Koshy, Nebu

PURPOSE Older patients with relapsed or refractory AML (RR AML) have dismal prognoses without allogeneic hematopoietic cell transplantation (alloHCT). SIERRA compared a targeted pretransplant regimen involving the anti-CD45 radioconjugate 131 I-apamistamab with conventional care. METHODS SIERRA (ClinicalTrials.gov identifier: NCT02665065 ) was a phase III open-label trial. Patients age ≥55 years with active RR AML were randomly assigned 1:1 to either an 131 I-apamistamab–led regimen before alloHCT or conventional care followed by alloHCT if initial complete remission (CR)/CR with incomplete platelet recovery (CRp) occurred. Initial response was assessed 28-56 days after alloHCT in the 131 I-apamistamab group and 28-42 days after salvage chemotherapy initiation; patients without CR/CRp or with AML progression could cross over to receive 131 I-apamistamab followed by alloHCT. The primary end point was durable complete remission (dCR) lasting 180 days after initial CR/CRp. Secondary end points were overall survival (OS) and event-free survival (EFS), assessed hierarchically in the intention-to-treat (ITT) population. RESULTS The ITT population included 153 patients ( 131 I-apamistamab [n = 76]; conventional care [n = 77]). In total, 44/77 conventional care arm patients crossed over and 40/77 (52%) received 131 I-apamistamab and alloHCT, with six patients (13.6%) experiencing a dCR. In the ITT population, the dCR rate was significantly higher with 131 I-apamistamab (17.1% [95% CI, 9.4 to 27.5]) than conventional care (0% [95% CI, 0 to 4.7]; P < .0001). The OS hazard ratio (HR) was 0.99 (95% CI, 0.70 to 1.41; P = .96), and the EFS HR was 0.23 (95% CI, 0.15 to 0.34), with HR <1 favoring 131 I-apamistamab. Grade ≥3 treatment-related adverse events occurred in 59.7% and 59.2% of the 131 I-apamistamab and conventional care groups, respectively. CONCLUSION The 131 I-apamistamab–led regimen was associated with a higher dCR rate than conventional care in older patients with RR AML. 131 I-apamistamab was well tolerated and could address an unmet need in this population.

Background : Allogeneic hematopoietic cell transplant (alloHCT) is the only potentially curative therapy for patients (pts) with relapsed or refractory (R/R) AML. Only a minority undergo alloHCT as they typically have dismal outcomes due to high relapse rates, especially those with TP53 mutations and active disease. Additionally, older pts cannot tolerate intensive treatment and hence are not eligible for alloHCT. 131I-apamistamab, an anti-CD45 radioimmunoconjugate, delivers high dose targeted radiation to hematopoietic cells, allowing for myeloablation and eradication of leukemic cells. 131I-apamistamab led induction and conditioning can thus provide these pts access to alloHCT potentially leading to better disease control and outcomes even in pts with the TP53 mutation. Methods: The SIERRA trial (NCT02665065) is a multi-center, randomized, controlled Phase 3 study comparing the rate of durable complete remission (dCR) lasting ≥6 months (mos) after complete remission with/without platelet recovery (CR/CRp) between two groups: 131I-apamistamab led induction and conditioning followed by alloHCT vs physician's choice of conventional care (CC). Pts were randomized (1:1) to CC or 131I-apamistamab with fludarabine and total body irradiation (2 Gy) followed by alloHCT. CR/CRp assessment was 28-56 days post alloHCT or 28-42 days post initiation of therapy in the CC group. Pts in the CC group not achieving leukemia-free state could crossover (CO) to 131I-apamistamab. We report the characteristics and outcomes of all pts with TP53 mutation who were enrolled in the SIERRA trial. Results: In total, 153 pts were randomized (CC, n=77; 131I-apamistamab, n=76). All pts who received the therapeutic dose of 131I-apamistamab (n=66) underwent HCT vs 14 (18.2%) in the CC group. Of evaluable pts, dCR rates at 6 months were 22% in the 131I-apamistamab group vs 0% in the CC group (95% CI;12.29, 34.73; p&lt;0.0001). A total of 37 pts with TP53 mutation were enrolled (CC=20; 131I-apamistamab =17) with a prevalence of 24.2%. Table 1 shows the baseline characteristics of these pts. Median overall survival (OS) for pts in the 131I-apamistamab group, who were TP53 negative was 6.37 mos compared to 5.72 mos for the TP53 mutation positive pts (HR=0.66; 95% CI [0.37, 1.18]; p=0.16). In the CC group (including CO pts), the median OS for TP53 positive pts was 2.96 mos. When the CC group without CO were analyzed, the median OS was 6.51 mos and 1.66 mos for the TP53 mutation negative and positive groups respectively (HR=0.28; 95% CI [0.12, 0.67]; p=0.0022). For TP53 mutation positive pts who received 131I-apamistamab ( 131I-apamistamab plus CO pts), the median OS was 5.49 mos compared to a median 1.66 mos in pts who did not receive 131I-apamistamab (CC pts without CO) [(HR=0.23; 95% CI [0.10, 0.52]; p=0.0002) (Figure 1)]. Conclusion: Pts with TP53 mutated R/R AML have a dismal prognosis and are seldom offered alloHCT due to high post-transplant relapse rates. 131I-apamistamab led alloHCT significantly improves survival outcomes in pts with TP53 mutations, commensurate with rates observed in pts with wildtype TP53, thereby overcoming the negative impact of this mutation. These data clearly support the use of 131I-apamistamab led induction and conditioning and alloHCT in R/R AML, including in patients with a TP53 mutation.

