Allogeneic HSCT

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Aric C. Hall, MD
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Unlike the other chemotherapy regimen pages, this one is not disease-specific. Rather, this is a gathering point for all allogeneic hematopoietic stem cell transplant (HSCT) conditioning regimens. Unless otherwise specified, the day before HSCT is day -1, the day of HSCT is day 0, and the day after HSCT is day +1.

24 regimens on this page
38 variants on this page

Contents


Myeloablative regimens, all lines of therapy

BuCyTBI

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BuCyTBI: Busulfan, Cyclophosphamide, Total Body Irradiation

Regimen

Study Evidence
Fefer et al. 1979 Pilot, <20 pts

Chemotherapy

Radiotherapy

References

  1. Fefer A, Cheever MA, Thomas ED, Boyd C, Ramberg R, Glucksberg H, Buckner CD, Storb R. Disappearance of Ph1-positive cells in four patients with chronic granulocytic leukemia after chemotherapy, irradiation and marrow transplantation from an identical twin. N Engl J Med. 1979 Feb 15;300(7):333-7. link to original article PubMed

Busulfan & Cyclophosphamide

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BuCy: Busulfan & Cyclophosphamide

Variant #1, 9.6/120

Study Evidence
Andersson et al. 2002 Phase II

Note: abstract is limited in detail including which days the treatments are given.

Chemotherapy

Variant #2, 12.8/120

Study Evidence Comparator Comparative Efficacy
Lee et al. 2013 Phase III (C) Busulfan & Fludarabine Seems to have superior OS
Rambaldi et al. 2015 Phase III (C) Busulfan & Fludarabine Seems to have inferior 1-year non-relapse mortality

Chemotherapy

Supportive medications

Variant #3, 16/200

Study Evidence
Santos et al. 1983 Non-randomized

Note: the day of allogeneic stem cell transplant is not specified in the protocol.

Chemotherapy

References

  1. Santos GW, Tutschka PJ, Brookmeyer R, Saral R, Beschorner WE, Bias WB, Braine HG, Burns WH, Elfenbein GJ, Kaizer H, Mellits D, Sensenbrenner LL, Stuart RK, Yeager AM. Marrow transplantation for acute nonlymphocytic leukemia after treatment with busulfan and cyclophosphamide. N Engl J Med. 1983 Dec 1;309(22):1347-53. link to original article contains protocol PubMed
  2. Andersson BS, Kashyap A, Gian V, Wingard JR, Fernandez H, Cagnoni PJ, Jones RB, Tarantolo S, Hu WW, Blume KG, Forman SJ, Champlin RE. Conditioning therapy with intravenous busulfan and cyclophosphamide (IV BuCy2) for hematologic malignancies prior to allogeneic stem cell transplantation: a phase II study. Biol Blood Marrow Transplant. 2002;8(3):145-54. link to original article contains partial protocol PubMed
  3. Lee JH, Joo YD, Kim H, Ryoo HM, Kim MK, Lee GW, Lee JH, Lee WS, Park JH, Bae SH, Hyun MS, Kim DY, Kim SD, Min YJ, Lee KH. Randomized trial of myeloablative conditioning regimens: busulfan plus cyclophosphamide versus busulfan plus fludarabine. J Clin Oncol. 2013 Feb 20;31(6):701-9. Epub 2012 Nov 5. link to original article contains verified protocol PubMed
  4. Rambaldi A, Grassi A, Masciulli A, Boschini C, Micò MC, Busca A, Bruno B, Cavattoni I, Santarone S, Raimondi R, Montanari M, Milone G, Chiusolo P, Pastore D, Guidi S, Patriarca F, Risitano AM, Saporiti G, Pini M, Terruzzi E, Arcese W, Marotta G, Carella AM, Nagler A, Russo D, Corradini P, Alessandrino EP, Torelli GF, Scimè R, Mordini N, Oldani E, Marfisi RM, Bacigalupo A, Bosi A. Busulfan plus cyclophosphamide versus busulfan plus fludarabine as a preparative regimen for allogeneic haemopoietic stem-cell transplantation in patients with acute myeloid leukaemia: an open-label, multicentre, randomised, phase 3 trial. Lancet Oncol. 2015 Nov;16(15):1525-36. Epub 2015 Sep 28. link to original article PubMed

Busulfan & Fludarabine

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BuFlu: Busulfan & Fludarabine
Flu/Bu: Fludarabine & Busulfan

Variant #1

Study Evidence Comparator Comparative Efficacy
Rambaldi et al. 2015 Phase III (E) Busulfan & Cyclophosphamide Seems to improve 1 & 2 year NRM, similar OS

Diseases Studied: Acute myeloid leukemia

Graft types studied: Bone Marrow, Mobilized Peripheral Blood Stem Cells

Chemotherapy

Immunosuppressive therapy

  • Antithymocyte globulin, rabbit ATG (Thymoglobulin) as follows:
    • Unrelated donors, identical: 0.5 mg/kg IV once on day -3, then 2 mg/kg IV once on day -2, then 2.5 mg/kg IV once on day -1
    • If donor mismatched total ATG dose could be increased to 7.5 mg/kg

GVHD prophylaxis

Variant #2

Study Evidence Comparator Comparative Efficacy
Andersson et al. 2008 Non-randomized Suggested improved outcomes, but shorter follow up
Kanakry et al. 2014 Phase II
Mielcarek et al. 2016 Phase II

Diseases Studied: Acute myeloid leukemia, Myelodysplastic syndrome, Acute lymphocytic leukemia, Chronic myelogenous leukemia, Non-Hodgkin lymphoma

Graft types studied: Matched Related / Unrelated Donor Bone Marrow, Mobilized Peripheral Blood Stem Cells

Chemotherapy

  • Busulfan (Myleran) 130 mg/kg IV over 3 hours once per day on days -6 to -3
    • Dosing targeted for optimal pharmacokinetics but different parameters each institution, please consult the original publication for optimal levels
  • Fludarabine (Fludara) 40 mg/m2 IV over 60 minutes once per day on days -6 to -3, given first

Immunosuppressive therapy

GVHD prophylaxis and key supportive medications

#1 Tacrolimus & methotrexate based (Andersson et al.)

#2 Post-Transplant Cy based (Kanakry et al. and Mielcarek et al.)

  • Cyclophosphamide (Cytoxan) 50 mg/kg IV once per day on days +3 & +4 (used alone in Kanakry et al. when all patients received bone marrow grafts)
  • ± Cyclosporine modified (Neoral) intravenous loading dose of CSP was given on day 5, followed by subsequent twice daily dosing adjusted to maintain whole blood trough at 120-360 ng/mL. In abscence of GVHD Cyclosporine was tapered from day +56 through day +126 (used in Mielcarek et al. with PBSCT grafts)

Variant #3

Study Evidence Comparator Comparative Efficacy
Lee et al. 2013 Phase III (E) Busulfan & Cyclophosphamide Seems to have inferior OS

Diseases Studied: Acute myeloid leukemia, Myelodysplastic syndrome, Acute lymphocytic leukemia, Chronic myelogenous leukemia, Myelofibrosis

Graft types studied: Matched Related / Unrelated Donor Bone Marrow, Mobilized Peripheral Blood Stem Cells

Chemotherapy

  • Busulfan (Myleran) 3.2 mg/kg IV once per day on days -7 to -4, given first on days overlapping with fludarabine (total dose: 12.8 mg/kg)
  • Fludarabine (Fludara) 30 mg/m2 IV once per day on days -6 to -2, given second on days overlapping with busulfan

GVHD prophylaxis and key supportive medications


Variant #4

Study Evidence
Russell et al. 2002 Phase II

Diseases Studied: Acute myeloid leukemia, Myelodysplastic syndrome, Chronic myelogenous leukemia, Chronic lymphocytic leukemia, Non-Hodgkin lymphoma, Hypereosinophilic syndrome

