Kooperativer Bibliotheksverbund

In: Blood Advances, American Society of Hematology, Vol. 4, No. 1 ( 2020-01-14), p. 122-126

Abstract: Disease relapse remains the leading cause of failure after autologous stem cell transplantation (ASCT) for patients with relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL). We conducted a phase 2, multicenter, single-arm study of the anti–PD-1 monoclonal antibody pembrolizumab given after ASCT in patients with chemosensitive DLBCL, hypothesizing that it would improve the progression-free survival (PFS) at 18 months after ASCT (primary endpoint) from 60% to 80%. Pembrolizumab was administered at 200 mg IV every 3 weeks for up to 8 cycles, starting within 21 days of post-ASCT discharge. Twenty-nine patients were treated on this study; 62% completed all 8 cycles. Seventy-nine percent of patients experienced at least one grade 3 or higher adverse event, and 34% experienced at least one grade 2 or higher immune-related adverse event. Overall, 59% of patients were alive and progression free at 18 months, which did not meet the primary endpoint. The 18-month overall survival was 93%. In conclusion, pembrolizumab was successfully administered as post-ASCT consolidation in patients with R/R DLBCL, but the PFS did not meet the protocol-specific primary objective and therefore does not support a larger confirmatory study. This trial was registered at www.clinicaltrials.gov as #NCT02362997.

Type of Medium: Online Resource

ISSN: 2473-9529 , 2473-9537

URL: Article

DOI: 10.1182/bloodadvances.2019000784

Language: English

Publisher: American Society of Hematology

Publication Date: 2020

detail.hit.zdb_id: 2876449-3

In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 3961-3961

Abstract: Introduction: Monitoring for minimal residual disease (MRD) in hematologic malignancies can identify patients at high risk of relapse after standard therapy and hematopoietic stem cell transplantation (HSCT). However, techniques are limited for MRD monitoring of most lymphoma subtypes. The LymphoSIGHTTM method (Sequenta, Inc.) is a high-throughput sequencing-based MRD assay that detects small amounts of circulating tumor DNA (CTD) in patients with lymphoid malignancies. This assayhas shown promise in the monitoring of patients with chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), and diffuse large B-cell lymphoma (DLBCL). We evaluated whether CTD measured by LymphoSIGHTTM pre- and post-allogeneic HSCT predicts relapse and outcome in patients with lymphoid malignancies. Methods: We retrospectively studied patients enrolled between 2009-2012 on a multicenter phase 3 trial comparing sirolimus-containing to non-sirolimus containing GVHD prophylaxis regimens in patients with lymphoma undergoing allogeneic HSCT. Only patients with available archival tumor tissue were included. Patients underwent conventional restaging at 3, 6, 12, 18 and 24 months per protocol. Genomic tumor DNA was extracted from formalin-fixed paraffin-embedded tissue or bone marrow aspirate mononuclear cells. PCR amplification of IGH and IGK regions was performed followed by high-throughput sequencing to determine the tumor clonotype(s). As part of the trial, peripheral blood mononuclear cell (PBMC) and plasma samples were collected pre-HSCT and at days 30, 60, 100, 180, 270, 365, 545 and 730 after HSCT. DNA from plasma (DLBCL) and PBMCs (other histologies) was amplified and sequenced to determine the level of CTD per million diploid genomes. Results: We studied 68 patients with B-cell non-Hodgkin lymphoma, classical Hodgkin lymphoma (HL), or CLL. Clonotype calibration was successful in 51 patients (75%; 82% when excluding diagnostic samples with insufficient DNA). MRD evaluation was performed at 〉 =1 time point in 40 patients (13 CLL, 4 DLBCL, 4 transformed indolent lymphoma (TIL), 8 follicular lymphoma (FL), 7 MCL, 4 HL). Overall, 9/40 patients in the cohort relapsed, with a 2y cumulative incidence of relapse/progression (CIR) of 18%. Thirteen of 26 patients (50%) tested were MRD+ pre-HSCT, including 27% of patients in complete remission (CR) and 71% of patients in partial remission (PR) by conventional criteria. The 2y CIR in MRD+ vs MRD- patients at baseline was 38% vs 7% (p=0.2), 2y non-relapse mortality (NRM) was 15% vs 8% (p=0.6), and 2y progression-free survival (PFS) was 46% vs 85% (p=0.12). At day 100, 12 of 32 patients (38%) tested were MRD+. The 2y CIR in day 100 MRD+ patients was 25% vs 0% for MRD- patients (p=0.25), 2y NRM was 25% vs 5% (p=0.05), and 2y PFS was 50% vs 95% (p=0.01). In multivariable models with histology and disease status at HSCT as covariates, the hazard ratio (HR) for progression or death associated with baseline MRD+ was 2.8 (p=0.3); for day 30 MRD+, HR=6.0 (p=0.1); and for day 100 MRD+, HR=8.3 (p=0.07). When entered into the models as a time-dependent covariate, MRD-positivity was associated with a significantly increased risk of progression or death (HR 5.2, 95% CI 1.8-15.4; p=0.03) and of disease relapse/progression (HR 12.7, 95% CI 2.5-64.3, p=0.002). Histology and disease status were not significantly associated with either outcome in the models. Nine patients relapsed or progressed at a median of 4 (range 1-28) months post-HSCT and 7 (78%) had an MRD+ PB sample at a median of 6 months prior to relapse (Figure). Five patients were persistently MRD+ in all PB samples tested prior to relapse and 2 were initially MRD- then became MRD+. All 5 patients who relapsed after day 100 were MRD+ prior to relapse. Among 31 patients who did not relapse: 16 were MRD- in all PB samples tested; 9 were initially MRD+ then became MRD- by day 365 (4 by d100, 3 by d180, 2 by d365); 2 had a mixed MRD pattern, initially MRD-, then MRD+, then MRD- thereafter; the remaining 4 patients, all of whom had CLL, were persistently MRD+ but had marrow or PB evidence of persistent disease without progression at MRD+ time points. Conclusions: MRD status based on CTD detection in patients with lymphoid malignancies is predictive of outcome after allogeneic HSCT. This technique may provide important prognostic information throughout the HSCT course and identify a target population for early intervention to prevent disease relapse. Figure 1 Figure 1. Disclosures Faham: Sequenta, Inc.: Employment, Equity Ownership, 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.V124.21.3961.3961

