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The survival of leukemic cells is significantly influenced by the bone marrow microenvironment, where stromal cells play a crucial role. While there has been substantial progress in understanding the mechanisms and pathways involved in this crosstalk, limited data exist regarding the impact of leukemic cells on bone marrow stromal cells and their potential role in drug resistance. In this study, we identify that leukemic cells prime bone marrow stromal cells towards osteoblast lineage and promote drug resistance. This biased differentiation of stroma is accompanied by dysregulation of the canonical Wnt signaling pathway. Inhibition of Wnt signaling in stroma reversed the drug resistance in leukemic cells, which was further validated in leukemic mice models. This study evaluates the critical role of leukemic cells in establishing a drug-resistant niche by influencing the bone marrow stromal cells. Additionally, it highlights the potential of targeting Wnt signaling in the stroma by repurposing an anthelmintic drug to overcome the microenvironment-mediated drug resistance.

Long term survivors of haematopoietic stem cell transplantation (HSCT) for [beta]-thalassemia major are designated \"ex-thalassaemics\". Whether ex-thalassaemics continue to harbour residual myocardial dysfunction and thereby stand the risk of heart failure-related morbidity and mortality is unknown. The aim of this study was to assess the prevalence and predictors of subclinical left ventricular (LV) dysfunction in an apparently normal ex-thalassaemic population. We conducted a single centre cross-sectional study among 62 ex-thalassaemic patients, who had undergone HSCT for [beta]-thalassaemia major at our centre. The primary outcome variable was LV systolic dysfunction, as assessed by 1) LV global longitudinal strain (GLS) derived by 2D speckle tracking echocardiography and 2) LV ejection fraction (EF) derived by 2D Simpsons Biplane method. Among the 62 patients included in the study, 7 [11.3%] were found to have LV systolic dysfunction, all of which were subclinical. Of these, 4 [6.5%] had abnormal GLS and LVEF, 2 [3.2%] had abnormal GLS with normal LVEF, and 1 [1.6%] had abnormal LVEF with low normal mean GLS. There were no statistically significant predictors of LV dysfunction in this cohort. There was a high prevalence of subclinical myocardial dysfunction in the ex-thalassaemic population reiterating the need for close follow up of these patients. 2D Speckle tracking echocardiography-derived LV global longitudinal strain is an effective tool in detecting subclinical myocardial dysfunction in this cohort.

Refractory acute myeloid leukemia (AML), defined as failure of two cycles of induction therapy at diagnosis or of one cycle at relapse, represents a subgroup with poor outcomes. Haploidentical natural killer cell (NK) therapy is a strategy that is being explored in refractory malignancies. Historically, at our center, patients with refractory AML have been treated with cytoreductive therapy (fludarabine + cytosine + granulocyte colony-stimulating factor ± idarubicin or mitoxantrone + etoposide) followed by 1-week rest and then reduced-intensity transplant with fludarabine + melphalan. We used the same backbone for this trial (CTRI/2019/02/017505) with the addition of CD56-positive cells from a family donor infused 1 day after the completion of chemotherapy. CD56-positive selection was done using a CliniMACS Prodigy system (Miltenyi Biotec, Bergisch Gladbach, Germany) followed by overnight incubation in autologous plasma with 2 micromolar arsenic trioxide and 500 U/mL of interleukin-2. From February 2019, 14 patients with a median age of 29 years (interquartile range [IQR]: 16.5–38.5) were enrolled in this trial. Six were females. Six had primary refractory AML while eight had relapsed refractory AML. The median CD56-cell dose infused was 46.16 × 106/kg (IQR: 25.06–70.36). One patient withdrew consent after NK cell infusion. Of the 13 patients who proceeded to transplant, five died of immediate post-transplant complications while two did not engraft but were in morphologic leukemia-free state (both subsequently died of infective complications after the second transplant). Of the remaining six patients who engrafted and survived beyond 1 month of the transplant, two developed disease relapse and died. The remaining four patients are alive and relapse free at the last follow-up (mean follow-up duration of surviving patients is 24 months). The 2-year estimated overall survival for the cohort was 28.6% ± 12.1% while the treatment-related mortality (TRM) with this approach was 38.5% ± 13.5%. Haploidentical NK cell therapy as an adjunct to transplant is safe and needs further exploration in patients with AML. For refractory AML, post-transplant NK infusion and strategies to reduce TRM while using pre-transplant NK infusion merit exploration.