Background: Most older patients (pts) with relapsed or refractory (R/R) AML cannot tolerate intensive treatment and are not eligible for curative allogeneic hematopoietic cell transplant (alloHCT). 131I-apamistamab, an anti-CD45 radioimmunoconjugate, delivers high dose targeted radiation to hematopoietic cells, allowing for myeloablation and eradication of leukemic cells. 131I-apamistamab led induction and conditioning can provide these pts with access to alloHCT. Methods: SIERRA (NCT02665065) was a multi-center, randomized, controlled phase 3 study comparing the efficacy of 131I-apamistamab led induction and conditioning versus physician's choice of conventional care (CC) in pts ≥55 years of age with active, R/R AML. Pts were randomized (1:1, n=153) to CC or 131I-apamistamab with fludarabine and total body irradiation (2 Gy) followed by alloHCT. Primary endpoint was durable complete remission (dCR), defined as CR ≥6 mos with or without platelet recovery (CRp). Pts not achieving CR in CC could crossover (CO) to receive 131I-apamistamab. Treatment with 131I-apamistamab was prescribed as an individualized dose for each pt following a dosimetric infusion and biodistribution analysis, with the prescribed activity of 131I set to deliver a maximum estimated radiation dose to the liver as the dose limiting organ of 24 Gy (determined as the maximum tolerable dose (MTD)) in earlier studies), thereby providing the highest dose to the diseased bone marrow and circulating leukemic cells without exceeding individual organ radiation dose tolerances. Here, we performed an analysis to determine whether a radiation dose-response relationship could be established based on either 1) administered radiation dose to liver and the rate of achieving the primary endpoint of dCR (with 95% binomial confidence intervals) or 2) dCR rate and the ratio of bone marrow/liver absorbed radiation dose as an indicator of favorable biodistribution between target/risk organ. Results: All pts receiving the therapeutic dose of 131I-apamistamab (n=66) were able to receive an alloHCT, and the primary endpoint (dCR) was achieved in 13 pts receiving 131I-apamistamab vs 0 pts in CC (p&lt;0.0001). The median absorbed liver dose was 21.6 Gy (IQR: 21.0 - 22.8 Gy), median absorbed dose to bone marrow was 16.0 Gy (IQR: 11.5 - 22.3 Gy), and median ratio between marrow/liver dose was 0.79 (IQR: 0.52 - 1.02). Table 1 shows the distribution and rate of dCR for pts who received above or below 22 Gy administered dose to liver (24 Gy to liver was the established MTD from earlier studies, in which doses were escalated in 2 Gy increment and thus, 22 Gy represented MTD-1), and for pts stratified by marrow/liver dose ratio (higher ratio representing more favorable biodistribution). Pts with ≤22 Gy liver dose had a dCR rate of 13.5% vs. 27.6% for pts with &gt;22 Gy liver dose, and pts with &lt;median dose to bone marrow had a dCR rate of 12.1% vs. 27.3% for pts with ≥median estimated marrow dose. Importantly, pts with increasingly favorable biodistribution had nominally higher dCR rates of 10.0%, 20.0% and 26.9% for a marrow/liver ratio &lt;0.6, 0.6-0.9 and &gt;0.9, respectively, as illustrated in Figure 1. Taken together this demonstrates a radiation dose-response for the primary endpoint in this study. Overall, safety was similar across doses to the liver. Conclusion: 131I-apamistamab led induction and conditioning followed by alloHCT resulted in statistically significant improvement in dCR at 6 mos vs conventional care. A dose-response was demonstrated for pts receiving 131I-apamistamab with those receiving a liver dose closer to the MTD of 24 Gy having about twice the dCR rate compared to pts 22 Gy (MTD-1) or less. We also found pts with higher marrow/liver ratio experienced considerably higher rates of dCR which highlights the importance of maximizing the dose to target tissues, within the limits of established risk organ dose tolerances.

