Antibody based therapies in Hodgkin lymphoma.

Multimodality treatment approaches, with systemic therapies at their core, have made Hodgkin Lymphoma a highly curable cancer. Unmet needs remain. Resistance to therapy manifested by refractory and relapsed disease, and treatment related short- and long-term morbidity are the key challenges. Patient outcomes have improved in the recent past with the advent of novel therapies and are borne out of a better understanding of the disease biology and translational medicine. Antibody based therapies, more broadly immunotherapies, are leading the change in the way we treat this disease. This review looks at the tumor antigen-directed immunotherapies, and immune checkpoint inhibitors that are attempting to overcome the unmet challenges.

Bispecific antibodies in indolent B-cell lymphomas.

The advent of immunotherapy in lymphomas, beginning with Rituximab, have led to paradigm shifting treatments that are increasingly bringing a greater number of affected patients within the ambit of durable disease control and cure. Bispecific antibodies harness the properties of the immunoglobulin antibody structure to design molecules which, apart from engaging with the target tumour associated antigen, engage the host's T-cells to cause tumour cell death. Mosunetuzumab, an anti-CD20 directed bispecific antibody was the first to be approved in follicular lymphoma, this has now been followed by quick approvals of Glofitamab and Epcoritamab in diffuse large B-cell lymphomas. This article reviews contemporary data and ongoing studies evaluating the role of bispecific antibodies in indolent b-cell non Hodgkin lymphomas. This is an area of active research and presents many opportunities in advancing the treatment of indolent lymphomas and potentially forge a chemo-free treatment paradigm in this condition.

Precursor B-cell acute lymphoblastic leukaemia-a global view.

As haematologists, we always seek to follow standardised guidelines for practice and apply the best treatment within our means for our patients with blood diseases. However, treatment can never follow an exact recipe. Opinions differ as to the best approach; sometimes more than one treatment approach results in identical outcomes, or treatments differ only by the manner in which they fail. Furthermore, the haematologist is faced with constraints relating to the local economic environment. Patients too are not the same the world over. Early presentation is commoner in the developed world, as is the patient's understanding of the disease process. This in turn has an impact on the way patients are managed, the rigorousness of patient adhesion to the treatment schedule and the outcome. Here we take a look at the precursor B-cell acute lymphoblastic leukaemia in an adolescent in a range of different settings from low- to high income countries with widely differing challenges for diagnosis, therpy and follow-up. For these reasons, given the same starting conditions, patients will be treated differently according to the institute and the country they are in. Experts from around the world have been tasked to describe their management plan and rationale for a specific disease presentation. Here they explore the management of precursor B-cell acute lymphoblastic leukaemia (pre-B ALL) in five different institutions worldwide with a focus on those with more or less strained economies. We end with a conclusion from an expert in the field comparing and contrasting these different management styles and considering their merits and limitations.

Comparison of Quality and Efficacy of Apheresis Platelets Stored in Platelet Additive Solution Vis a Vis Plasma.

PAS, by replacing part of the plasma in the platelet storage bag, reduces post transfusion allergic reactions and DHTR in the recipient. In this study we compared quality and efficacy of PAS and usual plasma stored platelets. Platelet concentration, content, MPV, pH, swirling, LDH and glucose concentration were tested in SDPs after preparation and on the day of transfusion; and compared between control (plasma-stored SDP) and study (PAS-stored SDP) groups. CCI was compared between the two groups. Transfusion reactions were also noted. In both groups quality parameters were similar except glucose [significantly decreased (p < 0.001) in plasma] and LDH [increased significantly (p: -0.005) in PAS]. CCI was similar in both groups. Transfusion reaction rate were 0.012% and 0.049% in both groups respectively. Quality and post-transfusion efficacy in both groups were similar. PAS stored platelets may be transfused in multi-transfused patients with allergic manifestations and in minor ABO incompatible transfusions.

Outcomes of diffuse large B-cell lymphoma in elderly patients-real-world experience from a middle-income country setting.

BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) is the commonest subtype of lymphoma in the elderly and poses unique challenges in this group of patients. There is a need for more information on real-world outcomes across economic disparities. METHODS: Electronic Medical Record of 3,087 lymphomas (>18 years) were evaluated retrospectively, of which 842 (27%) patients were ≥65 years. Two hundred and twelve patients who were ≥65 years received first line treatment for DLBCL between May 2011 and Dec 2016. Demography, clinical features, associated co-morbidities, first line treatment outcomes and hospital costs were analysed. Patients were followed up till March 2020. RESULTS: The median age at presentation was 71 years. Gender ratio was 2.5:1. 38% patients presented with early-stage disease, 37% with low and low-intermediate International prognostic index, 49% with nodal disease. One or more co-morbidities were present in 58%. The commonest extra nodal site was gastro-intestinal (29%). Two-thirds of the patients presented with non-Germinal centre B subtype. The overall response (OR) to treatment was 72.5%. Patients who received anthracycline-based therapy (n = 124) and rituximab-based therapy (n = 159) had a median progression free survival (PFS), not reached and 47.0 months, respectively, versus 10 months and 7.9 months, respectively, for patients receiving non-anthracycline and non-rituximab therapies. At a median follow-up of 24 months, the 5-year overall survival and PFS are 44% and 41%, respectively, for the entire cohort. CONCLUSIONS: DLBCL is a curable lymphoma in elderly patients with standard anthracycline and rituximab-based therapies. Improvement in outcomes largely depends on social and financial support to complete the scheduled treatments.

