Cost-effectiveness analysis of emicizumab prophylaxis in patients with haemophilia A in India.

INTRODUCTION: Emicizumab is the initial subcutaneously administered bispecific antibody approved as a prophylactic treatment for patients with haemophilia A (PwHA). AIM: This study assessed the economic evaluation of emicizumab treatment for non-inhibitor severe haemophilia A (HA) patients in India. METHODS: A Markov model evaluated the cost-effectiveness of emicizumab prophylaxis compared to on-demand therapy (ODT), low-dose prophylaxis (LDP; 1565 IU/kg/year), intermediate-dose prophylaxis (IDP; 3915 IU/kg/year) and high-dose prophylaxis (HDP; 7125 IU/kg/year) for HA patients without factor VIII inhibitors. Inputs from HAVEN-1 and HAVEN-3 trials included transition probabilities of different bleeding types. Costs and benefits were discounted at a 3.5% annual rate. RESULTS: In the base-case analysis, emicizumab was cost-effective compared to HDP, with an incremental cost-effectiveness ratio (ICER) per quality-adjusted life-years (QALY) of Indian rupees (INR) 27,869. Compared to IDP, ODT and LDP, emicizumab prophylaxis could be considered a cost-effective option if the paying threshold is >1 per capita gross domestic product (GDP) with ICER/QALY values of INR 264,592, INR 255,876 and INR 305,398, respectively. One-way sensitivity analysis (OWSA) highlighted emicizumab cost as the parameter with the greatest impact on ICERs. Probabilistic sensitivity analysis (PSA) indicated that emicizumab had a 94.7% and 49.4% probability of being cost-effective at willingness-to-pay (WTP) thresholds of three and two-times per capita GDP. CONCLUSION: Emicizumab prophylaxis is cost-effective compared to HDP and provides value for money compared to ODT, IDP, and LDP for severe non-inhibitor PwHA in India. Its long-term humanistic, clinical and economic benefits outweigh alternative options, making it a valuable choice in resource-constrained settings.

Haemophilia care in Asia: Learning from clinical practice in some Asian countries.

BACKGROUND: The healthcare systems in Asia vary greatly due to the socio-economic and cultural diversities which impact haemophilia management. METHODS: An advisory board meeting was conducted with experts in haemophilia care from Asia to understand the heterogeneity in clinical practices and care provision in the region. FINDINGS: The overall prevalence of haemophilia in Asia ranges between 3 and 8.58/100,000 patients. Haemophilia A was more prevalent as compared to haemophilia B with a ratio of around 5:1. There is under-diagnosis in the region due to lack of diagnosis, registries and/or lack of appropriate facilities in suburban areas. Most patients are referred to the haematologists by their families or primary care physicians, while some are identified during bleeding episodes. Genetic testing faces obstacles like resource constraints, services available at limited centres and unwillingness of patients to participate. Prophylaxis is offered for people with haemophilia (PWH) with a severe bleeding phenotype. Recombinant factors are approved in most countries across the region and are the preferred therapy. The challenges highlighted for not receiving a high standard of care include patients' reluctance to use an intravenous treatment, poor patient compliance due to frequency of infusions, budget constraints and lack of funding, insurance, availability and accessibility of factor concentrates. Prevalence of neutralizing antibodies ranged from 5% to 20% in the region. Use of immune tolerance induction and bypassing agents to treat inhibitors depends on their cost and availability. CONCLUSION: Haemophilia care in Asia has evolved to a great extent. However, some challenges remain for which a strategic approach along with multi-stakeholder involvement are needed.

Interferon-gamma and perforin-positive T cells in acquired aplastic anemia: implication in therapeutic response.

Acquired aplastic anemia (aAA) is an autoimmune disease, characterized by infiltration of T lymphocytes in the bone marrow with destruction of hematopoietic stem cells by the effector cells. Interferon-gamma (IFN-γ) and perforin are important mediators of cell destruction. In this flow cytometry-based study, we have investigated the percentage of intracellular IFN-γ+ and perforin+ CD5+ T cells in peripheral blood of newly diagnosed aAA patients before and after immunosuppressive therapy (IST). Patients were categorized as per standard disease severity and response to IST. The median percentage of IFN-γ+ and perforin+ CD5+ T cells was higher in untreated patients compared to healthy controls. The percentage of these cells was also increased in untreated severe and very severe aplastic anemia when compared with non-severe aplastic anemia patients. In patients before and after IST the median percentage of T cells producing IFN-γ and perforin was elevated in non-responders as compared to partial plus complete responders. The higher percentage of IFN-γ+ and perforin+ CD5+ T cells may be useful as an early diagnostic marker for aberrant activation of immune system and predict poor response to IST in aAA patients, who will benefit from alternative therapy.

