Induction therapy by frequent administration of doxorubicin with four other drugs, followed by intensive consolidation and maintenance therapy for adult acute lymphoblastic leukemia: the JALSG-ALL93 study

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Abstract

In order to improve the disappointing prognosis of adult patients with acute lymphoblastic leukemia (ALL), we applied similar induction therapy as that used for acute myeloid leukemia (AML), ie frequent administration of doxorubicin (DOX). DOX 30 mg/m2 was administered from days 1 to 3 and from days 8 to 10 together with vincristine, prednisolone, cyclophosphamide and L-asparaginase, followed by three courses of consolidation and four courses of intensification. From December 1993 to February 1997, 285 untreated adult patients with de novo ALL were entered. Of 263 evaluable patients (age 15 to 59; median 31), 205 (78%) obtained complete remission (CR). At a median follow-up period of 63 months, the predicted 6-year overall survival (OS) rate of all patients was 33%, and disease-free survival (DFS) rate of CR patients was 30%, respectively. By multivariate analysis, favorable prognostic factors for the achievement of CR were age <40 and WBC <50 000/μl; for longer OS were age <30 and WBC <30 000/μl; and for longer DFS of CR patients were FAB L1 and ALT <50 IU/l. Among 229 patients who had adequate cytogenetic data, 51 (22%) had Philadelphia (Ph) chromosome. Ph-negative chromosome was a common favorable prognostic factor for CR, longer OS and DFS. DFS was not different between early sequential intensification (n = 48) and intermittent intensification (n = 43) during the maintenance phase. Among CR patients under 40 years old, the 6-year survival was not different between the allocated related allo-BMT group (34 patients) and the allocated chemotherapy group (108 patients). However, among patients with Ph-positive ALL, the survival of patients who actually received allo-BMT was superior to that of patients who received chemotherapy (P = 0.046).

Introduction

The majority of childhood acute lymphoblastic leukemia (ALL) is now curable. Its complete remission (CR) rate exceeds 95% and event-free survival rate is nearly 80%.1,2 On the other hand, the treatment outcome of adult ALL is still poor. The long-term remission rate of adult ALL remains at 25 to 43%, despite the CR rate of around 80%.3,4,5,6,7,8 Thus, adult ALL is still considered as one of the intractable cancers.

Previously, the Japan Adult Leukemia Study Group (JALSG) conducted the ALL87 study with a response-oriented induction therapy, followed by three courses of intensive post-remission therapy and maintenance.9 The CR rate and predicted 6-year overall survival (OS) rate in 116 adult patients (median age, 38) were 84% and 23%, respectively. In the subsequent ALL90 study, we added mitoxantrone (MIT) to the induction therapy of the ALL87, followed by four courses of intensive post-remission therapy and maintenance.10 However, the results were disappointing, showing the CR rate and predicted 5-year OS rate in 180 adult patients (median age, 43) were 69% and 15%, respectively.

In most remission induction therapies for adult ALL, doxorubicin (DOX) is used once or twice a week. We assumed that frequent administration of anthracycline like the induction therapy of acute myeloid leukemia (AML) might eradicate more leukemic cells than the standard administration method for ALL and prolong survival. Therefore, in the present ALL93 study, we used the same five drugs as the ALL87 in the induction therapy, but increased the dose intensity of DOX by more frequent administration from days 1 to 3 and from days 8 to 10 in the induction therapy. Among CR patients younger than 40 years old, survival was prospectively compared between chemotherapy and allogeneic bone marrow transplantation (allo-BMT). Furthermore, the intensification therapy during the maintenance phase was randomized to early sequential or to intermittent. Major prognostic factors, such as age, leukocyte count, FAB classification, chromosome, immunophenotype, etc, were also analyzed.

Patients and methods

Patient eligibility criteria

Previously untreated patients with ALL, aged from 15 to less than 60, without major heart, lung, liver, renal, psychic and infectious diseases were eligible for this study. Diagnosis of ALL was made according to the French–American–British (FAB) classification11,12,13,14 at each institution, which was later re-evaluated by the central review committee. Participating institutions were asked to register eligible patients consecutively. Informed consent was obtained before the registration.

