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Tryptophan hydroxylase (TPH) is a rate-limiting enzyme for serotonin or 5-hydroxytryptamine (5-HT) synthesis. Previously, adipocyte TPH1 has been linked to increased adipose 5-HT, reduced brown adipose tissue (BAT) thermogenesis, and obesity. However, the role of TPH2, a neural isoform highly expressed in obese adipose tissue, is unknown. Here, we report that adipose tissue expression of TPH2 is dramatically elevated in mice with diet-induced obesity (DIO) and ob/ob mice, as well as in obese humans. In mice fed a high-fat diet, adipocyte TPH2 deficiency improved DIO-induced metabolic complications, enhanced BAT thermogenesis, and increased intestinal energy-harvesting efficiency without affecting adiposity. Conversely, TPH2 overexpression in epididymal adipocytes of chow-fed mice raised adipose and plasma 5-HT levels, suppressed BAT thermogenesis, and exacerbated obesity and metabolic dysfunction. We found that obesity-induced hyperinsulinemia upregulated adipocyte TPH2 expression via activation of mechanistic target of rapamycin complex 1 and SREBP1. In humans, TPH2 mRNA levels in subcutaneous adipose tissue, but not those of TPH1 , are positively correlated with fasting plasma insulin concentrations. In summary, our study demonstrates that obesity-associated increases in adipocyte TPH2 can regulate distal tissue physiology and energy metabolism, suggesting that TPH2 could be a potential therapeutic target for obesity and its associated complications.

BACKGROUND: Small, randomized trials of patients with cervical artery dissection showed conflicting results regarding optimal stroke prevention strategies. We aimed to compare outcomes in patients with cervical artery dissection treated with antiplatelets versus anticoagulation. METHODS: This is a multicenter observational retrospective international study (16 countries, 63 sites) that included patients with cervical artery dissection without major trauma. The exposure was antithrombotic treatment type (anticoagulation versus antiplatelets), and outcomes were subsequent ischemic stroke and major hemorrhage (intracranial or extracranial hemorrhage). We used adjusted Cox regression with inverse probability of treatment weighting to determine associations between anticoagulation and study outcomes within 30 and 180 days. The main analysis used an as-treated crossover approach and only included outcomes occurring with the above treatments. RESULTS: The study included 3636 patients (402 [11.1%] received exclusively anticoagulation and 2453 [67.5%] received exclusively antiplatelets). By day 180, there were 162 new ischemic strokes (4.4%) and 28 major hemorrhages (0.8%); 87.0% of ischemic strokes occurred by day 30. In adjusted Cox regression with inverse probability of treatment weighting, compared with antiplatelet therapy, anticoagulation was associated with a nonsignificantly lower risk of subsequent ischemic stroke by day 30 (adjusted hazard ratio [HR], 0.71 [95% CI, 0.45–1.12]; P =0.145) and by day 180 (adjusted HR, 0.80 [95% CI, 0.28–2.24]; P =0.670). Anticoagulation therapy was not associated with a higher risk of major hemorrhage by day 30 (adjusted HR, 1.39 [95% CI, 0.35–5.45]; P =0.637) but was by day 180 (adjusted HR, 5.56 [95% CI, 1.53–20.13]; P =0.009). In interaction analyses, patients with occlusive dissection had significantly lower ischemic stroke risk with anticoagulation (adjusted HR, 0.40 [95% CI, 0.18–0.88]; P interaction =0.009). CONCLUSIONS: Our study does not rule out the benefit of anticoagulation in reducing ischemic stroke risk, particularly in patients with occlusive dissection. If anticoagulation is chosen, it seems reasonable to switch to antiplatelet therapy before 180 days to lower the risk of major bleeding. Large prospective studies are needed to validate our findings.

