Cancer and Leukemia Group B (CALGB) Study 19802, a phase 2 study, evaluated whether dose intensification of daunorubicin and cytarabine could improve disease-free survival (DFS) in adults with acute lymphoblastic leukemia (ALL) and whether high-dose systemic and intrathecal methotrexate could replace cranial radiotherapy for central nervous system (CNS) prophylaxis.
One hundred sixty-one eligible, previously untreated patients ages 16 to 82 years (median age, 40 years) were enrolled, and 33 (20%) were aged ≥60 years.
One hundred twenty-eight patients (80%) achieved complete remission (CR). Dose intensification of daunorubicin and cytarabine was feasible. At a median follow-up of 10.4 years for surviving patients, the 5-year DFS rate was 25% (95% confidence interval, 18%-33%), and the overall survival (OS) rate was 30% (95% confidence interval, 23%-37%). Patients aged <60 years who received the 80 mg/m2 dose of daunorubicin had a DFS of 33% (95% confidence interval, 22%-44%) and an OS of 39% (95% confidence interval, 29%-49%) at 5 years. Eighty-four patients (52%) relapsed, including 9 patients (6%) who had isolated CNS relapses. The omission of cranial irradiation did not result in higher than historic CNS relapse rates.
During the last decade, attempts to improve the survival of adults with acute lymphoblastic leukemia (ALL) have focused on the role of early dose intensification to eradicate minimal residual disease and prevent the emergence of drug-resistant subclones.1-7 Several trials have explored the role of allogeneic hematopoietic cell transplantation performed in first remission.8, 9 Others have tested the efficacy of dose intensification of several of the drugs that are standard components of ALL regimens.4, 10-13 Todeschini et al13 used high doses of daunorubicin (cumulative dose, 270 mg/m2) during induction and high-dose cytarabine during postremission consolidation and reported a high complete remission (CR) rate of 93% and an estimated 6-year event-free survival of 55% in a small series of adults with ALL between ages 14 and 71 years.
Effective central nervous system (CNS) prophylaxis is also an essential component of therapy. Pediatric ALL regimens have tested a variety of approaches to reduce CNS relapses while minimizing the long-term toxicities of CNS-directed therapies. It has been demonstrated that the substitution of high doses of systemic methotrexate and cytarabine for cranial irradiation, given in combination with intrathecal (IT) methotrexate and/or cytarabine during postremission therapy, is feasible and safe in both children and adults with ALL and may result in lower cumulative neurotoxicity.4, 12, 14-17 Others have suggested that the combination of oral, intravenous, and IT methotrexate administered to achieve prolonged serum levels can result in effective CNS prophylaxis.18-20
Cancer and Leukemia Group B (CALGB) study 19802 was designed to test the hypothesis that dose intensification of daunorubicin during induction and of cytarabine during the first weeks of postremission treatment would result in rapid leukemia cytoreduction, lead to high CR rates, and improve disease-free survival (DFS) by preventing the emergence of drug-resistant leukemia clones that could lead to relapse. The second objective was to determine whether the administration of high-dose intravenous, oral, and IT methotrexate could result in prolonged serum exposure and safely and effectively replace the cranial irradiation that was used for CNS prophylaxis in all previous CALGB regimens.
MATERIALS AND METHODS
From January 1999 through January 2001, 163 adults (aged ≥16 years) with untreated ALL were enrolled on CALGB 19802. No prior treatment for ALL, including corticosteroids, was allowed with the exception of emergency treatment for hyperleukocytosis using hydroxyurea and/or leukapheresis or a single dose of cranial irradiation for CNS leukostasis. Patients with a mature B-cell (Burkitt) immunophenotype were not eligible for this study.