Remission induction

Remission induction therapy is shown in Table 1. If patients were in poor condition being complicated with severe infections or if the day 8 bone marrow showed less than 20% of leukemia cells, DOX on days 9 and 10 could be omitted. G-CSF was started from 2 days after the final dose of DOX, and terminated 2 days before the administration of cyclophosphamide (CY). If the marrow was severely hypocellular on day 28, administration of L-asparaginase (L-ASP) and CY could be postponed until day 35. If patients had severe pancreatitis, allergy to L-ASP and/or intractable hyperglycemia, the administration period of L-ASP could be shortened or omitted, and additional CY was given on day 36 in substitution for L-ASP. If patients did not achieve CR with the first course of induction therapy, consolidation I in Table 1 was applied as the second course of induction therapy. If this also failed, the patients were regarded as failure cases for remission induction.

Table 1 Treatment protocol of the ALL93 study (1)

Post-remission treatment

Consolidation regimens consisted of three courses as shown in Table 1. The first course should be started immediately after granulocyte counts were more than 1500/μl and fibrinogen recovered to more than 150 mg/dl. The second and third courses should be started immediately after WBC counts were higher than 3000/μl and platelet counts more than 100 000/μl.

After completion of the consolidation, 6-mercaptopurine (6MP) and methotrexate (MTX) were given orally as maintenance therapy. Patients were randomized to receive early sequential (arm A) or intermittent (arm B) intensification (Table 2). Total doses of drugs were the same in both arms.

Table 2 Treatment protocol of the ALL93 study (2)

CNS prophylaxis

Central nervous system (CNS) prophylaxis was performed by intrathecal (IT) injection of MTX, cytarabine (Ara-C) and prednisolone (PSL) during consolidation and intensification period (Tables 1 and 2). Patients who had CNS leukemia or more than 100 000/μl of WBC before the induction therapy were given 20 Gy cranial irradiation after the third course of consolidation.

Stem cell transplantation

All patients under 40 years old with HLA matched siblings were scheduled to receive bone marrow transplantation (BMT) after the end of consolidation I. Patients who found a matched donor through the Japan Marrow Donor Program (JMDP) could receive BMT.

Statistical analysis

Complete remission was defined as: (1) less than 5% of blasts in bone marrow; (2) existence of normal erythroblast, granulocyte and megakaryocyte series in bone marrow; (3) disappearance of blasts, more than 1500/μl of neutrophils and more than 100 000/μl of platelets in peripheral blood; (4) no extramedullary leukemia; and (5) persistence of these conditions for more than 4 weeks. The persistence of neutrophils and platelets at the indicated levels was not necessarily requested if the next therapy was started.

Overall survival (OS) was calculated from the first day of therapy to death. Event-free survival (EFS) was measured from the first day of therapy to relapse or death, and the EFS of patients who did not achieve CR was defined as 0. Disease-free survival (DFS) for patients who had achieved CR was measured from the date of CR to relapse or death. Patients who underwent stem cell transplantation (SCT) were censored at the date of SCT. Kaplan–Meier product-limit estimates were performed to determine OS, EFS and DFS. To test factors to predict CR, the chi-square test was used for univariate analysis, and the logistic regression model for multivariate analysis. For comparisons of OS, EFS and DFS, the log-rank test were used for univariate analysis, and the Cox proportional hazard regression model for multivariate analysis. The StatView programs (SAS Institute, Cary, NC, USA) were used for the analysis. The analysis was based on all data available as of July 2000.

Results

Patients’ characteristics

From December 1993 to February 1997, 285 patients were registered from 40 institutions of JALSG. Ten patients were not eligible because the diagnosis was changed to other types of leukemia such as FAB M0, blastic crisis of chronic myelogenous leukemia, etc after the registration. Ten patients were excluded because of inadequate age, and two others because other chemotherapy was given. Thus, 263 patients were evaluable and their ages ranged from 15 to 59 years with a median of 31. There were 154 males and 109 females. Peripheral leukocyte counts ranged from 600 to 733 000/μl (median, 12 100/μl); platelet counts from 3000 to 1 040 000/μl (median, 59 000/μl); and hemoglobin (Hb) from 2.0 to 17.5 g/dl (median, 9.2 g/dl). FAB classification was L1 in 77, L2 in 176 and L3 in eight. Two were unclassified. Seven patients initially had CNS involvement.

