Therapy of relapsed and refractory plasma cell myeloma in Polish population – analysis

The treatment of relapsed and refractory plasma cell myeloma is a real challenge, especially in case of resistance to proteasome inhibitors and immunomodulatory drugs (IMiDs). The situation is complicated by the lack of commonly accepted therapeutic guidelines. This study summarizes therapeutic strategies used to treat recurrent plasma cell myeloma in Polish population before 2015, when bortezomib has become available in the first-line therapy. We focused mainly on the use of IMiDs and proteasome inhibitors. To analyze the situation medical records of patients treated in 21 Polish hematological centers have been reviewed. In total data on 400 patients were analyzed and extrapolated to the national level to obtain data on 7293 patients (400/7293). Mean number of applied therapies was 1.7. Half of the patients were treated with two or more chemotherapy regimens. Second-line therapy most commonly included: VD, PAD, thalidomide in monotherapy and MP regimen. Combinations of two drugs, namely lenalidomide, thalidomide or bortezomib with dexamethasone, were most often used in third-line therapy. Fourth-line treatment most commonly consisted of MPT regimen and dexamethasone monotherapy. At least PR was observed in 73%, 82%, and 50% of patients treated with II, III and IV-line therapy, respectively. Complications were observed in at least half of the patients regardless the type of treatment. Polyneuropathy and myelotoxicity were the most common adverse events.The outcome of recurrent plasma cell myeloma treatment in Polish patients was relatively good, probably because of rare use of bortezomib and lenalidomide in first-line therapy

Early and late follow-up of patients with Hodgkin’s lymphoma. Recommendations of the Polish Lymphoma Research Group

Optymalny sposób monitorowania chorych na chłoniaka Hodgkina (HL) po zakończeniu leczenia przeciwnowotworowego nie jest do końca ustalony i opiera się w głównej mierze na praktyce klinicznej. Przez pierwsze lata obserwacji największy nacisk kładzie się na wykrycie ewentualnej wznowy, następnie większe znaczenie ma monitorowanie późnych powikłań terapii. W artykule przedstawiono dostępne zalecenia oraz rekomendacje monitorowania chorych po leczeniu chłoniaka Hodgkina przygotowane przez Polską Grupę Badawczą Chłoniaków.Post-treatment follow-up of patients with Hodgkin’s lymphoma has not yet been fully optimised and is still basedmainly on clinical practice and experience. During the first years of follow-up, the principal aims are to detectrelapse and monitor any post-treatment complications or side effects. Such as they are, current guidelines onfollow-up are herein considered and discussed, together with those now recommended by the Polish LymphomaResearch Group

Prognostic value of bone marrow tracer uptake pattern in baseline PET scans in hodgkin lymphoma: Results from an international collaborative study

PET/CT-ascertained bone marrow involvement (BMI) constitutes the single most important reason for upstaging by PET/CT in Hodgkin lymphoma (HL). However, BMI assessment in PET/CT can be challenging. This study analyzed the clinicopathologic correlations and prognostic meaning of Different patterns of bone marrow (BM)18F-FDG uptake in HL. Methods: One hundred eighty newly Diagnosed early unfavorable and advanced-stage HL patients, all scanned at baseline and after 2 adriamycin-bleomycinvinblastine-dacarbazine (ABVD) courses with18F-FDG PET, enrolled in 2 international stuDies aimed at assessing the role of interim PET scanning in HL, were retrospectively included. Patients were treated with ABVD 4-6 cycles and involved-field raDiation when needed, and no treatment adaptation on interim PET scanning was allowed. Two masked reviewers independently reported the scans. Results: Thirty-eight patients (21.1%) had focal lesions (fPET1), 10 of them with a single (unifocal) and 28 with multiple (multifocal) BM lesions. Fifty-three patients (29.4%) had pure strong (.liver) Diffuse uptake (dPET1) and 89 (48.4%) showed no or faint (#liver) BM uptake (nPET1). BM biopsy was positive in 6 of 38 patients (15.7%) for fPET1, in 1 of 53 (1.9%) for dPET1, and in 5 of 89 (5.6%) for nPET1. dPET1 was correlated with younger age, higher frequency of bulky Disease, lower hemoglobin levels, higher leukocyte counts, and similar Diffuse uptake in the spleen. Patients with pure dPET1 had a 3-y progression-free survival identical to patients without any18F-FDG uptake (82.9% and 82.2%, respectively, P 5 0.918). However, patients with fPET1 (either unifocal or multifocal) had a 3-y progressionfree survival significantly inferior to patients with dPET1 and nPET1 (66.7% and 82.5%, respectively, P 5 0.03). The k values for interobserver agreement were 0.84 for focal uptake and 0.78 for Diffuse uptake. Conclusion: We confirmed that18F-FDG PET scanning is a reliable tool for BMI assessment in HL, and BM biopsy is no longer needed for routine staging. Moreover, the interobserver agreement for BMI in this study proved excellent and only focal18F-FDG BM uptake should be considered as a harbinger of HL

