Kooperativer Bibliotheksverbund

In: Blood, American Society of Hematology, Vol. 92, No. 9 ( 1998-11-01), p. 3018-3024

Abstract: Fas (APO-1/CD95) is a cell-surface receptor involved in cell death signaling. Germline mutations in the Fas gene have been associated with autoimmune lymphoproliferative syndrome, and somaticFas mutations have been found in multiple myeloma. We have examined the entire coding region and all splice sites of theFas gene in 150 cases of non-Hodgkin’s lymphoma. Overall, mutations were identified in 16 of the tumors (11%). Missense mutations within the death domain of the receptor were associated with retention of the wild-type allele, indicating a dominant-negative mechanism, whereas missense mutations outside the death domain were associated with allelic loss. Fas mutations were identified in 3 (60%) MALT-type lymphomas, 9 (21%) diffuse large B-cell lymphomas, 2 (6%) follicle center cell lymphomas, 1 (50%) anaplastic large cell lymphoma, and 1 unusual case of B-cell chronic lymphocytic leukemia with a marked tropism for skin. Among the 16 patients with somaticFas mutations, 15 showed extranodal disease at presentation, and 6 relapsed in extranodal areas. Ten of 13 evaluable patients showed features suggestive of autoreactive disease. Our data indicate that somatic disruption of Fas may play a role in the pathogenesis of some lymphomas, and suggest a link between Fas mutation, cancer and autoimmunity. © 1998 by The American Society of Hematology.

Type of Medium: Online Resource

ISSN: 1528-0020 , 0006-4971

URL: Article

DOI: 10.1182/blood.V92.9.3018.421k52_3018_3024

Language: English

Publisher: American Society of Hematology

Publication Date: 1998

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 92, No. 9 ( 1998-11-01), p. 3018-3024

Abstract: Fas (APO-1/CD95) is a cell-surface receptor involved in cell death signaling. Germline mutations in the Fas gene have been associated with autoimmune lymphoproliferative syndrome, and somaticFas mutations have been found in multiple myeloma. We have examined the entire coding region and all splice sites of theFas gene in 150 cases of non-Hodgkin’s lymphoma. Overall, mutations were identified in 16 of the tumors (11%). Missense mutations within the death domain of the receptor were associated with retention of the wild-type allele, indicating a dominant-negative mechanism, whereas missense mutations outside the death domain were associated with allelic loss. Fas mutations were identified in 3 (60%) MALT-type lymphomas, 9 (21%) diffuse large B-cell lymphomas, 2 (6%) follicle center cell lymphomas, 1 (50%) anaplastic large cell lymphoma, and 1 unusual case of B-cell chronic lymphocytic leukemia with a marked tropism for skin. Among the 16 patients with somaticFas mutations, 15 showed extranodal disease at presentation, and 6 relapsed in extranodal areas. Ten of 13 evaluable patients showed features suggestive of autoreactive disease. Our data indicate that somatic disruption of Fas may play a role in the pathogenesis of some lymphomas, and suggest a link between Fas mutation, cancer and autoimmunity. © 1998 by The American Society of Hematology.

