ABSTRACT
Background And Aims: S100A8 and S100A9 alarmins and their heterodimer calprotectin are diversely involved in myeloid neoplasm pathophysiology as well as infectious and inflammatory diseases. In the context of COVID-19, circulating calprotectin was identified as a powerful biomarker of disease severity. Calprotectin impact on CD34+ hematopoietic stem and progenitor cells remains poorly understood. Method(s): Calprotectin effects on healthy donor and chronic myeloid neoplasm-derived CD34-positive hematopoietic stem and progenitor cells were tested in liquid culture for up to 7 days. The pro-inflammatory cytokine IL-6 was used as a control. Cytokine effects alone or in combination were explored by the use of bulk and single cell RNA sequencing, Assay for Transposase-Accessible Chromatin with high-throughput sequencing, cytokine secretion analyses and semi-solid cultures. Result(s): CD34+ cells exposed to IL-6 generate monocytic cells that overproduce calprotectin. Calprotectin inhibits erythroid differentiation of healthy CD34+ cells, possibly through CD36 receptor. Chronic myeloid neoplasm CD34+ cells over-react to calprotectin, with large transcriptomic rewiring of erythro-megakarocytic and granulo-monocytic populations. Calprotectin-induced inhibition of erythroid progenitor proliferation correlates with increased synthesis of ribosomal subunits and p53 pathway activation, while the cytokine impact on granulo-monocytic cells indicates an autocrine or paracrine amplification loop. Conclusion(s): Calprotectin secreted by monocytes generated by CD34+ cells upon IL-6 stimulation may be a pathophysiological component of inflammatory anemia, a role that is amplified in the context of myeloid neoplasms in which calprotectin effects extend to the granulo-monocytic lineage.Copyright © 2023 Elsevier Ltd. All rights reserved.
ABSTRACT
Introduction: We present the first case of appendiceal intussusception associated with myeloid sarcoma in a young patient. Minimally invasive techniques used along the clinical course are highlighted. Case description: A 2.5-year-old boy was admitted after three weeks of COVID-19 infection with ongoing symptoms of MIS-C. Due to constipation, distended belly and vomiting, US was done which showed ileocolic intussusception. After unsuccessful hydrostatic reduction laparoscopic exploration was performed, where the vermiform appendix was found to be thickened and partially intussuscepted into the coecum. The ileocecal region was exteriorized transumbilically. After manual reduction of the intussusception, a long, thickened, fragile appendix was removed. Histopathology revealed myeloid sarcoma. Bone marrow investigation identified acute myeloid leukemia. During the oncological treatment, laparoscopic cholecystectomy was necessary due to cholecystitis and cholelithiasis. The child recovered uneventfully in terms of surgical complications, with good cosmetic result. Conclusion(s): No similar case in childhood was found in the English literature. Unusual symptoms and radiological findings of intussusception can conceal unexpected disorders. Minimally invasive technique offered advantages in the treatment of the presented patient and can be recommended to treat intussusception or cholelithiasis, if applicable, during an ongoing oncological treatment as well.Copyright © 2023 The Authors
ABSTRACT
Introduction: Patients with hematological diseases have impaired humoral immunity secondary to disease itself and due to its treatment. Treatment can be either steroids, chemotherapy and chemoimmunotherapy. The immune response to covid 19 vaccine or disease may be significant impaired in haematological diseases. Aims & Objectives: None of the approved vaccine available in India (Covaxin, covishield and sputnik) has been approved for hemato oncology and transplant patients but most of our patients had received either of these vaccines as per national recommendations. Hereby we did retrospective study to look for antibody response in haematological diseases. Material(s) and Method(s): We retrospectively analysed the serological response to covid 19 disease and vaccination in 50 patients. Patients were divided into myeloid malignancies (Acute myeloid leukemia and MDS) n = 11, lymphoid malignacies n = 12 (CLL N = 8, Non Hodgkin Lymphoma n = 3, Pre B ALL n = 1), plasma cell dyscrasis (n = 8) (Multiple myeloma n = 6, AL amyloidosis n = 2), ITP N = 10 (patients on steroids, rituximab), MPNs n = 6 (CML N = 5, ET N = 1), AIHA N = 3. The complete history including the history of covid 19 diseases and covid vaccination was taken. Treatment history of the patient and antibody formation was analysed. Result(s): SARS COV2 IgG antibody was tested in a total of 50 patients. Overall antibody response was present in 90.1% patients. The total igG antibody in myeloid malignancies was 482.45 (12-2000) u/ml, while MPN, lymphoid malignancies, plasma cell dyscrasis had median antibody 140.04 u /ml (0.2-250), 47.9.9u/ml (3.04-200), 1416.9u/ml (20-40,000) respectively. 2 patients with plasma cell dyscrasis and 2 patients with CML had no antibody formation. The benign disorders including itp on steroids and rituximab had median antibody of 262.72 u/ml (6.54-1358) and AIHA had 281.6 (45- 400) u/ml. The results are shown in table 1. Conclusion(s): This Study demonstrates low immunogenicity, mainly in patients with lymphoproliferative disorders, as well as with certain drugs, including mainly anti-CD20 antibodies, Bruton tyrosine kinase inhibitors. However, better humoral response rates are seen in plasma cell dyscrasis on treatment. (Table Presented).
ABSTRACT
Background: The end of the pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for coronavirus disease-19 (COVID-19), is not foreseen. Vaccination using two subtypes of mRNA-based vaccines, BNT162b2 or mRNA-1273, is an effective public health measure to reduce the risk of infection and severe complications from COVID-19. However, COVID-19 vaccine response data for patients with myeloid malignancy, who are at severe risk in case of infection, has not emerged. Aims: We investigated the antibody titers of COVID-19 in patients with myeloid malignancies who received two doses of mRNA-based COVID-19 vaccine. Methods: Previously treated, currently treated, and newly diagnosed 46 patients with acute myeloid leukemia (AML) and 23 patients with myelodysplastic syndrome (MDS) were included in this study. Anti-spike SARS-CoV-2 antibody titers were measured at 3 months after the second vaccination and compared them to those in healthy controls. Results: Seroconversion rates for AML and MDS were 94.7% and 100%, without significant difference from healthy controls (100%). In AML patients, the median antibody titers of patients in complete remission (CR) (816.5 [interquartile range (IQR): 250.0-2063.5] U/ml vs 1023.0 [640.0-1535.0] U/ml, P=0.668), especially those who were under treatment-free observation in CR (1630.0 [806.0-2454.0] U/ml vs 1023.0 [640.0-1535.0] U/ml, P=0.1220), were comparable to those in healthy controls. On the other hand, even in CR, the antibody titer in AML patients under maintenance therapy was significantly lower than that in patients under treatment-free observation (154.0 [126.0-289.0] U/ml vs 1630.0 [806.0-2454.0] U/ml, P=0.0003). Among the AML patients in CR, patients receiving maintenance treatment had a significantly lower median absolute lymphocyte count (0.81 [0.71-1.46] x 109/l vs 1.58 [1.29-1.93] x 109/l, P=0.0094) and a significantly lower median absolute neutrophil count (1.45 [1.15-1.64] x 109/l vs 3.45 [2.68-4.28] x 109/l, P<0.0001) than that in patients under treatment-free observation. Significantly lower antibody titers were associated with current active treatment (92.2 [37.5-216.3] U/ml vs 1630.0 [806.0-2454.0] U/ml, P<0.0001), AML with myelodysplasia-related changes (50.8 U/ml [39.9-109.1] vs 816.5 [283.0-1935.3] U/ml, P=0.0022), advanced age more than the median age of 68 years (195.0 [43.3-743.0] U/ml vs 1630.0 [806.0-3391.0] U/ml, P=0.0002), and vaccine subtypes of BNT162b2 (285.0 [127.8-1045.3] U/ml vs 3037.0 [2198.50-4537.0] U/ml, P=0.0002) in AML patients and with current active treatment (41.0 [10.7-227.5] U/ml vs 623.5 [173.8-1613.3] U/ml, P=0.0233), subtypes of excess blasts (11.1 [4.8-34.1] U/ml vs 212.0 [81.7-600.0] U/ml, P=0.0293), and high and very high risk of the revised international prognostic scoring system in MDS patients (9.0 [3.4-41.0] U/ml vs 169.0 [48.5-327.0] U/ml, P=0.0380). Summary/Conclusion: This is one of the first studies on the effect of COVID-19 vaccines focusing on patients with AML and MDS, and there are many new findings. The response to COVID-19 vaccine appears to be related to disease and treatment status. Myeloid malignancies may have less impact than lymphoid malignancies on the vaccine response. AML patients under treatment-free observation in CR could be expected to have a vaccine effect that is comparable to that in healthy individuals. In contrast, since the response to vaccination might be insufficient in AML patients undergoing maintenance therapy, maintenance therapy should be continued with strict measures for prevention of infection even after vaccination.
