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Background and PurposeCardiac arrhythmia is a recognised potential complication of thoracic radiotherapy, but the responsible cardiac substructures for arrhythmogenesis have not been identified. Arrhythmogenic tissue is commonly located in the pulmonary veins (PVs) of cardiology patients with arrhythmia, however these structures are not currently considered organs-at-risk during radiotherapy planning. A standardised approach to their delineation was developed and evaluated.Materials and MethodsThe gross and radiological anatomy relevant to atrial fibrillation was derived from cardiology and radiology literature by a multidisciplinary team. A region of interest and contouring instructions for radiotherapy computed tomography scans were iteratively developed and subsequently evaluated. Radiation oncologists (n = 5) and radiation technologists (n = 2) contoured the PVs on the four-dimensional planning datasets of five patients with locally advanced lung cancer treated with 1.8–2.75 Gy fractions. Contours were compared to reference contours agreed by the researchers using geometric and dosimetric parameters.ResultsThe mean dose to the PVs was 35% prescription dose. Geometric and dosimetric similarity of the observer contours with reference contours was fair, with an overall mean Dice of 0.80 ± 0.02. The right superior PV (mean DSC 0.83 ± 0.02) had better overlap than the left (mean DSC 0.80 ± 0.03), but the inferior PVs were equivalent (mean DSC of 0.78). The mean difference in mean dose was 0.79 Gy ± 0.71 (1.46% ± 1.25).ConclusionA PV atlas with multidisciplinary approval led to reproducible delineation for radiotherapy planning, supporting the utility of the atlas in future clinical radiotherapy cardiotoxicity research encompassing arrhythmia endpoints.

The search for novel targets in chronic myeloid leukaemia (CML) is ongoing, to improve treatment efficacy in refractory disease and increase eligibility for tyrosine kinase inhibitor (TKI) discontinuation. Increased frequency of Tregs and effector Tregs was evident at diagnosis, together with increased expression of T-cell exhaustion markers, including in regulatory T cells at diagnosis and in patients with refractory disease. Plasma analysis revealed significantly increased levels of cytokines including tumour necrosis factor (TNF)-a and interleukin (IL)-6 at diagnosis, in keeping with a pro-inflammatory state prior to treatment. We hence demonstrate T-cell exhaustion and a pro-inflammatory state at diagnosis in CML, likely secondary to leukaemia-associated antigenic overload associated with increased disease burden.

Myelofibrosis, a life shortening clonal disorder, presents with a constellation of features: bone marrow fibrosis, abnormal blood counts, extramedullary hematopoiesis, splenomegaly, thrombohemorrhagic complications, and constitutional symptoms. Until recently Ruxolitinib, a JAK1 and 2 inhibitor, has been the only targeted therapy available for transplant-ineligible patients requiring treatment for splenomegaly and disease-related symptoms. However, most patients discontinue Ruxolitinib after 3-5 years, mostly due to loss of response. There has been an unmet need for this patient group. In August 2019, Fedratinib (INREBIC® capsules, Impact Biomedicines, Inc., a wholly owned subsidiary of Bristol Meyer Squibb), a JAK2 inhibitor, was approved by US FDA for treatment of myelofibrosis in both JAK inhibitor naïve and pre-treated patients for the management of symptoms and splenomegaly.Here, we discuss the development, evidence base to date for Fedratinib. Including early and late phase, and ongoing trials, safety issues, potential role and current position of Fedratinib in the treatment of myelofibrosis, as well as future direction of targeted therapy in myelofibrosis.Fedratinib presents a much needed option of treatment, particularly, for patients failing Ruxolitinib, with response rates that are quite similar. Nonetheless, there remain important questions including sequencing and options for combining therapy.

