scholarly journals Antibody Response to Vaccination with BNT162b2, mRNA-1273, and ChADOx1 in Patients with Myeloid and Lymphoid Neoplasms

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 218-218
Author(s):  
Jil Rotterdam ◽  
Margot Thiaucourt ◽  
Juliana Schwaab ◽  
Andreas Reiter ◽  
Sebastian Kreil ◽  
...  
Keyword(s):  
Antibody Response ◽  
Board Of Directors ◽  
Research Funding ◽  
Low Grade ◽  
Hematological Disease ◽  
Advisory Committees ◽  
Hematological Diseases ◽  
Myeloid Neoplasms ◽  
Lymphoid Neoplasms ◽  
Treatment Naïve

Abstract Background: In general, patients with hematological diseases are predisposed to develop infections. Severe COVID-19 infection associated with high mortality is more likely in these patient cohorts compared to the general population. Due to immune defects related to the primary disease and/or to immunosuppressive treatment regimes, vaccination efficacy may be reduced in patients with hematological diseases. So far, data on this area are limited. Aim: To evaluate vaccination-related antibody response to BNT162b2, mRNA-1273, and ChADOx1 in patients with hematological disorders. Patients and methods: In this interim analysis of a prospective, observational single-center study, we report antibody levels at least 2 weeks after COVID-19 vaccination. A FDA/CE approved electrochemiluminescent assay (ECLIA) (Elecsys®, Roche, Mannheim, Germany) was used to quantify antibodies, pan Ig (including IgG) against the receptor binding domain (RBD) of the SARS-CoV-2 spike protein. The assay has a measurement range of 0.4 to 250 U/mL, with a concentration ≥0.8 U/ml considered as positive. Data were analyzed for patients without detection of anti-N (nucleocapsid) SARS-CoV-2 antibody (i.e., without having passed SARS-CoV-2 infection). All tests were performed according to the manufacturer's instructions in an accredited laboratory at the University Hospital Mannheim. Results: Between February 2021 and July 2021, a total of 175 patients with hematological diseases were included in this study. The median age was 66 years (range 21-90 years), and 81 (46.3%) were female. The antibody levels were measured at least 14 days (median, 58 days) after the 2 nd vaccination. The patients were vaccinated with BNT162b2 (BioNTech, n=134), mRNA-1273 (Moderna, n=19), ChADOx1 (AstraZeneca, n=12), or got the first vaccination with BNT162b2 and the second with ChADOx1 (n=10). Overall, 145/175 (82.9%) were diagnosed with a malignant hematological disease (myeloid neoplasms, n=108; lymphoid neoplasms, n=37) and 30/175 with a non-malignant hematological disease (autoimmune disease, n=24; benign, n=6). 124 patients (70.1%) were on active therapy, and 51 patients (29.1%) were previously treated or treatment naïve. Correlation to specific therapies is ongoing and will be presented. In general, vaccination-related antibody response was positive (≥0.8 U/mL) in 148/175 (84.6%) patients with a median level of 208.6 U/mL (range 0.8-250.00) and negative (<0.8 U/mL) in 27/175 (15.4%) patients. The distribution of the negative cohort regarding the disease subgroups were as followed: myeloid neoplasms 7/27 (25.9%), lymphoid neoplasms 16/27 (59.3%), non-malignant hematological disease 4/27 (14.8%). Within the negative cohort, 21/27 (77.8%) were treated on active therapy, 6/27 (22.2%) were previously treated or treatment naïve. In myeloid neoplasms, patients with classical myeloproliferative neoplasm (MPN) had the highest negative result for antibodies with 4/7 (57.1%) followed by myelodysplastic syndrome (MDS) 2/7 (28.6%). Interestingly, all patients with chronic myeloid leukemia (CML) had a measurable immune response. In lymphoid neoplasms, patients with low-grade non-hodgkin lymphoma (NHL) (predominately chronic lymphocytic leukemia, CLL) had the highest negative antibody result 13/16 (81.3%) followed by high-grade NHL 4/8 (50%; predominately diffuse large b-cell lymphoma, DLBCL). In non-malignant hematological diseases, only patients with autoimmune diseases had a negative result. Conclusion: A remarkable group of patients with hematological disease were measured with no or low immune response after 2 nd COVID-vaccination, especially those with low-grade NHL, MDS and autoimmune disease. It seems that the percentage of patients with MPN and low response is less critical. No problems appeared in CML patients. Further explorations are needed with focus on potential risk of COVID infections despite full vaccination: The potential of 3 rd booster vaccination should be explored within clinical trials. Disclosures Reiter: AOP Orphan Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses, Research Funding; Celgene/BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support; Incyte: Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses; Blueprint Medicines: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses; Abbvie: Membership on an entity's Board of Directors or advisory committees; Deciphera: Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses. Kreil: Novartis: Research Funding. Hofmann: Amgen: Honoraria; BMS: Honoraria; Novartis: Honoraria. Jawhar: Takeda: Honoraria, Other: Travel support; Blueprint Medicines: Honoraria; Stemline: Consultancy, Honoraria; Celgene: Other: Travel support; Novartis: Consultancy, Honoraria, Other: Travel support, Speakers Bureau. Saussele: Roche: Honoraria; Pfizer: Honoraria; Incyte: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding.

scholarly journals Therapy-Related Myeloid Neoplasm Has a Distinct Pro-Inflammatory Bone Marrow Microenvironment and Delayed DNA Damage Repair

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 37-38
Author(s):  
Monika M Kutyna ◽  
Li Yan A Wee ◽  
Sharon Paton ◽  
Dimitrios Cakouros ◽  
Agnieszka Arthur ◽  
...  
Keyword(s):  
Dna Damage ◽  
Board Of Directors ◽  
Research Funding ◽  
High Dose ◽  
Cytotoxic Therapy ◽  
Advisory Committees ◽  
Myeloid Neoplasm ◽  
Myeloid Neoplasms ◽  
Damage Repair

