Ann Hematol (2004) 83:225–231 DOI 10.1007/s00277-003-0808-9
ORIGINAL ARTICLE
T. Robak · A. Szmigielska-Kapłon · A. Wrzesien´-Kus´ · A. Wierzbowska · A. B. Skotnicki · B. Pia˛tkowska-Jakubas · K. Kuliczkowski · G. Mazur · A. Zdun´czyk · B. Stella-Hołowiecka · J. Hołowiecki · J. Dwilewicz-Trojaczek · K. Ma˛dry · A. Dmoszyn´ska · M. Cioch
Acute lymphoblastic leukemia in elderly: the Polish Adult Leukemia Group (PALG) experience Received: 25 June 2003 / Accepted: 2 October 2003 / Published online: 26 November 2003 Springer-Verlag 2003
Abstract This is a retrospective, multicenter study to evaluate biological features and outcome of elderly patients diagnosed with acute lymphoblastic leukemia (ALL) during the last 10 years in ten hematological centers in Poland. Eighty-seven patients aged 60 years or older were studied. To our knowledge, this is one of the largest group of elderly patients with ALL evaluated. We have not observed differences in immunological subtypes and Ph chromosome incidence as compared with younger adult ALL presented in the literature. Induction chemotherapy was administered in 75 patients. We observed T. Robak ()) · A. Szmigielska-Kapłon · A. Wrzesien´-Kus´ · A. Wierzbowska Department of Hematology, Medical University of Lodz, Copernicus Memorial Hospital, Pabianicka 62 str, 93-513 Lodz, Poland e-mail:
[email protected] Tel.: +48-42-6895191 Fax: +48-42-6895192 A. B. Skotnicki · B. Pia˛tkowska-Jakubas Department of Hematology, Jagiellonian University, Cracow, Poland K. Kuliczkowski · G. Mazur Department of Hematology and Bone Marrow Transplantation, Medical University, Wroclaw, Poland A. Zdun´czyk Department of Hematology, Regional Hospital, Cracow, Poland B. Stella-Hołowiecka · J. Hołowiecki Department of Hematology and Bone Marrow Transplantation, Silesian Medical School of Medicine, Katowice, Poland J. Dwilewicz-Trojaczek · K. Ma˛dry Department of Hematology, Oncology and Internal Diseases, Medical University, Warsaw, Poland A. Dmoszyn´ska · M. Cioch Department of Hematology and Oncology, Medical University, Lublin, Poland
complete remission (CR) in 34 (45%, 95% CI: 33–56%) patients. Induction death occurred in 11 (15%) patients. Thirty patients (40%) showed primary resistance to chemotherapy. Median overall survival (OS) of all patients was 150 days. Median disease-free survival (DFS) of responding patients was 180 days. We observed four long-term survivors (DFS longer than 3 years) in our group of patients. Factors influencing OS were CR achievement, female gender, and WBC below 30109/l. Male gender was the only prognostic factor negatively affecting probability to achieve CR. We have not observed any differences in either biology or outcome between patients aged 60–69 years and those aged more than 70 years. ALL of the elderly is a rare disease with poor prognosis. Further clinical trials evaluating the disease features, outcome, and new therapeutic approaches are warranted. Keywords Acute lymphoblastic leukemia · ALL · Elderly · Treatment outcome
Introduction Acute lymphoblastic leukemia (ALL) in the elderly is a rare disease and has a poor prognosis [1, 9, 29, 32, 33]. According to registry data, the incidence of ALL increases from 0.39/100,000 in adults aged 35–39 years to 2.1/100,000 in patients above 85 years [1]. Moreover, approximately 30% of adult ALL cases arise in patients aged 60 years or older [2, 10, 28]. Some recent studies on elderly ALL patients indicate that in this population treatment outcome is worse than in younger patients in terms of complete response rate (CR), overall survival (OS), and remission duration [22, 24]. Long-term survival rates in older patients ranged from 4 to 15% and has not improved in recent decades [3, 10, 16, 18, 21, 26, 27, 29]. The major reasons for the poor outcome in elderly populations are higher prevalence of
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disease refractoriness to standard chemotherapy due to biology of leukemia and an increase in the number of early deaths during induction [10, 21]. In this study we present our experience in 87 patients with ALL aged 60 years or more referred to the ten hematological centers in Poland during the last 10 years. To our knowledge, this is one of the largest groups of elderly patients with this type of leukemia.
