A sequential approach with imatinib, chemotherapy and transplant for adult Ph+ acute lymphoblastic leukemia: final results of the GIMEMA LAL 0904 study

Abstract

In the GIMEMA LAL 0904 protocol, adult Philadelphia positive acute lymphoblastic leukemia patients were treated with chemotherapy for induction and consolidation, followed by maintenance with imatinib. The protocol was subsequently amended and imatinib was incorporated in the induction and post-remission phase together with chemotherapy. Due to the toxicity of this combined approach, the protocol was further amended to a sequential scheme based on imatinib plus steroids as induction, followed by consolidation with chemotherapy plus imatinib and, when applicable, by a hematopoietic stem cell transplant. Fifty-one patients (median age 45.9 years) were enrolled in the final sequential protocol. At the end of induction (day +50), 96% of evaluable patients (n=49) achieved a complete hematologic remission; after consolidation, all were in complete hematologic remission. No deaths in induction were recorded. Overall survival and disease-free survival at 60 months are 48.8% and 45.8%, respectively. At day +50 (end of imatinib induction), a more than 1.3 log-reduction of BCR-ABL1 levels was associated with a significantly longer disease-free survival (55.6%, 95%CI: 39.0-79.3 vs. 20%, 95%CI: 5.8-69.1; P=0.03), overall survival (59.1%, 95%CI: 42.3-82.6 vs. 20%, 95%CI: 5.8-69.1; P=0.02) and lower incidence of relapse (20.5%, 95%CI: 7.2-38.6 vs. 60.0%, 95%CI: 21.6-84.3; P=0.01). Mean BCR-ABL1 levels remained significantly higher in patients who subsequently relapsed. Finally, BCR-ABL1 p190 patients showed a significantly faster molecular response than BCR-ABL1 p210 patients (P=0.023). Though the study was not powered to evaluate the role of allogeneic stem cell transplant, allografting positively impacted on both overall and disease-free survival. In conclusion, a sequential approach with imatinib alone in induction, consolidated by chemotherapy plus imatinib followed by a stem cell transplant is a feasible, well-tolerated and effective strategy for adult Philadelphia positive acute lymphoblastic leukemia, leading to the best long-term survival rates so far reported. (clinicaltrials.gov identifier: 00458848).

BCR-ABL–specific T-cell therapy in Ph+ ALL patients on tyrosine-kinase inhibitors

“…The 3 patients received a mean of 10 monthly infusions (range, [6][7][8][9][10][11][12][13]. No immediate infusion-related adverse events were observed, and no grade 2-4 toxicities, including development of cytokine release syndrome, attributable to the T-cell infusions were recorded during follow-up.…”

“…1,4 Prolonged hematologic and cytogenetic remissions have been observed with imatinib mesylate (IM) alone, even in the presence of persisting levels of minimal residual disease (MRD). [5][6][7] Our group was able to demonstrate that attainment of such clinical responses directly correlated with the emergence of BCR-ABL-specific T cells in the bone marrow (BM) and, to a lesser extent, in the peripheral blood of nonallografted Ph 1 ALL patients undergoing postremission maintenance treatment with either IM or other second-generation TKIs. 8,9 These observations extended previous evidence of functional leukemia-specific cellular immune responses developing in patients receiving IM, and possibly acting in synergy with IM to reach disease control, 10,11 and represent the basis for a combined TKI and T-cell therapy approach to Ph 1 ALL in elderly patients, or in patients relapsing after alloHSCT.…”

How I treat Philadelphia chromosome–positive acute lymphoblastic leukemia

“…40 Other studies have also reported the occurrence of ABL1 kinase domain mutations at relapse. 18,19,47 These data suggest that development of ABL1 kinase domain mutations, and particularly T315I, is an important contributor to the development of relapse in Ph 1 ALL suggesting that a more potent inhibitor with activity against the resistanceinducing mutations, such as ponatinib, is likely to be beneficial in this disease. Indeed early reports of use of this agent in the frontline setting have suggested impressive activity with high response rates including high and early CMR rates.…”

“…15 However, a patient unable or unwilling to undergo transplantation likely requires the combination of ALL-based chemotherapy regimens with TKIs. 18,19 Potential benefits of the more intensive regimens including high doses of cytarabine and methotrexate may include deeper disease eradication and better central nervous system (CNS) penetration.…”

The changing face of clinical trials in the personalized medicine and immuno-oncology era: report from the international congress on clinical trials in Oncology & Hemato-Oncology (ICTO 2017)

“…In acute promyelocytic leukemia, the identification of specific genetic lesion(s), which imply exquisite sensitivity to targeted differentiating therapy, have led to the development of chemotherapy-free treatment approaches, such as the combination of all- trans retinoic acid (ATRA) and arsenic trioxide (ATO) [ 10 , 11 ], endowed with 100% complete response (CR) rate and no toxic deaths or induction of resistance, particularly when MRD is monitored by sensitive techniques, such as RT-PCR, as in the Italian AIDA trial [ 12 ]. Other examples include chronic myeloid leukemia (CML), in which life-expectancy of affected patients now approaches that of the general population after the introduction of different generations of tyrosine kinase inhibitors (TKI) [ 13 ] and the development of molecularly-based MRD monitoring strategies [ 14 , 15 ]; similarly, molecularly-based prognostic stratification and combined TKI-based treatment strategies have led to the implementation of chemotherapy-free induction regimens endowed with 97-100% CR rates and no induction deaths in Philadelhpia + ALL [ 16 ], suitable for the safe and effective treatment even of patients aged >90 years. In chronic lymphocytic leukemia (CLL), molecular characterization by high-throughput technologies are redefining risk groups and paving the way for truly individualized treatment strategies, based on the availability of a wealth of drugs targeted to specific molecular aberrations [ 17 ]; similarly, the discovery of pathogenic BRAF mutations in hairy cell leukemia (HCL) has had diagnostic and therapeutic implications [ 18 ].…”