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Table of Contents
ORIGINAL ARTICLE
Year : 2020  |  Volume : 3  |  Issue : 2  |  Page : 183-191

Outcomes and impact of minimal residual disease (MRD) in pediatric, adolescent and young adults (AYA) with acute lymphoblastic leukemia treated with modified MCP 841 protocol


1 Department of Medical Oncology, State Cancer Institute, Indira Gandhi Institute of Medical Sciences, Patna, Bihar, India
2 Consultant Hemato-Pathologist, Oncquest Laboratories, New Delhi, India

Date of Submission15-Mar-2020
Date of Decision10-Apr-2020
Date of Acceptance12-Apr-2020
Date of Web Publication19-Jun-2020

Correspondence Address:
Avinash Pandey
Room Number 83, 84, Department of Medical Oncology, State Cancer Institute, Indira Gandhi Institute of Medical Sciences, Patna, Bihar
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/CRST.CRST_85_20

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  Abstract 


Background: The impact of minimal residual disease (MRD) on overall survival (OS) is insufficiently studied in pediatric, adolescent, and young adults (AYA) with acute lymphoblastic leukemia (ALL) treated with modified MCP 841 protocol.
Objectives: We planned to evaluate the outcomes (post-induction response rates, MRD, and OS) with modified MCP 841 in pediatric and AYA ALL.
Materials and Methods: This was a retrospective audit of patients with ALL registered between March 01, 2017, and August 31, 2019. Patients who received at least 7 days of therapy on modified MCP 841 protocol were analyzed. Response evaluation was done on day 35 of induction with bone marrow aspiration, and MRD was assessed with flow cytometry with <0.01% as a “cutoff” for MRD-negative status. The primary endpoint was OS defined from start of therapy till death from any cause after day 35 of induction. Survival was evaluated by the Kaplan–Meier method, and log-rank test was used to compare the impact of variables on outcome in Statistical Package for the Social Sciences version 17.0.
Results: 130/167 (78%) patients were started on MCP 841 protocol; the remaining 37 (22%) patients defaulted after the first visit. B-cell ALL was more common at 78 (60%). 94 (72%) had National Cancer Institute High Risk. Day 8 good prednisolone response (GPR) was seen in 76 (58%) patients. Morphological remission was noted in 90/107 (84%) patients. MRD status was available in 84 (78%) patients. 46 (43%) patients achieved MRD-negative status. The median follow-up was 21 months (range, 10–31 months). The median OS was 30 months (95% CI, 15.5–42.8 months). One-year and 2-year survival was 87% and 60%, respectively. Patients who were MRD negative did better than those with MRD positive, 29 versus 22 months (P = 0.03). GPR performed better than those with Poor Prednisolone Response (PPR), 29 versus 15 months (P = 0.01).
Conclusion: Post-induction MRD is a useful prognostic tool for ALL patients treated with modified MCP 841 protocol. Outcomes are suboptimal compared to those reported from the developed western world.

Keywords: Acute lymphoblastic leukemia, adolescent and young adult, MCP 841, minimal residual disease, LMIC


How to cite this article:
Pandey A, Ahlawat S, Singh A, Singh S, Murari K, Aryan R. Outcomes and impact of minimal residual disease (MRD) in pediatric, adolescent and young adults (AYA) with acute lymphoblastic leukemia treated with modified MCP 841 protocol. Cancer Res Stat Treat 2020;3:183-91

How to cite this URL:
Pandey A, Ahlawat S, Singh A, Singh S, Murari K, Aryan R. Outcomes and impact of minimal residual disease (MRD) in pediatric, adolescent and young adults (AYA) with acute lymphoblastic leukemia treated with modified MCP 841 protocol. Cancer Res Stat Treat [serial online] 2020 [cited 2020 Jul 3];3:183-91. Available from: http://www.crstonline.com/text.asp?2020/3/2/183/287276




