Kooperativer Bibliotheksverbund

In: Blood, American Society of Hematology, Vol. 132, No. 21 ( 2018-11-22), p. 2280-2285

Abstract: The WHO Classification of Tumours of Haematopoietic and Lymphoid Tissue notes instances of Burkitt lymphoma/leukemia (BL) with IG-MYC rearrangement displaying a B-cell precursor immunophenotype (termed herein “preBLL”). To characterize the molecular pathogenesis of preBLL, we investigated 13 preBLL cases (including 1 cell line), of which 12 were analyzable using genome, exome, and targeted sequencing, imbalance mapping, and DNA methylation profiling. In 5 patients with reads across the IG-MYC breakpoint junctions, we found evidence that the translocation derived from an aberrant VDJ recombination, as is typical for IG translocations arising in B-cell precursors. Genomic changes like biallelic IGH translocations or VDJ rearrangements combined with translocation into the VDJ region on the second allele, potentially preventing expression of a productive immunoglobulin, were detected in 6 of 13 cases. We did not detect mutations in genes frequently altered in BL, but instead found activating NRAS and/or KRAS mutations in 7 of 12 preBLLs. Gains on 1q, recurrent in BL and preB lymphoblastic leukemia/lymphoma (pB-ALL/LBL), were detected in 7 of 12 preBLLs. DNA methylation profiling showed preBLL to cluster with precursor B cells and pB-ALL/LBL, but apart from BL. We conclude that preBLL genetically and epigenetically resembles pB-ALL/LBL rather than BL. Therefore, we propose that preBLL be considered as a pB-ALL/LBL with recurrent genetic abnormalities.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2018-03-842088