Type of Medium: Online Resource

ISSN: 1528-0020 , 0006-4971

URL: Article

DOI: 10.1182/blood.V92.9.3018

Language: English

Publisher: American Society of Hematology

Publication Date: 1998

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 601-601

Abstract: Background: Salvage autologous stem cell transplantation (ASCT) is used in selected patients with relapsed multiple myeloma after up-front ASCT. However, there are limited data on the optimal induction therapy before salvage ASCT. There is strong support for the use of maintenance therapy after upfront ASCT in newly diagnosed multiple myeloma whereas data on maintenance therapy after salvage ASCT are sparse. The Nordic Myeloma Study Group (NMSG) initiated the CARFI trial (NCT02572492), an open randomized phase II study, to investigate the efficacy and safety of carfilzomib as part of induction and conditioning in salvage ASCT and to evaluate the role of carfilzomib/dexamethasone maintenance after salvage ASCT. Methods: Patients with first relapse after up-front ASCT were treated with an induction regime containing four cycles of CAR-CY-DEX (iv carfilzomib 20 mg/sqm → 36 mg/sqm on days 1, 2, 8, 9, 15 and 16, tablet cyclophosphamide 300 mg/sqm on days 1, 8 and 15 and tablet dexamethasone 20 mg on days 1, 2, 8, 9, 15 and 16 in each 28-days cycle). The subsequent conditioning regimen contained iv carfilzomib 27 mg/sqm on day -2 and -1, and iv melphalan 200 mg/sqm on day -2. The patients had not received any maintenance therapy after upfront ASCT. Two months after ASCT patients were randomized (1:1) to observation or maintenance therapy with iv carfilzomib 27 mg/sqm → 56 mg/sqm every second week and tablet dexamethasone 20 mg every second week. The randomization was stratified according to relapse 1 - 2 year or & gt; 2 years after up-front ASCT, ISS stage and standard versus high-risk cytogenetics. Primary endpoint was comparison of time to progression (TTP) after up-front ASCT and TTP after salvage ASCT with CAR-CY-DEX induction. Another primary endpoint was to compare TTP between carfilzomib-dexamethasone maintenance and observation in patients treated with salvage ASCT. Results: 200 patients were enrolled in the study and 32 of these went off study during the induction and after ASCT. The remaining 168 patients were randomized to carfilzomib-dexamethasone (82 patients) or observation (86 patients). The median age was 62 (interquartile range: 56; 66) years and the median follow-up from time of inclusion was 20.1 (14.1 - 27.6) months. The median TTP after up-front ASCT was 33.2 (31.0-37.8) months compared with 28.1 (24.9-31.5) months after salvage ASCT. The two groups randomised to maintenance therapy or observation were balanced regarding age, time from myeloma diagnosis, treatment at diagnosis, performance status, ISS stage and high-risk cytogenetics (Table 1). The median TTP from randomisation was 28.8 (95% CI: 24.4-NR) months in the maintenance group and 18.5 (95% CI: 14.3-22.0) months in the observation group (hazard ratio 0.42 (95% CI: 0.26-0.68, P = 0.0003)) (Figure I). For the maintenance group TTP from inclusion was 35.4 (30.9-NR) months compared with TTP of 31.3 (29.4-37.8) months (P = 0.71) after up-front ASCT for these patients. A total of 53 serious adverse events (SAE) were reported in 25 patients on carfilzomib-dexamethasone maintenance and 33 SAEs in 21 patients in the observation group. The majority of the SAEs were infections; 39 in the maintenance group and 25 in the observation group, divided into viral infection (10 versus 3), septicemia (2 versus 0) and pneumonia (12 versus 7). Three SAEs classified as cardiac-pulmonary were observed in the maintenance group (syncope, atrial fibrillation and pulmonary embolism) in contrast to three in the observation group (atrial fibrillation and dyspnea(2)). Conclusion: In this randomized phase 2 trial, maintenance therapy with carfilzomib and dexamethasone prolonged median TTP with approximately 10 months following salvage ASCT in multiple myeloma. The difference between TTP after upfront ASCT and TTP after salvage ASCT with carfilzomib based induction therapy was small which supports the use of salvage ASCT followed by maintenance in selected patients at first relapse. Disclosures Remes: Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees, Other: Congress Support; Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Congress Support; Amgen: Other: Congress Support; Celgene: Other: Congress Support; Sanofi: Other: Congress Support. Schjesvold:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; MSD: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; SkyliteDX: Honoraria; Oncopeptides: Membership on an entity's Board of Directors or advisory committees. Abildgaard:Amgen: Research Funding; Celgene: Research Funding; Janssen: Research Funding; Takeda: Research Funding. Vangsted:Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Jansen: Honoraria. Blimark:Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2019-122141