  Introduction Top


About 9,000–10,000 cases of pediatric leukemia are diagnosed yearly in India.[1] Hematolymphoid malignancy is the sixth most common cancer in our hospital-based cancer registry.[2] Acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy among childhood cancers.[3] The National Cancer Institute (NCI), United States of America (USA), and Cancer Institute (WIA), Chennai, in collaboration developed a multiagent, multiphase, moderate-intensity treatment regimen, MCP 841, for use in developing countries crippled with limited resources.[4] Compared to contemporary Western treatment regimens using high-dose methotrexate such as BFM-90, 95, and UKALL, the use of MCP 841 requires less supportive care and hence saves money and resources.[5],[6],[7] Implementation of MCP 841 in three major academic centers, namely Tata Memorial Hospital (Mumbai), All India Institute of Medical Sciences (New Delhi), and Cancer Institute, i.e., WIA (Chennai), demonstrated improvement in the event free survival from <20% in the 1980s to 40% in the 1990s.[8],[9],[10] Further improvement in supportive care, trained workforce, nutritional and socioeconomic support, better blood component facility, and prompt administration of broad-spectrum antibiotics further boosted outcomes by 15%–20%.[11]

Our institute is the only government regional cancer institute located in the eastern state of India, Bihar, with a population of 120 million. We started the Department of Medical Oncology in 2017 and have been treating pediatric, adolescent, and young adults (AYA) with ALL with the modified MCP 841 regimen irrespective of the baseline risk, B-cell or T-cell type. Apart from morphological response from bone marrow examination, we also recommended minimal residual disease (MRD) evaluation using flow cytometry method at the end of induction for patients receiving the above protocol. MRD has been proven to have superior prognostic value compared to older standard criteria including age, sex, and total leukocyte count at presentation for risk stratification, prediction of recurrence, and survival.[12] However, its significance among patients receiving MCP 841 protocol has been insufficiently explored. We report our findings from the retrospective audit of patients treated with modified MCP 841 for ALL and evaluate the prognostic impact of MRD on survival outcomes.


  Materials and Methods Top


General study details

This study was a retrospective audit of patients diagnosed with ALL at our regional cancer center (RCC) between March 01, 2017, and August 31, 2019, irrespective of age. All patients who received modified MCP 841 protocol and continued on therapy for at least the first 7 days to undergo day 8 complete blood count and peripheral smear blast count for steroid response were analyzed. Written informed consent for the above treatment was obtained from all patients. The study was conducted according to the criteria mentioned in the International Conference on Harmonization Good Clinical Practices, Declaration of Helsinki, and guidelines established by the Indian Council of Medical Research. No funding was sought or received for this study. Institutional Ethics Committee approval for retrospective case audits is not required as per our institutional policy.

Selection criteria

Children aged over 12 months, adolescents, and adults diagnosed with ALL confirmed on flow cytometry were eligible for the study, provided they had completed at least 7 days of treatment as per the modified MCP 841 protocol. AYA age group was defined as between 15 and 39 years. All patients presenting with Eastern Cooperative Oncology Group Performance Status 0–2 were eligible. All patients received the same treatment (modified MCP 841), irrespective of the baseline NCI risk category, B-cell or T-cell type ALL. Patients presenting with underlying bacterial sepsis, organ dysfunction including deranged coagulation profile, and renal or hepatic dysfunction were included, provided they responded favorably to standard broad-spectrum antibiotics and blood/component support and went on to receive above standard antileukemia therapy.

Patients who had received prior antileukemia chemotherapy or steroids for more than 10 days at least 4 weeks ago and at presentation to our institute had visible blasts on peripheral smear were excluded. Patients diagnosed as acute myeloid leukemia, acute promyelocytic leukemia, and biphenotypic/mixed phenotypic acute leukemia were excluded. Similarly, patients who were serologically positive for human immunodeficiency virus (HIV) and hepatitis B or C virus were excluded. All eligible cases of ALL were discussed in the multidisciplinary tumor board comprising of pathologists, hematopathologists, medical oncologist, palliative care physician, nursing staff, and social worker. Cost of therapy, duration of treatment, requirement of blood donors, and need for prompt intravenous antibiotic use in case of fever were explained to the patient/caregiver in the language best understood by them. Final decision to treat was made solely by the treating medical oncologist.

Baseline tests and response evaluation

All patients underwent baseline investigations including complete blood count with peripheral smear examination, renal and hepatic profile, coagulation profile, and serology for HIV, hepatitis B, and hepatitis C. All patients were subjected to bone marrow aspiration and biopsy. Bone marrow aspirate smears were collected from the first pull and stained with Leishman stain. Bone marrow biopsies were decalcified and stained with standard hematoxylin and eosin stain. All slides were evaluated by a hematopathologist of our institute. Evaluation and comment were solicited in terms of adequacy of the specimen, cellularity, and degree of dyspoiesis in all the three lineages. Cerebrospinal fluid (CSF) cytology was done before beginning therapy on day 0; 5 or more white blood cells/mL with lymphoblasts was considered to be positive.

