The Hematology Journal (2004) 5, 123–129 & 2004 The European Hematology Association All rights reserved 1466-4680/04 $25.00 www.nature.com/thj
Rescue therapy combining intermediate-dose cytarabine with amsacrine and etoposide in relapsed adult acute lymphoblastic leukemia Oumedaly Reman*,1, Agnes Buzyn2, Veronique Lhe´ritier3, Francoise Huguet4, Mathieu Kuentz5, Aspasia Stamatoullas6, Andre Delannoy7, Nathalie Fegueux8, Jean-Michel Micle´a9, Jean-Michel Boiron10, Jean Paul Vernant11, Claude Gardin, Maurice Hacini13, Michel Georges4, Denis Fie`re3 and Xavier Thomas3 for the Groupe d’Etude et de Traitement de la Leuce´mie Aigue¨ Lymphoblastique de l’Adulte (GET-LALA Group) 1
Centre Hospitalier-Universitaire, Caen, France; 2Hoˆpital Necker, Paris, France; 3Hoˆpital Edouard Herriot, Lyon, France; 4Hoˆpital Purpan, Toulouse, France; 5Hoˆpital Henri Mondor, Cre´teil, France; 6Centre Henri Becquerel, Rouen, France; 7Hoˆpital de Jolimont, Haine St Paul, Belgium; 8Centre Hospitalier Lapeyronie, Montpellier, France; 9Hoˆpital Saint-Louis, Paris, France; 10Hoˆpital du Haut Leveˆque, Pessac, France; 11Hoˆpital Pitie´-Salpe´trie`re, Paris, France; 12Hoˆpital Beaujon, Clichy, France; 13Centre Hospitalier, Chambery, France
In all, 625 patients with acute lymphoblastic leukemia (ALL) entered the Leuce´mie Aigue¨ Lymphoblastique de l’Adulte-94 trial from June 1994 to June 1999, and received a 4-week induction therapy followed either by chemotherapy alone or stem cell transplantation (SCT). In a clinical phase II study, 40 patients with standard- or high-risk ALL – except Philadelphia chromosome-positive ALL –, relapsing at least 3 months after the beginning of therapy and who did not receive any SCT, received a rescue protocol combining amsacrine 120 mg/m2/day, days 1–3, cytarabine 1 g/m2/12 h, days 1–5, and etoposide 100 mg/m2/day, days 1–5. All relapses occurred ‘on therapy’. In all, 16 patients (40%) achieved a second complete remission. The median time to neutrophil recovery 40.5 109/l was 27 days. The median time to platelet recovery 450 109/l was 28 days. Extra-hematologic toxicity was mild (only one toxic death from severe infection). The median overall survival was 5.4 months. The median disease-free survival (DFS) was 3.2 months with a 3-year DFS of 12%. Unfavorable prognostic factors for complete remission achievement were: high-risk ALL at diagnosis (P ¼ 0.03), and white blood cell count at relapse 30 109/l (P ¼ 0.02). No relationship was found between survival and any characteristics of the disease. Four patients underwent allogeneic SCT (two phenoidentical and two genoidentical) and three patients received autologous SCT. This treatment combining amsacrine, cytarabine, and etoposide was therefore effective and well tolerated in ‘on-therapy’relapsed ALL. However, the median DFS was short requiring the rapid completion of effective intensive postremission therapy. The Hematology Journal (2004) 5, 123–129. doi:10.1038/sj.thj.6200353 Keywords:
relapse; acute lymphoblastic leukemia; bone marrow transplantation; prognosis
Introduction Despite substantial progress in the treatment of adult acute lymphoblastic leukemia (ALL), only 30–40% of patients treated by chemotherapy alone are survivors at 5 years. 1–6 Leukemic relapse in adult ALL remains a major therapeutic problem. Outcome with salvage therapy remains unsatisfactory.7 Although complete remission can be achieved in a substantial number of cases, the median disease-free survival (DFS) is only *Correspondence: O Reman, Service d’He´matologie Clinique, Avenue G. Clemenceau, Centre Hospitalo-Universitaire, 14000, CAEN, France; Tel: þ 33 2 31 27 25 39; Fax: þ 33 2 31 27 25 43; E-mail :
[email protected] Received 18 June 2003; accepted 22 October 2003
2–7.5 months. It is generally accepted that no cure can be achieved at this stage using chemotherapy alone. The only curative approach is hematopoietic stem cell transplantation (SCT). This necessitates generally to obtain a second complete remission with a rescue regimen. This treatment must be effective and as less toxic as possible. Numerous regimens have been previously described.8 In this setting, high- or intermediate-dose cytarabine combined with amsacrine have demonstrated a significant activity.9–11 Etoposide that is not used during the first-line therapy has also shown efficacy in relapsed ALL.10–13 Here we report the results obtained with a regimen combining intermediate-dose cytarabine with etoposide and, amsacrine
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in 40 adult ALL patients, initially included in the Leuce´mie Aigue¨ Lymphoblastique de l’Adulte (LALA-94) trial, relapsing after at least 3 months of first Complete remission (CR) duration.
