Primary oral histoplasmosis in an immunocompetent host masquerading as malignancy.

Histoplasma capsulatum is known to cause deep mycotic infections, the primary site being pulmonary, and may disseminate in immunosuppressed patients. Oral presentation is usually a part of disseminated disease however may rarely occur as an isolated event. Extensive literature search has shown that only 17 cases of primary oral histoplasmosis in immunocompetent hosts have been reported from India to date. We hereby report a rare case of primary oral histoplasmosis in a middle-aged, non-diabetic, and HIV-negative patient masquerading as malignancy.

Comparison of Outcomes of Donor Lymphocyte Infusions With or Without Lenalidomide in Patients with Hematological Malignancies Post Allogeneic HSCT.

Outcomes with DLI alone for post-transplant relapsed hematological malignancies are poor especially in acute leukemias. Addition of immunomodulatory drugs to DLI may augment GVL effect. Use of lenalidomide with DLI to augment GVL has not been previously reported. This retrospective analysis was to compare the outcomes of DLI with or without lenalidomide. All consecutive patients who received DLI from 01/2010 through 01/2020 were included. DLIs were given without any immunosuppression. Lenalidomide, when used, was given continuously, starting with 1st or subsequent DLI. Patients who received lenalidomide were compared with those who did not. Event (hematological relapse or death) free survival (EFS) and overall survival (OS) were calculated from 1st DLI. Primary objective was to compare OS. Secondary objectives were EFS, CR rates, acute GVHD, lenalidomide toxicities and DLI related mortality (TRM). Total 61 patients received DLI-43 without and 18 with lenalidomide; all outcomes in the 2 groups were similar. There were 26 patients with HLA-A*24 and/or HLA-B*40. Among these, trend towards improvement in OS (median OS not reached vs. 8 months, 4 year OS was 62% vs. 32%, p = 0.1) and EFS (median 9 vs. 1 month, 4 year EFS 50% vs. 22%, p = 0.1) was seen with lenalidomide. Overall, there was no improvement in outcomes by adding lenalidomide to DLI. However, among patients with HLA*24 or B*40, there was a trend to improved survival with lenalidomide. Use of lenalidomide to augment the GVL effect of DLI warrants further exploration.

Consensus guidelines and recommendations for infection prevention in multiple myeloma: a report from the International Myeloma Working Group.

Infection remains the leading cause of morbidity and mortality in patients with multiple myeloma because of the cumulative effect of disease, treatment, and host-related factors. Given that infectious risk is cumulative through the course of the disease, preventing infections is paramount. Optimal preventive strategies include vaccination against common pathogens, antimicrobial prophylaxis, infection control measures, and immunoglobulin replacement in a small subset of patients; however, there are no universally accepted guidelines for infection prevention. This Review provides a consensus statement from a panel of 36 experts with global representation, which was convened by The International Myeloma Society to review existing literature and current guidelines, address issues associated with the risk of infection and prevention of infectious complications in multiple myeloma in the context of emerging therapies, and offer recommendations for preventing these complications.

Current status of human papillomavirus vaccination in India's cervical cancer prevention efforts.

Efforts are being made to scale up human papillomavirus (HPV) vaccination for adolescent girls in India. Bivalent and quadrivalent HPV vaccines were licensed in the country in 2008, and a nonavalent vaccine was licensed in 2018. Demonstration projects initiated in Andhra Pradesh and Gujarat in 2009 introduced HPV vaccination in public health services in India. Following a few deaths in these projects, although subsequently deemed unrelated to vaccination, HPV vaccination in research projects was suspended. This suspension by default resulted in some participants in a trial evaluating two versus three doses receiving only one dose. Since 2016, the successful introduction of HPV vaccination in immunisation programmes in Punjab and Sikkim (with high coverage and safety), government-sponsored opportunistic vaccination in Delhi, prospects of a single dose providing protection, and future availability of an affordable Indian vaccine shows promise for future widespread implementation and evaluation of HPV vaccination in India.

Summary of the Highlights of 2019 ASTCT Meeting by iNDUS BMT Group at Chennai, India.

