Clonal hematopoiesis, myeloid disorders and BAX-mutated myelopoiesis in patients receiving venetoclax for CLL.

The BCL2 inhibitor venetoclax has established therapeutic roles in chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML). As BCL2 is an important determinant of survival of both myeloid progenitor and B cells, we investigated whether clinical and molecular abnormalities arise in the myeloid compartment during long-term continuous venetoclax treatment of CLL in 89 patients (87 with relapsed/refractory CLL). Over a median follow-up of 75 (range 21-98) months, persistent cytopenias (≥1 of neutropenia, thrombocytopenia, anemia) lasting ≥4 months and unrelated to CLL occurred in 25 patients (28%). Of these patients, 20 (80%) displayed clonal hematopoiesis, including 10 with therapy-related myeloid neoplasms (t-MNs). t-MNs occurred exclusively in patients previously exposed to fludarabine-alkylator combination therapy with a cumulative 5-year incidence of 10.4% after venetoclax initiation, consistent with rates reported for patients exposed to fludarabine-alkylator combination therapy without venetoclax. To determine whether the altered myelopoiesis reflected the acquisition of mutations, we analyzed samples from patients with no or minimal bone marrow CLL burden (n = 41). Mutations in the apoptosis effector BAX were identified in 32% (13/41). In cellular assays, C-terminal BAX mutants abrogated outer mitochondrial membrane localization of BAX and engendered resistance to venetoclax killing. BAX-mutated clonal hematopoiesis occurred independently of prior fludarabine-alkylator combination therapy exposure and was not associated with t-MNs. Single-cell sequencing revealed clonal co-occurrence of mutations in BAX with DNMT3A or ASXL1. We also observed simultaneous BCL2 mutations within CLL cells and BAX mutations in the myeloid compartment of the same patients, indicating lineage-specific adaptation to venetoclax therapy.

Esssential thrombocythaemia and pregnancy-A need for prospective study and a consensus on its management.

MPN are rare diseases, however young women with ET are increasingly being recognised. Management during pregnancy is often a recognised issue with no clear guidelines for management. Pregnancy is associated with considerable risk of complications and therefore warrants a multidisciplinary approach and early identification of high-risk pregnancies. Robust data is limited and therefore we advocate for more prospective (cohort and registry), multicentre, collaborative efforts to gather meaningful information about risk, and risk-adapted therapy, to guide management. The commentary reviews the study by How et al and compares the observations to other studies around the world. It recognises that previous pregnancies with complications increase the risk of further complications during future pregnancies. It is important to recognise the high-risk pregnancies and have a risk adapted approach to the same. The use of low dose aspirin is recommended throughout the pregnancy. The use of LMWH prophylaxis antepartum should be individualised to the thrombotic risk status and applied post-partum for at least 6 weeks. Interferon a remains the safest and effective approach for cytoreductive therapy. Collaborative expert efforts world-wide, as well as larger prospective trials and registry data, will enhance our knowledge to formulate standard guidelines for these group of patients.

The association of mobilising regimen on immune reconstitution and survival in myeloma patients treated with bortezomib, cyclophosphamide and dexamethasone induction followed by a melphalan autograft.

G-CSF only mobilisation has been shown to enhance immune reconstitution early post-transplant, but its impact on survival remains uncertain. We undertook a retrospective review of 12 transplant centres to examine overall survival (OS) and time to next treatment (TTNT) following melphalan autograft according to mobilisation method (G-CSF only vs. G-CSF and cyclophosphamide [CY]) in myeloma patients uniformly treated with bortezomib, cyclophosphamide and dexamethasone induction. Six centres had a policy to use G-CSF alone and six to use G-CSF + CY. Patients failing G-CSF only mobilisation were excluded. 601 patients were included: 328: G-CSF + CY, 273: G-CSF only. Mobilisation arms were comparable in terms of age, Revised International Staging System (R-ISS) groups and post-transplant maintenance therapy. G-CSF + CY mobilisation generated higher median CD34 + yields (8.6 vs. 5.5 × 106/kg, p < 0.001). G-CSF only mobilisation was associated with a significantly higher lymphocyte count at day 15 post-infusion (p < 0.001). G-CSF only mobilisation was associated with significantly improved OS (aHR = 0.60, 95%CI 0.39-0.92, p = 0.018) and TTNT (aHR = 0.77, 95%CI 0.60-0.97, p = 0.027), when adjusting for R-ISS, disease-response pre-transplant, age and post-transplant maintenance therapy. This survival benefit may reflect selection bias in excluding patients with unsuccessful G-CSF only mobilisation or may be due to enhanced autograft immune cell content and improved early immune reconstitution.

