Safety and efficacy of the BNT162b mRNA COVID-19 vaccine in patients with chronic lymphocytic leukemia

Patients with chronic lymphocytic leukemia (CLL) have a suboptimal humoral response to vaccination. Recently, BNT162b2, an mRNA COVID-19 vaccine with a high efficacy of 95% in immunocompetent individuals, was introduced. We investigated the safety and efficacy of the BNT162b2 mRNA COVID-19 vaccine in patients with CLL from nine medical centers in Israel, Overall 400 patients were included, of whom 373 were found to be eligible for the analysis of antibody response. The vaccine appeared to be safe and only grade 1-2 adverse events were seen in 50% of the patients. Following the second dose, an antibody response was detected in 43% of the cohort. Among these CLL patients, 61% of the treatment-na ve patients responded to the vaccine, while responses developed in only 18% of those with ongoing disease, 37% of those previously treated with a BTK inhibitor and 5% of those recently given an anti-CD20 antibody. Among patients treated with BCL2 as monotherapy or in combination with anti-CD20, 62% and 14%, respectively, developed an immune response. There was a high concordance between neutralizing antibodies and positive serological response to spike protein. Based on our findings we developed a simple seven-factor score including timing of any treatment with anti-CD20, age, treatment status, and IgG, IgA, IgM and hemoglobin levels. The sum of all the above parameters can serve as a possible estimate to predict whether a given CLL patient will develop sufficient antibodies. In conclusion, the BNT162b2 mRNA COVID-19 vaccine was found to be safe in patients with CLL, but its efficacy is limited, particularly in treated patients

AML in Israel: Younger Age at Diagnosis Does Not Improve Prognosis.

Abstract Abstract 4130 Introduction AML is generally considered a disease of the elderly, with a mean age of diagnosis in the Western world is approximately 60 years of age or older. Important prognostic parameters include: age, karyotype and new molecular markers (NPM1 and FLT3). Treatment in a tertiary care facility also may improve survival. We elected to examine these parameters and the long term outcome of AML patients (pts) treated in our institution which is an academic tertiary care center, among the largest in Israel. Methods We reviewed clinical data on pts with AML (de novo and secondary) treated at Hadassah in the years 1992-2009. Karyotype was determined by conventional cytogenetics and FISH analysis or molecular analysis when appropriate. Good prognosis karyotype was considered to include t(8;21), t(15;17) and inv16. FLT3 ITD (internal tandem duplications) and NPM1 analysis was determined on all pts for whom DNA was available, using PCR and either acrylamide gel electrophoresis (FLT3) or melting point analysis (NPM1). Kaplan Meier analysis determined duration of survival. Statistical significance was determined using Log rank and Chi square test, with significance set at a level of p&lt;0.01. Results 293 patients were included, of which 236 (80%) had de novo AML and 57 (19.5%) had secondary AML, either following an antecedent hematological disease (AHD) such as MDS (n= 32, 11%) or therapy related AML (t-AML) (n=25, 8.5%). Our standard protocol for AML includes 7+3 induction and high dose Ara-C consolidations. Bone marrow transplantation (BMT), either allogeneic or autologous, is performed in high risk cases depending on donor availability. The mean age at diagnosis of the 293 pts was relatively young (all pts= 47.7±18.3 yrs; de novo AML= 45.6±17.6 yrs; secondary AML= 56.2±18.6 yrs; t-AML= 48.6±16.6 yrs). Mean age at diagnosis for Arab pts was 44.2±16.7, as compared to Jewish pts (49.4±18.6). For de novo AML Arab pts, mean age at diagnosis was 43.3±16.4 as compared to de novo Jewish pts (46.9±18). The male to female ratio was 60/29 (2.06) for Arab pts and 99/102 (0.97) for Jewish pts, 53/25 (2.12) and 80/78 (1.02) for de novo Arab and Jewish pts respectively. In the de-novo AML group, 58 (24%) had a good prognosis karyotype. In the entire group of pts, 108 (37%) had normal karyotype and 62 (21%) had FLT3 ITD. Of the 108 normal karyotype pts, 34 (31%) were found to have FLT3 ITD, and 17 (16%) were found to harbor NPM1 mutations; of the NPM1 positive patients, 12 (70%) were FLT3 ITD negative. Treatment with intention to cure was administered to 218 (92%) of the de novo AML and 36 (63%) of the secondary AML pts. Other pts received best supportive care. Eighty six (29%) pts underwent allogeneic BMT and 12 (4%) underwent autologous BMT. The 5 year survival was 35% and the 10 year survival was 17% with no difference between Arabs and Jews. Good prognosis karyotype significantly improved survival as did younger age, and absence of FLT3 ITD. Conclusions We conclude that in our institution, the median age of diagnosis of AML is more than two decades younger than that reported in literature. The reason for this may be demographic or related to environmental exposures such as smoking. The preponderance of male Arab pts is most likely due referral bias. The young age of the Arab male pts may be due to occupational or environmental exposures, such as smoking. Our treatment protocols and supportive care are similar to those used in Western countries. Despite these factors, survival was not as good as might be expected according to age, karyotype and FLT3 ITD status. Further studies are needed to elucidate the etiology of these findings. Disclosures: No relevant conflicts of interest to declare. </jats:sec

