Kooperativer Bibliotheksverbund

In: Blood, American Society of Hematology, Vol. 121, No. 3 ( 2013-01-17), p. 440-446

Abstract: Patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN) have a poor prognosis with conventional chemotherapy. In the present study, we retrospectively analyzed the outcome of patients with BPDCN who underwent allogeneic stem cell transplantation (allo-SCT) or autologous stem cell transplantation (auto-SCT). A total of 39 patients (allo-SCT, n = 34; auto-SCT, n = 5) were identified in the European Group for Blood and Marrow Transplantation registry. The 34 allo-SCT patients had a median age of 41 years (range, 10-70) and received transplantations from sibling (n = 11) or unrelated donors (n = 23) between 2003 and 2009. MAC was used in 74% of patients. Nineteen allo-SCT patients (56%) received transplantations in first complete remission. The 3-year cumulative incidence of relapse, disease-free survival, and overall survival was 32%, 33%, and 41%, respectively. By univariate comparison, being in first remission at allo-SCT favorably influenced survival, whereas age, donor source, and chronic GVHD had no significant impact. We conclude that high-dose therapy followed by allo-SCT from related or unrelated donors can provide durable remission even in elderly patients with BPDCN. However, it remains to be shown if graft-versus-malignancy effects can contribute significantly to BPDCN control after allo-SCT.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2012-08-448613

Language: English

Publisher: American Society of Hematology

Publication Date: 2013

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detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 112, No. 11 ( 2008-11-16), p. 565-565

Abstract: In order to refine the indications for NST in CLL, we analyzed prognostic factors for various endpoints of the CLL3X trial. CLL3X was a phase-2 trial investigating in a multicenter setting feasibility, toxicity and efficacy of NST in patients with poor-risk CLL. Patients & lt;65 years were eligible if they had progressive disease in the presence of an unfavorable VH status, were fludarabine refractory, or had failed autoSCT. Central genetic work-up including FISH karyotyping was mandatory. Conditioning was based on fludarabine and cyclophosphamide. Centers could opt for routine addition of in-vivo T-cell depletion with alemtuzumab (TCD). Donors were HLA-matched (6/6) siblings or unrelated volunteers. Prospective longitudinal monitoring of minimal residual disease (MRD) was done centrally by MRD-flow or RQ-PCR. MRD results were communicated to the investigators for preemptive immunomodulation (restriction of immunosuppression or donor lymphocyte infusions). Results: Between June 2001 and March 2007, 113 patients were accrued in 16 centers. Thirteen patients had to be excluded due to ineligibility, and 10 patients did not proceed to NST because they lacked a donor, died or developed Richter’s transformation prior to NST, or refused NST. The 90 patients remaining had received 4 (1–11) pre-transplant regimens. 39/71 (55%) had an unfavorable FISH karyotype (del 11q- (37%) or del 17p- (18%)). 42/90 (47%) were fludarabine refractory, but only 24% had uncontrolled disease at NST. Allografts were obtained from related (39%) or unrelated donors (61%). TCD was performed in 12 patients. Due to logistical reasons, continuous sampling for prospective MRD monitoring was possible in only 4 centers representing 58% of the patients. With a median follow-up of 28 (6–80) months, 3-year non-relapse mortality, relapse incidence (REL), event-free survival (EFS) and overall survival (OS) from NST was 23% (95%CI 12%–34%), 42% (29%–56%), 42% (30%–54%), and 66% (55%–78%), respectively. Univariate log rank comparisons identified refractory disease at NST and TCD; but not age, fludarabine resistance, donor, and del 17p- as adverse factors for EFS. Three-year EFS was 43% (95%CI 14%–71%) with del 17p- vs 41% (27%–55%) without del 17p-. Cox regression models (adjusting for age, del 17p-, fludarabine resistance, remission status at NST, TCD, and donor) confirmed younger age (hazard ratio (HR)/year 0.94 (95%CI 0.89–0.99) and TCD (HR 3.68 (1.36–9.92)) as significant prognostic variables for REL; refractory disease at NST (HR 4.08 (1.9–8.74)) and TCD (HR 3.26 (1.53–6.94)) for EFS; and refractory disease at NST (HR 3.87 (1.62–9.25)) for OS. Three-year EFS was 57% (43%–72%) in patients who had sensitive disease at NST and no TCD employed, with no relapse occurring after the 3-year landmark. Only one relapse was observed in 25 patients (5 with del 17p-) who were MRD negative at month +12; and 15 out of 16 patients event-free more than 3 years after NST with MRD values available were MRD negative at last assessment. Conclusions: T-replete NST from related or unrelated donors results in sustained MRD-negative EFS in a significant proportion of patients with poor-risk CLL including those with del 17p-. NST should be performed before disease has become refractory. The potential benefit of preemptive post-transplant immunomodulation guided by real-time MRD monitoring remains to be settled.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V112.11.565.565

