Duration of Post-Autologous Hematopoietic Cell Transplant Anemia and Thrombocytopenia Are Associated with Prolonged Hospital Length-of-Stay for Multiple Myeloma Patients

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 5-6
Author(s):  
Binbin Zheng-Lin ◽  
Nirupama Krishnamurthi ◽  
Benjamin Diamond ◽  
Kylee H Maclachlan ◽  
Francesco Maura ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Research Funding ◽  
Demographic Data ◽  
Hospital Length Of Stay ◽  
Data Monitoring ◽  
Cell Transplant ◽  
Independent Data ◽  
Hematopoietic Cell Transplant ◽  
Post Transplant ◽  
Grade Iii

BACKGROUND: Anemia, neutropenia, and thrombocytopenia are expected complications of autologous hematopoietic cell transplant (AHCT) for multiple myeloma (MM). However, prolonged cytopenias may predispose patients to other infectious, cardiovascular, and/or hematological toxicities. Various factors have been implicated in the length of post-AHCT cytopenias including stem cell dose, marrow microenvironment, and clonal hematopoiesis. We hypothesize that the length of post-transplant anemia, neutropenia, and thrombocytopenia may negatively impact hospital length-of-stay (LOS) and in-hospital complications. METHODS: This is a single-center observational study of MM patients who underwent AHCT. Patients were part of a larger cohort with detailed single nucleotide polymorphism (SNP) array cytogenetic data. Exclusion criteria were concurrent amyloidosis and tandem transplant. Demographic data, comorbidities, cytogenetic features (presence of TP53 deletion, and translocation status of MMSET, CCDN3, CCDN1, MAF, and MAFB), therapy line, peri-transplant laboratory values, and clinical outcome were collected retrospectively. LOS was calculated from transplant day -2 to hospital discharge. Predictive factors for LOS were calculated with multiple linear regression. Multiple logistic regression was then used to calculate associating factors for in-hospital complications. Grade III and IV post-transplant cardiovascular, infectious, and hematological complications were collected following the Common Terminology Criteria for Adverse Events (CTCAE). Post-transplant anemia was defined as sustained hemoglobin (Hb) <8 g/dL despite transfusions. The cutoffs for neutropenia and thrombocytopenia were absolute neutrophil count (ANC) <1.5 K/uL, and platelet (PLT) count <50 K/uL, respectively. RESULTS: 158 AHCT cases of MM patients were identified. 95 patients received AHCT as frontline treatment, 35 patients were transplanted in the salvage setting, and 14 patients received both frontline and subsequent-line transplant. The most commonly used conditioning regimen was melphalan 200 mg/m2 in 123 cases, followed by melphalan 140 mg/m2 in 23 patients. 50.6% (80/158) developed grade III anemia with a median onset of 9 days after transplant (IQR 5-11 days) and median length of 2 days (IQR 1-6 days). Neutropenia had higher incidence of 96.8% (153/158) with an earlier onset of 5 days (IQR 5-6 days) and median length of 5 days (IQR 2-7 days). Grade III thrombocytopenia occurred in 98.1% (155/158), with median onset of 7 days (IQR 5-7 days) and a median duration of 8 days (IQR 6-10 days). When comparing patients who received frontline transplant vs subsequent line transplants, no statistical significance was observed between onset or length of cytopenias (p=0.40). Median LOS was 16 days (IQR 15-19 days). The most frequent post-AHCT complications in our cohort were neutropenic fever (N=27), followed by engraftment syndrome (N=12), pneumonia (N=4), urinary tract infection (N=2), cellulitis (N=2), and bacteremia (N=1). Cardiovascular events were uncommon (N=3) and included pericarditis, new onset atrial fibrillation, and new onset supraventricular tachycardia. Pulmonary embolism (N=1) and deep vein thrombosis (N=3) were recorded. No major bleeding was observed. Longer LOS was independently associated with post-AHCT anemia (p=0.03) and thrombocytopenia (p=0.0005). Notably, LOS and in-hospital complication rates were not significantly associated with demographic data, pre-existing comorbidities, pre-transplant cytopenias, or cytogenetic abnormalities. CONCLUSION: In our cohort, longer duration of post-transplant anemia and thrombocytopenia were statistically associated with longer hospital LOS, but not with post-transplant complications. Prospective validation in an independent cohort is warranted. Disclosures Landgren: Karyopharma: Research Funding; Binding Site: Consultancy, Honoraria; Takeda: Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Janssen: Consultancy, Honoraria, Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Merck: Other; Seattle Genetics: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Adaptive: Consultancy, Honoraria; Juno: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Cellectis: Consultancy, Honoraria; Juno: Consultancy, Honoraria; Glenmark: Consultancy, Honoraria, Research Funding; Seattle Genetics: Research Funding; Pfizer: Consultancy, Honoraria; Merck: Other; Karyopharma: Research Funding; Binding Site: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Cellectis: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Takeda: Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Glenmark: Consultancy, Honoraria, Research Funding. Chung:Genentech: Research Funding.

scholarly journals Copy Number Signatures Predict Chromothripsis and Poor Clinical Outcome in Newly Diagnosed Multiple Myeloma Patients

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 52-53
Author(s):  
Kylee H Maclachlan ◽  
Binbin Zheng-Lin ◽  
Venkata Yellapantula ◽  
Andriy Derkach ◽  
Even H Rustad ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Clinical Trials ◽  
Research Funding ◽  
De Novo ◽  
Data Monitoring ◽  
Signature Analysis ◽  
Independent Data ◽  
Genetics Research ◽  
Manual Curation ◽  
Low Coverage