Shifting gears to differentiation agents in acute promyelocytic leukemia with resource constraints-a cohort study.

BACKGROUND: Treatment of acute promyelocytic leukaemia has emerged as a major success in hemato-oncology. While literature from the developed world boasts of outstanding outcomes, there is a paucity of data from the developing world. This study aimed to assess complications and outcomes of acute promyelocytic leukaemia in a resource-constrained setting. METHODS: We retrospectively collected data from patients diagnosed with APL from January 2016 to December 2020. RESULTS: Sixty-four patients were treated-32 in both the Sanz high and low-risk groups. In the Sanz low-risk group, 12.5% of patients received ATRA with daunorubicin and 81.25% received ATRA with ATO. In the Sanz high-risk group, 18.8% of patients received ATRA with daunorubicin, 34.3% received ATRA with daunorubicin and ATO while 40.6% received ATRA with ATO. 56.25% of patients developed differentiation syndrome. The incidence was higher in Sanz high-risk group as compared to Sanz low-risk group. 57.4% of patients had an infection at the time of presentation. 62.5% of patients developed neutropenic fever during treatment. 17.2% of patients developed pseudotumor cerebri. The 4-year EFS and OS were 71.25 and 73.13%, respectively. Sanz low-risk group had a better 4-year EFS and OS as compared to the Sanz high-risk group. Haemoglobin at presentation and Sanz high-risk group were associated with poorer outcomes with a hazard ratio of 0.8 and 3.1, respectively. Outcomes in high-risk patients were better with the use of ATRA + ATO + daunorubicin. CONCLUSION: In the Indian population, APL patients have a high incidence of differentiation syndrome, pseudotumor cerebri, and infections during induction. CR, EFS, and OS compared to the developed world can be achieved with optimal therapy. Low haemoglobin at presentation and Sanz high-risk group were associated with poorer outcomes. ATRA, ATO, and daunorubicin combination is the preferred protocol for treating high-risk patients.

COVID-19 infection in patients with haematological disease - A tertiary centre experience from north India.

This retrospective study was aimed to understand the clinical, laboratory, radiological parameters and the outcome of COVID-19 patients with underlying haematological disease. All patients with known haematological disease admitted with COVID-19-positive status from April to August 2020 in the COVID-19 facility of a tertiary care centre in north India, were included. Their medical records were analyzed for outcome and mortality risk factors. Fifty four patients, 37 males, were included in the study. Of these, 36 patients had haematological malignancy and 18 had benign disorder. Fever (95.5%), cough (59.2%) and dyspnoea (31.4%) were the most common symptoms. Nine patients had severe disease at diagnosis, mostly malignant disorders. Overall mortality rate was 37.0 per cent, with high mortality seen in patients with aplastic anaemia (50.0%), acute myeloid (46.7%) and lymphoblastic leukaemia (40.0%). On univariate analysis, Eastern Cooperative Oncology Group performance status >2 [odd ratio (OR) 11.6], COVID-19 severity (OR 8.2), dyspnoea (OR 5.7) and blood product transfusion (OR 6.4) were the predictors of mortality. However, the presence of moderate or severe COVID-19 (OR 16.6, confidence interval 3.8-72.8) was found significant on multivariate analysis. The results showed that patients with haematological malignancies and aplastic anaemia might be at increased risk of getting severe COVID-19 infection and mortality as compared to the general population.

Thalassemia in India.