Language: English

Publisher: American Society of Hematology

Publication Date: 2008

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detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 3159-3159

Abstract: INTRODUCTION: T-prolymphocytic leukemia (T-PLL) is a rare T cell malignancy with an aggressive clinical course. Preliminary clinical data suggest that allogeneic stem cell transplantation (alloSCT) may provide long-term disease control in a proportion of patients. However, direct evidence that graft-versus-leukemia (GVL) activity is indeed effective in T-PLL is lacking. We sought to investigate GVL in T-PLL by correlating minimal residual disease (MRD) kinetics with immune modulatory interventions (immunosuppression tapering, donor lymphocyte infusions (DLI), chronic graft-versus-host disease (cGvHD)), and T cell receptor (TCR) repertoire diversity alterations after alloSCT. METHODS: The study sample consisted of 10 consecutive patients who received alloSCT for T-PLL at the University of Heidelberg between 2007 and 2015. Quantitative MRD monitoring was performed using clone-specific real-time quantitative PCR (RQ-PCR) of clonal TCR beta (TRB) and/or gamma (TRG) gene rearrangements. Data interpretation followed EuroMRD guidelines. In selected patients, TCR repertoire diversity was analyzed longitudinally by next-generation sequencing (NGS). TRBV-TRBD-TRBJ gene rearrangements were amplified according to BIOMED2 protocol on genomic DNA. PCR products were sequenced on Illumina's MiSeq platform. NGS data were analyzed through a purpose-built bioinformatics immunoprofiler (EuroClonality-NGS consortium). Rearrangements with very similar junctional amino acid sequences and identical TRBV and TRBJ gene usage were defined as clonotypes. RESULTS: Patients underwent alloSCT in remission after first-line (8) or salvage (2) alemtuzumab-based therapy. 5 patients were allografted with an unrelated donor, 4 with a related donor, and one received haploidentical alloSCT. Conditioning was fludarabine with cyclophosphamide and/or total body irradiation-based. All patients had a cytological complete response (CR) after alloSCT. 2 patients died early because of acute GvHD, and one had no MRD marker, leaving 7 patients for MRD monitoring. Of these, 3 were MRD- at alloSCT, whereas 5 patients remained or became MRD+ early after alloSCT. In all of these 5 patients, immunosuppression tapering (3) or DLI (2) resulted in significant reduction of MRD levels (range 1-3 log) and was accompanied by cGvHD in 3 patients. However, durable MRD- was obtained in only 2 patients (alive 81+ and 12+ months post transplant), whilst MRD re-increased in 3 patients after 5-28 months despite ongoing cGvHD in one of them. NGS of the TCR repertoire was performed longitudinally in 3 patients with the longest follow-up. A total of 104 samples (blood (n=91) and BM (n=10) plus 3 donor blood samples) were sequenced. The sample at diagnosis showed one or two major clonotypes in all 3 sequenced T-PLLs, predominantly reflecting a mono- or biallelic leukemic TRB gene rearrangement. Kinetics of this leukemic clonotype followed kinetics of RQ-PCR MRD measurement, demonstrating that NGS can be used to quantify MRD in T cell lymphoma. Immediately after transplantation, the TRB repertoire was heavily skewed in all 3 patients, but recovered over time. Also in all 3 patients, MRD responses were reproducibly associated with a shift from a clonal, T-PLL-driven profile to a polyclonal signature. This corresponded to the donor clonotype repertoire and disappeared with increasing MRD levels. In each of the samples after alloSCT, several expanded non-leukemic clonotypes were observed at a maximum frequency from 3% to 54% of total TRB sequences. However, during MRD response, novel dominant clonotypes that could explain a clonal GVL effect did not emerge. Figure 1 shows an example of a patient repeatedly showing MRD response to immune interventions. Currently, 5 patients are alive and in cytological CR (4-81 months after alloSCT), translating into a median relapse-free survival of 40 months. CONCLUSIONS: The MRD responses to immune interventions observed here provide the first direct evidence for the efficacy of GVL in T-PLL. However, the GVL effect in T-PLL appears to be often only limited or transient. It also does not seem to be caused by the emergence of novel dominant T cell clones but is rather relying on a poly-/oligoclonal T cell response. Figure 1. Example for MRD kinetics in relation to immune interventions. Figure 1. Example for MRD kinetics in relation to immune interventions. Disclosures No relevant conflicts of interest to declare.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V126.23.3159.3159

Language: English

Publisher: American Society of Hematology

Publication Date: 2015

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detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 116, No. 14 ( 2010-10-07), p. 2438-2447