TPS1125 Background: Despite the many available treatments for patients (pts) with HR+, HER2– recurrent/metastatic breast cancer (MBC), optimal treatment after progression on CDK4/6 inhibitors (CDK4/6i) is unclear. One possible CDK4/6i resistance mechanism is increased expression of Aurora kinase A (AURKA), a key mitosis regulator associated with poor prognosis. Further implicated in CDK 4/6i resistance, high c-Myc or RB1 loss of function (LOF) are associated with transcriptional co-regulation or synthetic lethality, respectively, with AURKA. Alisertib is a highly selective, reversible, ATP-competitive, orally administered, small-molecule AURKA inhibitor with antiproliferative activity in HR+ BC-derived cell lines and BC xenograft models. Models with elevated AURKA or c-Myc expression, or RB1 LOF show greater alisertib sensitivity. Alisertib had activity in phase 1 and 2 trials, including objective response rates (ORRs) of 19.6–20% and median progression-free survival (PFS) of 5.4–5.6 months alone or with fulvestrant in pts with HR+/HER2–, endocrine-resistant MBC. The most common treatment-related grade ≥3 adverse events (AEs) were neutropenia, anemia, and leukopenia. Methods: ALISCA-Breast1 (NCT06369285) is a randomized phase 2 study. Primary objective: to determine the optimal alisertib dose administered with endocrine therapy (ET) based on AEs and serious AEs per CTCAE v5.0 and efficacy (ORR, duration of response, disease-control rate, PFS, overall survival). Secondary objectives: to identify biomarkers of efficacy and alisertib pharmacokinetics (PK). Key inclusion criteria: ≥18 years; ECOG performance status 0 or 1; confirmed HR+, HER2–, recurrent/metastatic breast adenocarcinoma not amenable to curative therapy; available tumor tissue for biomarker analyses; progression on or after ≥2 prior ET lines in recurrent/metastatic setting; prior CDK4/6i with ET in recurrent/metastatic setting. Key exclusion criteria: prior chemotherapy in recurrent/metastatic setting; prior AURKA-specific or pan-Aurora-targeted agents; unstable brain metastases. Eligible pts will be randomized 1:1:1 to alisertib 30 mg, 40 mg, or 50 mg orally twice daily on days 1−3, 8–10, and 15–17 every 28 days, plus physician’s choice of anastrozole, letrozole, exemestane, fulvestrant, or tamoxifen not previously used in recurrent/metastatic setting or progressed upon in adjuvant setting; ≤50 pts will be enrolled per arm in the USA and Europe. All pts will undergo sparse PK sampling. Tumor tissue will be centrally assessed for biomarkers, including RB1, MYC, TP53, ESR1, PI3K/AKT pathway, HER2 and AURKA genomic alterations/expression levels. The study will determine the optimal alisertib dose to combine with ET and may identify biomarker(s) defining pts with the greatest benefit from alisertib-based therapy. Clinical trial information: NCT06369285 .

1586 Background: Black and Hispanic breast cancer (BC) survivors have a higher prevalence of obesity and experience less success with weight loss interventions (WLI) than White BC survivors. The BWEL trial (Alliance A011401; NCT02750826) is a phase III randomized trial evaluating the impact of a 2-year telephone-based WLI on invasive disease-free survival in participants (pts) with stage II-III HER2-negative BC and a BMI ≥ 27 kg/m 2 . At 12-months, the WLI induced significant weight loss across demographic factors, including race and ethnicity. However, Black and Hispanic pts lost less weight and completed fewer calls than White pts. Here, we evaluate intervention adherence, engagement and tool utilization in BWEL pts by race and ethnicity. Methods: BWEL randomized pts to a WLI plus health education (HE) or HE alone. WLI pts received semi-structured telephone-based health coaching, delivered in English or Spanish, and received an activity monitor and wireless scale. Pts self-reported