Jan Maciej Zaucha’s research while affiliated with Medical University of Gdansk and other places

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Publications (15)


Inclusion and exclusion criteria in both case and control group.
The association between lifestyle characteristics and the development of multiple myeloma.
The association between environmental factors and the development of multiple myeloma.
The association between environmental factors and the development of multiple myeloma, with regard to the time of exposure.
The Role of Lifestyle and Environmental Factors in the Pathogenesis of Multiple Myeloma
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January 2025

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Jan Maciej Zaucha

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Objectives The study evaluated the impact of lifestyle and environmental exposure on the etiology of multiple myeloma (MM). Methods A multicenter case–control study was conducted in 20 hematology centers and in 5 outpatient clinics in Poland. The questionnaire on exposure to potential risk factors including sociodemographic data, lifestyle, and environmental factors was completed. Results A total of 274 patients with newly diagnosed MM and 208 patients from primary healthcare centers in the control group were enrolled in the study. Regarding lifestyle, sports practiced systematically for at least half a year play a protective role in the development of myeloma (OR = 0.40, 95% CI, 0.28–0.58, p < 0.001). Among environmental factors harmful exposures that increase the likelihood of the development of MM include pesticides (OR = 3.29, p < 0.001), asphalt (OR = 2.42, p = 0.026), coal dust (OR = 2.27, p = 0.004), organic vapors (OR = 2.11, p = 0.001), metal dust (OR = 2.07, p = 0.023), exhaust fumes (OR = 2.03, p < 0.01), and chemicals (OR = 1.80, p < 0.01). Conclusions The pathogenesis of MM is complex with the impact of modifiable factors. Lifestyle, with physical activity, seems to play a key role.

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The role of transbronchial cryobiopsy in the detection of pulmonary GvHD

December 2024

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5 Reads

Respiration

Unlabelled: Purpose of the study We investigated the incidence of chronic pulmonary complications in allogeneic hematopoietic cell transplantation (allo-HCT) recipients and analyzed the role of transbronchial cryobiopsy (cryoTBB) as a tool to determine the nature of pulmonary changes and to guide clinical decisions. Methods: Patients who survived at least 6 months post HCT were included in the study. Pulmonary functional tests (PFTs) were performed in all patients as a screening tool. In case of abnormal results computed tomography (CT) was done to verify inflammatory changes and the presence of air-trapping. Next, patients were qualified for microbiological analysis of bronchoalveolar lavage fluid. If the results of non-invasive tests were inconclusive, cryoTBB was performed. Results: Among 186 patients, we identified 13 cases (7%) with abnormal PFTs. Mild, moderate, and severe chronic graft versus host disease (GvHD) was diagnosed in 1 (8%), 6 (46%), and 2 (15%) patients, respectively. Four (31%) patients did not present any manifestations of cGvHD at FEV1 decline. Eight 8 (62%) patients met the bronchiolitis obliterans syndrome criteria, 5 (48%) had restrictive disease, or mixed phenotype based on PFTs, only in 1 case air-trapping was present in CT. Pulmonary GvHD was confirmed by cryoTBB histopathology in 5 of 11 (45%) cases. Immunosuppression was either stopped or decreased in 6 patients with negative results for GvHD with further clinical improvement. Conclusion: CryoTBB can be a helpful tool to verify the cause of chronic pulmonary complications in the HCT population. Based on negative biopsy results, some patients may benefit from IST discontinuation or reduction to mitigate recurrences of infectious complications and further lung destruction.