Patients and methods In all, 625 patients with newly diagnosed ALL entered the LALA-94 trial from June 1994 to June 1999. During this period, an optional phase II rescue trial combining intermediate-dose cytarabine with etoposide and amsacrine has been proposed for relapsing patients included in the LALA-94 trial. From October 1995 to June 1999, 40 relapsed patients from 13 centers have been treated according to this phase II rescue trial. The decision of allocation to this trial was based on specific inclusion criteria and on center policy. Diagnosis of ALL was established on the basis of morphologic, cytochemical, and immunologic studies. ALL was initially classified morphologically according to the French–American– British (FAB) criteria.14 Studies of cell-surface markers were available for all patients and classified as previously described.15 Cytogenetic study was obtained in 33 patients at the time of initial diagnosis.
therapy and B-cell lineage ALL patients defined by the absence of CNS-positive ALL, the absence of specific chromosomal or molecular abnormalities such as Philadelphia chromosome-positive or BCR-ABL-positive, t(4;11)/MLL-AF4, t(1;19)/E2A-PBX1, or other abnormalities involving 11q23 rearrangements, a white blood cell (WBC) count o30 109/l, an immunophenotype characterized by CD10 and CD19 positivity, or CD20 and CD19 positivity and the absence of myeloid markers, and achievement of CR after the first course of induction chemotherapy) then received only chemotherapy and followed a second randomization between an intensive consolidation chemotherapy or a less intensive consolidation course. All high-risk ALL patients (defined as nonstandard-risk ALL without Philadelphia chromosome or CNS involvement) received the intensive consolidation chemotherapy. They then followed a genetic randomization and were proposed for either an allogeneic SCT in the presence of a sibling donor or a second randomization between an autologous SCT and the same chemotherapy as standard-risk ALL in the absence of a sibling donor. Philadelphia chromosome-positive and CNS-positive ALL patients received the intensive consolidation chemotherapy, and were then proposed for either an allogeneic SCT or an autologous SCT depending on the availability of a sibling donor (Figure 1).
Patient eligibility Eligibility criteria were: (i) non-Philadelphia chromosome-positive (or BCR-ABL-positive) B- or T-cell lineage ALL initially included in the LALA-94 trial; (ii) having achieved a first CR after only one course of induction therapy; (iii) not consolidated in first-line therapy by autologous or allogeneic SCT; (iii) having relapsed after at least 90 days of first CR duration; (iv) having a World Health Organization (WHO) performance status scale of 0, 1, or 2 at the time of starting salvage therapy. Relapse was defined as 45% of leukemic blast cells in bone marrow aspirates. Central nervous system leukemia was diagnosed when leukemia cell blasts were identified in centrifuged samples of cerebrospinal fluid (CSF) regardless of the CSF mononuclear cell count.