CALGB 19802 treatment consisted of 6 monthly modules of intensive therapy (modules A1, B1, C1, A2, B2, and C2) followed by 18 months of maintenance therapy (Fig. 1). Planned dose intensification of daunorubicin occurred during modules A1 and A2; patients received high-dose cytarabine during modules B1 and B2; and they received high-dose intravenous methotrexate, oral methotrexate, and IT methotrexate during both C modules. Patients also received IT therapy during each of the B modules, as detailed in Table 1. Previously, CALGB used 3 daily daunorubicin doses of 45 mg/m2 for patients aged <60 years and 30 mg/m2 for patients aged ≥60 years. In the current study, we escalated the daunorubicin dose to 60 mg/m2 intravenously on days 1 through 3 for the first 50 patients and then to 80 mg/m2 on days 1 through 3 for all subsequent patients aged ≤60 years. Patients aged >60 years received only the 60 mg/m2 daunorubicin dose. All treatment ended 24 months after diagnosis. For patients who had high-risk cytogenetics, including the t(9;22)(q34;q11.2) and t(4;11)(q21;q23) translocations, allogeneic hematopoietic cell transplantation was recommended soon after they achieved remission.
Table 1. Patient Characteristics, N = 161
No. of Patients (%)
Abbreviations: ALL, acute lymphoblastic leukemia; Ph+, Philadelphia chromosome-positive; WBC, white blood cells.
Age: Median [range], y
Presenting WBC: Median [range], ×103/μL
Age distribution, y
ECOG performance status
Immunophenotype, n = 124 evaluable
Cytogenetics, n = 98 evaluable
Unfavorable excluding Ph+
Age ≥60 y
Age <60 y
Age <60 y
The objective of this study was to evaluate the CR and DFS rates for this regimen as well as the rates of adverse events. The null hypothesis was a CR rate ≤70% versus the alternative hypothesis of a CR rate ≥80%. DFS was measured from the date of CR to the date of relapse or death. The precision for the 5-year DFS estimate was expected to be ±10%. Exact 95% confidence intervals (CIs) for the CR rate were computed based on binomial distribution. CR rates between groups were analyzed using the Fisher exact test. Survival estimates with 95% CIs were computed using the product-limit (Kaplan-Meier) method. Tests for differences in survival distributions between groups were performed using the Score (log-rank) statistic. SAS statistical software (version 9.1; SAS Institute, Inc., Cary, NC) was used for all statistical analyses, and S-Plus (version 7.0; Insightful Corporation, Seattle Wash) was used to generate the survival plots. The statistical analyses were completed on data as of February 22, 2012.
The patient characteristics are summarized in Table 1. The median patient age was 40 years (range, 16-82 years). There was no upper limit on age, and 33 patients (20%) were aged ≥60 years.
Pretreatment cytogenetic analyses were performed by CALGB-approved institutional cytogenetic laboratories on CALGB 8461, a prospective cytogenetic companion study, and the results were centrally reviewed (K.M., C.D.B.). Of the 163 enrolled patients, 2 had rearrangements involving 8q24 (v-myc myelocytomatosis viral oncogene homolog [MYC]), consistent with Burkitt-type ALL, and, thus, were ineligible for treatment on this study; and 63 patients (39%) were not submitted or were not evaluable. Thus, 98 patients (61%) were further characterized.21, 22 Forty-eight patients (49%) were classified with high-risk cytogenetics, defined as: t(9;22)(q34;q11.2) translocation or variants (n = 31), t(4;11)(q21;q23) translocation or other balanced translocation involving band 11q23 (n = 7), chromosome 7 loss (−7) (n = 1), chromosome 8 gain (+8) (n = 2), and hypodiploidy with a chromosome number ≤43 (n = 4). Thirty-one (32%) were classified with intermediate-risk cytogenetic, including normal karyotype (n = 18); abnormalities in the short arm of chromosome 9 (9p) (n = 4); high hyperdiploidy with a chromosome number ≥50 (n = 6), excluding near-tetraploidy; deletion of the long arm of chromosome 13 (del[13q]) (n = 2); and a derivative of chromosome 19 resulting from a t(1,19) translocation (dert[1,19]) (n = 1). Only 11 patients (11%) had a favorable karyotype (abnormalities involving region 11 of the long arm of chromosome 14 [14q11]; (n = 5; deletions and translocations involving 12p [n = 4]; and balanced rearrangements involving 7p14-15 and 7q34-36 [n = 2]). Eight patients (8%) had cytogenetic abnormalities with unknown prognostic significance: 3 had 14q32 abnormalities other than the t(8;14)(q24;q32), and 5 patients had a variety of other aberrations.