Management and control of hemoglobinopathies are a challenge in India where 67.0% of people reside in rural regions. The GDP spent on health is one of the lowest (1.3%) resulting in high out-of-pocket expenses. The ß-thalassemias are prevalent with an estimated 7500-12000 new births each year. Hb S (HBB: c.20A>T) and Hb E (HBB: c.79G>A) are also common regionally. Over 80 ß-thalassemia (ß-thal) mutations have been characterized in Indians. The δ gene mutations are increasingly being described and their coinheritance in ß-thal carriers leads to a reduction in Hb A2 levels and a misdiagnosis of carriers. Around 15-20 centers offer prenatal diagnosis (PND) mainly in urban regions. The projected annual cost of care of ß-thal patients over a decade (2016-2026) will increase from INR30,000 (US$448) million to INR55,000 (US$820) million if all patients are adequately treated. Cost comparisons are difficult to make with other international studies as the standard of care, cost of medicines and other services vary in different countries. Several centers provide hematopoietic stem cell transplants (HSCTs) for thalassemias, however, only around 250 HSCTs are done annually. Although the cost is high, financial assistance is available for a few patients. There are disparities in the quality of care and to address this a National Policy has been proposed for the management and prevention of hemoglobinopathies that will embark on a comprehensive program, providing adequate care and augmenting the existing public health care services. It will also include training, genetic counseling and easier access to preventive options and a National Registry.

Role of CMR feature-tracking derived left ventricular strain in predicting myocardial iron overload and assessing myocardial contractile dysfunction in patients with thalassemia major.

OBJECTIVE: Myocardial iron overload (MIO) in thalassemia major (TM) may cause subclinical left ventricular (LV) dysfunction which manifests with abnormal strain parameters before a decrease in ejection fraction (EF). Early detection of MIO using cardiovascular magnetic resonance (CMR)-T2* is vital. Our aim was to assess if CMR feature-tracking (FT) strain correlates with T2*, and whether it can identify early contractile dysfunction in patients with MIO but normal EF. METHODS: One hundred and four consecutive TM patients with LVEF > 55% on echocardiography were prospectively enrolled. Those fulfilling the inclusion criteria underwent CMR, with T2* being the gold standard for detecting MIO. Group 1 included patients without significant MIO (T2* > 20 ms) and group 2 with significant MIO (T2* < 20 ms). RESULTS: Eighty-six patients (mean age, 17.32 years, 59 males) underwent CMR. There were 68 (79.1%) patients in group 1 and 18 (20.9%) in group 2. Fourteen patients (16.3%) had mild-moderate MIO, and four (4.6%) had severe MIO. Patients in group 2 had significantly lower global radial strain (GRS). Global longitudinal strain (GLS) and global circumferential strain (GCS) did not correlate with T2*. T1 mapping values were significantly lower in patients with T2* < 10 ms than those with T2* of 10-20 ms; however, FT-strain values were not significantly different between these two groups. CONCLUSION: CMR-derived GRS, but not GLS and GCS, correlated with CMR T2*. GRS is significantly decreased in TM patients with MIO and normal EF when compared with those without. FT-strain may be a useful adjunct to CMR T2* and maybe an early marker of myocardial dysfunction in TM. KEY POINTS: • A global radial strain of < 29.3 derived from cardiac MRI could predict significant myocardial iron overload in patients with thalassemia, with a sensitivity of 76.5% and specificity of 66.7%. • Patients with any myocardial iron overload have significantly lower GRS, compared to those without, suggesting the ability of CMR strain to identify subtle myocardial contractile disturbances. • T1 and T2 mapping values are significantly lower in those with severe myocardial iron than those with mild-moderate iron, suggesting a potential role of T1 and T2 mapping in grading myocardial iron.

Transfusion practices during the COVID-19 pandemic: An experience from a hematology daycare in India.

The Coronavirus disease-19 (COVID-19) pandemic has in multiple ways affected healthcare delivery to non-COVID patients throughout the world. Adequate transfusion services are fundamental in ongoing therapy of patients with hematological ailments. We present the transfusion services in the hematology daycare under the department of Hematology and supported by the Blood Bank at our institution for the period 12th April 2020-30th June 2020, which saw the stringent lockdown and unlocking Phase I in India, declared in lieu of the pandemic. A 56 % reduction in total transfusion sessions was observed in 2020 (588 sessions given to 176 patients) compared to 1336 sessions in 516 patients over the same period in 2019. The reductions were seen across the different blood components (packed red blood cells [PRBC]: 585 vs. 1840, platelet rich plasma: 372 vs. 1313, single donor platelet 18 vs. 16), with a significant reduction in the mean PRBC transfused per PRBC transfusion session (1.11 vs 1.99, p<0.001) in 2020, compared to 2019. There were however no major differences in the transfusion practices across the different phases of the lockdown. Our study highlights the detrimental reduction in transfusion services due to the COVID-19 pandemic and related lockdown and showcases the remedial strategies taken to maximize transfusion support to patients during this period. Our observations might help to provide insights to adequately combat possible similar adverse situations in the future.