Graft types studied: Matched Related / Unrelated Donor Bone Marrow or Mobilized Peripheral Blood Stem Cells

Chemotherapy

Immunosuppressive therapy

GVHD prophylaxis and key supportive medications


References

  1. Andersson BS, de Lima M, Thall PF, Wang X, Couriel D, Korbling M, Roberson S, Giralt S, Pierre B, Russell JA, Shpall EJ, Jones RB, Champlin RE. Once daily IV busulfan and fludarabine (IV Bu-Flu) compares favorably with IV busulfan and cyclophosphamide (IV BuCy2) as pretransplant conditioning therapy in AML/MDS. Biol Blood Marrow Transplant. 2008;14(6):672-84. link to original article link to PMC article contains verified protocol Pubmed
  2. Lee JH, Joo YD, Kim H, Ryoo HM, Kim MK, Lee GW, Lee JH, Lee WS, Park JH, Bae SH, Hyun MS, Kim DY, Kim SD, Min YJ, Lee KH. Randomized trial of myeloablative conditioning regimens: busulfan plus cyclophosphamide versus busulfan plus fludarabine. J Clin Oncol. 2013 Feb 20;31(6):701-9. Epub 2012 Nov 5. link to original article contains verified protocol PubMed
  3. Kanakry CG, O'Donnell PV, Furlong T, de Lima MJ, Wei W, Medeot M, Mielcarek M, Champlin RE, Jones RJ, Thall PF, Andersson BS, Luznik L. Multi-institutional study of post-transplantation cyclophosphamide as single-agent graft-versus-host disease prophylaxis after allogeneic bone marrow transplantation using myeloablative busulfan and fludarabine conditioning. J Clin Oncol. 2014; 32(31):3497-505. Epub 2014 Sep 29. link to original article link to PMC article contains verified protocol Pubmed
  4. Mielcarek M, Furlong T, O'Donnell PV, Storer BE, McCune JS, Storb R, Carpenter PA, Flowers ME, Appelbaum FR, Martin PJ. Posttransplantation cyclophosphamide for prevention of graft-versus-host disease after HLA-matched mobilized blood cell transplantation. Blood. 2016;127(11):1502-8. link to original article contains verified protocol Pubmed
  5. Rambaldi A, Grassi A, Masciulli A, Boschini C, Micò MC, Busca A, Bruno B, Cavattoni I, Santarone S, Raimondi R, Montanari M, Milone G, Chiusolo P, Pastore D, Guidi S, Patriarca F, Risitano AM, Saporiti G, Pini M, Terruzzi E, Arcese W, Marotta G, Carella AM, Nagler A, Russo D, Corradini P, Alessandrino EP, Torelli GF, Scimè R, Mordini N, Oldani E, Marfisi RM, Bacigalupo A, Bosi A. Busulfan plus cyclophosphamide versus busulfan plus fludarabine as a preparative regimen for allogeneic haemopoietic stem-cell transplantation in patients with acute myeloid leukaemia: an open-label, multicentre, randomised, phase 3 trial. Lancet Oncol. 2015 Nov;16(15):1525-36. Epub 2015 Sep 28. link to original article PubMed
  6. Russell JA, Tran HT, Quinlan D, Chaudhry A, Duggan P, Brown C, Stewart D, Ruether JD, Morris D, Glick S, Gyonyor E, Andersson BS. Once-daily intravenous busulfan given with fludarabine as conditioning for allogeneic stem cell transplantation: study of pharmacokinetics and early clinical outcomes. Biol Blood Marrow Transplant. 2002;8(9):468-76. link to original article contains verified protocol PubMed

Cyclophosphamide & TBI

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Cy/TBI: Cyclophosphamide & Total Body Irradiation

Regimen

Study Evidence Comparator Efficacy Non-relapse mortality
Rudolph et al. 1973 Non-randomized
Thomas et al. 1979 Non-randomized
Blume et al. 1980 Non-randomized, <20 pts
Johnson et al. 1981 Non-randomized
Fefer et al. 1982 Non-randomized, <20 pts
Goldman et al. 1986 Non-randomized
Kersey et al. 1987 Quasi-randomized Auto HSCT Superior RFS
Brochstein et al. 1987 Non-randomized
Sebban et al. 1994 (LALA 87) Phase III (E) Chemotherapy or Auto HSCT Seems not superior
Thomas et al. 2004 (LALA-94) Non-randomized portion of RCT
Zittoun et al. 1995 Phase III (E) Intensive chemotherapy Superior DFS
Hansen et al. 1998 Non-randomized
Bornhäuser et al. 2012 Phase III (C) Fludarabine & TBI Seems not superior Seems not superior

Details in the manuscripts are limited.