Abstract: The purpose of this prospective multicenter phase 2 trial was to investigate the long-term outcome of reduced-intensity conditioning allogeneic stem cell transplantation (alloSCT) in patients with poor-risk chronic lymphocytic leukemia. Conditioning was fludarabine/ cyclophosphamide-based. Longitudinal quantitative monitoring of minimal residual disease (MRD) was performed centrally by MRD-flow or real-time quantitative polymerase chain reaction. One hundred eligible patients were enrolled, and 90 patients proceeded to alloSCT. With a median follow-up of 46 months (7-102 months), 4-year nonrelapse mortality, event-free survival (EFS) and overall survival (OS) were 23%, 42%, and 65%, respectively. Of 52 patients with MRD monitoring available, 27 (52%) were alive and MRD negative at 12 months after transplant. Four-year EFS of this subset was 89% with all event-free patients except for 2 being MRD negative at the most recent assessment. EFS was similar for all genetic subsets, including 17p deletion (17p−). In multivariate analyses, uncontrolled disease at alloSCT and in vivo T-cell depletion with alemtuzumab, but not 17p−, previous purine analogue refractoriness, or donor source (human leukocyte antigen-identical siblings or unrelated donors) had an adverse impact on EFS and OS. In conclusion, alloSCT for poor-risk chronic lymphocytic leukemia can result in long-term MRD-negative survival in up to one-half of the patients independent of the underlying genomic risk profile. This trial is registered at http://clinicaltrials.gov as NCT00281983.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2010-03-275420

Language: English

Publisher: American Society of Hematology

Publication Date: 2010

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detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 3077-3077

Abstract: Abstract 3077 Blastic plasmacytoid dendritic cell neoplasm (BPDC), formerly known as blastic NK cell lymphoma, is a rare hematopoietic malignancy preferentially involving the skin, bone marrow and lymph nodes. The overall prognosis of BPDC is dismal. Most patients show an initial response to acute leukemia-like chemotherapy, but relapses with subsequent drug resistance occur in virtually all patients resulting in a median overall survival of only 9–13 months. However, anecdotal long-term remissions have been reported in young patients who received early myeloablative allogeneic stem cell transplantation (alloSCT). We therefore performed a retrospective analysis of patients identified in the EBMT registry in order to evaluate the outcome of autologous stem cell transplantation (autoSCT) or alloSCT for BPDC. Eligible were all patients who had been registered with a diagnosis of BPDC or Blastic NK cell lymphoma and had received autologous stem cell transplantation (autoSCT) or alloSCT in 2000–2009. Centres were contacted to provide a written histopathology and immunophenotyping report and information about treatment and follow-up details. Patients who did not have a diagnostic score ≥ 2 as proposed by Garnache-Ottou et al. (BJH 2009) were excluded. RESULTS: Overall, 139 patients could be identified in the database who fulfilled the inclusion criteria (alloSCT 100, autoSCT 39). Of 74 patients for whom the requested additional information could be obtained, central review confirmed the diagnosis of BPDC in 39 patients (34 alloSCT, 5 autoSCT). The 34 patients who had undergone alloSCT had a median age of 41 years (range: 10–70 years), were transplanted from a related (n=11) or unrelated donor (n=23); received peripheral blood stem cells (n=9), bone marrow stem cells (n=19) or cord blood (n=6); and had been treated with a reduced intensity conditioning regimen (RIC, n=9) or myeloablative conditioning (MAC, n=25). Nineteen of 34 patients were transplanted in CR1. After a median follow up time of 28 months (range: 4–77+ months), 11 patients relapsed (median time to relapse: 8 months, range: 2–27 months) of whom 8 died due to disease progression. 9 patients died in the absence of relapse. No relapse occurred later than 27 months after transplant. Median disease free survival (DFS) was 15 months (range: 4–77+ months) and median overall survival (OS) was 22 months (range: 8–77+ months; Figure 1a). However, long-term remissions of up to 77 months after alloSCT could be observed. Patients allografted in CR1 tended to have a superior DFS (p=0.119) and OS (p=0.057; Figure 1b). MAC was associated with a better OS (p=0.001) which was attributable to the significantly higher non-relapse mortality (NRM) rate of patients after RIC (p=0.014), who had been significantly older (age RIC: 56 years, age MAC: 36 years, p=0.0014). The relapse rate was not different in patients after RIC and MAC, respectively. However, there was no survivor after RIC. Median age in the autoSCT group was 47 years (range: 14–62 years). Three of 5 patients were transplanted in CR1 of whom 1 patient relapsed after 8 months, 1 patient experienced treatment related mortality and 1 patient remained in CR for 28 months. The 2 remaining patients had more advanced disease at autoSCT and relapsed 4 and 8 months thereafter. CONCLUSION: AlloSCT is effective in BPDC and might provide curative potential in this otherwise incurable disease, especially when performed in CR1. However, it remains to be shown by prospective studies if the potential benefit of alloSCT in BPDC is largely due to conditioning intensity, or if there is a relevant contribution of graft-versus-leukemia activity. Disclosures: Tilly: Seattle Genetics, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau, Travel/accommodations/meeting expenses; Genentech: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Research Funding, Speakers Bureau; Pfizer: Speakers Bureau; Janssen Cilag: Speakers Bureau.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V118.21.3077.3077

