Treatment-related Acute Myeloid Leukemia Research Articles

Interim safety and efficacy of BP1001 in a phase II acute myeloid leukemia (AML) study.

6511 Background: Oncogenic tyrosine kinases induce AML progression via the growth factor receptor bound protein-2 (Grb2). BP1001, a liposome-incorporated Grb2 antisense oligonucleotide,enhanced cancer cell sensitivity to chemotherapy, such as decitabine (DEC) and venetoclax (VEN). A multi-center open-label Phase II study was initiated to assess whether the BP1001 + DEC + VEN combination provides higher response rates than historically reported responses of DEC + VEN in newly diagnosed AML (including secondary AML) (cohort 1) or refractory/relapsed (R/R; cohort 2) AML patients (pts) considered unsuitable for intensive chemotherapy. Per protocol, when 19 evaluable pts are enrolled in each cohort, interim analysis will be performed to determine which cohort has ≥5 complete responses and will continue with enrollment. Methods: BP1001 was given, beginning on Day 4, at 60 mg/m2 IV, 2x weekly for a total of 8 doses over a 28-day cycle. DEC was given IV on days 1 to 5 at 20 mg/m2. VEN was given PO at 100 mg on day 1, 200 mg on day 2, and 400 mg from day 3 to day 14 or 21. Eligible pts were considered unsuitable for or refused intensive chemotherapy and had ECOG performance status of 0-2. Interim analysis was performed on Jan 24, 2024 on pts enrolled between July 28, 2020 and December 26, 2023. Evaluability for efficacy was defined as: completion of at least 4 cycles of combination therapy, documented Progressive Disease (PD) or any drug toxicity at any time, or CR/CRi/CRh prior to 4 cycles. Results: In Cohort 1, 31 newly diagnosed pts were enrolled; 20 evaluable pts (9 male: 45%) with a median age of 75 years (range, 69 - 84), treated with at least 1 cycle of BP1001 + DEC + VEN, had adverse-risk (n=12, ELN 2017 classification) or secondary AML (sAML; n=7) evolved from MDS (n=4), CMML (n=1) or treatment-related AML (n=2). Fifteen pts (75% of evaluable; 54% of enrolled) achieved CR/CRi/CRh; 2 pts achieved partial remission (PR) and 2 achieved stable disease (SD). In Cohort 2, 38 R/R pts were enrolled; 23 evaluable pts (13 male: 57%) with a median age of 63 years (range, 24 - 89), treated with at least 1 cycle of BP1001 + DEC + VEN, had adverse-risk (n=13) or sAML (n=5). Twelve pts (55% of evaluable; 32% of enrolled) achieved CR/CRi/CRh; 1 pt achieved PR, 8 achieved SD and 1 had treatment failure. Among the evaluable pts of both cohorts, adverse events were consistent with those expected with DEC, VEN and/or AML, including fatigue (72%), anemia (60%) and neutropenia (49%), while the most frequent serious adverse events were febrile neutropenia (26%) and sepsis (5%). Conclusions: BP1001 + DEC + VEN has been safely administered to pts without drug-related toxicity. Since >5 responses are observed in both cohorts, the study will continue with enrollment up to 98 and 54 evaluable pts in cohorts 1 and 2, respectively. Efficacy data are encouraging in a challenging population of frontline adverse-risk, sAML and R/R pts. Clinical trial information: NCT02781883 .

Abstract 7123: Biomarker-targeted alkylator and DNA damage repair inhibitor combination for refractory and relapsed acute myeloid leukemia (AML)

