Radiation-Free Preparation for Allogeneic Bone Marrow Transplantation in Adults With Acute Lymphoblastic Leukemia

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1 Radiation-Free Preparation for Allogeneic Bone Marrow Transplantation in Adults With Acute Lymphoblastic Leukemia By Edward A. Copelan, James C. Biggs, Belinda R. Avalos, Jeffrey Szer, Isabel Cunningham, John P. Klein, Kerry Atkinson, Neena Kapoor, Jared L. Klein, Kate Downs, and Peter J. Tutschka Purpose: The study was undertaken to investigate the effectiveness of allogeneic bone marrow transplantation from HLA-identical siblings after preparation with busulfan and cyclophosphamide in adults with acute lymphoblastic leukemia (ALL). Patients and Methods: Thirty-nine patients aged 15 to 42 years underwent transplantation at three different centers from November 1984 through November All patients received 16 mg/kg busulfan and 120 mg/kg cyclophosphamide as preparative therapy. Cyclosporine plus methotrexate or cyclosporine plus corticosteroids with or without methotrexate were given for prevention of graft-versus-host disease (GVHD). Results: Twelve patients died of treatment-related complications, 12 patients relapsed, and 15 patients are leukemia-free survivors. For 27 patients in group 1 (first CHEMOTHERAPY trials indicate that as many as 35% of unselected adult patients with acute lymphoblastic leukemia (ALL) survive free of leukemia 5 years after diagnosis.'3 However, adults who relapse after first remission rarely achieve sustained leukemiafree survival (LFS). For patients who relapse, allogeneic bone marrow transplantation (BMT) after high-dose chemotherapy and total-body irradiation (TBI) increases the proportion of individuals with sustained LFS. 4 ' 5 In addition, many investigators have used highrisk prognostic factors to identify patients who are unlikely to achieve sustained LFS with chemotherapy and who might benefit from allogeneic BMT in first complete remission (CR). Still, the majority of adults who undergo BMT for ALL die as a result of leukemic relapse or treatment-associated complications. The development of more effective and/or less toxic preparative regimens could improve the results of allogeneic BMT in ALL. A radiation-free preparative regimen of busulfan 16 mg/kg and cyclophosphamide 120 mg/kg has proven sufficiently immunosuppressive to permit engraftment of HLA-identical marrow grafts, is associated with rates of treatment-related death similar to those after treatment with cyclophosphamide/tbi, and is effective in the treatment of acute myelogenous leukemia (AML) 6 and chronic myelogenous leukemia (CML). 7 The present study provides results in 39 patients aged 15 years or older with ALL who underwent remission, second remission, first relapse), the estimated leukemia-free survival (LFS) rate is 42.3% (95% confidence interval [CI], 22.9% to 71.7%) at 3 years. For 12 patients with more advanced disease (group 2), the 1-year LFS rate is 13.5% (95% CI, 0% to 37.1%). Chronic GVHD occurred at an estimated incidence of 63.3% and developed significantly more frequently among patients who received corticosteroids for prevention of acute GVHD. Chronic GVHD was associated with a significantly lower incidence of relapse and with improved LFS rates. Conclusion: LFS rate in this study is comparable to that obtained with radiation-containing regimens; however, the effectiveness of this preparative regimen in ALL requires further study. J Clin Oncol 10: C 1992 by American Society of Clinical Oncology. allogeneic marrow transplantation at three different institutions after receiving this preparative regimen. Patient Characteristics PATIENTS AND METHODS The study group consisted of 39 patients with ALL aged 15 to 42 years (median, 23 years) who were treated from November 1, 1984, through November 15, Twenty-one patients underwent BMT at The Ohio State University (OSU) Hospital in Columbus, OH; 10 at St Vincent's Hospital (SVH) in Sydney, Australia; and eight at Alfred Hospital (AH) in Melbourne, Australia. Twenty-seven patients were categorized as group 1, which included nine patients in first remission, six in second remission, and 12 in untreated first relapse. Eight of the nine patients transplanted in first remission had one or more of these poor prognostic signs: age over 35 years, initial WBC count greater than 30 x 10 9 /L, delayed attainment of first CR (> 6 weeks), or the Ph chromosome. Transplantation in first relapse was performed at the discretion of the individual transplantation center. None of the patients who underwent From the Departments of Internal Medicine and Statistics, The Ohio State University, Columbus, OH; the Department of Haematology, St Vincent's Hospital, Sydney; and the Bone Marrow Transplant Unit, Alfred Hospital, Melbourne, Australia. Submitted July 8, 1991; accepted August 30, Supported by Public Health Service grant no. 2 P30 CA A1 awarded by the National Cancer Institute, Department of Health and Human Services. Address reprint request to Edward A. Copelan, MD, The Ohio State University, 410 W 10th Ave, 303 E Doan Hall, Columbus, OH by American Society of Clinical Oncology X/92/ $3.00/0 Journal of Clinical Oncology, Vol 10, No 2 (February), 1992: pp