Relapsed plasmablastic lymphoma in a HIV-negative patient: Pushing the envelope.

This case emphasizes that, with the availability of novel immunotherapy agents (Daratumumab), and repurposed use of bortezomib, a patient with HIV-negative relapsed PBL can be treated successfully and consolidated with an allogeneic haploidentical hematopoietic cell transplantation.

Relapsed Refractory Hodgkin Lymphoma and Brentuximab Vedotin-Bendamustine Combination Therapy as a Bridge to Transplantation: Real-World Evidence From a Middle-Income Setting and Literature Review.

INTRODUCTION: Despite high cure rates with standard treatment, 30% patients with Hodgkin lymphoma develop relapsed or refractory (R/R) disease. Salvage therapy followed by autologous hematopoietic cell transplantation (HCT) is considered standard of care. Brentuximab Vedotin (Bv) in combination with Bendamustine (B) has been tested in the salvage setting with promising results. MATERIALS AND METHODOLOGY: We conducted a single centre retrospective chart review of patients who received BBv salvage therapy to determine its activity and safety in patients with R/R classical Hodgkin lymphoma (HL). Between May 2011- December 2019, 179 patients were diagnosed with R/R HL. RESULTS: Thirty patients received BBv [median age: 30 (15-59) years, females (n=15)]. Primary refractory disease in 19 patients (63%), and 26 patients (87%) had advanced stage at treatment. Most patients received BBv after 2 prior lines of therapy [n=16 (53%)]. The median number of cycles of BBv were 3 (1-6). The number of BBv cycles delivered as outpatient was 63%. The most common Grade III/IV hematological adverse event was neutropenia [n=21, (70%)], while grade III/IV non-hematological toxicities included infections in 4 (13%), neuropathy in 4(13%), skin rash in 2 (7%), GI toxicities in 3 (10%) and liver dysfunction in 2 (7%) patients. The ORR and CR rates were 79% and 62%, respectively. Seventeen patients (57%) underwent an autologous HCT and 8 (26%) underwent an Allogeneic HCT (all haploidentical). The median follow up time from BBv administration was 12 months. Six patients died: 2 = disease progression, and 4 = non-relapse causes (Infection and sepsis = 2, GVHD=2). In addition to this, one patient progressed soon after HCT and another patient relapsed 22 months post HCT. Three year Overall survival (OS) and Event free survival (EFS) probability post-BBv treatment was 75% and 58%, respectively. OS and EFS analysis based on response (viz., CMR) to BBv demonstrated that patients in CMR had better survival probability [93% (p=0.0022) 3yr-OS and 72% (p=0.038) 3yr-EFS probability]. CONCLUSIONS: BBv is an active and well-tolerated salvage treatment for patients with R/R HL, even in refractory and advanced settings. In middle-income settings, cost constraints and access determine patient uptake of this regimen.

Systematic Review of the Burden and Treatment Patterns of Adult and Adolescent Acute Lymphoblastic Leukemia in India: Comprehending the Challenges in an Emerging Economy.

BACKGROUND: In the present systematic literature review, we sought to describe the burden and treatment practices of adult acute lymphoblastic leukemia (ALL) in India, which reflect the realities and outcomes in a middle-income country. MATERIALS AND METHODS: We conducted a search for reported studies using terms such as "adult ALL," "epidemiology," and "treatment" in the Medline, Embase, Cochrane, and other database sources. We obtained 249 articles and 18 conference abstracts reported until December 2019. A total of 40 studies were selected to qualitatively summarize the data. RESULTS: The proportion of ALL among adult patients diagnosed with acute leukemia at reporting institutions from 16 Indian studies ranged from 7.3% to 57.8%. Most studies were performed in Northern India (n = 12), had a male preponderance (range, 57%-80%), and had a predominance of B-ALL (range, 65.2%-75.9%). The treatment protocols used for ALL included MCP-841, BFM (Berlin-Frankfurt-Münster)-90, chemotherapy plus a tyrosine kinase inhibitor, GMALL (German Multicenter Study Group for Adult Acute Lymphoblastic Leukemia), and hyper-CVAD (cyclophosphamide, vincristine, doxorubicin, dexamethasone). The complete remission rates and median overall survival for these protocols ranged from 46.7% to 91.4% and 7 to 46 months, respectively. The overall relapse rates were 24.3% to 57.1% within median time of 9 to 24 months, with bone marrow the most frequent relapse site. After relapse, most patients had chosen palliative therapy (range, 78.7%-96.0%). The major treatment-related toxicities included neutropenia, myelosuppression, and infection. CONCLUSIONS: The results from Indian studies on adult ALL are heterogeneous, reporting a diverse incidence and poor overall outcomes using varied non-contemporaneous treatment protocols adapted from the developed world. A comprehensive countrywide approach to diagnosis, treatment, and follow-up and the potential incorporation of novel therapies could improve the prognosis and outcomes of adult ALL in India.

