Elsevier

Leukemia Research

Volume 26, Issue 5, May 2002, Pages 461-471
Leukemia Research

Long-term follow-up of intensive ara-C-based chemotherapy followed by bone marrow transplantation for adult acute lymphoblastic leukemia: impact of induction Ara-C dose and post-remission therapy

https://doi.org/10.1016/S0145-2126(01)00175-8Get rights and content

Abstract

We report single institution outcome of brief, intensive ara-C-based chemotherapy using bone marrow transplantation as primary intensification for untreated adult patients with acute lymphoblastic leukemia (ALL). Overall disease-free and overall survival were inferior to those reported with prolonged chemotherapy modeled on pediatric protocols. Survival and disease-free survival were superior for patients receiving allogeneic BMT compared with chemopurged autologous transplant or maintenance chemotherapy (patients ineligible for or declining BMT). In multivariate analysis, non-L2-FAB, higher ara-C dose, absence of CNS disease, non-Ph1+ karyotype, allogeneic BMT, T cell phenotype, and younger age were associated with improved disease-free survival. Autologous BMT was not superior to chemotherapy, and appears unlikely to provide adequate curative treatment for most adult ALL patients if not followed by maintenance.

Introduction

Significant improvement in the management of children with acute lymphoblastic leukemia (ALL) has been achieved in the last 30 years as a result of more effective anti-leukemic combination chemotherapy, CNS prophylaxis and the earlier use of intensive chemotherapy. Rates of complete remission (CR) ranging from 90 to 95% and long-term disease-free survival approximating 70% are striking features of the successful management achieved in childhood ALL [1]. In sharp contrast, CR rates in adults with ALL range from 65 to 85%, the time to remission is longer, the relapse rate is higher, and cure rates are reported from 20 to 40% [2], [3]. Factors related to both the biology of leukemic cells and ability of host to tolerate treatment may contribute to the inferior prognosis in adults as compared with childhood ALL [2].

A variety of approaches have been used to try to overcome the problem of relapse in adult ALL. Intensive therapy with multiple chemotherapeutic drugs given early in the course of treatment for this initially sensitive, but rapidly resistant tumor has become a standard of care in modern ALL therapy, significantly improving the outcome in patients with ALL [4], [5], [6], [7], [8]. High dose chemotherapy followed by bone marrow transplant (BMT) may allow greater intensification of complete remission. However, the optimal indications for and timing of BMT in adult ALL remain unclear [2], [3]. While the benefit of allogeneic BMT in first remission in Ph1+ patients has been established [9], [10], [11], [12], significant controversy exists regarding the indications for BMT in adults with standard risk ALL.

In patients with acute myeloid leukemia (AML), we have previously shown that timed-sequential chemotherapy (TST) using two intensively timed cycles of ara-C and daunorubicin resulted in prolonged disease-free survival (DFS) [13]. On the basis of these clinical results as well as laboratory data demonstrating an increased cure rate in animals treated with maximal drug doses in timed sequence [14], [15], [16], we initiated two sequential Phase II protocols to assess whether intensive induction utilizing high dose infusional Ara-C in timed sequence followed by myeloablative therapy would improve long-term DFS of adult ALL. A preliminary analysis of the remission rates has been published [17]. The current manuscript provides long-term follow-up of the results of this therapeutic approach.

Section snippets

Patients and methods

Eighty-five consecutive unselected untreated patients with ALL age 17 or older were treated at The Johns Hopkins Oncology Center between the years 1983 and 1993. Diagnosis was confirmed by morphologic studies of bone marrow aspiration and biopsy according to the French–American–British (FAB) criteria. The diagnosis of L3 ALL was made on morphological basis alone; staining for surface immunoglobulin was not performed routinely. Cytochemical stains were performed according to standard techniques.

Patient characteristics

All adult ALL patients treated during the study period entered the study active at the time. The clinical characteristics of the 85 treated patients are detailed in Table 3. Patients in both studies were similar in age, FAB classification, WBC count, immunophenotype and unfavorable karyotype. Median age was 33 and median WBC was 22,000 μl−1. Only 8% were FAB-L1. 19% of those patients successfully karyotyped were Philadelphia chromosome positive; an additional 29% had assorted cytogenetic

Discussion and conclusion

In the early 1980s, long-term outcomes of adult ALL were vastly inferior to those achieved with pediatric ALL. While children with ALL continue to be cured with far greater frequency than adults, the initiation in the 1980s of clinical trials in adult ALL modeled on pediatric regimens have led to disease-free outcomes in 40% of B-lineage and 60% of T-lineage adult ALL patients [31], [8], [7]. These protocols include multi-drug induction, several modules of intensive consolidation, and prolonged

Acknowledgements

The authors gratefully acknowledge the superior service of the many nurses, house staff, physician assistants, bone marrow transplantation coordinators, and technologists in the bone marrow processing laboratory at The Johns Hopkins Oncology Center whose dedication enabled the superior care of the patients in this study. The authors thank Ms. Shirley Taylor and Loraine Keck for administrative support in preparation of this manuscript. E. M. Sotomayor collected and analyzed the data, drafted the

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