Language: English

Publisher: American Society of Hematology

Publication Date: 2018

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. 2639-2639

Abstract: Background: In early studies of venetoclax (ven) in CLL, severe tumor lysis syndromes (TLS) were observed leading to the implementation of multiple safety measures including a 5-week ramp up schedule. Since then, studies have consistently reported low rates of TLS in ven-treated patients (pts), most likely as a result of strict prophylactic and laboratory monitoring measures. Various lead-in regimens prior to the administration of ven were shown to be feasible and effective in reducing the risk of TLS in pts with CLL. However, no comparison of different pretreatment regimens has been performed so far in a prospective randomized trial. Using the set-up of the GAIA trial, we compared TLS incidence and formal TLS risk reduction between 3 different ven-based combinations. Methods: The phase 3 GAIA (CLL13) trial compared 3 different time-limited ven-based combinations against standard chemoimmunotherapy (CIT) in fit, treatment-naïve pts with CLL. Pts were randomized to receive CIT (FCR in pts ≤65 years; BR in pts & gt;65 years), ven and rituximab (RVe), ven and obinutuzumab (GVe), or ven, obinutuzumab and ibrutinib (GIVe). In RVe, GVe and GIVe, ven was added at cycle 1 day 22 (ramp up day 1) after a 21-day pretreatment with rituximab (1 dose), obinutuzumab (3 doses) or obinutuzumab (3 doses) plus ibrutinib (continuous) (Figure 1A). The safety population (i.e. all pts who received study treatment) of the ven-containing arms was used for this analysis. TLS was reported according to Cairo-Bishop criteria (Cairo M, Bishop M. Br J Haematol. 2004). For TLS risk evaluation, the most recent available CT/MRI and absolute lymphocyte count (ALC) were used. TLS risk was evaluated at baseline and at ramp up day 1, before the first dose of ven. The patients were categorized retrospectively according to the following TLS risk categories: high (any lymph node [LN] with largest diameter ≥10 cm or any LN with largest diameter ≥5 cm and ALC ≥25 G/L), intermediate (any LN ≥5 cm to & lt;10 cm or ALC ≥25 G/L), low (all LN & lt;5 cm and ALC & lt;25 G/L). Results: The safety population of all ven-containing arms comprised of 696 pts (RVe: 237, GVe: 228, GIVe: 231). Baseline TLS risk was high in 22%, 23% and 19% of pts in the RVe, GVe and GIVe arm, intermediate in 62%, 65%, 67% and low in 10.5%, 14.7% and 12.4% of pts, respectively. After the first 21 days of treatment (i.e. at ramp up day 1), the fraction of pts with a reduction in TLS risk varied between the treatment arms with 31.7% (RVe), 71.4% (GVe) and 47.3% (GIVe) of pts decreasing by at least one TLS risk category (Figure 1B). With regard to TLS risk reduction, GVe was superior to RVe (p & lt;0.001) and GIVe (p & lt;0.001) while GIVe was superior to RVe (p=0.001)). At ramp up day 1, 2 patients (1.0%) in the GVe arm versus 60 patients (29.6%) in the GIVe arm had an ALC ≥25 G/L, likely as a correlate of ibrutinib-associated redistribution of lymphocytes to the peripheral blood, readily explaining part of the difference in TLS risk reduction between GVe and GIVe. In total, 36, 30 and 19 cases of TLS occurred in 29 (12.2%), 26 (11.4%) and 19 (8.2%) pts in the RVe, GVe and GIVe arm. The majority of TLS cases were categorized as CTC grade 3 (28 [RVe], 19 [GVe] , 12 [GIVe]), only few CT C grade 4 TLS were reported (1 [RVe], 2 [GVe] , 3 [GIVe]). There were no cases of fatal TLS and no pts requiring dialysis due to TLS. In the obinutuzumab arms the majority of TLS cases occurred before ramp up day 1 (GVe: 76.7%, GIVe: 68.4%), i.e. before any venetoclax intake, in contrast 80.6% of TLS cases in the RVe arm were reported during ven ramp up (Figure 2). While there was no significant difference in the cumulative TLS incidence between the treatment arms (p=0.334), there was an increase in TLS occurring after ramp up day 1 in the RVe arm compared to GVe (p & lt;0.001) and GIVe (p=0.002). Conclusions: This analysis represents the first comparison of the formal TLS risk reduction and actual TLS incidence of different ven-based combinations in a randomized trial. GVe led to the highest TLS risk reduction, while the lowest number of TLS cases occurred in the GIVe arm. Most TLS cases in the GVe and GIVe arms occurred before the start of ven. RVe was least effective in reducing TLS risk and in contrast to the obinutuzumab-containing arms, the vast majority of TLS cases was reported during the ven ramp up. The relatively high incidence of TLS in comparison to other trials might partly be a consequence of using different reporting criteria (Cairo-Bishop vs Howard criteria). No fatal TLS occurred in any of the treatment arms. Figure 1 Figure 1. Disclosures Von Tresckow: AbbVie: Honoraria, Other: advisory board, travel grant; Celgene: Other: travel grant; AstraZeneca: Honoraria, Other; Roche: Honoraria, Other: Reasearch support, travel grant; Janssen: Honoraria, Other: Reasearch support, travel grant. Niemann: Novo Nordisk Foundation: Research Funding; CSL Behring, Genmab, Takeda, Octapharma: Consultancy; Abbvie, AstraZeneca, Janssen: Consultancy, Research Funding. Kater: Abbvie: Honoraria, Other: Ad Board, Research Funding; Janssen, AstraZeneca: Other: Ad Board, steering committee, Research Funding; Genmab, LAVA: Other: Ad Board, Steering Committee; BMS, Roche/Genentech: Other: Ad Board, , Research Funding. Staber: Roche: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Astra Zeneca: Consultancy, Honoraria; Takeda: Consultancy, Research Funding; MSD: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Incyte: Consultancy, Honoraria, Research Funding; Beigene: Consultancy, Honoraria. Tadmor: Janssen: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding. Levin: Roche, Janssen, Abbvie: Other: Travel Expenses, Ad-Board. Poulsen: Janssen: Consultancy; Abbvie: Consultancy. Janssens: Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Trael Grant, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy; Beigene, AstraZeneca: Consultancy, Speakers Bureau; Abbvie, Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Noesslinger: AbbVie: Honoraria; Celgene: Honoraria; Roche: Honoraria; Jansen: Honoraria; AstraZeneca: Honoraria; Gilead: Honoraria. Simon: Gilead: Other: Travel support. Fink: AbbVie: Other: travel grant; Janssen: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Research Funding; Celgene: Research Funding. Fischer: Abbvie: Honoraria; Roche: Honoraria, Other: Travel Grants. Wendtner: Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding; F. Hoffmann-LaRoche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding; Janssen Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding; Mundipharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding. Ritgen: MSD: Consultancy, Other: Travel support; Chugai: Consultancy; Abbvie: Consultancy, Other: Travel support, Research Funding; Roche: Consultancy, Other: Travel support, Research Funding; Celgene: Other: Travel support. Brüggemann: Amgen: Other: Advisory Board, Travel support, Research Funding, Speakers Bureau; Incyte: Other: Advisory Board; Janssen: Speakers Bureau. Stilgenbauer: AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann-La Roche, Janssen, Novartis, Sunesis: Honoraria; AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann-La Roche, Janssen, Novartis, Sunesis: Other: Research Support; AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann-La Roche, Janssen, Novartis, Sunesis: Research Funding; AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann-La Roche, Janssen, Novartis, Sunesis: Consultancy. Hallek: Roche: Honoraria, Speakers Bureau; Gilead: Honoraria, Speakers Bureau; Mundipharma: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Pharmacyclics: Honoraria, Speakers Bureau. Eichhorst: Gilead: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodation, expenses, Research Funding, Speakers Bureau; F. Hoffmann-La Roche Ltd: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodation, expenses, Research Funding, Speakers Bureau; AbbVie: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodation, expenses, Research Funding, Speakers Bureau; BeiGene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodation, expenses, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodation, expenses, Speakers Bureau; Adaptive Biotechnologies: Speakers Bureau; Hexal: Speakers Bureau; ArQule: Membership on an entity's Board of Directors or advisory committees; Oxford Biomedica (UK): Membership on an entity's Board of Directors or advisory committees; MSD: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodation, expenses, Research Funding, Speakers Bureau; Consultant Department I for Internal Medicine: Consultancy; University Hospital of Cologne: Current Employment. OffLabel Disclosure: The combination of obinutuzumab, venetoclax and ibrutinib is not approved for the treatment of CLL