Introduction: Therapy-related myeloid neoplasms (t-MN) are associated with extremely poor clinical outcomes in otherwise long-term cancer survivors. t-MN accounts for ~20% of cases of myeloid neoplasms and is expected to rise due to the increased use of chemotherapy/radiotherapy (CT/RT) and improved cancer survivorship. Historically, t-MN was considered a direct consequence of DNA damage induced in normal hematopoietic stem cells (HSC) by DNA damaging cytotoxics. However, these studies have largely ignored the bone marrow (BM) microenvironment and the effects of age and concurrent/previous cancers. Aim: We performed an exhaustive functional study of mesenchymal stromal cells (MSC) obtained from a comparatively large cohort of t-MN patients and carefully selected control populations to evaluate the long-term damage induced by cytotoxic therapy to BM microenvironment and its impact on malignant and normal haematopoiesis. Methods: Four different cohorts were used: (1) t-MN, in which myeloid malignancy occurred after CT/RT for a previous cancer (n=18); (2) patients with multiple cancer and in which a myeloid neoplasm developed following an independent cancer which was not treated with CT/RT (MC-MN; n=10); (3) primary MN (p-MN; n=7) untreated and without any prior cancer or CT/RT; (4) age-matched controls (HC; n=17). Morphology, proliferation, cellular senescence, differentiation potential and γH2AX DNA damage response was performed. Stem/progenitor supportive capacity was assessed by co-culturing haematopoietic stem cells on MSC feeder-layer in long-term culture initiating assay (LTC-IC). Cytokine measurements were performed using 38-plex magnetic bead panel (Millipore) and RNA sequencing libraries were prepared with Illumina TruSeq Total RNA protocol for 150bp paired-end sequencing on a NextSeq500 instrument. Functional enrichment analysis was performed using EnrichR software. Results: MSC cultured from t-MN patients were significantly different from HC, p-MN and MC-MN MSC according to multiple parameters. They exhibited aberrant morphology consisting of large, rounded and less adhesive cells compared to typical spindle-shaped morphology observed with controls. MSC from myeloid neoplasm also showed impaired proliferation, senescence, osteo- and adipogenic differentiation with t-MN MSC showing the greatest differences. DNA repair was dramatically impaired compared to p-MN and HC (Fig.1A). Importantly, these aberrant t-MN MSC were not able to support normal or autologous in vitro long-term haematopoiesis (Fig.1B). The biological characteristic and poor haematopoietic supportive capacity of MSC could be "cell-intrinsic" or driven by an altered paracrine inflammatory microenvironment. Interestingly, several inflammatory cytokines were higher in t-MN compared with marrow interstitial fluid obtained from p-MN patients (Fig.1Ci) and many of these including Fractalkine, IFNα2, IL-7 and G-CSF were also significantly higher in t-MN MSC conditional media (Fig.1Cii). Together, this data suggest that t-MN microenvironment is distinct from p-MN with paracrine production of pro-inflammatory milieu that may contribute to poor HSC supportive capacity. Preliminary whole transcriptome analysis revealed differential gene expression between t-MN and HC (Fig.1Di) and p-MN MSC. Importantly, the deregulated genes play critical role in cell cycle, DNA damage repair, and cellular senescence pathways explaining phenotypical characteristic of t-MN MSC (Fig.1Dii). Moreover CXCL12 expression, a key regulator of haematopoiesis, was significantly lower in t-MN compared to HC (p=0.002) and p-MN MSC (p=0.009), thus explaining poor HSC supportive capacity. The key difference between the p-MN, MC-MN and t-MN is prior exposure to CT/RT. To study this we obtained MSC from two t-MN patients for whom we had samples at the time of their primary cancer, post high-dose chemotherapy and at the time of t-MN. MSC displayed aberrant proliferation and differentiation capacity after high-dose cytotoxic therapy (2 to 4 years prior to developing t-MN) and remained aberrant at t-MN diagnosis (Fig.1E). Conclusions: BM-MSC from t-MN patients are significantly abnormal compared with age-matched controls and typical myeloid neoplasm. Importantly, prior CT/RT leads to long-term irreversible damage to the BM microenvironment which potentially contributes to t-MN pathogenesis. Disclosures Hughes: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Hiwase:Novartis Australia: Research Funding.

scholarly journals Efficacy and Safety of Ravulizumab in Older Patients Aged >65 Years with Paroxysmal Nocturnal Hemoglobinuria in the 301 and 302 Phase 3 Extension Studies

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 42-43
Author(s):  
Regis Peffault De Latour ◽  
Jeffrey Szer ◽  
Austin Kulasekararaj ◽  
Jin Seok Kim ◽  
Caroline I. Piatek ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Older Patients ◽  
Research Funding ◽  
Paroxysmal Nocturnal Hemoglobinuria ◽  
Complement Inhibitor ◽  
Efficacy And Safety ◽  
Phase 3 ◽  
Advisory Committees ◽  
Treatment Naïve ◽  
Secondary Endpoints

Background: In the two largest phase 3 studies in patients with paroxysmal nocturnal hemoglobinuria (PNH), ravulizumab given every 8 weeks was noninferior to eculizumab given every 2 weeks across all efficacy endpoints. Data on efficacy and safety of ravulizumab in patients aged >65 years with PNH are limited. Aims: To compare the efficacy and safety of ravulizumab in patients with PNH aged >65 years with those aged ≤65 years. Methods: The population included patients from two phase 3 studies that assessed ravulizumab vs eculizumab in complement-inhibitor-naïve (301; NCT02946463) and -experienced (302; NCT03056040) adults with PNH. In study 301, patients were aged ≥18 years with a confirmed PNH diagnosis by flow cytometry and had a lactate dehydrogenase (LDH) level ≥1.5x upper limit of normal (ULN; 246U/L). In study 302, patients were aged ≥18 years with a confirmed PNH diagnosis by flow cytometry, were clinically stable on eculizumab having received ≥6 months of treatment and had a LDH level ≤1.5x ULN. Patients were randomized to either ravulizumab or eculizumab for 26 weeks after which all received ravulizumab up to 52 weeks. This prespecified analysis stratified patients by age: ≤65 or >65 years. Primary endpoints included percentage change in LDH from baseline to weeks 26 and 52, percentage of patients achieving LDH-normalization (LDH-N; LDH levels: ≤1x ULN) at weeks 26 and 52 and transfusion avoidance (TA) from baseline to weeks 26 and 52. Breakthrough hemolysis (BTH), hemoglobin (Hgb) stabilization and FACIT-fatigue score were secondary endpoints. Treatment emergent adverse events (TEAEs) were assessed as an indicator of safety. Results: A total of 58 patients aged >65 years and 383 patients aged ≤65 years were included. Disposition and medical history were similar among subgroups at baseline (Table 1). Results for primary and secondary endpoints for the two subgroups were comparable across studies and efficacy was maintained through 52 weeks. A higher proportion of treatment-experienced patients (>65 years) achieved all endpoints vs -naïve patients (Table 2). The percentage change in LDH levels from baseline to 26 and 52 weeks was similar between subgroups in study 301 (-66.5 to -80.0%) whereas in study 302, LDH levels remained stable in all subgroups up to 52 weeks (-3.7 to 22%). The percentage of patients achieving LDH-N in both studies at 26 and 52 weeks differed; 43.8-63.9% of patients aged ≤65 years achieved LDH-N compared with 21.4-77.8% of patients aged >65 years. A higher proportion of older treatment-experienced patients (57.1‒77.8%) achieved LDH-N compared with older treatment-naive patients (21.4‒50.0%) at 26 and 52 weeks. In patients aged ≤65 years in both studies, 63.7‒89.4% achieved TA. In the >65 years subgroup, 14.3‒50.0% of treatment-naive patients achieved TA whereas in study 302, 54.5‒72.7% of patients achieved TA. The number of BTH events was low, with no events reported in older patients to date. Hgb stabilization was consistent in the ≤65 year subgroup between the studies; a higher proportion of older patients in study 302 (45.5‒71.4%) achieved stabilized Hgb compared with older patients in study 301 (14.3‒35.3%). A clinically significant 3-point change was seen in FACIT-fatigue scores (indicating improvements in fatigue), with higher scores observed for ravulizumab in both subgroups (Figure 1). One patient discontinued the extension of study 301 due to lung cancer onset during the 26-week period and died following discontinuation. Headache was the most frequent TEAE. The incidence of TEAEs reported during ravulizumab treatment up to 52 weeks did not increase vs the 26-week period, with few events (Table 3) and no difference between subgroups. Conclusions: We present clinical outcomes in the largest cohort of patients with PNH (>65 years) on ravulizumab in a clinical trial setting to date. Ravulizumab was associated with similar efficacy and safety in both age subgroups and showed consistent and durable efficacy through 52 weeks of treatment. A higher proportion of patients in study 302 achieved all efficacy endpoints than in study 301, which can be due to patients' prior complement inhibitor experience. This observation was more evident in older patients. There were no BTH events in the older patients to date, and the number of infections in both subgroups was low. Ravulizumab was well tolerated in older patients with no additional safety concerns compared to younger patients. Disclosures Peffault De Latour: Apellis: Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Alexion Pharmaceuticals Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Szer:Pfizer: Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Apellis: Consultancy; Alexion Pharmaceuticals Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Prevail Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Speakers Bureau. Kulasekararaj:Alexion Pharmaceuticals Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kim:Alexion Pharmaceuticals Inc.: Honoraria, Research Funding. Piatek:Alexion Pharmaceuticals: Consultancy, Research Funding. Kulagin:Alexion Pharmaceuticals Inc.: Consultancy, Research Funding. Hill:Alexion Pharmaceuticals Inc.: Current Employment. Wang:Alexion Pharmaceuticals Inc.: Current Employment. Yu:Alexion Pharmaceuticals Inc.: Current Employment. Ogawa:Alexion Pharmaceuticals Inc.: Current Employment. Schrezenmeier:Alexion Pharmaceuticals Inc.: Honoraria, Research Funding. Lee:Alexion Pharmaceuticals Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