A polygenic risk score for multiple myeloma risk prediction

This work was partially supported by intramural funds of the University of Pisa, DKFZ, and University Hospital of Southern Jutland, Denmark, and by a grant of the French National Cancer Institute (INCA). The authors wish to thank Dr. Dominic Edelmann (Division of Biostatistics, DKFZ) for helpful advice about data analysis.There is overwhelming epidemiologic evidence that the risk of multiple myeloma (MM) has a solid genetic background. Genome-wide association studies (GWAS) have identified 23 risk loci that contribute to the genetic susceptibility of MM, but have low individual penetrance. Combining the SNPs in a polygenic risk score (PRS) is a possible approach to improve their usefulness. Using 2361 MM cases and 1415 controls from the International Multiple Myeloma rESEarch (IMMEnSE) consortium, we computed a weighted and an unweighted PRS. We observed associations with MM risk with OR = 3.44, 95% CI 2.53-4.69, p = 3.55 x 10(-15) for the highest vs. lowest quintile of the weighted score, and OR = 3.18, 95% CI 2.1 = 34-4.33, p = 1.62 x 10(-13) for the highest vs. lowest quintile of the unweighted score. We found a convincing association of a PRS generated with 23 SNPs and risk of MM. Our work provides additional validation of previously discovered MM risk variants and of their combination into a PRS, which is a first step towards the use of genetics for risk stratification in the general population.University of Pisa, DKFZUniversity Hospital of Southern Jutland, DenmarkInstitut National du Cancer (INCA) Franc

Diagnosis of myelodysplastic syndromes in Poland: Polish Adult Leukemia Group (PALG) 2021 recommendations

Myelodysplastic syndromes (MDS) are a heterogeneous group of neoplastic diseases of the hematopoietic cells manifested by ineffective hematopoiesis and a tendency to transform into acute myeloid leukemia. MDS should be considered in the differential diagnosis of cytopenia, especially in the elderly. This article presents the recommendations of MDS experts of the Polish Adult Leukemia Group (PALG) for the diagnosis of myelodysplastic syndromes. We present current classifications and prognostic indices, as well as diagnostic examinations recommended for MDS: cytological, histopathological, immunophenotypic, cytogenetic and molecular tests. The aim of the study is to implement up-to-date knowledge about myelodysplastic syndromes into routine clinical practice, from the diagnosis of cytopenia to the specific diagnosis and prognosis in MDS patients.  Myelodysplastic syndromes (MDS) are a heterogeneous group of neoplastic diseases of the hematopoietic cells manifested by ineffective hematopoiesis and a tendency to transform into acute myeloid leukemia. MDS should be considered in the differential diagnosis of cytopenia, especially in the elderly. This article presents the recommendations of MDS experts of the Polish Adult Leukemia Group (PALG) for the diagnosis of myelodysplastic syndromes. We present current classifications and prognostic indices, as well as diagnostic examinations recommended for MDS: cytological, histopathological, immunophenotypic, cytogenetic and molecular tests. The aim of the study is to implement up-to-date knowledge about myelodysplastic syndromes into routine clinical practice, from the diagnosis of cytopenia to the specific diagnosis and prognosis in MDS patients.