This article summarises the main highlights of the abstracts presented at the annual meeting of American Society of Transplantation and Cellular Therapy (ASTCT). The highlights of ASTCT meeting were organised by iNDUS BMT group in Chennai, India. The purpose of the highlight meeting was to educate the students about the latest research in the field of hematopoietic stem cell transplantation and its applicability for the developing country perspective.

Choosing Wisely India: ten low-value or harmful practices that should be avoided in cancer care.

The Choosing Wisely India campaign was an initiative that was established to identify low-value or potentially harmful practices that are relevant to the Indian cancer health-care system. We undertook a multidisciplinary framework-driven consensus process to identify a list of low-value or harmful cancer practices that are frequently undertaken in India. A task force convened by the National Cancer Grid of India included Indian representatives from surgical, medical, and radiation oncology. Each specialty had representation from the private and public sectors. The task force included two representatives from national patient and patient advocacy groups. Of the ten practices that were identified, four are completely new recommendations, and six are revisions or adaptations from previous Choosing Wisely USA and Canada lists. Recommendations in the final list pertain to diagnosis and treatment (five practices), palliative care (two practices), imaging (two practices), and system-level delivery of care (two practices). Implementation of this list and reporting of concordance with its recommendations will facilitate the delivery of high-quality, value-based cancer care in India.

Dasatinib in Pediatric Patients With Chronic Myeloid Leukemia in Chronic Phase: Results From a Phase II Trial.

Purpose Safe, effective treatments are needed for pediatric patients with chronic myeloid leukemia in chronic phase (CML-CP). Dasatinib is approved for treatment of adults and children with CML-CP. A phase I study determined suitable dosing for children with Philadelphia chromosome-positive (Ph+) leukemias. Methods CA180-226/NCT00777036 is a phase II, open-label, nonrandomized prospective trial of patients < 18 years of age receiving dasatinib. There are three cohorts: (1) imatinib-resistant/intolerant CML-CP, (2) imatinib-resistant/intolerant CML in accelerated/blast phase or Ph+ acute lymphoblastic leukemia (n = 17), and (3) newly diagnosed CML-CP treated with tablets or powder for oral suspension. Major cytogenetic response > 30% for imatinib-resistant/intolerant patients and complete cytogenetic response (CCyR) > 55% for newly diagnosed patients were of clinical interest. Results Of 113 patients with CML-CP, 14 (48%) who were imatinib-resistant/intolerant and 61 (73%) who were newly diagnosed remained on treatment at time of analysis. Major cytogenetic response > 30% was reached by 3 months in the imatinib-resistant/intolerant group and CCyR > 55% was reached by 6 months in the newly diagnosed CML-CP group. CCyR and major molecular response by 12 months, respectively, were 76% and 41% in the imatinib-resistant/intolerant group and 92% and 52% in newly diagnosed CML-CP group. Progression-free survival by 48 months was 78% and 93% in the imatinib-resistant/intolerant and newly diagnosed CML-CP groups, respectively. No dasatinib-related pleural or pericardial effusion, pulmonary edema, or pulmonary arterial hypertension were reported. Bone growth and development events were reported in 4% of patients. Conclusion In the largest prospective trial to date in children with CML-CP, we demonstrate that dasatinib is a safe, effective treatment of pediatric CML-CP. Target responses to first- or second-line dasatinib were met early, and deep molecular responses were observed. Safety of dasatinib in pediatric patients was similar to that observed in adults; however, no cases of pleural or pericardial effusion or pulmonary arterial hypertension were reported.

The Cure of Chronic Myeloid Leukemia: Are We There Yet?