Chromothripsis is emerging as a strong and independent prognostic factor in multiple myeloma (MM), predicting shorter progression-free (PFS) and overall survival (Rustad BioRxiv 2019). Reliable detection requires whole genome sequencing (WGS), with 24% prevalence in 752 newly diagnosed multiple myeloma (NDMM) from CoMMpass (NCT01454297, Rustad BioRxiv 2019) compared with 1.3% by array-based techniques (Magrangeas Blood 2011). In MM, chromothripsis presents differently to solid cancers. Although the biological impact is similar across malignancies, in MM the structural complexity of chromothriptic events is typically lower. In addition, chromothripsis can occur early in MM development and remain stable over time (Maura Nat Comm 2019). Computational algorithms for chromothripsis detection (e.g. ShatterSeek; Cortes-Ciriano Nat Gen 2018) were developed in solid cancers and are accurate in that setting. Running ShatterSeek on 752 NDMM patients with low coverage WGS from CoMMpass, we observed a high specificity for chromothripsis (98.3%) but poor sensitivity (30.2%). ShatterSeek detected chromothripsis in 64/752 samples (8.5%), with 85% confirmed on manual curation; however, missed 114 cases located by manual curation. This indicates that MM-specific computational methods are required. We hypothesized that a signature analysis approach using copy number variation (CNV) may provide an accurate estimation of chromothripsis. We adapted CNV signature analysis, developed in ovarian cancer (Macintyre Nat Gen 2018), to now detect MM-specific CNV and structural features. The analysis utilizes 6 fundamental CN features: i) absolute CN of segments, ii) difference in CN in adjacent segments, iii) breakpoints per 10 Mb, iv) breakpoints per chromosome arm, v) lengths of oscillating CN segment chains, and vi) the size of segments. The optimal number of categories in each CNV feature was established using a mixed effect model (mclust R package). Using CoMMpass low-coverage WGS, de novo extraction using the hierarchical dirichlet process defined 5 signatures, 2 of which (CNV-SIG 4 and CNV-SIG 5) contain features associated with chromothripsis: longer lengths of oscillating CN states, higher numbers of breakpoints / chromosome arm, and higher total numbers of small segments of CN change. Next, we demonstrate that CNV signatures are highly predictive of chromothripsis (average area-under-the-curve /AUC = 0.9, based on 10-fold cross validation). Chromothripsis-associated CNV signatures are correlated with biallelic TP53 inactivation (p= 0.01) and gain1q21 (p<0.001) and show negative association with t(11;14) (p<0.001). Chromothriptic signatures were associated with shorter PFS, with multivariate analysis after correction for ISS, age, biallelic TP53 inactivation, t(4;14) and gain1q21 producing a hazard ratio of 2.9 (95% CI 1.07-7.7, p = 0.036). A validation set of 29 NDMM WGS confirmed the ability of CNV signatures to predict chromothripsis (AUC 0.87). As WGS is currently too expensive and computationally intensive to employ in routine practice, we investigated if CNV signatures can predict chromothripsis without using WGS. First, we performed de novo signature extraction using whole exome data from 865 CoMMpass samples. CNV signatures extracted without reference to WGS produced an AUC = 0.81 for predicting chromothripsis (in those with WGS to confirm; n =752), and the chromothriptic-signatures confirmed the association with a shorter PFS (HR=7.2, 95%CI 1.32-39.4, p = 0.022). Second, we applied CNV signature analysis to NDMM having either the myTYPE targeted sequencing panel (n= 113; Yellapantula, Blood Can J 2019) or a single nucleotide polymorphism (SNP) array (n= 217). CNV signature assessment by each technology was predictive of clinical outcome, likely due to the detection of chromothripsis. As with WGS, multivariate analysis confirmed CNV signatures to be independently prognostic (myTYPE; p = 0.003, SNP; p = 0.004). Overall, we demonstrate that CNV signature analysis in NDMM provides a highly accurate prediction of chromothripsis. CNV signature assessment remains reliable by multiple surrogate measures, without requiring WGS. Chromothripsis-associated CNV signatures are an independent and adverse prognostic factor, potentially allowing refinement of standard prognostic scores for NDMM patients and providing a more accurate risk stratification for clinical trials. Disclosures Hultcrantz: Amgen: Research Funding; Daiichi Sankyo: Research Funding; GSK: Research Funding; Intellisphere LLC: Consultancy. Dogan:Takeda: Consultancy; National Cancer Institute: Research Funding; Roche: Consultancy, Research Funding; Seattle Genetics: Consultancy; AbbVie: Consultancy; EUSA Pharma: Consultancy; Physicians Education Resource: Consultancy; Corvus Pharmaceuticals: Consultancy. Morgan:Bristol-Myers Squibb: Consultancy, Honoraria; Janssen: Research Funding; Karyopharm: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria; GSK: Consultancy, Honoraria. Landgren:Cellectis: Consultancy, Honoraria; Takeda: Other: Independent Data Monitoring Committees for clinical trials, Research Funding; BMS: Consultancy, Honoraria; Adaptive: Consultancy, Honoraria; Takeda: Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Glenmark: Consultancy, Honoraria, Research Funding; Seattle Genetics: Research Funding; Binding Site: Consultancy, Honoraria; Karyopharma: Research Funding; Merck: Other; BMS: Consultancy, Honoraria; Karyopharma: Research Funding; Merck: Other; Pfizer: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Seattle Genetics: Research Funding; Juno: Consultancy, Honoraria; Juno: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Pfizer: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Cellectis: Consultancy, Honoraria; Glenmark: Consultancy, Honoraria, Research Funding; Binding Site: Consultancy, Honoraria.

scholarly journals Initial Whole Genome Sequencing of Plasma Cell Neoplasms in First Responders and Recovery Workers Exposed to the World Trade Center Attack of September 11, 2001

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 50-51
Author(s):  
Benjamin Diamond ◽  
Kylee H Maclachlan ◽  
Andriy Derkach ◽  
Venkata Yellapantula ◽  
Even H Rustad ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Clinical Trials ◽  
Plasma Cell ◽  
Research Funding ◽  
First Responders ◽  
Data Monitoring ◽  
Independent Data ◽  
Mutational Signatures ◽  
Mutational Signature ◽  
Plasma Cell Neoplasms