Language: English

Publisher: American Society of Hematology

Publication Date: 2014

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. 3275-3275

Abstract: Umbilical cord blood transplantation (UCBT) is an alternative for patients who need hematopoietic stem cell transplant (HSCT), but lack HLA-matched adult donors. Rabbit anti-thymoglobulin (ATG) has been used in UCBT conditioning to achieve T cell depletion, but ATG-induced immunosuppression is associated with delayed immune reconstitution, increased infectious complications and higher non-relapse mortality. In a clinical trial of reduced intensity double-unit UCBT (dUCBT), we substituted low dose total body irradiation (TBI) for ATG to determine whether dUCBT without ATG would alter kinetics and quality of immune reconstitution. Thirty-one patients with hematopoietic malignancies and a median age of 58 yr were treated with Flu/Mel/TBI, followed by dUCBT and GVHD prophylaxis with tacrolimus and sirolimus. We examined reconstitution of immune cell populations, thymic regeneration by quantifying T cell receptor excision circles (TREC) and serum cytokines (IL-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12, IFN-γ, TNF-α, IL-12p70, GM-CSF) using the LUNARISTM Human 11-Plex Cytokine Biochip384 from AYOXXA Biosystems. Assessments were done prior to and at 1, 2, 3, 6, 12 and 24 months after dUCBT. Results are based on 28 evaluable patients. The 2-yr overall survival and progression-free survival were 53% and 48%. Median time to neutrophil and platelet engraftment was 25 and 52 days, respectively. Before UCBT, the median values for most leukocyte subsets were below normal limits, except for monocytes. CD3+ cells remained depressed until 2 months post-transplant when gradually began to re-emerge. However, CD4+ and CD8+ subsets had distinct reconstitution kinetics (Figure 1). CD4+ T cells declined at 1 month but gradually increased and exceeded pre-transplant levels by 9 months after UCBT. In contrast, at 9 months, CD8+ lymphocytes remained depressed to 50% of pre-transplant levels, but increased thereafter and reached normal values by 2-yr. NK cells and monocytes reached normal values at 3 months post-UCBT. B cells were mostly undetectable for the first 6 months, followed by a 10-fold increase at 9 months and exceeded the upper normal limit by 2-yr. TREC, which were within normal range before transplant, decreased after UCBT but remained detectable between 1-6 months and recovered to normal levels by 9 months. Among cytokines, only IL-8, IL-6 and TNF-α displayed significant changes. IL-8 and IL-6 peaked at day 100 and 9 months, and subsequently declined. In contrast, TNF-α increased by day 100 and remained elevated thereafter. To evaluate functional immunity, we assessed correlations between viral reactivation and reconstitution of immune cell populations and thymic function. Nineteen patients experienced 24 clinically significant viral reactivations or infections, with 1-year cumulative incidence of 62%, which was comparable to 53% observed in dUCBT cohorts receiving ATG-containing conditioning. Although there was no difference in CMV, EBV, adenovirus and VZV reactivation, there was a significant increase in the incidence of HHV-6 reactivation. HHV-6 viremia was observed in 24 of 28 (86%) patients during the first month after dUCBT. Six of these 24 (25%) patients developed HHV-6-related encephalitis. There was a correlation between development of encephalitis and HHV-6 viral load ≥50.000 copies/ml (p=0.007). Pre-transplant TREC levels ≥1.200 copies/ml negatively correlated with subsequent HHV-6 reactivation (p=0.04), indicating that baseline reserve of thymic function has a significant role in post-transplant immune reconstitution. On days 30, 60 and 100 post-transplant, higher TREC levels correlated with lack of HHV-6 viremia (p 〈 0.04). A tendency of higher CD4+ counts in the first 100 days was also observed in patients without HHV-6 reactivation. Neutrophil and platelet engraftment, reconstitution of CD4+ and CD8+ T effectors, NK cells and monocytes, IL-6, IL-8 and TNF-α levels, and development of GVHD did not correlate with HHV-6 reactivation or its absence. Our results indicate that substitution of low dose TBI for ATG in the conditioning regimen is characterized by superior recovery of thymopoiesis and reconstitution of CD4+ T cells, both of which have a protective role against HHV-6 reactivation and end organ disease. Further studies will identify why HHV-6 reactivation is selectively increased in UCBT recipients treated with TBI-containing conditioning. Figure 1 Disclosures Defilipp: Incyte: Research Funding. Politikos:Angiocrine Bioscience Inc: Research Funding. Armand:Otsuka: Research Funding; Roche: Research Funding; Affimed: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Infinity: Consultancy; Sigma Tau: Research Funding; ADC Therapeutics: Consultancy; Tensha: Research Funding; Genentech: Research Funding; Pfizer: Consultancy. Ho:Jazz Pharmaceuticals: Consultancy. Koreth:Amgen: Consultancy; Equillium: Consultancy; Cugene: Consultancy. Avigan:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Juno: Membership on an entity's Board of Directors or advisory committees; Partners Tx: Membership on an entity's Board of Directors or advisory committees; Partner Tx: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy; Parexel: Consultancy; Takeda: Consultancy. Rosenblatt:Celgene: Research Funding; Amgen: Other: Advisory Board; Merck: Other: Advisory Board; BMS: Other: Advisory Board ; Parexel: Consultancy; Imaging Endpoint: Consultancy; Partner Tx: Other: Advisory Board; Dava Oncology: Other: Education; BMS: Research Funding. Chen:Abbvie: Consultancy; Incyte: Consultancy; Magenta: Consultancy; Takeda: Consultancy; Kiadis: Consultancy. Soiffer:Gilead, Mana therapeutic, Cugene, Jazz: Consultancy; Juno, kiadis: Membership on an entity's Board of Directors or advisory committees, Other: DSMB; Mana therapeutic: Consultancy; Kiadis: Other: supervisory board; Jazz: Consultancy; Cugene: Consultancy. Cutler:Kadmon: Consultancy; Incyte: Consultancy; Pharmacyclics: Consultancy; Fate Therapeutics: Consultancy. Ritz:Equillium: Research Funding; Merck: Research Funding; Kite Pharma: Research Funding; Aleta Biotherapeutics: Consultancy; Celgene: Consultancy; Avrobio: Consultancy; LifeVault Bio: Consultancy; Draper Labs: Consultancy; Talaris Therapeutics: Consultancy; TScan Therapeutics: Consultancy.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2019-129154

