Molina, Arturo

Abstract Background: Polycythemia vera (PV) is a myeloproliferative neoplasm characterized by red blood cell overproduction. In the phase 2 REVIVE study (NCT04057040), rusfertide was superior to placebo in achieving hematocrit (Hct) levels <45% and reducing or eliminating the need for therapeutic phlebotomy (PHL) in patients (pts) with PV who were PHL dependent prior to study entry (Kremyanskaya M, et al. N Engl J Med. 2024;390(8):723-35). During the open-label extension portion of REVIVE (Part 3), combining rusfertide and PHL with or without cytoreductive therapy (CRT) controlled erythrocytosis, provided long-term control of Hct, and was associated with a greater than 8-fold reduction in the estimated annual PHL rate (Gerds AT, et al. Blood. 2024;144(Suppl. 1):4559). Pts who participated in REVIVE Part 3 were eligible to transition to the open-label phase 2 THRIVE extension study (NCT06033586) and receive up to 2 additional years of rusfertide treatment. Our objective is to present initial results describing the long-term durability of response and safety profile of rusfertide in pts with PV who participated in REVIVE and transitioned to THRIVE. Methods Pts with PV who participated in REVIVE, completed ≥12 months of rusfertide therapy, and had an end-of-treatment visit were eligible to transition to THRIVE. Pts who enrolled in THRIVE continued to receive subcutaneous rusfertide once weekly with or without CRT. Median Hct and the number of PHLs each pt received were assessed in all pts who received ≥1 dose of rusfertide and had ≥1 efficacy assessment on study. Safety data were also collected, including treatment-emergent adverse events (AEs), serious adverse events (SAEs), non-PV malignancies, and thromboembolic events (TEs). New-onset AEs (ie, AEs that were reported in THRIVE but not REVIVE) were also recorded. Results: Forty-six/58 pts (79%) who enrolled in Part 3 of REVIVE transitioned to THRIVE. At the data cutoff date (27 May 2025), 44 of the 46 pts (96%) who enrolled in THRIVE remained on study. Median (range) age was 58 (27-77), and the majority were male (74%). More than half (57%) had high-risk PV; 54% of pts were on concurrent CRT. Median (range) treatment duration in THRIVE was 48 (22-66) weeks; median (range) treatment duration in REVIVE and THRIVE combined was 198 (154-267) weeks, or 3.8 (3.0-5.1) years. At baseline, mean (standard deviation [SD]) Hct was 42.3% (3.7) in THRIVE. At Week 60, mean (SD) Hct was 43.0% (4.2). In addition, mean hemoglobin and erythrocyte levels remained stable throughout THRIVE. Prior to study entry in REVIVE, the mean (SD) annualized PHL rate (ie, PHL/year) for the 46 pts who eventually rolled over to THRIVE was 9.2 (5.2) PHL/year. The mean (SD) annualized PHL rate during REVIVE Part 3 and THRIVE was 0.6 (0.8) and 0.7 (1.1) PHL/year, respectively. Overall, the most common AEs in the pts who participated in REVIVE and THRIVE were Grade 1-2 injection site reactions (87%), fatigue (59%), COVID-19 (50%), pruritus (44%), arthralgia (39%), dizziness (35%), anemia (30%), paresthesia (28%), headache (26%), abdominal pain and nausea (24% each), and diarrhea, dyspnea, and upper respiratory tract infection (22% each). In THRIVE, the most common new-onset AEs were anemia (20%) and fatigue (15%). Twelve pts (26%) had a prior history of non-PV cancer. Six pts (13%) had a new-onset cancer event, including basal cell carcinoma (n=3; 7%), squamous cell carcinoma (n=2, 4%), non-invasive bladder cancer (n=1, 2%), and multiple myeloma (n=1; 2%). Of these 6 pts, 5 (83%) had a prior history of non-PV cancer. Nine pts (20%) had a history of TEs prior to enrolling in REVIVE. One patient with cardiovascular risk factors and a TE prior to enrollment in REVIVE had a new-onset TE of cerebrovascular accident in THRIVE. Overall, there were no TEs in pts with low-risk PV in either REVIVE or THRIVE. Conclusions: After transitioning to THRIVE, continued treatment with rusfertide with or without CRT demonstrated consistent, long-term Hct control with reduced therapeutic PHLs compared to baseline. With a median of 3.8 years of treatment, rusfertide's safety profile was consistent with prior observations. Support Protagonist Therapeutics, Inc.

