Citations

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.

BACKGROUND AND OBJECTIVES: Pediatric large-volume brain arteriovenous malformations (AVMs) carry a substantial lifelong hemorrhage risk, neurological symptoms, and treatment morbidity. Single-session stereotactic radiosurgery (SRS) is often unsuitable due to constraints on dose-volume toxicity. Volume-staged SRS (VS-SRS) enables sequential dosing of large nidus volumes, potentially enhancing safety while maintaining efficacy. Evidence in children remains limited. We aimed to evaluate outcomes of VS-SRS for large AVMs in pediatric patients. METHODS: A multicenter retrospective cohort was assembled from 21 centers, including patients aged younger than 21 years treated with VS-SRS for AVMs >10 cm 3 . Clinical and radiological end points included obliteration, hemorrhage, and permanent symptomatic radiation-induced changes (RIC). RESULTS: A total of 103 patients were included (median age 14 years; IQR, 12-17). The median nidus volume at first stage was 18.2 cm 3 (IQR, 12.3-25.6). Median prescription dose per stage was 17 Gy (IQR, 16-18). The median clinical follow-up from the first stage was 57.5 months (IQR, 25-138). Obliteration occurred in 42 of 103 patients (40.8%), with actuarial rates of 6.9% (95% CI: 2.8-14) at 3 years and 29% (95% CI: 20-39) at 5 years. Hemorrhage occurred in 17 of 103 patients (16.5%) during follow-up, and permanent RIC was observed in 9 of 103 patients (8.7%). CONCLUSION: VS-SRS is a reasonably safe, selected option for pediatric large-volume AVMs when microsurgical or endovascular cure is not feasible or prudent. Delivering ≥17 Gy per stage while limiting each treatment volume to <15 cm 3 supports durable nidus control with acceptable toxicity. VS-SRS represents a key modality in multidisciplinary management of this historically difficult-to-treat population.

OBJECTIVE Ruptured, large pediatric arteriovenous malformations (AVMs) pose a significant management challenge due to high rerupture risk and the morbidity of conventional treatments. Volume-staged stereotactic radiosurgery (VS-SRS) has emerged as an alternative; however, evidence for its use in this specific population is limited. This study aimed to evaluate the long-term efficacy and safety of VS-SRS for ruptured, large AVMs in a dedicated pediatric cohort. METHODS This international, multicenter, retrospective cohort study from 21 centers analyzed outcomes for 42 pediatric patients (age < 18 years) with previously ruptured, large AVMs treated with VS-SRS. The primary outcome was complete AVM obliteration, and secondary outcomes included post-SRS hemorrhage, radiation-induced changes (RICs), and favorable outcome. Favorable outcome in this study was defined as obliteration without post-SRS hemorrhage or permanent RIC. RESULTS At the initial SRS, the median patient age was 14.5 years, and the median AVM volume was 15.0 cm 3 ; most AVMs were high grade (Spetzler-Martin grades IV and V). With a median follow-up of 41.5 months, complete AVM obliteration was achieved in 21 patients (50.0%). The cumulative obliteration rate was 37% at 5 years and 56% at 10 years. Patients with a nidus volume of ≤ 10 cm 3 had significantly higher cumulative obliteration rates than those with a nidus volume > 10 cm 3 (log-rank test, p = 0.021). Similarly, patients treated with a prescription dose > 17 Gy showed significantly higher cumulative obliteration rates compared to those treated with a dose ≤ 17 Gy (log-rank test, p = 0.012). The cumulative 5-year incidences of hemorrhage and RICs following VS-SRS were 19% and 7%, respectively. In multivariable analysis, only larger total AVM volume was an independent predictor of a lower likelihood of favorable outcome (hazard ratio 0.89, 95% CI 0.80–0.99; p = 0.036). CONCLUSIONS In this multicenter pediatric cohort, VS-SRS for ruptured, large AVMs provides a reasonable chance of long-term obliteration, but generally acceptable risks of post-SRS hemorrhage and RICs exist. VS-SRS should be considered as an option for pediatric patients with large, ruptured AVMs.

