Search

Multiple myeloma (MM) and chronic lymphocytic leukemia (CLL) patients have increased morbidity and mortality rates of COVID-19 due to immunosuppression associated with the disease and ongoing therapy. The same immune impairment accompanying CLL and MM also affects suboptimal vaccine response. The study assessed the effectiveness of the humoral and T cell-mediated immunity following mRNA COVID-19 vaccination (using either BNT162b2 or mRNA-1273) in short-term (2-5 weeks after second dose) and long-term follow-up (12 weeks after vaccination). Between March and August 2021, blood samples were obtained from 62 CLL and 60 MM patients from eight different hematology departments in Poland. Total anti-RBD antibodies were detected in 37% MM patients before vaccination, increased to 91% and 94% in short- and long-term follow-up, respectively. In CLL, serological responses were detectable in 21% of patients before vaccination and increased to 45% in the short-term and 71% in long-term observation. We detected a tendency to higher frequencies of specific CD8+ T cells against SARS-CoV-2 after vaccination compared to samples before vaccination in MM patients and no changes in frequencies of specific T cells in CLL patients. Our study provides novel insights into mRNA vaccination efficacy in immunocompromised MM and CLL patients, and our findings highlight that specific CD8+ T cells against SARS-CoV-2 might be induced by vaccination but do not correlate positively with serological responses.

Membrane transporters are important determinants of drug bioavailability. Their expression and activity affect the intracellular drug concentration in leukemic cells impacting response to therapy. Pharmacogenomics represents genetic markers that reflect allele arrangement of genes encoding drug transporters associated with treatment response. In previous work, we identified SNP rs460089 located in the promotor of SLC22A4 gene encoding imatinib transporter OCTN1 as influential on response of patients with chronic myeloid leukemia treated with imatinib. Patients with rs460089-GC pharmacogenotype had significantly superior response to first-line imatinib treatment compared to patients with rs460089-GG. This study investigated whether pharmacogenotypes of rs460089 are associated with sustainability of treatment-free remission (TFR) in patients from the EUROpean Stop Kinase Inhibitor (EURO-SKI) trial. In the learning sample, 176 patients showed a significantly higher 6-month probability of molecular relapse free survival (MRFS) in patients with GC genotype (73%, 95% CI: 60–82%) compared to patients with GG (51%, 95% CI: 41–61%). Also over time, patients with GC genotype had significantly higher MRFS probabilities compared with patients with GG (HR: 0.474, 95% CI: 0.280–0.802, p = 0.0054). Both results were validated with data on 93 patients from the Polish STOP imatinib study. The SNP rs460089 was found as an independent predictor of TFR.

Agnieszka Karczmarczyk,1 Maciej Korpysz,2 Sylwia Bilska,3 Joanna Purkot,1 Marek Hus,3 Krzysztof Giannopoulos1,4 1Department of Experimental Hematooncology, Medical University of Lublin, Lublin, Poland; 2Department of Biochemical Diagnostics, Medical University of Lublin, Lublin, Poland; 3Department of Hematooncology and Bone Marrow Transplantation, Medical University of Lublin, Lublin, Poland; 4Department of Hematology, St. John’s Cancer Centre, Lublin, PolandCorrespondence: Krzysztof Giannopoulos, Department of Experimental Hematooncology, Medical University of Lublin, Chodzki 1, Lublin, 20-093, Poland, Tel + 48 81448 6632, Fax + 48 81448 6634, Email krzysztof.giannopoulos@gmail.comPurpose: Among hematological malignancies, the expression profile of programmed cell death-1 (PD-1) and its ligands in multiple myeloma (MM) is still debated by numerous research groups. In current study, we characterized the expression of PD-1 and its ligands both on RNA and protein levels in MM patients. We have also attempted to analyze whether daratumumab therapy might overcome CD38-mediated immunosuppression that inhibits in particular CD8+ T-cell function.Patients and Methods: This study included 149 newly diagnosed MM patients and 15 relapsed/refractory MM patients before and after daratumumab treatment. The mRNA levels of PDCD1, PDCD1LG1, PDCD1LG2 and their splicing variants was assessed by quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR). Flow cytometry was used to characterize the surface expression of PD-1 and its ligands on plasma cells, B and T cells. The surface expression of PD-1 on T cells was assessed by flow cytometry before and after daratumumab treatment.Results: The mRNA expression of PDCD1LG1, PDCD1LG2 and their splicing variants were higher in plasma cells as compared to bone marrow mononuclear cells (BMMCs). Our results show that the percentage of plasma cells expressing PD-L1 was significantly higher than plasma cells expressing PD-L2 (p< 0.0001) in bone marrow (BM) of MM patients. There was no significant difference between the percentage of plasma cells expressing PD-1 and B cells expressing PD-1 in BM of MM patients (11.19% vs 8.91%). We also found that the percentage of CD8+PD-1+ T cells was significantly higher than CD4+PD-1+T cells in BM (p< 0.0001) of MM patients. Here, we observed no change in PD-1 expression on CD4+ and CD8+ T cells after the daratumumab treatment.Conclusion: The PD-1 and its ligands might represent an interesting target for MM immunotherapy, as one would target both malignant plasma cells as well as the immune cells that play a key role in tumor escape mechanisms.Keywords: PD-1, PD-L1, PD-L2, daratumumab, multiple myeloma

