Discussion
ETP- ALL has been characterised by chemo-refractoriness and bad disease biology.
High percentage of persistent minimal residual disease and poor overall survival has been reported in ETP ALL patients treated with GRAALL 2003 and GRAALL 2005 protocol. However, response adapted treatment stratification and use of allogeneic stem cell transplant in CR1 has been shown to abrogate the negative effects of chemo-resistance in ETP ALL [5]. Patients with ETP ALL have low rates of CR with standard chemotherapy. In a small series from India only 1 of 6 patients of ETP- ALL could achieve complete remission after initial chemotherapy [6].
Novel therapeutic agents studied in ETP ALL include dasatinib (patient with NUP214-ABL1 aberration), ruxolitinib (JAK/STAT pathway), daratumumab (anti CD38 antibody), gemtuzumab ozagamycin(anti CD 33 antibody conjugate) and venetoclax (BCL-2 inhibitor)[7]. Table 1 summarises the reports of venetoclax use in ETP ALL [8-10]. In a study from MD Anderson Cancer Center, 13 patients of relapsed refractory T cell ALL which included 5 patients of ETP ALL were treated with venetoclax in combination with various chemotherapy regimens [11]. The median dose given was 200 mg with a total duration of 21 days in combination with HyperCVAD, fludarabine+ cytarabine + idarubicin, decitabine, nelarabine and asparaginase. Prolonged cytopenias were observed with dose of 400 mg/day or duration of therapy > 14 days. 60% of patients achieved complete remission. No association between bone marrow response and dose was observed. The median OS was 7.7 months. Only 1 ETP ALL patient achieved MRD negativity. Only 2 patients were alive at 1 year and both had ETP ALL. Duration of remission achieved with venetoclax was short lived. In our study we used 100mg on day 1, 200 mg on day 2, 300 mg on day 3 and 100 mg with oral posaconazole from day 4 to day 7 onwards in combination with BFM 95 regimen. Both patients attained complete remission after 1 course of venetoclax combination chemotherapy. One patient achieved MRD negativity after 1 course of venetoclax and the other patient achieved MRD negativity after 2nd course of venetoclax. In a study by El-Cheikh J et al, 3 patients of relapsed refractory T cell ALL were treated with venetoclax and BFM based therapy [12] . 2 patients achieved CR.
Combinations of venetoclax with other chemotherapeutic agents have been studied in relapsed refractory ALL. Navitoclax is a novel inhibitor of BCL-XL and in combination with Venetoclax has shown synergistic effect in phase 1 study in patients with relapsed/refractory B and T cell acute lymphoblastic leukemia [13]. The overall rate of combined complete response, CR with incomplete marrow recovery or incomplete platelet recovery was 49%. Responses of combination therapy of venetoclax(800 mg followed by 400 mg with azoles)with decitabine in relapsed T cell ALL post allogeneic stem cell transplant have also been described[14, 15]. Patient had also achieved MRD negativity. Individualized therapy based on drug response profiling of leukemia cells with venetoclax and bortezomib was done in 3 patients of relapsed refractory ETP ALL. 1 patient achieved CR and 2 PR. All patients underwent transplant and achieved remission [16]. Currently a phase I/II study is undergoing in MDACC of venetoclax in combination with low dose chemotherapy in relapsed refractory T cell ALL(NCT03808610). We used a short low dose regimen with posaconazole which was well tolerated and achieved good results in our patients.