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Chemotherapy Delays Are Associated with Inferior Outcome in Acute Lymphoblastic Leukemia: A Retrospective Study from a Tertiary Cancer Center in South India
Background Treatment protocols for acute lymphoblastic leukemia (ALL) have evolved over time to give excellent cure rates in children and moderate outcomes in adults; however, little is known how delays in chemotherapy affect long-term survival.
Objectives To find the association of delays during different treatment phases on the survival outcomes.
Materials and Methods Data from 149 ALL cases treated between 2009 and 2015 were retrospectively analyzed. Treatment course in commonly used protocols was divided into three phases—induction, consolidation (postremission), maintenance, and also a combined intensive phase (induction plus consolidation) for the purpose of analysis, and delay in each phase was defined based on clinically acceptable breaks. Analysis was done to find the impact of treatment delay in each phase on the survival outcomes.
Results The median age was 12 years (range, 1–57). Multi-center Protocol-841 (MCP-841) was used for 72%, German Multicenter Study Group for Adult ALL (GMALL) for 19%, and Berlin, Frankfurt, Muenster, 95 protocol (BFM-95) for 9% of patients. Delay in induction was seen in 52%, consolidation in 66%, and during maintenance in 42% of patients. The median follow-up was 41 months, and 3-year survival outcomes for the entire cohort were event-free survival (EFS)—60%, relapse-free survival (RFS)—72%, and overall survival (OS)—68%. On univariate analysis, delay in induction adversely affected EFS (hazard ratio [HR] = 1.78, p = 0.04), while delay in intensive phase had significantly worse EFS and RFS (HR = 2.41 [p = 0.03] and HR = 2.57 [p = 0.03], respectively). On separate analysis of MCP-841 cohort, delay in intensive phase affected both EFS (HR = 3.85, p = 0.02) and RFS (HR = 3.42, p = 0.04), whereas delay in consolidation significantly affected OS with (HR = 4.74, p = 0.04) independently.
Conclusion Treatment delays mostly in intensive phase are associated with worse survival in ALL; attempts should be made to maintain protocol-defined treatment intensity while adequately managing toxicities.
28 May 2021 (online)
© 2021. Indian Society of Medical and Paediatric Oncology. This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).
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- 1 Hunger SP, Lu X, Devidas M. et al. Improved survival for children and adolescents with acute lymphoblastic leukemia between 1990 and 2005: a report from the children’s oncology group. J Clin Oncol 2012; 30 (14) 1663-1669
- 2 Goldstone AH, Richards SM, Lazarus HM. et al. In adults with standard-risk acute lymphoblastic leukemia, the greatest benefit is achieved from a matched sibling allogeneic transplantation in first complete remission, and an autologous transplantation is less effective than conventional consolidation/maintenance chemotherapy in all patients: final results of the International ALL Trial (MRC UKALL XII/ECOG E2993). Blood 2008; 111 (04) 1827-1833
- 3 Radhakrishnan V, Gupta S, Ganesan P. et al. Acute lymphoblastic leukemia: A single center experience with Berlin, Frankfurt, and Munster-95 protocol. Indian J Med Paediatr Oncol 2015; 36 (04) 261-264
- 4 Bajel A, George B, Mathews V. et al. Treatment of children with acute lymphoblastic leukemia in India using a BFM protocol. Pediatr Blood Cancer 2008; 51 (05) 621-625
- 5 Malhotra P, Varma S, Varma N. et al. Outcome of adult acute lymphoblastic leukemia with BFM protocol in a resource-constrained setting. Leuk Lymphoma 2007; 48 (06) 1173-1178
- 6 Ganesan P, Sagar TG, Kannan K. et al. Acute lymphoblastic leukemia in young adults treated with intensive “pediatric” type protocol. Indian J Hematol Blood Transfus 2018; 34 (03) 422-429
- 7 Bhatia S, Landier W, Shangguan M. et al. Nonadherence to oral mercaptopurine and risk of relapse in Hispanic and non-Hispanic white children with acute lymphoblastic leukemia: a report from the children’s oncology group. J Clin Oncol 2012; 30 (17) 2094-2101
- 8 Yeoh A, Collins A, Fox K. et al. Treatment delay and the risk of relapse in pediatric acute lymphoblastic leukemia. Pediatr Hematol Oncol 2017; 34 (01) 38-42