Language: English

Publisher: American Society of Hematology

Publication Date: 2019

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 136, No. Supplement 1 ( 2020-11-5), p. 22-23

Abstract: Background: While autologous stem cell transplantation (ASCT) can be curative for patients (pts) with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), relapse remains common. With the emergence of novel effective therapies, it is even more important to identify pts at high risk of treatment failure who may not benefit from ASCT, and pts with impending post-ASCT relapse who may be candidates for pre-emptive interventions. We assembled cohorts of DLBCL pts who underwent ASCT and had apheresis stem cell (ASC) samples or serially collected post-ASCT peripheral blood mononuclear cell (PBMC) and plasma samples. We hypothesized that circulating tumor DNA (ctDNA) identified using immunoglobulin-based next generation sequencing (IgNGS) in ASC or PB samples could predict relapse. Methods: Samples from 3 cohorts were analyzed. Pts in cohort 1 (C1) underwent ASCT at Dana-Farber Cancer Institute (DFCI) from 2003-2013 (Herrera, ASH 2015). Archival tumor tissue and ASC samples were retrospectively collected for analysis. Pts in cohort 2 (C2) were prospectively enrolled on a banking protocol at DFCI and underwent ASCT from 2014-2016. Pts in cohort 3 (C3) underwent ASCT from 2015-2016 and participated in a multicenter phase II trial of post-ASCT pembrolizumab maintenance (PM) (Frigault, Blood Adv 2020). Pts in C2/C3 had tumor tissue and serially collected post-ASCT PBMC and plasma samples as mandated by protocol, and a subset had available pre-ASCT PB or ASC samples. Because PM did not demonstrate a clear benefit in the trial, all cohorts were analyzed together. IgNGS (Adaptive Biotechnologies; Seattle, WA) was performed, as previously described (Armand, BJH 2013). In all cases, ctDNA testing was not performed in real-time or used to drive clinical decisions. Results: 152 pts were enrolled. Among 141 pts with sufficient DNA for testing, a clonotype was identified in 112 (78%) with a higher detection rate in more recent cohorts - C2 (93%) and C3 (90%) vs C1 (67%). Among 97 pts with an available ASC sample, 23 (24%) were ctDNA-positive (pos). With a median follow-up among survivors of 69 months (m) (range 13-185), the 5-year (y) progression-free survival (PFS) for ASC ctDNA-pos and ASC ctDNA-negative (neg) pts were 13% (95% CI 3-30%) and 52% (95% CI 40-63%), respectively (HR 2.8, p & lt;0.001), while the 5y cumulative incidences of relapse were 83% (95% CI 66-99%) and 39% (95% CI 27-50%), respectively (HR 3.1, p & lt;0.001). The sensitivity and specificity of ASC ctDNA for progression or death were 36% and 95%, respectively. ASC ctDNA (HR 2.5, p=0.002) was the only significant predictor of PFS in a multivariable model that included pre-ASCT positron emission tomography (PET), lines of therapy, age, and primary refractory status. Inferior overall survival was observed for ASC ctDNA-pos pts (HR 2.1 p=0.037). In an exploratory analysis, we examined 14 pts with an available pre-ASCT plasma sample. 2/14 were ctDNA-pos (14%) and both pts relapsed (HR for PFS 9.4, p=0.03). Among 13 pts with both pre-ASCT PB and ASC samples (drawn a median of 19 days apart [range 11-47]), results were concordant in 12/13 pts (92%). 56 pts had a median of 3 (range 1-8) post-ASCT plasma samples available for analysis. Within this cohort, 25 pts relapsed and 2 pts died in remission. 