|Year : 2020 | Volume
| Issue : 2 | Page : 172-182
Oral Prednisolone, Etoposide, 6- Mercaptopurine (PREM) metronomic chemotherapy in treatment naïve and partially treated acute myeloid leukemia in a resource constrained setting
Avinash Pandey1, Prashant Deshpande2, Anjana Singh1, Shivkant Singh1, Krishna Murari1, Raj Aryan1
1 Department of Medical Oncology, State Cancer Institute, Indira Gandhi Institute of Medical Sciences, Patna, Bihar, India
2 Consultant Hemato- Pathologist, Molecular Pathology, AmPath Laboratories, Hyderabad, Telangana, India
|Date of Submission||08-Feb-2020|
|Date of Decision||12-Feb-2020|
|Date of Acceptance||18-Mar-2020|
|Date of Web Publication||19-Jun-2020|
Department of Medical Oncology, State Cancer Institute, Indira Gandhi Institute of Medical Sciences, Patna, Bihar
Source of Support: None, Conflict of Interest: None
Background: Standard 3 + 7 induction (anthracycline + cytarabine) and consolidation high-dose cytarabine are toxic, expensive, and resource intensive.
Objectives: The objective was to evaluate response rates and survival with PRednisolone, Etoposide and 6-Mercaptopurine (PREM) metronomic chemotherapy in treatment-naïve, and partially treated acute myeloid leukemia (AML).
Materials and Methods: All patients with AML, registered between June 01, 2017, and May 31, 2019, not willing for standard 3 + 7 induction (Group A) due to financial constraints and those who refused to complete at least two cycles of cytarabine consolidation (Group B) and received oral PREM therapy were analyzed. Bone marrow aspiration/biopsy was used for response evaluation in the 3rd month in Group A. Descriptive statistics and survival according to the Kaplan-Meier method were used to evaluate outcomes with SPSS v. 17. The follow-up was calculated using reverse Kaplan–Meier method.
Results: Fifteen patients were included in the study, 11 in Group A and 4 in Group B. The median follow-up was 13 months in Group A (range, 10–14 months). 5/11 (46%) and 2/11 (18%) achieved complete response (CR) and partial response (PR), respectively. The 1-year survival of patients in Group A (n = 11) was 45% with a median overall survival of 9 months (95% confidence interval [CI], 5.4–11.6 months). Among the 7 out of 11 patients (64%) who responded (CR + PR), the 1-year survival was 70% with a median survival of 12 months, versus 3 months for patients who failed to attain a response, P = 0.005 with hazard ratio of 0.05 (95% CI, 0.01–65.65). In the patients in Group B (n = 4), all patients sustained/achieved CR and were alive without relapse at a median follow-up of 24.5 months (range, 22–26 months). The ratio of total inpatient admissions in Group A patients (n = 11) was 1.7 in the first 3 months with median duration of 7 days (range, 4–14 days).
Conclusion: Oral PREM metronomic chemotherapy led to favorable responses in treatment naive AML patients. The regimen also led to sustained remissions in patients with partially treated AML.
Keywords: Acute myeloid leukemia, India, low- and middle-income country, metronomic, resource-constraint
|How to cite this article:|
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
|How to cite this URL:|
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 [serial online] 2020 [cited 2020 Sep 18];3:172-82. Available from: http://www.crstonline.com/text.asp?2020/3/2/172/287249
| Introduction|| |
”3 + 7” induction with anthracycline and cytarabine followed by three cycles of high-dose cytarabine consolidation is the standard of care for newly diagnosed acute myeloid leukemia (AML) in adults. However, “3 + 7” induction is expensive and may lead to severe life-threatening toxicities and risk for induction mortality. The problem is further compounded by requirements for broad spectrum antibiotics, antifungal agents, recurrent blood, and blood component therapies along with intensive monitoring under supervision of qualified, trained and skilled personnel. In the apex tertiary Indian centers treating AML, where there is no dearth of skilled workforce and which have systems well established for efficient healthcare delivery, only 17%–29% patients receive the standard “3 + 7” induction with an average cost of $12,300., The majority of Indian centers report a complete response (CR) rate of 55%, with 1 year survival of 55% and 25% induction mortality (range, 6%-45%) with “3 + 7” induction., Financial constraints (80%) followed by lack of social support are the most common reasons for not opting for “3 + 7” induction among patients. In the patients who could not afford a standard “3 + 7” induction, the median survival was only 1 month (95% confidence interval [CI], 0.89–1.10).