Chromosome analysis was available in 229 patients (87%), and Philadelphia (Ph) chromosome was found in 51 (22%). Only three patients had t(4;11). Surface marker analysis was obtained in 236 patients (90%). One hundred and eighty-two (77%) patients expressed at least one B-lineage antigen, 29 (12%) at least one T-lineage antigen, and 25 (11%) both B- and T-lineage antigens. Extensive surface marker analysis in 129 patients was as follows: one patient was pro-T-ALL, 12 were T-ALL, four were pro-B-ALL, 20 were c-ALL, 12 were pre-B-ALL, six were mature-B-ALL and three were expressed both T-lineage and myeloid antigens, 56 had both B-lineage and myeloid antigens and 15 had both B- and T-lineage antigens.

Prognostic factors and toxicity in remission induction

Two hundred and five (78%) patients attained CR: 196 after the first course and nine after the second course. The days to attain CR ranged from 11 to 92 days with a median of 28. Favorable factors for obtaining CR by univariate analysis were age younger than 40 years old, WBC count less than 50 000/μl and absence of Ph chromosome (Table 3). Gender, performance status, FAB classification, organomegaly, Hb, platelet count, LDH, AST, ALT and immunophenotype were not significant factors. Multivariate analysis by the logistic model indicated that age younger than 40 years (P = 0.003) and initial WBC counts less than 50 000/μl (P = 0.005) were significant favorable factors (Table 4). In 229 patients who had adequate cytogenetic data, Ph-negative chromosome (P < 0.0001) and age younger than 40 years (P = 0.05) were favorable factors for achieving CR by multivariate analysis (Table 4).

Table 3 Clinical and biological characteristics in relation to CR rates, survival and remission duration
Table 4 Favorable prognostic factors by multivariate analysis in the ALL93 study

Major adverse events observed during the induction therapy were infections (69%), disseminated intravascular coagulopathy (DIC) (16%) and hepatic damage (13%). Seventeen patients (6%) died within 50 days after the start of induction therapy and major causes of death were septicemia (nine patients) and cerebral hemorrhage (three patients).

Course of the patients

Figure 1 shows a summary of treatment schedule detailing the number of patients in each stage. Of 205 eligible patients who achieved CR, 13 were not entered for the consolidation portion of the study due to relapse (n = 6), death (n = 3), refusal by the patient (n = 2), refusal by the investigator (n = 1) or SCT (n = 1). Of 192 patients who entered into the consolidation phase, 65 were not entered for the maintenance portion of the study due to relapse (n = 28), SCT (n = 21), death (n = 8), refusal by the patient (n = 5) or refusal by the investigator (n = 3). At the time of randomization, 36 patients refused to register. Thus, 48 patients were assigned for early sequential maintenance and 43 for intermittent maintenance.

Figure 1
figure1

Summary of the treatment schedule and course of the patients.

Prognostic factors in survival and the risk model

At a median follow-up period of 63 months (range, 1+ to 80+ months), 114 (56%) of 205 patients had relapsed, including 16 patients (14%) with CNS leukemia as an initial relapse site. Seventeen patients (8%) died in remission. Sixty-one patients received SCT in their first CR: 31 related BMT, 20 unrelated BMT, eight autologous peripheral blood stem cell transplantation (PBSCT) and two autologous BMT. Twenty-nine patients received SCT after relapse. Patients who received SCT were censored at the time of transplantation. Predicted 6-year OS rate of 263 evaluable patients is 33% (95% confidential interval (CI), 29–38%), EFS rate 23% (95% CI, 20–27%), and DFS rate of 205 CR patients 30% (95% CI, 26–34%) (Figure 2).

Figure 2
figure2

Kaplan–Meier curves of 263 patients in the ALL93 study. Patients who underwent stem cell transplantation (SCT) were censored at the date of SCT. Median follow-up period was 63 months. The predicted 6-year overall survival rate was 33%, while the predicted 6-year event-free survival rate was 23%.