Comparison of CRP and procalcitonin for etiological diagnosis of fever during febrile neutropenia in hematology patients- an experience from a tertiary care center in Northern India.

INTRODUCTION: Febrile neutropenia is a common cause in morbidity and mortality during treatment of hematological neoplasms. METHODS: Subjects included all cases admitted under hematology department with febrile neutropenia from February to June 2018. Each febrile episode was investigated by standard investigations (Blood culture, Chest x ray etc.); Procalcitonin (PCT) and c reactive protein (CRP) was sent at fever onset 0, 24, 48 h, day 7 and day 14. RESULTS: Data was analyzed for 52 febrile episodes in 50 patients. PCT cut off value at 24 h of ≤1.2 ng/ml had a sensitivity and specificity of 62.5% and 87.5% for discriminating Invasive fungal infection (IFI) and Microbiologically documented infection (MDI) (p = 0.033). PCT had a negative predictive value of 70% for the diagnosis of IFI as compared to MDI. CRP cut off >160 mg/dl at 48 h was suggestive of fever due to fungal infection with a sensitivity of 100%, specificity of 48%, PPV of 33.3% and NPV of 100%. CRP at 24 and 48 h of fever was useful to distinguish non-infectious causes of fever from infectious causes. CONCLUSION: PCT at 24 h and CRP at 48 h was useful in identifying fungal infection. CRP was a better marker when compared to PCT for identifying disease fever.

Chloroquine and Hydroxychloroquine for the Treatment of COVID-19: a Systematic Review and Meta-analysis.

BACKGROUND: There is no effective therapy for COVID-19. Hydroxychloroquine (HCQ) and chloroquine (CQ) have been used for its treatment but their safety and efficacy remain uncertain. OBJECTIVE: We performed a systematic review to synthesize the available data on the efficacy and safety of CQ and HCQ for the treatment of COVID-19. METHODS: Two reviewers searched for published and pre-published relevant articles between December 2019 and 8 June 2020. The data from the selected studies were abstracted and analyzed for efficacy and safety outcomes. Critical appraisal of the evidence was done by Cochrane risk of bias tool and Newcastle Ottawa Scale. The quality of evidence was graded as per the GRADE approach. RESULTS: We reviewed 12 observational and 3 randomized trials which included 10,659 patients of whom 5713 received CQ/HCQ and 4966 received only standard of care. The efficacy of CQ/HCQ for COVID-19 was inconsistent across the studies. Meta-analysis of included studies revealed no significant reduction in mortality with HCQ use [RR 0.98 95% CI 0.66-1.46], time to fever resolution (mean difference - 0.54 days (- 1.19-011)) or clinical deterioration/development of ARDS with HCQ [RR 0.90 95% CI 0.47-1.71]. There was a higher risk of ECG abnormalities/arrhythmia with HCQ/CQ [RR 1.46 95% CI 1.04 to 2.06]. The quality of evidence was graded as very low for these outcomes. AUTHORS' CONCLUSION: The available evidence suggests that CQ or HCQ does not improve clinical outcomes in COVID-19. Well-designed randomized trials are required for assessing the efficacy and safety of HCQ and CQ for COVID-19.

Outcomes of paroxysmal nocturnal hemoglobinuria in the pediatric age group in a resource-constrained setting.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare acquired clonal stem cell disorder. Eculizumab and bone marrow transplantation are disease-modifying treatments for PNH but may not be readily available in resource-constrained settings. Of 52 pediatric patients with PNH, 20 had classical PNH and 32 had PNH/aplastic anemia (PNH/AA). Median time to diagnosis was 30 months in classical PNH patients. Renal failure was present in four patients (20%). Six (30%) achieved complete response, 10 (50%) achieved partial response with androgens in classical PNH. Two underwent allogenic stem cell transplantation. In the PNH/AA group, 16 (50%) were in CR and seven (21%) were in PR with anti-thymocyte globulin ± cyclosporine.

Pediatric myelofibrosis: WHO 2024 update on myeloproliferative neoplasms calling?