Flow cytometry and molecular studies were outsourced to a central private National Accreditation Board for Testing and Calibration Laboratories accredited laboratory which processed and reported as per the College of American Pathologists guidelines at New Delhi, as our institute did not have the facility for the same. 2–3 ml of bone marrow sample in sodium heparin vial was evaluated at the time of diagnosis for flow cytometry. Samples were transported at ambient temperature. Eight different color panel combinations were used for flow cytometry. The diagnostic panel included comprehensive markers for acute leukemia evaluation, namely CD3, CD5, CD7, CD10, CD19, CD20, CD22, CD33, CD34, CD38, CD45, CD117, SIgM, CD3, CD5, and CD7. Stain-Lyse–Wash technique was used and at least 20,000 events were acquired on BD FACSCanto flow cytometer. Polymerase chain reaction (PCR) for bcr-abl transcript was done at baseline for patients presenting with a total leukocyte count over 15,000/uL, to improve the yield and limit the cost.[13],[14] No other tests, including fluorescent in situ hybridization (FISH) or conventional cytogenetics, were done at baseline due to nonavailability at our center.

The preliminary response evaluation was done on day 8 with complete blood count and peripheral smear examination to quantify the blast percentage. No evidence of blasts on the peripheral smear on day 8 was considered as good prednisolone response (GPR), while evidence of blasts was labeled as poor prednisolone response (PPR). Treatment was not altered based on the above response. The final response evaluation was done on day 35 from the start of induction with complete blood count, peripheral smear examination, bone marrow aspiration, and biopsy. Patients were considered to have achieved complete remission if they had <5% blasts in the bone marrow, normal maturation of all cellular components in the bone marrow, no extramedullary disease, absolute neutrophil count ≥1000/μL, platelet count ≥100,000/μl, and transfusion independence.

For postinduction MRD evaluation, 2–3 ml of bone marrow aspirate in sodium heparin was taken. Samples were transported at ambient temperature and evaluated within 24 h, though sample stability until 72 h had been established at the time of validation studies. Red blood cells Lysate-stain-wash technique was used in order to acquire large number of events required for MRD. Two-tube, 8-color panel was used, including antibodies CD10, CD15, CD19, CD20, CD34, CD38, CD45, CD58, CD13/CD33, CD10, CD73, CD86, and CD123. At least 1.5 million events were acquired for each tube. Combination of LAIP (leukemia-associated immunophenotype) established at the time of diagnosis and different from the normal approach was used for MRD evaluation. In the latter, the discrimination of leukemic blasts from normal B lymphocyte progenitors was done based on qualitative or quantitative differences in antigen expression between leukemic cells and their normal counterparts and by comparison to the normal template for each monoclonal antibody combination. The threshold of <0.01% was defined as the “cutoff” for MRD-negative status. For both morphological response and MRD, the denominator was the patients who did not abandon treatment before completion of induction.

Study protocol

All patients were treated with the International Network of Cancer Treatment and Research, MCP 841 protocol, the details of which can be obtained from previous published literature [Supplementary Appendix 1].[4],[8],[9],[10] All patients with B-cell ALL were risk stratified into NCI standard risk and high risk. Patients with age more than 10 years, presenting counts more than 50,000/μL, or CSF positive were classified as high risk, while all others were standard risk. All T-cell ALL were classified as high risk at baseline. All patients received the same treatment irrespective of baseline NCI risk category.

We used modified MCP 841 protocol, in which, after completion of induction (Regimen I1), patients were treated with high-dose cytarabine (Regimen I2A) 2000 mg/m 2 every 12-hourly for four doses, repeated after 14 days once along with intravenous cyclophosphamide 750 mg/m 2 once in 2 weeks and tablet 6-mercaptopurine 75 mg/m 2 orally for 7 days every 14 days.[15],[16] This was introduced in order to reduce the dose of prophylactic cranial irradiation (PCI) to mitigate the risk of late neurocognitive adverse events with similar probability of intracranial failure events.[14] Incorporation of Regimen I2A led to reduction in PCI dose to 12.6 Gy/7 fractions at 180 cGy/dose/day in baseline CSF negative patients and 18.0 Gy/10 fractions at 180 cGy/dose/day for the central nervous system (CNS) positive cohort. Prophylactic granulocyte colony stimulating factor (G CSF) support was prescribed to all patients receiving high dose cytarabine in Regimen I2A. Treatment was not altered based on the MRD response postinduction.

