Line Treatment of Adult Ph+ Acute Lymphoblastic Leukemia (ALL) Patients. Final Results of the GIMEMA LAL1205 Study

Background: Dasatinib is a potent, oral inhibitor of the BCR-ABL, c-KIT and SRC kinase family, which has proven to be a more active inhibitor of BCR-ABL and c-KIT than imatinib in preclinical studies. Clinically, it has been shown to be effective in chronic myeloid leukemia and in Ph+ ALL patients resistant or intolerant to imatinib.

Aims: The primary objective of the study was to assess the activity of dasatinib in de novo adult Ph+ ALL patients in terms of complete hematological remission (CHR); the secondary objectives were treatment toxicity, rate of immunophenotypic and molecular responses, disease-free survival (DFS), relapse rate and overall survival (OS).

Methods: The GIMEMA LAL 1205 protocol was designed for patients ≥18 years (no upper age limit) who receive dasatinib po, 70 mg BID. A steroid pre-phase is started 7 days prior to dasatinib administration and continued up to day 31, and then tapered. The pre-phase allows identification of the BCR/ABL transcript. Dasatinib is given for 12 weeks. Two intrathecal methotrexates are administered at days +22 and +43. All cases are analyzed through a central handling of samples at presentation for morphology, immunophenotype, cytogenetics and molecular biology at the coordinating center in Rome. Minimal residual disease (MRD) is also centrally investigated by flow-cytometry and Q-RT-PCR at days +22, +43, +57 and +84. The protocol was designed for 48 patients.

Results: Recruitment started in November 2006 and was completed in August 2008. The median age of the 48 enrolled BCR/ABL+ ALL patients was 54 years (range 24-76), 26 were females and 22 males. The median WBC count was 20.1 (range 2.2–133). The last analysis has been conducted on 36 patients. One patient stopped treatment after 14 days due to intestinal toxicity and 1 patient refused treatment. Thus, to date 34 patients are evaluable for response. Nineteen cases were p190+ and 15 p210+ (5 were p190/p210+). A >75% response to the steroid pre-phase was recorded in 82.7% of patients. All 34 patients (100%) have witnessed a CHR: 32 (94.12%) at the 1^st determination at day +22, 1 at the 2^nd at day +43 and 1 at the 3^rd at day +57. No fatalities have been observed. In 13 patients, at least 1 severe adverse event (SAE) has been recorded, for a total of 26 SAEs. Overall, the compliance has been good; only 1 patient stopped treatment at day 67 due to toxicity while in CHR. The median follow-up is so far 11.2 months. The OS at 10 months is 80.7%. Immunophenotypic and BCR/ABL Q-RT-PCR monitoring of MRD has shown a very marked clearance of leukemic cells by day +22, progressively strengthened at the subsequent timepoints. In p190+ cases the minimal MRD value was reached at day +43, while in p210+ cases this was observed at day +84, documenting a lower susceptibility to dasatinib by this molecular subgroup. So far, 9 patients have relapsed, at a median of 72 days from the end of induction; in agreement with the MRD data, 7/9 relapses occurred within the p210+ cases and 2/9 within the p190+ cases. The presence of mutations has been investigated in 8/9 relapsed samples: 5 showed a T315I mutation, 1 an E255K mutation and 2 were wt. Cloning experiments allowed to detect in 2 cases low levels of T315I mutations already at presentation and on MRD cells at the end of the induction treatment. The first multivariate analysis has been conducted for DFS and the degree of PCR reduction − ≤10⁻³ vs ≥10⁻³ - has so far emerged as the only significant prognostic factor.

Conclusions: This study demonstrates that in adult Ph+ ALL dasatinib monotherapy is capable of inducing a CHR in virtually all patients, irrespective of age, without important toxicities and with no fatalities. The hematological response is associated with a very marked and rapid debulking of the neoplastic clone documented at the MRD level, particularly for p190+ cases. The degree of PCR response is of prognostic relevance. No relapses have been observed during the induction phase. The optimal post-induction treatment strategy, which was not part of the study, remains to be defined, particularly in light of the genetic instability of Ph+ ALL and of the selection/induction of mutations. These results, together with those previously reported by our group with imatinib alone for elderly patients, question the use of chemotherapy, with or without a TK inhibitor, for the remission induction of Ph+ ALL.