Risk Factors Associated with the Development of Infusion-Related Reactions in Patients with Chronic Lymphocytic Leukaemia Treated with Anti-CD20 Monoclonal Antibodies: Analysis of the CLL11 Study Dataset

Abstract Background: The administration of anti-CD20 monoclonal antibodies (mAb) in patients with B-cell lympho-proliferative disorders is frequently accompanied by a constellation of signs and symptoms that have been labelled as infusion-related reactions (IRR). The pathophysiology of IRR remains poorly understood as do predictors of risk, which may relate to the mechanism of action of the anti-CD20, disease-related factors such as tumour burden or host factors such as polymorphisms of Fc gamma receptor 3A (FcγRIIIA). In the CLL11 trial (NCT01010061), patients with previously untreated chronic lymphocytic leukaemia and comorbidities were randomised to receive either rituximab (type I anti-CD20 mAb) or obinutuzumab (type II and glycoengineered anti-CD20 mAb) in combination with chlorambucil for six cycles. Obinutuzumab led to faster depletion of B cells and achieved an improvement in outcome parameters such as response and progression-free survival compared with the rituximab arm, but was also associated with a higher rate and increased severity of IRR. To better understand the profile of risk for IRR in patients with CLL, we performed an exploratory analysis on data obtained from patients treated with either one of the two antibodies given in combination with chlorambucil. Methods: Patients from the prospective, randomized Phase III CLL11 study who received a first infusion of obinutuzumab (N=331) or rituximab (N=326) were included. Baseline pre-treatment risk factors thought to play a possible role in the development of IRR were identified a priori and included patient demographics, concurrent conditions and premedications, parameters of disease burden, prognostic factors, laboratory variables and FcγR genotype. Baseline values for mean fluorescence intensity (MFI) of CD20, gated on the circulating CLL clone, and MFI of CD16, gated on the natural killer (NK) cell population (CD56+16+) in peripheral blood were also available for N=510 patients. The primary outcome, development of an IRR with the first infusion, was defined as the occurrence of related signs and symptoms during or within 24 hours of administration of antibody. Due to the short-term nature of the initial IRR a multivariate logistical regression analysis was performed rather than a time to event analysis. Internal validation of this model, derived from a single dataset, was conducted using the established resampling technique of bootstrapping. This assessed the proportion of times each variable retained significance at α=0.10 when the model was fitted to bootstrapped samples of the dataset. Results: Patients that appeared to be at greater risk of developing any grade of IRR with the first infusion of rituximab or obinutuzumab were those treated with obinutuzumab, those with higher surface expression CD20 on CLL cells (MFI CD20) and greater FcγRIIIA (MFI CD16) on NK cells in peripheral blood, those with higher affinity FcγRIIIA genotype (VV), more pronounced neutropenia and splenomegaly at baseline (Table 1). Higher baseline absolute lymphocyte count and the presence of respiratory comorbidity also appeared to increase risk. All variables significant for inclusion in the model are shown in Table 1. Looking at those patients treated with obinutuzumab only, the most important determinant of risk was MFI CD20 (OR 3.6 95% CI 1.6-7.9). The impact of glucocorticoid premedication in reducing risk in obinutuzumab treated patients was not sufficient to reach significance, however, patients were not randomised to this intervention. Conclusion: This work identifies novel disease- and patient-specific biological variables that appear to play a role in the development of IRR in patients with CLL treated with anti-CD20 mAb, although the treatment received (obinutuzumab >rituximab) confers greatest risk. In addition to parameters of tumour burden, target antigen expression and gene polymorphisms of FcγR also appear to contribute to the risk of developing an IRR. Our results support the hypothesis that higher rates of IRR seen with the administration of obinutuzumab may result from stronger activation upon binding to CD20 on leukemic cells and subsequent enhanced cross-linking between CD20 expressing leukemic cells and FcγRIIIA bearing effector cells. Further studies involving obinutuzumab in this patient population will be needed to externally validate the results of this exploratory analysis. Disclosures Freeman: Roche Pharmaceuticals: clinical research fellowship supported by Roche Pharmaceuticals (secondment from Bart's) Other. Dixon:Roche Pharmaceuticals: Employment. Houghton:Roche Pharmaceuticals: Employment. Humphrey:Roche: Employment. Fingerle-Rowson:Roche Pharmaceuticals: Employment. Kreuzer:Roche Pharmaceuticals: Research Funding. Engelke:Roche: Travel grants Other. Hallek:Roche Pharmaceuticals: Consultancy, Research Funding, Speakers Bureau. Goede:Bristol Myers Squibb: Honoraria; Mundipharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Travel grants Other.

Download Full-text

Prolonged Lymphopenia and Infection Risk Is Mitigated By Antimicrobial Prophylaxis in Patients with Indolent Non-Hodgkin Lymphoma (iNHL) Treated with Bendamustine +/- Anti-CD20 Antibody: The Australasian Lymphoma Alliance Experience

Blood ◽

10.1182/blood-2020-138642 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 47-49

Author(s):

Kate Manos ◽

Masa Lasica ◽

Andrew Grigg ◽

Pietro R Di Ciaccio ◽

Jonathan Wong ◽

...

Keyword(s):

