KEY WORDS Busulfan Fludarabine Thymoglobulin AML ALL Remission

Transcription

1 Biology of Blood and Marrow Transplantation 13: (2007) 2007 American Society for Blood and Marrow Transplantation /07/ $32.00/0 doi: /j.bbmt Allogeneic Transplantation for Adult Acute Leukemia in First and Second Remission with a Novel Regimen Incorporating Daily Intravenous Busulfan, Fludarabine, 400 CGY Total-Body Irradiation, and Thymoglobulin James A. Russell, 1,2 Mary Lynn Savoie, 1,2 Alexander Balogh, 1,2 A. Robert Turner, 3 Loree Larratt, 3 M. Ahsan Chaudhry, 1,2 Jan Storek, 1,2 Nizar J. Bahlis, 1,2 Christopher B. Brown, 1,2 Diana Quinlan, 1,2 Michelle Geddes, 1,2 Douglas A. Stewart 1,2 1 Alberta Blood and Bone Marrow Transplant Program and Departments of Oncology, Foothills Hospital, 2 Tom Baker Cancer Centre, Calgary; and 3 Cross Cancer Institute, Edmonton, Alberta, Canada Correspondence and reprint requests: James A. Russell, FRCP, Department of Medicine, Tom Baker Cancer Centre, th St. N.W., Calgary, Alberta, Canada T2N 4N2 ( jamesrus@cancerboard.ab.ca). Received January 16, 2007; accepted March 6, 2007 ABSTRACT A myeloablative conditioning regimen incorporating daily intravenous busulfan, fludarabine, and 400 cgy total-body irradiation was given before allogeneic stem cell transplantation (SCT) to 64 adults with acute leukemia in first and second remission. Graft-versus-host disease (GVHD) prophylaxis included methotrexate, cyclosporine A, and rabbit antithymocyte globulin (Thymoglobulin). For 31 matched related (MRD) and 33 alternate donor (AD) SCT the incidence of acute GVHD grade II-IV was 11% 6% versus 35% 9% (P.047), acute GVHD grade III-IV was 0% versus 10% 6% (P.09), and chronic GVHD was 40% 9% versus 66% 9% (P NS), respectively. Overall transplant-related mortality (TRM) was 3% 2%. Projected disease-free (DFS) and overall survival (OS) at 3 years for acute myelogenous leukemia (AML) (n 36) are the same at 83% 6%, and for acute lymphoblastic leukemia (ALL) (n 28) are 65% 10% and 78% 8%, respectively. For MRD SCT DFS is 77% 9%, OS 87% 6%, for AD SCT the respective figures are 71% 8% and 74% 8%. OS and DFS in patients without and with high-risk features are 100% versus 71% 7% (P.007) and 88% 8% versus 68% 7% (P.04), respectively. This combination appears relatively well tolerated, gives equivalent final outcomes from MRD and AD, and may be a reasonable alternative to conventional myeloablative regimens American Society for Blood and Marrow Transplantation KEY WORDS Busulfan Fludarabine Thymoglobulin AML ALL Remission INTRODUCTION Allogeneic hematopoietic stem cell transplantation (HSCT) after myeloablative conditioning is commonly used to treat acute myelogenous leukemia (AML) and acute lymphoblastic leukemia (ALL). Results are significantly better when patients are in complete remission (CR), but there remains some controversy regarding which patients should be treated in first remission (CR1) [1-3]. The high transplant-related mortality (TRM) associated with myeloablative SCT limits the advantage conferred by lower relapse rates than alternatives such as autologous transplantation and chemotherapy. Moreover, the long-term morbidity, particularly that from chronic graft-versushost disease (cgvhd), makes SCT less attractive if there is no survival benefit [4]. The challenge therefore is to develop myeloablative regimens that give effective cytoreduction but with low TRM. The additional antileukemic effect of the graft (graft-versus-leukemia, GVL) should be maintained while controlling morbidity and mortality from GVHD. 814

2 SCT for Acute Leukemia in CR1 and CR2 815 Thus far, no regimens have proved superior to those incorporating total-body irradiation (TBI) in both AML and ALL. However, the TBI doses used (commonly 1200 cgy or more in 6-8 fractions) have significant long-term toxicities, particularly in children [5,6]. The widely used combination of busulfan (Bu) and cyclophosphamide (Cy) is effective in AML but less so in ALL [7-19]. Intravenous Bu is better tolerated than the oral form [20-22], but has not been fully evaluated in comparison with TBI containing regimens in acute leukemia. However, preliminary experience with an intravenous Bu and fludarabine (Flu) combination has shown impressive results in AML and myelodysplasia (MDS) [23]. The addition of 400 cgy TBI to