Abstract Isocitrate dehydrogenase 1 and 2 (IDH1/2) convert isocitrate to α-ketoglutarate in the tricarboxylic acid (TCA) cycle. A missense mutation in IDH1/2 leads to accelerated conversion of α-ketoglutarate into 2-hydroxyglutarate (2-HG), an oncometabolite that competitively inhibits α-ketoglutarate-dependent dioxygenases including Ten-Eleven Translocation (TET) enzymes. TET enzymes are DNA demethylases that convert 5-methylcytosine to 5-carboxycytosine and regulate CpG island promoter methylation signatures. In IDH1/2 mutant glioma, inhibition of TET2 enzyme by 2-HG can lead to promoter hypermethylation of O6-methylguanine methyltransferase (MGMT) and reduce its expression. Approximately 10-15% of de novo or treatment-related AML harbor mutually exclusive mutations in IDH1/2 or TET2, and emerging resistance towards clinical IDH1/2 inhibitors, therefore warrants novel therapeutic options. We performed a pan-cancer TCGA analysis and observed MGMT promoter hypermethylation and reduced expression in IDH1/2 AML. Our independent study on 10 AML patients (5 IDH1/2 and 5 TET2 mutant) corroborated the TCGA data and showed a significantly reduced expression of MGMT in comparison to 7 wild-type AML samples. As MGMT resolves O6-alkylguanine lesions during DNA damage, we performed an exhaustive alkylator screen, where temozolomide (TMZ) and our novel compound KL-50 emerged as the top hits that imparted a maximum therapeutic index in multiple MGMT (MGMT+/–) isogenic AML cell line models. Both TMZ and KL-50 induced MGMT-dependent DNA strand breaks and replication stress and activated ATM and ATR DNA damage response pathways in a time-dependent manner. Inhibition of ATR activation with Ceralasertib, an ATR inhibitor (ATRi) currently in clinical trials for chronic myelomonocytic leukemia and myelodysplastic syndromes, imparted a profound MGMT-dependent synergy with TMZ and KL-50. Researchers have established in glioma that mismatch repair (MMR) loss confers resistance to TMZ, and reported studies also show evidence of MMR loss in refractory or relapsed AML patients. Thus, we developed numerous MMR-deficient isogenic AML cell lines in an MGMT+/– background and observed MMR loss-mediated resistance to TMZ and abrogation of its synergy with ATRi. Unlike TMZ, KL-50 retained a profound synergy with ATRi in an MGMT-dependent manner irrespective of MMR status. We are currently investigating our novel KL-50 and ATRi combination in MGMT/MMR isogenic cell line-based in vivo AML models and in AML patient-derived xenografts to establish it as a promising novel biomarker-targeted therapy for AML patients. Citation Format: Prateek Bhardwaj, Ranjini Sundaram, Amro Baassiri, Martin Matthews, Jennifer VanOudenhove, Susan Gueble, Stephanie Halene, Ranjit Bindra. Biomarker-targeted alkylator and DNA damage repair inhibitor combination for refractory and relapsed acute myeloid leukemia (AML) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7123.

Analysis of the clinical characteristics of acute myeloid leukemia related to the treatment of hematological and solid tumors

Objective: To compare and analyze the clinical characteristics of acute myeloid leukemia (AML) related to the treatment of hematological tumors and solid tumors. Methods: The laboratory and clinical data of 41 patients with treatment-related AML (t-AML) in the Department of Hematology, Henan Cancer Hospital from January 2014 to December 2021 were retrospectively analyzed, and they were divided into hematological tumor group and solid tumor group. Survival analysis was performed using the Kaplan-Meier method and Log rank test. Results: The median interval from the first tumor diagnosis to t-AML in 41 patients was 21.0 (16.5-46.0) months; 24 (58.5%) had abnormal expression of lymphoid antigen, 28 (68.3%) had abnormal karyotype, 18 cases (43.9%) were positive for fusion gene, and 28 cases (68.3%) were positive for gene mutation; the median recurrence-free survival (RFS) was 11.0 months, and the median overall survival (OS) was 11.5 months. The proportion of acute promyelocytic leukemia ([APL], 0.0, 0/13), complete response ([CR],18.2%, 2/11), median OS (4.5 months) and median RFS (2.5 months) of t-AML patients in the hematological tumor group were significantly lower than those in the solid tumor group (35.7%, 10/28; 68.0%, 17/25; not reach; not reach), but the proportion of M4 /M5 (93.2%,12/13) was significantly higher than that in the solid tumor group (53.6%,15/18; all P values<0.05). Through subgroup analysis, the proportion of patients with positive PML-RARa and good prognosis karyotypes in the solid tumor group (35.7%, 10/28; 46.4%, 13/28) was significantly higher than that in the hematological tumor group (0.0, 0/13; 0.0, 0/13; P<0.05), while the proportion of patients with intermediate karyotypes (42.9%, 12/28) was significantly lower than that in the hematological tumor group (84.6%, 11/13; P<0.05), the difference was statistically significant. The CR rate (90.0%, 9/10), median OS (not reach) and median RFS (not reach) in the t-APL group were higher than those in the t-AML (without t-APL) group (38.5%, 10/26; 6 months; 8 months; P<0.05). After excluding the effect of t-APL patients, there was no significant difference in the CR rate, median OS and median RFS between the solid tumor group (8; 9 months; not reach) and the hematological tumor group (2; 4 months; 2 months; P>0.05). Univariate analysis showed that the primary tumor belongs to hematological tumor was a common risk factor for OS and RFS in t-AML patients (P<0.10). Conclusions: Compared with patients with t-AML secondary to solid tumors, patients with t-AML secondary to hematological tumors have poorer treatment effects and poorer prognosis. After excluding the effect of t-APL patients, there are no significant differences in the treatment efficacy and prognosis between the two types of t-AML patients.