Background: PV is a myeloproliferative neoplasm that leads to excessive production of erythrocytes and increased platelet and leukocyte counts. The current standard of care is to use therapeutic phlebotomy (TP) with or without cytoreductive therapy (CRT) to treat PV. Over time, the CRT dose often needs to be increased to treat PV progression. Preliminary results from the phase 2 REVIVE study (NCT04057040) demonstrated that rusfertide was superior to placebo in achieving hematocrit (Hct) levels <45% and reducing or eliminating the need for TP in patients who were phlebotomy-dependent prior to study entry (Kremyanskaya et al. EHA2023. [Abstract LB2710]; Kremyanskaya et al. New Engl J Med 2024;390:723-35).Final data from REVIVE will be presented. Methods: In Part 1 (Weeks 1-29), subcutaneous rusfertide (starting dose: 20 mg q1w) was initiated and titrated to control Hct to <45%. In Part 2 (Weeks 29-41; blinded randomized withdrawal phase), patients were randomized to receive rusfertide or placebo. Randomized patients were eligible to participate in the open-label extension (OLE) portion of the study (Part 3), in which all patients could receive rusfertide and investigators could make CRT dose adjustments. Results: In Part 1, 70 patients were enrolled; 59 were randomized in Part 2. Fifty-eight patients continued to Part 3. As of 9 July 2024, 50 (71.4%), 37 (52.9%), and 17 (24.3%) patients received rusfertide for ≥2, ≥2.5, or ≥3 years, respectively.Overall, median (range) patient age was 57.5 years (27-77); the majority were male (70%) and had high-risk disease (55.7%). Overall, 52.9% and 47.1% of patients were treated with TP alone or TP plus CRT, respectively. Prior to enrollment, the estimated average (mean) phlebotomy rate (EAPR) in patients who enrolled on study was 8.5/year, which was reduced to <1.0/year in Part 1. In Part 2, the EAPR was <1.0/year and 6.6/year in the rusfertide and placebo groups, respectively. For patients who continued onto Part 3 and received rusfertide, the EAPR remained at <1.0/year. In Parts 1, 2, and 3, the mean (SD) weekly average rusfertide dose was 30.7 mg (12.2), 38.5 mg (21.3), and 44.9 mg (20.3), respectively. Rusfertide consistently maintained Hct <45%, including in patients receiving therapy for ≥3 years. Platelets increased following initiation of rusfertide therapy and stabilized over time; mean leukocyte counts remained stable. Prior to enrollment, iron-related parameters were consistent with systemic iron deficiency. Throughout the study, rusfertide resulted in the normalization of mean serum ferritin levels, increased mean transferrin saturation, and increased mean serum iron levels. Overall, mean corpuscular volume increased slightly over the duration of the study. Throughout the study, there was no evidence of increased markers of inflammation (eg, C-reactive protein or interleukin 6). The most common (≥20%) treatment-emergent adverse events (TEAEs) were injection site reactions (85.7%), fatigue (38.6%), COVID-19 (32.9%), pruritus (34.3%), arthralgia (30.0%), dizziness (30.0%), nausea (24.3%), headache (24.3%), and anemia (21.4%). Grade 3 TEAEs occurred in 25.7% of patients.There were no Grade 4 or 5 TEAEs. One patient developed acute myeloid leukemia after treatment discontinuation. After more than 150 patient-years of rusfertide exposure, malignancies (most of which were skin cancers) were reported in 11 patients (all had risk factors that may have contributed to the development of these malignancies). There was no obvious correlation between increasing exposure to rusfertide and malignancies reported. Six thrombotic events (5 arterial and 1 venous) occurred in 5 patients with high-risk PV. Conclusions: In REVIVE, rusfertide added to TP with or without CRT provided long-term durable control of Hct and decreased the need for TP. Patients are eligible to roll over to the phase 2 THRIVE OLE study (NCT06033586), which will continue to assess the long-term safety and efficacy of rusfertide for a total period of up to 5.8 years. The randomized phase 3 VERIFY study (NCT05210790) is ongoing and will evaluate rusfertide vs placebo in PV patients.

