BACKGROUND:The JAK2V617F mutation is a driver mutation in Philadelphia-negative chronic myeloproliferative neoplasms (MPNs), including polycythemia vera, essential thrombocythemia, and myelofibrosis. Recent studies have revealed a significant prevalence of JAK2V617F as clonal hematopoiesis of indeterminate potential (CHIP) in the general population, particularly in individuals over 50 years. CHIP-JAK2V617F carriers exhibit increased mortality, driven by cardiovascular diseases and cancer. Given the prothrombotic and inflammatory nature of JAK2V617F, we investigated its prevalence in patients with acute coronary syndrome (ACS). METHODS:We screened 526 consecutive ACS patients for the JAK2V617F mutation using sensitive droplet digital PCR (ddPCR) and allele-specific real-time quantitative PCR (RQPCR). Clinical and laboratory data were analyzed to assess associations. RESULTS:The JAK2V617F mutation was detected in 6.1% (32/526) of ACS patients, significantly higher than the general population prevalence (3.1%). CONCLUSION:Our findings suggest that JAK2V617F may contribute to ACS pathogenesis through prothrombotic and inflammatory mechanisms. Screening for JAK2V617F in high-risk cardiovascular patients could identify individuals who may benefit from targeted therapies.

Az idült mieloproliferatív betegségek lefolyásuk során állandóan fokozott vaszkuláris és az idő előrehaladtával emelkedő malignus transzformációs rizikót jelentenek, amelyek jelentősen befolyásolják a betegek morbiditását és mortalitását. Fontos olyan kezelés választása, ami mindkét rizikótényezőt a legjobban csökkenti. Az effektivitás mellett a terápiától további elvárás, hogy biztonságos, tolerálható legyen, hiszen az idült mieloproliferatív betegek többnyire idősek, több társbetegséggel rendelkeznek. A szerzők jelen retrospektív vizsgálatuk során a pegilált interferon terápia hatékonyságát és tolerálhatóságát vizsgálták hat magyar hematológiai centrum bevonásával. Etikai engedély birtokában, 153 beteg adatait elemzik deskriptív statisztikai módszereket alkalmazva. A vizsgált periódusban (átlag 39 hónap) a pegilált interferon terápia mellett artériás és/vagy vénás tromboembóliás esemény 4,57%, malignus transzformáció a betegek 1,93%-ánál jelentkezett. Túlnyomóan enyhe mellékhatást – amelyek nem tették szükségessé a terápia megszakítását – minden negyedik betegnél észleltek. Eredményeik – a nemzetközi szakirodalmi adatokkal összevetve – alátámasztják a pegilált interferon kezelés hatékonyságát és tolerálhatóságát krónikus mieloproliferatív betegségben szenvedőknél.

The phase 3 SYMPATICO study included an open-label cohort to evaluate the efficacy and safety of first-line ibrutinib plus venetoclax in patients with non-blastoid mantle cell lymphoma (MCL) ≥65 years (n=65), or ≥18 years with a TP53 mutation (TP53m) (n=11). Eligible patients received oral ibrutinib 560 mg once daily and venetoclax (5-week ramp-up to 400 mg once daily) for 2 years, then single-agent ibrutinib 560 mg until disease progression or unacceptable toxicity. In total, 78 patients were enrolled. With median time on study of 40.5 months (range, 0.6+ to 46.9), the complete response (CR) rate was 69% (95% CI, 58-79), and the overall response rate was 95% (95% CI, 87-99). The median duration of response was 37.1 months (95% CI, 30.3-not estimable [NE]). Median progression-free survival (mPFS) was 40.2 months (95% CI, 29.4-NE); median overall survival (OS) was not reached (3-year OS rate, 79% [95% CI, 68-86]). In patients ≥65 years, CR rates were 76% (no TP53m) and 44% (with TP53m), mPFS was 40.2 and 22.0 months, and 3-year OS was 85% and 66%, respectively. In adult patients <65 years (with TP53m), the CR rate was 73%, mPFS was 15.4 months, and 3-year OS was 73%. The most common treatment-emergent adverse events were diarrhea (49%), fatigue (37%), neutropenia (35%), and COVID-19 (32%). First-line ibrutinib plus venetoclax showed promising efficacy, with high CR rates and durable remissions, in patients with previously untreated non-blastoid MCL and may be an option for patients ≥65 years or patients of any age with TP53m. NCT03112174