scholarly journals Subcutaneous Alemtuzumab Has Activity in Treatment-Naïve Patients with Acquired Aplastic Anemia

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2503-2503 ◽  
Author(s):  
Ana Rita Da Fonseca ◽  
Anita Hill ◽  
Patricia Eiko Yamakawa ◽  
Iara Baldim Rabelo ◽  
Andre Domingues Pereira ◽  
...  
Keyword(s):  
Total Dose ◽  
Aplastic Anemia ◽  
Board Of Directors ◽  
Research Funding ◽  
Overall Response Rate ◽  
Sao Paulo ◽  
São Paulo ◽  
Advisory Committees ◽  
First Line Therapy ◽  
Treatment Naïve

Introduction: Hematopoiesis is severely reduced in severe aplastic anemia (SAA) probably due to immunological destruction of hematopoietic stem and progenitor cells. Bone marrow transplantation is preferred as first-line therapy in patients younger than 40 years with a matched related sibling donor. For those who are not candidate for transplant, immunosuppressive therapy with horse antithymocyte globulin (hATG) plus cyclosporine (CsA) remains the standard of care. However, hATG was discontinued in most Asian, South American, and European countries with only rabbit ATG (rATG) available. rATG is a more potent immunosuppressant which has associated with a worst hematological response and survival at 6 months in prospective studies. Using rATG in first-line therapy appears to add little to what has been observed with CSA alone. Alemtuzumab (ALZ), a humanized anti-CD52 monoclonal antibody is also active in AA due to its lymphocytotoxic properties. The use of ALZ in monotherapy has shown an overall response rate (ORR) comparable to that of r-ATG (37% and 33%, respectively) when applied as salvage (following hATG failure) in a randomized study. Other experiences which combined ALZ and CsA led to a 58% ORR in SAA patients after a cumulative dose of 103 mg of subcutaneous (SC) ALZ. Here we describe a multicenter retrospective analysis of SC ALZ in association with CsA for patients with AA. Methods: We retrospectively analyzed all patients who received outpatient SC ALZ for the treatment of aplastic anemia in 2 centers: Universidade Federal de Sao Paulo (Sao Paulo-BRAZIL) and Leeds Teaching Hospitals, UK from March 2009 until March 2019. In Sao Paulo, alemtuzumab total dose was 103 mg in an escalating dose of 3-10-30-30-30 mg, except for three elderly patients who received a total dose of 73. In Leeds-UK, total dose varied from 120 mg to 150 mg. The primary outcome was overall response rate (ORR) at six months. Median follow up was 31 months (range 4-110 months). Results: We identified 35 treatments with SC ALZ in 32 AA patients of which 78% had SAA or very severe aplastic anemia. Calcineurin inhibitors were used in association with ALZ in 80% of cases (cyclosporine in 26 cases, tacrolimus in 2 cases). Median age was 44 years (range: 18-79), and nineteen patients (59%) were male. Seventeen patients (53%) were treatment-naïve, and six patients (19%) had one prior line of therapy. Nine patients (28%) were relapsed/refractory, and received ALZ after at least two lines of prior therapy. Seventeen patients (53%) presented a PNH clone at diagnosis. Median time between diagnosis and ALZ treatment was 6 months (range 1-293). No treatment-related serious adverse events were observed. Infectious complications were infrequent: there was only one case of successfully treated CMV reactivation and one case of fatal EBV-related infection. ORR at 6 months was 57% (complete response: 11%, partial response: 46%), with corresponding cumulative incidence of response of 47% at 6 months and 62% at 1 year (figure 1). ORR was 69% in treatment-naïve patients younger than 60 years. Overall survival was 72% at 2 years. Adverse events were of low grade and infectious events were infrequent. Conclusion: Subcutaneous alemtuzumab appears to be a feasible, effective and safe alternative to hATG in patients with AA requiring immunosuppressive treatment, especially in centers with limited access to hATG. Disclosures Hill: Apellis: Honoraria; Roche: Honoraria; Akari: Honoraria; Alexion: Honoraria; Bioverativ: Honoraria; Novartis: Honoraria; Regeneron: Honoraria; Ra Pharma: Honoraria. Munir:AbbVie: Honoraria; Alexion: Honoraria; Gilead: Honoraria; Janssen: Honoraria; Novartis: Honoraria; Roche: Honoraria; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sunesis: Consultancy; Pharmacyclics: Other: TBC; Acerta: Membership on an entity's Board of Directors or advisory committees. Hillmen:Roche: Research Funding; Acerta: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses, Research Funding; Apellis: Research Funding; Gilead: Research Funding. Risitano:Achillion: Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees; Samsung: Membership on an entity's Board of Directors or advisory committees; Biocryst: Membership on an entity's Board of Directors or advisory committees; Samsung: Membership on an entity's Board of Directors or advisory committees; Amyndas: Consultancy; Ra Pharma: Research Funding; Alnylam: Research Funding; Achillion: Research Funding; Alexion: Honoraria, Research Funding, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Alnylam: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Biocryst: Membership on an entity's Board of Directors or advisory committees; Apellis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amyndas: Consultancy; Ra Pharma: Research Funding; Apellis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Alexion: Honoraria, Research Funding, Speakers Bureau. Scheinberg:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer,: Speakers Bureau; Alexion: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees; Celgene: Speakers Bureau.