Venetoclax Combined with Azacitidine and Homoharringtonine in Adults with Secondary Acute Myeloid Leukemia

Secondary acute myeloid leukemia is an aggressive subset of acute myeloid leukemia (AML) that is, in general, is associated with a very poor prognosis and high mortality. Venetoclax combined with hypomethylating agents have showed relatively successful therapeutic effective in patients with relapse/refractory AML, while efficacy is limited in high-risk subset AML. We hypothesised that Venetoclax combined with Azacitidine and Homoharringtonine could have improved activity in patients with secondary acute myeloid leukemia, particularly in high-risk subgroups. Methods This single center, phase 2 trial was done at the first affiliated hospital of Nanjing medical university. The study enrolled adult patients with diagnosed of secondary AML (AML progressed after preexisting myeloid neoplasms or treatment AML arising from prior exposure of leukemogenic therapies). Patients were required to have an Easter Cooperative Oncology Group performance status of 3 or less, and adequate end-organ function. Patients who had received previous BLC2 inhibitor therapy were excluded. Patients received Azacytidine 75mg/m 2 and Homoharringtonine 3mg for 7 days with venetoclax 400mg daily. The primary endpoint was overall response rate. The secondary endpoints include safety, overall survival, and duration of response (according to recommendations of European LeukemiaNet 2017 guidelines). The trial was registered on ClinicalTrial.gov (NCT 05513131) and continues to accrue patients. Results Since now, we enrolled 11patients; 8(72.7%) patients had secondary AML, 3 (27.3%) patients had treatment related AML, while 2(18.2%) patients had TP53 mutation. The median age was 62 years (48-78 years). At the July 30, 2023 data cutoff, median follow-up time was 36.7 weeks (range 6.57-82.29 weeks). The overall response rate was 81.8% (9 of 11 patients). The most common treatment-emergent adverse events included bone marrow suppression with grades 3 or 4 neutropenia (n=11/11) and febrile neutropenia (n=10/11). The 30-day mortality for all patients was 9.1% (n=1). 2(18.2%) patients were eligible for allogeneic hematopoietic stem cell transplantation. The median overall survival was not achieved. Conclusion Venetoclax combined with Azacitidine and Homoharringtonine regimen had a tolerable safety profile and showed encouraging clinical activity characterised by a high response rate. further patients are needed to validate these findings.

CLEC2A Is a Novel AML-Restricted Immunotherapeutic Target Enriched in KMT2A-Rearranged Acute Myeloid Leukemia

KMT2A rearrangements (KMT2A-r) are a frequent event in childhood acute myeloid leukemia (AML) and in treatment related AML in adults leading to a highly refractory and deadly subtype of AML regardless of age. Targeted therapies for KMT2A-r AML have had limited success with novel therapies urgently needed. Despite successes in other leukemias, immunotherapy in AML is in its infancy in part due to significant overlap of antigens expressed in AML and normal hematopoietic cells, which would limit efficacy and increase hematopoietic toxicity. We interrogated the AML transcriptome compared to normal hematopoiesis to identify optimal targets that are silent in normal hematopoieisis and are highly expressed in AML. Here we describe a novel immunotherapeutic target, CLEC2A, a member of the C-type lectin family, that is highly enriched in high-risk AML, particularly KMT2A-r AML and absent in normal hematopoeisis. We evaluated the association between KMT2A fusions and CLEC2A expression identifying CLEC2A as a putative oncoprotein and the potential for CLEC2A to serve as an immunotherapeutic target in high-risk AML via antibody-mediated cytotoxicity. Diagnostic specimens from 1,864 patients with AML (Pediatric 0-29 years from COG Phase III trials N=1486; Adult 18-88 years SWOG N=199 and TCGA-LAML N=179) were interrogated using contemporary NGS to identify genetic aberrations. Conventional karyotyping and mutational analysis were used to determine additional cytogenetic and molecular abnormalities. As CLEC2A was entirely absent in normal bone marrow (TPM 0-0.15), positive CLEC2A expression was defined as mRNA transcripts per million (TPM) &amp;gt;1. Although, CLEC2A was detected in only 18% of AML patients (252/1486; 17% pediatric and 90/378; 24% adult patients), it was highly enriched in those with KMT2A-r AML with 77% (N=193) of CLEC2A positive patients having KMT2A-r, accounting for 48% of the total KMT2A-r cohort, Fig 1A. CLEC2A expression was enriched in specific fusion subgroups: MLLT10 (80%), MLLT4 (71%), and MLLT3 (48%), Fig 1B. CLEC2A expression was low to absent in a majority of other patients, though was seen in other high-risk groups including non-KMT2A MLLT10 fusions, NUP98 fusions, CBFA2T3-GLIS2 fusions, and monosomy 7. CLEC2A is also expressed in a subtype of T-ALL (HOXA activated), which is a fusion driven T-ALL. We further evaluated a potential causal link between KMT2A fusions and CLEC2A expression and inquired whether KMT2A fusion proteins might directly bind to the CLEC2A promoter and induce CLEC2A expression. We used AutoCUT&amp;RUN profiling of genome-wide occupancy of KMT2A oncoproteins to evaluate direct binding of the KMT2A fusion protein to the CLEC2A promoter in primary AML patient samples with three different KMT2A fusions (MLLT10, MLLT4 and MLLT3). We found direct binding of KMT2A fusion proteins to the CLEC2A promoter region, indicating a causal relationship between KMT2A fusions and CLEC2A expression. We then evaluated the potential of therapeutic targeting of CLEC2A by an antibody-drug conjugate using a HumZap cytotoxicy assay. CLEC2A antibody conjugated to saporin (a toxin with cytolytic activity when internalized) was incubated with CLEC2A+ and CLEC2A- cells with target-specific cytotoxicity evaluated by colorimetric assay. CLEC2A+ OCI-AML2 cells had significantly higher rate of cytotoxicity compared to CLEC2A- control cells at 10nM Ab-toxin conjugate. Clinical outcomes for patients with and without CLEC2A expression was evaluated. Patients with CLEC2A had significantly worse outcomes (EFS 23% vs. 45.5%, p&amp;lt;0.0001 and OS 38% vs. 63%, p&amp;lt;0.0001 for patients with and without CLEC2A expression, respectively). Given high rates of co-occurring KMT2A-r AML, particularly high-risk fusions (MLLT10 and MLLT4), we evaluated clinical outcomes within the KMT2A-r cohort as these patients have poor EFS and OS. KMT2A-r patients with CLEC2A had significantly worse EFS (24% vs. 39%, p=0.0063) and OS (38% vs. 60%, p=0.0002). Within the KMT2A-r cohort, high rates of relapse were seen for patients with CLEC2A expression compared to those without CLEC2A (72% vs. 55%, p=0.0039). Here we describe CLEC2A, a novel AML-restricted cell surface target that is an ideal immunotherapeutic target. CLEC2A is highly expressed in KMT2A-r AML, entirely absent in normal hematopoietic cells, directly and causally linked to the KMT2A fusion, and can be used for target-directed cytotoxicity.