Language: English

Publisher: American Society of Hematology

Publication Date: 2011

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In: Blood, American Society of Hematology, Vol. 116, No. 21 ( 2010-11-19), p. 2357-2357

Abstract: Abstract 2357 There is ample evidence that poor-risk CLL, as defined by fludarabine refractoriness or the presence of deletion 17p-, can be successfully treated by allogeneic stem cell transplantation (alloSCT). It is unknown, however, whether alloSCT can also overcome the treatment resistance associated with TP53 mutations seen under conventional fludarabine combination therapy. Therefore we have assessed the impact of TP53 mutations on the outcome of alloSCT with the patient cohort enrolled on the CLL3X trial of the German CLL Study Group. Patients and Methods: The CLL3X trial included 90 patients with poor-risk CLL who were allografted with unmanipulated blood stem cells from related or unrelated donors after nonmyeloablative conditioning. With a median follow-up of 46 months, 4-year event-free (EFS) and overall survival (OS) was 42% and 65%, respectively (Blood July 1, 2010). PFS and OS of 13 patients with deletion 17p- were similar to that of patients without this abnormality. TP53 mutations were identified by denaturating high-performance liquid chromatography (DHLPC) (exons 4–10). In addition, cases with deletion 17p- where no TP53 mutation was detected were also directly sequenced. Results: The TP53 mutational status could be obtained in 72 of 90 patients who had informative DNA samples from the time of study entry available. Of these, 19 (26%) showed TP53 mutations; 7 (10%) with a concurrent deletion 17p-, and 9 (12%) in the absence of deletion 17p-. 17p- status was not available in three TP53-mutated patients (4%). Three additional patients (4%) had 17p- without TP53 mutation. Four-year EFS and OS was 46% and 56% with TP53 mutation vs 38% and 66% without TP53 mutation (Figure). Within the TP53-mutated group, 4-year EFS and OS was 44% and 56% for patients without deletion 17p- vs 38% and 50% for patients with concurrent deletion 17p-. None of these differences were statistically significant. Among the patients who were event-free 12 months post alloSCT and had results of minimal residual disease (MRD) assessment available, the probability of being MRD-negative at this landmark was 71% with TP53 mutations and 63% without (p = 1.0). Finally, multivariate analysis using Cox regression modeling (adjusting for age, deletion 17p-, remission status at alloSCT, and T cell depletion) did not show a significant impact of TP53 mutations on EFS (Hazard ratio (HR) 0.71; 95%CI 0.31–1.61) and OS (HR 1.13; 95%CI 0.41–3.12). Conclusions: AlloSCT can provide long-term EFS in about 40% of patients with poor-risk CLL with TP53 mutation independent from the presence of concurrent deletion 17p-. Disease control appears to be similar in patients with and without TP53 mutation, suggesting that alloSCT can overcome the treatment resistance associated with this abnormality. Disclosures: Stilgenbauer: Amgen: Research Funding; Bayer: Consultancy, Honoraria, Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Genzyme: Consultancy, Honoraria, Research Funding; GSK: Consultancy, Honoraria, Research Funding; Mundipharma: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Sanofi Aventis: Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V116.21.2357.2357

Language: English

Publisher: American Society of Hematology

Publication Date: 2010

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In: Blood, American Society of Hematology, Vol. 137, No. 7 ( 2021-02-18), p. 923-928

Abstract: In hematopoietic cell transplantation (HCT), permissive HLA-DPB1 mismatches between patients and their unrelated donors are associated with improved outcomes compared with nonpermissive mismatches, but the underlying mechanism is incompletely understood. Here, we used mass spectrometry, T-cell receptor-β (TCRβ) deep sequencing, and cellular in vitro models of alloreactivity to interrogate the HLA-DP immunopeptidome and its role in alloreactive T-cell responses. We find that permissive HLA-DPB1 mismatches display significantly higher peptide repertoire overlaps compared with their nonpermissive counterparts, resulting in lower frequency and diversity of alloreactive TCRβ clonotypes in healthy individuals and transplanted patients. Permissiveness can be reversed by the absence of the peptide editor HLA-DM or the presence of its antagonist, HLA-DO, through significant broadening of the peptide repertoire. Our data establish the degree of immunopeptidome divergence between donor and recipient as the mechanistic basis for the clinically relevant permissive HLA-DPB1 mismatches in HCT and show that permissiveness is dependent on HLA-DM–mediated peptide editing. Its key role for harnessing T-cell alloreactivity to HLA-DP highlights HLA-DM as a potential novel target for cellular and immunotherapy of leukemia.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.2020008464

