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Busulfan & Fludarabine

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

Regimen #1

Study	Evidence	Comparator	Efficacy
Rambaldi et al. 2015	Phase III	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 intravenously on day –3 and 2∙0 mg/kg intravenously 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 #2

Study	Evidence	Comparator	Efficacy
Andersson et al. 2008	Retrospective	Busulfan & Cyclophosphamide	Suggested improved outcomes, but shorter follow up
Kanakry et al. 2014	Phase II

Diseases Studied: Acute myeloid leukemia, Myelodysplastic syndrome, Acute lymphocytic leukemia

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 one hour 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 2.0 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.)

• Cyclophosphamide (Cytoxan) 50 mg/kg on days +3 and +4 with Mesna (Mesnex)

Regimen #3

Study	Evidence	Comparator	Efficacy
Lee et al. 2013	Phase III	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 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/uL

Regimen #4

Study	Evidence
Russell et al. 2002	Phase II

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

Supportive medications

• Phenytoin (Dilantin) "loading" PO/IV, dosed to maintain therapeutic levels of 40 to 80 umol/L on days -5 to -2
• Ciprofloxacin (Cipro) 500 mg PO BID as prophylaxis
• Trimethoprim/Sulfamethoxazole (Bactrim DS) (dose not specified in reference, but assume 160/800 mg dose) PO 2 times a week as PCP prophylaxis
• No routine fungal prophylaxis
• No routine use of growth factors
• CMV negative blood

GVHD prophylaxis

• Antithymocyte globulin (Thymoglobulin, rabbit ATG) 0.5 mg/kg IV once on day -2; 2 mg/kg/day IV once per day on days -1 & 0 (total dose of 4.5 mg/kg)
• Cyclosporine modified (Neoral) or Cyclosporine non-modified (Sandimmune) PO/IV BID, 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
• Folinic acid (Leucovorin) 5 mg started 24 hours after each dose of Methotrexate (MTX) and continued Q6H until 12 hours before the next dose of Methotrexate (MTX)

References

1. 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
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. 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