PURPOSE OF REVIEW: A large number of chronic myeloid leukemia (CML) patients receiving tyrosine kinase inhibitors (TKIs) can now enjoy a deep molecular control of the disease and the life span could be approaching that of normal population. The purpose of the review is to evaluate current evidence and if we can talk of a cure. RECENT FINDINGS: The revolution in the treatment of CML was apparent since the exquisite efficacy of imatinib mesylate, a tyrosine kinase inhibitor, was proven and received approval for newly diagnosed cases in 2001. Subsequent development of second-generation TKIs, nilotinib and dasatinib, has increased our armamentarium. These TKIs, because of their safety and efficacy, are now offered as first-line therapy, thus relegating use of allogeneic transplant to the second line or beyond. It has also been possible to stop TKIs in selected subsets in whom leukemia burden became undetectable and ~ 40% of them remain drug-free for a number of years-treatment-free remission (TFR). Nevertheless, much work needs to be done to eradicate leukemia stem cells as current TKIs appear unable to eradicate leukemia stem cells (LSC). Effective treatment of more advanced phase CML remains elusive. Further efforts to develop newer molecules targeting BCR-ABL and beyond must be continued. Although TKIs have revolutionized treatment of chronic phase CML, longer follow-up is necessary to realize their curative potential. Equally important is to explore newer targets and development of more potent small molecules for eradication of leukemia clone in all patients.

Developments in the Field of Myeloma in the Last Decade.

The plasma cell disorders constitute a heterogeneous group of diseases. Accumulation of knowledge in the field has helped us to understand these diseases better, stage them more precisely, prognosticate more accurately and manage them more effectively. The paradigm shift in the management of multiple myeloma over the last one-and-a-half decades shows no signs of slackening. In addition to novel therapies, better supportive care and high-dose melphalan with autologous hematopoietic stem cells have contributed to this positive outcome. This review summarizes the developments in this sphere in the recent past.

Consensus in the Management of Multiple Myeloma in India at Myeloma State of the Art 2016 Conference.

The science of multiple myeloma (MM) and related plasma cell disorders is rapidly evolving with increased understanding of the disease biology and recent approval of the newer drugs widening the therapeutic armamentarium. Despite multiple international guidelines regarding the management of this disease, the practice of managing MM is not uniform amongst Indian physicians. There are challenges in management which are unique to the Indian patients. This review discusses these challenges and the consensus of the nation-wide experts in dealing with the same. We also briefly highlighted the perspective of international experts as discussed in the Myeloma State of the Art conference held in September 2016 at PGI, Chandigarh. An Indian Myeloma Academic Groupe (IMAGe) group was formed to strengthen the research, create awareness about myeloma and related disorders and form consensus guidelines/ recommendations that can be adapted to the Indian Scenario.

LACE versus BEAM conditioning in relapsed and refractory lymphoma transplant: retrospective multicenter analysis of toxicity and efficacy.

We compared the lomustine, cytarabine, cyclophosphamide and etoposide (LACE) and BCNU, etoposide, cytarabine, melphalan (BEAM) conditioning regimens for toxicity, engraftment kinetics, and efficacy in 139 patients undergoing autologous hematopoietic stem cell transplant for primary refractory or relapsed lymphoma. Ninety-two patients with Hodgkin lymphoma and 47 with non-Hodgkin lymphoma were enrolled. Seventy-five patients received LACE while 64 received BEAM. The incidence of grade 3-4 oral mucositis (9 vs 38%; P < 0.001) and parenteral nutrition requirement (32 vs 69%; P < 0.001) were significantly lower in the LACE cohort. The median days to myeloid (10 vs 11; P = 0.007) and platelet engraftment (13 vs 15; P = 0.026) were shorter for the LACE cohort. Transplant-related mortality in the LACE group was 9% compared to 13% in patients treated with BEAM (P = NS). The probability of overall survival (OS) and progression-free survival (PFS) at 5 years for entire cohort was 46 and 41%, respectively. Probability of OS (LACE 46% vs BEAM 47%; P = NS) and PFS (LACE 37% vs BEAM 47%; P = NS) at 5 years was comparable between two groups. We conclude that LACE has better toxicity profile compared to BEAM and results in similar long-term survival in primary refractory or relapsed lymphoma transplant.

Efficacy and safety of radotinib in chronic phase chronic myeloid leukemia patients with resistance or intolerance to BCR-ABL1 tyrosine kinase inhibitors.