a Flu/Bu combination with antithymocyte globulin (ATG) appears to reduce relapse rate in AML without increasing toxicity [24]. In AML, it was first used in patients with extramedullary disease and then applied to all patients after more experience with the combination. We have used this regimen in ALL throughout because of the reluctance to drop TBI entirely and a desire to avoid the toxicity of full-dose TBI. We now report the results of this combination in AML and ALL in CR1 and CR2. PATIENTS AND METHODS This report includes patients with both ALL and AML transplanted between June 1999 and June Outcomes are similar in these diseases with this regimen and a combined analysis allows a more accurate evaluation of TRM. Patients in CR1 and CR2 receiving SCT from matched related donors (MRD) and alternate donors (unrelated and mismatched related donors, AD) are included as outcomes and are similar with both donor types and disease stages. Details of the 64 patients are shown in Table 1. Patients were considered to be in CR if there were 5% blasts in the bone marrow regardless of other criteria including cytopenias and evidence of residual leukemia on karyotypic analysis or flow cytometry. Institutional inclusion criteria for allogeneic SCT included left ventricular ejection fraction 45%, pulmonary function (DLCO, FEV1, and FVC) 45% predicted, creatinine 150 mol/l, bilirubin, and ALT 3 times normal and ECOG performance status 0-2. All patients and donors had high-resolution typing for DR and DQ. Class I typing for A, B, and C was done until 2001 at medium resolution, thereafter at high resolution. Four patients (1 AML, 3 ALL) may therefore have had mismatched unrelated SCT recorded as fully matched. Table 1. Patient and transplant details AML % ALL % Number 36 28* Patient age, years median (range) 46 (20-60) 31 (18-63) CR Cytogenetic risk group NA Presenting white blood cell count greater than /L Pretransplant platelet count less than /L Minimal residual disease on flow cytometry &/or cytogenetics Secondary leukemia Associated myelodysplasia High-risk features Cytomegalovirus antibody positive recipient or donor Male Female-male transplant Alternate donor mismatched related matched unrelated mismatched unrelated Blood cell transplant TBI day Days from CR to transplant median (range) 62 (9-196) 69 (7-203) Follow-up of survivors, months median (range) 26 (12-66) 48 (12-73) Includes two with lymphoblastic lymphoma (one T cell) and another with T-ALL. *AML-low t(8:21), inv 16, t(15:17), high-complex karyotype, abnormalities of 5&7. ALL-high - t(9:22), t(4:11), 11q23 rearrangement. % of total. % of successful analyses. One or more of CR2, associated MDS, high risk cytogenetics. One or more of: CR2, presenting WBC /L, high risk cytogenetics, minimal residual disease, prolonged induction ( 3 mo). Blood cells were used for all related donor SCT. For unrelated donor (UD) transplants cell source was sometimes determined by availability. Later in the study a preference was expressed for blood cells as they became more available, and it seemed that cell doses requested were more likely to be provided than with bone marrow. Target doses for blood cells were CD34 cells/kg and for bone marrow nucleated cells/kg. The preparative regimen comprised Flu 50 mg/m 2 on days 6 to 2, intravenous Bu (Busulfex, PDL

3 816 J. A. Russell et al. Pharma, Fremont, CA) 3.2 mg/kg daily days 5to 2 inclusive and TBI 200 cgy 2 on days 1 or0.the day of TBI was determined by the capacity of the radiation therapy department and other constraints of the protocol, particularly the time at which stem cells became available. Supportive care was similar for all patients. No protective isolation was used [25]. Single donor platelets were given to maintain counts /L and red cells to keep hemoglobin levels 80 g/l. Growth factors were not given routinely. All patients received twice weekly trimethoprim/sulfamethoxazole as prophylaxis for P. carinii. Antibacterial prophylaxis was ciprofloxacin 500 mg twice daily until 2003 after which time no antibacterial antibiotics were given routinely. Blood products were all from cytomegalovirus (CMV) seronegative donors. A policy of surveillance for pp65 antigen and preemptive therapy with ganciclovir was used when donor and/or recipient were CMV antibody positive. Routine monitoring of