Journal of Clinical and Diagnostic Research, ISSN - 0973 - 709X

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Dr Mohan Z Mani

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Department of Dermatolgy,
Believers Church Medical College,
Thiruvalla, Kerala
On Sep 2018




Prof. Somashekhar Nimbalkar

"Over the last few years, we have published our research regularly in Journal of Clinical and Diagnostic Research. Having published in more than 20 high impact journals over the last five years including several high impact ones and reviewing articles for even more journals across my fields of interest, we value our published work in JCDR for their high standards in publishing scientific articles. The ease of submission, the rapid reviews in under a month, the high quality of their reviewers and keen attention to the final process of proofs and publication, ensure that there are no mistakes in the final article. We have been asked clarifications on several occasions and have been happy to provide them and it exemplifies the commitment to quality of the team at JCDR."



Prof. Somashekhar Nimbalkar
Head, Department of Pediatrics, Pramukhswami Medical College, Karamsad
Chairman, Research Group, Charutar Arogya Mandal, Karamsad
National Joint Coordinator - Advanced IAP NNF NRP Program
Ex-Member, Governing Body, National Neonatology Forum, New Delhi
Ex-President - National Neonatology Forum Gujarat State Chapter
Department of Pediatrics, Pramukhswami Medical College, Karamsad, Anand, Gujarat.
On Sep 2018




Dr. Kalyani R

"Journal of Clinical and Diagnostic Research is at present a well-known Indian originated scientific journal which started with a humble beginning. I have been associated with this journal since many years. I appreciate the Editor, Dr. Hemant Jain, for his constant effort in bringing up this journal to the present status right from the scratch. The journal is multidisciplinary. It encourages in publishing the scientific articles from postgraduates and also the beginners who start their career. At the same time the journal also caters for the high quality articles from specialty and super-specialty researchers. Hence it provides a platform for the scientist and researchers to publish. The other aspect of it is, the readers get the information regarding the most recent developments in science which can be used for teaching, research, treating patients and to some extent take preventive measures against certain diseases. The journal is contributing immensely to the society at national and international level."



Dr Kalyani R
Professor and Head
Department of Pathology
Sri Devaraj Urs Medical College
Sri Devaraj Urs Academy of Higher Education and Research , Kolar, Karnataka
On Sep 2018




Dr. Saumya Navit

"As a peer-reviewed journal, the Journal of Clinical and Diagnostic Research provides an opportunity to researchers, scientists and budding professionals to explore the developments in the field of medicine and dentistry and their varied specialities, thus extending our view on biological diversities of living species in relation to medicine.
‘Knowledge is treasure of a wise man.’ The free access of this journal provides an immense scope of learning for the both the old and the young in field of medicine and dentistry as well. The multidisciplinary nature of the journal makes it a better platform to absorb all that is being researched and developed. The publication process is systematic and professional. Online submission, publication and peer reviewing makes it a user-friendly journal.
As an experienced dentist and an academician, I proudly recommend this journal to the dental fraternity as a good quality open access platform for rapid communication of their cutting-edge research progress and discovery.
I wish JCDR a great success and I hope that journal will soar higher with the passing time."



Dr Saumya Navit
Professor and Head
Department of Pediatric Dentistry
Saraswati Dental College
Lucknow
On Sep 2018




Dr. Arunava Biswas

"My sincere attachment with JCDR as an author as well as reviewer is a learning experience . Their systematic approach in publication of article in various categories is really praiseworthy.
Their prompt and timely response to review's query and the manner in which they have set the reviewing process helps in extracting the best possible scientific writings for publication.
It's a honour and pride to be a part of the JCDR team. My very best wishes to JCDR and hope it will sparkle up above the sky as a high indexed journal in near future."



Dr. Arunava Biswas
MD, DM (Clinical Pharmacology)
Assistant Professor
Department of Pharmacology
Calcutta National Medical College & Hospital , Kolkata




Dr. C.S. Ramesh Babu
" Journal of Clinical and Diagnostic Research (JCDR) is a multi-specialty medical and dental journal publishing high quality research articles in almost all branches of medicine. The quality of printing of figures and tables is excellent and comparable to any International journal. An added advantage is nominal publication charges and monthly issue of the journal and more chances of an article being accepted for publication. Moreover being a multi-specialty journal an article concerning a particular specialty has a wider reach of readers of other related specialties also. As an author and reviewer for several years I find this Journal most suitable and highly recommend this Journal."
Best regards,
C.S. Ramesh Babu,
Associate Professor of Anatomy,
Muzaffarnagar Medical College,
Muzaffarnagar.
On Aug 2018




