ABSTRACT
Introduction: Croatian National Cancer Registry of Croatian Institute for Public Health reported that in year 2020 lung cancer was the second most common cancer site diagnosed in men with 16% and the third most common in women with 10% incidence among all cancer sites. Unfortunatelly lung cancer has the highest mortality in both men and women. Haematological malignancies had 7% share in all malignancies in both male and female cances cases. In 2020 190 newly diagnosed cases of lymphatic leukemia in men and 128 cases in women were reporeted, meaning 1.5 and 1.2% of all malignancies, respectively. Chronic lymphatic leukemia (CLL) is an advanced age disease and incidence increases with age. Impaired immunity, T and B cell dysfunction in CLL, chromosomal aberations, long-term immunosuppressive therapy and genetic factors can all cause secondary malignancies. Co- occurence of solid tumors and CLL is very rare. Although patiens with CLL have an increased risk of developing second primary malignancies including lung carcinoma, the data about their clinical outcomes are lacking. Parekh et al. retrospectively analyzed patients with simultaneous CLL and lung carcinoma over a 20-year period, and they found that ~2% of patients with CLL actually developed lung carcinoma. The authors claimed that up to 38% of patients will also develop a third neoplasm more likely of the skin (melanoma and basal cell carcinoma), larynx (laryngeal carcinoma) or colon. Currently there are no specific guidelines for concurrent CLL and non-small cell lung carcinoma (NSCLC) treatment. Usually, when the tumors are diagnosed simultaneously, treatment is based to target the most aggressive malignancy, as the clinical outcomes depend on the response of the tumor with the poorest prognosis. For this reason, a multidisciplinary approach is mandatory. Case report: A patient with history of coronary heart disease, myocardial infarction and paroxysmal atrial fibrillation was diagnosed in 2019 (at the age of 71) with B chronic lymphocytic leukemia with bulky tumor (inguinal lymph nodes 8x5 cm), stage B according to Binet, intermediate risk. He was treated with 6 cycles of chemoimmunotherapy (rituximab/cyclofosfamid/fludarabine). In 10/2019 remission was confirmed, but MSCT described tumor in the posterior segment of upper right lung lobe measuring 20x17 mm and bilateral metastases up to 11 mm. Bronchoscopy and biopsy were performed, and EGFR neg, ALK neg, ROS 1 neg, PD-L1>50% adenocarcinoma was confirmed. He was referred to Clinical Hospital Center Osijek where monotherapy with pembrolizumab in a standard dose of 200 mg intravenously was started in 01/2020. Partial remission was confirmed in October 2020. Immunotherapy was discontinued due to development of pneumonitis, dysphagia and severe weight loss (20kg), but without radiologically confirmed disease progression. At that time he was referred to our hospital for further treatment. Gastroscopy has shown erosive gastritis with active duodenal ulcus, Forrest III. Supportive therapy and proton pump inhibitor were introduced. After complete regression of pneumonitis, improvement of general condition and resolution of dysphagia, no signs of lung cancer progression were found and pembrolizumab was reintroduced in 12/2021. Hypothyroidism was diagnosed in 01/2021 and levothyroxine replacement ther apy was started. In 03/2021 he underwent surgical removal of basal cell carcinoma of skin on the right temporal region with lobe reconstruction. From 02/2021, when pembrolizumab was reintroduced, regression in tumor size was continously confirmed with complete recovery of general condition. He was hospitalized for COVID 19 infection in 09/2021, and due to complications pembrolizumab was discontinued till 11/2021. Lung cancer immunotherapy proceeded till 11/2022, when Multidisciplinary team decided to finish pembrolizumab because of CLL relapse. CLL was in remission till August 2022 when due to B symptoms, lymphcytosis, anemia and generalized lymphadenopathy, hematological workup including biopsy of cervical lymph node was performed and CLL/SLL relapse was confirmed. Initially chlorambucil was introduced, but disease was refractory. Based on cytogenetic test results (IGHV unmutated, negative TP53) and due to cardiovascular comorbidity (contraindication for BTK inhibitors) venetoclax and rituximab were started in 01/2023. After just 1 cycle of treatment normal blood count as well as regression of B symptoms and peripheral lymphadenopathy occured, indicating the probability of complete disease remission. In our patient with metastatic lung adenocarcinoma excellent disease control is achieved during 41 month of treatment in first line setting. Furthermore, relapsed/refractory CLL/SLL is currently in confirmed remission. Conclusion(s): Successful treatment of patients with multiple primary malignancies is based on multidisciplinarity, early recognition and management of side effects, treatment of comorbidities with the aim of prolonging life, controlling symptoms of disease and preserving quality of life.
ABSTRACT
During the pandemic, a large number of works devoted to COVID infection have appeared, which have made it possible to understand the pathogenetic features of the disease and to accumulate significant clinical experience. However, the question remains about the degree of participation of humoral and cellular (primarily T-cell) immunity in the mechanisms of immune defense and resistance to COVID-19, the individual features of the immune response in different subjects. Post-COVID syndrome is currently a separate diagnosis included in the ICD-10 International Classification of Diseases, but the long-term effects of the SARS-CoV-2 on the immune system are not yet well established. At the same time, a long-term increased activity of the immune system can contribute to the development of autoimmune reactions. The review of the literature presents the results of studies, mainly devoted to immune system disorders after COVID infection. The changes in subpopulations of T-lymphocytes, B-lymphocytes, their functional properties, the complement system and other factors of humoral immunity, as well as the production of a number of cytokines are described. Data on immune disorders in post-COVID syndrome and during the convalescence period are presented in detail. Since COVID-19 is an infection that has a significant impact on the hematopoietic system and hemostasis, special attention is paid to the category of subjects with an increased risk of severe complications. Among the latter are elderly patients, persons suffering from diabetes mellitus, oncological and oncohematological patients, in particular, with hematopoietic and lymphoid tissue neoplasia, such as chronic lymphocytic leukemia, lymphoma, multiple myeloma. The review pays special attention to the peculiarities of the course of COVID-19 and the response of the immune system to vaccination in patients with oncohematological diseases. Deciphering the significance of individual links of cellular and humoral immunity in patients who have undergone COVID-19 is an important issue in creating effective vaccines and improving therapeutic methods.Copyright © 2022 Interregional public organization Association of infectious disease specialists of Saint-Petersburg and Leningrad region (IPO AIDSSPbR). All rights reserved.
ABSTRACT
Context: CLL and indolent NHL are hematologic malignancies that typically result in immune dysfunction. Infection represents a major cause of morbidity and mortality in these patients. Patients with CLL and NHL are at higher risk of hospitalization and death from COVID-19.3 Data is lacking regarding the effectiveness of COVID-19 vaccination in this patient population. Objective: Determine antibody (Ab) response rate (RR) to the COVID-19 vaccination in patients with CLL and indolent NHL. Design: A retrospective, observational study of patients seen between January and October 2021. Updated data was collected until May 27, 2022. Setting: Patients followed in a lymphoma clinic at the Robert H. Lurie Comprehensive Cancer Center. Participants: 398 patients were screened for eligibility. Inclusion criteria were confirmed diagnosis of CLL or indolent NHL, completion of a full vaccination series with either Johnson & Johnson, Moderna, or Pfizer, and Ab testing within 6 months of the initial vaccination series. Main Outcome Measures: SARS-CoV-2 Ab titers were obtained after completion of a full vaccination series and, if applicable, after a third vaccine dose. Ab response was considered positive if either total Ab titer or IgG spike protein Ab was positive. Comparisons were performed using chi-square tests. Results: 240 patients were included in the final analysis. Ab response to the initial vaccination series was 50% (91/181) in CLL and 69% (41/59) in other indolent NHLs. For CLL patients, there was a higher Ab RR in patients receiving the Moderna compared to the Pfizer vaccine (61% vs 44%, p=0.028). Current or prior cancer therapy correlated with a lower Ab RR (36% vs 68%, p<0.0001). Use of anti-CD20 agents in the year prior to vaccination resulted in a lower Ab RR (12% vs 53%, p<0.0001). Of the 71 patients with negative Ab response who subsequently received a third vaccine dose, 38% (27/71) developed a measurable Ab response. Conclusions: Ab RR to COVID-19 vaccination is suboptimal in patients with CLL and indolent NHL, and continued infection precautions should be employed. The Moderna vaccine may provide superior humoral immunity to COVID-19 in patients with CLL. A third vaccine dose increases Ab RR in this patient population.