Background : Most older patients (pts) with relapsed or refractory (R/R) AML cannot tolerate intensive treatment and are not eligible for curative allogeneic hematopoietic cell transplant (alloHCT). 131I-apamistamab, an anti-CD45 radioimmunoconjugate, delivers high dose targeted radiation to hematopoietic cells, allowing for myeloablation and eradication of leukemic cells while sparing toxicity to healthy organs. 131I-apamistamab led induction and conditioning can thus provide these pts with access to alloHCT. Methods: The SIERRA trial (NCT02665065) is a multi-center, randomized, controlled Phase 3 study comparing the rate of durable complete remission (dCR) lasting &gt;6 months (mos) after complete remission with/without platelet recovery (CR/CRp) between two groups: 131I-apamistamab led induction and conditioning followed by alloHCT vs physician's choice of conventional care (CC). Pts were randomized (1:1) to CC or 131I-apamistamab with fludarabine and total body irradiation (2 Gy) followed by alloHCT. CR/CRp assessment was 28-56 days post alloHCT or 28-42 days post initiation of therapy on the CC group. Pts in the CC group not achieving leukemia-free state could crossover (CO) to 131I-apamistamab. Here we report the results of a post hoc analysis to determine if the presence of various risk factors (i.e., Karnofsky Performance Status (KPS) &lt;90, HCT Comorbidity Index &gt;3, age &gt;65, adverse-risk cytogenetics, venetoclax failure prior to randomization) influenced achievement of dCR in pts treated with 131I-apamistamab. Results: In total, 153 pts were randomized (CC, n=76; 131I-apamistamab, n=77). All pts who received the therapeutic dose of 131I-apamistamab (n=66) underwent alloHCT vs 14 (18.2%) in the CC group. Of evaluable pts, dCR rates at 6 mos were 22% in the 131I-apamistamab group vs 0% in the CC group (95% CI;12.29, 34.73; p&lt;0.0001). A total of 19 pts (13, 131I-apamistamab group; 6, CO) achieved dCR. Table 1 shows the pt, disease, and transplant characteristics of dCR vs. non-dCR pts. Eight of the 19 pts (42.1%) had primary induction failure and the median time to randomization from diagnosis was 5.4 mos. Approximately 50% of pts (9/19) had adverse-risk cytogenetics. Over 35% (7/19) of the pts had failed prior venetoclax and the median number of prior treatments was 3 (range 1-5). A total of 10/19 (52%) pts had KPS of &lt;90% and a comorbidity index of &gt;3. There was no difference in the rate of dCR when stratifying by number of risk factors for a given pt (0 to 5) with 27% for pts with 0-1 risk factors, 14% for pts with 2-3 risk factors, and 11% for pts with 4-5 risk factors (p=0.251). Conclusion: Pts with R/R AML who have multiple risk factors such as adverse risk cytogenetics, age &gt;65, venetoclax failure, high comorbidity index or poor KPS are typically not considered for alloHCT due to high transplant-related mortality and post-transplant relapse rates. 131I-apamistamab was effective in achieving durable responses in R/R AML pts irrespective of the presence of multiple risk factors and successfully enabled alloHCT in such pts due to its targeted mechanism of action.

