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☆
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
References (45)
Therapy of the newly diagnosed adult with acute lymphoblastic leukemia
Hematol.-Oncol. Clin. N. Am.
(1993)- et al.
A five-drug remission induction regimen with intensive consolidation for adults with acute lymphoblastic leukemia: cancer and leukemia group B study 8811
Blood
(1995) - et al.
Treatment of adult acute lymphoblastic leukemia with intensive cyclical chemotherapy: a follow-up report
Blood
(1991) - et al.
Bone marrow transplantation for Philadelphia chromosome-positive acute lymphoblastic leukemia
Blood
(1992) - et al.
Allogeneic bone marrow transplantation for high-risk acute lymphoblastic leukemia during first complete remission
Blood
(1991) - et al.
Long-term follow-up of allogeneic bone marrow recipients for Philadelphia chromosome-positive acute lymphoblastic leukemia [Letter]
Blood
(1995) - et al.
Bone marrow transplantation for patients with Philadelphia chromosome-positive acute lymphoblastic leukemia
Blood
(1987) - et al.
A two step timed sequential treatment for acute myelocytic leukemia
Blood
(1989) - et al.
A rationale for sequential high-dose chemotherapy of leukemia timed to coincide with induced tumor proliferation
Blood
(1980) - et al.
Induction of serum stimulation and plasma cell proliferation during chemotherapy of multiple myeloma
Blood
(1977)
Allogeneic bone marrow transplantation after high-dose busulfan and cyclophosphamide in patients with acute nonlymphocytic leukemia
Blood
Bone marrow graft engineering by counterflow centrifugal elutriation: results of a phase I–II clinical trial
Blood
Syndrome of idiopathic hyperammonemia after high-dose chemotherapy: review of nine cases
Am. J. Med.
Prognostic factors in a multicenter study for treatment of acute lymphoblastic leukemia in adults
Blood
Timed-sequential induction therapy improves post-remission outcome in acute myeloid leukemia: a report from the Children’s Cancer Group
Blood
Consolidation treatment of adult acute lymphoblastic leukemia: a prospective, randomized trial comparing allogeneic versus autologous bone marrow transplantation and testing the impact of recombinant interleukin-2 after autologous bone marrow transplantation. BGMT Group
Blood
Treatment of acute lymphoblastic leukemia. 30 years’ experience at St. Jude Children’s Research Hospital
N. Engl. J. Med.
Management of adult acute lymphocytic leukemia: present issues and key challenges
J. Clin. Oncol.
Treatment of adult acute lymphoblastic leukemia
Seminars Oncol.
Treatment of acute lymphoblastic leukemia in adults with intensive induction, consolidation, and maintenance chemotherapy
Blood
Results of the vincristine, doxorubicin, and dexamethasone regimen in adults with standard- and high-risk acute lymphocytic leukemia
J. Clin. Oncol.
Development in a rat model of a cell kinetic approach to curative treatment of acute myelocytic leukemia using the cell cycle specific drug 1-D arabinofuranosyl cytosine
Cancer Res.
Cited by (10)
The role of cytotoxic therapy with hematopoietic stem cell transplantation in the therapy of acute lymphoblastic leukemia in adults: An evidence-based review
2006, Biology of Blood and Marrow TransplantationIntensive therapy before or during the conditioning regimen of allogeneic marrow transplantation in adult acute lymphoblastic leukemia patients: We must choose to reduce toxicity-A Groupe Ouest-Est d'Etude des Leucémies et Autres Maladies du Sang Study
2005, Biology of Blood and Marrow TransplantationBetter outcome of adult acute lymphoblastic leukemia after early genoidentical allogeneic bone marrow transplantation (BMT) than after late high-dose therapy and autologous BMT: A GOELAMS trial
2004, BloodCitation Excerpt :Translocation t(9;22) or BCR/ABL rearrangement decreased the CR rate (54%) as reported.6,17,21,29,30 The prognostic impact of T-lineage ALL31-33 could not be ascertained, as young patients who had T-ALL with WBC count less than 30 × 109/L were not included. In this multicentric study, alloBMT was highly successful, with a 6-year DFS rate of 75% for the 41 patients younger than 50 years with HLA-identical sibling donors.
Adult acute lymphoblastic leukaemia
2004, Critical Reviews in Oncology/HematologyCitation Excerpt :Where feasible, allogeneic (see Section 6.3.1) rather than autologous (see Section 6.3.2) BMT is suitable for individual clinical use on a type 2 level of evidence [233,256,397,409]. Autologous haematopoietic stem-cell support may be suitable for individual clinical use in patients with high-risk features lacking compatible donors [358,393,395,404,414–418], although its superiority over chemotherapy was never proven in comparative clinical trials [248,370,394,399,401,419]. Prolonged survival could be obtained in a small fraction of very high-risk patients with Ph+ ALL using a purged autograft with a double autotransplantation procedure [355,357].
Clinical effectiveness and cost-effectiveness of stem cell transplantation in the management of acute leukaemia : A systematic review
2010, Health Technology Assessment
- ☆
Supported in part by: CA 15396 and CA 06973. SDG is recipient of a Scholar Award in Clinical Research from The Leukemia Society of America. Presented in part at The American Society of Hematology Meeting in 1998.