Epstein-Barr virus (EBV) viral load was not done. The acute GVHD (agvhd) prophylaxis protocol included Cyclosporin A (CSA) orally or intravenously twice daily to maintain blood levels between 150 and 400 mol/l. Methotrexate (MTX) was given at 15 mg/m 2 intravenously on days 1 and 10 mg/m 2 on days 3, 6, and 11. Folinic acid 5 mg intravenously or orally was started 24 hours after each MTX dose and continued every 6 hours until 12 hours before the next dose [26]. In addition, all patients were given rabbit ATG (Thymoglobulin, Genzyme, Cambridge, MA) 4.5 mg/kg intravenously in divided doses over 3 days. Each dose was given as a continuous infusion over 4-8 hours. To reduce reactions, the first dose was reduced to 0.5 mg/kg, the next 2 doses were 2 mg/kg, and the final infusion was given on the day of transplant. Premedication included methylprednisolone 40 mg intravenously every 12 hours for 6 doses and benadryl 50 mg intravenously before each dose of ATG. If no agvhd occurred CSA was tapered over 4-8 weeks with the intent to discontinue by 2 to 4 months. Engraftment Daily blood counts were done until discharge with bone marrow aspirations at 3 months for surviving patients and thereafter as clinically indicated. Granulocyte engraftment was defined as a count of /L. The platelet count needed to be above /L without transfusion for 3 days. GVHD Acute GVHD was graded according to standard criteria [27]. Grading was performed by physicians at onset and during treatment, with later confirmation and recording by data managers. Acute GVHD was treated with prednisone or methylprednisolone initially while continuing CSA. cgvhd was treated with prednisone with or without CSA with introduction of other agents if response was incomplete. Statistical Analysis The distributions of time to events were plotted on Kaplan-Meier curves and compared using the log rank test with patients being censored for relapse for estimation of nonrelapse mortality (NRH). For time to onset of cgvhd patients were censored at the time of death, donor lymphocyte infusion (DLI), or second transplant. Analysis was performed on a Macintosh computer using GraphPad Prism software (GraphPad Corp., San Diego, CA). Values for P of are referred to as trends, and below.05 as significant. RESULTS Engraftment All patients engrafted. Granulocytes recovered faster after BCT than bone marrow transplant (BMT) at a median of 15 days (range: 10-46) versus 20 days (range: 13-31), respectively (P.02). Platelets engrafted in a median of 15 days (range: 0-34) after BCT compared with 25 days (range: 20-40) after BMT (P.0007). GVHD The actuarial incidence of agvhd grades II-IV was 11% 6%, after MRD SCT compared with 35% 9% after those from AD (P.047; Figure 1a). The figures for grade III-IV disease were 0% and 10% 6%, respectively (P.09; Figure 1b). Incidence of cgvhd at 2 years was 40% 9% with MRD versus 66% 9% with AD (P NS; Figure 1c). Stem cell source from unrelated donors had no influence on GVHD (data not shown). At the time of analysis 2 of 32 patients developing cgvhd after their first SCT remained on systemic therapy. Transplant-related mortality (TRM) One MRD and 1 AD SCT recipient died without relapse. One was in CR2 of ALL and died at 76 days of posttransplant lymphoproliferative disease (PTLD). The second, with ALL in CR1, died 5 months after SCT from pneumonitis. TRM was 3% 2% for the combined group (Figure 2a). There were no transplant-related deaths in the 17 patients 50 years old. Relapse Relapse rate at 4 years was 29% 10% for ALL patients and 17% 6% for those with AML (Figure

4 SCT for Acute Leukemia in CR1 and CR2 817 Figure 1. Kaplan-Meier plots of GVHD. a, agvhd grades II-IV; b, agvhd grades III-IV; c, cgvhd according to donor. 