Imidacloprid poisoning: a case report.

Imidacloprid is a systemic, chloronicotinyl insecticide. It is generally considered nontoxic to humans based on available literature. Its effects are mediated through acetylcholine receptor blockade. We report a patient with such poisoning who had respiratory arrest, for which he had to be mechanically ventilated, and who subsequently recovered. This is only the second such case report.

Neuroprotective Efficacy of Mitochondrial Antioxidant MitoQ in Suppressing Peroxynitrite-Mediated Mitochondrial Dysfunction Inflicted by Lead Toxicity in the Rat Brain.

Lead (Pb) is one of the most pollutant metals that accumulate in the brain mitochondria disrupting mitochondrial structure and function. Though oxidative stress mediated by reactive oxygen species remains the most accepted mechanism of Pb neurotoxicity, some reports suggest the involvement of nitric oxide (•NO) and reactive nitrogen species in Pb-induced neurotoxicity. But the impact of Pb neurotoxicity on mitochondrial respiratory enzyme complexes remains unknown with no relevant report highlighting the involvement of peroxynitrite (ONOO-) in it. Herein, we investigated these effects in in vivo rat model by oral application of MitoQ, a known mitochondria-specific antioxidant with ONOO- scavenging activity. Interestingly, MitoQ efficiently alleviated ONOO--mediated mitochondrial complexes II, III and IV inhibition, increased mitochondrial ATP production and restored mitochondrial membrane potential. MitoQ lowered enhanced caspases 3 and 9 activities upon Pb exposure and also suppressed synaptosomal lipid peroxidation and protein oxidation accompanied by diminution of nitrite production and protein-bound 3-nitrotyrosine. To ascertain our in vivo findings on mitochondrial dysfunction, we carried out similar experiments in the presence of different antioxidants and free radical scavengers in the in vitro SHSY5Y cell line model. MitoQ provided better protection compared to mercaptoethylguanidine, N-nitro-L-arginine methyl ester and superoxide dismutase suggesting the predominant involvement of ONOO- compared to •NO and O2•-. However, dimethylsulphoxide and catalase failed to provide protection signifying the noninvolvement of •OH and H2O2 in the process. The better protection provided by MitoQ in SHSY5Y cells can be attributed to the fact that MitoQ targets mitochondria whereas mercaptoethylguanidine, N-nitro-L-arginine methyl ester and superoxide dismutase are known to target mainly cytoplasm and not mitochondria. Taken together the results from the present study clearly brings out the potential of MitoQ against ONOO--induced toxicity upon Pb exposure indicating its therapeutic potential in metal toxicity.

Clinico-aetiologic profile of macrocytic anemias with special reference to megaloblastic anemia.

PURPOSE OF STUDY: This study was conducted to study the clinical and laboratory parameters in patients with macrocytic anemia and to determine the etiology of macrocytic anemia with special reference to megaloblastic anemia. MATERIALS AND METHODS: This study was a cross-sectional descriptive study carried over a period of 18 months on 60 adult patients (age ≥13 years) of macrocytic anemia. Macrocytic anemia was identified when peripheral blood examination showed anemia with a mean red blood corpuscular volume of >95 fl. RESULT: The most common cause of macrocytic anemia was megaloblastic anemia (38.4%). The major causes of nonmegaloblastic macrocytic anemia were primary bone marrow disorders (35%), liver diseases (15%) and hemolytic anemia (8.3%). There was a significant male preponderance in the study (65%). The megaloblastic anemias observed were due to either vitamin B(12) deficiency (78.3%) or combined B(12) and folate deficiency (21.7%). A significant proportion of non-vegetarians (73.9%) had megaloblastic anemia. Patients with an MCV of >110fl were more likely to have megaloblastic anemia (p value 0.0007). Three patients (mean age 55 years) with a megaloblastic marrow did not respond to vitamin replacement and were found to have myelodysplastic syndrome. CONCLUSION: Megaloblastic anemia due to Vitamin B(12) or folate deficiency remains the most important cause of macrocytic anemia. In settings with limited laboratory facilities, a therapeutic trial of vitamins B(12) or folic acid is useful in determining the specific vitamin deficiency.