Sushil Selvarajan

PURPOSE: As there is a paucity of data comparing outcomes with different dosing regimens of PD-1 inhibitors in relapsed/refractory Hodgkin lymphoma (R/R HL), this retrospective analysis was undertaken to compare the efficacy of low-dose nivolumab (fixed at 40 mg) with the standard dose of 3 mg/kg. METHODS: Single-center retrospective analysis of patients with R/R HL who failed at least one salvage regimen and were treated with nivolumab between 2015 and 2023, at either 3 mg/kg (standard-dose nivolumab [SD-NIV]) or a flat dose of 40 mg (NIV40), both administered once in 2 weeks. Treatment response was assessed with ¹⁸ F-labeled fluorodeoxyglucose-positron emission tomography-computed tomography after four doses of nivolumab. RESULTS: A total of 45 patients were included: 25 received 3 mg/kg (SD-NIV) and 20 received a flat dose of 40 mg (NIV40). The mean dose of nivolumab administered once in 2 weeks was 2.9 mg/kg (stable disease 0.31) in the SD-NIV group compared with 0.6 mg/kg (stable disease 0.10) in the NIV40 group ( P < .001). Responses after four doses of nivolumab were similar in the SD-NIV versus NIV40 group: complete response (48% v 50%), partial response (12% v 10%), stable disease (20% v 20%), and progressive disease (20% v 20%; P = .997). Immune-related adverse effects were similar in the two groups (12% v 10%; P = .790). Two-year event-free survival (EFS) of the whole cohort treated with nivolumab with SD-NIV and NIV40 was 47% and 49.5%, respectively ( P = .788). Twenty-two of the 45 patients underwent stem cell transplant (11 from each group), with a 2-year EFS of 90.1% versus 81.8% ( P = .545) in the SD-NIV and NIV40 groups, respectively. CONCLUSION: Despite the inherent limitations of a retrospective analysis, the data suggests that nivolumab demonstrates biologic efficacy at doses as low as 0.6 mg/kg. Prospective trials comparing different dosing strategies are clearly warranted; such studies may facilitate approval of biologically active and cost-effective regimens, thereby broadening access to checkpoint inhibitors.

Treatment of Burkitt Lymphoma/Leukemia (BL/L) in adults has evolved from the use of pediatric inspired regimens (CODOX-M/IVAC, hyper-CVAD, GMALL) to the use of lower intensity EPOCH regimens. The addition of rituximab has led to improvements in overall survival. Survival with these regimens in the real world was shown to be inferior as compared to those found in the prospective trials. In low- and middle-income country (LMIC) settings, unique problems like delays in seeking care, treatment-related toxicities, and treatment abandonment may hamper outcomes. We performed this retrospective multicenter analysis amongst eight centers in India, to study the disease characteristics, treatment patterns, outcomes, and prognostic factors for BL/L. Between 2012–2019, 265 patients were treated at these centers. Common regimens were methotrexate-based (N – 108(40.7%)) and EPOCH-based (N – 103(38.8%)). After a median follow-up of 42 months, 3-year event-free and overall survival were 58% (95% CI: 55–61%) and 66% (95%CI: 63–69%) respectively. In a propensity matched analysis comparing methotrexate-based protocol and EPOCH-based protocol, the EFS and OS were similar with both the protocols. EPOCH based protocol yielded inferior outcomes in patients with bone marrow, and central nervous system involvement. Factors like rituximab incorporation, baseline ECOG PS 0–2, lower serum LDH, early stage(I/II), achievement of complete response (CR) and low/intermediate BL-IPI risk scores were associated with better survival. However, on multivariable analysis, major factor impacting outcome was achievement of CR.

Background: Abnormal coagulation and thrombotic complications prompted many guidelines to recommend thromboprophylaxis for patients hospitalised with COVID‐19, but the dose required for prophylaxis remains unclear. This systematic review (SR) analyses the safety and efficacy of therapeutic dose anticoagulation (TDA) versus non‐therapeutic dose anticoagulation (NDA) in COVID‐19 patients.Methods: According to the Cochrane Handbook of Systematic Review of Interventions, we performed an SR. The protocol is registered in Prospero (CRD42021269197, date 12 August 2021).Results: In this SR of 18 studies, TDA was shown to reduce all‐cause mortality (risk ratio [RR] 0.83; 95% confidence interval [95% CI] 0.70, 0.99) in COVID‐19 infection. TDA also reduced thrombosis (RR 0.55; 95% CI 0.48, 0.72) but increased major bleeding (RR 1.87; 95% CI 1.29, 2.69). A stratified analysis according to severity revealed that, in non‐critical patients, TDA resulted in mortality benefit (RR 0.79; 95% CI 0.67, 0.94). In critical patients, TDA did not affect all‐cause mortality (RR 1.03; 95% CI 0.89, 1.18) but reduced thrombosis (RR 0.65; 95% CI 0.48, 0.86) and increased major bleeding (RR 1.85; 95% CI 1.06, 3.23).Conclusion: TDA significantly reduced all‐cause mortality and thrombosis in non‐critical COVID‐19 patients at the expense of increased major bleeding. In critical COVID‐19, this mortality benefit was not observed.