Identification of miRSNPs associated with the risk of multiple myeloma

Accepted articleMultiple myeloma (MM) is a malignancy of plasma cells usually infiltrating the bone marrow, associated with the production of a monoclonal immunoglobulin (M protein) which can be detected in the blood and/or urine. Multiple lines of evidence suggest that genetic factors are involved in MM pathogenesis, and several studies have identified single nucleotide polymorphisms (SNPs) associated with the susceptibility to the disease. SNPs within miRNA-binding sites in target genes (miRSNPs) may alter the strength of miRNA-mRNA interactions, thus deregulating protein expression. MiRSNPs are known to be associated with risk of various types of cancer, but they have never been investigated in MM. We performed an in silico genome-wide search for miRSNPs predicted to alter binding of miRNAs to their target sequences. We selected 12 miRSNPs and tested their association with MM risk. Our study population consisted of 1,832 controls and 2,894 MM cases recruited from seven European countries and Israel in the context of the IMMEnSE (International Multiple Myeloma rESEarch) consortium. In this population two SNPs showed an association with p<0.05: rs286595 (located in gene MRLP22) and rs14191881 (located in gene TCF19). Results from IMMEnSE were meta-analyzed with data from a previously published genome-wide association study (GWAS). The SNPs rs13409 (located in the 3UTR of the POU5F1 gene), rs1419881 (TCF19), rs1049633, rs1049623 (both in DDR1) showed significant associations with MM risk. In conclusion, we sought to identify genetic polymorphisms associated with MM risk starting from genome-wide prediction of miRSNPs. For some mirSNPs, we have shown promising associations with MM risk. What's new? Even though deregulation of miRNA expression has been associated with human cancers little information is available regarding their relation with MM susceptibility. We performed an in silico genome-wide search for miRSNPs and selected the most promising ones for an association study. The SNPs with the strongest associations with MM risk are localized in genes which have never been related with MM.This work was partially funded by: intramural funds of German Cancer Research Center (DKFZ), Grant ref. HUS412A1271 from the “Gerencia Regional de Salud de la Junta de Castilla y Léon”. This work was supported by grants from the Instituto de Salud Carlos III (Madrid, Spain; PI12/02688). Catalan Government DURSI grant 2014SGR647 and Instituto de Salud Carlos III, co7funded by FEDER funds –a way to build Europe– grants PI11701439 and PIE13/00022info:eu-repo/semantics/publishedVersio

Genetically determined telomere length and multiple myeloma risk and outcome

This work was partially supported by intramural funds of Univerity of Pisa and DKFZ; by Fondo de Investigaciones Sanitarias (Madrid, Spain) [PI12/02688 to J. S., PI17/02276 to J.S.]; by Instituto de Salud Carlos III, co-funded by FEDER funds —a way to build Europe—[PI14-00613 to V.M.] and by Agency for Management of University and Research Grants (AGAUR) of the Catalan Government (Barcelona, Spain) [2017SGR723 to V.M.]. Open Access funding enabled and organized by Projekt DEAL.Telomeres are involved in processes like cellular growth, chromosomal stability, and proper segregation to daughter cells. Telomere length measured in leukocytes (LTL) has been investigated in different cancer types, including multiple myeloma (MM). However, LTL measurement is prone to heterogeneity due to sample handling and study design (retrospective vs. prospective). LTL is genetically determined; genome-wide association studies identified 11 SNPs that, combined in a score, can be used as a genetic instrument to measure LTL and evaluate its association with MM risk. This approach has been already successfully attempted in various cancer types but never in MM. We tested the "teloscore" in 2407 MM patients and 1741 controls from the International Multiple Myeloma rESEarch (IMMeNSE) consortium. We observed an increased risk for longer genetically determined telomere length (gdTL) (OR = 1.69; 95% CI 1.36-2.11; P = 2.97 x 10(-6) for highest vs. lowest quintile of the score). Furthermore, in a subset of 1376 MM patients we tested the relationship between the teloscore and MM patients survival, observing a better prognosis for longer gdTL compared with shorter gdTL (HR = 0.93; 95% CI 0.86-0.99; P = 0.049). In conclusion, we report convincing evidence that longer gdTL is a risk marker for MM risk, and that it is potentially involved in increasing MM survival.Univerity of PisaHelmholtz AssociationInstituto de Salud Carlos III PI12/02688 PI17/02276Instituto de Salud Carlos IIIEuropean CommissionFEDER funds-a way to build Europe PI14-00613Agency for Management of University and Research Grants (AGAUR) of the Catalan Government (Barcelona, Spain) 2017SGR723Projekt DEA