In recent years, targeted therapies have become the standard of care for refractory/relapsed mantle cell lymphoma (MCL). Although the mutational profile of MCL has been extensively studied, there is a lack of understanding of resistance mechanisms and genetic factors that impact the response to novel treatments. Since patients relapsing on targeted treatment experience poor clinical outcomes, understanding the genetic foundation of resistance mechanisms in MCL is essential. In this study, we aimed to scrutinize the copy number profile and clonal dynamics of double-resistant MCL patients treated sequentially with Bruton's tyrosine kinase inhibitor (BTKi) and venetoclax using low-coverage whole genome sequencing (lcWGS). Samples obtained after systemic therapy showed more copy number alterations (CNAs) (p = 0.039; Wilcoxon) compared to samples collected before treatment initiation. Patients showing early progression on BTKi demonstrated CNAs affecting cytobands encompassing the coding regions of NOTCH1, TRAF2, BIRC2, BIRC3, and ATM. A deletion in chromosome 9p21.3 was identified in two out of three venetoclax-resistant patients. For patient MCL2, progressing on ibrutinib but showing venetoclax resistance, a 9p21.3 deletion was found throughout the disease course, with acquired SMARCA4-del(19)(p13.3-q13.11) and DLC1-del(8)(p23.2-q11.1) observed at relapse, highlighting their role in disease progression and therapy resistance. Using lcWGS, an innovative genome-wide approach, this study revealed novel putative primary and acquired resistance mechanisms in BTKi and venetoclax double-resistant MCL patients. © 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

7017 Background: The phase 3 SYMPATICO study evaluated ibrutinib (Ibr) combined with venetoclax (Ven) in 3 cohorts of patients (pts) with MCL: an open-label safety run-in phase to evaluate concurrent initiation of Ibr+Ven in relapsed/refractory (R/R) MCL; a randomized phase to evaluate Ibr+Ven vs Ibr+placebo (Pbo) in R/R MCL; and an open-label cohort to evaluate first-line Ibr+Ven in treatment-naive (TN) MCL. Primary analysis of the randomized phase showed superior PFS with Ibr+Ven vs Ibr+Pbo in pts with R/R MCL (Wang M et al, Lancet Oncol , in press). Here, we report efficacy and safety of Ibr+Ven in pts with TN MCL in older pts (≥65 y) or younger pts with a TP53 mutation ( TP53 mut) (≥18 y) who are in need of novel and better tolerated treatment options. Methods: Older pts (≥65 y) or pts with a TP53 mut with TN MCL received oral Ibr 560 mg once daily and Ven (5-wk ramp-up to 400 mg once daily) for 2 y, then single-agent Ibr 560 mg until PD or unacceptable toxicity. Primary endpoint was complete response (CR) rate assessed by investigator per Lugano. Key secondary endpoints included overall response rate (ORR), duration of response (DOR), PFS, OS, and time to next treatment. Subgroup analyses were performed according to TP53 mut status and age. Results: In total, 78 TN MCL pts were enrolled. At baseline, 83% of pts were ≥65 y, 97% had ECOG PS of 0–1, 45% had high-risk simplified MIPI score, 31% had bulky disease (≥5 cm), 78% had bone marrow involvement, 46% had splenomegaly, and 37% had TP53 mut. Median time on study was 40.5 mo (range, 0.6+–46.9). CR rate was 69% (95% CI, 58–79), and ORR was 95% (95% CI, 87–99). Median DOR was 37.1 mo (95% CI, 30.3–NE). Median PFS was 40.2 mo, and 3-y OS was 79%. CR rate was 76% in pts ≥65 y without TP53 mut, 44% in pts ≥65 y with TP53 mut, and 73% in pts <65 y with TP53 mut; median PFS was 40.2, 22.0, and 15.4 mo, and 3-y OS was 85%, 66%, and 73%, respectively (Table). Median duration of treatment was 24.0 mo (range, 0.3–46.9). Most common AEs were diarrhea (49%), fatigue (37%), neutropenia (35%), and COVID-19 (32%). Most common grade ≥3 AE was neutropenia (29%). Conclusions: First-line Ibr+Ven showed promising efficacy with high CR rates and durable remissions in pts with TN MCL with and without TP53 mut. Safety was acceptable and trended better in younger pts. Ibr+Ven may be an option for older pts with TN MCL or pts of any age with TP53 mut. Clinical trial information: NCT03112174 . Outcomes (95% CI) Without TP53 mutn=44 With TP53 mut n=29 ≥65 y without TP53 mutn=42 ≥65 y with TP53 mutn=18 <65 y without TP53 mutn=2 <65 y with TP53 mutn=11 TotalN=78 CR rate, % 77(62–89) 55(36–74) 76(61–88) 44(22–69) 100(16–100) 73(39–94) 69(58–79) ORR, % 98(88–100) 90(73–98) 98(87–100) 89(65–99) 100(16–100) 91(59–100) 95(87–99) Median PFS, mo 40.2 (37.2–NE) 22.0(9.2–NE) 40.2(37.2–NE) 22.0(11.3–NE) NR(11.1–NE) 15.4(8.2–NE) 40.2(29.4–NE) 3-y OS, % 86(71–93) 68(47–82) 85(70–93) 66(39–83) 100(100–100) 73(37–90) 79(68–86)

