Kooperativer Bibliotheksverbund

In: Frontiers in Oncology, Frontiers Media SA, Vol. 11 ( 2021-12-9)

Abstract: Sezary Syndrome (SS) is a rare leukemic variant of primary cutaneous T-cell lymphoma. Relapsed or refractory disease is generally considered incurable by conventional therapeutic approaches, although durable responses can be achieved with novel monoclonal antibodies. Allogeneic hematopoietic stem cell transplantation (alloHSCT) may have potential value by inducing graft vs-lymphoma (GvL) effects, but there is currently no consensus regarding the timing of alloHSCT or type of conditioning regimen. Here we present the case of a male patient who achieved a complete remission (CR) of primary refractory SS after non-myeloablative alloHSCT. Patient: Two years prior to HSCT, the patient had been refractory to CHOEP-based chemotherapy, interferon, extracorporeal photopheresis (ECP), and bexarotene. Directly prior to alloHSCT brentuximab-vedotin (BV) was applied resulting in a partial remission of the skin compartment and overall in a stable disease. Prior to HSCT, flow cytometry of the bone marrow and peripheral blood showed an infiltration with T-cells positive for CD5, CD4, low CD3, low CD2 and negative for CD7, CD38, HLA-DR and CD8. The trephine biopsy showed a 7% infiltration of SS cells. The CD4:CD8 ratio in peripheral blood (pb) was massively increased at 76.67, with 63.5% of white blood cells expressing a SS immune phenotype. The conditioning regimen included 30 mg/m2 fludarabine on days -5, -4 and -3 and total body irradiation with 2 Gy on day -1. Immunosuppression consisted of cyclosporine A from day-1 and mycophenolate mofetil from day 0. The patient received 6.55x106 CD34+ cells and 1.11x108 CD3+ cells/kg body weight. Bone marrow evaluation on day 28 still showed persistent SS cells by flow cytometry. After tapering immunosuppression until day 169, the CD4:CD8 ratio in pb normalized. CR was documented on day 169 after alloHSCT and is now ongoing for almost 3 years after alloHSCT. Conclusions: We confirm that an alloHSCT can be a curative option for refractory patients with SS. The achievement of a CR after tapering the immunosuppressive therapy indicates a significant role of the GvL effect. In present treatment algorithms for patients with SS, the timing of an alloHSCT and the intensity of conditioning should be further explored.

Type of Medium: Online Resource

ISSN: 2234-943X

URL: Article

DOI: 10.3389/fonc.2021.749691

Language: Unknown

Publisher: Frontiers Media SA

Publication Date: 2021

detail.hit.zdb_id: 2649216-7

In: Blood, American Society of Hematology, Vol. 110, No. 11 ( 2007-11-16), p. 3059-3059

Abstract: Allogeneic hematopoietic cell transplantation (HCT) using reduced intensity conditioning (RIC) regimens offers a potential curative therapy to patients with advanced NHL. RIC HCT induces potent graft-versus-lymphoma effects with best results in patients with low tumor burden at time of HCT. Combined use of radioimmunotherapy (RIT) with RIC may increase anti-lymphoma activity of RIC while HCT provides rescue from hematologic toxicity of RIT. This may allow dose escalation of RIT. A multicenter phase I/II study of allogeneic HCT combining RIT using yttrium-90-ibritumomab tiuxetan (Y90-CD20) with two RIC regimens for treatment of patients with NHL has been initiated. Patients with indolent NHL (Arm A) receive RIT with Y90-CD20 (0.4 mCi/kg) on day −14 combined with RIC using fludarabine (30 mg/m^2 day −4 to−2) and 2 Gy TBI (day 0). Patients with aggressive NHL (Arm B) receive an escalated dose of Y90-CD20 (0,6–0,8 mCi/kg) on day −14 combined with RIC using fludarabine (30 mg/m^2 day −8 to−4), melphalan (140 mg/m^2 day −3) and campath (20–30 mg day −3 to−2). For postgrafting immunosuppression either CSA/MMF (Arm A) or CSA alone (Arm B) is used. To date, 31 patients have been enrolled (Arm A=23, Arm B=8). Diagnoses in Arm A were FL (n=12), MCL (n=6), CLL (n=4) and Immunocytoma (n=1). Diagnoses in Arm B were DLBCL (n=6), blastoid MCL (n=1) and transformed CLL (n=1). Median age was 55 (range, 34–67) years. PBSC grafts were either from matched related (n=10) or matched unrelated donors (n=21). All patients were high risk with refractory disease or relapse after preceding HCT. Disease status after salvage therapy at time of HCT was in Arm A: CR=1, PR=18, SD=4 and in Arm B: PR=8. No additional toxicity due to RIT was observed. Engraftment was rapid and sustained with no graft rejections. In Arm A median time to 〉 500 granulocytes/μL was 13 (range, 0–69) days and to 〉 20000 platelets/μL 3 (range, 0–69) days (in 11 patients platelets never dropped 〈 20000/μL). In Arm B median time to 〉 500 granulocytes/μL was 17 (range, 9–23) days and to 〉 20000 platelets/μL 11 (range, 8–29) days. TRM in the first 100 days was 3%, overall 19%. Incidence of grade II-IV GVHD in Arm A was 35% (II=3, III=4, IV=1) and in Arm B 25% (II=2). Best disease response observed was in Arm A: CR=18, PR=5 and in Arm B: CR=3, PR=5. To date, 16/23 patients in Arm A and 6/8 patients in Arm B are alive with a median follow-up of 271 (range, 20–390) days, resulting in a Kaplan-Meier 1 year survival estimate of 65% in Arm A and 62% in Arm B. Causes of death were infection=5, GVHD=1, relapse=1 in Arm A and relapse=2 in Arm B. A combination of RIT with RIC is feasible with no additional toxicity due to RIT and stable engraftment in all patients. Preliminary response data suggest that this strategy may improve early post-transplant disease control, but long-term disease-free survival remains to be determined.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V110.11.3059.3059

