Chronic activation of B-cell receptor (BCR) signaling via Bruton tyrosine kinase (BTK) is largely considered to be one of the primary mechanisms driving disease progression in B–Cell lymphomas. Although the BTK-targeting agent ibrutinib has shown promising clinical responses, the presence of primary or acquired resistance is common and often leads to dismal clinical outcomes. Resistance to ibrutinib therapy can be mediated through genetic mutations, up-regulation of alternative survival pathways, or other unknown factors that are not targeted by ibrutinib therapy. Understanding the key determinants, including tumor heterogeneity and rewiring of the molecular networks during disease progression and therapy, will assist exploration of alternative therapeutic strategies. Towards the goal of overcoming ibrutinib resistance, multiple alternative therapeutic agents, including second- and third-generation BTK inhibitors and immunomodulatory drugs, have been discovered and tested in both pre-clinical and clinical settings. Although these agents have shown high response rates alone or in combination with ibrutinib in ibrutinib-treated relapsed/refractory(R/R) lymphoma patients, overall clinical outcomes have not been satisfactory due to drug-associated toxicities and incomplete remission. In this review, we discuss the mechanisms of ibrutinib resistance development in B-cell lymphoma including complexities associated with genomic alterations, non-genetic acquired resistance, cancer stem cells, and the tumor microenvironment. Furthermore, we focus our discussion on more comprehensive views of recent developments in therapeutic strategies to overcome ibrutinib resistance, including novel BTK inhibitors, clinical therapeutic agents, proteolysis-targeting chimeras and immunotherapy regimens.

IntroductionHistoplasmosis is a rare fungal disease caused by dimorphic fungi Histoplasma capsulatum. The causative fungus persists in soil, infects through inhalation and manifests in three main types-acute primary, chronic cavitary and progressive disseminated histoplasmosis. Disseminated Histoplasmosis (DH) is defined as a clinical condition where the fungus is present in more than one location. Among the forms of histoplasmosis, DH is the rarest and mostly found in an immuno-compromised individual.Here we are presenting our experiences of the series of cases of DH in immuno-competent individuals who have been diagnosed in our institute in last 5 years.Materials and methodsThis is a single centre retrospective observational study, conducted in Institute of Haematology and Transfusion Medicine, which is a referral centre for Eastern India, from May 2009 to April 2014. Only cases with DH in otherwise healthy immuno-competent individuals were included in the study. The histoplasmosis was confirmed either by presence of Histoplasma in biopsy specimen from an extrapulmonary organ or by positive growth in fungal cultureResultTotal seven patients met the inclusion criteria. Five out of 7 patients were male. The mean age was 35 years. Five of the 7 patients presented with fever for a long duration. Six patients complained of significant weight loss before diagnosis. On examination, one patient had skin nodules, five patients had hepato-splenomegaly, and two patients had lymphadenopathy.The laboratory investigations revealed anaemia in six out of 7 patients, and pancytopenia in 3 patients. Two patients had features of the hemophagocytic syndrome in the bone marrow.All patients were treated with conventional amphotericin B deoxycholate and azole antifungal. One patient with adrenal involvement died in hospital. The patient with skin nodule had recurrent relapses. The other patients had resolution of symptoms and were clinically cured.ConclusionDH is not an uncommon aetiology of fever of prolonged duration even in immuno-competent individual and should be kept as a differential diagnosis. Targeted investigation through early bone marrow biopsy and fungal culture may help in the diagnosis of DH. Imaging study to exclude adrenal involvement prevents case fatality. Cytopenia may be due to a secondary hemophagocytic syndrome, which improves with anti-fungal therapy. Treatment with either amphotericin B or itraconazole gives excellent outcome though therapy may have to be given for a prolonged period in case of relapses.

Background Cancer is the second most common cause of deaths worldwide. Likewise, in India, it is a major health problem, and disease burden is escalating every year. Cancer chemotherapy produces unfavorable effects on the well‐being of an individual. Since the past few years, quality of life (QoL) is considered as the main goal of cancer treatment in the survival of a patient. Aim This current study aimed to assess the QoL and factors affecting it in adult cancer patients undergoing chemotherapy treatment. Methods and Results An analytical, cross‐sectional study was conducted to achieve the objectives, employing the consecutive sampling method. A total of 120 adult (>19 years) patients were recruited from daycare chemotherapy unit of a tertiary care hospital. The data were collected using patient record form and Functional Assessment of Cancer Therapy‐General (FACT‐G), a quality of life (QoL) questionnaire. The overall mean score of quality of life (QoL) was 61.933 ± 5.85502. The domains of functional well‐being and emotional well‐being were most negatively affected after cancer chemotherapy. Education (illiteracy) and occupation (unemployment) were negatively associated with overall quality of life (QoL) of cancer patients on chemotherapy. Adverse drug reactions due to cancer chemotherapy negatively affect the quality of life (QoL) of cancer patients. Education (illiteracy) affects social well‐being domain of cancer patients. Working in the government/private sector has a positive impact on functional well‐being domain of quality of life (QoL). Conclusion The study findings suggest an overall low quality of life (QoL) among adult cancer patients undergoing chemotherapy at our setup. It has been identified as a stressful therapy, also affecting both psychological and physical well‐being. Poor infrastructure, illiteracy, poverty, and lack of proper treatment facilities at most centres often lead to poor survival outcomes and hence focus has always been on achieving quantity of life rather than quality of life (QoL). This is further complicated due to nonavailability of validated tools in local vernacular, apathy of the treating physicians in the context of QoL aspects and social and cultural factors that are unique to this society. Psycho‐oncology needs to become an integral entity of comprehensive cancer care.

Over the past 20 years, hydroxyurea (HU) has emerged as an important therapeutic agent to augment Hb F and thus total hemoglobin (Hb) in Hb E [β26(B8)Glu→Lys; HBB: c.79G > A]-β-thalassemia (Hb E-β-thal), albeit used in varying doses with little consensus on its optimal dose. We report the interim analysis findings of a broader study to assess the impact of Comprehensive Thalassemia Care, of which the present report was a part. Sixty-one Hb E-β-thal patients who were transfusion independent or requiring occasional transfusions [β-thal intermedia (β-TI)] were randomized to one of two groups; A (n = 32) and B (n = 29) to receive 10 and 20 mg/kg/day HU, respectively. The primary objective of the study was to assess the differences in responses to different doses of HU. Secondary end points were to see the tolerability and safety of HU in different doses. Good response (GR) was defined as a rise of Hb by > 1.0 g/dL; intermediate response (IR) as a rise in Hb by 0.6-1.0 g/dL anytime during the study period. No response (NR): rise in Hb by < 0.5 g/dL in 12 weeks or drop in Hb level from the previous value. Over a follow-up period of 24 weeks, we had 18 (56.2%) GRs, nine (28.2%) IRs and five (15.6%) NRs, while the number of GRs, IRs and NRs in group B were five (17.2%) 12 (41.4%) and 12 (41.4%), respectively. Adverse effects were more common in group B, making this dose (20 mg/kg/day) of HU more myelo-suppressive than Hb F inducing.

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