ABSTRACT
Introduction: Axicabtagene ciloleucel (axi-cel) is an autologous anti-CD19 Chimeric Antigen Receptor (CAR) T-cell therapy that induces durable responses in patients with relapsed or refractory large B-cell lymphoma. At a median of 27.1 months follow-up on the ZUMA-1 trial, median overall survival (OS) was 25.8 months with 39% progression free survival (PFS) at 2 years post-infusion (Locke, Lancet Onc 2019). We previously reported outcomes of axi-cel patients treated with standard of care therapy at a median follow up of 12.9 months, including 42% who did not meet eligibility criteria for ZUMA-1 based on co-morbidities (Nastoupil, JCO 2020). Here we report results from this cohort at a median follow up of 32.4 months, as well as late outcomes of interest including cytopenias, infections and secondary malignancies. Methods and Results: The US Lymphoma CAR-T Consortium comprised of 17 US academic centers who contributed data independent of the manufacturer. Two hundred and ninety-eight patients underwent leukapheresis with intent to manufacture standard of care axi-cel as of September 30, 2018. In infused patients (n=275), OS and PFS were calculated from date of infusion. After median follow-up of 32.4 months (95% CI 31.1 - 34.3), median OS was not reached (95% CI 25.6 - not evaluable) (Figure 1A) with 1-, 2- and 3-year OS of 68.5% (95% CI 62.6-73.7), 56.4% (95% CI 50.1-62.2) and 52.2% (95% CI 45.7-58.2%), respectively. Median PFS was 9 months (95% CI 5.9-19.6) (Figure 1B);1-, 2- and 3-year PFS was 47.4% (95% CI 41.4-53.2), 41.6% (95% CI 35.6-47.5) and 37.3% (95% CI 31.3-43.2), respectively. Twenty-seven PFS events occurred at or after 1 year post infusion;19 events were progressive lymphoma, with the latest relapse observed 28 months after axi-cel infusion. Eight patients died while in remission from their lymphoma: 4 from secondary malignancy, 3 from infection, and 1 from unknown causes. Results of multivariable modeling were similar to our prior analysis: factors associated with both a shorter PFS and shorter OS included male sex, elevated pre-lymphodepletion LDH, and poor ECOG status. Complete blood count and B- and T-cell recovery data were collected at 1 and 2-years post-infusion, excluding patients who had relapsed or been treated for secondary malignancy at time of collection (Table 1). Rates of neutropenia (absolute neutrophil count ≤1000) at 1- and 2- years were 9.2% (10/109) and 11.2% (9/80) and rates of CD4 count ≤200/ul were 62% (23/37) and 27% (7/26). Recovery of B cells was seen in 54% (15/28) and 57% (13/23) at 1-and 2-years post infusion. Infections were reported in 31.2% (34/109) patients between 6- and 12-months post infusion, and 17% (18/109) were severe, requiring either hospitalization and/or IV antibiotics. Twenty-one patients (24%, 21/89) had an infection between 1- and 2- years, 11% of which were severe. Twenty percent (10/49) of patients between 2- and 3-years had an infection and 4 (8%) were severe. Neutropenia, low CD4 counts, and IgG levels were not associated with infection, though patients with infection between 6-12 months were more likely to have received IVIG (p<0.001). No patient in this cohort died of COVID-19. Twenty-two of 275 (8%) patients were diagnosed with subsequent malignancy after axi-cel treatment: 14/275 (5%) patients were diagnosed with myeloid malignancies (MDS (n=12), AML (n=1), CMML (n=1));other malignancies included squamous cell carcinoma of skin (n=3);sarcoma (n=1);endometrial (n=1);lung (n=1);mesothelioma (n=1) and AITL (n=1). Patients with myeloid malignancy had a median age of 62 at axi-cel apheresis (IQR 56-67), 64% were male and median lines of prior therapy was 4 (IQR 3-6), including 36% with a prior autologous stem cell transplant. Eleven patients were in remission from lymphoma at myeloid malignancy diagnosis, while 3 were diagnosed after progression and interval therapy. Conclusion: This multi-center retrospective study showed similar long-term results to the ZUMA-1 trial, despite including patients who did not meet ZUMA-1 eligibility criteria ba ed on comorbidities. Sixteen percent of PFS events were seen after 1 year, largely due to disease progression. Late infection was common but was not explained by persistent neutropenia or low CD4 counts. Subsequent malignancy, including MDS, occurred in 8% of patients and require further study to better identify patients at risk. (Figure Presented).
ABSTRACT
Introduction: COVID19 can be considered as one of the worstpandemics humans have faced. There haven't been many casesreported, specifically looking at its severity and outcome in patientswith hematological malignancies.Aims &Objectives: Presenting a diagnosed case of AML, on Azacytidine therapy, manifesting with COVID19 disease.Materials &Methods: On 13th July 2021, a 43 year old female,diagnosed with AML came to the OPD with history of cough, feverand running nose from last 7 days. She was receiving antimicrobialprophylaxis with levofloxacin and fluconazole. Her temperature was38 °C, BP 110/60 mm Hg, heart rate 88 bpm, and SpO2 was 97% inroom air. She tested positive for COVID19 the same day. She wasstarted on Azithromycin, Ivermectin and vitamin supplements. Herstay in COVID ward was uneventful, except for the significantchanges in her laboratory data [Table 1].Result: The patient's cell lineages went down after the chemotherapy.During COVID19 infection, she developed leukocytosis with 60%blast cells while still having neutropenia. Despite persistent neutropenia, she didn't develop any major respiratory symptoms orcomplications. Chest X-ray was normal. Her KFT, RBS, electrolytes,LFT and PT-INR were in normal range. CRP and D-Dimer wereraised. On day 10, after testing negative for COVID 19, third cycle ofchemotherapy was started, and she was discharged on day 17.Conclusions: Typical Covid19 presentation is neutrophilia and lymphopenia, which is in contrast to our result depicting increased totalleucocyte count (lymphocytosis and blasts), with consistent neutropenia. This difference could be attributed to underlying AML andtreatment received. Although there are few published reports indicating patients with myeloid malignancies and COVID19 havinghigher mortality, our patient with active AML and no other comorbidities, made a full recovery without any antiviral therapy, and hadmild respiratory symptoms only. This also calls for the need ofadditional studies to further delineate risk factors contributing tomortality in this subgroup of patients.
