Treatment of Philadelphia Chromosome (Ph)-Positive Acute Lymphoblastic Leukemia (ALL) with Concurrent Chemotherapy and Imatinib Mesylate.

Abstract

Imatinib mesylate as a single agent has modest activity in refractory/relapsed Ph-positive ALL. Use of concurrent chemotherapy and imatinib mesylate in newly diagnosed Ph-positive ALL was explored. Nineteen patients (pts) with de novo Ph-positive ALL were included in a prospective trial. Induction chemotherapy consisted of imatinib mesylate (400 mg/d, p.o.) and VCR (1.5mg/m2/wk), DNR (60 mg/m2/wk) and PDN (60mg/m2/d) for 4 weeks if adequate bone marrow response (<5% blast cells) at day +14 was observed. If not mitoxantrone (12 mg/m2, d15, 16, 17) and HD-ARAC (1,000mg/m2/12h d 18, 19) were administered. Consolidation chemotherapy (C1) included imatinib mesylate and MP, HD-MTX (1.5 g/m2), VM-26 and ARA-C. Pts with a HLA-identical family or MUD donor were submitted to SCT. IF no MUD donor was found a second consolidation cycle (C2) with imatinib mesylate, VCR, DNR, DXM and CPM was administered. Pts without family donor or with no MUD donor after 6 mo. of active search were submitted to autologous SCT. After SCT imatinib mesylate was administered from the sustained hematological recovery to the eventual relapse or at least up to 1 yr. of continuous molecular remission. Sequential MRD study was performed by cytofluorometry and quantitative RT-PCR. Up to July 2004, 19 pts (10 males, mean [SD] age 43[12] yr., range 17–62, p190bcr-abl in 75% of the cases) were included. One pt is still on treatment, 1 died in induction because of infection, 1 was refractory and the remaining 16 (89%) attained CR. Slow bone marrow response was observed in 4 out of 14 evaluable pts. Three patients have relapsed before SCT, 8 are on consolidation therapy and SCT was performed in 5 (3 from family donor and 2 MUD). 1 pt died after SCT and no relapses after SCT have been observed to date (range 1–6 months from SCT). With a median follow-up of 5 (0.2–14) mo., 3 pts have died, 2 are alive in second CR and 13 are in first CR, with a median DFS of 8 mo. and an OS probability of 66±30%. Levels of BCR-ABL/GUS x100 less than 0.05 were observed in 6/12 (50%) pts at the end of induction therapy. There was a further 1–2 log median reduction of BCR/ABL transcripts at the end of C1, (BCR-ABL/GUS x100 less than 0.05 in 5/6 cases). No additional reduction of transcripts was observed between C1 and SCT. A good correlation between molecular and cytofluorometric MRD data was observed. Use of concurrent chemotherapy and imatinib mesylate in newly diagnosed Ph-positive ALL pts is feasible and the preliminary data are promising in terms of high rate of clinical and molecular CR. Continued accrual and longer follow-up of the current cohort is needed.