Chromosome-positive Adult Acute Lymphoblastic Leukemia Research Articles

Evaluating outcomes of adult patients with acute lymphoblastic leukemia and lymphoblastic lymphoma treated on the GMALL 07/2003 protocol.

Chemotherapy-based approaches still constitute an essential feature in the treatment paradigm of adult acute lymphoblastic leukemia (ALL). The German Multicenter Study Group (GMALL) is a well-established protocol for ALL. In this study, we assessed our recent experience with the GMALL 07/2003 protocol reviewing all adult ALL patients who were treated with GMALL in three major centers in Israel during 2007-2020. The analysis comprised 127 patients with a median age of 41 years (range 17-83). Sixty-two were B-ALL (49%), 20 (16%) patients were Philadelphia chromosome positive ALL, and 45 (35%) were T-ALL. The 2-year and 5-year overall survival rates were 71% and 57%, respectively. The 2-year relapse rate was 30% with 2-year and 5-year leukemia-free survival rates of 59% and 50%, respectively. Adolescents and young adults experienced significantly longer overall survival (84 months versus 51 months; p=0.047) as well as leukemia-free survival compared with older patients (66 months versus 54 months, p=0.003; hazard ratio=0.39, 95% confidence interval, 0.19-0.79; p=0.009). T-ALL patients had longer survival compared to B-ALL patients while survival was comparable among Philadelphia chromosome positive patients and Philadelphia chromosome negative patients. An increased number of cytogenetic clones at diagnosis were tightly associated with adverse prognosis (15-month survival for ≥2 clones versus 81 months for normal karyotype; p=0.003). Positive measurable residual disease studies following consolidation were predictive for increased risk of relapse (64% versus 22%; p=0.003) and shorter leukemia-free survival (11 months versus 42 months; p=0.0003). While GMALL is an effective adult regimen, a substantial patient segment still experiences relapse.

Evaluating Outcomes of Adult Patients with Acute Lymphoblastic Leukemia Treated on the GMALL Protocol

Background Chemotherapy based approaches still constitute an essential feature in the treatment paradigm of adult acute lymphoblastic leukemia (ALL). The German Multicenter Study Group (GMALL) is a well-established and commonly used protocol for ALL (Gökbuget 2012). Over the years evolving versions of the protocol have been developed with the aim of improving patient outcome (Apel 2014). In view of the recent advancements in the treatment of adult ALL we now analyzed our more recent data. Aims Assess the clinical outcomes of adult ALL patients treated on the GMALL protocol in real world settings, and establish prognostic parameters associated with long term survival and risk of relapse. Methods Retrospective analysis of all adult ALL patients who were treated with GMALL in our institution between the years 2008-2020. Demographic, clinical, cytogenetic, treatment, and transplant related data were collected using our institution's electronic medical records system. Baseline characteristics were evaluated by Fisher's exact test and Wilcoxon rank sum tests. Kaplan-Meier estimates were used to estimate overall survival (OS) and relapse-free survival (RFS). Hazard ratios and 95% confidence intervals were generated using a Cox proportional hazards model. Results The analysis comprised 81 evaluable patients with a median age of 36 years (range 18-73), 36% were adolescents and young adults (AYA). Forty-three were B-ALL (53%), 12 (15%) patients were Philadelphia chromosome positive ALL (Ph+ ALL), and 26 (32%) were T-ALL. Median duration of follow-up was 24.4 months (range 0.7-112.1 months), at the time of data analysis 51 patients (63.8%) were alive. Seventy patients (88%) attained a first remission (CR1) and 4 (5%) died during the first two induction phases. The 2-year and 5-year overall survival rates were 62% and 44%, respectively. Estimated 2-year and 5-year leukemia-free survival rates were 52% and 35%, respectively. Overall, disease relapse (31%), lethal infection (28%), and graft-versus-host disease (14%) accounted for most patient deaths. Of patients achieving CR1, 20 (29%) eventually relapsed after a median time of 9.8 months (range 1.1-69.3). Fifty-five patients (68%) underwent an allogeneic stem cell transplantation using matched sibling (47%), matched unrelated (31%), haploidentical (7%), partially mismatched (12%), and cord blood donors (3%). Of the 50 patients transplanted in CR1, 15 relapsed (30%) after a median time of 10.9 months (range 3.8-32.8). Multivariate analysis revealed that in terms of overall survival, increasing patient age was associated with inferior outcome [Hazard ratio (HR)=1.026, confidence interval (CI) 95%, 1.002-1.05, p=0.035) as was outcome for patients whose baseline cytogenetic analysis detected a higher number of clones (HR=2.69, CI 95%, 1.57-4.62, p=0.0002). T-ALL patients experienced longer survival compared with B-ALL (87 months versus 56 months, p=0.019) while patients transplanted using cord blood donors had inferior survival, 12.8 months, compared with matched sibling donors, 71.3 months, and fully matched unrelated donors, 73.4 months (p=0.001, and p=0.003, respectively). Relapse-free survival was significantly better in patients with T-ALL compared with B-ALL (90 months vs. 50 months, p=0.039), and in patients without t(12;21)(p13;q22) (75 months vs. 11.7 months, p=0.034). Gender, AYA status, extramedullary disease at diagnosis, initial white blood cell count, treatment delays, presence of MLL rearrangement, specific measurable residual disease modality used, GMALL risk category, and cytogenetic hyperdiploidy did not significantly impact on survival or disease relapse. Treatments for relapse following GMALL included blinatumomab (6), inotuzumab (3), nelarabine (3), and CAR-T (2). Conclusions While results are improving for patients treated on GMALL, a substantial patient segment still experiences relapse. It is conceivable that in the near future new novel therapeutic modalities for adult ALL involving the use of monoclonal antibodies and CAR-T cell therapy will help reduce relapse rates and further improve the current outcomes of patients treated on the GMALL protocol. Disclosures Avigdor: Takeda, Gilead, Pfizer: Consultancy, Honoraria; Janssen, BMS: Research Funding. Canaani:Abbvie: Consultancy, Honoraria, Research Funding.

