Swiss Survey on current practices and opinions on clinical constellations triggering the search for PNH clones.

This national survey investigated the current practice in Switzerland by collecting participants' opinions on paroxysmal nocturnal hemoglobinuria (PNH) clone assessment and clinical practice. Aim: This study aimed to investigate clinical indications prompting PNH clones' assessment and physician's accessibility of a flow cytometry facility, and also to understand clinical attitudes on the follow-up (FU) of patients with PNH clones. Methods: The survey includes 16 multiple-choice questions related to PNH and targets physicians with a definite level of experience in the topic using two screener questions. Opinion on clinical management was collected using hypothetical clinical situations. Each participant had the option of being contacted to further discuss the survey results. This was an online survey, and 264 physicians were contacted through email once a week for 5 weeks from September 2020. Results: In total, 64 physicians (24.2%) from 23 institutions participated (81.3% hematologists and 67.2% from university hospitals). All had access to flow cytometry for PNH clone testing, with 76.6% having access within their own institution. The main reasons to assess for PNH clones were unexplained thrombosis and/or hemolysis, and/or aplastic anemia (AA). Patients in FU for PNH clones were more likely to be aplastic anemia (AA) and symptomatic PNH. In total, 61% of the participants investigated PNH clones repetitively during FU in AA/myelodysplastic syndromes patients, even when there was no PNH clone found at diagnosis, and 75% of the participants tested at least once a year during FU. Opinions related to clinical management were scattered. Conclusion: The need to adhere to guidelines for the assessment, interpretation, and reporting of PNH clones emerges as the most important finding, as well as consensus for the management of less well-defined clinical situations. Even though there are several international guidelines, clear information addressing specific topics such as the type of anticoagulant to use and its duration, as well as the indication for treatment with complement inhibitors in some borderline situations are needed. The analysis and the discussion of this survey provide the basis for understanding the unmet needs of PNH clone assessment and clinical practice in Switzerland.

Low Plasma Levels of Hyaluronic Acid Might Rule Out Sinusoidal Obstruction Syndrome after Hematopoietic Stem Cell Transplantation.

Background: Sinusoidal obstructive syndrome (SOS) is a potentially fatal complication secondary to hematopoietic stem cell transplant (HSCT) conditioning. Endothelial damage plasma biomarkers such as plasminogen activator inhibitor-1 (PAI-1), hyaluronic acid (HA), and vascular adhesion molecule-1 (VCAM1) represent potential diagnostic tools for SOS. Methods: We prospectively collected serial citrated blood samples (baseline, day 0, day 7, and day 14) in all adult patients undergoing HSCT at La Paz Hospital, Madrid. Samples were later analyzed by ELISA (enzyme-linked immunosorbent assay) for HA, VCAM1, and PAI-1 concentrations. Results: During sixteen months, we prospectively recruited 47 patients. Seven patients (14%) were diagnosed with SOS according to the EBMT criteria for SOS/VOD diagnosis and received treatment with defibrotide. Our study showed a statistically significant elevation of HA on day 7 in SOS patients, preceding clinical SOS diagnosis, with a sensitivity of 100%. Furthermore, we observed a significant increase of HA and VCAM1 levels on day 14. Regarding risk factors, we observed a statistically significant association between SOS diagnosis and the fact that patients received 3 or more previous lines of treatment before HSCT. Conclusions: The early significant increase in HA levels observed opens the door to a noninvasive peripheral blood test which could have the potential to improve diagnosis and facilitate prophylactic and therapeutic management of SOS before clinical/histological damage is established.

Defibrotide Shows Efficacy in the Prevention of Sinusoidal Obstruction Syndrome After Allogeneic Hematopoietic Stem Cell Transplantation: A Retrospective Study.