Chemotherapy

Radiotherapy


References

  1. Rudolph RH, Fefer A, Thomas ED, Buckner CD, Clift RA, Storb R. Isogeneic marrow grafts for hematologic malignancy in man. Arch Intern Med. 1973 Aug;132(2):279-85. link to original article PubMed
    1. Update: Fefer A, Einstein AB, Thomas ED, Buckner CD, Clift RA, Glucksberg H, Neiman PE, Storb R. Bone-marrow transplantation for hematologic neoplasia in 16 patients with identical twins. N Engl J Med. 1974 Jun 20;290(25):1389-93. link to original article PubMed
  2. Thomas ED, Sanders JE, Flournoy N, Johnson FL, Buckner CD, Clift RA, Fefer A, Goodell BW, Storb R, Weiden PL. Marrow transplantation for patients with acute lymphoblastic leukemia in remission. Blood. 1979 Aug;54(2):468-76. link to original article contains protocol PubMed
  3. Blume KG, Beutler E, Bross KJ, Chillar RK, Ellington OB, Fahey JL, Farbstein MJ, Forman SJ, Schmidt GM, Scott EP, Spruce WE, Turner MA, Wolf JL. Bone-marrow ablation and allogeneic marrow transplantation in acute leukemia. N Engl J Med. 1980 May 8;302(19):1041-6. link to original article PubMed
  4. Johnson FL, Thomas ED, Clark BS, Chard RL, Hartmann JR, Storb R. A comparison of marrow transplantation with chemotherapy for children with acute lymphoblastic leukemia in second or subsequent remission. N Engl J Med. 1981 Oct 8;305(15):846-51. link to original article PubMed
  5. Fefer A, Cheever MA, Greenberg PD, Appelbaum FR, Boyd CN, Buckner CD, Kaplan HG, Ramberg R, Sanders JE, Storb R, Thomas ED. Treatment of chronic granulocytic leukemia with chemoradiotherapy and transplantation of marrow from identical twins. N Engl J Med. 1982 Jan 14;306(2):63-8. link to original article PubMed
  6. Goldman JM, Apperley JF, Jones L, Marcus R, Goolden AW, Batchelor R, Hale G, Waldmann H, Reid CD, Hows J, Gordon-Smith E, Catovsky D, Galton DAG. Bone marrow transplantation for patients with chronic myeloid leukemia. N Engl J Med. 1986 Jan 23;314(4):202-7. PubMed
  7. Kersey JH, Weisdorf D, Nesbit ME, LeBien TW, Woods WG, McGlave PB, Kim T, Vallera DA, Goldman AI, Bostrom B, Hurd D, Ramsay NKC. Comparison of autologous and allogeneic bone marrow transplantation for treatment of high-risk refractory acute lymphoblastic leukemia. N Engl J Med. 1987 Aug 20;317(8):461-7. link to original article PubMed
  8. Brochstein JA, Kernan NA, Groshen S, Cirrincione C, Shank B, Emanuel D, Laver J, O'Reilly RJ. Allogeneic bone marrow transplantation after hyperfractionated total-body irradiation and cyclophosphamide in children with acute leukemia. N Engl J Med. 1987 Dec 24;317(26):1618-24. link to original article PubMed
  9. LALA 87: Sebban C, Lepage E, Vernant JP, Gluckman E, Attal M, Reiffers J, Sutton L, Racadot E, Michallet M, Maraninchi D, Dreyfus F, Fiere D; French Group of Therapy of Adult Acute Lymphoblastic Leukemia. Allogeneic bone marrow transplantation in adult acute lymphoblastic leukemia in first complete remission: a comparative study. J Clin Oncol. 1994 Dec;12(12):2580-7. link to original article PubMed
    1. Update: Thiebaut A, Vernant JP, Degos L, Huguet FR, Reiffers J, Sebban C, Lepage E, Thomas X, Fière D. Adult acute lymphocytic leukemia study testing chemotherapy and autologous and allogeneic transplantation: a follow-up report of the French protocol LALA 87. Hematol Oncol Clin North Am. 2000 Dec;14(6):1353-66. link to SD article PubMed
  10. Zittoun RA, Mandelli F, Willemze R, de Witte T, Labar B, Resegotti L, Leoni F, Damasio E, Visani G, Papa G, Caronia F, Hayat M, Stryckmans P, Rotoli B, Leoni P, Peetermans ME, Dardenne M, Vegna ML, Petti MC, Solbu G, Suciu S; European Organization for Research and Treatment of Cancer (EORTC) and the Gruppo Italiano Malattie Ematologiche Maligne dell'Adulto (GIMEMA) Leukemia Cooperative Groups. Autologous or allogeneic bone marrow transplantation compared with intensive chemotherapy in acute myelogenous leukemia. N Engl J Med. 1995 Jan 26;332(4):217-23. link to original article contains protocol PubMed
  11. Hansen JA, Gooley TA, Martin PJ, Appelbaum F, Chauncey TR, Clift RA, Petersdorf EW, Radich J, Sanders JE, Storb RF, Sullivan KM, Anasetti C. Bone marrow transplants from unrelated donors for patients with chronic myeloid leukemia. N Engl J Med. 1998 Apr 2;338(14):962-8. link to original article PubMed
  12. LALA-94: Thomas X, Boiron JM, Huguet F, Dombret H, Bradstock K, Vey N, Kovacsovics T, Delannoy A, Fegueux N, Fenaux P, Stamatoullas A, Vernant JP, Tournilhac O, Buzyn A, Reman O, Charrin C, Boucheix C, Gabert J, Lhéritier V, Fiere D. Outcome of treatment in adults with acute lymphoblastic leukemia: analysis of the LALA-94 trial. J Clin Oncol. 2004 Oct 15;22(20):4075-86. Epub 2004 Sep 7. link to original article contains verified protocol PubMed
    1. Update: Vey N, Thomas X, Picard C, Kovascovicz T, Charin C, Cayuela JM, Dombret H, Dastugue N, Huguet F, Bastard C, Stamatoulas A, Giollant M, Tournilhac O, Macintyre E, Buzyn A, Bories D, Kuentz M, Dreyfus F, Delannoy A, Raynaud S, Gratecos N, Bordessoule D, de Botton S, Preudhomme C, Reman O, Troussard X, Pigneux A, Bilhou C, Vernant JP, Boucheix C, Gabert J; GET-LALA Group the Swiss Group for Clinical Cancer Research (SAKK). Allogeneic stem cell transplantation improves the outcome of adults with t(1;19)/E2A-PBX1 and t(4;11)/MLL-AF4 positive B-cell acute lymphoblastic leukemia: results of the prospective multicenter LALA-94 study. Leukemia. 2006 Dec;20(12):2155-61. Epub 2006 Oct 12. link to original article PubMed
  13. Bornhäuser M, Kienast J, Trenschel R, Burchert A, Hegenbart U, Stadler M, Baurmann H, Schäfer-Eckart K, Holler E, Kröger N, Schmid C, Einsele H, Kiehl MG, Hiddemann W, Schwerdtfeger R, Buchholz S, Dreger P, Neubauer A, Berdel WE, Ehninger G, Beelen DW, Schetelig J, Stelljes M. Reduced-intensity conditioning versus standard conditioning before allogeneic haemopoietic cell transplantation in patients with acute myeloid leukaemia in first complete remission: a prospective, open-label randomised phase 3 trial. Lancet Oncol. 2012 Oct;13(10):1035-44. Epub 2012 Sep 7. link to original article contains protocol PubMed
  14. Retrospective: Copelan EA, Hamilton BK, Avalos B, Ahn KW, Bolwell BJ, Zhu X, Aljurf M, van Besien K, Bredeson C, Cahn JY, Costa LJ, de Lima M, Gale RP, Hale GA, Halter J, Hamadani M, Inamoto Y, Kamble RT, Litzow MR, Loren AW, Marks DI, Olavarria E, Roy V, Sabloff M, Savani BN, Seftel M, Schouten HC, Ustun C, Waller EK, Weisdorf DJ, Wirk B, Horowitz MM, Arora M, Szer J, Cortes J, Kalaycio ME, Maziarz RT, Saber W. Better leukemia-free and overall survival in AML in first remission following cyclophosphamide in combination with busulfan compared with TBI. Blood. 2013 Dec 5;122(24):3863-70. Epub 2013 Sep 24. link to original article link to PMC article PubMed

Etoposide & TBI

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Variant #1

Study Evidence Comparator Comparative Efficacy
Balduzzi et al. 2005 Quasi-randomized Chemotherapy Seems to have superior DFS
Peters et al. 2015 (ALL-SCT-BFM 2003) Non-randomized

This regimen was evaluated in the treatment of high-risk pediatric acute lymphoblastic leukemia in CR1.

Chemotherapy

Radiotherapy


Variant #2

Study Evidence
Rowe et al. 2005 (MRC UKALL XII/ECOG E2993) Non-randomized portion of RCT

Note: this is the same preparative regimen used for autologous transplant for certain patients; see reference for details. This regimen was evaluated in the treatment of acute lymphoblastic leukemia in CR1.

Chemotherapy

Radiotherapy


References

  1. Balduzzi A, Valsecchi MG, Uderzo C, De Lorenzo P, Klingebiel T, Peters C, Stary J, Felice MS, Magyarosy E, Conter V, Reiter A, Messina C, Gadner H, Schrappe M. Chemotherapy versus allogeneic transplantation for very-high-risk childhood acute lymphoblastic leukaemia in first complete remission: comparison by genetic randomisation in an international prospective study. Lancet. 2005 Aug 20-26;366(9486):635-42. link to original article contains verified protocol PubMed
  2. 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 verified protocol PubMed
    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 verified protocol link to PMC article PubMed
  3. ALL-SCT-BFM-2003: Peters C, Schrappe M, von Stackelberg A, Schrauder A, Bader P, Ebell W, Lang P, Sykora KW, Schrum J, Kremens B, Ehlert K, Albert MH, Meisel R, Matthes-Martin S, Gungor T, Holter W, Strahm B, Gruhn B, Schulz A, Woessmann W, Poetschger U, Zimmermann M, Klingebiel T. Stem-cell transplantation in children with acute lymphoblastic leukemia: a prospective international multicenter trial comparing sibling donors with matched unrelated donors-the ALL-SCT-BFM-2003 trial. J Clin Oncol. 2015 Apr 10;33(11):1265-74. Epub 2015 Mar 9. link to original article PubMed

Fludarabine, Busulfan, Cyclophosphamide

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FluBuCy: Fludarabine, Busulfan, Cyclophosphamide

Regimen

Study Evidence
Glass et al. 2014 (DSHNHL R3) Phase II

This is described by the authors as a lymphoma-directed myeloablative conditioning regimen