Dr. Arundhathi. S
"Journal of Clinical and Diagnostic Research (JCDR) is a reputed peer reviewed journal and is constantly involved in publishing high quality research articles related to medicine. Its been a great pleasure to be associated with this esteemed journal as a reviewer and as an author for a couple of years. The editorial board consists of many dedicated and reputed experts as its members and they are doing an appreciable work in guiding budding researchers. JCDR is doing a commendable job in scientific research by promoting excellent quality research & review articles and case reports & series. The reviewers provide appropriate suggestions that improve the quality of articles. I strongly recommend my fraternity to encourage JCDR by contributing their valuable research work in this widely accepted, user friendly journal. I hope my collaboration with JCDR will continue for a long time".



Dr. Arundhathi. S
MBBS, MD (Pathology),
Sanjay Gandhi institute of trauma and orthopedics,
Bengaluru.
On Aug 2018




Dr. Mamta Gupta,
"It gives me great pleasure to be associated with JCDR, since last 2-3 years. Since then I have authored, co-authored and reviewed about 25 articles in JCDR. I thank JCDR for giving me an opportunity to improve my own skills as an author and a reviewer.
It 's a multispecialty journal, publishing high quality articles. It gives a platform to the authors to publish their research work which can be available for everyone across the globe to read. The best thing about JCDR is that the full articles of all medical specialties are available as pdf/html for reading free of cost or without institutional subscription, which is not there for other journals. For those who have problem in writing manuscript or do statistical work, JCDR comes for their rescue.
The journal has a monthly publication and the articles are published quite fast. In time compared to other journals. The on-line first publication is also a great advantage and facility to review one's own articles before going to print. The response to any query and permission if required, is quite fast; this is quite commendable. I have a very good experience about seeking quick permission for quoting a photograph (Fig.) from a JCDR article for my chapter authored in an E book. I never thought it would be so easy. No hassles.
Reviewing articles is no less a pain staking process and requires in depth perception, knowledge about the topic for review. It requires time and concentration, yet I enjoy doing it. The JCDR website especially for the reviewers is quite user friendly. My suggestions for improving the journal is, more strict review process, so that only high quality articles are published. I find a a good number of articles in Obst. Gynae, hence, a new journal for this specialty titled JCDR-OG can be started. May be a bimonthly or quarterly publication to begin with. Only selected articles should find a place in it.
An yearly reward for the best article authored can also incentivize the authors. Though the process of finding the best article will be not be very easy. I do not know how reviewing process can be improved. If an article is being reviewed by two reviewers, then opinion of one can be communicated to the other or the final opinion of the editor can be communicated to the reviewer if requested for. This will help one’s reviewing skills.
My best wishes to Dr. Hemant Jain and all the editorial staff of JCDR for their untiring efforts to bring out this journal. I strongly recommend medical fraternity to publish their valuable research work in this esteemed journal, JCDR".



Dr. Mamta Gupta
Consultant
(Ex HOD Obs &Gynae, Hindu Rao Hospital and associated NDMC Medical College, Delhi)
Aug 2018




Dr. Rajendra Kumar Ghritlaharey

"I wish to thank Dr. Hemant Jain, Editor-in-Chief Journal of Clinical and Diagnostic Research (JCDR), for asking me to write up few words.
Writing is the representation of language in a textual medium i e; into the words and sentences on paper. Quality medical manuscript writing in particular, demands not only a high-quality research, but also requires accurate and concise communication of findings and conclusions, with adherence to particular journal guidelines. In medical field whether working in teaching, private, or in corporate institution, everyone wants to excel in his / her own field and get recognised by making manuscripts publication.