Chronic lymphocytic leukemia (CLL) is a disease of the elderly, with a median age at diagnosis of approximately 70 years. The natural course of the disease varies greatly, and patients with nonprogressive and asymptomatic leukemia do not require treatment. The results of CLL treatment have improved significantly in recent years, mainly due to the introduction of new, more effective drugs, including BCR inhibitors and BCL2 inhibitors. The new drugs are used continuously, while venetoclax in combination with anti-CD20 antibodies is used for 24 (rituximab) or 12 (obinutuzumab) months, depending on the type of antibody and line of therapy. The choice of treatment protocol should largely depend on the assessment of 17p deletion/ TP53 mutation and immunoglobulin variable heavy chain (IGVH) mutation status, which correlate with a worse response to immunochemotherapy. The role of immunochemotherapy, which until recently was the mainstay of CLL treatment, has now significantly decreased. In the first-line, it is recommended only in patients without 17p deletion/ TP53 mutation, with mutated IGVH . Other patients should receive novel targeted therapies. However, at the time of the preparation of these recommendations, these therapies are not available in the firs-line of treatment in Poland. Novel targeted therapies play a major role in the treatment of refractory/relapsed CLL, and immunochemotherapy is recommended primarily in patients with a long-term response to first-line therapy. In this article, we present an update of the guidelines for the diagnosis and treatment of CLL, including the treatment of autoimmune complications, as well as the prophylaxis and treatment of infections, developed by the Polish Society of Haematologists and Transfusiologists and PALG-CLL Working Group.

This is the first large-scale cross-country analysis of patients with chronic lymphocytic leukemia (CLL) aimed to evaluate the incidence, types, and key prognostic factors of secondary malignancies, and to assess the impact on overall survival based on retrospective claims data from three Central European countries. We analyzed 25,814 newly diagnosed CLL patients from Czechia, Hungary, and Poland; 10,312 (39.9%) patients were treated for CLL in study periods between 2004 and 2016. Out of the treated patients, 1986 (19.3%) received the FCR therapy in the first line and 779 (7.6%) received FCR in subsequent lines. We observed that 33.7% of treated patients developed secondary malignancies during the study. Based on country estimates, the probability to develop a secondary malignancy within 4 years since starting the first-line FCR therapy ranged between 28.0% and 36.8%. We found the age at diagnosis, male gender, any malignancy prior to the CLL diagnosis, and the CLL treatment to be the key risk factors for developing secondary malignancies. Specifically, the FCR therapy was a statistically significant (p 0.001) prognostic factor for risk increase with the hazard ratio between 1.46 and 1.60. Across the three Central European countries, we observed consistent results indicating FCR increased the risk of secondary malignancies in CLL patients. We conclude that secondary malignancies are clearly an undervalued burden for CLL patients, caregivers, and the healthcare system. When evaluating new therapies in regulatory and reimbursement decision making, the factor of secondary malignancies deserves deeper considerations.

Chronic lymphocytic leukemia (CLL) is characterized by the existence of subsets of patients with (quasi)identical, stereotyped B-cell receptor (BcR) immunoglobulins. Patients in certain major stereotyped subsets often display remarkably consistent clinicobiological profiles, suggesting that the study of BcR immunoglobulin stereotypy in CLL has important implications for understanding disease pathophysiology and refining clinical decision-making. Nevertheless, several issues remain open, especially pertaining to the actual frequency of BcR immunoglobulin stereotypy and major subsets, as well as the existence of higher-order connections between individual subsets. To address these issues, we investigated clonotypic IGHV-IGHD-IGHJ gene rearrangements in a series of 29 856 patients with CLL, by far the largest series worldwide. We report that the stereotyped fraction of CLL peaks at 41% of the entire cohort and that all 19 previously identified major subsets retained their relative size and ranking, while 10 new ones emerged; overall, major stereotyped subsets had a cumulative frequency of 13.5%. Higher-level relationships were evident between subsets, particularly for major stereotyped subsets with unmutated IGHV genes (U-CLL), for which close relations with other subsets, termed “satellites,” were identified. Satellite subsets accounted for 3% of the entire cohort. These results confirm our previous notion that major subsets can be robustly identified and are consistent in relative size, hence representing distinct disease variants amenable to compartmentalized research with the potential of overcoming the pronounced heterogeneity of CLL. Furthermore, the existence of satellite subsets reveals a novel aspect of repertoire restriction with implications for refined molecular classification of CLL. Key Points: • In a series of 29 856 CLL patients, the incidence of BcR stereotypy peaked at 41%. • Higher-order relations exist between stereotyped subsets, particularly for those from U-CLL, for which satellite subsets were identified.

