Final report of a phase II study of imatinib mesylate with hyper-CVAD for the front-line treatment of adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia

Daver, Naval; Thomas, Deborah A.; Ravandi, Farhad; Cortés, Jorge E.; Garris, Rebecca; Jabbour, Elias; Garcia‐Manero, Guillermo; Borthakur, Gautam; Kadia, Tapan M.; Rytting, Michael; Konopleva, Marina; Kantarjian, Hagop M.; O’Brien, Susan

doi:10.3324/haematol.2014.118588

Cited by 187 publications

(146 citation statements)

References 46 publications

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“…CMR rates vary on the basis of which TKI is added to chemotherapy, ranging from 28% to 50% with imatinib, 7,15,16 45% to 65% with dasatinib, 9,12 and 78% with ponatinib, 13 and the survival rates achieved seem to be better with each successive generation of TKI, although no randomized trials have yet been performed to confirm this observation. In our cohort, the CMR rate at 3 months in patients who received ponatinib was more than twofold that of patients who received imatinib.…”

Section: Resultsmentioning

confidence: 99%

Impact of complete molecular response on survival in patients with Philadelphia chromosome–positive acute lymphoblastic leukemia

Short¹,

Jabbour

Sasaki

et al. 2016

Blood

197

173

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• In patients with Ph 1 ALL, achievement of CMR at 3 months is independently associated with improved survival.• CMR at 3 months may identify patients with Ph 1 ALL who have excellent long-term outcomes without SCT in first CR.The impact of achieving complete molecular response (CMR) in Philadelphia chromosomepositive (Ph 1 ) acute lymphoblastic leukemia (ALL) remains undefined. We evaluated the impact of CMR on outcomes among 85 patients with Ph 1 ALL who received first-line hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with methotrexate and high-dose cytarabine plus a tyrosine kinase inhibitor, had minimal residual disease (MRD) assessments for BCR-ABL1 by quantitative polymerase chain reaction at complete remission (CR) and at 3-month time points, and did not undergo allogeneic stem cell transplantation (SCT). MRD status at 3 months had better discrimination for overall survival (OS; P 5 .005) and relapse-free survival (RFS; P 5 .002) than did MRD status at CR (P 5 .11 and P 5 .04, respectively). At 3 months, achievement of CMR vs response less than CMR was associated with longer median OS (127 vs 38 months, respectively; P 5 .009) and RFS (126 vs 18 months, respectively; P 5 .007). By multivariate analysis, only CMR at 3 months was prognostic for OS (hazard ratio, 0.42; 95% confidence interval, 0.21-0.82; P 5 .01). Patients with Ph 1 ALL who achieve CMR at 3 months have superior survival compared with those with lesser molecular responses and have excellent long-term outcomes even without SCT. (Blood. 2016;128(4):504-507)

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Section: Resultsmentioning

confidence: 99%

Impact of complete molecular response on survival in patients with Philadelphia chromosome–positive acute lymphoblastic leukemia

Short¹,

Jabbour

Sasaki

et al. 2016

Blood

197

173

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“…The details of these regimens have been published previously. 1,[25][26][27][28][29] The choice of the 2 regimens was based on a variety of factors: time period (hyper-CVAD, year 2000 onwards; augmented BFM, years 2006-2012); age (18 years and older for hyper-CVAD-based regimens; 40 years and younger for augmented BFM); clinical trial eligibility; insurance coverage of clinical trials; and patient or physician preference. In the Ph 1 cohort, all but 3 patients received TKIs (imatinib, n 5 12; dasatinib, n 5 24; ponatinib, n 5 7).…”

Section: Study Groupsmentioning

confidence: 99%

Ph-like acute lymphoblastic leukemia: a high-risk subtype in adults

Jain

Roberts

Jabbour

et al. 2017

Blood

290

350

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“…In terms of CHR, these results compare favorably with those reported by other studies in which imatinib was administered concomitantly to chemotherapy or in various schedules during induction or consolidation, with CHR rates ranging from 72% to 96%. 5,6,10,12,13,15,[18][19][20][21]34,35 Furthermore, our schedule has the advantage that there are fewer deaths during induction treatment, in contrast to the majority of the combination studies in which, with few exceptions, 5 toxic deaths were recorded in 2%-7% of cases. 6,8,[12][13][14][18][19][20] Indeed, toxicity was recorded in the initial combination protocol (imatinib+chemotherapy) that led to the final amendment to a sequential strategy.…”