ABSTRACT
Background: We have previously described AUTO1, a CD19 CAR with a fast off-rate CD19 binding domain, designed to reduce CAR T-cell immune toxicity and improve engraftment. Its clinical activity has been tested in r/r paediatric and adult B-ALL (Ghorashian S et al., Nat Med 2019;Roddie C et al., JCO 2021). This data confirms the intended function of the receptor, with low levels of CRS/ICANS and long-term engraftment of CAR T-cells observed in both patient groups. Aims: We have initiated testing of AUTO1 in the setting of B-NHL and CLL/SLL (NCT02935257). Methods: Manufacturing: CAR T-cell products were generated using a semi-automated closed process from non-mobilised patient leukapheresate. Study design: Subjects ≥ 16y underwent lymphodepletion with fludarabine (30mg/m x3) and cyclophosphamide (60mg/kg x1) prior to AUTO1 infusion, with the exception of the DLBCL cohort who additionally received a single dose of pembrolizumab (200mg) on day -1 to potentiate CAR-T expansion. AUTO1 dose varies based on the indication. Split dosing of 230 x106 CD19 CAR T-cells at day 0 and day 9 is employed in the CLL cohort. A single dose of 200 x106 CD19 CAR T-cells is delivered to patients with B-NHL. Study endpoints include feasibility of manufacture, grade 3-5 toxicity and remission rates at 1 and 3 months. Results: As of 8th February 2022, we enrolled 23 patients: 11 low grade NHL (LG-NHL:7 with FL and 3 with MCL), 7 DLBCL and 5 CLL. Apheresis was successful in all 23 patients and product manufacture was successful in 22 (pending in the last). 19 patients were infused: 10 with LG-NHL, 6 with DLBCL and 3 with CLL. 1 CLL patient was pending infusion at time of data cut-off and 2 patients died pre-infusion: 1 MCL patient, from COVID-19 and 1 CLL patient, from intracerebral haemorrhage. Patients treated with AUTO1 had a median age of 60 years (range 39-79), had received a median of 3 prior lines of treatment (range 2-8). Grade 1 CRS was reported in 6/19 and Grade 2 CRS in 3/19. No ICANS was observed in the B-NHL and CLL cohorts. CAR engraftment was observed in 13/13 patients evaluated by qPCR with ongoing persistence in 12/13 patients at last follow-up. In the LG-NHL and DLBCL cohorts 10/10 and 4/5 evaluable patients respectively were in CMR by 18FDG PET-CT post-treatment. Responses were ongoing in 9/10 LG-NHL at 12 months and in 4/4 DLBCL at months 1, 3, 3 and 6. In the CLL cohort, 2/3 evaluable patients achieved MRD negative remission in the bone marrow with residual small volume lymph nodes by CT at 6 and 3 months of follow-up respectively. 1 CLL patient did not engraft and had SD at month 1. Summary/Conclusion: AUTO1 has a tolerable safety profile in patients with r/r B-NHL and CLL despite high disease burden. Early data shows excellent complete remission rates and excellent CAR engraftment/expansion. Additional patients, updated data and longer follow up will be presented.
ABSTRACT
Background: Patients with haemato-oncological malignancies are one of the high-risk groups for a severe course in case of Covid-19 infections. Furthermore, vaccination results in signifcantly lower response rates in haematological malignancies and lower antibody levels in patients with solid cancer. We investigated efcacy and safety of a heterologous booster vaccination with Ad26.COV2.S DNA vector vaccine in haemato-oncological patients without antibody response after doubledose BNT162b2 mRNA Covid-19 vaccine. Methods: A total of 32 haemato-oncological non-respond-ers to double-dose BNT162b2 received a heterologous booster vaccination with Ad26.COV2.S. Blood samples were assessed directly before the vaccination (T0) and 4 weeks after (T1). Safety assessment was performed using a standardised questionnaire. Results: The overall response rate was 31 %, with a mean (SD) antibody titre of 693.79 (1096.99) BAU/ml. Patients with chronic lymphocytic leukaemia or lymphoma showed a sig-nifcantly lower response rate (P = 0.048). Adverse events were reported in 29.6 % of patients, whereby 7.1 % were graded as severe, which includes grade III and IV events following CTCAE. Conclusions: The heterologous booster vaccination with Ad26.COV2.S led to a serological response in 9 out of 29 patients without response after double-dose BNT162b2. Furthermore, the vaccination was safe in our cohort, leading to mainly mild local and systemic reactions. Overall, this vaccination regimen should be further evaluated to increase the response rate in the highly vulnerable population of haemato-oncological patients.
ABSTRACT
Introduction: CLL is characterized by deficient immunity which clinically manifests as an increased predisposition toward malignancies and infectious complications. T-cells from patients with CLL exhibit a skewed repertoire with a predominance of Tregs as well as impaired immune synapse formation and cytotoxic function. Unlike chemotherapy, novel targeted agents may have beneficial immunomodulatory effects, which may be particularly relevant in the COVID-19 era. Small ubiquitin-like modifier (SUMO) family proteins regulate a variety of cellular processes, including nuclear trafficking, gene transcription, and cell cycle progression, via post-translational modification of target proteins. Sumoylation regulates NFjB signaling, IFN response, and NFAT activation, processes indispensable in immune cell activation. Despite this, the role of sumoylation in T cell biology in the context of cancer is not known. TAK-981 is a small molecule inhibitor of the SUMO-activating enzyme (SAE) that forms a covalent adduct with an activated SUMO protein, thereby preventing its transfer to the SUMO-conjugating enzyme (Ubc9). Here, we investigated the immunomodulatory effects of TAK-981 in CLL. Methods: T cells from patients with CLL were purified using Dynabeads. Activation, proliferation, and apoptosis of CD3+ T cells were studied following T-cell receptor engagement (TCR;aCD3/CD28) with/without 0-1 lM TAK-981. Cytokines were measured after in vitro stimulation. For polarization assays, FACS-sorted naïve CD4+ T cells were cultured for 7 days in control or differentiation media. For gene expression profiling (GEP;Clariom S), RNA was harvested after 3 and 24 h of TCR engagement from FACS-sorted naïve CD4+ T cells. For in vivo immunization experiments, CD4+KJ1-26+ cells were inoculated IV into BALB/cJ mice. Mice received 100 mg IV ovalbumin ± R848 followed by TAK-981 7.5 mg/kg or vehicle control IV twice weekly for 10 days before spleen collection. Both recipient and transplanted splenocytes were analyzed. For analysis of tumor-infiltrating lymphocytes (TILs), BALB/c mice were injected with 1×106 A20 lymphoma cells and treated as above. TAK-981 was provided by Millennium Pharmaceuticals, Inc. (Cambridge, MA, USA). Results: T cells from patients with CLL demonstrated high baseline protein sumoylation that slightly increased following TCR engagement. Treatment with TAK-981 significantly downregulated SUMO1 and SUMO2/3-modified protein levels, yet did not disrupt early TCR signaling as evidenced by sustained ZAP70, p65/NFjB, and NFAT activation detected by immunoblotting, immunocytochemistry, and GEP. Treatment with TAK-981 resulted in dose-dependent upregulation of the early activation marker CD69 in CD4+ T cells following 72 and 96 h of TCR stimulation vs. control. Meanwhile, the expression of CD25, HLA-DR, and CD40L was delayed in the presence of TAK-981. Interestingly, CD38, an IFN response target, was induced 2-fold in TAK-981-treated cells after 24 h and persisted at high levels at subsequent timepoints. T cell proliferation was reduced in the presence of high (1 lM) but not low/intermediate concentrations of TAK-981, accompanied by reduced S phase entry and decreased synthesis of IL- 2. However, T cells did not undergo apoptosis under those conditions. Targeting SAE in either control or Th1/Treg polarizing conditions facilitated an increase in IFNc and loss of FoxP3 expression (accompanied by decreased IL-2/STAT5), suggesting a shift toward Th1 and away from Treg phenotype, respectively. GEP (Reactome, GSEA) confirmed a dramatically upregulated IFN response in TAK-981-treated CD4+ naïve T cells. Furthermore, targeting SAE enhanced degranulation (CD107a), IFNc, and perforin secretion in cytotoxic CD8+ T cells and potentiated T cell cytotoxicity in allogeneic assays with lymphoma cells (OCI-LY3, U2932) as targets. Consistent with our in vitro data, OVA-stimulated transplanted transgenic KJ1-26+ splenocytes, as well as total CD4+ T cells from recipient mice treated with TAK-981 in vivo exhibited a significant reduction in express on of FoxP3 and an increased production of IFNc. In the A20 syngeneic model, treatment with TAK-981 similarly downregulated FoxP3 expression in CD4+ TILs and induced IFNc secretion in CD8+ TILs. Conclusion: Using a combination of in vitro and in vivo experiments, we demonstrate that pharmacologic targeting of sumoylation with TAK-981 does not impair proximal TCR signaling in T cells obtained from patients with CLL, but leads to rebalancing toward healthy immune T cell subsets via induction of IFN response and downmodulation of Tregs. These data provide a strong rationale for continued investigation of TAK-981 in CLL and lymphoid malignancies.
ABSTRACT
Introduction: Bruton tyrosine kinase inhibitor (BTKi) therapy is remarkably effective in a number of B-cell malignancies;however, its continuous use is limited by adverse events (AE) leading to discontinuation. Zanubrutinib is a potent and selective BTKi with the potential to be a safe and effective therapy after intolerance to previous BTKi therapy. Here, we report preliminary results of a phase 2 study of zanubrutinib in patients with B-cell malignancies intolerant to ibrutinib and/or acalabrutinib based on a median follow-up of 6 months. Methods: Patients meeting protocol criteria for intolerance to ibrutinib, acalabrutinib, or both (without documented progressive disease on ibrutinib or acalabrutinib) were given zanubrutinib monotherapy (160mg twice daily or 320mg once daily at investigator's discretion). Recurrence of adverse events that led to intolerance to prior BTKi and additional safety measures were assessed based on the Common Terminology Criteria for AEs v5.0. Investigators determined responses using disease status at study entry as baseline and standard established disease response criteria. Results: As of 1 March 2021 (cutoff), 64 patients (n=48 chronic lymphocytic leukemia/small lymphocytic lymphoma, n=10 Waldenström macroglobulinemia, n=3 mantle cell lymphoma, n=3 marginal zone lymphoma) were enrolled, received ≥1 dose of zanubrutinib, and were analyzed for safety. The median age was 71 y (range, 49-91);the median duration of treatment was 5.9 months (range, 0.6-16.6). The median number of prior regimens was 2 (range, 1-12). Regarding prior BTKi, 55 patients had received ibrutinib monotherapy, eight had received ibrutinib combination therapy, and seven had received acalabrutinib monotherapy. The median number of ibrutinib- or acalabrutinib-intolerant adverse events per patient was 2 (range, 1-5). Most ibrutinib- (75%) and acalabrutinib-intolerant events (75%) did not recur with zanubrutinib (Table 1). A majority (90%) of the recurrent ibrutinib-intolerant events were less severe with zanubrutinib than with ibrutinib. Ibrutinib intolerance events present in >1 patient that did not recur on zanubrutinib were alanine aminotransferase increased, aspartate transaminase increased, neutropenia, and pain in extremity. The ibrutinib-intolerant events that recurred were diarrhea, dizziness, insomnia, nausea, constipation, myalgia, stomatitis, arthralgia, headache, muscle spasm, rash, atrial fibrillation, fatigue, hemorrhage, and hypertension. One-third of the recurrent acalabrutinibintolerant events were less severe with zanubrutinib than with acalabrutinib. The acalabrutinib-intolerant events that recurred were myalgia and arthralgia. Two events of arthralgia that induced acalabrutinib intolerance did not recur with zanubrutinib. No ibrutinib- or acalabrutinib-intolerant events recurred at a higher severity while patients were on zanubrutinib. At cutoff, 57 patients remained on treatment;one withdrew consent due to zanubrutinib-unrelated grade 3 syncope. Grade ≥3 adverse events were reported in 14 patients (21.9%), serious adverse events in five patients (7.8%;pain in jaw;COVID-19 pneumonia;anemia;febrile neutropenia and salmonella infection [occurred in the same patient]), adverse events requiring dose interruptions in 15 patients (23.4%), and adverse events leading to dose reduction in three patients (4.7%). Adverse events led to zanubrutinib discontinuation for three patients (4.7%). One death was reported (COVID-19 pneumonia). Among efficacy evaluable patients (n=48), the disease control rate was 89.6% and the overall response rate was 50.0%. Conclusions: In patients with B-cell malignancies intolerant to ibrutinib and/or acalabrutinib, zanubrutinib therapy was effective and controlled patient's disease or induced responses to therapy, and was well-tolerated;most adverse events that led to discontinuation of previous BTKi therapy did not recur while patients were on zanubrutinib.