21 pts (38%) had detectable ctDNA in a median of 2 post-ASCT samples (range 1-5); among them, 18 (86%) relapsed with a median lead time from first ctDNA detection to relapse of 52 days (range 0-518). Among the 3 ctDNA-pos pts who did not relapse, 2 had detectable ctDNA at a single time point and subsequently became ctDNA-neg, and 1 developed acute myeloid leukemia and underwent allogeneic transplantation. Among 20 pts who relapsed and had ≥1 plasma sample available within 100 days of relapse, 18 (90%) had detectable ctDNA. PBMC testing had inferior performance characteristics (Table). Conclusions: Identification of ctDNA using IgNGS within an ASC sample is a powerful predictor of post-ASCT relapse and provides (at least in this cohort) a better way to predict relapse than pre-ASCT PET. Detection of ctDNA in pre-ASCT plasma also appears to be predictive of relapse. In ctDNA-pos pts, given the dismal PFS, strong consideration could be given to alternative treatment strategies, e.g. CAR-T cell therapy. Furthermore, detection of ctDNA in post-ASCT plasma samples is closely associated with impending relapse, which provides an attractive platform for pre-emptive therapeutic intervention. Figure Disclosures Brown: Dynamo Therapeutics: Consultancy; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other; Octapharma: Consultancy; Pfizer: Consultancy; Acerta: Consultancy; Sun: Research Funding; Genentech: Consultancy; Rigel Pharmaceuticals: Consultancy; Eli Lilly and Company: Consultancy; Juno/Celgene: Consultancy; Invectys: Membership on an entity's Board of Directors or advisory committees, Other: DSMC; Gilead: Consultancy, Research Funding; Astra-Zeneca: Consultancy; Janssen: Honoraria; Sunesis: Consultancy; Novartis: Consultancy; Loxo: Consultancy, Research Funding; Nextcea: Consultancy; MEI Pharma: Consultancy; Kite: Consultancy; Pharmacyclics: Consultancy; AbbVie: Consultancy; Catapult: Consultancy; BeiGene: Consultancy; Verastem: Consultancy, Research Funding; TG Therapeutics: Consultancy. Crombie:AbbVie: Research Funding; Bayer: Research Funding. Davids:Gilead Sciences: Consultancy; Zentalis: Consultancy; Sunesis: Consultancy; Syros Pharmaceuticals: Consultancy; Research to Practice: Honoraria; Merck: Consultancy; Bristol Myers Squibb: Research Funding; Janssen: Consultancy; Genentech: Consultancy, Research Funding; Eli Lilly: Consultancy; Celgene: Consultancy; AstraZeneca: Consultancy, Research Funding; BeiGene: Consultancy; Ascentage Pharma: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy; AbbVie: Consultancy; Novartis: Consultancy, Research Funding; Verastem: Consultancy, Research Funding; MEI Pharma: Consultancy, Research Funding; Surface Oncology: Research Funding; Pharmacyclics: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding. Fisher:Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees. Jacobsen:Merck, Pharmacyclics, F. Hoffmann-LaRoche, Novartis: Research Funding; Takeda: Honoraria; Acerta, AstraZeneca, Merck: Consultancy. LaCasce:BMS: Consultancy; Research to Practice: Speakers Bureau; UptoDate: Patents & Royalties. Dahi:Kite: Consultancy. Nieto:Secura Bio: Other: Grant Support; Novartis: Other: Grant Support; Affimed: Consultancy, Other: Grant Support; Astra Zeneca: Other: Grant Support. Chen:Incyte Corporation: Consultancy; Takeda: Consultancy; Magenta: Consultancy; Kiadis: Consultancy; Actinium: Other: Data and Safety Monitoring Board Member; Equillium: Other: Data and Safety Monitoring Board Member; AbbVie: Other: Data and Safety Monitoring Board Member. Herrera:Pharmacyclics: Research Funding; Bristol Myers Squibb: Consultancy, Other: Travel, Accomodations, Expenses, Research Funding; Karyopharm: Consultancy; Merck: Consultancy, Research Funding; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Gilead Sciences: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Immune Design: Research Funding; AstraZeneca: Research Funding. Armand:IGM: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Affimed: Consultancy, Research Funding; ADC Therapeutics: Consultancy; Celgene: Consultancy; Pfizer: Consultancy; Infinity: Consultancy; Otsuka: Research Funding; Genentech: Research Funding; Roche: Research Funding; Tensha: Research Funding; Merck: Consultancy, Honoraria, Research Funding; Adaptive: Consultancy, Research Funding; Sigma Tau: Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2020-140965