Language: English

Publisher: American Society of Hematology

Publication Date: 2021

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detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, ( 2022-03-22)

Abstract: CD19-directed chimeric antigen receptor (CAR) T cells have evolved as new standard-of-care (SOC) treatment in patients with relapsed/refractory large B-cell lymphoma (LBCL). Here, we report the first German real-world data on SOC CAR-T cell therapies with the aim to explore risk factors associated with outcome. Patients who received SOC axicabtagene ciloleucel (axi-cel) or tisagenlecleucel (tisa-cel) for LBCL and were registered with the German Registry for Stem Cell Transplantation (DRST) were eligible. Main outcomes analyzed were toxicities, response, overall survival (OS), and progression-free survival (PFS). We report 356 patients who received axi-cel (n=173) or tisa-cel (n=183) between November 2018 and April 2021 at 21 German centers. Whereas the axi-cel and tisa-cel cohorts were comparable for age, sex, LDH, IPI, and pretreatment, the tisa-cel group comprised significantly more patients with poor performance status, ineligibility for ZUMA-1, and need for bridging, respectively. With a median follow-up alive of 11 months, Kaplan-Meier estimates of OS, PFS, and non-relapse mortality (NRM) 12 months after dosing were 52%, 30%, and 6%, respectively. While NRM was largely driven by infections subsequent to prolonged neutropenia and/or severe neurotoxicity and significantly higher with axi-cel, significant risk factors for PFS on multivariate analysis included bridging failure, elevated LDH, age, and tisa-cel use. In conclusion, this study suggests that important outcome determinants of CD19-directed CAR-T cell treatment of LBCL in the real-world setting are bridging success, CAR-T product selection, LDH, and the absence of prolonged neutropenia and/or severe neurotoxicity. These findings may have implications for designing risk-adapted CAR-T cell therapy strategies.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.2021015209

Language: English

Publisher: American Society of Hematology

Publication Date: 2022

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detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 138, No. Supplement 1 ( 2021-11-05), p. 3822-3822