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2021-147790

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. 139, No. 9 ( 2022-03-03), p. 1318-1329

Abstract: Despite considerable treatment advances with targeted therapies for patients with chronic lymphocytic leukemia (CLL) deemed high-risk [del(17p) and/or TP53 mutation], the outcome is still inferior compared with other CLL patients. Combining multiple agents with distinct mechanisms of action may further improve outcomes. CLL2-GIVe is an open-label, multicenter trial which enrolled patients with previously untreated CLL with del(17p) and/or TP53 mutation. Patients received induction therapy with obinutuzumab (GA-101), ibrutinib, and venetoclax (GIVe) for cycles 1 through 6 and consolidation therapy with venetoclax and ibrutinib for cycles 7 through 12. Ibrutinib monotherapy was continued for cycles 13 through 36 in patients not reaching a complete response (CR) with serial undetectable minimal residual disease (uMRD) after consolidation. The primary endpoint was CR rate at cycle 15 (final restaging). Secondary endpoints included MRD, survival, and safety. All 41 patients enrolled between September 2016 and August 2018 received study treatment and were included in efficacy and safety populations. With a CR rate of 58.5% at cycle 15, the primary endpoint was met (95% CI: 42.1-73.7; P & lt; .001). At final restaging, 78.0% of patients had uMRD in peripheral blood (PB); 65.9% of patients had uMRD in bone marrow (BM). Estimated progression-free survival (PFS) and overall survival (OS) rates at 24 months were both 95.1%. Adverse events were reported in all patients; most were low grade (grade ≥3: 23.9%). Two deaths were reported (cardiac failure and ovarian carcinoma), neither related to study treatment. The CLL2-GIVe treatment regimen has a manageable safety profile and is a first-line treatment of good efficacy for patients with high-risk CLL.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.2021013208

Language: English

Publisher: American Society of Hematology

Publication Date: 2022

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 137, No. 9 ( 2021-03-4), p. 1219-1232

