Peterson, Jennifer

Background/Objectives: Patients with relapsed/refractory multiple myeloma (RRMM) have poor survival outcomes and limited treatment options. The increasing utilization of multiagent therapies for earlier lines of treatment and novel drug classes including BCMA-targeting agents in subsequent lines of therapy has created a need for innovative treatment platforms in patients who have relapsed after or are refractory to these current standard-of-care approaches. Iopofosine I 131 is a 131iodide (131I)–phospholipid conjugate that exploits the selective uptake and retention of phospholipid ethers through lipid rafts to facilitate tumor delivery of 131I. Methods: The objective of this phase 1 dose-escalation study was to assess the safety and tolerability of single and fractionated dose schedules of iopofosine I 131 + low-dose dexamethasone in heavily pretreated patients with RRMM. Results: The most common AEs overall were cytopenias, notably thrombocytopenia (93.5%), lymphopenia (74.2%), anemia (71%), leukopenia (61.3%), and neutropenia (58.1%). All patients experiencing hematologic adverse events recovered from those events with median time of recovery 21 days post-nadir. Nonhematologic adverse events were mostly limited to Grade 1 and 2. Dose-limiting toxicities included four Grade 4 thrombocytopenia events lasting longer than 7 days, one Grade 4 neutropenia, and one Grade 3 insomnia. The DMC determined 31.25 mCi/m2 was the maximum tolerated dose in the single-dose group, and 20 mCi/m2 × 2 doses was the maximum tolerated dose in the fractionated-dose group. For patients monitored through 85 days following the first infusion, 22 of 26 (84.6%) achieved stable disease after treatment, and 4 of 26 (15.4%) achieved a partial response. Conclusions: A favorable safety and tolerability profile and preliminary clinical activity support further development of iopofosine I 131 in RRMM.

Abstract Background: Allogeneic hematopoietic cell transplantation (allo-HCT) is the only curative option for myelofibrosis (MF) but carries significant non-relapse mortality (NRM). Splenomegaly in MF patients undergoing allo-HCT is linked to delayed engraftment, poor graft function, and worse overall survival (OS). Strategies to reduce spleen size pre-HCT have been explored. Splenic irradiation (SI) offers a non-invasive approach for rapid spleen size reduction, though data on transplant outcomes are limited. Retrospective studies suggest SI just before HCT may reduce relapse and effectively shrink spleens with acceptable toxicity. Methods: We conducted a single-center observational study on MF patients with splenomegaly undergoing allo-HCT between 2022–2024. SI (100 cGy in 5 fractions) was delivered within 6 weeks pre-HCT. Primary endpoints: engraftment kinetics (including primary engraftment failure), time to neutrophil/platelet engraftment, and transfusion independence. Secondary endpoints: OS, progression-free survival (PFS), relapse, NRM, and rates of acute/chronic GVHD. Kaplan–Meier methods were used for OS/PFS; cumulative incidence functions with competing risks were used for relapse/NRM. Results: Thirteen patients were analyzed. Median age was 63 (range 40–74) years, and 54% were male. Eight (62%) patients had primary MF, 3 (23%) post-essential thrombocytosis, and 2 (17%) post-polycythemia vera. Eleven (94.6%) patients had prior Ruxolitinib therapy, and 10 (76.9%) harbored a JAK2 mutation with a median variant allele frequency of 51% (range 34%–94%). DIPSS risk at transplant was low in 1 (7.7%), intermediate-1 in 8 (61.5%), and intermediate-2 in 4 (30.8%) patients. Median pretransplant spleen size was 22.4 (range 14.5–28) cm. Two patients had a history of thrombosis, including 1 with portal vein thrombosis. The median interval between SI and stem cell infusion was 14 (range 10–43) days. The median HCT-CI score was 2 (range 0–6), and the median KPS was 80% (range 80–100%). Most patients (76.9%) received a HLA-matched unrelated donor transplantation, while 3 (23.1%) received haploidentical donor grafts. All grafts used peripheral blood stem cells. Reduced-intensity conditioning (RIC) was used in 11 (84.6%) patients, while 2 (15.4%) received myeloablative conditioning (MAC). Five (38.5%) patients received total body irradiation (TBI) as part of conditioning, with all receiving a TBI dose of 200 cGy. All patients received post-transplant cyclophosphamide (PTCy)-based GVHD prophylaxis. With a median follow-up of 17.1 months, median neutrophil engraftment occurred at 18 (range 14–45) days, platelet engraftment at 30 (range 15–434) days, red blood cell transfusion independence at 35 (range 11–341) days, and platelet transfusion independence at 24 (range 10–312) days. Median hospital stay was 26 (range 14–86) days. Primary engraftment failure occurred in 1 (8.3%) patient. One (7.7%) patient developed veno-occlusive disease. Four (33.3%) patients experienced CMV reactivation, and 3 developed CMV disease requiring systemic therapy. Median post-transplant spleen size was 16.6 (range 12.2–25.2) cm, and 30% of patients achieved >50% spleen size reduction, with a median time of 114 (range 45–212) days, with none having a normal spleen at day 30 post-transplant but 2 (15%) patients having a normal spleen at day 100 post-transplant. At 1 year, OS was 73.3% (95%CI, 51.5–100%), and PFS was 66% (95%CI, 44%–100%). The 1-year cumulative incidence of relapse was 7.6%, while 1-year NRM was 25.7%. Seven (53%) patients developed acute GVHD, with 1 patient experiencing grade III acute GVHD that progressed to sepsis and death at day 248 post-transplant. Two additional deaths occurred (graft failure=1, multiorgan failure=1). Two (15%) patients developed moderate chronic GVHD Conclusion: In this single-center cohort, SI pre-allo-HCT was feasible, tolerated, and associated with promising OS and PFS. Engraftment occurred in >90%, with one case of primary engraftment failure and most achieving transfusion independence within reasonable time frames. SI reduced spleen size in >30%, though acute GVHD was frequent. It remains uncertain whether the incidence and severity of GVHD may be influenced using TBI as part of the conditioning regimen (albeit reduced in intensity) in addition to splenic irradiation. Larger prospective studies are needed to clarify SI's impact on engraftment, transfusion dependence, GVHD, and outcomes in MF patients.