Abstract: Introduction The CD19 targeting CAR-T cell constructs axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel) have become an accepted standard salvage treatment of LBCL beyond the second line. Patients scheduled for approved CAR-T cell therapies usually have 4-8 weeks wait time for CAR-T cell infusion, thus often requiring bridging strategies in rapidly progressing patients to achieve disease control until start of lymphodepletion. It is still unclear, however, if the adverse impact of active progressive lymphoma can be overcome by successful bridging. We have addressed this question using registry data provided by the German Registry for Stem Cell Transplantation (DRST), the national partner of the EBMT. Methods We analyzed 356 consecutive patients who received standard of care axi-cel (n=173) or tisa-cel (n=183) treatment of LBCL between November 2018 and April 2021 at 21 German centers and were registered with the DRST/EBMT. Baseline patient, disease, and transplant data were collected from MED-A cellular therapy forms. Centers were contacted to provide additional treatment and follow-up information. Predictors of progression-free survival (PFS) were analyzed by uni- and multivariate comparisons. Results Compared to the approval trials, patients were of poor risk with 58% presenting with elevated LDH at lymphodepletion and 71% having received ≥3 pretreatment lines, resulting in ineligibility for the ZUMA-1 study in 87% of cases. Kaplan-Maier estimates of overall survival, PFS and non-relapse mortality (NRM) 12 months after dosing were 52%, 30% and 7%, respectively. Information on bridging was available for 355 patients (99%). Of these, 279 patients (78%) underwent at least one line of bridging attempt, whereas bridging was deemed unnecessary in 76 patients (22%). A wide variety of modalities were employed for bridging, with the most frequent being chemoimmunotherapy (n=188), chemotherapy (n=41), radiation (n=30), immunotherapy (n=12) and steroids (n=6). Bridging resulted in disease control (CR/PR) in 58 of 270 patients evaluable for response (21%). With a median follow-up of 11 months, 12-month PFS rates for patients without bridging, successful bridging, and bridging failure were 41%, 52%, and 20%, respectively, p= & lt;0.001 (Figure). Of note, an increased LDH at lymphodepletion did not impair PFS within the bridging responders, but affected the outcome of those patients who did not respond or not undergo bridging (p & lt;0.0001). The adverse impact of bridging failure on PFS was confirmed after multivariable adjustment for confounders (p=0.001, HR 2.083; 95% CI 1.358-3.195). Other significant risk factors for PFS on multivariate analysis were elevated LDH (p=0.012, HR 1.46; 95% CI 1.08-1.96), tisa-cel (p=0.0109, HR 1.41; 95% CI 1.06-1.88) and ECOG (p=0.021, HR 1.22; 95% CI 1.03-1.45). Conclusion The results of this large German GLA/DRST analysis suggest that effective bridging can overcome the adverse impact of active disease on the outcome of standard-of-case CD19 CAR-T therapy. With current treatment strategies, however, bridging is often unsuccessful, highlighting the need for exploring innovative tools for inducing temporary LBCL control for CAR-T therapy preparation. Figure 1 Figure 1. Disclosures Bethge: Novartis: Consultancy, Honoraria, Speakers Bureau; Kite-Gilead: Consultancy, Honoraria, Speakers Bureau; Miltenyi Biotec: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau. Schmitt: TolerogenixX: Current holder of individual stocks in a privately-held company; Novartis: Other: Travel grants, Research Funding; Kite Gilead: Other: Travel grants; Apogenix: Research Funding; MSD: Membership on an entity's Board of Directors or advisory committees; Bluebird Bio: Other: Travel grants; Hexal: Other: Travel grants, Research Funding. Holtick: Celgene: Honoraria; Sanofi: Honoraria. Borchmann: Gilead Sciences: Honoraria; BMS/Celgene: Honoraria; Janssen: Honoraria; Miltenyi Biotech: Honoraria; Novartis: Honoraria. Subklewe: Klinikum der Universität München: Current Employment; Pfizer: Consultancy, Speakers Bureau; Roche: Research Funding; Novartis: Consultancy, Research Funding, Speakers Bureau; MorphoSys: Research Funding; Janssen: Consultancy; Seattle Genetics: Consultancy, Research Funding; Takeda: Speakers Bureau; Miltenyi: Research Funding; Gilead: Consultancy, Research Funding, Speakers Bureau; Amgen: Consultancy, Research Funding, Speakers Bureau; BMS/Celgene: Consultancy, Research Funding, Speakers Bureau. von Tresckow: Roche: Consultancy, Honoraria; Kite-Gilead: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Pentixafarm: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Other: congress and travel support, Research Funding; MSD: Consultancy, Honoraria, Other: congress and travel support, Research Funding; BMS-Celgene: Consultancy, Honoraria, Other: congress and travel support; AstraZeneca: Honoraria, Other: congress and travel support; Amgen: Consultancy, Honoraria; AbbVie: Other: congress and travel support; Takeda: Consultancy, Honoraria, Other, Research Funding. Ayuk: Gilead: Honoraria; Mallinckrodt/Therakos: Honoraria, Research Funding; Janssen: Honoraria; Takeda: Honoraria; Miltenyi Biomedicine: Honoraria; Celgene/BMS: Honoraria; Novartis: Honoraria. Kroeger: Novartis: Honoraria; AOP Pharma: Honoraria; Gilead/Kite: Honoraria; Riemser: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Sanofi: Honoraria; Neovii: Honoraria, Research Funding. Wulf: Takeda: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Clinigen: Consultancy, Honoraria. Marks: Merck: Consultancy; Kite/Gilead: Honoraria; AbbVie: Other: Meeting attendance; Kite/Gilead: Membership on an entity's Board of Directors or advisory committees. Penack: Astellas: Honoraria; Gilead: Honoraria; Jazz: Honoraria; Omeros: Consultancy; Shionogi: Consultancy; Priothera: Consultancy; Incyte: Research Funding; Takeda: Research Funding; Therakos: Honoraria; Pfizer: Honoraria; Neovii: Honoraria; Novartis: Honoraria; MSD: Honoraria. Koenecke: Kite/Gilead: Consultancy; BMS/Celgene: Consultancy; Janssen: Consultancy; Novartis: Consultancy; EUSA Pharm: Consultancy. Von Bonin: Kite/Gilead: Other: traveling support and advisory fees; Novartis: Other: traveling support and advisory fees; Daiichi Sankyo: Other: traveling support and advisory fees. Stelljes: Amgen: Consultancy, Speakers Bureau; Celgene/BMS: Consultancy, Speakers Bureau; Medac: Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Pfizer: Consultancy, Research Funding, Speakers Bureau; MSD: Consultancy, Speakers Bureau; Kite/Gilead: Consultancy, Speakers Bureau. Glass: BMS: Consultancy; Helios Klinik Berlin-Buch: Current Employment; Kite: Consultancy; Novartis: Consultancy; Riemser: Research Funding; Roche: Consultancy, Research Funding, Speakers Bureau. Baldus: Novartis: Honoraria; Amgen: Honoraria; Celgene/BMS: Honoraria; Jazz: Honoraria. Vucinic: Janssen: Honoraria, Other: Travel Sponsoring; Novartis: Honoraria; Abbvie: Honoraria, Other: Travel Sponsoring; Gilead: Honoraria, Other: Travel Sponsoring; MSD: Honoraria. Topp: Celgene: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Novartis: Consultancy; Janssen: Consultancy; Amgen: Consultancy, Research Funding; Gilead: Research Funding; Regeneron: Consultancy, Research Funding; Macrogeniecs: Research Funding; Universitatklinikum Wurzburg: Current Employment. Schroers: BMS/Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; GSK: Consultancy, Honoraria; Takeda: Honoraria. Thomas: Abbvie: Honoraria, Speakers Bureau; Art tempi: Honoraria, Speakers Bureau; BMS-Celgene: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; EUSA Pharma: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: travel support; Kite-Gilead: Honoraria, Other: travel support, Research Funding, Speakers Bureau; Medigene: Consultancy, Honoraria, Other: Travel support; Novartis: Consultancy, Honoraria, Other: travel support, Speakers Bureau; Pfizer: Consultancy, Honoraria, Other: Travel support, Speakers Bureau. Dreger: Bluebird Bio: Consultancy; BMS: Consultancy; AbbVie: Consultancy, Speakers Bureau; Riemser: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Gilead Sciences: Consultancy, Speakers Bureau; Janssen: Consultancy; AstraZeneca: Consultancy, Speakers Bureau.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2021-146120