race and ethnicity. Mean values for call duration, call density (time to complete the initial 12-week intensive intervention phase), intervention attrition, and frequency of Fitbit use and weight tracking over 12-months were compared by race and ethnicity, comparing least squares means with Tukey-Kramer adjustment for multiple comparisons with adjusted p-values. Results: Of 3181 pts randomized to the study between 08/2016 and 02/2021, 1591 pts were allocated to the WLI arm. 80.5% of pts were White, 12.8% Black, and 7.1% Hispanic. Average BMI was 34.5 (±5.7) kg/m2. Compared to White pts, Black pts had fewer days of Fitbit usage (113.6 vs. 159.8, p<0.0001) and weight tracking (77.9 vs. 135.6 days, p< 0.0001). Hispanic pts had fewer days of Fitbit usage (108.8 vs. 154.9, p= 0.001) and weight tracking (87 vs. 129.5 days, p=0.0002) compared to non-Hispanic pts. There were no differences in attrition rate, average call duration, or call density by race or ethnicity. Conclusions: In a phase III WLI trial, engagement with tools designed to support weight loss was significantly lower in Black and Hispanic pts. Future work is needed to explore ways to enhance engagement and improve weight loss outcomes for racial and ethnic minority pts. Support: U10CA180821, U10CA180882, UG1CA189823; https://acknowledgments.alliancefound.org . Clinical trial information: NCT02750826 . Measure of engagement Race Ethnicity WhiteN=1281 BlackN=204 p-value Non-HispanicN=1459 HispanicN=113 p-value Withdrew from intervention n (%) 58 (4.5%) 13 (6.4%) 0.56 70 (4.8%) 6 (5.3%) 0.51 Call Duration (min)Mean (SD) 34.5 (7.6) 34.6 (9.1) 0.99 34.6 (7.8) 33.3 (7.9) 0.25 Call density(weeks)Mean (SD) 14.2 (7.2) 14.2 (8.8) 0.99 14.2 (7.3) 14.2 (9.7) 0.99 Days of Fitbit UseMean (SD) 159.8 (132.2) 113.6 (124.7) < 0.0001 154.9 (131.8) 108.8 (125.7) 0.001 Days of weight trackingMean (SD) 135.6 (109.5) 77.9 (87.5) < 0.0001 129.5 (108.8) 87 (96.5) 0.0002

526 Background: The PALLAS trial (NCT02513394) investigated the efficacy of the addition of palbociclib (palbo) to standard adjuvant endocrine therapy (ET) to reduce breast cancer recurrence. Previous analyses of this trial have not shown significant benefit of combination palbo+ET over ET alone. Given prior data showing that extent of neutropenia is associated with response to palbo and other cell cycle-specific therapies, we evaluated whether extent of neutropenia could identify responders to palbo in the adjuvant setting. Methods: PALLAS is a global, open-label, phase III trial that randomized patients (pts) with stage II-III hormone-receptor positive, HER2-negative breast cancer to receive ET for ≥5 years with or without standard-dose palbo for 2 years in 28-day cycles. The primary endpoint is invasive disease-free survival (iDFS). For this exploratory analysis, the palbo population was classified into pts with treatment-emergent high-grade neutropenia (HGN) with maximum grade ≥3 (absolute neutrophil count <1000), or low-grade/no neutropenia (LGN) with maximum grade <2; these groups were compared to each other and to the ET alone group for 5-year iDFS outcomes. Logistic regression examined individual baseline characteristics associated with HGN during the first 3 cycles within the palbo group. Impact of HGN during the first 3, 6, and 12 cycles on iDFS was tested using univariate and multivariable landmark Cox regression. Results: The safety population included 5736 pts, 2840 allocated to palbo+ET, 2896 to ET alone. Prior publications reported no new safety signals, low rates of serious infection, and no grade 5 treatment-related events. The palbo+ET group consisted of 1006 (35.4%) LGN and 1834 (64.6%) HGN. 5-year iDFS results are shown in the table. Pts who received palbo+ET and developed HGN by the end of cycle 6 had significantly improved 5-year iDFS compared to those who received