Maintenance Therapy with Chidamide Plus Azacitidine after Allogeneic Hematopoietic Stem Cell Transplantation for High-Risk Acute Myeloid Leukemia Patients

Background: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is theoretically the only curative option for high-risk acute myeloid leukemia (AML) patients. However, many patients relapse after allo-HSCT, and treatment options are very limited. Azacitidine, a DNA methyltransferase inhibitor exhibits anti-leukemia activity in myeloid diseases. Chidamide, a selective histone deacetylase inhibitor, effectively induces apoptosis of AML cells. They have synergistic inhibitory effect on AML cells when combined together. Therefore, we conducted a multicentre, prospective study (ChiCTR2300067593) to examine the tolerability and efficacy of a combination of both chidamide and azacitidine as a maintenance therapy for high-risk AML patients after allo-HSCT. Patients and methods： Patients ≤ 60 years of age with high-risk AML post- allo-HSCT were enrolled. The high-risk characteristics of AML were defined as one or more of the following criteria: a) Patients with poor prognosis according to the genetic risk stratification assessment of European Leukmia Net (ELN) in 2022; b) Primary refractory or recurrent AML; c) Secondary AML (secondary to MDS or treatment-related AML). All patients received Chidamide 5 mg/d combined with azacitidine 75 mg/m2/d for 5 days. The cycle interval was 6-8 weeks. A total of 6 cycles was recommended. Treatment started as early as 3 months after transplantation. The primary endpoint of this study was cumulative incidence of relapse (CIR). The secondary endpoints included rates of overall survival (OS) and event-free survival (EFS). Survival outcomes were estimated using Kaplan-Meier analysis. Results： Thirty-six patients have been recruited. The median age was 42 years (range, 16-59). Baseline characteristics are shown in Table 1. With a median follow-up time of 412（185-762）days, the 1-year CIR was 12.3 (6.5-18.1) %, the 1-year OS and EFS rates were 100.0% and 87.7 (81.9-93.5) %, respectively. The median OS and EFS time were not reached. Four patients relapsed, two died, and two are still alive and ready for the second transplantation. The most common adverse events (AEs) were thrombocytopenia reaction and gastrointestinal tract reaction. Grade 2 or 3 AEs were observed in 16.7% (6/36) and 25.0% (9/36) of the patients, respectively. No grade &amp;gt;3 AEs were noted. 9 patients (6/36,16.7%) developed grade 3-4 thrombocytopenia, without active hemorrhage. All of them received blood transfusion and thrombopoietin receptor agonist. The median persistence of thrombocytopenia was 3 (2-5) d. Chronic graft-versus-host-disease (cGVHD) occurred in 25.0% (9/36) of patients. Four cases (4/36, 11.1%) were complicated with infection. They were one case of intestinal infection, one case of pulmonary and EBV infections, one case of hepatitis B virus activation and one case of herpes zoster. And all infected patients recovered safely after anti-infection and symptom-oriented treatment. CMV activation was not observed. Non relapse mortality (NRM) was zero. Conclusions： We conclude that chidamide plus azacitidine can be administered safely after allo- HSCT with no evidence of an increased incidence of GVHD, and this combination may decrease the relapse rate in high-risk AML patients. This novel maintenance therapy may be a promising way to prevent relapse in high-risk AML patients.