In not-for-profit government hospitals in smaller non-metropolitan cities, where there is a lack of skilled manpower, absence of immunophenotyping, molecular and cytogenetic laboratories and suboptimal blood/component facilities, delivering standard “3 + 7” induction is a major challenge. Moreover, patients with poor socioeconomic status often find it difficult to travel a long distance to tertiary apex centers in the major metropolitan cities. Hence, there is a large unmet need for effective, low cost, less toxic alternatives for patients who cannot afford standard induction and consolidation. Oral metronomic therapy has shown some promise in patients with AML who are older and not eligible for “3 + 7” induction therapy and as maintenance or palliative therapy in pediatric AML.,,, We report our data on the use of oral PRednisolone, E toposide and 6-M ercaptopurine (PREM) metronomic chemotherapy in treatment-naive and partially treated AML patients who could not afford the “3 + 7” induction regimen and in those who refused to continue consolidation after receiving the standard of care “3 + 7” induction.
| Materials and Methods|| |
General study details
This was a retrospective analysis of a prospectively collected database. The study was conducted at Indira Gandhi Institute of Medical Sciences (IJMS), which is the Regional Cancer Center in the state of Bihar in East India. All patients diagnosed with AML were eligible for the study, provided they had either refused standard “3 + 7” induction due to financial constraints (Group A) or had abandoned treatment at two or less cycles of consolidation high-dose cytarabine after completion of “3 + 7” induction (Group B). We included patients registered between June 1, 2017 and May 31, 2019 in the outpatient department (OPD) of Medical Oncology. Patients were offered oral metronomic therapy, explaining to them that it is not the approved standard of care for both the indications, i.e. for the induction or for consolidation and that its use may or may not result in disease resolution. Written informed consent for therapy was obtained from all patients.
This was a retrospective audit and as per institutional policy, retrospective audits are exempted from Ethics Committee approval. The study was conducted as per the criteria laid down by the International Conference on Harmonisation Good Clinical Practices, Declaration of Helsinki and guidelines established by the Indian Council of Medical Research. There was no extramural or intramural funding for the study.
All patients underwent baseline investigations including a complete blood count with peripheral smear examination, renal and hepatic profile, coagulation profile and serology for Human Immunodeficiency Virus (HIV), Hepatitis B, and Hepatitis C. A bone marrow aspiration and biopsy were performed in all patients. 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 at our institute. Evaluation and comments were solicited in terms of adequacy of the specimen, cellularity and degree of dyspoiesis in all the three lineages. Manual differential count was performed (500 cells) to calculate the exact blast count (percentage), and the presence of Auer rods. Cytochemical staining with Perls' Stain, Myeloperoxidase, Sudan Black, or Nonspecific Esterase was performed at the pathologist's discretion, depending on the morphological picture obtained on the bone marrow smear. In addition to the above parameters, bone marrow biopsies were assessed for the degree of fibrosis using reticulin stain.
Immunophenotyping is essential and critical for confirming the diagnosis of AML on bone marrow examination. Flow cytometric immunophenotyping was performed either from the baseline bone marrow aspirate specimen or subsequently from peripheral blood, if the peripheral blood smear contained adequate blasts. All flow cytometry samples were outsourced to a central private National Accreditation Board for Testing and Calibration Laboratories-Accredited Laboratory in New Delhi, which processes and reports as per the College of American Pathologists guidelines, as our institute does not have the facility for flow cytometry. 3–
5 ml bone marrow aspirate/peripheral blood was collected in a sodium heparin vacutainer which was transported to the central laboratory. Cells were prepared using the “Stain-Lyse-Wash” protocol. The following markers were used in eight different color panel combinations: markers of precursors (CD34, CD117), myeloid (CD13, CD64, CD14, CD15 and CytoMPO), T-lymphoid (cytoCD3, CD5, CD7), and B-lymphoid (CD10, CD19, CD22) markers. Cells were acquired on BD FACS Canto II and results were analyzed using BD FACS DIVA software. Blasts were gated using standard CD45 versus side scatter (CD45 vs. SSC) strategy and expression of different markers on blasts was assessed to confirm the diagnosis of AML. The average turnaround time for the above report was 72 hours.
None of the patient samples were samples were tested for baseline baseline cytogenetic or molecular profiling which are required for prognostication and risk stratification of AML. This was due to financial constraints, lack of in-house facility in our institute, and low likelihood of change of standard therapy, irrespective of the results of the above reports. Due to low affordability in selected population, the option of bone marrow transplant and use of midostaurin for poor risk AML and FLT3-ITD mutation positive patients remains largely inconceivable for our patient population.