First-line therapy The LALA-94 trial was started in 1994 and included ALL patients aged 15–55 years.16 After receiving a 4week four-drug induction course consisting of prednisone (60 mg/day from day 1 to 7 and from day 15 to 21), vincristine (2 mg total dose at days 1, 8, 15, and 22), cyclophosphamide (750 mg/m2/day at days 1 and 8), and daunorubicin (30 mg/m2/day from day 1 to 3 and from day 15 to 16) or idarubicin (9 mg/m2/day from day 1 to 3 and day 8) according to initial randomization; patients followed a risk-adapted therapeutic strategy and were allocated to risk groups according to initial characteristics at diagnosis and to initial response to therapy. Standard-risk ALL patients (T-cell lineage ALL patients achieving CR after one course of induction chemoThe Hematology Journal
Rescue therapy after relapse Rescue therapy consisted of amsacrine 120 mg/m2/day from day 1 to 3, cytarabine 1 g/m2 twice daily from day 1 to 5, and etoposide 100 mg/m2/day from day 1 to 5. Colony-stimulating factor could be administered during induction therapy according to each center policy. After CR achievement, allogeneic SCT was planned for all patients with a matched HLA compatible donor. For the other patients, consolidation chemotherapy was scheduled after CR achievement and combined cyclophosphamide 1.5 g/m2/day from on days 1 and 2, with etoposide 100 mg/m2/day from day 1 to 5. Patients were then planned for autologous SCT or could receive nine courses of maintenance therapy according to Prednisone, Intermediate-dose Cytanabine, Mitoxantrone and Etoposide chemotherapy (PAME) trial.10 In patients with clinical or cytological evidence of CNS disease, therapy consisted of triple intrathecal injections (cytarabine, 40 mg; methotrexate, 15 mg; methylprednisolone, 40 mg) eventually associated with a cranial irradiation.
Definition of response CR was defined as the presence of 5% or fewer blasts in a normocellular or hypercellular bone marrow aspirate, no extramedullary disease, no symptoms or physical findings suggestive of leukemia, and normal peripheral blood counts (neutrophils count greater than 1.5 109/ l,. platelet count greater than 100 109/l). Treatment failures were classified, according to Preisler,17 as nonresponse (NR), including all patients with proven blastic
Treatment in relapsed ALL O Reman et al
125 Randomization
Induction
Standard-risk ALL
High-risk ALL
Ph+ ALL/CNS+ ALL
Randomization
MTZ-IDaraC
MTZ-IDaraC
Chemotherapy with early intensive consolidation MTZ-IDaraC
Chemotherapy without intensive consolidation
Genetic Randomization
Sibling donor
No sibling donor
Allo SCT
Randomization
Auto SCT
Sibling donor
No sibling donor
Allo SCT
Auto SCT
Chemotherapy
Figure 1
Schema of LALA-94 trial. After receiving a 4-week four-drug induction course, patients followed a risk-adapted therapeutic strategy and were allocated to risk groups according to initial characteristics at diagnosis and to initial response to therapy. Standard-risk ALL patients received then only chemotherapy and followed a second randomization between an early intensive consolidation chemotherapy and a chemotherapy without early intensification. High-risk ALL patients received an intensive chemotherapy corresponding to a salvage therapy or a first consolidation. In case of CR achievement, they then followed a genetic randomization and were proposed for either an allogeneic SCT in the presence of a sibling donor or a second randomization between an autologous SCT and the same chemotherapy as in the standard-risk ALL in absence of a sibling donor. Philadelphia-positive and CNS-positive ALL patients first received an intensive chemotherapy corresponding to a salvage therapy or a first consolidation, and were then proposed for either an allogeneic SCT or an autologous SCT depending on the availability of a sibling donor.
regrowth, and other failures (OF) corresponding to patients who died while nonblastic. The severity of treatment-related toxicity was graded according to the WHO criteria.18
Statistical considerations Univariate analysis was performed using the w2 statistic test to examine the relationship between patient characteristics and CR rate. Simultaneous effects of multiple covariates (risk group at the time of initial diagnosis, leukocyte count and age at time of rescue induction therapy, duration of first CR) were estimated with the maximum-likelihood logistic regression model for response. In all, 95% confidence intervals (CIs) on proportions of CR, NR, and OF patients were calculated using the exact binomial formula. Overall survival was calculated from the start of salvage therapy to death from any cause or last patient contact. DFS was defined as the interval from the date of CR achievement to either relapse or death due to any cause or last contact in patients with continuous CR. DFS and OS probabilities were calculated using the Kaplan and Meier product-limit estimate method, and their 95% symmetrical CI limit was calculated according to Greenwood’s method. Survival curves were compared using the log-rank test. All computations were carried out using BMDP software (BMDP Statistical Software, Los Angeles, CA, USA).