Language: English

Publisher: American Society of Hematology

Publication Date: 2007

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. 4232-4232

Abstract: While the discovery of BCR-ABL and the respective tyrosine kinase inhibitors (TKI) resulted in a significant prolongation of patient survival rates, there still is no curative treatment for chronic myeloid leukemia (CML) except for allogeneic stem cell transplantation. The concept of T cell-based immunotherapy is a promising opportunity to eliminate residual leukemic cells, which might promote disease relapse after TKI discontinuation. As effective antigen-specific immunotherapy requires exact knowledge of tumor-associated epitopes that can act as rejection antigens, we have developed a mass spectrometry-based approach, which allows for the direct identification of naturally presented tumor-associated HLA ligands in hematological malignancies. In this study we used this approach to identify HLA class I and II CML-associated peptides as targets for T cell-based immunotherapy. Analysis of HLA class I ligandomes of primary CML cells (n=16) identified 8,291 HLA ligands representing 4,337 source proteins. Comparative ligandome profiling using a benign HLA class I database, which includes various healthy tissues (n=188, 65,949 HLA ligands, 14,030 source proteins) originating from peripheral blood, bone marrow, kidney, lung, liver, colon, spleen and others, revealed 38 CML-exclusive HLA class I ligands with frequencies ≥ 25% of CML patients. Because of the important indirect and direct roles of CD4+ T cells in anti-cancer immune responses, an optimal immunotherapy approach requires the inclusion of HLA class II epitopes. Hence we also analyzed the HLA class II ligandomes of primary CML cells (n=15, 2,822 HLA ligands, 794 source proteins). Comparative ligandome analysis (benign tissue, n=114, 54,149 HLA ligands, 8,584 source proteins) identified 44 CML-associated HLA class II ligands showing CML-exclusive representation in 〉 25% of the analyzed CML samples. To validate the immunogenicity of our HLA class I and II CML-associated peptides, we performed IFNγ- ELISPOT assays after 12-days of in vitro peptide stimulation. For HLA class II antigens, a panel of 4 peptides was implemented for stimulation of PBMCs obtained from CML patients and healthy volunteers (HV). The ELISPOT assay revealed peptide-specific immune recognition of 4/4 (100%) CML-exclusive peptides in CML patients. The frequencies of the detected immune responses ranged from 17% (4/23 patients) to 4% (1/23 patients) within the tested CML samples. These immune responses were mediated by functional CML patient-derived CD4+ T cells and strictly CML-directed, as no immune response against CML-associated peptides could be detected in HV (0/8). For HLA class I antigens, ELISPOT assays were performed using a panel of 8 peptides. Immune responses were only detected for 1/8 (13%) peptides with a low frequency of 6% (1/18 patients) of tested CML patient samples. A possible explanation for the observed weak immune response to our HLA class I CML-associated peptides compared to the immune responses shown for HLA class II peptides and for HLA class I peptides in other hematological malignancies (e.g. CLL (Kowalewski et. al. PNAS 2015)) might be an inhibition of CD8+ T cell-responses, that reportedly occurs upon TKI treatment of CML patients. To prove this hypothesis in our CML patient cohort (all patients included were under TKI treatment at the time of sample collection), we compared the ELISPOT positive controls (stimulated with a set of 5 Epstein-Barr viral peptides) of all analyzed CML samples with positive controls derived from HV and CLL samples. We could show a highly significant mean spot count reduction (per 100,000 cells) in CML samples (mean 74±16 spots, n=19) compared to HV (mean 241±24 spots, n=42, p 〈 0.001, two-tailed t-test) or CLL (mean 218±16 spots, n=125, p=0.008) samples, confirming the general debilitated CD8+ T cell-response in CML patients under TKI treatment. To prove the immunogenicity of our HLA class I CML-associated peptides, we performed in vitro artificial antigen-presenting cell (aAPC)-based priming experiments of HV CD8+ cells. For one HLA-A*03-restricted peptide we observed tetramer-positive CD8+ populations with frequencies ranging from 0.12% to 1.41% of viable cells in 2/2 HVs so far. Taken together, these results are a first step towards a successful validation of these newly defined HLA class I and II CML-associated antigens as prime targets for further T cell-based immunotherapy approaches in CML patients. Disclosures Kowalewski: Immatics Biotechnologies GmbH: Employment. Brümmendorf:Ariad: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Patent on the use of imatinib and hypusination inhibitors: Patents & Royalties. Niederwieser:Amgen: Speakers Bureau; Novartis Oncology Europe: Research Funding, Speakers Bureau.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V128.22.4232.4232