Language: English

Publisher: American Society of Hematology

Publication Date: 2020

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 138, No. Supplement 1 ( 2021-11-05), p. 3491-3491

Abstract: Background: Autologous stem cell transplantation (ASCT) can be curative for a subset of patients (pts) with relapsed/refractory classical Hodgkin lymphoma (cHL). Post-ASCT maintenance therapy with brentuximab vedotin (BV) improves progression-free survival (PFS) among pts with high-risk clinical features, and PD-1 blockade is also being investigated in this setting. Ideally, novel biomarkers could be used to guide pt selection for these post-ASCT therapies. We hypothesized that the presence of minimal residual disease (MRD), quantified using immunoglobulin-based next generation sequencing (IgNGS), could predict post-ASCT relapse. As a preliminary test of this hypothesis, we analyzed a cohort of cHL pts who had serial peripheral blood mononuclear cell (PBMC) and plasma samples collected before or after ASCT. Methods: Samples from 2 cohorts (n=36) were analyzed. 28 pts were prospectively enrolled on a biobanking protocol and underwent ASCT at Dana-Farber Cancer Institute between 2014-2016 (biobank cohort). In addition, 8 pts underwent ASCT between 2015 and 2016 and subsequently participated in a multicenter phase II trial of post-ASCT pembrolizumab maintenance (PM) (trial cohort) (Armand, Blood 2020). Tumor tissue and serial post-ASCT plasma and PBMC samples were collected for all pts, and some pts also had pre-ASCT PB samples available for analysis. NGS of Ig receptor sequences (IgNGS) (clonoSEQ Ò, Adaptive Biotechnologies) was used to identify and track tumor clonotypes, as previously described (Ching, BMC Cancer 2020). MRD testing was not used for clinical decision making. Results: The 36 enrolled pts received a median of 2 lines of therapy, and 30 pts (83%) achieved a complete response (CR) on pre-ASCT positron emission tomography (PET). In total, 19 pts received post-ASCT treatment - PM (n=8, all on trial), radiation therapy (n=5), BV maintenance (n=4), and allogeneic stem cell transplantation as part of a planned tandem transplant (n=2). Among 36 enrolled pts, 12 (33%) had an identifiable clonotype (11/28 biobank and 1/8 trial). Higher rates of clonotype detection were seen in pts aged & lt;32 (median) (56% vs 11%, p=0.012) and pts with primary refractory disease (56% vs 16%, p=0.030). With a median follow-up of 50 (range 4-75) months, there were no significant differences in PFS or overall survival among pts with and without a detectable tumor clonotype. The 12 clonotyped pts had a median of 4 (range 1-13) post-ASCT plasma and 3 (range 1-17) post-ASCT PBMC samples. Among the 4 pts who relapsed, 3 had MRD detected within plasma samples with lead times of 0, 11, and 909 days (Figure 1). The pembrolizumab trial pt had detectable MRD early after ASCT which cleared within 9 weeks of starting pembrolizumab therapy, remained undetectable for the duration of pembrolizumab treatment, and became detectable again 5 months after completing PM in conjunction with clinical relapse. All pts with detectable MRD in a post-ASCT plasma sample subsequently relapsed (100% specificity). One pt relapsed without detectable MRD, but had a long interval (312 days) from last plasma sample to relapse. IgNGS testing from PBMC samples did not correlate with clinical outcomes; only two PBMC samples had detectable MRD and both were from a pt who did not relapse. 3 pts had pre-ASCT plasma samples collected concurrently with post-salvage PET scans. One pt achieved a partial response (PR) after 2 cycles of bendamustine and BV (Benda-BV), progressive disease after 4 cycles of Benda-BV, and a CR after pembrolizumab. MRD was detected after two cycles of Benda-BV (6.52 counts per million), was rising after 4 cycles of benda-BV (8.99 counts per million) and was undetectable after pembrolizumab. The pt remains in remission after a tandem transplant. Pre-ASCT samples were MRD negative in two other pts (1 CR, 1 PR) following salvage chemotherapy, both of whom remain in remission after ASCT. Conclusions: The clonotype detection rate among pts with cHL was considerably lower than has been reported for other B-cell lymphomas, likely due to the scarcity of Reed Sternberg cells within cHL tumor samples. Novel MRD techniques for cHL should be investigated. In this pilot study, among pts with a detectable clonotype, MRD was a dynamic marker of response to different therapies and was a specific indicator of impending relapse, suggesting that additional studies of MRD in cHL are warranted. Figure 1 Figure 1. Disclosures Brown: Gilead, Loxo/Lilly, SecuraBio, Sun, TG Therapeutics: Research Funding; Invectys: Other: Data Safety Monitoring Committee Service; Abbvie, Acerta/Astra-Zeneca, Beigene, Bristol-Myers Squibb/Juno/Celgene, Catapult, Eli Lilly, Genentech/Roche, Janssen, MEI Pharma, Morphosys AG, Nextcea, Novartis, Pfizer, Rigel: Consultancy. Crombie: Roche: Research Funding; Incyte: Consultancy; Karyopharm: Consultancy; Merck: Research Funding; Abbvie: Research Funding; Bayer: Research Funding. Davids: TG Therapeutics: Consultancy, Research Funding; Verastem: Consultancy, Research Funding; Takeda: Consultancy; Surface Oncology: Research Funding; AbbVie: Consultancy; Genentech: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Astra-Zeneca: Consultancy, Research Funding; MEI Pharma: Consultancy, Research Funding; Ascentage Pharma: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy; BeiGene: Consultancy; Celgene: Consultancy; Eli Lilly and Company: Consultancy; Janssen: Consultancy; MEI Pharma: Consultancy; Merck: Consultancy; Research to Practice: Consultancy. Jacobsen: Takeda: Consultancy; Syros: Consultancy; Janssen: Research Funding; Novartis: Research Funding; Pharmacyclics: Research Funding; Acerta: Research Funding. Jacobson: Lonza: Consultancy, Honoraria, Other: Travel support; Precision Biosciences: Consultancy, Honoraria, Other: Travel support; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel support; Axis: Speakers Bureau; Clinical Care Options: Speakers Bureau; Nkarta: Consultancy, Honoraria; Novartis Pharmaceuticals Corporation: Consultancy, Honoraria, Other: Travel support; Pfizer: Consultancy, Honoraria, Other: Travel support, Research Funding; Humanigen: Consultancy, Honoraria, Other: Travel support; AbbVie: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Other: Travel support. LaCasce: Bristol-Myers Squibb Company.: Other: Data Safetly and Monitoring. Dahi: Kite / Gilead: Membership on an entity's Board of Directors or advisory committees. Chen: Gamida: Consultancy; Incyte: Consultancy. Herrera: ADC Therapeutics: Consultancy, Research Funding; Merck: Consultancy, Research Funding; Tubulis: Consultancy; Kite, a Gilead Company: Research Funding; Seagen: Consultancy, Research Funding; Takeda: Consultancy; Gilead Sciences: Research Funding; AstraZeneca: Consultancy, Research Funding; Karyopharm: Consultancy; Genentech: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding. Armand: IGM: Research Funding; Tensha: Research Funding; Roche: Research Funding; Genentech: Consultancy, Research Funding; AstraZeneca: Consultancy; Regeneron: Consultancy; Epizyme: Consultancy; Enterome: Consultancy; Daiichi Sankyo: Consultancy; Miltenyi: Consultancy; Tessa Therapeutics: Consultancy; GenMab: Consultancy; C4: Consultancy; Kite: Research Funding; Pfizer: Consultancy; Infinity: Consultancy; Otsuka: Research Funding; Sigma Tau: Research Funding; Morphosys: Consultancy; Celgene: Consultancy; ADC Therapeutics: Consultancy; Adaptive: Consultancy, Research Funding; Affimed: Consultancy, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2021-147263