Patients and methods Patients Between January 1992 and December 2002 all patients aged 60 years or more with newly diagnosed ALL were included in this study. In all patients general assessment including performance status, cardiac, hepatic, and renal conditions was made. Performance status (PS) was determined according to the WHO scale (0=asymptomatic, 1=symptomatic, fully ambulatory, 2=symptomatic in bed less than 50% of the day, 3=symptomatic in bed more than 50% of the day but not bedridden, 4=bedridden). The diagnosis was based on the French-American-British (FAB) morphological and cytochemical criteria [4]. Immunophenotyping was also performed by using flow cytometry and by immunocytochemical techniques to define immunological subtypes of ALL. Classification of ALL was used as follows: pre-pre-B (CD19+, HLA-DR+, CD10€, CD22€, CD7, cIg, sIg), common (CD19+ or CD20+, CD10+), pre-B (cIg+) and B (sIG+), T-ALL (CD7+, CD3+, CD5+, or CD2+) [5]. In cytogenetic analysis standard G-banding techniques were used to stain metaphases from unstimulated cultures in bone marrow cells. Treatment As induction treatment most patients received within the first 4 weeks of therapy prednisone (PDS) 1 mg/kg orally, days 1–28, vincristine (VCR) 1–2 mg i.v., daunorubicin (DNR) 30–60 mg/m2 i.v. once a week, and six to eight doses of L-asparaginase (10,000 U/dose every 2 days, from day 15 of the cycle). Some of the patients in this group received additionally cyclophosphamide (CTX, 100 mg/m2 i.v. once a week, four doses). COAP was also used as induction treatment (VCR 1.5 mg/m2 day 1, CTX 100 mg/ m2, cytarabine (AraC) 100 mg/m2, and PDS 100 mg/daily, days 1– 5) as well as VAD regimen [VCR 0.4 mg daily continuous intravenous infusion (c.i.i.), adriamycin (ADR) 12 mg/m2 c.i.i. days 1–4, and dexamethasone 40 mg daily on days 1–4, 9–12, and 17– 20] [21, 33, 34]. During induction treatment transfusional support was provided to maintain the hemoglobin level >8 g/dl and platelet count >15– 20109/l. Prophylactic antibiotics were not administered. Febrile neutropenic patients received empirical broad-spectrum antibiotic therapy until culture and sensitivity results were available; then treatment was modified according to the results of microbiological study. Consolidation treatment was based mainly on CTX at doses from 0.2 to 1.0 g/m2,with AraC at standard (100 mg/m2) to high doses (HDAraC, 1–2 g/m2). Some patients received methotrexate (MTX) at the dose of 0.5–1.0 g/m2 and etoposide (VP-16) at the dose of 0.1 g/m2, alone or in a combination with CTX and AraC. Maintenance therapy consisted of VCR, PDS, MTX, and 6mercaptopurine (6-MP) and was given to 3 years or until relapse. Central nervous system prophylaxis and treatment Central nervous system prophylaxis consisted of intrathecal chemotherapy with MTX at the dose of 12 mg/m2 six times during
induction and consolidation treatment and than once a month or cranial irradiation. In the majority of patients the CNS prophylaxis with MTX was conducted for 1 year. The patients with meningeal leukemia received intrathecal chemotherapy with MTX 12 mg/m2 twice a week until clearance of leukemic cells from cerebrospinal fluid and monthly intrathecal therapy 1 year thereafter or CNS irradiation. Response criteria Complete response required normal marrow cellularity with less than 5% of blast cells, neutrophil count >1109/l, and platelets >100109/l for at least 30 days. Resistance was defined as persistent leukemia in blood and/or bone marrow in patients surviving more than 1 month after start of induction treatment. Death during induction was defined as death, which occurred while the patient was receiving induction therapy. Overall survival (OS) was defined as time from the date of diagnosis to the date of death or last follow-up. The duration of disease-free survival (DFS) was measured from the date of CR to date of relapse or death in CR. Hematological relapse was considered when more than 5% blasts were seen in bone marrow aspirates [15]. Statistical analysis The significance of differences was evaluated by the MannWhitney test at the level of significance p2), age (