ET alone (p=0.04), which remained statistically significant when adjusting for body mass index (BMI), prior chemotherapy, and race. Multivariable logistic regression showed lower BMI, prior chemotherapy, Asian race, and prior mastectomy were significantly associated with HGN (all p<0.05). Conclusions: In this exploratory analysis of the phase III PALLAS adjuvant trial, addition of palbo to ET appeared to be superior to ET alone in pts who developed HGN in the first 6 cycles of treatment but not in those who had LGN. These findings are consistent with observations in the metastatic setting suggesting that neutropenia could be a useful biomarker for palbo concentration and efficacy. Clinical trial information: NCT02513394 . Maximum grade neutropenia measured at end of cycle: 5-year iDFS Palbo+ET HGN (%) Palbo+ET LGN (%) ET alone (%) Hazard Ratio p-value 3 84.9 84.4 1.06 0.54 84.9 82.9 1.17 0.06 6 85.6 84.9 1.08 0.44 85.6 83.4 1.19 0.04 12 86.3 85.9 1.06 0.57 86.3 85.0 1.12 0.20

561 Background: Obesity and other lifestyle factors are associated with breast cancer (BC) risk and outcomes. These relationships appear to vary in pre- vs postmenopausal women. Here we explore associations between pathological features, diet quality and physical activity (PA) in patients (pts) with BC enrolled in the BWEL (Alliance for Clinical Trials in Oncology A011401) trial, stratifying for menopausal status. Methods: BWEL is a phase III trial evaluating the impact of a weight loss intervention on disease outcomes in 3180 pts with stage II-III HER2– BC and body mass index ≥27 kg/m 2 . The first 542 BWEL pts underwent assessment of PA (7-Day PA Recall) and diet (24-hour Diet Recall) at enrollment. Healthy Eating Index 2020 (HEI) score (0-100, higher value = healthier diet) and minutes/week (min/wk) of moderate/vigorous PA (MVPA) were calculated. Estrogen receptor (ER) and progesterone receptor (PR) expression level (%) were abstracted from pathology reports. Analyses of links between HEI score, MVPA min/wk, % ER/PR, stratified by menopausal status, were conducted using t-tests; differential associations by menopausal status used linear regression models with interaction term. Results: In 523 pts with available pathology data, 76.5% had ER/PR+ BC, 56.2% were postmenopausal. Median HEI score was 50.1 (range 18.1-96.4), median MVPA min/wk was 0 (range 0-630), median time from diagnosis to enrollment was 10.0 months (range 2.4-13.1). In postmenopausal pts, higher diet quality was linked to increased % ER and PR (HEI above vs below median, mean % ER 78.0 vs 66.1, p=0.012; mean % PR 57.7 vs 43.1, p=0.004). The relationship between HEI score and % ER/PR differed significantly by menopausal status (interaction term of menopausal status and % ER: p=0.006; and % PR: p=0.012); there were no significant associations between HEI scores and % ER/PR in premenopausal pts. There were no significant associations between PA and % ER/PR. Conclusions: Healthier diet was associated with higher % ER and PR in postmenopausal pts with BC, but no relationship was seen in premenopausal pts. These data suggest that lifestyle factors may influence BC pathologic features related to outcomes in older women. Support: U10CA180821, U10CA180882, UG1CA189823, U24CA196171, https://acknowledgments.alliancefound.org . Clinical trial information: NCT02750826 . % ER mean (SD) p value % PR mean (SD) p value Post-Menopausal HEI* score≤50.1 [n=134]>50.1 [n=156] 66.1 (43.3)78.0 (36.8) 0.012 43.1 (41.8)57.7 (41.0) 0.004 MVPA † min/wk0 [n=147]≥1 [n=147] 74.5 (39.3)70.3 (41.2) 0.37 50.0 (41.8)53.0 (42.0) 0.41 Pre-Menopausal HEI* score≤50.1 [n=124]>50.1 [n=103] 70.5 (38.5)65.5 (43.0) 0.15 53.5 (41.1)49.1 (43.0) 0.43 MVPA † min/wk0 [n=112]≥1 [n=113] 66.3 (41.0)66.3 (41.2) 0.99 49.5 (41.4)52.6 (42.7) 0.59 *Healthy Eating Index. † Moderate/Vigorous Physical Activity.