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. 138, No. Supplement 1 ( 2021-11-05), p. 1748-1748

Abstract: Introduction Although the labeled CD19 targeting CAR-T cell constructs axi-cel and tisa-cel are generally associated with an acceptable safety profile, non-relapse deaths can occur. Little is known about timing, causes and predictors of NRM following SOC CAR-T cell therapy for LBCL. Here, we analyzed frequency, causes, and risk factors of non-relapse deaths with focus on late NRM (beyond 4 weeks after dosing) using registry data provided by the DRST, the national partner of the EBMT. Methods Patients were selected from 356 consecutive patients who received SOC CAR-T treatment of LBCL between November 2018 and April 2021 at 21 German centers and were registered with the DRST/EBMT. Baseline patient, disease, and transplant data were collected from MED-A cellular therapy forms. Centers were contacted to provide additional treatment and follow-up information. Patients with late NRM (defined as NRM occurring beyond 4 weeks after dosing without prior LBCL relapse or progression) were compared with all patients surviving progression-free the 4-week landmark after dosing without subsequent NRM. Cumulative incidences of NRM were calculated considering relapse/progression as competing event. Results The analysis set consisted of 312 patients surviving progression-free at least 28 days after CAR-T treatment and remained alive until the end of follow-up or had a documented cause of death. Median age was 61 years (19-83), 66% were male, 52% had an IPI ≥3, 13 had an ECOG score & gt;1, 70% had received ≥3 treatment lines, 33% had failed a prior HCT, and 78% were refractory at lymphodepletion. 50% had been treated at a center contributing ≥20 cases with axi-cel (52%) or tisa-cel (48%). Grade ≥3 CRS and grade ≥3 neurotoxicity (NT) had occurred in 11% each, and 7% had no neutrophil recovery at day 100 post dosing or at last follow-up, whatever was earlier. With a median follow-up of 11.2 months, 124 patients (40%) had died, 109 (35%) LBCL-related, and 15 (5%) because of NRM. The cumulative incidence of late NRM at 12 months post dosing was 4.3% (95%CI 2.0-6.6). Causes of NRM were infections in 10 patients (bacterial or fungal sepsis/pneumonia 6; viral/atypical pneumonia/encephalitis 4); late NT 2; hyperinflammatory syndrome 1; 2 nd malignancy 1; unknown 1). Of note, 5 of the 6 lethal fungal/bacterial infections occurred subsequent to high grade NT. There was no significant difference between patients experiencing and not experiencing NRM in terms of age, gender, IPI, ECOG, pretreatment lines, prior HCT, disease status at lymphodepletion, and grade ≥3 CRS frequency. However, a significantly larger proportion of patients with late NRM had failed neutrophil recovery (27% vs 5%, p 0.011), had experienced grade ≥3 NT (40% vs 10%, p 0.0031), and/or had received axi-cel (93% vs 51%, p 0.001). Patients having neutrophil non-recovery and/or grade ≥3 NT had a 12-month NRM incidence of 16% (95%CI 5.1-26.9) vs 2.5% (95%CI 0.3-4.7) in patients with none of these 2 factors. Conclusions Late NRM in patients receiving SOC CAR-T treatment for LBCL is largely driven by infections. Risk factors for late NRM appear to be protracted neutropenia and higher grade NT, suggesting that intensified anti-bacterial/anti-fungal prophylaxis may be considered in patients with persisting critical neutropenia or exposed to high-dose steroids for NT treatment. Figure 1 Figure 1. Disclosures Dreger: BMS: Consultancy; AstraZeneca: Consultancy, Speakers Bureau; Bluebird Bio: Consultancy; AbbVie: Consultancy, Speakers Bureau; Gilead Sciences: Consultancy, Speakers Bureau; Janssen: Consultancy; Novartis: Consultancy, Speakers Bureau; Riemser: Consultancy, Research Funding, Speakers Bureau; Roche: Consultancy, Speakers Bureau. Schubert: Gilead: Consultancy. Holtick: Sanofi: Honoraria; Celgene: Honoraria. Subklewe: Miltenyi: Research Funding; Takeda: Speakers Bureau; Gilead: Consultancy, Research Funding, Speakers Bureau; Klinikum der