Primary analyses of cohort 1a of the REFINE trial showed that addition of navitoclax to ruxolitinib induced a 35% or greater reduction in spleen volume (SVRREFINE is a phase 2, multicentre, open-label trial designed to assess the activity and safety of navitoclax alone or in combination with ruxolitinib in patients with primary or secondary (post-polycythaemia vera or post-essential thrombocythaemia) myelofibrosis. Cohort 1a of the study included patients who had disease progression or suboptimal response on stable ruxolitinib monotherapy. Patients in cohort 1a, who had previously received ruxolitinib for 12 weeks or more, continued their current stable dose, and navitoclax was orally administered at 50 mg per day and escalated weekly to a maximum of 300 mg per day, based on tolerability. The primary activity endpoint was SVRBetween Nov 14, 2017, and April 10, 2019, 34 patients in cohort 1a received at least one dose of navitoclax plus ruxolitinib. 23 (68%) patients were male, with 32 (94%) being White. At data cutoff (May 6, 2021), the median follow-up for survivors was 26·2 months (IQR 21·9-32·3). 33 patients were evaluable for biomarker analyses; 19 (58%) had high molecular risk mutations. Five (31%) of 16 patients had SVRThese biomarker analyses reveal clinically meaningful splenic responses independent of high molecular risk mutation status in patients treated with navitoclax plus ruxolitinib who were not benefiting from ruxolitinib monotherapy. Furthermore, the overall survival benefit observed in those with an improvement in fibrosis or a reduction in variant allele frequency is suggestive of disease modification, implying the therapeutic potential of adding navitoclax to ruxolitinib for patients with myelofibrosis who had disease progression or suboptimal response to ruxolitinib monotherapy.AbbVie.

Not available.

Splenomegaly is a hallmark of myelofibrosis, a debilitating haematological malignancy for which the only curative option is allogeneic haematopoietic cell transplantation (HCT). Considerable splenic enlargement might be associated with a higher risk of delayed engraftment and graft failure, increased non-relapse mortality, and worse overall survival after HCT as compared with patients without significantly enlarged splenomegaly. Currently, there are no standardised guidelines to assist transplantation physicians in deciding optimal management of splenomegaly before HCT. Therefore, the aim of this Position Paper is to offer a shared position statement on this issue. An international group of haematologists, transplantation physicians, gastroenterologists, surgeons, radiotherapists, and radiologists with experience in the treatment of myelofibrosis contributed to this Position Paper. The key issues addressed by this group included the assessment, prevalence, and clinical significance of splenomegaly, and the need for a therapeutic intervention before HCT for the control of splenomegaly. Specific scenarios, including splanchnic vein thrombosis and COVID-19, are also discussed. All patients with myelofibrosis must have their spleen size assessed before allogeneic HCT. Myelofibrosis patients with splenomegaly measuring 5 cm and larger, particularly when exceeding 15 cm below the left costal margin, or with splenomegaly-related symptoms, could benefit from treatment with the aim of reducing the spleen size before HCT. In the absence of, or loss of, response, patients with increasing spleen size should be evaluated for second-line options, depending on availability, patient fitness, and centre experience. Splanchnic vein thrombosis is not an absolute contraindication for HCT, but a multidisciplinary approach is warranted. Finally, prevention and treatment of COVID-19 should adhere to standard recommendations for immunocompromised patients.

Myeloproliferative disease Enfermedad mieloproliferativa Malaltia mieloproliferativa The study was supported by a research grant by the COVID “3 × 1 project”, BREMBO S.p.A., Bergamo, Italy (T.B.) and by AIRC 5 × 1000 call “Metastatic disease: the key unmet need in oncology” to MYNERVA project, #21267 (MYeloid NEoplasms Research Venture AIRC). A detailed description of the MYNERVA project is available at https://progettomynerva.it (A.M.V., P.G.). The study was also supported by HARMONY PLUS, which is funded through the Innovative Medicines Initiative (IMI), Europe’s largest public–private initiative aiming to speed up the development of better and safer medicines for patients. The HARMONY Alliance has received funding from IMI 2 Joint Undertaking and is listed under grant agreement No. 945406. This Joint Undertaking receives support from the European Union’s Horizon 2020 Research and Innovation Programme and the European Federation of Pharmaceutical Industries and Associations (EFPIA). IMI supports collaborative research projects and builds networks of industrial and academic experts in order to boost pharmaceutical innovation in Europe.