Chemotherapy

Immunosuppressive therapy

GVHD prophylaxis


References

  1. DSHNHL R3: Glass B, Hasenkamp J, Wulf G, Dreger P, Pfreundschuh M, Gramatzki M, Silling G, Wilhelm C, Zeis M, Görlitz A, Pfeiffer S, Hilgers R, Truemper L, Schmitz N; German High-Grade Lymphoma Study Group. Rituximab after lymphoma-directed conditioning and allogeneic stem-cell transplantation for relapsed and refractory aggressive non-Hodgkin lymphoma (DSHNHL R3): an open-label, randomised, phase 2 trial. Lancet Oncol. 2014 Jun;15(7):757-66. Epub 2014 May 11. link to original article link to original protocol (in German) contains verified protocol PubMed

BEAM

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BEAM: BiCNU (Carmustine), Etoposide, Ara-C (Cytarabine), Melphalan

Regimen

Study Evidence
Przepiorka et al. 1999 Phase II
Sobol et al. 2013 Phase II

Chemotherapy

GVHD prophylaxis and key supportive medications


References

  1. Przepiorka D, van Besien K, Khouri I, Hagemeister F, Samuels B, Folloder J, Ueno NT, Molldrem J, Mehra R, Körbling M, Giralt S, Gajewski J, Donato M, Cleary K, Claxton D, Braunschweig I, Andersson B, Anderlini P, Champlin R. Carmustine, etoposide, cytarabine and melphalan as a preparative regimen for allogeneic transplantation for high-risk malignant lymphoma. Ann Oncol. 1999 May;10(5):527-32. link to original article contains protocol PubMed
  2. Sobol U, Rodriguez T, Smith S, Go A, Vimr R, Parthasarathy M, Guo R, Stiff P. Seven-year follow-up of allogeneic transplant using BCNU, etoposide, cytarabine and melphalan chemotherapy in patients with Hodgkin lymphoma after autograft failure: importance of minimal residual disease. Leuk Lymphoma. 2014 Jun;55(6):1281-7. Epub 2013 Oct 3. link to original article PubMed

BFR

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BFR: Bendamustine, Fludarabine, Rituximab

Regimen

Study Evidence
Khouri et al. 2014 (MDACC 2008-0246) Phase II

Chemotherapy

GVHD prophylaxis

  • See article for GVHD prophylaxis information


References

  1. MDACC 2008-0246: Khouri IF, Wei W, Korbling M, Turturro F, Ahmed S, Alousi A, Anderlini P, Ciurea S, Jabbour E, Oran B, Popat UR, Rondon G, Bassett RL Jr, Gulbis A. BFR (bendamustine, fludarabine, and rituximab) allogeneic conditioning for chronic lymphocytic leukemia/lymphoma: reduced myelosuppression and GVHD. Blood. 2014 Oct 2;124(14):2306-12. Epub 2014 Aug 21. link to original article contains verified protocol link to PMC article PubMed

Reduced-intensity conditioning (RIC), all lines of therapy

Busulfan & Fludarabine

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BuFlu: Busulfan & Fludarabine
Flu/Bu: Fludarabine & Busulfan

Regimen

Study Evidence
Devine et al. 2015 (CALGB 100103) Phase II, <20 pts in subgroup

This regimen is meant for related donors; only 8 patients received this regimen before the addition of ATG (rabbit) after 2006.

Chemotherapy

GVHD prophylaxis

  • Tacrolimus (Prograf) with doses adjusted to maintain levels of 5 to 10 ng/mL, tapered on day +90 to off by day +180 (if no GVHD)
  • Methotrexate (MTX) 5 mg/m2 IV once per day on days +1, +3, +6, +11


References

  1. Devine SM, Owzar K, Blum W, Mulkey F, Stone RM, Hsu JW, Champlin RE, Chen YB, Vij R, Slack J, Soiffer RJ, Larson RA, Shea TC, Hars V, Sibley AB, Giralt S, Carter S, Horowitz MM, Linker C, Alyea EP. Phase II study of allogeneic transplantation for older patients with acute myeloid leukemia in first complete remission using a reduced-intensity conditioning regimen: results from Cancer and Leukemia Group B 100103 (Alliance for Clinical Trials in Oncology)/Blood and Marrow Transplant Clinical Trial Network 0502. J Clin Oncol. 2015 Dec 10;33(35):4167-75. Epub 2015 Nov 2. link to original article contains verified protocol link to PMC article PubMed

Clofarabine & Melphalan

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Regimen

Study Evidence
Middeke et al. 2015 (BRIDGE) Phase II

Limited details are available in the abstract. Treatment is meant to be given during aplasia.

Preceding treatment

Chemotherapy


References

  1. BRIDGE: Middeke JM, Herbst R, Parmentier S, Bug G, Hänel M, Stuhler G, Schäfer-Eckart K, Rösler W, Klein S, Bethge W, Bitz U, Büttner B, Knoth H, Alakel N, Schaich M, Morgner A, Kramer M, Sockel K, von Bonin M, Stölzel F, Platzbecker U, Röllig C, Thiede C, Ehninger G, Bornhäuser M, Schetelig J. Clofarabine salvage therapy before allogeneic hematopoietic stem cell transplantation in patients with relapsed or refractory AML: results of the BRIDGE trial. Leukemia. 2016 Feb;30(2):261-7. Epub 2015 Aug 18. link to original article contains protocol PubMed

Cyclophosphamide, Fludarabine, Thiotepa

Regimen

Study Evidence
Corradini et al. 2002 Non-randomized

Details to be completed.

Chemotherapy

References

  1. Corradini P, Tarella C, Olivieri A, Gianni AM, Voena C, Zallio F, Ladetto M, Falda M, Lucesole M, Dodero A, Ciceri F, Benedetti F, Rambaldi A, Sajeva MR, Tresoldi M, Pileri A, Bordignon C, Bregni M. Reduced-intensity conditioning followed by allografting of hematopoietic cells can produce clinical and molecular remissions in patients with poor-risk hematologic malignancies. Blood. 2002 Jan 1;99(1):75-82. link to original article PubMed

FC

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FC: Fludarabine & Cyclophosphamide

Variant #1, BSA-based Cy

Study Evidence
Dreger et al. 2010 (GCLLSG CLL3X) Phase II

This regimen is intended for related donors.

Chemotherapy


Variant #2, weight-based Cy

Study Evidence
Childs et al. 2000 Non-randomized, <20 pts

Chemotherapy


References

  1. Childs R, Chernoff A, Contentin N, Bahceci E, Schrump D, Leitman S, Read EJ, Tisdale J, Dunbar C, Linehan WM, Young NS, Barrett AJ. Regression of metastatic renal-cell carcinoma after nonmyeloablative allogeneic peripheral-blood stem-cell transplantation. N Engl J Med. 2000 Sep 14;343(11):750-8. link to original article contains verified protocol PubMed
  2. GCLLSG CLL3X: Dreger P, Döhner H, Ritgen M, Böttcher S, Busch R, Dietrich S, Bunjes D, Cohen S, Schubert J, Hegenbart U, Beelen D, Zeis M, Stadler M, Hasenkamp J, Uharek L, Scheid C, Humpe A, Zenz T, Winkler D, Hallek M, Kneba M, Schmitz N, Stilgenbauer S; German CLL Study Group. Allogeneic stem cell transplantation provides durable disease control in poor-risk chronic lymphocytic leukemia: long-term clinical and MRD results of the German CLL Study Group CLL3X trial. Blood. 2010 Oct 7;116(14):2438-47. Epub 2010 Jul 1. link to original article contains verified protocol PubMed
    1. Update: Dreger P, Schnaiter A, Zenz T, Böttcher S, Rossi M, Paschka P, Bühler A, Dietrich S, Busch R, Ritgen M, Bunjes D, Zeis M, Stadler M, Uharek L, Scheid C, Hegenbart U, Hallek M, Kneba M, Schmitz N, Döhner H, Stilgenbauer S. TP53, SF3B1, and NOTCH1 mutations and outcome of allotransplantation for chronic lymphocytic leukemia: six-year follow-up of the GCLLSG CLL3X trial. Blood. 2013 Apr 18;121(16):3284-8. Epub 2013 Feb 22. link to original article PubMed
    2. Update: Krämer I, Stilgenbauer S, Dietrich S, Böttcher S, Zeis M, Stadler M, Bittenbring J, Uharek L, Scheid C, Hegenbart U, Ho A, Hallek M, Kneba M, Schmitz N, Döhner H, Dreger P. Allogeneic hematopoietic cell transplantation for high-risk CLL: 10-year follow-up of the GCLLSG CLL3X trial. Blood. 2017 Sep 21;130(12):1477-1480. Epub 2017 Jul 17. link to original article PubMed

FCR

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FCR: Fludarabine, Cyclophosphamide, Rituximab

Regimen

Study Evidence
Khouri et al. 2001 Phase II

Details are best described in Khouri et al. 2008.