e12562 Background: Previous research has suggested that breast cancer (BC) diagnosed during pregnancy or the postpartum period exhibits more aggressive clinical features, possibly due to pregnancy-related hormonal changes, immune modulation, and alterations in the mammary microenvironment compared to nulligravid or women many years out from pregnancy. Emerging data have demonstrated potential worse outcomes for patients (pts) diagnosed in post-partum. This study evaluated the influence of timing of diagnosis in relation to pregnancy history and recency of childbirth on long-term outcomes in a modern cohort of young pts with early-stage BC. Methods: Pts with stage I–III BC age < 40y in the prospective Young Women’s Breast Cancer Study (YWBCS) were categorized at diagnosis as Nulligravid (no prior pregnancy), Nulliparous (prior pregnancy without live birth), Currently Pregnant, or Parous (subdivided by time since last childbirth: within 5 years [≤ 5y PP], and 5–10 years postpartum [5–10y PP]). Baseline characteristics and outcomes were compared across BC subtypes (estrogen receptor+/HER2- [ER+/HER2-], HER2+, and triple-negative BC [TNBC]). Prognostic analyses for distant recurrence-free survival (DRFS) used Cox models. Results: 859 pts were included, 257 (30%) nulligravid, 50 (6%) nulliparous, 37 (4%) pregnant, and 515 (60%) parous (348 [68%] were ≤5y PP, and 167 [32%] were 5–10y PP). Median follow-up was 133 (6–209) months. Median age at diagnosis was lower in nulligravid pts (33 vs. 35–38 years); T1 tumors were most common in pts >5y PP (62%), and N0 status was highest in nulligravid pts (64%) (all p < 0.0001). Pregnant pts had higher rates of TNBC (27%), and T3 tumors (14%), N1 status, N1 (41%), and Grade 3 (81%) tumors compared to other groups (all p < 0.0001). Overall, only tumor size (T2-T4 vs T1, HR 2.03; 95% CI 1.37–3.03) and nodal status (N1 vs N0, HR 2.22; 1.48–3.34; N2/3 vs N0, HR 3.23; 1.96-5.33) were independently associated with worse DRFS; pregnancy history was not: nulligravid + nulliparous pts had no significant differences in DRFS compared to Pregnant (HR 1.46; 0.75–2.86), Parous <5y PP (HR 0.86; 0.58–1.26), and Parous 5–10y PP (HR 0.89; 0.54–1.48). Subgroup analyses by BC subtype (Table) and sensitivity analyses (excluding currently pregnant pts or separating nulligravid and nulliparous pts) demonstrated no significant associations between pregnancy history and DRFS. Conclusions: In this cohort study of very young patients with early breast cancer with contemporary treatment including management of breast cancer during pregnancy, pregnancy history and recency of pregnancy were not independent predictors of long-term disease outcomes. DRFS results by subgroup. Pregnancy Group N (%) HR (95% CI) ER+/HER2- Nulligravid + Nulliparous 173 (38.1) Ref Pregnant 16 (3.5) 0.93 (0.32–2.70) Parous ≤5y PP 177 (39.0) 0.77 (0.45–1.29) Parous 5–10y PP 88 (19.4) 0.78 (0.39–1.53) HER2+ Nulligravid + Nulliparous 77 (30.8) Ref Pregnant 11 (4.4) 3.27 (0.80–13.38) Parous ≤5y PP 113 (45.2) 1.50 (0.60–3.75) Parous 5–10y PP 49 (19.6) 1.45 (0.45–4.66) TNBC Nulligravid + Nulliparous 56 (36.8) Ref Pregnant 10 (6.6) 1.92 (0.61–6.09) Parous ≤5y PP 57 (37.5) 0.68 (0.28–1.63) Parous 5–10y PP 29 (19.1) 1.16 (0.43–3.14)

5069 Background: Ra-223 improves the overall survival in patients with mCRPC to the bone. We assessed the safety of standard-of-care Ra-223 in combination with peposertib, a DNA-dependent protein kinase inhibitor, with or without avelumab, an anti-PD-L1 antibody. Methods: Patients with mCRPC and two or more skeletal metastases identified by bone scintigraphy with or without lymph node metastases up to 3 cm in size, but no visceral metastases, were eligible. Progression after progression after at least one androgen receptor pathway inhibitor or taxane was required. Phase 1 consisted of a two-step sequential safety lead-in using a 3+3 design. Step 1 combined 6 standard cycles of Ra-223 (55 kBq/kg), with increasing doses of peposertib: 50, 100, and 200 mg PO bid on days 3-26 of each cycle. Step 2 combined Ra-223 with the maximum tolerated dose of peposertib and added standard avelumab 800 mg IV every 14 days, starting at cycle 2 of Ra-223. Results: A total of 9 patients participated in Step 1, where the maximum tolerated peposertib dose of 200 mg PO bid with Ra-223 was deemed tolerable. A total of 6 patients participated in Step 2 and the combination of Ra-223, peposertib at 200 mg PO bid, and standard avelumab was deemed tolerable. Of the 15 patients in Phase 1, none experienced grade 4 or higher treatment-related toxicities, while 7 experienced grade 3 toxicities, including neutropenia (1), anemia (1), cardiac chest pain (1), fall (1), maculopapular rash (2), and lymphopenia (2). The median (Q1, Q3) PSA velocity from the beginning to the end of treatment was lower for Step 2 versus Step 1: 2.1 (-0.1, 4.6) versus 23.5 (18.6, 77.1) ng/mL/month (p = 0.0067). OS and PFS were calculated with the limitation that the Phase 1 was non-randomized. Median OS was not reached for Step 2, as only 1 of 6 patients had died, versus 15.2 months for Step 1, where 8 out of 9 patients had died (p = 0.0537). The patient who died in Step 2 discontinued therapy prematurely after 3 cycles due to progression and survived 15.2 months (the 5 alive completed all 6 cycles). The median radiographic PFS was 7 months for Step 2 versus 12.7 months for Step 1 (p = 0.8910). Conclusions: The combination of Ra-223 and peposertib, with or without avelumab was well tolerated. The triplet combination showed the most promising results at this early evaluation. We continue to accrue in the randomized Phase II portion of the trial. Clinical trial information: NCT04071236 .