Radotinib (IY5511HCL), a novel and selective BCR-ABL1 tyrosine kinase inhibitor, has shown pre-clinical and phase I activity and safety in chronic myeloid leukemia. This phase II study investigated the efficacy and safety of radotinib in Philadelphia chromosome-positive chronic phase-chronic myeloid leukemia patients with resistance and/or intolerance to BCR-ABL1 tyrosine kinase inhibitors. Patients received radotinib 400 mg twice daily for 12 cycles based on results from the phase I trial. The primary end point was rate of major cytogenetic response by 12 months. A total of 77 patients were enrolled. Major cytogenetic response was achieved in 50 (65%; cumulative 75%) patients, including 36 (47%) patients with complete cytogenetic response by 12 months. Median time to major cytogenetic response and complete cytogenetic response were 85 days and 256 days, respectively. Major cytogenetic response and complete cytogenetic response rates were similar between imatinib-resistant and imatinib-intolerant patients, but were higher in patients without BCR-ABL1 mutations. Overall and progression-free survival rates at 12 months were 96.1% and 86.3%, respectively. All newly-occurring or worsening grade 3/4 hematologic abnormalities included thrombocytopenia (24.7%) and anemia (5.2%); grade 3/4 drug-related non-hematologic adverse events included fatigue (3.9%), asthenia (3.9%), and nausea (2.6%). The most common biochemistry abnormality was hyperbilirubinemia (grade 3/4 23.4%), and 12 of 18 cases were managed with dose modification. Study findings suggest radotinib is effective and well tolerated in chronic phase-chronic myeloid leukemia patients with resistance and/or intolerance to BCR-ABL1 tyrosine kinase inhibitors and may represent a promising alternative for these patients. (clinicaltrials.gov identifier: 01602952).

Analysis of ABL kinase domain mutations conferring resistance to tyrosine kinase inhibitors in chronic myeloid leukemia cases from India.

BACKGROUND: The current study was undertaken to find out the frequency and distribution of ABL kinase domain (KD) mutations showing resistance to tyrosine kinase inhibitors (TKI) in CML patients from India. METHODS: A total of 24 TKI resistant CML patients were screened for ABL KD mutation by semi-nested reverse transcription PCR and sequencing. The expression of BCR-ABL transcripts was quantified by Real Time Taqman assay. RESULTS: Sixteen different point mutations were detected in 14 (58.3%) of 24 TKI resistant patients. Five out of the 16 mutations were located at the four hot spots of ABL kinase domain: one at the P-loop (Q252H), one at the imatinib binding site (T315I), two at the catalytic domain (M351, Y353F) and one at the active A loop (H396P). The three mutations, viz. M244V, T315I and A380V, were the most frequent mutations and accounted for 40.9% of all resistance associated mutations. CONCLUSIONS: In the present study, the presence of ABL KD mutations was found to be a major cause of drug resistance. The T315I mutation was found to be resistant to second generation drugs such as dasatinib. The study reinforces the need for new therapeutic options which can target this mutation.

Clinical profile of dasatinib in Asian and non-Asian patients with chronic myeloid leukemia.

Resistance and intolerance to imatinib are of particular clinical relevance to Asian patients because of their lower body surface area. Dasatinib is 325-fold more potent than imatinib in inhibiting BCR-ABL in vitro and is indicated for the treatment of chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia resistant or intolerant to imatinib. Data from a series of phase I/II research trials were analyzed to compare the efficacy, safety and pharmacokinetic profile of dasatinib 70 mg twice daily in Asian and non-Asian patients. Results from 55 Asian and 615 non-Asian patients demonstrated that the efficacy and safety of dasatinib was comparable. Dasatinib was well tolerated, with no observed toxicities exclusive to Asian patients. A higher incidence of adverse events and lower rate of response observed among Asian patients with myeloid blast phase CML reflected the aggressive nature of the disease. Analyses of noncompartmental pharmacokinetics (5 Asian and 49 non-Asian patients) and population pharmacokinetics (17 Asian and 382 non-Asian patients) were also comparable. The efficacy, safety and pharmacokinetic profile of dasatinib 70 mg twice daily is similar in Asian and non-Asian patients with CML. Dasatinib is therefore an important therapeutic option for this patient population.

Chronic myeloid leukemia in Asia.

