Clinical Impact of Q-RT-PCR Monitoring of Minimal Residual Disease in Newly Diagnosed Adult Patients with BCR-ABL+ Acute Lymphoblastic Leukemia Receiving Imatinib Mesylate Alone as a Post-Consolidation Treatment According to the Italian GIMEMA LAL 0201/A Protocol.

Abstract

Twenty-six adult patients (pts) aged between 22 and 60 years (median age: 46) with BCR-ABL+ acute lymphoblastic leukemia (ALL) were prospectively monitored by Q-RT-PCR between August 2001 and July 2004. All pts entered the GIMEMA LAL 0201/A protocol, in which Imatinib alone, at the dosage of 400 mg x 2 daily for at least six months, was administered as post-consolidation therapy in responding pts after intensive chemotherapy (CHT). Eighteen pts (69%) were p190+and 8 (31%) p210+ with/without the p190. In these two groups, the mean number of BCR-ABL copies at diagnosis (ie: BCR-ABL/ABL x 104) was 13,052 (range: 1,466–35,449) and 22,487 (range: 7,315–78,000) (p=ns), respectively. All pts were in 1st complete hematologic remission (25 pts after the first induction-consolidation course; 1 pt after a salvage treatment). Before Imatinib, 8 of the 18 p190+ pts (44%) showed a BCR-ABL copy reduction of ≥ 3 log compared to the levels at diagnosis, (mean BCR-ABL copies 3.6; range: 0–10), and they were defined as good responders to CHT. The remaining 10 pts (56%), defined as poor responders, showed a reduction of < 3 log (mean copies 2,825.8; range: 12 – 25,245). In the 10 poor responders, BCR-ABL copies constantly increased over time and this was predictive of an hematologic relapse in 8/10 patients. By contrast, 7 of the 8 good responder pts during Imatinib treatment persistently showed levels of BCR-ABL below 10. These 7 pts are in CCR maintained by Imatinib alone at 6, 9, 13, 13, 17, 21 and 23 months, respectively. In 1 pt, at 6 months from the start of Imatinib, a CNS relapse preceded a marked increase in the BCR-ABL copy numbers in BM cells. Therefore, after a median follow-up of 6 months (range 3 – 23), for poor responders, and of 13 months (range 6 – 30), for good responders, the actuarial probability of relapse was 100% and 12.5%, at 24 months (p=.027), respectively. p210+ pts achieved a molecular response rate slightly different respect to the p190+ cases. In fact, before starting Imatinib, only 2 of the 8 cases (25%) analyzed showed a reduction in BCR/ABL copies ≥ 3 log whereas in the remaining 6 pts, 1 relapsed at 6 months, but the other 5 showed a decrease of the BCR-ABL copies that in 2 cases fell below the 3 log reduction after 8 and 12 months, respectively. Altogether, after a median follow-up of 6 months (range: 2–28), 7/8 p210+ pts were in CCR maintained by Imatinib alone without transplant at 2, 4, 5, 6, 19, 24 and 28 months, respectively. In conclusion, Imatinib is a highly effective post-consolidation treatment for adult Ph+ ALL pts being able to maintain and/or to induce a minimum level of BCR-ABL expression, without the high morbidity and mortality relating to allografting procedures. In addition, in the p190+ cases an unsatisfactory molecular response rate after CHT was a powerful predictor of a subsequent clinical resistance to Imatinib.