ABSTRACT
Decitabine (Dec) and Azacitidine (Aza) that target DNA methyltransferase 1 (DNMT1) are hypomethylating agents (HMAs) approved to treat acute myeloid leukemia (AML) in combination with Venetoclax (Ven). The combination is also used to treat high-risk myelodysplastic syndromes, especially TP53-mutated (TP53mut) cases in which responses to HMA alone are short-lived. In most patients (pts), however, myelosuppression from treatment leads to frequent Ven duration and/or dose-reductions, and/or cycle delays. An approach to decrease HMA-mediated myelosuppression but maintain S-phase dependent DNMT1-targeting, evaluated in a previous clinical trial (https://doi.org/10.1111/bjh.16281), is to administer noncytotoxic doses/concentrations of Dec (0.2 mg/kg;~5 mg/m 2) by a frequent-distributed schedule of 1X/week. An approach to decrease Ven mediated myelosuppression but maintain cooperation with HMA, shown in pre-clinical studies, is to administer a single-dose prior to HMA. Ven can depolarize mitochondrial membranes;mitochondrial membrane-potential is essential to function of the mitochondrial enzyme DHODH that produces cytidine/deoxycytidine that competes with HMA in cells. Thus, Ven prior to HMA dosing temporarily inhibits de novo pyrimidine synthesis, to counter a major mechanism of resistance to HMA in MDS/AML, without suppressing normal myelopoiesis (https://doi.org/10.1182/blood-2020-143200). We conducted a retrospective analysis of all pts with TP53mut MDS or AML treated with weekly Ven and low-dose subcutaneous Dec at our institution. We analyzed the characteristics of these pts, response to therapy, and outcomes using standard descriptive statistics. Mutational testing was performed using a commercial next-generation sequencing (NGS) panel. Five pts, 3 male and 2 female, with TP53mut MDS or AML were treated with weekly Ven 400 mg on D1 and subcutaneous Dec 0.2 mg/kg on D2, administered weekly in 28 day cycles. Two pts had MDS (1 de novo, 1 treatment related) and 3 pts had AML (1 de novo, 2 secondary from prior MDS). Four pts (80%) received the treatment in frontline, all with poor performance status (PS), and 1 pt (20%) had R/R disease. Median age at diagnosis was 79 years [41-82]. The only young pt had prolonged severe cytopenias after 1 cycle Dec standard dosing during the peak of COVID-19 pandemic so was switched to this regimen. Of the 4 frontline treated pts, 2 pts had high-risk MDS, and 2 pts had adverse risk AML. The R/R pt had high-risk MDS transformed to AML that was refractory to 2 prior lines of therapy: standard Aza/Ven x5 cycles, then standard Vyxeos. Disease cytogenetics were complex in all pts. 60% (3/5) pts had sole TP53mut on NGS, with median variant allelic frequency (VAF) 48% [28-79]. 80% (4/5) pts were transfusion dependent prior to treatment. Median time to initiating therapy was 7 days from initial or refractory diagnosis [3-59] and median follow-up was 7.8 months (mo) [2.9-11.4]. The overall response rate (ORR) was 100%: 4/4 frontline pts had complete remissions (CR), and the 1 R/R pt achieved morphologic leukemia-free state (MLFS). Median time to best response was 2.9 mo. 50% (2/4) pts became transfusion independent. 40% (2/5) pts lost their TP53mut at best response, and another 40% (2/5) pts had significant reductions (83% and 38%) in TP53 mut VAF. The regimen was well tolerated with no pts stopping therapy due to adverse effects (AE). AE included G3/G4 neutropenia (80%), G1 thrombocytopenia (40%), nausea (20%), fatigue (20%), lower extremity edema (20%), pneumonia (60%), and neutropenic fever (20%) with a median of 1 unplanned hospitalization per pt during follow-up. 60% (3/5) pts remain in CR on continued therapy for a median of 7.8 mo [7.2-9.4] thus far. One pt underwent allogeneic stem cell transplantation, however, died 11.4 mo after conditioning due to transplant related mortality. The R/R pt died after being lost to follow-up 2.9 mo after therapy initiation. No pt had measurable relapse during follow-up. Combination weekly Ven with subcutaneous low-dose Dec is well tolerated yielding igh rates of clinical and molecular response in pts with TP53mut MDS/AML. Although small, this case-series extends previous clinical trial proof-of-activity of non-cytotoxic DNMT1-targeting to a high-risk, poor PS, historically chemorefractory patient population. The regimen allowed frequent, sustained exposure to therapy often not possible with standard HMA/Ven regimens. [Formula presented] Disclosures: Shastri: Kymera Therapeutics: Research Funding;Guidepoint: Consultancy;GLC: Consultancy;Onclive: Honoraria. Gritsman: iOnctura: Research Funding. Feldman: Glycomimetics: Current Employment, Current holder of stock options in a privately-held company. Verma: Celgene: Consultancy;Acceleron: Consultancy;Novartis: Consultancy;Stelexis: Consultancy, Current equity holder in publicly-traded company;Eli Lilly: Research Funding;Curis: Research Funding;Medpacto: Research Funding;Incyte: Research Funding;GSK: Research Funding;BMS: Research Funding;Stelexis: Current equity holder in publicly-traded company;Throws Exception: Current equity holder in publicly-traded company. Saunthararajah: EpiDestiny: Consultancy, Current holder of individual stocks in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties.
ABSTRACT
Background: The Revised International Prognostic Scoring System (IPSS-R) classifies pts with MDS into risk categories, from very low-risk (vLR) to very high-risk (vHR), which guide treatment (tx) options. Pts with intermediate-risk MDS (IR-MDS) are heterogenous and real-world tx practices and outcomes for these pts are unknown. In Spain, the GESMD is an MDS registry containing more than 16,000 pts registered from 142 study sites which represent the country. We evaluated the real-world tx patterns and survival outcomes of pts with MDS from this registry across IPSS-R risk groups (with a focus on IR-MDS) and explored factors driving tx decisions among pts with IR-MDS. Methods: We analyzed the data collected by the GESMD registry from January 2008 to June 2020. Pts included were adults diagnosed with MDS, with informed consent and ≥6-mo follow up if the pt was alive. Pts who did not have available data on their MDS risk score or their use of hypomethylating agent for MDS were excluded. Prior to inclusion in the registry, a curation process was performed to ensure that each pt had the minimum data set and to avoid duplication and errors. Data queries were responded to by physicians at study sites, and the final data included were reviewed by the investigators. Descriptive statistics were used to summarize demographics, clinical, and tx characteristics overall and by risk groups. Overall survival (OS) was analyzed by risk group and tx type using the Kaplan-Meier estimator and 95% confidence intervals (CIs) were calculated. In pts with IR-MDS, a number of baseline variables (including sex, diagnosis year, transfusion status, risk score, age, and blood and blast counts) were explored to assess their relationship with tx selection between either azacitidine (AZA) or best supportive care (BSC) only (eg, transfusions, growth factors). Results: In total, 4,604 pts were included in this analysis. The median age of enrolled pts was 76 y and 39% were female. Other baseline characteristics are seen in Table 1. Seven hundred sixty-one pts (16.5%) were classified as IR-MDS with similar distribution across IPSS-R risk score subgroups 3.5, 4.0, and 4.5. Txs received by pts in the cohort included AZA, chemotherapy, allogeneic stem cell transplant (alloSCT), BSC, and others (eg, immunosuppressors, androgens;Table 2). The majority of pts with IR-MDS were treated with BSC (61%) and AZA (38%). The median time from diagnosis to start of AZA tx ranged from 1 mo in pts with high-risk (HR) and vHR-MDS to 26 mo in pts with vLR-MDS;pts with IR-MDS started AZA at a median of 3 mo from diagnosis. Survival analysis by IPSS-R group shows that median OS decreased with increased risk score (vLR: 81.3 mo [95% CI, 73.6-89.0], low-risk (LR): 59.0 mo [95% CI, 55.2- 62.8], IR: 29.4 mo [95% CI, 27.0-31.8], HR: 15.2 mo [95% CI, 13.3-17.1], vHR: 9.4 mo [95% CI, 7.7-11.1]). When analyzed by tx type, pts with IR-MDS had longer median OS when treated with AZA or chemotherapy ± alloSCT than with BSC (AZA: 30.1 mo [95% CI, 27.3-32.9], chemotherapy ± alloSCT: 30.1 mo [95% CI, 23.8-36.4], BSC: 24.6 mo [95% CI, 18.5-30.7];Figure 1). No relevant factors associated with decision to treat pts with IR-MDS with AZA or BSC