Ninety-one patients were randomized to the early sequential or intermittent intensification. There was no difference between the two arms in terms of adherence to the schedule, rate of severe infections and death in CR. The DFS curves according to this randomization were not significantly different. The predicted 6-year DFS rate for the early sequential intensification group (44 patients) was 36% (95% CI, 27–45%), while that for the intermittent intensification group (38 patients) was 49% (95% CI, 40–55%), and there was no statistically significant difference (P = 0.85).

Favorable factors for longer OS by univariate analysis using the log-rank test were age younger than 30 years, WBC count less than 30 000/μl, initial platelet count higher than 50 000/μl and Ph-negative chromosome. The multivariate analysis in all evaluable patients by the Cox regression model revealed that age younger than 30 years (P = 0.001) and WBC count less than 30 000/μl (P = 0.026) were the significant factors for longer OS (Table 4). In 229 patients who had adequate cytogenetic data, Ph-negative chromosome (P = 0.006) was the only favorable factor for longer OS by the multivariate analysis (Table 4).

Favorable factors for longer DFS in 205 CR patients by the univariate analysis were FAB L1, AST less than 40 IU/l, ALT less than 50 IU/l and Ph-negative chromosome (Table 3). By the multivariate analysis, FAB L1 (P = 0.018) and ALT less than 50 IU/l (P = 0.019) were significant factors for longer DFS in all CR patients (Table 4). In 174 patients who had adequate cytogenetic data, FAB L1 (P = 0.014) and Ph-negative chromosome (P = 0.025) were favorable factors for longer DFS by the multivariate analysis (Table 4).

Thus, the risk model is proposed by the presence of the following unfavorable factors: age 30 years, WBC count 30 000/μl and Ph chromosome. Table 5 shows the definition of the risk model. In 229 patients who had adequate cytogenetic data, the predicted 6-year OS rate for 63 patients of the low-risk group was 53% (95% CI, 41–64%), while those for 97 of the intermediate-risk group and 69 of the high-risk group were 35% (95% CI, 28–41%) and 15% (95% CI, 9–21%), respectively (Figure 3).

Table 5 Risk model based on prognostic factors
Figure 3
figure3

Overall survival by the risk model for 229 patients who had adequate cytogenetic data. The predicted 6-year overall survival rate for the low-risk group was 53%, while those for the intermediate-risk group and the high-risk group were 33% and15%, respectively. Patients who underwent stem cell transplantation (SCT) were censored at the date of SCT.

Stem cell transplantation

CR patients under 40 years of age who had at least one HLA-identical related donor were scheduled to receive allo-BMT. Among 142 CR patients under 40 years old, 34 were allocated to the related allo-BMT group and 24 actually received related allo-BMT in their first CR. One hundred and eight patients were allocated to the chemotherapy group. Seventeen of them received unrelated allo-BMT, eight had autologous PBSCT and two autologous BMT in their first CR. Ten CR patients of age 40 years (up to 52 years) received allo-BMT: seven related and three unrelated, in their first CR. Among CR patients under 40 years old, the 6-year survival was not different (P = 0.58) between the allocated related allo-BMT group (34 patients) and the allocated chemotherapy group (108 patients) (Figure 4).

Figure 4
figure4

Overall survival by the genetic randomization for 142 CR patients under 40 years old. The predicted 6-year overall survival for allocated related allogeneic BMT was 46%, while that for chemotherapy was 40%. The CR patients who had relapsed or died before the 36th day of CR were excluded.

Comparison between actual therapies was also performed. Among all CR patients, the 6-year survival was not different (P = 0.20) between the actual allo-BMT group (51 patients) and the actual chemotherapy group (133 patients). Among CR patients under 40 years old, the 6-year survival was not different (P = 0.31) between the actual allo-BMT group (41 patients) and the actual chemotherapy group (91 patients). Ten patients who received auto-PBSCT or auto-BMT were excluded from the analyses. The CR patients who had relapsed or died before the 36th day of CR were also excluded from the analyses, because BMT was performed after this time.

