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Fludarabine and Busulfan
BuFlu: Busulfan & Fludarabine Flu/Bu: Fludarabine & Busulfan
Regimen variant #1
Study | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|
Rambaldi et al. 2015 | Phase 3 | 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
- Busulfan (Myleran) 0.8 mg/kg IV four times per day for 2 hour infusions on days -6 to -3
- Fludarabine (Fludara) 30 mg/m2 IV once per day on days -6 to -3
Graft Vs. Host Disease prophylaxis and key supportive medications
- Cyclosporine with methotrexate
- For unrelated donors Antithymocyte globulin, rabbit ATG (Thymoglobulin) 0∙5 mg/kg IV on day –3 and 2∙0 mg/kg IV on day –2 and, if the donor was identical, 2∙5 mg/kg on day –1 (If donor mismatched total ATG dose could be increased to 7.5 mg/kg)
Regimen variant #2
Study | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|
Andersson et al. 2008 | Retrospective | Busulfan & Cyclophosphamide | Suggested improved outcomes, but shorter follow up |
Kanakry et al. 2014 | Phase 2 | ||
Mielcarek et al. 2016 | Phase 2 |
Diseases Studied: Acute myeloid leukemia, Myelodysplastic syndrome, Acute lymphocytic leukemia, Chronic myeloid leukemia, Non-Hodgkin lymphoma
Graft types studied: Matched Related / Unrelated Donor Bone Marrow, Mobilized Peripheral Blood Stem Cells
Chemotherapy
- Fludarabine (Fludara) 40 mg/m2 IV once per day over 60 minutes on days -6 to -3 followed by
- Busulfan (Myleran) 130 mg/kg IV once per day over three hours on days -6 to -3 (busulfan dosing targeted for optimal pharmacokinetics but different parameters each institution, please consult the original publication for optimal levels)
Graft versus Host Disease prophylaxis and key supportive medications:
#1 Tacrolimus & methotrexate based (Andersson et al.)
- Tacrolimus (Prograf) with methotrexate
- For unrelated or mismatched donors Antithymocyte globulin, rabbit ATG (Thymoglobulin) 0.5 mg/kg on day –3, 1.5 mg/kg on day –2, and 2 mg/kg on day –1
- All patients received Filgrastim (Neupogen) from day +7 until achieving an absolute neutrophil count (ANC) ≥1.5 × 109/L for three days
- Phenytoin prophylaxis used during and for one day after IV busulfan
#2 Post-Transplant Cy based (Kanakry et al. and Mielcarek et al.)
- Cyclophosphamide (Cytoxan) 50 mg/kg on days +3 and +4 with mesna (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)
Regimen variant #3
Study | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|
Lee et al. 2013 | Phase 3 | Busulfan & Cyclophosphamide | Seems to have inferior OS |
Diseases Studied: Acute myeloid leukemia, Myelodysplastic syndrome, Acute lymphocytic leukemia, Chronic myeloid 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 followed by
- Fludarabine (Fludara) 30 mg/m2 IV once per day on days -6 to -2
Graft versus Host Disease prophylaxis and key supportive medications:
- "Cyclosporine alone or with methotrexate according to the discretion of the attending physician"
- Filgrastim (Neupogen) 450 mcg SC once per day, starting on day +5 and continued until ANC greater than 3000/μL
Regimen variant #4
Study | Evidence |
---|---|
Russell et al. 2002 | Phase 2 |
Diseases Studied: Acute myeloid leukemia, Myelodysplastic syndrome, Chronic myeloid 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
- Fludarabine (Fludara) 50 mg/m2 IV once per day on days -6 to -2
- Busulfan (Myleran) 3.2 mg/kg (ideal body weight) IV once per day over 3 hours on days -5 to -2
Graft versus Host Disease prophylaxis and key supportive medications:
- Antithymocyte globulin, rabbit ATG (Thymoglobulin) 0.5 mg/kg IV once on day -2; 2 mg/kg IV once per day on days -1 & 0 (total dose of 4.5 mg/kg)
- Cyclosporine modified (Neoral) or Cyclosporine non-modified (Sandimmune) IV or PO twice per day, with doses adjusted to maintain cyclosporine levels of 150 to 400 umol/L
- Methotrexate (MTX) 15 mg/m2 once on day 1; 10 mg/m2 once per day on days 3, 6, 11
- Leucovorin (Folinic acid) 5 mg started 24 hours after each dose of methotrexate and continued every 6 hours until 12 hours before the next dose of methotrexate
- Phenytoin (Dilantin) "loading" PO/IV, dosed to maintain therapeutic levels of 40 to 80 umol/L on days -5 to -2
References
- 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 i.v. busulfan and fludarabine (i.v. Bu-Flu) compares favorably with i.v. busulfan and cyclophosphamide (i.v. BuCy2) as pretransplant conditioning therapy in AML/MDS. Biol Blood Marrow Transplant. 2008;14(6):672-84. link to original article contains dosing details in manuscript PubMed
- 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. link to original article contains dosing details in manuscript PubMed
- 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 dosing details in manuscript PubMed
- 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 dosing details in manuscript PubMed
- 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
- 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 dosing details in manuscript PubMed