The number of newly diagnosed haematological malignancies in Polish adults and children is about 9,000 a year, which constitutes about 5.5% of all malignancies in the country. Adult patients with haematological malignancies are diagnosed and treated in 42 institutions in Poland. The scientific and educational support for this activity is provided under the umbrella of the Polish Society of Haematologists and Transfusiologists (PTHiT, Polskie Towarzystwo Hematologow i Transfuzjologow ), the Polish Adult Leukemia Group (PALG), the Polish Lymphoma Research Group (PLRG), the Polish Myeloma Study Group (PMSG), the Polish Myeloma Consortium (PMC), and consultants in haematology. The aim of this position paper is to present the current status and progress in therapy of haematological malignancies in Polish haematology adult centres, focusing on the activity of PALG, PLRG, and PMSG. The achievements of Polish haemato-oncology at the beginning of the third decade of the 21 st century are set out in this paper. Polish haemato-oncology today has an important international position based on contributions to the development of knowledge, international cooperation, and a high quality of patient care. In many instances, clinical trials run by Polish collaborative groups have influenced international standards. Polish haematologists have been the authors of treatment recommendations, and their research has indicated areas for further research.

Purpose Mean platelet volume (MPV) is a readily accessible and commonly tested hematological indicator. Recent studies revealed a significant impact of MPV on the course and prognosis of many diseases, including some types of cancer, as well as on the incidence of atrial fibrillation and bleeding. The study aimed to perform a retrospective analysis of MPV in terms of time to first treatment (TTFT) and to determine its prognostic value in the group of patients with chronic lymphocytic leukemia (CLL). Moreover, the study includes a retrospective analysis of platelet parameters in patients treated with ibrutinib concerning bleeding and atrial fibrillation. Patients and methods The study included 523 patients with CLL, for 344 the most important cytogenetic aberrations were reported. The Mann-Whitney, Kruskal-Wallis, Kaplan-Meier, chi-squared, log‑rank tests and multivariate Cox proportional hazard regression model were used to analyze collected data. Results The receiver operating characteristic curve analysis was performed to identify optimal cut-off value for MPV. The analysis of survival curves showed that in the group of patients with higher values of MPV TTFT was significantly longer than in the group with lower MPV (17.9 vs 36 months, p=0.0015, cut-off value for MPV= 10.4 fl). In multivariate Cox proportional hazard regression model low MPV, the presence of del11q and del13q provided independent prognostic value for TTFT (HR=0.69, 95%-CI, 0.5293 to 0.9081; p=0.0078; HR=1.76, 95%-CI, 1.3000 to 2.3882, p=0.0003, HR=0.74, 95%-Cl, 0.5674 to 0.9588, p=0.0229, respectively). In the group treated with ibrutinib, 59 patients had no significant correlation between MPV level and the incidence of therapy complications, although in the group of patients with low MPV there was a tendency for more frequent occurrence of atrial fibrillation (p=0.259). Conclusion Low MPV values are associated with unfavorable prognosis and might represent a novel, independent prognostic factor in CLL.

BACKGROUND Neuropilin-1 (NRP1) is a receptor for vascular endothelial growth factor A (VEGFA), and has been reported to be overexpressed in several malignancies. Since angiogenesis plays an important role in pathogenesis of multiple myeloma (MM) and the role of NRP1 in MM has not been studied yet, we characterized the expression of NRP1 in this disease. MATERIALS AND METHODS The expression level of NRP1 was measured in 140 patients newly diagnosed with MM and 28 healthy controls by flow cytometry and quantitative reverse transcriptase polymerase chain reaction. RESULTS Expression of NRP1 was significantly reduced on plasma cells (median=2.05%) compared to that on B-cells (median=10.05%, p

Background/aim To study the long-term clinical efficacy and tolerability of ibrutinib monotherapy in real-world relapsed and refractory chronic lymphocytic leukemia (RR-CLL) patients outside clinical trials. Patients and methods Clinical data of 171 RR-CLL patients treated with ibrutinib were collected within the observational study of the Polish Adult Leukemia Study Group. Results Median patient age was 64 years. Patients were pretreated with 3 (1-10) median lines of therapy, while 42 (24.6%) had 17p deletion. The median observation time was 40 months (range=1-59 months), while median ibrutinib monotherapy reached 37.5 months (range=0.4-59.2 months). Response was noted in 132 (77.2%) patients. The estimated 5-year progression-free survival (PFS) and overall survival (OS) rates were 61.1% (95%CI=49.3-70.9%) and 56.8% (95%CI=45.6-66.6%), respectively. At the time of analysis 97 (56.7%) remained under ibrutinib monotherapy. Conclusion Ibrutinib is clinically effective and tolerable as a monotherapy in real-world RR-CLL patients.