Chemotherapy

Immunosuppressive therapy

GVHD prophylaxis

  • Tacrolimus (Prograf) adjusted to level of 5 to 10 ng/mL for 6 months in patients in remission
  • Methotrexate (MTX) as follows:
    • Related donors: 5 mg/m2 IV once per day on days +1, +3, +6
    • Unrelated donors: 5 mg/m2 IV once per day on days +1, +3, +6, +11


References

  1. Khouri IF, Saliba RM, Giralt SA, Lee MS, Okoroji GJ, Hagemeister FB, Korbling M, Younes A, Ippoliti C, Gajewski JL, McLaughlin P, Anderlini P, Donato ML, Cabanillas FF, Champlin RE. Nonablative allogeneic hematopoietic transplantation as adoptive immunotherapy for indolent lymphoma: low incidence of toxicity, acute graft-versus-host disease, and treatment-related mortality. Blood. 2001 Dec 15;98(13):3595-9. link to original article PubMed
    1. Update: Khouri IF, McLaughlin P, Saliba RM, Hosing C, Korbling M, Lee MS, Medeiros LJ, Fayad L, Samaniego F, Alousi A, Anderlini P, Couriel D, de Lima M, Giralt S, Neelapu SS, Ueno NT, Samuels BI, Hagemeister F, Kwak LW, Champlin RE. Eight-year experience with allogeneic stem cell transplantation for relapsed follicular lymphoma after nonmyeloablative conditioning with fludarabine, cyclophosphamide, and rituximab. Blood. 2008 Jun 15;111(12):5530-6. Epub 2008 Apr 14. Erratum in: Blood. 2009 Feb 12;113(7):1613. link to original article contains verified protocol link to PMC article PubMed
    2. Update: Khouri IF, Saliba RM, Erwin WD, Samuels BI, Korbling M, Medeiros LJ, Valverde R, Alousi AM, Anderlini P, Bashir Q, Ciurea S, Gulbis AM, de Lima M, Hosing C, Kebriaei P, Popat UR, Fowler N, Neelapu SS, Samaniego F, Champlin RE, Macapinlac HA. Nonmyeloablative allogeneic transplantation with or without 90yttrium ibritumomab tiuxetan is potentially curative for relapsed follicular lymphoma: 12-year results. Blood. 2012 Jun 28;119(26):6373-8. Epub 2012 May 14. link to original article contains verified protocol link to PMC article PubMed

Fludarabine & TBI

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Variant #1

Study Evidence Comparator Comparative Efficacy Non-relapse mortality
Bornhäuser et al. 2012 Phase III (E) Cyclophosphamide & TBI Seems not superior Seems not superior

Details in the abstract are limited.

Chemotherapy

Radiotherapy

Variant #2, low-dose TBI

Study Evidence Comparator Comparative Efficacy
Maris et al. 2003 Phase II
Sorror et al. 2005 Phase II
Gyukocza et al. 2010 Non-randomized
Björkstrand et al. 2011 (EBMT-NMAM2000) Non-randomized portion of RCT
Kornblit et al. 2013 Phase III (E) Low-dose TBI Might have superior OS

Details are best described in Maris et al. 2003.

Chemotherapy

Radiotherapy

GVHD prophylaxis

  • Cyclosporine A (type not specified) 6.25 mg/kg PO twice per day starting 4 to 6 hours after transplant, tapered at day 100 over 80 days (if no GVHD)
  • Mycophenolate mofetil (CellCept) 15 mg/kg PO twice per day starting 4 to 6 hours after transplant, tapered at day 40 over 56 days (if no GVHD)

References

  1. Maris MB, Niederwieser D, Sandmaier BM, Storer B, Stuart M, Maloney D, Petersdorf E, McSweeney P, Pulsipher M, Woolfrey A, Chauncey T, Agura E, Heimfeld S, Slattery J, Hegenbart U, Anasetti C, Blume K, Storb R. HLA-matched unrelated donor hematopoietic cell transplantation after nonmyeloablative conditioning for patients with hematologic malignancies. Blood. 2003 Sep 15;102(6):2021-30. Epub 2003 Jun 5. link to original article contains verified protocol PubMed
  2. Sorror ML, Maris MB, Sandmaier BM, Storer BE, Stuart MJ, Hegenbart U, Agura E, Chauncey TR, Leis J, Pulsipher M, McSweeney P, Radich JP, Bredeson C, Bruno B, Langston A, Loken MR, Al-Ali H, Blume KG, Storb R, Maloney DG. Hematopoietic cell transplantation after nonmyeloablative conditioning for advanced chronic lymphocytic leukemia. J Clin Oncol. 2005 Jun 1;23(16):3819-29. Epub 2005 Apr 4. link to original article PubMed
    1. Update: Sorror ML, Storer BE, Sandmaier BM, Maris M, Shizuru J, Maziarz R, Agura E, Chauncey TR, Pulsipher MA, McSweeney PA, Wade JC, Bruno B, Langston A, Radich J, Niederwieser D, Blume KG, Storb R, Maloney DG. Five-year follow-up of patients with advanced chronic lymphocytic leukemia treated with allogeneic hematopoietic cell transplantation after nonmyeloablative conditioning. J Clin Oncol. 2008 Oct 20;26(30):4912-20. Epub 2008 Sep 15. link to original article link to PMC article PubMed
  3. Gyurkocza B, Storb R, Storer BE, Chauncey TR, Lange T, Shizuru JA, Langston AA, Pulsipher MA, Bredeson CN, Maziarz RT, Bruno B, Petersen FB, Maris MB, Agura E, Yeager A, Bethge W, Sahebi F, Appelbaum FR, Maloney DG, Sandmaier BM. Nonmyeloablative allogeneic hematopoietic cell transplantation in patients with acute myeloid leukemia. J Clin Oncol. 2010 Jun 10;28(17):2859-67. Epub 2010 May 3. link to original article contains verified protocol link to PMC article PubMed
  4. EBMT-NMAM2000: Björkstrand B, Iacobelli S, Hegenbart U, Gruber A, Greinix H, Volin L, Narni F, Musto P, Beksac M, Bosi A, Milone G, Corradini P, Goldschmidt H, de Witte T, Morris C, Niederwieser D, Gahrton G. Tandem autologous/reduced-intensity conditioning allogeneic stem-cell transplantation versus autologous transplantation in myeloma: long-term follow-up. J Clin Oncol. 2011 Aug 1;29(22):3016-22. Epub 2011 Jul 5. Erratum in: J Clin Oncol. 2011 Sep 20;29(27):3721. link to original article contains protocol PubMed
    1. Update: Gahrton G, Iacobelli S, Björkstrand B, Hegenbart U, Gruber A, Greinix H, Volin L, Narni F, Carella AM, Beksac M, Bosi A, Milone G, Corradini P, Schönland S, Friberg K, van Biezen A, Goldschmidt H, de Witte T, Morris C, Niederwieser D, Garderet L, Kröger N; EBMT Chronic Malignancies Working Party Plasma Cell Disorders Subcommittee. Autologous/reduced-intensity allogeneic stem cell transplantation vs autologous transplantation in multiple myeloma: long-term results of the EBMT-NMAM2000 study. Blood. 2013 Jun 20;121(25):5055-63. Epub 2013 Mar 12. link to original article PubMed
  5. Bornhäuser M, Kienast J, Trenschel R, Burchert A, Hegenbart U, Stadler M, Baurmann H, Schäfer-Eckart K, Holler E, Kröger N, Schmid C, Einsele H, Kiehl MG, Hiddemann W, Schwerdtfeger R, Buchholz S, Dreger P, Neubauer A, Berdel WE, Ehninger G, Beelen DW, Schetelig J, Stelljes M. Reduced-intensity conditioning versus standard conditioning before allogeneic haemopoietic cell transplantation in patients with acute myeloid leukaemia in first complete remission: a prospective, open-label randomised phase 3 trial. Lancet Oncol. 2012 Oct;13(10):1035-44. Epub 2012 Sep 7. link to original article contains protocol PubMed
  6. Kornblit B, Maloney DG, Storb R, Storek J, Hari P, Vucinic V, Maziarz RT, Chauncey TR, Pulsipher MA, Bruno B, Petersen FB, Bethge WA, Hübel K, Bouvier ME, Fukuda T, Storer BE, Sandmaier BM. Fludarabine and 2-Gy TBI is superior to 2 Gy TBI as conditioning for HLA-matched related hematopoietic cell transplantation: a phase III randomized trial. Biol Blood Marrow Transplant. 2013 Sep;19(9):1340-7. Epub 2013 Jun 11. link to original article link to PMC article contains verified protocol PubMed