were identified. Conclusions: This study shows that more than one-third of pts with IR-MDS were treated with AZA shortly after their diagnosis, similar to the HR/vHR group. This cohort represents what we know about MDS and its distribution by risk group, while bringing new information on the use of AZA and its potential value in improving the OS of pts with IR-MDS. It is possible that other factors not included in the analysis (comorbidities, distance to the hospital, social and familial support) might have had an influence on the decision to treat pts with IR-MDS with AZA or offer BSC instead. Selection bias, misclassification, and confounding might occur when using registry data and this may limit the interpretation;however, the study shows important insights into the use of real-world therapies for pts with MDS, especially IR-MDS. The COVID-1 pandemic had an impact on the study, delaying the availability and curation process of data from recent years. Analysis of length of AZA tx in relation to response to tx is ongoing. [Formula presented] Disclosures: Diez-Campelo: BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau;Takeda Oncology: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau;Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Sasse: Novartis: Current Employment, Current holder of stock options in a privately-held company. Wormser: Roche: Current equity holder in publicly-traded company;Novartis: Current Employment, Current equity holder in publicly-traded company. Hernandez Donoso: Novartis: Current Employment, Current holder of stock options in a privately-held company. Colicino: Novartis: Current Employment, Current holder of stock options in a privately-held company. Tormo: Astellas, Novartis, Jazz, Pfizer, Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Sanz: Gilead Sciences: Other: Travel, accommodations, and expenses;Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, and expenses, Speakers Bureau;Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Boehringer Ingelheim: Consultancy, Membership on an entity's Board of Directors or advisory committees;Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees;Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, and expenses;Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees;Helsinn Healthcare: Consultancy, Membership on an entity's Board of Directors or advisory committees;Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees;Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, and expenses, Research Funding. Díaz-Beyá: 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;Astellas: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Jazz: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Jerez: Novartis: Consultancy;BMS: Consultancy;GILEAD: Research Funding. Valcárcel: Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Sobi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Pfizzer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;MSD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Jazz: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Jansen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Celgene/BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Astellas: Consultancy, 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 advis ry committees, Speakers Bureau. OffLabel Disclosure: Sabatolimab is a novel immuno-myeloid therapy targeting TIM-3 and is under investigation for the treatment of patients with myeloid malignancies
ABSTRACT
Background: De novo nucleotide synthesis is necessary to meet the enormous demand for nucleotides, other macromolecules associated with acute myeloid leukemia (AML) progression 1, 2, 34. Hence, we hypothesized that targeting de novo nucleotide synthesis would lead to the depletion of the nucleotide pool, pyrimidine starvation and increase oxidative stress preferentially in leukemic cells compared to their non-malignant counterparts, impacting proliferative and differentiation pathways. Emvododstat (PTC299) is an inhibitor of dihydroorotate dehydrogenase (DHODH), a rate-limiting enzyme for de novo pyrimidine nucleotide synthesis that is currently in a clinical trial for the treatment of AML. Objectives: The goals of these studies were to understand the emvododstat-mediated effects on leukemia growth, differentiation and impact on Leukemia Stem Cells(LSCs). Comprehensive analyses of mitochondrial function, metabolic signaling in PI3K/AKT pathways, apoptotic signatures, and DNA damage responses were carried out. The rationale for clinical testing emvododstat was confirmed in an AML-PDX model. Results: Emvododstat treatment in cytarabine-resistant AML cells and primary AML blasts induced apoptosis, differentiation, and reduced proliferation, with corresponding decreased in cell number and increases in annexin V- and CD14-positive cells. Indeed, the inhibition of de novo nucleotide synthesis compromises the dynamic metabolic landscape and mitochondrial function, as indicated by alterations in the oxygen consumption rate (OCR) and mitochondrial ROS/membrane potential and corresponding differentiation, apoptosis, and/or inhibition of proliferation of LSCs. These effects can be reversed by the addition of exogenous uridine and orotate. Further immunoblotting and mass cytometry (CyTOF) analyses demonstrated changes in apoptotic and cell signaling proteins (cleaved PARP, cleaved caspase-3) and DNA damage responses (TP53, γH2AX) and PI3/AKT pathway downregulation in response to emvododstat. Importantly, emvododstat treatment reduced leukemic cell burden in a mouse model of AML PDX ( Complex karyotype, mutation in ASXL1, IDH2, NRAS), decreased levels of leukemia stem cells frequency (1 in 522,460 Vs 1 in 3,623,599 in vehicle vs emvododstat treated mice), and improved survival. The median survival 40 days vs. 30 days, P=0.0002 in primary transplantation and 36 days vs 53.5 days, P=0.005 in secondary transpantation in a PDX mouse model of human AML. This corresponded with a reduction in the bone marrow burden of leukemia and increased expression of differentiation markers in mice treated with emvododstat (Fig. 1). These data demonstrate effect of emvododstat on mitochondrial functions. Conclusion: Inhibition of de novo pyrimidine synthesis triggers differentiation, apoptosis, and depletes LSCs in AML models. Emvododstat is a novel dihydroorotate dehydrogenase inhibitor being tested in a clinical trial for the treatment of myeloid malignancies and COVID-19. Keywords: AML, emvododstat, DHODH, apoptosis, differentiation References: 1 Thomas, D. & Majeti, R. Biology and relevance of human acute myeloid leukemia stem cells. Blood 129, 1577-1585, doi:10.1182/blood-2016-10-696054 (2017). 2 Quek, L. et al. Genetically distinct leukemic stem cells in human CD34- acute myeloid leukemia are arrested at a hemopoietic precursor-like stage. The Journal of experimental medicine 213, 1513-1535, doi:10.1084/jem.20151775 (2016). 3 Villa, E., Ali, E. S., Sahu, U. & Ben-Sahra, I. Cancer Cells Tune the Signaling Pathways to Empower de Novo Synthesis of Nucleotides. Cancers (Basel) 11, doi:10.3390/cancers11050688 (2019). 4 DeBerardinis, R. J. & Chandel, N. S. Fundamentals of cancer metabolism. Sci Adv 2, e1600200, doi:10.1126/sciadv.1600200 (2016). [Formula presented] Disclosures: Weetall: PTC therapeutics: Current Employment. Sheedy: PTC therapeutics: Current Employment. Ray: PTC therapeutics: Current Employment. Andreeff: Karyopharm: Research Funding;AstraZeneca: Research Funding;Oxford Biomedica UK: Research Funding;Aptose: Consultancy;Daiich -Sankyo: Consultancy, Research Funding;Syndax: Consultancy;Breast Cancer Research Foundation: Research Funding;Reata, Aptose, Eutropics, SentiBio;Chimerix, Oncolyze: Current holder of individual stocks in a privately-held company;Novartis, Cancer UK;Leukemia & Lymphoma Society (LLS), German Research Council;NCI-RDCRN (Rare Disease Clin Network), CLL Foundation;Novartis: Membership on an entity's Board of Directors or advisory committees;Senti-Bio: Consultancy;Medicxi: Consultancy;ONO Pharmaceuticals: Research Funding;Amgen: Research Funding;Glycomimetics: Consultancy. Borthakur: ArgenX: Membership on an entity's Board of Directors or advisory committees;Protagonist: Consultancy;Astex: Research Funding;University of Texas MD Anderson Cancer Center: Current Employment;Ryvu: Research Funding;Takeda: Membership on an entity's Board of Directors or advisory committees;Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees;GSK: Consultancy.