Language: English

Publisher: American Society of Hematology

Publication Date: 2019

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detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 106, No. 11 ( 2005-11-16), p. 1260-1260

Abstract: Allogeneic hematopoietic cell transplantation (HCT) has a well-documented ability to cure a number of malignant hematological diseases. The curative principle in allogeneic HCT is the Graft-versus-Leukemia (GVL) effect and nonmyeloablative (NMA) conditioning HCT relies exclusively on this anti-tumor effect to eliminate tumor cells. Donor T-cells are documented to be responsible for the GVL effect, however, often they also cause Graft-versus-Host disease (GVHD) which is associated with high morbidity and mortality. Characterization of cells and molecules involved in both GVL and GVHD would potentially set the stage for separation of GVL and GVHD in order to augment GVL in the absence of GVHD. In the present study, we analyzed the clonotype composition of CD8+ T cells following NMA conditioning and HCT, in two patients with chronic lymphocytic leukemia (CLL). T-cell receptor (TCR) clonotype mapping (RT-PCR combined with denaturing gradient gel electrophoresis (DGGE)) was used to identify clonally expanded CD8+ T cells in blood samples. This method provides a “molecular fingerprint” of each unique T cell based on junctional diversity of the TCR CDR3 region and, thus, offers the means to track T-cell clonotypes in time and space. Longitudinal comparative analyses showed that CD8+ T-cell clonality was highly dynamic during early phases after transplantation with various clonotypes emerging and disappearing. However, clonal diversity decreased after 4–5 months and stable CD8+ T-cell clonotypes appeared and persisted throughout the analyzed period (up to two years). One patient received donor lymphocyte infusion (DLI) due to disease progression and this was shown to lead to establishment of recurrent (detected prior to DLI) CD8+ T-cell clonotypes as well as new CD8+ T-cell clonotypes. The appearance of these cells correlated with disease remission strongly suggesting their engagement in anti-CLL reactivity. To examine the functional capacities of clonally expanded T cells after HCT, recipient CD8+ T cells were stimulated ex vivo with pre-transplant patient CLL cells and/or normal hematopoietic cells and the T-cell surface expression of CD107a (marker for cytotoxicity) was detected by FACS. Clonotype mapping analyses of FACS sorted CD107a positive CD8+ T cells after stimulation with CLL cells demonstrated that such cytotoxic CD8+ T cells were present as stable clonally expanded T cells in vivo strongly implying their involvement in an ongoing anti-CLL-response. Furthermore, co-culture with normal hematopoietic cells resulted in a unique CD107a positive expanded T-cell clonotype. Our results strongly suggest that clonally expanded CD8+ T cells are involved in an ongoing tumor response and support data which demonstrate that GVL and GVHD are the result of distinct responses.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V106.11.1260.1260

Language: English

Publisher: American Society of Hematology

Publication Date: 2005

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detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 3777-3777