Fludarabine, Busulfan, ATG

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Variant #1

Study Evidence
Devine et al. 2015 (CALGB 100103) Phase II

This regimen is meant for all types of donors.

Chemotherapy

Immunosuppressive therapy

  • ATG (Rabbit) 2.5 mg/kg IV over 6 hours once per day on days -4 to -2

GVHD prophylaxis

  • Tacrolimus (Prograf) with doses adjusted to maintain levels of 5 to 10 ng/mL, tapered on day +90 to off by day +180 (if no GVHD)
  • Methotrexate (MTX) 5 mg/m2 IV once per day on days +1, +3, +6, +11


Variant #2

Study Evidence
Mohti et al. 2014 Phase II

Chemotherapy

Immunosuppressive therapy


Variant #3

Study Evidence
Garban et al. 2006 (IFM99-03) Non-randomized

This regimen was meant for patients who had an HLA-identical sibling donor, and was evaluated in multiple myeloma patients.

Chemotherapy

Immunosuppressive therapy

GVHD prophylaxis

  • Cyclosporine A (type not specified) with starting dose on day -1 of 3 mg/kg/day, doses adjusted to "serum levels", tapered on day +60 to off by day +100 (if no GVHD)
  • Methotrexate (MTX) 10 mg/m2 (route not specified) once per day on days +1, +3, +6

Variant #4

Study Evidence
Slavin et al. 1998 Phase II
Schetelig et al. 2003 Phase II

Chemotherapy

Immunosuppressive therapy

  • ATG-Fresenius 10 mg/kg/day IV once per day on days -4 to -1 (4 consecutive days)


References

  1. Slavin S, Nagler A, Naparstek E, Kapelushnik Y, Aker M, Cividalli G, Varadi G, Kirschbaum M, Ackerstein A, Samuel S, Amar A, Brautbar C, Ben-Tal O, Eldor A, Or R. Nonmyeloablative stem cell transplantation and cell therapy as an alternative to conventional bone marrow transplantation with lethal cytoreduction for the treatment of malignant and nonmalignant hematologic diseases. Blood. 1998 Feb 1;91(3):756-63. link to original article contains verified protocol PubMed
  2. Schetelig J, Thiede C, Bornhauser M, Schwerdtfeger R, Kiehl M, Beyer J, Sayer HG, Kroger N, Hensel M, Scheffold C, Held TK, Hoffken K, Ho AD, Kienast J, Neubauer A, Zander AR, Fauser AA, Ehninger G, Siegert W; Cooperative German Transplant Study Group. Evidence of a graft-versus-leukemia effect in chronic lymphocytic leukemia after reduced-intensity conditioning and allogeneic stem-cell transplantation: the Cooperative German Transplant Study Group. J Clin Oncol. 2003 Jul 15;21(14):2747-53. link to original article contains reference to protocol PubMed
  3. IFM99-03: Garban F, Attal M, Michallet M, Hulin C, Bourhis JH, Yakoub-Agha I, Lamy T, Marit G, Maloisel F, Berthou C, Dib M, Caillot D, Deprijck B, Ketterer N, Harousseau JL, Sotto JJ, Moreau P. Prospective comparison of autologous stem cell transplantation followed by dose-reduced allograft (IFM99-03 trial) with tandem autologous stem cell transplantation (IFM99-04 trial) in high-risk de novo multiple myeloma. Blood. 2006 May 1;107(9):3474-80. Epub 2006 Jan 5. link to original article contains verified protocol PubMed
    1. Update: Moreau P, Garban F, Attal M, Michallet M, Marit G, Hulin C, Benboubker L, Doyen C, Mohty M, Yakoub-Agha I, Leyvraz S, Casassus P, Avet-Loiseau H, Garderet L, Mathiot C, Harousseau JL; IFM Group. Long-term follow-up results of IFM99-03 and IFM99-04 trials comparing nonmyeloablative allotransplantation with autologous transplantation in high-risk de novo multiple myeloma. Blood. 2008 Nov 1;112(9):3914-5. link to original article PubMed
  4. Mohty M, Malard F, Blaise D, Milpied N, Furst S, Tabrizi R, Guillaume T, Vigouroux S, El-Cheikh J, Delaunay J, Le Gouill S, Moreau P, Labopin M, Chevallier P. Reduced-toxicity conditioning with fludarabine, once-daily intravenous busulfan, and antithymocyte globulins prior to allogeneic stem cell transplantation: results of a multicenter prospective phase 2 trial. Cancer. 2015 Feb 15;121(4):562-9. Epub 2014 Oct 3. Erratum in: Cancer. 2015 Mar 1;121(5):800. link to original article contains verified protocol PubMed
  5. CALGB 100103: Devine SM, Owzar K, Blum W, Mulkey F, Stone RM, Hsu JW, Champlin RE, Chen YB, Vij R, Slack J, Soiffer RJ, Larson RA, Shea TC, Hars V, Sibley AB, Giralt S, Carter S, Horowitz MM, Linker C, Alyea EP. Phase II study of allogeneic transplantation for older patients with acute myeloid leukemia in first complete remission using a reduced-intensity conditioning regimen: results from Cancer and Leukemia Group B 100103 (Alliance for Clinical Trials in Oncology)/Blood and Marrow Transplant Clinical Trial Network 0502. J Clin Oncol. 2015 Dec 10;33(35):4167-75. Epub 2015 Nov 2. link to original article contains verified protocol link to PMC article PubMed

Fludarabine, Busulfan, ATG, Ibritumomab tiuxetan

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Regimen

Study Evidence
Bouabdallah et al. 2015 Phase II

Chemoradioimmunotherapy

Immunosuppressive therapy

GVHD prophylaxis

  • Cyclosporine A (type and dose not specified) until day +90 and tapered off by day +180 based on chimerism and GVHD
  • Methotrexate (MTX) as follows (for unrelated donors with HLA mismatch):
    • 15 mg/m2 (route not specified) once on day +1
    • 10 mg/m2 (route not specified) once per day on days +3 & +6


References

  1. Bouabdallah K, Furst S, Asselineau J, Chevalier P, Tournilhac O, Ceballos P, Vigouroux S, Tabrizi R, Doussau A, Bouabdallah R, Mohty M, Le Gouill S, Blaise D, Milpied N. 90Y-ibritumomab tiuxetan, fludarabine, busulfan and antithymocyte globulin reduced-intensity allogeneic transplant conditioning for patients with advanced and high-risk B-cell lymphomas. Ann Oncol. 2015 Jan;26(1):193-8. Epub 2014 Oct 30. link to original article contains verified protocol PubMed

Fludarabine, Cyclophosphamide, ATG

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Regimen

Study Evidence
Dreger et al. 2010 (GCLLSG CLL3X) Phase II

This regimen is intended for unrelated donors.