ABSTRACT
Introduction The COVID-19 pandemic disrupted non-urgent and preventive medical care. During the early peak of the pandemic, an estimated 41% of US adults delayed or avoided medical care (Czeisler et al, CDC, 2020). While there were documented declines in the number of emergency department visits for myocardial infarction, stroke and hyperglycemia, similar data is not available related to acute myeloid leukemia (AML) (Lange et al, CDC, 2020). A delay in the diagnosis of AML could lead to presentation when patients are less able to withstand chemotherapy or have a higher disease burden which could compromise overall survival (OS). In this retrospective analysis, we aim to elucidate if there was a difference in clinical, cytogenetic, or molecular presentations and if there was an effect on early mortality as determined by overall survival at 1 and 6 months. Methods We compared the clinical, cytogenetic, and baseline molecular genetics of consecutive adult patients diagnosed with de novo AML at Dana-Farber Cancer Institute/Brigham and Women's (DFCI/BWH) Hospital from March 23, 2020, the date of the Massachusetts COVID State of Emergency, to August 23, 2020 to a historical cohort of similar patients between presenting between March 23, 2017 and August 23, 2020. Data was obtained from the Hematological Malignancy Data Repository and via review of the medical record. Patients were excluded from this cohort if they were diagnosed with acute promyelocytic leukemia, had known antecedent myeloid malignancy, or if they did not have DFCI/BWH 96-gene next-generation sequencing panel (RHP) performed at the time of diagnosis. Baseline clinical, laboratory, cytogenetic, and molecular characteristics and outcomes were compared between the pre-pandemic and pandemic cohorts using chi-squared, Fisher's exact, and Wilcoxon rank sum analyses (where appropriate) at a significance of p<0.05. Results Thirty-eight AML patients presented during the COVID-19 pandemic (PAN) and 308 in the pre-pandemic (PREPAN) period. There was no statistically significant difference in the monthly rate of new patients presenting in PREPAN and PAN cohorts (8 vs. 6 new patients/month, p=0.73). The median age at presentation (64 PREPAN vs. 65 PAN, p=0.77), sex, and therapeutic approach (intensive, non-intensive, supportive care, other) were not statistically different between cohorts. Presenting white blood cell count, platelet count, and fibrinogen were not different between cohorts, while hematocrit was significantly lower in the PAN cohort (23.8% vs. 26.0%, p=0.001). There was a trend for a higher median blast percentage (28.5% vs. 13%, p=0.09) in the PAN cohort. There were no differences between the cohorts in the median number of cytogenetic abnormalities, nor in the incidence of complex karyotype, (25.3% vs. 23.7%) across PREPAN and PAN respectively. There were also no significant differences in the European LeukemiaNet (ELN) risk classification scores across the PREPAN and PAN time periods, with 57.8% vs. 52.6% of total patients presenting with adverse risk disease respectively. When specific mutations of TP53, NPM1, and FLT3 were evaluated, only FLT3 demonstrated a statistical difference with a higher proportion in the pandemic group (p=0.04). OS at 1-month (97.4% and 93.2%, p=0.15) and 6-months (71.1% and 75.0%, p-0.87) were not statistically different in the PREPAN and PAN cohorts, respectively. Conclusion These data represent a novel analysis of the presenting clinical, cytogenetic and molecular characteristics of de novo AML during the COVID-19 pandemic. In contrast to other diseases, we did not see fewer de novo AML presentations during the peak of the COVID pandemic. While the reasons are unknown and require validation in large cohorts, the symptoms of leukemia including symptomatic anemia (low hematocrit) and higher WBC and blast count possibly driven by FLT3 mutations may drive patients to seek emergent clinical evaluation despite COVID pandemic barriers. The lack of difference in cytogenetic or other prognostic entities may demonstrate a lack of ymptom correlation causing patients to present for care. The higher incidence of FLT3 mutations and lower hematocrit could reflect more symptomatic presentation of AML during the COVID pandemic. Since these differences may be a surrogate for a higher disease burden, it will be important to compare outcomes at longer time points. [Formula presented] Disclosures: DeAngelo: Pfizer: Consultancy;Novartis: Consultancy, Research Funding;Jazz: Consultancy;Incyte: Consultancy;Forty-Seven: Consultancy;Autolus: Consultancy;Amgen: Consultancy;Agios: Consultancy;Takeda: Consultancy;Glycomimetrics: Research Funding;Blueprint: Research Funding;Abbvie: Research Funding;Servier: Consultancy. Stone: Bristol Meyers Squibb: Consultancy;Astellas: Membership on an entity's Board of Directors or advisory committees;BerGen Bio: Membership on an entity's Board of Directors or advisory committees;Boston Pharmaceuticals: Consultancy;Innate: Consultancy;Foghorn Therapeutics: Consultancy;Gemoab: Membership on an entity's Board of Directors or advisory committees;Glaxo Smith Kline: Consultancy;Celgene: Consultancy;Elevate Bio: Membership on an entity's Board of Directors or advisory committees;OncoNova: Consultancy;Syntrix/ACI: Membership on an entity's Board of Directors or advisory committees;Syndax: Membership on an entity's Board of Directors or advisory committees;Janssen: Consultancy;Agios: Consultancy, Research Funding;Amgen: Membership on an entity's Board of Directors or advisory committees;Aprea: Consultancy;Arog: Consultancy, Research Funding;Jazz: Consultancy;Macrogenics: Consultancy;Novartis: Consultancy, Research Funding;Actinium: Membership on an entity's Board of Directors or advisory committees;Abbvie: Consultancy;Syros: Membership on an entity's Board of Directors or advisory committees;Takeda: Consultancy. Garcia: AstraZeneca: Research Funding;Prelude: Research Funding;Pfizer: Research Funding;Genentech: Research Funding;Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees;Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees;AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Winer: Abbvie: Consultancy;Takeda: Consultancy;Novartis: Consultancy.
ABSTRACT
Patients with secondary AML or MDS derived AML have poor outcomes compared to de-novo AML. The benefits of intensive chemotherapy without anticipated transplant consolidation have been previously doubted. Outcomes in USA trial centres have not often been closely replicable in real world settings. From November 2018 CPX-351 has been available in the UK for secondary AML, therapy related AML, AML with MDS related Karyotype (AML-MRC) and licensed but not funded for AML with myelodysplastic related changes. Objectives Here we report our experience specifically on patient outcomes and toxicity across 5 Hospitals in West Midlands, UK Methods Patients receiving CPX 351 outcomes were evaluated retrospectively from 2018 to 2021. Baseline genetics, CPX 351 indications, patient's comorbidities, overall survival, remission status, number of cycles delivered, early mortality, reasons for early discontinuation, intensive care admission and time for neutrophil recovery (>0.5) was recorded. Time-to-event outcomes reported here are from a data cut on 01-06-21 Results In a total cohort of 57 patients baseline characteristics are shown on table 1 and compared with the original trial CPX-351 group. Median follow up was 376 days (range 21 to 1248 days). The mean age was 63, 17 patients were under 60, 31 males and 26 females. The most common indication for CPX-351 was AML with antecedent MDS/MPN 51% (N=29), therapy related 14% (N=8), MDS related karyotype (AML-MRC) 19% (N=11) and 16% (N=9) other patients. Mean Charleston co-morbidity score was 2.7 (range 0-6), 10.5% (N=6) had previous non myeloid malignancies, 8.7% (N=5) had prior ischaemic heart disease, only 3.5% (N=2) had ejection fractions under 50%. The most common mutations were TP53 21% (N=12), ASXL1 15.7% (N=9), TET2 15.7% (N=9), IDH2 10.5% (N=6), RUNX1 10.5% (N=6), SRSF2 7% (N=4), JAK2 3.5% (N=2), FLT3 5% (N=3), NPM1 5%(N=3) and IDH1 5% (N=3). MRC cytogenetic risk was adverse in 19 patients (33%), intermediate in 35 patients (61%) and favourable in 3 patients (5%). 30 patients (53%) had adverse European Leukaemia Network classification, 17 (30%) had intermediate and 10 (17%) had favourable. 30-day mortality was 3/57 (5%), 60-day mortality was 6 (10.5%) comparable to the 5.9% and 10.6% rates for the original trial. 9% or 5/57 patients were admitted to ITU with 2 survivors beyond 60 days. Neutropenic fever requiring antibiotics was 100% whereas only 5/57 (9%) had radiological evidence of fungal infection. Only one patient died from COVID 19. The mean time to neutrophil recovery was 35 days with a range of 12 to 84 days. 29 patients completed 1 cycle, 25 completed 2 cycles, only 3 completed 3 cycles. The reasons for stopping were death, refractory disease, drop in performance status, alternative chemotherapy chosen or moving to transplantation (39%). Composite remission rate including CRi was 61% 36/57, adverse ELN group demonstrated 50% 15/30, intermediate 76% 13/17 and favourable 80% 8/10. Mutated P53 was associated with a 50% 6/12 rate whereas in wild type P53 the remission rate was 60% 30/45. Overall median survival from diagnosis was 429 days [95% CI 274 to 788 days]. To compare with the original trial, we removed the under 60s and those with less than 1 year follow up, in this cohort of 30 patients the median survival was 289 days (9.5 months) with 95% CI of 255 to 476 days. P53 mutated patients had an estimated median survival of 257 days versus wild type p53 with 524 days hazard ratio of 2.418 (CI 1.077 to 5.248) with p value of 0.032. Median survival for ELN groups was 373 days (adverse), 413 days (intermediate) and not reached for favourable. Of the 36 patients who achieved a remission, 22 went on to receive an allogenic transplant with follow from 254 to 1248 days, median survival estimated 706 days (95% CI 429-not reached). Patients in remission who haven't received a transplant have a similar estimated survival of 788 days (305-not reached) pending longer follow up. Conclusion This is the first UK multicentre analysis to show comparable results to the landmark trial ( edian survival 9.5 months in equivalent cases). The improved overall remission rate 61% versus the 47% in the trial and the longer median survival 14 months versus 9.5 months in the trial is expected given the younger age and increase in favourable risk genetics. This study therefore supplies further data of CPX-351 efficacy in younger patients not included in the original studies and may now be used as a standard comparator arm. [Formula presented] Disclosures: No relevant conflicts of interest to declare.