OBJECTIVES: Pediatric myelofibrosis is a rare entity with the largest reported series of 19 cases. We describe here the clinicopathological spectrum and outcomes of 15 cases of pediatric myelofibrosis. METHODS: Case files of myelofibrosis of patients less than 18 years were retrieved from January 2016 to January 2019, and patients with idiopathic myelofibrosis after exhaustive work-up were studied. Their clinicopathological profiles were studied and then followed up for resolution and malignant transformation. RESULTS: Of the 15 cases of idiopathic myelofibrosis, transfusion-dependent anemia (14/15) was most common presentation. Only one patient showed leukoerythroblastosis with dacryocytes. Myeloid hyperplasia was seen in 13 of 15 patients and megakaryocytic hyperplasia in 10 patients. Dysmegakaryopoiesis was seen in 8 of 15 patients, and only three had small loose megakaryocytic clustering. None showed hyperchromatic megakaryocytes, intrasinusoidal hematopoiesis, or osteosclerosis. One patient with trisomy 8 tested positive for JAK2V617F. Bone marrow biopsy was hypercellular in 13, and 8 had world health organization (WHO) MF-3 fibrosis. None of the patients developed malignancy, one had spontaneous resolution, and one patient required allogenic stem cell transplant. CONCLUSIONS: Pediatric myelofibrosis is a distinct entity from primary myelofibrosis in adults and merits mention in the WHO manual as a distinct entity.

Targeting of stromal versican by miR-144/199 inhibits multiple myeloma by downregulating FAK/STAT3 signalling.

The abnormal growth of malignant plasma cells in Multiple Myeloma (MM) requires bone marrow (BM) niche consisting of proteoglycans, cytokines, etc. Versican (VCAN), a chondroitin sulphate proteoglycan promotes progression in solid tumours but there is dearth of literature in MM. Hence, we studied the involvement of VCAN in MM and its regulation by microRNAs as a therapeutic approach. Thirty MM patients and 20 controls were recruited and BM stromal cells (BMSCs) were isolated by primary culture. Molecular levels of VCAN, miR-144, miR-199 & miR-203 were determined in study subjects and cell lines. The involvement of VCAN in myeloma pathogenesis was studied using BMSCs-conditioned medium (BMSCs-CM) and VCAN-neutralizing antibody or microRNA mimics. Elevated expression of VCAN was observed in patients especially in BM stroma while microRNA expression was significantly lower and showed negative correlation with VCAN. Moreover, BMSCs-CM showed the presence of VCAN which upon supplementing to MM cells alter parameters in favour of myeloma progression, however, this effect was neutralized by VCAN antibody or miR (miR-144 and miR-199) mimics. The downstream signalling of VCAN was found to activate FAK and STAT3 which subsides by using VCAN antibody or miR mimics. The neutralization of oncogenic effect of BMSCs-CM by VCAN blockage affirms its plausible role in progression of MM. VCAN was observed as a paracrine mediator in the cross-talk of BMSCs and myeloma cells in BM microenvironment. Therefore, these findings suggest exploring VCAN as novel therapeutic target and utilization of microRNAs as a therapy to regulate VCAN for better management of MM.

Anti-interleukin-6 therapies for Covid-19: A systematic review, critical appraisal and meta-analysis.

Background: . Coronavirus disease 2019 (Covid-19) has emerged as a pandemic by end-January 2020. Of the infected patients, 10%-15% may develop severe or critical illness. So far, no definite treatment is available for Covid-19. Cytokine release syndrome may underlie the pathogenesis of severe and critical disease. Anti-interleukin (IL)-6 therapies are being tried to improve clinical outcomes. Methods: . We did a systematic review to identify the available literature on anti-IL-6 therapies in the treatment of Covid-19 and used the GRADE method to assess the quality of evidence. Results: . Four case series and 10 case reports were identified. On critical assessment, we found that these studies reported some beneficial effect of anti-IL-6 therapy, but all the studies had a high risk of bias. The pooled estimate showed that 42% of patients improved but with a very wide confidence interval (CI) (95% CI 1%-91%) and substantial heterogeneity (I2 = 95%). The overall quality of evidence was graded as 'very low'. Conclusions: . Although promising, anti-IL-6 therapy for Covid-19 needs to be tested in randomized controlled trials to provide robust evidence.