Zanubrutinib is a next-generation, selective Bruton tyrosine kinase inhibitor with efficacy in relapsed chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). We compared zanubrutinib with bendamustine-rituximab to determine its effectiveness as frontline therapy in patients with CLL or SLL.We conducted an open-label, multicentre, phase 3 study at 153 academic or community hospitals in 14 countries and regions. Eligible patients had untreated CLL or SLL requiring treatment as per International Workshop on CLL criteria; were aged 65 years or older, or 18 years or older and had comorbidities; and had an Eastern Cooperative Oncology Group performance status score of 0-2. A central interactive web response system randomly assigned patients without del(17)(p13·1) to zanubrutinib (group A) or bendamustine-rituximab (group B) by sequential block method (permutated blocks with a random block size of four). Patients with del(17)(p13·1) were enrolled in group C and received zanubrutinib. Zanubrutinib was administered orally at 160 mg twice per day (28-day cycles); bendamustine at 90 mg/mBetween Oct 31, 2017, and July 22, 2019, 590 patients were enrolled; patients without del(17)(p13·1) were randomly assigned to zanubrutinib (group A; n=241) or bendamustine-rituximab (group B; n=238). At median follow-up of 26·2 months (IQR 23·7-29·6), median progression-free survival per independent review committee was not reached in either group (group A 95% CI not estimable [NE] to NE; group B 28·1 months to NE). Progression-free survival was significantly improved in group A versus group B (HR 0·42 [95% CI 0·28 to 0·63]; two-sided p0·0001). The most common grade 3 or worse adverse event was neutropenia (27 [11%] of 240 patients in group A, 116 [51%] of 227 in group B, and 17 [15%] of 111 patients in group C). Serious adverse events occurred in 88 (37%) of 240 patients in group A, 113 (50%) of 227 patients in group B, and 45 (41%) of 111 patients in group C. Adverse events leading to death occurred in 11 (5%) of 240 patients in group A, 12 (5%) of 227 patients in group B, and three (3%) of 111 patients in group C, most commonly due to COVID-19 (four [2%] of 240 patients in group A), diarrhoea, and aspiration pneumonia (two each [1%] of 227 patients in group B).Zanubrutinib significantly improved progression-free survival versus bendamustine-rituximab, with an acceptable safety profile consistent with previous studies. These data support zanubrutinib as a potential new treatment option for untreated CLL and SLL.BeiGene.

Background: Monoclonal gammopathies and multiple myeloma should be screened in the primary care setting. Methods: The screening strategy consisted of an initial interview supported with the analysis of basic laboratory test results and the increasing laboratory workload in the following steps was developed based on characteristics of patients with multiple myeloma. Results: The developed 3-step screening protocol includes evaluation of myeloma-related bone disease, two renal function markers, and three hematologic markers. In the second step, the erythrocyte sedimentation rate (ESR) and the level of C-reactive protein (CRP) were cross-tabulated to identify persons qualifying for confirmation of the presence of monoclonal component. Patients with diagnosed monoclonal gammopathy should be referred to a specialized center to confirm the diagnosis. The screening protocol testing identified 900 patients with increased ESR and normal level of CRP and 94 of them (10.4%) had positive immunofixation. Conclusions: The proposed screening strategy resulted in an efficient diagnosis of monoclonal gammopathy. The stepwise approach rationalized the diagnostic workload and cost of screening. The protocol would support primary care physicians, standardizing the knowledge about the clinical manifestation of multiple myeloma and the method of evaluation of symptoms and diagnostic test results.

Background Relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) is associated with a poor prognosis despite the availability of multiple treatment options. Preliminary evidence suggests that DLBCL may be responsive to programmed death ligand 1 (PD-L1)/programmed death 1 inhibitors. Objective The JAVELIN DLBCL study was conducted to assess whether a combination of agents could augment and sustain the antitumor immunity of avelumab, an anti-PD-L1 antibody, in R/R DLBCL. Methods This was a multicenter, randomized, open-label, parallel-arm study with a phase Ib and a phase III component. Reported here are the results from the phase Ib study, wherein 29 adult patients with DLBCL were randomized 1:1:1 to receive avelumab in combination with utomilumab (an immunoglobulin G2 4-1BB agonist) and rituximab (arm A), avelumab in combination with utomilumab and azacitidine (arm B), or avelumab in combination with bendamustine and rituximab (arm C). The primary endpoints were dose-limiting toxicities and objective response as assessed by the investigator per Lugano Response Classification criteria. Results Of the seven patients in arm A, one (14.3%) experienced two grade 3 dose-limiting toxicities (herpes zoster and ophthalmic herpes zoster); no dose-limiting toxicities were reported in arms B or C. No new safety concerns emerged for avelumab. One partial response was reported in arm A, three complete responses in arm C, and no responses in arm B. Given the insufficient antitumor activity in arms A and B and the infeasibility of expanding arm C, the study was discontinued before initiation of the phase III component. Conclusions The low level of clinical activity suggests that PD-L1 inhibitor activity may be limited in R/R DLBCL. ClinicalTrials.gov Identifier NCT02951156. Supplementary Information The online version contains supplementary material available at 10.1007/s11523-021-00849-8.

