Deepesh Lad

Regulatory T-cells in B-cell chronic lymphocytic leukemia: their role in disease progression and autoimmune cytopenias

Abstract Regulatory T-cells (Tregs) have been shown to be important for the balance of autoimmunity and oncogenesis. Tregs have a protective role in autoimmune diseases and conversely promote oncogenesis. Chronic lymphocytic leukemia (CLL) is unique in being at the cross-roads of oncogenesis and autoimmunity. We studied Tregs, defined as CD4+CD25highCD127lowFOXP3+, in 32 treatment-naive patients with CLL. Our study shows that patients with CLL had a higher absolute Treg count than the control group (p < 0.001). A progressive increase of Tregs was noted in advanced stages of the disease (p < 0.001). The increase in absolute Treg count is more significant than the increase in percentage Tregs. The absolute Treg count appears to be more important in disease pathogenesis. The absolute Treg count was significantly higher in those patients having autoimmune cytopenias. There was an inverse correlation between lymphocyte doubling time and absolute Treg count (p = 0.03). The absolute Treg count may be used as a prognostic marker in CLL.

Regulatory T-cell and T-helper 17 balance in chronic lymphocytic leukemia progression and autoimmune cytopenias

The reasons for progression and autoimmune cytopenias (AIC) in chronic lymphocytic leukemia (CLL) are not entirely clear, with previous studies suggesting a role for regulatory T-cells (Treg). In this study we prospectively studied Treg (CD3 + CD4+ CD25highCD127low), interleukin-10 (IL-10) producing Treg and T-helper 17 (Th17) (CD3 + CD4+ IL-17+) cells in 40 treatment-naive patients with CLL. The percentage of Th17 and not Treg cells was significantly higher in the AIC cohort than in those without AIC (p < 0.0001). The Treg:Th17 ratio was skewed in favor of Th17 in the AIC cohort (p = 0.02). Th17 cells are responsible for AIC of CLL. Analysis of lymph-node aspirates showed that the percentage of Treg and IL-10 expression in Treg and not Th17 was significantly higher than in peripheral blood (p < 0.01). Treg cells play a major role in the microenvironment where disease progression occurs. This shows the importance of maintaining the Treg:Th17 equilibrium, for imbalance leads to CLL progression or AIC.

Regulatory T-cells drive immune dysfunction in CLL

Deepesh Lad, Romy Hoeppli, Qing Huang, Rosa Garcia, Lixin Xu, Cynthia Toze, Raewyn Broady and Megan Levings Department of Internal Medicine, Post Graduate Institute of Medical Education and Research, Chandigarh, India; British Columbia Children’s Hospital Research Institute, Vancouver, Canada; Leukemia/BMT Program of BC, British Columbia Cancer Agency, University of British Columbia, Vancouver, Canada

Cost of Treatment of Multiple Myeloma in a Public Sector Tertiary Care Hospital of North India

Multiple myeloma (MM) is a neoplastic disorder, which accounts for 13% of all hematological malignancies globally. While, conventional chemotherapy used to be the mainstay treatment for the disease, the landscape of treatment witnessed a paradigm shift with the introduction of high-dose chemotherapy and autologous stem cell transplant (ASCT). In this paper, we present a cost analysis of various services provided to multiple myeloma patients, using either of the two modalities of treatments i.e. conventional chemotherapy or ASCT. Bottom-up costing methodology was used to collect data on all health system resources, i.e. capital or recurrent, which were used to provide various services to MM patients. Capital costs were annualized for their useful life using a discount rate of 5%. Out of pocket expenditure on treatment was also ascertained. Cost was assessed for various services, including outpatient consultation, bed day hospitalization in general ward, high dependency unit intensive care setting and bone marrow transplant unit. Unit costs were calculated from both health system and patient perspective. The overall cost per patient for ASCT (including high dose chemotherapy) and conventional chemotherapy from societal perspective was INR 395,527 (USD 6085) and INR 62,785 (USD 966) respectively. Estimates on cost from our study could be used for planning health services, and evaluating cost effectiveness of different modalities of care for multiple myeloma.

Real world experience with “generic” pomalidomide in relapsed refractory multiple myeloma

