Outcome of treatment in adults with acute lymphoblastic leukemia: analysis of the LALA-94 trial.

PURPOSE: We analyzed the benefits of a risk-adapted postremission strategy in adult lymphoblastic leukemia (ALL), and re-evaluated stem-cell transplantation (SCT) for high-risk ALL. PATIENTS AND METHODS: A total of 922 adult patients entered onto the trial according to risk groups: standard-risk ALL (group 1), high-risk ALL (group 2), Philadelphia chromosome-positive ALL (group 3), and CNS-positive ALL (group 4). All received a standard four-drug/4-week induction course. Patients from group 1 who achieved a complete remission (CR) after one course of induction therapy were randomly assigned between intensive and less intensive postremission chemotherapy, whereas those who achieved CR after salvage therapy were then included in group 2. Patients in groups 2, 3, and 4 with an HLA-identical sibling were assigned to allogeneic SCT. In groups 3 and 4, autologous SCT was offered to all other patients, whereas in group 2 they were randomly assigned between chemotherapy and autologous SCT. RESULTS: Overall, 771 patients achieved CR (84%). Median disease-free survival (DFS) was 17.5 months, with 3-year DFS at 37%. In group 1, the 3-year DFS rate was 41%, with no difference between arms of postremission randomization. In groups 2 and 4, the 3-year DFS rates were 38% and 44%, respectively. In group 2, autologous SCT and chemotherapy resulted in comparable median DFS. Patients with an HLA-matched sibling (groups 2 and 4) had improved DFS. Three-year DFS was 24% in group 3. CONCLUSION: Allogeneic SCT improved DFS in high-risk ALL in the first CR. Autologous SCT did not confer a significant benefit over chemotherapy for high-risk ALL.     

Outcome of treatment after first relapse in younger adults with acute myeloid leukemia initially treated by the ALFA-9802 trial

Forty-seven percent of adults with acute myeloid leukemia (AML) who entered the ALFA-9802 trial and achieved a first complete remission (CR) experienced a first relapse. We examined the outcome of these 190 adult patients. Eighty-four patients (44%) achieved a second CR. The median overall survival (OS) after relapse was 8.9 months with a 2-year OS at 25%. Factors predicting a better outcome after relapse were stem cell transplant (SCT) performed in second CR and a first CR duration >1 year. Risk groups defined at the time of diagnosis and treatment received in first CR also influenced the outcome after relapse. The best results were obtained in patients with core binding factor (CBF)-AML, while patients initially defined as favorable intermediate risk showed a similar outcome after relapse than those initially entering the poor risk group. We conclude that most adult patients with recurring AML could not be rescued using current available therapies, although allogeneic SCT remains the best therapeutic option at this stage of the disease.     

Secondary or concomitant neoplasms among adults diagnosed with acute lymphoblastic leukemia and treated according to the LALA-87 and LALA-94 trials

BACKGROUND: Second malignant neoplasms are a serious complication after successful treatment of childhood acute lymphoblastic leukemia (ALL). Although treatment intensity and outcome were not comparable, with improvements in survival it is important to evaluate the rate and the type of second neoplasms in adults with ALL. METHODS: The data from the GET-LALA group were analyzed. A cohort of 1494 patients, aged 15 to 60 years and enrolled in 2 successive multicenter protocols between 1987 and 2002, was observed to determine the incidence of second neoplasms and associated risk factors. The median follow-up from diagnosis was 6 years. RESULTS: By February 2005 secondary or concomitant neoplasms were documented in 23 patients, including 9 acute myeloid leukemias (AML) or myelodysplasias (MDS), 4 non-Hodgkin lymphomas (NHL), 5 skin tumors, and 5 other solid tumors (1 lung cancer, 1 tongue carcinoma, 1 thymoma, 1 condrosarcoma, 1 histiocytosis). Neoplasms developed 0.5 to 13.8 years (median, 4.5 years) after the diagnosis of ALL. There were 22 patients in first remission and 1 was in second remission. The overall cumulative risk of secondary neoplasms was 2.1% at 5 years, 4.9% at 10 years, and 9.4% at 15 years. The cumulative risk of developing a second hematologic malignancy was 1.8% at 5 years, 2.2% at 10 years, 3.3% at 18 years; that of developing a solid tumor was 0.2% at 5 years, 2.8% at 10 years, 6.2% at 15 years. The development of secondary neoplasm was not associated with the use of any specific cytotoxic agent. However, the risk of skin tumor increased with radiation dose and transplantation (P = .01). Overall survival (OS) after the diagnosis of a second malignant neoplasm was 55% at 10 years. However, the median OS in patients developing AML/MDS was 5.7 months. CONCLUSIONS: The data document that adult ALL survivors are at an increased risk of later malignancy. The risk of secondary or concomitant neoplasm appeared higher than that of childhood ALL previously reported in the literature. Considering the low survival rate of this large unselected adult ALL cohort (32% at 10 years) as compared with that observed in childhood ALL, the risk of second malignancy remains underestimated. Larger series with long-term follow-up are necessary, as well as methods of screening and identification of patients at increased risk.     

