Allogeneic Bone Marrow Transplantation as Therapy for Primary Induction Failure for Patients With Acute Leukemia By Stephen J. Forman, Gerhard M. Schmidt, Auayporn P. Nademonee, Michael D. Amylon, Nelson J. Chao, John L. Fahey, Patricia N. Konrad, Kim A. Margolin, Joyce C. Niland, Margaret R. O'Donnell, Pablo M. Parker, Eileen P. Smith, David S. Snyder, George Somlo, Anthony S. Stein, and Karl G. Blume The survival of patients with acute leukemia who do not achieve a remission with primary therapy is very poor. High-dose chemoradiotherapy followed by allogeneic bone marrow transplantation (BMT) has been shown to be effective therapy for patients with acute and chronic leukemia. Therefore, we determined the long-term disease-free survival of patients who did not achieve a remission and were then treated with highdose therapy and bone marrow allografting from matched sibling donors. Twenty-one patients (median age, 28 years) who did not achieve a remission with induction chemotherapy were subsequently treated with allogeneic BMT. After BMT, 90% achieved a

complete remission. Six died of complications of the therapy, and six patients relapsed between 27 and 448 days after BMT. Nine patients (43%; median age, 25 years) are alive between 556 and 4,174 days after BMT. The cumulative probability of disease-free survival at 10 years is 43%. This study suggests that allogeneic BMT can be an effective therapy to achieve long-term control of acute leukemia, even in those patients who do not achieve a remission with primary therapy. J Clin Oncol 9:1570-1574. © 1991 by American Society of Clinical Oncology.

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in different stages of the disease, relapse becomes the major difference in outcome. Over the last two decades there has been a steady improvement in the rate of remission for patients newly diagnosed with acute leukemia. Chemotherapy induction programs for both ALL and AML have resulted in remissions for 65% to 90% of patients.9'" Despite this progress, there are still patients who do not achieve a complete remission even with aggressive induction therapy. These patients represent a therapeutic dilemma; the long-term survival of such patients is obviously

LLOGENEIC BONE marrow transplantation (BMT) is an effective therapy for the treatment of patients with a variety of hematologic neoplastic disorders.' Many studies have suggested that the chances for long-term control and cure of the disease are best when patients undergo marrow transplantation early in the course of their disease. 2' 3 Thus, the results of BMT for acute

lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), and chronic myelogenous leukemia (CML) have been best when patients were treated during first complete remission or in chronic phase.48 Since complications due to BMT do not differ between patient groups transplanted

From the Departments of Hematology and Bone Marrow Transplantation and Biostatistics, City of Hope National Medical Center,Duarte; and The Bone Marrow Transplantation Program, Department of Medicine, Stanford University, Stanford, CA. Submitted April 3, 1991; acceptedApril 8, 1991. Supported by United States Public Health Service grants no. CA 30206, CA 33572, and CA 49605 from the National Cancer Institute,Departmentof Health and Human Services. Address reprint requests to Stephen J. Forman, MD, Director, Department of Hematology and Bone Marrow Transplantation, City of Hope NationalMedical Center, 1500 E Duarte Rd, Duarte, CA 91010. © 1991 by American Society of Clinical Oncology. 0732-183X/91/0909-0013$3.00/0

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quite limited. 12 In this report, we review our experience with 21 patients with acute leukemia who, with the exception of one patient, did not achieve a complete remission after more than one cycle of induction chemotherapy. Transplantation was undertaken in these patients to determine whether long-term control of disease could be accomplished in this clinical circumstance. PATIENTS AND METHODS Between 1976 and 1989, 585 patients were treated with high-dose chemoradiotherapy or high-dose chemotherapy and allogeneic BMT from matched siblings at the City of Hope National Medical Center and at Stanford University. Twenty-one of these patients with acute leukemia underwent BMT because they did not achieve remission after initial primary therapy, usually after more than one attempt