APAL2020SC Pediatric Acute Leukemia (PedAL) Screening Trial - Developing New Therapies for Relapsed Leukemias

Background: Outcomes for children with relapsed acute myeloid leukemia (AML) and subgroups with relapsed acute lymphoblastic leukemia (ALL) remain poor, and therapeutic options are limited. There is no standard of care for relapsed disease, and data collection after relapse is lacking. In recent years, extensive molecular studies of pediatric leukemias have advanced target identification and clinical trial development. Such studies have shown that pediatric leukemias are biologically distinct from adult leukemias. The current paradigm of requiring new agent studies in adults prior to conducting pediatric trials is thus not appropriate. However, the rarity of relapsed leukemia in children makes the conduct of randomized registration trials for new agents infeasible. Recognizing that impactful progress requires international collaboration, the Leukemia &amp; Lymphoma Society is sponsoring the Pediatric Acute Leukemia (PedAL) Initiative in North America, Australia and New Zealand. In parallel, the European Pediatric Acute Leukemia (EuPAL) Foundation has established a registry for pediatric relapsed leukemia. The principal goal of this international PedAL/EuPAL collaboration is to establish a data-driven developmental therapeutics program for children with relapsed/refractory leukemias. Trial Summary: A central component of the PedAL Initiative is the screening protocol APAL2020SC (NCT04726241), which serves as the entry point for associated therapeutic sub-trials. The primary aims of APAL2020SC are (1) to use clinical and biological characteristics to screen for eligibility for therapeutic sub-trials; and (2) to maintain a longitudinal data registry and biobank for relapsed leukemia. Eligible patients are &amp;lt;22 years old and have one of the following leukemias in first or greater relapse, or primary refractory: AML, myeloid leukemia of Down syndrome, T-ALL, mixed phenotype acute leukemia, and KMT2A-rearranged B-ALL. Additional eligible diagnoses include any B-ALL in second or greater relapse, and de novo or relapsed treatment-related AML. All leukemia specimens are profiled by multiparameter flow cytometry (MFC) at a central lab (Hematologics). Families have the option to submit biospecimens for banking. Patients with myeloid leukemia also have molecular testing through Foundation Medicine. Clinical data collected include demographics, cytomolecular features at diagnosis, prior treatment and post-relapse treatment. Patients are encouraged to submit follow-up bone marrow samples for central MFC. The MFC assay determines lineage and blast percent and quantifies expression of markers relevant to therapeutic sub-trials. Trial Progress: APAL2020SC opened in April 2022. As of July 25, 2023, 148 patients have enrolled and 97 have had leukemia confirmed centrally. The distribution of diagnoses is shown in Table 1. All patients had blast enumeration and target expression assessed by MFC at study entry and when follow-up samples were provided. Of the patients with myeloid leukemia (n=71), targeted DNA/RNA sequencing was successful for 69%. The distribution of AML-associated alterations is shown in Table 2. Of the patients with confirmed leukemia at enrollment, 79% submitted at least 1 follow-up sample, and 77% submitted a sample for biobanking. To date, two therapeutic trials have opened that require enrollment to the screening trial. APAL2020D/ITCC101 is a randomized phase III study comparing fludarabine-cytarabine (FLA) to FLA-venetoclax. APAL2020E/PEPN2113 is a phase 1 study of the E-selectin inhibitor uproleselan in combination with FLA. Pediatric-specific therapeutic trials for menin inhibitors and other new agents are in development. The study is collecting treatment information for children who do not enroll on a subtrial, with the goal of describing current practices and outcomes (Table 2). Conclusion: APAL2020SC will accrue patients with relapsed acute leukemias and treatment-related AML for 5 years. This protocol will promote clinical trial development by engaging industry partners and providing a single entry point to therapeutic studies with biological rationale. APAL2020SC and the EuPAL Foundation registry will generate a large, comprehensive and longitudinal dataset that will inform future trials. The biobank component will support innovative translational research to feed the pipeline of new agents.

Risk of Therapy-Related Acute Myeloid Leukemia (t-AML) in Adolescent and Young Adults Cancer Patients Treated with Chemotherapy with or without Radiotherapy: A National Population-Based Cohort Study Using SEER Registry