BACKGROUND AND OBJECTIVES: Single-session stereotactic radiosurgery (SRS) has limited role for large arteriovenous malformations (AVM). Volume-staged SRS (VS-SRS) is used to optimize outcomes, but studies reporting results are limited. METHODS: This multicenter retrospective cohort of 378 patients from 21 centers reports results of VS-SRS for the entire AVM nidus. We report favorable outcome, obliteration, hemorrhage, and permanent symptomatic adverse radiation effect rates. RESULTS: The median age was 31 years (IQR: 19-44) at the first volume stage, with patients treated in 2–4 stages. The median total nidus volume was 21 cm 3 (IQR: 13.9-30.1 cm 3 ), and a median prescription dose of 17 Gy (IQR: 16-18 Gy) was used. The median radiographic and clinical follow-up were 48 and 55 months, respectively. Seventy-seven patients (20.4%) had a favorable outcome, with the 3-year and 5-year rates being 3.9% and 18%, respectively. 127 patients (33.6%) achieved obliteration, with the 3-year and 5-year rates being 6.8% and 26%, respectively. Obliteration rates of AVMs <15 cm 3 were 81% and 31%, respectively. The latency period hemorrhage incidence rate was 3.02 cases per 100 patient-years; 52 patients (13.8%) had a bleed. Seventy-two patients (19%) had symptomatic adverse radiation effect; in 38 patients (10.1%), these were permanent. Total nidus volume, prescription dose at first stage, diffuse nidus, and prior hemorrhage were all independent affecting outcome rates. CONCLUSION: VS-SRS can be used to treat large AVMs as a standalone treatment. Obliteration rates and favorable outcomes are lower than that with smaller AVMs, and repeat treatment is often required. Optimizing treatment plans, by increasing prescription doses, reducing treatment volume at each stage, and increasing the number of stages, may lead to better outcomes.