The Experience of Commercially Available CPX-351 Use As First-Line Treatment for Patients with Acute Myeloid Leukemia - a Report of Polish Adult Leukemia Group (PALG)

November 2024

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9 Reads

Blood

Introduction: Acute myeloid leukemia (AML) is a heterogeneous disease and one-fourth of cases are secondary to prior myelodysplastic or myeloproliferative neoplasms (sAML) or therapy related developing after former chemotherapy or radiotherapy (tAML). sAMLs and tAMLs are more frequent in older patients (pts) and their prognosis are often unfavorable due to adverse karyotype, high-risk molecular aberrations and resistance to standard chemotherapy (chtx). CPX-351 is a liposomal encapsulation of cytarabine and daunorubicin, with a molar ratio of 5:1. Phase II and III trials have shown an increased complete remission (CR) rate, progression free survival (PFS) and overall survival (OS) in patients with sAML and tAML receiving CPX-351, compared to standard 3 + 7 chtx. Most of real-world trials have shown an advantage of CPX-351 induction treatment, but the hematological and non-hematological toxicity of this schema is underlined. Aim: The aim of the study was to evaluate the real-world experience (RWE) with CPX-351 in Polish pts with sAML/tAML. Material and methods: PALG's center was searched for pts treated with commercially available CPX-351 from September 2022 to June 2024. A treatment outcome was assessed using U-Mann-Whitney, Chi-Square, Cox models and Kaplan-Meier estimate. Results: From 10 PALG's centers 45 sAML/tAML pts were identified, with 23 (51%) tAML. The median age was 60.4 years (range 51-65). Analysis of cytogenetic-molecular risk factors based on European Leukemia Net 2017 stratification revealed favorable, intermediate and poor risk groups in 7%, 42% and 51% AML pts, respectively. Response evaluation was available in 98% (n=44) of pts, after one or two induction cycles complete remission (CR)/CR with incomplete recovery (CRi) was 68% (n=30/44) and non-remission (NR) and early death was 24.7% (n=11/44), 2.3% (n=1/44), respectively. Negative minimal residual disease (MRD) after one or two induction cycle was documented in 42% pts with CR/CRi. Till June 2024, in patients who achieved CR/CRi, allogeneic hematopoietic cell transplantation (alloHCT) was performed in 33.3% (n=15) of pts, however, there are still pts who are awaiting for alloHCT. During the CPX-351 induction the median number of days with grade 4 neutropenia was 28 (range 19-37) and grade >3 thrombocytopenia was 31 (range 23-44). The median number of transfused packed red blood cell (PRBC) was 13 (range 10-16) and the number of platelet concentrate units was 36 (range 25-66). The median duration of antibiotic therapy was 22 days (range 14-31). Infectious complications were observed in 87% pts. Thirty eight percent of pts developed grade > 3 infections; including bacteriemia, neutropenic fever, pneumonia and colitis. The median time of follow up was 6.6 months (range 3.6-10.9). The median overall survival (OS) was not reached, with probability of 1-year survival 59% (95%CI: 38-81). The median disease-free survival (DFS) was 11.7 months (95%CI: 6.4-11.8) with the probability of 1-year DFS 21% (95%CI: 0-58). In the univariate Cox proportional hazard regression, a positive prognostic effect on the OS was observed only for CR/CRi achievement (HR=0.24, 95%CI: 0.06-0.95; p=0.041). The ELN 2017 risk groups, number of bone marrow blasts, white blood cell count, lactate dehydrogenase concentration, alloHCT did not affect the OS. In the multivariate Cox proportional hazard model none of the variables had a significant impact on the OS. Conclusions: Based on the results of our trial we may conclude that CPX-351 induction is a highly effective regimen in sAML/tAML with high CR/CRi rate as well as high number of CR/CRi with negative MRD and low early death rate. The tolerability and toxicity of the treatment is acceptable. The further continuing of this trial to collect higher number of pts and longer follow up is designed. AP and OR equivalently contributed to the study.