INTRODUCTION The risk of treatment-related acute myeloid leukemia (t-AML) in adolescents and young adults (AYA) with first cancers treated with chemotherapy with or without radiation is not well characterized. We analyzed Surveillance, Epidemiology and End Result (SEER) data for the past 45-years (1975-2020) to identify the overall risk of t-AML in treated AYA cancer patients (pts) and by index cancer sites as well as latency periods. METHOD We analyzed NCI's SEER-8 registries. ICD-O-3/WHO-2008 codes were used to identify pts with index cancer types between the ages of 15-39 years (AYA), treated with either chemotherapy or radiotherapy, and with a subsequent diagnosis of acute myeloid leukemia (AML) at least one year after index cancer, between January 1975 and December 2020. The risk of t-AML was estimated by standardized incidence ratio (SIR), defined as the ratio of observed t-AML-cases in the AYA-with-cancer, to the expected number of AML-cases in the matched general US population. A reference rate file for AML incidence in age, gender, race and calendar-year matched US population is available in SEERStat software. A Poisson distribution of observed t-AML was assumed for the calculation of 95% confidence intervals (CIs). A P-value &amp;lt;.05 was considered statistically significant. We stratified the risk of t-AML for index cancer types with ten or more pts, by attained-calendar-years, and latency at multiple time intervals (Table-1) from index cancer diagnosis. RESULT Among 102,879 AYA cancer pts eligible for analysis, 236 pts developed t-AML with SIR of 6.19 (95%CI: 5.43-7.04, P &amp;lt;.05) with excess risk of 1.46 per-10000 person-years (pyrs). (Table-1). We stratified risk for index cancer types with at least ten patients developing t-AML, these included breast, Hodgkin lymphoma (HL), non-Hodgkin lymphoma (NHL), testicular, thyroid, bone and joint, and soft tissue including heart. As a general trend, risk of t-AML was highest during 1-3 years after index cancer diagnosis compared to subsequent latency periods. However, risk for t-AML was significantly greater than the matched-general US population even after 20-40 years of breast cancer, HL, and NHL (Table-1). When stratified by attained calendar-year periods (1975-1985, 1986-1995, 1996-2005, 2006-2015, 2016-2020), risk for t-AML was higher than general population in all time periods. However, overall SIR was comparatively lower for recent time periods, particularly lowest during 2016-2020 [SIR: 3.49 (2.51-4.72, P &amp;lt;.05)]. Notably, the highest risk for t-AML in 2016-2020 was observed with index cancer of soft tissue including heart [SIR: 10.12 (1.23-36.57), P &amp;lt;.05]. CONCLUSION In this study spanning between 1975-2020, we observed the risk of t-AML trending down among AYA in recent years, albeit higher than the age matched general population. The risk of t-AML remained significantly elevated even after 20-40 from diagnosis of breast cancer, HL and NHL. Since these pts likely received radiation and older (higher intensity) chemotherapy based-regimens, it is essential to analyze the long-term impact of newer therapies for these cancers and assess the risk of t-AML in future studies.

Therapy-related myeloid neoplasm in early breast cancer patients treated with adjuvant chemotherapy

BackgroundLong-term complications are becoming more important as the survival rate of breast cancer improves. Treatment-related myeloid neoplasm is an important long-term complication in breast cancer survivors as it has a poor prognosis. ObjectiveWe evaluated the incidence and risk factors for the development of treatment-related acute myeloid leukaemia (AML)/myelodysplastic syndrome (MDS) in patients treated with early breast cancer. MethodsWe accessed the national Korean database to identify 153,565 patients diagnosed with breast cancer between January 2007 and October 2016 who underwent surgery for breast cancer. We estimated the cumulative incidence of AML/MDS and analysed the risk factors for developing AML/MDS. ResultsOf 153,575 patients, 79,321 received anthracycline-based adjuvant therapy, 14,317 received adjuvant therapy without anthracyclines and 46,657 did not receive adjuvant chemotherapy. Overall, 120 developed AML (105 in the anthracycline group, 9 in the non-anthracycline group and 6 in the control group), and 128 developed MDS (96, 9 and 23 in each group). The 10-year cumulative incidence of AML/MDS was the highest in the anthracycline group (0.221% and 0.199%), followed by the non-anthracycline group (0.122% and 0.163%) and the control group (0.024% and 0.089%). The risk of developing AML/MDS was significantly higher in patients treated with anthracyclines (hazard ratio [HR] 9.531; p < 0.0001 for AML and HR 2.559; p < 0.0001 for MDS) compared to patients in the control group. ConclusionThis study found that anthracycline-based adjuvant therapy significantly increased the risk of AML/MDS in Korean breast cancer patients, with the risk persisting for at least 10 years. While the cumulative incidence was low, the long-term risks of AML/MDS should be taken into account considering the poor outcomes associated with these neoplasms.

Palbociclib in Acute Leukemias With KMT2A-rearrangement: Results of AMLSG 23-14 Trial.

Palbociclib in Acute Leukemias With KMT2A-rearrangement: Results of AMLSG 23-14 Trial.