Abstract Radioimmunotherapy (RIT) is a therapeutic modality indicated for the treatment of patients with relapsed or refractory low-grade, follicular, or transformed non-Hodgkin’s lymphoma (NHL), where the mechanism of action involves the intrinsic activity of the monoclonal antibody and the cytotoxic effects of radiation. The primary toxicity is a late-occurring, transient, and reversible myelosuppression. Because of concerns regarding the long-term effects of radiation on the bone marrow, we investigated the incidence of treatment-related myelodysplastic syndrome (t-MDS) and treatment-related acute myelogenous leukemia (t-AML) after ibritumomab tiuxetan RIT. A total of 746 patients with NHL were treated with the ibritumomab tiuxetan regimen in registration and compassionate-use trials between 1996 and 2002. Patients had a median age of 61 years (range, 24–87) and had received a median of 3 prior therapies (range, 0–9+). The crude incidence of t-MDS or t-AML was 2.3% (17/746), with an incidence of 4.7% (10/211) in patients enrolled in registration trials and of only 1.3% (7/535) in patients included in the compassionate-use trial, with a median follow-up of 5.7 and 3.5 years, respectively. These malignancies were documented at a median of 5.6 years (range, 1.2–13.9) after the diagnosis of NHL and 1.5 years (range, 0.1–5.8) after RIT. The annualized rates were 0.3% (95% CI, 0.2%–0.4%) a year after the diagnosis of NHL and 0.7% (95% CI, 0.4%–1.0%) a year after RIT. Cox multivariate regression analysis found that previous treatment with a purine nucleoside analog was a significant risk factor for t-MDS or t-AML (hazard ratio, 3.9 [95% CI, 1.5–10.4]; P = .006). All patients in whom t-MDS or t-AML developed and in whom cytogenetic data were available (n = 15) had multiple cytogenetic aberrations, commonly of chromosomes 5 and 7, suggesting an association with previous exposure to chemotherapy. There were documented bone marrow cytogenetic abnormalities before treatment in 2 patients who developed t-MDS or t-AML. These data suggest that the annualized incidence of t-MDS or t-AML following ibritumomab tiuxetan RIT is consistent with that expected on the basis of the patients’ history of treatment for NHL. Cytogenetic testing before administration of RIT may identify existing chromosomal abnormalities in previously treated patients, particularly in those who have been treated with alkylating agents and/or purine nucleoside analogs and who are thereby at a higher risk for t-MDS or t-AML.

Abstract Twenty-eight patients with relapsed or refractory CD20+ NHL have been enrolled in an ongoing phase I trial of dose-escalated 90YZ followed by high-dose BEAM and autotransplant in which the 90YZ dose is patient-specific based on dosimetry. 90YZ doses are calculated to deliver cohort-defined radiation doses (100, 300, 500, ... cGy) to critical organs (liver, lung or kidney), with 3–6 patients per group. On D -22, rituximab (R) 250 mg/m2 is infused followed by the imaging dose of 111In Zevalin® (5 mCi). Imaging is performed immediately post-injection and at 4, 24, 72, and 144 hours; dosimetry is performed on D -15. On D -14, R 250 mg/m2 is administered followed immediately by 90YZ at the dose calculated to deliver the cohort-prescribed absorbed radiation dose to the critical organ. On D -6 through -1, patients receive high-dose BEAM. On D0, a minimum of 2.0 X 106 CD34+ cells/kg is infused and G-CSF 5 μg/kg SQ daily begun. The median age was 54 (range: 25–72) years. NHL histologic subtypes were as follows: mantle cell 5, diffuse aggressive 13, low grade 5, and transformed 5. Most had received 3 or more treatment regimens, including R. The toxicity profile was similar to that associated with high-dose BEAM and included a decrease in DLCO for most patients with one patient at the 500 cGy dose level experiencing a transient decline to below 50% of the predicted value corrected for hemoglobin. The most common grade III/IV toxicities were infection, fever, stomatitis, nausea, vomiting, diarrhea, hemorrhage, and edema. One patient experienced transient veno-occlusive disease at the 700 cGy dose level. Engraftment occurred at a median of 10 days (range:8–18) to granulocytes ≥ 500/μL, and 21 days (range:13–40days) to platelets ≥20,000/μL . With a median follow-up of one year, the 3 year overall and progression-free survivals are 60% and 50%, respectively. Figure Figure 90-Y Zevalin Dosing by Cohort (median; range) Cohort (cGy) Total Dose (mCi) mCi/kg 100 (n=3) 5 (2–14) .06(.05–.12) 300 (n=7) 22(14–57) .25(.18–.63) 500 (n=6) 31(16–48) .40(.14–.63) 700 (n=6) 37(26–55) .38(.27–.73) 900 (n=3) 28(27–37) .32(.27–.44) 1100 (n=3) 48(29–65) .57(.50–.75) The liver was the critical organ in nearly all cases. Patient-specific doses calculated to deliver a cohort-prescribed absorbed radiation dose to the critical organ were highly variable suggesting that dosing based on weight and not dosimetry is likely to result in a wide range of absorbed dose to critical organs. In the context of this study, 90YZ has been administered to eight patients at doses of .5 mCi/kg or greater. We conclude that with careful dosimetry, 90YZ doses higher than the conventional .4 mCi/kg may be safely combined with BEAM and autotransplant. Accrual continues at the 1300 cGy dose level.