Background: T-cell prolymphocytic leukemia (T-PLL) is a rare mature T-cell lymphoma that is usually associated with poor prognosis and short overall survival. Methods: We present a case of a 61-year-old woman presenting with T-PLL and the leukemic cells harboring BCR::ABL1 (BCR—breakpoint cluster region; ABL1—ABL protooncogene 1) fusion transcripts as the result of a variant of t(9;22)(q34;q11) called Philadelphia translocation: t(9;22;18)(q34;q11;q21). Sequencing revealed a rare BCR transcript with an exon 6 breakpoint corresponding to e6a2 transcripts, which has thus far been reported in only 26 cases of leukemias. Results: After 9 months of follow-up, the disease progressed and required treatment. Following alemtuzumab and chemotherapy, a short course of imatinib therapy stabilized the disease for six months, which was followed by progression and the demise of the patient. Conclusions: To the best of our knowledge, this is the first report of a mature T-cell lymphoma with a variant Philadelphia-translocation and a very rare type of BCR::ABL1 transcript. This case highlights the importance of comprehensive genetic testing of malignancies, as abnormal molecular pathways may be uncovered that may be specifically targeted by drugs.

ABSTRACT:Acalabrutinib is a Bruton tyrosine kinase inhibitor approved for the treatment of chronic lymphocytic leukemia. We present results from ELEVATE-TN after a median follow-up of 74.5 months. Overall, 535 patients were randomized (acalabrutinib-obinutuzumab, n = 179; acalabrutinib, n = 179; chlorambucil-obinutuzumab, n = 177). Median age was 70 years, 63.0% had unmutated immunoglobulin heavy chain variable region gene (uIGHV), 13.6% had del(17p) and/or mutated TP53, and 17% had complex karyotype (CK; ≥3 chromosomal abnormalities). Median progression-free survival (PFS) was not reached (NR) for acalabrutinib-obinutuzumab and acalabrutinib vs 27.8 months for chlorambucil-obinutuzumab (both P < .0001); estimated 72-month overall PFS rates were 78.0%, 61.5%, and 17.2%, respectively. Acalabrutinib-obinutuzumab resulted in improved PFS vs acalabrutinib monotherapy (hazard ratio [HR], 0.58; P = .0229). Patients with uIGHV, del(17p) and/or mutated TP53, or CK had significantly improved PFS with acalabrutinib ± obinutuzumab vs chlorambucil-obinutuzumab (P < .0001, P ≤ .0009, and P < .0001 for both acalabrutinib-containing arms, respectively). Median overall survival (OS) was NR for all treatments, with significantly longer OS for acalabrutinib-obinutuzumab than chlorambucil-obinutuzumab (HR, 0.62; P = .0349). Estimated 72-month OS rates were 83.9%, 75.5%, and 74.7% for acalabrutinib-obinutuzumab, acalabrutinib, and chlorambucil-obinutuzumab, respectively. Adverse events (AEs) occurring after >4 years were mostly grade 1 to 2. Rates of AEs, serious AEs, and events of clinical interest were similar between acalabrutinib-containing arms and consistent with the known safety profiles of acalabrutinib and obinutuzumab. Efficacy and safety of acalabrutinib-containing arms were maintained, with longer PFS in both acalabrutinib arms than chlorambucil-obinutuzumab including in patients with high-risk features. This trial was registered at www.ClinicalTrials.gov as #NCT02475681.