Results Patient characteristics The main characteristics of the 40 patients are summarized in Table 1. All patients had relapsed ‘on therapy’. The median duration of first CR was 12.2 months
(range, 3–36 months). There were 27 males and 13 females with a median age of 27 years (range, 16–54 years). In all, 24 patients (60%) had B-lineage phenotype, while 16 patients had T-lineage ALL. A total of 34 patients (85%) were initially classified as being at standard-risk and six patients were initially classified as high-risk ALL. Morphological FAB classifications were available in 36 cases, while karyotypic analysis was available in 33 cases at the time of diagnosis. By cytogenetic classification, nine patients (27%) displayed a normal karyotype. At the time of relapse, the incidence of organomegaly (splenomegaly and/or hepatomegaly and/or adenopathies) was 37%. All patients displayed medullary relapse. Nine patients (22%) also presented with CNS involvement. WBC count ranged from 0.6 to 194.8 x 109/l (median, 5.3 109/l).
Efficacy of salvage therapy Overall, salvage chemotherapy resulted in CR in 16 patients (40%; 95% CI: 24–56%). In all, 23 patients (57%; 95% CI: 40–73%) had resistant disease and one (3%; 95% CI: 0–13%) died from toxicity. Three patients, who achieved CR, did not receive any further therapy because of a severe infectious toxicity of the induction course (one patient) or because of early relapse (two patients). One patient was autografted and another was allografted (genoidentical allogeneic SCT) without consolidation after CR achievement. In all, 11 patients received consolidation therapy. As postconsolidation therapy, two of them received maintenance therapy, three underwent allogeneic SCT (two phenoidentical and one genoidentical) and two received autologous SCT. Four patients relapsed early before receiving any postconsolidation therapy. The time from CR achievement and transplantation ranged from 2.5 to 8.2 months (median, 2.9 months). The median DFS of the entire cohort was 3.2 months (95% CI: 2.2–4.6 The Hematology Journal
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Table 1 Characteristics of the 40 ALL patients Characteristics
Value (range)
Age (years) Sex (male/female) Initial risk of relapse Standard-risk ALL High-risk ALL
27 (16–54) 27/13 34 6
WBC count at relapse ( 109/l)
5.3 (0.6–194.8)
First remission duration Median (months) Patients with first CR X12 months Patients with first CR o12 months
12.2 (3–36) 20 20
Survival probability
0.8
0.6 median, 5.4 months 0.4
0.2 [7%] 0.0
Consolidation during first-line therapya Early intensification No early intensification
0
26 14 23 13 4
Immunophenotypeb B-lineage ALL CD19+, CD10-, CD20CD19+, CD10+, CD20CD19-, CD10+, CD20+ T-lineage ALL CD7+, CD57, CD27, CD1, CD3 CD7+, CD5+, CD2+, CD1+, CD3 CD7+, CD5+, CD2+, CD1, CD3+
24 3 9 12 16 3 6 7
Karyotype Normal karyotype t(1;19) t(11;14) t(10;14) Other abnormalities Failure
9 2 2 1 19 7
30
45
60
75
Time from diagnosis (months)
Figure 3
FAB classification L1 L2 Not determined
15
a
In the LALA-94 trial, patients with standard-risk ALL or belonging to high-risk ALL, but without HLA sibling donor received either an early intensive consolidation chemotherapy combining mitoxantrone (10 mg/m2/day from day 3 to 5) with intermediate-dose cytarabine (1 g/ m2/12 h from day 1 to 4), or a less intensive consolidation course combining cyclophosphamide (1 g/m2/day at days 1, 15, and 29) with cytarabine (75 mg/m2/day from day 3 to 6, 10 to 13, and 17 to 20), and 6-mercaptopurine (60 mg/m2/day from day 1 to 28); bImmunophenotypic classification was made according to Boucheix et al. (1994)15.