Non-Coding Mutations of BCL6 in Classical Hodgkin Lymphoma

November 2024

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12 Reads

Blood

Introduction: Non-coding regions, constituting a substantial part of the human genome, are crucial for gene regulation. In cancer, somatic non-coding regulatory mutations can significantly alter gene expression by either disrupting or creating transcription factor-binding sites. This phenomenon is notably well-known in diffuse large B-cell lymphoma (DLBCL), where activation-induced cytidine deaminase (AID) misfires during the germinal center (GC) reaction, leading to numerous non-coding mutations that disrupt gene regulation and contribute to malignancy. Classical Hodgkin lymphoma (cHL) is the most prevalent lymphoma among young adults. Although cHL originates from GC B cells, research into AID-associated hypermutation affecting non-coding regulatory regions has not yet been carried out. Methods: We investigated somatic mutations in 155 coding genes and thirty-three genomic regions (mostly non-coding) known to be foci of AID-associated hypermutation and contained within regulatory regions of genes involved in GC B cell biology and transformation. ctDNA was analyzed using LyV4.0 ctDNA CAPP-seq in 297 cHL patients from the IOSI-EMA003-NCT03280394 and FIL-RougeBIO-NCT05066555 studies, and in 235 DLBCL for comparison. Results: Mutations of in at least one of region of AID-associated hypermutation was detected in 83% of cHL, a prevalence comparable to that observed in DLBCL (88%). The region of AID-associated hypermutation within the BCL6 locus was the most frequently mutated, found in 56% of cHL cases. Other hypermutated regions occurring in >10% of patients mapped in the SOCS1, CD83, RHOH, ST6GAL1, PAX5, BTG1, BCL7A, LRMP and HIST1H1E loci. We then scanned the sequenced non-coding spaces to detect recurrently mutated hotspots. This analysis involved evaluating overlapping 20 bp intervals through a sliding window of one bp while accounting for the nucleotide context. A hotspot located at chr3:187462671-187462703 of BCL6-intron 1 (designated as BCL6 Hotspot 7) was mutated in 30% of cases, a proportion that closely resembled that of DLBCL patients where it is a validated somatic expression quantitative trait locus (seQTL). BCL6 Hotspot 7 aligned with an area of accessible chromatin and heightened H3K27 acetylation in cHL, which was also nominated a super enhancer in 33% cHL cell lines. Moreover, ChIP-seq analysis of BCL6 Hotspot 7 revealed increase in H3K27ac in mutant cHL cell lines that suggested differential binding of transcription factors. BCL6 Hotspot 7 sequence predicted to bind the PRDM1 transcriptional repressor of BCL6, and mutations therein were found to impede BLIMP1 binding in cHL cells. Notably, BCL6 Hotspot 7 mutations were found to co-occur with BCL6 expression in cHL cell lines and HRS cells of primary biopsies, despite the co-expression of PRDM1. BCL6 protein expression ranging from weak to strong was detected in the nucleus of HRS cells of 68% of primary biopsies. The core set of genes that are directly bound and regulated by BCL6 exhibited similar expression levels in GC B cells and in BCL6 expressing cHL cell lines and in primary HRS cells. Furthermore, the core set of genes directly bound and regulated by BCL6 had a nearly identical chromatin accessibility patterns in GC B cells and in BCL6 expressing cHL cell lines. BCL6 protein degradation was observed with BI-3802 in four cHL cell lines expressing BCL6. After BCL6 degradation, the core set of genes directly bound and regulated by BCL6 was similarly derepressed in cHL cell lines as in the SU-DHL4 DLBCL cell line, indicating that BCL6 is involved in their repression in cHL as in DLBCL. Compared to the BI-5372 control molecule, treatment with BI-3802 significantly decreased proliferation in all cell lines where BCL6 degradation was observed, as well as in the BCL6-dependent SU-DHL4 DLBCL cell line, which was used as a control. Conclusion: This study broadens the understanding of known oncogenic mechanisms in cHL development and identifies BCL6 as a vulnerability in a fraction of cHL and as a potential therapeutic target.