Sinusoidal obstruction syndrome (SOS), also known as hepatic veno-occlusive disease (VOD), is a well-known complication of allogeneic hematopoietic stem cell transplantation (HSCT) associated with a mortality rate of up to 85%.  Defibrotide has shown efficacy in treatment of SOS/VOD. Moreover, evidence exists supporting the efficacy of defibrotide as SOS/VOD prophylaxis. We have previously reported our single center experience on 52 HSCT recipients receiving defibrotide as SOS/VOD prophylaxis, which has shown that the patients did not develop any SOS/VOD under this prophylaxis. The aim of the present study was to see if we can confirm the previous results, mainly on the decrease incidence of SOS/VOD, as well as improve event-free survival (EFS) on a larger study population. We extended our previous study in a single-center retrospective analysis to include 237 consecutive patients (248 transplantations) who underwent transplantation between 1999 and 2009 for hematological diseases and receiving intravenous defibrotide as prophylaxis. This cohort was compared to 241 patients (248 transplantations) treated before 1999 or after 2009 when defibrotide prophylaxis was not routinely used in our center. Median follow-up for the study group was 10 (range 2-16) years and for the control group 2.7 (range 1-18) years. None of the 237 patients in the defibrotide group developed SOS/VOD. The cumulative incidence (CI) of SOS/VOD was 0% in the defibrotide group as compared to 4.8% (95% confidence interval [CI], 2.6-8%; P= .00046) in the control group. There was also a better 1-year EFS with 38% (95% CI, 32%-44%) in the defibrotide group versus 28% (95% CI, 22%-34%) (P= .00969) and decreased cumulative incidence of acute graft-versus-host disease (GvHD) in the defibrotide group 31% (95% CI, 25%-37%) versus 42% (95% CI, 36%-48%) (P= .026). The 1-year overall survival, relapse incidence, and non-relapse mortality were not statistically different. Multivariable analysis, performed taking into account clinical factors known to influence the risk of SOS/VOD, confirmed the favorable impact of defibrotide on SOS/VOD (HR 1.38e-08 [95% CI, 3.28e-09-5.80e-08]; P< .00001). Conversely, multivariable analysis failed to confirm the impact of defibrotide on 1-year EFS or acute GvHD. This large retrospective study on SOS/VOD-prophylaxis with defibrotide suggests that this approach may be of benefit. These results need to be confirmed in a prospective randomized trial.

Real-world study of children and young adults with myeloproliferative neoplasms: identifying risks and unmet needs.

Myeloproliferative neoplasms (MPNs) are uncommon in children/young adults. Here, we present data on unselected patients diagnosed before 25 years of age included from 38 centers in 15 countries. Sequential patients were included. We identified 444 patients, with median follow-up 9.7 years (0-47.8). Forty-nine (11.1%) had a history of thrombosis at diagnosis, 49 new thrombotic events were recorded (1.16% patient per year [pt/y]), perihepatic vein thromboses were most frequent (47.6% venous events), and logistic regression identified JAK2V617F mutation (P = .016) and hyperviscosity symptoms (visual disturbances, dizziness, vertigo, headache) as risk factors (P = .040). New hemorrhagic events occurred in 44 patients (9.9%, 1.04% pt/y). Disease transformation occurred in 48 patients (10.9%, 1.13% pt/y), usually to myelofibrosis (7.5%) with splenomegaly as a novel risk factor for transformation in essential thrombocythemia (ET) (P= .000) in logistical regression. Eight deaths (1.8%) were recorded, 3 after allogeneic stem cell transplantation. Concerning conventional risk scores: International Prognostic Score for Essential Thrombocythemia-Thrombosis and new International Prognostic Score for Essential Thrombocythemia-Thrombosis differentiated ET patients in terms of thrombotic risk. Both scores identified high-risk patients with the same median thrombosis-free survival of 28.5 years. No contemporary scores were able to predict survival for young ET or polycythemia vera patients. Our data represents the largest real-world study of MPN patients age < 25 years at diagnosis. Rates of thrombotic events and transformation were higher than expected compared with the previous literature. Our study provides new and reliable information as a basis for prospective studies, trials, and development of harmonized international guidelines for the specific management of young patients with MPN.

A Unique Case of Acquired Hemophilia A Presenting with Transient Ischemic Attack.

Acquired hemophilia A (AHA) is a rare but serious condition, usually associated with significant spontaneous or traumatic bleeding and a high mortality rate. In this report, we describe the case of an elderly patient presenting a transient ischemic attack concurrently with AHA. A thrombotic event in AHA is occasionally associated with the use of bypassing agents for treatment, but a spontaneous thrombotic event has not ever been described.

Evaluation of Disease Risk Comorbidity Index after Allogeneic Stem Cell Transplantation in a Cohort with Patients Undergoing Transplantation with In Vitro Partially T Cell Depleted Grafts.

