Haematologica 2003 - Supplements

Before Thal treatment in responding patients group median MVD
measured in immunohistochemical CD34 stained bone marrow
biopsies was 32.1 vessels/mm2 (range 2 - 63) vessels/mm2, and
in non-responding patients group was 39.3 vessels/mm2 (range
17 - 90 vessels/mm2). After Thal treatment in responding patients
group median MVD was 20.1 vessels/mm2 (range 5 - 40
vessels/mm2), and in non-responding patients 22.6 vessels/mm2
(range 7-45 vessels/mm2).
Conclusions: We found no statistical significant differences in
bone marrow MVD after thalidomide treatment in relapsed or
refractory to chemotherapy MM patients. Microvessels in the
bone marrow appear to persist even after therapy with
thalidomide an agent with postulated antiangiogenic properties,
however the lack of resolution of microvessels may not be an
accurate way to measure the effect of antiangiogenic therapy.
11.4 Thalidomide: side effects
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Venous thrombo-embolism in patients with MM treated
with high dose chemotherapy and thalidomide.
Preliminary results of a prospective HOVON/GMMG
phase III trial.
M.C. Minnema, P. Sonneveld, P.C. Huijgens, B. van der
Holt, P.H.M. Westveer, A. van Marion and H.M. Lokhorst
For the Dutch-Belgium Hemato-Oncology Cooperative Group
(HOVON)
A high incidence of venous thrombo-embolism (VTE) up to 30%
is reported when thalidomide is combined with chemotherapy.
In an ongoing Dutch/Belgium/German multicenter study
(HOVON50 MM/GMMG HD-3), patients with MM are
randomized to receive induction therapy consisting of 3 cycles of
vincristine, doxorubicin and dexamethasone (arm A) or 3 cycles
of vincristine, doxorubicin and thalidomide (arm B).
Thalidomide, starting dose of 200 mg/day and may be escalated
to maximum 400 mg, is administered from day 1 throughout the 3
cycles and is combined with VTE prophylaxis (Nadoparine 2850
IE/day). Following induction PBSC are collected after
mobilization with cyclophosphamide, doxorubicin, dexamethason
and G-CSF (CAD). Patients then may proceed to High Dose
Melphalan (HDM 200 mg/m2). As maintenance therapy patients
continue with α-interferon 3 × 106 IU/day s.c. 3 times a week
(arm A) or thalidomide 50 mg/day (arm B) until relapse or
progression. Patients with an HLA-identical may proceed to
nonmyeloablative Allo-SCT after HDM.
From November 2001 till February 2003, 150 patients have been
included in the HOVON-50 trial, of whom 75 have been assigned
to arm B. Sixty patients completed the induction therapy with
VAD or TAD.
Ten cases of VTE have been recorded, 5 in arm A and 5 in arm B
(incidence 8.3%) which all occurred in the induction phase. All 5
patients in arm A had DVT of the leg, one patient also presented
with signs of a pulmonary embolism. Two patients had additional
risk factors (long travel and an ankle fracture), no additional risk
factors were found in the other 3 patients.
In arm B, three patients presented with DVT of the leg, one with
pulmonary embolism and one patient with thrombosis of the arm.
All patients used nadoparine prophylaxis, except one patient with
atrial fibrillation who used acenocoumarol. He developed a DVT
of the leg after the oral anticoagulation was stopped 5 days earlier
to perform a bone marrow biopsy. In the other 4 patients no
additional risk factors could be identified.
In conclusion, 8.3% of the patients in treatment arm A developed
VTE during induction therapy, which is comparable with the
incidence reported before in patients with intensive chemotherapy
(about 10%). However, the patients receiving both thalidomide
and doxorubicin seem to have a lower incidence of VTE when
compared with the incidence reported in previous publications
(16 to 30%). We therefore conclude that the use of Nadoparin
prophylaxis seems effective in reducing the occurrence of VTE in
patients with MM during intensive chemotherapy and use of
thalidomide.
356
Preliminary analysis of a double blind randomised
study comparing Thalidomide (Thal) or placebo in
combination with a (V)AD-like regimen in relapsing
patients with Multiple Myeloma (MM)
B. Arnulf, V.Levy, V.Leblond, M.Divine, M.Macro,
D.Bouscary, X.Mariette, A.Jaccard, and J.P.Fermand
For the group "Myélome-Autogreffe", Caen, Créteil, Limoges,
Paris, France.
In 2002, we initiated a prospective multicenter randomised double
blind trial in which myeloma patients in first or second relapse after
high dose (HDT) or conventional chemotherapy (CCT) were
randomly assigned to receive a (V)AD-like regimen (without
vincristine) combined with thalidomide (Thal arm) or placebo. In
both arms, patients received monthly courses of doxorubicin (9
mg/m2/day by continuous infusion, Day 1 to 4) and dexamethasone
(40 mg/day Day 1 to 4 and day 14 to 17 during the first 2 cycles)
for a maximum duration of one year. Thalidomide (or placebo) was
administrated at a daily dose of 200 mg during 15 days with serial
increments at 15 days interval according to tolerance to a maximum
dose of 400 mg po qhs. Screening for deep venous thrombosis
(DVT) was performed monthly by Doppler ultrasound during the
first 3 months of treatment and later when appropriate. There was
no systematic thrombosis prevention.
At randomisation, characteristics of the first forty five enrolled
patients were the following: median age 63 years; IgG, IgA and BJ
alone MM, 58, 22 and 10%, respectively; in first relapse after CCT
33%, after HDT 51%; median beta 2 microglobulin level 3.3mg/L.
Five patients had a past-story of DVT or pulmonary embolism
(PE). None of these presented a thrombotic event whereas DVT
was diagnosed in 8 patients, 7 in the Thal arm (28%), one in the
placebo arm (5%). DVT were usually observed during the first two
months on therapy, were bilateral in 3 cases and were complicated
by PE in 3 cases. Patients were treated by heparin derivative
followed by full-dose oral anti-vitamin K. Thalidomide or placebo
was stopped during one month. After that, patients were either
maintained on or withdrawn from the study according to outcome
and results of control venous Doppler.
During follow-up, 3 patients died (MM progression n=2, septic
shock n=1), none because of DVT or PE. Four patients were
withdrawn from the study because of a thrombotic event, three in
the thal arm and one in the control group. Otherwise, treatment
complications that caused patient’s withdrawal were vertigo and
dyspepsia (n=1, control arm), tremor and severe neutropenia (one
each, thal arm).
Preliminary results of this study confirm the high venous toxicity of
the combination of doxorubicin, dexamethasone and thalidomide.
Accordingly, the study design was modified by excluding
doxorubicin and the trial is ongoing comparing dexamethasone plus
thalidomide with dexamethasone plus placebo.
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