Background: Previous reports of ELEVATE-TN (NCT02475681) at median follow-up of up to 58.2 months (mo) demonstrated superior efficacy of acalabrutinib (A) ± obinutuzumab (O) compared with O + chlorambucil (Clb) in patients (pts) with treatment-naive (TN) chronic lymphocytic leukemia (CLL). Herein, updated results at 74.5 mo of follow-up are reported. Methods: Pts received A monotherapy, A+O, or O+Clb. Pts who progressed on O+Clb could cross over to A monotherapy. Investigator (INV)-assessed progression-free survival (PFS), INV-assessed overall response rate (ORR), overall survival (OS), and safety were evaluated. All analyses are ad-hoc and P-values are descriptive. Results: A total of 535 pts (A, n=179; A+O, n=179; O+Clb, n=177) were randomized: median age was 70 years, 63% had unmutated immunoglobulin heavy chain variable region genes (uIGHV), and 14% had del(17p) and/or TP53 mutation ( TP53m). At a median follow-up of 74.5 mo (range, 0.0-89.0; data cutoff March 3, 2023), median PFS was not reached (NR) for A+O and A vs 27.8 mo for O+Clb (hazard ratio [HR] vs O+Clb: 0.14 and 0.23, respectively; P<0.0001 for both; HR A+O vs A: 0.58; P=0.0229); estimated 72-mo PFS rates were 78%, 62%, and 17%, respectively (Figure 1). For the 79 pts who crossed over from O+Clb to A, median PFS2 (time to second disease progression or death) was NR; estimated 72-mo PFS2 rate was 54%. Median OS was NR in any treatment arm and was significantly longer with A+O vs O+Clb (HR: 0.62; P=0.0349); estimated 72-mo OS rates were 84% for A+O, 76% for A, and 75% for O+Clb ( Figure 2). In 337 pts with uIGHV, median PFS was NR in both the A+O and A arms vs 22.2 mo for O+Clb (HR: 0.08 and 0.12, respectively; P<0.0001 for both), and estimated 72-mo PFS rates were 75%, 60%, and 5%, respectively, with median OS NR in all treatment arms and estimated 72-mo OS rates of 84%, 76%, and 74%, respectively. In 73 pts with del(17p) and/or TP53m, median PFS was 73.1 mo for A+O and NR for A vs 17.5 mo for O+Clb (HR: 0.28 and 0.23, respectively; P≤0.0009 for both), and estimated 72-mo PFS rates were 56%, 56%, and 18%, respectively. Median OS was NR in both the A+O and A arms vs 74.9 mo for O+Clb (HR: 0.53 and 0.46, respectively, neither statistically significant) and estimated 72-mo OS rates were 68%, 72%, and 53%, respectively. ORR was significantly higher with A+O (96%; 95% confidence interval [CI]: 92-98; P<0.0001) and A (90%; 95% CI: 85-94; P=0.0499) vs O+Clb (83%; 95% CI: 77-88). Combined complete response (CR) plus CR with incomplete hematologic recovery rates were higher with A+O (37%) and A (19%) vs O+Clb (14%; P≤0.0499 for both). Median treatment exposure was 74.4 mo and 72.0 mo for A in the A+O and A arms, respectively; 5.5 mo and 5.6 mo for O in the A+O and O+Clb arms, respectively; and 5.5 mo for Clb in O+Clb arm. Adverse events (AEs) for the O+Clb arm have been previously reported. The most common (≥5% of pts) grade ≥3 AEs for A+O and A, respectively, were neutropenia (31% and 12%), thrombocytopenia (8% and 3%), diarrhea (6% and 1%), COVID-19 (9% and 7%), pneumonia (7% and 6%), syncope (5% and 2%), and hypertension (4% and 5%). For events of clinical interest, grade ≥3 atrial fibrillation, hypertension, and secondary primary malignances were reported in 2%, 4%, and 10% of pts treated with A+O and 2%, 5%, and 5% of pts treated with A, respectively. Treatment is ongoing in 54% (A+O; n=96) and 47% (A; n=84) of pts; the most common reasons for treatment discontinuation were AEs, observed in 21% (n=38) of pts treated with A+O and 18% (n=32) of pts treated with A, and progressive disease, observed in 6% (n=10) of pts treated with A+O and 14% (n=25) of pts treated with A. For pts who crossed over from O+Clb to A, 41% (n=32) discontinued A due to AEs in 13% (n=10) of pts and progressive disease in 16% (n=13) of pts. Conclusions: With a median follow-up of 74.5 mo, the efficacy and safety of A+O and A monotherapy were maintained in pts with TN CLL, including in pts with high-risk genetic features. At 6 years of follow-up, PFS was significantly longer in pts treated with A+O vs A. Median OS was NR in any treatment arm and was significantly longer in pts treated with A+O vs O+Clb.