Section: Discussionmentioning

confidence: 99%

“…35 Thus, our long-term outcome results appear superior; this could be due to the fact that we have had no deaths in induction nor major toxicities associated to chemotherapy, which was delivered to patients (96% of cases) already in hematologic remission. All relapses occurred after completing the imatinib plus steroids induction phase and took place during/after the post-consolidation therapy; in fact, the median time to relapse from achievement of the first CHR was 7.6 months.…”

mentioning

confidence: 96%

“…Survival probability Survival probability studies from the MDACC, 5 20 English UKALLXII/ECOG2993 21 and MDACC 35 studies, the 4-5 year OS and DFS rates were 38% and 39%, 12 30% for both, 13 52% and 44%, 20 38% of OS and 50% at four years of relapse-free survival, 21 and 43% for both. 35 Thus, our long-term outcome results appear superior; this could be due to the fact that we have had no deaths in induction nor major toxicities associated to chemotherapy, which was delivered to patients (96% of cases) already in hematologic remission.…”

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confidence: 99%

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A sequential approach with imatinib, chemotherapy and transplant for adult Ph+ acute lymphoblastic leukemia: final results of the GIMEMA LAL 0904 study

et al. 2016

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In the GIMEMA LAL 0904 protocol, adult Philadelphia positive acute lymphoblastic leukemia patients were treated with chemotherapy for induction and consolidation, followed by maintenance with imatinib. The protocol was subsequently amended and imatinib was incorporated in the induction and post-remission phase together with chemotherapy. Due to the toxicity of this combined approach, the protocol was further amended to a sequential scheme based on imatinib plus steroids as induction, followed by consolidation with chemotherapy plus imatinib and, when applicable, by a hematopoietic stem cell transplant. Fifty-one patients (median age 45.9 years) were enrolled in the final sequential protocol. At the end of induction (day +50), 96% of evaluable patients (n=49) achieved a complete hematologic remission; after consolidation, all were in complete hematologic remission. No deaths in induction were recorded. Overall survival and disease-free survival at 60 months are 48.8% and 45.8%, respectively. At day +50 (end of imatinib induction), a more than 1.3 log-reduction of BCR-ABL1 levels was associated with a significantly longer disease-free survival (55.6%, 95%CI: 39.0-79.3 vs. 20%, 95%CI: 5.8-69.1; P=0.03), overall survival (59.1%, 95%CI: 42.3-82.6 vs. 20%, 95%CI: 5.8-69.1; P=0.02) and lower incidence of relapse (20.5%, 95%CI: 7.2-38.6 vs. 60.0%, 95%CI: 21.6-84.3; P=0.01). Mean BCR-ABL1 levels remained significantly higher in patients who subsequently relapsed. Finally, BCR-ABL1 p190 patients showed a significantly faster molecular response than BCR-ABL1 p210 patients (P=0.023). Though the study was not powered to evaluate the role of allogeneic stem cell transplant, allografting positively impacted on both overall and disease-free survival. In conclusion, a sequential approach with imatinib alone in induction, consolidated by chemotherapy plus imatinib followed by a stem cell transplant is a feasible, well-tolerated and effective strategy for adult Philadelphia positive acute lymphoblastic leukemia, leading to the best long-term survival rates so far reported. (clinicaltrials.gov identifier: 00458848).

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Final report of a phase II study of imatinib mesylate with hyper-CVAD for the front-line treatment of adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia

Cited by 187 publications

References 46 publications

Impact of complete molecular response on survival in patients with Philadelphia chromosome–positive acute lymphoblastic leukemia

Impact of complete molecular response on survival in patients with Philadelphia chromosome–positive acute lymphoblastic leukemia

Ph-like acute lymphoblastic leukemia: a high-risk subtype in adults

A sequential approach with imatinib, chemotherapy and transplant for adult Ph+ acute lymphoblastic leukemia: final results of the GIMEMA LAL 0904 study

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