Acute myeloid leukemia (AML) remains difficult to cure despite recent advances. Off-target side effects of drugs currently used lead to significant morbidity and mortality. There is recognition that in AML, there is an increased dependence on OXPHOS metabolism, especially in the leukemia stem cell compartment (AML-LSC). It is also recognized that there is potential to exploit this vulnerability to treat AML. Drug re-purposing screens have suggested the potential use of artesunate (ART) to inhibit mitochondrial respiration. We have explored the potential role of ART as an additive agent in treating AML in combination with conventional therapy. Through in-vitro and in-vivo mouse model studies, we demonstrate the mechanism and efficacy of these combinations and their potential to overcome venetoclax resistance. We further demonstrate the specificity of these combinations with minimal off-target effects on normal hematopoietic stem cells (HSC). These observations warrant exploration of the additive role of ART in clinical trials.

There is limited data on iron reduction therapy (IRT) after successful allogeneic haematopoietic stem cell transplantation (aHSCT) for patients with thalassemia major (TM). We present the long term outcome of IRT in 149 patients with TM who underwent aHSCT during January, 2001-December, 2012. The median age was 7 years (range:1–18) and 92 (61.7%) belonged to Pesaro class 3 with a median ferritin at aHSCT of 2480ng/ml (range:866–8921). IRT was reinitiated post-aHSCT at a median of 14 months (range:5–53) post aHSCT with phlebotomy alone in 10 (6.7%) patients or iron chelation alone in 60 (40.3%) patients while 79 (53%) were treated with the combination. Reduction in serum ferritin/month [absolute quantity (ng/ml/month) was as follows: 87 (range:33–195), 130 (range:17–1012) and 147 (range:27.7–1427) in the phlebotomy, chelation and combination therapy groups, respectively (p = 0.038). With a median follow up of 80 months (range:37–182), target ferritin level of <300ng/ml was achieved in 59(40%) while a level <500ng/ml was achieved in 88 patients (59%) in a median duration of 41 months of IRT (range: 3–136). Patients in class III risk category and higher starting serum ferritin levels (>2500ng/ml) were associated with delayed responses to IRT. Our data shows that IRT may be needed for very long periods in ex-thalassaemics to achieve target ferritin levels and should therefore be carefully planned and initiated as soon as possible after aHSCT. A combination of phlebotomy and iron chelators is more effective in reducing iron overload.

Improving clinical outcomes among high risk Class III β thalassemia major patients (Class IIIHR) receiving an allogeneic SCT remains a challenge. From October, 2009 a treosulfan based regimen (TreoFluT) was used for all consecutive Class III patients (n = 50). The clinical outcomes were compared with the historical conventional busulfan (BuCy) based regimen (n = 139). Use of TreoFluT was associated with a significantly reduced incidence of sinusoidal obstruction syndrome (SOS) among Class IIIHR cases (78% to 30%; P = 0.000) and early TRM (46% to 13%; p = 0.005). There was also a trend towards better engraftment in the Class IIIHR subset (P = 0.055). However, the use of bone marrow (BM) as source of stem cells along with the TreoFluT regimen was associated with 50% early mixed chimerism which reduced to 8.5% with the use of a peripheral blood stem cell graft (PBSC). Use of a PBSC graft was not associated with a significant increase in the incidence of acute or chronic graft versus host disease (GVHD). The overall and event free survival was significantly better among the Class IIIHR subset with the use of TreoFluT Vs. BuCy (86.6 ± 7.3 Vs. 39.4 ± 6.8%; P = 0.002 and 77.8 ± 8.8 Vs. 32.4 ± 6.5%; P = 0.003 respectively). A TreoFluT conditioning regimen with a PBSC graft can significantly improve clinical outcomes of Class IIIHR patients.