Overall survival (40 patients).
months) with a 3-year DFS rate of 12% (Figure 2). The median OS was 5.4 months (95% CI: 4–6 months) with a 3-year OS rate of 7% (Figure 3). CNS involvement did not confer a worse outcome than only marrow involvement (median OS, 6 months versus 4.9 months). At the time of last follow-up, 11 patients have relapsed (69%) of whom 10 finally died. The median time to relapse was 2.5 months (range, 0.5–5 months). Two of the three autografted patients died (one from relapse and one from toxicity), while three of the four allografted patients died (one from relapse and two from toxicity). Four patients could undergo SCT (two phenoidentical and one genoidentical allogeneic SCT and one autologous SCT), while in the blastic phase after failure of rescue induction therapy or in further CR after a third line of therapy. Overall, only three patients are still alive (two in CR and one after relapse) with OS durations of 3.7, 4.2, and 5.2 years, respectively. All three patients have received SCT: autologous SCT or phenoidentical allogeneic SCT for the two patients still in second CR, and genoidentical allogeneic SCT for the patient in third CR.
Toxicity of salvage therapy 1.0
DFS probability
0.8
0.6 median, 3.2 months 0.4
0.2
[12%]
0.0 0
10
20
30
Time from CR achievement (months)
Figure 2 The Hematology Journal
Disease-free survival (16 patients).
40
50
Significant hematologic toxicity was observed in all patients. The median time to neutrophil recovery (40.5 109/l) was 27 days (range, 25–39 days), and the median time to platelet recovery (450 109/l) was 28 days (range, 19–37 days). All patients, but two, were evaluable for nonhematologic toxicity (Table 2). The main nonhematologic toxicity was infectious complications. In all, 15 (39%) patients experienced severe (WHO grade 3) infectious toxicity. One patient died from severe infectious disease during aplasia. Six patients (16%) presented WHO grade three hepatic toxicity. Four patients (11%) had WHO grade 3 or 4 mucositis. Nausea and vomiting were generally mild to moderate and easily controllable. No patients presented severe cardiac toxicity, nor renal toxicity.
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WHO grade o3 WHO grade 3 WHO grade >3 29 (76%) 37 (97%) 34 (90%) 32 (84%) 38 (100%) 23 (61%) 38 (100%)
8 (21%) 1 (3%) 2 (5%) 6 (16%) 0 (0%) 13 (34%) 0 (0%)
1 0 2 0 0 2 0
(3%) (0%) (5%) (0%) (0%) (5%) (0%)
Prognostic factors Several clinical, biological, and treatment-related data were analyzed for prognostic significance for CR, DFS, and OS. In the univariate analysis, CR achievement was mainly related to WBC count at the time of rescue induction therapy with poorer outcome for patients with more aggressive leukemia (WBC count 10 109/l) (CR rates, 54% (13/24 patients) versus 19% (3/16 patients); P ¼ 0.02). Risk group at time of initial diagnosis also influenced CR rate (47% (16/34 patients) for standardrisk ALL versus no CR (0/6 patients) for high-risk ALL; P ¼ 0.03). WBC count at relapse and risk group at diagnosis were confirmed to be of prognostic value for response in the multivariate analysis (P ¼ 0.02 and P ¼ 0.03, respectively). Using these two objective parameters of proven significance, we devised a prognostic system of immediate clinical utility for prognostic stratification after relapse. Patients with WBC count o10 109/l at relapse and standard-risk ALL at diagnosis achieved CR in 62% of cases, while those with WBC count 10 109/l at relapse and standardrisk ALL at diagnosis obtained CR in only 23% of cases (P ¼ 0.001). All patients with high-risk ALL at diagnosis displayed a very poor outcome. The first CR duration was not a significant prognostic factor for CR achievement. No factor was found to be of prognostic value for DFS or OS.