ABSTRACT
Introduction COVID-19 poses a serious concern for mB-cell NHL patients given their advanced age, high burden of comorbidities, and immune dysfunction. Limited by smaller sample sizes during the early period of the COVID-19 pandemic, previous studies were unable to thoroughly evaluate the impact of COVID-19 on patients with mB-cell NHL 1,2. We aim to describe demographics and clinical characteristics, outcomes, and risk factors associated with death and other severe outcomes among COVID-19 patients with mB-cell NHL in a large US nationwide database. Methods This retrospective cohort study was conducted using the Optum EHR database, comprising data from an integrated network of ambulatory and hospital care providers across the US. Patients with COVID-19 (diagnosis code of U07.1, U07.2, or a positive result of SARS-Cov-2 virus PCR or antigen tests) between Feb. 1, 2020 and Jan 7, 2021 (index date) and mB-cell NHL diagnosis prior to the COVID-19 diagnosis were included. Patients were excluded if they were under 18 years of age, had missing age or sex, or had <1year continuous eligibility prior to their index date (pre-index period). All baseline characteristics, including demographics and comorbidities, were determined during the one-year pre-index period. Severe outcomes, including death, hospitalization, ICU admission, and acute respiratory insufficiency (ARI), were evaluated within 30 days post-index date. Multivariable logistic regression was conducted to identify variables independently associated with severe outcomes. Results Among 2,767 patients with mB-cell NHL who were infected with SARS-CoV-2 between Feb. 1, 2020 and Jan. 7, 2021 (mean age±SD: 67.9 years±14.7, 53.9% male), majority were white (73.9%), followed by African American (10.9%), Hispanic (6.9%), and Asian (1.2%). The most common subtypes of mB-cell NHL were chronic lymphocytic leukemia/small lymphocytic lymphoma (26.9%), multiple myeloma (22.4%), diffuse large B-cell lymphoma (13.2%), and follicular lymphoma (7.3%). Of these patients, 93.4% have at least one comorbidity. The most common comorbidities were hypertension (58.5%), neurological disease (49.4%), diabetes (28.2%), ischemic heart disease (25.5%), cardiac arrhythmia/conduction disorders (24.4%), chronic kidney disease (CKD, 19.2%), heart failure/cardiomyopathy (18.1%), and COPD (12.3%). Overall, 960 patients (34.7%) developed severe outcomes, among which, 847 patients (30.6%) were hospitalized, 214 patients (7.7%) were admitted to the ICU, 201 patients (7.3%) experienced ARI, and 220 patients (8.0%) died. Multivariable logistic regression showed that increased odds of severe outcomes were independently associated with older age (85+ years vs. <65 years;adjusted odds ratio [OR], 2.0;95% CI, 1.4-2.7), male gender (OR, 1.4;95% CI, 1.1-1.6), insurance coverage with Medicaid (OR, 1.8;95% CI, 1.1-2.9) and/or Medicare (vs. commercial only;OR, 1.9;95% CI, 1.5-2.5), infected during the first quarter (OR, 5.6;95% CI, 3.4-9.4) or second quarter of 2020 (vs. fourth quarter of 2020;OR, 1.7;95% CI, 1.4-2.1), having CKD (OR, 1.3;95% CI, 1.0-1.6), COPD (OR, 1.4;95% CI, 1.0-1.8), diabetes (OR, 1.3;95% CI, 1.1-1.6), and receiving active treatment for NHL (OR, 1.4;95% CI, 1.0-2.0) within 30 days prior to COVID-19 diagnosis (Figure). Conclusions This study demonstrated key demographic and clinical characteristics associated with severe outcomes among COVID-19 patients with mB-cell NHL using one of the largest nationwide databases. Risk factors for severe outcomes identified in the general population, such as older age, male gender, and having certain underlying medical conditions were also identified in this study. In addition, COVID-19 infection occurring earlier in the pandemic and receiving active NHL treatments were associated with severe outcomes. These latter two observations might reflect the improvement in patient management during the latter period of the pandemic and that active mB-cell NHL disease and treatment rendered an increased risk of severe outcomes in COVID-19 patients with mB- ell NHL. These insights highlight the importance of utilizing demographic, clinical and treatment information to estimate the risk for severe outcomes, whereas prospective studies focusing on optimal COVID-19 management are required to identify specific actions that can be taken to improve outcomes of COVID-19 in patients with mB-cell NHL. [Formula presented] Disclosures: Yue: Joule: Current Employment. Hallett: AbbVie: Current Employment. Liu: AbbVie: Current Employment. Iyengar: AbbVie: Current Employment. Basa: AbbVie: Current Employment. Yang: AbbVie: Current Employment.
ABSTRACT
Background: Continuous Bruton's tyrosine kinase (BTK) inhibition represents an effective and easily administered oral therapy for patients with CLL;however, it is not curative, can have serious side effects, and is expensive. Novel combinations may provide deep remissions allowing fixed duration therapy. The second generation BTK inhibitor acalabrutinib (ACALA) has demonstrated an improved safety profile compared to ibrutinib. Importantly, unlike ibrutinib, ACALA does not inhibit anti-CD20 monoclonal antibody dependent cellular phagocytosis (VanDerMeid et al, Cancer Immuno Res 2018). Using standard doses, rituximab (RTX) rapidly exhausts the finite innate immune system cytotoxic capacity (Pinney, et al Blood 2020) and also causes loss of cell membrane CD20 from CLL cells by trogocytosis. Previous studies have shown that high frequency low dose (HFLD) IV RTX (20mg/m 2 three times per week) was effective and limited loss of CD20 (Zent, et al Am J Hematol, 2014). Subcutaneous (SQ) RTX is FDA approved in CLL, has similar efficacy and pharmacokinetics, and can be self-administered. This phase II study tested the efficacy and tolerability of the combination of ACALA and HFLD RTX as initial treatment for patients with treatment-naïve CLL. Methods: Eligible patients were treated with 50mg RTX on day 1 and 3 of each week for six 28-day cycles. The first dose was administered IV over 2 hours. If tolerated, subsequent doses were SQ and could be self-administered at home by trained patients. ACALA 100mg BID therapy was initiated on cycle 1 day 8 for a minimum of 12 cycles. Treatment response was assessed during cycles 12 and 24. Patients achieving an iwCLL complete response (CR) with undetectable minimal residual disease (uMRD) by 6-color flow cytometry (£ 1:10 -4)at either time point could stop therapy. The primary objective was to determine the rate of iwCLL CR with a secondary endpoint of rate of uMRD. Results: 37 patients have been treated with a median follow-up of 14 months. Baseline demographics were male/female (22/15) and median age 67 years (range 40-78). High-risk genetic features included TP53 mutation (21.6%), del17p (13.5%), del 11q (16.2%), unmutated IGHV (62.2%), NOTCH1 mutation (21.6%) and SF3B1 mutation (10.8%). Grade 3/4 AEs occurring in ≥5% of patients were infections (13.5%), neutropenia (8.1%) and anemia (8.1%). No patients discontinued therapy due to AEs and there were no deaths on treatment. The most common (≥20%) AEs (all grades and all causality) were infusion-related reactions (62.1%), infections (56.8%) (upper respiratory infections in 29.7% of patients, urinary tract infections in 18.9%, COVID-19 pneumonia in 8.1%), fatigue (51.3%), anemia (51.3%), headache (43.2%), rash or other skin changes (32.4%), thrombocytopenia (29.7%), bruising (27.0%), and diarrhea (21.6%). Injection site reactions (8.1%) from SQ RTX were grade 1. Three patients contracted COVID-19 while on study during times of high community transmission prior to the availability of vaccines. Two required hospitalization, one contracted the virus following cycle 1 requiring a delay in RTX, and all patients remained on ACALA while COVID-19 positive. 27 patients have completed 12 cycles and been evaluated for response. All patients responded with 1 MRD+ CR, 20 partial responses (PR), and 6 PR with sustained lymphocytosis. 10 of these patients have completed 24 cycles and had a sustained PR. One patient with del17p and TP53 mutation had progressive disease after 25 cycles of therapy. All other patients remain on treatment per protocol. Conclusion: HFLD RTX and ACALA is a tolerable, effective and convenient therapy that could be the basis for regimens incorporating other novel agents. It is notable that three patients have contracted COVID-19 during the trial;however, none required intubation, and all remained on ACALA during their infection. This at-home combination markedly decreased patient infection risk during the COVID-19 pandemic. This regimen has the potential to enable RTX to be administered at facilities with limited medica IV infusion capacity which could be very useful in rural and economically disadvantaged areas. While all patients have responded to therapy, no patients to date have achieved an uMRD CR, suggesting that additional agents are required to allow for time-limited treatment. Disclosures: Baran: AstraZeneca/Acerta: Research Funding. Friedberg: Novartis: Other: DSMC;Acerta: Other: DSMC;Bayer: Other: DSMC. Reagan: Kite, a Gilead Company: Consultancy;Genentech: Research Funding;Seagen: Research Funding;Curis: Consultancy. Casulo: Verastem: Research Funding;Genentech: Research Funding;BMS: Research Funding;Gilead: Research Funding. Zent: TG Therapeutics: Research Funding;Acerta/AstraZeneca: Research Funding. Barr: Morphosys: Consultancy;Janssen: Consultancy;Bristol Meyers Squibb: Consultancy;AstraZeneca: Consultancy;Genentech: Consultancy;TG Therapeutics: Consultancy;Beigene: Consultancy;Seattle Genetics: Consultancy;Abbvie/Pharmacyclics: Consultancy;Gilead: Consultancy.