Chronic myeloid leukemia (CML) in Asia has an incidence rather lower than in Western countries yet tends to afflict a younger population. As in the West, imatinib mesylate (IM, Glivec) has supplanted busulphan, hydroxyurea and interferon-alpha as first-line treatment. Its use has resulted in a dramatic decline in the number of hematopoietic stem cell transplantations (HSCT) performed. Although it is expensive, IM induces a complete cytogenetic response in 60-90% of newly diagnosed patients, and up to 10% for those in blastic phase. The standard dose of 400 mg is well tolerated by most patients, although adverse events have been observed, including drug-induced cytopenia. Through the Glivec International Patient Assistance Program, the majority of CML patients has access to IM and can expect prolonged survival, even in the absence of HSCT. However, just as in Western countries, resistance to imatinib has emerged in Asian countries. They will require the novel tyrosine kinase inhibitors (dasatinib, nilotinib) becoming available through either clinical trials or market approval. This review examines the available data on CML in China, Hong Kong, India, the Philippines, Singapore, South Korea, Taiwan and Thailand.

Emergence of an unrelated highly aberrant clone in an AML patient at relapse four months after peripheral blood stem cell transplantation.

We report a case of AML-M1 with 5q aberration at diagnosis. The patient was treated with high-dose chemotherapy (HDCT). After remission induction, he received allogenic peripheral blood stem cell transplantation (PBSCT) from an HLA-match donor brother. The successive follow-up conventional cytogenetics investigations in remission after HDCT and PBSCT revealed cytogenetic remission. The most interesting observation in this case is that relapsed marrow revealed the emergence of an entirely new, highly aberrant, unrelated clone with unusual translocations t(6;17)(p23;p11.2),+8,der(8)dup inv(8)(q23qter), t(10;19)(q26;q13.3) 4½ months after PBSCT. Our findings suggest the possibility of a mutagenic effect of HDCT and myeloablative intense chemotherapy before PBSCT that could have induced a genetic lesion in the recipient's genetically unstable stem cells in an environment of immunosuppression. The highly complex nature of the clone and the rapid clonal evolution indicates the possibility of selective pressure with proliferative advantage.

Safety and efficacy of an indigenous recombinant interferon-alpha-2b in patients with chronic myelogenous leukaemia: results of a multicentre trial from India.

BACKGROUND: Compared to hydroxyurea, treatment with interferon-alpha (IFN-alpha) is known to prolong survival in patients with chronic phase of chronic myelogenous leukaemia (CML) and was considered as first-line therapy till recently. We conducted a multicentre trial using an indigenous recombinant IFN-alpha-2b to evaluate its efficacy and toxicity in chronic phase CML. METHODS: Between September 2000 and August 2001, patients with chronic phase CML were recruited within 8 weeks of diagnosis at 7 centres in India. The study was approved by the Ethics Committee of each participating Institute and Informed, written consent was obtained from all patients. All patients were given the study drug in a dose of 5 million units daily subcutaneously. Response and survival analyses were done with intent-to-treat analysis. RESULTS: One hundred and fourteen patients (75 men and 39 women) were included in the study. Their ages ranged from 18 to 62 years (median 37 years). Fifty-seven per cent of patients had a haematological response; complete response in 31.6% and partial response in 25.4%. The median time to achieve complete haematological response was 6 months (range 3-12 months). Cytogenetic response was seen in 39.4% of patients; complete in 1.8%, partial in 28% and minimal in 9.6%. The median time to achieve partial and complete cytogenetic response was 6 and 12 months, respectively. Nineteen patients had progression (blast crisis n=15, accelerated phase n=4) while on treatment. Two patients refused further treatment after the initial 4 weeks due to IFN-a toxicity, mainly bone pains and fever. The major toxic effects of treatment were fever (78%), fatigue (25.4%) and myalgia (52%). No patient died of toxicity. Currently, 95 patients are alive, 91 in the chronic phase and 4 in the accelerated phase. Four patients were lost to follow up and all 15 patients with blast crisis died of progressive disease at a median Interval of 6.5 months (range 1-15 months). The Kaplan-Meier probability of survival at 36 months was 76%. CONCLUSION: This study confirms the efficacy of the indigenous recombinant IFN-alpha-2b in chronic phase CML. The drug has a toxicity profile similar to that of other preparations.