Should adolescents with acute lymphoblastic leukemia be treated as old children or young adults? Comparison of the French FRALLE-93 and LALA-94 trials.

PURPOSE: To compare pediatric and adult therapeutic practices in the treatment of acute lymphoblastic leukemia (ALL) in adolescents. PATIENTS AND METHODS: From June 1993 to September 1994, 77 and 100 adolescents (15 to 20 years of age) were enrolled in the pediatric FRALLE-93 and adult LALA-94 protocols, respectively. Among the different prognostic factors, we retrospectively analyzed the effect of the trial on achieving complete remission (CR) and event-free survival (EFS). RESULTS: Patients were younger in the FRALLE-93 than in the LALA-94 protocol (median age, 15.9 v 17.9 years, respectively), but other characteristics were similar, including median WBC count (18 x 10(9) cells/L v 16 x 10(9) cells/L), B/T-lineage (54 of 23 v 72 of 28 patients), CD10-negative ALL (13% v 15%), and poor-risk cytogenetics (t(9;22), t(4;11), or hypodiploidy less than 45 chromosomes: 6% v 5%). The CR rate depended on WBC count (P =.005) and trial (94% v 83% in FRALLE-93 and LALA-94, respectively; P =.04). Univariate analysis showed that unfavorable prognostic factors for EFS were as follows: the trial (estimated 5-year EFS, 67% v 41% for FRALLE-93 and LALA-94, respectively; P <.0001), an increasing WBC count (P <.0001), poor-risk cytogenetics (P =.005), and T-lineage (P =.01). The trial and WBC count remained significant parameters for EFS in multivariate analysis (P <.0001 and P =.0004). Lineage subgroup analysis showed an advantage for the FRALLE-93 trial for CR achievement (98% v 81%; P =.002) and EFS (P =.0002) in B-lineage ALL and for EFS (P =.05) in T-lineage ALL. Age was not a significant prognostic factor in this population of adolescents. CONCLUSION: This study's findings indicate that adolescents should be included in intensive pediatric protocols and that new trials should be designed, inspired by pediatric protocols, for the treatment of young adults with ALL.     

Autologous stem cell transplantation in adults with acute lymphoblastic leukemia in first complete remission: analysis of the LALA-85, -87 and -94 trials.

To evaluate the results of autologous stem cell transplantation (ASCT) in a large population of adults with acute lymphoblastic leukemia (ALL) in first complete remission (CR), we performed an individual data-based overview of the last three trials from the LALA group. Overall, 349 patients with ALL prospectively randomized in the consecutive LALA-85, -87, and -94 trials to receive either ASCT or chemotherapy as post-CR treatment were analyzed. Eligibility criteria were 15-50-year-old patients without sibling donors in both LALA-85/87 trials and 15-55-year-old patients with high-risk ALL and no sibling donors in the LALA-94 trial. Intent-to-treat analysis, which compared 175 patients from the ASCT arm to 174 patients from the chemotherapy arm, showed that ASCT was associated with a lower cumulative incidence of relapse (66 vs 78% at 10 years; P=0.05), without significant gain in disease-free or overall survival. Despite a possible lack of statistical power, a nested case-control analysis performed in 85 patient pairs adjusted for time to transplant and prognostic covariates confirmed these intent-to-treat results in patients actually transplanted. Of interest, the reduced relapse risk after ASCT translated in better disease-free survival in the 300 rapid responders who reached CR after the first induction course.     