Glofitamab Induces High Response Rates and Durable Remissions in Patients (Pts) with Heavily Pretreated Relapsed/Refractory (R/R) Mantle Cell Lymphoma (MCL), Including Those with a Poor Prognosis: Subgroup Results from a Phase I/II Study

November 2024

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7 Reads

Blood

Background: Pts with R/R MCL continue to have a poor prognosis, especially those whose disease has become R/R to Bruton tyrosine kinase inhibitor (BTKi)-containing therapies. Additional treatments are needed for pts with R/R MCL. Glofitamab is a CD20xCD3 T-cell-engaging bispecific antibody that is approved for the treatment of pts with R/R diffuse large B-cell lymphoma who have received ≥2 prior lines of therapy. In an ongoing Phase I/II study (NP30179; NCT03075696), fixed-duration glofitamab monotherapy induced high response rates and durable remissions, and had a manageable safety profile, in heavily pretreated pts with R/R MCL (Phillips et al. ASCO 2024). We report updated results for the R/R MCL cohort, including efficacy in clinically and/or histologically defined high-risk subgroups, as well as initial analysis of minimal residual disease (MRD). Methods: Eligible pts were those with R/R MCL who had received ≥1 prior line of therapy. All pts received obinutuzumab pretreatment (1000mg or 2000mg) on Cycle (C) 1 Day (D) 1. Glofitamab was then given as step up doses on C1D8 (2.5mg) and C1D15 (10mg) and at the target dose (16mg or 30mg) on D1 of each subsequent cycle (C2-12). Investigators assessed the tumor response using Lugano 2014 criteria. Formalin-fixed paraffin-embedded tumor biopsies were classified as classical, blastoid or pleomorphic and analyzed by immunohistochemistry for Ki-67 or p53 expression. MRD was evaluated in genomic or plasma DNA by clonoSEQ. Results: As of May 17, 2024, 60 pts received treatment (safety population; median age: 72 years, range: 41-86). Most pts (86.7%) had Ann Arbor stage III or IV disease at entry. The median number of prior lines of therapy was 2 (range: 1-5); 46.7% of pts had received ≥3 prior therapies and 55.0% had received ≥1 prior BTKi therapy. The majority of pts (73.3%) were refractory to their last prior therapy and 51.7% were refractory to any prior BTKi. Among pts with an evaluable baseline biopsy, 53.0% (25/46) had ≥1 high-risk histological feature, defined as blastoid morphology, Ki-67 expression >50% or p53 expression >50%. Median overall survival (OS) follow-up was 24.2 months (range: 0-50) at cut-off. In the intent-to-treat population of all enrolled pts (N=61), the overall response rate was 82% and complete response (CR) rate was 77%. Median time to response was 42 days (range: 29-164) and median duration of CR (DOCR) was 46.5 months (range: 1-47), with 57.4% of complete responders still in response at cut-off. Median progression-free survival (PFS) was 18.0 months (95% CI: 11.3, not estimable [NE]) and median OS was NE (95% CI: 21.6, NE). Response rates were consistent in patient subgroups defined by baseline clinical characteristics. CR rates were: 76% and 78% in those aged <70 (n=25) and ≥70 (n=36) years; 80%, 78%, and 75% in those with 1 (n=15), 2 (n=18) and ≥3 (n=28) prior lines of therapy; 71% and 85% in those with (n=34) and without (n=27) prior BTKi exposure; and 76% and 81% in those who were (n=45) and were not (n=16) refractory to their last prior therapy, respectively. Among pts with an evaluable baseline biopsy, CR rates were 68.0% and 81.0% in those with (n=25) and without (n=21) ≥1 high-risk features. In detail, CR rates were: 60% and 73% in those with (n=5) and without (n=37) blastoid morphology; 68% and 78% in those with (n=19) and without (n=27) Ki-67 expression >50%; and 67% and 76% in those with (n=9) and without (n=37) p53 expression >50%. Median DOCRs in those with or without ≥1 high-risk features were 21.5 months (95% CI: 17.7, NE) and 19.2 months (95% CI:17.4, 42.8), respectively. Landmark analyses indicated that most pts who were in CR at end of treatment (EOT) were progression free and alive at 18 months after EOT (PFS rate: 71.8%; OS rate: 83.0%). A trackable MRD clone was identified in 17/31 (54.8%) pts in CR at EOT. Among these pts, 11/12 (91.6%) with evaluable samples had undetectable MRD at C3. Exploratory data on B-cell recovery and Ig levels after EOT will be presented. No new or unexpected safety signals were reported. Conclusions: Glofitamab induces high response rates in pts with heavily pretreated R/R MCL, including those who have clinical and/or histological features associated with poor prognosis. Clinical and molecular remissions are achieved early in the course of treatment, with durable responses lasting beyond the length of the treatment.