Group A: After confirmation of diagnosis, patients were given a cost estimate of ₹500,000 ($7150) for standard “3 + 7” induction and three cycles of high-dose cytarabine consolidation. Patients were given 2 weeks to decide regarding feasibility and affordability of this treatment. Meanwhile, all patients received symptomatic treatment until they had made the above decision, without any chemotherapy. Patients who did not opt for the “3 + 7” induction due to financial constraints were then given the option of oral metronomic therapy. Our analysis is restricted to those patients who opted to receive oral metronomic therapy instead of standard induction therapy and had completed at least 30 days of induction oral metronomic therapy.
Eligibility criteria included patients over 18 years old, Eastern Cooperative Oncology network (ECOG) performance status 0–2, non-M3 AML (non-APML), and serologically negative for HIV, Hepatitis B, and C. Patients had normal organ function and coagulation profile and no active life threatening bacterial or fungal infections. Exclusion criteria included age over 60 years old, active treatment with steroids (more than 10 mg prednisolone equivalent), more than two uncontrolled comorbidities including coronary artery disease, patients who had received any oral or intravenous chemotherapeutic agents, active disseminated coagulation and major bleeding.
Group B: As a part of standard practice guidelines, we offered three cycles of high-dose cytarabine consolidation to newly diagnosed fit patients with AML after standard “3 + 7” induction. However, a subset of patients chose to discontinue therapy after “3 + 7” induction or after receiving one to two cycles of consolidation cytarabine due to prior experience of life-threatening toxicities and rising financial constraints. We offered maintenance oral metronomic therapy for 2 years to the above subset of patients who had received standard induction but received two or fewer cycles of high-dose cytarabine consolidation. Patients were counseled that receiving less than 3 cycles of consolidation increased the chance of relapse, and oral metronomic therapy maintenance did not guarantee sustained prolonged remissions.
All patients with AML were discussed in the multidisciplinary tumor board comprising of pathologists, hematopathologists, medical oncologist, palliative care physician, nursing staff, and social worker. The standard treatment along with the option of oral metronomic therapy, cost of therapy, duration of treatment, and the requirement of blood donors were explained to the patient in the language best understood by him/her. The final decision to treat with standard therapy or oral metronomic therapy induction (Group A) and/or oral metronomic therapy maintenance (Group B) was made by the medical oncologist in consultation and agreement with the patient and the patient's family.
All patients who opted for oral metronomic induction therapy (Group A) were advised tablet prednisolone 6 mg/m 2 twice a day (after meals) on days 1–14, capsule etoposide 35 mg/m 2 in the morning after breakfast on days 1–21, and tablet 6-mercaptopurine 35 mg/m 2 after dinner before bedtime on days 1–21. This cycle was repeated every 28 days. The dose of prednisolone was reduced to 3 mg/m 2 twice daily in the event of any proven or probable invasive fungal infection and for all patients from cycle two onward. Oral metronomic therapy induction was continued for at least 90 days (three cycles) before response evaluation. For all patients in Group B, the same treatment dose and schedule was used, except prednisolone was used in the dose of 3 mg/m 2 twice daily. In Group B, the total duration of therapy offered was 24 months. All patients in both groups received the histamine2-receptor antagonist, tablet ranitidine 150 mg twice daily before meals for the entire duration of therapy as prophylaxis for gastric ulcers. None of the patients received any prophylactic antibacterial or antifungal therapy.
In Group B, Standard “3 + 7” induction was daunorubicin 60 mg/m 2 on days 1–3 and cytarabine 100 mg/m 2 on days 1–7 as a continuous infusion, while high-dose consolidation cytarabine was 15–18 g/m 2, divided in a twice daily dose on days 1, 3, and 5 with prednisolone eye drops. In both the induction and consolidation regimes, granulocyte colony stimulation factor was started 48 hours after chemotherapy and continued until the recovery of the absolute neutrophil count to 500 × 10e 9/L.
Study endpoints and response evaluation
The primary endpoint was the response rate in treatment naive patients (Group A) and the remission duration in patients with partially treated AML (Group B) with oral metronomic therapy. The secondary endpoint was overall survival in both the groups of patients receiving induction oral metronomic therapy (Group A) and maintenance 24 months oral metronomic therapy (Group B). Response evaluation was done at the end of three cycles in Group A, with a complete blood count, peripheral smear examination, bone marrow aspiration, and biopsy. Responses were categorized as complete, partial, treatment failure, or progressive disease as per the revised European Leukemia Net (ELN) recommendations and the Centre for International Blood and Marrow Transplant Research (CIBMTR) guidelines., Minimal residual disease (MRD) evaluation with flow cytometry was done at the time of response evaluation from the bone marrow aspirate based on the clinician's discretion and patient affordability. The threshold cutoff for MRD was >0.1% as per the ELN criteria.