2 238 transplantation at the time of first relapse had extramedullary sites of relapse identified. Only four of these 12 patients had more than 30% blasts in the marrow at the time of transplantation. Twelve patients, four with primary refractory disease, six with second or subsequent relapse, one in third and one in fourth remission were categorized as group 2. Informed consent was obtained for each patient as required by the institutional review boards of the participating centers. Table 1 describes the clinical characteristics of the patients. All donors were siblings who were HLA-A, -B, and -DR identical to the recipient as determined by standard serotyping. Cells from donor-recipient pairs were mutually nonreactive in mixed lymphocyte cultures. Preliminary information on some patients has been published. 8 ' Preparation for Transplantation All patients received prophylactic intrathecal therapy with methotrexate (< 12 mg) before the administration of busulfan. Two patients with active CNS disease underwent a series of intrathecal treatments (combined with radiation in one) before busulfan administration. A total dose of 16 mg/kg of busulfan was administered orally over 4 days in four divided daily doses. Cyclophosphamide 60 mg/kg was administered intravenously on each of the next 2 days. Marrow was infused approximately 48 hours after the second dose of cyclophosphamide. Graft- Versus-Host Disease Prophylaxis and Treatment For graft-versus-host disease (GVHD) prophylaxis, 15 patients at SVH or AH received methotrexate and cyclosporine; three received methotrexate, cyclosporine, and methylprednisolone. Twenty-one patients at OSU received cyclosporine plus methylprednisolone.' In this regimen, cyclosporine was administered intravenously beginning the day before marrow infusion at a daily dose of 5 mg/kg, was decreased to 3 mg/kg on the fourth posttransplant day, and was increased to 3.75 mg/kg on the 15th day after BMT. Administration was switched to the oral route, and the dose was tapered until day 180, when it was stopped. Methylprednisolone was begun on day 7 at a daily dose of.5 mg/kg/d, was increased on day 15 to 1 mg/kg/d and was tapered over 3 months (before 1988) or over 6 months. Acute GVHD was graded according to the criteria reported by Glucksberg et al." Chronic GVHD was diagnosed according to the criteria reported by Shulman et al.' 2 Primary treatment of documented acute GVHD was with corticosteroids. Patients who were receiving corticosteroids as part of their GVHD prophylactic regimen generally received substantially higher doses of corticosteroids when they developed acute GVHD. Chronic GVHD was treated with corticosteroids with or without azathioprine or cyclosporine. Statistical Methods COPELAN ET AL Analysis was performed on all data obtained as of March 1, Time on-study was defined as the shorter of the times from transplantation to relapse, death, or most recent follow-up. Estimates of the LFS and relapse rates were obtained using the Kaplan-Meier estimator." To estimate the effects of potential risk factors, a series of univariate Cox analyses4--each corrected for potential differences between the risk groups-were performed. Factors considered were sex, age, WBC count at presentation, presence of cytogenetic abnormalities (Ph chromosome, t(4;11), t(8;14)), history of extramedullary disease, time from diagnosis to CR, duration of first CR, and GVHD prevention regimen (with or without corticosteroids). Time to chronic GVHD and time to acute GVHD were treated as time-dependent covariates. Those risk factors found to be significant were included in a stepwise Cox regression analysis to judge their relative importance in predicting either relapse or LFS. These analyses were performed in lieu of a multivariate analysis due to the relatively small sample sizes. Engraftment RESULTS Marrow engraftment occurred in 38 of the 39 patients. One patient died on the day after BMT and was not assessable. The median duration of neutropenia (< 500 x 10 9 /L neutrophils) was 11 days (range, 7 to 41 days). A self-sustaining platelet count > 40,000 x 10 9 /L was achieved at a median of 22 days (range, 9 to 100 days) after BMT. Engraftment of neutrophils (P =.03) and platelets (P =.001) occurred more rapidly in patients who did not receive methotrexate as part of their graft-versus-host disease prophylaxis. GVHD The Kaplan-Meier estimate of the incidence of > grade 2 acute GVHD was 24.1% (95% confidence interval [CI], 10.1% to 38.1%) and of extensive chronic GVHD, 63.3% (95% CI, 44.7% to 81.9%). Chronic GVHD did not remain limited in any patients. The development of > grade 2 or > grade 3 acute GVHD was not different (P >.2) when analyzed according to prophylactic regimens. However, patients who received Table 1. Clinical Characteristics of 39 Adult Patients With ALL Undergoing BMT Median WBC Median Median Cytogenetic Count at Median Time Duration of No. of Age, Years Male/ Abnormalities: Diagnosis, to CR, Days Initial CR, Extramedullary Patients (range) Female Ph+ /t(4;11 )/t(8;14) x 109/L (range) (range) Months (range) Disease (CNS) Group /10 2/2/ (3) (15-40) ( ) (28-150) (1-73) Group /2 4/0/ (4) (15-42) ( ) (20-70) (2-24) Total /12 6/2/ (7) (15-42) ( ) (1-73)

3 ALLOGENEIC MARROW TRANSPLANTATION IN ALL 239 corticosteroids to prevent acute GVHD were more likely to develop chronic GVHD (P =.04). Transplant-Related Complications Seven of 27 patients (26%) in group 1 and five of 12 (42%) in group 2 died of treatment-related complications. Hepatic venoocclusive disease (VOD) was identified in nine patients; in three, it was a contributing cause of death. Four patients developed cytomegalovirus interstitial pneumonia; two died of it. Table 2 lists the causes of death by phase of disease at the time of BMT. Relapse Eight of 27 patients (30%) in group 1 relapsed; the projected relapse rate was 40.1% (95% CI, 18.7% to 61.5%; Fig 1). Four of 12 (33%) patients in group 2 relapsed. For group 2, the estimated relapse rate was 56.9% (95% CI, 14.7% to 99.1%). All relapses occurred within 2 years of transplantation. Only one of these patients survives. Relapse occurred in five of 24 patients (21%) who received corticosteroids for prevention of GVHD and in seven of 15 (47%) who did not receive corticosteroids. Univariate analysis revealed that those who received corticosteroids as part of their GVHD prophylaxis were less likely to relapse than patients who did not receive corticosteroids (P =.02). Among patients who survived more than 100 days after BMT and did not develop chronic GVHD, eight of 15 (53%) relapsed. Four of 22 patients (18%) who developed chronic GVHD relapsed. The development of chronic GVHD was associated with a markedly reduced relapse rate (P =.008). Patients with a history of extramedullary disease were more likely to relapse after transplantation (P =.08). Disease phase (group 1 v group 2), presenting WBC count, the presence of cytogenetic abnormalities, time interval from diagnosis to remission, or duration of first remission did not predict for relapse (P >.2). A stepwise analysis found the development of chronic GVHD (P =.02) to be the most important factor influencing the time to relapse (relative risk [RR] of relapse before development of chronic GVHD compared with postdevelopment is 5.5), followed by the effect of the inclusion of corticosteroids in GVHD prophylaxis (P =.08; RR, 2.7). Table 2. Causes of Death No. of Interstitial Patients Pneumonia Relapse Infection Other Group Group LFS Twelve patients in group 1 are surviving free of leukemia with follow-up between 4 and 64 months (median, 36 months) following transplantation (Fig 2). The Kaplan-Meier estimate of 3-year LFS for these patients is 42.3% (95% CI, 22.9% to 71.7%). Four of nine patients who underwent BMT in first remission and three of six in second remission are leukemia-free survivors. Four of eight patients who underwent BMT in first relapse with < 30% blasts in the marrow and one of four with higher percentages of blasts are leukemia-free survivors at a median of 43 months (range, 4 to 64 months) after BMT. Three patients in group 2 are surviving free of leukemia 8, 12, and 38 months after BMT. The patient with 38 months follow-up was in third remission at the time of BMT. For patients in group 2, the estimated 1-year LFS is 13.5% (95% CI, 0% to 37.1%). Of five patients less than 18 years of age at the time of transplantation, only one survives free of leukemia. Two of these younger patients died of transplantrelated complications, and two died with relapsed disease. Two of six patients with Ph-positive metaphases before transplantation are surviving free of disease 8 months and 12 months, respectively, from the time of transplantation. The presence of chronic GVHD was associated with a significantly greater likelihood of LFS (P =.03) in univariate analysis. A history of CNS disease (P =.06) and short first remission (P =.07) were adversely associated with LFS. Acute GVHD, time interval from diagnosis to first CR, initial WBC count, the presence of cytogenetic abnormalities, and corticosteroids in the GVHD prevention regimen were not associated with LFS in a univariate analysis (P >.2). Stepwise analysis identified clinical group (P =.01; RR of group 2 v group 1, 3.2) and time to development of chronic GVHD (P =.04; RR, 3.0) as significant variables for LFS, whereas the inclusion of corticosteroids in the GVHD prophylaxis had no effect (P =.6). DISCUSSION The most commonly used preparative regimen for allogeneic BMT in ALL consists of cyclophosphamide and TBI. 4,5 Modifications in the preparative regimen have included adjustments of the total dose and method of administration of TBI, 15,1 6 as well as the use of a variety of chemotherapeutic agents before or after TBI. 17 " 18 The regimen described here substitutes a chemotherapeutic agent for TBI. Although the busulfancyclophosphamide regimen used in this study has proven effective in AML and CML, the modest effects of high

4 240 COPELAN ET AL W in 0- -J W C- 0 In a. 0o.o s MONTH Fig 1. Actuarial probability of relapse among patients undergoing BMT for ALL in first or second remission or first relapse (group 1; bottom curve) or with more advanced disease (group 2; top curve). Tick marks depict the duration of survival of patients who did not relapse. doses of busulfan on rodent and human lymphocytes'9' 20 has raised questions as to its effectiveness in lymphoid malignancies. Nevertheless, preliminary information in a variety of lymphoid malignancies has been promising.8, 21, 22 The present study provides results in 39 adults with ALL who underwent allogeneic BMT at three institutions. LFS is comparable to that reported for radiation-containing regimens. 4, 5 However, these results must be cautiously interpreted in view of the relatively small number of patients and limited follow-up. In addition, compared with other studies, 4, 5 these patients experienced a high incidence of chronic GVHD, which Fig 2. Actuarial probability of LFS among patients transplanted for ALL in first or second remission or first relapse (group 1; top curve) or with more advanced disease (group 2; bottom curve). The duration of survival for leukemia-free survivors is depicted by tick marks. 0 a 12 i MONTH

5 ALLOGENEIC MARROW TRANSPLANTATION IN ALL 241 was strongly associated with freedom from relapse and with sustained LFS. Individuals in the present study who received corticosteroids for prevention of GVHD developed chronic GVHD significantly more frequently than those who did not receive corticosteroids, supporting a recent observation by Storb et al. 23 The relationship between chronic GVHD and freedom from relapse might represent a graft-versus-leukemia effect plus an antileukemic effect of corticosteroids used in the prevention and/or treatment of GVHD. A large review of BMT in ALL from the International Bone Marrow Transplant Registry' found that the addition of corticosteroids to either methotrexate or cyclosporine was associated with a decreased incidence of relapse and improved LFS. Although patients who relapse after initial remission are generally induced into second remission before BMT, the merit of this strategy has not been adequately studied. Based on observations in AML by Appelbaum et al, patients in the present study underwent BMT in initial relapse. Four of the eight who had less than 30% blasts in their marrow at the time of transplantation are leukemia-free survivors, demonstrating that patients in early initial relapse can successfully undergo BMT without induction of remission. However, there are not sufficient data to compare the merit of this approach with induction of a second remission. Radiation-free preparative regimens might be partic- ularly useful in individuals who are not candidates for TBI (eg, because of previous radiation to the CNS or mediastinum).25 However, additional patient accrual and longer follow-up will be necessary before the effectiveness of busulfan-cyclophosphamide in ALL can be meaningfully evaluated. The proportion of patients who achieved sustained LFS in the present study was favorably influenced by the development of chronic GVHD, which occurred in high incidence, at least in part as a result of early posttransplant administration of corticosteroids in a majority of patients. Although ongoing studies of busulfan dose modification 2 6 based on plasma levels may result in a lower incidence of transplantrelated complications and may lower relapse rates, these potential benefits are speculative. The development of more effective preparative regimens, definition of proper timing of transplantation in individual patients, and determination of the usefulness of corticosteroids after transplantation are important areas for future clinical studies of BMT in ALL. ACKNOWLEDGMENT We thank the nursing staffs and house staffs of the participating transplant centers, all referring physicians, Judy Fisher and Brenda Berstler for their assistance in management of data, S.T. 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