Efficacy of Hyper-CVAD/MA and CHALL-01 regimens in the treatment of Philadelphia chromosome-positive adult acute lymphoblastic leukemia patients under 60 years old

目的比较传统Hyper-CVAD/MA方案及借鉴儿童急性淋巴细胞白血病（ALL）的新化疗方案CHALL-01在≤60岁成人Ph阳性ALL（Ph+ ALL）中的临床疗效。方法回顾性分析2007年1月至2017年12月第二军医大学附属长海医院及长征医院收治的158例Ph+ ALL患者（除外慢性髓性白血病急变期患者），其中Hyper-CVAD/MA组63例，CHALL-01组95例，诱导及巩固化疗期间联合酪氨酸激酶抑制剂（TKI）治疗，有合适供者的患者进行造血干细胞移植，并用TKI进行维持治疗。结果经过1~2个疗程的诱导治疗，91.1%（144/158）患者获得完全缓解（CR），其中Hyper-CVAD/MA组CR率为90.5%（57/63），CHALL-01组CR率为91.6%（87/95），两组间差异无统计学意义（χ2=0.057，P=0.811）。随访截止于2018年6月，共134例CR患者可进一步分析，其中Hyper-CVAD/MA组53例，CHALL-01组81例。CHALL-01组达到分子学缓解的比例显著高于Hyper-CVAD/MA组（完全分子学反应率：44.4%对22.6%，主要分子学反应率：9.9%对18.9%）（χ2=7.216，P=0.027）。Hyper-CVAD/MA组和CHALL-01组4年总生存率分别为44.81%（95%CI 30.80%~57.86%）和55.63%（95%CI 39.07%~69.36%）（P=0.037），4年无病生存率分别为37.95%（95%CI 24.87%~50.93%）和49.06%（95%CI 34.24%~62.29%）（P=0.015）。两组在4年累积复发率（P=0.328）及无复发死亡率（P=0.138）上差异无统计学意义。CHALL-01组肺部感染发生率较Hyper-CVAD/MA组明显减低（43.4%对67.9%，χ2=7.908，P=0.005）。结论CHALL-01方案治疗成人Ph+ ALL疗效优于Hyper-CVAD/MA方案，肺部感染发生率低，分子学缓解率高，可以提高Ph+ ALL患者的生存率。

New insights into the pathophysiology and therapy of adult acute lymphoblastic leukemia.