Abstract Background: As the first radiolabled monoclonal antibody approved for the treatment for the treatment of cancer, yttrium 90 (90Y) ibritumomab tiuxetan (Zevalin®) achieves both high response rates and durable remissions in patients with relapsed or refractory, low-grade, follicular, or transformed B-cell NHL. Because of the stability of 90Y ibritumomab tiuxetan and its favorable pharmacokinetic profile (ie, predictable urinary clearance and absence of dehalogenation), dosing is based on patient weight and platelet counts. Yttrium 90 ibritumomab tiuxetan is typically delivered at a dose of 0.4 mCi/kg (in patients with platelets >150,000/mm3) or 0.3 mCi/kg (in patients with platelets ≤150,000/mm3) to a maximum recommended dose (MRD) of 32 mCi. However, patients >80 kg with platelet counts exceeding 150,000/mm3 may receive a lower drug concentration (ie, <0.4 mCi/kg 90Y) as a result of dose capping. We evaluated whether the 32 mCi dose cap influences the safety or efficacy of ibritumomab tiuxetan therapy in patients >80 kg. Methods: Efficacy and safety data were collected for patients from 3 registrational trials that received either 0.4 mCi/kg 90Y (patients ≤80 kg) or 32 mCi 90Y (patients >80 kg). Results: Clinical responses in 170 patients were evaluated. Patients ≤80 kg (n = 103) had a median weight of 70 kg (range, 45–80 kg) versus a median weight of 95 kg (range, 81–159) for patients >80 kg (n = 67). Gender (41% M vs 73% M, respectively; P <.01) was the only significantly different baseline characteristic between the ≤80 kg and >80 kg groups. Similar efficacy and safety results were reported for both subsets of patients. Overall response rates of 79% and 70% were observed for patients ≤80 kg and >80 kg, respectively (P =.27); and no significant differences were seen in complete response rates (28% vs 34%, respectively; P =.40). Median TTP (8.9 months vs 9.5 months; P =.53) and median DR (8.5 months vs 11.5 months; P =.34) were equivalent between the 2 weight-based groups. In addition, there were no statistically significant differences in safety measures including grade 3/4 nonhematologic adverse events, neutropenia, thrombocytopenia, or anemia. Conclusions: As a consequence of dose capping at an MRD of 32 mCi, 39% of patients received a lower dose/kg of 90Y ibritumomab tiuxetan. However, despite the difference in dose administered on a unit of body weight basis, the efficacy and safety results were similar between patients ≤80 kg and >80 kg. We conclude that the 32 mCi dose cap does not influence the efficacy or safety profile of 90Y ibritumomab tiuxetan for patients >80 kg.

