General AML

CLAG plus imatinib Mesylate for R/R AML – a phase II study

Previously published data from the phase I study (NCT00258271) combining cladribine, cytarabine (Ara-C), Granulocyte Colony Stimulating Factor (G-CSF [CLAG Regimen]) plus imantinib mesylate (IM), a specific tyrosine kinase inhibitor, in patients with Relapsed or Refractory (R/R) Acute Myeloid Leukemia (AML) demonstrated that this regimen was well tolerated with acceptable toxicities.1

Subsequently, a phase II study (NCT00955916) which furthered explored the safety and efficacy of CLAG plus IM was conducted  and the results were reported by Abu-Sayeef Mirza et al. from the University of South Florida in Clinical Lymphoma, Myeloma & Leukemia in September 2017.2

Overall, 38 R/R AML patients with a median age of 62 years were enrolled between August 2009 and April 2011 at the Moffitt Cancer Center. Patients were administered CLAG regimen in combination with oral IM. The primary endpoint of the study was Overall Response Rate (ORR). The secondary endpoints of the study were Overall Survival (OS) and Progression Free Survival (PFS).

Key highlights:
  • Treatment regimen
    • Oral IM; 400 mg twice daily on Days 2–15
    • Cladribine; 5 mg/m2 Intravenous (IV), Days 2–6
    • Ara-C; 2 g/m2 IV starting 2 h after cladribine, Days 1–6
    • GCSF; 300µg subcutaneously daily, Days 1–6
  • Response and survival in all evaluable patients (n = 38)
    • ORR; 37%
    • Median OS; 11.1 months
    • Median PFS; 4.9 months
    • OS in responders was significantly longer than non-responders; P = 0.0002
  • Safety
    • Most common grade ≥ 3adverse events included febrile neutropenia (58%), pneumonia (34%), sepsis (29%), hypokalemia (24%), diarrhea (11%) and rash (3%)
    • Death occurred in two patients due to hemorrhage and hepatic failure respectively

In summary, CLAG plus IM, was well tolerated and demonstrated promising anti-leukemic activity in R/R AML patients. However, the authors discussed that the clinical benefits of adding IM to the CLAG regimen was not very clear and also that clinical variables to predict response to this regimen could not be identified.

Recently, midostaurin, a multi-targeted tyrosine kinase inhibitor, in combination with standard chemotherapy, was approved by the US Food and Drug Administration (FDA) and the European Medicines Association (EMA) for FLT3 mutated AML and more importantly, the findings of this phase II study further demonstrate the feasibility of combining tyrosine kinase inhibitors with chemotherapy.

Given this, several mutations could possibly be targeted by additional chemotherapy which could lead to more effective salvage therapy for AML patients.


No standard salvage chemotherapy regimen is available for relapsed or refractory (RR) acute myeloid leukemia (AML). Preclinical data have suggested synergy in vitro between cytarabine and imatinib mesylate (IM) on AML cell growth inhibition. After demonstrating the safety and feasibility in a phase I study, we conducted a phase II clinical study of CLAG (cladribine, cytarabine, granulocyte colony-stimulating factor) regimen combined with IM for patients with RR-AML.

Patients and Methods

We performed a single-institution 2-stage phase II study. The primary endpoint was the remission rate measured using the standard AML response criteria. The secondary endpoints included overall survival (OS) and progression-free survival (PFS).


From August 2009 to April 2011, 38 patients were treated at the Moffitt Cancer Center. Their median age was 62 years (range, 26-79 years). Of the 38 patients, 7 (18%) had refractory AML, 19 (50%) had early relapse, and 12 (32%) had late relapse. At the original diagnosis, only 2 patients had favorable risk factors, 18 had intermediate risk, and 16 had poor risk; for 2 patients, the karyotype was missing. The overall response rate for all 38 evaluable patients was 37%. The median OS was 11.1 months (95% CI, 4.8-13.4 months), the median PFS was 4.9 months (95% CI, 1.6-11.7 months). Among the responders, 8 of 14 patients subsequently underwent allogeneic hematopoietic cell transplantation.


CLAG plus IM was well tolerated, with encouraging signs of activity in patients with poor-risk AML.

  1. Walker A. R. et al. Phase I study of cladribine, cytarabine (Ara-C), granulocyte colony stimulating factor (G-CSF) (CLAG Regimen) and simultaneous escalating doses of imatinib mesylate (Gleevec) in relapsed/refractory AML. Leuk Res. 2008 Dec;32(12):1830-6. DOI: 10.1016/j.leukres.2008.04.026.
  2. Mirza A.S. et al. A Phase II Study of CLAG Regimen Combined With Imatinib Mesylate for Relapsed or Refractory Acute Myeloid Leukemia. Clin Lymphoma Myeloma Leuk. 2017 Sep 19. DOI: 10.1016/j.clml.2017.09.007.
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