ABSTRACT
Background: Patients (pts) with malignancies are at increased risk of morbidity and mortality from COVID-19. Among these pts, some of the higher case fatality ratios (CFR) reported are among pts with myeloid malignancies, ranging from 37 to 50% (Mehta V, Cancer Discov 2020;Ferrara F, Leukemia 2020). Levine Cancer Institute (LCI) has a robust hematologic malignancy and cellular therapy program that serves many pts with myeloid malignancies, seeing nearly 100 new diagnoses of acute myeloid leukemia per year. A strategy to mitigate risks associated with COVID-19 was established at LCI in partnership with Atrium Health's (AH) Hospital at Home (HAH). HAH was a system wide platform using telemedicine and home health services to assess and monitor COVID-19 + pts at high risk of complications. To augment HAH for our medically complex cancer pts, a virtual health navigation process involving expertise from across LCI, including a specialized nurse navigation team, was developed to rapidly identify LCI pts + for SARS-CoV-2, monitor them under physician supervision, and escalate care as needed with AH HAH. Along with the navigation platform, data-driven guidelines for detecting, monitoring, and managing LCI pts + for SARS-CoV-2 were swiftly employed across the extensive LCI network. Herein we report on the outcomes for LCI pts with myeloid malignancies + for SARS-CoV-2 and outline the employed risk mitigation strategies and their potential impact on these outcomes. Methods: An automated daily list of LCI pts + for SARS-CoV-2 was provided by AH Information Services. Each pt's chart was reviewed by a nurse navigator for hematologic or oncologic diagnosis, outpatient or inpatient status, and COVID-19 symptoms. Pts without a cancer diagnosis were not assigned a navigator. If hospitalized, a pt was not assigned a navigator;following discharge, if enrolled in HAH, a navigator was assigned. In collaboration with HAH, an algorithm for directing care was utilized (Figure 1). A diagnosis-specific navigator contacted and screened the pt with an assessment tool, which scored pts for surveillance and treatment needs (Table 1). Documentation was forwarded to the primary hematologist/oncologist. Comprehensive guidelines for testing, scheduling, management of + pts, research, and process changes were created, disseminated, and actively updated through LCI's EAPathways. For outcome analysis for pts with myeloid malignancies, pt vital status was updated through data cutoff (7/3/21). Results: From inception on 3/20/20 to 12/2/20, 974 LCI patients were identified as SARS-CoV-2 + and reviewed for nurse navigation. Of the 974 pts, including pts with benign and malignant diagnoses, 488 were navigated. Among all SARS-CoV-2 + LCI pts, 145 (15%) had a hematologic malignancy, including 37 (4%) pts with myeloid malignancies. Characteristics are shown in Table 2. Of the 37 pts, 18 (49%) were navigated. 70% with myeloid malignancies were on active treatment at the time of + test. Nearly 50% of those on active treatment were navigated. 46% were hospitalized with COVID-19, with this being the main reason for no assigned navigator. 24% of hospitalized pts were eventually assigned a navigator. Only 3 pts had undergone allogeneic stem cell transplantation (allo-SCT) with a median time from transplant to detection of SARS-CoV-2 of 9 months (range, 7-23). 2 out of 3 cases post allo-SCT were asymptomatic. No pt died from COVID-19 following allo-SCT. Among the navigated pts with myeloid malignancies, there was no death related to COVID-19. 4 pts, all of whom were hospitalized, died from COVID-19 (N=2, myelodysplastic syndrome with 1 on azacitidine;N=2, myeloproliferative neoplasm, both on hydrea). A CFR of 11% was demonstrated for LCI pts with myeloid malignancies. Conclusions: A multidisciplinary response strategy liaising between AH HAH and LCI followed, assessed, and assisted cancer pts + for SARS-CoV-2. With our embedded nurse navigation team's specialized attention along with enhanced physician oversight and close collaboration with AH HAH, opportunities f r care escalation or adjustments in cancer-focused care were promptly identified. In this setting, among the high-risk population of pts with myeloid malignancies, a lower CFR than has been reported was observed. A virtual navigation platform with HAH capabilities is a feasible, safe, and effective way to monitor and care for this high-risk population. [Formula presented] Disclosures: Moyo: Seattle Genetics: Consultancy. Chai: Cardinal Health: Membership on an entity's Board of Directors or advisory committees. Avalos: JUNO: Membership on an entity's Board of Directors or advisory committees. Grunwald: Amgen: Consultancy;Agios: Consultancy;Astellas: Consultancy;Daiichi Sankyo: Consultancy;Stemline: Consultancy;Bristol Myers Squibb: Consultancy;PRIME: Other;Trovagene: Consultancy;Blueprint Medicines: Consultancy;AbbVie: Consultancy;Med Learning Group: Other;Pfizer: Consultancy;Sierra Oncology: Consultancy;Janssen: Research Funding;Incyte: Consultancy, Research Funding;Gilead: Consultancy;MDEdge: Other;PER: Other;Cardinal Health: Consultancy;Karius: Consultancy. Copelan: Amgen: Consultancy.
ABSTRACT
Introduction: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to unprecedented healthcare challenges on a global scale. Impressive efforts have led to rapid development of multiple efficacious vaccines against SARS-CoV-2, however concerns remain over the degree of protection vaccination offers to immunocompromised recipients. To answer this question, we have designed a prospective study to evaluate response to vaccination in patients with haematological malignancies (Harrington, Leukaemia 2021;Harrington, BJHaem, 2021). 103 patients were included with samples collected in 60 patients after first dose and 71 patients following second dose. We have analysed humoral and T cell response to a first dose of vaccine against SARS-CoV-2 in patients post allogeneic stem cell transplantation (HSCT) and compared those to patients with CML or MPN. Methods: ELISA plates were coated with antigen Nuclear (N) protein or the S protein. Serial dilutions of plasma were added to wells and incubated for 2 h at room temperature. Control reagents included N-specific monoclonal antibody, S-specific monoclonal antibody, negative control plasma, positive control plasma and blank wells. Secondary antibody was added and incubated for 1h at room temperature. IgG was detected using goat-anti-human-Fc-AP and plates read at 405 nm. Where an EC50 was not reached at 1:25, a plasma was considered seropositive if the OD at 405nm was 4-fold above background and a value of 25 was assigned. T cell functionality was assessed using intracellular cytokine staining after incubation with SARS-CoV-2 specific peptides covering immunogenic domains of the Spike (S) protein. A response was considered positive if there was a 3-fold increase in pro-inflammatory cytokine expression from baseline, and above a threshold of 0.01. Specific peptides (0.25 µg/ml), anti-CD28 and BFA were added to cells. Unstimulated cells were utilised as negative controls. Cells were stained with viability dye, then with antibodies directed against surface markers, and fixed and permeabilised prior to staining for intracellular cytokines TNFa and IFNg. Gating on lymphocytes, single cells, live cells, CD3+ cells, CD4+ cells and CD4- (CD8+) was performed. Results: Of the 103 patients included in this study, post vaccination evaluation on 56 patients have been analysed so far, including 37 patients with chronic myeloid malignancies (MPN n=21 and CML n=16) and 19 patients post HSCT. From the latter group, median time since transplant was 53.9 months (18.7 to 76.8) with 12 participants on extracorporeal photopheresis (ECP) therapy for graft versus host disease (GvHD) with median frequency of 24.5 days (14-42). BNT162b2 vaccine was administered to 48 patients (85.7%). An anti-S IgG response was observed after a first dose in 16/21 (76.1%) of the MPN group and 14/16 (87.5%) of CML patients, but in only 7/19 (36.8%) of post HSCT patients (Fishers Exact Test - p=0.02/0.002, Fig 1a). Of the latter group a low positive value where an EC50 was not reached was observed in 4/19 (21.1%) and a moderate response in 3/19 patients (15.8%). Of the 12 patients with active GvHD on ECP, a positive response was observed in 4 patients (33.3%), however only one patient recorded a response where an EC50 was measurable. A T cell response was observed in 16/20 (80%) of the MPN group and 14/15 (93.3%) of those with CML after a single dose, with a polyfunctional T cell response (>1 cytokine) observed in 65% and 80% respectively. In comparison only 5/19 patients (38.5%) post HSCT mounted a T cell response (p=0.027/p=0.002, Fig 1b), with a CD4+ response in 4 (30.8%) and a CD8+ response in 3 (23.1%). In this group, a polyfunctional T cell response was found in 4/19 patients (30.8%). 