Risk Factors ◽

Board Of Directors ◽

Research Funding ◽

Antimicrobial Prophylaxis ◽

Advisory Committees ◽

Cd20 Antibody ◽

Grade 3 ◽

Anti Cd20 ◽

The Relationship

Background: Bendamustine +/- anti-CD20 antibody is a highly effective regimen for iNHL. Though initially favoured for its toxicity profile, subsequent analyses demonstrate profound and prolonged lymphopenia and the landmark phase III GALLIUM study showed a grade 3-5 infection rate of 20-26% in the bendamustine arms (Hiddemann JCO 2018). The relationship between severity and duration of lymphopenia and infection, and the role of antimicrobial prophylaxis (ppx), are not fully characterised. We performed a multicentre, retrospective analysis of bendamustine-treated iNHL patients (pts) to define the type and onset of infections, identify concomitant risk factors and evaluate the role of ppx. Methods: iNHL pts aged ≥18 yrs, treated with bendamustine +/- anti-CD20 in 1st-3rd line from 2011-2019, were identified from 9 Australian centres. HIV, prior transplant and long-term immunosuppression were excluded. Demographics, treatment, lymphocyte counts, infections and ppx were collected from baseline to 24 months post end of bendamustine treatment (EOT) or subsequent lymphoma therapy. Association between potential risk factors and infection was evaluated by logistic regression (odds ratio, OR) and negative binomial regression (incidence rate ratio, IRR) with Stata 16.1. Results: 302 pts were eligible. Baseline and treatment characteristics are summarised in Table 1. 252 infection episodes occurred across 134 pts (44%), equally divided between during therapy and after EOT (Figure 1A, Table 2). Infections on treatment occurred in 30% of pts (n=92) with 18% hospitalised (n = 54; n = 20 with febrile neutropenia (FN)) and dose delay /modification/ discontinuation in 11%. Late infections post EOT occurred in 23% of pts (n=70) with 11% hospitalised (n = 32; n = 12 with FN); infection post EOT was more common in pts on maintenance anti-CD20 (infection rate 49% v 16%, OR 5.1 p<0.001). Opportunistic infections (OI) occurred in 21 pts: VZV (n=9; 4 on treatment, 5 post EOT, 1 on ppx); HSV (n=5, all on treatment without ppx); PJP (n=1, on treatment without ppx); nocardiosis (n=1, on treatment); other fungal infections (n=3, all on treatment); PML (n=1, 1-yr post EOT); CMV (n=1, at EOT). Lymphopenia was near universal and prolonged; 98% of pts became lymphopenic (53% grade 3, 9% grade 4) with a median nadir of 0.4x109/L (range 0-2.3). Median time to recovery (>1x109/L) was 10 months post EOT; 39% of pts remained lymphopenic (4% grade 3/4) at 2 yrs (Figure 1B). However, neither lymphopenia nadir nor duration correlated with infection post EOT (OR 0.53 p=0.26 and 0.97 p=0.29 respectively) and the relationship between lymphocyte nadir and OI was not significant (OR 0.09 p=0.053). VZV/HSV and PJP ppx were prescribed to 42% and 54% respectively during treatment and continued for a median of 3 months post EOT (range 0-27, cessation date unknown in 60%). PJP ppx (sulfamethoxazole/trimethoprim) was associated with fewer bacterial infections (OR 0.44 p=0.003) but did not reduce the incidence of FN (OR 0.83 p=0.63). Antiviral ppx (aciclovir/valaciclovir) was associated with fewer VZV/HSV infections (OR 0.10 p=0.026). More ppx was prescribed in 2018-2019 (post GALLIUM) than 2011-2017 (PCP ppx - OR 5.19 p<0.001; VZV ppx - OR 3.76 p<0.001; Figure 2) with an associated fall in the number of infections per pt (IRR 0.55, p=0.011). Factors independently associated with an increased number of infections (during and post EOT) were obinutuzumab vs rituximab (IRR 2.76, p<0.001), maintenance anti-CD20 (IRR 3.43 p<0.001), and stage III/IV disease (IRR 2.55, p=0.002). Factors specifically associated with infection post EOT were maintenance (OR 5.10 p<0.001) and obinutuzumab (OR 3.51 p=0.001). ECOG, hypogammaglobulinaemia, comorbidity index, treatment line and disease subtype were not associated with infections during or post treatment. Conclusion: iNHL pts receiving bendamustine are at high risk of prolonged lymphopenia and infectious complications extending beyond treatment completion, with half of infections occurring post treatment cessation. Lymphopenia duration and nadir did not correlate with infection. PJP and antiviral ppx reduced risk of bacterial and VZV/HSV infections respectively, though rates of PJP and VZV/HSV were low. Prolonged ppx to mitigate the risk of late infections should be considered, particularly in pts with additional risk factors such as concomitant obinutuzumab and anti-CD20 maintenance. Disclosures Manos: Bristol-Myers Squibb: Other: Travel. Di Ciaccio:Jansen: Honoraria, Other: travel and accomodation grant. Hamad:Abbvie: Honoraria; Novartis: Honoraria. Gregory:Janssen: Consultancy; F. Hoffmann-La Roche, Genentech, Inc., MSD, AbbVie, BeiGene, AstraZeneca, Celgene, BMS: Research Funding; F. Hoffmann-La Roche, Novartis, Sandoz, Gilead, AbbVie, MSD: Honoraria; F. Hoffmann-La Roche, Novartis, AbbVie: Speakers Bureau; F. Hoffmann-La Roche, Novartis, Sandoz, Gilead: Membership on an entity's Board of Directors or advisory committees. Gangatharan:Roche: Other: Travel grant. Hawkes:Merck Sharpe &Dohme: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Research Funding, Speakers Bureau; BMS celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck KgA: Research Funding; takeda: Speakers Bureau.

Download Full-text

Clinical and Biomarker Predictors for Avascular Necrosis in Sickle Cell Disease

Blood ◽

10.1182/blood-2021-147829 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3091-3091

Author(s):

Michael Rabaza ◽

Maria Armila Ruiz ◽

Liana Posch ◽

Faiz Ahmed Hussain ◽

Franklin Njoku ◽

...

Keyword(s):

Risk Factors ◽

Sickle Cell Disease ◽

Board Of Directors ◽

Avascular Necrosis ◽

Sickle Cell ◽

Research Funding ◽

Medical Attention ◽

Cell Disease ◽

Advisory Committees ◽

Early Management

Abstract Introduction Sickle cell disease (SCD) affects 1 in 365 African Americans and approximately 25 million people world-wide. A common skeletal system complication is avascular necrosis (AVN), which can cause substantial pain and a reduced quality of life. While early management of AVN is focused on increasing range of motion with physical therapy and pain relief, there are no clear predictors for who is more likely to develop AVN and earlier institution of these preventive measure could help decrease disease progression. Vascular endothelial growth factor (VEGF) is a biomarker of endothelial injury and may indicate reduced vascular supply to the femoral or humeral head. Here we describe potential risk factors and biologic pathways for AVN in SCD, as understanding these may lead to improvements in future monitoring, early detection, and early intervention practices. Methods We investigated clinical and laboratory risk factors associated with AVN in a cohort of 435 SCD patients from our center. Blood samples, clinical, and laboratory data were collected at the time of enrollment during a clinic visit. Genotyping for alpha thalassemia was performed by PCR and the serum concentration of VEGF was measured by ELISA. AVN status was confirmed by review of the medical record and available imaging. We conducted a cross-sectional analysis comparing categorical and linear variables by AVN status using the chi-square and Kruskal-Wallis test, respectively. The independent association of the clinical and laboratory variables with AVN status was determined by logistic regression analysis. The initial model included variables with a P-value < 0.1 on univariate analysis and the final model was ascertained by stepwise forward and backward selection. Median values and interquartile range (IQR) are provided. Results The median age of the cohort was 32 (IQR, 24 - 43) years, 57% (250/435) were female, and 46% (198/435) were on hydroxyurea. AVN was observed in 34% (149/435) of SCD patients. SCD patients with AVN were older, had more frequent vaso-occlusive crises requiring medical attention, and had a higher body mass index (Table I) (P ≤ 0.002). We measured VEGF in 241 of the SCD patients with serum samples available at the time of enrolment. Serum VEGF concentrations trended higher in SCD patients with versus without AVN (420 vs. 359 pg/mL, respectively; P = 0.078). In the multivariate analysis model, AVN was independently associated with increased number of vaso-occlusive crises (OR 1.1, 95% CI: 1.0 - 1.14; P = 0.02), AST concentration (natural log OR 0.5, 95% CI: 0.2 - 0.9; P = 0.03), VEGF concentration (natural log OR 1.4, 95% CI: 1.0 - 1.9; P = 0.047), and tobacco use (OR 1.9, 95% CI: 0.9 - 3.7; P = 0.078). Discussion In conclusion, we demonstrate a high prevalence of AVN in an adult cohort of SCD patients. The presence of AVN was independently associated with a greater frequency of vaso-occlusive pain episodes, which may demonstrate a shared pathophysiology between AVN and vaso-occlusion that merits further investigation. We demonstrate that serum VEGF concentrations are higher in SCD patients with AVN and may be a clinical tool to identify those at high-risk and for earlier intervention for this complication. Figure 1 Figure 1. Disclosures Gordeuk: Modus Therapeutics: Consultancy; Novartis: Research Funding; Incyte: Research Funding; Emmaus: Consultancy, Research Funding; Global Blood Therapeutics: Consultancy, Research Funding; CSL Behring: Consultancy. Saraf: Pfizer: Research Funding; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Download Full-text

