High relapse rate of T cell acute lymphoblastic leukemia in adults treated with Hyper-CVAD chemotherapy in Sweden
Hyper-CVAD is widely used to treat acute lymphoblastic leukemia (ALL) and aggressive lymphomas. This multicenter, population-based study assessed the efficacy of Hyper-CVAD as first line therapy in patients with T cell ALL (T-ALL).
Between October 2002 and September 2006, 24 patients were diagnosed with T-ALL in Sweden; 19 were eligible for treatment with the protocol.
The median age was 32 years (range 18-72 years). Complete remission (CR) was obtained in 17/19 (89%) patients, and the treatment was relatively well tolerated. Allogeneic stem cell transplantation (SCT) was recommended in high-risk disease and was performed in four patients upfront. Two and 5-year leukemia-free survivals (LFS) in 17 patients with CR achievement were identical, at 29% (95% confidence interval [CI]: 8-51). Two and 5-year overall survival (OS) in whole cohort were 63% (95% CI: 42-85) and 47% (95% CI: 26-69), respectively. The 5-year LFS for 15 patients who did not receive allogeneic SCT upfront was 20% (95%CI: 0-40), although 14/15 completed the protocol (eight cycles). Relapse occurred in 2/4 upfront-transplanted patients and in 12/15 patients treated with chemotherapy alone, six of whom received allogeneic SCT in CR2. Age ≥ 35 years influenced OS negatively in univariate analysis (HR 5.1, 95% CI: 1.55-16.7).
Hyper-CVAD treatment resulted in a high CR rate and appeared safe, but it showed poor efficacy at preventing relapse. Therefore, this treatment is no longer recommended for adults with T-ALL in Sweden. This article is protected by copyright. All rights reserved.
Available from: PubMed Central
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ABSTRACT: To investigate the effectiveness of a combination of 6-thioguanine (6-TG) and pralatrexate (PDX) in methylthioadenosine phosphorylase (MTAP)-deficient T-cell acute lymphoblastic leukemia (T-cell ALL).
CCRF-CEM (MTAP(-/-)) and Molt4 (MTAP(+/+)) T-cell ALL cell lines were treated with 6-TG or PDX and evaluated for efficacy 72 h later. NOD/SCID gamma mice bearing CEM or Molt4 xenografts were treated with 6-TG and PDX alone or in combination to evaluate antitumor effects.
CEM cells were more sensitive to 6-TG and PDX in vitro than Molt4. In vivo, CEM cells were very sensitive to PDX and 6-TG, whereas Molt4 cells were highly resistant to 6-TG. A well-tolerated combination of PDX and 6-TG achieved significant tumor regression in CEM xenografts.
The loss of MTAP expression may be therapeutically exploited in T-cell ALL. The combination of 6-TG and PDX, with the inclusion of leucovorin rescue, allows for a safe and effective regimen in MTAP-deficient T-cell ALL.
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ABSTRACT: Acute lymphoblastic leukemia (ALL) of the T-cell immunophenotype (T-ALL) is an uncommon aggressive leukemia that can present with leukemic and/or lymphomatous manifestations. An early T-cell precursor ALL has been identified as a poor prognostic subtype. Molecular studies are enhancing our understanding of the pathogenesis, and the discovery of activating mutations of NOTCH1 and FBXW7 in a majority of patients with T-ALL has been a seminal observation. Use of pediatric intensive combination chemotherapy regimens in adolescents and young adults has significantly improved the outcome of patients with T-cell ALL. The use of nelarabine for relapsed and refractory T-ALL results in responses in a substantial minority of patients. Allogeneic hematopoietic cell transplantation (HCT) still plays a key role in patients with high-risk or relapsed/refractory disease. Gamma-secretase inhibitors hold promise for treatment of patients with NOTCH1 and FBXW7 mutations, and the results of clinical trials with these agents in the relapsed/refractory setting are eagerly awaited. It is recommended that suitable, generally younger, patients receive a pediatric-intensive regimen for induction therapy and, based on response and genetic factors, be considered for allogeneic HCT if felt to be at high risk for recurrence. Older and unfit patients can receive suitable multi-agent chemotherapy and be allocated to HCT based on their response, risk factors, and co-morbidities. Although advances in the treatment of T-ALL have lagged behind those of B-ALL, it is hoped that the molecular revolution will enhance our understanding of the pathogenesis and treatment of this aggressive lymphoid malignancy.
Copyright © 2015 American Society of Hematology.
Available from: Nicolas Boissel
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ABSTRACT: The inclusion of asparaginase in chemotherapy regimens to treat acute lymphoblastic leukemia (ALL) has had a positive impact on survival in pediatric patients. Historically, asparaginase has been excluded from most treatment protocols for adolescent and young adult (AYA) patients because of perceived toxicity in this population, and this is believed to have contributed to poorer outcomes in these patients. However, retrospective analyses over the past 12 years have shown that 2-, 5-, and 7-year overall survival of AYA patients is significantly improved with pediatric versus adult protocols. The addition of asparaginase to adult protocols yielded high rates of first remission and improved survival. However, long-term survival remains lower compared with what has been seen in pediatrics. The notion that asparaginase is poorly tolerated by AYA patients has been challenged in multiple studies. In some, but not all, studies, the incidences of hepatic and pancreatic toxicities were higher in AYA patients, whereas the rates of hypersensitivity reactions did not appear to differ with age. There is an increased risk of venous thromboembolic events, and management with anti-coagulation therapy is recommended. Overall, the risk of therapy-related mortality is low. Together, this suggests that high-intensity pediatric protocols offer an effective and tolerable approach to treating ALL in the AYA population.
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