Persistent Impairments in Humoral and Cellular Immunity in Patients with Immune Thrombocytopenia Treated with Rituximab: A Sub-Study of a Randomized Controlled Trial

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 492-492
Author(s):  
Ishac Nazi ◽  
John G. Kelton ◽  
Mark Larche ◽  
Denis P. Snider ◽  
Jane C. Moore ◽  
...  
Keyword(s):  
T Cells ◽  
Placebo Group ◽  
B Cells ◽  
Antibody Response ◽  
Board Of Directors ◽  
Bactericidal Activity ◽  
Research Funding ◽  
Fold Increase ◽  
Advisory Committees ◽  
Adequate Antibody Response

Abstract Abstract 492 Background: The anti-CD20 antibody, rituximab, is increasingly being used as a treatment for immune thrombocytopenia (ITP). The concern about rare occurrences of progressive multifocal leukoencephalopathy in this population and the reliance on vaccine responses in patients who ultimately require splenectomy calls for additional studies into the integrity of the immune system after rituximab treatment. The objective of this study was to evaluate both the antibody and cellular responses to the Streptococcus pneumoniae polysaccharide vaccine and to the Haemophilus influenza type b (Hib) conjugate vaccine in rituximab-treated patients with ITP. Methods: Adults with primary ITP and a platelet count below 30 x109/L who had participated in a randomized trial of rituximab or placebo were eligible for this prospective sub-study. Six months after the study intervention, patients were given the S. pneumoniae polysaccharide vaccine (Pneumovax-23®, Merck) and the Hib conjugate vaccine (ActHIB®, Aventis). Antibodies against the pneumococcal capsular polysaccharide (anti-PCP) and Hib polyribosyl-ribitol phosphate (anti-PRP) were measured by EIA. A bactericidal assay was used to measure the ability to eradicate Hib in culture. An adequate antibody response was defined as a 4-fold increase in antibody concentration from baseline in the first month post vaccination. IgG anti-PRP ≥ 1 μg/mL was considered protective. For the bactericidal assay, a 4-fold increase from baseline was considered positive. CD3+ T-cells and total (CD19+), naïve (CD19+, CD27−), memory (CD19+, CD27+, CD38−) and pre-plasma (CD19low, CD27hi, CD38hi) B-cells were determined by flow cytometry before and after vaccinations. Interferon-γ (IFN-γ) secreting T-cells were measured by elispot. Results: Patients who had been randomized to receive rituximab (n=14) or placebo (n=6) participated in this prospective study. Compared with placebo, fewer patients in the rituximab group achieved an adequate antibody response to S. pneumonia vaccine (21.4% versus 66.7%) or the Hib vaccine (28.6% versus 83.3%). These results correlated with a reduced bactericidal effect of anti-PRP antibodies observed in patients treated with rituximab compared with placebo (14.2% versus 83.3%). Two patients in the rituximab group demonstrated an adequate rise in antibody titer but with no functional bactericidal activity. In addition, 3 patients who did not mount an adequate antibody response, had IgG anti-PRP titers below protective levels and did not demonstrate bactericidal activity in vitro were considered Hib vaccine failures. There were no Hib vaccine failures in the placebo group. In the rituximab group, total number of B-cells declined rapidly after treatment (1.895 × 104/mL) relative to the placebo group (5.65 × 104/mL) and never fully recovered even 1 year post-treatment. Resting memory B-cells were significantly reduced after rituximab and remained at low levels even up to 1 year. Conversely, naïve B-cells recovered to near normal levels within 6 months of treatment. Activated pre-plasma B-cells increased following vaccination in the placebo group; yet, this response was variable in patients who had received rituximab. CD3+ T-cell numbers were unaffected by rituximab and vaccination; however, the number of IFN-γ- secreting T-cells were lower in the rituximab group. Conclusions: Rituximab treatment was associated with an impaired antibody response to vaccination, which in some patients was only demonstrated by impaired bactericidal activity. The expected increase in B-cell subsets was not observed following vaccination in the rituximab group, and T-cells, while normal in number, demonstrated functional impairments. Our findings characterize subtle defects in immunity which may persist after rituximab treatment. Disclosures: Off Label Use: Rituximab is not licensed for use with ITP patient. Kelton:Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees, Research Funding; Hoffman-LaRoche: Research Funding. Arnold:Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees, Research Funding; Hoffman-LaRoche: Research Funding.

scholarly journals Interim Results from Fight-203, a Phase 2, Open-Label, Multicenter Study Evaluating the Efficacy and Safety of Pemigatinib (INCB054828) in Patients with Myeloid/Lymphoid Neoplasms with Rearrangement of Fibroblast Growth Factor Receptor 1 (FGFR1)

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 690-690 ◽  
Author(s):  
Srdan Verstovsek ◽  
Alessandro M. Vannucchi ◽  
Alessandro Rambaldi ◽  
Jason R. Gotlib ◽  
Adam J. Mead ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Board Of Directors ◽  
Research Funding ◽  
Phosphate Binders ◽  
Phase 2 ◽  
Open Label ◽  
Employment Equity ◽  
Advisory Committees ◽  
Lymphoid Neoplasms ◽  
Equity Ownership

Abstract Introduction: Myeloid/lymphoid neoplasms (MLNs) with rearrangement of FGFR1 on chromosome band 8p11 are rare but aggressive neoplasms characterized by heterogeneous presentation with myeloid and/or lymphoid proliferation, extramedullary involvement, and rapid progression to blast phase (Strati P, et al., Leuk Lymphoma. 2018;59:1672-1676). FGFR1 gets constitutively activated through fusion genes involving various partner genes, most frequently ZMYM2-FGFR1 or BCR-FGFR1 as consequence of a t(8;13)(p11;q12) or a t(8;22)(p11;q11), respectively. Chemotherapy is usually ineffective, effective targeted treatment has not been described, and allogeneic hematopoietic stem cell transplant (alloHSCT) is the only potentially curative option. Pemigatinib, a selective, potent, oral inhibitor of FGFR1, 2, and 3, has shown efficacy in patients with FGF/FGFR-activated tumors, including cholangiocarcinoma and urothelial carcinoma. We report interim results from the ongoing fight-203 study (NCT03011372) of pemigatinib in patients with FGFR1-rearranged MLNs. Methods: Fight-203 is a phase 2, open-label study enrolling patients ≥ 18 years of age with FGFR1-rearranged MLN. Patients enrolled in the study must have progressed on ≥ 1 prior treatment and be ineligible for alloHSCT. Patients receive a daily oral dose of pemigatinib 13.5 mg on a 21-day cycle (2 weeks on, 1 week off) until disease progression or unacceptable toxicity. The primary endpoint is overall clinical benefit rate, which includes complete clinical (CR) or partial clinical response (PR), and either complete or partial cytogenetic response (CCyR, PCyR). Secondary endpoints include duration of response/benefit, progression-free survival, overall survival, and safety/tolerability. Efficacy is assessed by evaluation of bone marrow histomorphology changes, standard cytogenetic and FISH evaluation of the FGFR1 rearrangement, and PET/CT scan. Results: At data cutoff (July 23, 2018), 14 patients were enrolled. Ten patients who had ≥ 1 response assessment were included in the analysis (Table). Patients received an average of 6.9 cycles of pemigatinib (range, 2-12 cycles). Median number of prior lines of therapy was 3 (range, 0-5), including 2 patients who received alloHSCT. Eight patients (80%) had a major CyR, including 6 patients with CCyR and 2 with PCyR. Eight patients (80%) had a CR or PR in bone marrow, peripheral blood, and extramedullary disease. One patient died of progression to myeloid blast crisis, 2 patients were bridged to alloHSCT, and 7 patients are ongoing. The most common treatment-emergent adverse events (AEs) were hyperphosphatemia (n=7 [70%]), diarrhea (n=5 [50%]) and anemia (n=5 [50%]); hyperphosphatemia was managed with diet and phosphate binders. Nine events in 4 patients (40%) were grade 3/4; 2 of these events (diarrhea and leukopenia) in 2 patients were related to pemigatinib. There were no drug-related AEs leading to dose interruption, dose reduction, or discontinuation. Conclusions: Pemigatinib showed promising efficacy, with an 80% major CyR rate accompanied by complete or partial remission, and was generally well tolerated by patients with FGFR1-rearranged MLN. The protocol was amended to allow continuous dosing, and the study is currently enrolling. Disclosures Verstovsek: Celgene: Membership on an entity's Board of Directors or advisory committees; Italfarmaco: Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Gotlib:Blueprint Medicines: Consultancy, Honoraria, Research Funding; Deciphera: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Research Funding; Promedior: Research Funding; Kartos: Consultancy; Incyte: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Mead:Celgene: Research Funding; Bristol-Myers Squibb: Consultancy; Evotek: Research Funding; ARIAD: Consultancy; Cell Therapeutics: Consultancy; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Elstar: Research Funding. Hochhaus:Bristol-Myers Squibb: Research Funding; Novartis: Research Funding; Incyte: Research Funding; Takeda: Research Funding; Pfizer: Research Funding. Kiladjian:AOP Orphan: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees. Hernandez Boluda:Incyte: Consultancy; Novartis: Consultancy. Asatiani:Incyte: Employment, Equity Ownership. Lihou:Incyte: Employment, Equity Ownership. Zhen:Incyte: Employment, Equity Ownership. Reiter:Incyte: Consultancy, Honoraria.