Authors are the souls of any journal, and deserve much respect. To publish a journal manuscripts are needed from authors. Authors have a great responsibility for producing facts of their work in terms of number and results truthfully and an individual honesty is expected from authors in this regards. Both ways its true "No authors-No manuscripts-No journals" and "No journals–No manuscripts–No authors". Reviewing a manuscript is also a very responsible and important task of any peer-reviewed journal and to be taken seriously. It needs knowledge on the subject, sincerity, honesty and determination. Although the process of reviewing a manuscript is a time consuming task butit is expected to give one's best remarks within the time frame of the journal.
Salient features of the JCDR: It is a biomedical, multidisciplinary (including all medical and dental specialities), e-journal, with wide scope and extensive author support. At the same time, a free text of manuscript is available in HTML and PDF format. There is fast growing authorship and readership with JCDR as this can be judged by the number of articles published in it i e; in Feb 2007 of its first issue, it contained 5 articles only, and now in its recent volume published in April 2011, it contained 67 manuscripts. This e-journal is fulfilling the commitments and objectives sincerely, (as stated by Editor-in-chief in his preface to first edition) i e; to encourage physicians through the internet, especially from the developing countries who witness a spectrum of disease and acquire a wealth of knowledge to publish their experiences to benefit the medical community in patients care. I also feel that many of us have work of substance, newer ideas, adequate clinical materials but poor in medical writing and hesitation to submit the work and need help. JCDR provides authors help in this regards.
Timely publication of journal: Publication of manuscripts and bringing out the issue in time is one of the positive aspects of JCDR and is possible with strong support team in terms of peer reviewers, proof reading, language check, computer operators, etc. This is one of the great reasons for authors to submit their work with JCDR. Another best part of JCDR is "Online first Publications" facilities available for the authors. This facility not only provides the prompt publications of the manuscripts but at the same time also early availability of the manuscripts for the readers.
Indexation and online availability: Indexation transforms the journal in some sense from its local ownership to the worldwide professional community and to the public.JCDR is indexed with Embase & EMbiology, Google Scholar, Index Copernicus, Chemical Abstracts Service, Journal seek Database, Indian Science Abstracts, to name few of them. Manuscriptspublished in JCDR are available on major search engines ie; google, yahoo, msn.
In the era of fast growing newer technologies, and in computer and internet friendly environment the manuscripts preparation, submission, review, revision, etc and all can be done and checked with a click from all corer of the world, at any time. Of course there is always a scope for improvement in every field and none is perfect. To progress, one needs to identify the areas of one's weakness and to strengthen them.
It is well said that "happy beginning is half done" and it fits perfectly with JCDR. It has grown considerably and I feel it has already grown up from its infancy to adolescence, achieving the status of standard online e-journal form Indian continent since its inception in Feb 2007. This had been made possible due to the efforts and the hard work put in it. The way the JCDR is improving with every new volume, with good quality original manuscripts, makes it a quality journal for readers. I must thank and congratulate Dr Hemant Jain, Editor-in-Chief JCDR and his team for their sincere efforts, dedication, and determination for making JCDR a fast growing journal.
Every one of us: authors, reviewers, editors, and publisher are responsible for enhancing the stature of the journal. I wish for a great success for JCDR."



Thanking you
With sincere regards
Dr. Rajendra Kumar Ghritlaharey, M.S., M. Ch., FAIS
Associate Professor,
Department of Paediatric Surgery, Gandhi Medical College & Associated
Kamla Nehru & Hamidia Hospitals Bhopal, Madhya Pradesh 462 001 (India)
E-mail: drrajendrak1@rediffmail.com
On May 11,2011




Dr. Shankar P.R.