PURPOSE : The World Trade Center (WTC) attack of September 11, 2001 created an unprecedented environmental exposure to known and suspected carcinogens. A higher incidence of multiple myeloma (MM) and precursor disease has been reported among first responders to the WTC disaster compared to the unexposed population (Landgren, 2018). To expand on prior screening studies, and to characterize the genomic impact of the exposure to known and potential carcinogens in the WTC debris, we were motivated to perform whole genome sequencing (WGS) of WTC first responders and recovery workers who were diagnosed with a plasma cell disorder after the attack. PATIENTS AND METHODS: We performed WGS of 9 CD138-positive bone marrow mononuclear samples from patients who were diagnosed with plasma cell disorders after exposure to the WTC disaster: 4 monoclonal gammopathy of undetermined significance (MGUS), 2 smoldering multiple myeloma (SMM), 2 MMs, and 1 patient with plasma cell leukemia (PCL). Eight patients (88%) were first responders and one was a recovery worker. Peripheral blood mononuclear cells were used as normal match. Median coverage for tumor and normal samples was 50.9X (range 47-76) and 37X (range 35-41), respectively. The landscape of genomic drivers and complex structural events was compared to 752 MM patients enrolled in the CoMMpass trial with available whole exome and low-coverage long-insert WGS data (IA15; NCT01454297). To characterize the mutational signature landscape we combined the WTC cohort with 110 whole genomes from 56 patients with multiple myeloma and myeloma precursor disease (Rustad et al. 2020; Landau et al. 2020) and we ran our three-step workflow: de novo extraction (i.e. sigprofiler), assignment, and fitting (i.e. mmsig). To exclude contribution of any environmental agents in the WTC debris with known mutational signatures (Kucab et al., 2019), we ran our fitting algorithm mmsig in each post-WTC case, including and forcing the extraction of these mutational signatures. RESULTS: No significant differences were observed in comparing the post-WTC driver and mutational signatures landscape with 110 previously published WGS from 56 patients with MM and the CoMMpass WGS cohort (n=752). Likewise, we did not observe any new or distinct mutational signatures among WTC-exposed patients. Following forced extraction of 5 mutational signatures associated with environmental agents detected in the WTC debris (e.g. PAHs), we did not find significant contributions from any of these described environmental mutational signatures. To reconstruct the temporal activity of each mutational process we divided all single nucleotide variants into subclonal and clonal. Clonal mutations were further subdivided into duplicated (acquired before a chromosomal gain) and unduplicated (Rustad et al. 2020). WTC-exposed patients had differing patterns in mutational signature timelines of AID and APOBEC activity. Overall, the mutational signature activity over time in post-WTC plasma cell dyscrasia reflects what has been previously observed in multiple myeloma without WTC-exposure (Rustad et al., 2020). Finally, leveraging constant activity of the clock-like single base substitution mutational signatures 1 and 5 over time and our molecular time workflow (Rustad et al., 2020), we estimated the age at which each evaluable patient acquired a tumor-initiating chromosomal gain and found that they were windowed to both pre- and post-WTC exposure across neoplasms (Figure 1). In some cases, clonal multi-chromosomal gain events were acquired decades before both the diagnosis and the WTC exposure. Specifically, of 6 patients with large clonal chromosomal gains, 1 MM case, 1 SMM, and 1 MGUS showed evidence of a pre-existing clone prior to WTC exposure, two MGUS showed evidence of multi-gain events following the exposure, and one MM case had a 1q gain in the same time window as the attack. CONCLUSIONS: Post-WTC plasma cell neoplasms had similar genomic landscapes to non-exposed cases. Although limitations in sample size preclude any definitive conclusions, our findings suggest that the observed increased incidence of plasma cell neoplasms in this population is due to complex and heterogeneous effects of the WTC exposure that may have initiated or contributed to progression of malignancy. The existence of pre-malignant clonal entities at time of WTC exposure may therefore be relevant for future WTC-related study. Figure 1 Disclosures Hultcrantz: Intellisphere LLC: Consultancy; Amgen: Research Funding; Daiichi Sankyo: Research Funding; GSK: Research Funding. Shah:Physicians Education Resource: Honoraria; Celgene/BMS: Research Funding. Iacobuzio-Donahue:BMS: Research Funding. Papaemmanuil:Isabl: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria; Illumina: Consultancy, Honoraria; Kyowa Hakko Kirin: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Prime Oncology: Consultancy, Honoraria; MSKCC: Patents & Royalties. Verma:BMS: Consultancy, Research Funding; acceleron: Consultancy, Honoraria; stelexis: Current equity holder in private company; Janssen: Research Funding; Medpacto: Research Funding. Dogan:National Cancer Institute: Research Funding; EUSA Pharma: Consultancy; Takeda: Consultancy; Seattle Genetics: Consultancy; Corvus Pharmaceuticals: Consultancy; Physicians Education Resource: Consultancy; Roche: Consultancy, Research Funding; AbbVie: Consultancy. Landgren:Celgene: Consultancy, Honoraria, Research Funding; Seattle Genetics: Research Funding; Cellectis: Consultancy, Honoraria; Juno: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Merck: Other; Karyopharma: Research Funding; Janssen: Consultancy, Honoraria, Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Pfizer: Consultancy, Honoraria; Merck: Other; Karyopharma: Research Funding; Binding Site: Consultancy, Honoraria; Takeda: Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Seattle Genetics: Research Funding; Takeda: Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Janssen: Consultancy, Honoraria, Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria; Juno: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Adaptive: Consultancy, Honoraria; Cellectis: Consultancy, Honoraria; Glenmark: Consultancy, Honoraria, Research Funding; Binding Site: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Glenmark: Consultancy, Honoraria, Research Funding.

scholarly journals Monotherapy Activity with the First CD20-Targeted Immunotoxin, MT-3724, in Subjects with Relapsed/Refractory (R/R) Diffuse Large B-Cell Lymphoma (DLBCL)

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4098-4098
Author(s):  
Paul A. Hamlin ◽  
Vasile Musteata ◽  
Mamia Zodelava ◽  
Steven I Park ◽  
Christine Burnett ◽  
...  
Keyword(s):  
Clinical Trials ◽  
B Cell ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Data Monitoring Committee ◽  
Data Monitoring ◽  
Independent Data ◽  
Safety And Efficacy ◽  
Peripheral Edema ◽  
Monitoring Committee