33.3% of patients with GVHD requiring ECP had a T cell response, compared with 42.9% in post HSCT without GVHD. Summary: Despite encouraging results of antibody and T cell response to a first vaccination dose in patients with chronic myeloid malignancies, these results raise concerns regarding the humoral and T cell respo ses to vaccination in patients post HSCT, recognised as a particularly immunosuppressed group. Further longitudinal data is required to determine if these results translate into a reduction in cases and severity of infection in these groups. We are currently analysing the response to a second vaccine injection and responses to sequential doses of vaccination across the whole cohort will be presented. [Formula presented] Disclosures: Harrington: Bristol Myers Squibb: Research Funding;Incyte: Honoraria. Radia: Blueprint Medicines Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Study steering group member, Research Funding;Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Education events;Cogent Biosciences Incorporated: Other: Study Steering Committee;EXPLORER and PATHFINDER studies: Other: Member of the Response Adjudication Committee. Kordasti: Beckman Coulter: Honoraria;Celgene: Research Funding;Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding;Alexion: Honoraria. Dillon: Menarini: Membership on an entity's Board of Directors or advisory committees;Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Session chair (paid to institution), Speakers Bureau;Astellas: Consultancy, Other: Educational Events, Speakers Bureau;Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Research Support, Educational Events;Amgen: Other: Research support (paid to institution);Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: educational events;Jazz: Other: Education events;Shattuck Labs: Membership on an entity's Board of Directors or advisory committees. Harrison: Promedior: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;AOP Orphan Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Incyte Corporation: Speakers Bureau;Gilead Sciences: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Constellation Pharmaceuticals: Research Funding;Galacteo: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Geron: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;BMS: 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, Research Funding, Speakers Bureau;Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau;Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Sierra Oncology: Honoraria;Roche: 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;Shire: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;CTI BioPharma: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Keros: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. de Lavallade: Bristol Myers Squibb: Research Funding;Incyte: Honoraria, Research Funding;Novartis: Speakers Bureau.
ABSTRACT
Introduction: The severity of acute clinical outcomes and mortality in hematologic malignancy (HM) patients infected by SARS-CoV-2 was exhaustively documented in the first weeks of the pandemic. A consistent increased mortality compared to non-cancer patients was observed across studies. In this study we aimed to estimate survival in COVID-19 HM patients by type of malignancy, to describe acute and post-acute clinical outcomes, and to compare outcomes in early and later pandemic periods. Methods: In this population-based registry study sponsored by the Madrid Society of Hematology (Asociación Madrileña de Hematología y Hemoterapia), we collected de-identified data on clinical characteristics, treatment and acute and post-acute outcomes in adult patients with hematologic malignancies and confirmed SARS-CoV-2 infection within the Madrid region of Spain. Our case series included all eligible patients admitted to 26 regional health service hospitals and 5 private healthcare centers between February 28, 2020 and February 18, 2021 with a coverage of 98% on a population of 6.6 million inhabitants. The study outcomes were all-cause mortality, severity of disease (WHO), oxygen support, ICU admission, and follow-up symptoms and signs and complications. Survival probabilities were estimated with the actuarial method and reported overall and stratified by type of malignancy and for two study periods (early cohort,-COVID-19 diagnosis from February 28 to 31 May, 2020, and later cohort, up to February 18, 2021). Results: Of the 1408 patients reported to the HEMATO-MADRID COVID-19 registry, 1166 were included in the present analyses;839 (72%) had a lymphoid malignancy, including 325 (28%) with non-Hodgkin lymphoma, 50 (4%) with Hodgkin lymphoma and 263 (23%) with multiple myeloma;and 327 (28%) had a myeloid malignancy, including 115 (10%) with myelodysplastic syndrome, 92 (8%) with acute myeloid leukemia (AML) and 87 (7%) with Philadelphia chromosome (Ph)-negative myeloproliferative neoplasms. Overall COVID-19 clinical severity was classified as critical in 19% of patients, severe in 36%, moderate in 22%, and mild in 22%;10% were admitted to an ICU;8% were on mechanical ventilation and 19% on noninvasive ventilation. Mild disease increased between early and later period from 15% to 38% of patients;severe disease decreased from 42% to 24%, p<0.001. COVID-19 treatment with steroids increased from 38% to 59%, p<0.001. At follow-up, 22% reported persistent symptoms related to COVID-19 at 2 months, 16% at 4 months and 14% at 6 months. 381 of 1166 (33%) patients died. Overall 30-day survival was 68%;2 and 3-month overall survival probabilities were 56% and 53%, respectively. Survival was more favorable for patients with myeloproliferative neoplasms (82%, 69% and 65% at 30-days, 2 and 3 months, respectively) than for those with lymphoid malignancies (68%, 56% and 54%) or myelodysplastic syndrome/acute myeloid leukemia (61%, 51%, 46%), p=001. 285 (37%) patients died in the early period vs 96 (24%) in the later, p<0.001, but median (interquartile range) follow-up time was much higher in the early vs later, 45 (20-116) days vs. 26 (11-86), respectively. Overall survival was not different between periods, p=0.5 (hazard ratio [95%C], 0.93 [0.73-1.17]). In the later cohort, 30 and 60-day survival probabilities were 71% and 56% vs. 67% and 56% in the early cohort Conclusions. A population-based registry in Spain provided strong evidence that although COVID-19 severity decreased over year 1 of the pandemic, mortality remained high, and survival was stable over time in the group of patients with hematological malignancy infected by SARS-Coc-2. A relevant proportion of the infected patients (1 in 6) referred persistent symptoms attributable to COVID-19. The improved clinical management of severe COVID-19 in non-cancer patients that followed the dissemination of evidence-based recommendations did not translate in more favorable survival in patients with hematological malignancies. Research is needed to address the specific characteristics nd improve the clinical management of this vulnerable population. Disclosures: Martinez-Lopez: Novartis: Consultancy, Speakers Bureau;BMS: Consultancy, Research Funding, Speakers Bureau;Janssen: Consultancy, Speakers Bureau;Incyte: Consultancy, Research Funding, Speakers Bureau;Roche: Consultancy, Research Funding, Speakers Bureau;Astellas: Research Funding, Speakers Bureau. Jiménez-Yuste: Pfizer: Consultancy, Honoraria, Research Funding;Grifols: Consultancy, Honoraria, Research Funding;CSL Behring: Consultancy, Honoraria, Research Funding;Sanofi: Consultancy, Honoraria, Research Funding;Bayer: Consultancy, Honoraria, Research Funding;NovoNordisk: Consultancy, Honoraria, Research Funding;BioMarin: Consultancy;Sobi: Consultancy, Honoraria, Research Funding;Octapharma: Consultancy, Honoraria, Research Funding;Takeda: Consultancy, Honoraria, Research Funding;F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding. Kwon: Gilead: Honoraria.
