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©Ferrata Storti Foundation Stem Cell Transplantation • Research Paper Successful engraftment following allogeneic stem cell transplantation with busulfan as a single agent in very high-risk patients Menachem Bitan Background and Objectives. Busulfan is the most commonly used myeloablative alkylat- Reuven Or ing agent, but is considered a poor anti-lymphocyte agent. Since engraftment of allogeneic Michael Y Shapira stem cells depends not only on adequate immunosuppression but also on successful Igor B Resnick hematopoietic competition, and considering the fact that residual lymphocytes of host ori- Aliza Ackerstein gin may play a beneficial role in preventing graft-versus-host disease (GVHD), we used low Simcha Samuel doses of oral busulfan as a single agent for conditioning prior to stem cell transplantation Sharon Elad (SCT) in recipients of transplants from a variety of donors. Shimon Slavin Design and Methods. Fifteen heavily pretreated high-risk patients (age 25-66, median 42 years) with hematologic malignancies were conditioned with busulfan alone, 4mg/kg/day for 2, 3, or 4 consecutive days. No additional pre- or post-transplant immunosuppressive agents were used in order to exploit the capacity of donor lymphocytes to induce graft-ver- sus-malignancy (GVM) effects. Results. Conditioning was well tolerated, trilineage engraftment was documented in all patients and none exhibited immune-mediated rejection. Time to recovery of absolute neu- trophil count >0.5 109/L and 1.0 109/L was 12 - 38 (median 15) days and 12 - 41 (medi- ¥ ¥ 9 an 15) days, respectively. The time to platelet recovery ≥20 and ≥50¥10 /L ranged from 0 to 26 (median 11) days, and from 0 to 83 (median 14) days, respectively. Acute GVHD (£grade I) occurred in 13/15 patients. Three patients benefited from long-term survival. Interpretations and Conclusions. We suggest that using busulfan alone for the preparation of patients for SCT may be sufficient for engraftment, in very high-risk heavily pre-treated patients. Key words: stem cell transplantation, graft-versus-malignancy effects, busulfan, reduced intensity conditioning, hematologic malignancies, leukemia. Haematologica 2005; 90:1089-1095 ©2005 Ferrata Storti Foundation All authors from the Department of Bone Marrow Transplantation & usulfan, a sulfonic acid ester, is an hepatic toxicity, mainly veno-occlusive dis- Cancer Immunotherapy, alkylating agent with potent toxicity ease, especially in patients undergoing allo- Hadassah-Hebrew University for hematopoietic and sinusoidal geneic SCT.5-6 Other toxicities of the drug Medical Center Jerusalem 91120, B Israel. endothelial cells. The drug was initially included electroencephalographic abnor- introduced in 1952, as a treatment modali- malities and an increased risk of convul- Correspondence: ty for patients with chronic myeloid sions due to the drug penetrating into the Shimon Slavin, MD, Department leukemia.1 It was only around 20 years later central nervous system,7-8 inhibition of stro- of Bone Marrow Transplantation that this agent was first used as part of the mal cell function,9-11 occasional pulmonary & Cancer Immunotherapy Hadassah University Hospital conditioning regimen in bone marrow toxicity and an association with increased Jerusalem 91120, Israel. transplantation, substituting total body transplant-related mortality when used at E-mail: [email protected]/ irradiation.2 Considering the fact that high doses for allogeneic SCT.12 In recent [email protected] busulfan was considered as a potent mye- years, busulfex, an intravenous preparation loablative rather than immunosuppressive of busulfan, has gradually been replacing agent, most transplant centers used the oral busulfan in SCT regimens. Its main combination of busulfan and cyclophos- advantages are reduced liver toxicity and phamide or other alkylating agents or total dosage assurance with predictable pharma- body irradiation with the aim of accom- cokinetics.13-15 Given its known myeloabla- plishing maximal myeloablation as well as tive properties, busulfan was considered in optimal immunosuppression prior to trans- many centers as the treatment of choice for plantation of allogeneic stem cells. Since myeloid disorders, however, busulfan, was then, the use of busulfan spread widely and never recommended as a suitable single it was also used in conjunction with autol- agent in a preparative regimen for allogene- ogous stem cell transplantation (SCT).3-4 ic SCT because of its limited toxicity to However, it was soon discovered that the mature lymphocytes. Combinations of use of busulfan could be associated with busulfan with cyclophosphamide or other haematologica/the hematology journal | 2005; 90(8) | 1089 | M. Bitan et al. agents were used not only to control mature lympho- Table 