Decreased Chronic GvHD with Post-Transplant Cyclophosphamide (PTCY) Compared to ATG in Patients with Myelofibrosis Allografted with Unrelated Donor: A Study from the Chronic Malignancies Working Party of the EBMT

November 2024

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5 Reads

Blood

Background Prospective randomized trials have reported a benefit for anti-thymoglobuline (ATG)-based graft-versus-host disease (GvHD) prophylaxis in the setting of allogeneic hematopoietic stem cell transplantation (alloHSCT) using unrelated donors (UD). However, the optimal GvHD prophylaxis has been recently challenged by emerging post-transplant cyclophosphamide (PTCY) data. We here present the outcomes of PTCY vs ATG as GvHD prophylaxis in myelofibrosis (MF) patients transplanted with UD from the EBMT registry. Method A total of 2607 MF patients transplanted from 2012 to 2022 with unrelated donors across 234 participating centers, receiving either PTCY or ATG, were included. Primary endpoints were relapse-free survival (RFS) and the cumulative incidence of aGvHD grade II-IV. Secondary endpoints included overall survival (OS) and the cumulative incidences of engraftment, relapse, non-relapse mortality (NRM), aGvHD grade III-IV and cGvHD. Cox (cause-specific) proportional hazards models were used to obtain adjusted estimates of the effect of PTCY compared to ATG on all endpoints, with a predefined set of adjustment factors (age, DIPSS, donor HLA matching, prior ruxolitinib, comorbidity score, MF subtype (PMF vs sMF)) and a frailty term for transplant center. Results Overall, 192 patients received PTCY and 2415 received ATG. Patients in the ATG group were older (median 61 years [IQR 55-65] vs 60 years [IQR 53-64]). Among patients with available data for DIPSS classification at alloHSCT (n=1726), there were more patients in the intermediate-II and high risk in the ATG group (59% vs 48%) than in the PTCY one. Patients in the PTCY cohort had less CMV negative patients-CMV negative donors (17% vs 34%), more patients with Karnofsky ≥90 (73% vs 64%), were more frequently transplanted from an HLA mismatched 9/10 donor (40% vs 21%) and more often transplanted in later/more recent years (42% vs 20%), PBSC as stem cell source was 96% for both. Engraftment by day 28 was significantly better with ATG (88% vs 74.5%, p<0.001). With a median follow-up of 36.6 (95% CI 35.4 - 38.7) months, 4-year OS was 61% (53-69) with PTCY, 55.1% (53-57%) with ATG, p=0.6. 4-year RFS was 57.5% (49-66) with PTCY vs 47.3% (45-50) with ATG, p=0.2 The 4-year cumulative incidence of relapse (CIR) was 13.5% (8-19) with PTCY vs 22.9% (21-25) with ATG, p=0.07, whereas 4-year NRM was 29% (21-37%) vs 29.7% (28-32) in PTCY and ATG respectively, p=0.9. Grade II-IV aGvHD was 26.7% (20-33%) with PTCY vs 31.8% (30-34%) with ATG, p=0.15 and grade III-IV aGvHD was 14.4% (9-19%) with PTCY vs 15.3% (14-17%) with ATG, p=0.7 while there was a lower incidence at 4 years of cGvHD with PTCY, 28.4% (20-37%) vs 43.8% (42-46) with ATG, p<0.001 as well as for extensive cGvHD with 13.2% (7-20%) vs 22.1% (20-24%), p=0.02. At multivariable analysis, there were no difference between GvHD prophylaxis groups for the primary endpoints with, for RFS, a HR with PTCY of 0.80 (0.59-1.08), p=0.15 and for aGvHD grade II-IV of 0.83 (0.58-1.19), p=0.31. However, the multivariable analysis confirmed the benefit of PTCY for cGvHD with a HR of 0.57 (0.38-0,84), p=0.005, with a tendency for extensive cGvHD with a HR of 0.58 (0.31-1.07), p=0.08 and showed a tendency of decrease relapse incidence for PTCY with a HR of 0.63 (0.38-1.05), p=0.08 as well as for GRFS with a HR of 0.80 (0.61-1.04), p=0.097. Conclusion: This study suggests that MF patients undergoing UD alloHSCT had a decreased incidence of cGvHD using PTCY compared to ATG as GvHD prophylaxis. PTCY is a valid option and considering availability and costs of ATG this may offer a good choice/alternative for regions which do have difficulties to have access to ATG. However, engraftment remains an issue in this setting.