Language: English

Publisher: American Society of Hematology

Publication Date: 2016

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 122, No. 18 ( 2013-10-31), p. 3220-3229

Abstract: HLA mismatches at the allele and antigen level (possibly with the exception of HLA-DQB1) should be treated equally in donor selection. HLA mismatches at 〉 1 locus (including HLA-DQB1) have additive detrimental effects.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2013-02-482547

Language: English

Publisher: American Society of Hematology

Publication Date: 2013

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. 517-517

Abstract: Allogeneic hematopoietic cell transplantation (HSCT) is a powerful consolidation option for acute myeloid leukemia (AML) patients (pts) in hematologic complete remission (CR). Disease recurrence after HSCT remains a major clinical problem & early identification of AML pts at risk of relapse is crucial to improve outcomes. High expression of the AML associated gene BAALC (Brain and acute leukemia, cytoplasmic) at diagnosis adversely impacts on outcomes in AML pts. Little is known about its prognostic capacity during disease course & as a marker of residual disease. Here we adopted digital droplet polymerase chain reaction (ddPCR) for absolute quantification of BAALC copy numbers in peripheral blood (PB) prior to HSCT in AML pts in hematologic CR. We identified 82 AML pts with PB in first (60%) or second CR (23%) or CRi (17%) up to 28 days prior to HSCT available. Median age at HSCT was 63.9 (range 50.8-76.2) years (y). All pts received non-myeloablative (NMA) conditioning (fludarabine 3x30 mg & 2 Gy total body irradiation). At diagnosis, mutation status (mut) of the NPM1, CEBPA, IDH1, IDH2, & DNMT3A gene & presence of FLT3-ITD or FLT3-TKD were assessed. In pre-HSCT PB, absolute quantification of BAALC copy numbers was performed by ddPCR & results were normalized to ABL1 copy numbers.Additionally, absolute BAALC copy numbers wereassessedin PB of healthy controls (n=7) with a median age of 62.7 (range 39.6-82.0) y. Pts were grouped according to the European LeukemiaNet (ELN) classification in 21% favorable, 23% intermediate-I, 24% intermediate-II, 23% adverse & 9% unknown. Pts & healthy control were evenly matched in age (P=1) & sex (P=1). BAALC/ABL1 copy numbers did not differ between AML pts at HSCT (median 0.03 [range 0.01-2.48]) & the healthy controls (median 0.04 [range 0.03-0.10], P=.34, Figure 1). A cut-off point of 0.14absolute BAALC/ABL1 copies was determined using the R package 'OptimalCutpoints' & used to define pts with high (26%) & low (74%) pre-HSCT BAALC/ABL1 copy numbers. The copy number at this cut-off point was higher than the two-fold standard deviation over the median of the healthy controls (0.10 BAALC/ABL1). Pts with high & low pre-HSCT BAALC/ABL1 copy numbers did not differ significantly in pre-treatment characteristics (i.e. hemoglobin, white blood count, platelets, blasts in bone marrow or PB, ELN genetic group, FLT3-ITD, FLT3-TKD, NPM1, CEBPA, DNMT3A, IDH1 or IDH2 mut) or remission status at HSCT (CR1 vs. CR2 vs. CRi). However, pts with high pre-HSCT BAALC/ABL1 copy numbers had a significantly higher cumulative incidence of relapse (CIR, P=.02, Figure 2a) & shorter overall survival (OS, P=.02, Figure 2b). High pre-HSCT BAALC/ABL1 copy numbers especially impacted on CIR when we restricted our analysis to pts with normal cytogenetics (P=.003). In multivariate analysis for the entire cohort, high pre-HSCT BAALC/ABL1 copy numbers retained the prognostic impact on CIR (Hazard Ratio [HR] 3.6, Confidence Interval [CI] 1.6-8.2, P=.002) after adjustment for disease status at HSCT (P=.006) & the prognostic impact on OS (HR 2.2, CI 1.1-4.3, P=.02). In conclusion, ddPCR is a feasible method for absolute quantification of BAALC copy numbers in PB, which may indicate residual disease burden in AML pts. High PB BAALC/ABL1 copy numbers ( 〉 0.14) in AML pts in hematologic CR at HSCT associated with higher CIR & shorter OS in univariate & multivariate models. AML pts with high PB BAALC/ABL1 copy numbers at HSCT should be closely monitored for relapse in the post-transplant period. In the future prospective studies will be required to validate the absolute PB BAALC/ABL1 copy number cut-off point & to evaluate whether AML pts with high BAALC/ABL1 copy numbersmight benefit from additional treatment before HSCT. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Poenisch: Mundipharma: Research Funding. Niederwieser:Amgen: Speakers Bureau; Novartis Oncology Europe: Research Funding, Speakers Bureau.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V128.22.517.517