Chemotherapy

Immunosuppressive therapy

  • ATG-Fresenius 10 mg/kg/day IV on days -4 to -1 (4 consecutive days)


References

  1. GCLLSG CLL3X: Dreger P, Döhner H, Ritgen M, Böttcher S, Busch R, Dietrich S, Bunjes D, Cohen S, Schubert J, Hegenbart U, Beelen D, Zeis M, Stadler M, Hasenkamp J, Uharek L, Scheid C, Humpe A, Zenz T, Winkler D, Hallek M, Kneba M, Schmitz N, Stilgenbauer S; German CLL Study Group. Allogeneic stem cell transplantation provides durable disease control in poor-risk chronic lymphocytic leukemia: long-term clinical and MRD results of the German CLL Study Group CLL3X trial. Blood. 2010 Oct 7;116(14):2438-47. Epub 2010 Jul 1. link to original article contains verified protocol PubMed
    1. Update: Dreger P, Schnaiter A, Zenz T, Böttcher S, Rossi M, Paschka P, Bühler A, Dietrich S, Busch R, Ritgen M, Bunjes D, Zeis M, Stadler M, Uharek L, Scheid C, Hegenbart U, Hallek M, Kneba M, Schmitz N, Döhner H, Stilgenbauer S. TP53, SF3B1, and NOTCH1 mutations and outcome of allotransplantation for chronic lymphocytic leukemia: six-year follow-up of the GCLLSG CLL3X trial. Blood. 2013 Apr 18;121(16):3284-8. Epub 2013 Feb 22. link to original article PubMed
    2. Update: Krämer I, Stilgenbauer S, Dietrich S, Böttcher S, Zeis M, Stadler M, Bittenbring J, Uharek L, Scheid C, Hegenbart U, Ho A, Hallek M, Kneba M, Schmitz N, Döhner H, Dreger P. Allogeneic hematopoietic cell transplantation for high-risk CLL: 10-year follow-up of the GCLLSG CLL3X trial. Blood. 2017 Sep 21;130(12):1477-1480. Epub 2017 Jul 17. link to original article PubMed

Fludarabine, Cyclophosphamide, TBI for dUCB or haploidentical transplant

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dUCB: double Umbilical Cord Blood

Variant #1, dUCB transplantation

Study Evidence
Brunstein et al. 2011 Phase II

Chemotherapy

Radiotherapy

Supportive medications

  • Mesna (Mesnex) (dose/route/schedule not specified) and "vigorous IV hydration for uroprotection."
  • Filgrastim (Neupogen) 5 mcg/kg SC once per day, starting on day +1, continued until ANC greater than or equal to 2000/uL for 3 consecutive days

GVHD prophylaxis

  • Mycophenolate mofetil (CellCept) 1000 mg (route not specified) every 8 hours for patients greater than 50 kg, starting on day -3 "and continuing until day +30 or 7 days after engraftment, whichever was later"
    • Patients less than 50 kg received 15 mg/kg (route not specified) every 8 hours, starting on day -3 "and continuing until day +30 or 7 days after engraftment, whichever was later"
  • Cyclosporine A (Neoral vs. Sandimmune not specified, route not specified) with a goal trough of 200 to 400 ng/mL (starting date not specified) until day +100. Patients without GVHD had their dose tapered by 10% each week starting on day +101, with discontinuation of cyclosporine A around day +180 to +200.
  • Tacrolimus (Prograf) (route not specified) with a goal trough level of 5 to 10 ng/mL could be substituted for cyclosporine.


Variant #2, Haploidentical

Study Evidence
Brunstein et al. 2011 Phase II

Chemotherapy

Radiotherapy

Supportive medications

  • Mesna (Mesnex) (dose/route/schedule not specified) and "vigorous IV hydration for uroprotection."
  • Filgrastim (Neupogen) 5 mcg/kg SC once per day, starting on day +5, continued until ANC greater than or equal to 1000/uL for 3 consecutive days

GVHD prophylaxis

  • Cyclophosphamide (Cytoxan) 50 mg/kg IBW IV over 1 to 2 hours once per day on days +3 & +4, started 60 to 72 hours after marrow infusion
  • Mycophenolate mofetil (CellCept) 15 mg/kg (maximum daily dose of 3000 mg; route not specified) every 8 hours, starting on day +5, continued until day +35 or longer at physician discretion if active GVHD was present
  • Tacrolimus (Prograf) (route not specified) with a goal trough level of 5 to 10 ng/mL, starting on day +5, continued until day +180


References

  1. Brunstein CG, Fuchs EJ, Carter SL, Karanes C, Costa LJ, Wu J, Devine SM, Wingard JR, Aljitawi OS, Cutler CS, Jagasia MH, Ballen KK, Eapen M, O'Donnell PV; Blood and Marrow Transplant Clinical Trials Network. Alternative donor transplantation after reduced intensity conditioning: results of parallel phase 2 trials using partially HLA-mismatched related bone marrow or unrelated double umbilical cord blood grafts. Blood. 2011 Jul 14;118(2):282-8. link to original article contains verified protocol link to PMC article PubMed

Fludarabine & Melphalan

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Flu-Mel: Fludarabine & Melphalan

Variant #1, 132/140

Study Evidence
Anderlini et al. 2008 Phase II

Chemotherapy

Immunosuppressive therapy

  • Recipients of stem cells from matched unrelated donors also received:
    • ATG (type not specified) 2 mg/kg IV once per day on days -4 to -2

GVHD prophylaxis

  • Tacrolimus (Prograf) IV starting on day -2, dosed to achieve serum levels 4 to 12 ng/mL and switched to PO as soon as possible. Continued for at least 6 months and then "tapered off" (instructions not given).
  • Methotrexate (MTX) 5 mg/m2 IV once per day on days +1, +3, +6 (extra dose on day +11 for MUD recipients)

Variant #2, 150/140

Study Evidence
Alvarez et al. 2006 Prospective
Sureda et al. 2011 (HDR-ALLO) Phase II

Note: Alvarez et al. 2006 began CsA on day -1 and did not give day +11 MTX.

Chemotherapy

Immunosuppressive therapy

GVHD prophylaxis

  • Cyclosporine A (not specified whether modified or non-modified) starting on day -2 at 1.5 mg/kg IV twice per day
    • If no acute GVHD of grade 2 or more, cyclosporine A is tapered down by 10% per week starting on day +90 with planned discontinuation by day +150 (Alvarez et al. 2006) or +180 (HDR-ALLO).
  • Methotrexate (MTX) 10 mg/m2 IV once per day on days +1, +3, +6, +11