The prognosis of elderly AML patients had not even been improved by using hypomethylating agents; however, synergistic effect of combining azacitidin with venetoclax had resulted in a remarkable therapeutic advance. Our goal was to study the latter treatment with a new dosing regimen in a retrospective/observational study. In our department, we analyzed the data of AML patients who were unfit for curative high-dose treatment and accepted the medication with a fixed-dose of azacitidin and venetoclax combination (AZA-VEN, 100 mg sc for 7 days-100 mg per os continuously). The primary end point was the overall survival. In total, 55 AML patients received the treatment between OCT/2019-DEC/2022. Mean age was 69.4-year (48-84), median overall survival was 17.2-month (95% CI, 14.3-20.10) Composite CR: (CR + CRi) 62%. Side effect CTCAE 3 or higher: neutropenia with fever: 36.4%, anemia: 29.1%, thrombocytopenia: 16.4% and nausea 20%. AZA-VEN combination treatment of our unfit AML patients was found to be a good therapeutic option. The results achieved with significantly lower doses of the fixed dose of AZA-VEN are comparable to the conclusions of the VIALE-A study, and the less severe side effects we have observed are explained by the milder neutropenia of the newly introduced regimen.

Bruton tyrosine kinase (BTK) inhibitors have improved chronic lymphocytic leukemia (CLL) outcomes and offer a chemotherapyfree option [1].The BTK inhibitor ibrutinib, alone or with a CD20 antibody, demonstrated better efficacy versus chemoimmunotherapy in treatment-naïve (TN) CLL [2][3][4].However, cardiovascular toxicity is a concern with continuous ibrutinib use [5,6].Acalabrutinib is a next-generation, selective BTK inhibitor approved for CLL/small lymphocytic leukemia (SLL).Acalabrutinib, alone or with obinutuzumab, showed favorable efficacy in clinical trials [7,8].ELEVATE-TN demonstrated superior efficacy for acalabrutinib-obinutuzumab versus obinutuzumab-chlorambucil with acceptable tolerability in TN CLL [9].We report 4-year followup results from ELEVATE-TN.ELEVATE-TN is a phase 3, randomized, multicenter, open-label study (NCT02475681) that enrolled patients aged ≥65 years, or 18-65 years with comorbidities (Cumulative Illness Rating Scale-Geriatric score >6, creatinine clearance 30-69 mL/min by Cockcroft-Gault), who had TN CLL or SLL requiring treatment, Eastern Cooperative Oncology Group performance status score of ≤2, and adequate hematologic, hepatic, and renal function [9].Patients were randomized (1:1:1) to acalabrutinib 100 mg twice daily (until disease progression or unacceptable toxicity) with or without obinutuzumab (fixed-duration, up to 6 cycles) or obinutuzumab plus chlorambucil (up to 6 cycles).Crossover to acalabrutinib monotherapy was permitted in patients who progressed on obinutuzumab-chlorambucil. The primary study endpoint was independent review committee (IRC)-assessed progression-free survival (PFS).After primary analysis, PFS was investigatorassessed.Key secondary/exploratory endpoints were investigator-assessed PFS, investigator-assessed overall response rate (ORR), overall survival (OS), undetectable minimal residual disease (uMRD) rate, and safety.The study was not powered to compare acalabrutinib versus acalabrutinib-obinutuzumab.Informed consent was obtained from all patients before enrollment.Study details were previously published [9].In total, 535 patients were randomized (acalabrutinib-obinutuzumab, n = 179; acalabrutinib, n = 179; obinutuzumab-chlorambucil, n = 177).Median age was 70 years (range, 41.0-91.0);14% had del(17)(p13.1)and/or mutated TP53 and 63% had unmutated immunoglobulin heavy chain variable (IGHV) gene (Supplementary Table 1).At a median follow-up of 46.9 months (range, 0.0-59.4),treatment was ongoing in 74.9% (n = 134) and 69.3% (n = 124) of patients in the acalabrutinib-obinutuzumab and acalabrutinib monotherapy arms, respectively (Supplementary Table 2).Sixty-

