Bendamustine lymphodepletion is a well-tolerated alternative to fludarabine and cyclophosphamide lymphodepletion for axicabtagene ciloleucel therapy for aggressive B-cell lymphoma.

Fludarabine/cyclophosphamide (Flu/Cy) is established for lymphodepletion (LD) prior to standard-of-care CAR T-cell therapy for lymphoma. There is ongoing need to test alternative LD regimens to preserve efficacy, improve safety, and address challenges including the recent national fludarabine shortage. We retrospectively evaluated outcomes among patients with relapsed/refractory aggressive B-cell lymphoma who received bendamustine (n = 27) or Flu/Cy (n = 42) LD before axicabtagene ciloleucel (axi-cel) at our institution. The median change in absolute lymphocyte count from pre-LD to time of axi-cel infusion was -0.6×109 /L in bendamustine cohort and -0.7×109 /L in Flu/Cy cohort. The best overall response/complete response rates were 77.8% (95% CI: 57.7%-91.4%)/48.1% (95% CI: 28.7%-68.1%) among bendamustine cohort and 81.0% (95% CI: 65.9%-91.4%)/50.0% (95% CI: 34.2%-65.8%) among Flu/Cy cohort. Six-month progression-free survival were 43.8% (95% CI: 24.7%-61.3%) and 55.6% (95% CI: 39.0%-69.3%) in bendamustine and Flu/Cy cohorts, while 6-month overall survival were 81.5% (95% CI: 61.1%-91.8%) and 90.4% (95% CI: 76.4%-96.3%), respectively. Relative to Flu/Cy-treated patients, bendamustine-treated patients did not show an increase in hazards associated with experiencing progression/relapse/death (aHR:1.4 [95% CI: 0.7-2.8]; p = .32) or death (aHR:1.6 [95% CI: 0.5-5.6]; p = .46), after adjusting for baseline number of prior therapies and refractory disease. Any grade/grade ≥3 CRS were observed in 89%/3.7% and 86%/4.8% among bendamustine and Flu/Cy cohorts, while any grade ICANS/grade ≥3 ICANS were observed in 30%/19% and 55%/31% respectively. While more Flu/Cy-treated patients experienced grade ≥3 neutropenia compared with bendamustine-treated patients (100% vs. 68%), grade ≥3 infectious complications were comparable (24% vs. 19% respectively). More patients received bendamustine LD and axi-cel as outpatient than Flu/Cy cohort, without increased toxicities and with shorter median inpatient stays. In conclusion, we observed comparable efficacy and lower any grade ICANS among patients receiving bendamustine relative to Flu/Cy LD, followed by axi-cel.

A phase II trial of BAY 43-9006 (sorafenib) (NSC-724772) in patients with relapsing and resistant multiple myeloma: SWOG S0434.

The authors assessed the overall response rate, including confirmed complete response (CR) and partial response, in patients with relapsed/refractory multiple myeloma treated with sorafenib. Qualitative and quantitative toxicities associated with this regimen were evaluated. Patients were eligible if they had a confirmed diagnosis of refractory or relapsed (RR) multiple myeloma (MM) with measurable monoclonal protein. Patients had to have adequate renal, hepatic, hematologic, and cardiac function with a Zubrod performance status of 0-2. Patients were given 400 mg sorafenib by mouth twice daily for 28-day treatment cycles. These patients were followed up for a maximum of 3 years to assess responses and adverse events. Twenty-three patients were enrolled. Of these, five were found to be ineligible for the following reasons: four had insufficient documentation of the baseline disease and one patient did not have measurable disease. All eighteen eligible patients were evaluable for toxicities. Three patients experienced grade 4 toxicities: one with thrombocytopenia, one with anemia, and one with renal failure. Four of the eighteen eligible patients were not assessable for response due to removal from protocol treatment prior to adequate disease assessment. Specifically, three were removed for either grade 4 toxicity or progression of disease and one was removed per patient choice (due to reasons unrelated to treatment). Of the 18 patients who were assessed for toxicities, 5 (27.8%) received at least one fully dosed cycle, 2 (11.1%) of whom had all cycles fully dosed. No responses were observed on this study of the 14 patients who were assessable for response. All patients have discontinued protocol treatment as of August 2008. Overall survival at 12 months was 50% (95% CI 27-73%) and median progression-free survival was 1.2 months (95% CI 1.0-5.4). The trial did not exhibit activity by the International Uniform Response Criteria for MM. Further research should focus on combination therapy of sorafenib with standard treatments in selected patients with RR MM.

