SummaryUbiquitin-mediated protein modification plays a key role in many cellular signal transduction pathways. The Arabidopsis gene XBAT32 encodes a protein containing an ankyrin repeat domain at the N-terminal half and a RING finger motif. The XBAT32 protein is capable of ubiquitinating itself. Mutation in XBAT32 causes a number of phenotypes including severe defects in lateral root production and in the expression of the cell division marker CYCB1;1::GUS. The XBAT32 gene is expressed abundantly in the vascular system of the primary root, but not in newly formed lateral root primordia. Treatment with auxin increases the expression of XBAT32 in the primary root and partially rescues the lateral root defect in xbat32-1 mutant plants. Thus, XBAT32 is a novel ubiquitin ligase required for lateral root initiation.

Ponatinib is associated with cardiovascular adverse events (CAEs), and its frequency in the real world is limited. In this retrospective study, we examined the survival outcomes and associated toxicities in 78 consecutive ponatinib-treated patients with chronic myeloid leukemia (CML) at the Moffitt Cancer Center from January 2011 through December 2017. The most common non-CAE was thrombocytopenia (39.7%), occurring in a dose-dependent fashion. Eighteen patients (23.1%) experienced some form of CAE, with the most common being arrhythmia (9%) and hypertension (7.7%), whereas 3 patients experienced myocardial infarction (3.8%). Before 2014, most patients were started on ponatinib 45 mg daily. There was an inverse correlation between cardio-oncology referral and the number of CAEs (P = .0440); however, a lower ponatinib starting dose, more frequent dose reduction, and increased cardio-oncology referral all were likely to have contributed to the observed decrease in CAEs after 2014. The response rate and 5-year overall survival (OS) were higher than those observed in the Ponatinib Ph+ ALL and CML Evaluation (PACE) trial (major molecular response, 58.7% vs 40% and OS, 76% vs 73%; median follow-up of 32.5 months). Ponatinib-treated patients with chronic phase–CML did not show a significant improvement with allogeneic stem cell transplantation, whereas those with accelerated phase/blast phase–CML had a much better outcome (median OS of 32.9 months vs 9.2 months; P = .01). These results demonstrate that ponatinib is highly effective. Dose adjustments and increased awareness of the cardiotoxicities associated with ponatinib may help maximize its benefits.

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Our previous phase I/II trial of pegylated liposomal doxorubicin (PLD), low-dose dexamethasone, and lenalidomide in patients with relapsed and refractory myeloma showed an overall response rate of 75%, with 29% achieving ≥VGPR. Here, we investigated this combination (PLD 30 or 40 mg/m2 intravenously, day 1; dexamethasone 40 mg orally, days 1-4; lenalidomide 25 mg orally, days 1-21; administered every 28 days) in a phase II study in patients with newly diagnosed symptomatic multiple myeloma to determine its efficacy and tolerability (ClinicalTrials.gov NCT00617591). At best response, patients could proceed with high-dose melphalan or with maintenance lenalidomide and dexamethasone. In 57 patients, we found that the overall response rate and rate of very good partial response and better on intent-to-treat, our primary endpoints, were 77.2% and 42.1%, respectively, with responses per the International Myeloma Working Group. Median progression-free survival was 28 months (95% CI 18.1-34.8), with 1- and 2-year overall survival rates of 98.1 and 79.6%. During induction, grade 3/4 toxicities were neutropenia (49.1%), anemia (15.8%), thrombocytopenia (7%), fatigue (14%), febrile neutropenia (8.8%), and venous thromboembolic events (8.8%). During maintenance, grade 3/4 toxicities were mainly hematologic. We found this combination to be active in patients with newly diagnosed myeloma, with results comparable to other lenalidomide-based induction strategies without proteasome inhibition. In addition, maintenance therapy with lenalidomide was well tolerated.