One hundred sixty-one patients were eligible and evaluable for response, and 128 patients (80%) achieved a CR (95% CI, 72%-85%) (Table 2). There were 16 (10%) treatment-related deaths during induction, and only 1 of those patients was aged <30 years (2%).
Table 2. Patient Characteristics and Outcomes
No. of Patients (%)
No. With CR (%)
95% CI, %
DFS at 5 Years [95% CI], %
OS at 5 Years [95% CI], %
Abbreviations: CI, confidence interval; CR, complete remission; DFS, disease-free survival; OS, ,overall survival; Ph, Philadelphia chromosome; WBC, white blood cells.
Age <60 y
Age ≥60 y
All patients who began treatment were evaluated for toxicity. Twenty-one patients (13%) died of treatment-related complications: 16 during induction therapy and 5 during postremission treatment. It is noteworthy that no significant cardiomyopathy was reported for any patient who received treatment at the daunorubicin 80 mg/m2 dose level. Life-threatening (grade 4) mucosal toxicities were reported in 5 patients during treatment, including 4 patients aged <60 years who had received the 80 mg/m2 daunorubicin dose. Grade 4 ataxia attributed to high-dose cytarabine was reported in 2 patients, both of whom were aged <60 years. Grade 3 or 4 mucositis and stomatitis rarely were reported during the C1 and C2 treatment modules; however, grade 3/4 cytopenia was reported in approximately 68% of patients who had mean serum methotrexate levels >2 μM in contrast to 38% of patients who had lower methotrexate levels (P = .004)
Disease-Free and Overall Survival
After a median follow-up of 10.4 years (range, 1.5-12.7 years) for 39 surviving patients, the 5-year DFS and overall survival (OS) rates for the entire study population were 25% (95% CI, 18%-33%) and 30% (95% CI,23%-37%), respectively (Table 2, Fig. 2). It is worth noting that, with longer follow-up, there were only 3 additional events (all bone marrow relapses) reported between years 3 and 5 of follow-up. After year 5, there were only 3 more events, only 1 of which was caused by disease relapse. Thus, there were very few relapses after 3 years. Patients aged <60 years fared significantly better than patients aged ≥60 years, who had 3-year DFS and OS rates of only 10% and 6%, respectively (P < .001) (Fig. 3, top). For younger adults who received the 80 mg/m2 daunorubicin dose during induction and postremission therapy, the 5-year DFS and OS rates were 33% and 39%, respectively, compared with a DFS rate of 18% and an OS rate of 29% for patients aged <60 years who received the 60 mg/m2 daunorubicin dose (Fig. 4).
Neither initial white blood cell count nor sex had an impact on DFS or OS in this study. However, survival differed according to both immunophenotype and cytogenetic subset. Patients who had precursor B-cell ALL had a hazard ratio for DFS of 1.5 compared with patients who had precursor T-cell ALL (P = .21) and had a significantly worse OS than the precursor T-cell group (hazard ratio, 1.9; P = .035). Cytogenetics remained an important prognosticator (Fig. 3, bottom). For the 11 patients who had a favorable karyotype, the DFS rate was 45% at 5 years, and the OS rate was 82%.
Central Nervous System Prophylaxis
One goal of CALGB 19802 was to replace CNS irradiation by combining weekly, high-dose, systemic, intravenous and sequential oral methotrexate administration with IT methotrexate. Approximately a third of evaluable patients achieved an average serum methotrexate level in the target range of 1 to 2 μM at 30 hours during these CNS-directed treatment modules. There was a trend toward lower CNS relapse rates when higher 30-hour methotrexate concentrations were achieved; however, the difference was not statistically significant.
Overall, 14 patients (9%) experienced a CNS relapse, including 9 patients (6%) who had an isolated CNS relapse and 5 patients (3%) who had simultaneous CNS and bone marrow relapses. It is noteworthy that isolated CNS relapses were reported more frequently in patients who had favorable cytogenetics. Five of 11 patients (45%) with favorable cytogenetics relapsed in the CNS, and those relapses occurred from 0.4 to 2.7 years after remission. Two of the CNS relapses in the favorable cytogenetics group occurred in patients who had translocations involving T-cell receptor genes, and the other 3 relapses occurred in patients with precursor B-cell ALL who had 12p deletions. In comparison, 6 of 31 patients (19%) who had intermediate cytogenetics and only 1 of 47 patients (2%) who had unfavorable karyotypes had an isolated CNS relapse (P = .0007).