"On looking back through my Gmail archives after being requested by the journal to write a short editorial about my experiences of publishing with the Journal of Clinical and Diagnostic Research (JCDR), I came across an e-mail from Dr. Hemant Jain, Editor, in March 2007, which introduced the new electronic journal. The main features of the journal which were outlined in the e-mail were extensive author support, cash rewards, the peer review process, and other salient features of the journal.
Over a span of over four years, we (I and my colleagues) have published around 25 articles in the journal. In this editorial, I plan to briefly discuss my experiences of publishing with JCDR and the strengths of the journal and to finally address the areas for improvement.
My experiences of publishing with JCDR: Overall, my experiences of publishing withJCDR have been positive. The best point about the journal is that it responds to queries from the author. This may seem to be simple and not too much to ask for, but unfortunately, many journals in the subcontinent and from many developing countries do not respond or they respond with a long delay to the queries from the authors 1. The reasons could be many, including lack of optimal secretarial and other support. Another problem with many journals is the slowness of the review process. Editorial processing and peer review can take anywhere between a year to two years with some journals. Also, some journals do not keep the contributors informed about the progress of the review process. Due to the long review process, the articles can lose their relevance and topicality. A major benefit with JCDR is the timeliness and promptness of its response. In Dr Jain's e-mail which was sent to me in 2007, before the introduction of the Pre-publishing system, he had stated that he had received my submission and that he would get back to me within seven days and he did!
Most of the manuscripts are published within 3 to 4 months of their submission if they are found to be suitable after the review process. JCDR is published bimonthly and the accepted articles were usually published in the next issue. Recently, due to the increased volume of the submissions, the review process has become slower and it ?? Section can take from 4 to 6 months for the articles to be reviewed. The journal has an extensive author support system and it has recently introduced a paid expedited review process. The journal also mentions the average time for processing the manuscript under different submission systems - regular submission and expedited review.
Strengths of the journal: The journal has an online first facility in which the accepted manuscripts may be published on the website before being included in a regular issue of the journal. This cuts down the time between their acceptance and the publication. The journal is indexed in many databases, though not in PubMed. The editorial board should now take steps to index the journal in PubMed. The journal has a system of notifying readers through e-mail when a new issue is released. Also, the articles are available in both the HTML and the PDF formats. I especially like the new and colorful page format of the journal. Also, the access statistics of the articles are available. The prepublication and the manuscript tracking system are also helpful for the authors.
Areas for improvement: In certain cases, I felt that the peer review process of the manuscripts was not up to international standards and that it should be strengthened. Also, the number of manuscripts in an issue is high and it may be difficult for readers to go through all of them. The journal can consider tightening of the peer review process and increasing the quality standards for the acceptance of the manuscripts. I faced occasional problems with the online manuscript submission (Pre-publishing) system, which have to be addressed.
Overall, the publishing process with JCDR has been smooth, quick and relatively hassle free and I can recommend other authors to consider the journal as an outlet for their work."



Dr. P. Ravi Shankar
KIST Medical College, P.O. Box 14142, Kathmandu, Nepal.
E-mail: ravi.dr.shankar@gmail.com
On April 2011
Anuradha

Dear team JCDR, I would like to thank you for the very professional and polite service provided by everyone at JCDR. While i have been in the field of writing and editing for sometime, this has been my first attempt in publishing a scientific paper.Thank you for hand-holding me through the process.


Dr. Anuradha
E-mail: anuradha2nittur@gmail.com
On Jan 2020

Important Notice

Original article / research
Year : 2022 | Month : March | Volume : 16 | Issue : 3 | Page : SC01 - SC05 Full Version

Tolerance of ALL Induction Therapy in Children with Limited Resources: A Retrospective Study from a Teaching Hospital


Published: March 1, 2022 | DOI: https://doi.org/10.7860/JCDR/2022/51295.16087
Tanvi Khanna , Nitika Agrawal , Kunal Das , Brahma Prakash Kalra

1. Former Senior Resident, Department of Paediatrics, Himalayan Institute of Medical Sciences, Dehradun, Uttarakhand, India. 2. Associate Professor, Department of Paediatrics, Himalayan Institute of Medical Sciences, Dehradun, Uttarakhand, India. 3. Associate Professor, Department of Paediatrics, Himalayan Institute of Medical Sciences, Dehradun, Uttarakhand, India. 4. Professor, Department of Paediatrics, Himalayan Institute of Medical Sciences, Dehradun, Uttarakhand, India.

Correspondence Address :
Kunal Das,
B 9/6, HIHT Campus, Jolly Grants, Dehradun, Uttarakhand, India.
E-mail: drkunaloncology@gmail.com

Abstract

Introduction: Acute Lymphoblastic Leukaemia (ALL) is the most common malignancy in children. Due to the better understanding of biology, intensive multi-agent chemotherapy and improved supportive care, ALL is curable in majority of children. Induction phase is the most intense and critical phase of therapy.

Aim: To examine the feasibility of high-intensity induction and its tolerance in a resource-limited setting in children with acute lymphoblastic leukaemia.

Materials and Methods: This retrospective analysis was done on children admitted for ALL treatment. Data was collected for January 2016 to July 2018, regarding baseline characteristics, tolerance to induction therapy, morbidity, mortality, deviations from protocol, and induction outcomes among children with ALL treated at a tertiary care teaching hospital (Cancer Research Institute, Himalayan Institute of Medical Sciences, Dehradun, Uttrakhand, India). Confirmed cases of ALL with age upto 18 years, who took more than a week of planned induction were included in the study. Data was analysed using Chi-square and Fisher’s-exact test.

