Adult Acute Lymphoblastic Leukemia: A Cost Effective Strategy and Limitations of Intensification of Therapy in India
Authors: Jain Punit , Deshpande Prashant , Korula Anu , P N Nisham , Alex Ansu Abu , NA Fouzia , Lakshmi Kavitha , Abraham Aby , Balasubramanian Poonkuzhali , Srivastava Alok , George Biju , Mathews Vikram 
Published: October 2019

Abstract

Current treatment strategies in adult acute lymphoblastic leukemia (ALL) demonstrate a long term overall survival (OS) of 30 to 54%. Improvements in OS have been attributed to increased intensification (HD-MTX), novel intensive combination therapies such as HCVAD (Kantarjian et al. JCO: 2000) and allogeneic HSCT. There is paucity of real world data, especially from developing countries on impact of such therapeutic intensifications in context of challenges such as cost of therapy, multi-drug resistant bacterial infections and poor compliance. In this retrospective study, we present the clinical and biologic risk factors, challenges and long term clinical outcomes of 507 adults with ALL (≥ 15 years) diagnosed and treated at our center from January 2004 to November 2014 using a modified GMALL protocol, as previously reported by us (Bajel et al. Leukemia: 2007). We have also described and compared the outcome of a high risk (HR) subset treated either with the intensive HCVAD regimen followed by an HSCT/maintenance therapy or the modified GMALL protocol.
High risk ALL were defined as presence of any of the following 4 criteria: (i) Poor prednisolone response (peripheral blood blast count ≥1000/μL on day 8 of steroids) (ii) Cytogenetics: t(9:22) or t(4:11) (iii) Residual disease (RD) at end of induction (>5 % blasts on BM or presence of extramedullary disease) and (iv) early precursor T (ETP) cell ALL immunophenotype. All other patients were stratified as standard risk (SR). All SR cases were treated with the modified GMALL protocol. 51 (46.3%) of the HR cases with financial constraints had opted for palliation, while 59 (54.05%) of continued with the modified GMALL protocol. HR cases without financial constraints were treated with HCVAD therapy (n=53). Based on the donor availability and the patient preference for a HSCT, the HCVAD group either received 3 - 4 cycles followed by an allogeneic HSCT or 6 - 8 cycles followed by 2 years of standard maintenance.
The median age was 26 years (range; 15-67 years) with 334 (65.8%) patients ≤ 35 years and 117 (23.07%) patients presenting with counts ≥ 50 x 109/L. Baseline characteristics of entire cohort has been summarized in Table 1. Four hundred thirty three patients (94.5%) achieved remission at the end of induction. Among HR subset, there was no significant difference in baseline characteristics between the groups receiving GMALL versus HCVAD. Among the HR subset, 18 (33.9%) patients in the HCVAD arm received an allogeneic HSCT. In total, there were 33 (62.2%) deaths in the HCVAD subset ± HSCT compared to 29 (49.1%) deaths in the GMALL HR arm. Among the 33 deaths in patients on the HCVAD±HSCT arm, the cause of death was; infection 17 (51.5%), relapse/progressive disease 16 (48.4%). Among the 29 deaths in the modified GMALL HR group, 24 (82.7%) deaths were due to relapse/progressive disease and 5 (17.2%) deaths due to infections. OS and event free survival (EFS) of the entire cohort is illustrated in Figure 1A and 1B. There was no significant advantage of intensifying treatment in the HR subset as illustrated in Figure 1C and 1D. The mean cost of adult GMALL protocol (excluding HSCT) was $5,100 while mean cost for HCVAD followed by maintenance/ HSCT was $30,948.
This study illustrate that a modified GMALL protocol, in India, was cost effective with acceptable EFS and OS. Intensifying treatment in the HR subset did not appear to be beneficial as a result of increased treatment related mortality in this arm, which were mainly related to infections.
Table 1. Baseline characteristics and of all patients with newly diagnosed ALL: Variables Patients (n = 507)n (%)/Median (range) Age in years 26 (15 - 67) Male 351 (69.2) WBC ( x 109/ L) 9.2 (0.30 - 821.4) CNS III 63 (12.4) Immunophenotype 497 (98.0) · B cell ALL 371 (74.6) · T cell ALL 126 (25.4) RT PCR 394 (77.7) · BCR ABL (+) 89 (22.6) · TEL AML (+) 8 (2.1) · MLL AF4 (+) 8 (2.1) · E2A PBX (+) 12 (3.1) Risk group · Standard risk (SR) 344 (67.9) · High risk (HR) 163 (32.1)

Disclosures
No relevant conflicts of interest to declare.