Abstract: The F7 gene mutations p.Q160R and p.A354V-p.P464Hfs are associated with very low factor VII (FVII) activity and antigen levels and a bleeding phenotype. We have previously demonstrated reduced secretion of the recombinant (r) variants rFVII-160R and rFVII-354V-464Hfs in vitro, possibly caused by a misfolding mechanism resulting in intracellular retention and increased endoplasmic reticulum (ER) stress. Chemical chaperones are compounds that can enable proteins to recover from a misfolded state and rescue intracellular processing. The aim of the study was to determine whether chemical chaperones could increase the secretion and enhance the biological activity of the above mentioned FVII mutants. Chinese hamster ovary (CHO-K1) cells stably expressing rFVII-160R or rFVII-354V-464Hfs were treated with the chemical chaperones 4-phenylbutyrate (4-PBA), betaine, taurine, taurourosdeoxycholic acid (TUDCA), trimethylamine N-oxide (TMAO) or lumacaftor (VX-809). The intracellular and secreted levels of FVII antigen were measured by ELISA and F7 mRNA levels were assessed by quantitative RT-PCR. Treatment of cells with 4-PBA for 48 hours increased F7 mRNA levels and increased the ratio of secreted/intracellular of both FVII mutants by ~2-2.5-fold, indicating an effect of 4-PBA FVII expression and secretion. 4-PBA is known to inhibit the activity of histone deacetylases, thereby inducing hyperacetylation of histones and increasing gene transcription. To measure histone acetylation, we next performed Western blot analysis of acetylated histone H3 (AcH3). We found that the levels of AcH3 were significantly increased after treatment with 4-PBA, indicating that induced transcription of F7 by 4-PBA could be a result of increased global histone acetylation. Since 4-PBA treatment increased the secretion of the FVII mutants, we questioned whether this also would alleviate ER stress. Using an ER stress luciferase assay, we observed that the ER stress levels in 4-PBA treated cells were significantly lower than in non-treated cells. To determine whether 4-PBA treatment could restore the intracellular trafficking of the FVII mutants from the ER to Golgi, confocal immunofluorescence microscopy was utilized The studies revealed that upon treatment with 4-PBA, the p.Q160R mutant had a strong co-localization with the Golgi marker GM130 and with the Golgi stacking protein GRASP55, known to be associated with unconventional protein secretion. A vesicular pattern of staining could be observed in cells expressing the p.A354V-p.P464Hfs. However, these structures did not overlap with endosomal markers or markers of the ER-Golgi transport remaining the secretory route of this FVII mutant elusive. Finally, to assess the activity of FVII mutants, we measured the generation of activated (a) factor X (FXaG) in FVII deficient plasma supplemented with conditioned medium from cells stably expressing rFVII mutants before and after 4-PBA treatment. To increase the assay sensitivity to very low FVII activity levels we also boosted the coagulation initiation phase by inhibiting the tissue factor pathway inhibitor (TFPI) through an anti-TFPI RNA aptamer. We found that treatment of cells with 4-PBA gave rise to a modest, but measurable FXaG activity in conditioned medium for both FVII mutants. Furthermore, inhibition of TFPI proportionally potentiated FXaG activity of both 4-PBA-induced FVII variants. The present study demonstrates that chemical chaperones, such as 4-PBA, can increase intracellular trafficking through the secretory pathway of misfolded FVII mutants. Importantly, the secreted mutant proteins were found to be biologically regulated and active in the coagulation pathway. Thus, 4-PBA could have therapeutic effect in FVII deficiency caused by misfolded FVII mutants. Disclosures No relevant conflicts of interest to declare.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2018-99-118246

Language: English

Publisher: American Society of Hematology

Publication Date: 2018

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In: Blood, American Society of Hematology, Vol. 117, No. 7 ( 2011-02-17), p. 2200-2210

Abstract: Indoleamine 2,3-dioxygenase (IDO) is an immunoregulatory enzyme that is implicated in suppressing T-cell immunity in normal and pathologic settings. Here, we describe that spontaneous cytotoxic T-cell reactivity against IDO exists not only in patients with cancer but also in healthy persons. We show that the presence of such IDO-specific CD8+ T cells boosted T-cell immunity against viral or tumor-associated antigens by eliminating IDO+ suppressive cells. This had profound effects on the balance between interleukin-17 (IL-17)–producing CD4+ T cells and regulatory T cells. Furthermore, this caused an increase in the production of the proinflammatory cytokines IL-6 and tumor necrosis factor-α while decreasing the IL-10 production. Finally, the addition of IDO-inducing agents (ie, the TLR9 ligand cytosine-phosphate-guanosine, soluble cytotoxic T lymphocyte–associated antigen 4, or interferon γ) induced IDO-specific T cells among peripheral blood mononuclear cells from patients with cancer as well as healthy donors. In the clinical setting, IDO may serve as an important and widely applicable target for immunotherapeutic strategies in which IDO plays a significant regulatory role. We describe for the first time effector T cells with a general regulatory function that may play a vital role for the mounting or maintaining of an effective adaptive immune response. We suggest terming such effector T cells “supporter T cells.”

