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Purpose: Female Hodgkin lymphoma (HL) survivors treated with chest radiotherapy (RT) at a young age have a strongly increased risk of breast cancer (BC). Studies in childhood cancer survivors have shown that doxorubicin exposure may also increase BC risk. Although doxorubicin is the cornerstone of HL chemotherapy, the association between doxorubicin and BC risk has not been examined in HL survivors treated at adult ages., Methods: We assessed BC risk in a cohort of 1,964 female 5-year HL survivors, treated at age 15-50 years in 20 Dutch hospitals between 1975 and 2008. We calculated standardized incidence ratios, absolute excess risks, and cumulative incidences. Doxorubicin exposure was analyzed using multivariable Cox regression analyses., Results: After a median follow-up of 21.6 years (IQR, 15.8-27.1 years), 252 women had developed invasive BC or ductal carcinoma in situ. The 30-year cumulative incidence was 20.8% (95% CI, 18.2 to 23.4). Survivors treated with a cumulative doxorubicin dose of >200 mg/m 2 had a 1.5-fold increased BC risk (95% CI, 1.08 to 2.1), compared with survivors not treated with doxorubicin. BC risk increased 1.18-fold (95% CI, 1.05 to 1.32) per additional 100 mg/m 2 doxorubicin ( P trend = .004). The risk increase associated with doxorubicin (yes v no) was not modified by age at first treatment (hazard ratio [HR] age <21 years , 1.5 [95% CI, 0.9 to 2.6]; HR age ≥21 years , 1.3 [95% CI, 0.9 to 1.9) or chest RT (HR without mantle/axillary field RT , 1.9 [95% CI, 1.06 to 3.3]; HR with mantle/axillary field RT , 1.2 [95% CI, 0.8 to 1.8])., Conclusion: This study shows that treatment with doxorubicin is associated with increased BC risk in both adolescent and adult HL survivors. Our results have implications for BC surveillance guidelines for HL survivors and treatment strategies for patients with newly diagnosed HL.

Purpose: Proteasome inhibitors are effective in Waldenström's macroglobulinemia (WM) but require parenteral administration and are associated with polyneuropathy. We investigated efficacy and toxicity of the less neurotoxic oral proteasome inhibitor ixazomib combined with rituximab, in patients with relapsed WM., Methods: We conducted a multicenter phase I/II trial with ixazomib, rituximab, and dexamethasone (IRD). Induction consisted of eight cycles IRD wherein rituximab was started in cycle 3, followed by rituximab maintenance. Phase I showed feasibility of 4 mg ixazomib. Primary end point for phase II was overall response rate (ORR [≥ minimal response]) after induction., Results: A total of 59 patients were enrolled (median age, 69 years; range, 46-91 years). Median number of prior treatments was 2 (range, 1-7); 70% had an intermediate or high WM-IPSS (International Prognostic Scoring System for WM) score. After eight cycles, ORR was 71% (42 out of 59) (14% very good partial response [PR], 37% PR, and 20% minor response). Depth of response improved until month 12 (best ORR 85% [50 out of 59]: 15% very good PR, 46% PR, and 24% minor response). Median duration of response was 36 months. The average hematocrit level increased significantly (0.33-0.38 L/L) after induction ( P < .001). After two cycles of ixazomib and dexamethasone, immunoglobulin M levels decreased significantly (median 3,700-2,700 mg/dL, P < .0001). Median time to first response was 4 months. Median progression-free survival and overall survival were not reached. After median follow-up of 24 months (range, 7.4-54.3 months), progression-free survival and overall survival were 56% and 88%, respectively. Toxicity included mostly grade 2 or 3 cytopenias, grade 1 or 2 neurotoxicity, and grade 2 or 3 infections. No infusion-related reactions or immunoglobulin M flare