2b). Three of 7 relapsing ALL patients survive having achieved another remission after a second BCT, 2 from the same donor, after conditioning with etoposide 60 mg/kg and 800 cgy TBI. All 3 have had significant morbidity from cgvhd but have had a longer remission after the second SCT than after the first. Transient responses were achieved in 1 ALL patient with DLI and in 1 with DLI and imatinib mesylate. Of 6 relapsing AML patients 1 had radiation therapy for a chloroma and 1 had chemotherapy but all died with leukemia. Disease-Free and Overall Survival Projected disease-free survival (DFS) and overall survival (OS) at 3 years for AML is the same at 83% 6%, and for ALL is 65% 10% and 78% 8%, respectively (Figure 3a and 4a). For MRD SCT DFS is 77% 9%, OS 87% 6%, for AD SCT the respective figures are 71% 8% and 74% 8% (Figure 3b and 4b). OS and DFS in patients without and with high-risk features is 100% versus 71% 7% (P.007) and 88% 8% versus 68% 7% (P.04), respectively (Figures 3c and 4c). Figure 2. Kaplan-Meier plots of a, relapse and b, transplant-related mortality according to disease. DISCUSSION Myeloablative regimens including TBI have never been entirely superceded in SCT for acute leukemia. Combinations of drugs alone, particularly BuCy, were developed in the hope that they could be employed by centers without TBI facilities and might avoid some of the long-term complications of TBI. Comparisons of BuCy2 (with Cy 120 mg/kg) and CyTBI show remarkably similar outcomes in AML, whereas survival is better after CyTBI in ALL [7-14,16-19]. Combinations of etoposide and TBI may be at least as effective as the above regimens in both ALL and AML [28-30]. Some single-center reports of combinations of 3 agents for acute leukemia transplants have been encouraging [31,32]. In general, however, attempts to

5 818 J. A. Russell et al. Figure 3. Kaplan-Meier plots of disease-free survival by a, disease, b, donor, and c, high-risk features. reduce relapse by increasing TBI dose or adding other agents to standard regimens have largely been unsuccessful because of increased toxicity [33-36]. Many nonmyeloablative or reduced intensity regimens have been designed to minimize the morbidity and mortality of allogeneic SCT and take advantage of the GVL effect, particularly in older patients or those with comorbidities [39,40]. Despite some success in reducing TRM, so far the role of these regimens in ALL and AML has not been established. Our data give no indication that the FLUBUP/TBI regimen should be restricted to younger patients. Figure 4. Kaplan-Meier plots of overall survival by a, disease, b, donor, and c, high-risk features.

6 SCT for Acute Leukemia in CR1 and CR2 819 The comparisons referred to above of BuCy2 with CyTBI or VP16TBI were done with oral busulfan without pharmacokinetic monitoring to achieve optimal drug exposures. Intravenous Bu has not been fully tested in acute leukemia, but it is better tolerated and gives more predictable exposures than oral Bu [20-22,37]. The myeloablative combination of intravenous Bu with Flu was developed because Flu is an effective antileukemic agent and better tolerated than Cy [38]. It was thought that the substitution of Flu for Cy might allow greater cytoreduction from higher Bu exposures, but this does not seem to be the case [37]. Our previous studies with MRD SCT for AML in CR1 indicated that BCT produced better OS compared with BMT but that quality of life was significantly worse because of cgvhd [41]. Including ATG in the GVHD prophylaxis may have reduced morbidity and mortality from this cause at the expense of a trend to more relapse [42]. The attempt to compensate for this by adding 400 cgy TBI to the regimen appears to have had some success in AML, reducing relapse without an increase in TRM [24]. Outcomes are very similar to those reported by de Lima et al. [23] using a very similar Flu/Bu combination. Tacrolimus and MTX was used for GVHD prevention with horse ATG added for alternative donor SCT only. Possibly the less aggressive GVHD prophylaxis for MRD allowed a greater GVL effect than was our experience with FLUBUP alone [42]. The critical issue might ultimately be that of long-term quality of life offered by these alternative approaches. It would take a randomized study to clarify this issue further. The decision to investigate this regimen in ALL was based on the more predictable pharmacokinetics of intravenous compared with oral Bu and the ability of both Bu and Flu to penetrate the nervous system. We were, however, reluctant to drop TBI altogether for this disease. It is difficult to compare outcomes even for early acute leukemia with those in the literature because of the heterogeneity of patient populations with respect to prognostic factors. Outcomes of SCT may also be improving with time. Our study patients with highrisk features in addition to age have a survival of about 70% at 3 years. All patients