Outcomes of hematopoietic stem cell transplantation (HSCT) are influenced by comorbidities, disease type, and status at transplantation. Several prognostic scores can be used, such as the disease risk index (DRI) or the hematopoietic cell transplantation-specific comorbidity index (HCT-CI). Recently, a new prognostic tool, the disease risk comorbidity index (DRCI), combining the DRI and the HCT-CI, was published. The DRCI determines 6 patient groups (very low risk [VLR], low risk [LR], intermediate risk 1 [IR-1], intermediate risk 2 [IR-2], high risk [HiR], and very high risk [VHR]) with a significant predictive value for overall survival (OS), disease-free survival (DFS), relapse incidence (RI), and graft-versus-host disease-free/relapse-free survival (GRFS). However, the DRCI has not been evaluated for patients allografted with partially in vitro T cell depleted (pTDEP) grafts. In our center, we offer pTDEP to reduce graft-versus-host disease for patients in complete remission at transplant time. In this retrospective study, we investigated the DRCI in 404 adult patients (including 37.6% pTDEP) undergoing a first HSCT for hematological malignancies from 2008 to 2018. Because of the small number of patients in LR, VLR and LR were combined for analysis. In the entire cohort, 2-year OS was 84.4% (95% CI, 71.6% to 97.2%) for LR, 61.6% (54.8% to 68.4%) for IR-1, 45.7% (33.3% to 58.1%) for IR-2, 31% (19.4% to 42.6%) for HiR, and 30.9% (14.5% to 47.3%) for VHR (P < .001). In addition, the DRCI was predictive of DFS, RI, and GRFS but not of nonrelapsed mortality and graft-versus-host disease. Our study confirms similar results with the original publication but gives less accurate prognosis information than the DRI and HCT-CI when used separately. In conclusion, the DRCI does not seem to offer more relevant information than the DRI and HCT-CI to help physicians and patients for the HSCT decision.

COVID-19 infection and treatment with hydroxychloroquine cause severe haemolysis crisis in a patient with glucose-6-phosphate dehydrogenase deficiency.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an inherited genetic disorder caused by red cell enzymatic defects and is associated with haemolytic crisis when patients are exposed to oxidative agents (fava beans, drugs, infections). Hydroxychloroquine is suspected to trigger haemolytic crisis in G6PD-deficient patients, and off-label administration of this drug to patients infected with the novel coronavirus (SARS-CoV-2) could cause concern. We report here the first case of severe haemolytic crisis in a patient with G6PD deficiency, initiated by severe COVID-19 infection and hydroxychloroquine use. With worldwide spread of COVID-19, especially in regions with a high prevalence of G6PD deficiency, our case should alert physicians to this possible correlation.

Partial T-cell depletion improves the composite endpoint graft-versus-host disease-free, relapse-free survival after allogeneic hematopoietic stem cell transplantation.

Graft-versus-host disease (GvHD)-free, relapse-free survival (GRFS) is a recently reported composite endpoint that allows to simultaneously estimate risk of death, relapse and GvHD after allogeneic hematopoietic stem cell transplantation (HSCT). In this retrospective study comprising 333 patients transplanted for hematologic malignancies, we compared GRFS in patients receiving partial T-cell-depleted (pTCD) grafts with patients receiving T-cell-replete grafts (No-TCD). pTCD was associated with a significantly improved GRFS. The beneficial effect of pTCD on GRFS remained highly significant in multivariable analysis taking into account clinical factors differing between patient groups. We observed no effect of pTCD on overall survival, progression-free survival, and relapse cumulative incidence, while non-relapse mortality cumulative incidence was significantly lower in patients receiving pTCD. The results of our retrospective analysis suggest that pTCD could improve GRFS in allogeneic HSCT recipients without significantly affecting OS and PFS, thus improving patients' quality of life without impairing the curative potential of allogeneic HSCT.

[Splanchnic vein thrombosis]. / Thromboses veineuses splanchniques.

Splanchnic vein thromboses include thrombosis of the portal venous system (including the portal, mesenteric and splenic vein) and hepatic vein thrombosis (also called Budd-Chiari syndrome). They are rare manifestations of venous thromboembolism. These thromboses are frequently associated with local or systemic factors. The therapeutic approach is often complex due to heterogeneity of patients and limited available data in the literature. The cornerstone of treatment is anticoagulation. However, the bleeding risk, related to portal hypertension, should be accurately assessed to individualize the treatment. A multidisciplinary consultation team including several specialists is provided at the University Hospitals of Geneva for the optimal management of those patients.