3G8 and GMA161, Anti FcγRIII Inhibitory Monoclonal Antibodies in the Treatment of Chronic Refractory ITP. (Summary of 2 Pilot Studies).

Blood ◽

10.1182/blood.v114.22.2404.2404 ◽

2009 ◽

Vol 114 (22) ◽

pp. 2404-2404 ◽

Cited By ~ 8

Author(s):

Charles T Nakar ◽

James B. Bussel

Keyword(s):

Monoclonal Antibodies ◽

Board Of Directors ◽

Research Funding ◽

Therapeutic Modality ◽

Fab Fragment ◽

Advisory Committees ◽

Pilot Studies ◽

Heavily Pretreated ◽

Moderate Nausea ◽

Refractory Itp

Abstract Abstract 2404 Poster Board II-381 Immune thrombocytopenia (ITP) is mediated by anti-platelet antibodies causing accelerated destruction and impaired production of platelets (PLTs). The clearance of IgG- coated PLTs is by Fcγ receptor- bearing macrophages in the spleen and liver. Patients (pts) with ITP, who despite splenectomy maintain low PLT counts, exhibit significant morbidity and mortality. For these pts inhibition of the mononuclear phagocytic system was targeted as a therapeutic modality. The clinical and immunological results of 15 pts treated with mouse and humanized versions of anti FcγRIII (anti-CD16) inhibitory monoclonal antibodies (mAbs), 3G8 and GMA161, are reported here. Pts were adults with chronic refractory ITP. Baseline PLT counts were <20K/ul and <30K/ul for pts treated with 3G8 and GMA16 respectively, and all had significant bleeding histories. All pts had limited or no response to splenectomy, steroids, IVIG and multiple other treatments. 3G8, a mouse mAb was infused at an initial dose of 25mg (0.25–0.5mg/kg). Subsequent infusions of 50mg on day 3-4 and 75mg on day 6-7 were administered if no response was seen. Two pts treated with Fab fragment of 3G8 with no response received a single infusion of 25mg of intact 3G8 on day 7-8. GMA161 is a humanized version of 3G8 which also has the Fc piece denuded of carbohydrates. In the 1st 4 pts, it was infused once at 0.1mg/kg. Response was defined as a PLT increase >20K. 6/11 (55%) pts treated with 25mg of 3G8 responded. The mean peak PLT increase was 93K for all 11 pts and 160K for the 6 responders (median PLT increases were 32 and 147, respectively). The peak PLT count was seen on day 3 and was significantly above baseline on days 1-6 in responders and remained above baseline for a median of 14 days following the initial treatment. Three responders were treated again. 2/3 pts had high HAMA titers and failed to respond. Two pts (a responder and a non-responder) were treated again 4 years later, after their HAMA titer had decreased to almost baseline. Both had short-lived PLT responses >30K after re-challenge. Two pts remained stable for more than 3 years; one after receiving a 2nd infusion 4 years following the first, and the second after 3 infusions of 3G8 at 3-month intervals. There was marked transient neutropenia and decrease in NK cells activity following infusion in all pts. Pts developed significant fever-chill-vomiting reactions. Prevention required a cocktail of methylprednisolone, diphenhydramine, acetaminophen and metaclopramide. One patient who suffered from significant pre-existing pulmonary disease including heart failure, bronchopneumonia and (silent) lung cancer, developed ARDS at the time of the second 3G8 infusion and unfortunately died the following day. Another patient developed GI bleeding following a methylprednisolone infusion. No abnormalities in liver, renal function tests or coagulation studies were detected. 2/4 pts treated with GMA161 responded with peak PLT counts of 108K/ul and 45K/ul. The responses to GMA161 were short-lived, lasting between 7 and 10 days. A dramatic, transient decrease in the WBC was seen with GMA161 as with 3G8. The first patient had marked chills, fever, and vomiting 2 hours after infusion which resolved with methylprednisolone. The second patient had mild-moderate nausea. The third and fourth patients received acetaminophen, diphenhydramine and ondansetron premedication and had no adverse events. Six additional patients were treated; their data is being analyzed. FcγRIII is the primary receptor implicated in the destruction of immune complexes. 3G8 an anti FcγRIII blocking antibody resulted in dramatic but transient responses in approximately 50% of heavily-pretreated, very refractory ITP pts. Certain pts did not respond which may be due to decreased PLT production or the use of other FcγR's to achieve PLT phagocytosis. However acute reactions occurred and infusions could not be repeated because of HAMA so GMA161 was created to overcome both of these issues via humanizing the antibody and denuding the Fc piece of carbohydrates. Unfortunately this was not an entirely successful approach; complete results are being collated. In summary, the redundancy of the FcγR system may limit the utility of blocking specific FcγR's; alternatively impaired PLT production may be of paramount importance in refractory patients. Disclosures: Off Label Use: 3G8 and GMA161 are Anti FcγRIII Inhibitory Monoclonal Antibodies used to treat refractory patients. The abstract presents the results of two pilot trials. . Bussel:Immunomedics: Research Funding; Sysmex: Research Funding; Cangene: Research Funding; Scienta: Speakers Bureau; Genzyme: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, My family owns stocks, Research Funding; Shionogi: Membership on an entity's Board of Directors or advisory committees; Ligand: Membership on an entity's Board of Directors or advisory committees, Research Funding; Eisai: Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees, My family owns stocks, Research Funding; Inc: Research Funding.