Background Hydroxyurea (HU) is a commonly used first-line treatment in patients with polycythemia vera (PV). However, approximately 15%-24% of PV patients report intolerance and resistance to HU.Methods This phase IV, European, real-world, observational study assessed the efficacy and safety of ruxolitinib in PV patients who were resistant and/or intolerant to HU, with a 24-month follow-up. The primary objective was to describe the profile and disease burden of PV patients.Results In the 350 enrolled patients, 70% were >60 years old. Most patients (59.4%) had received >= 1 phlebotomy in the 12 months prior to the first dose of ruxolitinib. Overall, 68.2% of patients achieved hematocrit control with 92.3% patients having hematocrit <45% and 35.4% achieved hematologic remission at month 24. 85.1% of patients had no phlebotomies during the study. Treatment-related adverse events were reported in 54.3% of patients and the most common event was anemia (22.6%). Of the 10 reported deaths, two were suspected to be study drug-related.Conclusion This study demonstrates that ruxolitinib treatment in PV maintains durable hematocrit control with a decrease in the number of phlebotomies in the majority of patients and was generally well tolerated.

AbstractBone marrow fibrosis (BMF) is a pathological feature of myelofibrosis, with higher grades associated with poor prognosis. Limited data exist on the association between outcomes and BMF changes. We present BMF data from Janus kinase (JAK) inhibitor–naive patients from SIMPLIFY‐1 (NCT01969838), a double‐blind, randomized, phase 3 study of momelotinib vs ruxolitinib. Baseline and week 24 bone marrow biopsies were graded from 0 to 3 as per World Health Organization criteria. Other assessments included Total Symptom Score, spleen volume, transfusion independence status, and hemoglobin levels. Paired samples were available from 144 and 160 patients randomized to momelotinib and ruxolitinib. With momelotinib and ruxolitinib, transfusion independence was achieved by 87% and 44% of patients with BMF improvement of ≥1 grade and 76% and 56% of those with stable/worsening BMF; there was no association between BMF changes and transfusion independence for either arm (momelotinib, p = .350; ruxolitinib, p = .096). Regardless of BMF changes, hemoglobin levels also generally increased on momelotinib but decreased on ruxolitinib. In addition, no associations between BMF changes and spleen (momelotinib, p = .126; ruxolitinib, p = .407)/symptom (momelotinib, p = .617; ruxolitinib, p = .833) outcomes were noted, and no improvement in overall survival was observed with ≥1‐grade BMF improvement (momelotinib, p = .395; ruxolitinib, p = .407). These data suggest that the anemia benefit of momelotinib is not linked to BMF changes, and question the use of BMF assessment as a surrogate marker for clinical benefit with JAK inhibitors.

A myeloma multiplex kezelése az elmúlt években számottevően változott köszönhetően a diagnosztikai eljárások fejlődésének, az indikációban törzskönyvezett korszerű készítményeknek. A betegség kezelésében tapasztalható folyamatos innováció, a legújabb klinikai vizsgálati eredmények és valós életbeli adatok, továbbá a nemzetközi irányelvek követése ugyanakkor Európa-szerte kihívás elé állítja a finanszírozókat, döntéshozókat.A Myeloma multiplex: a jelen kihívásai és a korszerű ellátás feltételei áttekintő tanulmány elkészítésével célunk egy rendszerszemléletű javaslati anyag kidolgozása volt, amely az ellátás minden területét érintve átfogó értékelést nyújt, kitérve a lehetséges beavatkozási pontokra.Jelen közlemény a myeloma multiplex korszerű kezelési elvei, a Magyarországon elérhető terápiák és kielégítetlen szükséglet továbbá a magyarországi betegellátásban mutatkozó főbb kihívások, szűk keresztmetszetek alapján elemzi a hazai myelomaellátást, amely alapján széles körű javaslatok készültek a magyarországi ellátás fejlesztésére.