Les thromboses veineuses splanchniques sont une forme rare de maladie thromboembolique veineuse. Elles incluent les thromboses porto-mésentériques (thrombose de la veine porte et/ou de la veine mésentérique supérieure et/ou de la veine splénique) et les thromboses des veines hépatiques (Budd-Chiari). Elles peuvent être favorisées par des causes locales ou systémiques. L'approche thérapeutique est souvent complexe en raison de l'hétérogénéité des patients et des données limitées sur le sujet. Le traitement repose sur l'anticoagulation, qui doit être individualisée en fonction du risque hémorragique du patient, notamment en présence d'hypertension portale concomitante. Une consultation multidisciplinaire est en place aux Hôpitaux universitaires de Genève et permet d'optimiser la prise en charge de ces patients.

Disease characteristics and outcomes in younger adults with primary and secondary myelofibrosis.

Myelofibrosis (MF) is a rare haematopoietic disorder, commonly diagnosed in the 6th decade: less than 20% are diagnosed before the age of 50 years. In this retrospective study we included all patients given a diagnosis of World Health Organization-defined primary or secondary MF when aged ≤50 years. Forty-three patients with a median age of 43 years were included. Median follow up was 44 months. Twenty-two (51%) harboured the JAK2 V617F mutation, 18/43 (42%) CALR, 0/43 (0%) MPL mutations and 3/43 (7%) were 'Triple Negative' (TN). At the time of diagnosis, no significant differences existed in haematological and clinical phenotypes between JAK2, CALR and TN patients. The frequency of splenomegaly was greater (P = 0·047) in the JAK2-mutated group compared to CALR-mutated patients. In the whole cohort, the 5-year probability of developing anaemia, thrombocytopenia and marked leucocytosis was 24%, 10% and 13% respectively. Finally, the cumulative incidence of thrombotic events and progression to acute myeloid leukaemia was 1% and 0·5% patient-year respectively. No death was reported during the follow-up. These findings suggest that MF in younger patients may have a more indolent course when compared to older patients.

Ruxolitinib: evolution or revolution in treatment of patients with polycythemia vera?

Current treatments for polycythemia vera have remained unchanged for decades with phlebotomy, hydroxycarbamide (also named hydroxyurea) and to a lesser extent interferon being the cornerstones in our therapeutic armamentarium. However, some patients do not respond to, or indeed experience significant side effects to, these current agents and development of alternative therapeutic options is required. Ruxolitinib, a potent JAK1/2 inhibitor, initially approved for myelofibrosis, was recently approved for patients with polycythemia vera refractory or intolerant to hydroxycarbamide. In this article, we review the currently available efficacy and safety data.

Pacritinib: a new agent for the management of myelofibrosis?

INTRODUCTION: Myelofibrosis (MF) is a clonal haematological disease associated with recurrent somatic gene mutations (JAK2V617F, MPL, CALR) and constitutive activation of the Janus kinase (JAK)/Signal Transducer and Activator of Transcription pathway. MF is often characterised by debilitating symptoms and JAK inhibitors (JAKIs) have revolutionised available therapeutic options. Ruxolitinib, a JAK1 and 2 inhibitor, is the only currently approved agent. Several other JAKIs are undergoing evaluation in the clinical trial setting and Pacritinib , a novel JAK2 and FLT3 inhibitor, is at an advanced stage of investigation with recent completion of a Phase III trial and another ongoing. AREAS COVERED: Within this article we focus on pacritinib, summarising the development, preclinical and up-to-date results from the Phase I - III trials. We present the most recent data on efficacy and safety and indirectly compare this novel JAKI with ruxolitinib. EXPERT OPINION: The kinome array data for pacritinib suggests that it has a range of targets differing to those for ruxolitinib. Pacritinib appears to be an effective agent for the control of MF-related symptoms and splenomegaly with potentially fewer haematological side-effects when compared with ruxolitinib and seems a particularly promising agent for anaemic and thrombocytopenic patients. It is also an attractive drug for potential combination studies due to its good tolerability.

Hematologic modifications in natalizumab-treated multiple sclerosis patients: An 18-month longitudinal study.

