Haematologica 2003 - Supplements

their leukocytes and platelets. No dose limiting toxicity or cases
of thrombotic thrombocytopenic purpura, radiation nephritis or
bladder toxicity have been observed during the 10.1 months
median follow-up, range 0.25- 32 months. Forty-nine patients are
evaluable for response and five are too early to be evaluable for
response. For the 18 patients in the phase I cohort, continued or
new CR, VGPR, and PR rates were as follows: 28% (5/18), 39%
(7/18), and 28% (5/18), respectively. There was one minimal
response. Conclusions: Addition of high dose153-Sm EDTMP to
the Melphalan conditioning regimen appears to be safe and well
tolerated. The additional therapeutic benefit is not known but the
preliminary very good and complete response rates are
promising.
284
A Phase I/II Clinical Trial of High-dose Melphalan,
Topotecan and VP-16 Phosphate (MTV) Followed by
Autologous Stem Cell Rescue in Patients with Multiple
Myeloma.
Sullivan, DM, Alsina, M, Dalton WS, Gump, JL, Valkov, NI,
Derderian, JA, Turner, JG, McIsaac, CE, Lush, RM,
Sullivan, PA, Crann, ME, Fields, KK, Goldstein, SC, Field,
TL, Djulbegovic, B, Smith, CA, Perkins, JB
Experimental Therapeutics and BMT Programs, H Lee Moffitt
Cancer Center & Research Institute, University South Florida,
Tampa, FL.
Pre-clinical data suggest that myeloma cell kill may be optimal
when cells are exposed to drugs in the sequence, alkylator →
topoisomerase (topo) I inhibitor → topo II inhibitor. To explore
this paradigm, a 30 min infusion of melphalan (50 mg/m2/d x 3d)
was immediately followed the same day by a 30 min infusion of
dose-escalated topotecan (TPT) each d x 3d (days -7, -6, -5),
followed by a 4h infusion of VP-16P days -4 and -3 (1200
mg/m2/d total etoposide equivalents x 2d). CD34+ cells (≥
2x106/kg) collected after cyclophosphamide priming (50 mg/kg/d
x 2d) were given on day 0. Eighty-two patients (ages 27-69; 48%
female) were treated, and the maximum tolerated dose (MTD) of
TPT was found to be 20 mg/m2 total dose (dose level 4 (DL)).
The dose limiting toxicity was grade 4 mucositis and enteritis.
The median time to an ANC >500/µl was day 10 (range, 8-15),
and day 18 (range, 12-200+) for a platelet count >50,000/µl.
100-day non-relapse mortality was 4.1%. The MTD was
expanded to 30 patients, and a modified DL 4 (4M) that did not
include VP-16P enrolled 22 patients. Grade 4 mucositis
decreased from 80% (DL 4) to 13% at DL 4M. The overall
response rate in 81 evaluable patients was 53.1% (33.3% CR and
19.8% PR), with 34.6% stable disease. The overall and event
free survival were significantly increased in those that received
TPT (DLs 2-4), compared to the 10 patients in DL 1 that did not
receive TPT. Analyses of pre-treatment and d-4 plasma cells
obtained from bone marrow aspirates by confocal microscopy
showed: (1) 5- to7-fold higher levels of topo I (compared to topo
II α and β) in pre-treatment and d-4 plasma cells, (2) significantly
increased whole cell topo I, IIα and IIβ protein in plasma cells at
d-4, (3) significantly more cytoplasmic IIα and IIβ at d-4, and (4)
increased breast cancer resistance protein (BCRP) expression in
d-4 plasma cells compared to pre-treatment cells. Drug levels of
TPT, VP-16P and melphalan were obtained in all patients and
correlated with response and topo levels/location. In summary,
DNA topoisomerase I appears to be a relevant target in the
treatment of myeloma. Drug resistance may be related to
cytoplasmic trafficking of topoisomerases and increased
expression of BCRP. A follow-up study of high-dose melphalan
+ dose-escalated TPT, stratified for age (≤ or > 60 yrs), has
enrolled 20 patients with minimal mucositis at a total TPT dose
thus far of 54 mg/m2 (younger group). [TPT and VP-16P were
provided by GlaxoSmithKline and Bristol-Myers Squibb,
respectively. Supported in part by NIH grants CA82050 and
CA82533].
285
Melphalan vs Busulphan plus Melphalan in the
conditioning for ABMT in the treatment of patients with
multiple myeloma
Roberto Ria, Stelvio Ballanti, Franca Falzetti, Olivia Minelli,
Mauro Di Ianni, Flavio Falcinelli, Massimo Fabrizio Martelli,
Antonio Tabilio
Department of Clinical and Experimental Medicine, Section of
Hematology and Clinical Immunology, University of Perugia,
Perugia, Italy
30 patients out of 101 with stage III multiple myeloma that have
undergone transplantation at our Institution over the past 12 years
were included in this study. The selection criteria included: age
less than 70 years, creatinine less than 200 mg/ml, cardiac
ejection fraction >50%, DLCO >50%, no active infection disease
or other co-morbidity conditions. 16 patients were treated with
Melphalan 180 mg/m2 (arm A) and 14 with Busulphan 16 mg/Kg
+ Melphalan 100 mg/m2 (arm B) for ABMT conditioning. The
median age at transplantation was 52,2 years (range 34-64) for
arm A and 49,5 years (range 34-60) for arm B. In the arm A were
included 9 male and 7 female and in the arm B 9 male and 5
female. All patients received 3 cycles of VAD and were
mobilized with Cyclophosphamide 7 gr/m2 and rHuG-CSF (10
µg/Kg b.w./die).
The dose of CD34+ cells infused range from 1.5 to 15.6 x106/Kg
(median 9.2 x106/Kg) for the arm A, and from 1.5 to 15.8
x106/Kg (median 8.9 x106/Kg) for the arm B.
Days to achieve engrafment (neutrophyls > 500/µl) were similar
in the two arms (arm A: median 11, range 9-20; arm B: median
11, range 9-21), all the patients received rHuG-CSF 10 µg/Kg
b.w./die after reinfusion of PBSC. No difference in the incidence
of transplant-related infective and non-infective complication
were evidenced in the two arms and no transplant-related deaths
were observed.
The best percentage of response (complete or partial response)
were observed in the arm B (85% vs 75%), 2 progression after
ABMT were observed in the arm A.
All patients received maintaining therapy with Interferon 3 MU x
3/week after ABMT.
Disease free survival at 5 years were 45% in the arm A (median
3,6 years) and 64% in the arm B (median 4,7 years) (p