Abstract: Clinically relevant brain metastases (BMs) frequently form in cancer patients, with limited options for effective treatment. Circulating cancer cells must first permanently arrest in brain microvessels to colonize the brain, but the critical factors in this process are not well understood. Here, in vivo multiphoton laser-scanning microscopy of the entire brain metastatic cascade allowed unprecedented insights into how blood clot formation and von Willebrand factor (VWF) deposition determine the arrest of circulating cancer cells and subsequent brain colonization in mice. Clot formation in brain microvessels occurred frequently ( & gt;95%) and specifically at intravascularly arrested cancer cells, allowing their long-term arrest. An extensive clot embedded ∼20% of brain-arrested cancer cells, and those were more likely to successfully extravasate and form a macrometastasis. Mechanistically, the generation of tissue factor-mediated thrombin by cancer cells accounted for local activation of plasmatic coagulation in the brain. Thrombin inhibition by treatment with low molecular weight heparin or dabigatran and an anti-VWF antibody prevented clot formation, cancer cell arrest, extravasation, and the formation of brain macrometastases. In contrast, tumor cells were not able to directly activate platelets, and antiplatelet treatments did reduce platelet dispositions at intravascular cancer cells but did not reduce overall formation of BMs. In conclusion, our data show that plasmatic coagulation is activated early by intravascular tumor cells in the brain with subsequent clot formation, which led us to discover a novel and specific mechanism that is crucial for brain colonization. Direct or indirect thrombin and VWF inhibitors emerge as promising drug candidates for trials on prevention of BMs.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.2020005710

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. 19 ( 2021-11-11), p. 1805-1816

Abstract: Fifty-one of 189 evaluable patients from 3 prospective phase 2 trials evaluating a sequential targeted treatment had high-risk chronic lymphocytic leukemia (CLL) with a 17p deletion, TP53 mutation, or both. Twenty-seven patients started treatment with bendamustine debulking before induction and maintenance treatment, which was ibrutinib/ofatumumab (IO) in 21 patients, ibrutinib/obinutuzumab (IG) in 13, and venetoclax/obinutuzumab (AG) in 17. The primary end point was overall response rate after 8 months of induction treatment, which was 81%, 100%, and 94% for IO, IG, and AG, respectively. Minimal residual disease (MRD) was undetectable (uMRD) in peripheral blood ( & lt;10−4 by flow cytometry) in 0%, 23%, and 82% of patients, respectively. Median progression-free survival (PFS) was 45 months. Seventeen patients discontinued maintenance treatment due to uMRD: 9 progressed, 2 died without progression (median PFS, 28 months after discontinuation of treatment), and 6 remained in remission after a median observation time of 46 months (range, 6-47 months) after treatment discontinuation. Thus, MRD-guided fixed-duration therapies combining obinutuzumab with venetoclax or ibrutinib can induce deep and durable remissions in CLL patients with high-risk genetic lesions, which can persist after treatment discontinuation (due to a predefined fixed-duration or MRD-guided early termination). The median PFS was 45 months. These trials were registered at www.clinicaltrials.gov as #NCT02345863, #NCT02401503, and #NCT02689141.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.2020010484

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. 140, No. Supplement 1 ( 2022-11-15), p. 834-836