Treatment-related Acute Myeloid Leukemia Following Capecitabine Chemotherapy: A case report

Treatment-related Acute Myeloid Leukemia Following Capecitabine Chemotherapy: A case report

Distinct clonal identities of B-ALLs arising after lenolidomide therapy for multiple myeloma

AbstractPatients with multiple myeloma (MM) who are treated with lenalidomide rarely develop a secondary B-cell acute lymphoblastic leukemia (B-ALL). The clonal and biological relationship between these sequential malignancies is not yet clear. We identified 17 patients with MM treated with lenalidomide, who subsequently developed B-ALL. Patient samples were evaluated through sequencing, cytogenetics/fluorescence in situ hybridization (FISH), immunohistochemical (IHC) staining, and immunoglobulin heavy chain (IgH) clonality assessment. Samples were assessed for shared mutations and recurrently mutated genes. Through whole exome sequencing and cytogenetics/FISH analysis of 7 paired samples (MM vs matched B-ALL), no mutational overlap between samples was observed. Unique dominant IgH clonotypes between the tumors were observed in 5 paired MM/B-ALL samples. Across all 17 B-ALL samples, 14 (83%) had a TP53 variant detected. Three MM samples with sufficient sequencing depth (>500×) revealed rare cells (average of 0.6% variant allele frequency, or 1.2% of cells) with the same TP53 variant identified in the subsequent B-ALL sample. A lack of mutational overlap between MM and B-ALL samples shows that B-ALL developed as a second malignancy arising from a founding population of cells that likely represented unrelated clonal hematopoiesis caused by a TP53 mutation. The recurrent variants in TP53 in the B-ALL samples suggest a common path for malignant transformation that may be similar to that of TP53-mutant, treatment-related acute myeloid leukemia. The presence of rare cells containing TP53 variants in bone marrow at the initiation of lenalidomide treatment suggests that cellular populations containing TP53 variants expand in the presence of lenalidomide to increase the likelihood of B-ALL development.

Frontline Venetoclax (ven) Based Combination Therapy in Older Adults with Acute Myeloid Leukemia Treated in the Real-World Setting; A Multi-Institutional Retrospective Study

Introduction: Acute myeloid leukemia (AML) is a disease of the older population, with a median age at diagnosis of 68 years. Outcomes remain poor for patients (pts) older than 60 years of age who are unfit to receive intensive chemotherapy. Ven based combination therapy has become the standard of care based on the results of the Viale-A and Viale-C in combination with hypomethylating agents (HMA) or low dose cytarabine (LDAC), respectively. This combination therapy is myelosuppressive leading to multiple dose adjustments in the real-world setting, which may impact the validity of the trial responses and overall survival (OS) in a community-based practice. We therefore sought to investigate the outcomes of pts treated with ven based combination therapy in the real-world setting to better understand efficacy and patterns of adverse events.Methods: Pts 65 years of age or older, diagnosed with AML on or after January 1, 2019, and who received frontline ven based combination therapy with azacitidine (aza), decitabine (dac) or LDAC were identified in the COTA real-world database. The COTA database is a USA-based dataset comprised of longitudinal, Health Insurance Portability and Accountability Act (HIPAA)-compliant data on the diagnosis, clinical management, and outcomes of pts with cancer. Clinical outcomes, including real-world overall response rate (rwORR), OS and adverse events were calculated by treatment group. Responses were defined per treating physician as complete response (CR) or partial (PR) or progressive disease (PD). Categorical variables and rwORR were compared using Fisher's exact test. Survival outcomes were calculated using the Kaplan-Meier method and compared amongst groups using log-rank test.Results: A cohort of 112 pts were treated with ven based combination: ven/aza (n=54), ven/dac (n=52) and ven/LDAC (n=6). Across all treatment groups, the majority (91.1%) of pts were treated in the community setting. The median age at diagnosis was 77 yrs (IQR: 71-81 yrs). Per ELN risk, 6.2% had favorable, 19.6% had intermediate and 62.5% had high-risk AML. Five of the 6 pts receiving ven/LDAC had secondary AML (Table 1). The most common molecular abnormalities across the cohort were TP53 (38.4%), TET2 (26.8%), ASXL1 (27.7%), and DNMT3A (20.5%). The rwORR by treatment was 57.7% for ven/dac, 55.6% for ven/aza and 33.3% for ven/LDAC (ven/dac vs. ven/aza, p=0.85). Median OS (mOS) was similar for ven/dac with a longest mOS of 13.9 mo, followed by ven/aza with a mOS of 11.3 mo, and ven/LDAC mOS of 6.5 mo (ven/dac vs. ven/aza, p=0.77). The most common reasons for treatment discontinuation were toxicity (32.1%) followed by progression/inadequate response (10.7%). The most common toxicities were related to myelosuppression/cytopenias (Table 3). In this cohort, only 6 pts underwent an allogeneic stem cell transplant in first remission and no pts underwent an allogeneic transplant in second remission.Conclusions: To our knowledge, this dataset represents the largest cohort of pts treated with ven based combination therapy in the real world setting across multiple community practices. As less intense regimens are used to treat AML, more pts are receiving induction in the community setting, making these findings relevant in clinical practice. Although ven/dac combination had the longest OS, this was not significantly different from ven/aza. The ven/HMA response rates were lower and survival outcomes were shorter than those reported in the Viale-A trial, which raises concerns about early discontinuation of therapy in the real world setting due to myelosuppression. Ven/LDAC combination had the shortest OS, though most of these patients had sAML. Despite this enriched population for targeted therapies, the outcomes remained poor overall.There are drawbacks to interpreting retrospective outcomes data. First, there were no treatment related AML cases in this dataset, which would be highly unusual in an elderly population of 112 cases of AML. It is more plausible that the diagnosis of treatment related AML was not utilized in the patient's chart. Other data points that were not adequately captured were cause of death and International Working Group response criteria. Mutational panel testing remains underutilized for AML patients in a community-based practice setting. However, this dataset highlights the need for larger datasets to compare the outcomes of AML therapy by practice setting. [Display omitted] DisclosuresMadanat: Blue Print Pharmaceutical: Honoraria; Stem line pharmaceutical: Honoraria; Onc Live: Honoraria; Geron Pharmaceutical: Consultancy. Belli: COTA, Inc.: Current Employment, Other: Equity ownership. Hansen: COTA, Inc.: Current Employment. Foss: COTA, Inc.: Current Employment. Schulte: COTA, Inc.: Current Employment. Wang: COTA, Inc.: Current Employment, Other: Equity ownership.