In order to maintain transparency in reporting and confirmation of responses, a set of bone marrow aspiration slides and microphotograph (baseline and response evaluation) were sent to a different expert hematopathologist in a different city apart from the institutional hematopathologists. None of the experts were made aware of the kind of treatment received as induction therapy or the duration of induction therapy to prevent any bias in reporting. For patients in Group B, bone marrow for response evaluation was performed at the end of the 3rd month of oral metronomic therapy only for patients who did not achieve CR after standard “3 + 7” induction. Subsequent bone marrow studies were done only for patients who were found to have abnormal hemograms or blasts on the peripheral smear during the 24 months of oral metronomic therapy maintenance.
Monitoring, duration of therapy, and follow-up
In Group A, all patients were monitored with weekly complete blood count, peripheral smear examination, hepatic and renal profile for the 1st month and then once in 2 weeks in the 2nd and 3rd month. In Group B, monitoring was done with the above parameters but only once a month, provided patients had attained a CR on evaluation.
In Group A, after the response evaluation, irrespective of the response, patients were again offered the standard “3 + 7” therapy. However, they were allowed to continue receiving oral metronomic therapy for a longer duration (up to a maximum of 2 years), in case, they still chose not to proceed with the standard induction with complete or partial response (PR) to oral metronomic therapy induction. Patients were closely monitored with monthly complete blood count and peripheral smear examination to detect relapses. In the event of a relapse or treatment failure, they were strongly advised to consider standard induction, provided they could arrange adequate finances for this. All Group B patients received maintenance oral metronomic therapy for 24 months.
At every visit, the clinician evaluated the patient and recorded clinical and laboratory data. All patients were followed up with monthly telephone calls as well as clinical visits until the end of the study. Any patient who failed to return or respond to the telephone call or failed to visit for more than two consecutive visits was termed as lost-to-follow up and deemed to have had an event in Group A, but not in Group B.
For patients in Group A, from the start of induction oral metronomic therapy until the bone marrow examination for response evaluation at 3 months, any inpatient admission for reasons apart from exclusive blood and component transfusion were recorded. Discharge summaries of admissions in nursing homes and private hospitals apart from our parent institute were also scanned to evaluate the indication for admission, duration of admission and the kind of treatment received. The volume of packed cell transfusion and the type of platelet transfusion consumed during the 3-month duration were noted. Abnormalities and the trend of change in the complete blood count, peripheral smear blast percentage and organ function parameters were recorded. Toxicities were graded as per the Common Terminology Criteria for Adverse Events (CTCAE v4.0). Once the patient had achieved a CR or PR with a normal hemogram, further toxicities if any, and the requirement for hospital admissions were not recorded. Similarly, they were not recorded for patients in Group B, other than inpatient hospital admission for treatment induced toxicities during the 2 years of maintenance oral metronomic therapy.
Demographic profile including age, sex, performance status at baseline and comorbidities were recorded. Descriptive statistics and frequency distribution were used to analyze patient and treatment-related variables. Chi square test was used to compare the influence of categorical variables on response rates. Kaplan–Meier survival plot was used to evaluate the overall survival and log rank test was used to compare the outcomes in appropriate dichotomous variables. Cox Regression Analysis was to use to calculate the Hazard Ratio between competing binary covariates., The follow-up duration was calculated using the reverse Kaplan–Meier method. Statistical Package for the Social Sciences (SPSS) software version 17.0 sheet (IBM Corp. Released 2017. IBM SPSS Statistics for Windows, Version 25.0. Armonk, NY, USA) was used to evaluate all above parameters.
| Results|| |
Patient and clinical profile
We analyzed the data of 15 patients who were diagnosed with AML and received oral metronomic therapy. Eleven patients (patient numbers 1–11) were in Group A and received induction oral metronomic therapy instead of the standard “3 + 7” induction, while another four patients (patient numbers 12–15) were in Group B and went on to receive 24 months of maintenance oral metronomic therapy after “3 + 7” induction. The median age in the combined population was 41 years (range, 19–53 years) with male to female ratio of 3:2. In both the cohorts, only two patients had hypertension as a comorbidity which was controlled on calcium channel blockers. ECOG performance status was 0 or 1 in all patients except for patient numbers 9, 10 and 11 (Group A), who had a performance status of 2. At presentation, in Group A, the median hemoglobin was 5.7 g/dL (range, 3.4–7.9), the median total leukocyte count was 22.7 × 109/L (range, 1.2–121.1) and the median platelet count was 0.41 × 109/L (range, 0.2–0.81). The median blast percentage on the peripheral smear was 48% (range, 22%–72%). The non-AML-M3 subtypes at diagnosis were AML-M0 (n = 3), AML-M1 (n = 6), AML-M2 (n = 5), and AML-M4 (n = 1) [Table 1].