scholarly journals The Use of Venetoclax for Acute Myeloid Leukemia in a Real-Life Setting: A Multicenter National Experience

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5098-5098
Author(s):  
Jacopo Nanni ◽  
Giacomo Gianfaldoni ◽  
Gianluca Cristiano ◽  
Giovanni Marconi ◽  
Matteo Piccini ◽  
...  
Keyword(s):  
Adverse Events ◽  
Board Of Directors ◽  
Research Funding ◽  
Real Life ◽  
Advisory Committees ◽  
The Real ◽  
Real Life Setting ◽  
Treatment Naïve ◽  
Grade Iii

Background The oral anti-apoptotic B-cell lymphoma 2 protein inhibitor venetoclax has shown strong activity in R/R AML in controlled clinical trials, and recently impressive results in treatment-naïve AML elderly patients with acute myeloid leukemia. However, limited data are available in the real-life setting. Methods This is a multi-center (n=4), retrospective study involving patients with treatment-naïve or Relapsed/Refractory (R/R) AML treated with Venetoclax in combination with HMAs. Data were collected after anonymous aggregation, in accordance with GCP and Helsinky declaration. Adverse events (AEs) were graded according CTCAE v4.03. Survival is estimated with Kaplan-Meyer method. Results Forty-four patients have been prescribed Venetoclax from March 2018 to June 2019 and completed at least 1 course of venetoclax (range 1-8, median 2, IQR 2.0 - 4.0), being evaluable in this analysis. Patients's characteristics are summarized in Table 1. Five/44 (11.4%) patients had a low risk AML, 21/44 (47.7%) had an intermediate risk AML and 14/44 (31.8%) patients had a high risk AML, according to ELN 2017 risk stratification (4 patients had no available ELN risk at baseline). Six out of 44 (13.6%) patients received Venetoclax in combination with HMAs as first line of therapy, whereas 14/44 (31%) as first line rescue for resistant AML, 15/44 (34.1%) at first relapse, 9/44 (20.5%) for second or further R/R AML. Among R/R patients who received Venetoclax, 17/38 (44.7%) and 21/38 (55.2 %) had received chemotherapy or HMAs as induction therapy, respectively. Overall, Venetoclax was combined with azacitidine in 19/44 patients (43.2%), with decitabine in 19/44 patients (43.2%), with Low-dose of Cytarabine in 5/44 (11.4%), and was performed in monotherapy in 1/44 (2.3%) patient. Three out of 44 patients (6.8%) received a maximum dosage of 100 mg daily, 2/44 (4.5%) received 200 mg, 37/44 (84.1%) received 400mg and 2/44 (4.5%) received 600 mg. Fifteen out of 44 (34.1%) patients reduced the dosage of venetoclax for concomitant Azole administration. The median follow-up is 75.5 (IQR 45.2 - 178.5) days for patients who received upfront venetoclax therapy, while 143 (IQR 49.2 - 235.7) days for R/R patients. In the first-line setting, no patients reduced venetoclax dosage for concomitant adverse events; two neutropenia grade IV and two thrombocytopenia grade III have been documented. In the R/R setting, 14/38 (36.6%) patients reduced venetoclax dosage for concomitant adverse events. Specifically, we reported 22 adverse events, of which 10 were grade III-IV (5 neutropenia grade IV, 2 pancytopenia grade IV, 1 neutropenia grade III and 2 febrile neutropenia grade III). The overall CR rate is 16.7 % in newly-onset AML patients and 28.9 % in R/R patients, respectively. Two out of 6 treatment-naive patients had an evaluable response at 2 months after the beginning of Venetoclax treatment, and 2/6 had an evaluable 4-months response: 1 stable disease (SD) and 1 disease progression (PD) at 2 months,1 SD e 1 complete remission (CR )at 4 months. Thirty-one out of 38 R/R patients had an evaluable response at 2 months and 21/38 had an evaluable 4-month response: 10 CR, 1 complete response with incomplete hematologic recovery (CRi), 14 SD and 6 PD at 2 months; 6 CR, 10 SD and 3 PD at 4 months have been documented. After a short follow-up period (75.5 days), no patients who received Venetoclax as upfront therapy underwent an allogeneic hematopoietic stem cell transplantation (HSCT). On the other hand, after a longer follow-up period (143 days), 5 out of 38 patients (13.2%) received a HSCT after Venetoclax therapy among R/R patients. Median Overall Survival was not reached in the newly-onset cohort. In R/R setting, median OS was 253 days (95% C.I. 157-349). Interpretation These data extend to the real-life setting some previous evidence obtained from trials. In particular, our data confirm that venetoclax plus HMAs or LDAC has an acceptable toxicity profile and is safe and manageable. However, especially in the R/R setting, hematological toxicity represents the most frequent adverse event, arising some concerns about the optimal drugs management. Although our data suggest a similar clinical activity of venetoclax combinations to that reported in clinical trials, further studies from the real-life setting are highly warranted to confirm venetoclax efficacy under normal clinical practice. GG and JN equally contributed CP and AC equally contributed Disclosures Boccadoro: Janssen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; AbbVie: Honoraria; Mundipharma: Research Funding; Sanofi: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Amgen: Honoraria, Research Funding. Cavo:celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accommodations, Speakers Bureau; janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accommodations, Speakers Bureau; bms: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; novartis: Honoraria; takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Papayannidis:Shire: Honoraria; Pfizer: Honoraria; Incyte: Honoraria; Novartis: Honoraria; Amgen: Honoraria; Teva: Honoraria. OffLabel Disclosure: Venetoclax is not approved to treat Acute Myeloid Leukemia in Italy

scholarly journals Clonal Hematopoiesis Is Associated with Increased Risk for Therapy-Related Myeloid Neoplasms in Chronic Lymphocytic Leukemia Patients Treated with Chemo(immuno)Therapy

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 19-20
Author(s):  
Maria Teresa Voso ◽  
Tatjana Pandzic ◽  
Michail Iskas ◽  
Marija Denčić-Fekete ◽  
Eleonora De Bellis ◽  
...  
Keyword(s):  
Health Care ◽  
Chronic Lymphocytic Leukemia ◽  
Board Of Directors ◽  
Research Funding ◽  
Lymphocytic Leukemia ◽  
Advisory Committees ◽  
For Profit ◽  
Myeloid Neoplasms ◽  
Health Care Company ◽  
Care Company

