Duvelisib (also known as IPI-145) is an oral, dual inhibitor of phosphatidylinositol 3-kinase δ and γ (PI3K-δ,γ) being developed for treatment of hematologic malignancies. PI3K-δ,γ signaling can promote B-cell proliferation and survival in clonal B-cell malignancies, such as chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). In a phase 1 study, duvelisib showed clinically meaningful activity and acceptable safety in CLL/SLL patients. We report here the results of DUO, a global phase 3 randomized study of duvelisib vs ofatumumab monotherapy for patients with relapsed or refractory (RR) CLL/SLL. Patients were randomized 1:1 to oral duvelisib 25 mg twice daily (n = 160) or ofatumumab IV (n = 159). The study met the primary study end point by significantly improving progression-free survival per independent review committee assessment compared with ofatumumab for all patients (median, 13.3 months vs 9.9 months; hazard ratio [HR] = 0.52; P < .0001), including those with high-risk chromosome 17p13.1 deletions [del(17p)] and/or TP53 mutations (HR = 0.40; P = .0002). The overall response rate was significantly higher with duvelisib (74% vs 45%; P < .0001) regardless of del(17p) status. The most common adverse events were diarrhea, neutropenia, pyrexia, nausea, anemia, and cough on the duvelisib arm, and neutropenia and infusion reactions on the ofatumumab arm. The DUO trial data support duvelisib as a potentially effective treatment option for patients with RR CLL/SLL. This trial was registered at www.clinicaltrials.gov as #NCT02004522.

We report the long-term outcome of a multicenter, prospective study examining fludarabine and rituximab in Waldenströ m macroglobulinemia (WM). WM patients with less than 2 prior therapies were eligible. Intended therapy consisted of 6 cycles (25 mg/m 2 per day for 5 days) of fludarabine and 8 infusions (375 mg/m 2 per week) of rituximab. A total of 43 patients were enrolled. Responses were: complete response (n ‫؍‬ 2), very good partial response (n ‫؍‬ 14), partial response (n ‫؍‬ 21), and minor response (n ‫؍‬ 4), for overall and major response rates of 95.3% and 86.0%, respectively. Median time to progression for all patients was 51.2 months and was longer for untreated patients (P ‫؍‬ .017) and those achieving at least a very good partial response (P ‫؍‬ .049). Grade 3 or higher toxicities included neutropenia (n ‫؍‬ 27), thrombocytopenia (n ‫؍‬ 7), and pneumonia (n ‫؍‬ 6), including 2 patients who died of non-Pneumocystis carinii pneumonia. With a median follow-up of 40.3 months, we observed 3 cases of transformation to aggressive lymphoma and 3 cases of myelodysplastic syndrome/ acute myeloid leukemia. The results of this study demonstrate that fludarabine and rituximab are highly active in WM, although short-and long-term toxicities need to be carefully weighed against other available treatment options. This study is registered at clinicaltrials.gov as NCT00020800. IntroductionWaldenström macroglobulinemia (WM) is a distinct B-cell lymphoproliferative disorder characterized primarily by bone marrow infiltration with lymphoplasmacytic cells, along with demonstration of an immunoglobulin M (IgM) monoclonal gammopathy. [1][2][3] Among treatment options for patients with WM, nucleoside analogs, as well as the CD20-directed monoclonal antibody rituximab, have been commonly used. Response rates of 30% to 70% and durations of response of 20 to 24 months have been reported with the use of nucleoside analogs in WM patients. [4][5][6][7][8][9][10][11][12][13] Importantly, similar response rates were reported in these studies whether nucleoside analogs were used as first line or salvage therapy. The use of rituximab has also been extensively evaluated in patients with WM. Using standard dose (ie, 4 weekly infusions at 375 mg/m 2 ), overall response rates of 25% to 30% have been observed. More recently, an extended dose regimen giving rituximab at 375 mg/m 2 per week for 4 weeks, then repeated again at week 12, has resulted in higher (40%-50%) overall response rates. 4,[14][15][16][17][18][19] In preclinical studies, the potential for rituximab and fludarabine to enhance each other's activity has been demonstrated and may involve a spectrum of intracellular as well as extracellular mechanisms. [20][21][22] Moreover, in other indolent B-cell malignancies, the combination of rituximab and fludarabine has led to higher response rates than those observed with either agent alone. [23][24][25][26][27] The potential for enhanced clinical benefit by giving rituximab with fludarabine concurrently vs sequentially has also bee...

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Qutenza® is a capsaicin patch used to treat peripheral neuropathic pain, including postherpetic neuralgia (PHN) and human immunodeficiency virus-associated neuropathy (HIV-AN). The Qutenza Clinical Trials Database has been assembled to more fully characterize the effects of Qutenza. We conducted a within-subject meta-analysis of Qutenza studies to further define the medication's efficacy profile across studies. The meta-analysis combined individual patient data from randomized, controlled studies of Qutenza in peripheral neuropathic pain (1458 subjects treated with approved doses of Qutenza or control patches; 1120 with PHN and 338 with HIV-AN). These 7 studies had similar designs and were performed with the high-dose 8% capsaicin Qutenza patch and a 0.04% low-dose control patch. The difference between treatment groups for the primary efficacy end point of percentage change from baseline to weeks 2 to 12 on pain intensity score was calculated. Response was defined as a ≥ 30% decrease in mean pain intensity score during weeks 2 to 12. The overall between-group difference in percentage change from baseline in pain intensity was 8.0% (95% confidence interval 4.6, 11.5; P<.001), which statistically significantly favored Qutenza over low-dose control. Qutenza superiority was demonstrated for both PHN and HIV-AN patients for the primary end point and the end point proportion of 30% pain reduction response, and for PHN patients for the end point of proportion of 50% pain reduction response. These results confirm that Qutenza is effective for the treatment of both PHN and HIV-AN compared to low-dose control patch.

The results of these studies therefore support a predictive role for FcgammaRIIIA-158 polymorphisms and responses to rituximab in WM.