Language: English

Publisher: American Society of Hematology

Publication Date: 2021

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 41-41

Abstract: Chronic graft-versus-host disease (cGVHD) after allogeneic hematopoietic cell transplantation (HCT) results from incomplete reconstitution of immune tolerance. CD4+CD25+FOXP3+ regulatory T cells (Treg) are required for tolerance and function as dominant suppressors of innate and adaptive immune effector cells. In our prior phase 1 cGVHD study daily subcutaneous (SC) low-dose interleukin-2 (IL-2) for 8 weeks induced Treg expansion in vivo and objective clinical responses in 12 of 23 evaluable participants (NEJM 2011). We now report on a phase 2 trial of daily low-dose SC IL-2 at 1x106 IU/m2/d for 12 weeks in steroid-refractory cGVHD. The study comprised 35 HCT recipients (51% male, 91% HLA-matched PBSC grafts). Median participant age was 51 years (range, 22-72). Median time from HCT and from cGVHD onset to start of IL-2 treatment was 616 days (range, 270-2145) and 252 days (range, 28-1880) respectively. Participants had a median of 4 cGVHD organ sites (range, 1-7), and 2 concurrent cGVHD therapies (range, 1-3) at enrollment. The median baseline prednisone dose was 20 mg (range, 2.5-50). The median follow-up in survivors was 21 months (range, 4-35). 12 week low dose IL-2 was well tolerated: 2 participants withdrew and 5 required IL-2 dose reduction for constitutional AE (n=6) and thrombocytopenia (n=1); 1 had Gr 3 infection (bacteremia); and none experienced relapse. At week 12, objective cGVHD responses (PR) were documented in 21 of 33 evaluable participants (64%). Two (6%) had cGVHD progression. cGVHD response sites included skin (n=9), joint/fascia/muscle (n=4), liver (n=7), lung (n=3), and GI tract (n=4). Overall 2-year OS/PFS was 91% (responders 94%; non-responders 83%). 23 participants with clinical benefit (PR or SD with minor response) proceeded on extended IL-2 therapy. Immunologically, low dose IL-2 induced a 〉 4-fold increase in median Treg count/µL (p 〈 0.001): a rapid rise from a baseline of 17.1 (Q1-Q3, 8.6-40.6) to a week 4 peak of 137.9 (Q1-Q3, 51.8-188) and subsequent stabilization with a week 12 count of 104.1 (Q1-Q3, 53.9-167.1). No significant change in CD4 conventional T cell (Tcon), CD8 T cell, or CD20 B cell count was noted. NK cell count increased 〉 3-fold (p 〈 0.001). The median Treg:Tcon ratio increased 〉 4-fold (p 〈 0.001): a rapid rise from baseline of 0.06 (Q1-Q3, 0.05-0.13) to a week 2 peak of 0.35 (Q1-Q3, 0.26-0.48) that remained elevated through a week 12 ratio of 0.31 (Q1-Q3, 0.27-0.39) (Figure). Treg count and Treg:Tcon ratio declined during 4 weeks off IL-2 and rose thereafter on restarting IL-2. Clinical responders were younger (50 vs. 61.5 years, p=0.01) and initiated IL-2 earlier (499 vs. 903 days post HCT, p=0.015). Responders had a higher median Treg:Tcon ratio at study baseline (0.09 vs. 0.06, p=0.052) and at week 1 of IL-2 (0.3 vs. 0.14, p=0.01). Combining phase 1 and 2 data, Treg:Tcon ratios of ≥0.07 at baseline and ≥0.2 at week 1 of IL-2 were highly predictive of clinical response (p=0.007; p=0.0013 respectively). The combined phase 1 and 2 extended IL-2 cohort comprised 35 participants with a median follow up of 16.2 months (range, 4.1-66.8), with 20 and 12 participants receiving over 1 and 2 years of IL-2 respectively. Extended daily low dose IL-2 was well tolerated, and only 4 participants had Gr 3 AEs deemed IL-2 related: lung infection (n=1), arthralgia (n=1), and injection site induration (n=2). 5 participants required IL-2 dose reduction and 1 had hematologic malignancy relapse. Clinical responses were typically sustained during taper of concomitant immunosuppression. Treg augmentation persisted for the duration of IL-2 therapy. Tcon count slowly recovered to normal levels and Treg:Tcon ratio gradually normalized over a 2 year period. There was no change in CD8 count. The median steroid taper was 50% (range, -20-100). In summary, daily low dose IL-2 therapy induced profound Treg enhancement, and clinical responses in over half of refractory cGVHD patients. Early clinical response predictors suggest IL-2 is more effective earlier in the cGVHD course and when starting numbers of Treg are higher. Sustained clinical and immunologic response during extended IL-2 was documented. Long term tolerance induction with daily low dose IL-2 is a promising and feasible strategy. Optimizing IL-2 clinical response by further augmenting Treg and the Treg;Tcon ratio early in the course of cGVHD is worth exploring. Figure 1 Figure 1. Disclosures Koreth: Prometheus Laboratories Inc: Research Funding; Millennium Pharmaceuticals Inc: Research Funding; Takeda Pharmaceuticals Inc: Membership on an entity's Board of Directors or advisory committees. Off Label Use: Low-dose Interleukin-2 for immune tolerance. Chen:Bayer Pharmaceuticals, Inc.: Other, Research Funding. Avigan:Astex Pharmaceuticals : Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V124.21.41.41

Language: English

Publisher: American Society of Hematology

Publication Date: 2014

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 116, No. 21 ( 2010-11-19), p. 903-903