ABSTRACT
Background: Currently, asymptomatic patients with CLL/SLL are observed without treatment until development of symptoms or cytopenias. Historically, early intervention studies in patients with CLL/SLL with non-specific chemoimmunotherapy agents have not resulted in an overall survival (OS) benefit and have resulted in toxicity. The introduction of targeted therapies, such as venetoclax (an oral BCL2 inhibitor;V) and obinutuzumab (an intravenous anti-CD20 monoclonal antibody;O), have provided tolerable/efficacious options for patients with CLL. In the CLL14 study, symptomatic patients with CLL receiving frontline therapy with VO had longer progression-free survival (PFS) and deeper remissions [more undetectable minimal residual disease (uMRD)] compared with those receiving chlorambucil and O (Fischer 2019). The CLL-International Prognostic Index (CLL-IPI;Table 1) is a validated prognostic model to predict which patients are at highest risk of a shorter time to first therapy and shorter OS. A score of ≥4 is considered high-risk on this scale. We aim to use VO as early intervention in asymptomatic, high-risk CLL patients, assessed by CLL-IPI, to potentially improve OS and thus alter the natural history of the disease. Methods: On 12/14/20, we activated the S1925 study (NCT#04269902 ) for adult patients with CLL or SLL, who were diagnosed within 12 months of enrollment. Eligible patients have a CLL-IPI score ≥4 (Table 1) or complex cytogenetics (≥3 cytogenetic abnormalities) and do not meet any criteria for initiation of treatment by the International Working Group for CLL (IWCLL;Hallek 2018) guidelines. Enrolled patients are randomized in a 2:1 manner to early versus delayed (at the time IWCLL indication for treatment is met) therapy with VO (Figure 1). VO is administered as previously described (Fischer 2019). The primary endpoint is OS. We hypothesize that early intervention with VO will improve the rate of 6-year OS from 60% to 80%. This design requires 222 eligible patients for 88% power (2-sided a=0.05) for the primary comparison. To allow for 10% ineligibility, we will enroll 247 patients. Estimated accrual time is 4 years. Secondary endpoints include: rates of response, PFS, and relapse-free survival;safety;time to second CLL-directed therapy;and quality of life (assessed by FACT-Leukemia). As COVID19 is an infection with particularly high morbidity and mortality in patients with CLL, incidence of this infection and complications including death will be recorded and compared between patients followed on the early versus delayed intervention arms. The primary translational objective is to evaluate the prognostic association between OS and peripheral blood MRD status at 15 months after treatment initiation by flow cytometry. Secondary translational objectives include describing the association of other clinical outcomes, baseline prognostic factors, and IWCLL-defined response with MRD status at multiple timepoints. Current Status: At the time of submission, 7 patients have been registered and randomized per protocol. Accrual is ongoing. [Formula presented] Disclosures: Stephens: Adaptive: Membership on an entity's Board of Directors or advisory committees;TG Therapeutics: Membership on an entity's Board of Directors or advisory committees;Epizyme: Membership on an entity's Board of Directors or advisory committees;Beigene: Membership on an entity's Board of Directors or advisory committees;Innate Pharma: Membership on an entity's Board of Directors or advisory committees;AstraZeneca: Consultancy;CSL Behring: Consultancy;Celgene: Consultancy;Novartis: Research Funding;Abbvie: Consultancy;JUNO: Research Funding;Arqule: Research Funding;Mingsight: Research Funding;Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding. Moseley: BioSight Ltd: Consultancy. Hill: AbbVie: Consultancy, Honoraria, Research Funding;Gentenech: Consultancy, Honoraria, Research Funding;Beigene: Consultancy, Honoraria, Research Funding;Pfizer: Consultancy, Honoraria;Kite, Gilead Company: Consultancy, Honoraria, Other: Travel Support, Research Funding;Karyopharm: Consultancy, Honoraria, Research Funding;AstraZenica: Consultancy, Honoraria;Celgene (BMS): Consultancy, Honoraria, Research Funding;Novartis: Consultancy, Honoraria, Research Funding;Epizyme: Consultancy, Honoraria;Incyte/Morphysis: Consultancy, Honoraria, Research Funding. Pagel: Pharmacyclics/AbbVie: Consultancy;Actinium Pharmaceuticals: Consultancy;Incyte/MorphoSys: Consultancy;BeiGene: Consultancy;Epizyme: Consultancy;Kite, a Gilead Company: Consultancy;AstraZeneca: Consultancy;Gilead: Consultancy;MEI Pharma: Consultancy. Shadman: Mustang Bio, Celgene, Bristol Myers Squibb, Pharmacyclics, Gilead, Genentech, Abbvie, TG Therapeutics, Beigene, AstraZeneca, Sunesis, Atara Biotherapeutics, GenMab: Research Funding;Abbvie, Genentech, AstraZeneca, Sound Biologics, Pharmacyclics, Beigene, Bristol Myers Squibb, Morphosys, TG Therapeutics, Innate Pharma, Kite Pharma, Adaptive Biotechnologies, Epizyme, Eli Lilly, Adaptimmune, Mustang Bio and Atara Biotherapeutics: Consultancy. Danilov: Genentech: Consultancy, Honoraria, Research Funding;Takeda Oncology: Research Funding;TG Therapeutics: Consultancy, Research Funding;Abbvie: Consultancy, Honoraria;Beigene: Consultancy, Honoraria;Pharmacyclics: Consultancy, Honoraria;Gilead Sciences: Research Funding;Bristol-Meyers-Squibb: Honoraria, Research Funding;Rigel Pharm: Honoraria;Bayer Oncology: Consultancy, Honoraria, Research Funding;SecuraBio: Research Funding;Astra Zeneca: Consultancy, Honoraria, Research Funding. Mato: Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding;DTRM BioPharma: Consultancy, Research Funding;Acerta/AstraZeneca: Consultancy, Research Funding;Sunesis: Consultancy, Research Funding;BeiGene: Consultancy, Research Funding;Johnson and Johnson: Consultancy, Research Funding;Genentech: Consultancy, Research Funding;AbbVie: Consultancy, Research Funding;Nurix: Research Funding;Genmab: Research Funding;LOXO: Consultancy, Research Funding;Janssen: Consultancy, Research Funding;AstraZeneca: Consultancy;Adaptive Biotechnologies: Consultancy, Research Funding;MSKCC: Current Employment;TG Therapeutics: Consultancy, Other: DSMB, Research Funding. Brander: Juno Therapeutics/Celgene/Bristol Myers Squibb: Research Funding;Pfizer: Consultancy, Other: Biosimilars outcomes research panel;TG Therapeutics: Consultancy, Research Funding;Novartis: Research Funding;ArQule/Merck: Consultancy;Verastem: Consultancy;BeiGene: Research Funding;ArQule: Research Funding;NCCN: Other: panel member;AstraZeneca: Research Funding;Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding;LOXO: Research Funding;Ascentage: Research Funding;Genentech: Consultancy, Research Funding;DTRM: Research Funding;MEI Pharma: Research Funding;AbbVie: Consultancy, Other: informCLL registry steering committee, Research Funding. Coutre: Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding;Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding;AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees;Beigene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Data Safety Monitoring Committee, Research Funding;Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees;Acerta: Other: Data Safety Monitoring Committee, Research Funding. O'Brien: Kite, Regeneron, Acerta, Caribou, Gilead, Pharmacyclics, TG Therapeutics, Pfizer, Sunesis: Research Funding;Amgen, Astellas, Celgene, GlaxoSmithKline, Janssen Oncology, Aptose Biosciences Inc., Vaniam Group LLC, AbbVie, Alexion, Verastem, Juno Therapeutics, Vida Ventures, Autolus, Johnson and Johnson, Merck, Bristol Myers Squibb, NOVA Research Company, El Lill: Consultancy. Erba: AbbVie Inc;Agios Pharmaceuticals Inc;Bristol Myers Squibb;Celgene, a Bristol Myers Squibb company;Incyte Corporation;Jazz Pharmaceuticals Inc;Novartis: Speakers Bureau;AbbVie Inc: Other: Independent review committee;AbbVie Inc;Agios Pharmaceuticals Inc;ALX Oncology;Amgen Inc;Daiichi Sankyo Inc;FORMA Therapeutics;Forty Seven Inc;Gilead Sciences Inc;GlycoMimetics Inc;ImmunoGen Inc;Jazz Pharmaceuticals Inc;MacroGenics Inc;Novartis;PTC Therapeutics: Research Funding;AbbVie Inc;Agios Pharmaceuticals Inc;Astellas;Bristol Myers Squibb;Celgene, a Bristol Myers Squibb company;Daiichi Sankyo Inc;Genentech, a member of the Roche Group;GlycoMimetics Inc;Incyte Corporation;Jazz Pharmaceuticals Inc;Kura Oncology;Nov: Other: Advisory Committee. OffLabel Disclosure: The trial studies early intervention with venetoclax and obinutuzumab in patients with CLL/SLL who are asymptomatic and observation would be standardly recommended.
