Peter V. Pickens

Left atrial abnormality (LAA) as a predictor of ibrutinib-associated atrial fibrillation in patients with chronic lymphocytic leukemia

ABSTRACT Results from several recent studies in chronic lymphocytic leukemia (CLL) have demonstrated an association between ibrutinib exposure and the development of atrial fibrillation, estimated incidence of 11% with long-term follow up. This is a common cause of ibrutinib discontinuation. Risk factors for atrial fibrillation include advanced age, hypertension (HTN), mitral valve disease (MVD), left atrial remodeling, coronary artery disease (CAD) and risk factors for cardiovascular dysfunction We conducted a retrospective case control study using the presence of left atrial abnormality identified on pre-ibrutinib EKGs, defined as either (1) Lead II-bifed p wave, with 40 mcsec between peaks for ≥ 2.5 mm wide ≥ 100 msec in duration, (2) Lead V1-biphasic P wave with terminal portion ≥ 40 msec in duration or terminal portion ≥ 1 mm deep or (3) PR interval ≥ 200 msec (intra-atrial conduction delay) as a predictor for development of atrial fibrillation. 183 consecutively CLL patients treated with ibrutinib were identified. 44 patients met inclusion criteria (20 cases, 24 controls). 20 (11.3%) of patients developed atrial fibrillation. Left atrial enlargement was identified as a significant predictor of development of atrial fibrillation (OR 9.1, 95% CI 2.2–37.3, p=0.02). Age, baseline HTN, CAD, diabetes, age and sex were not significant predictors. Area under the ROC curve for the model was estimated to be 75%. LAA identified by EKG is a moderately specific and sensitive finding that can identify patients at increased risk for this toxicity.

Outcomes of front-line ibrutinib treated CLL patients excluded from landmark clinical trial.

Ibrutinib demonstrated superior response rates and survival for treatment‐naïve chronic lymphocytic leukemia (CLL) patients in a pivotal study that excluded patients younger than 65 (<65) and/or with chromosome 17p13 deletion (del[17p13]). We examined outcomes and toxicities of CLL patients who would have been excluded from the pivotal study, specifically <65 and/or those with del[17p13]. This multicenter, retrospective cohort study examined CLL patients treated with front‐line ibrutinib at 20 community and academic centers, categorizing them based on key inclusion criteria for the RESONATE‐2 trial: <65 vs ≥65 and present vs absent del[17p13]. Of 391 included patients, 57% would have been excluded from the pivotal study. Forty‐one percent of our cohort was <65, and 30% had del(17p13). Patients <65 were more likely to start 420 mg of ibrutinib daily; those who started at reduced doses had inferior PFS. The most common adverse events were arthralgias, fatigue, rash, bruising, and diarrhea. Twenty‐four percent discontinued ibrutinib at 13.8 months median follow‐up; toxicity was the most common reason for discontinuation, though progression and/or transformation accounted for a larger proportion of discontinuations in <65 and those with del(17p13). Response rates were similar for <65 and those with del(17p13). However, patients with del(17p13) had inferior PFS and OS. Ibrutinib in the front‐line setting has extended beyond the population in which it was initially studied and approved. This study highlights and compares important differences in ibrutinib dosing, treatment interruptions, toxicities, reasons for discontinuation, and survival outcomes in two important patient populations not studied in RESONATE‐2.

Immunoglobulin D Multiple Myeloma, Plasma Cell Leukemia and Chronic Myelogenous Leukemia in a Single Patient Treated Simultaneously with Lenalidomide, Bortezomib, Dexamethasone and Imatinib.

Multiple myeloma (MM) is a neoplastic lymphoproliferative disorder characterized by uncontrolled monoclonal plasma cell proliferation. Among different isotypes of MM, immunoglobulin D (IgD) MM is very rare, representing only 1 to 2% of all isotypes. Chronic myelogenous leukemia (CML) is a neoplastic myeloproliferative disorder of pluripotent hematopoietic stem cell, which is characterized by the uncontrolled proliferation of myeloid cells. An 88-year-old male was diagnosed simultaneously with IgD kappa MM and CML. A distinctive feature in this patient was the progression to plasma cell leukemia without any symptomatic myeloma stage. He was treated simultaneously with lenalidomide, bortezomib and imatinib. Synchronous occurrence of these rare hematological malignancies in a single patient is an exceedingly rare event. Multiple hypotheses to explain co-occurrence of CML and MM have been proposed; however, the exact etiological molecular pathophysiology remains elusive.

Analysis of Efficacy and Tolerability of Bruton Tyrosine Kinase Inhibitor Ibrutinib in Various B-cell Malignancies in the General Community: A Single-center Experience