With keen interest, we read the experience shared by Scott et al. regarding the efficacy of pomalidomide in an Australian cohort of 151 patients with relapsed/refractory multiple myeloma (RRMM) treated in ‘real-world’ settings between 2010 and 2015 [1]. The authors reported an overall response rate (ORR) of 32% with a median progression-free survival (PFS) of 3.4 months and overall survival (OS) of 7.5 months. However, we would like to add that high cost and unavailability of newer anti-myeloma drugs have conventionally conferred a poor prognosis upon RRMM patients in resource-constrained settings [2,3]. Generic preparations of original formulations are commonly used in developing countries because of their low cost [4]. We would like to complement the observations of Scott et al. by sharing our experience of generic pomalidomide in RRMM since May 2017 when it became available in India. RRMM patients generally have a poor outcome because of poor performance status, cumulative burden of complications from previous therapies, and advanced disease per se [5]. Prospective randomized trials and realworld studies from developed countries have clearly demonstrated the role of pomalidomide in relapsed/ refractory myeloma [6–9]. We concur with the authors’ view that introduction of a therapy into routine clinical practice may or may not reflect the results of prospective randomized trials. Population-based studies are indispensable especially when they describe the patients who otherwise might not find representation in clinical trials. However, there are additional attributes which are unique to the developing world. Majority of the patients can’t afford the original (imported) drug formulations. Hence, it is reasonable to explore the efficacy and tolerability of generic formulations as an alternative in such patients who would otherwise be candidates for palliative care. Generic pomalidomide has been available in India since May 2017 (Pomalid launched by Natco Pharma Ltd., India). Although the same company continues to be its sole manufacturer in India, other indigenous companies have also started marketing generic pomalidomide under different brand names [Pomalong (Cipla Inc., India), Pomyelo (Intas pharmaceuticals Ltd., India), Pomahope (Abbott India Ltd., India), Pomired (Dr. Reddy’s Laboratories Ltd., India)] [10]. We used generic pomalidomide for a total of 24 RRMM patients from May 2017 to May 2018 at our institute. The choice of generic brand was decided by the patients. The median age was 63.5 years (range 3876). Ten patients had age >65 years and GFR less than 60ml/min was found in 9 patients. The patients had received a median of 4 prior therapies (range 2–7) and the median time from diagnosis to initiation of pomalidomide was 4.2 years (range 1–11.6); and, 13/24 patients (54.1%) had ECOG performance status 2. Fourteen patients (58.3%) had ISS stage 3 disease and 8 were prior autologous HSCT recipients. Seventy-five percent of patients (18 out of 24) were refractory to bortezomib as well as lenalidomide. Low platelet count (<75 10/L) before starting pomalidomide was found in 4/24 patients (16.7%). Results of FISH analysis were available for only 4 patients (1 patient had 17p deletion and 3 patients had 13q deletion). Majority of the patients (17/ 24) received pomalidomide plus dexamethasone (doublet therapy) and remaining 7 patients received a third drug [carfilzomib [3], bortezomib [2], or melphalan [2]] additionally (triplet therapy) since the beginning. Majority of the patients (16/24) received pomalidomide starting dose of 4mg daily for 21/28 days. The patients received a median of 6 cycles (range <1– 12). Five patients (20.8%) died during the study period, and 3 patients were lost to follow up. Three died because of febrile neutropenia with pneumonia before they could complete first cycle; one patient had progressive disease; and one patient with underlying coronary artery disease, who had discontinued pomalidomide after 2 weeks due to grade 4 thrombocytopenia, developed sudden cardiac arrest after receiving the first dose of daratumumab [11]. Grade 3 cytopenias were the most common serious adverse events (Table 1). Five patients (20.8%) required pomalidomide dose reduction. The overall response rate [defined as partial response (PR) or better] was 50%.

Long-term mucocutaneous adverse effects of imatinib in Indian chronic myeloid leukemia patients

Short‐term mucocutaneous adverse effects are well documented with imatinib. However, studies on long‐term adverse effects and in the ethnic population are lacking.

Pyrexia, Lung nodules, Granulomas: Pulmonary Lymphomatoid Granulomatosis.

The differential diagnosis of pyrexia, lung nodules and granulomas includes tuberculosis, vasculitis and rarely a malignancy. In countries where tuberculosis or histoplasmosis is endemic, these are the first consideration and often ruled out by microbiological investigations. Vasculitis like granulomatosis with polyangitis (Wegener’s granulomatosis), Churg strauss syndrome and sarcoidosis, which are the second consideration, are ruled out by serological investigations. Confirmation of malignancy merits histopathology. This case highlights how a rare diagnosis of pulmonary lymphomatoid granulomatosis was reached after an open lung biopsy. The following case also describes the natural history of this rare disease as it showed transient spontaneous remission but ultimately required therapy.

Chronic lymphocytic leukemia: inception to cure: are we there?

There have been remarkable advances in our understanding of the biology and therapeutics of chronic lymphocytic leukemia. B cell receptor signaling and micro-environment in CLL biology have been the most modern areas of research. In CLL therapeutics, we have come a long way from alkylating agents to chemo-immunotherapy. Despite this there remain significant lacunae in the disease biology that has hindered our quest to achieve the ultimate in CLL: Cure. This review aims to summarize the past, present and future in the biology and treatment of CLL.

