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A randomized trial of hydroxyurea versus VP16 in adult chronic
myelomonocytic leukemia. Groupe Francais des Myelodysplasies and European
CMML Group
E Wattel, A Guerci, B Hecquet, T Economopoulos, A Copplestone, B Mahe, ME Couteaux, L Resegotti, V Voglova, C Foussard, B Pegourie, JL Michaux, E Deconinck, AM Stoppa, G Mufti, D Oscier and P Fenaux
Groupe Francais des Myelodysplasies, Lille, France.
We performed a randomized study of hydroxyurea (HY) versus VP16 in advanced
chronic myelomonocytic leukemia (CMML) patients with CMML (according to
French-American-British group criteria) and either documented visceral
involvement (excluding liver and spleen infiltration) or at least 2 of the
following: (1) neutrophils > 16 x 10(9)/I (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 dosage was 1
g/d for HY and 150 mg/week for VP16, orally (doubled in case of 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 adjusted to maintain
white blood cells (WBCs) between 5 and 10 x 10(9)/L. Crossing over was
scheduled only in case of life threatening visceral involvement or major
progression. The major endpoint of the study was 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 months later, are presented here.
Median age was 71 (range 38 to 91), median WBC count 20.10(9)/L (range 10
to 187). Thirteen pts had visceral involvement (3 serous effusions, 8
cutaneous infiltrations, 1 kidney, 1 bone infiltrations). Initial
characteristics were similar in the HY and VP16 groups. Median follow up
was 11 months in both groups (range 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 months, in the VP16 group, P = .003) and response duration
was significantly 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 pts of
the 11 pts crossed over from VP16 to HY. HY yielded better response on
leukocytosis (P = .002). The effect on splenomegaly platelets, on
hemoglobin level and transfusion requirement was similar in the 2 treatment
groups. A significantly higher incidence of alopecia was noted in the VP16
arm (20% v 3%, P = .03). Fourteen (27%) and 20 (38%) patients in the HY and
the VP16 group respectively, progressed to acute myeloid leukemia
(difference NS). Twenty five (53%) and 44 (83%) patients in the HY and the
VP16 group, respectively, had died (P = .002). Median 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 (ie, monosomy 7 or complex abnormalities)
and anemia. In the HY group, unfavorable karyotype (P = .006), and low
hemoglobin level (P = .004) were significantly associated with low response
rates. Prognostic factors for poor 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 advanced CMML. However, even with HY responses were
only partial and survival was generally poor. This stresses the need for
new agents in the treatment of CMML, that will have to be compared with HY
in future randomized studies.
Volume 88,
Issue 7,
pp. 2480-2487,
10/01/1996
Copyright © 1996 by The American Society of Hematology
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