Efficacy and safety of antivirals for Covid-19: A systematic review and meta-analysis.

Background: Coronavirus disease 2019 (Covid-19) has led to a severe medical, social and economic crisis globally. Use of antivirals has given inconsistent results; thus systematic summaries of available evidence are required for any recommendations for treatment. We conducted a systematic review and meta-analysis on the use of antivirals for Covid-19. Methods: The databases we searched were-Medline, Embase, Cochrane CENTRAL and Medrxiv. Title/abstract screening, full-text screening and data abstraction were carried out in duplicate by two researchers. Pooled effect sizes and 95% confidence intervals (CI) were calculated using the Mantel-Haenszel method of random effects for meta-analysis. Results: Twenty studies were found eligible for inclusion: 6 randomized controlled trials, 9 cohort studies and 5 case series. Moderate-quality evidence suggests a likely clinical benefit from the use of remdesivir in improving the number of recoveries (RR 1.18; 95% CI 1.07-1.31; I2 = 0%) and time to recovery in days (median -3.02; 95% CI -4.98 to -1.07; I2 = 97%). A possibility of lower mortality is suggested by low-quality evidence with remdesivir (RR 0.74; 95% CI 0.40-1.37, I2 = 58%). Moderate-quality evidence suggests no certain benefit of using lopinavir/ritonavir for Covid-19 compared to arbidol, lopinavir/ritonavir combined with arbidol or other medications used as controls. Conclusion: Further evidence from randomized controlled trials is required for all antivirals to treat Covid-19. At present, remdesivir seems more promising than other antivirals.

Convalescent plasma therapy for Covid-19: A systematic review.

Background: Covid-19 has emerged as a pandemic affecting more than 20 million people till date with few, if any, proven therapy. Convalescent plasma (CP) containing antibodies against the virus has been used with some success. We did a systematic review to synthesize the available data on CP therapy for treatment of Covid-19 to study the efficacy and safety outcomes. Methods: Two reviewers searched the published and pre-published literature between 1 January 2019 and 23 June 2020 for studies comparing the use of CP with standard therapy for Covid-19 patients. Data from the selected studies were abstracted and analysed for efficacy and safety outcomes. Critical appraisal of the evidence was done by using the Joanna Briggs Institute tool and the quality of evidence was graded as per GRADE. Results: We found 13 case series and 1 randomized trial that fulfilled our search criteria. Of the 12 case series with a total of 264 patients that reported the efficacy outcomes, 11 studies showed favourable results with survival benefit. The only RCT with 103 patients did not show any mortality benefit but was terminated early prior to complete enrolment. A single large study of 5000 patients reported safety outcomes and showed no major adverse events in patient streated with CP. Conclusion: There is very low-quality evidence to suggest efficacy and safety of CP in patients with Covid-19 infection. Well-designed randomized trials are urgently needed to provide robust data.

Concomitant Existence of Paroxysmal Nocturnal Hemoglobinuria in a Patient with Hb E (HBB: c.79G>A) Trait.

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal disorder that manifests with bone marrow failure, thrombosis and hemolysis. We present a 28-year-old male who presented with weakness, jaundice and transfusion dependence. On initial investigation, he was found to have anemia with jaundice with hemoglobin (Hb) capillary zone electrophoresis suggestive of Hb E (HBB: c.79G>A) trait. The same anomaly was also found in his mother. However, transfusion requirement was an unusual feature in the patient. As his corrected reticulocyte count was raised along with lactate dehydrogenase (LDH), which was suggestive of a hemolytic process, he was worked-up for the same. However, the direct Coombs test was negative. A bone marrow aspiration and biopsy was done to rule out hypersplenism but it revealed erythroid hyperplasia with reduced iron stores despite normal ferritin and iron studies. This was unusual as the patient had anemia requiring transfusions. He had no history of hemoglobinuria but a PNH by flowcytomety revealed a large clone of 81.2% in granulocytes and 88.5% in monocytes. The patient was started on Danazol and steroids for anemia which improved. He was counseled for matched sibling stem cell transplant. He had a full match with his brother. At the time of this study he awaits his transplant.

A Randomized Trial of Factor VIII and Neutralizing Antibodies in Hemophilia A.