Abstract: Abstract 903 Background: High-dose chemotherapy (HDC) with autologous stem cell transplant (ASCT) is a standard component of therapy for some patients with hematologic malignancies, particularly those with relapsed or refractory lymphoma. No high-dose chemotherapy regimen has been shown to be superior to another, and thus regimens are chosen based on institutional standards and toxicity profiles. Pneumonitis is a recognized complication of HDC regimens containing BCNU. There has not been a large study of uniformly-treated lymphoma patients to define the incidence and risk factors for developing pneumonitis in the modern era. Methods: We retrospectively examined the medical records of patients who were treated with HDC-ASCT at the Dana-Farber Cancer Institute and Massachusetts General Hospital Cancer Center from 2007–2009 using a regimen containing cyclophosphamide 750 mg/m2 Q12h x4d, BCNU 112.5 mg/m2 daily x4d, and VP-16 (etoposide) 200 mg/m2 Q12h x4d (CBV). Overall (OS) and progression-free survival (PFS), and the incidence of pneumonitis were determined. Univariable and multivariable analyses were performed for characteristics likely to be associated with an increased risk of pneumonitis, which was defined based on a combination of clinical, laboratory, and radiographic factors, with or without bronchoscopy. Results: 222 patients were analyzed. The age range was 21–77 (median 54). 61% were male. 71% had non-Hodgkin lymphoma and 29% had Hodgkin lymphoma. The median number of prior chemotherapy regimens was 2; 65% of patients had received prior rituximab, 31% prior bleomycin, and 12% prior gemcitabine. 71% had disease involvement of the mediastinum, and 11% had received prior mediastinal radiation therapy. 43% were past or present smokers. The median follow-up among all living patients was 12 months. The total cumulative incidence of pneumonitis was 22% (49 patients), with 41 patients (19%) receiving corticosteroid treatment, and 18 patients (8%) requiring inpatient hospitalization for pneumonitis. The time range to development of pneumonitis was 26–199 days post-transplant, with a median of 50 days. There were four treatment-related deaths (1.8%): three related to pneumonitis and one related to veno-occlusive disease. On univariable analysis, age, diagnosis of Hodgkin lymphoma, prior mediastinal radiation, prior bleomycin, total BCNU dose delivered, and lack of complete remission status at the time of ASCT were associated with the development of pneumonitis. Gender, body mass index, history of smoking, mediastinal disease involvement, prior rituximab, prior gemcitabine, and pretransplant pulmonary function testing were not found to be statistically significantly different between patients with and without pneumonitis. Stepwise multivariable logistic regression analysis, excluding 31 patients without pneumonitis who had death, relapse, or censoring in the first four months post-transplant, revealed the following variables as independently associated with development of pneumonitis: prior mediastinal radiation (odds ratio 6.5, 95% CI 2.2–18.9, P=0.0005), total BCNU dose above 1000 mg (OR 3.4, 95% CI 1.3–8.7, P=0.012), and age less than 54 (OR 3.0, 95% CI 1.4–6.5, P=0.0037). One year overall survival was 92%, and progression-free survival was 71%. There were no variables, including pneumonitis, associated with PFS on multivariable analysis. Only lack of complete or partial disease response prior to ASCT was associated with inferior OS on multivariable Cox regression modeling (hazard ratio 0.2, 95% CI 0.05–0.72, P=0.01). Conclusions: Pneumonitis is relatively common after HDC-ASCT using CBV conditioning. Increased vigilance for symptoms of pneumonitis is warranted for patients with prior mediastinal radiation and for younger patients. Our data suggests an increased risk with total BCNU dose above 1000 mg, suggesting a possible threshold toxicity effect. Empiric dose reduction may be considered for patients who would receive greater than 1000 mg of BCNU, particularly if they are also younger and/or have had prior mediastinal radiation. Disclosures: No relevant conflicts of interest to declare.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V116.21.903.903