Abstract Background: Several targeted therapies have been recently approved as treatment options for acute myeloid leukemia (AML), however, complete remissions (CR) in relapsed/refractory (R/R) patients remain low. Due to suboptimal responses to standard therapies, most of these patients do not receive an allogeneic hematopoietic cell transplant (HCT). In addition, AML patients ≥55 years have poor tolerance and high morbidity from a myeloablative HCT. The SIERRA trial (Study of Iomab-B in Elderly Relapsed or Refractory AML) has been investigating the use of Iomab-B, an 131I-labeled anti-CD45 monoclonal antibody, to reduce relapse in patients with active, R/R AML who receive HCT as compared to Conventional Care (CC) therapies. With the recent approval of various targeted therapies like BCL-2 inhibitors (e.g., venetoclax), FLT-3 inhibitors (e.g., midostaurin and gilteritinib) and IDH inhibitors (e.g., ivosidenib), the protocol was amended to include patients refractory to these therapies. We are reporting on the success rate of engraftment and tolerability of Iomab-B among the CC patients who cross-over to receive Iomab-B and HCT after failing these agents. Methods: Approximately 150 older patients with R/R AML are to be randomized (1:1) to receive Iomab-B followed by fludarabine, total body irradiation (2 Gy) and allogeneic HCT, or to conventional care (CC). CC patients receive physician's choice of therapy, including targeted therapies, and may proceed to standard of care allogeneic HCT if they achieve CR. CC patients not achieving CR may cross over to Iomab-B-based HCT. Results: Available data for 136 patients (&gt;90% of target enrollment; median age 65) demonstrated they had a median of 3 (range: 1-7) prior lines of AML therapies. Median marrow blast at time of study entry was 25%. Prior to enrollment, 85 (63%) patients received targeted therapies, including BCL-2 inhibitors (62%), FLT-3 inhibitors (18%), IDH inhibitors (7%) and others (13%; e.g., gemtuzumab ozogamicin). Among the 50 evaluable patients in the Iomab-B group that received HCT, all successfully engrafted after a median radiation dose delivered to marrow of 14.7 Gy (range: 4.6 - 44.6) with a median time to neutrophil and platelet engraftment of 14.5 (range: 9-28) and 18 (range: 4-58) days, respectively. Of 63 patients randomized to the CC arm and with data available, 11 (17%) achieved CR and proceeded to standard of care HCT without Iomab-B while 52 (83%) did not respond to CC therapy. Twenty-seven of 63 (43%) CC patients received targeted therapy, of whom 21 received venetoclax with hypomethylating agents (HMA) or low-dose Cytarabine (LDAC). Seven of the 27 (26%) CC patients remission after targeted therapy and received standard of care HCT. Of the 20 patients who did not respond to targeted therapies, 11 (55%) crossed-over and received Iomab-B/HCT with a median radiation dose delivered to marrow of 18 Gy (range: 12.6 - 22.6). Median time to neutrophil and platelet engraftment was 12 (range: 10-27) and 20 (range: 15-38) days, respectively. Safety data are available for 103 transplanted patients in both groups and are presented in table. The incidence of Grade ≥3 febrile neutropenia (FN) was 37% vs 55%, sepsis 5% vs 30%, and mucositis 10% vs 20% in the Iomab-B group compared to all transplanted patients in the CC group. In patients who received targeted therapy and HCT (crossover or standard HCT), incidences of FN, sepsis and mucositis were 39%, 28% and 22%, respectively. Conclusion: SIERRA trial patients not achieving CR with recently approved targeted therapies who then crossed-over to receive HCT with Iomab-B successfully engrafted. Time to engraftment was similar to those who were randomized to receive Iomab-B and HCT. Available data suggest incidences of sepsis and mucositis are lower in the Iomab-B group. (www.sierratrial.com or clinicaltrials.gov NCT02665065) Figure 1 Figure 1. Disclosures Gyurkocza: Actinium Pharmaceutical Inc.: Research Funding. Nath: Actinium: Consultancy, Honoraria; Incyte: Consultancy, Honoraria. Litzow: Amgen: Research Funding; Biosight: Other: Data monitoring committee; Jazz: Other: Advisory Board; Pluristem: Research Funding; Astellas: Research Funding; Actinium: Research Funding; Omeros: Other: Advisory Board; AbbVie: Research Funding. Koshy: Astellas; Actinium Pharmaceuticals: Other: Principal Investigator, SIERRA Trial, Actinium, Speakers Bureau. Stiff: Seagen: Research