Monitoring and follow-up

In the 1st month of induction therapy, complete blood count and peripheral smear were checked twice a week, and hepatic, renal, and coagulation profile with electrolytes were evaluated once a week. In the subsequent 4 months of therapy, once in 2 weeks, hemogram, hepatic, renal, and coagulation profile were obtained; any clinical worsening, toxicity, or sepsis warranted prompt evaluation. All patients were administered broad-spectrum intravenous antibiotics and were promptly admitted if they presented with symptoms consistent with febrile neutropenia or sepsis. Patients presenting with tumor lysis syndrome (TLS) were treated in accordance with standard guidelines incorporating intravenous aggressive hydration, rasburicase, febuxostat, and correction of dyselectrolytemia and renal dysfunction.

Patients were asked to follow-up as per the schedule of blood investigations and drug administration mentioned in the protocol. No extra attempt, except for routine outpatient department (OPD) consultation, was made to ensure compliance to regular OPD visits or to ensure strict protocol adherence during the course of treatment. This was due to lack of workforce and limited resources available to the department. Demographic data and baseline clinical profile were retrieved from the case files of the patients who continued entire treatment and were compliant with regular OPD visits. At the end of the study period, two phone numbers of each patient who was irregular on treatment or had abandoned treatment were obtained from the hospital medical records. Short telephonic interviews were conducted with the relatives to enquire about the patient's current status including completion, continuation, compliance to therapy, and death. In noncomplaint patients or those who abandoned treatment, the date of relapse was difficult to obtain, but the date of death was obtained either through telephonic calls or death records/certificates.

Study endpoints

The primary endpoint of our study was overall survival (OS). OS was defined as the time between the start of therapy and death from any cause after completion (day 35) of induction therapy. We chose OS rather than event-free survival as the primary endpoint as considerable number of patients had abandoned treatment and, later on, from telephonic calls were found to be dead, but their dates of relapse could not be ascertained. Similarly, due to treatment abandonment and poor compliance-related toxic deaths during the 1st month of therapy, we excluded these patients by censoring from the survival analysis as they marred our main objective, which was to evaluate the efficacy of modified MCP 841 protocol. The dates of relapses in complaint patients were recorded. A detailed analysis of the toxicity pattern was beyond the purview of our current study.

Statistics

Descriptive statistics and frequency distribution were used to evaluate baseline demographic, clinical, and laboratory data. Kaplan–Meier survival estimator was used to measure OS, while log-rank test was utilized to compare the impact of several dichotomous categorical prognostic variables on OS.[17] Cox regression analysis was used to obtain the hazard ratio of events in competing groups.[18],[19] Statistical Package for the Social Sciences (SPSS) software version 17.0 sheet (released 2017. IBM SPSS Statistics for Windows, version 25.0. IBM Corp., Armonk, NY, USA) was used to evaluate all above parameters.


  Results Top


Demographic, clinical, and treatment profile of patients

Total 130 out of 167 patients diagnosed with ALL were taken for final analysis as 11 of them refused any treatment, while another 26 defaulted after the first visit of being diagnosed with ALL [Figure 1]. The median age was 13 years (range, 1–41 years) with male-to-female ratio of 2:1 [Table 1]. More than two-third (72%) were NCI high risk with 35% of patients presenting with or developing TLS with onset of antileukemic therapy. PCI was received by 58% of patients with a median delay of 23 days (range, 8–42 days) compared to the original schedule mentioned in the protocol [Table 2].
Figure 1: The flow diagram for patients eligible for retrospective clinical study of modified MCP 841 protocol in acute lymphoblastic leukemia

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Table 1: Patient related factors for those who received modified MCP 841 protocol-based treatment for acute lymphoblastic leukemia

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Table 2: Treatment related Factors for those who received modified MCP 841 protocol based treatment for acute lymphoblastic leukemia

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Response and survival

After 7 days of prephase prednisolone 40 mg/m 2, GPR was seen in 76 (58%) patients on day 8 of induction. After excluding patients who abandoned treatment before completion of induction, 90/107 (84%) patients achieved complete morphological remission on bone marrow examination on day 35 of induction. MRD was positive in 38 (36%) patients, negative in 46 (43%) patients, while not available for the remaining 23 (21%) patients. MRD nonavailability in 7 patients was because the sample of MRD postinduction on D35 had undergone significant degeneration. This could have been the result of improper collection or storage that could have resulted in the preferential loss of target cell populations, as samples were outsourced for processing. For the remaining patients for whom the MRD was not available, the reason was not known due to retrospective nature of study. Three out of five patients who did not achieve morphological remission on day 35 of induction achieved this on day 70 of therapy.