Introduction: TG-1701 is a selective, covalent BTK inhibitor administered once daily (QD). Both the “U2” combination (anti-CD20 mAb ublituximab + the PI3Kδ-CK1ϵ inhibitor umbralisib) and BTK inhibition are highly active in treatment-naive (TN) and relapsed/ refractory (R/R) CLL, each having previously demonstrated superiority over standard chemoimmunotherapy. Herein we report the results of the dose escalation of TG-1701 monotherapy and TG-1701+U2. Methods: Patients (pts) with R/R CLL, MCL and Waldenstrom's (WM) were enrolled in an ongoing Ph 1 study initially evaluating dose escalation (DE) of oral TG-1701 QD continuously administered in 28-day cycles (100, 200, 300, and 400 mg). After characterizing the safety profile of TG-1701 monotherapy, we implemented a parallel DE arm of TG-1701+U2. Select dose levels of TG-1701 monotherapy were expanded. All pts were treated until disease progression, unacceptable toxicity, or investigator/patient decision to withdraw. Results: As of 03 February 2021, 123 pts were treated with TG-1701 as follows: 25 in the monotherapy DE arm, 61 in the 200 mg disease-specific cohorts (20 CLL [5 TN], 21 MCL [4 TN], 20 WM [8 TN]), 20 in the 300 mg CLL cohort (4 TN), and 17 in the 1701+U2 DE arm. The median # of prior therapies was 1 (range, 1-10). All pts were BTKi-naive. All 123 pts were evaluable for safety. TG-1701 was well tolerated and the maximum tolerated dose (MTD) for monotherapy was not reached at 400 mg (demonstrating near 100% saturation of the BTK at all dose levels studied). Treatment emergent adverse events (TEAE) of clinical interest included atrial fibrillation (AF 4.0% of pts, G ≥3 in 1 case), G ≥3 hypertension (2.4%), and bleeding events (18.7%, all G1-2). No cases of ventricular tachyarrhythmia were reported. TEAEs leading to TG-1701 dose reduction occurred in 6.5% of pts. TEAEs leading to treatment discontinuation occurred in 1.6% of pts (AF, COVID-19). At the data cut-off, 119 pts were evaluable for response, including 40 in DE (Table). The median duration of response has not been reached among responders overall. The median follow-up (mFU range) was 15.9 mos (1.3-28.6+) in DE and 8.5 mos (1.4-15.6+) in disease-specific cohorts. Best change from baseline in tumor burden in pts in the 1701+U2 combination arm is presented in the figure below. Conclusions: TG-1701 exhibits an encouraging safety and efficacy profile. The combination of 1701+U2 has been well tolerated and dose escalation continues. The combination shows enhanced depth of response over TG-1701 monotherapy.