Discussion The prognosis of relapsing adult ALL is generally considered to be poor. A second complete response occurred generally in 25–50% of patients with a median DFS of less than 6 months.7 In this setting, new drug combinations must be employed with the aim of overcoming drug resistance and it seems logical to administer a combination of drugs not used during the first-line therapy, especially when relapse occurred ‘on therapy’. In the present study, the amsacrine/cytarabine/ etoposide combination showed antileukemic efficacy with a CR rate of 40%. The predominant side effect was profound myelosuppression, which caused 39% of severe infectious toxicity. However, hematologic toxicity remained easily manageable, and extra-hematologic toxicity was acceptable. Our results were in the range
of results previously reported.7,8 Heterogeneity of results regarding CR rates is related to the small number of patients in published series and to the degree of selection of treated patients. In our study, the CR rate could nevertheless be considered as low compared to other studies, considering that it only included patients with non-Philadelphia chromosome-positive ALL and presenting a first CR duration of more than 3 months. Anyway, the main problem in relapsing ALL remains the limited duration of DFS. This could be attributed to the low quality of remission achieved with rescue therapy. Two of our patients relapsed early before receiving any postremission therapy, while four patients relapsed early after one consolidation course. This low quality of remission is generally related to drug resistance, especially in patients as ours, relapsing ‘on therapy’. Drug resistance can develop by the selection of a resistant subpopulation of malignant cells or by induction of specific cellular changes in response to drug treatment.19 This could explain the absence of the prognostic value of first remission duration in the present study, while it is generally recognized as being of major prognostic value in most series. Another explanation could be the small number of patients in our series. Allogeneic SCT remains the only therapeutic option for cure at that stage of the disease. It can offer longterm DFS in 15–20% of adult ALL patients after relapse, and must be scheduled as quickly as possible after CR achievement.20–22 The outcome of allogeneic SCT is influenced by the length of first CR, age, tumor burden, and disease biology. High-risk ALL patients therefore have a probability of survival lower than that of standard-risk ALL patients.23 Often the question arises whether to attempt reinduction therapy or to proceed directly to allogeneic transplantation. However, most series report a longer DFS in patients who were transplanted in CR rather than with active relapse, and it is generally admitted that patients with a durable first remission should receive salvage chemotherapy before transplantation.20 Short second remission leaves only a brief window of time to perform SCT. When no sibling donor is available, identifying an unrelated donor in a timely fashion can be difficult. The median time from patient referral to donor identification has been estimated at 10 weeks, and 19% of referred patients died before transplant.24 Furthermore, organization of allogeneic SCT obliged us to administer a consolidation therapy before allogeneic transplant in three patients that could favor graft-related toxicity. Autologous SCT is still not really validated at that stage of the disease. However, in our series, one autografted patient achieved long-term survival. DFS after autologous SCT in second CR seemed related to the burden of leukemia cells reinfused and therefore has been reported of interest only in patients with favorable disease characteristics.25 For standard-risk ALL patients following a chemotherapy program, cell harvest could be discussed in CR1 in absence of a sibling donor with The Hematology Journal
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the aim to undergo an autologous SCT as postremission therapeutic option if needed in second-line therapy. We conclude that our schedule combining amsacrine, etoposide, and intermediate-dose cytarabine has a certain efficacy in relapsed ALL and an acceptable toxicity as compared to regimens proposed previously.7,8 Further insights into the biology of ALL are required, and novel therapeutic agents are needed to counter mechanisms of resistance. Attainment of a second CR should be systematically followed by SCT when feasible owing to the paucity of long-term survivors with salvage chemotherapy alone. In this setting, allogeneic SCT (geno or phenoidentical) appears as the treatment of choice, autologous SCT being still under investigation.
Owing to the short second CR duration, further efforts are needed to speed up the process of donor selection for patients with ALL. This could include the identification of potential donors at the time of initial disease presentation rather than at relapse. Introduction of new drugs, such as alemtuzumab (Campath-1H)26 or rituximab,27 could also probably improve salvage therapeutic schedules. Another approach to improving treatment in relapsed ALL is to base treatment decisions on the detection and quantitation of leukemia cells during postremission treatment. Molecular techniques appear to be useful tests for predicting relapse after a first-line therapy and may identify patients who might benefit from early therapeutic interventions.
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