Eosinophilic dermatosis of hematologic malignancy in patients with chronic lymphocytic leukemia/non-Hodgkin's B lymphoma: a single center prospective clinico-pathological study.

Background: The pathogenesis of eosinophilic dermatosis of hematologic malignancy (EDHM) is poorly understood. Previously thought to be a hypersensitivity reaction to insect bites, immune dysregulation and cytokine imbalance are now thought to be responsible. Its prognostic significance is unclear. Objective: To describe the clinical, pathological and immunological findings in a series of oncohematological patients with EDHM. Methods: An observational prospective cohort study of oncohematological patients receiving a diagnosis of EDHM between April 2017 and December 2018. Results: A total of 15 patients with EDHM (10 females and 5 males) were identified among 422 oncohematological patients. Disease presentation varied from firm erythematous papules to more polymorphic presentations. The lesions were most prevalent on the exposed sites, 8/15 patients recalled an insect bite. Lesion seasonality was reported in 13/15 patients. IgE levels were elevated in six patients, circulating IL-4 and IL-5 were within a normal range. Twelve out of 15 patients developed skin manifestations after chemotherapy. The infiltrate could be eosinophil-rich or lymphocytic-rich. Interestingly, the histopathologic findings were in accordance with arthropod bites. Conclusion: A role for insect bites in EDHM is supported by our findings. EDHM may be related to aggressive hematologic disease.

Secreted mutant calreticulins as rogue cytokines in myeloproliferative neoplasms.

Mutant calreticulin (CALR) proteins resulting from a -1/+2 frameshifting mutation of the CALR exon 9 carry a novel C-terminal amino acid sequence and drive the development of myeloproliferative neoplasms (MPNs). Mutant CALRs were shown to interact with and activate the thrombopoietin receptor (TpoR/MPL) in the same cell. We report that mutant CALR proteins are secreted and can be found in patient plasma at levels up to 160 ng/mL, with a mean of 25.64 ng/mL. Plasma mutant CALR is found in complex with soluble transferrin receptor 1 (sTFR1) that acts as a carrier protein and increases mutant CALR half-life. Recombinant mutant CALR proteins bound and activated the TpoR in cell lines and primary megakaryocytic progenitors from patients with mutated CALR in which they drive thrombopoietin-independent colony formation. Importantly, the CALR-sTFR1 complex remains functional for TpoR activation. By bioluminescence resonance energy transfer assay, we show that mutant CALR proteins produced in 1 cell can specifically interact in trans with the TpoR on a target cell. In comparison with cells that only carry TpoR, cells that carry both TpoR and mutant CALR are hypersensitive to exogenous mutant CALR proteins and respond to levels of mutant CALR proteins similar to those in patient plasma. This is consistent with CALR-mutated cells that expose TpoR carrying immature N-linked sugars at the cell surface. Thus, secreted mutant CALR proteins will act more specifically on the MPN clone. In conclusion, a chaperone, CALR, can turn into a rogue cytokine through somatic mutation of its encoding gene.

Do age, fitness, and concomitant medications influence management and outcomes of patients with CLL treated with ibrutinib?

Functional reserve of organs and systems is known to be relevant in predicting immunochemotherapy tolerance. Age and comorbidities, assessed by the cumulative illness rating scale (CIRS), have been used to address chemotherapy intensity. In the ibrutinib era, it is still unclear whether age, CIRS, and Eastern Cooperative Oncology Group performance status (ECOG-PS) retain their predictive role on treatment vulnerability. In this series of 712 patients with chronic lymphocytic leukemia (CLL) treated with ibrutinib outside clinical trials, baseline ECOG-PS and neutropenia resulted as the most accurate predictors of treatment feasibility and outcomes. Age did not independently influence survival and ibrutinib tolerance, indicating that not age per se, but age-related conditions, may affect drug management. We confirmed the role of CIRS > 6 as a predictor of a poorer progression- and event-free survival (PFS, EFS). The presence of a severe comorbidity was significantly associated with permanent dose reductions (PDRs), not translating into worse outcomes. As expected, del(17p) and/or TP53mut and previous therapies affected PFS, EFS, and overall survival. No study so far has analyzed the influence of concomitant medications and CYP3A inhibitors with ibrutinib. In our series, these factors had no impact, although CYP3A4 inhibitors use correlated with Cox regression analysis, with an increased risk of PDR. Despite the limitation of its retrospective nature, this large study confirmed the role of ECOG-PS as the most accurate predictor of ibrutinib feasibility and outcomes, and importantly, neutropenia emerged as a relevant tool influencing patients' vulnerability. Although CIRS > 6 retained a significant impact on PFS and EFS, its value should be confirmed by prospective studies.