Universität München: Current Employment; MorphoSys: Research Funding; Novartis: Consultancy, Research Funding, Speakers Bureau; Roche: Research Funding; Seattle Genetics: Consultancy, Research Funding; Pfizer: Consultancy, Speakers Bureau; Janssen: Consultancy; BMS/Celgene: Consultancy, Research Funding, Speakers Bureau; Amgen: Consultancy, Research Funding, Speakers Bureau. Bastian: Abbvie: Other; Amgen: Consultancy, Honoraria; Astra Zeneca: Honoraria, Other; BMS and Celgene: Consultancy, Honoraria, Other; Kite-Gilead: Consultancy, Honoraria; MSD: Consultancy, Honoraria, Other, Research Funding; Novartis: Consultancy, Honoraria, Other, Research Funding; Pentixafarm: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Other, Research Funding. Ayuk: Gilead: Honoraria; Celgene/BMS: Honoraria; Janssen: Honoraria; Takeda: Honoraria; Miltenyi Biomedicine: Honoraria; Mallinckrodt/Therakos: Honoraria, Research Funding; Novartis: Honoraria. Marks: Kite/Gilead: Membership on an entity's Board of Directors or advisory committees; Kite/Gilead: Honoraria; Merck: Consultancy; AbbVie: Other: Meeting attendance. Penack: Priothera: Consultancy; Takeda: Research Funding; Incyte: Research Funding; Neovii: Honoraria; Pfizer: Honoraria; Therakos: Honoraria; Novartis: Honoraria; MSD: Honoraria; Jazz: Honoraria; Gilead: Honoraria; Astellas: Honoraria; Shionogi: Consultancy; Omeros: Consultancy. Koenecke: EUSA Pharm: Consultancy; Kite/Gilead: Consultancy; BMS/Celgene: Consultancy; Janssen: Consultancy; Novartis: Consultancy. Von Bonin: Daiichi Sankyo: Other: traveling support and advisory fees; Novartis: Other: traveling support and advisory fees; Kite/Gilead: Other: traveling support and advisory fees. Stelljes: Novartis: Consultancy, Speakers Bureau; MSD: Consultancy, Speakers Bureau; Pfizer: Consultancy, Research Funding, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Medac: Speakers Bureau; Celgene/BMS: Consultancy, Speakers Bureau; Kite/Gilead: Consultancy, Speakers Bureau. Glass: BMS: Consultancy; Helios Klinik Berlin-Buch: Current Employment; Kite: Consultancy; Novartis: Consultancy; Riemser: Research Funding; Roche: Consultancy, Research Funding, Speakers Bureau. Baldus: Novartis: Honoraria; Amgen: Honoraria; Celgene/BMS: Honoraria; Jazz: Honoraria. Vucinic: MSD: Honoraria; Novartis: Honoraria; Gilead: Honoraria, Other: Travel Sponsoring; Janssen: Honoraria, Other: Travel Sponsoring; Abbvie: Honoraria, Other: Travel Sponsoring. Topp: Universitatklinikum Wurzburg: Current Employment; Celgene: Consultancy, Research Funding; Janssen: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; Novartis: Consultancy; Roche: Consultancy, Research Funding; Gilead: Research Funding; Regeneron: Consultancy, Research Funding; Macrogeniecs: Research Funding; Amgen: Consultancy, Research Funding. Schroers: BMS/Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; GSK: Consultancy, Honoraria; Takeda: Honoraria. Hanoun: AstraZeneca: Honoraria; Abbvie: Other: travel expenses; Novartis: Research Funding. Thomas: AbbVie: Honoraria, Speakers Bureau; Art tempi: Honoraria, Speakers Bureau; BMS/Celgene: Consultancy, Honoraria, Other, Research Funding, Speakers Bureau; EUSA Pharma: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other; Kite/Gilead: Honoraria, Other, Research Funding, Speakers Bureau; Medigene: Consultancy, Honoraria, Other; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other; Pfizer: Consultancy, Honoraria, Other, Speakers Bureau. Kröger: Novartis: Research Funding; Riemser: Honoraria, Research Funding; Sanofi: Honoraria; Neovii: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Gilead/Kite: Honoraria; Celgene: Honoraria, Research Funding; AOP Pharma: Honoraria. Bethge: Novartis: Consultancy, Honoraria, Speakers Bureau; Miltenyi Biotec: Consultancy, Honoraria, Research Funding, Speakers Bureau; Kite-Gilead: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2021-151469

Language: English

Publisher: American Society of Hematology

Publication Date: 2021

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7