Central nervous system relapse in adults with acute lymphoblastic leukemia

BACKGROUND: Recurrence of acute lymphoblastic leukemia (ALL) in the central nervous system (CNS) in adults is considered a poor prognostic feature. Few reports have analyzed this issue. The objective of this study was to analyze the experience with CNS recurrence in adult patients with ALL. METHODS: Between December 1982 and April 2000, the records of 527 consecutive, newly diagnosed patients with ALL who were treated at the M. D. Anderson Cancer Center were reviewed. Patients were treated with one of two published regimens: vincristine, doxorubicin, and dexamethasone (VAD; n = 237 patients) or hyperfractionated cyclophosphamide plus VAD (hyper-CVAD) (n = 290 patients). Among 439 patients (83%) who achieved complete remission (CR), 32 patients (7%) had a CNS recurrence. All patients had received CNS prophylaxis tailored to the risk of CNS recurrence with systemic chemotherapy with or without intrathecal (IT) chemotherapy; none received cranial radiotherapy for prophylaxis. The records of these patients were reviewed. RESULTS: The median age at the time of diagnosis was 33 years. The median CR duration prior to CNS recurrence was 36 weeks (range, 2-185 weeks). Three groups were identified: 1) patients with an isolated CNS recurrence (n = 17 patients), 2) patients with CNS recurrences after bone marrow (BM) recurrence (n = 8 patients), and 3) patients with simultaneous CNS and BM recurrences (n = 7 patients). IT chemotherapy was effective in achieving a CNS CR in 30 patients (94%), but 10 patients (31%) had a second CNS recurrence. The median survival from CNS recurrence was 6 months; 28% of patients were alive at 1 year, and 6% of patients were alive at 4 years. CONCLUSIONS: Adults with ALL and CNS recurrences have a poor prognosis despite effective IT chemotherapy. Future studies should investigate better approaches in the treatment of these patients to improve their long-term survival. Effective CNS prophylaxis remains the single best approach for treating patients with CNS leukemia.     

Outcome following late marrow relapse in childhood acute lymphoblastic leukemia

Thirty-four children with acute lymphoblastic leukemia, who developed bone marrow relapse after treatment was electively stopped, received reinduction, consolidation, continuing therapy, and intrathecal (IT) methotrexate (MTX). Sixteen children who relapsed within six months of stopping treatment had a median second-remission duration of 26 weeks; all next relapses occurred in the bone marrow. In 18 children who relapsed later, the median duration of second remission was in excess of two years, but after a minimum of four years' follow-up, 16 patients have so far relapsed again (six in the CNS). CNS relapse occurred as a next event in four of 17 children who received five IT MTX injections only and in two of 14 children who received additional regular IT MTX. Although children with late marrow relapses may achieve long second remissions, their long-term out-look is poor, and regular IT MTX does not afford adequate CNS prophylaxis. It remains to be seen whether more intensive chemotherapy, including high-dose chemoradiotherapy and bone marrow transplantation, will improve the prognosis in this group of patients.     

Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia after first relapse.

Using flow cytometric techniques capable of detecting 0.01% leukemic cells, we prospectively studied minimal residual disease (MRD) in patients with acute lymphoblastic leukemia (ALL) after first relapse. At the end of remission reinduction, 41 patients had a bone marrow sample adequate for MRD studies; 35 of these were in morphologic remission. Of the 35 patients, 19 (54%) had MRD >/=0.01%, a finding that was associated with subsequent leukemia relapse. The 2-year cumulative incidence of second leukemia relapse was 70.2+/-12.3% for the 19 MRD-positive patients and 27.9+/-12.4% for the 16 MRD-negative patients (P=0.008). Among patients with a first relapse off therapy, 2-year second relapse rates were 49.1+/-17.8% in the 12 MRD-positive and 0% in the 11 MRD-negative patients (P=0.014); among those who received only chemotherapy after first relapse, the 2-year second relapse rates were 81.5+/-14.4% (n=12) and 25.0+/-13.1% (n=13), respectively (P=0.004). Time of first relapse and MRD were the only two significant predictors of outcome in a multivariate analysis. We conclude that MRD assays should be used to guide the selection of postremission therapy in patients with ALL in first relapse.     