- 9 Kumar AJ, Gimotty PA, Gelfand JM. et al. Delays in postremission chemotherapy for Philadelphia chromosome negative acute lymphoblastic leukemia are associated with inferior outcomes in patients who undergo allogeneic transplant: an analysis from ECOG 2993/MRC UK ALLXII. Am J Hematol 2016; 91 (11) 1107-1112
- 10 Arya LS, Kotikanyadanam SP, Bhargava M. et al. Pattern of relapse in childhood ALL: challenges and lessons from a uniform treatment protocol. J Pediatr Hematol Oncol 2010; 32 (05) 370-375
- 11 Gökbuget N, Hoelzer D, Arnold R. et al. Treatment of Adult ALL according to protocols of the German Multicenter Study Group for Adult ALL (GMALL). Hematol Oncol Clin North Am 2000; 14 (06) 1307-1325, ix
- 12 Möricke A, Reiter A, Zimmermann M. et al. German-Austrian-Swiss ALL-BFM Study Group. Risk-adjusted therapy of acute lymphoblastic leukemia can decrease treatment burden and improve survival: treatment results of 2169 unselected pediatric and adolescent patients enrolled in the trial ALL-BFM 95. Blood 2008; 111 (09) 4477-4489
- 13 Suarez A, Piña M, Nichols-Vinueza DX. et al. A strategy to improve treatment-related mortality and abandonment of therapy for childhood ALL in a developing country reveals the impact of treatment delays. Pediatr Blood Cancer 2015; 62 (08) 1395-1402
- 14 Arigela RS, Gundeti S, Ganta RR, Nasaka S, Linga VG, Maddali LS. Trends in management of acute lymphoblastic leukemia: Influence of insurance based healthcare and treatment compliance on the outcome of adolescents and adults with acute lymphoblastic leukemia. Indian J Med Paediatr Oncol 2016; 37 (01) 32-37
- 15 Viana MB, Fernandes RA, de Oliveira BM, Murao M, de Andrade Paes C, Duarte AA. Nutritional and socio-economic status in the prognosis of childhood acute lymphoblastic leukemia. Haematologica 2001; 86 (02) 113-120
- 16 Gupta S, Wilejto M, Pole JD, Guttmann A, Sung L. Low socioeconomic status is associated with worse survival in children with cancer: a systematic review. PLoS One 2014; 9 (02) e89482
- 17 Prucker C, Attarbaschi A, Peters C. et al. Austrian Berlin-Frankfurt-Münster (BFM) Study Group. Induction death and treatment-related mortality in first remission of children with acute lymphoblastic leukemia: a population-based analysis of the Austrian Berlin-Frankfurt-Münster study group. Leukemia 2009; 23 (07) 1264-1269
- 18 Seif AE, Fisher BT, Li Y. et al. Patient and hospital factors associated with induction mortality in acute lymphoblastic leukemia. Pediatr Blood Cancer 2014; 61 (05) 846-852
- 19 Teachey DT, Hunger SP. Predicting relapse risk in childhood acute lymphoblastic leukaemia. Br J Haematol 2013; 162 (05) 606-620
- 20 Ceppi F, Cazzaniga G, Colombini A, Biondi A, Conter V. Risk factors for relapse in childhood acute lymphoblastic leukemia: prediction and prevention. Expert Rev Hematol 2015; 8 (01) 57-70
- 21 de BM Oliveira, Valadares MT, Silva MR, Viana MB. Compliance with a protocol for acute lymphoblastic leukemia in childhood. Rev Bras Hematol Hemoter 2011; 33 (03) 185-189
- 22 Lancaster D, Lennard L, Lilleyman JS. Profile of non-compliance in lymphoblastic leukaemia. Arch Dis Child 1997; 76 (04) 365-366
- 23 Wahl SK, Gildengorin G, Feusner J. Weekend delay in initiation of chemotherapy for acute lymphoblastic leukemia: does it matter?. J Pediatr Hematol Oncol 2012; 34 (01) e8-e11
- 24 Laughton SJ, Ashton LJ, Kwan E, Norris MD, Haber M, Marshall GM. Early responses to chemotherapy of normal and malignant hematologic cells are prognostic in children with acute lymphoblastic leukemia. J Clin Oncol 2005; 23 (10) 2264-2271
- 25 Koka A, Saygin C, Uzunaslan D, Ozdemir N, Apak H, Celkan T. A 17-year experience with ALL-BFM protocol in acute lymphoblastic leukemia: prognostic predictors and interruptions during protocol. Leuk Res 2014; 38 (06) 699-705
- 26 Sitaresmi MN, Mostert S, Gundy CM, Sutaryo. Veerman AJ. Health-care providers’ compliance with childhood acute lymphoblastic leukemia protocol in Indonesia. Pediatr Blood Cancer 2008; 51 (06) 732-736
- 27 Peeters M, Koren G, Jakubovicz D, Zipursky A. Physician compliance and relapse rates of acute lymphoblastic leukemia in children. Clin Pharmacol Ther 1988; 43 (03) 228-232
- 28 Brandalise SR, Viana MB, Pinheiro VR. et al. Shorter maintenance therapy in childhood acute lymphoblastic leukemia: The experience of the prospective, Randomized Brazilian GBTLI ALL-93 protocol. Front Pediatr 2016; 4: 110