Abstract Background The current treatment of glioblastoma involves resection followed by radiotherapy (RT) and temozolomide. Rapid early progression (REP) of tumor in the surgery-to-radiotherapy interval (SRI) has been described using categorical or semi-quantitative assessments and is associated with inferior clinical outcomes. This study seeks to establish and validate a quantitative definition for REP and examine how REP could inform future therapy. Methods Volumes of tumor and resection cavity at 3 time points—preoperative, postoperative and RT-planning (pre-RT)—were contoured among patients who had undergone standard of care. A minimal, but clinically appreciable, threshold for defining REP based on change in tumor volume was established, validated, and subsequently used to assess actionable predictors of REP and its prognostic value. Results An increase of &gt;2 cc in volume or a new satellite tumor between the post-operative to planning MRI was found to be a sensitive, pragmatic, and statistically significant cutoff for REP (P = .002). Actionable predictors such as SRI of 6 weeks and a &gt; 5 cc residual immediate post-operative tumor volume were found to be statistically significant predictors of REP. REP was also found to be a statistically significant prognostic indicator for overall survival (P = .002) and progression-free survival. Conclusion These findings support that an increase in tumor volume between post-operative and pre-RT MRI of &gt;2 cc is the ideal working definition of REP in this clinical setting. Furthermore, REP could serve as a prognostic ­biomarker to track treatment response. Additionally, 2 actionable predictors of REP, post-op residual tumor volume and SRI, are identified.

7094 Background: Waldenström Macroglobulinemia (WM) remains incurable with current available therapeutic options. Treatment options for relapsed/refractory pts are limited and often continuous, underscoring the need for new agents with novel mechanisms of action and pt-centered, fixed duration therapy. Iopofosine I 131 is a novel radiopharmaceutical compound composed of a lipid raft-targeting phospholipid ether covalently bound to 131 I, a beta emitting radioisotope. Here, we report preliminary sub-group results of the CLOVER-WaM study [NCT02952508] in WM pts treated with a Bruton’s Tyrosine Kinase inhibitor (BTKi) immediately prior to iopofosine. Methods: Eligible WM pts had received >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/m 2 on days 1 and 15 of each 57-day cycle. The primary efficacy endpoint was major response rate (MRR; partial response or better, as determined by the modified IWWM-VI). Secondary and exploratory endpoints included overall response rate (ORR), treatment-free survival (TFS), progression free survival (PFS), duration of response (DOR), and clinical benefit rate (CBR; stable disease or better). Herein, efficacy endpoints were assessed in the modified intent-to-treat (mITT) population (all pts who received ≥60 mCi total administered dose of iopofosine I 131), and whose treatment regimen prior to iopofosine included a BTKi. Safety was evaluated using CTCAE v4.03 in pts who received ≥1 dose of iopofosine. Data cut off for this analysis was Jan. 16, 2026. Results: As previously reported, 65 pts were dosed and 55 are included in the mITT population. Of those, 22 (40%) had received a BTKi containing regimen immediately prior to iopofosine; and 11 who previously received at least 2 regimens utilizing BTKis and 12 who were refractory to rituximab. In this subgroup, median age was 70.5 (range 55-88), 17 (77%) were male, and 5 (23%) were female. The median number of prior therapies was 3 (range 2-7), 15/22 (68%) were MYD88 mutated and 18/22 (82%) were TP53 wildtype. The MRR was 15/22 (68.2%), ORR was 19/22 (86.4%) and CBR was 100%, median PFS was 12 months (range 1.6 to 28.0) and median TFS was 19.1 months (range 2.5-34.4). Grade ≥ 3, related treatment emergent adverse events (TEAE) occurring in > 10% of pts included anemia (41%), leukopenia (41%), neutropenia (58%), and thrombocytopenia (86%). Conclusions: Iopofosine I 131 demonstrated significant efficacy; 100% CBR, 86.4% ORR and 68.2% MRR with a median PFS of 12 months (range: 1.6 – 28.0 months) in a pt population with no current standard of care therapy. The treatment was well-tolerated with a manageable toxicity profile with cytopenias as the only Grade 3 or greater TEAE. Based on the results of this pivotal trial, iopofosine I 131 could be a promising novel treatment for WM pts after BTKi therapy. Clinical trial information: NCT02952508 .

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 &gt;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 &gt;90%, with one case of primary engraftment failure and most achieving transfusion independence within reasonable time frames. SI reduced spleen size in &gt;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.