OBJECTIVE: To monitor the hematologic modifications in the peripheral blood of patients with relapsing-remitting multiple sclerosis treated with natalizumab. METHODS: The cohort included 44 patients with relapsing-remitting multiple sclerosis treated monthly with natalizumab for 18 months. Peripheral blood was collected before treatment initiation and on a monthly basis during the treatment course. Complete blood cell count was performed using automated hematology systems. Blood smears were prepared and analyzed when abnormal values were detected. RESULTS: Mean total white blood cell, lymphocyte, and eosinophil counts were significantly higher 1 month after treatment initiation and remained stable during the 18 months of follow-up. Monocyte counts increased progressively during the 18-month treatment with natalizumab. Erythroblasts and neutrophil precursors were absent before treatment initiation but were present in 16% and 6.8% of patients, respectively, 1 month after the first natalizumab infusion. The proportion of patients with erythroblasts and neutrophil precursors remained stable throughout the 18-month follow-up period. On an individual patient basis, a fluctuating level of erythroblasts and neutrophil precursors was observed. No difference in mean erythrocyte, hemoglobin, hematocrit, thrombocyte, and neutrophil levels was observed before and after 18 months of natalizumab treatment. No cases of myelodysplastic syndrome or acute leukemia were observed. CONCLUSION: Chronic treatment with natalizumab is associated with significant modifications in complete blood cell count, including emergence of hematopoietic precursors that are not present in peripheral blood under normal conditions. None of these modifications were associated with malignancy.

Suspicion of heparin-induced thrombocytopenia in internal medicine: How appropriate is the ordering of anti-PF4/heparin antibody testing?

Thrombocytopenia is frequent in hospitalized patients, and heparin-induced thrombocytopenia (HIT) is often suspected when a decrease in platelet count is concomitant with heparin treatment. ELISA tests used for anti-PF4/heparin antibodies detection usually have high sensitivity but only fair specificity for HIT. Pre-test probability scores (such as 4 Ts or HEP scores) have been validated and a low probability score rules out HIT without anti-PF4/heparin testing. The aims of this study are to evaluate the appropriateness of anti-PF4/heparin testing according to pre-test probabilities of HIT and to compare the abilities of the 4 Ts and HEP scores to avoid inappropriate anti-PF4/heparin testing. This retrospective observational study included 74 consecutive patients hospitalized in a general internal medicine division who had anti-PF4/heparin testing for suspicion of HIT. 4 Ts and HEP scores were computed retrospectively. About 73% of patients who had ordering of an anti-PF4/heparin were at low risk according to the 4 Ts score, and 46% according to the HEP score. Heparin was discontinued in 61% and 62% of low-risk patients according to 4 Ts and HEP scores and switched to alternative anticoagulant in 31% and 32% of them, respectively. No case of HIT was diagnosed in patients with a low-risk score. One major bleeding and no thrombosis were observed. For the 4 Ts score, the sensitivity was 100%, the negative predictive value (NPV) was 100%, the specificity was 77%, and the positive predictive value (PPV) was 20% (95% CI: 7-44). For the HEP score, the sensitivity was 100%, the NPV was 100%, the specificity was 49%, and the PPV was 10%. In conclusion, pre-test probability scores were vastly underused in this internal medicine population despite their ability to rule out HIT without laboratory testing in a large proportion of patients. Appropriate use of those instruments should be actively promoted.

Acute respiratory distress syndrome in a patient with primary myelofibrosis after ruxolitinib treatment discontinuation.

Ruxolitinib is a Janus kinase (JAK) inhibitor used for the treatment of myelofibrosis with demonstrated efficacy for the alleviation of disease-related symptoms and splenomegaly. Anemia and thrombocytopenia are the main secondary effects. However, there are case reports of rare but serious adverse events following drug withdrawal. We present a case of a 76-year-old man diagnosed with primary myelofibrosis who presented with constitutional symptoms and symptomatic splenomegaly. Ruxolitinib was started (15 mg twice daily) and his disease-related symptoms disappeared. Six weeks later, he developed grade 4 thrombocytopenia and grade 3 anemia. Ruxolitinib was stopped and corticosteroid treatment (prednisone 1 mg/kg/day) was started to avoid a cytokine-rebound reaction. The patient then developed fever, chills, a biological inflammatory syndrome, and an acute respiratory disease syndrome. Full workup excluded an infection and we concluded that ruxolitinib withdrawal syndrome was the likely cause. Continued treatment with corticosteroids, as well as oxygen supply and continuous positive airway pressure, allowed an alleviation of his symptoms. This case report describes acute respiratory distress syndrome as another potential complication of ruxolitinib withdrawal syndrome.