A RANDOMIZED TRIAL OF HYDROXYUREA VERSUS VP16 IN ADULT CHRONIC MYELOMONOCYTIC LEUKEMIA

We performed a randomized study of hydroxyurea (HY) versus VP16 in adv anced chronic myelomonocytic leukemia (CMML) patients with CMML (accor ding to French-American-British group criteria) and either documented visceral involvement (excluding liver and spleen infiltration) or at l east 2 of the following: (1) neutrophils >16 x 10(9)/l (2) Hemoglobin <10 g/dL (3) platelets <100 x 10(9)/L (4) marrow blasts >5% (5) spleen >5 cm below costal margin were eligible for this trial. Initial dosag e was 1 g/d for HY and 150 mg/week for VP16, orally (doubled in case o f visceral involvement). Doses were scheduled to be escalated up to HY 4 g/d and VP16 600 mg/week in the absence of response, and finally ad justed to maintain white blood cells (WBCs) between 5 and 10 x 10(9)/L . Crossing over was scheduled only in case of life threatening viscera l involvement or major progression. The major endpoint of the study wa s survival. The study was closed on first interim analysis that showed a superiority of HY over VP16, after inclusion of 105 pts (HY arm: 53 , VP16 arm: 52). Results of the second interim analysis, performed 7 m onths later, are presented here. Median age was 71 (range 38 to 91), m edian WBC count 20.10(9)/L (range 10 to 187). Thirteen pts had viscera l involvement (3 serous effusions, 8 cutaneous infiltrations, 1 kidney , 1 bone infiltrations). Initial characteristics were similar in the H Y and VP16 groups. Median follow up was 11 months in both groups (rang e 1 to 43(+)). Response to treatment was seen in 60% of the pts in the HY group, versus 36%, respectively, in the VP16 group (P = .02). Time to response was significantly shorter in the HY group (2.1 v 3.5 mont hs, in the VP16 group, P = .003) and response duration was significant ly longer in the HY group (median 24 v 9 months, in the VP16 group, P = .0004). The response rate of patients with visceral involvement was 3 out of 7 in the VP16 arm versus 5 out of 6 in the HY group. Three of the 10 pts crossed over from HY to VP16 responded as compared to 6 pt s of the 11 pts crossed over from VP16 to HY. HY yielded better respon se on leukocytosis (P = .002). The effect on splenomegaly platelets, o n hemoglobin level and transfusion requirement was similar in the 2 tr eatment groups, A significantly higher incidence of alopecia was noted in the VP16 arm (20% v 3%, P = .03). Fourteen (27%) and 20 (38%) pati ents in the HY and the VP16 group respectively, progressed to acute my eloid leukemia (difference NS). Twenty five (53%) and 44 (83%) patient s in the HY and the VP16 group, respectively, had died (P = .002). Med ian actuarial survival was 20 months in the HY arm, versus 9 months in the VP16 arm (P < 10(-4)). Main factors associated with poor survival were allocation to the VP16 arm, ''unfavorable'' karyotype tie, monos omy 7 or complex abnormalities) and anemia. In the HY group, unfavorab le karyotype (P = .006), and low hemoglobin level (P = .004) were sign ificantly associated with low response rates. Prognostic factors for p oor survival in the HY group were also unfavorable karyotype (P = .001 ), and low hemoglobin level (P < 10(-4)). In conclusion, we found that HY gave higher response rates and better survival than VP16 in advanc ed CMML. However, even with HY responses were only partial and surviva l was generally poor. This stresses the need for new agents in the tre atment of CMML, that will have to be compared with HY in future random ized studies. (C) 1996 by The American Society of Hematology.