Significant advances have been made in the last decade toward a better understanding of the disease pathogenesis and the development of novel therapies that target specific subsets of adult acute lymphoblastic leukemia (ALL). Risk-adapted strategies are transforming the disease treatment and prognosis. With current treatment regimens, long-term survival is achieved by approximately 50% of patients with B-cell ALL, 50% to 60% of patients with Philadelphia chromosome-positive ALL, and approximately 80% of patients with Burkitt's leukemia. Genomic profiling in ALL has identified new prognostic markers, new therapeutic targets, and novel ALL subtypes. These may be amenable to future targeted therapies that can further improve outcomes. The early recognition of early precursor T-cell ALL, a distinct pathobiological entity with a poor prognosis, is essential for the development of an effective clinical management strategy. The role of monoclonal antibodies and cytotoxic T-cell therapies continues to be defined. Many of the approaches are currently being evaluated for ALL salvage. Their incorporation into frontline adult ALL therapy, in concomitant or sequential strategies, may increase the cure rates to levels achieved in pediatric ALL and may reduce the need for prolonged intensive and maintenance chemotherapy.

Ponatinib for the treatment of chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia

Ponatinib is a novel, next-generation, small-molecule tyrosine kinase inhibitor with potent activity against the BCR-ABL fusion oncogene as well as all other ABL kinase domain mutations that confer resistance to earlier generation tyrosine kinase inhibitors. Due to its unique structure, it is the only tyrosine kinase inhibitor with the capability to counter the highly resistant T315I or gate-keeper mutation in leukemic cells that express the Philadelphia chromosome. This review will focus on the preclinical pharmacology, pharmacokinetics and clinical utility of ponatinib in the treatment of chronic myeloid leukemia and Philadelphia chromosome-positive adult acute lymphoblastic leukemia.

IK6 isoform with associated cytogenetic and molecular abnormalities in Chinese patients with Philadelphia chromosome-positive adult acute lymphoblastic leukemia

The IK6 isoform plays an important role in Philadelphia chromosome-positive adult acute lymphoblastic leukemia (Ph + ALL). This study was designed to monitor the expression of the IK6 isoform with associated cytogenetic and molecular abnormalities. The IK6 isoform, cytogenetic and molecular abnormalities were detected in 100 Chinese patients with de novo Ph+ adult ALL. Expression levels of the IK6 isoform and BCR–ABL1 transcripts were monitored during treatment. BCR–ABL1 mutation was identified in 45 paired samples. Strong correlations were found between the expression status of the IK6 isoform and blast cells, additional cytogenetic abnormalities, BCR–ABL1 transcripts, increased risk of relapse, shorter relapse-free survival and overall survival at diagnosis. Higher frequencies of single IK6 expression and ABL mutation, including the types and shifts thereof, were confirmed in relapsed patients. Furthermore, expression of the IK6 isoform was dynamically consistent with BCR–ABL1 transcript levels during treatment in the single expression group, whereas no such correlation was observed in the co-expression group. The expression pattern of the IK6 isoform was altered in three patients from the co-expression group. The findings of this study in Chinese patients with Ph+ adult ALL exhibit some discrepancies with data reported in other countries, thereby enhancing current knowledge on the therapeutic response and prognosis of this disease.

Central Nervous System Involvement in Adult Acute Lymphoblastic Leukemia (ALL) at Diagnosis and/or at First Relapse: Results from the GET-LALA Group.