1. Characteristics of patients undergoing stem cell trans- cytes in order to prevent rejection, but also to exploit plantation following conditioning with busulfan as a single agent. synergistic activity against target tumors or genetical- ly abnormal stem cells. The use of busulfan, or nowa- UPN Age Basic Disease No. Survival Cause and (years) disease status of Tx. time of death days busulfex, avoiding the need for ionizing irradia- at Tx. post Tx. tion, is considered the preferred treatment for malig- (days) nant and non-malignant indications especially in the pediatric age group. However, there are situations in 977 33 CML – Blastic Resistant 2nd No Infection which heavily pre-treated patients cannot safely transformation blast and acute receive extensive immunosuppressive and myeloabla- to AML-M7 Crisis s/p GVHD (83) SCT tive conditioning; furthermore, in patients with resist- ant disease, it seems unlikely that all tumor cells can 1170 47 MM Resistant 2nd No Disease be eliminated by chemotherapy alone. We, therefore, Disease s/p SCT progression (12) investigated the feasibility of accomplishing durable 1242 26 AML-M2 Resistant 1st 1st Yes Survived and consistent engraftment of donor stem cells with Relapse after PR only low doses of busulfan alone, avoiding the use of post- transplant immunosuppression as GVHD prophylaxis 1251 50 AML-M4 Resistant 1st 1st Yes Survived in order to maximize induction of graft-versus-malig- Relapse after PR only nancy effects following tumor debulking with busul- fan alone. Indeed, O’Brien and Goldman described the 1253 35 CML 2nd resistant 1st No acute GVHD (16) use of busulfan as a sole preparative agent in a group blast crisis of patients with chronic myelogenous leukemia, but 1283 59 AML* 2nd resistant 1st No Disease this was in the setting of autologous stem cell trans- relapse progression (76) 16 plantation. The present report summarizes our 1323 28 T-cell ALL Resistant 1st No Disease cumulative experience in a cohort of 15 patients who 1st relapse progression (95) received allogeneic stem cell allografts after prepara- 1354 25 AML-M5 Resistant 1st No Infection and tion with busulfan as a single agent. 1st relapse acute GVHD (34) 1358 44 Biphenotypic Resistant 1st No acute GVHD (43) disease – Design and Methods refractory to therapy Fifteen high-risk patients with advanced and fully 1362 52 CML 2nd CP 1st No acute GVHD (75) resistant disease, most of whom had been heavily 1374 46 AML-M5 Resistant 1st No Disease pre-treated, were enrolled in this study between disease - progression December 1997 and June 2000. Indications for trans- refractory (120) plantation and disease status are shown in Table 1. to therapy Patients were included if they had an absolute indica- 1378 36 CML Resistant 1st Yes Survived tion for allogeneic SCT but were not eligible for a blast crisis standard transplant procedure, or if their potential to 1380 42 CML 2nd CP 1st No Disease survive the standard protocol was judged to be low progression due to poor performance status, prior SCT or relapse (278) after SCT, provided they had not previously been 1381 66 NHL Resistant 1st No acute GVHD (47) given busulfan. The series comprised 10 males and 5 1st Relapse females, ranging in age from 25-66 (median 42) years after PR only (Table 1). The mean Karnofsky performance status 1382 31 AML-M4 2nd resistant 2nd No Infection score was 88 (range 60-100). Each patient signed relapse s/p SCT and acute GVHD informed consent to the protocol which had been (110) approved by the Institutional Review Board. Twelve UPN: unique patient number; Tx: transplantation; AML: acute myeloid leukemia; CML: chronic myeloid leukemia; MM: multiple myeloma; patients were transplanted from fully matched HLA NHL: Non-Hodgkin’s lymphoma; HD - Hodgkin’s disease; ALL: acute class I and II family members, two patients were lymphoblastic leukemia; CP: chronic phase; PR: partial remission; transplanted from mismatched sibling donors (one GVHD: graft-versus-host disease; *:sub-classification not defined. from a haploidentical sibling and the other from a one-locus mismatched sibling). One patient received a marrow allograft from a fully matched unrelated Pre-transplant conditioning consisted of oral busul- donor (MUD); this graft was non-reactive in mixed fan 4 mg/kg/day in four divided daily doses. The lymphocyte culture, as shown in Table 2. decision about the exact amount of busulfan each | 1090 | haematologica/the hematology journal | 2005; 90(8) Conditioning for transplantation with busulfan alone Table 2. Characteristics of donors, donations and conditioning reg- transplant immunosuppression was administered. imen. Fourteen patients were reconstituted with mobilized peripheral blood stem cells and one with bone mar- UPN Sex Matching Origin of Dose
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