Preliminary Results From a Phase III Trial of Imatinib Versus Imatinib in Combination with Cytarabine in Patients with First Chronic Phase Myeloid Leukemia

Imatinib (IM) is considered the first line therapy for newly diagnosed chronic myeloid leukemia (CML). Despite the increased overall survival and event free survival attained with IM, patients with unsatisfactory responses due to IM resistance still pose a considerable challenge. Addition of cytarabine to IM has shown synergistic anti-proliferative effects in in-vitro studies as well as in clinical trials. We conducted a prospective, multicenter, phase III trial (HOVON 78) comparing high dose IM or high dose IM combined with 2 successive cycles of standard-dose cytarabine in newly diagnosed CML patients. At the time our study was set out, high dose IM (600 or 800 mg) showed significantly higher molecular response rates than 400 mg in a HOVON dose escalation study (HOVON 51) of the combination of IM and cytarabine.

This study started in June 2006, but was closed prematurely in April 2010 because of declining inclusion most probably due to excellent evolving results of IM monotherapy and the introduction of second generation tyrosine kinase inhibitors. Newly diagnosed CML patients between the age of 18 and 65 years in first chronic phase ≤ 2 months were randomized between IM monotherapy 800 mg daily (arm A) or IM 800 mg combined with 2 successive cycles of daily cytarabine 200 mg/m² in 1–2 hours infusion for 7 days (arm B), followed by IM monotherapy. The first cycle of cytarabine was given as soon as possible, preferably within 14–28 days from the start of IM, whereas the second cycle was started after hematopoietic recovery (i.e. platelets > 100×10⁹/l and WBC > 2.0×10⁹/l). Response to treatment was assessed by hematological, cytogenetic and molecular analyses at regular intervals and was scored according to the ELN criteria. Reasons for going off protocol treatment were progression, excessive toxicity or intolerance of treatment, intercurrent death, no compliance of the patient or major protocol violation. The primary endpoint was the achievement of a major molecular response (MMR) at 12 months, and was compared between the 2 treatment arms using logistic regression. Secondary endpoints were progression free survival, overall survival and toxicity. The analyses were done according to the intention to treat principle, and were based on data available as of August 8, 2011. In order to detect with 80% power an improvement in 12-months' MMR from 60% to 75% (2-sided significance level alpha=0.05), 330 patients were required.

One hundred and ten eligible patients from 19 Dutch and 2 Belgian centers were enrolled, 55 in each arm. One patient in arm B withdrew consent. The median age of the patients was 45 years (range, 17–65). Sokal risk scores were equally divided between the two groups, but arm A contained more patients with high Euro risk score (24 vs 7%, p = 0.03). Median follow up is 31 months (range, 0–57). So far, 34 patients went off protocol treatment; 16 in arm A and 18 in arm B. Reasons for going off protocol were progression to accelerated phase, blast crisis or progression from major molecular response (3 and 1 patients in arm A and arm B, respectively), excessive toxicity (7 vs 11), and other (6 vs 6). Nine patients in arm B only received one cycle of cytarabine. Cytarabine dose was reduced in one patient only in the first cycle. Although the molecular response data of 4 patients are not yet available, the proportion of patients who achieved a MMR at 12 months was similar between the two treatment arms; 51% in arm A and 47% in arm B (OR = 0.82, 95% CI 0.38–1.76, p = 0.60; adjusted for Sokal score), PFS at 48 months was 91% in both treatment arms (p = 0.80). OS at 48 months was 100% in arm A and 92% in arm B. Three patients died. One patient in arm A died of conduction abnormality, 49 months after start of therapy. This patient had switched to dasatinib treatment because of IM resistance. Two patients in arm B died, both having progressed to blast crisis. One died at 39 months due to aspergillus infection after allogenic stem cell transplantation, and one patient on dasatinib treatment died at 9 months due to an intracerebral bleeding. Forty SAEs occurred in 29 patients, 7 (in 6 patients) in arm A and 33 (23 patients) in arm B (p<0.001). The most common toxicities were pain, constitutional symptoms and gastro-intestinal complaints.

IM in combination with cytarabine is not superior compared to IM alone in achieving MMR at 12 months. Patients receiving combination therapy had significantly more toxicity.

Janssen:Novartis: Consultancy. Ossenkoppele:Novartis: Consultancy.