Background: Umbralisib is an oral, once-daily, novel, dual inhibitor of phosphatidylinositol-3-kinase-delta (PI3Kδ) and casein kinase-1ε (CK1ε) that exhibits improved selectivity for the delta isoform of PI3K. Ublituximab is a novel anti-CD20 monoclonal antibody glycoengineered for enhanced antibody-dependent cellular cytotoxicity that targets a unique epitope on CD20. U2 has been well-tolerated and demonstrated promising activity in heavily pre-treated CLL patients. Herein, results are presented for the randomized, multicenter, Phase 3 UNITY-CLL trial (NCT02612311), which evaluated U2 vs O+Chl in patients with TN and R/R CLL. Methods: Patients ≥18 years of age with treatment-naïve (TN) or relapsed/refractory (R/R) CLL requiring treatment per iwCLL criteria with adequate organ function and ECOG PS ≤2 were eligible. Stratification factors included treatment status (TN vs R/R) and del(17p) status. Patients were initially randomized 1:1:1:1 to receive U2, O+Chl, umbralisib monotherapy, or ublituximab monotherapy. Following establishment of contribution comparing U2 to the single agents, patients were randomized 1:1 to U2 or O+Chl. Umbralisib was given orally at 800 mg once-daily until progression or removal from treatment for other reasons. Ublituximab was administered intravenously at 900 mg on Days 1/2 [split 150/750 mg], 8, and 15 of Cycle 1, Day 1 of Cycles 2 - 6, and on Day 1 every 3 cycles after Cycle 6. O was given intravenously at 1000 mg on Days 1/2 [split 100/900], 8, and 15 of Cycle 1, and Day 1 of Cycles 2 - 6. Chl was given orally at 0.5 mg/kg on Day 1 and 15 of Cycles 1 - 6. Each cycle was 28 days. The primary endpoint was independent review committee (IRC)-assessed progression-free survival (PFS) of U2 vs O+Chl. Key secondary endpoints included IRC-assessed overall response rate (ORR), complete response (CR), undetectable minimal residual disease (uMRD), duration of response (DOR), and safety (assessed from the first dose until 30 days after the last dose of study medication in each arm) as well as contribution of umbralisib and ublituximab to the U2 combination. Results: From Feb 2016 - Oct 2017, 421 pts were randomized to the U2 (n=210) or O+Chl (n=211) arms. The median age was 67 y (range, 36-91); 57% of patients (n=240) were treatment-naïve; 43% (n=181) had R/R CLL (median number of prior treatments = 1); 10% had del(17p), 20% del(11q), and 56% were IgHV unmutated. 66% were male. Demographics were well-balanced between treatment arms. At a median follow-up of 36.2 mos, U2 significantly prolonged PFS vs O+Chl (median 31.9 mos vs 17.9 mos; HR 0.546, 95% CI 0.413-0.720, P The median treatment duration was 23 mos for U2 (range, 0.1 - 49 mos) and 5 mos (range, 0.1 - 7 mos) for O+Chl. G3/4 AEs of interest regardless of causality (U2 vs O+Chl) included neutropenia (30.6% vs 34.7%), thrombocytopenia (3.4% vs 13.1%), diarrhea (12.1% vs 2.5%), infusion related reaction (1.9% vs 3.5%), elevated AST/ALTs (8.3% vs 2%), colitis (3.4% vs 0%) and pneumonitis (2.9% vs 0%). AEs led to treatment discontinuation in 34 patients (16.5%) on U2 and 16 patients (7.6%) on O+Chl. Conclusions: UNITY-CLL is the first randomized Phase 3 study in CLL of a PI3Ki vs. chemoimmunotherapy, and the first randomized study of a PI3Ki in treatment-naive CLL. U2 exhibited a well-tolerated safety profile, and significantly improved PFS vs. standard of care chemoimmunotherapy in patients with treatment-naive and relapsed/refractory CLL. Figure Disclosures Gribben: Janssen: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; Celgene: Research Funding; Abbvie: Honoraria. Jurczak:Celgene: Research Funding; Afimed: Research Funding; Sandoz-Novartis: Consultancy; European Medicines Agency,: Consultancy; AstraZeneca: Consultancy; Takeda: Research Funding; Janssen China R&D: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; Bayer: Research Funding; Acerta: Consultancy, Research Funding; Pharmacyclics: Research Funding; Maria Sklodowska-Curie National Research Institute of Oncology, Krakow, Poland: Current Employment; MEI Pharma: Research Funding; Nordic Nanovector: Research Funding; Servier: Research Funding; Merck: Research Funding; Gilead Sciences: Research Funding; Epizyme: Consultancy; Roche: Research Funding; MorphoSys: Research Funding; TG Therapeutics, Inc.: Research Funding; Jagiellonian University, Krakow, Poland: Ended employment in the past 24 months. Jacobs:Sanofi Genzyme: Speakers Bureau; Genentech: Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Verastem: Consultancy; Seattle Genetics: Consultancy; Astra Zeneca: Consultancy, Speakers Bureau; AbbVie: Consultancy, Speakers Bureau; Pharmacyclics: Research Funding, Speakers Bureau; TG Therapeutics, Inc.: Research Funding. Giannopoulos:BMS-Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; Janssen: Honoraria. Wrobel:Janssen-Cilag: Honoraria, Research Funding, Speakers Bureau. Zafar:Bristol Meyers Squibb: Honoraria, Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company); Florida Cancer Specialists and Research Institute: Current Employment; Sarah Canon Research Institute: Research Funding; Karyopharm: Honoraria; AstraZeneca: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Danilov:Nurix: Consultancy; Celgene: Consultancy; Astra Zeneca: Consultancy, Research Funding; Aptose Biosciences: Research Funding; Gilead Sciences: Research Funding; Verastem Oncology: Consultancy, Research Funding; Pharmacyclics: Consultancy; Abbvie: Consultancy; BeiGene: Consultancy; Takeda Oncology: Research Funding; Karyopharm: Consultancy; TG Therapeutics: Consultancy; Genentech: Consultancy, Research Funding; Rigel Pharmaceuticals: Consultancy; Bristol-Myers Squibb: Research Funding; Bayer Oncology: Consultancy, Research Funding. Burke:Gilead: Consultancy; Epizyme: Consultancy; Adaptive: Consultancy; Kura: Consultancy; Astra Zeneca: Consultancy; Bayer: Consultancy; Bristol Myers Squibb: Consultancy; AbbVie: Consultancy; Adaptive Biotechnologies: Consultancy; Morphosys: Consultancy; Verastem: Consultancy; Roche: Consultancy; Seattle Genetics: Speakers Bureau; Celgene: Consultancy. Goldschmidt:Bristol-Myers Squibb: Speakers Bureau; Amgen: Consultancy; Blue Ridge Cancer Care: Current Employment. Huntington:Genentech: Consultancy; Astrazeneca: Honoraria; TG Therapeutics: Research Funding; Pharmacyclics: Honoraria; Novartis: Consultancy; Celgene: Consultancy, Research Funding; Bayer: Consultancy, Honoraria; AbbVie: Consultancy; DTRM: Research Funding. Pinilla Ibarz:AstraZeneca: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Novartis: Consultancy; Sunesis Pharmaceuticals: Consultancy; TG Therapeutics: Consultancy; Sanofi: Consultancy; Pharmacyclics: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau. Sharman:Bristol Meyers Squibb: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Acerta: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; BeiGene: Research Funding. Siddiqi:AstraZeneca: Consultancy, Research Funding, Speakers Bureau; Pharmacyclics: Consultancy, Research Funding, Speakers Bureau; Celgene: Consultancy, Research Funding; Juno: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; Oncternal: Research Funding; TG Therapeutics: Research Funding; Janssen: Speakers Bureau; Seattle Genetics: Speakers Bureau. Brander:MEI Pharma: Other, Research Funding; Pfizer: Consultancy, Other; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Other, Research Funding; Novartis: Consultancy, Other; Teva: Consultancy, Honoraria; Tolero: Research Funding; ArQule: Consultancy, Other, Research Funding; Ascentage: Other, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Tolero: Research Funding; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; NCCN: Other; Verastem: Consultancy, Honoraria, Other, Research Funding; Teva: Consultancy, Honoraria; Novartis: Consultancy, Other; AstraZeneca: Consultancy, Honoraria, Other, Research Funding; BeiGene: Other, Research Funding; DTRM: Other, Research Funding; NCCN: Other; Genentech: Consultancy, Honoraria, Other, Research Funding; Juno/Celgene/BMS: Other, Research Funding. Kolibaba:TG Therapeutics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Research Funding; Sumitomo Dainippon Pharma Oncology: Consultancy, Other; Verastem: Honoraria; Genentech: Research Funding; Gilead: Research Funding; Janssen: Research Funding; McKesson Life Sciences: Consultancy; Novartis: Research Funding; Pharmacyclics: Research Funding; Acerta: Research Funding; AbbVie: Research Funding; Atara Biotech: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Cell Therapeutics: Research Funding; Compass Oncology: Ended employment in the past 24 months. Ghosh:Karyopharm: Consultancy; Genmab: Consultancy, Speakers Bureau; AbbVie: Speakers Bureau; AstraZeneca: Speakers Bureau; Celgene/Bristol-Myers Squibb: Speakers Bureau; Forty Seven Inc: Consultancy, Other: Research Bureau, Research Funding; Janssen: Consultancy, Research Funding, Speakers Bureau; Juno/Celgene/Bristol-Myers Squibb: Consultancy, Research Funding; Kite/Gilead: Consultancy, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding, Speakers Bureau; SGN: Consultancy, Research Funding, Speakers Bureau; TG Therapeutics: Consultancy, Research Funding; Roche/Genentech: Research Funding. Sportelli:TG Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company. Miskin:TG Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company. O'Connor:Astex Pharmaceuticals: Honoraria, Research Funding; Celgene: Honoraria, Other: Data Safety Monitoring Committee, Research Funding; TG Therapeutics: Current Employment, Current equity holder in publicly-traded company; Kymera Therapeutics: Current equity holder in private company, Honoraria, Membership on an entity's Board of Directors or advisory committees; Nomocan: Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; Mundipharma: Other: Consulting; Servier: Consultancy. Weiss:TG Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees. Flinn:Iksuda Therapeutics: Consultancy; Curis: Research Funding; Infinity Pharmaceuticals: Research Funding; F. Hoffmann-La Roche: Research Funding; Vincera Pharma: Consultancy; Karyopharm Therapeutics: Research Funding; Gilead Sciences: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Verastem: Consultancy, Research Funding; Triphase Research & Development Corp.: Research Funding; Trillium Therapeutics: Research Funding; TG Therapeutics: Consultancy, Research Funding; Teva: Research Funding; Seattle Genetics: Consultancy, Research Funding; ArQule: Research Funding; Unum Therapeutics: Consultancy, Research Funding; Incyte: Research Funding; Forma Therapeutics: Research Funding; Loxo: Research Funding; BeiGene: Consultancy, Research Funding; Kite Pharma: Consultancy, Research Funding; MorphoSys: Consultancy, Research Funding; Forty Seven: Research Funding; Genentech, Inc.: Research Funding; Great Point Partners: Consultancy; IGM Biosciences: Research Funding; Juno Therapeutics: Consultancy, Research Funding; Acerta Pharma: Research Funding; AbbVie: Consultancy, Research Funding; Celgene: Research Funding; Johnson & Johnson: Other; Yingli Pharmaceuticals ≠: Consultancy, Research Funding; Rhizen Pharmaceuticals: Research Funding; Roche: Consultancy, Research Funding; Curio Science: Consultancy; Nurix Therapeutics: Consultancy; Takeda: Consultancy, Research Funding; Calithera Biosciences: Research Funding; Merck: Research Funding; Constellation Pharmaceuticals: Research Funding; Agios: Research Funding; Portola Pharmaceuticals: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Pfizer: Research Funding; Novartis: Research Funding.