COVID-19 and haematology services in a cancer centre from a middle-income country: adapting service delivery, balancing the known and unknown during the pandemic.

The COVID-19 pandemic has caused major disruptions in multiple spheres of healthcare delivery in the world. Developing nations have had to tackle this unanticipated crisis in the midst of various other healthcare delivery issues and resource constraints. As a tertiary level cancer care provider located in an eastern Indian city, a COVID-19 hotspot, we share our experience from the perspective of haematology and haematopoietic stem cell transplantation (HSCT) services. The primary challenges related to infection control included infection screening and decreasing exposure among patients and healthcare workers. Logistic challenges include maintaining essential patient care services, personnel redeployment, blood bank inventory constraints and maintaining the supply chain for a continuum of care. Clinical management challenges were dealt with by rationalising treatment delivery by modification of treatment regimens, risk-based deferral of HSCT, management of COVID-19 in patients, and staggering the follow-up schedules in survivors and those on maintenance therapies, among other strategies. These challenges were compounded by the restrictions imposed by a countrywide lockdown in the initial period of the pandemic, which also affected the socio-economic aspects of treatment delivery. As a training institution, this period also impacted academics and research activities. This overview details our response to these challenges during the COVID-19 pandemic, which has many unknowns.

Thalidomide in Patients with Transfusion-Dependent E-Beta Thalassemia Refractory to Hydroxyurea: A Single-Center Experience.

Transfusion-dependent E-Beta (EB) thalassemia is one of the major causes of hereditary hemoglobinopathies in India. Hydroxyurea has been tried for HbF induction and amelioration of the transfusion frequency in EB thalassemia. The primary objective of this retrospective study, conducted between January 2017 and December 2018, was to determine the efficacy of thalidomide in reducing transfusion frequency in patients with EB thalassemia who have failed a reasonable trial of hydroxyurea. Of the 21 patients studied, 15 (71.4%) attained transfusion independence (complete responders) and 1 (4.7%) attained partial response (50% decrease in transfusion requirement) while 5 (23.9%) were non-responders. 12 patients attained their response within 1 month, 2 patients achieved within 1-3 months, and 1 patient beyond 3 months. Median time to transfusion independence in complete responders was 1 month. The median time on thalidomide for the complete responders and partial responders was 16.48 months. No major grade 3/4 toxicities were documented. This approach needs larger randomised controlled studies. Thalidomide is a safe and effective strategy at reducing or abrogating transfusion requirement in patients with EB thalassemia. This approach requires further testing in systematic clinical trials.

Hypoxic Transformation of Immune Cell Metabolism Within the Microenvironment of Oral Cancers.

Oral squamous cell carcinoma (OSCC) includes tumors of the lips, tongue, gingivobuccal complex, and floor of the mouth. Prognosis for OSCC is highly heterogeneous, with overall 5-year survival of ~50%, but median survival of just 8-10 months for patients with locoregional recurrence or metastatic disease. A key feature of OSCC is microenvironmental oxygen depletion due to rapid growth of constituent tumor cells, which triggers hypoxia-associated signaling events and metabolic adaptations that influence subsequent tumor progression. Better understanding of leukocyte responses to tissue hypoxia and onco-metabolite expression under low-oxygen conditions will therefore be essential to develop more effective methods of diagnosing and treating patients with OSCC. This review assesses recent literature on metabolic reprogramming, redox homeostasis, and associated signaling pathways that mediate crosstalk of OSCC with immune cells in the hypoxic tumor microenvironment. The likely functional consequences of this metabolic interface between oxygen-starved OSCC and infiltrating leukocytes are also discussed. The hypoxic microenvironment of OSCC modifies redox signaling and alters the metabolic profile of tumor-infiltrating immune cells. Improved understanding of heterotypic interactions between host leukocytes, tumor cells, and hypoxia-induced onco-metabolites will inform the development of novel theranostic strategies for OSCC.

MYD88 and CXCR4 Mutation Profiling in Lymphoplasmacytic Lymphoma/Waldenstrom's Macroglobulinaemia.

Recurrent mutations affecting MYD88 and CXCR4 gene nowadays form the basis for the diagnosis, risk stratification and use of inhibitors targeting these signalling pathways in LPL/WM which are rare B cell neoplasms. MYD88 L265P mutation analysis was performed on 33 cases of LPL/WM by AS-PCR (positivity-84.8%, n = 28/33) and by Sanger sequencing (positivity-39.3%, n = 13/33). We had only two cases with CXCR4 non-sense (NS) mutation (p.S338*) using Sanger sequencing. MYD88 (L265P) mutation detection by AS-PCR can form reliable biomarker for the diagnosis of LPL/WM in molecular labs. Although the cohort is small, still the CXCR4 mutation frequency in our study is low as compared to the published literature.