Outcome of adult ALL with central nervous system (CNS) involvement is not clearly defined. We studied 104 patients presenting with CNS involvement at diagnosis among 1493 patients (7%) included into the LALA-87 or LALA-94 trials, and 109 patients (9% of first remitters) presenting CNS disease at the time of first relapse among the 709 relapsing patients (15%) included initially in these trials. Treatment of patients presenting CNS involvement at diagnosis consisted in initial chemotherapy completed by 18 double or triple intrathecal injections associated with 15 to 20 Gy cranial irradiation, followed when possible by intensification by allogeneic or autologous stem cell transplantation (SCT). At diagnosis, 43 patients (41%) presenting with CNS involvement had T-lineage ALL, 53 (51%) had B-lineage ALL (of whom 9 were diagnosed as Philadelphia (Ph) chromosome positive ALL), 8 had undifferentiated ALL or unknown immunophenotype. Eighty-seven of 104 (84%) patients with CNS involvement at diagnosis achieved complete remission (CR). Fifty-three patients underwent SCT (25 allogeneic SCT from matched related or unrelated donor, 28 autologous SCT). Overall survival at 7 years was 34% in those with CNS involvement at diagnosis versus 29% (p = NS) for those without. DFS at 7 years was 35% versus 28% (p = NS). There were no significant differences between patients with CNS involvement and those without CNS involvement regarding T lineage ALL, B lineage ALL (including or not Ph ALL). There were also no significant differences regarding patients who underwent transplantation as consolidation intensification, while in patients receiving only chemotherapy patients without initial CNS involvement had a better outcome (p = 0.01). Among the 709 patients with primary relapse, 66 patients (61%) presented a CNS relapse combined with bone marrow relapse, whereas 17 relapses (15%) and 26 relapses (24%) were CNS relapses combined with another extramedullary relapse or isolated CNS relapses respectively. Median time to relapse was 6.7 months (range, 1–62) in patients with CNS relapse versus 11.2 months (1.7–111) in relapsing patients without CNS involvement. Eleven patients (10%) with CNS relapse had CNS involvement at diagnosis, while 98 patients were diagnosed with CNS disease only at the time of first relapse. Overall, 38 out of 109 patients with CNS relapse (35%) achieved CR. The median OS was 6.3 months. Outcome was similar in terms of CR proportion and OS in relapsing patients without CNS involvement. The 2-year OS rates did not show any difference among patients with CNS relapse who had CNS involvement at diagnosis and those with CNS disease only diagnosed at the time of first relapse.Overall, CNS leukemia in adult ALL is uncommon at diagnosis. Patients have a similar outcome than those who did not present with CNS involvement. However, patients benefit from intensification therapy by autologous or allogeneic SCT. CNS leukemia at first relapse are also uncommon but probably underestimated. Outcome is particularly poor as this of all adult ALL in first relapse.

528 POSTER Clinical characteristics, treatment outcome, and prognosis of Philadelphia chromosome-positive adult acute lymphoblastic leukemia

528 POSTER Clinical characteristics, treatment outcome, and prognosis of Philadelphia chromosome-positive adult acute lymphoblastic leukemia

Treatment of adult acute lymphoblastic leukemia (ALL): long-term follow-up of the GIMEMA ALL 0288 randomized study

AbstractThe GIMEMA ALL 0288 trial was designed to evaluate the impact of a 7-day prednisone (PDN) pretreatment on complete remission (CR) achievement and length, the influence of the addition of cyclophosphamide (random I) to a conventional 4-drug induction on CR rate and duration, and whether an early post-CR intensification (random II) by an 8-drug consolidation could improve CR duration. Median follow-up of this study was 7.3 years. From January 1988 to April 1994, among 794 adult (> 12 but < 60 years) patients registered, 778 were eligible. Their median age was 27.5 years; 73% had B-lineage acute lymphoblastic leukemia (ALL) and 22% had T-lineage disease; 18% showed associated myeloid markers; 47 of 216 analyzed patients (22%) had Philadelphia chromosome–positive ALL. Response to PDN pretreatment was observed in 65% of cases. CR was achieved in 627 patients (82%). Resistant patients and induction death rates were 11% and 7%, respectively. Random II was applied to 388 patients with CR; 201 had maintenance alone and 187 had consolidation followed by maintenance. The relapse rate was 60%; isolated central nervous system relapses were 8% of all CRs and 13% of all relapses. Median survival (overall survival [OS]), continuous complete remission (CCR), and disease-free survival (DFS) were 2.2, 2.4, and 2 years, respectively. PDN pretreatment response resulted the main independent factor influencing CR achievement, OS, CCR, and DFS; the addition of cyclophosphamide in induction significantly influenced CR achievement in a multivariate analysis. Neither induction intensification nor early consolidation appeared to influence CCR and DFS duration. For the first time PDN pretreatment response proved to be a powerful factor predicting disease outcome in adult ALL patients.

