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Table of Contents
EDITORIAL
Year : 2020  |  Volume : 3  |  Issue : 2  |  Page : 287-289

Optimizing acute leukemia treatment in resource-constrained settings


Department of Medical Oncology, Tata Memorial Hospital, Homi Bhabha National Institute, Mumbai, Maharashtra, India

Date of Submission21-Apr-2020
Date of Decision21-Apr-2020
Date of Acceptance22-Apr-2020
Date of Web Publication19-Jun-2020

Correspondence Address:
Lingaraj Nayak
Department of Medical Oncology, Room No-81, Main Building, Tata Memorial Hospital, Homibhaba National Institute, Dr. E, Dr Ernest Borges Road, Parel, Mumbai - 400 012, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/CRST.CRST_162_20

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How to cite this article:
Nayak L. Optimizing acute leukemia treatment in resource-constrained settings. Cancer Res Stat Treat 2020;3:287-9

How to cite this URL:
Nayak L. Optimizing acute leukemia treatment in resource-constrained settings. Cancer Res Stat Treat [serial online] 2020 [cited 2020 Sep 23];3:287-9. Available from: http://www.crstonline.com/text.asp?2020/3/2/287/287212



Acute myeloid leukemia (AML) is a heterogeneous disease in terms of its genetic makeup. However, the aggressiveness of the disease varies even for the same genetic abnormality. Researchers from the University of Basel, Switzerland, have shown, using a mouse model, that the aggressiveness depends on the type of the myeloid precursor, in which the genetic alteration has occurred.[1] Therefore, sometimes, AML presents with a long natural history, where less intensive therapies become effective in inducing remissions.

In the current issue of the journal, Pandey et al. have reported a retrospective analysis of an oral chemotherapy regimen called prednisolone, etoposide, and 6-mercaptopurine (PREM) as definitive therapy in patients with AML in whom standard induction therapy was not feasible and as maintenance therapy in patients who could not receive full consolidation because of the toxicity. In patients who received oral chemotherapy as definitive therapy, the complete remission (CR) rate and 1-year survival rate were 46% and 45%, respectively. The four patients who received the PREM regimen as maintenance therapy for 2 years continue to be in CR after a median follow-up of 2 years.[2]

The use of less intensive approaches in AML treatment is always sought in a situation where intensive therapies are difficult. Hypomethylating (HMA) agents,[3] combination of HMA and venetoclax,[4] and low dose cytarabine are some of the available options in these clinical scenarios. Till date, the best response rates and durability of response have been achieved with a combination of HMA and venetoclax. However, the regimen is costly and requires hospitalization. An oral regimen with a CR rate of 46% certainly needs to be explored in a larger prospective study, specifically in the older population, where alternative options are either costly or require more supportive care.

However, in the young and fit individuals, the use of less intensive therapy until intensive therapy becomes feasible because of the logistic concerns can be counterproductive. The response rates with standard therapy can go down to 30% or less,[5] and the toxicities will be higher because of the prolonged active disease state. This is also evident from the study by Pandey et al. in which a young patient in group A who received 3 + 7 induction after a period of oral chemotherapy, developed severe toxicity in the form of enterocolitis and a fungal infection leading to treatment-related mortality.[2]

Studies on maintenance therapy in AML have always remained a challenge for investigators because of the slow randomization rate due to the prolonged duration of therapy, requiring hospitalization in the older population.[6],[7],[8],[9] Among all the maintenance studies in AML, the HOVON-97 is the largest and most intriguing.[10] Despite an improvement in the disease-free survival with maintenance azacytidine, there was no improvement in the overall survival (OS). However, only two-thirds of the patients could complete the planned therapy. Hence, oral azacytidine became a more feasible and patient-friendly option, which was explored in a Phase III randomized controlled trial called QUAZAR AML-001, with OS as the primary endpoint.[11] The preliminary results of this trial were presented in the recent American Society of Hematology meeting held in December 2019, which showed a 10-month improvement in the OS compared to the placebo. The complete trial results have not been published at the time of writing this editorial; however, the abstract appears promising. Pandey et al. had used oral metronomic chemotherapy in four patients who were in CR after induction, and few received consolidation chemotherapy. All the four patients remained in CR after a median follow-up of two years. Although the patient number is too small to determine the efficacy outcome, the feasibility is well evident from these data. A concern that emerges from this approach is the possibility of refractoriness at relapse. This could be one of the reasons why in the HOVON-97 study, there was no improvement in the OS despite having a disease-free survival benefit. Hence, maintenance studies in AML should have OS as the primary endpoint, like the recent QUAZAR study, in which the preliminary data appear promising.

Oral metronomic chemotherapy in AML has a strong biological rationale; however, it is limited by proper dose finding and larger studies. With the due caveats of a retrospective analysis, this paper is thought provoking, but more prospective studies are warranted before we can arrive at any definitive conclusion regarding the efficacy. However, the feasibility in terms of toxicity is well established from this paper.