Ph-positive patients were significantly inferior to Ph-negative ones in both OS and DFS (Table 3). Among 22 Ph-positive CR patients, the actual allo-BMT group (eight patients) had significantly superior survival to the actual chemotherapy group (14 patients) (P = 0.046), and only one surviving patient in the chemotherapy group was transplanted after relapse (Figure 5). However, there seemed to be an age bias between the allo-BMT and the chemotherapy group, because median age were 30 and 43, respectively.

Figure 5
figure5

Overall survival of patients who received allogeneic BMT in their first CR and those who received chemotherapy among 22 Ph-positive CR patients. The predicted 6-year DFS rate for patients with allogeneic BMT in their first CR was 44%, while that for chemotherapy was 7%. The CR patients who had relapsed or died before the 36th day of CR were excluded.

Discussion

Complete remission rate of the present ALL93 study was 78%, which was better than that of our previous JALSG-ALL90 study (69%)10 but not superior to that of the JALSG-ALL87 study (84%).9 The drugs used in the induction therapy were the same in the ALL93 and ALL87 studies, namely DOX, VCR, PSL, CY and L-ASP, but in the ALL90 study MIT was added to these five drugs.10 Superior CR rate of the ALL93 to that of the ALL90 is probably explained by the fact that, in the ALL93 study, younger patients (median age, 31) were enrolled compared with the age of the ALL90 (median age, 43), and partly by insufficient dose intensity of DOX and L-ASP in the ALL90. Compared with the ALL87 study, in the present ALL93, the dose of DOX was increased but that of CY was decreased. Thus, the increased dose intensity of DOX alone did not seem to contribute to the increase of CR rate in adult ALL, although the decreased dose intensity of CY might have offset the effect of increased dose intensity of DOX. Recently, Todeschini et al15 reported 93% of CR rate using a 3-day administration of daunorubicin (DNR), and 55% 6-year EFS in adult ALL (median age, 34) employing high-dose cytarabine (Ara-C) in post-remission therapy. They used three courses of 3-day DNR (30 mg/m2/day) at around 3-week intervals, while we used two courses of 3-day DOX (30 mg/m2/day) within 10 days. Thus, the dose intensity of anthracycline during the first 2 weeks is higher in our study, but our multicenter study could not obtain such a high CR rate as reported by them.

The predicted 6-year OS rate (33%) of all patients and DFS rate of CR patients (30%) of this study were superior to those of the ALL87 (23% and 25%, respectively) and of the ALL90 (15% and 14%, respectively). Again this may be explained by the younger age population in the present study (median age, 31) compared with the older age population of the ALL90 (median age, 43) and of the ALL87 (median age, 38). Although OS in the present study is not inferior to hitherto reported large-scale studies,3,4,6,7 recent studies which include high-dose Ara-C and/or high-dose MTX in the post-remission therapy report better OS.15,16,17 Since April 2000, our National Health Insurance policy has been changed to allow us to use high-dose Ara-C. Therefore, we plan to employ high-dose Ara-C regimens in post-remission therapy in the next JALSG ALL study.

Favorable prognostic factors for OS in this study were age <30 years, WBC <30 000/μl and absence of Ph chromosome. Similar favorable factors have been reported in the previous JALSG studies. The ALL90 study showed that age <30 years, WBC <30 000/μl, blasts <10% on day 15 and normal karyotype were the favorable factors for OS.10 The ALL87 study revealed that age <50 years, WBC <30 000/μl, days to CR <50 were significant favorable factors for DFS.9 These prognostic factors are common in other reports on adult ALL.3,18,19 Although T-lineage ALL is reported to have higher CR rates and better survival than B-lineage ALL,18,20 the present study showed no difference in terms of CR rate, OS and DFS as our previous studies.9,10

Here, we have proposed a risk model for adult ALL using age, WBC count and karyotype. It is slightly different from the previous risk models,3,18 because Ph chromosome is included as the worst prognostic factor in our model. There is a clear separation of OS by these risk groups in this study (Figure 3). We applied the same risk model to the previous JALSG studies to examine whether this model is generally relevant or not. As shown in Figure 6, this model also separates OS clearly in both studies.