Abstract Background: Radioimmunotherapy (RIT) is an emerging clinical treatment option for patients with non-Hodgkin’s lymphoma (NHL). Yttrium 90 (90Y) ibritumomab tiuxetan (Zevalin®) RIT was approved by the FDA in February 2002 for the treatment of patients with relapsed or refractory low-grade, follicular, or transformed B-cell NHL, including patients with rituximab-refractory follicular NHL. In 4 registrational trials of 90Y ibritumomab tiuxetan conducted between 1996 and 1999, 211 patients with B-cell NHL were treated. Of these 211 patients, 153 patients (73%) had follicular lymphoma (FL). With ongoing follow-up, long-term durable responses have been observed, but until now have not been more fully characterized. Methods: Responding patients with time to progression (TTP) of ≥12 months were identified and characterized as long-term responding (LTR) patients. Results: In the 4 registrational trials, 78 of the 211 patients (37%) were identified as LTR patients. Characteristics of these LTR patients were as follows: median age 58 years (range, 24 to 80), 44% >60 years old, 55% male, 76% with follicular lymphoma, and 41% with lymphomatous marrow involvement. LTR patients had a median of 2 prior regimens (range, 1–9): 59% had ≥2 prior therapies, 33% had ≥3 prior therapies, and 37% had no response to their last prior therapy. Thirty percent of LTR patients had bulky disease (tumor size >5 cm) and 83% had stage III/IV disease. At the time of this analysis, the median duration of response (DR) and TTP for LTR patients were 28 months (range 11–80) and 29 months (range 12–82), respectively, with a median follow-up of 50 months (range 13–82). The median DR to the last prior therapy for LTR patients was 12 months. The complete response rate (confirmed [CR] and unconfirmed [CRu]) among LTR patients was 65%, and the median DR and TTP were 29 and 31 months, respectively, for CR/CRu patients. In ongoing responders the median DR is 52 months (range 48–80). Among the 153 patients with FL, 59 (39%) were identified as LTR patients. Compared to the overall LTR patients, LTR patients with FL had similar disease characteristics, DR, TTP, and CR/CRu rates. Conclusions: Ongoing follow-up indicates that 90Y ibritumomab tiuxetan frequently produces durable long-term responses (TTP ≥12 months) in patients with relapsed or refractory B-cell NHL. Failure to respond to the therapy immediately prior to treatment with 90Y ibritumomab tiuxetan does not appear to affect the ability to achieve long-term responses with 90Y ibritumomab tiuxetan. Durable long-term responses were achieved in 37% of all patients and 39% of patients with FL treated in 4 registrational trials of 90Y ibritumomab tiuxetan at 30 centers in the US. Of these LTR patients, a high proportion were >60 years old and had received ≥3 prior therapies.

Abstract 44 patients with relapsed or refractory CD20+ NHL were enrolled on a phase I trial of dose-escalated 90YZ followed by high-dose BEAM and autotransplant in which the 90YZ dose was patient-specific based on dosimetry. 90YZ doses were calculated to deliver cohort-defined radiation doses (100–1700 cGy) to critical organs (liver, lung or kidney) with 3–6 patients per cohort. On D-22, rituximab (R) 250 mg/m2 was infused followed by 111In Zevalin®. Imaging was performed immediately and at 4, 24, 72 and 144 hours; dosimetry was performed on D-15. On D-14, R was followed immediately by 90YZ at the cohort-prescribed dose. On D-6 through D-1, patients received high-dose BEAM. On D0, a minimum of 2.0 × 106 CD 34+ cells/kg was infused and G-CSF 5 μg/kg SQ daily begun. The median age was 54 (range: 25–73) years. NHL histologic subtypes were as follows: 16% mantle cell, 57% diffuse aggressive, 11% low-grade and 16% transformed. 43% had recieved 3 or more chemotherapy regimens, and 70% had received R either alone or in combination with chemotherapy. The toxicity profile was similar to that associated with high-dose BEAM. The most common grade III/IV toxicities were infection, fever, stomatitis, nausea, vomiting, diarrhea. One patient experienced transient veno-occlusive disease at the 700 cGy dose level. Two dose-limiting toxicities occurred at the 1700 cGy dose level: one patient with grade 4 stomatitis died of pneumonia and sepsis on D+10, and one patient experienced septic emboli to the lung on D+13. Engraftment occurred at a median of 10 days (range: 8–18 ) to granulocytes ≥ 500/μL, and 21 days (range: 11–40 days) to platelets ≥20,000/μL. One heavily pretreated patient developed MDS on D+291 and expired of sepsis on D+483. With a median follow-up of 21 months, the three year overall and progression-free survivals are 52% and 37%, respectively. 90YZ Zevalin ® Dosing for Cohorts 5–9 (median;range) Cohort (cGy) Total Dose (mCi) mCi/kg 900(n=3) 28(27–37) 0.3(0.3–0.4) 1100(n=5) 51(29–65) 0.6(0.5–0.8) 1300(n=5) 61(39–98) 0.6(0.5–1.1) 1500(n=6) 73(51–99) 0.9(0.5–1.4) 1700(n=3) 98(82–104) 1.2(1.1–1.2) For dosimetry-based trials, 1500 cGy to the critical organ (nearly always liver) is the recommended dose. Although patient-specific doses calculated to deliver a cohort-prescribed absorbed radiation dose to the critical organ were highly variable, the two dose-limiting toxicities ocurred at nearly identical doses (1.14, 1.20 mCi/kg) when calculated according to weight. Whereas eight other patients safely received at least twice the conventional 0.4 mCi/kg dose, 0.8 mCi/kg is the recommended dose for phase II studies, if dosing is to be based on weight and not dosimetry. Outcomes are encouraging given the high-risk patient population. A phase III trial will be required to establish whether or not the addition of 90YZ to high-dose BEAM improves outcomes in NHL patients undergoing autotransplant.