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2022-163245

Language: English

Publisher: American Society of Hematology

Publication Date: 2022

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 1209-1209

Abstract: About 20-25% of patients with Acute Myeloid Leukemia (AML) have primary drug resistant disease and fail to achieve complete remission after induction therapy. These patients have an extremely poor prognosis and cannot reliably be identified prior to therapy with current methods. The aim of this work was to develop a predictive tool that can identify therapy resistant patients with high accuracy at the time of diagnosis. We used two independent Affymetrix gene expression (GE) data sets and standard molecular and clinical variables to develop a predictive score for response to cytarabine/anthracycline-based induction chemotherapy. The "training set 1" consisted of 407 adult AML patients enrolled in the AMLCG-1999 trial (GSE37642). Training set 2 included 449 adults treated in various HOVON trials (GSE6891). GE-based classifiers for primary treatment resistance were developed in training set 1 using a penalized logistic regression approach (Lasso). A cut off with a specificity of 90% was predefined in training set 1. Training set 2 was used to select the best classifier. The predictive score and cut off were then validated in a third, fully independent data set, comprising 260 patients enrolled in AMLCG-1999 and 2008 trials studied by RNA sequencing. Additionally, targeted amplicon sequencing data for 68 recurrently mutated genes in AML was available for training set 1 and the validation set. The final classifier (Predictive score 29 MRC - PS29MRC) consisted of 29 gene expression values and the cytogenetic risk group (defined according to the United Kingdom Medical Research Council (MRC) classification) and was calculated as a weighted sum of Lasso coefficients and predictor values. PS29MRC was a highly significant predictor of resistant disease in the validation set with an odds ratio of 2.32 (p=1.53x10-8, AUC: 0.75). We tested the signature in a multivariable model including all variables with univariate p-value & lt;0.05. TP53 mutations, age and PS29MRC (OR: 1.70; p=0.0020) were left significant in the validation set. In comparison to published predictive classifiers like the model by Walter et al. (integrating information on age, performance status, white blood cell count, platelet count, bone marrow blasts, gender, type of AML, cytogenetics and NPM1 and FLT3-ITD status; OR: 1.27; p=0.00083; AUC: 0.70) or the modified molecular version of this score (OR: 1.37; p=0.0027; AUC: 0.63) PS29MRC reached superior predictive accuracy. (Walter et al.; Leukemia 2015) Since we aimed to develop a clinically useful score, we categorized PS29MRC to distinguish between patients who have a high probability of refractory disease and those who are likely to benefit from induction therapy (complete remission or complete remission with incomplete hematologic recovery). By applying the predefined cut off, we were able to reach a specificity of 90% and sensitivity of 46% in the validation set (OR: 7.83; p=6.06x10-9). The accuracy of PS29MRC was 77%. In the multivariable model the categorized classifier was highly significant (OR: 4.45; p=0.00040) and only age and TP53 mutations were left as significant variables again. Within the cytogenetic subgroups favorable (n=14; refractory: n=0; responders: n=13), intermediate (n=189; refractory: n=43; responders: n=136) and adverse (n=49; refractory: n=29; responders: n=15) the classifier showed an accuracy of 100%, 78% and 66%, respectively. Furthermore, the classifier predicted survival and was able to unravel the intermediate MRC subgroup (Figure). Additionally, genes included in our predictive signature seem to be involved in AML pathogenesis and potentially actively contribute to mechanisms responsible for primary therapeutic resistance. For example MIR-155HG, an already known parameter of inferior outcome in AML, contributed significantly to PS29MRC. There are currently ongoing trials with the novel inhibitor Pevonedistat that aim to modulate this target in AML. In summary we were able to develop a predictive risk classifier summarizing 29 gene expression values and the MRC classification that outperformed all currently used methods to predict refractory disease in intensively treated adult AML patients. PS29MRC demonstrates that it is possible to identify patients at risk of treatment failure in AML at diagnosis with high specificity. Figure 1. Kaplan-Meier estimates showing overall survival of AML patients in the validation set according to PS29MRC Figure 1. Kaplan-Meier estimates showing overall survival of AML patients in the validation set according to PS29MRC Figure 2. Figure 2. Disclosures No relevant conflicts of interest to declare.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V128.22.1209.1209

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. 126, No. 23 ( 2015-12-03), p. 101-101