Funding; Incyte: Research Funding; Gamida Cell: Research Funding; Janssen: Research Funding; CRISPR Therapeutics: Consultancy, Honoraria; Kite, a Gilead Company: Research Funding; Macrogenics: Research Funding; Bristol Myers Squibb: Research Funding; Cellectar: Research Funding; BioLineRX: Research Funding; MorphoSys: Consultancy, Honoraria; Amgen: Research Funding; Karyopharm: Consultancy, Honoraria; Cellectar: Research Funding; Actinium: Research Funding. Abhyankar: Incyte/Therakos: Consultancy, Research Funding, Speakers Bureau. Hari: Karyopharm: Consultancy; Millenium: Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; Celgene-BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau. Chen: Actinium Pharmaceuticals: Other: Principal Investigator, SIERRA Trial, Actinium. Sabloff: Novartis: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; TaiHo: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Jaxx: Membership on an entity's Board of Directors or advisory committees; ROCHE: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees. Orozco: Actinium Pharmaceuticals: Other: Principal Investigator, SIERRA Trial, Actinium, Research Funding. Foran: abbvie: Research Funding; revolution medicine: Honoraria; novartis: Honoraria; certara: Honoraria; actinium: Research Funding; OncLive: Honoraria; aptose: Research Funding; trillium: Research Funding; gamida: Honoraria; takeda: Research Funding; boehringer ingelheim: Research Funding; bms: Honoraria; taiho: Honoraria; syros: Honoraria; sanofi aventis: Honoraria; pfizer: Honoraria; servier: Honoraria; kura: Research Funding; h3bioscience: Research Funding; aprea: Research Funding; sellas: Research Funding; stemline: Research Funding. Jamieson: Actinium Pharmaceuticals: Other: Principal Investigator, SIERRA Trial, Actinium. Magalhaes-Silverman: Actinium Pharmaceuticals; Incyte; Marker Therapeutics: Other: Principal Investigator, SIERRA Trial, Actinium, Research Funding. Schuster: Takeda: Consultancy, Speakers Bureau; MorphoSys Ag: Consultancy, Speakers Bureau; Astellas: Consultancy, Speakers Bureau; Intellisphere: Consultancy, Speakers Bureau; AbbVie Incorporated: Consultancy, Speakers Bureau; Pharmacyclics: Consultancy, Research Funding, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Epizyme: Consultancy, Speakers Bureau; Bristol Myers Squibb: Consultancy, Speakers Bureau; BeiGene: Consultancy, Speakers Bureau; Actinium Pharmaceuticals: Other: Principal Investigator, SIERRA Trial, Actinium Pharmaceuticals, Research Funding; Rafael Pharmaceuticals: Research Funding; GSK: Research Funding; AlloVir: Research Funding; Incyte: Research Funding; Seattle Genetics: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Genentech: Consultancy, Speakers Bureau; Amgen: Consultancy, Current equity holder in publicly-traded company, Speakers Bureau; Celgene: Consultancy, Current equity holder in publicly-traded company, Speakers Bureau. Law: Actinium Pharmaceuticals: Research Funding; Novartis: Consultancy. Levy: Takeda, Celgene, Seattle Genetics, AbbVie, Jazz Pharmaceuticals, Gilead Sciences, Bristol-Myers Squibb, Amgen, Spectrum Pharmaceuticals,Janssen.: Consultancy. Lazarus: Bristol Myer Squibb: Membership on an entity's Board of Directors or advisory committees. Giralt: PFIZER: Membership on an entity's Board of Directors or advisory committees; AMGEN: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; SANOFI: Membership on an entity's Board of Directors or advisory committees; CELGENE: Membership on an entity's Board of Directors or advisory committees; JAZZ: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; JENSENN: Membership on an entity's Board of Directors or advisory committees; Actinnum: Membership on an entity's Board of Directors or advisory committees. Berger: Actinium Pharmaceuticals, Inc: Current Employment. Spross: Actinium Pharmaceuticals: Current Employment, Current holder of stock options in a privately-held company. Desai: Actinium Pharmaceuticals: Current Employment, Current holder of stock options in a privately-held company. Reddy: Actinium Pharmaceuticals: Current Employment, Current holder of stock options in a privately-held company. Pagel: AstraZeneca: Consultancy; MEI Pharma: Consultancy; Epizyme: Consultancy; Actinium Pharmaceuticals: Consultancy; Kite, a Gilead Company: Consultancy; BeiGene: Consultancy; Pharmacyclics/AbbVie: Consultancy; Gilead: Consultancy; Incyte/MorphoSys: Consultancy.