Background: Invasive fungal disease (IFD) is a sinister complication encountered in patients with haematological disorders. When occurring in the central nervous system (CNS), IFDs can have catastrophic outcomes.Objectives: To study the clinical presentation, predisposing etiological factors, and prognosis of a CNS‐IFD in a patient with a haematological disorder.Patients and Methods: This is a retrospective study focusing on the clinical profile, diagnosis, treatment strategy and outcomes of 43 patients with an underlying haematological disorder, who were diagnosed with CNS‐IFD between 2018 and 2022.Results: Of the 43 patients, 18 were chemotherapy recipients, while 23 were stem cell transplant (SCT) recipients and 2 presented with CNS‐IFD at diagnosis. AML/MDS (37.2%) and ALL (18.6%) were the predominant underlying diagnoses. A sudden deterioration in sensorium (53.5%) was the earliest clinical sign, while T2 hyperintensities (26.8%), vascular involvement (26.8%) and ring‐enhancing lesions (16.3%) were the commonest radiological findings, with all patients exhibiting diffusion restriction in diffusion‐weighted images. Microbiological evidence of infection was obtained in all patients; however, culture positivity was established in only 25 patients. Rhizopus spp (23.2%) and Aspergillus spp (20.9%) were implicated in most cases. Overall survival of the cohort was 27.9% at a median follow‐up of 6 months. In patients who succumbed, the median time to death was 4 days (0–46).Conclusion: CNS‐IFD is associated with very poor survival in patients undergoing chemotherapy or an SCT, urging the need for prompt diagnosis and initiation of suitable antifungal therapy.

We studied the incidence of relapse, transformation to myelodysplastic syndrome/acute myeloid leukemia, and survival in patients with aplastic anemia (AA) surviving more than 1 year after ATG/ALG-based immunosuppressive therapy (IST) between 1985 and 2020. Four-hundred seventy patients (413 adults and 57 children) were studied, and data were compared with 223 patients who underwent matched sibling donor transplant (MSD HSCT). Median follow-up is 50 months (12–359). Relapse occurred in 21.9% at a median time of 33.5 months (5–228) post IST. Twenty-six (5.5%) patients progressed to PNH, while 20 (4.3%) evolved to MDS/AML. Ten-year estimated overall survival (OS) is 80.9 ± 3% and was significantly better in patients without an event (85.1 ± 4%) compared to relapse (74.6% ± 6.2%) or clonal evolution (12.8% ± 11.8%) (p = 0.024). While the severity of AA (p = 0.011) and type of ATG (p = 0.028) used predicted relapse, only age at IST administration influenced clonal evolution (p = 0.018). Among HSCT recipients, relapse rates were 4.9% with no clonal evolution, and the 10-year OS was 94.5 ± 2%. In patients who survived 1 year following IST, outcomes were good except with clonal evolution to MDS/AML. These outcomes, however, were still inferior compared to matched sibling donor HSCT.

Haplo-identical stem cell transplant using post-transplant cyclophosphamide is increasingly being used in children without a matched sibling donor. Between 2010 and June 2021, 127 children underwent 138 transplants with a median age of 7.1 years for malignant and non-malignant disorders. Conditioning regimens included both myeloablative and reduced intensity regimens with peripheral blood stem cells as the main graft source. Engraftment occurred in 113 [81.9%] at a median of 16 days [range: 10–32] with primary graft failure in 10.2%. Cumulative incidence of grade II–IV acute graft versus host disease (GVHD) was 49.5% and chronic GVHD in 40.7%. Majority [92.7%] had at least one infection with 31% incidence of bacterial infection, 76% incidence of viral and 16% incidence of fungal infection. The 2-year overall survival (OS) is 54.9 ± 4.6% with a lower survival among young children aged 0–5 years [28.2 ± 6.4%] compared to 5–10 years [71.3 ± 6.8%] and 11–15 years [55.7 ± 8.8%] [p = 0.032]. 2-year OS has gradually improved from 25.0 ± 2.1% for 2010–2013 to 47.5 ± 6.2% for 2014–2017 and 67.1 ± 6.6% for 2018–2021 [p = 0.049]. On multivariate analysis, bacterial infection [p = 0.017], invasive fungal disease [p = 0.002] and graft failure [p = 0.029] negatively impacted overall survival. Haplo-identical SCT with post-transplant cyclophosphamide is a reasonable option for children who do not have a matched sibling donor. Strategies to reduce graft failure, infection related mortality and GVHD needs to be explored.