Download Full-text

IGHV Unmutated Chronic Lymphocytic Leukemia (CLL) B Cells Are More Susceptible to Spontaneous Apoptosis Than Mutated CLL B Cells and Are Subject to the Anti-Apoptotic Effect of Environmental Signals

Blood ◽

10.1182/blood.v116.21.2431.2431 ◽

2010 ◽

Vol 116 (21) ◽

pp. 2431-2431

Author(s):

Marta Coscia ◽

Francesca Pantaleoni ◽

Chiara Riganti ◽

Candida Vitale ◽

Micol Rigoni ◽

...

Keyword(s):

T Cells ◽

B Cells ◽

Board Of Directors ◽

Stromal Cells ◽

Peripheral Blood ◽

Research Funding ◽

Lymphocytic Leukemia ◽

Leukemic Cells ◽

Spontaneous Apoptosis ◽

Advisory Committees

Abstract Abstract 2431 Chronic lymphocytic leukemia (CLL) is a clinically heterogeneous disease. A very reliable prognosticator is the mutational status of the tumor immunoglobulin heavy chain variable region (IGHV): patients with unmutated (UM) IGHV have a worse prognosis than patients with mutated (M) IGHV. Soluble factors (i.e. IL-4 and CD40L) and cellular components of the local microenvironment [i.e. bone marrow stromal cells (BMSC) and nurse-like cells (NLCs)] are important survival factors for CLL B cells. It is currently unknown to what extent UM and M CLL cells depend on the local microenvironment for their survival. We have evaluated the spontaneous apoptotic rate of tumor cells isolated by immunomagnetic selection from the peripheral blood (PB) of M and UM CLL patients. Both M and UM CLL B cells underwent spontaneous apoptosis throughout the culture period. However, the UM CLL B cells showed a significantly higher degree of apoptosis in 7-day cultures as compared to M CLL B cells. In both M and UM CLL B cells, high basal levels of Bcl-2 expression and NF-kB activity were detected. On day 7, the percentage of Bcl-2+ leukemic cells was significantly lower in UM than in M CLL B cells. EMSA test showed that NF-kB was totally inactivated in UM CLL B cells and only partially reduced in M CLL B cells. Quantitative analysis of RelA and RelB subunits showed that NF-kB inactivation in UM CLL B cells consisted in a strong reduction of both RelA and RelB nuclear expression. CD40L, IL-4 and stromal cells significantly improved UM CLL B cells viability and significantly recovered Bcl-2 expression. The protective effect exerted by these stimuli was totally independent from the recovery of NF-kB expression. Indeed, after 7 days of culture, the UM CLL B cells had completely lost the nuclear form of NF-kB, and none of the stimuli was capable of restoring it. We observed that UM CLL cells were less susceptible to spontaneous apoptosis when cultured as unfractionated peripheral blood mononuclear cells (M or UM PBMC) as compared to purified leukemic cells (M and UM CLL B cells). The reduced apoptosis detected in UM PBMC was accompanied by a retained expression of Bcl-2 and by a restored activity of NF-kB and suggested the presence of a pro-survival element in the peripheral blood of these patients. To investigate the role of NLC in rescuing UM CLL B cells from apoptosis we first evaluated whether M and UM PBMC generated NLC with the same efficiency. Unexpectedly, the former generated significantly higher numbers of NLC than UM PBMC. Despite the lack of generation of NLC, CLL B cells viability was very similar in the non-adherent fraction of M and UM PBMC on day 7 and 14 of culture. This observation ruled out a role for NLC in supporting UM CLL B cells survival. Conversely, a pro-survival effect on UM CLL B cells was exerted by autologous T cells. Indeed, a significant reduction in the apoptotic rate of leukemic cells was observed when purified UM CLL B cells were cultured in the presence of autologous peripheral blood T cells (UM CLL B cell/T cell co-cultures). NF-kB activity was completely lost in UM CLL B cells cultured for 7 days in medium alone whereas it was restored in UM CLL B cells / T cells co-cultures. The prosurvival effect of circulating T cells was exerted both in cell-to-cell contact and in trans-well condition and was associated to increased secretions of tumor necrosis factor-alpha (TNF-α), platelet-derived growth factor (PDGF)-BB and interleukin-8 (IL-8) as detected by analyses of supernatants through a Multiplex system. These data indicate that despite their more aggressive features, UM CLL B cells are more susceptible to spontaneous apoptosis and depend from environmental prosurvival signals. This vulnerability of UM CLL B cells can be exploited as a selective target of therapeutic interventions. Disclosures: Boccadoro: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Massaia: Novartis: Honoraria, Research Funding.

Download Full-text

Hypercholesterolemia In Imatinib Intolerant/Resistant CML-CP Patients Treated With Nilotinib: A Retrospective Analysis

Blood ◽

10.1182/blood.v122.21.1503.1503 ◽

2013 ◽

Vol 122 (21) ◽

pp. 1503-1503 ◽

Cited By ~ 9

Author(s):

Devendra K. Hiwase ◽

David T Yeung ◽

Lisa Carne ◽

David Ross ◽

Andrew Grigg ◽

...

Keyword(s):