Language: English

Publisher: American Society of Hematology

Publication Date: 2016

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. 33-33

Abstract: Background In a recent phase-III trial CPX-351 (Jazz Pharmaceuticals, Palo Alto, CA), a liposomal encapsulation of cytarabine and daunorubicin, has shown higher remission rates and longer overall survival (OS) in patients aged 60 to 75 years with AML with myelodysplasia-related changes (AML-MRC) or therapy-related AML (t-AML) in comparison to conventional 7+3 regimen. Based on this CPX-351 has been approved in the USA 2017 and in Europe 2018 for adult patients with newly-diagnosed AML-MRC or t-AML. Still, several issues such as age ( & lt;60 years), measurable residual disease (MRD), molecular subgroups and outcome after allo-HCT were not addressed in the phase-III trial. Aiming to investigate these open aspects and to provide more clinical experience with CPX-351, we performed a real-world analysis of patients with AML treated with CPX-351 as first-line therapy. Design/Methods: For this retrospective analysis, we collected data on baseline characteristics, treatment details including allo-HCT and outcome from patients with newly-diagnosed AML-MRC or t-AML, who were treated with CPX-351 according to the EMA label between 2018 and 2020 in 25 German centers participating in the Study Alliance Leukemia (SAL), German Cooperative Transplant Study Group and the AML Study Group (AMLSG). Results: A total of 188 patients (median age 65 years, range 26 to 80) with t-AML (29%) or AML-MRC (70%) including 46 patients (24%) & lt;60 years could be analyzed. Eigthy-six percent received one, 14% two induction cycles and 10% received consolidation with CPX-351. Following induction, CR/CRi rate was 47% including 64% of patients with available information achieving measurable residual disease (MRD) negativity ( & lt;10-3) as measured by flow cytometry at local laboratories. Additionally, 35 patients were categorized as MLFS at first remission control, which achieved CRi (n=16) or CR (n=10) in the further course without additional therapy. After median follow-up of 9.3 months, median overall survival (OS) was 21 months and 1-year OS rate was 64%. In multivariate analysis, complex karyotype predicted lower response (p=.0001), and pretreatment with hypomethylating agents (p=.02) and adverse European LeukemiaNet 2017 genetic risk (p & lt;.0001) were associated with lower OS. Allo-HCT was performed in 116 patients (62%) including 101 of these patients with CR prior transplant and resulted in 1-year OS of 73% (median survival not reached), especially in MRD negative patients (p=.048). With 69% of patients developing grade III/IV non-hematologic toxicity following induction and a day 30-mortality of 8% the safety profile was consistent with previous findings. Conclusion: The results from this real-world analysis confirm CPX-351 as an efficient treatment for these high-risk AML patients bridging to facilitating allo-HCT in many patients with encouraging outcome after transplantation. Disclosures Röllig: AbbVie: Honoraria, Research Funding; Amgen: Honoraria; Bristol-Meyer-Squibb: Honoraria, Research Funding; Janssen: Honoraria; Jazz: Honoraria; Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Roche: Honoraria, Research Funding. Stelljes: Pfizer: Consultancy, Research Funding, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Medac: Speakers Bureau; Celgene/BMS: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; MSD: Consultancy, Speakers Bureau; Kite/Gilead: Consultancy, Speakers Bureau. Gaidzik: Janssen: Speakers Bureau; Pfizer: Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Unglaub: Novartis: Consultancy, Other: travel costs/ conference fee; JazzPharma: Consultancy, Other: travel costs/ conference fee. Thol: Abbvie: Honoraria; Astellas: Honoraria; BMS/Celgene: Honoraria, Research Funding; Jazz: Honoraria; Novartis: Honoraria; Pfizer: Honoraria. Krause: Siemens: Research Funding; Takeda: Honoraria; Pfizer: Honoraria; art-tempi: Honoraria; Kosmas: Honoraria; Gilead: Other: travel support; Abbvie: Other: travel support. Haenel: Celgene: Consultancy, Honoraria; Amgen: Consultancy; Novartis: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Bayer Vital: Honoraria; Jazz: Consultancy, Honoraria; GSK: Consultancy. Vucinic: Novartis: Honoraria; Janssen: Honoraria, Other: Travel Sponsoring; Abbvie: Honoraria, Other: Travel Sponsoring; Gilead: Honoraria, Other: Travel Sponsoring; MSD: Honoraria. Fransecky: Novartis: Honoraria; Medac: Honoraria; Abbvie: Honoraria, Research Funding; Amgen: Honoraria; Takeda: Honoraria. Holtick: Celgene: Honoraria; Sanofi: Honoraria. Kobbe: Celgene: Research Funding. Holderried: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Speakers Bureau; Gilead Sciences: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; MSD: Speakers Bureau; Daiichi Sankyo: Other: travel support; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Therakos: Other: Travel support; Janssen: Other: Travel support; Abbvie: Other: Travel support; Eurocept Pharmaceuticals: Other: Travel support; Medac: Other: Travel support. Heuser: Astellas: Research Funding; Bayer AG: Honoraria, Research Funding; BMS/Celgene: Research Funding; Jazz Pharmaceuticals: Honoraria, Research Funding; BergenBio: Research Funding; Daichi Sankyo: Honoraria, Research Funding; Karyopharm: Research Funding; Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Roche: Research Funding; Tolremo: Honoraria; AbbVie: Honoraria; Janssen: Honoraria. Sauer: Pfizer: Consultancy, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau; Matterhorn Biosciences AG: Consultancy, Other: DSMB/SAB Member; Takeda: Consultancy, Other: DSMB/SAB Member. Goetze: Abbvie: Other: Advisory Board; BMS/Celgene: Other: Advisory Board, Research Funding. Döhner: Jazz Roche: Consultancy, Honoraria; Agios and Astex: Research Funding; Astellas: Research Funding; Abbvie: Consultancy, Honoraria; Janssen: Honoraria, Other: Advisory Board; Daiichi Sankyo: Honoraria, Other: Advisory Board; Novartis: Consultancy, Honoraria, Research Funding; Celgene/BMS: Consultancy, Honoraria, Research Funding. Döhner: Jazz Pharmaceuticals: Honoraria, Research Funding; Agios: Honoraria, Research Funding; Pfizer: Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Gilead: Honoraria; Janssen: Honoraria; Helsinn: Honoraria; GEMoaB: Honoraria; Amgen: Honoraria, Research Funding; Astellas: Honoraria, Research Funding; Astex Pharmaceuticals: Honoraria; AstraZeneca: Honoraria; Berlin-Chemie: Honoraria; Oxford Biomedica: Honoraria; Roche: Honoraria. Schliemann: Philogen S.p.A.: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Other: travel grants; Astellas: Consultancy; AstraZeneca: Consultancy; Boehringer-Ingelheim: Research Funding; BMS: Consultancy, Other: travel grants; Jazz Pharmaceuticals: Consultancy, Research Funding; Novartis: Consultancy; Roche: Consultancy; Pfizer: Consultancy. Schetelig: Roche: Honoraria, Other: lecture fees; Novartis: Honoraria, Other: lecture fees; BMS: Honoraria, Other: lecture fees; Abbvie: Honoraria, Other: lecture fees; AstraZeneca: Honoraria, Other: lecture fees; Gilead: Honoraria, Other: lecture fees; Janssen: Honoraria, Other: lecture fees . Germing: Novartis: Honoraria, Research Funding; Janssen: Honoraria; Bristol-Myers Squibb: Honoraria, Other: advisory activity, Research Funding; Celgene: Honoraria; Jazz Pharmaceuticals: Honoraria. Schroeder: JAZZ: Honoraria, Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2021-153440

