Aby Abraham

Introduction: Over the recent years, the introduction of nonfactor replacement (NFR) prophylaxis for haemophilia has allowed to reduce the burden of treatment and to offer effective prophylaxis also for patients with inhibitors, with an excellent successful prevention of spontaneous bleeding, often approaching a median annual bleeding rates close to 0. However, patients on NRF prophylaxis require traditional replacement treatment for breakthrough bleeds and to manage especially major surgery. Real‐world experiences with the use of emicizumab are accumulating, showing excellent outcomes, while these are still significantly limited data available with rebalancing agents (concizumab, marstacimab and fitusiran). Aim: The present overview is focused on surgical procedures with nonfactor replacement prophylaxis. Methods: Review of the literature and report of personal experiences with the use of emicizumab and replacement treatment during surgery. Results: Combined used of emicizumab prophylaxis together with factor replacement in patients with Haemophilia A with and without inhibitors provided excellent results. Multiple elective orthopaedic procedures, oral and abdominal surgical interventions, and trauma surgery confirmed the feasibility of this combined approach, without significant side effects. Conclusions: The association of nonfactor prophylaxis with recombinant factors has provided safe, reproducible and effective results, with low rates of complications. However, the experience with rebalancing agents is still limited, and more real‐world studies are needed to confirm the most appropriate approach.

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.

Introduction: Cytogenetic findings are critical for determining prognosis, therapy and risk assessment in acute lymphoblastic leukaemia (ALL). Data on the epidemiology of cytogenetic findings in ALL from southern Asia is limited. This report documents the cytogenetic changes in ALL seen at a referral hospital in southern India and compares it with the literature. Methods: Clinical profiling and conventional cytogenetic analysis (CCA) of all patients with reverse-transcription polymerase chain reaction for detection of cryptic t(12;21). Results: Of 1,968 ALL, 1,819 (92.4%) patients aged 0.3–84 years (median 17) had successful CCA. There were 979 children (≤18 years) and 840 adults. Abnormal karyotypes were found in 1,368 (75.2%), B-ALL-78%, and T-ALL-69%. The favourable-risk group included high hyperdiploidy (HeH, 17.4%), t(12;21) (9.8%), and t(1;19) (4.3%), with >80% of HeH and t(12;21) in children. The unfavourable-risk group included t(9;22) (11.2%, 80% adults), hypodiploidy (8.0%), MYC (8q24) translocations (2.3%), and KMT2A (11q23) translocations (1.6%). In children, the frequency of HeH (26.8%) was lower than the West (30.7%) but higher than South-East (S.E.) Asia (15.5%) while t(9;22) (4.2%) was higher than the West (2%) but lower than S.E. Asia (6.8%). In adults, frequencies again differed from S.E. Asia (HeH, 6.4% vs. 2.7% and t(9;22), 19.4% vs. 29.3%) but were comparable to the West. Conclusion: CCA effectively provides diagnostic information in over 90% of ALL cases. While the spectrum of cytogenetic changes is similar to global data, there are significant regional variations in the frequencies of specific abnormalities.

Acute myeloid leukemia (AML) remains a difficult disease to cure despite recent advances. Off-target side effects of therapy, especially prolonged cytopenia, lead to significant morbidity and mortality. There is an increased recognition that in AML, there is a potentially vulnerable dependence on OXPHOS metabolism, more so in the leukemia stem cell compartment (AML-LSC) that could be exploited. Drug re-purposing screens have suggested the possible role of artesunate (ART) in inhibiting mitochondrial respiration and arsenic trioxide (ATO) in inhibiting glycolysis. Here, we explore the potential of using a combination of ART and ATO to treat AML. Through in-vitro and in-vivo studies, we demonstrate the potential of this combination along with hypo-methylating agents and other mitocans, such as BCL-2 inhibitor venetoclax, to be used in the treatment of AML with minimal off-target effect on normal hematopoietic stem cells (HSC). These observations warrant further exploration of such novel combinations in clinical trials.

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.

A toxicity-reduced conditioning regimen with treosulfan, fludarabine, and thiotepa in patients with high-risk β-thalassemia major has significantly improved hematopoietic stem cell transplantation (HCT) outcomes. However, complications resulting from regimen-related toxicities (RRTs), mixed chimerism, and graft rejection remain a challenge. We evaluated the dose–exposure-response relationship of treosulfan and its active metabolite S, S-EBDM, in a uniform cohort of patients with β-thalassemia major to identify whether therapeutic drug monitoring (TDM) and dose adjustment of treosulfan is feasible. Plasma treosulfan/S, S-EBDM levels were measured in 77 patients using a validated liquid chromatography with tandem mass spectrometry method, and the pharmacokinetic parameters were estimated using nlmixr2. The influence of treosulfan and S, S-EBDM exposure, and GSTA1/NQO1 polymorphisms on graft rejection, RRTs, chimerism status, and 1-year overall survival (OS), and thalassemia-free survival (TFS) were assessed. We observed that treosulfan exposure was lower in patients with graft rejection than those without (1,655 vs. 2,037 mg•h/L, P = 0.07). Pharmacodynamic modeling analysis to identify therapeutic cutoff revealed that treosulfan exposure ≥1,660 mg•hour/L was significantly associated with better 1-year TFS (97% vs. 81%, P = 0.02) and a trend to better 1-year OS (90% vs. 69%, P = 0.07). Further, multivariate analysis adjusting for known pre-HCT risk factors also revealed treosulfan exposure P = 0.03) and GSTA1*B variant genotype (HR = 3.75; 95% CI = 1.04–13.47; P = 0.04) to be independent predictors for inferior 1-year TFS. We conclude that lower treosulfan exposure increases the risk of graft rejection and early transplant-related mortality affecting TFS. As no RRTs were observed with increasing treosulfan exposure, TDM-based dose adjustment could be feasible and beneficial.

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.