Language: English

Publisher: American Society of Hematology

Publication Date: 2010

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 830-830

Abstract: Background: Double-hit lymphomas (DHL) - diffuse large B-cell lymphomas (DLBCL) with concurrent rearrangements of MYC and BCL2 and/or BCL6, and double-expressor lymphomas (DEL) - DLBCL with co-expression of MYC and BCL2 by immunohistochemistry (IHC), are associated with poor outcomes after standard chemoimmunotherapy. We have previously demonstrated that patients with relapsed or refractory (rel/ref) DHL and DEL have inferior outcomes after autologous stem cell transplantation (autoSCT) compared to patients with neither DEL nor DHL [Herrera et al, ASH 2015]. Although patients with DEL and DHL have inferior outcomes after chemotherapy-based treatment modalities, we hypothesized that allogeneic SCT (alloSCT) could potentially abrogate that negative prognostic impact. Data are extremely limited regarding the outcome of patients with DHL who undergo alloSCT, and no study has examined alloSCT outcomes in patients with DEL. We studied alloSCT outcomes in a multicenter cohort of rel/ref DLBCL patients and evaluated the prognostic impact of DEL and DHL status. Methods: We retrospectively studied patients with rel/ref DLBCL, transformed indolent lymphoma (TIL), or high-grade B-cell lymphoma unclassified (BCLU) who had available tumor tissue and underwent alloSCT at Dana-Farber Cancer Institute, Massachusetts General Hospital, or City of Hope between 1/2000 and 5/2014. IHC for MYC, BCL2, and BCL6 were performed. DEL was defined as MYC expression in ≥ 40% tumor cells and BCL2 expression in ≥ 50% tumor cells. FISH for MYC was performed using dual-color break-apart probes. Cases with MYC-rearrangement had FISH performed for BCL2 and BCL6 using break-apart probes. Rearrangement was defined as ≥ 10% nuclei with break-apart signals. DHL was defined as concurrent rearrangement of MYC and BCL2 and/or BCL6. Results: Tumor tissue was available in 103 patients, among whom we could obtain complete IHC and FISH data in 74. In these 74 patients, the median age was 54 years (range 24-69); 69% had DLBCL/BCLU whereas 31% had TIL; the median number of prior therapies was 4 (range 2-9); 58% had prior autoSCT; 73% were in complete or partial remission (CR/PR) at alloSCT; 77% had reduced intensity conditioning (RIC); 78% had a matched related or unrelated donor. 4y progression-free survival (PFS), overall survival (OS), cumulative incidence of relapse (CIR), and non-relapse mortality (NRM) in the overall cohort were 34%, 40%, 44% and 22%, respectively, with a median follow-up of 46 months for survivors. 47% of patients had DEL and 14% had DHL. The proportion of patients with a history of primary refractory disease was higher among DHL (60%) and DEL (52%) patients compared to nonDHL/nonDEL patients (37%), although the difference was not significant (p=0.3). Overall, there were no significant differences in clinical characteristics between patients with DHL, DEL, and nonDHL/nonDEL. Neither DEL nor DHL were significantly associated with outcome (Figure). The 4y PFS in DEL v non-DEL patients was 29% v 39% (p=0.2), 4y OS 30% v 49% (p=0.11), 4y CIR 50% v 40% (p=0.3), and 4y NRM 21% v 22% (p=1.0). The 4y PFS in DHL v non-DHL patients was 40% v 33% (p=0.6), OS 50% v 37% (p=0.4), CIR 40% v 45% (p=0.9), and NRM 20% v 22% (p=0.8). In multivariable Cox models for PFS and OS, age ≥ 55 (PFS: HR 0.4, p=0.002; OS: HR 0.4, p=0.005), refractory disease (not CR/PR) at alloSCT (PFS: HR 2.4, p=0.009; OS HR 2.6, p=0.007), and TIL (PFS HR 0.4, p=0.018; OS HR 0.4, p=0.028) were associated with PFS and OS, but DEL (PFS HR 1.2, p=0.5; OS HR 1.6, p=0.12) and DHL (PFS HR 0.8, p=0.7; OS HR 0.8, p=0.7) were not. We also constructed multivariable competing risk regression models for CIR and NRM. Age, remission status, histology, and conditioning intensity were associated with relapse, while no factor was significantly associated with NRM. Neither DEL (CIR HR 1.2, p=0.7, NRM HR 0.8, p=0.7) nor DHL (CIR HR 1.1, p=0.9, NRM HR 0.8, p=0.8) were associated with either outcome in those models. Conclusions: AlloSCT produced durable remissions in heavily treated rel/ref DLBCL patients, regardless of DEL and DHL status. In our cohort, DEL and DHL status did not have a significant prognostic impact. Although patients with DEL or DHL have poorer outcomes after chemoimmunotherapy and autoSCT, our results suggest that alloSCT may overcome the chemoresistance of double-hit/double-expressor tumors. Figure Progression-Free Survival After AlloSCT in DEL, DHL, and nonDEL/nonDHL Patients Figure. Progression-Free Survival After AlloSCT in DEL, DHL, and nonDEL/nonDHL Patients Disclosures Herrera: Adaptive Biotechnologies: Research Funding; Genentech: Research Funding; Immune Design: Research Funding; Merck: Research Funding; Pharmacyclics: Research Funding; Seattle Genetics: Research Funding. Song:Seattle Genetics: Consultancy. Chen:Genentech: Consultancy, Speakers Bureau; Millenium: Consultancy, Research Funding, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Research Funding, Speakers Bureau; Merck: Consultancy, Research Funding. Chen:Incyte Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding. Koreth:LLS: Research Funding; amgen inc: Consultancy; takeda pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; kadmon corp: Membership on an entity's Board of Directors or advisory committees; prometheus labs inc: Research Funding; millennium pharmaceuticals: Research Funding. Pillai:Trillium Therapeutics: Research Funding. Siddiqi:Janssen Biotech: Research Funding, Speakers Bureau; Seattle Genetics: Speakers Bureau; Juno Therapeutics: Research Funding; Kite Pharma: Research Funding; Acerta Pharma: Research Funding; MedImmune: Research Funding; Genentech: Research Funding; TG Therapeutics: Research Funding. Zain:Seattle Genetics: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau. Kwak:XEME BioPharma: Consultancy, Equity Ownership; Antigenics: Equity Ownership; Celltrion: Consultancy; Sella Life Sciences: Consultancy. Nademanee:Celgene: Consultancy; Seattle Genetics: Consultancy, Research Funding. Weinstock:Novartis: Consultancy, Research Funding. Soiffer:Kiadis: Membership on an entity's Board of Directors or advisory committees; Juno: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Rodig:Bristol-Myers Squibb: Honoraria, Research Funding; Perkin Elmer: Membership on an entity's Board of Directors or advisory committees. Armand:Roche: Research Funding; Pfizer: Research Funding; Sequenta Inc: Research Funding; Merck: Consultancy, Research Funding; Infinity Pharmaceuticals: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V128.22.830.830

Language: English

Publisher: American Society of Hematology

Publication Date: 2016

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Biology of Blood and Marrow Transplantation, Elsevier BV, Vol. 23, No. 3 ( 2017-03), p. S82-S83

Type of Medium: Online Resource

ISSN: 1083-8791

URL: Article

DOI: 10.1016/j.bbmt.2016.12.039

Language: English

Publisher: Elsevier BV

Publication Date: 2017

detail.hit.zdb_id: 3056525-X

detail.hit.zdb_id: 2057605-5

In: Biology of Blood and Marrow Transplantation, Elsevier BV, Vol. 21, No. 9 ( 2015-09), p. 1583-1588

Type of Medium: Online Resource

ISSN: 1083-8791

URL: Article

DOI: 10.1016/j.bbmt.2015.05.016

Language: English

Publisher: Elsevier BV

Publication Date: 2015

detail.hit.zdb_id: 3056525-X

detail.hit.zdb_id: 2057605-5