|Table 1: Pattern of responses and outcomes obtained when oral metronomic therapy was used instead of standard induction in treatment naive adult acute myeloid leukemia patients|
Click here to view
Response and outcomes
The median follow-up in Group A was 13 months (range, 10–14 months) and it was 24.5 months (range, 22–26 months) in Group B. In Group A, five out of eleven (46%) attained a CR and two out of 11 (14%) attained a PR [Figure 1]. There was 100% concordance between the reports of the institutional and the external hematopathologist in reporting of the response rate. Three patients who died before completion of the 3rd month of induction oral metronomic therapy were considered to have progressive disease, while one patient was lost-to-follow up in Group A. One patient in Group A with morphological remission had achieved MRD at the 3rd month of oral metronomic therapy induction, however only 2/11 patients in Group A were evaluated for MRD with waiver of cost from outsourced lab on compassionate basis. In the 3rd month of induction oral metronomic therapy, on complete blood count and peripheral smear examination, the median hemoglobin was 7.1 g/dL (range, 3.4–7.7), the median total leukocyte count was 4.1 × 109/L (range, 1.2–5.6) and the median platelet count was 0.82 × 109/L (range, 0.1–1.2). The median blast percentage on peripheral smear was 0 (0-7%).
|Figure 1: Top row (a-c) showing pretreatment bone marrow examination: (a) Low magnification (×4) photomicrograph showing hypercellular bone marrow with reduced megakaryocytes, (b and c) showing high power microphotographs (×100) showing sheets of blasts (black arrow). Bottom row (d-f) showing post-treatment bone marrow examination: (d) low magnification (×4) showing normocellular bone marrow, (e-f) regenerating bone marrow showing trilineage hematopoiesis (orange arrow: Myeloid precursors, green arrow: Megakaryocyte, yellow arrow: Erythroid precursor) and occasional blast (black arrow)|
Click here to view
Four out of five patients who achieved CR in the 3rd month declined to receive “3 + 7” induction and chose to continue oral metronomic therapy until the end of study. One patient who relapsed in the 7th month of induction oral metronomic therapy after achieving CR, was treated with “3 + 7” induction but succumbed on day 19 of induction due to neutropenic sepsis, enterocolitis, and probable fungal pneumonia. One patient who relapsed in the 9th month after achieving CR initially in the 3rd month, continued on oral metronomic therapy and is alive in the 15th month of oral metronomic therapy. One patient with PR at the 3rd month continued oral metronomic therapy while another patient who attained a PR died in the 4th month due to rapid progression. Among those who progressed on oral metronomic therapy in Group A, the median time to progression was 3.5 months (range, 2–9 months) [Table 1].
In Group B, one patient received maintenance oral metronomic therapy when his post induction “3 + 7” bone marrow showed PR, but not in remission status and he declined to receive re-induction or high-dose cytarabine consolidation. Three other patients received maintenance oral metronomic therapy after declining to continue beyond first consolidation with high-dose cytarabine due to previous life-threatening toxicities or financial constraints to continue intensive therapy. The first patient achieved CR status at 3rd month of maintenance oral metronomic therapy on bone marrow examination. All four patients were alive and in sustained CR at the end of 2 years of maintenance oral metronomic therapy [Table 2].
|Table 2: Outcomes with maintenance oral metronomic therapy among patients who completed standard 3 + 7 induction but refused to complete optimum (2-3 cycles ) of high dose cytarabine consolidation|
Click here to view
The 1-year survival in Group A was 45% with a median overall survival of 9 months (95% CI, 5.4–11.6 months). Among the responders (CR + PR), the 1-year survival was 70% with a median overall survival of 12 months (95% CI, 9.1–14.5 months). Patients who failed to have a favorable response (non-CR/PR) to oral metronomic therapy died at a median of 3 months (95% CI, 2.2–3.2 months) from the start of induction oral metronomic therapy. Patients with ECOG performance status 0–1 had a significantly better survival at 12.3 months compared to 2.6 months in those with ECOG performance status 2 (P = 0.001) with hazard ratio of 0.31 (95% CI, 0.10–0.79). There was no difference in survival outcomes according to sex. For younger patients (age <41 years), the median survival was numerically but not statistically better at 12.7 months than that in the older age group (age >41 years) at 6.6 months (P = 0.81).