The median follow-up was 21 months (range, 10–31 months) by the reverse Kaplan–Meier method. No patients were lost to follow-up after taking into account the status/events on telephonic interviews. The median OS was 30 months (95% confidence interval [CI], 15.5–42.8 months). One-year and 2-year survival was 87% and 60%, respectively [Figure 2]. Patients with MRD-negative and GPR did better than those with MRD-positive and PPR, 29 versus 22 months (P = 0.03) and 29 versus 15 months (P = 0.01), respectively [Figure 3] and [Figure 4]. Patients who presented with or developed TLS did worse compared to those who did not, 24 versus 30 months, respectively (P = 0.03) [Figure 5]. OS was not significantly different according to the sex, type of ALL (B-cell or T-cell type), or baseline NCI risk category (standard or high) [Table 3]. The hazard ratio for death was 0.14 (95% CI, 0.06–0.30), P = 0.005 favoring MRD-negative status on the Cox proportional hazard model.
Figure 2: Overall survival of patients treated with modified MCP 841 protocol

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Figure 3: Overall Survival of patients treated with modified MCP 841 protocol with respect to MRD status (MRD-Minimal Residual Disease)

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Figure 4: Overall Survival of patients treated with modified MCP 841 protocol with respect to prednisolone response status (GPR: Good prednisolone response, PPR: Poor prednisolone response)

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Figure 5: Overall survival of patients treated with modified MCP 841 protocol with respect to tumor lysis syndrome status

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Table 3: Evaluation of prognostic factors for overall survival for those who received modified MCP 841 protocol-based treatment for acute lymphoblastic leukemia

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Deaths and relapses

Before completion of the induction phase, there were 12 toxic chemotherapy-related deaths: 9 due to neutropenic sepsis and 3 due to worsened TLS after the start of therapy. During the 28 months of study enrolment, 23 patients abandoned treatment, 11 in the first 14 months (March 2017–June 2018), and the remaining 12 in the next 14 months (July 2018–August 2019). Later on, through telephonic calls with relatives, we found that 21 of them had died within the 1st month of treatment abandonment, while 2 died in the 2nd month. After completion of the induction phase, there were 8 toxic chemotherapy-related deaths, 4 due to high-dose cytarabine (I2A regimen)-induced neutropenic sepsis despite prophylactic growth factor support, while 3 deaths during the 12 regimen CNS prophylactic phase with 1 death during oral maintenance phase in the 7th month of therapy.

There were 25 relapses after the completion of the induction phase, out of which 5 were between the 6th–12th months of therapy, while 4 were after 12 months of therapy. The remaining 16 patients had relapsed during the 6 months of active therapy. 18 (72%) had medullary only relapse, while 5 (20%) had intracranial and 2 (8%) had combined (intracranial and medullary) relapse. None of the relapsed patients received intensive salvage chemotherapy or went on to receive hematopoietic stem cell transplant, due to socioeconomic factors. All patients relapsing within 12 months received best supportive care/palliative care only, while those relapsing after 12 months of therapy received oral metronomic therapy with 6-thioguanine and oral etoposide. The median time to relapse was 5 months (range, 2–20 months). 15/25 relapses were seen in MRD-positive patients, while 5/25 were in MRD-negative ones (P = 0.02); for another 5 patients, MRD status was not available. All above patients were compliant to therapy. 23/25 patients who relapsed died due to cytopenic complication or sepsis at a median of 2 months from the date of relapse (range, 1–3 months), while 2 patients were alive at the time of the data lock.


  Discussion Top


In our retrospective analysis of AYA patients diagnosed with ALL and treated with modified MCP 841 protocol at our RCC, the 2-year OS was 60% with a median OS of 30 months (95% CI, 15.5–42.8 months). 46 (43%) patients achieved MRD-negative status after completion of induction. Patients achieving MRD-negative status had a longer OS, 29 versus 22 months (P = 0.03) and fewer relapses during and after completion of therapy. This is one of the few studies where the impact of MRD determined by flow cytometry after the completion of the induction phase has been evaluated for OS outcome in patients treated with modified MCP 841 protocol for ALL.

