First Results of the GRAAPH-2005 Study in younger Adult Patients with De Novo Philadelphia Positive Acute Lymphoblastic Leukemia

Author:

Chalandon Yves1,Thomas Xavier1,Hayette Sandrine1,Cayuela Jean-Michel2,Abbal Claire1,Escoffre-Barbe Martine3,Maury Sebastien1,Lepretre Stephane1,Witz Francis4,Benboubker Lofti1,Malfuson Jean-Valère1,Leguay Thibaut5,Buzyn Agnes1,Lheritier Veronique1,Bene Marie-Christine1,Lafage Marina1,Ifrah Norbert1,Dombret Herve1

Affiliation:

1. GRAALL Group, Lyon, France

2. Hôpital St-Louis, Paris, France

3. Hématologie clinique, Hôpital Pontchaillou, Rennes, France

4. Hématologie - Médecine interne, Hôpitaux de Brabois, Nancy, France

5. Hematology, CHU de Bordeaux, Bordeaux, France

Abstract

Abstract The GRAAPH-2005 International study for adults with newly diagnosed chromosome Philadelphia positive (Ph+) acute lymphoblastic leukemia (ALL) was designed to compare an imatinib-based induction regimen with an imatinib-HyperCVAD induction regimen and to evaluate the role of imatinib prior to stem cell transplantation (SCT). The protocol enrolled patients > 18 years and < 60 years. Among 118 enrolled patients from May 2006 onwards, 83 had a follow-up long enough to allow at least induction and consolidation evaluation. Median age was 42 years; 60% were male. A 7-day prephase steroid regimen (prednisone 60 mg/m2/day) allowed identification of the BCR/ABL transcript. In arm A (imatinib-based), imatinib 800 mg was given days 1–28, only combined with vincristine (2 mg at days 1, 8, 15, 22) and dexamethasone (40 mg at days 1–2, 8–9, 15–16, and 22–23). In arm B (imatinib-HyperCVAD), imatinib 800 mg was given days 1–14 of each course, combined with adriamycin (50 mg/m2 at day 4), cyclophosphamide (300 mg/m2/12h at day 1, 2, 3), vincristine (2 mg at days 4 and 11), and dexamethasone (40 mg at days 1–4 and 11–14) in the induction course, and combined with high-dose methotrexate (1 g/m2 at day 1) and high-dose cytarabine (3 g/m2/12h at days 2 and 3) in the salvage/consolidation course. Salvage/consolidation course was similar for patients initially following arm A. Four intrathecal infusions (methotrexate + cytarabine + methylprednisolone) were included within induction/consolidation courses. Complete hematological remission (CR) rate at the end of the two courses of induction/consolidation was 100% with arm A (42 patients of whom 2 after salvage course) and 95% with arm B (39/41 patients; all after induction course): overall 97.5% vs 70% in the pre imatinib era (LALA-94 trial). One patient died during the first course and 2 during the second course (of which 1 in CR after the induction course). Overall, median number of days to response was 37 (range, 28–136 days). Minimal residual disease (MRD) was centrally evaluated by quantitative RT-PCR at the end of induction (MRD-1) and at the end of salvage/consolidation chemotherapy (MRD-2). Molecular disease was undetectable in 11% at the time of MRD-1 and in 18% at the time of MRD-2, and at a level < 0.1% in 40% at the time of MRD-1 and in 60% at that of MRD-2. Although this did not translate into significant difference in terms of survival, monitoring of MRD (< 0.1%) documented that arm B was capable of inducing a deeper marked clearance of leukemic cells than arm A at the end of salvage/consolidation chemotherapy: 35% in arm A and 45% in armB (p = 0.3) for MRD-1, and 48% in arm A and 72% in arm B (p = 0.05) for MRD-2. After the two phases of induction/consolidation, patients received intensification by allogeneic SCT using related or unrelated donor stem cells or autologous SCT when a donor was not available and MRD < 0.1%. In absence of potential SCT, they underwent repeated cycles of imatinib-HyperCVAD regimen. Of the 61 patients with enough follow-up after induction/consolidation courses, 52 (85%) actually received SCT: 41 allogeneic SCT (of which 25 from related- and 16 from unrelated-donor) and 11 autologous SCT. Overall survival (OS) was 62% at 2-year (68% and 54% in arm A and arm B, respectively; p = 0.3), which differ significantly from the 29% observed in the pre imatinib era (LALA-94 trial). Disease-free survival (DFS) was 43% at 2-year (54% and 32% in arm A and arm B, respectively; p = 0.7). After a median follow-up of 12.6 months (95% CI, 10.6–15 months), 18 relapses (22%) were observed. Eighteen patients have died after induction/consolidation phase: 8 patients with progressive disease and 10 patients in CR (1 from septic shock waiting for allogeneic SCT, and 9 from toxicity during allogeneic SCT). The preliminary data of this study suggest that an imatinib-based regimen induces a high rate of hematological CR, similar to a more intensive (HyperCVAD) regimen. However the rate of molecular response has a tendency to be lower with imatinib-based regimen. The combination of imatinib with chemotherapy allows a majority of patient to have consolidation with SCT.

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

Cited by 9 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3