BACKGROUND: The B-cell receptor (BCR) signaling pathway plays a pivotal pathogenic role in chronic lymphocytic leukemia (CLL). Ibrutinib is an irreversible Bruton's tyrosine kinase (BTK) inhibitor that effectively treats patients with CLL, including those harboring poor-risk mutations such as del17p. Here we present the outcomes of CLL patients (pts) who discontinued ibrutinib while being treated outside clinical trials. METHODS: The primary objective was to describe the clinical characteristics, reasons for of discontinuation and outcomes after stopping Ibrutinib. Using the Moffitt Cancer Center, Total Cancer Care and pharmacy registry, we identified and reviewed the charts of all CLL pts that had been treated with ibrutinib from January 2013 to July 2015. Pts were evaluated for time to discontinuation, reason for discontinuation and overall survival (OS) after discontinuation. Survival outcomes were estimated using the Kaplan-Meier method and the log-rank test. All analyses were done using SPSS version 19.0. RESULTS: We identified 54 relapsed/refractory (R/R) CLL pts treated with ibrutinib. The median age was 62 (36-80) and female/male ratio 0.1. The median number of prior therapies was 2 (1-6), 60% had unmutated IgVH, 36% had del17p and 14% had complex karyotype. Eighty percent received and failed fludarabine-based regimens (Table 1). After a median follow up of 9.1 months (0.5-23.3) for survivors, there were 22 (41%) CLL pts who discontinued ibrutinib; 7 due to disease progression (PD), 8 due to toxicity and 7 due to proceeding with hematopoietic stem cell transplantation (HSCT). The most common side effects that lead to ibrutinib discontinuation were: major bleeding events (3), atrial fibrillation (2), grade 3 constipation (1) and grade 2 recurrent skin rashes (1). The median duration of ibrutinib therapy was 3.7 (0.9 - 10.9) months. The median OS for CLL pts with PD after ibrutinib and HSCT was 5.5 and 10.8 months, respectively. In pts who discontinued ibrutinib due to toxicity, the median OS was not reached. Of the seven patients who underwent HSCT, 71% had unmutated IgVH, 43% had del17p, one had complex karyotype and all of them had a clinical response to ibrutinib (PR= 1 and SD =6) prior to HSCT. Four patients developed RichterÕs transformation (RT) upon progression with median OS of 3 months; 3 had del17p/complex karyotype. By univariate analysis RT was associated with inferior OS. CONCLUSION: R/R CLL patients that are treated with ibrutinib and experience disease progression have a dismal prognosis, especially in those who develop RT that appears to be the most important prognostic factor for OS in this group. In addition, ibrutinib appears to be an effective therapy for CLL pts as a bridge for allogeneic HSCT and in general for patients with R/R CLL. Table 1. Main characteristics of CLL patients that discontinued Ibrutinib outside clinical trials Patients characteristics Patients (N=22) Age at discontinuation* 62 (36-80) Unmutated IgVH 13 (60%) Del17p# 8 (36 %) Complex karyotype 3 (14%) Number of prior therapies* 2 (1-5) Clinical responseá Stable disease (SD)á Partial response (PR)á Progressive disease (PD) 12 (52%) 3 (13%) 2 (9%) *Median; #one patient had both del17p and TP53 mutation. Disclosures Shah: Acetylon: Membership on an entity's Board of Directors or advisory committees; Rosetta Genomics: Research Funding; Spectrum: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bayer: Honoraria; Pharmacyclics: Speakers Bureau; PLexus Communications: Honoraria; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Seattle Genetics: Research Funding. Sokol:Spectrum: Consultancy; Seatle Genetics: Research Funding; Celgene: Consultancy. Pinilla-Ibarz:BMS: Consultancy, Honoraria, Other: Consulting & Advisory Role, Speakers Bureau; Pfizer: Consultancy, Other: Consulting & Advisory Role, Research Funding, Speakers Bureau; Novartis: Consultancy, Other: Consulting & Advisory Role, Research Funding; ARIAD Pharmaceuticals, Inc.: Consultancy, Other: Consulting & Advisory Role, Research Funding; Teva: Consultancy, Speakers Bureau.