Adherence to Protocol Therapy
Reasons for protocol discontinuation included failure to achieve a remission in 6 patients (4%), death during treatment in 21 patients (12%), recurrent disease during treatment in 43 patients (27%), treatment-related toxicity in 16 patients (10%)m withdrawal of consent in 10 patients (6%), removal for alternative therapies (other than transplantation) in 2 patients, and miscellaneous other reasons in 11 patients (7%). Thirty-five patients (22%) completed all planned therapy on this multicenter study. Another 14 patients (9%) with adverse cytogenetics (either Philadelphia chromosome-positive or 11q23 translocation) underwent allogeneic transplantation in first CR, as recommended by the protocol. Four additional patients were removed from protocol therapy at their physician's discretion and received hematopoietic cell transplantation in first CR; only 1 of those patients had centrally reviewed cytogenetics and had a complex karyotype.
The importance of anthracyclines for the achievement of higher CR rates among adults with ALL was demonstrated in an early CALGB randomized clinical trial23; however, higher CR rates have not translated into significant prolongation in DFS or OS. In the current study, in which the median patient age was 40 years (older than all previous CALGB studies of adult ALL), we demonstrated that it was feasible to intensify daunorubicin and cytarabine during induction and postremission therapy and to give effective CNS prophylaxis without cranial irradiation. However, the CR rate of 80% for all patients and the overall DFS and OS rates of 25% and 30%, respectively, were not better than what was reported previously in 3 previous CALGB studies of adults with ALL. In partial explanation, the percentage of patients with adverse prognostic features on this study was higher than in any previous CALGB study—the patients were older, and 49% had an adverse karyotype.
Because the CR rate of adults with ALL already is high and requires only an approximately 2-log reduction in the leukemic mass, we hypothesized that the benefit of dose escalation would be observed in a better DFS and OS, but probably not in a higher CR rate. This was true (Fig. 4, top): The DFS curve for the 80 mg/m2 daunorubicin dose cohort crossed the 60 mg/m2 cohort DFS curve after 2 years and plateaued at a higher level with 10 years of follow-up. It is noteworthy that, among patients who received the 80 mg/m2 daunorubicin dose, there were only 4 relapses reported more than 3 years after the achievement of CR.
The outcomes for patients aged <60 who received the highest cumulative dose of daunorubicin were similar to, but not better than, the 41% 3-year DFS rate reported by Bassan et al in their study of non-Philadelphia chromosome-positive patients who received daunorubicin dose intensification during induction or postremission therapy1 or the results of Todeschini et al,13 who reported that daunorubicin dose intensification during induction did not improve CR rates but resulted in improved DFS. In their study, Todeschini et al reported that patients who received a cumulative daunorubicin dose of ≥175 mg/m2 during induction had a DFS rate of 44% in contrast to only 22% for those who received a cumulative daunorubicin dose <175 mg/m2. Among our patients aged ≥60 years, we observed no benefit to dose intensification up to a cumulative daunorubicin dose of 180 mg/m2 during induction; the treatment-related death rate was 21%, and the DFS (10%) and OS (6%) rates remained very poor. A similar increase in toxicity among older adults and lack of an OS benefit from liposomal daunorubicin and cytarabine intensification also was noted in a recently published study from Thomas and colleagues at The University of Texas M. D. Anderson Cancer Center.24 Previously defined intermediate-risk and high-risk cytogenetic risk groups21, 22, 25, 26 did not predict for different outcomes on this study. One interpretation of this observation is that the more dose-intensive use of daunorubicin and cytarabine actually did provide a survival benefit to these patients with poor-risk ALL.