Journal of Clinical Oncology, Vol 9, No 9 (September), 1991: pp 1570-1574

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BMT THERAPY FOR INDUCTION FAILURE FOR LEUKEMIA at remission (Table 1). The median age of the patients at BMT was 28 years (range, 2 to 41 years). The patients' diagnoses, remission induction treatments, preparatory regimens used for BMT, and outcomes are listed in Table 1. Sixteen patients had acute nonlymphoblastic leukemia (ANLL), and five had ALL. WBC counts at the time of diagnosis ranged from 1,300/4LL to 100,000/iL (median, 12,500/gL). Seventeen patients had cytogenetics performed, and 11 were abnormal. The median time from diagnosis to BMT was 3 months. Nine patients had _ 25% blasts in the marrow at the time of BMT; 11 patients had greater than 25% blasts. All patients were prepared for BMT using either highdose chemoradiotherapy or high-dose chemotherapy on research protocols approved by the institutional review boards at the City of Hope National Medical Center and Stanford University. Graft-versus-host disease (GVHD) prophylaxis was accomplished with either methotrexate and prednisone or cyclosporin and prednisone for all patients based on institutional research protocols. Survival estimates were calculated using the product-limit method of Kaplan and Meier, and comparisons between subgroups were made by performing the log-rank test. The 95% confidence intervals for the cumulative probability of survival were calculated using the logit transformation and Greenwood's estimate of the variance.

RESULTS Of the 21 patients who underwent BMT, 20

received more than one course of induction. Only one patient, City of Hope unique patient number

(UPN) 466, had no response to the first course of chemotherapy and did not receive a second course. After receiving the preparatory regimen, the marrow of all 21 patients was cleared of leukemic blasts. Nineteen patients (90%) achieved a complete remission. Two died of septic complications, four died of complications related to GVHD and/or interstitial pneumonia, and six suffered a relapse 27 to 448 days after BMT. Nine patients (43%) are alive and well between 556 and 4,174 days after BMT (median, 2,606 days). Of 11 patients with cytogenetic abnormalities, three relapsed, and two of six patients without abnormalities relapsed (P > .80). Five of 10 patients who underwent BMT with marrow showing _ .64). Among patients under age 30 years at BMT, eight of 14 have become long-term survivors, whereas one of seven patients aged 30 years or older at BMT remain alive and well (P = .14). The median age of the survivors is 25 years. Eight of the nine surviving patients have a Karnofsky

performance status of 100, while one has a score of 80 due to chronic GVHD. Figure 1 shows the product-limit estimate of the cumulative disease-free survival after BMT for the group of patients as a whole and the follow-up times of the censored observations for patients in continuous complete remission. The median disease-free survival is 333 days for the group and 2,606 days for the surviving patients. The cumulative probability of survival at 10 years after BMT is 43% (95% confidence interval, 24% to 64%). DISCUSSION Advances in the treatment of acute leukemia using both BMT and conventional chemotherapy have resulted in an increased proportion of patients becoming long-term disease-free survivors. Although relapse is still a problem for many patients with acute leukemia, current chemotherapy regimens are very effective in obtaining initial control of the disease and achieving complete remission. Those patients who do not achieve a complete remission usually die of their disease within the first year after diagnosis. The increase in intensity of the induction regimens may further select for resistant disease and, thus, lower the likelihood of achieving complete remission with second-line therapy. Remissions, if they are achieved in such patients, are usually of short duration.' 2 The use of BMT in patients whose initial induction chemotherapy fails is designed to achieve both a complete remission and cure.13 The data in this report suggest that such patients may become long-term, disease-free survivors when treated with high-dose chemoradiotherapy and allogeneic BMT. In this study in which all patients were initially refractory to conventional chemotherapy, 19 achieved a complete remission, and nine have become long-term survivors. Although some patients had either very high WBC counts at presentation, cytogenetic abnormalities, or numerous blasts in the marrows, long-term disease-free survival was achieved in some of these patients. A larger number of patients is required to determine whether these are prognostic features among patients whose primary induction therapy fails and who then go on to treatment with BMT. These observations suggest that histocompatibility testing of the patient should be performed at the time of diagnosis. This information would be

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FORMAN ET AL

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Allogeneic bone marrow transplantation as therapy for primary induction failure for patients with acute leukemia.

The survival of patients with acute leukemia who do not achieve a remission with primary therapy is very poor. High-dose chemoradiotherapy followed by...
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