Pandey et al.[12] have also reported a retrospective analysis of 130 acute lymphocyic leukemia (ALL) patients who were treated with MCP-841 protocol in a single center from Bihar. The MCP-841 protocol was designed by the Cancer Institute (WIA) Chennai, India, in collaboration with the National Cancer Institute, United States of America and two other tertiary cancer institutes of India (Tata Memorial Center, Mumbai and All India Institute of Medical Sciences, New Delhi) for the Indian setting with limited resources, for more intensive chemotherapy and methotrexate drug level monitoring.[13] In the current time, most of the referral and tertiary centers have moved to more intensive and high-dose methotrexate-based protocols (BFM, UKALL, etc.) with an improvement in the supportive care system. However, in resource-constrained settings, the old MCP-841 protocol remains the most feasible one.

The median age of the cohort was 13 years, with age ranging from 1 to 41 years. Treating such a wide age group of patients in a resource-constrained setting is commendable for a stand-alone adult medical oncologist. Treatment abandonment of 18% is too high in a curable malignancy. A better support system could have possibly helped in curbing the abandonment rates.[14] Minimal residual disease (MRD) in ALL is the single most prognostic tool.[15] Around 60% of MRD-positive patients relapsed, whereas relapse was seen in only 20% of the MRD-negative patients (P = 0.02). MRD in ALL is prognostic as well predictive in terms of intensification of therapy in the form of allogeneic stem cell transplantation. Though the median follow-up is short (21 months), the 2-year OS was 60%, considering a mixed population of pediatric, adolescent, and adult patients. The compliance-related toxic deaths should have been considered as events, as they otherwise mask the compromised supportive care system which needs improvement.

MRD in pediatric ALL is also predictive of the need for a change in the treatment.[16] The MRD-guided escalation approach in pediatric ALL has shown promise. It will select the poor performers where resources for intensive therapy can be utilized to improve the overall outcome. This could be an important area for intervention studies.

I congratulate the oncologists for managing such a diverse age group of patients and providing them with equitable and the best possible care in a resource-limited setting.

Acknowledgments

I would like to thank Dr Samarpita Mohanty, MD, from radiation oncology for helping me write this manuscript.



 
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Stavropoulou V, Kaspar S, Brault L, Sanders MA, Juge S, Morettini S, et al. MLL-AF9 expression in hematopoietic stem cells drives a highly invasive AML expressing EMT-related genes linked to poor outcome. Cancer Cell 2016;30:43-58.  Back to cited text no. 1
    
2.
Pandey A, Deshpande P, Singh A, Singh S, Murari K, Aryan R. Oral Prednisolone, Etoposide, 6- Mercaptopurine (PREM) metronomic chemotherapy in treatment naïve and partially treated acute myeloid leukemia in a resource constrained setting. Cancer Res Stat Treat 2020;3:172-82.  Back to cited text no. 2
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Brune M, Castaigne S, Catalano J, Gehlsen K, Anthony DH, Hofmann WK, et al. Improved leukemia-free survival after post consolidation immunotherapy with histamine dihydrochloride and interleukin-2 in acute myeloid leukemia: Results of a randomized phase 3 trial. Blood 2006;108:88-96.  Back to cited text no. 7
    
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Buyse M, Squifflet P, Lange BJ, Alonzo TA, Larson RA, Kolitz JE, et al. Individual patient data meta-analysis of randomized trials evaluating IL-2 monotherapy as remission maintenance therapy in acute myeloid leukemia. Blood 2011;117:7007-13.  Back to cited text no. 8
    
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Baer MR, George SL, Caligiuri MA, Sanford BL, Bothun SM, Mrózek K, et al. Low-dose interleukin-2 immunotherapy does not improve outcome of patients age 60 years and older with acute myeloid leukemia in first complete remission: Cancer and Leukemia Group B Study 9720. J Clin Oncol 2008;26:4934-9.  Back to cited text no. 9
    
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Huls G, Chitu DA, Havelange V, Jongen-Lavrencic M, van de Loosdrecht AA, Biemond BJ, et al. Azacitidine maintenance after intensive chemotherapy improves DFS in older AML patients. Blood 2019;133:1457-64.  Back to cited text no. 10
    
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Pandey A, Ahlawat S, Singh A, Singh S, Krishna M, Aryan R. Outcomes and impact of minimal residual disease in pediatric, adolescent, and young adults with acute lymphoblastic leukemia treated with modified MCP 841 protocol. Cancer Res Stat Treat 2020;3:183-91.  Back to cited text no. 12
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Magrath I, Shanta V, Advani S, Adde M, Arya LS, Banavali S, et al. Treatment of acute lymphoblastic leukaemia in countries with limited resources; lessons from use of a single protocol in India over a twenty year peroid. Eur J Cancer 2005;41:1570-83.  Back to cited text no. 13
    
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