Results: Four-drug induction was feasible and given to 76 patients during the study period. Mean age of the group was 9.3 years. Male: female ratio was 1.3:1. Remission was achieved in 63 (82.8%) patients. Four deaths occurred, and were attributed to infection. Hyperglycaemia (4), CNS events (2), peripherally inserted central line related thrombosis (2) and pulmonary tuberculosis (1) were noted. Febrile neutropenia was noted in 65 cases and seven cases required ICU care; two of them succumbed in the ICU. Baseline blood parameters, subtype of disease, protocol of treatment and age did not affect the induction outcome statistically.

Conclusion: Intensive induction chemotherapy has varying complications and can be employed even in resource-limited settings with acceptable results

Keywords

Acute lymphoblastic leukaemia, Induction chemotherapy, Leukaemia, Sepsis, Supportive care

Paediatric ALL has witnessed a dramatic success with multi-agent therapy over the last four decades. Children oncology group experiences showed a dismal cure rate less than 10% in 1960’s, which improved to more than 80% in 1990’s and more than 90% in 2001-2005 data (1). Improvement in survival is to the extent that focus has been partly shifted to decreasing the dose thus minimising the long-term complications of treatment. Better risk stratification and tailoring treatment based on risk, response and minimal residual disease has led to more than 80% cure rate among paediatric ALL cases (2),(3). While data from developing countries is scarce, public health sector in India has failed to display such results and cure rates are remarkably low varying from 25-40% (4),(5),(6).

Induction period is the most critical period for any ALL children. Children often present with deranged haematological parameters, infections and poor nutritional state. Multi-agent chemotherapy protocols are myelo-suppressive and vulnerability of children to organ damage, sepsis and death is high (6). A good supportive system is required for induction phase of chemotherapy. Indian pooled data noted about 10% of death in induction phase of chemotherapy (7). Infection-related deaths have been noted to be one of the main reasons of poor outcome in childhood leukaemia. Resource constrains in form of poor staff training and staff to patient ratio has been noted in low/middle income country. Cross-sectional data survey from 54 countries showed direct relation of quality of childhood cancer nursing with country income and health expenditure (8). Availability of healthcare workers in Africa is far less than recommended by developed countries (9). Data from India also showed poor nurse to patient ratio in multi-hospital survey (10). Availability and use of Pegylated L-Asparaginase, which has shown to improve the result of childhood ALL, has been noted to be poor in India (11). Non affordability to newer treatment plans incorporating minimal residual disease assessment also contribute to poor outcome. In a survey done by International Society of Paediatric Oncology in 2014, nursing care in paediatric oncology wards in low-middle income countries were found sub-optimal and probably the cause of poor outcome (12). A survey of Government hospitals in Delhi, India also noted sub-optimal ratio of staff to patient in children oncology unit (13).

Cancer research institute is a referral cancer centre in the state of Uttarakhand in India. It is the main referral centre for paediatric malignancies in the region. It caters the middle-income and low-income group population, the majority of who are partly sponsored by various agencies. Authors present the data on childhood ALL induction depicting tolerance, complications and induction outcome. This study will address the feasibility of using intensive multidrug induction chemotherapy in public health sector.

Material and Methods

This was a retrospective observational study conducted at Paediatric Oncology Unit, Cancer Research Institute, Himalayan Institute of Medical Sciences, Dehradun, Uttrakhand, India. Study was conducted in October 2019 to March 2020. Data of children admitted to Paediatric Oncology Unit was collected. Patients enrolled from January 2016 to July 2018 were selected for analysis. Ethical Clearance was taken from research and Ethics Committee (HIMS/RC/2019/04).

Inclusion criteria: All confirmed case of ALL (either on Flow cytometry, or on morphology and PAS block positivity) with age group of less than 18 years in the defined study period and relapsed ALL cases started on salvage chemotherapy, were included in the study.

Exclusion criteria: Patients who had not received induction chemotherapy in this centre were excluded. Patients who died before eighth day of chemotherapy were also excluded from the study.

Procedure

Data (chemotherapy protocol, agents and dose) were collected from digital case records and physical files from medical record section. Any reduction in dose or deviation from schedule of chemotherapy was noted with reason mentioned in records. Day 8 absolute blast counts were noted to check prednisolone response criteria. Central Nervous System (CNS) disease status was noted based on baseline Cerebrospinal Fluid (CSF) cytology, noted clinical features and brain imaging, if done.

