Real-world data of adolescents and young adults with acute lymphoblastic leukemia treated with a modified GMALL protocol in India: Treatment outcomes and challenges

Abstract Adolescents and young adults (AYA) with acute lymphoblastic leukemia (ALL) treated using pediatric-inspired regimens have improved survival compared to those treated with the adult protocols across the global north. However, in resource-limited settings, the benefit of intensification might be offset by increased toxicities and poor treatment adherence. We have previously reported our experience with a modified GMALL protocol (Jain et al, JGO 2018) and a large proportion of AYA ALL at our center continue to be treated with the modified GMALL protocol. Between 2015-2023, 506 patients aged 20 to 40 years were diagnosed with ALL at our center. Of these, 346 (68.4%) opted for treatment at our center. Among these, 272 (78.6%) were treated with the modified GMALL protocol, 58 (16.8%) with a modified BFM 95 pediatric intermediate-risk protocol, and 16 (4.6%) with HyperCVAD protocol. We retrospectively analyzed the outcomes of patients with AYA ALL uniformly treated with the modified GMALL protocol. The median age was 29 years (range 20-40 years) with 91(33.5%) females. The median WBC count at diagnosis was 9.7 x 109/L (range 0.3-723 x 109/L) with a median circulating blasts of 30% (range 0 to 98%). One hundred seventeen (43%) were CNS-2, while 19(7%) were CNS-3. On immunophenotyping, 178(65.4%) had B ALL, 56(20.6%) had T ALL, 36(13.2%) had Early T cell precursor (ETP) ALL, while 2(0.7%) had mixed phenotype acute leukemia (MPAL). On RT-PCR, 47(23.6%) were BCR::ABL positive (data available for 199 patients), 5(3.2%) had KMT2A::AF4 (data available for 158 patients), 1(0.6%) had TEL::AML1 (data available for 157 patients), and 9(5.7%) had E2A::PBX (data available for 157 patients). Thirty(11%) had tumor lysis as per the Cairo Bishop criteria. After initiating the protocol, 10 patients opted to continue treatment elsewhere and were excluded from the analysis. Of the remaining 262 patients who started phase 1 induction, 17 died in the hospital and 9 left the hospital in a poor clinical condition with active infection or a CNS event and were considered as induction deaths (9.9%). Of the remaining, 38(14.5%) had refractory disease following phase 1 induction. Of these, 12 opted for palliative chemotherapy while 12 continued the same protocol and 14 underwent salvage chemotherapy. Of these 38, 13 underwent allotransplant in CR1. A total of 198(75.6%) achieved morphologic complete remission (CR) at the end of induction. Flowcytometry-based measurable residual disease (MRD) testing at the end of Phase I induction was performed in 177 patients of whom 93(52.6%) were negative while 84(47.4%) had detectable MRD. After achieving end-induction CR, 6 opted for palliative chemotherapy, 6 discontinued treatment, 38 received intensified treatment (HyperCVAD (n=35), ALL-REZ BFM 2002 protocol (n=2), medium dose methotrexate (n=1) followed by allotransplant in CR1 in 29 patients), while the remaining 148 continued the same protocol (including 6 who opted to continue the same protocol due to financial constraints despite being offered treatment intensification for MRD positivity). During the subsequent treatment phases, 2 opted for palliative chemotherapy, 15 lost follow-up before completing treatment, while 8 underwent allotransplant in CR1. At a median follow of 63 months for surviving patients, 67(25.6%) have relapsed. Of these, 18 were very early, 30 were early, and 19 were late relapses. A total of 53 patients have undergone allotransplant of which 50 were in CR1. At last contact, 97 (37.0%) were alive and in remission with recent follow up within last 1 year, 4(1.5%) were alive but not in remission with follow up within the last 1 year, 132(50.4%) have died while 29(11.1%) were in remission without follow up for the last 1 year. Of the deaths, 35 were following treatment discontinuation/palliation chosen out of financial constraints, while another 35 were due to non-relapse causes during treatment, including transplant. The estimated 5-year overall survival for the entire cohort is 46.0%±3.3% while the estimated 5-year event-free survival is 41.7%±3.3%. This data is similar to the survival in the AYA subset following the use of pediatric-inspired protocols reported from our region (Ganesan et al IJHBT 2018, Ganesan et al BJH 2021). We conclude that, in addition to the relapse risk, inferior outcomes in the AYA ALL in our region are driven by high treatment-related toxicities and high treatment discontinuations due to financial constraints.