Clonal haematopoiesis of indeterminate potential (CHIP) is defined by the detection of somatic mutations in genes recurrently mutated in myeloid neoplasms (MNs), in the blood of healthy individuals with normal blood values and lack of morphological evidence of MN. Recent studies have highlighted the potential association between CHIP and the development of MN, in particular therapy-related MN (t-MN) in patients with lymphoma treated with chemotherapy and/or autologous stem-cell transplantation. In the present study, we investigated whether the presence of CHIP is associated with a higher risk for the development of t-MN in patients with chronic lymphocytic leukemia (CLL) treated with chemo(immuno)therapy, including fludarabine and cyclophosphamide combinations. To this end, we studied 9 patients with CLL who developed a t-MN [acute myeloid leukemia (AML): n=6, myelodysplastic syndrome (MDS): n=3] after the administration of chemo(immuno)therapy (FCR: n=7, other, n=2), with available samples collected both before CLL treatment and at diagnosis of t-MN. The median interval between the two samples was 26 months (range: 9-38months). NGS was performed on DNA extracted from bone marrow mononuclear cells (MNCs) at t-MN diagnosis, using the Trusight Myeloid Sequencing Panel (n=4) and the Archer VariantPlex Myeloid kit (n=5). Backtracking of the variants detected at the t-MN phase was performed by NGS of DNA extracted from peripheral blood MNCs (n=8) or CD19+ selected cells (n=1) in the samples from the CLL phase. In case no variants were detected in the t-MN phase, targeted digital droplet PCR (ddPCR) was also performed in paired CLL samples to confirm the presence of the variants. Moreover, using the Trusight Myeloid Sequencing Panel, we evaluated the prevalence of CHIP in a population cohort of 285 patients with CLL at the time of diagnosis. The variant allele frequency (VAF) cut-off for the detection of the variants was set to 5%. Variants were reported if meeting the following criteria: (i) located within an exonic or splicing region; (ii) be non-synonymous; (iii) not listed in the gnomAD database, if not also recurrently reported in Cosmic v85. Overall, 16 variants were detected in 7/9 cases analyzed at the time of t-MN [NRAS (n=4), DNMT3A (n=3), TET2 (n=2), EH2 (n=2), TP53 (n=2), KRAS (n=1), U2AF1 (n=1) and SF3B1 (n=1)], while no variants were detected in 2 t-MN samples. In 6/7 cases with detectable variants at t-MN diagnosis, the same variants were present at the CLL phase with either lower (n=4) or similar (n=2) VAF. Overall, CHIP was detectable in 6/9 (66.7%) CLL patients who later developed a t-MN. Among the untreated CLL patients, 45 CHIP-related variants were detected in 35/285 cases (12%) as 7 patients harbored more than one variant. The median VAF was 12.7% (5.1-58.6%) with 27/45 (60%) having a VAF<20%. The affected genes were: DNMT3A (n=9), ASXL1 (n=8), KRAS (n=7), BCOR (n=3), NRAS (n=3), TET2 (n=2), U2AF1 (n=2), PTPN11 (n=2), HRAS (n=2), JAK2 (n=1), CBL (n=1), CALR (n=1), IDH2 (n=1), MPL (n=1), PHF6 (n=1) and ETV6 (n=1). CHIP was not associated with advanced age. Subgroup-analysis amongst CHIP-patients revealed: (i) enrichment of additional CHIP-related variants, male gender and younger age in carriers of ASXL1 variants and (p=0.1, p=0.008 and p=0.06; (ii) a bias towards female gender in patients with DNMT3A variants (p=0.008). The difference in the prevalence of CHIP between patients with CLL developing a t-MN (6/7) and those in the untreated cohort (35/285) was statistically significant (p<0.001). In conclusion, CHIP is significantly enriched in patients with CLL developing t-MNs after the administration of chemo(immuno)therapy, with obvious therapeutic implications especially in the era of targeted agents. The significance of CHIP in CLL should be further evaluated in the context of large clinical studies. MTV and TP contributed equally. EF and PB contributed equally. Disclosures Voso: Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Scarfo:Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AstraZeneca: Honoraria; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees. Ghia:ArQule: Consultancy, Honoraria; BeiGene: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Acerta/AstraZeneca: Consultancy, Honoraria; Adaptive, Dynamo: Consultancy, Honoraria; Novartis: Research Funding; Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Sunesis: Consultancy, Honoraria, Research Funding; MEI: Consultancy, Honoraria; Lilly: Consultancy, Honoraria; Celgene/Juno: Consultancy, Honoraria. Stamatopoulos:AstraZeneca: Honoraria; Janssen, Gilead, Abbvie: Honoraria, Research Funding.

scholarly journals Molecular Characterization of Diffuse Large B-Cell Lymphoma Associated to Hepatitis C Virus Infection

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2402-2402
Author(s):  
Roberta Sciarra ◽  
Caterina Cristinelli ◽  
Michele Merli ◽  
Marco Lucioni ◽  
Silvia Zibellini ◽  
...  
Keyword(s):  
B Cell ◽  
Board Of Directors ◽  
Immune Regulation ◽  
Research Funding ◽  
Notch Pathway ◽  
B Cell Lymphoma ◽  
Fish Analysis ◽  
Low Grade ◽  
Advisory Committees