Evaluating ibrutinib for the treatment of relapsed/refractory marginal zone lymphoma.

Introduction: Marginal zone lymphoma (MZL) is a heterogeneous disease with a wide range of possible frontline therapies depending on the subtype; there are no shared guidelines for the treatment of relapsed/refractory MZLs. The growing evidence of the importance of the BCR pathway in the pathogenesis of B lymphoproliferative forms has led researchers to consider BTK as a potential therapeutic target in MZL.Area covered: The authors provide the reader with an evaluation of ibrutinib as a treatment option for refractory marginal zone lymphoma. The review includes an overview of the drug's pharmacokinetics and pharmacodynamics, efficacy, and safety. The authors also provide the reader with their expert perspectives on the drug and its place in the treatment of MZL.Expert opinion: The availability of new non-chemotherapeutic agents represents an important opportunity to spare excessive exposure to cytotoxic compounds. Immunomodulators and targeted agents, alone or often in combination with immunotherapy, have been shown to be effective and safe therapies in patients with relapsed/refractory (R/R) MZL. In addition, numerous studies involving new generation targeted agents, alone or in combination, are currently active in both R/R and untreated patient populations, some with encouraging preliminary results.

A multistate model of survival prediction and event monitoring in prefibrotic myelofibrosis.

Among 382 patients with WHO-defined prefibrotic myelofibrosis (pre-PMF) followed for a median of 6.9 years, fibrotic or leukemic transformation or death accounts for 15, 7, and 27% of cases, respectively. A multistate model was applied to analyze survival data taking into account intermediate states that are part of the clinical course of pre-PMF, including overt PMF and acute myeloid leukemia (AML). Within this multistate framework, multivariable models disclosed older age (>65 years) and leukocytosis (>15 × 109/L) as predictors of death and leukemic transformation. The risk factors for fibrotic progression included anemia and grade 1 bone marrow fibrosis. The outcome was further affected by high molecular risk (HMR) but not driver mutations. Direct transition to overt PMF, AML, or death occurred in 15.2, 4.7, and 17.3% of patients, respectively. The risk of AML was the highest in the first 5 years (7%), but leveled off thereafter. Conversely, the probability of death from overt PMF or AML increased more rapidly over time, especially when compared to death in the pre-PMF state without disease progression. The probability of being alive with pre-PMF status decreased to 70 and 30% at 10 and 20 years, respectively. This study highlights the aspects of the clinical course and estimates of disease progression in pre-PMF.

Impaired virus-specific T cell responses in patients with myeloproliferative neoplasms treated with ruxolitinib.

Ruxolitinib is effective in myeloproliferative neoplasms (MPN) but can cause reactivation of silent infections. We aimed at evaluating viral load and T-cell responses to human cytomegalovirus (HCMV) and Epstein-Barr virus (EBV) in a cohort of 25 MPN patients treated with ruxolitinib. EBV-DNA and HCMV-DNA were quantified monthly using real-time polimerase chain reaction (PCR) on peripheral blood samples, and T-cell subsets were analyzed by flowcytometry. HCMV and EBV-directed T-cell responses were evaluated using the IFN-γ ELISPOT assay. Most patients had CD4+ and/or CD8+ T-cells below the normal range; these reductions were related to the duration of ruxolitinib treatment. In fact, reduced T-lymphocytes' subsets were found in 93% of patients treated for ≥5 years and in 45% of those treated for <5 years (P = .021). The former also had lower median numbers of CD4+ and CD8+ cells. Subclinical reactivation of EBV and HCMV occurred in 76% and 8% of patients. We observed a trend to an inverse relationship between EBV and CMV-specific CD4+ and CD8+ T-cell responses and viral load, and a trend to an inverse correlation with ruxolitinib dose. Therefore, our data suggest that the ruxolitinib treatment may interfere with immunosurveillance against EBV and HCMV.