Figure 6
figure6

Overall survival according to the risk model for all patients who had adequate cytogenetic data in the ALL87 and the ALL90 study. (a) The ALL 87 study: predicted 5-year overall survival (OS) rate for the low-risk group was 46%, while those for the intermediate-risk group and the high-risk group were 27% and 12%, respectively. (b) The ALL 90 study: predicted 5-year OS rate for the low-risk group was 48%, while those for the intermediate-risk group and the high-risk group were 20% and 3%, respectively.

Risk-adapted chemotherapy has been applied to pediatric studies for ALL, and the treatment outcome has much improved.1,21,22 In adult ALL studies, regimens for mature B-ALL (FAB L3) have generally been separated from others, and have improved prognosis in this subgroup.23 Therefore, we plan to tailor the treatment according to the above three risk groups in the next JALSG study after separating FAB L3 patients.

In this study, we prospectively compared the DFS between early sequential intensification and intermittent intensification during the maintenance phase, and observed no significant difference. On the other hand, the UKALL trial XA compared the DFS between early intensification and late intensification in randomized fashion, and concluded that early intensive treatment prevented relapses.7 However, the timing of their early intensification was the same as the consolidation therapy in our study. All our CR patients received early intensive treatment, which we termed as consolidation. Therefore, this may be the reason why we observed no difference between early sequential and intermittent intensification during maintenance. Sufficient number of patients would be needed to draw any conclusion, because only 91 patients were randomized in this study.

According to the JMDP, 5-year survival rates of adult ALL patients who received HLA-matched related BMT or HLA-matched unrelated BMT in their first CR are 51% and 54%, respectively.24 Thus, survival of patients who receive BMT in their first CR seems better than that of patients who receive chemotherapy. However, BMT is performed only in such patients as the relatively young with no impaired organ function. In our study, related allo-BMT in first CR did not result in superior survival than chemotherapy in an intent-to-treat analysis (Figure 4). We also compared the survival between the patients who actually received allo-BMT and those who underwent chemotherapy, and revealed no difference. In the previous ALL90 study, survival for the allo-BMT group was not superior to that of the chemotherapy group.10 Moreover, the matched-pair analysis between patients who received chemotherapy in the JALSG ALL 87 study and patients who received allo-BMT in their first CR and were registered with the International Bone Marrow Transplantation Registry revealed that leukemia-free survival was better following transplants than chemotherapy in patients aged 30 years or less but comparable in patients aged more than 30 years.25 Therefore, the role of allo-BMT in first CR remains controversial in adult ALL.

The CR rate of Ph-positive ALL was only 54%, and similar to that of the ALL87 (64%)9 and of the ALL90 (58%).10 Thus, an AML-like induction therapy employed in this study could not raise the CR rate in Ph-positive ALL. OS and DFS of these patients were much worse than those of Ph-negative cases (Table 3), which confirmed the well-known poor prognosis of adult patients with Ph-positive ALL. Recently, a 90% CR rate for Ph-positive ALL was attained using hyper-CVAD.26 STI-571 is also reported to be effective for Ph-positive ALL.27,28 However, the durations of response were short in both studies.26,28 Therefore, SCT in CR is a promising treatment for long-term survival, however, its efficacy remains unsolved. In this study, Ph-positive patients who received allo-BMT in their first CR had better survival than those who received chemotherapy (Figure 5). However, further studies are needed to draw any conclusion, because small numbers of patients were analyzed in this study.

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Acknowledgements

The authors are grateful to all participating physicians from 40 institutions in the Japan Adult Leukemia Study Group for their cooperation with this study. Thanks also to Ms Yuko Makino for her excellent secretarial assistance. This study was supported, in part, by Grants-in-Aid for Cancer Research 9–2 from the Ministry of Health and Welfare, Japan.

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Correspondence to J Takeuchi.

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Takeuchi, J., Kyo, T., Naito, K. et al. Induction therapy by frequent administration of doxorubicin with four other drugs, followed by intensive consolidation and maintenance therapy for adult acute lymphoblastic leukemia: the JALSG-ALL93 study. Leukemia 16, 1259–1266 (2002) doi:10.1038/sj.leu.2402526

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Keywords

  • acute lymphoblastic leukemia
  • doxorubicin
  • allogeneic bone marrow transplantation
  • prognostic factors
  • Japan Adult Leukemia Study Group (JALSG)

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