ABSTRACT
Introduction: Recent data suggest a suboptimal antibody response to COVID-19 vaccination in patients with hematological malignancies, especially under therapy with monoclonal antibodies targeting B-cells. Herein, we evaluated the development of neutralizing antibodies (NAbs) against SARS-CoV-2 in patients with chronic lymphocytic leukemia (CLL), Non-Hodgkin Lymphoma (NHL) and Hodgkin's Lymphoma (HL) after vaccination with the mRNA BNT162b2 vaccine, up to 50 days post their first vaccine dose. Methods: This is a large prospective study (NCT04743388) evaluating the kinetics of anti-SARS-CoV-2 antibodies after COVID-19 vaccination in healthy subjects and patients with hematological malignancies. We report here the results in CLL, NHL and HL patients in comparison to age- and gender-matched controls who were vaccinated at the same time period (January to May 2021). After vein puncture, the serum of both patients and controls was collected on day 1 (D1;before the first BNT162b2 dose), on day 22 (D22;before the second dose of the BNT162b2) and on day 50 (D50;3 weeks post second dose of the BNT162b2). Serum was separated within 4 hours from blood collection and stored at -80°C until the day of measurement. NAbs against SARS-CoV-2 were measured using FDA approved methodology (ELISA, cPass™ SARS-CoV-2 NAbs Detection Kit;GenScript, Piscataway, NJ, USA) on the abovementioned timepoints. A NAb titer of at least 30% is considered as positive, according to manufacturer, whereas a NAb titer of at least 50% has been associated with clinically relevant viral inhibition [Walsh et al. N Engl J Med 2020, 383, 2439-50]. Samples of the same individual were measured in the same ELISA plate. Results: We evaluated 132 patients with CLL/Lymphomas after vaccination with the BNT162b2. Patient population included 53 with CLL, 57 with NHL and 22 with HL, while 214 healthy controls, of similar age and gender, were also studied. At the time of vaccination, 30% (n=40) of patients had asymptomatic disease and out of 92 symptomatic patients, 49% (n=45) were on active treatment. Vaccination with two doses of the BNT162b2 led to lower production of NAbs against SARS-CoV-2 in patients compared with controls, both on day 22 and on day 50 (P<0.001 for all comparisons) for all subgroups. After the first dose of the vaccine, on D22, the patient group had lower NAb titers compared with controls: the median NAb inhibition titer was 18% (IQR: 8.5-29%) for patients versus 41.6% (IQR: 25.3-59%) for controls;p<0.001. On D50, the median NAb inhibition titer was 32.5% (IQR: 13.5-93%) for patients versus 94.7% (IQR: 89-97%) for controls;p<0.001. More specifically, only 50.8% (67/132) of the patients versus 98.1% (210/214) of the controls developed NAb titers ≥30% and 43.9% (58/132) of patients versus 95.3% (204/214) titers ≥50% (high protective titers) at day 50 (p<0.0001 for all comparisons;Figure-left part). Importantly, active treatment (which included anti-CD antibodies, Bruton's tyrosine kinase inhibitors, a combination of the above, chemotherapy-only regimens or Bcl-2 inhibitors) was an independent prognostic factor for suboptimal antibody response at day 50 (<50%) in the patient subgroup (p<0.001). Rituximab administration in the last 12 months correlated with decreased antibody response at day 50 (p<0.01). Patients with HL were more likely to achieve humoral responses (>50% at day 50) compared to other disease types (p<0.05;Figure-right part). Disease-related immune dysregulation and therapy-related immunosuppression were therefore involved in the low humoral responses seen in patients. Regarding adverse events, 9% and 9.8% patients reported mild reactions after the first and second dose of the BNT162b2 vaccine, respectively. Conclusion: Patients with CLL/NHL/HL have a low humoral response following SARS-CoV-2 vaccination, particularly patients who are on active treatment with rituximab or BTK inhibitors. These patient subgroups therefore should continue utilizing protective measures against SARS-CoV-2 (masks, social distancing, etc) as they re at high risk for COVID-19. Further studies on the kinetics of immune subpopulations following COVID-19 vaccination will elucidate the underlying immune landscape and determine the potential need for additional booster vaccine doses or protective administration of antibodies against SARS-CoV-2 in CLL/NHL/HL patients with poor response after full vaccination. [Formula presented] Disclosures: Terpos: Sanofi: Consultancy, Honoraria, Research Funding;Novartis: Honoraria;Celgene: Consultancy, Honoraria, Research Funding;Janssen-Cilag: Consultancy, Honoraria, Research Funding;GSK: Honoraria, Research Funding;Genesis: Consultancy, Honoraria, Research Funding;Takeda: Consultancy, Honoraria, Research Funding;BMS: Honoraria;Amgen: Consultancy, Honoraria, Research Funding. Gavriatopoulou: Janssen: Honoraria;GSK: Honoraria;Genesis: Honoraria;Takeda: Honoraria;Sanofi: Honoraria;Amgen: Honoraria;Karyopharm: Honoraria. Baltadakis: Amgen: Honoraria;Bristol-Myers Squibb: Honoraria;Alexion: Honoraria;Astellas: Honoraria;Pfizer: Honoraria, Other: Travel Grants;Gilead: Honoraria;Novartis: Honoraria;Abbvie: Honoraria;Genesis Pharma: Other: Travel Grants;Gilead: Other: Travel Grants;WinMedica: Other: Travel Grants;Baxalta Hellas: Other: Travel Grants. Dimopoulos: BMS: Honoraria;Amgen: Honoraria;Janssen: Honoraria;Takeda: Honoraria;Beigene: Honoraria.
ABSTRACT
Background: The BCL-2 inhibitor venetoclax in combination with an anti-CD20 monoclonal antibody (rituximab or obinutuzumab) has demonstrated superior outcomes and manageable safety as compared to chemo-immunotherapy in phase III clinical trials for chronic lymphocytic leukemia (CLL). Moreover, venetoclax-based regimens induced high rates of undetectable minimal residual disease (uMRD). Prospective data on the effectiveness of venetoclax-based regimens specifically with regard to achieving uMRD in a real-world setting are still lacking. Here we report the first interim analysis for efficacy and safety of an ongoing nationwide real-world study of venetoclax based therapy for CLL/small lymphocytic lymphoma (SLL). Method: A prospective observational nationwide multicenter study. Treatment-naïve (TN) and relapsed/refractory (R/R) CLL/SLL patients were enrolled in 13 medical centers in Israel. The primary endpoint was clinical response, per physician assessment 12-months after the initiation of venetoclax treatment. Key secondary endpoints included progression free survival (PFS), overall survival (OS) and uMRD as assessed at a central laboratory by 8-color flow-cytometry. Results: Between February 10, 2019, and Jun 17, 2021 (data cut), 199 CLL/SLL patients were enrolled from 13 medical centers in Israel to receive venetoclax based therapy. The study included 83 TN and 116 R/R evaluable CLL/SLL patients with a median age of 69 years (range, 34-85) and 70.5 years (range, 25-91), respectively (Table 1). R/R patients had received a median of one prior therapy with a range up to 8, of these patients 60 (51.7%) were previously treated with a B-cell receptor inhibitor (BCRi) including ibrutinib in 52 (44.8%) and idelalisib in combination with rituximab in 6 (5.2%). TN patients had been treated with venetoclax in combination with obinutuzumab (92.8%) or rituximab (4.8%) and R/R patients received either venetoclax with rituximab (60.3%) or obinutuzumab (9.5%), venetoclax monotherapy (25.8%) or triple therapy with venetoclax, rituximab and ibrutinib in 5 (4.3%). Dose escalation of venetoclax to the recommended dose of 400 mg daily was achieved in 80.7% (n=67) of TN and 81% (n=94) of R/R patients. The median duration of ramp-up was 38 and 42 days in TN and R\R patients, respectively. Prior to therapy, tumor lysis syndrome (TLS) risk was considered high in 12% and 29.3% of TN and R/R patients, respectively (Table 1). Laboratory TLS occurred in one TN patient and 4 R/R patients, whereas 3 of the R/R patients experienced clinical TLS. Nineteen TN and 75 R/R patients had a follow-up of at least 12 months or discontinued study prematurely. The 12-month overall response rate (ORR) for TN and R/R patients was 89.5% [complete response (CR) 13 (68.4%), partial response (PR) 4 (21.1%)] and 73.3% [CR 37 (49.3%), PR 18 (24%)], respectively. In the R/R cohort, the 12-month ORR among assessed patients was 67.6% (25/37) in BCRi-exposed versus 85.7% (30/35) in BCRi-naïve patients. At 12 months, peripheral blood uMRD (<0.01%) was achieved in 12 out of 14 (85.7%) TN and 26 out of 38 (68.4%) R/R evaluated patients. At a median follow-up of 5.1 months (range, 0.5-15.6) for TN and 10.1 months (range, 0-25.7) for R/R patients, the median PFS and OS, for both cohorts have not been reached. The estimated 12-month PFS was 90.9% for TN and 81.1% for R/R patients. For R/R patients with prior exposure to BCRi, the estimated 12-month PFS was 69.6% versus 94.8% in BCRi-naïve patients (figure 1). Grade ≥3 adverse events (AEs) were reported in 34.9% of TN patients and 43.9% R/R patients. The most frequent grade ≥3 AEs documented were neutropenia (TN: 19.2% and R/R 17.2%), infections (TN: 4.8% and R/R: 21.5%) and febrile neutropenia (TN: 2.4% and in R/R: 2.6%). COVID-19 occurred in 7 patients including one death. At the time of data cut, 10 deaths occurred, one TN and 9 R/R patients. Causes for death included infections (5 patients), disease progression (2 patients), acute myeloid leukemia/ myelodysplastic syndrome (2 patients) and a soft-tissue sarcoma (1 patient). Conclusions: This first interim analysis of our ongoing prospective real-world study of venetoclax-based treatment for TN and R/R CLL/SLL, demonstrates high efficacy together with a high proportion of undetectable MRD levels and a favorable toxicity profile. These efficacy results are comparable to those reported in previous Phase III clinical trials for CLL, with no new safety signals. [Formula presented] Disclosures: Herishanu: AbbVie: Consultancy, Honoraria, Research Funding;Janssen: Honoraria;Roche: Honoraria;AstraZeneca: Honoraria. Goldschmidt: AbbVie: Consultancy, Research Funding. Itchaki: Janssen: Consultancy, Honoraria, Research Funding;AbbVie: Consultancy, Honoraria, Research Funding. Levi: AbbVie: Consultancy, Research Funding. Aviv: AbbVie: Honoraria, Research Funding. Fineman: AbbVie: Research Funding. Dally: AbbVie: Honoraria, Research Funding. Tadmor: Janssen: Consultancy, Honoraria, Research Funding;AbbVie: Consultancy, Honoraria, Research Funding. Ruchlemer: AbbVie: Consultancy, Honoraria, Research Funding. Abadi: AbbVie: Honoraria, Research Funding. Shvidel: AbbVie: Honoraria, Research Funding. Braester: AbbVie: Honoraria, Research Funding. Cohen: AbbVie: Current Employment, Current equity holder in publicly-traded company. Frankel: AbbVie: Current Employment, Current equity holder in publicly-traded company. Ofek: AbbVie: Current Employment, Current equity holder in publicly-traded company. Berelovich: AbbVie: Current Employment, Current equity holder in publicly-traded company. Grunspan: AbbVie: Current Employment, Other: May hold equity. Benjamini: Janssen: Consultancy, Honoraria, Research Funding;AbbVie: Consultancy, Honoraria, Research Funding.