Validation of the IPSET score for thrombosis in patients with prefibrotic myelofibrosis.

Pre-fibrotic myelofibrosis (pre-PMF) and essential thrombocythemia (ET) are characterized by similarly increased rate of thrombotic events, but no study specifically analyzed risk factors for thrombosis in pre-PMF. In a multicenter cohort of 382 pre-PMF patients collected in this study, the rate of arterial and venous thrombosis after diagnosis was 1.0 and 0.95% patients/year. Factors significantly associated with arterial thrombosis were age, leukocytosis, generic cardiovascular risk factors, JAK2V617F and high molecular risk mutations, while only history of previous thrombosis, particularly prior venous thrombosis, was predictive of venous events. The risk of total thromboses was accurately predicted by the the international prognostic score for thrombosis in essential thrombocythemia (IPSET) score, originally developed for ET, and corresponded to 0.67, 2.05, and 2.95% patients/year in the low-, intermediate-, and high-risk categories. IPSET was superior to both the conventional 2-tiered score and the revised IPSET in this cohort of pre-PMF patients. We conclude that IPSET score can be conveniently used for thrombosis risk stratification in patients with pre-PMF and might represent the basis for individualized management aimed at reducing the increased risk of major cardiovascular events. Further refinement of the IPSET score in pre-PMF might be pursued by additional, prospective studies evaluating the inclusion of leukocytosis and/or adverse mutational profile as novel variables.

Second primary malignancies in postpolycythemia vera and postessential thrombocythemia myelofibrosis: A study on 2233 patients.

Patients with myeloproliferative neoplasms (MPN) are known to have higher incidence of nonhematological second primary malignancies (SPM) compared to general population. In the MYSEC study on 781 secondary myelofibrosis (SMF) patients, the incidence of SPM after SMF diagnosis resulted 0.98/100 patient-years. When including non-melanoma skin cancers (NMSC), the incidence arose to 1.56/100 patient-years. In SMF, JAK inhibitor treatment was associated only with NMSC occurrence. Then, we merged the MYSEC cohort with a large dataset of PV and ET not evolving into SMF. In this subanalysis, we did not find any correlation between SPM and SMF occurrence. These findings highlight the need of studies aimed at identifying MPN patients at higher risk of SPM.

Diagnosis and management of prefibrotic myelofibrosis.

INTRODUCTION: The 2016 WHO classification comprises two stages of primary myelofibrosis (PMF): early/prefibrotic primary myelofibrosis (pre-PMF) and overt fibrotic PMF (overt PMF). Diagnostic criteria rely on bone marrow morphology, fibrosis grade (0-1 in pre-PMF, 2-3 in overt PMF), and clinical features (leukoerythroblastosis, anemia, leucocytosis, increased lactate dehydrogenase, and palpable splenomegaly). An accurate differentiation from essential thrombocythemia (ET) is pivotal because the two entities show different clinical presentation and outcome, in terms of survival, leukemic evolution, and rates of progression to overt myelofibrosis. Areas covered: The current review provides an overview on how to diagnose and stratify patients with pre-PMF, taking into account their definite and peculiar risk of vascular event, which is often neglected, and their milder disease course, compared with overt PMF, with the aim of improving and individualizing their counseling and management. Expert commentary: Pre-PMF is a new entity characterized by a unique combination of both a thrombo-hemorrhagic risk (that brings it closer to PV and ET) and a definite risk of disease evolution (that places pre-PMF somewhat closer to the overt PMF variant).