Abstract BACKGROUND. HCV-positive DLBCL has distinct clinical and pathologic characteristics compared to its negative counterpart: patients (pts) are usually older with more frequent splenic and extranodal involvement and elevated LDH. Differently from its clinical hallmarks, the molecular landscape of this pathological entity has been scarcely outlined. METHODS. In this bicentric study, we investigated the clinical and molecular features and outcome of 54 pts with HCV-positive DLBCL. Targeted next generation sequencing (NGS) was performed on DNA extracted from formalin-fixed paraffin-embedded tissue biopsies. A core panel probes covering coding exons from 184 genes frequently mutated in mature B cell neoplasms was designed using IDT tool and libraries were prepared using Illumina DNA-prep-with enrichment. Sequencing was performed on Illumina HiSeq 2500. Cluster analysis was performed using LymphGen tool. We also applied fluorescence in situ hybridization (FISH) for MYC, BCL2 and BCL6. RESULTS. Median age was 71 (33-84; IQR: 61.9-77). Stage was III/IV in 34 pts (63%). Extranodal sites were involved in 21 pts (38%), spleen in 20 pts (37%). LDH was higher than the upper limit in 40 pts (74%). R-IPI was good for 2 pts (4%), intermediate for 24 pts (44%), poor for 28 pts (52%). HPS score was intermediate or high in 33 of 44 assessed pts (75%). A histological low-grade component was identified in 15 pts (27%). Hans algorithm differentiated pts almost equally in GCB (26/50, 52%) and non-GCB (24/50, 48%) subtype. HCV-RNA was detectable in 52 pts (96%) and quantifiable in 43 pts (79%). Of 29 pts assessed, genotype was 1 in 9 (31%), 2 in 16 (55%), 3 in 4 pts (14%). Among 37 pts whose data were available, 11 pts (30%) received direct antiviral agents, 7 pts (19%) received interferon-containing regimen, 19 pts (51%) were not treated for HCV. Twenty-seven pts (50%) received rituximab-enriched protocols, 23 pts (43%) were treated with chemotherapy alone, 1 pt (2%) with surgery alone, 3 pts (5%) were lost to follow up. With a median follow up of 7.7 years (yrs) (IQR: 4.6-10.6), 5-yrs overall survival (OS) (95%CI) was 49.3% (34.1-62.8%) and 5-yrs progression free survival (PFS) (95%CI) was 39.5% (25.5-53.3%). Median OS and PFS were 4.9 and 3.1 yrs, respectively. FISH analysis showed lack of BCL2 (0/19) and MYC translocations (0/15). BCL6 fusions were found in 76% of pts (16/21). NGS showed mutations in 154 of the 184 analyzed genes. The informativity of the panel was 100% with all pts presenting at least one oncogenic variant. Gene mutation frequencies are presented in Fig. 1. The median mutation load (MML) was 13 mutated genes per case (2-32; IQR: 9-16). Most frequently mutated genes were the epigenetic regulators KMT2D, mutated in 23 pts (42.6%), and SETD1B, mutated in 17 pts (31.5%). FAS, PM1 and RERE were mutated in 15 pts each (27.8%). TBL1XR1, BCL11A and SGK1 were mutated in 14 (26%), 13 (24%) and 12 pts (22%), respectively. Considering genes in their specific pathway, 94% of pts harbored mutations in genes involved in epigenetic regulation (MML: 3; range 1-7; IQR: 1.25-4), 90% of pts in apoptosis-related genes (MML: 2; 1-7; IQR: 1-3) and 77% of pts in genes belonging to BCR/NFkB signaling pathway (MML: 2; 1-7; IQR: 1-3). Of note, 56% of pts carried mutations in genes related to immune regulation (MML: 1.7; 1-5; IQR: 1-2) and 25% of pts had mutations within the NOTCH pathway (MML: 1.2; range 1-2). Via the LymphGen 1.0 tool, we classified 26 pts (48%) into 4 genetic clusters: BN2 (11/26, 42%), ST2 (8/26, 31%), MCD (4/26, 15%), EZB (3/26, 12%). Twenty-eight pts (52%) were classified as "others". Among those belonging to BN2 cluster, 7 pts (64%) had a histologically confirmed transformed DLBCL. No significant differences in terms of OS and PFS were identified according to cluster subgroups. CONCLUSIONS. The prevalence of the BN2 cluster and enrichment of mutations of genes involved in NOTCH pathway seem to indicate a preferential marginal-zone origin in HCV-positive DLBCL. In addition, our data confirm the absence of BCL2 translocation in this subset of DLBCL and show a high prevalence of mutated genes within the epigenetic and immune regulation pathways in HCV-positive DLBCL, pointing out their compelling role in the pathogenesis and suggesting potential implications for molecularly targeted therapies. Figure 1 Figure 1. Disclosures Passamonti: Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Arcaini: Celgene: Speakers Bureau; Gilead Sciences: Research Funding; Bayer, Celgene, Gilead Sciences, Roche, Sandoz, Janssen-Cilag, VERASTEM: Consultancy; Celgene, Roche, Janssen-Cilag, Gilead: Other: Travel expenses.

Ricolinostat (ACY-1215), the First Selective HDAC6 Inhibitor, in Combination with Bortezomib and Dexamethasone in Patients with Relapsed or Relapsed-and-Refractory Multiple Myeloma: Phase 1b Results (ACY-100 Study)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1827-1827 ◽  
Author(s):  
Dan T. Vogl ◽  
Noopur S. Raje ◽  
Sundar Jagannath ◽  
Paul G. Richardson ◽  
Parameswaran Hari ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Clinical Benefit ◽  
Research Funding ◽  
Low Grade ◽  
Advisory Committees ◽  
Acetylated Tubulin ◽  
Clinical Benefit Rate ◽  
Phase 1B ◽  
Grade 3

Abstract Background: Ricolinostat, an oral selective HDAC6 inhibitor, is well tolerated as monotherapy (Raje Blood 2012;120:4061). HDAC6 inhibition impairs the aggresome/autophagy pathway, an alternate pathway to proteasome clearance of misfolded proteins (Santo Blood 2012;119:2578-89) providing the rationale for combining ricolinostat with bortezomib (Btz). Pan-HDAC inhibitors vorinostat and panobinostat are active in multiple myeloma (MM) in combo with Btz, but toxicities (thrombocytopenia, fatigue, and GI events) limit dosing exposure. This trial explores activity of ricolinostat in combo with Btz and dexamethasone (Dex) in patients with relapsed or relapsed-and-refractory MM. Methods: Phase 1b was a 3+3 design that explored ricolinostat combined with Btz (1.0-1.3 mg/m2 IV or SQ on days 1, 4, 8, 11) and Dex (20 mg PO on days 1, 2, 4, 5, 8, 9, 11, 12). Patients previously received at least 2 lines of therapy including a proteasome inhibitor and an immunomodulatory agent, had either progressed after or were ineligible for autologous stem cell transplant, and had adequate BM reserve, hepatic function and CrCl ≥30 mL/min. Patients with prior HDAC inhibitor therapy were excluded. Peripheral blood samples were obtained for PK/PD assessment of acetylated tubulin and histones. Results: 50 patients were enrolled to 8 combination dose cohorts to date. Median age was 65, median number of prior regimens was 5 (2-12) and 33 patients were refractory to Btz. The first combination cohort was expanded due to a DLT of asymptomatic increase in amylase. No other DLTs have been observed in the cohort escalations. Common toxicities were predominately low grade (grade 1/2) and included diarrhea (46%), anemia (38%), thrombocytopenia (22%), increased creatinine (18%), fatigue (16%), and nausea (16%). Important grade 3/4 related toxicity included thrombocytopenia (9 patients, 18%) and anemia (6 patients, 12%). Cohorts were expanded sequentially at two dose levels: 160 mg BID and 160 mg QD. Of the 22 patients receiving ricolinostat 160 mg BID common toxicities were diarrhea (68%, grade 1/2), thrombocytopenia (50%, grade 3/4), anemia (45%, grade 2/3), fatigue (36%, grade 1/2), and nausea (36%, grade 1/2). There was a marked increase in the incidence of SAEs related to diarrhea leading to dehydration and hospitalization (27%). Therefore a second cohort expansion at 160 mg QD was initiated. Of the 15 patients receiving ricolinostat at 160 or 240 mg QD common toxicities were diarrhea (33%, grade 1/2), thrombocytopenia (20%, grade 4), anemia (20%, grade 3), increased creatinine (20%, grade 3), hyponatremia (20%, grade 1), and increased ALT (20% grade 3), and peripheral neuropathy (20%, grade 1/2). PK for ricolinostat is similar to that observed in Phase 1a monotherapy, indicating that co-administration of Btz does not significantly impact ricolinostat exposure. Maximal blood levels of ricolinostat were ≥0.5 µM at ≥80 mg correlating with a >2x increase in the HDAC6 PD marker acetylated tubulin. 48 patients were evaluable for response with median follow-up of 3 (1-18) months; ORR (≥PR) was 39% and clinical benefit rate (≥MR) was 44% with 81% SD or better. Of the 22 patients receiving ricolinostat 160 mg BID with median follow-up of 3 (1-18) months, ORR (≥PR) was 32% and clinical benefit rate (≥MR) was 41% with 62% SD or better. Of the 12 patients receiving ricolinostat at 160 or 240 mg QD with median follow-up of 4 (1-8) months, ORR (≥PR) was 33% and clinical benefit rate (≥MR) was 33% with 67% SD or better. Of the 33 Btz refractory patients, 42% had SD or better, and 12% responded including 1 VGPR. Conclusion: Overall, ricolinostat in combination with Btz and Dex was well tolerated. Diarrhea and hematologic toxicity, mostly low grade, was less prevalent with QD than BID dosing and led to fewer hospitalizations and early treatment discontinuation. Response rates were similar between both QD and BID dosing. 160 mg QD is the recommended dose in combination with Btz and Dex. Disclosures Vogl: Constellation Pharmaceuticals: Research Funding; GSK: Research Funding; Millennium Pharmaceuticals: Research Funding; Calithera Biosciences: Research Funding; Celgene Corporation: Consultancy; Acetylon Pharmaceuticals, Inc.: Research Funding. Raje:Acetylon: Research Funding; Amgen: Consultancy; Eli Lilly: Research Funding; Onyx: Consultancy; Celgene Corporation: Consultancy; AstraZeneca: Research Funding; BMS: Consultancy; Takeda: Consultancy; Millenium: Consultancy; Novartis: Consultancy. Jagannath:Celgene: Honoraria; MERCK: Honoraria; Janssen: Honoraria; Novartis Pharmaceuticals Corporation: Honoraria; BMS: Honoraria. Richardson:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium Takeda: Membership on an entity's Board of Directors or advisory committees; Gentium S.p.A.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Hari:Sanofi: Consultancy; Takeda: Consultancy; Spectrum: Consultancy; Novartis: Consultancy; Janssen: Consultancy; BMS: Consultancy; Celgene: Consultancy. Orlowski:Millennium Pharmaceuticals: Consultancy, Research Funding; Array BioPharma: Consultancy, Research Funding; Onyx Pharmaceuticals: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; BioTheryX, Inc.: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Research Funding; Acetylon: Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy; Spectrum Pharmaceuticals: Research Funding; Forma Therapeutics: Consultancy. Tamang:Acetylon Pharmaceuticals, Inc.: Employment. Jones:Acetylon Pharmaceuticals, Inc.: Employment, Equity Ownership. Wheeler:Acetylon Pharmaceuticals, Inc: Employment. Markelewicz:Acetylon Pharmaceuticals, Inc: Employment. Lonial:Millennium: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Onyx: Consultancy, Research Funding.