Modern treatment programs for adults with acute lymphoblastic leukemia

The current treatment programs for adult patients with acute lymphoblastic leukemia are modeled on pediatric regimens. The result has been complete remission rates comparable to those seen in children, but a significant proportion of adult patients relapse. Salvage therapy for patients with acute lymphoblastic leukemia continues to have limited success. Advances in molecular biology have discovered new targets for therapeutic intervention, and the introduction of some targeted agents, such as the new tyrosine kinase inhibitors and monoclonal antibodies, has led to improvements in response and survival in some subsets. The development of techniques for identification and monitoring of minimal residual leukemia has provided possible ways to predict relapse and consider early intervention. It is likely that we will further refine therapeutic approaches and improve patient outcome through the translation of biologic and molecular discoveries into effective and risk-adapted strategies.     

Low-dose oral etoposide-based induction regimen for children with acute lymphoblastic leukemia in first bone marrow relapse.

We evaluated the clinical response to low-dose etoposide in relapsed acute lymphoblastic leukemia (ALL). Of the 45 patients with ALL in first bone marrow relapse enrolled on the ALL R15 protocol, 44 had received epipodophyllotoxins during frontline therapy. In the first week of remission induction therapy, patients received etoposide (50 mg/m(2) per day) administered orally as a single agent once or twice daily. On Day 8, patients started to receive dexamethasone, vincristine, and L-asparaginase. Etoposide was administered until Day 22. Two courses of consolidation therapy were followed by continuation therapy or hematopoietic stem cell transplantation. After 7 days of single-agent etoposide treatment, peripheral blast cell counts (P=0.013) and percentages of bone marrow blasts (P=0.016) were significantly reduced. In all, 38 (84.4%) attained second remission. Only time to relapse was significantly associated with outcome (P=0.025): the 5-year event-free survival estimates (+/-se) were 52.0+/-9.6% for those with late relapse and 20.0+/-8.0% for those with early relapse. We conclude that low-dose etoposide administered orally has a cytoreductive effect in relapsed ALL.     

Outcome of children treated for relapsed acute lymphoblastic leukemia in Central America

BACKGROUND:

Outcomes for relapsed childhood acute lymphoblastic leukemia (ALL) have not been documented in resource‐limited settings. This study examined survival after relapse for children with ALL in Central America.

METHODS:

A retrospective cohort study was performed and included children with first relapse of ALL in Guatemala, Honduras, or El Salvador between 1990 and 2011. Predictors of subsequent event‐free survival (EFS) and overall survival (OS) were examined.

RESULTS:

There were 755 children identified with relapsed disease. The median time from diagnosis to relapse was 1.7 years (interquartile range, 0.8‐3.1 years). Most relapses occurred during (53.9%) or following (24.9%) maintenance chemotherapy, and the majority occurred in the bone marrow (63.1%). Following the initial relapse, subsequent 3‐year EFS (± standard error) and OS were 22.0% ± 1.7%, and 28.2% ± 1.9%, respectively. In multivariable analysis, worse postrelapse survival was associated with age ≥ 10 years, white blood cell count ≥ 50 × 10⁹/L, and positive central nervous system status at the original ALL diagnosis, relapse that was not isolated central nervous system or testicular, and relapse < 36 months following diagnosis. Site and time to relapse were used to identify a favorable risk group whose 3‐year EFS and OS were 50.0% ± 8.9% and 68.0% ± 8.1%, respectively.