KLF1 Mutations Are Not Common in Israel but Can Explain Occasional Cases of Elevated HbA2 or Very Elevated Fetal Hemoglobin

Abstract Introduction: Mutations in KLF1 (Kruppel Like Factor1) have been noted to cause a number of different phenotypes of erythrocyte abnormalities, as KLF1 is known as a master regulator of many genes expressed in red blood cells. One important manifestation caused by KLF1 mutations is the upregulation of γ- or δ-globin genes, with associated microcytosis, thus mimicking beta thalassemia (β-thal) trait. Such findings cause difficulty in counseling couples referred for prenatal diagnosis of β-thal. KLF1 mutations have been reported to be more frequent in geographic regions where β-thal is common. Therefore we undertook to analyze for the presence of KLF1 mutations in Israeli individuals. Materials and Methods: We selected 100 individuals for analysis belonging to one of 4 different groups: 1. Individuals with isolated elevated HbA2 (n=14), or isolated elevation of HbF (n=13) or elevation of both HbA2 and HbF (n=6), who are not carriers of a β-thal mutation by sequence analysis. 2. Individuals with β-thal trait (n=19) who have a higher HbF (and/or HbA2) than is expected for β-thal trait, who do not have β-thal intermedia on clinical criteria (blood count, peripheral smear, spleen size). These individuals carried one of 8 mutations known to cause β-thal in our region 3. Two patients (pts) with a history of transfusions (one with massive splenomegaly and sickle trait, suspected to have coinherited CDA, and one with β-thal intermedia with HbF elevation unexpectedly high for his mutation (TATA box -28 A to C; HBB:c.-78A&gt;C). This patient had HbF levels ranging from 23-33% and HbA2 ranging from 7.8-8.9% over years of followup from age 39-50 years. 4. Anonymous controls (n=46) who are pts with a hematological malignancy not suspected of carrying a hemoglobinopathy. KLF1 (exons 1, 2 and 3) was amplified using PCR (exon 1: 564 base pair product and exons 2 and 3: 1703 base pair product). PCR products were subjected to DNA sequence analysis using an Applied Biosystems ABI apparatus. The sequence obtained was analyzed using BLAST alignment and deviations from the published sequence were analyzed using the Mutation Taster program. Results: Two pts were found to carry substitutions with possible or proven clinical significance. One pt is heterozygous for a substitution at c.972C&gt;A (codon 324 exon 3, E324D, aspartic acid to glutamine) which has not been previously reported. According to Mutation Taster this substitution may have clinical significance. This pt, who has normal hematological parameters, had isolated HbA2 elevation (4.1%) with no β-thal mutation identified. The second pt was found to be heterozygous for a substitution at c.901C&gt;T (codon 301 exon 2, R301C, arginine to cysteine). This substitution has been reported by Gallienne et al, 2012, to be associated with elevated Hb F. This young pt was found to have 28% Hb F with a low HbA2 level of 1.4% and MCV of 63.8. His father also had 28% HbF. No β-thal mutation was identified in the pt or his father but the patient was found to be homozygous for a single alpha globin gene deletion. In addition to these 2 substitutions, many pts and controls carried known polymorphisms in KLF1. These polymorphisms are: c.304T&gt;C, exon 2 residue 102 (S102P) (found in 24 pts and 19 controls); -148(G&gt;A), in the upstream noncoding region (found in 11 pts and 8 controls); c.544T&gt;C codon 182 exon 2 (F182L) (found in 3 pts and 4 controls); and c.115A&gt;C, codon 39 in exon 2, M39L (found in 1 pt and 3 controls). One rare, previously unreported substitution was found in heterozygous form in the thal intermedia pt, located at c.259C&gt;G codon 87 exon 2, P87A (proline to alanine). This was not found in the controls, however according to the location in the gene, and to Mutation Taster, this is not suspected to be a functional variant. Conclusions: Functional variants in KLF1 were rarely found in this group of patients. One out of 14 (7%) of individuals with isolated elevated HbA2 and 1/13 patients with isolated HbF elevation (7.7%) were identified as carrying heterozygous KLF1 functional variants. Two novel substitutions were found: E324D which is suspected to have clinical significance and P87A which is not presently suspected to be a functional variant. We conclude that KLF1 analysis may explain occasional individuals with high HbA2, or marked HbF elevation, in the absence of β-thal trait in our patient population. Larger studies are needed to confirm these findings. Disclosures No relevant conflicts of interest to declare. </jats:sec

Low Molecular Weight Heparin (LMWH) for Venous Thromboembolism (VTE) Prophylaxis in Patients with Primary Central Nervous System Lymphoma (PCNSL)

Abstract Introduction: Venous thromboembolism (VTE) is a frequent, potentially lethal, complication in patients with cancer. Patients with brain tumors are at a particularly high risk for VTE. Primary central nervous system lymphoma (PCNSL) is a rare subtype of diffuse large B-cell lymphoma, involving the cranio-spinal axis. The incidence of VTE in patients with PCNSL is as high as 30-60% in various series, occurring mostly in the early period of therapy. Due to this high incidence, the policy in our medical center since the year 2005, is to treat with prophylactic low molecular weight heparin (LMWH) from the time of PCNSL diagnosis until the end of treatment. We aimed to evaluate the incidence of VTE in patients with PCNSL treated with prophylactic LMWH. Material and methods: All patients ≥18 years who were diagnosed and treated for PCNSL in Hadassah-Hebrew University Medical Center between the years 2005-2017 were included in the study. We retrospectively reviewed their medical records for demographic details and initial disease characteristics (age at diagnosis, sex, performance status, laboratory results such as LDH, cerebrospinal fluid content and location of the growth), for details of risk factors for VTE such as diabetes, smoking or heart failure, and for personal or familial history of thrombosis. Therapeutic details including chemotherapy protocol, response to treatment and supportive care were compiled. Specifically we noted if prophylactic LMWH was given, if any complications developed due to the LMWH treatment and whether a VTE event occurred. Results: Forty four patients were included in the study. Mean age at diagnosis was 60.2 years and there were 27 (61%) females. Three (6.8%) patients had a personal history of thrombosis and 13 (29%) had a history of diabetes or smoking. Thirty two (72%) had an ECOG performance study of 0-1 at diagnosis and seven (16%) had leptomeningeal involvement. Forty one (93%) of patients were treated with a systemic high dose methotrexate (HDMTX) based protocol (mean of 7.6 courses of HDMTX per patient) and thirty two (73%) patients were treated with systemic rituximab. All 44 patients were treated with prophylactic LMWH, mostly at a dose of 40 mg per day (41 patients, 93%). Of the 44 patients, five (11%) discontinued treatment; 2 due to side effects (abnormal liver function tests and subdural hematoma (SDH)) and 3 for an unknown reason. Three (7%) patients had a minor bleeding event (gum, conjunctival, Ommaya reservoir catheter tract). One patient (2.3%) had a major bleeding event (SDH) while on LMWH treatment which was found on routine MRI imaging of the brain as he was asymptomatic. No VTE events (0%) were recorded in patients treated with LMWH. Two patients had a VTE, however both patients were off LMWH treatment at the time of VTE (one stopped LMWH, the other was diagnosed with VTE concurrently with the diagnosis of PCNSL). Conclusions: In our group of 44 PCNSL patients, prophylactic use of LMWH was highly effective, with no VTE events. Two cases of VTE occurred in our patient group, both occurred while the patients were off LMWH treatment. Only one, asymptomatic, intracranial bleed was recorded, indicating the relative safety of this treatment in PCNSL patients. Further prospective studies should be done to support the routine use of this prophylactic strategy. Disclosures No relevant conflicts of interest to declare. </jats:sec

Topical propranolol improves epistaxis in patients with hereditary hemorrhagic telangiectasia - a preliminary report

Abstract Background Severe epistaxis is often difficult to control in patients with hereditary hemorrhagic telangiectasia (HHT). Propranolol has been shown to have antiangiogenic properties in vitro and in vivo and is commonly used to treat hemangiomas. We present our experience with topical nasal propranolol for the treatment of moderate to severe epistaxis in patients with HHT. Methods Retrospective case series. Six patients with HHT were treated with 0.5 cm3 of 1.5% propranolol gel, applied to each nostril twice daily for at least 12 weeks. Outcome measures were epistaxis severity score (ESS), hemoglobin level, and number of blood transfusions prior to and while on treatment. Local and systemic side effects were recorded. Results The mean duration of treatment was 30 ± 5.6 weeks. A significant improvement in the ESS was found in all patients, with a mean decrease from 6.4 ± 2.1 at treatment onset to 3.5 ± 1.7 at 12 weeks (p = 0.028). Hemoglobin level increased significantly from 8.4 ± 3.1 to 11.0 ± 1.8 g/dL at 12 weeks (p = 0.043). The mean number of blood transfusions decreased from 4.5 ± 4.9 before treatment to 2.5 ± 2.9 at 12 weeks and 0.3 ± 0.8 at 24 weeks, but the difference did not reach statistical significance (p = 0.109 for both). No significant side effects of treatment were recorded. Conclusions These preliminary results suggest that topical propranolol may be effective for the treatment of epistaxis in patients with HHT. A prospective controlled trial is required to confirm our findings