ABSTRACT
Background: Venetoclax (VEN), an oral B-cell lymphoma 2 inhibitor, is approved for use in adult patients (pts) with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). As a targeted and highly active antitumor agent, VEN induces rapid and profound tumor reduction. Inpatient monitoring for initial doses of VEN is recommended by US Prescribing Information for pts with medium tumor burden and reduced renal function or high tumor burden. Administration of debulking agents, such as obinutuzumab (G), help reduce tumor burden and, consequently, facilitate subsequent administration of VEN in the outpatient setting. However, tumor reduction data are needed to definitively establish the utility of a debulking strategy. This study performed disease restaging after every 2 cycles of debulking to evaluate the safety and efficacy of G ± bendamustine (B) as a debulking regimen before VEN treatment in the outpatient community setting. The safety and efficacy of subsequent VEN+G treatment after debulking was also evaluated. Methods: This open-label, Phase 3b study (NCT03406156) enrolled adult pts with previously untreated CLL/SLL (except those with 17p deletion) who had medium (any lymph node [LN] 5 to <10 cm or absolute lymphocyte count [ALC] ≥25×10 9/L) or high (any LN ≥10 cm or any LN ≥5 cm and ALC ≥25×10 9/L) tumor burden. A maximum of six 28-day cycles of G±B were administered, and disease restaging was performed after every 2 cycles. Once low tumor burden was achieved (all LN <5 cm and ALC <25x10 9/L), VEN+G was administered for 5 cycles followed by VEN monotherapy for a total time on VEN of up to 1 year. Disease assessments were performed at the end of combination therapy (EoCT;5 mo after last dose of G) and at the end of therapy (EoT;3 mo after last dose of VEN), and peripheral blood was collected for assessment of minimal residual disease (MRD) using the clonoSEQ assay (Adaptive Biotechnologies). Undetectable MRD was defined as <1 CLL cell/10 4 leukocytes (<10 -4;uMRD4), <10 -5 (uMRD5), or <10 -6 (uMRD6). The primary endpoints were the percentage of pts achieving low tumor burden after 2, 4, and 6 cycles of G±B debulking and complete remission (CR) and CR with incomplete marrow recovery (CRi) rates among pts receiving VEN. Results: Of 120 pts treated, 81 received G for debulking and 39 received G+B. As of 13 May 2021, 2 pts remained on study treatment, 108 were in posttreatment follow-up, and 10 had discontinued the study for reasons including death (n=7), withdrawn consent (n=2), and COVID-19 infection (n=1). At baseline, 82.5% of pts had ALC ≥25x10 9/L, 33.3% had LN ≥5 cm, and 24.2%/75.0%/0.8% had high/medium/low tumor burden, respectively. Low tumor burden was achieved in 91.6% (109/119) of evaluable pts receiving G±B debulking. In the all-treated population (N=120), the objective response rate (ORR) was 90.0% and the CR/CRi rate was 35.8%. Among pts receiving VEN with disease assessment at EoT (N=76), the ORR was 98.7% and the CR/CRi rate was 44.7% (Table). The best uMRD4 rates in peripheral blood were 89.2% (107/120) for all-treated and 98.2% (107/109) for evaluable pts. Among evaluable pts, the uMRD4 rates were 100% (100/100) and 97.1% (68/70) at EoCT and EoT, respectively. Among pts with MRD assessments at both timepoints (N=67), 19.4% had a deepening of their MRD response from EoCT to EoT, and 67.2% maintained the same MRD level (Figure). At a median follow-up of 24.0 mo, 7 deaths (6 related to COVID-19 infection and 1 from cardiac complication after pancreatic mass resection) and no incidences of disease progression were reported;the estimated 18-mo PFS was 94.1%. In pts treated with G vs G+B debulking, respectively, the incidences of Grade ≥3 TEAEs were 71.6% vs 84.6% (most common was neutropenia at 28.4% vs 41.0%) and serious AEs were 23.5% vs 17.9% (most common were pneumonia and COVID-19 pneumonia, each at 3.7% vs 2.6%). Conclusion: In this study, most (91.6%) pts achieved low tumor burden after debulking. The uMRD4 rate was 98.2% among MRD-evaluable pts (89.2% among al pts), with 100% and 97.1% uMRD4 rates at EoCT and EoT, respectively. Overall, these results highlight the utility of G±B as an effective debulking strategy that can facilitate VEN treatment initiation in the outpatient setting. The efficacy and safety results are consistent with other VEN+G trials. Preventive measures for COVID-19 should be continuously emphasized for pts with CLL. [Formula presented] Disclosures: Flinn: AstraZeneca: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding;Merck: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding;Karyopharm Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding;Teva: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding;Janssen: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding;Kite, a Gilead Company: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding;Genentech: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding;Trillium Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding;BeiGene: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding;Novartis: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding;Loxo: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding;Yingli Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute;ArQule: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding;Celgene: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding;Roche: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding;Constellation Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding;AbbVie: Consultancy, Other: All Consultancy and Research Funding payments made to Sarah Cannon Research Institute, Research Funding;Portola Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding;Rhizen Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding;Incyte: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding;Infinity Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding;IGM Biosciences: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding;Forty Seven: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding;Forma Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding;Curis: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding;Verastem: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding;Seagen: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding;Juno Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding;Gilead Sciences: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding;Acerta Pharma: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding;Agios: Other All research funding payments made to Sarah Cannon Research Institute, Research Funding;Calithera Biosciences: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding;Takeda: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding;Pfizer: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding;Iksuda Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute;Unum Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding;TG Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding;Pharmacyclics LLC, an AbbVie Company: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding;MorphoSys: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding;Nurix Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute;Great Point Partners: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute;Triphase Research & Development Corp.: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding;Century Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute;Hutchison MediPharma: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute;Vincerx Pharma: Consultancy, Other: All consultancy payments made to Sarah CannonResearch Institute;Sarah Cannon Research Institute: Current Employment;Servier Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute;Yingli Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute;Seagen: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute;Servier Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute;Unum Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute, Research Funding;Johnson & Johnson: Current holder of individual stocks in a privately-held company;Seattle Genetics: Research Funding. Andorsky: AbbVie: Research Funding;Celgene/Bristol Myers Squibb: Consultancy;Celgene/Bristol Myers Squibb: Research Funding;Epizyme: Research Funding;AstraZeneca: Other: served on steering committees;AbbVie: Consultancy. Melear: TG Therapeutics: Speakers Bureau;Astrazeneca: Speakers Bureau;Janssen: Speakers Bureau. Manda: Morphosys: Honoraria;Genmab: Current equity holder in publicly-traded company. Kolibaba: TG Therapeutics: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company;Atara Biotechm: Consultancy;McKesson Specialty Health: Consultancy;Sunitomo Dainippon Pharma: Consultancy;Tolero Pharma: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES. Yimer: GSK: Speakers Bureau;Beigene: Speakers Bureau;Janssen: Speakers Bureau;Astrazeneca: Speakers Bureau;Karyopharm: Current equity holder in publicly-traded company, Speakers Bureau;Sanofi: Speakers Bureau;Amgen: Speakers Bureau;Pharmacyclics: Speakers Bureau;Texas Oncology: Current Employment. Burke: Kura: Consultancy;Epizyme: Consultancy;Kymera: Consultancy;Adaptive Biotechnologies: Consultancy;Roche/Genentech: Consultancy;Beigene: Consultancy, Speakers Bureau;MorphoSys: Consultancy;Verastem: Consultancy;AstraZeneca: Consultancy;AbbVie: Consultancy;Bristol Myers Squibb: Consultancy;X4 Pharmaceuticals: Consultancy;SeaGen: Consultancy, Speakers Bureau. Fanning: BMS: Speakers Bureau;TG Pharma: Membership on an entity's Board of Directors or advisory committees, Speakers Bur au;Genmab: Membership on an entity's Board of Directors or advisory committees;ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees;Sanofi: Speakers Bureau;Takeda: Speakers Bureau;Genentech: Membership on an entity's Board of Directors or advisory committees. Islas-Ohlmayer: OHC/USON: Current Employment;AbbVie: Honoraria;Rigel: Honoraria, Speakers Bureau. Vizkelety: AbbVie: Current Employment, Current equity holder in publicly-traded company. Pesko: AbbVie: Current Employment, Current equity holder in publicly-traded company. Chyla: AbbVie: Current Employment, Current equity holder in publicly-traded company. Jiang: AbbVie: Current Employment, Current equity holder in publicly-traded company. Sharman: Pharmacyclics LLC, an AbbVie Company: Consultancy;BMS: Consultancy;Lilly: Consultancy;BeiGene: Consultancy;Centessa: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees;AstraZeneca: Consultancy;TG Therapeutics: Consultancy;AbbVie: Consultancy.