Background: The near ubiquity and persistence of CD20 expression in B-cell malignancies provides a strong rationale for novel CD20-directed therapies. MT-3724 is a novel engineered toxin body comprised of an anti-CD20 single chain variable fragment genetically fused to Shiga-like toxin A subunit, which forces internalization of CD20-bound MT-3724, irreversibly inactivating ribosomes and triggering apoptosis. As MT-3724 competes with rituximab (RTX) for the same CD20 binding domain, undetectable or low (< 500 ng/mL) RTX levels (RTX-neg) allow potential response to MT-3724. We present final safety and efficacy results from dose escalation to maximum tolerated dose (MTD) in Non-Hodgkin Lymphoma (NHL) subjects (subj) and dose expansion in RTX-neg DLBCL subj. Methods: In Part 1, MT-3724 dose was escalated in 21 subj with B-cell NHL according to the 3+3 design based on ≤1 subj exhibiting DLT during Cycle 1 (28 days) in 6 sequential dose cohorts (5, 10, 20, 50, 75, and 100 μg/kg/dose IV over 2 hours 3 times per week for 2 of 4 consecutive weeks) for up to 5 cycles. In Part 2, the safety and efficacy of MT-3724 was further evaluated in 6 RTX-neg subj with DLBCL. Tumor response was assessed by the International Working Group Response Criteria for Clinical Trials (Cheson 2007). Results: Twenty-seven subj with NHL (DLBCL:16, composite DLBCL/Follicular Lymphoma (FL): 3, FL: 6, Mantle Cell Lymphoma: 2 were enrolled. Seventeen (63%) were female, mean age was 65 yrs (34-78). Performance status was ECOG 0: 44%, 1: 44%, 2: 11%; median follow-up was 50 (11-372) days; median cycles 2 (1-11). The most common AEs (%) of all grades were peripheral edema (63), fatigue (41), diarrhea (41), myalgia (41), muscle weakness (33), insomnia (30); 27 subj had AEs (%) with related causality, the most common were: peripheral edema (41), myalgia (33), fatigue (26). The most common related grade (G) ³3 AEs included neutropenia, myalgia, and infections (all 11%); There were 9 related SAEs among 6 subj. One subj died on study from disease progression. MT-3724 was not tolerated at 100 µg/kg/dose (DLTs: G3 pneumonia, G2 ileus). After 2 obese (BMI >35) subj treated at 75 µg/kg/dose in the expansion cohort had G2 capillary leak syndrome (CLS), the MTD was set at 50 µg/kg/dose with a 6000 mg/dose cap. Innate immune responses such as CLS or manifestations thereof (hypotension, hypoalbuminemia, peripheral edema) were noted with increasing frequency with higher doses of MT-3724. No cases of >G2 CLS have been observed. Of the 13 RTX-neg DLBCL subj, 5 (38%) responded across the range of 5 to 50 μg/kg/dose. All responses were partial responses (PRs) including 1 subj with composite DLBCL/FL post autologous stem cell transplantation (SCT) who had a complete metabolic response of a large mesenteric mass and proceeded to allogeneic SCT. Three subj had stable disease (SD) including two with 49% and 47% tumor reductions, one of whom had FL transformed from DLBCL post autologous SCT; another 5 had progressive disease. Given a limited prescribed period of treatment with MT-3724, duration of response cannot be calculated, however, generally the tumor burden in responders decreased with repeat treatment. Among the responders, mean age was 61 (50-76) yrs, and the median number of prior lines of NHL therapy received was 3 (1-8). Subj with detectable baseline RTX levels did not benefit from MT-3724. Of all 20 subj measured, 6 developed anti-drug antibodies (ADAs) during the first cycle of therapy; 5 developed ADAs at a later timepoint; 6 did not develop ADAs. ADAs were observed in all subj who showed a response, and in 4 of 5 subj with SD. Increasing MT-3724 dose was associated with a dose-dependent peripheral B-cell depletion, evidenced by decreasing CD19+ cells. Conclusions MT-3724 is the first CD20 targeted immunotoxin to enter clinical trials. Safety events were mostly mild-moderate, and DLTs were in line with the mechanism of action of MT-3724. A tolerable dose and schedule have been identified: 50 μg/kg/dose up to a maximum of 6000 μg/dose infused over 1 hour on days 1, 3, 5, 8, 10, and 12 of a 21-day cycle. A 38% objective response rate has been observed with monotherapy in a heavily pretreated, RTX-neg DLBCL population; of these subj, 5 were treated at 50 ug/kg (MTD) and 3 of whom responded. The development of ADAs did not preclude benefit of MT-3724. An ongoing phase 2 monotherapy study to confirm efficacy and safety in RTX-neg subj with DLBCL (NCT02361346) is open for recruitment. Disclosures Musteata: Institute of Oncology: Employment; Arensia EM: Other: Principal Investigator. Park:BMS: Consultancy, Research Funding; Rafael Pharma: Membership on an entity's Board of Directors or advisory committees; G1 Therapeutics: Consultancy; Teva: Consultancy, Research Funding; Gilead: Speakers Bureau; Seattle Genetics: Research Funding, Speakers Bureau. Burnett:Molecular Templates, Inc.: Employment. Dabovic:Molecular Templates, Inc.: Employment. Williams:Molecular Templates, Inc.: Employment. Higgins:Molecular Templates, Inc.: Employment, Equity Ownership. Persky:Sandoz: Consultancy; Morphosys: Other: Member, Independent Data Monitoring Committee; Debiopharm: Other: Member, Independent Data Monitoring Committee; Bayer: Consultancy.

scholarly journals Whole-Genome Sequencing Reveals Evidence of Two Biologically and Clinically Distinct Entities: Progressive Versus Stable Myeloma Precursor Disease

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 47-48
Author(s):  
Bénedith Oben ◽  
Guy Froyen ◽  
Kylee H Maclachlan ◽  
Binbin Zheng-Lin ◽  
Venkata Yellapantula ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Clinical Trials ◽  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Research Funding ◽  
Data Monitoring ◽  
Whole Genome ◽  
Independent Data ◽  
Genetics Research ◽  
Complex Events