PURPOSE Several lines of treatment can be used sequentially in patients with metastatic colorectal cancer. We investigated the evolution of patient/tumor characteristics and their prognostic impact across treatment lines to develop an overall prognostic score (OPS). PATIENTS AND METHODS Individual patient data from 48 randomized trials were analyzed. The end point was overall survival (from random assignment to death). Missing data were imputed. The complete data set was then separated into construction (80%) and validation sets (20%). The Cox's model was used to define risk groups for survival using the OPS. The discrimination capability was assessed in each treatment-line via bootstrapping to obtain optimism-corrected calibration and discrimination C-indices. Internal validation was done in the validation set. RESULTS A total of 37,560 patients (26,974 in first-line [1L], 7,693 in second-line [2L], and 2,893 in third-line [3L]) were analyzed. Some clinical, biological, and molecular characteristics of patients/tumors included in therapeutic trials evolve over the lines. Seven independent prognostic variables were retained in the final multivariate model common to all lines: Eastern Cooperative Oncology Group performance status, hemoglobin, platelet count, WBC/absolute neutrophil count ratio, lactate dehydrogenase, alkaline phosphatase, and the number of metastatic sites. The OPS was used to define four patient subgroups with significantly different prognoses in 1L, 2L, and 3L, separately, with adequate C-indices: 0.65, 0.66, and 0.69 in the construction set and 0.65, 0.66, and 0.68 in the validation set, respectively. The OPS was not predictive, with 3L drugs ( v placebo) or subsequent line (2L/1L or 3L/2L) extending survival in all prognostic groups. CONCLUSION The same prognostic model using practical variables can be used before all treatment lines. The OPS could better stratify patients in future clinical trials and help to therapeutic decision in routine practice.

PURPOSE The combination of the Bruton tyrosine kinase inhibitor ibrutinib with bendamustine-rituximab for first-line treatment of mantle cell lymphoma (MCL) prolonged progression-free survival (PFS), but without improvement in overall survival (OS), likely because of toxicity. Acalabrutinib was shown to be efficacious and less toxic than ibrutinib in a head-to-head trial in chronic lymphocytic leukemia and therefore might lead to better outcomes in MCL. METHODS Patients 65 years and older with previously untreated MCL received acalabrutinib (100 mg twice daily) or placebo (until disease progression or unacceptable toxicity), plus six cycles of bendamustine (90 mg/m 2 once daily; days 1 and 2) and rituximab (375 mg/m 2 as a single dose; day 1) followed by rituximab maintenance in responding patients for 2 years. Crossover to acalabrutinib at disease progression was permitted. The primary end point was PFS per the independent review committee; overall response rate and OS were secondary end points. RESULTS In total, 598 patients were randomly assigned, with 299 in each arm. At a median follow-up of 49.8 months using the reverse Kaplan-Meier method, the median PFS was 66.4 months in the acalabrutinib arm and 49.6 months in the placebo arm (hazard ratio [HR], 0.73 [95% CI, 0.57 to 0.94]; P = .0160). Benefit was seen across all subgroups, including those with high-risk features. Overall response/complete response rates were 91.0%/66.6% and 88.0%/53.5% in the acalabrutinib and placebo arms, respectively. OS was not significantly different (HR, 0.86 [95% CI, 0.65 to 1.13]; P = .27). Grade 3 or greater adverse events were reported in 88.9% and 88.2% in the acalabrutinib and placebo arms, respectively. CONCLUSION The combination of acalabrutinib with bendamustine-rituximab significantly improved PFS. Clinical benefit of acalabrutinib with bendamustine-rituximab was achieved with manageable toxicity.