Risk Factors ◽

Lipid Profile ◽

Retrospective Analysis ◽

Board Of Directors ◽

Research Funding ◽

Lipid Profiles ◽

Cvd Risk Factors ◽

Cvd Risk ◽

Advisory Committees ◽

Before And After

Abstract Background CML patients (pts) enjoy prolonged leukaemia-free survival with tyrosine kinase inhibitor (TKI) treatment. Addressing common non-CML causes of morbidity and mortality such as cardiovascular disease (CVD) and its associated risk factors is therefore increasingly important. Anecdotal evidence suggests a possible association between nilotinib (NIL) therapy and vascular events though there is little good quality evidence in this regard. The incidence of hyperlipidaemia and hyperglycaemia is higher in NIL-treated pts compared to imatinib- (IM) treated pts; conversely IM treatment may retard development of dyslipidaemia and hyperglycaemia. This retrospective analysis assessed the lipid profile of CML-CP pts before and after changing from IM to NIL therapy. Method Plasma lipid profile (total cholesterol, LDL, HDL and triglycerides), TKI exposure, and CVD risk factors before and after switchover to NIL of chronic phase CML pts were analysed. Baseline measurements were done during IM treatment or within 2 weeks of changing from IM to NIL. Follow-up results were obtained at least 1 month after starting NIL. Results Thirty-one CML pts were switched to NIL (median dose 400mg bd) after a median of 27 (1-96) months of IM therapy, predominantly for intolerance (16/31, 52%) or for failure to achieve deep molecular responses (13/31, 42%). Median age at NIL start was 51 (17-80) years (Table I). After switching to NIL, three pts had new onset PVD/IHD and one patient had multiple recurrences of PVD. Antihypertensive and hypoglycaemic medications were started in one additional patient each after switching over to NIL. Three pts were excluded from further analysis because of lack of data (n=2) or pre-existing dyslipidemia (n=1). The remaining pts had 90 TC assays, 72 of which were full lipid profiles whilst on NIL. Observations were censored at the time of statin commencement. Median time to 1st lipid measurement on NIL was 108 days (28-633) after switching. Median TC on IM was 4.7mM (2.1-6.4), compared to 6.1mM on NIL (3.1-8.5). Median peak TC on NIL was 6.8mM. Full fasting lipid profiles available for 11 pts before and after switching showed significantly increased LDL to be the major contributor to the increase in TC (Fig. 2). Thirteen pts had a fasting TC >5.5 mM (210 mg/dL) whilst on NIL, peaking at 312 days (medians). Eight of 13 pts started statins treatment for dyslipidemia whilst on NIL; (all retrospectively confirmed to be appropriate according to Australian National Heart Foundation guidelines, using a composite measure of CVD risk); whilst the other 5 were offered lifestyle modifications only. Of note, 2 pts had dyslipidaemia prior to starting IM treatment, discontinued statins whilst on IM, and had recurrence of dyslipidaemia after switching to NIL necessitating resumption of statin treatment. In addition, the 2 pts with PVD were also offered statins (total starting statin n=10) Discussion This retrospective analysis showed a high incidence of dyslipidemia in a cohort of CML pts treated with second-line NIL after IM therapy; 10/31 pts required lipid lowering agent. While the epidemiological association between nilotinib and CVD remains controversial, the increase in TC may have a contributing effect. Monitoring lipid levels in NIL-treated pts is prudent, along with screening for and minimisation of concomitant CVD risk factors, especially in pts previous treated with IM which may mask underlying metabolic syndromes. # DKH DTY and LC contributed equally to this work. Disclosures: Hiwase: Novartis Pharmaceuticals: Research Funding. Yeung:Novartis: Honoraria, Research Funding; BMS: Honoraria. Hughes:Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Ariad: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding.

Download Full-text

Ublituximab (TG-1101), a Novel Glycoengineered Anti-CD20 Monoclonal Antibody, in Combination with Ibrutinib Is Highly Active in Patients with Relapsed and/or Refractory CLL and MCL; Results of a Phase II Trial

Blood ◽

10.1182/blood.v124.21.4679.4679 ◽

2014 ◽

Vol 124 (21) ◽

pp. 4679-4679 ◽

Cited By ~ 5

Author(s):

Jeff P. Sharman ◽

Charles M. Farber ◽

Daruka Mahadevan ◽

Marshall T. Schreeder ◽

Heather D. Brooks ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Alkylating Agent ◽

Single Agent ◽

Employment Equity ◽

Advisory Committees ◽

Highly Active ◽

Efficacy Assessment ◽

Equity Ownership ◽

Anti Cd20

Abstract Introduction: Ublituximab (UTX) is a novel, chimeric monoclonal antibody (mAb) which targets a unique epitope on the CD20 antigen and has been glycoengineered to enhance affinity for all variants of FcγRIIIa receptors, demonstrating greater antibody-dependent cellular cytotoxicity (ADCC) activity than rituximab and ofatumumab, particularly against cells that express low CD20 levels. Two Phase I trials of single agent UTX in relapsed/refractory CLL reported significant response rates with rapid and sustained lymphocyte depletion and a manageable safety profile. Ibrutinib, a novel oral BTK inhibitor approved for patients with previously treated CLL and MCL, displays high single agent activity and has reported increased activity in combination with non-glycoengineered anti-CD20 mAbs. Herein we report safety and efficacy data on the first combination of ibrutinib with a glycoengineered anti-CD20 mAb, UTX, from an ongoing Phase 2 trial. Methods: Eligible patients have relapsed or refractory CLL/SLL or MCL with an ECOG PS ≤ 2. The study was designed to assess safety, tolerability, and early overall response rate, with an initial safety run-in period consisting of 6 patients followed by open enrollment. UTX (Cohorts of 600 and 900 mg for CLL and at 900 mg for MCL patients) is administered on Days 1, 8, and 15 in Cycle 1 followed by Day 1 of Cycles 2 - 6. Ibrutinib is started on Day 1 and continues daily at 420 mg and 560 mg for CLL and MCL patients respectively. Following Cycle 6, patients come off study but remain on ibrutinib. Primary endpoint for safety: Adverse Events and Dose Limiting Toxicities (DLT) during safety run-in. Phase II primary efficacy endpoint: ORR with an emphasis on early activity with response assessments by CT scan scheduled prior to cycles 3 and 6 only. Results: 40 patients (33 CLL/ 7 MCL) have been enrolled to date with enrollment continuing. 23 M/17 F, median age 72 yr (range 52-86), ECOG 0/1/2: 20/19/1, median prior Tx = 2 (range 1-6), 38% with ≥ 2 prior anti-CD20 therapies; prior purine analog = 43%; prior alkylating agent = 68%; and prior purine and alkylating agent = 43%. No DLTs were observed during the safety run-in. Gr 3/4 AE’s occurring in at least 5% of patients and at least possibly related to UTX and/or ibrutinib included: neutropenia, thrombocytopenia, diarrhea, rash, leukocytosis, and infusion related reaction. There were no Grade 3/4 adverse events reported in ≥ 10% of patients. Ibrutinib was dose reduced due to an AE in 2 patients (1 diarrhea, 1 rash) and discontinued in 2 patients due to ibrutinib related AE’s (diarrhea and rash). IRR’s were managed with infusion interruptions with no patient requiring an ublituximab dose reduction. As of July 2014, 24/40 patients are evaluable for response. Best response to treatment is as follows: TableTypePts (n)CR (n)PR (n)SD (n)ORR (%)CLL non 17p/11q10-9190%17p/11q817-100%Total CLL18116194%MCL632183% The one CLL patient who achieved stable disease had a 46% nodal reduction. UTX appears to control ibrutinib related lymphocytosis with more than half of the patients within normal range for ALC by first efficacy assessment. Conclusions: Data suggests ublituximab, a glycoengineered anti-CD20 mAb, in combination with ibrutinib is both well-tolerated and highly active in patients with relapsed or refractory CLL and MCL. ORR was 94% in patients with CLL (100% in patients with high risk CLL: 17p, 11q del with 1 CR), with responses attained rapidly (median TTR: 8 weeks). In MCL, 83% of patients achieved a response at first efficacy assessment, with 50% of patients achieving a CR by week 20. For most patients, responses improved by the second efficacy assessment. The addition of ublituximab appears to mitigate ibrutinib related lymphocytosis producing earlier clinical responses than historically seen with ibrutinib monotherapy. Efficacy and safety will be updated on all enrolled patients. Disclosures Sharman: TG Therapeutics: Research Funding; Gilead: Consultancy, Research Funding; Roche: Research Funding; Pharmacyclics: Research Funding; Celgene: Consultancy, Research Funding. Farber:Leukemia Lymphoma Society NJ Chapter: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Alexion: Stock ownership Other. Schreeder:TG Therapeutics, Inc.: Research Funding. Kolibaba:TG Therapeutics: Research Funding; Gilead: Research Funding; Glaxo Smithkline: Research Funding. Sportelli:TG Therapeutics: Employment, Equity Ownership. Miskin:TG Therapeutics, Inc.: Employment, Equity Ownership. Weiss:TG Therapeutics, Inc.: Employment, Equity Ownership. Greenwald:TG Therapeutics: Research Funding.

Download Full-text

Emergence of Fc-Gamma-Riib-Dominance Contributes to Resistance to Therapeutic Antibodies in Patients with Chronic Lymphocytic Leukaemia

Blood ◽

10.1182/blood.v126.23.447.447 ◽

2015 ◽

Vol 126 (23) ◽

pp. 447-447

Author(s):

Melinda Burgess ◽

Sally Mapp ◽

Roberta Mazzieri ◽

Jonathan Ellis ◽

Catherine Cheung ◽

...

Keyword(s):

Chronic Lymphocytic Leukaemia ◽

Board Of Directors ◽

Research Funding ◽

Lymphocytic Leukaemia ◽

Primary Cultures ◽

Differential Sensitivity ◽

Moderate Activity ◽

Therapeutic Antibodies ◽

Advisory Committees ◽

Antibody Resistance

Abstract Aim: Chronic lymphocytic leukaemia (CLL) is the most common adult leukaemia. Whilst therapeutic antibodies show clinical activity in CLL patients, resistance develops. Thus, identifying mechanisms of antibody resistance and methods to reduce resistance would be valuable in managing CLL. Results: In this study we show that a therapeutic antibody against CD62L is able to induce antibody-dependent cell mediated cytotoxicity (ADCC) and phagocytosis (ADP) in primary cultures of CLL cells. Significantly, we observed that patients with stable disease retained sensitivity to CD62L-Ab whilst untreated patients, whose disease progressed, became progressively resistant to CD62L-Ab. Using strategies to enrich for monocytes we were able to show that the CD62L-Ab dependent killing was attributable to an FcγR-dependent mechanism within the monocyte derived cell (MDC) fraction of PBMCs. Transcriptomic profiling and marker analysis indicated that the MDCs acquired a macrophage phenotype. Both MDCs from antibody-sensitive or antibody-resistant patients were able to bind Ab-bound CLL cells equally. Moreover, resistance could not be attributed to reduced numbers of monocytes or macrophages or to distinct subtypes of monocytes or macrophages. Using pharmacological inhibitors of the activating pathway of FcγR signaling and the inhibitory FcγRIIB pathway we were able to show that the antibody resistance in MDCs, derived from patients with CLL, was due to the emerging dominance of the FcγRIIb pathway relative to the activating FcγR pathways. We examined whether the differential sensitivity to CD62L-Ab was also evident for anti-CD20 antibodies used clinically for CLL. Rituximab showed only moderate activity in vitro and no clear difference in cytotoxicity was observed between patients who were previously identified as being resistant or sensitive to the CD62L antibody. Obinutuzumab invoked similar differential cell killing in PBMCs from patients sensitive to, or resistant to, CD62L-Ab. Further comparison indicated that CD62L-Ab and obinutuzumab induced similar malignant B cell binding to MDCs and ADP in contrast to rituximab. Finally, similar to anti-CD62L, ADCC/ADP response to obinutuzumab was reduced following treatment of sensitive cultures with a syk or BTK inhibitor and increased in MDCs derived from resistant patients treated with a Ship1 inhibitor. Conclusions: These data establish, for the first time, that MDCs derived from CLL patients may switch from an antibody sensitive phenotype to an antibody-resistant phenotype as disease progresses. Significantly, we show that the resistance to MDC-mediated ADCC/ADP may be reversed by the inhibition of FcγRIIB with pharmacological modifiers. Disclosures Mollee: Onyx: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Gill:Sanofi Aventis: Research Funding; Roche: Honoraria; AbbVie: Honoraria; Roche: Research Funding.

Download Full-text

FLT3 Splice Variant (FLT3Va) As a Potential Immunotherapeutic Target in Patients with Acute Myeloid Leukemia (AML)

Blood ◽

10.1182/blood.v128.22.1681.1681 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1681-1681

Author(s):

Sophia Adamia ◽

Jeffrey Nemeth ◽

Shruti Bhatt ◽

Sarah R Walker ◽

Natalie I Voeks ◽

...

Keyword(s):