Gynecological Graft-Versus-Host Disease Mimics Cervical Intraepithelial Neoplasia in Pap Smear- Single Center Prospective Study

November 2024

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7 Reads

Blood

The true incidence of gynecological graft-versus-host disease (gynGvHD) is difficult to determine because symptoms may result from hypoestrogenism, and predefined histopathological diagnostic criteria do not exist. We previously reported that gynGvHD was diagnosed in 29% female allogeneic hematopoietic cell transplantation (HCT) recipients and high rates (60%) of abnormal pap smear results were observed in that population (Klasa L. et al. Annals of Hematology, 2020). To determine the incidence of gynGvHD and to verify the frequency of false positive pap smear results, we conducted a prospective analysis of patients who underwent HCT at our institution. STUDY POPULATION The study population included 111 female HCT recipients transplanted between 2018-2023 and who survived to the time of the first gynGvHD evaluation. From further analyses we excluded 3 patients suffering from human papillomavirus (HPV) related disorders before HCT, 18 monitored by local physicians, 10 without follow up, 2 virgins, and 4 patients shortly after 2nd HCT. The final cohort consisted of 74 (67%) women supervised by one dedicated, trained gynecologist. The median age at HCT was 44 (16-69), and the main indication for HCT was acute myeloid leukemia/myelodysplastic syndrome (46%) and acute lymphoblastic leukemia (24%). Matched related (MRD), unrelated (MUD) or haploidentical donors were used in 22 (30%), 43 (58%) and 9 (12%) cases respectively, and most of the patients received myeloablative conditioning regimen (76%). The main immunosuppression consisted of cyclosporine with methotrexate (MRD), with addition of anti-thymocyte globulin (MUD), mismatched transplants received post-transplant cyclophosphamide based GvHD prophylaxis. After discharge from the transplant unit, unless contraindicated, all patients received vaginal estrogen therapy twice weekly up to 18 months after HCT, and hormone replacement therapy if they were younger than 45. GynGvHD diagnosis was based on morphological changes detected in physical examination (lichen planus like, vaginal scarring, stenosis, labial agglutination, erosions, ulcers). Pap smear was collected during the first visit and repeated at 6-12 months intervals depending on the result. Patients with abnormal results were qualified for diagnostic colposcopy with histopathological examination of obtained tissue. RESULTS With the median time of 36 (8-77) months of follow up, gynGvHD was diagnosed in 16 (21%) patients, with score 1, 2 and 3 in 4 (25%), 3 (18%) and 9 (56%) cases respectively. Clinical improvement was observed in 44% cases after local steroid therapy, but only in 1 patient with score 3. Other manifestations of chronic GvHD were documented in 40 (54%) cases (mild 40%, moderate 38%, severe 22%) There was a significant association between oral (93%), ocular (50%), liver (43%) involvement and gynGvHD (p<0.05). An abnormal Pap smear was found in 29 patients (39%), of which 17 (59%) had high-grade intraepithelial lesions (HSIL). In colposcopy-guided histopathological examination, HPV related neoplasia was confirmed in only 2 cases (3% of the study cohort), with no signs of gynGvHD. Abnormal cytology was observed in 11 out of 16 (68%, p<0.05) women diagnosed with gynGvHD. This association was not observed in patients without any gynGvHD signs (18 out of 58 cases, 31%, p=NS). The median time to the first smear collection did not differ between groups: 5 (2-35 months) vs 6 (2-21months), and no correlation was observed between the time of collection, age at HCT, type of conditioning and abnormal result (p=NS). Histopathological features of mucosal or skin GvHD were suggested in 5 cases of cervical biopsy, including 3 patients without any clinical signs of gynGvHD. CONCLUSIONS In female HCT recipients receiving topical estrogens to alleviate symptoms resulting from mucosal atrophy, gynGvHD occurred in 21% of cases. Early initiation of local treatment should be applied to ensure proper tissue healing, unless contraindicated. Compared to the general population where the false-positive rate in cytology reaches 10%, pap smear seems to perform poorly in HCT population, with false positive results detected in 40% of the cases. Additional tests including colposcopy with histopathology and HPV molecular testing should be performed, especially in female patients with gynGvHD.