Multicolor flow cytometry using laser can identify aberrant leukemic antigen expression with a sensitivity of 10-4.[20] MRD monitoring is a reliable predictor of relapse in AYA patients.[21],[22] Though MRD by flow cytometry provides one log less sensitivity that PCR-based methods, it supersedes PCR because of wider applicability beyond selected advanced molecular hematological laboratories, faster results, less cost, and lack of requirement regarding initial testing to determine unique clonal rearrangements.[23] MCP 841 has been one of the most commonly used protocols in resource-limited countries such as India since the 1980s for the treatment of ALL.[4],[8],[9],[10],[11],[15] However, very few studies have been published to demonstrate the impact of novel contemporary response evaluation methods, such as MRD evaluation, on OS in patients treated with this protocol.

In 269 children diagnosed with T-ALL treated with MCP 841 protocol, Temhare et al. found 46% MRD positive rate by flow cytometry method. Patients with MRD-positive disease post-day 35 of induction had significantly higher relapses and poorer event-free survival, but there was no impact on OS.[24] A smaller study showed 36% MRD-negative rate in children with early T cell precursor ALL; however, no outcome analysis was reported based on the MRD status due to the small sample size (n = 14).[25] Few other studies have explored PCR-based Clonal T-cell Receptor γ and δ Gene Rearrangements in T-cell ALL patients treated with MCP 841 protocol, but due to small sample sizes and only 30% patients exhibiting clonal T cell rearrangement, its wider applicability remains restricted.[26],[27] Our study is the first, with predominantly B-cell ALL (60%), to show that patients with MRD-negative status on day 35 post-induction, treated with modified MCP 841 protocol, have a significant OS benefit.

The median age in our study was 13 years, which is higher as compared to other reported series, as we included adolescents and adults apart from children.[8],[9],[10],[11],[15] Our study had 40% patients with T-ALL, which is higher than that reported by centers in North and West India, but similiar to that of Eastern and Southern centers.[8],[9],[10],[11],[28] We had a higher percentage of patients presenting with white blood cells more than 50,000/cm 3, baseline CNS involvement and TLS compared to other studies as we had more higher risk older age patients with mediastinal mass and T-ALLs in our population.[8],[9],[10],[11],[15],[28] There were 23% relapses in our study, which is consistent with other published series treated with MCP 841; however, we had shorter follow-up available and more relapses are anticipated. Many centers had selected patients for therapy with high likelihood of commitment and ability to remain close to the treatment centers.[8],[9],[10],[11],[29] Our study had patients without the above preconditions; hence, our abandonment rates were much higher (18%) and these cases were censored for survival analysis similar to that done by Bajel et al.[29],[30] In our study, there were 19% toxic deaths of which 11% were in the induction phase, similar to that reported by previous studies.[8],[9],[10],[11],[29],[30],[31] As per recent reported outcomes on the largest pooled sample size (n = 1454) of AYA patients, published by the Indian Acute Leukemia Research Database of the hematology cancer consortium, the 2-year survival was 75%. Our study demonstrated an OS of 60% at 2-year which is inferior to above but similar to that reported by Yadav et al.[32],[33]

Our RCC is a small subunit of a large multispecialty tertiary government medical college and hospital in Bihar. Until recently (year 2017), in the absence of a medical oncology or hematology department, most patients diagnosed with leukemia were referred to apex cancer centers such as Tata Memorial Hospital (Mumbai), All India Institute of Medical Sciences (New Delhi), or Christian Medical College (Vellore) (personal communication, Chief, RCC). Since the inception in 2017 to date, the Medical Oncology Department here is a single faculty department where patients of adult solid cancers, hematological malignancies, and childhood tumors have been looked after and daily OPD numbers exceed 100.[3],[34] Our abandonment rates are very high (18%) due to lack of supportive staff, social workers, counselors, dieticians, trained pediatric oncology nurses, psychologists, and limited financial resources, which otherwise play a major role in outcome improvement in pediatric ALLs.[35] Further, lack of another trained dedicated physician in our set-up, either medical oncologist or hematologist, compounds the challenge of treatment abandonment and toxic deaths. The prominent reasons due to which qualified doctors are hesitant to work in busy government hospitals are scarce infrastructure and less remuneration, especially in tier two and three cities.[36] Prevailing baseline malnutrition worsened by recurrent diarrhea and poor socioeconomic conditions also contributed to early toxic deaths and abandonment.[37]