BACKGROUND AND OBJECTIVES: Gynecological cancers represent 10% to 15% of cancers in women, but brain metastases (BM) are uncommon, with limited evidence regarding their management. This study investigates the role of stereotactic radiosurgery (SRS) for BM from primary gynecological cancers. METHODS: Institutions of the International Radiosurgery Research Foundation participated in this study. Inclusion criteria required histological diagnosis of epithelial ovarian, cervical, or endometrial cancer, SRS between 2000 and 2020, and at least 1 imaging or clinical follow-up. RESULTS: A total of 276 patients having SRS for 977 BM were included. Median age at SRS was 62 years (IQR, 55-70). Primary cancer origin was ovarian in 128 (46%), cervical in 43 (16%), and endometrial in 105 patients (38%). Median Karnofsky Performance Scale was 80%, and systemic disease was active in 124 (45%) of patients. A median of 1 metastasis was treated (IQR, 1-3) per patient. Median individual metastasis volume was 0.27 cc (IQR, 0.05-1.59 cc). The majority (91%) received single-fraction SRS, using a median margin dose of 18 Gy (IQR, 16-20 Gy). Actuarial overall survival was 77%, 65%, and 44% at 6, 12, and 24 months, respectively. Predictors of worsened survival included older age, cervical and endometrial primary, previous whole-brain radiation therapy (WBRT), active systemic disease, worsened Karnofsky Performance Scale, absence of subsequent surgery, and increasing number of BM. Actuarial local control was 94% at 6 months, 89% at 12 months, and 78% at 24 months. Previous SRS or WBRT, tumor bed treatment, and cervical histology increased the risk of local failure. New remote BM and leptomeningeal dissemination occurred in 44% and 11% of patients, respectively. Adverse radiation effects (ARE) occurred in 13% of cases but were symptomatic in only 3%. Previous WBRT or SRS and increased tumor diameter increased the risk of ARE. CONCLUSION: SRS is an effective management for BM from gynecological cancers with low risks of symptomatic ARE.

This study evaluated the effectiveness of using a traditional computed tomography (CT) simulation scan in the Leksell Gamma Knife® Icon™ workflow for stereotactic radiosurgery. We compared two workflows, one involving a traditional CT simulation co-registered with the magnetic resonance imaging (MRI) and cone-beam CT (CBCT) (MRI-CT-CBCT) and another without the CT scan, co-registering the MRI directly with CBCT (MRI-CBCT). The cohort included 50 frame-based (54 targets) and 55 frameless (124 targets) patients treated between August 2020 and December 2022. Target coverage was assessed by the percentage of each target covered by the prescription isodose line. The mean coverage differences for the frame-based and frameless cohorts were −1.20% ± 1.43% and −1.06% ± 1.51%, respectively, with 95% confidence intervals of −1.59, −0.81 and −1.32, −0.79. The MRI-CBCT workflow was deemed noninferior to the MRI-CT-CBCT workflow. Our data indicate that both workflows yield similar results, suggesting that a traditional CT simulation scan is unnecessary.

Introduction: Waldenström macroglobulinemia (WM)remains incurable with current therapies. Treatment options for patients beyond initial therapy are limited, underscoring the need for new agents with novel mechanisms of action. Iopofosine I 131 is a novel radiopharmaceutical composed of a lipid raft-targeting phospholipid ether covalently bound to 131I, a beta-emitting radioisotope. Herein, we report the results of the CLOVER-WaM study [NCT02952508] in patients with previously treated WM. Methods: Eligible WM patients had received &gt;2 prior therapies and had symptomatic disease requiring therapy according to consensus recommendations for WM. Treatment consisted of 2 cycles of iopofosine I 131 administered at 15 mCi/m2 on days 1 and 15 of each 57-day cycle. Dose reduction to 10 mCi/m2 was allowed in the second cycle in patients with incomplete hematologic recovery or if the expected total dose exceeded 132 mCi. Supportive care with growth factors and transfusions was permitted per treating physician discretion. The primary endpoint was major response rate (MRR, defined as partial response or better) as determined by the modified VIth International Workshop on Waldenström Macroglobulinemia Response Criteria. Secondary endpoints included overall response rate (ORR), treatment-free survival (TFS), duration of response (DOR), and clinical benefit rate (CBR, defined as stable disease or better). Efficacy endpoints were assessed in the modified intent-to-treat (mITT) population, defined as all patients who received ≥60 mCi total administered dose of iopofosine I 131. MRR was analyzed with a 95% 2-sided confidence interval (CI) using the Clopper-Pearson interval method. In this population, MRR &gt;20% was considered statistically significant. Time-dependent efficacy endpoints were analyzed using the Kaplan-Meier method. Safety was evaluated using CTCAE v4.03 in patients who received &gt;1 dose of iopofosine I 131. The data cut-off for this analysis was May 31, 2024. Results: In 65 patients enrolled (safety population), the median age was 70 (range, 50-88) years; 48 (73.8%) were male, and 17 (26.2%) were female. Sixty-one (93.8%) were White, 1 (1.5%) was Black/African American, and 3 (4.6%) were other or unknown. Fifty-five patients met mITT criteria and were evaluable for efficacy. The median number of prior therapies was 4 (range, 2-15). Bruton's tyrosine kinase inhibitor (BTKi) exposure was noted in 39 (71%) patients, of whom 31 (56%) were BTKi-refractory. Sixteen (29%) patients had MYD88-wild type, and 5 (9%) had CXCR4-mutated disease. The MRR was 56.4% (95% CI, 42.3-69.7). ORR was 80%; among MYD88-wild type patients, ORR was 81%, and among post-BTKi patients, ORR was 72%. CBR was 98%. The median DOR and TFS were not reached at a median follow-up of 8.8 months, with an estimated 72% of responding patients remaining progression-free at 18 months. In the safety population, any-grade adverse events, regardless of causality, were reported in 57 (87%) patients. Grade 3 or higher treatment-emergent adverse events (TEAEs) occurring in &gt;10% of patients included thrombocytopenia (80%), neutropenia (69.2%), anemia (44.6%), lymphopenia (13.8%), infections (12.3%), and febrile neutropenia (10.8%). Adverse event-related death occurred in 1 patient due to bacterial sepsis. Conclusion: Iopofosine I 131 demonstrated durable efficacy in previously treated WM patients, with no current standard of care therapy. The treatment was well-tolerated with a manageable toxicity profile across broad biologic and clinical subgroups, irrespective of risk stratification. Based on the results of this trial, iopofosine I 131 shows promise as a novel treatment for WM patients.