A Comprehensive Genetic Study of Classical Hodgkin Lymphoma Using Ctdna

November 2024

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14 Reads

Blood

Introduction. We leveraged advanced analytical methods focusing on ctDNA to provide an in-depth overview of the genetic landscape of classical Hodgkin lymphoma (cHL) and its connection to disease pathophysiology and clinical course. Methods. Our study investigated somatic mutations, somatic copy number abnormalities (SCNA), fusions, and whole genome duplication (WGD) in ctDNA from 297 patients enrolled in the IOSI-EMA003-NCT03280394 (treatment-naïve - TN: 215; relapsed/refractory - RR treated with checkpoint inhibitors: 37) and FIL-RougeBIO-NCT05066555 studies (N=45, all TN) using LyV4.0 CAPP-seq. Results. The genes most frequently affected by non-synonymous mutations were SOCS1, TNFAIP3, STAT6, B2M, GNA13, and ITPKB. When considering SCNA, we identified gains in 2p16.1 (REL, XPO1), 3q29 (BCL6), 7q36.3 (EZH2), 9p24.2 (JAK2, CD274, PDCD1LG2), 8q24.23 (MYC), 15q26.3 (IGF1R), and deletions in 1p36.13 (TNFRSF14), 1p12 (CD58), 3q27.1 (KLHL6), 6q23.3 (TNFAIP3), 13q13.3 (FOXO1), 14q12 (NFKBIA), 15q25.3 (B2M), 16p13.3 (CREBBP), 20q13.13 (PTPN1). Recurrent fusions were observed in 32% of cases. No mutations or SCNA were found to correlate with reduced progression-free survival (PFS) in TN cHL. WGD was detected in 24% of patients, which is higher than the frequency observed in other mature B-cell malignancies. cHL with WGD showed a higher incidence of CCNE1 gain, which affects the checkpoint associated with polyploidization. In contrast, multi-hit TP53 lesions or RB1 abnormalities were infrequent and did not correlate with WGD. WGD was significantly linked to a shorter PFS in TN cHL of the IOSI-EMA003 training cohort by univariate and multivariate analyses (HR: 2.4; p=0.02) and further confirmed as a prognostic factor for PFS in the FILRougeBIO validation cohort (HR: 8.9, p=0.01). EBV infection was detected in 18% of cases. EBV+ cases were mostly mutated in SOCS1, infrequently mutated in STAT6, and lacked the loss of PTPN1 and NFKBIA. EBV+ cHL exhibited a significantly lower burden of mutations and SCNA. Two major classes of microenvironments emerged through digital cytometry deconvolution and tissue microarray analysis of cHL biopsies. One class was marked by macrophages (52% of cases) and the other by T-cells and immune checkpoints (48% of cases). Mutations, SCNA, and WGD were evenly distributed across both microenvironmental classes. Conversely, cHL cases with a T-cell-enriched microenvironment had fewer subclonal MHC-I neoantigens, indicating selective pressure exerted from T-cells. Consistently, RR cHL treated with checkpoint inhibitors had longer PFS if they lacked subclonal MHC-I neoantigens. LyV4.0 CAPP-seq together with NMF clustering, reproduced the classification of the C1-C5 genetic subtypes in 235 untreated DLBCL patients. In cHL, two clusters were identified using the same approach. Although the two clusters had similar baseline characteristics, EBV infection rates, ctDNA load, and outcomes, the two clusters differed in their underlying mechanisms of genetic instability. One cluster was defined by aneuploidy and a higher number of SCNA (36% of cases), while the other was characterized by mutations in genes targeted by AID-hypermutation (64% of cases) and had a higher fraction of mutations associated with AID activity signatures (SBS39, SBS84, SBS85). Both clusters shared hallmark lesions of cHL, including STAT6 mutations, and gains in 2p/2p16.1 and 9p/9p24.2. In multivariate regression analysis, MTV and WGD were the most important variables influencing pre-treatment ctDNA quantity. Conversely, the fraction of tumor cells and proliferating cells in the biopsy, and levels of DNASE1L3 showed minimal importance in explaining ctDNA concentration. While we could confirm pre-treatment ctDNA levels above 2.5 Log10 hGE/ml of plasma as a prognostic factor for DLBCL patients, they did not impact PFS in either the IOSI-EMA003 or in the FILRougeBIO cohorts. Conclusions. WGD is the only confirmed genetic factor for predicting the prognosis of TN cHL. MHC-I neoantigen load correlates with the microenvironment characteristics and the response to checkpoint inhibitors rather than specific genetic mutations. The genetic subtypes of cHL are mainly defined by the mechanisms driving genetic instability rather than by individual genetic lesions or EBV infection. The ctDNA load has no prognostic significance in cHL.