Institutional protocol of febrile neutropenia was taken as standard practice and data were collected regarding all febrile episodes in induction. For all practical purpose, fever in initial 3 weeks of induction was taken as febrile neutropenia. Data regarding antibiotic choice, use, duration, and escalation were noted. Cases treated for pulmonary aspergillosis on presumptive basis were noted for Computed Tomography (CT) chest findings and cases with reactivation of tuberculosis was noted in detail regarding basis of starting antitubercular medications.

Postinduction bone marrow report was noted for each case and blasts less than 5% were considered in complete remission. More than 5% blasts were considered induction failure cases. Persistent CNS positivity at this point is also taken as induction failure. Deaths during induction were noted along with cause.

Statistical Analysis

Patient’s demographic parameters and baseline characteristics were summarised as descriptive variables. Categorical variables were reported with frequency and percentage while continuous variables were reported as median and range or mean and standard deviation. Cases were grouped into two, based on protocol used and induction mortality and toxicities were compared by using Fisher’s-exact test. All cases were further divided into two groups based on outcome of induction. Achieved remission included cases that achieved complete remission and no remission included cases that had induction failure, drop out or death as induction outcome. Both groups were compared using Chi-square test for various affecting variables. The p-value <0.05 was considered as statistically significant. The statistical analysis was done by Statistical Package for the Social Sciences (SPSS) statistics for windows, version 16.0 (SPSS Inc. Chicago 1II., USA).

Results

Total of 86 children were diagnosed with ALL during this study period. Out of those diagnosed ALL, 10 cases left treatment in less than a week due to various reasons and were thus, excluded from the study. All analyses were done on 76 cases.

Mean age of the group was 9.3 years (5.3). Male: female ratio was 1.3:1. Pre B- ALL was the most common subtype (54%) followed by T- ALL (23%). ALL phenotype could not be ascertained in 23% patients. Those were diagnosed as ALL based on PAS block positivity along with morphology of blasts on bone marrow.

At diagnosis, two patients were detected to have malignant cells in CSF analysis. None of them had focal sign or headache. One case had headache and evaluation showed multiple CNS bleed. He was also treated as CNS positive case. Anaemia was noted among 81.5% children. Total 33% cases had Total Leucocyte Count (TLC) more than 50,000/cmm at presentation, and 10.5% had more than 0.1 million/cmm. Platelet less than 20000/cmm were noted among 81.5% cases (Table/Fig 1). Serum Lactate Dehydrogenase (LDH) was elevated (>250 IU) in 34 patients (44.7%) and serum uric acid was elevated in three patients (0.4%). Only one case was noted to experience tumourlysis syndrome based on laboratory criteria, and he was managed conservatively.

Allopurinol and hydration were given to all cases, however, three cases required Rasburicase for high uric acid (>9 mg/dL). Allopurinol was not given to them simultaneously with Rasburicase. Total 16 cases presented with high fever and oral antibiotic (cefixime) was started in them. Five cases required up gradation to injectable antibiotics (Cefeperazone- Salbactum) at onset due to sick condition and sepsis. Cases with fever at presentation, without any obvious infection focus and stable general condition were started on oral antibiotics considering possibility of disease related fever. However, escalation of antibiotics were done to injectable 3rd generation cephalosporin in case of detoriation. None of them showed any culture positivity for baseline fever. Fever episode during induction was noted among 86% of cases however, only four of them showed culture positivity (two for Klebsiella, one each for Staphylococcus aureus and Escherichia coli). Antibiotics were modified based on culture report. Three patients were noted pulmonary aspergillosis and treated with amphotericin B. Two of them were shifted to oral voriconazole after one week. Intensive care unit shifting was required for seven cases and sepsis was the most common cause (among five) followed by seizure and respiratory distress. Ventilation was required for two cases and both of them succumbed to clinical sepsis, although cultures were sterile. Mucositis was the most common side effect noted among 15 cases (more than or equal to grade II as per CTCAE version 4) (14). Pleural effusion was noticed in one patient and two patients developed hyperglycaemia warranting insulin therapy during induction. Peripherally Inserted Central Catheter (PICC) was placed among 13 cases and four cases, required removal of it during induction, two due to thrombosis and two due to non resolving fever. One case was diagnosed to have pulmonary tuberculosis during 3rd week of induction. Three drugs antitubercular treatment was started to him.