In the first 3 months, the ratio of total inpatient admissions for Group A patients (n = 11) was 1.7 with a median duration of 7 days (range, 4–14 days). The average number of random donor platelet units (RDP) consumed per patient was 3.36, and the average number of packed cell transfusion units used per patient was 3.9 in the first 3 months of oral metronomic induction therapy in Group A. There were 16 events of oral metronomic therapy drug interruptions with an average of 8 days per event. Most patients resumed oral metronomic therapy later at full doses except for two patients in whom the dose of prednisolone was reduced due to fungal pneumonia [Table 3]. None of the patients in Group B required inpatient admission for toxicities or blood/platelet transfusion support.
|Table 3: Toxicity profile (hematology, renal and hepatic profile only) and hospital admissions when oral metronomic therapy was used instead of standard induction in treated naive acute myeloid leukemia in the first three months of induction oral metronomic chemotherapy|
Click here to view
| Discussion|| |
Oral PREM induction metronomic chemotherapy in our study resulted in CR of 45% and PR of 18% in treatment naive, newly diagnosed young AML patients who were unable to receive the standard “3 + 7” induction due to financial constraints. In the patients who achieved a favorable response to induction oral metronomic therapy, the 1-year survival was 70% with a median overall survival of 12 months. Among the patients with partially or incompletely treated AML, maintenance oral metronomic therapy prescribed for 2 years resulted in sustained durable remissions extending beyond 2 years. As per our best knowledge, ours is one of the few studies done in young fit adult AML patients who were otherwise eligible for standard “3 + 7” induction but could not receive this due to financial constraints and received induction oral metronomic therapy instead. The results of our study reiterate the feasibility of low-cost, outpatient-based oral metronomic chemotherapy rather than ”no treatment” or best supportive care in economically poor AML patients who are unable to afford expensive, toxic and resource-intensive standard “3 + 7” induction. Our oral PREM protocol may also be useful as a bridge to definitive therapy, especially during national emergency or 'lockdown' arising out of global pandemic, such as recent outbreak of novel corona virus.
Our institute is the only government multispecialty hospital that has a medical oncology department in the regional cancer institute and caters to a population of over 100 million persons in the state of Bihar in India. The Department of Medical Oncology here was started 3 years ago and to date has a single faculty member to address the needs of cancer patients, especially patients with hematolymphoid malignancies. The daily OPD patient numbers exceed 100, all of whom are cared for by the single faculty member and one junior resident. In such a setting, it becomes increasingly difficult to offer individualized care to every patient. As per the data published from our hospital-based cancer registry, hematolymphoid malignancies are the fifth most common malignancy here. Bihar also happens to be the poorest state in India with a poverty rate exceeding 42%.
The standard treatment of “3 + 7” induction followed by three cycles of high-dose consolidation cytarabine for which we give a modest cost estimate of ₹5 lakhs ($7150) was beyond the scope of the start of our patients diagnosed with AML. Even the standard recommended diagnostic investigations for prognostication and risk stratification such as fluorescence in-situ hybridization (FISH) for the detection of recurrent cytogenetic abnormalities, conventional cytogenetic, and molecular studies (NPM1, FLT2-ITD and D835 and CEBPA) which cost ₹10,000 ($142), ₹3,600 ($52), and ₹8,450 ($120) respectively were beyond the scope of poor AML patients. Moreover, these tests if prescribed, need to be outsourced to a major metropolitan city as no government or private laboratory in Bihar currently offers the tests routinely, thus further escalating the cost. The cost of 1 month of our oral PREM therapy is ₹1300 ($18).
The standard “3 + 7” induction necessitates close supervision and constant vigil by experienced trained healthcare professionals as neutropenic fever may progress rapidly to severe sepsis with multi-organ failure or refractory septic shock if prompt identification and immediate intervention with broad spectrum antibiotics and antifungals are not administered. This becomes difficult in the “real-world” scenario in tier two to three cities such as ours due to lack of trained workforce to exercise “round the clock” clinical monitoring, thus making “3 + 7” induction a real challenge. Moreover, the blood bank in our institute, in the absence of an apheresis machine, can only provide RDPs and packed cells for transfusion. This often-limited supply pool is equally vied for simultaneously by other departments in multi-specialty hospitals, hence leading to unwanted delays when blood products are required urgently during standard AML induction.
Oral low-dose, less toxic continuous chemotherapy using the principles of drug repositioning has shown favorable response in solid malignancies by proposed anti-angiogenic hypothesis., The use of metronomic chemotherapy has found its place as a useful tool in the therapeutic armamentarium of clinicians working in low-income countries., Angiogenesis with increased micro-vessel density in the bone marrow of AML patients plays a major role in de novo and relapsed refractory AML., For AML, Banavali et al. from Tata Memorial Hospital, have proposed oral prednisolone, etoposide, 6-thioguanine (PRET) in older AML patients and pediatric AML patients not eligible for standard “3 + 7” induction upfront.,, Tandon et al. and Kapoor et al., have shown benefit in terms of achieving durable CRs in older patients with AML when treated with oral PRET or 6-mercaptopurine alone respectively., Using the oral PRET protocol, Banavali et al. earlier have demonstrated CR rates of 90% with median overall survival exceeding 20 months in young adults. They also concluded that metronomic chemotherapy may be a superior alternative to conventional induction especially in AML-M0 cohort. Hypomethylating agents have proven to be of value in older unfit AML patients as treatment of choice over best supportive care. There is lack of data for its use in young fit adults with AML not receiving standard “3 + 7” induction. We preferred oral metronomic induction as hypomethylating agents would cost ₹42,000 ($600) per month and the median time to best response is 4–6 months from onset of therapy.