Citations (3)


... There is no precise data regarding the help available so far. However, recently published real-life data from almost half of the Polish transplant centers (10/24) shows that 65 HSCT and cell therapy procedures were performed on refugee patients from Ukraine during the first year of the war [2]. So far, that is the only summary of performing such procedures on Ukrainian refugees. ...

Reference:

A helping hand
International cooperation to secure access of patients in Ukraine to cellular therapies in conditions of Russian aggression

Acta Haematologica Polonica

... This may be due to the heterogeneity in treatment modalities and population characteristics including prior lines of treatment and variable refractoriness to drug classes. Furthermore, serological assessment of MRD by evaluating circulating tumor cells or by means of mass spectrometry are promising approaches that may be able to substitute the need for bone marrow aspiration [63][64][65][66][67]; however, these should be prospectively evaluated in clinical studies. ...

Mass Spectrometry-Based Assessment of M-protein in Peripheral Blood During Maintenance Therapy in Multiple Myeloma
  • Citing Article
  • May 2024

Blood

... The immunophenotypic profile of MF and SS cells typically includes the expression of CD2, CD3, CD5, CD4, CCR4, TCR-beta, and CD45RO, with a lack of CD7 and CD26 markers [6]. Additionally, adverse prognostic factors in MF, independent of clinical stage, include older age (>60 years), large cell transformation, elevated lactate dehydrogenase (LDH) levels, and low CD30+ expression (<10%) [7,8]. The staging of MF and SS is based on the tumor-node-metastasis (TNM) classification system, which was first introduced in 1979 [9]. ...

Primary cutaneous lymphomas. Diagnostic and therapeutic guidelines of the Polish Dermatological Society (PTD) and Polish Lymphoma Research Group (PLRG)
  • Citing Article
  • January 2023

Dermatology Review