Nilotinib with or without cytarabine for Philadelphia-positive acute lymphoblastic leukemia

• Published in: Blood 2024-06, Vol.143 (23), p.2363-2372
• Main Authors: Chalandon, Yves, Rousselot, Philippe, Chevret, Sylvie, Cayuela, Jean-Michel, Kim, Rathana, Huguet, Françoise, Chevallier, Patrice, Graux, Carlos, Thiebaut-Bertrand, Anne, Chantepie, Sylvain, Thomas, Xavier, Vincent, Laure, Berthon, Céline, Hicheri, Yosr, Raffoux, Emmanuel, Escoffre-Barbe, Martine, Plantier, Isabelle, Joris, Magalie, Turlure, Pascal, Pasquier, Florence, Belhabri, Amine, Guepin, Gabrielle Roth, Blum, Sabine, Gregor, Michael, Lafage-Pochitaloff, Marina, Quessada, Julie, Lhéritier, Véronique, Clappier, Emmanuelle, Boissel, Nicolas, Dombret, Hervé
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols - administration & dosage; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Cytarabine - administration & dosage; Cytarabine - therapeutic use; Female; Fusion Proteins, bcr-abl - genetics; Hematopoietic Stem Cell Transplantation; Humans; Male; Middle Aged; Precursor Cell Lymphoblastic Leukemia-Lymphoma - drug therapy; Precursor Cell Lymphoblastic Leukemia-Lymphoma - mortality; Precursor Cell Lymphoblastic Leukemia-Lymphoma - therapy; Pyrimidines - administration & dosage; Pyrimidines - therapeutic use; Young Adult
• ISSN: 0006-4971; 1528-0020; 1528-0020
• DOI: 10.1182/blood.2023023502

•Alternating reduced-intensity and conventional chemotherapy with nilotinib followed by SCT resulted in 4-year OS of 79.4% in Ph+ ALL.•The omission of high-dose Ara-C during consolidation resulted in a significantly higher rate of relapses without affecting overall survival. [Display omitted] We previously demonstrated that a reduced-intensity chemotherapy schedule can safely replace hyper-CVAD (cyclophosphamide-vincristine-doxorubicin [Adriamycin]-dexamethasone) cycle 1 when combined with imatinib in adults with Philadelphia-positive acute lymphoblastic leukemia. In the present randomized GRAAPH-2014 trial, we used nilotinib and addressed the omission of cytarabine (Ara-C) in consolidation. The primary objective was the major molecular response (MMR) rate measured by BCR::ABL1 quantification after cycle 4 (end of consolidation). All patients were eligible for allogeneic stem cell transplant (SCT), whereas those in MMR could receive autologous SCT, followed by 2-year imatinib maintenance in both cases. After the enrollment of 156 of 265 planed patients, the data and safety monitoring board decided to hold the randomization because of an excess of relapse in the investigational arm. Among the 155 evaluable patients, 76 received Ara-C during consolidation (arm A) and 79 did not (arm B). Overall, 133 patients (85%) underwent SCT, 93 allogeneic and 40 autologous. The noninferiority end point regarding MMR was reached with 71.1% (arm A) and 77.2% (arm B) of patients reaching MMR. However, the 4-year cumulative incidence of relapse was higher in arm B compared with arm A (31.3% [95% confidence interval {CI}, 21.1%-41.9%] vs 13.2% [95% CI, 6.7%-21.9%]; P = .017), which translated to a lower relapse-free survival. With a median follow-up of 3.8 years, 4-year overall survival was 79.0% (95% CI, 70.6%-89.3%) in arm A vs 73.4% (95% CI, 63.9%-84.4%) in arm B (P = .35). Despite a noninferior rate of MMR, more relapses were observed when ARA-C was omitted without impact on survival. ClinicalTrials.gov ID, NCT02611492. The introduction of tyrosine kinase inhibitors has transformed the prognosis of Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL). Chalandon and colleagues previously demonstrated that reduced-intensity chemotherapy plus imatinib was effective in induction of patients with Ph+ ALL. In the current study, the authors examined whether high-dose cytarabine (Ara-C) consolidation can be omitted from therapy. Nilotinib replaced imatinib, and 85% of pat