CNS event in form of seizure was noted among two cases, MRI showed normal finding in both. Steroid induced hyperglycaemia was noted among four cases, all had polyuria and polydipsia. They were managed with insulin. No routine sugar monitoring protocol was in place for asymptomatic induction cases.

Treatment deviations: Nine cases required premature tapering of steroid due to sepsis/aspergillosis. Steroid was restarted among four of them and target of giving minimum of three weeks steroid with tapering was achieved. Remaining five cases received median of 17 days of steroid only. Dose of chemotherapy was reduced (>20%) among six cases, all due to sepsis. Two cases received only two doses of anthracyclins during induction. Maximum dose tempering was done during 3rd week of therapy. Vincristine related neuropathy was noted in one case in form of foot drop. Constipation was noted among 32 cases, however as everyone was on ondensetrone and fluconazole, causation and association with vincristine could not be ascertained. No pancreatitis or thrombosis was noted. L-asparaginase was well-tolerated in all cases. Interruption and delay was noted in following order- daunomycin, steroid and vincristine. Three cases required two additional doses of intrathecal methotrexate for their CNS positivity. Tolerance of chemotherapy had no association with initial haematological parameters.

Outcome of Induction: Out of 76 cases analysed, 82.8% achieved complete remission. Four deaths were noted during induction, all due to sepsis (fever with organ system involvement features). Median timing of death was day 19 of induction. Induction failure was noted among five cases. Four cases left hospital before induction completion despite counselling, three due to financial constrain and one opted out of allopathic treatment. Eight out of 76 cases were relapsed ALL, earlier treated with another protocols {three on UK-ALL, two on Berlin-Frankfurt-Munich (BFM) ALL 95 and two on Multi- Centric Protocol (MCP)-841 protocol}. Out of these relapsed cases, five achieved remission (four on BFM-ALL 95 protocol and one on BFM-REZ protocol). No difference in induction outcome was noted between high TLC, low platelets, chemotherapy protocol, baseline anemia, age with induction outcome (Table/Fig 2). Biochemical parameters except createnine, serum LDH and uric acid were not evaluated in all cases at baseline. Levels of createnine, LDH and uric acid at baseline did not affect induction outcome. Sepsis, interruption of treatment or baseline characteristics was not associated with induction outcome in term of disease control among survivors.

Discussion

India has approximate 10,000 cases of ALL yearly. Lack of national registry and reporting system makes this figure doubtful for the true prevalence of disease (15). While about 56% of population is residing in villages and accessibility to healthcare is poor, exact estimation of occurrence including undiagnosed cases are not feasible. Despite all this disparity, focal data published from individual centres has shown improvement in survival (4),(16).

Majority of protocols are based on four drug induction with steroid, anthracyclins, vincristine and L-asparaginase along with CNS prophylaxis with intrathecal methotrexate. Results noted by these trials are also comparable. Our centre opted two different protocols, based on consultant preference and experience, BFM ALL 95 and Children’s cancer group study 1961 protocol. Both protocols are having same drugs with minor reshuffling of sequences.

Baseline parameters were variable in this study regarding haemogram. High Total Leucocyte Counts (TLC) has been noted to have negative impact on final outcome in studies. Earlier concept of tumour burden was there for affecting outcome, but not considered significant now. Probably increased intensity of induction surpasses the ill effects of tumour burden. Steroid response is more accurately associated with outcome and has been included in risk stratification in BFM and other major trials (17),(18),(19). Initial haemogram variables were not different in remission and induction failure cohorts. This study was having limited number of cases to conclude impact of haemogram variables on induction outcome.

Infections and sepsis remains major cause of death during induction treatment. Gram negative septicaemia has been noted in majority of deaths in various studies from India and abroad. Klebsiella and Pseudomonas has been noted as most common pathogens (20),(21). Decreased immunity due to disease and on-going ablative induction chemotherapy makes the patient a vulnerable prey of microbes. Intestine microbes remain the main source of infection and with gut mucositis, risk increases significantly (22). This study noted four febrile neutropenic cases having growth in blood culture, out of which three were gram-negative organism. Spore of aspergillus is common in dust and environment where dust exposure is common, risk of aspergillus remains high. Central Research Institute (CRI) facility is located at outskirt area and patient coming to this center often travel variable geographical terrains. Aspergillosis risk further increases with on-going constructions in state for government proposed highways. This study noted three cases of pulmonary aspergillosis during induction. As aspergillosis was detected only by CT chest, some cases might have been missed. Serological detection has better detection sensitivity.