Most of our patients received government-sponsored funds for treatment, but with a delay in the initial 6 weeks, during which most treatment abandonments and early toxic deaths happened. However, post-induction therapy and discounted outsourced MRD evaluation was sponsored through above grants/funds in the majority of patients either partially or fully. Half of the toxic deaths post-induction happened due to late presentation and delayed intervention with intravenous broad-spectrum antibiotics for patients presenting with febrile neutropenia after high-dose cytarabine in the 12A regimen of the protocol, despite prophylactic growth factor support. This problem was further compounded by the unavailability of a trained oncology physician “round the clock” in the multispecialty emergency room and delayed presentation by patients, especially on weekends, holidays, or major festivals despite strong recommendation against doing so.[38] Hence, we suggest extreme caution for anticipated life-threatening febrile neutropenia episodes after high-dose cytarabine. Our CNS relapse rates were higher due to high baseline CSF positivity, higher numbers of T-ALL with mediastinal mass, and delayed PCI. Delay in PCI was largely due to the long waiting list and higher shutdown time of the only available cobalt machine at our center necessitating the referral of our patients to other nearby radiotherapy centers for PCI. Due to all above-mentioned factors and shorter follow-up, our reported survival is modest in comparison to other reported contemporary studies across India.[8],[9],[10],[11],[15],[28],[29],[30],[31],[32],[33]


  Conclusion Top


Achieving MRD-negative status by flow cytometry post-induction improves OS in ALL patients treated with modified MCP 841 protocol. In centers with limited-resource availability, less intensive, non-high dose methotrexate-based protocols such as MCP 841 produce acceptable, although modest, survival rates. Better availability of skilled workforce and upgraded infrastructure support at government hospitals may reduce treatment abandonment and toxic deaths with potential for further improving the outcomes.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.


  Supplementary Appendix Top


Supplementary Appendix 1: Modified MCP 841 protocol

SUPPLEMENTARY APPENDIX

Case number: / Weight: kg Height: cm BSA: m2

MODIFIED MCP 841 PROTOCOL

Treatment of Acute Lymphoblastic Leukemia


  REGIMEN I1 Top


Fill in actual dose given for each drug. If a drug dose has been modified or delayed, indicate the drug, reason (use the codes provided), date given and percentage of the planned dose in the corresponding spaces



VCR = Vincristine 1.4 mg/m2, IV (Push)

PRED = Prednisone 40 mg/m2 PO

L-ASP = Asparaginase 6000 U/m2, IM

ITM = Methotrexate 12 mg IT

DAUNO = Daunorubicin 30 mg/m2 IV (Push).


  EVALUATION (End of induction) Top


BLOOD COUNTS SHOULD BE PERFORMED 3X WEEKLY AND BONE MARROW ON RECOVERY

Bone Marrow____________ BM Cytogenetics: ______________

CSF: ___________(% blasts/tumor cells) Bone Lesions: ______________

Liver: __________ Spleen: ____________ Lymph nodes: _____________

BEGIN NEXT CYCLE WHEN GRANULOCYTES >1000/m3 AND PLATELETS >100,000/m3

SEND PATIENT FOR CRANIAL RT APPOINMTMENT - WRITE THE DATE ________

• Consider replacing Leunase with C. Etoposide 50 mg PO OD (in C/o Pancreatitis/Venous Thrombosis/Hypersensitivity).

Case number: / Weight: kg Height: cm BSA: m2



MODIFIED MCP 841 PROTOCOL


  REGIMEN I2A Top


Fill in actual dose given for each drug. If a drug dose has been modified or delayed, indicate the drug, reason (use the codes provided), date given and percentage of the planned dose in the corresponding spaces



6MP =6-Mercaptopurine 75 mg/m2 PO

CTX = Cyclophosphamide 750 mg/m2 IV (30 Minute infusion)

ARAC = Cytosine Arabinoside 2000 mg/m2 IV every 12 hours (4 total doses); infuse over 3 hrs.