Introduction: BK polyomavirus-associated hemorrhagic cystitis (BKPyV-HC) is a well-recognized infective complication of hematopoietic cell transplant (HCT) with increased organ dysfunction and mortality. This study was performed to describe the local incidence, risk factors, and outcomes of BKPyV infection. Methods: This retrospective case-control study was conducted between 2007 and 2016 from a tertiary hospital in South India. We identified HCT recipients diagnosed with BKPyV-HC and compared them with recipients over the same period who did not develop BK virus infection matched for age, sex, diagnosis, and donor type. We collected data from central electronic medical records and databases maintained in the departments of hematology and virology. Results: Over the study period, 1276 transplants were performed, of which 262 patients (20.5%) developed HC and 105 (8.2%) were BKPyV-positive. Grade 3 HC was most commonly (57.1%) seen, and the median time to develop BKPyV-HC was 35 (range 0-858) days. Survival was significantly lower in the cases (42.9% vs. 61%, P < 0.05). On univariate analysis, the protective effect of nonmyeloablative conditioning (P = 0.04), residual disease at the time of transplant in malignant conditions (P = 0.001), lower CD34 dose (P = 0.006), presence of acute graft versus host disease (GVHD, P < 0.001), reactivation of cytomegalovirus infection (P < 0.001), and presence of bacterial urinary tract infection (UTI) (P < 0.001) were significant factors. Multivariate logistic regression confirmed the presence of acute GVHD (P = 0.041), bacterial UTI (P < 0.001), and residual disease (P = 0.009) at HCT as significant risk factors for BKPyV-HC. Conclusions: Our study affirms the homogeneity of BKPyV-HC disease in low- and middle-income HCT settings with prior reports and the need for therapeutic strategies to reduce its resultant mortality.

IntroductionDespite the known haemostatic action of emicizumab (Hemlibra) in haemophilia A patients, its role in the prevention and control of bleeding in high-demand haemostatic situations, such as major surgery, remains to be determined. Patients receiving regular emicizumab prophylaxis often require concomitant factor VIII (FVIII) therapy during major surgery to prevent uncontrolled bleeding and to promote postoperative healing. However, there are limited prospective surgical data relating to concomitant FVIII and emicizumab use. Simoctocog alfa (Nuwiq) is a B-domain deleted recombinant FVIII produced in a human cell line without chemical modification or protein fusion with proven efficacy as surgical prophylaxis in adult and paediatric patients. The Nuwiq for Perioperative management Of patients With haemophilia A on Emicizumab Regular prophylaxis (NuPOWER) study aims to examine perioperative efficacy and safety of simoctocog alfa in haemophilia A patients on emicizumab prophylaxis undergoing major surgery.Methods and analysisNuPOWER is a prospective, open-label, single-arm, multicentre study that will be conducted at approximately 15 centres worldwide. Up to 28 male patients ≥12 years with severe haemophilia A and no FVIII inhibitors will be recruited. All patients must be receiving regular emicizumab prophylaxis and scheduled to undergo a major surgical procedure during which concomitant simoctocog alfa will be administered. The primary endpoint is the overall haemostatic efficacy of simoctocog alfa, adjudicated by an independent data monitoring committee using a pre-defined algorithm, and will consider intraoperative and postoperative efficacy assessments by the surgeon and investigator, respectively. Secondary endpoints include intraoperative haemostatic efficacy, postoperative haemostatic efficacy, number of allogeneic blood products transfused, perioperative FVIII plasma levels (as measured by FVIII activity) and thrombin generation, and safety parameters. In the era of non-factor therapy, NuPOWER will generate valuable prospective data on concomitant use of simoctocog alfa and emicizumab prophylaxis in patients with severe haemophilia A undergoing major surgery.Ethics and disseminationEthical approval has been received from institutional review boards/independent ethics committees, and the study will be conducted in compliance with the Declaration of Helsinki. This work will be disseminated by publication of peer-reviewed manuscripts and presentations at scientific meetings.Trial registration numberCT EU 2022-502060-21-00; NCT05935358.