Paediatric oncology facility at this center is facing resource constrains in form of high nurse to patient ratio, congested wards and lack of proper training of nurses and residents in paediatric oncology. However, improvement guided steps has been initiated. Arrangements have been made for isolated ward and non rotational nursing staffs. Supportive care has been improving due to:

1. Regular nurses training for complications, febrile neutropenia, cannulation, line handling and oral and anal care has been started. Twining with other tertiary cancer centre has been done to enhance their skills.
2. Concept of standing orders and procurement of medicines in anticipation has been implemented to delay the time gap of fever and antibiotics.
3. Step up facilities- General ward has segregated beds for neutropenic cases. There are two step-up units available, one a high dependency unit and other as intensive care unit.

Facility of graded step up has helped in escalation of supportive care. Impact of dose reduction and deferred schedule of induction is not known. Studies about asparaginase activity in plasma have noted better result with steady level of L-Asparaginase (23),(24). It seems reasonable to consider that deviations will cause sub-optimal leukaemia clearance, extent not known as of now. However, balancing the mortality due to sepsis or other life threatening condition, available support system and chemotherapy schedule will remain individual consultant decision and study is needed to document all deviations and effects. Induction response in term of bone marrow remission was not associated with treatment deviations. But, it is noteworthy that all cases received minimum 2 doses of anthracyclins, 3 doses of vincristine and 6 doses of L-asparaginase along with steroid. How much reduction will actually cause induction failure is hard to conclude based on small number of cases. This study noted a high induction failure rate as compared to published Indian literature (20). Reason might be related to inclusion of eight relapse cases, out of which three failed to achieve complete remission. Absence of cytogenetics and molecular tests is a hindrance to explore the reason of induction failure further.

Hyperglycaemia and other non sepsis side effects of induction chemotherapy have been noted rarely (25),(26). Hyperglycaemia is attributed to high dose of steroid as well as L-Asparaginase. Insulin therapy should be used to keep blood sugar in check. This study also noted four cases with hyperglycaemia, steroid induced, occurred during first week of steroid. As first week of therapy was not having L-Asparaginase, steroid was considered as causation. Two cases developed seizure during induction and both were having no CNS disease at onset. Causation of seizure in CNS disease free induction cases are variable and it might be due to posterior reversible encephalopathy syndrome, thrombosis, and bleeding or methotrexate toxicity by intrathecal methotrexate administration (27),(28),(29). The concentration of intrathecal methotrexate was 5 mg/mL which was higher than recommended concentration by paediatric ALL protocols. L-Asparaginase related CNS events were less likely as MRI were normal in all cases. Transient methotrexate toxicity was considered and next dose on-ward; methotrexate was administered in more dilution (in 10 mL sterile water).

Limitation(s)

Study has limitations of inadequate baseline information regarding biochemical, and molecular parameters. Karyotyping was not done on any of patient and mutation data were also very limited. Logistic limitations were the cause. Effect of poor risk features like complex karyotype, hypoploidy, Philadelphia or MLL positivity on induction response and tolerance is not known. Sepsis workup was more focused on bacterial culture and no viral culture was attempted even in cases with no growth in bacterial culture. Baseline nutritional assessment was limited to height and weight and no details of other nutritional marker were present in evaluated files. It could have bearing on tolerance of therapy.

Conclusion

This study depicts feasibility of administrating high intensity induction chemotherapy in ALL cases even in limited infrastructure setting. Despite logistic limitations and lack of isolation for all cases, a good result and acceptance of induction is feasible in paediatric oncology unit at peripheral area.

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DOI and Others

DOI: 10.7860/JCDR/2022/51295.16087

Date of Submission: Jul 08, 2021
Date of Peer Review: Oct 14, 2021
Date of Acceptance: Dec 03, 2021
Date of Publishing: Mar 01, 2022

AUTHOR DECLARATION:
• Financial or Other Competing Interests: None
• Was Ethics Committee Approval obtained for this study? Yes
• Was informed consent obtained from the subjects involved in the study? NA
• For any images presented appropriate consent has been obtained from the subjects. NA

PLAGIARISM CHECKING METHODS:
• Plagiarism X-checker: Aug 10, 2021
• Manual Googling: Nov 19, 2021
• iThenticate Software: Dec 01, 2021 (2%)

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