Introduction Multiple myeloma (MM) is consistently preceded by an asymptomatic expansion of clonal plasma cells, clinically recognized as monoclonal gammopathy of undetermined significance (MGUS) or smoldering multiple myeloma (SMM). Here, we present the first comprehensive whole-genome sequencing (WGS) analysis of patients with MGUS and SMM. Methods To characterize the genomic landscape of myeloma precursor disease (i.e. SMM and MGUS) we performed WGS of CD138-positive bone marrow mononuclear samples from 32 patients with MGUS (N=18) and SMM (N=14), respectively. For cases with low cellularity resulting in low amounts of extracted DNA (N=15), we used the low-input enzymatic fragmentation-based library preparation method (Lee-Six et al, Nature 2019). Myeloma precursor disease samples were compared with 80 WGS of patients with MM. All WGSs (N=112) were investigated using computational tools available at the Wellcome Sanger Institute. Results After a median follow up of 29 months (range: 2-177), 17 (53%) patients with myeloma precursor disease progressed to MM (13 SMM and 4 MGUS). To interrogate the genomic differences between progressive versus stable myeloma precursor disease we first characterized the single base substitution (SBS) signature landscape. Across the entire cohort of plasma cell disorders, all main MM mutational signatures were identified: aging (SBS1 and SBS5), AID (SBS9), SBS8, SBS18, and APOBEC (SBS2 and SBS13). Interestingly, only 2/15 (13%) stable myeloma precursor disease cases showed evidence of APOBEC activity, while 14/17 (82%) and 68/80 (85%) patients with progressive myeloma precursor disease (p=0.0058) and MM (p=0.004), respectively, had APOBEC mutational activity. The two stable cases with detectable APOBEC were characterized by a high APOBEC3A:3B ratio, a feature which defines a group of MAF-translocated MM patients whose pathogenesis is characterized by intense and early APOBEC activity (Rustad et al Nat Comm 2020) and is distinct from the canonical ~1:1 APOBEC3A:3B mutational activity observed in most cases. When exploring the cytogenetic landscape, no differences were found between progressive myeloma precursor disease and MM cases. Compared to progressors and to MM, patients with stable myeloma precursor disease were characterized by a significantly lower prevalence of known recurrent MM aneuploidies (i.e. gain1q, del6q, del8p, gain 8q24, del16q) (p&lt;0.001). This observation was validated using SNP array copy number data from 78 and 161 stable myeloma precursor disease and MM patients, respectively. To further characterize differences between progressive versus stable myeloma precursor disease, we leveraged the comprehensive WGS resolution to explore the distribution and prevalence of structural variants (SV). Interestingly, stable cases were characterized by low prevalence of SV, SV hotspots, and complex events, in particular chromothripsis and templated insertions (both p&lt;0.01). In contrast, progressors showed a genome wide distribution and high prevalence of SV and complex events similar to the one observed in MM. To rule out that the absence of key WGS-MM defining events among stable cases would reflect a sample collection time bias, we leveraged our recently developed molecular-clock approach (Rustad et al. Nat Comm 2020). Notably, this approach is based on pre- and post-chromosomal gain SBS5 and SBS1 mutational burden, designed to estimate the time of cancer initiation. Stable myeloma precursor disease showed a significantly different temporal pattern, where multi-gain events were acquired later in life compared to progressive myeloma precursor disease and MM cases. Conclusions In summary, we were able to comprehensively interrogate for the first time the whole genome landscape of myeloma precursor disease. We provide novel evidence of two biologically and clinically distinct entities: (1) progressive myeloma precursor disease, which represents a clonal entity where most of the genomic drivers have been already acquired, conferring an extremely high risk of progression to MM; and (2) stable myeloma precursor disease, which does not harbor most of the key genomic MM hallmarks and follows an indolent clinical outcome. Disclosures Hultcrantz: Intellisphere LLC: Consultancy; Amgen: Research Funding; Daiichi Sankyo: Research Funding; GSK: Research Funding. Dogan:Roche: Consultancy, Research Funding; Corvus Pharmaceuticals: Consultancy; Physicians Education Resource: Consultancy; Seattle Genetics: Consultancy; Takeda: Consultancy; EUSA Pharma: Consultancy; National Cancer Institute: Research Funding; AbbVie: Consultancy. Landgren:Pfizer: Consultancy, Honoraria; Adaptive: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Juno: Consultancy, Honoraria; Cellectis: Consultancy, Honoraria; Merck: Other; Seattle Genetics: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Glenmark: Consultancy, Honoraria, Research Funding; Takeda: Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Janssen: Consultancy, Honoraria, Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Binding Site: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Karyopharma: Research Funding; Binding Site: Consultancy, Honoraria; BMS: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Takeda: Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Merck: Other; Seattle Genetics: Research Funding; Glenmark: Consultancy, Honoraria, Research Funding; Karyopharma: Research Funding; Cellectis: Consultancy, Honoraria; Juno: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Bolli:Celgene: Honoraria; Janssen: Honoraria.

scholarly journals The Genomic Complexity of Multiple Myeloma Precursor Disease Can be Predicted Using Copy Number Signatures on Targeted Sequencing and SNP Array Data

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 10-10
Author(s):  
Kylee H Maclachlan ◽  
Binbin Zheng-Lin ◽  
Venkata Yellapantula ◽  
Even H Rustad ◽  
Benjamin Diamond ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Clinical Trials ◽  
Copy Number ◽  
Research Funding ◽  
Snp Array ◽  
Targeted Sequencing ◽  
Data Monitoring ◽  
Independent Data ◽  
Genetics Research ◽  
Chromosome Arm

Introduction Current clinical models for predicting the progression from myeloma precursor disease (smoldering multiple myeloma (SMM) and monoclonal gammopathy of undetermined significance (MGUS)) to multiple myeloma (MM) are based on tumor burden, and not designed to capture heterogeneity in tumor biology. With the advent of whole genome sequencing (WGS), complex genomic change including the catastrophic event of chromothripsis has been detected in a significant fraction of MM patients. Chromothripsis is associated with other features of aggressive biology (i.e. biallelic TP53 deletion and increased APOBEC activity), and in newly diagnosed MM (NDMM), patients harboring chromothripsis have a shorter progression free survival (PFS) (Rustad BioRxiv 2019). Chromothripsis has also been demonstrated in SMM which later progressed to MM (Maura Nat Comm 2019) and our preliminary results indicate that the absence of chromothripsis is associated with stable precursor disease (Oben ASH 2020). We have demonstrated that chromothripsis can be accurately predicted in NDMM using copy-number variation (CNV) signatures on both WGS and whole exome sequencing (Maclachlan ASH 2020). As with WGS, CNV signature analysis in less comprehensive assays (e.g. targeted sequencing panels and single nucleotide polymorphism (SNP) arrays) demonstrated that chromothripsis-associated CNV signatures are associated with shorter PFS. The aim of this study was to define the landscape of CNV signatures in myeloma precursor disease, and to compare the results with CNV signatures in NDMM. Methods CNV signature analysis uses 6 fundamental features: i) breakpoint count per 10 Mb, ii) absolute CN of segments, iii) difference in CN between adjacent segments, iv) breakpoint count per chromosome arm, v) lengths of oscillating CN segments, and vi) the size of segments (Macintyre Nat Gen 2018). The number of subcategories for each feature (which may differ between cancer and assay types) was established using a mixed effect model (mclust R package). For both targeted sequencing (myTYPE panel; (n=19, 4 MGUS, 15 SMM) and SNP array (n=78, 16 MGUS, 62 SMM), de novo CNV signature extraction was performed by hierarchical dirichlet process, running the analysis together with NDMM samples for reliable signature detection. Results Our analysis identified 4 and 6 CNV signatures from myTYPE and SNP array data respectively, with the extracted signatures being analogous to those from WGS, which are highly predictive of chromothripsis (Maclachlan ASH 2020). Compared with NDMM (myTYPE; n=113; SNP array; n=217), precursor samples contained significantly fewer breakpoints / chromosome arm (myTYPE; p= 0.0003, SNP; p &lt;0.0001), fewer breakpoints / 10 Mb (both; p &lt;0.0001), shorter lengths of oscillating CN (myTYPE; p= 0.013, SNP; p= 0.018), fewer jumps between CN states (myTYPE; p= 0.0043, SNP; p &lt; 0.0001), lower absolute CN (myTYPE; p= 0.0059, SNP; p &lt; 0.0001) and fewer small segments of CN change (myTYPE; p= 0.0007, SNP; p= 0.0008). Chromothripsis-associated CNV signatures were significantly enriched in NDMM compared to precursor disease (p&lt;0.0001), with only 8.2% of precursors having a significant contribution from these signatures (NDMM; 38.7%). Overall, every CNV feature consistent with chromothripsis was measured at a significantly lower level in precursors than NDMM. As &lt;5% of the precursors have progressed to MM, and given that we see heterogeneity in the pattern of CNV abnormalities both between MM and precursor disease, and within patients with precursor disease, we are currently investigating the role of CNV abnormalities in relation to clinical progression. As an interim measure; restricting analysis to patients with clinical stability &gt;5 years (n=11), we observed chromothripsis-associated signatures to be absent in all samples. Conclusion All individual CN features comprising chromothripsis-associated CNV signatures are significantly lower in stable myeloma precursor disease compared with NDMM when assessed by targeted sequencing and SNP array, along with a lower contribution from chromothripsis-associated signatures. Given the adverse impact of chromothripsis in MM, these data show great promise towards the future refinement of risk prediction estimation in myeloma precursor disease. Our ongoing work involves extending CNV analysis into larger datasets, including precursor patients who subsequently progressed to MM. Disclosures Hultcrantz: Intellisphere LLC: Consultancy; Amgen: Research Funding; Daiichi Sankyo: Research Funding; GSK: Research Funding. Dogan:Roche: Consultancy, Research Funding; Physicians Education Resource: Consultancy; Corvus Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy; Takeda: Consultancy; EUSA Pharma: Consultancy; AbbVie: Consultancy; National Cancer Institute: Research Funding. Morgan:Bristol-Myers Squibb: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; GSK: Consultancy, Honoraria. Landgren:Amgen: Consultancy, Honoraria, Research Funding; Karyopharma: Research Funding; Janssen: Consultancy, Honoraria, Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Seattle Genetics: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Glenmark: Consultancy, Honoraria, Research Funding; Takeda: Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Janssen: Consultancy, Honoraria, Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Cellectis: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Takeda: Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Binding Site: Consultancy, Honoraria; Adaptive: Consultancy, Honoraria; Merck: Other; Pfizer: Consultancy, Honoraria; Juno: Consultancy, Honoraria; Cellectis: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Binding Site: Consultancy, Honoraria; Karyopharma: Research Funding; Merck: Other; Pfizer: Consultancy, Honoraria; Seattle Genetics: Research Funding; Juno: Consultancy, Honoraria; Glenmark: Consultancy, Honoraria, Research Funding.