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2010-06-288498

Language: English

Publisher: American Society of Hematology

Publication Date: 2011

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detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 932-932

Abstract: Abstract 932 The Nordic Lymphoma Group has since 1996 conducted three consecutive phase II trials for front-line treatment of MCL patients ≤ 65 years of age. The first protocol (MCL1) 1996-2000 introduced high-dose chemotherapy with autologous stem cell support (unpurged or ex vivo purged) as consolidation after 4 cycles of intensified CHOP (maxi-CHOP). The results were disappointing, as the majority of patients relapsed. 1 Being in CR pre-transplant was the most important factor for outcome. Hence, in the second trial (MCL2) 2000-2006 induction therapy was intensified by adding high-dose Ara-C and rituximab to the regimen. Compared to MCL1 this led to significant improvement of event-free and overall survival, and the rate of PCR negative stem cell grafts and bone marrow samples.2 Again, responders in less than CR pre-transplant had a significantly poorer outcome. We therefore made a further intensification for the MCL3 study (2006-2009) by adding 90Y-Ibritumomab tiuxetan (Zevalin®) to the high-dose BEAC/BEAM to responders not in CR. Methods: As in the MCL1 and 2 studies newly diagnosed stage II-IV MCL patients ≤ 65 years were included. Induction treatment was identical to that of the MCL2 study with alternating cycles of maxi-CHOP-rituximab (3 cycles) and Ara-C-rituximab (3 cycles). Response evaluation was done after cycle 5. PET/CT was recommended, but could not influence the response evaluation, which was done according to the International Workshop criteria. Responders underwent in vivo purged harvest of stem cells after cycle 6 (Ara-C + 2 doses of rituximab). Patients in CRu or PR received a standard dose 90Y-Ibritumomab tiuxetan (0.4 mCi/kg) one week prior to the BEAM/BEAC, CR patients received BEAM/BEAC alone. Patients are followed by CT-scans, bone marrow and blood samples, including PCR for minimal residual disease or molecular relapse. For molecular relapse preemptive treatment with 4 standard doses of rituximab, as in the MCL2 study3, is given. Results: The planned accrual of 160 patients was reached in June 2009. The patient characteristics are similar to those of the MCL2 trial with a median age of 57 years (28-65), the majority male (80%) and in stage IV (89%) with bone marrow involvement (74%). The response rates pre-transplant so far compare favorably with data from MCL2 with 50% in CR, 18% in CRu, and 28% in PR. Only 4 out of 128 evaluable patients did not respond (3%) and there was one case (1%) of treatment-related mortality during induction therapy. While it is still too early to assess the impact of the 90Y-Ibritumomab tiuxetan on the progression-free survival, the side effects were similar to those of the MCL2 study including a treatment related mortality of 4%. Fifty-five patients in CRu or PR have so far been treated with 90Y-Ibritumomab tiuxetan, with no indication of any added toxicity. Only 12 out of 133 patients (10%) have not undergone transplant, 5 due to stem cell harvest failure, 3 due to toxicity and 4 due to non response to induction treatment. PET-scan prior to transplant was positive in 2% of CR patients, 20% of CRu patients and 54% of PR patients. Patients with a positive PET-scan pre-transplant had a 36% chance of achieving a molecular remission post-transplant, compared to 92% of cases with a negative PET-scan (p 〈 0.001) Conclusion: The high response rates after induction treatment achieved in the MCL2 study are confirmed in the present study. Adding 90Y-Ibritumomab tiuxetan to high-dose chemotherapy for responding patients not in CR prior to transplant is feasible and does not increase toxicity. A negative PET-scan prior to transplant predicts for a molecular remission after the transplant. References: Andersen et al, Eur J Cancer, 2002, 38: 401-408 Geisler et al, Blood, 2008, 112: 2687-2693 Andersen et al J Clin Oncol 2009 epub ahead of press Disclosures: Kolstad: Bayer Schering Pharma: Research Funding. Geisler:Bayer Schering Pharma: Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V114.22.932.932