Janus kinase inhibitors (JAKi) approved for myelofibrosis provide spleen and symptom improvements but do not address anemia, a negative prognostic factor. Momelotinib, an inhibitor of ACVR1/ALK2, JAK1 and JAK2, demonstrated activity against anemia, symptoms, and splenomegaly in the phase 3 SIMPLIFY trials. Here, we report mature overall survival (OS) and leukemia-free survival (LFS) from both studies, and retrospective analyses of baseline characteristics and efficacy endpoints for OS associations. Survival distributions were similar between JAKi-naïve patients randomized to momelotinib, or ruxolitinib then momelotinib, in SIMPLIFY-1 (OS HR = 1.02 [0.73, 1.43]; LFS HR = 1.08 [0.78, 1.50]). Two-year OS and LFS were 81.6% and 80.7% with momelotinib and 80.6% and 79.3% with ruxolitinib then momelotinib. In ruxolitinib-exposed patients in SIMPLIFY-2, two-year OS and LFS were 65.8% and 64.2% with momelotinib and 61.2% and 59.7% with best available therapy then momelotinib (OS HR = 0.98 [0.59, 1.62]; LFS HR = 0.97 [0.59, 1.60]). Baseline transfusion independence (TI) was associated with improved survival in both studies (SIMPLIFY-1 HR = 0.474, p = 0.0001; SIMPLIFY-2 HR = 0.226, p = 0.0005). Week 24 TI response in JAKi-naïve, momelotinib-randomized patients was associated with improved OS in univariate (HR = 0.323; p p

Summary Patients receiving targeted cancer treatments such as tyrosine kinase inhibitors (TKIs) have been classified in the clinically extremely vulnerable group to develop severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2), including patients with chronic myeloid leukaemia (CML) taking TKIs. In addition, concerns that immunocompromised individuals with solid and haematological malignancies may not mount an adequate immune response to a single dose of SARS‐CoV‐2 BNT162b2 (Pfizer‐BioNTech) vaccine have been raised. In the present study, we evaluated humoral and cellular immune responses after a first injection of BNT162b2 vaccine in 16 patients with CML. Seroconversion and cellular immune response before and after vaccination were assessed. By day 21 after vaccination, anti‐Spike immunoglobulin G was detected in 14/16 (87·5%) of the patients with CML and all developed a neutralising antibody response [serum dilution that inhibits 50% infection (ID50) >50], including medium (ID50 of 200–500) or high (ID50 of 501–2000) neutralising antibodies titres in nine of the 16 (56·25%) patients. T‐cell response was seen in 14/15 (93·3%) evaluable patients, with polyfunctional responses seen in 12/15 (80%) patients (polyfunctional CD4+ response nine of 15, polyfunctional CD8+ T‐cell response nine of 15). These data demonstrate the immunogenicity of a single dose of SARS‐CoV‐2 BNT162b2 vaccine in most patients with CML, with both neutralising antibodies and polyfunctional T‐cell responses seen in contrast to patients with solid tumour or lymphoid haematological malignancies.