ABSTRACT
Background: Bruton tyrosine kinase inhibitors (BTKis) are important tools to treat B-cell malignancies. However, duration of treatment may be limited by adverse events (AEs). Zanubrutinib (zanu) is a BTKi approved for mantle cell lymphoma (MCL) and is in development for other hematologic malignancies. Data from phase 3 head-to-head trials of zanu vs ibrutinib (ibr) in pts with Waldenström macroglobulinemia (WM) or chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) demonstrated that pts treated with zanu showed lower rates of AEs leading to discontinuation (Blood 2020;136(18):2038-50;EHA 2021 LB1900). Preliminary results from BGB-3111-215 (NCT04116437) show that zanu was well-tolerated in pts who discontinued ibr and/or acalabrutinib (acala) treatment due to AEs (EHA 2021 EP642). Here, we report updated results from the BGB-3111-215 study with a median follow-up of 9 months. Methods: This study is an ongoing US, phase 2, multicenter, single-arm, open-label study. The safety and efficacy of zanu monotherapy (160 mg twice daily or 320 mg once daily) were evaluated in pts with B-cell malignancies who met criteria for continued treatment after having become intolerant to prior BTKi therapy. Pts were divided into cohort 1 (pts who were intolerant to ibr only) and cohort 2 (pts who were intolerant to acala alone/and ibr). Pts with documented progressive disease (PD) on prior BTKi therapy were excluded. Efficacy and safety, including recurrence of intolerant AEs to the prior BTKi, were evaluated. AEs were assessed for severity, seriousness, and relation to zanu;as well as dose reductions, holds, or discontinuations. Response was assessed by investigators based on response criteria for their respective indications (Blood 2008;131:2745;J Clin Oncol 2012;30:2820;J Clin Oncol 2014;32:3059;Br J Haemtol 2013;160:171). Disease parameters from study entry were the baseline for response assessment. Mutational analysis was performed on pts who discontinued treatment, and data will be shared once available. To support clinical findings, kinase selectivity was assessed using Kinome profiling at 100X IC50 (against BTK) for zanu, ibr, acala and its major metabolite, M27 (Reaction Biology Corp). Results: As of 7 June 2021 (data cutoff), 57 pts (n=44 CLL/SLL;n=9 WM;n=2 MCL;n=2 marginal zone lymphoma [MZL]) were enrolled in cohort 1, and 7 pts were enrolled in cohort 2 (n=4 CLL;n=1 WM;n=1 MCL;n=1 MZL). All received ≥1 dose of zanu and were analyzed for safety. The median age was 71 years (range, 49-91) in cohort 1 and 71 years (range, 65-76) in cohort 2;median duration of treatment was 8.7 months (range, 0.6-17.9) in cohort 1 and 8.2 months (range, 6.4-11.4) in cohort 2;median number of prior regimens was 1 (range, 1-12) in cohort 1 and 3 (range, 2-5) in cohort 2. Within cohort 2, 5 pts were intolerant to both ibr and acala. Median number of intolerant events per pt for both cohorts 1 and 2 was 2 (range, 1-5). Overall, 73% of pts did not experience recurrence of their ibr or acala intolerant events and 79% of recurrent events recurred at a lower severity (Figure 1). At cutoff, 54 pts remained on treatment. Reasons for treatment discontinuation were AEs (n=4), PD (n=4), physician's decision (n=1), and consent withdrawal (n=1). Grade ≥3 AEs were reported in 18 pts (28%), and serious AEs occurred in 7 pts (11%). AEs requiring dose interruptions occurred in 17 pts (27%), and AEs leading to dose reduction occurred in 3 pts (5%). One death, due to COVID-19, was reported. Pts demonstrated maintained (41%) and improved (53%) response with zanu treatment from their reported best overall response on prior BTKis for a total disease control rate of 94% (including a 42% partial response rate in pts with CLL/SLL, 30% in pts with WM, and a 20% very good partial response rate in pts with WM). Zanu also demonstrated good selectivity by kinase profiling. It showed >50% inhibition on 7/370 kinases, while ibr, acala, and M27 had more off-target binding (17, 15 and 23 kinases, respectively) at their respective 100X IC50 (BTK) c ncentrations (Figure 2). Conclusion: In pts with B-cell malignancies intolerant to ibr and/or acala, zanu treatment resulted in continued disease control or improved response. Zanu was well-tolerated, and most AEs that led to discontinuation of previous BTKi therapy did not recur or recurred at a lower grade. In support of clinical findings, differentiation between BTKi selectivity profiles favor zanu over ibr and acala. [Formula presented] Disclosures: Shadman: Abbvie, Genentech, AstraZeneca, Sound Biologics, Pharmacyclics, Beigene, Bristol Myers Squibb, Morphosys, TG Therapeutics, Innate Pharma, Kite Pharma, Adaptive Biotechnologies, Epizyme, Eli Lilly, and Atara Biotherapeutics, Adaptimmune: Consultancy;Mustang Bio, Celgene, Bristol Myers Squibb, Pharmacyclics, Gilead, Genentech, Abbvie, TG Therapeutics, Beigene, AstraZeneca, Sunesis, Atara Biotherapeutics, GenMab: Research Funding;Abbvie, Genentech, AstraZeneca, Sound Biologics, Pharmacyclics, Beigene, Bristol Myers Squibb, Morphosys, TG Therapeutics, Innate Pharma, Kite Pharma, Adaptive Biotechnologies, Epizyme, Eli Lilly, and Atara Biotherapeutics, Adaptimmune: Membership on an entity's Board of Directors or advisory committees. Flinn: Nurix Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute;Seagen: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding;MorphoSys: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding;Forty Seven: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding;Calithera Biosciences: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding;Verastem: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding;Curis: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding;Takeda: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding;Yingli Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute;IGM Biosciences: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding;AbbVie: Consultancy, Other: All Consultancy and Research Funding payments made to Sarah Cannon Research Institute, Research Funding;Portola Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding;Trillium Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding;Rhizen Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding;Incyte: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding;Acerta Pharma: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding;Agios: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding;Kite, a Gilead Company: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding;Gilead Sciences: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding;Pharmacyclics LLC, an AbbVie Company: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding;Karyopharm Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding;Forma Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding;Genentech: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding;ArQule: Other: All research funding payments mad to Sarah Cannon Research Institute, Research Funding;Triphase Research & Development Corp.: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding;Roche: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding;Pfizer: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding;Teva: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding;Infinity Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding;Unum Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding;Celgene: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding;Constellation Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding;Juno Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding;AstraZeneca: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding;Iksuda Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute;Loxo: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding;Merck: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding;Novartis: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding;Great Point Partners: Consultancy, Other: All consultancy payments made toSarah Cannon Research Institute;BeiGene: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding;Janssen: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding;TG Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding;Century Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute;Hutchison MediPharma: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute;Vincerx Pharma: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute;Sarah Cannon Research Institute: Current Employment;Servier Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute;Yingli Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute;Seagen: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute;Servier Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute;Unum Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute, Research Funding;Johnson & Johnson: Current holder of individual stocks in a privately-held company;Seattle Genetics: Research Funding. Levy: Epizyme: Consultancy, Other: Promotional speaker;Amgen Inc.: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau;Gilead Sciences, Inc.: Consultancy, Honoraria, Speakers Bureau;GSK: Consultancy, Other: Promotional speaker;Morphosys: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau;AbbVie: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau;Beigene: Consultancy, Honoraria, Speakers Bureau;Karyopharm: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau;AstraZeneca: Consultancy, Honoraria, Speakers Bureau;Takeda: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau;Novartis: Consultancy, Other: Promotional speaker;Dova: Consultancy, Other: Promotional speaker;TG Therapeutics: Co sultancy, Honoraria, Speakers Bureau;Bristol Myers Squibb: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau;Seattle Genetics: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau;Jazz Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau;Janssen Pharmaceuticals: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau. Burke: SeaGen: Consultancy, Speakers Bureau;Beigene: Consultancy, Speakers Bureau;MorphoSys: Consultancy;Bristol Myers Squibb: Consultancy;AstraZeneca: Consultancy;Epizyme: Consultancy;Verastem: Consultancy;Kura: Consultancy;Kymera: Consultancy;AbbVie: Consultancy;Adaptive Biotechnologies: Consultancy;Roche/Genentech: Consultancy;X4 Pharmaceuticals: Consultancy. Cultrera: Beigene: Research Funding. Yimer: Astrazeneca: Speakers Bureau;Karyopharm: Current equity holder in publicly-traded company, Speakers Bureau;Janssen: Speakers Bureau;Beigene: Speakers Bureau;GSK: Speakers Bureau;Sanofi: Speakers Bureau;Amgen: Speakers Bureau;Pharmacyclics: Speakers Bureau;Texas Oncology: Current Employment. Chaudhry: Medical Oncology Associates, PS (dba Summit Cancer Centers): Current Employment;Novartis, Immunomedics: Current holder of individual stocks in a privately-held company. Gandhi: TG Therapeutics: Honoraria;Karyopharm Therapeutics: Honoraria;GlaxoSmithKline: Honoraria. Kingsley: Comprehensive Cancer Centers of Nevada: Current Employment. Tumula: Texas Oncology: Current Employment. Manda: Morphosys: Honoraria;Genmab: Current equity holder in publicly-traded company. Chen: BeiGene: Current Employment, Divested equity in a private or publicly-traded company in the past 24 months. Cohen: BeiGene: Current Employment, Current equity holder in publicly-traded company, Other: Travel, Accommodations, Expenses. By: BeiGene, Ltd: Current Employment. Xu: Beigene: Current Employment;AstraZeneca: Ended employment in the past 24 months. Liu: BeiGene Co., Ltd: Current Employment, Current equity holder in publicly-traded company. Sharman: TG Therapeutics: Consultancy;Centessa: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees;Pharmacyclics LLC, an AbbVie Company: Consultancy;BMS: Consultancy;AbbVie: Consultancy;BeiGene: Consultancy;AstraZeneca: Consultancy;Lilly: Consultancy.