In our study, we used oral PREM in young fit adult patients who were otherwise eligible for standard “3 + 7” induction but due to financial constraints could not afford it. We demonstrated an overall response rate of 65% (45% CR and 18% PR) in the 3rd month of induction oral metronomic therapy with median survival exceeding 12 months among responders. In a similar study reported by Singh et al. done in adults who were unable to receive standard aggressive chemotherapy due to poor general condition, the CR rate was 6.25% with overall response rate of 22% and median survival of 7–8 months. The doses of prednisolone, etoposide and 6-mercaptopurine used in our study were lower than those used in the above studies.,, Despite lower doses used in our study, the inpatient admission rate per patient was 1.7 with a median duration of 7 days of admission, and a requirement of 3.36 and 3.9 units of RDPs and packed cell transfusion consumed per patient during the first 3 months of oral metronomic therapy induction. Our study unlike any previous reported studies, led to sustained durable CRs extending beyond 2 years among adults who could not complete at least two high-dose consolidation cytarabine cycles after receiving standard “3 + 7” induction and went on to receive 2 years of maintenance oral metronomic therapy.
Apart from having a small sample size, short term follow-up and retrospective nature, our study had several other limitations. We did not perform FISH for the detection of recurrent cytogenetic abnormalities, conventional cytogenetics, and molecular markers for patients in Group A due to cost considerations. Hence, our results could not be interpreted differentially with respect to risk stratification and prognostication of AML. In the absence of this information and limited sample size, we could not analyze whether any particular cytogenetic subset performed unusually better or worse with oral metronomic therapy. None of the five patients who achieved CR at the end of 3 months of induction oral metronomic therapy went on to receive standard “3 + 7” induction therapy as initially planned. One of the five patients despite relapse in the 9th month on oral metronomic therapy chose to continue oral metronomic therapy despite our strong suggestion to switch to standard induction. However, she continues to survive on OMT. We could not perform any comparison with historical cohorts or matched pair analysis from our institute where standard “3 + 7” induction followed by three cycles of high-dose consolidation cytarabine was used. In Group B, all patients were t (8,21), inv16, and t (15,17) negative on FISH, but we do not have information on conventional cytogenetics or molecular markers, hence we had to classify them either as intermediate or high risk AML.
| Conclusion|| |
Oral metronomic chemotherapy may be a better option in patients who cannot afford standard “3 + 7” induction and three cycles of high-dose cytarabine consolidation instead of “no treatment” or best supportive care alone, especially in low income countries. Low-dose cytarabine or hypomethylating agents in young fit adults who cannot afford toxic and expensive standard induction in comparison to oral metronomic therapy needs to be explored further in prospective randomized studies.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Byrd JC, Dodge RK, Carroll A, Baer MR, Edwards C, Stamberg J, et al
. Patients with t(8;21)(q22;q22) and acute myeloid leukemia have superior failure-free and overall survival when repetitive cycles of high-dose cytarabine are administered. J Clin Oncol 1999;1s7:3767-75.
Singh G, Mathur A, Rastogi N, Malhotra H. Low dose metronomic chemotherapy in patients of acute myeloid leukemia. Astrocyte 2017;4:164.
Philip C, George B, Ganapule A, Korula A, Jain P, Alex AA, et al
. Acute myeloid leukaemia: Challenges and real world data from India. Br J Haematol 2015;170:110-7.
Kayal S, Sengar M, Jain H, Bonda A, George B, Kulkarni UP, et al
. Induction Related Mortality in Acute Myeloid Leukemia: Multivariate Model of Predictive Score from the Indian Acute Leukemia Research Database (INwARD) of the Hematology Cancer Consortium (HCC). Blood 2019;134 (Supplement_1):2615.
Philip CC, Mathew A, John MJ. Cancer care: Challenges in the developing world. Cancer Res Stat Treatment 2018;1:58.
Tandon N, Banavali S, Menon H, Gujral S, Kadam PA, Bakshi A. Is there a role for metronomic induction (and maintenance) therapy in elderly patients with acute myeloid leukemia? A literature review. Indian J Cancer 2013;50:154-8. [Full text]
Banavali S, Singh R, Prasad M, Arora B, Nahar A, Vora T, et al
. Is there a role for a novel maintenance therapy in pediatric patients with AML: PB015. Pediatr Blood Cancer 2011;57:770-1.