scholarly journals The Role of 18f-FDG-PET/CT in Characterizing Depth of Response in High Risk Smoldering Multiple Myeloma Patients Treated with Carfilzomib, Lenalidomide, and Dexamethasone (KRd)

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 11-12
Author(s):  
Elizabeth Hill ◽  
Neha Korde ◽  
Candis Morrison ◽  
Alexander Dew ◽  
Ashley Carpenter ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Flow Cytometry ◽  
Clinical Trials ◽  
Maintenance Therapy ◽  
Research Funding ◽  
Data Monitoring ◽  
Independent Data ◽  
Genetics Research ◽  
Pet Ct

Introduction A direct association exists between minimal residual disease (MRD) negativity and prolonged survival in multiple myeloma (MM) (Landgren et al, BMT 2016). 18F-fluoro-deoxy-glucose (FDG) positron emission tomography-computed tomography (PET/CT) is a recommended monitoring technique for patients with MM as persistence of FDG uptake after induction therapy, prior to maintenance, is an independent risk factor for progression. Therefore PET/CT and MRD detection in the bone marrow are complementary prognostic tools prior to initiation of maintenance therapy. In patients with smoldering multiple myeloma (SMM), the presence of a focal FDG-avid lesion without underlying osteolytic lesion on PET/CT is associated with rapid progression to MM. However, little is known about the prognostic value of PET/CT for SMM patients receiving treatment. Herein, we show that treatment of high risk (HR)-SMM with carfilzomib, lenalidomide, and dexamethasone with lenalidomide maintenance (KRd-R) leads to sustained remissions detected on PET/CT imaging. Methods Trial design including key results for KRd-R in HR-SMM (NCT01572480) has been submitted to the meeting separately (abstract ID: 136148). As part of the study design, all eligible patients had bone marrow biopsies with multicolor flow cytometry (MRD sensitivity, 10-5) and whole-body PET/CT performed at baseline and at key time points, including achievement of complete response (CR) or completion of KRd induction (8 cycles), after 1 and 2 years of -R maintenance, and annually thereafter. PET/CTs were evaluated by nuclear medicine radiologists blinded to flow cytometry and considered positive if at least one focal hypermetabolic (above background reference) lesion and/or heterogenous bone marrow involvement were present, as defined by the IMWG (Hillengass et al. Lancet Oncol 2019). Results As of data cutoff, 46 patients had completed at least 8 cycles of therapy and had 2 sequential PET/CTs performed. By the end of induction therapy, no patient developed progressive disease and the overall response rate was 100%. Approximately 72% of patients with baseline negative PET/CTs remained negative, 11% of patients had resolution of previous focal/heterogenous FDG avidity, 15% of patients had decrease or stable focal/ heterogenous lesions, and 2% developed new focal lesions. Table 1 shows the results at subsequent time points of one and two years of maintenance therapy. Throughout this time period, one patient developed a lytic lesion after 1 year of maintenance therapy. However, 3 patients had either resolution or decrease in focal/heterogenous lesions. Specifically, after 8 cycles of combination therapy, 33 patients (70.2%, 95% CI 55.9 - 81.4%) had a response of MRD negative CR based on bone marrow flow cytometry and 26 patients (55.3%; 95% CI 41.2-68.6%) had a negative PET/CT in addition to MRD negative CR (Table 2). Conclusions It is important to evaluate the tools used in MM response assessment specifically in the SMM population as more studies report results of treatment in this population. MRD information can be used as a biomarker to evaluate the efficacy of different treatment strategies. This study demonstrates an exceptionally high rate of concordance between MRD negativity by flow cytometry and negative PET/CT after 8 cycles of KRd. However, 15% of patients were MRD negative yet had positive findings on PET/CT. While these lesions were not biopsy proven, some resolved during maintenance therapy. Further follow-up is needed to determine whether early MRD negativity in bone marrow with negative PET/CT correlates to longer overall survival and decreased progression to MM compared to those patients with a positive PET/CT. The use of PET/CT imaging may increase our understanding in assessing depth response to treatment in HR-SMM patients and be an important outcome predictor. Disclosures Korde: Astra Zeneca: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding. Landgren:Adaptive: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Takeda: Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Glenmark: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Seattle Genetics: Research Funding; Janssen: Consultancy, Honoraria, Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Karyopharma: Research Funding; Binding Site: Consultancy, Honoraria; Takeda: Other: Independent Data Monitoring Committees for clinical trials, Research Funding; BMS: Consultancy, Honoraria; Cellectis: Consultancy, Honoraria; Glenmark: Consultancy, Honoraria, Research Funding; Juno: Consultancy, Honoraria; Seattle Genetics: Research Funding; Pfizer: Consultancy, Honoraria; Merck: Other; Karyopharma: Research Funding; Binding Site: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Cellectis: Consultancy, Honoraria; Juno: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Merck: Other.