CONCLUSIONS:

Prognosis after relapsed ALL in Central America is poor, but a substantial number of those with favorable risk features have prolonged survival, despite lack of access to stem cell transplantation. Stratification by risk factors can guide therapeutic decision‐making. Cancer 2013. © 2012 American Cancer Society.     

成人急性淋巴细胞白血病治疗进展

【指示性摘要】尽管应用各种不同的诱导缓解方案,80％-95％的成人急性淋巴细胞白血病（ALL）可获得形态学上的完全缓解,但大部分病人很快复发。能否获得免疫学或分子水平的微小残留病（MRD）状态及达到MRD的速度极为重要。缓解后治疗是病人长期生存的关键。接受异基因移植的病人复发率明显降低。但在年龄35—40岁以上的移植患者中,较高的移植相关死亡率抵消了异基因移植的生存优势。相配无关供体移植的应用日益广泛,可用于所有高危病人。降低强度的移植可能增加老年患者的生存率。伊马替尼甲磺酸的应用彻底改变了ph阳性ALL的治疗方法,特别是该型老年患者。诊断时有CNS累及的患者,只要给予及时治疗,对预后无明显不利影响。     

Outcome of 40 adults aged from 18 to 55 years with acute lymphoblastic leukemia treated with double-delayed intensification pediatric protocol

Adolescents ALL have a better outcome when treated with pediatric protocol compared to adult protocol. We have tested the feasibility of pediatric protocol to treat 40 consecutive adults ALL. DFS and OS were 73 ± 7%, and 72 ± 7%, and were significantly longer in patients under 40 yo (81 ± 9% vs 51 ± 15%, p = 0.05 [DFS] and 83 ± 7.8% vs 45 ± 15%, p = 0.003 [OS], respectively) or cortico/chemo-sensitive (86 ± 9% vs 36 ± 16%, p = 0.001 [DFS] and 95 ± 4.4% vs 28 ± 13%, p < 0.0001 [OS]) than in other patients. Overall tolerance was acceptable. We have shown the feasibility of using this unmodified pediatric protocol to treat adult with ALL up to 40 years.     

成人急性淋巴细胞白血病治疗进展

尽管应用各种不同的诱导缓解方案,80%-95%的成人急性淋巴细胞白血病(ALL)可获得形态学上的完全缓解,但大部分病人很快复发.能否获得免疫学或分子水平的微小残留病(MRD)状态及达到MRD的速度极为重要.缓解后治疗是病人长期生存的关键.接受异基因移植的病人复发率明显降低.但在年龄35-40岁以上的移植患者中,较高的移植相关死亡率抵消了异基因移植的生存优势.相配无关供体移植的应用日益广泛,可用于所有高危病人.降低强度的移植可能增加老年患者的生存率.伊马替尼甲磺酸的应用彻底改变了ph阳性ALL的治疗方法,特别是该型老年患者.诊断时有CNS累及的患者,只要给予及时治疗,对预后无明显不利影响.     

Immunologic monitoring in adults with acute lymphoblastic leukemia

Investigation of minimal residual disease (MRD) by immunophenotyping and molecular techniques has proven to be a powerful approach for disease monitoring in patients with acute leukemia. Multiparameter flow cytometry, through the use of triple or quadruple marker combinations, identifies aberrant or uncommon phenotypic profiles in more than 90% of adult patients with acute lymphoblastic leukemia (ALL) at diagnosis. These profiles allow identification of residual leukemic cells in bone marrow or peripheral blood once morphologic complete remission is achieved. Until now, most immunophenotypic MRD studies in ALL have focused on children. In contrast, information on the value of MRD in adults with ALL is scanty and usually restricted to polymerase chain reaction studies. In this review, we focus on technical aspects of MRD detection by flow cytometry and on the clinical data concerning the value of immunologic MRD studies as a tool for relapse prediction in adult ALL. Although prospective studies are needed, we assert that immunophenotypic MRD studies are clinically useful. Such studies should be incorporated into the routine management of adult ALL patients for identification of those at high risk of relapse, who could benefit from new alternative therapeutic approaches, and to distinguish these patients from others who could be cured with more conventional approaches.