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. 1797-1797

Abstract: Background: For most acute myeloid leukemia (AML) patients an allogeneic hematopoietic stem cell transplantation (HSCT) offers the highest chance of cure and long-term survival. Higher age and/or comorbidities may confine this option in a considerable number of AML patients due to toxic myeloablative preparation regimens. Non-myeloablative conditioning (NMA) regimes were developed to allow HSCT in these patients. The HSCT comorbidity index (HCT-CI) has been shown to predict outcome after allogeneic HSCT in cohorts of unselected patients. However, there is no separate evaluation of its prognostic significance in older ( & gt; 60 years) AML patients undergoing less-toxic NMA-HSCT. We evaluated the prognostic impact of the HCT-CI in a large, homogenously treated AML patient cohort that received NMA-HSCT. Methods: We retrospectively analyzed 289 AML patients older than 60 years (median age 66, range 60-77 years) at the time of NMA-HSCT. The conditioning regimen consisted of fludarabine 30 mg/m 2 for 3 consecutive days in addition to 2 (n=278) or 3 Gy (n=6) total body irradiation (TBI), five patients received 2 Gy TBI alone. Graft versus host disease prophylaxis contained cyclosporine and mycophenolate mofetil, none of the patients received in vivo or in vitro T-cell depletion. Disease risk at diagnosis was assessed according to the European LeukemiaNet (ELN) 2017 classification. In patients transplanted in morphologic remission, measurable residual disease (MRD) at HSCT was assessed based on NPM1 mutations and BAALC, MN1, and WT1 expression levels. The pre-transplant HCT-CI was calculated prior to the start of the conditioning regimen. Median follow up after HSCT was 3.8 years. Results: 97% of the patients (n=281) engrafted. 36% of the patients (n=104) had a low risk (0 points), 31% (n=90) an intermediate risk (1-2 points), and 33% (n=95) a high risk (≥3 points) HCT-CI score. The performance score at HSCT (ECOG, 0/1 vs. 2/3) was not different between HCT-CI risk groups (P=.86). Incidences of chronic graft-versus-host disease (GvHD) were 16% limited and 52% extensive disease. The non-relapse mortality (NRM) did not differ significantly between HCT-CI risk groups after NMA-HSCT (P=.56, Figure 1A, at 5 years HCT-CI low 24% vs. HCT-CI intermediate 20% vs. HCT-CI high 27%, respectively). Likewise, neither the cumulative incidence of relapse (P=.88, Figure 1B, at 5 years 46% vs. 45% vs. 43%) nor the overall survival (P=.70, Figure 1C, at 5 years 40% vs. 44% vs. 41%) differed according to the HCT-CI risk groups. The HCT-CI also did not impact outcomes in separate analyses according to ELN2017 risk at diagnosis (OS, P=.20, P=.30, and P=.70 for favorable, intermediate, and adverse, respectively) or MRD status prior to HSCT (OS, P=1 and P=.30 for MRD-negative and MRD-positive patients, respectively). In the favorable risk subgroup of patients being MRD-negative at the time of NMA-HSCT, the median overall survival reached 49% at 5 years after NMA-HSCT, irrespective of the HCT-CI. Conclusion: In the here presented cohort of older AML patients a higher HCT-CI did not have a negative impact on NRM or survival. In general, the NRM following NMA-HSCT was relatively low. Our data indicates that comorbidities per se - reflected by a higher HCT-CI score - should not impede NMA-HSCT. Independently from the HCT-CI score MRD-negative patients had notably good survival of 49 % at 5 years following NMA-HSCT. As the incidences of chronic graft-versus host disease were relatively high, alternative immunosuppressive strategies may help to further improve outcomes. Our data aid in informed clinical decisions regarding HSCT consolidation in older AML patients since we show that HSCT with this reduced toxicity regimen represents a feasible treatment option in older and comorbid AML patients also with higher HCT-CI scores. Figure 1 Figure 1. Disclosures Backhaus: Bayer: Other: Current Employment of Family Member. Jentzsch: Astellas: Honoraria; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Honoraria. Vucinic: Janssen: Honoraria, Other: Travel Sponsoring; Novartis: Honoraria; Gilead: Honoraria, Other: Travel Sponsoring; Abbvie: Honoraria, Other: Travel Sponsoring; MSD: Honoraria. Franke: BMS: Honoraria; Gilead: Honoraria, Other: Travel Sponsoring; Jazz Pharmaceuticals: Honoraria, Other: Travel Sponsoring; MSD: Honoraria; Novartis: Honoraria; Pfizer: Honoraria. Platzbecker: Celgene/BMS: Honoraria; AbbVie: Honoraria; Janssen: Honoraria; Novartis: Honoraria; Geron: Honoraria; Takeda: Honoraria. Schwind: Novartis: Honoraria, Research Funding; Pfizer: Honoraria.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2021-150712

