Allogeneic Stem Cell Transplantation (BMT) for AML and MDS Following Iv Busulfan and Cyclophosphamide
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Bone Marrow Transplantation (2000) 25, Suppl. 2, S35–S38 2000 Macmillan Publishers Ltd All rights reserved 0268–3369/00 $15.00 www.nature.com/bmt Allogeneic stem cell transplantation (BMT) for AML and MDS following i.v. busulfan and cyclophosphamide (i.v. BuCy) BS Andersson1, J Gajewski1, M Donato1, S Giralt1, V Gian2, J Wingard2, S Tarantolo3, H Fernandez4,WWHu5, K Blume5, A Kashyap6, SJ Forman6 and RE Champlin1 1UT MD Anderson Cancer Center, Houston TX; 2UF Shands Cancer Center, Gainesville, FL; 3U Nebraska, Omaha, NE; 4U Miami, Miami, FL; 5Stanford U Medical Center, Palo Alto, CA; and 6City of Hope Natl. Med. Center, Duarte, CA, USA Summary: plant conditioning therapy prior to allogeneic BMT for patients with AML or MDS. Bone Marrow Transplan- Pretransplant conditioning therapy with i.v. BuCy fol- tation (2000) 25, Suppl. 2, S35–S38. lowed by allogeneic hematopoietic stem cell transplan- Keywords: acute myeloid leukemia; myelodysplastic tation (BMT) was investigated in a phase II trial in syndrome; bone marrow transplantation; stem cell trans- patients with acute myeloid leukemia (AML) or myelod- plantation; i.v. busulfan; conditioning therapy ysplastic syndrome (MDS). We gave i.v. Bu at a dose of mg/kg every 6 h ؋ 16 doses, followed by Cy 0.8 60 mg/kg daily for 2 days. Twenty-six AML patients (18 males/eight females) were treated, only eight of whom High-dose oral busulfan (Bu) in combination with cyclo- were in CR1. The rest were either refractory to induc- phosphamide (Cy) or other cytotoxic agents is often used tion chemotherapy (four patients) or in a more as an alternative to total body irradiation (TBI)-based ther- advanced stage of their disease (14 patients). In apy in pretransplant conditioning regimens, especially in addition, nine patients with MDS (1M/8F) were treated. previously irradiated patients. Bu-based treatment is felt to Their median age was 41 years (range 21–64). be convenient and efficacious, although the few available Engraftment to у500 neutrophils/l was reached at 14 randomized studies have failed to conclusively demonstrate 1–5 days (range 10–29 days) post BMT, and the median time an advantage of Bu-based vs TBI-based treatment. of neutropenia was only 11 days (range 4–28 days). The A major shortcoming of oral Bu in high-dose therapy most common regimen-related toxicity was grade 2–3 is its very erratic and unpredictable intestinal nausea. In the post-BMT period (including BMT day absorption/bioavailability. This is a problem, since the ؉30), two patients died, one each from pulmonary resulting plasma concentration pattern has been correlated hemorrhage secondary to CMV pneumonia and hepatic with both toxicity in patients with high/complete drug 6–9 veno-occlusive disease (VOD), for an early treatment- absorption, and graft rejection/recurrent leukemia in related mortality (TRM) of 5.7%. Three patients patients who absorb a suboptimal fraction of the delivered 10,11 developed VOD and two of them died. There was no dose. To overcome this drawback we developed an 12,13 direct regimen-related pulmonary or neurologic tox- intravenous Bu formulation. In a modified phase I dose- icity. Overall, the clinical side-effect spectrum was anal- finding study we determined that a parenteral Bu dose of ogous to what would be expected from a high-dose oral 0.8 mg/kg should give similar pharmacokinetic (PK) para- Bu-based regimen; there was no unique toxicity experi- meters to those obtained after an oral dose of 1.0 mg/kg enced with the used solvent system. The disease-free BW. We here report the use of this Bu formulation in com- survival in the high-risk subgroup (all patients not in bination with Cy in 35 patients undergoing allogeneic stem CR1) at 1 and 2 years post transplant was 44% and cell transplantation (BMT) for acute myeloid leukemia 31%, respectively. The 13 patients still alive in CR have (AML) or myelodysplastic syndromes (MDS). been followed for a median of 24 months (range 18–32). Pharmacokinetic analysis showed very good interdose reproducibility, and limited interpatient variability in Patients and methods area under the plasma concentration vs time curve, peak concentration, and clearance of Bu after this i.v. Thirty-five patients with AML or MDS were included in formulation. We conclude, that this new i.v. Bu formu- this study (not eligible for a treatment protocol of higher lation is well tolerated; it has an impressive safety pro- institutional priority). This included patients with AML past file, and we suggest that it should be considered as first remission (CR, 14 patients), or in first CR but were appropriate replacement for oral busulfan in pretrans- considered at high risk for recurrent disease (eight patients). It also included those who had