BACKGROUND: The development of neutralizing anti-factor VIII alloantibodies (inhibitors) in patients with severe hemophilia A may depend on the concentrate used for replacement therapy. METHODS: We conducted a randomized trial to assess the incidence of factor VIII inhibitors among patients treated with plasma-derived factor VIII containing von Willebrand factor or recombinant factor VIII. Patients who met the eligibility criteria (male sex, age <6 years, severe hemophilia A, and no previous treatment with any factor VIII concentrate or only minimal treatment with blood components) were included from 42 sites. RESULTS: Of 303 patients screened, 264 underwent randomization and 251 were analyzed. Inhibitors developed in 76 patients, 50 of whom had high-titer inhibitors (≥5 Bethesda units). Inhibitors developed in 29 of the 125 patients treated with plasma-derived factor VIII (20 patients had high-titer inhibitors) and in 47 of the 126 patients treated with recombinant factor VIII (30 patients had high-titer inhibitors). The cumulative incidence of all inhibitors was 26.8% (95% confidence interval [CI], 18.4 to 35.2) with plasma-derived factor VIII and 44.5% (95% CI, 34.7 to 54.3) with recombinant factor VIII; the cumulative incidence of high-titer inhibitors was 18.6% (95% CI, 11.2 to 26.0) and 28.4% (95% CI, 19.6 to 37.2), respectively. In Cox regression models for the primary end point of all inhibitors, recombinant factor VIII was associated with an 87% higher incidence than plasma-derived factor VIII (hazard ratio, 1.87; 95% CI, 1.17 to 2.96). This association did not change in multivariable analysis. For high-titer inhibitors, the hazard ratio was 1.69 (95% CI, 0.96 to 2.98). When the analysis was restricted to recombinant factor VIII products other than second-generation full-length recombinant factor VIII, effect estimates remained similar for all inhibitors (hazard ratio, 1.98; 95% CI, 0.99 to 3.97) and high-titer inhibitors (hazard ratio, 2.59; 95% CI, 1.11 to 6.00). CONCLUSIONS: Patients treated with plasma-derived factor VIII containing von Willebrand factor had a lower incidence of inhibitors than those treated with recombinant factor VIII. (Funded by the Angelo Bianchi Bonomi Foundation and others; ClinicalTrials.gov number, NCT01064284; EudraCT number, 2009-011186-88.).

Engulfment of Hb-activated platelets differentiates monocytes into pro-inflammatory macrophages in PNH patients.

The distinct response shown by different phenotypes of macrophages and monocytes under various clinical conditions has put the heterogeneity of these cells into focus of investigation for several diseases. Recently, we have described that after engulfing hemoglobin (Hb)-activated platelets, classical monocytes differentiated into pro-inflammatory phenotypes, which were abundant in the circulation of paroxysmal nocturnal hemoglobinuria (PNH) and sickle cell disease patients. Our current study shows that upon engulfment of Hb-activated platelets, monocytes differentiate into M1-macrophages under M1-polarization stimulus (GM-CSF, IFN-γ + LPS). When grown under M2-polarization stimulus (M-CSF, IL-4 + IL13), the cells exhibited an M1-like phenotype, secreted elevated levels of pro-inflammatory cytokines including TNF-α and IL-1ß, and displayed loss of the secretion of cytokine such as IL-10 and also phagocytic ability unlike the conventional M2 macrophages. Interestingly, when differentiated under the above polarization stimulus, monocytes from PNH patients expressed high levels of CD80 and phospho-STAT1, like M1 macrophages. Hemolytic mice also exhibited a gradual increase in monocyte-platelet aggregates in circulation and accumulation of CD80high macrophages in thioglycollate-induced inflamed peritoneum. The spleen of the mice was also populated by CD80high macrophages with compromised phagocytic capacity. Our findings suggest that the hemolytic environment and specifically the Hb-activated platelets, which are abundant in circulation during intravascular hemolysis, closely regulate monocyte differentiation.

Pulmonary Langerhans Cell Histiocytosis: A not so Benign Lesion.

Langerhans cell histiocytosis is a multisystem disease affecting young children. Lung involvement has a myriad of manifestations and the outcomes for these patients have been poorly defined. We present a 2-year-old child who presented with multisystem disease with multiple lung cysts. Treatment consisted of multiagent chemotherapy for 18 months and was associated with a slow but favorable response.