Language: English

Publisher: American Society of Hematology

Publication Date: 2009

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detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 112, No. 11 ( 2008-11-16), p. 3766-3766

Abstract: PTCL are a heterogeneous group of uncommon lymphoid malignancies. Geographical differences have been reported, the NK/T-cell-derived nasal type being more common in Asia and the entheropathy-type more common in western countries. Except for the alk-positive anaplastic large cell lymphoma (ALCL) subtype, PTCL have generally a poorer outcome than their B-cell counterparts when treated with conventional therapeutic strategies. In recent years, as a result of an improved biologic understanding and definition of PTCL entities, an increasing number of PTCL-specific clinical trials have been initiated. The purpose of this analysis was to describe epidemiological and clinico-pathological features of the major subtypes in PTCL, as they occur in an unselected western population, in order to provide population-based data that may be useful for the design of future PTCL-specific studies. Although the LYFO registry was initiated in 1983, the present analysis only includes patients diagnosed in the 15-year period from 1990 (when immunhistochemistry was routinely applied to all biopsy specimen) to 2004. Within this 15 yr period, 485 PTCL cases were diagnosed. They had an age range of 16–92 yrs and a male to female ratio of 1.4 (59% male and 41% female cases). The most frequent histological subtypes were PTCL unspecified (PTCLu) (44%), non-cutaneous ALCL (alk-status not available) (35%) and angioimmunoblastic (AIL) (17%). The incidence trend for PTCL, taken as one group, did not show significant changes over the 15 years observation period. Approximately two thirds of the patients (65%) had disseminated disease (stage III–IV) at diagnosis, while half of the patients (49%) presented with B-symptoms. AIL had a higher frequency of cases with disseminated disease (93%, p 〈 0.05), mainly due to bone marrow involvement, while ALCL had a significantly higher frequency of localized cases (46%, p 〈 0.05). Surprisingly, the majority of PTCL patients (69%) were registered at diagnosis with a good performance score (WHO) of 0–1, with figures for PTCLu and ALCL of 65% and 69%, respectively, and slightly lower (52%, p 〉 0.05) for AIL. All three major subtypes had predominantly nodal disease at presentation (PTCLu 56%, ALCL 57%, AIL 61%). Pre-therapeutic s-LDH was elevated in 40 % of all PTCL patients (PTCLu 44%, ALCL 39%). AIL cases presented more often with elevated s-LDH (61% of the cases, p 〈 0.05). In line with these findings, AIL also had a higher frequency of cases with IPI ≥2, which translated into an inferior 5-yr overall survival value (25%, as opposed to 33% and 39% for PTCLu and ALCL, respectively). These survival values represent the comparative background on which the potential impact of the new PTCL trial program of our nordic collaborative group will be evaluated.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V112.11.3766.3766

Language: English

Publisher: American Society of Hematology

Publication Date: 2008

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In: Blood, American Society of Hematology, Vol. 140, No. Supplement 1 ( 2022-11-15), p. 6706-6707