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. 3399-3399

Abstract: Older patients (pts) with newly diagnosed ALL are ineligible for unmodified pediatric-based therapies. Even with age-adapted, dose-reduced regimens early death rates (ED) are considerable and overall survival (OS) poor. Thus, 412 pts treated according to the GMALL Elderly Protocol showed a CR rate of 75%, with 16% early death (ED) and the 3 years (yrs) OS was only 30%. Therefore, the GMALL study group developed a trial to evaluate Blinatumomab (Blina), a CD19 directed bi-specific T-cell engager, in sequence with chemotherapy in this patient population with high medical need (NCT 03480438). Blina replaces several cycles of chemotherapy being part of the standard GMALL protocol for older pts. Pts aged 56 - 76 yrs with CD19-positive, Ph-neg B-precursor ALL are eligible. The primary endpoint is complete hematologic remission (CR) after induction i.e. one dose-reduced cycle chemotherapy induction (IP1) and one cycle Blina (Blina 1), and the key secondary endpoint is molecular response (table 1). The efficacy population includes pts treated with IP1 and Blina 1 or ED. The trial is ongoing and scheduled to recruit 50 pts. After a 5-d prephase with dexamethasone (dexa) and cyclophosphamide (cyclo) pts receive dexa (10 mg/m 2 d 7-8 and 14-17), vincristine (2 mg d 7 and 14) and idarubicin (10 mg d 7 and 15) together with i.th. triple prophylaxis (d 6 and d 20) and G-CSF as IP1. Rituximab is given to pts with CD20+ ALL. Thereafter, pts with CR, CRu or PR receive Blina 1 (28 µg/d, 28 d). Pts with failure to IP1 are treated with IP2 (cytarabine, cyclo) followed by Blina 1. A dose step after one week (9µg/d to 28µg/d) is scheduled in all pts starting Blina while not in CR/CRu. Consolidation treatment consists of alternating cycles of intermediate-dose methotrexate/ PEG-asparaginase, intermediate-dose cytarabine and reinduction and 3 further cycles of Blina. This is followed by a standard maintenance (6-MP/MTX) up to a total treatment duration of 2 yrs. Pts receive up to 9 doses of i.th. triple combination. MRD is measured in bone marrow in the central reference laboratory in Kiel with quantitative IG/TR PCR according to EuroMRD standards after IP1, Blina 1, consolidation 1 and 2 and thereafter approximately every 2-3 months. 34 pts with a median age of 65 (56-76) yrs were included from 13 centers in Germany. 7 pts were older than 70 yrs (21%). 7 pts (26%) had pro-B-ALL (N=2 KMT2A rearranged) and 25 pts c-/pre-B-ALL. 47% of the pts had comorbidities according to the Charlson Score; most frequent were diabetes (18%) myocardial infarction (12%), chronic pulmonary disorder (12%). In one pt study treatment was terminated in CR due to subdural hemorrhage in IP1 considered as contraindication for Blina 1. 33 pts were evaluable for IP1: 76% achieved CR/CRu, 9% PR (N=3) 3 pts had treatment failure (9%) and 2 pts (6%) died due to infections. 29% (N=9) had a molecular response (17% MolCR) (table 1). 1/3 pts with failure after IP1 had a CR after IP2. 29 pts were evaluable for the primary endpoint after Blina 1. 24 were in hematologic CR (83%), 3 had failure (10%) and 2 experienced ED (7%; both during IP1 as mentioned above; no additional ED). 82% of the CR pts (N=19) had a molecular response (69% MolCR). 8 / 9 pts with pro-B-ALL had a CR after Blina 1 (89%) and the molecular response rate was 62% (37% MolCR). The median follow-up is 363 (26-1001) days. Survival probability for the efficacy population (N=29) after 1 yr was 84% (figure 1) and 86% for the total population. The 1y OS was 89% for c/pre-B-ALL and 75% for pro-B-ALL. OS was 100% at 1 yr for pts aged 55-65 yrs and 66% for those older than 65 yrs. 2 pts were transplanted in CR1. 2 pts relapsed, both pro-B-ALL, 1 pt developed a secondary malignancy (Colonic Ca) and 2 pts died in CR (1 HLH, 1 arterial disease). Disease Free Survival was 89% at 1 yr. Blinatumomab was well tolerated. No death occurred during Blina 1. The pt with HLH died after consolidation I but correlation to prior Blina is possible. Overall tolerability and efficacy of the regimen was promising with a high cytologic and molecular response rate and low mortality for this age group. Dose-reduced chemo induction intended for leukemia debulking was effective but was also associated with two cases of ED. Age and subtype appeared to have an impact on the outcome with poorer results for older pts and those with pro-B-ALL. Confirmation of the results in a larger, potentially randomized trial and with longer follow-up is warranted. Figure 1 Figure 1. Disclosures Goekbuget: Incyte: Other: Research funding for Institution; Amgen: Consultancy, Other: Invited talks for company sponsored symposia (with honoraria); Research funding for institution; Astra Zeneca: Other: Invited talk for company sponsored symposia (with honor); Gilead/Kite: Consultancy; Novartis: Consultancy, Other: Research funding for Institution; Pfizer: Consultancy, Other: Research funding for institution; Jazz Pharmaceuticals: Other: Research funding for institution; Cellestia: Consultancy; Erytech: Consultancy; Morphosys: Consultancy; Servier: Consultancy, Other; Abbvie: Other. Topp: Macrogeniecs: Research Funding; Amgen: Consultancy, Research Funding; Regeneron: Consultancy, Research Funding; Gilead: Research Funding; Roche: Consultancy, Research Funding; Novartis: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Janssen: Consultancy; Universitatklinikum Wurzburg: Current Employment. Schwartz: Novartis: Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Other: Travel grants, Speakers Bureau; Basilea: Other: Travel grants; MSD Sharp & Dohme: Membership on an entity's Board of Directors or advisory committees; BTG International Inc: Membership on an entity's Board of Directors or advisory committees; Morphosys: Research Funding; Gilead: Other: Travel grants, Speakers Bureau; Jazz Pharmaceuticals: Other: Travel grants, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau. Hertenstein: Novartis: Honoraria; Sanofi: Honoraria; Celgene: Honoraria; BMS: Honoraria. Vucinic: Gilead: Honoraria, Other: Travel Sponsoring; Abbvie: Honoraria, Other: Travel Sponsoring; MSD: Honoraria; Janssen: Honoraria, Other: Travel Sponsoring; Novartis: Honoraria. Brüggemann: Amgen: Other: Advisory Board, Travel support, Research Funding, Speakers Bureau; Incyte: Other: Advisory Board; Janssen: Speakers Bureau. Viardot: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kite/Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; University Hospital of Ulm: Current Employment. OffLabel Disclosure: Blinatumomab in newly diagnosed ALL

