematologic and cytogenetic responses in adult patients with Philadelphia chromosome positive acute lymphoblastic leukemia with resistance or intolerance to imatinib: interim results of a phase 2 study. Blood. 2007 Oct 1;110(7):2309-15. Epub 2007 May 11. link to original article contains verified protocol PubMed
  2. Lilly MB, Ottmann OG, Shah NP, Larson RA, Reiffers JJ, Ehninger G, Müller MC, Charbonnier A, Bullorsky E, Dombret H, Brigid Bradley-Garelik M, Zhu C, Martinelli G. Dasatinib 140 mg once daily versus 70 mg twice daily in patients with Ph-positive acute lymphoblastic leukemia who failed imatinib: Results from a

phase 3 study. Am J Hematol. 2010 Mar;85(3):164-70. link to original article contains verified protocol PubMed

Nilotinib (Tasigna)

Regimen

Phase II

References

  1. Kantarjian H, Giles F, Wunderle L, Bhalla K, O'Brien S, Wassmann B, Tanaka C, Manley P, Rae P, Mietlowski W, Bochinski K, Hochhaus A, Griffin JD, Hoelzer D, Albitar M, Dugan M, Cortes J, Alland L, Ottmann OG. Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL. N Engl J Med. 2006 Jun 15;354(24):2542-51. link to original article PubMed

Ponatinib (Iclusig)

As of 12/20/2013, this drug is now available again with a REMS program due to the excess arterial vascular events observed.

Regimen

Phase II

given until progression of disease or unacceptable toxicity

References

  1. Cortes JE, Kantarjian H, Shah NP, Bixby D, Mauro MJ, Flinn I, O'Hare T, Hu S, Narasimhan NI, Rivera VM, Clackson T, Turner CD, Haluska FG, Druker BJ, Deininger MW, Talpaz M. Ponatinib in refractory Philadelphia chromosome-positive leukemias. N Engl J Med. 2012 Nov 29;367(22):2075-88. link to original article contains verified protocol PubMed
  2. Cortes JE, Kim DW, Pinilla-Ibarz J, le Coutre P, Paquette R, Chuah C, Nicolini FE, Apperley JF, Khoury HJ, Talpaz M, Dipersio J, Deangelo DJ, Abruzzese E, Rea D, Baccarani M, Müller MC, Gambacorti-Passerini C, Wong S, Lustgarten S, Rivera VM, Clackson T, Turner CD, Haluska FG, Guilhot F, Deininger MW, Hochhaus A, Hughes T, Goldman JM, Shah NP, Kantarjian H; the PACE Investigators. A Phase 2 Trial of Ponatinib in Philadelphia Chromosome-Positive Leukemias. N Engl J Med. 2013 Nov 1. [Epub ahead of print] link to original article PubMed
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