ABSTRACT
Introduction: Patients with lymphoma and chronic lymphocytic leukemia (CLL) share immune-deficiencies due to the biological features of these diseases per se and to their treatments. They are at risk to develop severe and/or prolonged forms of Covid-19. The efficacy of vaccination against COVID in lymphoma/CLL patients also raises specific concerns: Antibody response to mRNA COVID-19 vaccine was shown to be negatively affected by CLL stage and its treatments, especially in case of previous administration of anti-CD20 antibodies (Herishanu et al). Therefore, the addition of a third dose of vaccine in immunosuppressed patients is currently recommended in France. Methods: To analyse the determinants of the antibody response after anti-SARS-Cov2 mRNA vaccines (Pfizer or Moderna), we conducted a retrospective monocentric study among adults with a past or current lymphoma/CLL who underwent serology 2 weeks or more after 2 or 3 previous injections. The decision of a third dose was at the discretion of each physician. Data were extracted from the patients' medical charts on their demographics, lymphoma history and detailed treatments, vaccinations and biological parameters (immunoglobulin (Ig) G dosage, lymphocytic, B-cell and T-cell counts) and serology (Elecsys ® Anti-SARS-CoV-2 S). Statistical tests were two-tailed and p-values < 0.05 were considered significant. Multivariable analysis was conducted using independent variables having univariate significance below 0.1. This study was conducted in accordance with the Declaration of Helsinki, and approved by the ethics committee of our institution. Results: Ninety-one patients with non-Hodgkin's lymphomas (NHL) (n=48), CLL (32) or Hodgkin's lymphoma (11) were enrolled. With a median interval since last dose of 47 days (range 15-125), 48 patients (53%) had a negative serology (Table). Gender and age were not associated with antibody response. The proportion of seronegativity was 57% among patients with B-cell NHL, and 41% among those with CLL. Among the biological variables reflecting immune deficiency, lymphocytopenia (<1.5G/L), low B-cell counts (<0.2G/L) and IgG levels (<6g/L) were significantly associated with a higher risk of seronegativity with odds-ratios (OR, [95% confidence interval]) of 5.1 [1.8-15.3], p<7x10 -4, 15.0 [3.0-147.9], p<7x10 -5, and 15.3 [3.7-93.0], p<9x10 ⁻6 respectively). Patients under watch and wait attitude and those who did not have a lymphoma/CLL treatment since at least 12 months before vaccination had a much lower risk of negative serology (OR: 0.08 [<0.01;0.4], p< 2.10 -4). Among lymphoma/CLL therapies, chemotherapy overall or targeted therapy with BTK inhibitors or Venetoclax were not significantly associated with a lower risk of negative serology. In contrast, the administration of anti-CD20 therapy during the year before first dose of vaccine was associated with a higher risk of negative serology (OR: 4.5 [1.7;12.1], p<8.10 -4). Of note, this treatment was also significantly associated with both lymphocytopenia and low B-cell counts. There was no association between the number of vaccine doses and the risk of negative serology, 59% of the patients who received 3 doses remained seronegative.A multivariable analysis associating IgG level and treatment history showed that negative serology is significantly associated with a low level of IgG (OR: 25.74 [5.58;201.14], p < 10 -3) and anti-CD20 treatment (OR: 28.70 [4.14, 382.60], p = 3x10 -3). Conclusion: Overall, previous anti-CD20 therapy and low IgG levels are the main independent factors associated with a lack of serological response after anti-SARS-Cov2 mRNA vaccine. Administration of a third vaccine does not overcome their pejorative impact. This should contribute to the elaboration of guidelines for the management of lymphoma/CLL patients during the Covid-19 era. In particular, in all non-critical clinical situation, SARS-CoV-2 vaccination should be proposed before the onset of lymphoma/CLL therapy. Meanwhile, individuals with CLL/lymphoma should receive the Covid-19 vaccine, be in ormed that they are unlikely to be protected and continue social distancing and adhere to other proven mitigation strategies. Systematic vaccination of their proxies and hospital workers should also benefit directly to patients. [Formula presented] Disclosures: Rigaudeau: Takeda: Membership on an entity's Board of Directors or advisory committees.
ABSTRACT
Updated analysis confirms sustained poor prognosis of COVID-19 in patients with lymphoma in Latin America: A cohort of 160 patients from GELL. Introduction: Ongoing SARS-COV-2 pandemic has impacted the management of cancer patients worldwide. Several reports have demonstrated inferior outcomes of patients with hematological malignancies, including higher rates of intensive care unit admission, need for mechanical ventilation and death. The impact of COVID-19 is profound in resource-restricted countries, including Latin America. Most cohorts reported have not included patients from Latin America, and there is paucity of data of the outcome of cancer patients with COVID-19 in low- and middle-income countries. Grupo de Estudio De Linfoproliferativos En Latino-America (GELL )is a collaborative network of hematological centers in 13 countries in Latin America. We report updated outcomes of lymphoma patients diagnosed with COVID-19 in Latin America. Methods: We conducted a retrospective study including patients with a diagnosis of lymphoma and COVID-19 infection. Patients with chronic lymphocytic leukemia/small lymphocytic lymphoma were excluded from the analysis We defined active disease as follow: (1) patients with detectable disease either prior to initiating therapy or upon relapse, and/or (2) patients undergoing active cancer treatment. The primary outcome was overall survival at 100 days. Survival curves were estimated using the Kaplan Meier method. Uni and multivariable analysis were carried out with Cox model. Results: A total of 160 patients were available for analysis. Median age was 60 years old. Hypertension was the most common comorbidity (33%). Most patients had aggressive lymphomas (62%), including 43% of patients with diffuse large B-Cell lymphoma (DLBCL). Follicular lymphomas were observed in 13% of patients and Hodgkin lymphoma in 12.5% of patients. With a median follow-up of 37 days, the 100-day OS was 64% (95CI 56-74%, fig. 1). In univariate analysis, age (HR 1.03, p=0.0025), hypertension (HR 2.01, p=0.017), >1 number of prior lines (HR 2.78, p=0.011), patients currently on treatment (HR 1.83, p=0.043), ferritin >2000 ng/mL (HR 4.74 p=0.00047) were associated with inferior OS. In multivariate analysis, age (HR 1.03, p=0.0026) and patients currently on treatment (HR 1.82, p=0.04) had inferior OS. There was a trend towards inferior outcomes in patients receiving monoclonal antibodies in univariate analysis (HR 1.82, p=0.081) but not in multivariable analysis (HR=1.29, p=0.48). Use of steroids was not statistically related to mortality (HR 1.79, p=0.074). Finally, contrary to other cohorts, no improvement in OS was observed in patients diagnosed later on the pandemic (fig. 2). Conclusion: In this large cohort of Latin American patients with lymphoma malignancies, our updated analysis showed a maintained dismal prognosis with COVID-19 infection. With a median follow up of 37 days, the 100-day OS was 64%. Older age and ongoing active cancer treatment were significantly associated with mortality. The use of monoclonal antibodies and systemic corticosteroids were not statistically associated to poor survival. Current efforts are focused on improving immunization in the Latin American population. There is an unmet need for improving survival in patients with hematologic malignancies and COVID-19 infection. [Formula presented] Disclosures: Perini: Janssen: Honoraria, Speakers Bureau;Takeda: Honoraria, Speakers Bureau;Astra Zeneca: Honoraria, Speakers Bureau;MSD: Honoraria, Speakers Bureau. Otero: ASTRA ZENECA: Current Employment. Abello: Dr Reddy's: Research Funding;Amgen: Honoraria;Janssen: Honoraria. Castillo: Abbvie: Consultancy, Research Funding;BeiGene: Consultancy, Research Funding;Pharmacyclics: Consultancy, Research Funding;Janssen: Consultancy;Roche: Consultancy;TG Therapeutics: Research Funding.