Cytarabine with high-dose mitoxantrone induces rapid complete remissions in adult acute lymphoblastic leukemia without the use of vincristine or prednisone.

To evaluate the efficacy and safety of a new induction regimen for adult acute lymphoblastic leukemia (ALL) that does not contain vincristine or corticosteroids. Thirty-seven adult patients with newly diagnosed ALL and lymphoblastic lymphoma were treated with a dose-intense induction regimen. This regimen was designed to increase the fraction of patients achieving an early complete remission (CR) in an attempt to increase long-term disease-free survival. The induction regimen was cytarabine (Ara-C) 3 g/m2/d for 5 days and mitoxantrone 80 mg/m2 as a single dose on day 3. Granulocyte colony-stimulating factor (G-CSF) 200 micrograms/ m2/d beginning on day 7 was used to promote early myeloid recovery. There were 31 CRs (84%). Median time to CR was 34 days, median hospital stay was 28 days, and the median number of days with a neutrophil count less than 500/microL was 18. There were three patients with resistant disease who experienced treatment failure and three early deaths from sepsis. Four patients with Philadelphia chromosome-positive (Ph+) ALL achieved hematologic and cytogenetic CRs. This dose-intense induction regimen produced a high incidence of CRs with acceptable toxicity without the use of vincristine or corticosteroids. Comparisons with our prior vincristine/prednisone-based induction regimen (the L-20 protocol) suggest that patients treated on the current study were more likely to achieve a CR and that they achieved this remission earlier than patients treated with a traditional four-drug (vincristine, prednisone, doxorubicin, and cyclophosphamide) induction regimen.

The bcr gene in Philadelphia chromosome positive acute lymphoblastic leukemia

In chronic myelogenous leukemia (CML) and in a percentage of childhood and adult acute lymphoblastic leukemia (ALL) the Philadelphia (Ph') chromosome is present in the leukemic cells of patients. This chromosome is the result of a reciprocal translocation between chromosomes 9 and 22. In CML the break on chromosome 22 occurs within the major breakpoint cluster region (Mbcr) of the bcr gene. In this study, we report on the examination of DNAs from nine Ph'-chromosome positive ALL patients for rearrangements within the bcr gene using Southern blot analysis. Of nine patients having a karyotypically identifiable Ph'-chromosome, only five exhibited rearrangements of the bcr gene. This could indicate that in ALL, chromosome 22 sequences other than the bcr gene are involved in the Ph'-translocation. Within the group of Ph'-positive ALL patients having a bcr gene breakpoint, a correlation appears to exist between the age of the patient and the location of the breakpoint within the gene: all or the vast majority of pediatric patients analyzed to date do not have a Mbcr breakpoint as found in CML and in adult ALL.

The bcr Gene in Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia

Abstract In chronic myelogenous leukemia (CML) and in a percentage of childhood and adult acute lymphoblastic leukemia (ALL) the Philadelphia (Ph′) chromosome is present in the leukemic cells of patients. This chromosome is the result of a reciprocal translocation between chromosomes 9 and 22. In CML the break on chromosome 22 occurs within the major breakpoint cluster region (Mbcr) of the bcr gene. In this study, we report on the examination of DNAs from nine Ph′-chromosome positive ALL patients for rearrangements within the bcr gene using Southern blot analysis. Of nine patients having a karyotypically identifiable Ph′-chromosome, only five exhibited rearrangements of the bcr gene. This could indicate that in ALL, chromosome 22 sequences other than the bcr gene are involved in the Ph′-translocation. Within the group of Ph′-positive ALL patients having a bcr gene breakpoint, a correlation appears to exist between the age of the patient and the location of the breakpoint within the gene: all or the vast majority of pediatric patients analyzed to date do not have a Mbcr breakpoint as found in CML and in adult ALL.