lacking these features are alive, an indication that survival at least was not compromised by early transplant for these patients. This regimen may therefore give outcomes at least equivalent to those incorporating full dose TBI [1,3,7-9,11-13,15,29,30]. The higher TRM of allogeneic SCT with myeloablative protocols has limited any survival advantage it may have had over alternatives such as autologous transplants and chemotherapy alone [1-3]. Although some studies, usually from single centers, have reported TRM below 10% for early leukemia in adults, most multicenter and registry-based reports indicate figures in the 20%-30% range for MRD transplants [1,3,7-9,11-13,15,29,30]. In the current series only 2 patients died without relapse. One of these was from PTLD, occurring before rituxan was available. In over 300 SCT in the last 6 years we have seen only 1 further death from PTLD where ATG was only used prophylactically. We have some evidence that safety of this regimen could be improved further by monitoring Bu pharmacokinetics to avoid toxic exposures [37]. If survival is not demonstrably better with allotransplant than alternative treatments, this option should generally not be chosen because of the longterm morbidity of cgvhd [4]. It is difficult to compare reports of cgvhd, particularly with respect to quality of life. However, It does seem that the incidence of cgvhd and its complications are reduced when Thymoglobulin is added to the GVHD prophylaxis [42-44]. Although a substantial number of our patients still developed cgvhd after the first SCT, most are now off treatment. Many patients can be spared these effects and second transplants are feasible for some who relapse. Thus, 3 of our ALL patients relapsing beyond 2 years are in second remissions longer than the first ones but at the expense of morbidity from cgvhd. This is circumstantial evidence for a GVL effect in at least in some patients with ALL, for whom cgvhd may be the price to pay for longterm disease control. Allogeneic transplantation in CR1 is generally accepted as reasonable treatment for adults with highrisk ALL [3]. Likewise SCT for AML is often reserved for those with intermediate and high-risk karyotypes [1,2]. These recommendations are based on data indicating that TRM will be about 20%-30% for MRD SCT. There is more reluctance to use AD for CR1 patients because TRM has tended to be higher, although some reports indicate similar survival [45-49]. Conditioning that could achieve low TRM and equivalent results from AD and MRD might make allogeneic SCT in CR1 an option for more patients particularly if the detrimental effects of cgvhd can be minimized. Our policy is to offer SCT to all adults with acute leukemia in CR1 apart from those with AML with goodrisk karyotypes. Although some might benefit by delay of SCT until relapse, not all patients achieve a second remission, regardless of risk factors. It will be some time before the long-term morbidity of this regimen can be evaluated, especially with respect to second malignancies, but these are unlikely to be more frequent than after full-dose TBI. Currently this combination appears to offer a well-tolerated alternative to more conventional myeloablative regimens. If these results can be substantiated, the regimen could also be considered for children in whom the use of full dose TBI can have serious lifelong consequences.

7 820 J. A. Russell et al. ACKNOWLEDGMENTS We are grateful to the nursing staff at the Tom Baker Cancer Centre, Foothills Hospital, and Cross Cancer Institute for their care of these patients. REFERENCES 1. Burnett AK, Wheatley K, Goldstone AH, et al. The value of allogeneic bone marrow transplant in patients with acute myeloid leukaemia at differing risk of relapse: results of the UK MRC AML 10 trial. Br J Haematol. 2002;118: Burnett AK. Current controversies: which patients with acute myeloid leukaemia should receive a bone marrow transplantation? An adult treater s view [annotation]. Br J Haematol. 2002;118: Hahn T, Wall D, Camitta B, et al. The role of cytotoxic therapy with hematopoietic stem cell transplantation in the therapy of acute lymphoblastic leukemia in adults: an evidencebased review. Biol Blood Marrow Transplant. 2006;12: Watson M, Buck G, Wheatley K, et al. 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