ABSTRACT
Background: The risk of severe COVID-19 is increased in patients (pts) with hematologic malignancies, with a reported risk of death of 34% (Vijenthira et al, 2020). The ASH-ASTCT COVID-19 vaccine guidelines indicate that certain immunocompromised patient populations could have an attenuated response to the SARS-CoV-2 vaccine. However, most SARS-CoV-2 vaccine trials required pts to be off immune suppression to be eligible and therefore excluded most pts with hematologic malignancies. Little is known about the efficacy of SARS-CoV-2 vaccines in pts with hematologic malignancies. In this study, we aimed to evaluate the serological response of Pfizer and Moderna vaccination after two doses given in pts with hematologic malignancies with a focus on pts with myeloid malignancies. Methods: Patients with a history of hematologic malignancies treated at the University of Texas Southwestern Medical Center and received two doses of vaccination with quantitative measurement of SARS-CoV-2 IgG Spike antibody to assess vaccination response were included in this study. Baseline patient and disease characteristics including disease status and therapy given at the time of vaccination were collected. Time to vaccine response was defined as having a positive quantifiable spike IgG antibody titer per the lab reference range. The development of COVID-19 infection as well as antibody titer levels were collected. Categorical variables were compared using Chi-square and Fisher's exact tests and student t-test and ANOVA test were used to compare continuous variables. Results: A total of 61 pts with hematologic malignancies had spike IgG antibody testing after receiving 2 doses of the vaccine were included in this study. The median age at the time of vaccination was 72 (22-85) and 46% of pts were female. Eighty five percent of pts were Caucasian. The majority of pts (67.3%) had a myeloid malignancy (MDS/CMML 29.5%, AML 14.8%, myelofibrosis 16.4%, CML 6.6%), followed by chronic lymphocytic leukemia (16.4%), and others (6.6%). The median time from hematologic malignancy diagnosis to the first vaccine dose was 51 months (0.4-337 months). At the time of vaccine administration, 46 (75%) of pts were on active therapy and 39 (64%) of pts had active disease. Median time from the second vaccine dose to IgG spike antibody testing was 64 days (26-268 days). Most pts (75%) mounted a serological response with quantifiable COVID-IgG spike antibodies, 85% and 56% in myeloid and lymphoid malignancy, respectively. All pts with MDS/CMML/CCUS and CML mounted an immune response (100%), followed by acute myeloid leukemia (n: 7/9, 78%) and myelofibrosis (n: 6/10, 60%). Eight (13%) of pts were receiving hypomethylating agent therapy at the time of vaccination and all (100%) had a positive IgG response. Only one patient developed COVID-19 infection post vaccination with a documented IgG response and 2 pts had COVID-19 infection prior to the first dose of vaccination, both of these pts had IgG titers >10,000. Sixty percent of pts (9/15) with negative IgG response received treatment with either CD20 monoclonal antibodies or BTK inhibitors within 12 months of the first vaccine dose. Two out of three pts (67%) receiving Ruxolitinib had negative serology. Seven pts were on treatment with hydroxyurea, interestingly, all but the 2 pts with polycythemia vera had a negative antibody titer while on treatment with hydroxyurea. There was a strong positive correlation between vaccine titer and absolute lymphocyte count (r 2=0.27, p<0.001) (Figure). Conclusions: In this retrospective study, we demonstrate a higher rate of COVID-19 vaccine efficacy in pts with myeloid malignancy with varying responses per treatment and disease subtype compared to pts with B-cell malignancy with variable anti-CD20 or BTK inhibitor therapy. Pts with myelodysplastic syndromes, overlap syndromes of clonal cytopenia of undetermined significance all developed spike antibodies irrespective of hypomethylating therapy or Hydrea as did pts with chronic myeloid leukemia. However, pts with polycythemia vera nd those on treatment with Ruxolitinib had an attenuated response to the vaccine. Albeit this single center study, pts with myelodysplastic syndromes should be offered COVID vaccines irrespective of their blood counts or ongoing treatment. Our findings should be validated in a larger group of patients. [Formula presented] Disclosures: Patel: Agios: Membership on an entity's Board of Directors or advisory committees;Celgene-BMS: Membership on an entity's Board of Directors or advisory committees;PVI: Honoraria. Anderson: Celgene, BMS, Janssen, GSK, Karyopharm, Oncopeptides, Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Awan: Cardinal Health: Consultancy;BMS: Consultancy;Dava Oncology: Consultancy;Karyopharm: Consultancy;Merck: Consultancy;Johnson and Johnson: Consultancy;Incyte: Consultancy;Beigene: Consultancy;Verastem: Consultancy;MEI Pharma: Consultancy;Celgene: Consultancy;Kite pharma: Consultancy;Gilead sciences: Consultancy;Pharmacyclics: Consultancy;Janssen: Consultancy;Abbvie: Consultancy;ADCT therapeutics: Consultancy;Astrazeneca: Consultancy;Genentech: Consultancy. Madanat: Blue Print Pharmaceutical: Honoraria;Onc Live: Honoraria;Stem line pharmaceutical: Honoraria;Geron Pharmaceutical: Consultancy.
ABSTRACT
Introduction: Primary care physicians are essential to cancer care. They frequently identify signs and symptoms leading to a diagnosis of cancer, and provide ongoing support and management of non-cancer health conditions during cancer treatment. Both primary care and cancer care have been greatly affected by the COVID-19 pandemic. In the United States, cancer-related patient encounters and cancer screening decreased over 40% and 80% respectively in January to April 2020 compared to 2019 (London et al. JCO Clin Cancer Inform 2020). However, the impact of the COVID-19 pandemic on primary care access for cancer patients remain unclear. Methods: We undertook a population-based, retrospective cohort study using healthcare databases held at ICES in Ontario, Canada. Patients with a new lymphoid or myeloid malignancy diagnosed within the year prior to the COVID-19 pandemic, between July 1, 2019 and September 30, 2019 (COVID-19 cohort) were compared to patients diagnosed in years unaffected by the COVID-19 pandemic, between July 1, 2018 - September 30, 2018 and July 1, 2017 - September 30, 2017 (pre-pandemic cohort). Both groups were followed for 12 months after initial cancer diagnosis. In the COVID-19 cohort, this allowed for at least 4 months of follow-up data occurring during the COVID-19 pandemic. The primary outcome was number of in-person and virtual visits with a primary care physician. Secondary outcomes of interest included number of in-person and virtual visits with a hematologist, number of visits to the emergency department (ED), and number of unplanned hospitalizations. Outcomes, reported as crude rates per 1000 person-months, were compared between the COVID-19 and pre-pandemic cohorts using Poisson regression modelling. Results: We identified 2882 individuals diagnosed with a new lymphoid or myeloid malignancy during the defined COVID-19 timeframe and compared them to 5997 individuals diagnosed during the defined pre-pandemic timeframe. The crude rate of in-person primary care visits per 1000 person-months significantly decreased from 574.4 [95% CI 568.5 - 580.4] in the pre-pandemic cohort to 402.5 [395.3 - 409.7] in the COVID-19 cohort (p < 0.0001). Telemedicine visits to primary care significantly increased from 5.3 [4.8 - 5.9] to 173.0 [168.4 - 177.8] (p < 0.0001). The rate of combined in-person and telemedicine visits to primary care did not change from 579.8 [573.8 - 585.8] in the pre-pandemic cohort to 575.5 [566.9 - 584.2] in the COVID-19 cohort (p = 0.43). In-person visits to hematologists decreased from 504.1 [498.5 - 509.7] to 432.8 [425.3 - 440.3] (p < 0.0001), and telemedicine visits to hematologists increased from 6.6 [6.0 - 7.3] to 75.9 [72.8 - 79.1] (p < 0.0001). The rate of combined visits to hematologists did not change from 510.7 [505.1 - 516.4] to 508.7 [500.6 - 516.8] (p = 0.68). The rate of ED visits significantly decreased from 95.1 [92.7 - 97.6] in the pre-pandemic cohort to 84.7 [81.4 - 88.0] in the COVID-19 cohort (p < 0.0001). The rate of unplanned hospitalizations did not change from 64.8 [62.8 - 66.8] to 65.7 [62.9 - 68.7] (p = 0.60). Conclusions: Primary care visits for patients with hematologic malignancies did not significantly change during the pandemic, but there was a sizeable shift from in-person to telemedicine visits. Similar findings were seen for visits to hematologists. While the rate of visits to the ED decreased, potentially due to concern of being exposed to the COVID-19 virus, the shift in ambulatory practices did not seem to impact the rate of unplanned hospitalizations. Disclosures: No relevant conflicts of interest to declare.