In our current study, we demonstrated that it is possible to replace cranial irradiation by administering intensive, systemic methotrexate together with IT methotrexate prophylaxis. Isolated CNS relapses occurred in 9 patients (6%), which is comparable to the CNS relapse rates reported on 4 prior CALGB studies that included cranial irradiation. CNS relapse rates on those 4 studies ranged from 9% to 14%. Our results also are similar to the 4% isolated CNS relapse rate that was reported by The M. D. Anderson Cancer Center group in their long-term follow-up of their hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone regimen, which does not use cranial irradiation.4 We attempted to adjust methotrexate dosing to maintain 1-μM or 2-μM concentrations 30 hours after the initiation of high-dose, systemic methotrexate and IT methotrexate based on a report of its favorable effect on reducing CNS relapses.20 Among 101 evaluable patients, there were no significant differences in CNS relapse rates noted as a function of mean 30-hour methotrexate levels. Although we noted a trend toward fewer CNS relapses in patients who had higher circulating methotrexate levels, 30-hour methotrexate levels >2 μM also were associated with more systemic toxicities, including mucositis and prolonged myelosuppression.
Further reductions in CNS relapse rates may be achieved by the earlier introduction of specific CNS-directed prophylaxis in future study regimens (rather than beginning 29 days after diagnosis, as in CALGB 19802); or by the substitution of dexamethasone for prednisone, which has been associated with lower CNS and systemic relapse rates in pediatric and adult ALL regimens27, 28; and/or by the use of CNS irradiation only for patients at high risk of CNS relapse, such as patients with T-cell ALL who have high initial white blood cell counts.29 A recent, large, retrospective analysis of CNS relapses in 467 adults with ALL reported no differences in relapse rates for those who received CNS prophylaxis with cranial irradiation compared with those who did not receive CNS irradiation.17 It was noted that the only clinical factor associated with CNS relapse was a high initial lactate dehydrogenase level of >1000 U/μL.30 In our study, we could not identify any associations between the CNS relapse rate and immunophenotype or high initial white blood cell count; the pretreatment lactate dehydrogenase level was not routinely recorded.
One of the sobering observations in our study was that 27% of patients relapsed before they completed protocol treatment. Another 22% of patients were not able to complete therapy because of toxicity, death during treatment (mostly during remission induction for younger adults who received the 80 mg/m2 daunorubicin dose and in older adults during both remission induction and postremission therapy), or removal from protocol therapy because of toxicity. Thus, early dose intensification of the myelosuppressive drugs daunorubicin and cytarabine was not a successful strategy to improve DFS or OS. It would be informative for other clinical investigators to report the percentage of all enrolled patients who complete all planned therapy on pediatric and adult ALL studies as well as adherence to the timing of scheduled treatment for comparative purposes.
Recent retrospective studies examining outcomes of adolescents and younger adults with ALL have suggested that the nonmyelosuppressive agents that are active in ALL, such as glucocorticoids, vincristine, and L-asparaginase, are critical drugs for intensification to improve DFS in higher risk children and older adolescents with ALL.31-33 Although the intensification of these agents in regimens for older adults with ALL may pose a clinical challenge because of their own unique toxicities, early results from several pilot trials suggest that it is possible to use this approach in adults up to ages 30 to 40 years with encouraging, albeit, preliminary results.34-36
In conclusion, a singular dose-intensive approach to the treatment of all adults with ALL is not likely to result in further significant survival benefits, and there remains much room for improvement. The biologic heterogeneity of adults with ALL suggests that this may be achieved best by the incorporation of biologically targeted agents into frontline therapy, as demonstrated recently with the addition of tyrosine kinase inhibitors to frontline therapy for adults and children with Philadelphia chromosome-positive ALL, the promising early data from the pediatric groups on the addition of nelarabine to frontline therapy for children with T-cell leukemia/lymphoma, and the addition of rituximab to frontline therapy that reportedly improved relapse-free survival and OS in younger adults with CD20-positive ALL compared with historic controls.37 Thus, rather than further exploration of dose intensification as described here in CALGB 19802, innovative therapeutic strategies for adult ALL should be tailored to specific age groups and/or cytogenetic/molecular genetic subsets.
This work was supported in part by National Cancer Institute grants CA31946, CA33601, CA41287, CA32291, CA35279, CA03927, CA02599, CA101140, and CA77658; by the Coleman Leukemia Research Foundation; and by the University of Chicago Comprehensive Cancer Center.