Background: Tyrosine Kinase Inhibitors (TKI) have been shown to be very effective for the treatment of Acute Lymphoblastic Leukemia (ALL), with a Com- plete Hematologic Response (CHR) rate close to 100%, and a high rate of Complete Cytogenetic and Molecular responses (CCgR and CMR). However, when they are used alone, as single agents, most patients relapse, so that they are currently used in combination with chemotherapy and as a preparation to allogeneic stem cell transplantation (SCT). Since Ph+ ALL is more frequent in the elderly, many patients cannot tolerate intensive chemotherapy and are not eligible for SCT. We have explored if the administration of two TKIs, Nilotinib (NIL) and Imatinib (IM) can improve the results without increasing the toxicity. Aims: To evaluate the response and the outcome of Ph+ ALL patients treated with the sequential administration of NIL and IM, and to investigate the type and number of BCR-ABL kinase domain mutations developing during and after the study. Methods: We have designed a study (ClinicalTrials.gov. NCT01025505) in which patients more than 60 years old or unfit for intensive chemotherapy and SCT where treated with two TKIs, NIL 400 mg twice daily, and IM 300 mg twice daily, alternating for 6 weeks for a minimum of 24 weeks (study core) and indef- initely in case of response. The 6-weeks rotation schedule was respected, irre- spectively of temporary discontinuations. The primary end-point was the rate of Disease Free Survival (DFS) at 24 weeks (4 courses of treatment); the second- ary end points included the evaluation of CHR, CCgR and CMR rates. Mutation analysis was performed by nested RT-PCR amplification of the ABL kinase domain of the BCR-ABL transcript (codons 206 through 421). Amplified products were screened by denaturing-high performance liquid chromatography (D- HPLC). Samples scored positive for the presence of sequence variations were then subjected to direct automatic sequencing to characterize the mutation. Results: 39 patients have been enrolled in 15 Italian hematologic Centers (medi- an age 66 years, range 28-84, M/F=19/20). Among these, 8 patients were unfit for standard chemotherapy or SCT (median age 50 years, range 28-59). 27 patients were p190, 5 were p210 and 7 were p190/p210. After 6 weeks of treat- ment, 37 patients obtained a CHR (95%) and 2 a PHR (5%). All the patients were evaluable for response after 12 weeks of treatment: 35 patients were still in CHR (90%), 2 relapsed (5%) and one patient died. 25/26 patients who have completed the study core (24 weeks), were in CHR, and 22 continued therapy in the protocol extension phase.Thus, the OS at 1 year is 82%, and 64% at 2 years (median follow up 34.9 months, range 3.5-42.4 months). Overall, 25 patients relapsed, with a median time to relapse of 9.2 months (range 1.2-28.4 months), for a DFS of 48.7% at 12 months. Most of mutations detected at relapse were T315I, E255K, E255V and Y253H. Further details about Cytogenetic and Molecular responses, and about Adverse Events will be provided on site. Summary and Conclusions: In this small cohort of Ph+ ALL elderly/unfit patients, the rates of relapse and progression were not likely to be different from the rates observed with Imatinib alone. It’s important to notice that the mutations that occurred at the time of relapse were sensitive to other TKIs (Dasatinib and Ponatinib).
High rate of complete hematological response in elderly Ph+ acute lymphoblastic leukemia (ALL) patients by innovative sequential use of nilotinib and imatinib: a GIMEMA clinical trial LAL 1408.
BONIFACIO, Massimiliano;
2015-01-01
Abstract
Background: Tyrosine Kinase Inhibitors (TKI) have been shown to be very effective for the treatment of Acute Lymphoblastic Leukemia (ALL), with a Com- plete Hematologic Response (CHR) rate close to 100%, and a high rate of Complete Cytogenetic and Molecular responses (CCgR and CMR). However, when they are used alone, as single agents, most patients relapse, so that they are currently used in combination with chemotherapy and as a preparation to allogeneic stem cell transplantation (SCT). Since Ph+ ALL is more frequent in the elderly, many patients cannot tolerate intensive chemotherapy and are not eligible for SCT. We have explored if the administration of two TKIs, Nilotinib (NIL) and Imatinib (IM) can improve the results without increasing the toxicity. Aims: To evaluate the response and the outcome of Ph+ ALL patients treated with the sequential administration of NIL and IM, and to investigate the type and number of BCR-ABL kinase domain mutations developing during and after the study. Methods: We have designed a study (ClinicalTrials.gov. NCT01025505) in which patients more than 60 years old or unfit for intensive chemotherapy and SCT where treated with two TKIs, NIL 400 mg twice daily, and IM 300 mg twice daily, alternating for 6 weeks for a minimum of 24 weeks (study core) and indef- initely in case of response. The 6-weeks rotation schedule was respected, irre- spectively of temporary discontinuations. The primary end-point was the rate of Disease Free Survival (DFS) at 24 weeks (4 courses of treatment); the second- ary end points included the evaluation of CHR, CCgR and CMR rates. Mutation analysis was performed by nested RT-PCR amplification of the ABL kinase domain of the BCR-ABL transcript (codons 206 through 421). Amplified products were screened by denaturing-high performance liquid chromatography (D- HPLC). Samples scored positive for the presence of sequence variations were then subjected to direct automatic sequencing to characterize the mutation. Results: 39 patients have been enrolled in 15 Italian hematologic Centers (medi- an age 66 years, range 28-84, M/F=19/20). Among these, 8 patients were unfit for standard chemotherapy or SCT (median age 50 years, range 28-59). 27 patients were p190, 5 were p210 and 7 were p190/p210. After 6 weeks of treat- ment, 37 patients obtained a CHR (95%) and 2 a PHR (5%). All the patients were evaluable for response after 12 weeks of treatment: 35 patients were still in CHR (90%), 2 relapsed (5%) and one patient died. 25/26 patients who have completed the study core (24 weeks), were in CHR, and 22 continued therapy in the protocol extension phase.Thus, the OS at 1 year is 82%, and 64% at 2 years (median follow up 34.9 months, range 3.5-42.4 months). Overall, 25 patients relapsed, with a median time to relapse of 9.2 months (range 1.2-28.4 months), for a DFS of 48.7% at 12 months. Most of mutations detected at relapse were T315I, E255K, E255V and Y253H. Further details about Cytogenetic and Molecular responses, and about Adverse Events will be provided on site. Summary and Conclusions: In this small cohort of Ph+ ALL elderly/unfit patients, the rates of relapse and progression were not likely to be different from the rates observed with Imatinib alone. It’s important to notice that the mutations that occurred at the time of relapse were sensitive to other TKIs (Dasatinib and Ponatinib).
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