Analysis of ibrutinib efficacy in a subgroup of chronic lymphocytic leukemia patients with 17p deletion: observational study of the Polish Adult Leukemia Group (PALG)

BackgroundThe 17p deletion is regarded as the strongest poor prognostic factor in chronic lymphocytic leukemia (CLL). Results of recently performed clinical trials have suggested that ibrutinib significantly improves the outcome in this patient group.AimThe study aimed at analyzing the efficacy and adverse events profile of ibrutinib monotherapy in CLL patients with 17p deletion treated in routine clinical practice outside clinical trials.Materials and MethodsClinical response and adverse events profile of ibrutinib monotherapy were assessed in thirty-five CLL patients with 17p deletion treated within the ibrutinib named patients program in Poland.ResultsOverall response rate was 80% (28/35 patients) with median observation time of 24.2 months (range 0,1 – 30,9). Complete remission was observed in 5 patients (14.3%), partial remission in 11 (31.4%), partial remission with lymphocytosis in 13 (37.1%), whereas stable disease and progression was noted in 4 (11.4%) and 1 (2.9%) respectively. Response was not assessed in 1 patient. Median progression-free survival was 29.5 months, whereas median overall survival was not reached. Eleven patients died (7 because of infection, 1 of CLL progression, 1 of sudden cardiac death, 1 of disseminated breast cancer and 1 of unknown causes). In 13 patients (37.1%) at least one 3 or 4 grade adverse event occurred. In 11 patients (31.4%) the treatment was temporary withheld or the dose reduced due to adverse events.ConclusionIbrutinib is characterized by high clinical efficacy and acceptable toxicity in CLL patients with 17p deletion in daily clinical practice

Polymorphisms within autophagy-related genes as susceptibility biomarkers for multiple myeloma: a meta-analysis of three large cohorts and functional characterization