Abstract Unirradiated patients with relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma (NHL) who undergo anti-CD19 chimeric antigen receptor T-cell therapy (CART) have a predominant localized pattern of relapse, the significance of which is heightened in individuals with limited/localized disease before CART. This study reports on the outcomes of patients with R/R NHL and limited (&lt;5 involved sites) disease bridged with or without radiotherapy. A multicenter retrospective review of 150 patients with R/R NHL who received CART with &lt;5 disease sites before leukapheresis was performed. Bridging treatment, if any, was administered between leukapheresis and CART infusion. Study end points included relapse-free survival (RFS), event-free survival (EFS), and overall survival. Before CART infusion, 48 patients (32%) received bridging radiotherapy (BRT), and 102 (68%) did not. The median follow-up was 21 months. After CART infusion, BRT patients had higher objective response (92% vs 78%; P = .046) and sustained complete response rates (54% vs 33%; P = .015). Local relapse in sites present before CART was lower in the BRT group (21% vs 46%; P = .003). BRT patients had improved 2-year RFS (53% vs 44%; P = .023) and 2-year EFS (37% vs 34%; P = .039) compared with patients who did not receive BRT. The impact of BRT was most prominent in patients who had ≤2 pre-CART involved disease sites, with 2-year RFS of 62% in patients who received BRT compared with 42% in those who did not (P = .002). BRT before CART for patients with limited (&lt;5 involved disease sites) R/R NHL improves response rate, local control, RFS, and EFS without causing significant toxicities.

This cohort study examines the role of comprehensive bridging radiotherapy in the setting of chimeric antigen receptor T-cell therapy for non-Hodgkin lymphoma.

Abstract Background Minimal clinically important differences (MCIDs) quantify the clinical relevance of quality of life results at the individual patient and group level. The aim of this study was to estimate the MCID for the Brief Fatigue Inventory (BFI) and the Worst and Usual Fatigue items in patients with brain or CNS cancer undergoing curative radiotherapy. Methods Data from a multi-site prospective registry was used. The MCID was calculated using distribution-based and anchor-based approaches. For the anchor-based approach, the fatigue item from the PROMIS-10 served as the anchor to determine if a patient improved, deteriorated, or had no change from baseline to end of treatment (EOT). We compared the unadjusted means on the BFI for the 3 groups to calculate the MCID. For the distribution-based approaches, we calculated the MCID as 0.5 SD of the scores and as 1.96 times the standard error of measurement. Results Three-hundred and fifty nine patients with brain or CNS tumors undergoing curative radiotherapy filled out the 9-item BFI at baseline and EOT. The MCID for the BFI was 1.33 (ranging from 0.99 to 1.70 across the approaches), 1.51 (ranging from 1.16 to 2.02) and 1.76 (ranging from 1.38 to 2.14) for the usual and worst fatigue items, respectively. Conclusions This study provides the MCID ranges for the BFI and Worst and Usual fatigue items, which will allow clinically meaningful conclusions to be drawn from BFI scores. These results can be used to select optimal treatments for patients with brain or CNS cancer or to interpret BFI scores from clinical trials.