Variation in Adherence Measures to Imatinib Therapy

Purpose The introduction of tyrosine kinase inhibitors has transformed the care of patients with chronic myeloid leukemia, with survival approaching that of healthy individuals. Current-day challenges in chronic myeloid leukemia care include adherence to tyrosine kinase inhibitor therapy. We studied adherence from resource-constrained settings and tried to analyze the factors responsible for nonadherence in these individuals. We also correlated adherence to current molecular status. Patients and Methods This was a single-center, cross-sectional, observational study from north India. It consisted of a questionnaire-based survey in which a one-to-one interview technique was used by trained nursing staff administering the Modified Morisky Adherence Scale (MMAS-9) questionnaire. Adherence was also measured on the basis of physician’s assessment. JMP 13.0.0 was used for statistical analysis. Results A total of 333 patients with a median age of 42 years were included in the study. The median BCR-ABL/ABL ratio (IS) was 0.175 (0.0 to 98.0). The mean MMAS-9 score was 11 ± 2. Adherence was seen in 54.95% on the basis of MMAS-9, whereas physician’s assessment reported adherence in 90.39% of patients. Using the χ2 test, no relationship was found between the two assessment techniques. There was a significant relationship between major molecular response status and adherence by physician’s assessment and MMAS-9 (P < .001). Bivariate analysis by logistic fit showed a good relation between the MMAS-9 score and the BCR-ABL/ABL ratio (IS), χ2 (1,220) = 135.45 (P < .001). On multivariate analysis, enrolment in the Novartis Oncology Access program (a patient assistance program) was significantly associated with adherence (P = .012). Conclusion This study highlights the lack of adherence in real-world settings and the various factors responsible. Such studies are important from a public health services perspective in various settings around the world because they may lead to corrective action being taken at the institutional level.

Necrotising Ulcerative Gingivitis: A Rare Manifestation of Pseudomonas Infection

Management of intra-oral infections in immunocompromised patients can be potentially challenging and deceiving [1]. Opportunistic pathogens including bacteria, viruses and fungi are the major cause of necrotising intra-oral infections in immunocompromised patients [2]. Overlapping clinical features produced by various infective agents acting alone or in combination may challenge clinical judgement at bedside. We present a case of acute myeloid leukemia (AML) who developed Pseudomonas aeruginosa related necrotising ulcerative gingivitis. A 19-year-old girl, known case of AML, post allogenic hematopoietic stem cell transplant (HSCT) with graft failure was planned for second allogenic-HSCT. She presented on Day ? 128 with fever and exquisite gingival pain in right maxillary pre-molar region of 1-day duration. She also complained difficulty in opening the mouth and pain on chewing food. Neither she had any such complaint in the past nor did she develop any such symptoms during high dose chemotherapy and HSCT. At presentation, she had fever (101.2 F), tachycardia (112 beats/min) and tachypnea (26 breaths/min); her blood pressure was normal (114/72 mmHg). On oral cavity examination, generalised gingival erythema and edema was present (Fig. 1a) which was most conspicuous in right lateral maxillary region. A necrotic gingival plaque measuring 10 mm 9 10 mm was present alongside the right upper premolar tooth (Fig. 1b). Investigations revealed Hemoglobin 94 g/L, total leucocyte count 0.3 9 10/L, absolute neutrophil count 0.1 9 10/L and platelet count 64 9 10/L. Peripheral smear was unremarkable for blasts/atypical cells. A panoramic dental radiograph was normal. Blood and urine cultures were sterile. On bacterial culture, swab from necrotic gingival plaque revealed growth of Pseudomonas aeruginosa on day 3 of admission. Fungal smear and culture were unremarkable. Inj. Cefoperazone ? sulbactam (2 g IV TDS) and Inj. Vancomycin (1 g IV BD) were empirically started with supportive measures (Fentanyl transdermal patch and morphine IV boluses for pain relief; 1% clotrimazole mouth paint and chlorhexidine mouth rinses). On day 3 of admission, in view of high grade fever and persistent pain, gram negative cover was escalated from Cefoperazone ? sulbactam to Inj. Cefepime (2 g IV TDS) and Inj. Amikacin (750 mg IV OD). Vancomycin was stopped after sterile blood culture report. She became afebrile by day 5 of admission. Gingival pain subsided completely by day 9. Gingival swab culture repeated on day 5 of admission was sterile. By day 17 of admission, necrotic gingival tissue got completely dislodged by underlying healthy granulation tissue (Fig. 1c, d). Cefepime and Amikacin were administered for a total of 3 weeks. Intra-oral infections in immunocompromised patients result in substantial morbidity and mortality. These infections frequently lead to substantial pain and impaired feeding which in turn compromise tolerance and compliance to treatment especially in patients with haematological malignancies. It is well recognised that soft tissue infections in neutropenic patients have frequent association with little or no pus formation and favourably respond to prompt antimicrobial therapy. Clinical & Pankaj Malhotra hematpgi@gmail.com