Vusirikala, Madhuri

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.

The NCCN Guidelines for Hematopoietic Cell Transplantation (HCT) provide an evidence- and consensus-based approach for the use of autologous and allogeneic HCT in the management of malignant diseases in adult patients. HCT is a potentially curative treatment option for patients with certain types of malignancies; however, recurrent malignancy and transplant-related complications often limit the long-term survival of HCT recipients. The purpose of these guidelines is to provide guidance regarding aspects of HCT, including pretransplant recipient evaluation, hematopoietic cell mobilization, and treatment of graft-versus-host disease—a major complication of allogeneic HCT—to enable the patient and clinician to assess management options in the context of an individual patient’s condition. These NCCN Guidelines Insights provide a summary of the important recent updates to the NCCN Guidelines for HCT, including the incorporation of a newly developed section on the Principles of Conditioning for HCT.

The NCCN Guidelines for Acute Lymphoblastic Leukemia (ALL) focus on the classification of ALL subtypes based on immunophenotype and cytogenetic/molecular markers; risk assessment and stratification for risk-adapted therapy; treatment strategies for Philadelphia chromosome (Ph)-positive and Ph-negative ALL for both adolescent and young adult and adult patients; and supportive care considerations. Given the complexity of ALL treatment regimens and the required supportive care measures, the NCCN ALL Panel recommends that patients be treated at a specialized cancer center with expertise in the management of ALL This portion of the Guidelines focuses on the management of Ph-positive and Ph-negative ALL in adolescents and young adults, and management in relapsed settings.

Abstract Background: Chronic GVHD contributes to morbidity and mortality after allogeneic transplantation. Several phase 2 and 3 open label studies suggested that ATLG (formerly referred to as ATG-F) reduces cGVHD without impacting relapse or survival. This report describes the first prospective randomized double blind phase 3 trial to assess the effect of ATLG (Neovii) when added to tacrolimus / methotrexate prophylaxis on cGVHD free survival. Patients and Methods: This study was conducted at 27 sites in the United States and Australia. 260 patients were randomized (132 placebo, 128 ATLG). 6 patients who were randomized never received ATLG/placebo (4 placebo and 2 ATLG). Data presented include the 128 placebo and 126 ATLG patients who underwent treatment and transplant. Patients were ages 18-65 years with a diagnosis of acute myeloid (AML, 64%) or lymphoblastic (ALL, 21%) leukemia in first or subsequent complete remission or myelodysplastic syndrome (MDS, 15%) with less than 10% marrow blasts. Median age was 48 years (18-65) with 55% males. All patients received 8/8 HLA (A, B, C, DR) allele matched unrelated products (80% mobilized peripheral blood, 20% bone marrow). Myeloablative conditioning was with cyclophosphamide and total body irradiation (Cy/TBI, 27%), busulfan and cyclophosphamide (Bu/Cy, 33%), or busulfan and fludarabine (Bu/Flu, 40%). All patients received tacrolimus starting on Day -1 and standard mtx on days 1, 3, 6, and 11 for GVHD prophylaxis. Patients received ATLG or placebo on Days -3, -2, -1 at an ATLG dose of 20 mg/kg per day (60 mg/kg total). The primary endpoint of the study was moderate/severe chronic GVHD free survival. cGVHD was scored by the investigator and then confirmed or overturned by an independent adjudication committee. Secondary endpoints included engraftment, acute GVHD , moderate/severe cGVHD, non-relapse mortality, GVHD and relapse free survival (GRFS), progression free (PFS) and overall survival (OS). The impact of ATLG on immune reconstitution was assessed in 91 patients. Results: Treatment arms were balanced with respect to age, diagnosis, remission status, cytogenetics, graft source (PB or BM), CMV serostatus and conditioning regimen. Median follow up of survivors was 745 days (61, 1425). Regarding the primary endpoint, there was no difference in 2 year moderate/severe cGVHD free survival between ATLG and placebo (48 vs 44%, p = 0.57), nor was there a difference in GRFS (Table 1). Neutrophil engraftment at Day 30 was less in the ATLG arm (85% vs 95%, p=0.00001). Grade 2 or higher infusion reactions were higher in the ATLG arm (16% vs 2.3%, p=0.0001). Reactivation of CMV was similar (27% vs 31%, p=0.58). The Day 180 cumulative incidence of grades 2-4 acute GVHD was lower in the ATLG arm (23 vs 40%, p = 0.003) as was the 2-year cumulative incidence of moderate/severe cGVHD (12 vs 33%, p = 0.000006). However, both 2-year OS and PFS were lower in ATLG treated patients (58 v 76% and 47 vs 67%, respectively) due in part to a higher incidence of relapse (32 vs 19%, p=0.068). Multivariable models confirmed that ATLG was associated with inferior OS, HR 1.85 (1.1-2.9, p=.0075) and PFS, HR 1.63 (1.1-2.41, p=0.015). We then conducted an unplanned post-hoc analysis and discovered a striking influence of conditioning regimen on outcomes. There were no differences in OS or PFS between ATLG and placebo arms in patients receiving Bu/Cy or Bu/Flu but a dramatic difference in patients receiving Cy/TBI conditioning (OS, 88% vs 48% p =0.006 and PFS, 75 vs 29%, p=0.007 in placebo and ATLG arms, respectively). 91 patients (44 ATLG, 47 placebo) participated in the immune reconstitution study. ATLG treatment was associated with lower CD3, CD4, and CD8 counts at Days 30, 100, and 360, respectively. In turn lower CD3, CD4, and CD8 counts assessed as time dependent variables were all associated with inferior OS and PFS as well as higher NRM (data not shown). Conclusion: In this first ever prospective, randomized, double blind trial of ATLG added to tacrolimus /methotrexate in recipients of matched unrelated donor grafts after myeloablative conditioning, there was no significant difference in 2 year moderate/severe cGVHD free survival or GRFS. ATLG did significantly reduce grades 2-4 acute and moderate/severe chronic GVHD. However, overall survival was higher in the placebo arm, driven mainly by patients who received Cy/TBI conditioning. Further analyses are needed to understand the proper role for ATLG in HCT. Disclosures Soiffer: Juno: Membership on an entity's Board of Directors or advisory committees; Kiadis: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Porter:Genentech: Employment; Novartis: Patents & Royalties, Research Funding. Jagasia:Therakos: Consultancy. Szer:Alnylam: Honoraria, Membership on an entity's Board of Directors or advisory committees; Ra Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Alexion Pharmaceuticals, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees. Ritz:Kiadis: Membership on an entity's Board of Directors or advisory committees. Glavin:Neovii Biotech: Employment. Chen:Incyte Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding.