Six-year follow-up and subgroup analyses of a phase 2 trial of venetoclax for del(17p) chronic lymphocytic leukemia.

ABSTRACT: Chromosome 17p deletion (del[17p]) is associated with poor prognosis in patients with chronic lymphocytic leukemia (CLL). Venetoclax is approved for treatment of previously untreated and relapsed/refractory (R/R) CLL, including patients with del(17p), based on the open-label, multicenter, phase 2 M13-982 trial (NCT01889186). Here, we detail the 6-year follow-up analysis for M13-982. A total of 158 patients with previously untreated (n = 5) or R/R (n = 153) del(17p) CLL received 400 mg venetoclax daily after initial ramp-up until progressive disease. After a median follow-up of 70 months, the best objective response rate (ORR) was 77% (21% complete remission [CR] and 49% partial remission [PR]), with a median duration of response (DOR) of 39.3 months (95% confidence interval [CI], 31.1-50.5). The median progression-free survival (PFS) was 28.2 months (95% CI, 23.4-37.6), and median overall survival (OS) was 62.5 months (95% CI, 51.7-not reached), with 16% of patients remaining on treatment after 6 years. Multivariable analysis did not identify statistically significant correlation between patient subgroups defined by clinical or laboratory variables and ORR or PFS. The most common grade ≥3 adverse events were neutropenia (42%), infections (33%), anemia (16%), and thrombocytopenia (16%). Post hoc comparative analyses of PFS and OS from treatment initiation, from a 24-month landmark, and by minimal residual disease status were performed between patients with del(17p) in the M13-982 and MURANO studies in the interest of understanding these data in another context. These long-term data show the continued benefits of venetoclax in patients with del(17p) CLL. The trial was registered at www.clinicaltrials.gov as #NCT01889186.

Recurrent Stroke in a Child With Atlantoaxial Instability Following Chiropractic Manipulation.

Pediatric stroke presents with a variety of signs and symptoms. Correct modality of imaging is essential in decreasing the time from symptom onset to appropriate management. Evaluation of pediatric stroke should include both blood work as well as imaging in a parallel rather than a sequential matter. We report a case of a child with a bow hunter's stroke that was challenging to diagnose. This type of stroke happens when the vertebral artery is occluded at the atlantoaxial or subaxial level during neck rotation. This case demonstrates that workup of stroke should be comprehensive to include all mechanical and anatomic possibilities before investigating rarer hypercoagulable disorders.

Immune Hemolytic Anemia (Paroxysmal Cold Hemoglobinuria) Preceding Burkitt Lymphoma in a 12-Year-Old Child.

Autoimmune hemolytic anemia (AIHA) in childhood, including paroxysmal cold hemoglobinuria, is an uncommon, potentially life-threatening disorder. AIHA is a recognized complication of several varieties of lymphoproliferative disorders, including high-grade B-cell lymphoma, but it has not been associated with Burkitt lymphoma in people without an underlying immunodeficiency. When AIHA occurs in association with lymphoproliferative disorders, it may precede or accompany the diagnosis of malignant disease or herald relapse. We report a novel case of a previously healthy child diagnosed with paroxysmal cold hemoglobinuria 14 months preceding the development of Burkitt lymphoma.

Association between ADAM33 polymorphisms and susceptibility with adult and childhood asthma among Jordanians.

Disintegrin and metalloprotease 33 (ADAM33) have been associated with childhood and adult asthma in many populations. ADAM33 mutations might predispose to altered lung function in early infancy. In this study, we investigated the association between single-nucleotide polymorphisms in ADAM33 and the incidence of adult and childhood asthma among Jordanians. One hundred seven pediatric asthmatic patients, 115 healthy pediatric patient controls, 160 adult asthmatic patients, and 110 healthy adults were enrolled in this study. ADAM33 polymorphisms were genotyped using the polymerase chain reaction/restriction fragment length polymorphism method. A strong association between the V4 genotype and incidence of childhood asthma was found. In the single-locus analyses of asthma risk, V4 C/G single nucleotide polymorphism (SNP) showed a trend toward significance with p=0.07. Interestingly, the CC homozygous mutant genotype frequency was significantly higher in asthmatic subjects (15.9%) than in control subjects (2.6%), resulting in an odds ratio of 7.05. In adult cases, S2, the F+1 and Q-1 genotype showed a significant association (p≤0.05) with the incidence of asthma. Two haplotypes also exhibited a significant association with asthma (p≤0.05). In conclusion, the findings of this study confirm the already reported association between V4 SNP and the incidence of childhood asthma as well as between S2, F+1, and Q-1 SNPs and the incidence of adult asthma in several populations.

Incidence of bcr­abl fusion transcripts in healthy individuals.

Bcr­abl fusion transcripts, resulting from translocation t(9;22), are hallmarks of Philadelphia chromosome positive (Ph+) leukemias. This translocation is detected in >90% of patients with chronic myelogenous leukemia and ~20% of acute lymphoblastic leukemia patients, which predominantly express the p210 and p190 proteins, respectively. Although the occurrence of t(9;22) in healthy individuals has been previously demonstrated, the number of studies is limited and the results are inconsistent. The present study screened for the presence of bcr­abl transcripts in the blood of a group of healthy individuals using a sensitive­nested reverse transcription polymerase chain reaction (RT­PCR) assay. Samples were collected from 189 healthy volunteers (145 adults and 44 children). RNA was reverse transcribed and amplified by two rounds of PCR, amplifying the two common variants of bcr­abl transcripts, p190 and p210. While the bcr­abl p190 transcript was not detected, the p210 transcript was detected in ~10% of samples. Notably, the incidence of p210 translocation was higher in males (12.2%) compared with females (7.7%) and males were 2.4 times more likely to have the translocation. A significant incidence was also observed in adults compared with children, where adults were 6 times more likely to have the translocation. The presence of bcr­abl transcripts in the blood of a significant proportion of healthy individuals should be considered in long­term investigations to establish its exact association with the risk of developing leukemia. Furthermore, the current assays should be revised to consider the proportion of normal samples carrying the p210 transcripts when making a differential diagnosis.

Thymoquinone efficiently inhibits the survival of EBV-infected B cells and alters EBV gene expression.

Epstein--Barr virus (EBV) is a human virus with oncogenic potentials that is implicated in various human diseases and malignancies. In this study, the modulator activity of the potent herbal extract drug thymoquinone on EBV was assessed in vitro. Thymoquinone was tested for cytotoxicity on human cells of lymphoblastoid cells, Raji Burkitt's lymphoma, DG-75 Burkitt's lymphoma, peripheral blood mononuclear cells, and periodontal ligament fibroblast. Apoptosis induction was analyzed via TUNEL assay and activity studies of caspase-3. The effect of thymoquinone on EBV gene expression was determined using real-time polymerase chain reaction. We report here, for the first time, a promising selective inhibitory affect of thymoquinone on EBV-infected B cell lines in vitro, compared with lower activity on EBV negative B cell line and very low toxicity on human peripheral blood mononuclear cells and periodontal ligament fibroblasts. Moreover, the drug was found to efficiently suppress the RNA expression of EBNA2, LMP1, and EBNA1 genes. Specifically, EBNA2 expression levels were the most affected indicating that this gene might have a major contribution to thymoquinone potency against EBV infected cells. Overall, our results suggest that thymoquinone has the potential to suppress the growth of EBV-infected B cells efficiently.