failed to achieve complete remission after induction chemotherapy (four patients), and Correspondence: Dr BS Andersson, Dept of Blood and Marrow Transplan- finally nine MDS patients, five of whom had a history of tation, Box 65 UT MD Anderson Cancer Center, 1515 Holcombe Blvd, a previous malignancy. Patients were eligible for study Houston, TX, 77005 USA treatment if they were between the physiologic ages of 15 Pretransplant conditioning with i.v. busulfan and cyclophosphamide BS Andersson et al S36 and 55 years. They must have normal hepatic function tive statistics were calculated for pharmacokinetic para- р Ͻ ϫ (bilirubin 1.0 mg%, SGPT 3 upper reference limit) meters—AUC, T1/2 and CL. and renal function (creatinine р1.5 mg%), and have a car- diac LVEF у50%, and DLCO у50%, and a matched related allogeneic marrow or stem cell donor available. All Results patients volunteered a written informed consent in accord- ance with institutional guidelines. All patients engrafted at a median of 14 days (range 10– The i.v. Bu Busulfex (Busulfan) injection (Orphan Medi- 29 days), and the median time of neutropenia was 11 days cal, Minnetonka, MN, USA) was administered through a (range 4–28 days). However, if only the patients who central venous catheter at 0.8 mg/kg BW over 2 h every 6 h entered the study with a normal absolute neutrophil count for 16 doses. The i.v. Bu was diluted in 5% dextrose in (у1500 cells/l) are considered, we observed a delayed water (D5W) or normal saline (NS). This was followed by onset of neutropenia after completion of the chemotherapy. two daily doses of cyclophosphamide at 60 mg/kg BW,14 Thus, the patients would not be neutropenic until day 4–5 and BMT was performed after a day of rest. Supportive post BMT, effectively reducing the median time of chemo- care was provided per each site’s institutional guidelines. therapy-induced neutropenia to 8.5 days prior to This included prophylactic treatment with phenytoin during engraftment. Further, donor-derived hematopoiesis was Bu administration, hydration and Mesna during the cyclo- demonstrated in all 25 evaluable patients who had RFLP phosphamide phase of conditioning and immunosuppres- studies, or who had a sex-mismatched donor. The efficacy sive therapy with low-dose methotrexate and either tacrol- of i.v. BuCy with BMT as intensification/salvage therapy imus or cyclosporin. is demonstrated in Table 1, with 33 of the 35 patients There were 19 males and 16 females with a median age remaining in or achieving a CR when restaged 1 month of 41 years (range 21–64). Sixteen of the 35 patients were after BMT. Three of the eight CR1 patients remain in CR considered heavily pretreated because they had received a at 21, 24 and 24 months. The higher-risk patient population previous therapeutic XRT regimen, у3 chemotherapy regi- (18 AML patients not in CR1, and nine MDS patients), mens or had a previous BMT (three patients). Successful demonstrated an OS of 64% and a DFS of 44%, and 31% engraftment, overall survival (OS) and (long-term) disease- at 1 and 2 years, respectively (Figure 1). The 13 patients free survival (DFS) were the endpoints of the study. who remain in CR have now been followed for a median Engraftment was recorded as the first day that the absolute of 24 months (range 18–32 months). The most common neutrophil count (ANC) exceeded 0.5 ϫ 109/l. Failure to toxicity was grade 2–3 nausea, mostly during the cyclopho- engraft would be defined as a failure to reach an ANC sphamide phase of the treatment. Among the serious treat- у0.5 ϫ 109/l within 100 days after transplantation. Patients ment-related events we had two deaths in the first 30 days; who engrafted within the first 100 days after transplan- one patient died from respiratory failure after pulmonary tation, but who later developed an ANC Ͻ0.5 ϫ 109/l hemorrhage as a complication of CMV pneumonia, and one would be classified as having late graft failure, unless the patient developed lethal VOD (incidence 2/35, ie 5.7%). neutropenia was caused by recurrence of the underlying Between days BMT ϩ31 and ϩ100, five additional patients disease. Relapse was recorded as the day of detection. Sur- died: one patient from VOD; one developed interstitial vival was recorded as the day of death with the cause of pneumonitis with ARDS, and then died in a clinical picture death noted. Patients were monitored for engraftment, of progressive ARDS vs bronchiolitis obliterans (BOOP). relapse and adverse events from BMT day Ϫ7 to day ϩ28, This patient had previously received approximately 40 Gy or until discharge from the hospital, and thereafter a mini- mantle XRT for Hodgkin’s disease. Finally, one patient mum of twice weekly until day ϩ28. All patients were developed hemorrhagic complications after intensified monitored for clinical chemistry laboratory parameters immunosuppressive therapy for graft-versus-host disease, twice weekly.