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2022-167897

Language: English

Publisher: American Society of Hematology

Publication Date: 2022

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 607-607

Abstract: Background: Somatic driver mutations in hematopoietic cells may lead to clonal hematopoiesis of indeterminate potential (CHIP). In patients with lymphoma CHIP has been associated with increased risk of therapy-related myeloid neoplasms (tMN) and inferior survival after autologous stem cell transplantation as demonstrated in a large single center study and in a case-control study (Gibson CJ et al., JCO 2017 and Berger G et al., Blood 2018). Here, we investigated the clinical impact of clonal hematopoiesis in a nation-wide population-based cohort of Danish lymphoma patients undergoing autologous transplant with prospective data from four national patient registries. Methods: Patients with lymphoma who had undergone leukapheresis at all danish transplant centers from 2000 to 2012 were identified. DNA and RNA was extracted from mobilized peripheral blood products. Targeted sequencing of all samples was performed using an Illumina TruSeq Custom Amplicon panel (Illumina, San Diego, CA, USA) designed to cover 〉 95% of mutations associated with CHIP (ASXL1, ASXL2, BCOR, BRCC3, CBL, CREBBP, DNMT3A, ETV6, GNB1, IDH1, IDH2, JAK2, KRAS, NRAS, PPM1D, RAD21, SF3B1, SRSF2, TET2, TP53). To allow detection of low-level mutations and secure variant calling, unique molecular identifiers (UMI's) were used. Filtering of variants was done by stringent criteria consistent with earlier studies. Assessment of mutations was performed blinded to the patients' clinical data. Prospective clinical patient data was obtained for all patients from four national registries, including the Danish Lymphoma Registry (diagnosis, involvement, lymphoma treatment, relapse and death), the Danish National Patient Registry (hospital admission diagnoses and treatments), the Danish Cancer Registry (primary and secondary cancer diagnoses) and the Danish Pathology Database (histopathological examinations and diagnoses), respectively. Results: Samples from 574 patients were included. The median age was 55.5 years (IQR: 45.3 - 62.2) and the median follow-up time for survivors was 9.2 years (IQR: 7.1 - 11.2). The lymphoma subtypes were typical of patients selected for autologous transplantation; diffuse large B-cell lymphoma (191 pts), follicular lymphoma (102 pts), mantle cell lymphoma (88 pts), Hodgkin's lymphoma (80 pts), peripheral T-cell lymphoma (77 pts) and other histologies (36 pts). Of the 574 patients analyzed, 191 (33.3%) of the patients had somatic mutations meeting CHIP criteria (total mutations called=210). The most commonly mutated genes were DNMT3A (n=59, 28%), TET2 (n=48, 23%), PPM1D (n=34, 16%), ASXL1 (n=21, 10%) and TP53 (n=18, 8%). As expected CHIP mutations were more frequent in patients above 60 years (p=0.002). Prevalence of CHIP was associated with an inferior overall survival (p=0.004) and event-free survival (p=0.03). It was also associated with increased risk of biopsy-confirmed tMN (p=0.03) and higher probability of receiving blood transfusions after autologous transplant (p=0.027). Especially patients with mutations in DNA damage response genes PPM1D and TP53 (found in 48 pts, 8.3%) had a significantly increased risk of adverse outcomes. Both overall survival and event-free survival were significantly poorer with the presence of DNA damage pathway mutations (p 〈 0.0001 for both, Figure 1A), as well as risk of tMN (p=0.01). In addition, PPM1D/TP53 mutations were associated with increased rates of any secondary cancer (p=0.004), including non-hematological cancer, and hospital admissions with severe infections (p=0.01, Figure 1B). The impact of low-level mutations and statistical modelling of interactions between parallel outcomes will be presented at the meeting. Conclusion: To our knowledge this is the first population-based study of clonal hematopoiesis in patients with lymphoma. We find that CHIP and particularly mutations in DNA damage response genes (PPM1D/TP53) are associated with increased mortality, which confirms findings from single center studies. These data support the evaluation of CHIP for risk assessment in lymphoma patients before high-dose chemotherapy. Our study also identifies increased rates of several clinically relevant adverse outcomes (severe infections, blood transfusions and secondary cancers) in lymphoma patients with clonal hematopoiesis. Figure 1. Figure 1. Disclosures Grønbæk: Janssen Pharma: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Otsuka Pharma: Membership on an entity's Board of Directors or advisory committees.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2018-99-109893

Language: English

Publisher: American Society of Hematology

Publication Date: 2018

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detail.hit.zdb_id: 80069-7