GRAN must be >1000/mm3 and PLT >100,000 required prior to administration of ARAC

ITMTX = Methotrexate 12 mg IT


  Evaluation Top


CBC to be done before D1 and D15 and then Twice a week after D8 and D12 till recover the counts

LFT/RFT should be done before starting D1 and D15

BEGIN NEXT CYCLE WHEN GRANULOCYTES >1000/m3 AND PLATELETS >100,000/m3

Case number: / Weight: kg Height: cm BSA: m2


  MODIFIED MCP 841 PROTOCOL Top



  REGIMEN I2 Top


Fill in actual dose given for each drug. If a drug dose has been modified or delayed, indicate the drug, reason (use the codes provided), date given and percentage of the planned dose in the corresponding spaces



6MP = 6-Mercaptopurine 75 mg/m2 PO

CTX = Cyclophosphamide 750 mg/m2 IV (30 Minute infusion)

ITM = Methotrexate 12 mg IT

CRANR = Cranial radiation 180 cGy/dose 1260 for patients without CNS disease and those who have received HDAC; 1800 for others


  Evaluation Top


BLOOD COUNTS SHOULD BE PERFORMED ATLEAST WEEKLY

BEGIN NEXT CYCLE WHEN GRANULOCYTES >1000/M3 AND PLATELETS >100,000/M3

Case number: / Weight: kg Height: cm BSA: m2

MODIFIED MCP 841 PROTOCOL

Treatment of Acute Lymphoblastic Leukemia


  REGIMEN RI1 Top


Fill in actual dose given for each drug. If a drug dose has been modified or delayed, indicate the drug, reason (use the codes provided), date given and percentage of the planned dose in the corresponding spaces



VCR = Vincristine 1.4 mg/m2, IV (Push)

PRED = Prednisone 40 mg/m2 PO

L-ASP = Asparaginase 6000 U/m2, IM

ITM = Methotrexate 12 mg IT (>3 years of age; see protocol for dose for <3 years)

DAUNO = Daunorubicin 30 mg/m2 IV (Push).


  Evaluation Top


BLOOD COUNTS SHOULD BE PERFORMED TWICE A WEEK

BEGIN NEXT CYCLE WHEN GRANULOCYTES >1000/M3 AND PLATELETS >100,000/M3

• Consider replacing Leunase with C. Etoposide 50 mg PO OD (in C/o Pancreatitis/Venous Thrombosis/Hypersensitivity). To be given from D1 – D21

Case number: / Weight: kg Height: cm BSA: m2


  MODIFIED MCP 841 PROTOCOL Top


Treatment of Acute Lymphoblastic Leukemia


  Regimen c Top


Fill in actual dose given for each drug. If a drug dose has been modified or delayed, indicate the drug, reason (use the codes provided), date given and percentage of the planned dose in the corresponding spaces



6MP =6-Mercaptopurine 75 mg/m2 PO

CTX = Cyclophosphamide 750 mg/m2 IV (30 Minute infusion)

VCR = Vincristine 1.4 mg/m2, IV (Push)

ARAC = Cytosine Arabinoside 100 mg/m2 SC every 12 hours (6 total doses)

DNR = Daunorubicin 30 mg/m2 IV (Push).


  Evaluation Top


BLOOD COUNTS SHOULD BE PERFORMED BEFORE D1 AND D15 AND TWICE A WEEK FROM D8 AND D22 TILL RECOVER COUNTS.

BEGIN NEXT CYCLE WHEN GRANULOCYTES >1000/M3 AND PLATELETS >100,000/M3

Case number: / Weight: kg Height: cm BSA: m2

MODIFIED MCP 841 PROTOCOL


  Maintenance regimen Top


Fill in actual dose given for each drug. If a drug dose has been modified or delayed, indicate the drug, reason (use the codes provided), date given and percentage of the planned dose in the corresponding spaces



Case number: / Weight: kg Height: cm BSA: m2



MTX = Methotrexate 15 mg/m2 PO

6MP = 6- Mercaptopurine 75mg/m2 PO


  Evaluation Top


BLOOD COUNTS SHOULD BE PERFORMED AT LEAST ONCE EVERY 15 DAYS.

Liver function tests once every 2 weeks for 2 months and then if normal monitor once in 6 weeks

Continue chemotherapy in the same dose if

TLC- 2500–3000/cumm

ANC-1000–1500/cumm,

Platelets >100,000/cumm

T Bilirubin <2.5 times ULN

OT/PT- <5 times ULN

If any dose escalation is being considered it should not be more than 25% of one drug at a time.

In case of 2 dose interruptions due to cytopenias please reduce the dose by 25% of 6MP.



 
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

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  In this article
Abstract
Introduction
Materials and Me...
Results
Discussion
Conclusion
Supplementary Ap...
REGIMEN I1<...
EVALUATION (End ...
REGIMEN I2<...
Evaluation
MODIFIED MCP 841...
REGIMEN I2<...
Evaluation
REGIMEN RI1...
Evaluation
MODIFIED MCP 841...
Regimen c
Evaluation
Maintenance regimen
Evaluation
References
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