Flow Cytometry ◽

Cell Surface ◽

Board Of Directors ◽

Research Funding ◽

Leukemic Cells ◽

Advisory Committees ◽

Gm Csf ◽

Nsg Mice ◽

Blocking Antibodies ◽

Pdx Models

Abstract Alternative pre-mRNA splicing (AS) is a normal epigenetic phenomenon, a key regulator of gene expression, yields multiple transcripts and thus a variety of proteins from a single gene. Mutations in the spliceosome components resulting in aberrant splicing isoforms are common in AML, and other myeloid neoplasms, and may generate leukemia-specific neoantigens targetable with an antibody-drug conjugates (ADCs) or blocking antibodies. Our previous studies revealed that the FLT3 cell surface receptor is one of the most commonly misspliced genes in AML (54-63% of ~400 AML patients). We conducted cloning and sequencing analyses in AML cells and identified multiple aberrant splice-variants of FLT3 that resulted from either skipping of one or more exons or activation of cryptic splicing sites. Transfection of cDNA with three of these variants in TF-1 (AML cell line) cells resulted in expression of Flt3 variant proteins on the cell surface. We successfully generated rabbit polyclonal antiserum against a unique peptide sequence present in the most commonly expressed abnormal splice variant, which we termed Flt3Va. Immunoblots performed with the polyclonal antibody identified a ~160 kDa protein expressed by TF-1 cells transfected with FLT3Va, and the antibody did not react with untransfected TF-1 cell lysate. Using standard techniques, we generated rabbit hybridomas and evaluated the clones by flow cytometry and western blotting experiments. Based on these data, we selected one antibody clone (15-7) for further experiments. The 15-7 anti-Flt3Va rabbit monoclonal antibody identified Flt3Va protein expressed on the cell surface and within the cytoplasm of transfected TF-1 cells by flow cytometry and western blotting. However, no Flt3Va protein was detected in untransfected TF-1 cells or normal CD34+ bone marrow cells. The 15-7 antibody bound to 26 of 52 primary AML samples and 5 of 10 primagraft samples (PDX models) of human AML. Immunoblotting analyses of PDX models and patient samples confirmed binding to a protein of the expected size (130-160 kDa). Additionally, multi-parameter flow cytometry in 10 PDX models and 52 primary demonstrated that putative AML stem cells (as defined by the CD45dim, CD34, CD38, CD33, c-Kit cell surface expression) co-expressed Flt3Va antigen in 50% samples evaluated. An analysis of Flt3Va protein localization by live cell imaging showed a punctate distribution of Flt3Va on the cell surface. Furthermore, we observed that overexpression of Flt3Va in TF-1 cells led to GM-CSF growth factor independence. Analysis of TF-1 cells in the absence of GM-CSF and Flt3 ligand demonstrated constitutive activation of STAT5, an important mediator of Flt3 signaling, in Flt3Va overexpressing cells. In addition, Erk1/2 phosphorylation was also increased in Flt3Va overexpressing cells, another downstream effector of Flt3. In an effort to determine if Flt3Va+ cells had tumor repopulating ability, we sorted 0.3X10^6 Flt3Va+ and Flt3Va- cells from a PDX sample and injected the sorted populations or unsorted bulk tumor cells into NSG mice. The human cell engraftment in the mice was detected by the expression of human CD45, CD33, CD34, CD38, and c-kit antigens in the peripheral blood. In two experiments, mice injected with Flt3Va+ cells had detectable circulating leukemic cells by ~18 days after injection, while those injected with Flt3Va- cells had detectable circulating leukemic cells after the 4th week. These results suggest both Flt3Va+ and Flt3Va- cell populations are able to reconstitute leukemia after transplantation in NSG mice. However, Flt3Va+ may be expressed by an aggressive AML clone that facilitate early tumor engraftment. Overall, these studies suggest that Flt3Va is a leukemia-specific neoantigen and is an attractive potential immunotherapeutic target in AML. Proteins such as Flt3Va generated by alternative splicing are common in AML and may be targets for of novel blocking antibodies or ADCs, minimizing effects on normal tissues. Disclosures Adamia: Janssen: Research Funding. Nemeth:Janssen: Employment. Attar:Janssen: Employment. Letai:AbbVie: Consultancy, Research Funding; Tetralogic: Consultancy, Research Funding; Astra-Zeneca: Consultancy, Research Funding. Steensma:Millenium/Takeda: Consultancy; Celgene: Consultancy; Amgen: Consultancy; Janssen: Consultancy; Ariad: Equity Ownership; Genoptix: Consultancy. Weinstock:Novartis: Consultancy, Research Funding. DeAngelo:Novartis: Consultancy; Ariad: Consultancy; Pfizer: Consultancy; Baxter: Consultancy; Celgene: Consultancy; Incyte: Consultancy; Amgen: Consultancy. Stone:Agios: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celator: Consultancy; Juno Therapeutics: Consultancy; Roche: Consultancy; Jansen: Consultancy; Pfizer: Consultancy; ONO: Consultancy; Sunesis Pharmaceuticals: Consultancy; Merck: Consultancy; Xenetic Biosciences: Consultancy; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; Amgen: Consultancy; Karyopharm: Consultancy; Seattle Genetics: Consultancy. Griffin:Janssen: Research Funding; Novartis: Consultancy, Research Funding.

Download Full-text

Targeting BTN2A1 By a Unique Activating Mab Improves Vγ9Vδ2 T Cell Cytotoxicity Against Primary Acute Lymphoblastic Blasts

Blood ◽

10.1182/blood-2021-152577 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 2302-2302

Author(s):

Anne-Charlotte Le Floch ◽

Caroline Imbert ◽

Aude De Gassart ◽

Florence Orlanducci ◽

Aude Le Roy ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Board Of Directors ◽

Cell Lines ◽

Research Funding ◽

Leukemic Cells ◽

Target Cells ◽

Advisory Committees ◽

Vγ9vδ2 T Cells ◽

Privately Held

Abstract Introduction Vγ9Vδ2 T cells are new promising cytotoxic effectors in hematological malignancies. In acute myeloid leukemia and in non-Hodgkin lymphomas, Vγ9Vδ2 T cells-based immunotherapy has shown encouraging results both in preclinical models and in early phase clinical trials. Acute lymphoblastic leukemia (ALL) includes very heterogeneous clinico-biological entities, for which recent immunotherapy approaches are currently being developed. Nevertheless, global prognosis of ALL patients still be poor with a 5 years-overall survival of less than 40% and therefore, treatments need to be improved. Very few data are currently available on susceptibility of ALL blasts to Vγ9Vδ2 T cell cytotoxic activity. Vγ9Vδ2 T cells are activated by phosphoantigens bound to BTN3A1 on target cells. BTN3A molecules are targeted at clinical level, with the ICT01 agonist monoclonal antibody (mAb), that is currently tested in a multicentric phase ½ study (EVICTION study). Biology of Vγ9Vδ2 T cells has recently undergone a new paradigm with the identification of BTN2A1 as the direct ligand for Vγ9 chain of γδ TCR. BTN2A1 is mandatory for Vγ9Vδ2 T cell activation but its precise role in modulating functions of Vγ9Vδ2 T cells remains unknown. Here, we show that allogenic and autologous Vγ9Vδ2 T cells exert cytolytic functions against ALL cell lines and primary ALL blasts, and we report that Vγ9Vδ2 T cell cytotoxic activity is enhanced after treatment with a unique agonist mAb targeting BTN2A1. Material and methods 5 ALL cell lines (697, RS4;11, NALM-6, HPB-ALL, SUP-T1) and PBMC from 11 adults ALL patients at diagnosis (B-ALL, T-ALL and Ph+ ALL) were tested in functional assays. We evaluated apoptosis of ALL cell lines and of primary ALL blasts after coculture with allogenic Vγ9Vδ2 T cells. ALL samples were also tested for their expansion capacities and a degranulation assay was performed at D14. We assessed in parallel relative quantification of the level expression of BTN2A1 (ICT0302 and 7.48 epitopes), and BTN3A (20.1 and 108.5 epitopes) on surface of ALL blasts. DAUDI-BTN2AKO+2A1 and HEK293-BTN2AKO+2A1 cells were used in binding assays, and modulation of TCR binding was assessed using recombinant tetramerized Vγ9Vδ2 TCR. Results We showed that Vγ9Vδ2 T cells exert spontaneous cytotoxicity against ALL cell lines and primary ALL blasts with a heterogeneous susceptibility depending on the target. We demonstrated that anti-BTN2A1 ICT0302 agonist mAb significantly enhanced Vγ9Vδ2 T cells mediated apoptosis in comparison to control condition, even for the less spontaneously susceptible cells. We confirmed these observations with degranulation of autologous Vγ9Vδ2 T cells expanded from 5 ALL patients at diagnosis that was increased after treatment with anti-BTN2A1 ICT0302 agonist mAb. BTN3A and BTN2A1 were detected on surface of ALL blasts, and BTN3A 108.5 was the most expressed epitope. Interestingly, we observed that anti-BTN2A1 ICT0302 strongly increased binding of a recombinant Vγ9Vδ2 TCR to target cells using with HEK293 and DAUDI cells. Discussion Our results highlighted that Vγ9Vδ2 T cells exert cytolytic functions against ALL cells, both in allogenic and autologous setting and demonstrated that BTN2A1 targeting with our unique agonist mAb could potentiate effector activities of Vγ9Vδ2 T cells against ALL blasts. These results indicate that the sensitization of leukemic cells can be induced by activation BTN3A as well as BTN2A1 mAbs. These data bring novel understanding on the biology of BTN2A1 on leukemic cells and our ability to enhance both binding and function. These findings could be of great interest for the design of innovative Vγ9Vδ2 T cells-based immunotherapy strategies for treating ALL that could be extended to other cancer types. Disclosures De Gassart: ImCheck Therapeutics: Current Employment, Current holder of individual stocks in a privately-held company. Vey: Amgen: Honoraria; BMS: Honoraria; BIOKINESIS: Consultancy, Research Funding; NOVARTIS: Consultancy, Honoraria, Research Funding; SERVIER: Consultancy; JAZZ PHARMACEUTICALS: Honoraria; JANSSEN: Consultancy. Cano: ImCheck Therapeutics: Current Employment, Current holder of individual stocks in a privately-held company. Olive: Emergence Therapeutics: Current holder of individual stocks in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Alderaan Biotechnology: Current holder of individual stocks in a privately-held company, Membership on an entity's Board of Directors or advisory committees; ImCheck Therapeutics: Current holder of individual stocks in a privately-held company, Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Anti-BTN2A1 ICT0302 is a murine agonist monoclonal antibody targeting BTN2A1 whose aim is to increase Vgamma9Vdelta2 T cells functions.