Myelofibrosis is characterized by splenomegaly, symptoms, cytopenias, and bone marrow (BM) fibrosis. Pelabresib is an investigational, oral, small-molecule BET inhibitor designed to selectively inhibit the BD1 and BD2 bromodomains of BET proteins.Evaluation of pelabresib combined with ruxolitinib in patients with myelofibrosis.In Arm 3 of the Phase 2 MANIFEST study (NCT02158858), JAKi-naïve myelofibrosis patients are treated with pelabresib combined with ruxolitinib. In Arm 2, myelofibrosis patients with suboptimal response to ruxolitinib are treated with pelabresib as 'add-on' to ruxolitinib (Arm 2A: transfusion-dependent [TD]; Arm 2B: non-TD). The primary endpoints are ≥35% spleen volume reduction (SVR35) at Week 24 for Arms 3 and 2B and TD to transfusion independence (TI) in Arm 2A. The key secondary endpoint is ≥50% total symptom score reduction (TSS50) at Week 24; in Arm 2A, SVR35 is an additional key secondary endpoint. BM biopsies to assess BM fibrosis and safety data are also evaluated.As of September 2021, at Week 24 in Arm 3 (N=84), 68% (57/84) of patients achieved SVR35 (median change: -50%), and 56% (46/82) of patients achieved TSS50 (median change: -59%). At Week 24 in Arm 2 (N=86), 20% (16/81; 17% in Arm 2A and 26% in Arm 2B) of patients achieved SVR35 (median change: -18%), and 37% (30/81) of patients achieved TSS50 (median change: -47%). In Arm 2A, the TD to TI rate was 16% (6/38). At Week 24, BM fibrosis improvement ≥ 1 grade was achieved in 28% (16/57) and 26% (12/47) of patients in Arms 3 and 2, respectively. Hematologic treatment-emergent adverse events (TEAEs) included thrombocytopenia, in 52% (≥Grade 3: 12%) and 52% (≥Grade 3: 33%) of patients, and anemia, in 42% (≥Grade 3: 35%) and 27% (≥Grade 3: 19%) of patients in Arms 3 and 2, respectively. Low-grade gastrointestinal TEAEs and respiratory infections were observed but rarely resulted in discontinuation.In ruxolitinib treatment-naïve and previously treated patients with myelofibrosis, pelabresib combined with ruxolitinib resulted in splenic and symptom responses and BM fibrosis improvement and was generally well tolerated. The Phase 3 MANIFEST-2 study is evaluating pelabresib combined with ruxolitinib in JAKi treatment-naïve patients with myelofibrosis (NCT04603495).

The upcoming 5th edition of the World Health Organization (WHO) Classification of Haematolymphoid Tumours is part of an effort to hierarchically catalogue human cancers arising in various organ systems within a single relational database. This paper summarizes the new WHO classification scheme for myeloid and histiocytic/dendritic neoplasms and provides an overview of the principles and rationale underpinning changes from the prior edition. The definition and diagnosis of disease types continues to be based on multiple clinicopathologic parameters, but with refinement of diagnostic criteria and emphasis on therapeutically and/or prognostically actionable biomarkers. While a genetic basis for defining diseases is sought where possible, the classification strives to keep practical worldwide applicability in perspective. The result is an enhanced, contemporary, evidence-based classification of myeloid and histiocytic/dendritic neoplasms, rooted in molecular biology and an organizational structure that permits future scalability as new discoveries continue to inexorably inform future editions.

Recent Advancements in Hematology: Knowledge, Methods and Dissemination is a series of editorials which is published on a biannual basis by the editorial board of the journal Bloods [...]

Polycythaemia vera is associated with a reduced quality of life, a high rate of vascular events, and an intrinsic risk of disease evolution. The results of several randomised trials for the treatment of this disorder are now available, and both a new ropegylated formulation of interferon alfa-2b (ropeginterferon alfa-2b; 2018) and ruxolitinib (2015) have been approved in Europe. European LeukemiaNet (ELN) investigators have therefore deemed it appropriate to provide recommendations for the use of these drugs in clinical practice. An expert panel of 14 senior haematologists from ELN centres that had actively participated in previous ELN projects or relevant randomised trials, chaired by a member of the ELN Steering Committee, developed a list of clinical questions, and a methodologist established three patient, intervention, comparator, outcome (PICO) questions and systematically reviewed the evidence. Recommendations were approved by six Delphi consensus rounds and two virtual meetings (on Jan 26, 2021, and June 24, 2021). The expert panel recommended that patients with polycythaemia vera who are younger than 60 years and have not had previous thrombotic events should start cytoreductive drug therapy if at least one of the following criteria are fulfilled: strictly defined intolerance to phlebotomy, symptomatic progressive splenomegaly, persistent leukocytosis (15 × 10

Pacritinib (PAC) is a novel JAK2/IRAK1 inhibitor approved for patients with myelofibrosis (MF) and platelets50×10This analysis included PERSIST-2 patients with platelet count ≤100×10The analysis included 106 patients on PAC 200mg BID, 104 on 400mg QD and 98 on BAT. Patients at baseline, were severely cytopenic, with a median platelet count of 55×10Improvement in hemoglobin levels and transfusion requirements was greater on PAC than BAT, in PERSIST-2. This anemia benefit could be due to PAC's ability to inhibit the iron regulator ACVR1, which has been linked to hepcidin reduction and anemia benefit. These data suggest an important role for PAC in anemic patients with myelofibrosis. This study was supported by CTI BioPharma.

