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A PHASE II STUDY OF INTENSIVE CHEMOTHERAPY (IC) WITH FLUDARABINE, CYTARABINE, AND MITOXANTRONE IN P GLYCOPROTEIN (PGP) NEGATIVE MYELODYSPLASTIC SYNDROMES (MDS). GROUPE FRANÇAIS DES MYELODYSPLASIES ( ).

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  1. A PHASE II STUDY OF INTENSIVE CHEMOTHERAPY (IC) WITH FLUDARABINE, CYTARABINE, AND MITOXANTRONE IN P GLYCOPROTEIN (PGP) NEGATIVE MYELODYSPLASTIC SYNDROMES (MDS). GROUPE FRANÇAIS DES MYELODYSPLASIES ( ). T Prébet, A Merlat, S Ducastelle, A Stamatoullas, E Deconinck, C Fruchart, B Mahé, N Ifrah, N Gratecos, P Casassus, P Lepelley, F Dreyfus, P Fenaux, and E Wattel. Groupe Français des Myélodysplasies (GFM), France.

  2. Background (1) • Quinine increases complete remission (CR) rates and survival in PGP-positiveMDS patients treated with intensive chemotherapy (IC) (Br J Haematol 102:1015-24., 1998) • Present trial: improve the CR rate in PGP-negative MDS.

  3. Background (2) • Leukemic cells primed by exposure to fludarabine exhibit enhanced accumulation of cytarabine triphosphate (the cytotoxic nucleotide of cytarabine), especially with continuous AraCinfusion (Clin Cancer Res. 1998;4:45-52) • Phase II trial explore the potential feasibility and efficacy of a combination chemotherapy associating fludarabine, mitoxantrone, and cytarabine, administered by continuous IV infusion for high-risk MDS.

  4. Patients & methods (1) • Inclusion criteria • age ≤ 65 years • MDS with an excess of PGP negative marrow blasts (RAEB, RAEB-T) or having progressed to AML (MDS-AML). • Treatment (FAM protocol): • mitoxantrone 12mg/m2/d (over 30 min) d2-5 • fludarabine, 30mg/m2/d (over 5 min) d2-5 • AraC 1.5g/m2/24h (continuous infusion started 5 h prior to fludarabine) d1-5. • CR criteria • marrow blasts < 5%, • normalization of cytopenia and of karyotype, • disappearance of MDS features.

  5. Patients & methods (2) • Consolidation • Patients <60 years • with HLA identical donor: allogeneic stem cell transplantation • with no HLA identical donor and who achieved CR: scheduled to receive autologous stem cell transplantation (ASCT) preceded by a moderate consolidation chemotherapy (CT) course. • Older patients received several consolidation CT courses. • FLAM versus MA protocol • The outcomes of FLAM-treated patients were compared with the outcomes of 32 MDR-negative MDS patients who fulfilled the same inclusion and response criteria, and who received: mitoxantrone 12mg/m2/d d2-5 + AraC 1g/m2/12h d1-5 (MA protocol), between October 1992 and May 1996 (Br J Haematol 102:1015-24, 1998).

  6. Results (1) • Between March 1998 and January 2000, 29 patients were included: • 14 MDS-AML, 8 RAEB-T, and 7 RAEB. • Median age was 55 years (range: 32-70). • Response • 6 patients (21%) died from the procedure • 16 (55%) achieved CR.

  7. Results (2) • Consolidation (16 patients in CR) • sequential consolidation CT: 9 patients • allogeneic stem cell transplantation in CR: 2 patients • autologous stem cell transplantation: 5 patients • = 5 of the 8 patients <60 years with no HLA identical donor and who achieved CR. • reasons for not performing ASCT in the remaining 3 patients were: early relapse in 2 patients, and poor marrow stem cell harvest in 1. • Overall survival (KM): • 72 ± 8% at 6 months, • 32 ± 9% at 12 months, • 8 ± 8% at 24 months.

  8. Results (3) • Prognostic factors (Cox’s univariate analysis) • Abnormal karyotype (26 successfully karyotyped patients) was the only factor associated with poor survival (p=0.0088). • IPSS cytogenetic subgroups, 1-year survival rates (p=0.08): • good- (n=9): 56% • intermediate- (n=8): 25%, • poor (n=9): 0%. • FLAM versus MA protocol (PGP-negative high-risk MDS) FLAM MA Fludarabine: 30 mg/m2/d (over 5 min) d2-5 - AraC: 1.5 g/m2/24h (continuous) 1 g/m2/12h d1-5 (bolus) Mitoxantrone: 12 mg/m2/d d2-5 12 mg/m2/d d2-5

  9. Results (4) • Comparison with the MA protocol (no difference in patients’ characteristics): FLAM MA p CR rate: 55% 47% ns TRM: 21% 25% ns Leukopenia*: 26 d 24 d ns Neutropenia 27 d 25 d ns Thrombocytopenia: 33 d 25 d 0.027 ASCT feasibility 62% 57% ns Relapse-free survival** 7.4 months 13 months ns Overall survival** 11.4 months 14 months ns *mean, ** median KM

  10. Median KM overall survival: 11.4 months

  11. Median KM DFS: 7.4 months

  12. Survival according to the karyotype (Abn vs. Nl, 26 patients) (p=0.0088)

  13. Survival: FLAM vs. MA regimen (DNS)

  14. DFS: FLAM vs. MA regimen (DNS)

  15. Conclusion • Present results suggest that adding fludarabine to mitoxantrone and AraC, administred under continuous infusion, had no effect on CR rate, survival, or DFS in high-risk PGP negative MDS.

  16. Groupe Français des Myélodysplasies ( ) and GOELAMS, France • T Prébet, A Merlat, S Ducastelle, A Stamatoullas, E Deconinck, C Fruchart, B Mahé, N Ifrah, N Gratecos, P Casassus, P Lepelley, F Dreyfus, P Fenaux, and E Wattel.

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