Download Full-text

Risk Factors for Severe Form of COVID-19 after Allogeneic Hematopoietic Stem Cell Transplantation: A SFGM-TC Multicentre Cohort Study

Blood ◽

10.1182/blood-2020-138411 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 34-34

Author(s):

Alienor Xhaard ◽

Constance Xhaard ◽

Maud D'Aveni ◽

Hélène Salvator ◽

Marie-Laure Chabi-Charvillat ◽

...

Keyword(s):

Risk Factors ◽

Multivariate Analysis ◽

Intensive Care ◽

Platelet Count ◽

Board Of Directors ◽

Research Funding ◽

Univariate Analysis ◽

Immunosuppressive Treatment ◽

Severe Form ◽

Advisory Committees

COVID-19 greatly affected Europe between March and May 2020. Initial reports suggest cancer and haematological malignancies as risk factors for severity and mortality, but the role of allogeneic stem cell transplantation (alloHSCT) remains unclear. The Société Francophone de Greffe de Moelle et Thérapie Cellulaire conducted a multicentre retrospective study of alloHSCT recipients diagnosed with COVID-19. We described the COVID-19 disease characteristics in this population and examined risk factors for severity and mortality. Data were collected retrospectively from the patients' charts and the ProMISe database. Diagnosis was retained only if a reverse transcription polymerase chain reaction assay test from a nose swab was positive for SARS-CoV-2. Patients were classified as severe if they were transferred to an intensive care unit (ICU) due to COVID-19 or died of COVID-19, and non-severe in other cases. Comparisons of characteristics were performed using student's t-tests and Mann-Whitney U tests for normally and abnormally distributed data, respectively, for continuous variables and χ2 or Fisher's exact tests, when appropriate for categorical variables. Risk factors associated with a severe form of COVID-19 were assessed using both univariate and multivariate logistic regressions. All analyses were performed using SAS version 9.4.6 (SAS Institute Inc., Cary, NC, USA. A two-tailed significance level p<0.05 was used. Fifty-four patients were diagnosed, including 21 with severe forms (intensive care transfer and/or death). Haematological characteristics did not vary between patients with severe or non-severe forms of COVID-19. Patients with a severe form of COVID-19 were more likely to be diagnosed earlier after alloHSCT (0.78 vs. 2.1 years, p=0.01), to have comorbidities (80.9% vs. 54.5%, p=0.05) and to receive immunosuppressive treatment (81% vs. 51.5%, p=0.03). Severe COVID-19 patients were more likely to have symptoms at COVID-19 diagnosis (100% vs. 81.8%, p=0.04), especially pneumonia and symptoms other than respiratory or digestive (asthenia, neurological symptoms, myalgia, dysgeusia, skin lesions and arthralgia), and to experience co-infection during the course of the disease (52.4% vs. 21.2%, p= 0.001). At COVID-19 diagnosis, patients with a non-severe form were more likely to have a higher platelet count (226 G/L vs. 98 G/L, p= 0.01), while other biological characteristics did not vary between the two cohorts. In univariate analysis, shorter time from transplant to COVID-19 (before 211 days, p=0.01), pneumonia (OR 12.21 [95% CI 2.43 - 61.46], p=0.002), symptoms other than pulmonary or digestive (OR 1.21 [95% CI 1.02 - 11.16], p=0.04), immunosuppressive treatment (OR 5.97 [95% CI 0.75 - 47.42], p=0.03) , co-infection (OR 5.84 [95% CI 1.65-20.63], p=0.006) and comorbidity (OR 3.54 [95% CI 0.98-12.83], p=0.05) were associated with severe COVID-19. The only biological parameter associated with severity was a lower platelet count <71G/L (OR 28.00 [95% CI 2.07-379.25]), p=0.008. In multivariate analysis, pneumonia and other symptoms retained a significant association with severe COVID-19. Thirteen patients died of COVID-19: in univariate analysis, risk factors for death from COVID-19 were similar to the risk factors for severe COVID-19 (i.e. shorter time from alloHSCT, p=0.03; pneumonia, p=0.01; co-infection during the course of COVID-19, p<0.01, and lower platelet count, p<0.01). In multivariate analysis, none of the above mentioned factors remained significantly associated with death from COVID-19. As SARS-CoV-2 continues to spread internationally, given the lack of vaccine or treatment, alloHSCT recipients should maintain a high level of awareness to avoid contamination. Figure Disclosures Dalle: Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria; Bellicum: Consultancy, Honoraria; AbbVie Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Orchard: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; bluebird bio: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi-Genzyme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Medac: Consultancy, Honoraria; Jazz Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Rubio:MSD: Honoraria; Novartis: Honoraria; Neovii: Research Funding; Medac: Consultancy; Gilead: Honoraria.

Download Full-text