Pelabresib (CPI-0610) combined with ruxolitinib showed encouraging spleen and symptom responses in Janus kinase inhibitor (JAKi)-naïve patients with intermediate or high-risk myelofibrosis in Arm 3 of the Phase 2 MANIFEST study (NCT02158858). Cross-trial comparisons with JAKi monotherapy have limitations due to potential imbalances in baseline characteristics.Matching-adjusted indirect comparison (MAIC) analysis was conducted to correct for potential imbalances in baseline characteristics, comparing primary (SVR35) and secondary (TSS50) endpoints at Week 24 for pelabresib and ruxolitinib (MANIFEST Arm 3) with JAKi monotherapy from Phase 3 studies (COMFORT-I and II, SIMPLIFY-1, and JAKARTA).Individual patient-level data were available for MANIFEST Arm 3 vs. only published summary data for the four comparator studies. Unanchored MAIC was conducted, adjusting for imbalances in gender, myelofibrosis subtype, International Prognostic Scoring System risk status, previous hydroxyurea use, platelet count, hemoglobin levels, spleen volume, and JAK2 V617F status. Weighted mean outcomes of treatment effects were estimated; weights were also used to calculate the effective sample size. Treatment effect outcomes for SVR35 and TSS50 are presented in terms of response rates (RRs) and response rate ratios (RRRs, RR in MANIFEST Arm 3/RR in comparator arm; RRR1 favors MANIFEST Arm 3). Bias due to potential unmeasured differences in baseline characteristics cannot be excluded.Complete summary-level balance in weighted distributions of prognostic factors was achieved. For SVR35 at Week 24, significant MAIC-adjusted RRRs (95% CI) were 1.57 (1.10-2.24; p=0.012), 1.82 (1.17-2.83; p=0.008), 2.13 (1.51-3.02; p0.0001), 2.26 (1.57-3.27; p0.0001), 1.76 (1.16-2.66; p=0.008) and 1.55 (1.06-2.27; p=0.023) for MANIFEST Arm 3 (pelabresib with ruxolitinib) versus COMFORT-I, COMFORT -II, SIMPLIFY-1 (ruxolitinib), SIMPLIFY-1 (momelotinib), JAKARTA (fedratinib 400 mg), and JAKARTA (fedratinib 500 mg), respectively, consistent with the significant results of unadjusted analyses. RRRs1 were observed for TSS50 at Week 24 for all comparisons.Results suggest that MAIC-adjusted improvements observed in SVR35 and TSS50 at Week 24 with pelabresib and ruxolitinib vs. ruxolitinib, fedratinib, or momelotinib monotherapy were consistent with unadjusted comparisons. Phase 3 MANIFEST-2 (NCT04603495), assessing pelabresib or placebo combined with ruxolitinib in JAKi-naïve patients with myelofibrosis, is ongoing.

Standard first-line therapy choice for essential thrombocythaemia (ET) requiring cytoreduction, supported by randomized trials, is low-dose aspirin with hydroxycarbamide, but the role of recombinant interferon-alfa (IFNα)-2a/2b and pegylated (PEG)-IFN-α-2a/2b is increasingly highlighted. Longer-term outcome data, however, remains somewhat scarce, particularly in the 'real world'. We hereby report on a large, well-annotated cohort of ET patients from a single referral centre undergoing therapy with either IFNα or (PEG)-IFN-α-2a/2b and demonstrate high rates of complete haematological responses, good tolerability and safety, low rates of thromboembolic events in compliant patients and confirm feasibility of long-term therapy in a significant proportion of patients.