Background. Chronic lymphocytic leukemia (CLL) is one of the most common types of leukemia in adults with highly heterogeneous clinical course of the disease. Currently available prognostic factors are not fully efficient in predicting the course of CLL. New molecular mutations such as NOTCH1 and MYD88 could partly explain the CLL heterogeneity and help in identifying clinically relevant groups of patients. Material and methods. NOTCH1 c.7544_7545delCT (n = 200) in PEST domain (exon 34) and MYD88 L265P (n = 60) mutations was investigated by amplification refractory mutation system (ARMS). Expression of MYD88 in CLL was assessed in peripheral blood (PB) (n = 60) and bone marrow (BM) (n = 92) of CLL patients and 25 healthy volunteers (HVs) using qRT-PCR. Results. NOTCH1 mutation occurred in 18/200 (9.0%) CLL patients. Patients harboring NOTCH1 mutations prevalently belonged to aggressive cases, i.e. cases with an unmutated IGVH gene status, expression of CD38 and ZAP-70. MYD88 mutation occurred in 2/60 (3.3%) CLL patients. MYD88 mutations were strikingly enriched among patients expressing mutated IGVH genes. Our study demonstrated significantly higher PB MYD88 expression than in HVs and relevantly higher PB MYD88 expression in comparison with BM (respectively p < 0.0001 and p = 0.0015). There was no correlation between MYD88 expression in PB and BM and expression of ZAP-70, CD38 and IGVH mutational status. Conclusions. NOTCH1 mutations are more frequently detected in cases with unfavorable biological markers and seem to be independent predictive markers for worse outcome in CLL patients. Further collaborative studies in CLL are obligate to study the prognostic and predictive relevance of MYD88 mutations and expression.