occurred with use of subcutaneous rituximab. Quality of life improved significantly after induction. In total, 48 patients (81%) completed at least six cycles of IRD., Conclusion: Combination of IRD shows promising efficacy with manageable toxicity in patients with relapsed or refractory WM., Competing Interests: Marie José KerstenHonoraria: Novartis, Kite, a Gilead Company, RocheConsulting or Advisory Role: Novartis, Kite, a Gilead Company, Miltenyi Biotec, TakedaResearch Funding: Kite, a Gilead CompanyTravel, Accommodations, Expenses: Novartis, Kite, a Gilead Company, Roche, Celgene Monique C. MinnemaConsulting or Advisory Role: Janssen-Cilag, Alnylam, Gilead SciencesSpeakers' Bureau: Celgene/Bristol Myers SquibbTravel, Accommodations, Expenses: Celgene Josephine M. I. VosConsulting or Advisory Role: Sanofi PasteurTravel, Accommodations, Expenses: Celgene Efstathios KastritisHonoraria: Amgen, Genesis Pharma, Janssen Oncology, Takeda, Prothena, PfizerConsulting or Advisory Role: Amgen, Janssen Oncology, Takeda, Genesis Pharma, Prothena, PfizerResearch Funding: Janssen Oncology, AmgenTravel, Accommodations, Expenses: Janssen Oncology, Genesis Pharma, Takeda, Pfizer Maria GavriatopoulouHonoraria: Amgen, Janssen, Celgene, TakedaConsulting or Advisory Role: Amgen, Karyopharm TherapeuticsResearch Funding: NovartisTravel, Accommodations, Expenses: Takeda, Genesis Pharma, Janssen Martine ChamuleauResearch Funding: BMS, Gilead Sciences, Genmab Dries DeerenConsulting or Advisory Role: Celgene, Alexion Pharmaceuticals, Amgen, Janssen-Cilag, Roche, Takeda, SanofiTravel, Accommodations, Expenses: Gilead Sciences Jeanette K. DoorduijnConsulting or Advisory Role: LillyTravel, Accommodations, Expenses: Celgene Lara H. BöhmerTravel, Accommodations, Expenses: Servier Meletios A. DimopoulosHonoraria: Amgen, Takeda, Janssen-Cilag, Bristol Myers Squibb, BeigeneConsulting or Advisory Role: Amgen, Janssen-Cilag, Takeda, Bristol Myers Squibb, BeigeneNo other potential conflicts of interest were reported.

Purpose: Immunochemotherapy with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) has become standard of care for patients with diffuse large B-cell lymphoma (DLBCL). This randomized trial assessed whether rituximab intensification during the first 4 cycles of R-CHOP could improve the outcome of these patients compared with standard R-CHOP., Patients and Methods: A total of 574 patients with DLBCL age 18 to 80 years were randomly assigned to induction therapy with 6 or 8 cycles of R-CHOP-14 with (RR-CHOP-14) or without (R-CHOP-14) intensification of rituximab in the first 4 cycles. The primary end point was complete remission (CR) on induction. Analyses were performed by intention to treat., Results: CR was achieved in 254 (89%) of 286 patients in the R-CHOP-14 arm and 249 (86%) of 288 patients in the RR-CHOP-14 arm (hazard ratio [HR], 0.82; 95% CI, 0.50 to 1.36; P = .44). After a median follow-up of 92 months (range, 1-131 months), 3-year failure-free survival was 74% (95% CI, 68% to 78%) in the R-CHOP-14 arm versus 69% (95% CI, 63% to 74%) in the RR-CHOP-14 arm (HR, 1.26; 95% CI, 0.98 to 1.61; P = .07). Progression-free survival at 3 years was 74% (95% CI, 69% to 79%) in the R-CHOP-14 arm versus 71% (95% CI, 66% to 76%) in the RR-CHOP-14 arm (HR, 1.20; 95% CI, 0.94 to 1.55; P = .15). Overall survival at 3 years was 81% (95% CI, 76% to 85%) in the R-CHOP-14 arm versus 76% (95% CI, 70% to 80%) in the RR-CHOP-14 arm (HR, 1.27; 95% CI, 0.97 to 1.67; P = .09). Patients between ages 66 and 80 years experienced significantly more toxicity during the first 4 cycles in the RR-CHOP-14 arm, especially neutropenia and infections., Conclusion: Early rituximab intensification during R-CHOP-14 does not improve outcome in patients with untreated DLBCL.