Background Ibrutinib, an irreversible inhibitor of Bruton tyrosine kinase (BTK), is a novel drug that has shown significant efficacy and survival benefit for treatment of various B‐cell malignancies. The primary objective of the present study was to investigate the efficacy of ibrutinib therapy in various B‐cell malignancies in the general community. The secondary objectives included studying the adverse effects, ibrutinib‐induced peripheral lymphocytosis, and effect on immunoglobulin levels. Patients and Methods The present study was a retrospective observational cohort analysis conducted at Abington Jefferson Health. The clinical response was determined from the hematologists assessment and evaluated independently using the response criteria for each B‐cell malignancy. Adverse effects were graded according to the Common Terminology Criteria for Adverse Events, version 4.0. The Wilcoxon signed‐rank test was used to compare immunoglobulin levels before and after ibrutinib. Forty five patients with B‐cell malignancies and receiving ibrutinib therapy were eligible. Results The median age was 73 years (range, 49‐96 years), and 84.4% of the patients had received ≥ 1 previous therapy. The best overall response rate of all cohorts combined was 63.8%. The greatest overall response rate was observed in patients with chronic lymphocytic leukemia or small lymphocytic lymphoma (76.1%), followed by those with Waldenström macroglobulinemia (75%). Of the 45 patients, 88.9% experienced adverse effects. Antiplatelet activity of ibrutinib was most commonly observed (30.5%). Of note, 5 patients (11%) developed new‐onset atrial fibrillation after drug initiation. Peripheral lymphocytosis after drug initiation was observed in most patients, with a peak level at 1 month (median lymphocyte count, 2.7 × 103 cells/&mgr;L). Although the IgG levels at 3, 6, and 12 months had decreased (P = .01 for all) compared with the levels before ibrutinib, the IgA levels had not increased at 3, 6, 12, and 24 months (P = .6, P = .5, P = .3, and P = .9, respectively). Conclusion Ibrutinib is a highly effective and tolerable drug for B‐cell malignancies in the general community. In contrast to the previously reported rate of 5% to 7%, we observed a higher rate (11%) of atrial fibrillation, which might have resulted from the smaller sample size in the present study and the multiple comorbidities. Nonetheless, this treatment‐limiting side effect requires further elucidation. Paradoxical lymphocytosis at the outset of therapy was a common and benign finding. In conjunction with the reported trials, the IgG levels decreased in the first year of continued therapy. However, the IgA levels did not increase, even after 2 years of therapy. Micro‐Abstract Ibrutinib, a novel Bruton tyrosine kinase inhibitor, has revolutionized the treatment of various B‐cell malignancies. In this retrospective study, we analyzed the data of 45 patients with various B‐cell malignancies to determine ibrutinibs clinical efficacy and adverse effects in a real‐world setting. Results showed an excellent efficacy and a favorable toxicity but a higher incidence of atrial fibrillation.

Bulky scalp melanoma with metastasis responding completely to ipilimumab

A 69-year-old man noticed a ‘pimple’ on the scalp vertex for the first time about 4 months prior to presentation. The lesion was associated with itching, bleeding and an accelerated growth noticed by his wife. Examination demonstrated a 6×7 cm fungating mass with numerous satellite lesions measuring 3–5 mm and associated alopecia (figure 1A). Right occipital and supraclavicular lymphadenopathy was also noted. Biopsy of the lesion revealed BRAF (V600K) mutated malignant melanoma with ulceration, high mitotic index and vascular invasion. Systemic staging with positron emission tomography (PET) and CT scans detected an avid 6 mm right lung nodule and a 1.5 cm mass in the right lobe of the …

Coagulopathy and functional hyposplenism during an episode of thrombotic thrombocytopenic purpura in a HgbS/β+-thalassemia patient

We report a case of TTP in a sickle cell/β+‐thalassemia heterozygote with nonspecific complaints and a evidence of hemolysis, initially attributed to sickle crisis. Included in this case is a discussion of the development of functional hyposplenism, a rarely reported complication, limitation of ADAMTS‐13 in diagnosis, and the use of platelet transfusion.

Real world outcomes and management strategies for venetoclax-treated chronic lymphocytic leukemia patients in the United States

Venetoclax is a BCL2 inhibitor approved for 17p-deleted relapsed/refractory chronic lymphocytic leukemia with activity following kinase inhibitors. We conducted a multicenter retrospective cohort analysis of patients with chronic lymphocytic leukemia treated with venetoclax to describe outcomes, toxicities, and treatment selection following venetoclax discontinuation. A total of 141 chronic lymphocytic leukemia patients were included (98% relapsed/refractory). Median age at venetoclax initiation was 67 years (range 37-91), median prior therapies was 3 (0-11), 81% unmutated IGHV, 45% del(17p), and 26.8% complex karyotype (≥ 3 abnormalities). Prior to venetoclax initiation, 89% received a B-cell receptor antagonist. For tumor lysis syndrome prophylaxis, 93% received allopurinol, 92% normal saline, and 45% rasburicase. Dose escalation to the maximum recommended dose of 400 mg daily was achieved in 85% of patients. Adverse events of interest included neutropenia in 47.4%, thrombocytopenia in 36%, tumor lysis syndrome in 13.4%, neutropenic fever in 11.6%, and diarrhea in 7.3%. The overall response rate to venetoclax was 72% (19.4% complete remission). With a median follow up of 7 months, median progression free survival and overall survival for the entire cohort have not been reached. To date, 41 venetoclax treated patients have discontinued therapy and 24 have received a subsequent therapy, most commonly ibrutinib. In the largest clinical experience of venetoclax-treated chronic lymphocytic leukemia patients, the majority successfully completed and maintained a maximum recommended dose. Response rates and duration of response appear comparable to clinical trial data. Venetoclax was active in patients with mutations known to confer ibrutinib resistance. Optimal sequencing of newer chronic lymphocytic leukemia therapies requires further study.

Brentuximab Vedotin Therapy for Cutaneous Lesions in T-Prolymphocytic Leukemia: A Case Report

We present an 88-year-old male with simultaneous T-cell prolymphocytic leukemia and stable smoldering myeloma with excellent initial response to three months of alemtuzumab. The patient relapsed at twelve months with severe cutaneous disease. Biopsy of a representative plaque demonstrated CD30 positivity in rare malignant lymphocytes. The patient demonstrated no response to reintroduction with a full course of alemtuzumab. He was therefore treated with brentuximab vedotin, resulting in partial remission of skin involvement that persisted for three months.