Basic hematological indices, such as platelets count (PLT), platelet distribution width (PDW), mean platelet volume (MPV), and plateletcrit (PCT), are readily accessible and commonly tested indicators. As platelets play a significant role in many physiological and patho- logical pathways, the abnormalities in these indices inference about irregularities within the organism, such as homeostatic disorders or inflammation. Recent studies revealed a significant impact of MPV on the course and prediction in different types of neoplasms. This review summarizes the most important studies on the impact of MPV levels on outcome and prognosis in different types of cancer conducted in recent years. MPV levels have a significant impact on the length of progression-free survival (PFS) and overall survival (OS) in many types of solid tumors, such as colorectal carcinoma, gastric cancer, pancreatic cancer, esophageal cancer, non-small cell lung cancer, breast cancer, and thyroid cancer. They also affect the prognosis in some lymphoproliferative diseases, such as diffuse large B-cell lymphoma, acute lymphoblastic leukemia, or primary and secondary myelofibrosis.

Purpose Daratumumab is a promising new agent for relapsed/refractory multiple myeloma (RRMM). However, there are limited data on its clinical activity and tolerability in the real-world patients. The purpose of this study is to determine the efficacy and toxicity profile of daratumumab monotherapy in the real-life setting. Patients and methods Thirty RRMM patients treated with daratumumab who had previously received at least three treatment lines including a proteasome inhibitor and an immunomodulatory drug or had been double refractory (DR MM) were included to the Polish Myeloma Group observational study. Results The objective response rate to daratumumab was 42.8%. Median progression-free survival (PFS) and overall survival reached 9.5 and 13.8 months, respectively. Importantly, patients with DR-MM had a significantly shorter PFS than other patients (median PFS of 4.1 vs. 12.1 months). Daratumumab was generally well tolerated, however two patients had their therapy interrupted due to adverse events. Conclusion Daratumumab monotherapy has significant activity and good tolerance in heavily pretreated RRMM patients.

StreszczenieLeki biopodobne odgrywają coraz większą rolę w terapii wielu chorób wraz z wygaśnięciem ochrony patentowej dla kolejnych leków biologicznych. Celem niniejszego opracowania jest przybliżenie terminologii i zasad wprowadzania na rynek leków biopodobnych, zagadnień dotyczących ich etykietowania, ekstrapolacji, wymienialności i automatycznej substytucji. Opracowanie to przedstawia stanowisko Polskiego Towarzystwa Hematologów i Transfuzjologów dotyczące leków biopodobnych, oparte na wytycznych EMA (European Medicine Agency) i stanowisku ESMO (European Society of Medical Oncology).

Chronic lymphocytic leukemia (CLL) constitutes the most common leukemia in adults living in western countries. The clinical course of the disease is extremely heterogeneous and pathogenesis is still unknown. Immune system disorders in CLL patients are observed in the early stages of the disease and worsen during clinical observation. On the one hand, CLL patients are characterized by immunosupresion and on the other hand, autoimmune processes. The immunosuppression observed in patients with CLL is associated with disorders of non‑specific immune response as well as T‑cell and B‑cell response, leading to frequent and severe infections. The immune system of patients with CLL could be also inhibited by many immunosuppressive factors occurred in tumor microenvironment, including populations of immune cells, which include myeloid‑derived suppressor cells (MDSCs), T regulatory cells (Treg) and the newly described B regulatory cells (Breg). It was shown that CLL cells can regulate immune response and escape from the surveillance of the immune system through the PD‑1/PD‑L signalling pathway. Interestingly, reduced immune response in CLL patients may be accompanied by autoimmune processes clinically manifested as autoimmune cytopenias. The secondary autoimmune cytopenias complicating the course of the disease include autoimmune hemolytic anemia (AIHA), immune thrombocytopenia purpura (ITP), pure red cell aplasia (PRCA) and autoimmune granulocytopenia (AG). Identification of immunological disorders in patients with CLL is necessary to understand the biology of the disease and to select appropriate treatment patterns based on modulation of the immune system.