Purpose To determine the maximum-tolerated radiation-absorbed dose (RAD) to critical organs delivered by yttrium-90 (90Y) ibritumomab tiuxetan in combination with high-dose carmustine, etoposide, cytarabine, and melphalan (BEAM) chemotherapy with autologous transplantation. Patients and Methods Eligible patients had relapsed or refractory CD20+ non-Hodgkin's lymphoma (NHL). Individualized 90Y activities were based on dosimetry and were calculated to deliver cohort-defined RAD (1 to 17 Gy) to critical organs with three to six patients per cohort. The therapeutic dose of 90Y ibritumomab tiuxetan was followed by high-dose BEAM and autologous transplantation. Results Forty-four patients were treated. Thirty percent of patients had achieved less than a partial remission to their most recent therapy and would not have been eligible for autologous transplantation at most centers. The toxicity profile was similar to that associated with high-dose BEAM chemotherapy. Two dose-limiting toxicities occurred at the 17 Gy dose level, which made 15 Gy the recommended maximum-tolerated RAD. Although eight patients received at least twice the conventional dose of 0.4 mCi/kg, a weight-based strategy at 0.8 mCi/kg would have resulted in a wide range of RAD; nearly 25% of patient cases would have received 17 Gy or more, and many would have received less than 10 Gy. With a median follow-up of 33 months for all patients, the estimated 3-year progression-free and overall survivals were 43% and 60%, respectively. Conclusion Dose-escalated 90Y ibritumomab tiuxetan may be safely combined with high-dose BEAM with autologous transplantation and has the potential to be more effective than standard-dose radioimmunotherapy. Careful dosimetry is required to avoid toxicity and undertreatment.

Purpose To investigate the incidence of treatment-related myelodysplastic syndrome (t-MDS) and treatment-related acute myelogenous leukemia (t-AML) after treatment with ibritumomab tiuxetan radioimmunotherapy. Patients and Methods Analysis of the incidence of t-MDS and t-AML in 746 patients with non-Hodgkin's lymphoma (NHL) treated with the ibritumomab tiuxetan regimen in registration and compassionate-use trials between 1996 and 2002. Results Nineteen patients (2.5%) developed t-MDS or t-AML at a median follow-up of 4.4 years (range, 0 to 9.3). These malignancies were diagnosed at a median of 5.6 years (range, 1.4 to 13.9) after the diagnosis of NHL and 1.9 years (range, 0.4 to 6.3) after radioimmunotherapy. The annualized rates were 0.3% per year after the diagnosis of NHL and 0.7% per year after treatment. Most patients with t-MDS or t-AML had multiple cytogenetic aberrations, commonly on chromosomes 5 and 7, suggesting an association with previous exposure to chemotherapy. Conclusion Analysis of data from patients in registration and compassionate-use trials suggests that the annualized incidences of t-MDS and t-AML are consistent with that expected in patients with NHL who have had extensive previous chemotherapy treatment and do not appear to be increased after treatment with the ibritumomab tiuxetan regimen. Cytogenetic testing before treatment with radioimmunotherapy may identify existing chromosomal abnormalities in previously treated patients, particularly those who have been treated with alkylating agents and purine nucleoside analogs and would be at higher risk for t-MDS or t-AML.