References

  1. Alvarez I, Sureda A, Caballero MD, Urbano-Ispizua A, Ribera JM, Canales M, García-Conde J, Sanz G, Arranz R, Bernal MT, de la Serna J, Díez JL, Moraleda JM, Rubió-Félix D, Xicoy B, Martínez C, Mateos MV, Sierra J. Nonmyeloablative stem cell transplantation is an effective therapy for refractory or relapsed Hodgkin lymphoma: results of a Spanish prospective cooperative protocol. Biol Blood Marrow Transplant. 2006 Feb;12(2):172-83. link to original article contains verified protocol PubMed
  2. Anderlini P, Saliba R, Acholonu S, Giralt SA, Andersson B, Ueno NT, Hosing C, Khouri IF, Couriel D, de Lima M, Qazilbash MH, Pro B, Romaguera J, Fayad L, Hagemeister F, Younes A, Munsell MF, Champlin RE. Fludarabine-melphalan as a preparative regimen for reduced-intensity conditioning allogeneic stem cell transplantation in relapsed and refractory Hodgkin's lymphoma: the updated MD Anderson Cancer Center experience. Haematologica. 2008 Feb;93(2):257-64. Epub 2008 Jan 26. link to original article contains verified protocol link to PMC article PubMed
  3. HDR-ALLO: Sureda A, Canals C, Arranz R, Caballero D, Ribera JM, Brune M, Passweg J, Martino R, Valcárcel D, Besalduch J, Duarte R, León A, Pascual MJ, García-Noblejas A, López Corral L, Xicoy B, Sierra J, Schmitz N. Allogeneic stem cell transplantation after reduced intensity conditioning in patients with relapsed or refractory Hodgkin's lymphoma: results of the HDR-ALLO study - a prospective clinical trial by the Grupo Español de Linfomas/Trasplante de Médula Osea (GEL/TAMO) and the Lymphoma Working Party of the European Group for Blood and Marrow Transplantation. Haematologica. 2012 Feb;97(2):310-7. Epub 2011 Oct 11. link to original article contains protocol link to PMC article PubMed

Fludarabine, Melphalan, Alemtuzumab

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Regimen

Study Evidence
Peggs et al. 2005 Non-randomized

Chemotherapy


References

  1. Peggs KS, Hunter A, Chopra R, Parker A, Mahendra P, Milligan D, Craddock C, Pettengell R, Dogan A, Thomson KJ, Morris EC, Hale G, Waldmann H, Goldstone AH, Linch DC, Mackinnon S. Clinical evidence of a graft-versus-Hodgkin's-lymphoma effect after reduced-intensity allogeneic transplantation. Lancet. 2005 Jun 4-10;365(9475):1934-41. link to original article contains verified protocol PubMed

Low-dose TBI

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TBI: Total Body Irradiation

Regimen

Study Evidence
Gyukocza et al. 2010 Non-randomized

Radiotherapy

GVHD prophylaxis


References

  1. Gyurkocza B, Storb R, Storer BE, Chauncey TR, Lange T, Shizuru JA, Langston AA, Pulsipher MA, Bredeson CN, Maziarz RT, Bruno B, Petersen FB, Maris MB, Agura E, Yeager A, Bethge W, Sahebi F, Appelbaum FR, Maloney DG, Sandmaier BM. Nonmyeloablative allogeneic hematopoietic cell transplantation in patients with acute myeloid leukemia. J Clin Oncol. 2010 Jun 10;28(17):2859-67. Epub 2010 May 3. link to original article contains verified protocol link to PMC article PubMed

TLI & ATG

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TLI & ATG: Total Lymphocyte Irradiation & Anti-Thymocyte Globulin

Regimen

Study Evidence
Lowsky et al. 2005 Non-randomized
Kohrt et al. 2009 Non-randomized

Note: the schedule for TLI in Kohrt et al. 2009 is slightly different, although the manuscript states that the protocol from Lowsky et al. 2006 was followed. See paper for details.

Radiotherapy

  • TLI 800 cGy once per day on days -11 to -1 (10 fractions)

Immunosuppressive therapy


References

  1. Lowsky R, Takahashi T, Liu YP, Dejbakhsh-Jones S, Grumet FC, Shizuru JA, Laport GG, Stockerl-Goldstein KE, Johnston LJ, Hoppe RT, Bloch DA, Blume KG, Negrin RS, Strober S. Protective conditioning for acute graft-versus-host disease. N Engl J Med. 2005 Sep 29;353(13):1321-31. Erratum in: N Engl J Med. 2006 Feb 23;354(8):884. link to original article contains verified protocol PubMed
  2. Kohrt HE, Turnbull BB, Heydari K, Shizuru JA, Laport GG, Miklos DB, Johnston LJ, Arai S, Weng WK, Hoppe RT, Lavori PW, Blume KG, Negrin RS, Strober S, Lowsky R. TLI and ATG conditioning with low risk of graft-versus-host disease retains antitumor reactions after allogeneic hematopoietic cell transplantation from related and unrelated donors. Blood. 2009 Jul 30;114(5):1099-109. link to original article link to PMC article contains verified protocol PubMed

(90)YFC

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(90)YFC: Ibritumomab tiuxetan, Fludarabine, Cyclophosphamide

Regimen

Study Evidence
Khouri et al. 2012 (ID01-233) Non-randomized

Chemoradioimmunotherapy

Immunosuppressive therapy

GVHD prophylaxis


References

  1. ID01-233: Khouri IF, Saliba RM, Erwin WD, Samuels BI, Korbling M, Medeiros LJ, Valverde R, Alousi AM, Anderlini P, Bashir Q, Ciurea S, Gulbis AM, de Lima M, Hosing C, Kebriaei P, Popat UR, Fowler N, Neelapu SS, Samaniego F, Champlin RE, Macapinlac HA. Nonmyeloablative allogeneic transplantation with or without 90yttrium ibritumomab tiuxetan is potentially curative for relapsed follicular lymphoma: 12-year results. Blood. 2012 Jun 28;119(26):6373-8. Epub 2012 May 14. link to original article contains verified protocol link to PMC article PubMed

Hepatic veno-occlusive disease (VOD), all lines of therapy

Also known as sinusoidal obstructive syndrome (SOS)

Defibrotide monotherapy

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Variant #1, treatment

Study Evidence Comparator Comparative Efficacy
Richardson et al. 2016 Phase III (E) "32 historical controls" Seems to have superior survival at day +100

If after 21 days signs and symptoms of VOD have not resolved, give until VOD is resolved, up to a maximum of 60 days.

Supportive therapy

21- to 60-day course

Variant #2, prophylaxis

Study Evidence Comparator Comparative Efficacy
Corbacioglu et al. 2012 Phase III (E) Observation Seems to have lower incidence of VOD

Supportive therapy

Begins on first day of preparative regimen, continues for at least 14 days or until day +30

References

  1. Corbacioglu S, Cesaro S, Faraci M, Valteau-Couanet D, Gruhn B, Rovelli A, Boelens JJ, Hewitt A, Schrum J, Schulz AS, Müller I, Stein J, Wynn R, Greil J, Sykora KW, Matthes-Martin S, Führer M, O'Meara A, Toporski J, Sedlacek P, Schlegel PG, Ehlert K, Fasth A, Winiarski J, Arvidson J, Mauz-Körholz C, Ozsahin H, Schrauder A, Bader P, Massaro J, D'Agostino R, Hoyle M, Iacobelli M, Debatin KM, Peters C, Dini G. Defibrotide for prophylaxis of hepatic veno-occlusive disease in paediatric haemopoietic stem-cell transplantation: an open-label, phase 3, randomised controlled trial. Lancet. 2012 Apr 7;379(9823):1301-9. Epub 2012 Feb 23. contains verified protocol PubMed
  2. Richardson PG, Riches ML, Kernan NA, Brochstein JA, Mineishi S, Termuhlen AM, Arai S, Grupp SA, Guinan EC, Martin PL, Steinbach G, Krishnan A, Nemecek ER, Giralt S, Rodriguez T, Duerst R, Doyle J, Antin JH, Smith A, Lehmann L, Champlin R, Gillio A, Bajwa R, D'Agostino RB Sr, Massaro J, Warren D, Miloslavsky M, Hume RL, Iacobelli M, Nejadnik B, Hannah AL, Soiffer RJ. Phase 3 trial of defibrotide for the treatment of severe veno-occlusive disease and multi-organ failure. Blood. 2016 Jan 29. contains verified protocol link to PMC article PubMed