scholarly journals Development of immunosuppressive myeloid cells to induce tolerance in solid organ and hematopoietic cell transplant recipients

2021 ◽  
Author(s):  
Kent P Jensen ◽  
David Hongo ◽  
Xuhuai Ji ◽  
Pingping Zheng ◽  
Rahul D Pawar ◽  
...  
Keyword(s):  
Clinical Trials ◽  
T Cells ◽  
Conditioning Regimen ◽  
Myeloid Cells ◽  
Hematopoietic Cell ◽  
Mixed Chimerism ◽  
Solid Organ ◽  
Cell Transplant ◽  
Hematopoietic Cell Transplant ◽  
Post Transplant

Replacement of failed organs followed by safe withdrawal of immunosuppressive drugs have long been the goals of organ transplantation. We studied changes in the balance of T and myeloid cells in blood of HLA-matched and -mismatched patients given living donor kidney transplants (KTx) followed by total lymphoid irradiation (TLI), anti-thymocyte globulin (ATG) conditioning, and donor hematopoietic cell transplant (HCT) to induce mixed chimerism and immune tolerance. The clinical trials were based on a conditioning regimen used to establish mixed chimerism and tolerance in mice. In pre-clinical murine studies, there was a profound depletion of T cells and an increase in immunosuppressive, polymorphonuclear (pmn), myeloid derived suppressor cells (MDSCs) in the spleen and blood following transplant. Selective depletion of the pmn-MDSCs in mice abrogated mixed chimerism and tolerance. In our clinical trials, patients given an analogous tolerance conditioning regimen developed similar changes including profound depletion of T cells and a marked increase in MDSCs in blood post-transplant. Post-transplant pmn-MDSCs transiently increased expression of lectin-type, oxidized LDL receptor-1 (LOX-1), a marker of immunosuppression, and production of the T cell inhibitor, arginase-1. These post-transplant pmn-MDSCs suppressed the activation, proliferation, and inflammatory cytokine secretion of autologous, TCR microbead-stimulated, pre-transplant T cells when co-cultured in vitro. In conclusion, we elucidated changes in receptors, and function of immunosuppressive myeloid cells in patients enrolled in the tolerance protocol that were nearly identical to the that of MDSCs required for tolerance in mice. The clinical trials are registered in Clinicaltrials.gov under NCT #s 00319657 and 01165762.

scholarly journals Humoral and T Cell Immune Responses to Sars-Cov-2 Vaccination in Hematopoietic Cell Transplant Recipients

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2896-2896
Author(s):  
Eleni Gavriilaki ◽  
Anastasia Papadopoulou ◽  
Tasoula Touloumenidou ◽  
Fani Stavridou ◽  
Evdoxia Koravou ◽  
...  
Keyword(s):  
Immune Response ◽  
Clinical Trials ◽  
T Cell ◽  
Immune Responses ◽  
Research Funding ◽  
Hematopoietic Cell ◽  
Cell Transplant ◽  
Transplant Recipients ◽  
Hematopoietic Cell Transplant ◽  
Cell Responses

Abstract Background. Hematopoietic cell transplant (HCT) recipients who develop coronavirus disease 2019 (COVID-19), have dismal prognosis with approximately 20% mortality. Given the lack of a specific and effective therapy, the availability of various vaccination platforms against SARS-CοV-2 has generated optimism towards the development of a robust herd immunity. Notwithstanding the prioritization of HCT recipients to COVID-19 vaccination, limited information is available on whether and to what extent, they mount an immune response to SARS-CοV-2 vaccination as they were generally excluded from vaccination trials. Aim. To gain insights in the immune responses developed to SARS-CoV-2 vaccines under immunosuppression, we studied the humoral and cellular immune responses to SARS-CoV-2 vaccination in HCT recipients. Methods. We prospectively studied (April-July 2021), adult patients who had undergone HCT in our Unit and received two doses of a SARS-CoV-2 vaccine (as per international guidelines) after providing written informed consent. Responses were studied before each vaccination dose and 12-51 days later after the second dose. Neutralizing antibodies against SARS-CoV-2 (CoV-2-NAbs) were measured using an FDA approved methodology for diagnostic use (ELISA, cPass™ SARS-CoV-2 NAbs Detection Kit; GenScript, Piscataway, NJ, USA; cut-off value for a positive result set at ≥30%) and SARS-CoV-2 spike-specific T cells (spike-STs) by interferon-γ Elispot after pulsing peripheral blood mononuclear cells with spike pepmixes. Results. Humoral responses were studied on 65 patients, (50 allo-HCT/15 auto-HCT, Figure A). T cell responses were measured on 38/65 vaccinated patients (32 allo-HCT/6 auto-HCT) with a median of 3 (0.17-31) and 2 years (1.25-8) post allo- and auto-HCT respectively, and 19 healthy, unexposed vaccinees. One patient with prior COVID-19, was excluded from analysis. All patients were vaccinated with the Pfizer-BioNTech, except for 2 vaccinated with the AstraZeneca vaccine. Both CoV-2-NAbs and spike-STs were barely detectable before vaccination but could be detected in both allo- and auto-HCT patients after the first vaccination dose, reaching statistically significant increase after the second vaccination dose (p&lt;0.001 and p=0.036, respectively). Circulating spike-STs in allo-HCT recipients, although present, were lower over their counterparts in healthy volunteers (p&lt;0.001) and auto-HCT patients (p=0.080). In the latter patient cohort, the rather long period post auto-HCT (≥1.25 years for all patients) might have generated unintended bias towards elevated immune responses. The longer time post HCT in all patients was associated with increased CoV-2-NAbs and spike-STs (p=0.004 and p=0.030). Allo-HCT recipients under immunosuppression had lower levels of CoV-2-NAbs and spike-STs after the booster dose compared to patients off-treatment (Figure B and C, p&lt;0.001 and p=0.021 respectively). In particular, only 50% and 40% of patients on systemic immunosuppression reached adequate CoV-2-Nab and spike-ST levels after the second dose, as compared to 98% and 94% of immunosuppression-free patients. One allo-HCT recipient with failure to mount any immune response post booster vaccination, developed 40 days later COVID-19 infection and succumbed. The one allo-HCT recipient off treatment who did not elicit protective immune response after vaccination, was suffering from metabolic syndrome, a potentially immunosuppressive entity. Overall, there was a good correlation between humoral and T-cellular responses (p=0.013), although few cases were observed with sufficient T-cell response but no humoral reactivity and vice versa. Conclusion . Herein, we report for first time humoral and T cell responses post SARS-CoV-2 vaccination in HCT recipients. Transplant recipients not under active and intense immunosuppression at the time of vaccination may benefit significantly from COVID-19 vaccination even though these responses are blunted compared to healthy individuals. However, for the severely immunocompromised patients it seems highly unlikely that they could be protected by vaccination and for this vulnerable population, different vaccination schemes or therapeutic platforms should be developed along with collateral measures including minimal exposure and immunization of caregivers and health care providers. Figure 1 Figure 1. Disclosures Gavriilaki: Alexion, Omeros, Sanofi Corporation: Consultancy; Pfizer Corporation: Research Funding; Gilead Corporation: Honoraria. Yannaki: SANDOZ: Speakers Bureau; Gilead: Speakers Bureau; Novartis: Speakers Bureau; bluebird bio, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding. Anagnostopoulos: Abbvie: Other: clinical trials; Sanofi: Other: clinical trials ; Ocopeptides: Other: clinical trials ; GSK: Other: clinical trials; Incyte: Other: clinical trials ; Takeda: Other: clinical trials ; Amgen: Other: clinical trials ; Janssen: Other: clinical trials; novartis: Other: clinical trials; Celgene: Other: clinical trials; Roche: Other: clinical trials; Astellas: Other: clinical trials .