Does follicularity in large cell lymphoma predict outcome after autologous stem cell transplantation?

The purpose of this study was to evaluate whether follicular histology in large cell lymphoma influences treatment outcomes after autologous stem cell transplantation (ASCT). It remains an area of controversy whether the natural history of follicular large cell lymphoma (FLCL) is akin to diffuse large cell lymphoma (DLCL) with curative potential or is more similar to indolent follicular lymphomas with a pattern of late relapses after intensive chemotherapy. Although ASCT is a potentially curative treatment for patients with recurrent DLCL, the effectiveness of this approach in patients with FLCL is unclear. We undertook a retrospective analysis of 332 patients with large cell lymphoma who underwent ASCT at the City of Hope Comprehensive Cancer Center. With a median follow-up of 31 months, the projected 10-year overall survival and disease-free survival were similar between patients with FLCL and DLCL. Analysis of prognostic factors demonstrated that although age, chemotherapy refractoriness, and disease status at the time of ASCT were predictive of overall survival/disease-free survival, follicularity did not influence the outcome. Furthermore, the similar plateau in the survival curve for the DLCL and FLCL patients suggests that the behavior of FLCL is similar to that of DLCL and that FLCL is potentially curable with ASCT.

Targeted total marrow irradiation using three-dimensional image-guided tomographic intensity-modulated radiation therapy: an alternative to standard total body irradiation.

Total body irradiation (TBI) is an important part of bone marrow transplantation conditioning regimens. In TBI, dose escalation is difficult, because of associated normal organ toxicities. A method to deliver a more targeted dose of TBI preferentially to sites of greatest tumor burden is needed to reduce the dose to normal organs, reduce toxicities, and permit dose escalation. The purpose of this study was to evaluate, through a dosimetric analysis, the potential advantages and feasibility of selectively delivering targeted myeloablative doses of radiation to bone and marrow using a recently developed image-guided tomographic intensity-modulated radiation therapy delivery system (helical tomotherapy). Whole-body computed tomography datasets from 3 patients, age 5, 20, and 53 years, were used for treatment planning studies to evaluate 2 targeted TBI strategies: total marrow irradiation (TMI), in which the target region was defined as the skeletal bone, and total marrow and lymphoid irradiation (TMLI), in which the target regions were defined as bone, major lymph node chains, liver, spleen, and sanctuary sites, such as brain. Organ doses and dose distributions were compared with those in conventional TBI. A 1.7- to 7.5-fold reduction in median organ doses was observed with TMI and TMLI compared with conventional TBI. With this more targeted approach, a dose-volume histogram analysis predicted the potential to escalate the dose to bone (and containing marrow) up to 20 Gy, while maintaining doses to normal organs at lower levels than in conventional TBI to 12 Gy. Results were similar for the adult and pediatric patients, indicating that this form of targeted TBI will be applicable to most patients regardless of frame size. TMI to 10 Gy was delivered as part of a tandem transplant regimen to the 53-year-old patient with multiple myeloma. Clinical results confirmed the treatment planning predictions. After TMI, the patient experienced the expected blood count nadir, followed by successful engraftment. Grade 2 nausea and grade 1 emesis occurred only briefly on day 2 of TMI. Skin erythema, oral mucositis, esophagitis, and enteritis were not observed. This report demonstrates the feasibility and potential dosimetric advantages of selectively delivering myeloablative doses of radiation to bone and marrow using an image-guided tomographic intensity-modulated radiation therapy delivery system. Organ doses are substantially lower than those associated with standard TBI and predict the potential to significantly reduce associated toxicities and allow for dose escalation. The results also suggest that this form of targeted TBI may have potential advantages over other forms of targeted TBI, such as radioimmunotherapy or bone-seeking radionuclide therapy. Ongoing clinical trials will define the maximum TMI and TMLI doses achievable and define the potential advantages and limitations of this new approach for patients undergoing hematopoietic stem cell transplantation.