Functional data used in this project have been meticulously catalogued and archived in the BBMRI-NL data infrastructure (https://hfgp.bbmri.nl/, accessed on 12 February 2020) using the MOLGENIS open-source platform for scientific data.Multiple myeloma (MM) arises following malignant proliferation of plasma cells in the bone marrow, that secrete high amounts of specific monoclonal immunoglobulins or light chains, resulting in the massive production of unfolded or misfolded proteins. Autophagy can have a dual role in tumorigenesis, by eliminating these abnormal proteins to avoid cancer development, but also ensuring MM cell survival and promoting resistance to treatments. To date no studies have determined the impact of genetic variation in autophagy-related genes on MM risk. We performed meta-analysis of germline genetic data on 234 autophagy-related genes from three independent study populations including 13,387 subjects of European ancestry (6863 MM patients and 6524 controls) and examined correlations of statistically significant single nucleotide polymorphisms (SNPs; p < 1 × 10−9) with immune responses in whole blood, peripheral blood mononuclear cells (PBMCs), and monocyte-derived macrophages (MDM) from a large population of healthy donors from the Human Functional Genomic Project (HFGP). We identified SNPs in six loci, CD46, IKBKE, PARK2, ULK4, ATG5, and CDKN2A associated with MM risk (p = 4.47 × 10−4−5.79 × 10−14). Mechanistically, we found that the ULK4rs6599175 SNP correlated with circulating concentrations of vitamin D3 (p = 4.0 × 10−4), whereas the IKBKErs17433804 SNP correlated with the number of transitional CD24+CD38+ B cells (p = 4.8 × 10−4) and circulating serum concentrations of Monocyte hemoattractant Protein (MCP)-2 (p = 3.6 × 10−4). We also found that the CD46rs1142469 SNP corre lated with numbers of CD19+ B cells, CD19+CD3− B cells, CD5+ IgD− cells, IgM− cells, IgD−IgM− cells, and CD4−CD8− PBMCs (p = 4.9 × 10−4−8.6 × 10−4 ) and circulating concentrations of interleukin (IL)-20 (p = 0.00082). Finally, we observed that the CDKN2Ars2811710 SNP correlated with levels of CD4+EMCD45RO+CD27− cells (p = 9.3 × 10−4 ). These results suggest that genetic variants within these six loci influence MM risk through the modulation of specific subsets of immune cells, as well as vitamin D3−, MCP-2−, and IL20-dependent pathways.This work was supported by the European Union’s Horizon 2020 research and innovation program, N° 856620 and by grants from the Instituto de Salud Carlos III and FEDER (Madrid, Spain; PI17/02256 and PI20/01845), Consejería de Transformación Económica, Industria, Conocimiento y Universidades and FEDER (PY20/01282), from the CRIS foundation against cancer, from the Cancer Network of Excellence (RD12/10 Red de Cáncer), from the Dietmar Hopp Foundation and the German Ministry of Education and Science (BMBF: CLIOMMICS [01ZX1309]), and from National Cancer Institute of the National Institutes of Health under award numbers: R01CA186646, U01CA249955 (EEB).This work was also funded d by Portuguese National funds, through the Foundation for Science and Technology (FCT)—project UIDB/50026/2020 and UIDP/50026/2020 and by the project NORTE-01-0145-FEDER-000055, supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF)

Długotrwała odpowiedź na leczenie brentuksymabem vedotin u pacjenta z nawrotem chłoniaka Hodgkina po auto-HSCT

The standard of care for patients with refractory or relapsed Hodgkin lymphoma is salvage chemotherapy followed by autologous hematopoietic stem cell transplantation. This method is not always effective, however. For patient who do not respond or those who relapse again treatment opportunities are limited. Before of the brentuximab vedotin ”era” the prognosis of such patients was poor, with a 5-year overall survival not exceeding 30%. Allogeneic stem cell transplantation (allo-HSCT) may be curative, but its success is highly dependent on prior good disease control. Brentuximab vedotin can be effective bridging treatment before allo-HSCT because 34% of patients can achive complete remission. In addition, in some patients, used as monotherapy without additional consolidation treatment allows for long-term responses.Standardowym postępowaniem w przypadku opornego na leczenie lub nawrotowego chłoniaka Hodgkina jest ratunkowa chemioterapia zakończona przeszczepieniem autologicznych krwiotwórczych komórek macierzystych. Jednak metoda ta nie zawsze jest skuteczna. W przypadku pacjentów, którzy nie reagują na tę formę leczenia lub u których dochodzi do kolejnego nawrotu, możliwości leczenia są ograniczone. Przed „erą” brentuksymabu vedotin rokowanie u takich chorych było bardzo złe, z 5-letnim całkowitym przeżyciem nieprzekraczającym 30%. Przeszczepienie allogenicznych krwiotwórczych komórek macierzystych (allo-HSCT) może spowodować wyleczenie, ale jego powodzenie jest silnie uzależnione od wcześniejszej dobrej kontroli choroby. Brentuksymab vedotin jest skutecznym leczeniem pomostowym przed allo-HSCT, ponieważ u 34% pacjentów pozwala uzyskać całkowitą remisję. Dodatkowo u części pacjentów, zastosowany w monoterapii bez dodatkowego leczenia konsolidującego, pozwala uzyskać długotrwałe odpowiedzi