TP53 aberrations predict chemoresistance and represent a contraindication for the use of standard chemoimmunotherapy in chronic lymphocytic leukaemia (CLL). Recent next-generation sequencing (NGS)-based studies have identified frequent low-burden TP53 mutations with variant allele frequencies below 10%, but the clinical impact of these low-burden TP53 mutations is still a matter of debate. In this study, we aimed to scrutinise the subclonal architecture and clinical impact of TP53 mutations using a sensitive, NGS-based mutation analysis in a 'real-world' cohort of 901 patients with CLL. In total, 225 TP53 mutations were identified in 17.5% (158/901) of the patients; 48% of these alterations represented high-burden mutations, while 52% were low-burden TP53 mutations. Low-burden mutations as sole alterations were identified in 39% (62/158) of all mutated cases with 82% (51/62) of these being represented by a single low-burden TP53 mutation. Patients harbouring low-burden TP53 mutations had significantly lower time to first treatment compared to patients with wild-type TP53. Our study has expanded the knowledge on the frequency, clonal architecture, and clinical impact of low-burden TP53 mutations. By demonstrating that patients with sole low-burden TP53 variants represent more than one-third of patients with TP53 mutations and have an increased risk for treatment initiation, our findings strengthen the need to redefine the threshold of TP53 variant reporting to below 10% in the routine diagnostic setting.

Objective: The Hungarian National Registry for Philadelphia chromosome negative myeloproliferative neoplasms was used to analyse the thromboembolic events (TE) of Hungarian patients with polycythemia vera (PV).Methods: Data from 351 JAK2 V617F-positive patients diagnosed with PV were collected online from 15 haematology centres reporting clinical characteristics, therapeutic interventions and thromboembolic events. TE events were evaluated before and after diagnosis based upon the Landolfi and Tefferi risk assessment scales.Results: TE were reported on 102 patients before diagnosis and 100 during the follow-up period. Comparing to the frequency of major arterial events before PV diagnosis, we can notice a decreasing tendency after diagnosis: from 12.3% to 2.6% (p < .00003). There was no significant change in the rate of major venous events (from 5.1% to 8.5%; p = .1134) or minor arterial events (from 11.7% to 17.4%; p = .073). Bleeding events were recorded in 5.7% of patients. Despite treatment with HU + ASA, 44 patients (43.1%) with prior TE had recurrent thromboembolic complications. The particular analysis of our data revealed a new TE scoring system based on: age, gender, previous TE and iron deficiency at the time of diagnosis.Conclusions: Our registry enables characterisation of patients with PV. The high level of recurrent TE events highlights the need for more effective and risk-adapted therapy.

