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AbstractBackgroundSecond hematologic cancers in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) are well documented and include Hodgkin lymphoma, therapy‐related acute myeloid leukemia/myelodysplastic syndromes, and transformation to diffuse large B‐cell lymphoma. Although cutaneous T‐cell lymphoma (CTCL) has been reported in patients with CLL, the incidence and comparison to expected rates are unknown. We evaluated the incidence of CTCL among patients with CLL or other non‐Hodgkin lymphoma (NHL) subtypes using data from the Surveillance, Epidemiology, and End Results (SEER) Program.MethodsWe searched the SEER 13 registries for patients with a diagnosis of CLL and NHL between 1992 and 2008. Among patients identified, we evaluated the incidence of CTCL.ResultsAmong 31,286 patients with CLL, the incidence of CTCL was not significantly higher in men than women: 104.2 (95% CI, 50.0–191.8) and 28.1 (95% CI, 3.4–101.3) per 1,000,000 person‐years, respectively (P = 0.06). Among 97,691 patients with NHL, the incidence of CTCL was similar in men and women (97.9 [95% CI, 62.0–146.9] and 92.0 [95% CI, 56.2–142.1] per 1,000,000 person‐years, respectively; P = 0.84). The incidence of CTCL among males with CLL (standardized incidence ratio [SIR], 3.0 [95% CI, 1.4–5.5]), males with NHL (SIR, 3.7 [95% CI, 2.3–5.5]), and females with NHL (SIR, 5.9 [95% CI, 3.6–9.1]) was significantly higher than expected in the general population (all P < 0.001).ConclusionThe risk of CTCL is greater in men with CLL than in the general population. In patients with NHL, both men and women are at greater risk for CTCL than in the general population.

Summary This study aimed to describe the patterns of care and outcomes of diffuse large B cell lymphoma ( DLBCL ) after failure of front line anthracycline‐based immunochemotherapy ( IC ). Patients with newly diagnosed lymphoma were prospectively enrolled in Molecular Epidemiology Resource ( MER ) of the University of Iowa/Mayo Clinic Lymphoma Specialized Program of Research Excellzence. All DLBCL and primary mediastinal B‐cell lymphoma ( PMBL ) patients treated with front‐line anthracycline‐based IC were followed for relapse. Patients with relapse on follow‐up and subsequently retreated were included in this analysis. 1039 patients received anthracycline‐based IC between 2002 and 2012, of which 244 relapsed and were subsequently retreated. Across all therapies, overall survival at 4 years ( OS 4) from relapse was 28% and 103 patients ultimately underwent autologous haematopoietic cell transplant (auto HCT ) with OS 4 from auto HCT of 51%. Patients relapsing after 12 months from initial diagnosis had OS 4 of 47% but those with a transient or no response to initial therapy had OS 4 of only 13%. Outcomes of relapsed or refractory DLBCL differ substantially when categorized by response to initial therapy, timing of relapse and opportunity to undergo auto HCT . The design and interpretation of uncontrolled trials should account for this heterogeneity in patients with relapsed DLBCL .

SummaryHistological transformation (HT) of follicular lymphoma (FL) to an aggressive lymphoma after chemotherapy remains a key issue. The incidence of HT after radioimmunotherapy (RIT) is unknown. This single institution study analysed the risk of HT in FL after treatment with yttrium‐90 ibritumomab tiuxetan in 115 consecutive patients treated during 1987–2012. RIT was administered for progressive FL in 111 (97%) patients and as first‐line therapy in the remaining 4. 28% (n = 32) had HT, occurring at a median of 60 months from diagnosis and 20 months after RIT. 48% (12/25) of patients who received fludarabine developed HT. The estimated 10‐year risk of HT in the fludarabine and non‐fludarabine groups was 67% and 26% respectively (P = 0·015). Only prior fludarabine was significantly associated with predicting the risk of HT after RIT. 8% (9/115) of patients developed therapy‐related myelodysplastic syndrome/acute myeloid leukaemia (tMDS/AML) at a median of 41·4 months (range, 5–89). The estimated 10‐year risk of tMDS/AML in non‐fludarabine treated patients (n = 90) versus fludarabine treated (n = 25) was 13% and 29%, respectively. The estimated overall risk of FL undergoing HT at 10 years without fludarabine exposure appears similar to patients reported in the literature that have not received RIT. Patients with prior purine‐analogue therapy are at significantly higher risk of HT.

Key Points Pembrolizumab was first shown to be clinically active in CLL patients with RT. PD-1 and PD-L1 expression in tumor microenvironment are promising biomarkers to select RT patients for PD-1 blockade.

Akt is a downstream target of B cell receptor signaling and is a central regulator of CLL cell survival. We aim to investigate the safety and efficacy of the Akt inhibitor MK‐2206 in combination with bendamustine and rituximab (BR) in relapsed and/or refractory CLL in a phase I/II study. A standard phase I design was used with cohorts of three plus three patients to determine the maximum tolerated dose (MTD) of MK‐2206 in combination with BR in relapsed CLL. Single‐agent MK‐2206 (weekly dosed) was administered one‐week in advance before BR on cycle 1 and subsequently was given with BR at the same time for cycle 2‐6. Phase II employed the MTD of MK‐2206 with BR to evaluate safety and efficacy of this study combination. Thirteen relapsed/refractory CLL were treated for maximal 6‐cycle of therapy. The maximum tolerated dose of MK‐2206 was 90 mg by mouth once weekly. The most common grade 3/4 adverse events were neutropenia (46%), febrile neutropenia (23%), rash (15%), diarrhea (15%), and thrombocytopenia (15%). Overall response rate was 92% with a median progression free survival and treatment free survival of 16 and 24 months, respectively. Five patients (38%) achieved complete remission or complete remission with incomplete count recovery, two of whom were MRD negative. The efficacy and tolerability of this combination indicates that Akt inhibition combined with chemoimmunotherapy is a promising novel treatment combination in CLL and deserves further prospective clinical trial.