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2021-146214

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. 280-280

Abstract: Treatment of elderly patients with AML remains challenging. While increasing doses of induction and consolidation chemotherapy have failed to improve outcome, efforts to decrease relapse rates using the graft-versus-leukemia effect have shown promising results in phase II studies. In the present analysis of the prospective OSHO 2004 study we evaluated the effect of post-induction hematopoietic cell transplantation (HCT) in comparison to conventional consolidation chemotherapy (CT) on outcome in elderly patients with AML. The OSHO 2004 study is part of the German intergroup study. Upon achieving complete remission (CR) after induction, patients were assigned to CT or HCT depending on the availability of a matched related or unrelated donor. Unrelated, single antigen mismatched donors were accepted in high risk situations. By April 2014 from 817 eligible patients, 505 entered CR (62%) after one or two induction therapies. From the 452 patients who received consolidation in CR 1, 31 patients (7%) relapsed and 10 (2%) died of complications during consolidation. No further therapy for medical reasons was given to 73 patients, 206 patients received second consolidation with cytarabine (0.5 g/m2 i.v. bid d1, 3, 5) plus mitoxantrone (10 mg/m² d1-2) and 132 patients underwent HCT. Most frequent conditioning regimens for HCT were low dose TBI (83%) and treosulfan/fludarabine (12%). Most of the patients received HCT from unrelated (80%) donors and the majority received grafts from HLA-identical (78%) donors. Our analysis was restricted to the 315 patients 〈 75 years receiving either CT or HCT. Probabilities for overall survival (OS) and leukemia free survival (LFS) were estimated according to the Kaplan-Meier method and differences tested by the log-rank test. Relapse incidence (RI) and non relapse mortality (NRM) were described by estimating the cumulative incidence and testing the differences using the Gray's test. Multivariate Cox regression models and competing risks regression models were used to identify independent prognostic variables for outcomes. The median age was 67 (60-74) and 65 (60-74) years in the CT and the HCT groups (p 〈 0.0005), respectively. There were no differences between CT and HCT regarding gender, AML type (de novo, secondary or therapy related) and FLT3 mutation status. However more patients with mutated NPM1 were observed in the CT as compared to the HCT group (39% vs 28%; p=0.07) and more patients entered into remission after one induction in the CT as compared to the HCT group (89% vs. 81%; p=0.05). Low risk cytogenetics and normal karyotype were present more frequently in the CT than in the HCT arm (p 〈 0.0005). The interval from CR to CT was 50 days and from CR to HCT 72 days (p 〈 0.0005). Patients receiving related or unrelated matched/mismatched HCT had superior LFS than those receiving CT (32±5% vs. 13±4% at 8 years, respectively; p 〈 0.0005). The difference was more distinct when only those patients with matched related or unrelated donors were compared to those receiving CT (36±6% vs. 13±4% at 8 years; p 〈 0.0005). Similar figures were obtained for overall survival [OS, 35±5% matched/mismatched HCT vs. 24±4% for CT (p=0.18) and 41±6% for matched HCT patients vs. 24±4% for CT (p=0.09)]. RI was lower after HCT (40±5%) than after CT (79±5%; p 〈 0.0001). In contrast, NRM was higher in HCT patients (28±7%) than in CT patients (9±11%; p 〈 0.0001). Subpopulation analyses identified no difference in LFS and OS between matched related versus unrelated HCT. The difference in LFS between HCT and CT was highest in patients with normal karyotype, high risk cytogenetics and patients with non-monosomal karyotyp. Prognostic factors for LFS, OS, RI and NRM were analyzed in a multivariate analysis. Significant prognostic factors for LFS were cytogenetic risk (p=0.04), HCT (p=0.01) and FLT3 mutation status (p=0.07). OS was determined by cytogenetics p 〈 0.01) with a trend for lower age (p=0.07) and HCT (p=0.14). Prognostic factors for RI were cytogenetics (p 〈 0.0006), FLT3 mutation status (p 〈 0.03) and HCT (p 〈 0.0005). NRM was influenced by HCT (p=0.002). Conclusions: HCT from related or unrelated donors improved LFS and OS in patients with AML over the age of 60 years and in particular in those with high risk cytogenetics or normal karyotype disease. The LFS of over 30% after 8 years achieved by HCT represents a marked improvement in the prognosis of patients with AML aged 60-75 years in CR1. Disclosures Al-Ali: Novartis: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Wolf:Bayer: Honoraria; Geo Pharma: Honoraria. Hochhaus:ARIAD Pharmaceuticals, Inc.: Research Funding. Maschmeyer:Celgene: Consultancy.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V124.21.280.280

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. 140, No. Supplement 1 ( 2022-11-15), p. 7750-7751

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2022-169478

Language: English

Publisher: American Society of Hematology

Publication Date: 2022

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7