Introduction: MMB, an oral JAK1/JAK2/ACVR1 inhibitor, was evaluated in 3 RCTs (SIMPLIFY-1 [S1], SIMPLIFY-2 [S2], and MOMENTUM) in patients (pts) with high- and intermediate-risk myelofibrosis (MF). We conducted an integrated analysis of MMB to characterize its long-term safety, with pooled data from the 3 RCTs, representing a spectrum of MF disease from early (JAK inhibitor-naive) to late (JAK inhibitor-experienced) stages. Methods: Adult pts with high- and intermediate-risk MF were randomized to receive MMB or ruxolitinib (RUX; S1); MMB or best available therapy, which was RUX in 89% (S2) of patients; and MMB or danazol (MOMENTUM). At the end of the 24-week randomized treatment period, pts in the MMB arms could continue treatment with open-label (OL) MMB, and pts in the control arms could cross over to receive OL MMB. Pts from all 3 RCTs continued to receive long-term extended access to MMB in the extended access protocol (XAP) study. Median follow-up time was 20 months in S1, 10 months in S2, and 7 months in MOMENTUM. Results: As of December 3, 2021, across these 3 studies, 725 pts (1261 person-years) with MF received MMB; 12% remained on therapy for ≥5 years, with a median MMB exposure of 11.3 months, and mean (range) MMB exposure of 20.3 (0.1-90.4) months. Nonhematologic treatment-emergent adverse events (TEAEs) were mostly grade 1/2, with diarrhea (26.8% any grade, 2.6% grade ≥3) and nausea (19.4% any grade, 1.1% grade ≥3) the most frequent TEAEs, in the absence of antidiarrheal and antiemetic prophylaxis. The most frequently occurring hematologic any-grade TEAEs included thrombocytopenia (23.4%), anemia (23.0%), and neutropenia (5.7%). Infections occurred in 55.4% of patients, but serious opportunistic infections were rare (1.5%). Study drug discontinuations due to any treatment-related adverse events (AEs) were not common (15.6%). Thrombocytopenia most frequently led to study discontinuation but only occurred in 3.7% of pts. Malignancies (13.4%), including nonmelanoma skin cancer (4.8%), were infrequent. Acute myeloid leukemia (AML), or leukemic transformation, occurred in 3.0% of pts, and led to MMB discontinuation in 2.1% of pts. Peripheral neuropathy was infrequent (14.8% any grade), rarely severe (n=2 (1.2%) grade ≥3, both resolved on MMB withdrawal), mostly sensory, and rarely led to treatment discontinuation. Frequent and clinically important AEs did not increase in incidence over time (Table). Mean baseline hemoglobin and platelet count levels were and 9.9 g/dL and 238.9 x 109/L, respectively. Hemoglobin levels were increased at first on-study assessment (week 2) on MMB and were maintained thereafter. Hemoglobin levels increased in the OL phase in pts who switched to MMB from RUX (Figure A); platelet counts improved or were maintained (Figure B). Conclusion: We report the largest trial safety database to date for a JAK inhibitor in MF. MMB demonstrated a consistent safety profile without unexpected long-term or cumulative toxicity. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Topic: 16. Myeloproliferative neoplasms - Clinical Background: According to recent real-world evidence, patients with high-risk polycythemia vera (PV) receiving standard care spend <30% of time in response for blood count targets recommended by European LeukemiaNet (ELN) (Carpenter et al 2022; eJHaem). Individual responses fluctuated considerably; a novel observation not detectable by conventional evaluation at predefined timepoints. Ropeginterferon alfa-2b induces higher response rates than standard treatment (hydroxyurea [HU]/best available treatment [BAT]) after long-term therapy, but whether this corresponds with cumulative time in response is unknown. Therefore, final PROUD-PV/CONTINUATION-PV data were evaluated regarding time in peripheral blood count remission. Aims: To assess the cumulative proportion of time in response for blood counts according to ELN targets in patients treated with ropeginterferon alfa-2b vs HU/ BAT over a period of ≥6 years. Methods: Patients with PV (WHO 2008 criteria) who were HU-naïve/pre-treated and gave informed consent were randomized 1:1 to ropeginterferon alpha-2b or control (HU) for one year in PROUD-PV (EudraCT: 2012-005259-18). Dosing was optimized per protocol in both arms. In the extension CONTINUATION-PV (2014-001357-17), patients in the control arm could switch from HU to BAT. Hematology was evaluated at intervals of 2-12 weeks for 5 years, and 6-monthly in the final year. Complete hematologic response (CHR) was defined per modified ELN criteria (hematocrit <45% with no phlebotomy for ≥3 months, PLT<400x109/L and WBC<10x109/L). Cumulative time in CHR and in response for individual parameters were assessed in the CONTINUATION-PV full analysis set based on the last response at each assessment, up to study completion/discontinuation. All safety data were analyzed. Results: The full analysis set comprised 169 patients: 95 in the ropeginterferon alfa-2b arm and 74 in the control arm. Individual patient data for time spent in CHR over ≥6 years demonstrate more consistent blood count responses among patients treated with ropeginterferon alfa-2b than in the standard treatment arm, in which 88% received HU as of the last assessment (Figure 1). Despite a more gradual onset of response in the ropeginterferon alfa-2b arm, on average, patients spent 60.9% of time in CHR vs. 41.2% for patients in the control arm (p=0.0437). These findings align with results of log-binomial modelling of longitudinal blood count assessments over the entire 6 years, indicating a higher CHR rate for ropeginterferon alfa-2b vs. standard treatment (RR: 1.27 [95% C.I. 1.05 to 1.53; p=0.0152]). Differences were also observed for individual parameters, with significantly more time spent with WBC counts on target in the ropeginterferon alfa-2b arm vs. control (mean: 93.7% vs. 80.9% p=0.0249). The respective mean proportion of time in response was 65.1% vs 57.0% (p=0.4501) for hematocrit and 87.7% vs 75.6% (p=0.0875) for PLT counts. Including PROUD-PV (N=254), 5 thromboembolic events occurred in the ropeginterferon alfa-2b arm; CHR was recorded at the preceding visit in only 1 case. On standard treatment, 7 thromboembolic events occurred, 3/7 preceded by CHR. Statistical correlation with CHR was precluded by the low incidence of events. Summary/Conclusion: These results underscore the difficulty of maintaining PV patients within peripheral blood count targets during standard treatment and indicate that more consistent control of these parameters can be achieved with ropeginterferon alfa-2b. Thromboembolic events were rare during ropeginterferon alfa-2b therapy and largely occurred during periods of non-response, in agreement with current response criteria.Keywords: Myeloproliferative disorder, Interferon alpha, Polycythemia vera