Kumar K, Radhakrishnan V, Dhanushkodi M, Kalaiyarasi JP, Mehra N, Kumar AR, et al
. Oral etoposide and cyclophosphamide: A low-cost palliative metronomic chemotherapy in advanced pediatric cancers. Cancer Res Stat Treatment 2020;3:64.
Amegan-Aho KH. Surviving on less. Cancer Res Stat Treatment 2020;3:87.
Döhner H, Estey E, Grimwade D, Amadori S, Appelbaum FR, Büchner T, et al
. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood 2017;129:424-47.
Chakraborty S. A step-wise guide to performing survival analysis. Cancer Res Stat Treat 2018;1:41-5. [Full text]
Dessai S, Simha V, Patil V. Stepwise cox regression analysis in SPSS. Cancer Res Stat Treat 2018;1:167-70. [Full text]
Dessai S, Patil V. Testing and interpreting assumptions of COX regression analysis. Cancer Res Stat Treat 2019;2:108-11. [Full text]
Pandey A, Singh A, Singh S, Kumar A. Patient-doctor ratio across nine super specialty clinics in government hospital: A cross sectional study. Int J Community Med Public Health 2019;6:4421.
Pandey A, Raj S, Madhawi R, Devi S, Singh RK. Cancer trends in Eastern India: Retrospective hospital-based cancer registry data analysis. South Asian J Cancer 2019;8:215-7.
] [Full text]
Singh KM, Meena M, Singh R, Kumar A. Dimensions of poverty in Bihar. SSRN 2017506; 13 Sep 2011.
Pandey A, Abhay D, Sunny J, Vikas O, Vijay P, Rajeshri K, et al
. Outcomes of advanced epithelial ovarian cancer with integration of metronomic chemotherapy: An Indian rural cancer centre experience. South Asian J Cancer 2016;5:59-62.
] [Full text]
Pandey A, Desai A, Ostwal V, Patil V, Kulkarni A, Kulkarni R, et al
. Outcome of operable oral cavity cancer and impact of maintenance metronomic chemotherapy: A retrospective study from rural India. South Asian J Cancer 2016;5:52-5.
] [Full text]
André N, Banavali S, Snihur Y, Pasquier E. Has the time come for metronomics in low-income and middle-income countries? Lancet Oncol 2013;14:e239-48.
Pasquier E, Kavallaris M, André N. Metronomic chemotherapy: New rationale for new directions. Nat Rev Clin Oncol 2010;7:455-65.
Trujillo A, McGee C, Cogle CR. Angiogenesis in acute myeloid leukemia and opportunities for novel therapies. J Oncol 2012;2012:128608.
Padró T, Ruiz S, Bieker R, Bürger H, Steins M, Kienast J, et al
. Increased angiogenesis in the bone marrow of patients with acute myeloid leukemia. Blood 2000;95:2637-44.
Banavali SD, Biswas G, Nair CN, Kurkure PA, Saikia TK, Parikh PM. PRET: An effective oral protocol for out-patient therapy in patients with acute myeloid leukemia. Pediatr Blood Cancer 2004;43:355.
Sengar M, Nair R, Banavali SD, Menon H. Metronomic approach for treatment of acute myeloid leukemia (aml): Dose intensity does not always matter. Haematologica 2009;94 Suppl 2:551.
Kapoor A, Beniwal SK, Kalwar A, Singhal MK, Nirban RK, Kumar HS. Metronomic therapy with oral 6-mercaptopurine in elderly acute myeloid leukemia: A prospective pilot study. South Asian J Cancer 2016;5:70-2.
] [Full text]
Banavali S, Goyal L, Padhye B, Arora B, Bhagwat R, Gujral S, et al
. Novel Therapeutic Approach Yields Excellent Results in Minimally Differentiated Acute Myeloid Leukemia (AML-M0): Time To Think out of the Box. Blood 2005;106:4615.
Fenaux P, Mufti GJ, Hellstrom-Lindberg E, Santini V, Finelli C, Giagounidis A, et al
. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: A randomised, open-label, phase III study. Lancet Oncol 2009;10:223-32.
Pleyer L, Burgstaller S, Girschikofsky M, Linkesch W, Stauder R, Pfeilstocker M, et al
. Azacitidine in 302 patients with WsHO-defined acute myeloid leuksemia: Results from the Austrian Azacitidine Registry of the AGMT-Study Group. Ansn Hematol 2014;93:1825-38.
[Table 1], [Table 2], [Table 3]