scholarly journals Increased Early Mortality after Fludarabine and Melphalan Conditioning with Peripheral Blood Grafts in Haploidentical SCT with Post-Transplant Cyclophosphamide

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4496-4496 ◽  
Author(s):  
Luke Eastburg ◽  
David A. Russler-Germain ◽  
Ramzi Abboud ◽  
Peter Westervelt ◽  
John F. DiPersio ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
T Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Early Mortality ◽  
Cell Transplant ◽  
Advisory Committees ◽  
Post Transplant ◽  
Equity Ownership

The use of post-transplant cyclophosphamide (PTCy) in the context of haploidentical stem cell transplant (haplo-SCT) has led to drastically reduced rates of Graft-vs-Host (GvH) disease through selective depletion of highly allo-reactive donor T-cells. Early trials utilized a reduced-intensity Flu/Cy/TBI preparative regimen and bone marrow grafts; however, relapse rates remained relatively high (Luznik et al. BBMT. 2008). This led to the increased use of myeloablative (MA) regimens for haplo-SCT, which have been associated with decreased relapse rates (Bashey et al. J Clin Oncol. 2013). Most studies have used a MA total body irradiation (TBI) based regimen for haplo-SCT. Preparative regimens using fludarabine and melphalan (FluMel), with or without thiotepa, ATG, and/or low dose TBI have also been reported using bone marrow grafts. Reports on the safety and toxicity of FluMel in the haplo-SCT setting with PTCy and peripheral blood stem cell (PBSC) grafts are lacking. In this two-center retrospective analysis, the safety/toxicity of FluMel as conditioning for haplo-SCT was evaluated. We report increased early mortality and toxicity using standard FluMel conditioning and PBSC grafts for patients undergoing haplo-SCT with PTCy. 38 patients at the University of Rochester Medical Center and the Washington University School of Medicine underwent haplo-SCT with FluMel conditioning and PBSC grafts between 2015-2019. Outcomes were measured by retrospective chart review through July 2019. 34 patients (89.5%) received FluMel(140 mg/m2). Two patients received FluMel(100 mg/m2) and two patients received FluMel(140 mg/m2) + ATG. The median age at time of haplo-SCT was 60 years (range 21-73). 20 patients were transplanted for AML, eight for MDS, two for PMF, two for NHL, and five for other malignancies. The median Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI) score was 4 (≥3 indicates high risk). 11 patients had a history of prior stem cell transplant, and 16 patients had active disease prior to their haplo-SCT. Seven patients had sex mismatch with their stem cell donor. Median donor age was 42 (range 21-71). 20 patient deaths occurred by July 2019 with a median follow up of 244 days for surviving patients. Nine patients died before day +100 (D100, "early mortality"), with a D100 non-relapse mortality (NRM) rate of 24%. Median overall and relapse free survival (OS and RFS, respectively) were 197 days (95% CI 142-not reached) and 180 days (95% CI 141-not reached), respectively, for the entire cohort. The 1 year OS and NRM were 29% and 50%. The incidence of grades 2-4cytokine release syndrome (CRS) was 66%, and 52% of these patients were treated with tocilizumab. CRS was strongly associated with early mortality, with D100 NRM of 36% in patients with grade 2-4 CRS compared to 0% in those with grade 0-1. The incidence of acute kidney injury (AKI) was 64% in patients with grade 2-4 CRS, and 8% in those without (p < 0.001). 28% of patients with AKI required dialysis. Grade 2-4 CRS was seen in 54% of patients in remission prior to haplo-SCT and in 92% of those with active disease (p = 0.02). Of the 9 patients with early mortality, 89% had AKI, 44% needed dialysis, and 100% had grade 2-4 CRS, compared to 31%, 10%, and 55% in those without early mortality (p = 0.002, p = 0.02, p = 0.01). Early mortality was not significantly associated with age, HCT-CI score, second transplant, disease status at transplant, total dose of melphalan, volume overload/diuretic use, or post-transplant infection. In conclusion, we observed a very high rate of NRM with FluMel conditioning and PBSC grafts for haplo-SCT with PTCy. The pattern of toxicity was strongly associated with grade 2-4 CRS, AKI, and need for dialysis. These complications may be mediated by excessive inflammation in the context of allo-reactive donor T-cell over-activation. Consistent with this, multiple groups have shown that FluMel conditioning in haplo-SCT is safe when using bone marrow or T-cell depleted grafts. Based on our institutional experiences, we would discourage the use of FluMel as conditioning for haplo-SCT with PTCy with T-cell replete PBSC grafts. Alternative regimens or variations on melphalan-based regimens, such as fractionated melphalan dosing or inclusion of TBI may improve outcomes but further study and randomized controlled trials are needed. This study is limited in its retrospective design and sample size. Figure Disclosures DiPersio: WUGEN: Equity Ownership, Patents & Royalties, Research Funding; Karyopharm Therapeutics: Consultancy; Magenta Therapeutics: Equity Ownership; Celgene: Consultancy; Cellworks Group, Inc.: Membership on an entity's Board of Directors or advisory committees; NeoImmune Tech: Research Funding; Amphivena Therapeutics: Consultancy, Research Funding; Bioline Rx: Research Funding, Speakers Bureau; Macrogenics: Research Funding, Speakers Bureau; Incyte: Consultancy, Research Funding; RiverVest Venture Partners Arch Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees. Liesveld:Onconova: Other: Data safety monitoring board; Abbvie: Membership on an entity's Board of Directors or advisory committees.

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