Abstract: Natural killer (NK) cells mediate anti-AML responses and previously published clinical trials of adoptive allogeneic NK cell therapy provide proof-of-principle that NK cells may eliminate leukemia cells in patients. However, complete remissions occur in 30-50% of patients with active AML and are typically of limited duration. Thus, improvements are needed for this promising cellular immunotherapy strategy. Following paradigm-shifting studies in mice, it was established that human NK cells exhibit an innate 'memory-like' responses following a brief, combined pre-activation with IL-12, -15, and -18 (Romee R et. al., Blood, 2012). These long-lived memory-like NK cells have an enhanced ability to produce IFN-g in response to restimulation with cytokines or activating receptor ligation, even following extensive proliferation. We hypothesized that memory-like NK cells exhibit enhanced responses to myeloid leukemia. Compared to control NK cells from the same donor, IL-12/15/18-induced memory-like NK cells produced significantly increased IFN-g upon co-culture with primary AML blasts in vitro (P 〈 0.001), following 7 days of rest in low dose IL-15 vitro. In addition, memory-like NK cells had increased granzyme B expression (P 〈 0.01), and enhanced killing of K562 leukemia targets in vitro (P 〈 0.05). Utilizing an in vivo xenograft model of human NK cells in NSG mice (Leong J et. al., BBMT, 2014), IL-12/15/18-induced memory-like NK cells that differentiated in NSG mice for 7 days exhibited increased IFN-g responses after ex vivo re-stimulation with K562 leukemia, confirming their memory-like functionality (P 〈 0.05). To test in vivo responses to human leukemia in this model, luciferase-expressing K562 cells were engrafted into NSG mice (1x106/mouse, IV), and on day 3, groups of mice were injected with IL-12/15/18-pre-activated or control NK cells from the same donor (4x106/mouse). Mice treated with a single dose of memory-like NK cells exhibited significantly improved in vivo leukemia control measured by whole mouse bioluminescent imaging (P=0.03), as well as overall survival (P 〈 0.05), compared to mice treated with control or no NK cells. Based on these pre-clinical findings, we initiated a first-in-human clinical trial of HLA-haploidentical IL-12/15/18-induced memory-like NK cells in patients with AML (NCT01898793). Relapsed/refractory (rel/ref) AML patients receive lymphodepleting non-myeloablative flu/cy conditioning, infusion of a single dose of CD56+CD3- memory-like donor NK cells, followed by two weeks of low dose rhIL-2. Three patients were treated at dose level 1 (0.5x106 cells/kg) and two patients treated at dose level 2 (1.0x106/kg) with no DLTs observed, and accrual continues. Correlative analyses utilizing donor-specific HLA mAbs allow tracking of donor memory-like NK cell frequency and function following adoptive transfer. Donor memory-like NK cells were detectable in the PB and BM of all tested patients with informative HLA (4/5), peak in frequency at 7-8 days post-infusion, and contract after 14-21 days as expected following recipient T cell recovery (Figure). Memory-like NK cells exhibit significantly increased Ki67%+ as a marker of proliferation at day 7 [97.8+1.0% (donor) vs. 21.6+5.5% (recipient), mean+SEM, P 〈 0.001]. Moreover, functional analyses of NK cells at days 7-8 post-infusion reveal increased numbers of donor IFN-g+ NK cells following restimulation with K562 leukemia cells in the same blood [1009+590 (donor) vs. 8+3 (recipient) IFN-g+ NK cells] or BM [686+423 (donor) vs. 4+2 (recipient) IFN-g+ NK cells] samples. Two of four evaluable patients treated with memory-like NK cells had leukemia free BM and PB at days 14 post-therapy, which correlated with BM NK cell frequency and IFN-g production (Figure). CIML007 had rel/ref AML with 48% BM blasts pre-therapy, and had no evidence of leukemia on day 14, 28, and 100 BM biopsies, and has an ongoing complete remission more than 100 days after this therapy. CIML009 had 80% BM blasts pre-therapy, and had no evidence of leukemia on day 14 BM biopsy post-infusion. Thus, human IL-12/15/18-induced memory-like NK cells expand and have enhanced anti-AML function following adoptive transfer in patients, thereby constituting a promising translational innovation for immunotherapy of AML. Figure 1. Figure 1. Disclosures Fehniger: Celgene: Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V126.23.101.101

Language: English

Publisher: American Society of Hematology

Publication Date: 2015

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. 842-845

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2022-164786

Language: English

Publisher: American Society of Hematology

Publication Date: 2022

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 142, No. 11 ( 2023-09-14), p. 961-972

Abstract: The final analysis of the open-label, multicenter phase 2 CLL2-GIVe trial shows response and tolerability of the triple combination of obinutuzumab, ibrutinib, and venetoclax (GIVe regimen) in 41 previously untreated patients with high-risk chronic lymphocytic leukemia (CLL) with del(17p) and/or TP53 mutation. Induction consisted of 6 cycles of GIVe; venetoclax and ibrutinib were continued up to cycle 12 as consolidation. Ibrutinib was given until cycle 15 or up to cycle 36 in patients not achieving a complete response and with detectable minimal residual disease. The primary end point was the complete remission rate at cycle 15, which was achieved at 58.5% (95% CI, 42.1-73.7; P  & lt; .001). The last patient reached the end of the study in January 2022. After a median observation time of 38.4 months (range, 3.7-44.9), the 36-month progression-free survival was 79.9%, and the 36-month overall survival was 92.6%. Only 6 patients continued ibrutinib maintenance. Adverse events of concern were neutropenia (48.8%, grade ≥3) and infections (19.5%, grade ≥3). Cardiovascular toxicity grade 3 occurred as atrial fibrillation at a rate of 2.4% between cycles 1 and 12, as well as hypertension (4.9%) between cycles 1 and 6. The incidence of adverse events of any grade and grade ≥3 was highest during induction and decreased over time. Progressive disease was observed in 7 patients between cycles 27 and 42. In conclusion, the CLL2-GIVe regimen is a promising fixed-duration, first-line treatment for patients with high-risk CLL with a manageable safety profile.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.2023020013

Language: English

Publisher: American Society of Hematology

Publication Date: 2023

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7