scholarly journals Impact of Sars-CoV2 Infection on 491 Hematological Patients: The Ecovidehe Multicenter Study

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 5-6
Author(s):  
Cristina De Ramón ◽  
Jose Angel Hernandez-Rivas ◽  
Jose Antonio Rodríguez García ◽  
Enrique M. Ocio ◽  
María Teresa Gómez-Casares ◽  
...  
Keyword(s):  
Risk Factors ◽  
Mortality Rate ◽  
Hospital Admission ◽  
Board Of Directors ◽  
Research Funding ◽  
Performance Status ◽  
Biological Data ◽  
Advisory Committees ◽  
Hematological Diseases ◽  
Hematological Patients

INTRODUCTION Coronavirus disease 2019 (COVID-19) caused by SARS-CoV2 virus is thought to be more severe in patients with prior hematological diseases. There is evidence suggesting that hematological patients are particularly vulnerable and have a higher risk of developing severe events, with higher mortality rate than general population. However, the available data are limited, and prognostic factors at admission still remain unclear. With this background, our aims were to analyze the impact of hematological diseases and their therapy on the COVID-19 severity and to identify clinical and biological risk factors to predict the outcome in these patients. METHODS We carried out a multicenter retrospective observational study with data collection from 19 Spanish centers. A total of 491 patients with hematological diseases who developed COVID-19 (HEMATOCOVID patients) from March 8th to June 9th were included in the study. Clinical and biological data were collected at the time of emergency room assistance or hospital admission. For statistical analysis, chi-square test and Mann-Whitney U-test were used to identify differences between groups. The effects of multiple predictor variables on COVID-19 outcomes were assessed by logistic binary regression. RESULTS The geographic distribution of the studied HEMATOCOVID patients was similar to the national geographic spread of the COVID-19 (Figure 1). Most patients (94,3%) were confirmed cases of COVID-19 with a positive result on SARS-CoV2 RT-PCR on a nasopharyngeal swab or serologic testing, and 15% were nosocomial infections. The mean age was 71 years with 57% males, and 70% had at least one associated comorbidity. The most frequent hematological diseases among COVID-19 patients were Lymphoid Malignancies (53,8%), and 51,7% of patients were on active treatment. Most common symptoms were fever (59%), cough (54%) and dyspnea (46%), with associated pneumonia in 70% of cases. Hospital admission was required in 89% of patients and 6,3% were admitted to intensive care units. Mortality rate was about 36%. Non-survival patients were older and had a higher Charlson comorbidity index and ECOG performance status. Furthermore, patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS), and those with an active or progressive hematological disease at the diagnosis of COVID-19 had higher mortality. Patients who had undergone hematopoietic stem cell transplantation (autologous, allogeneic, and both) had better outcomes. Other factors such as low lymphocyte and platelets counts, or high lactate dehydrogenase (LDH), C-reactive protein (CRP) and procalcitonin values were also associated with poorer outcomes (Table 1). In addition, COVID-19 therapy had no impact on survival, except for corticosteroids, that correlated with a negative impact (p < 0,001) probably because they were not administrated to patients with less severe COVID-19. Multivariate regression analysis showed the following risk factors for death: age >70 years, ECOG ≥2, absolute lymphocyte count ≤0.6·109/L, platelet count ≤40·109/L, high LDH (higher than upper normal limit) and CRP >11 mg/dL (Table 2). CONCLUSIONS SARS-CoV2 infection causes more severe disease and higher mortality rates in hematological patients, especially those with AML/MDS or active/progression status disease. In addition, advanced age, co-morbidities, poor performance status, low lymphocyte and platelet counts and high LDH and CRP at admission are associated with poorer survival. This worse disease evolution could be explained by the immunosuppression state induced by underlying disease and treatments received. These particular features should be taken into account for a population that is highly exposed to SARS-CoV2 contagion due to high number of hospital visits for treatment. Disclosures Hernandez-Rivas: Janssen: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Membership on an entity's Board of Directors or advisory committees; Rovi: Membership on an entity's Board of Directors or advisory committees. Ocio:MDS: Honoraria; Asofarma: Honoraria; Takeda: Honoraria; GSK: Consultancy; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Secura-Bio: Consultancy; Oncopeptides: Consultancy. López Jiménez:Gilead: Research Funding, Speakers Bureau; Janssen: Research Funding, Speakers Bureau; Roche: Research Funding, Speakers Bureau; MSD: Speakers Bureau; Takeda: Speakers Bureau; Abbvie: Research Funding, Speakers Bureau. Córdoba:Takeda Farmacéutica España S.A.: Speakers Bureau; Janssen: Honoraria, Other: travel and accommodation; Abbvie: Honoraria, Other: travel and accommodation; Roche: Honoraria, Other: travel and accommodation; Gilead: Honoraria, Other: travel and accommodation. Moraleda:Takeda: Consultancy, Other: Travel Expenses; Sandoz: Consultancy, Other: Travel Expenses; Novartis: Consultancy, Other: Travel Expenses; Gilead: Consultancy, Other: Travel Expenses; Jazz Pharmaceuticals: Consultancy, Research Funding. Garcia-Sanz:Takeda: Consultancy, Research Funding; Pharmacyclics: Honoraria; Novartis: Honoraria; Janssen: Honoraria, Research Funding; Incyte: Research Funding; Gilead: Honoraria, Research Funding; BMS: Honoraria; Amgen: Membership on an entity's Board of Directors or advisory committees.

Sign in / Sign up

Export Citation Format

Share Document