Diagnostic Red Blood Cell Distribution Width As a Prognostic Factor in Acute Myeloid Leukemia

Introduction: A high red blood cell distribution width (RDW) mirrors dysregulated erythrocyte homeostasis and is associated with a higher mortality in several solid cancers and myelodysplastic syndrome (MDS). A high RDW may also identify individuals more likely to develop a MDS or an acute myeloid leukemia (AML). The prognostic relevance of the RDW in patients diagnosed with AML has not been previously evaluated.Methods: We analyzed 294 newly diagnosed AML patients (median age at diagnosis 61, range 14-77 years [y]) that underwent an allogeneic hematopoietic stem cell transplantation (HSCT) at the University Hospital Leipzig in complete remission (CR, 63%), CR with incomplete peripheral recovery (CRi, 18%) or with active disease (19%). The RDW was measured at diagnosis and a cut-off of 20.7% was determined using the R package “OptimalCutpoints” to define patients with a low (87%) or high (13%) diagnostic RDW. Disease risk was assessed according to European LeukemiaNet (ELN) 2017. Median follow up after HSCT was 3.0 y. To verify the results irrespective of the consolidating therapy, a validation set of 392 AML patients (median age at diagnosis 63, range 18-87 years) treated at the University Hospital Dresden was analyzed. Here, 46% of patients received chemotherapy alone and patients that underwent allogeneic HSCT were censored at the time of HSCT.Results: The diagnostic RDW was above the local upper limit of normal (> 15%) in the majority (73%) of AML patients. The RDW as continuous parameter was higher in patients with AML developing from an antecedent myeloid disorder (sAML, after MDS, MPN, or MDS/MPN) than in patients with de novo (P=.01) or treatment-related AML (tAML, after lymphatic or solid neoplasm, P=.02, Figure 1A). A higher RDW was also observed in patients harboring gene mutations previously linked to AML of secondary origin (i.e. mutated JAK2 [P=.03], ASXL1 [P=.004], or spliceosome mutation [P=.03, compromising SF3B1, SRSF2, U2AF1, and ZRSR2, Figure 1B], which was particularly driven by SRSF2 mutations [P=.002]). Adapting an optimal cut, a higher RDW (> 20.7%) was associated with a higher non-relapse mortality (NRM, P=.02), shorter overall survival (OS, P=.009, Figure 1C), but similar relapse incidence (P=.96). In multivariate analyses, the RDW retained its prognostic significance for a higher NRM after adjustment for age at diagnosis. A RDW > 20.7% was also associated with lower hemoglobin levels at diagnosis and a trend for lower incidence of NPM1 mutations (P=.06), which are enriched in de novo AML. In contrast, RDW levels were not associated with chromosomal abnormalities (P=.72) or ELN2017 disease risk (P=.55). Despite known association of a high RDW with a higher cardiovascular/inflammatory risk, neither the comorbidity index at HSCT (HCT-CI, P=.77) nor the incidence of an acute (P=1) or chronic (P=.63) graft-versus-host disease differed according to the diagnostic RDW. Comparably, in the validation set, higher RDW levels were observed in patients with sAML compared to de novo (P=.02) or tAML (P=.02). Introducing the established 20.7% cut into the validation set, patients with high RDW levels again had lower hemoglobin levels at diagnosis (P<.001), less NPM1 mutations (P=.005) and no different ELN2017 disease risk (P=.25). A high RDW in the validation set was associated with a significantly shorter OS (P<.001, Figure 1D) and shorter event-free survival (P=.05).Conclusions: Our study is the first to evaluate the diagnostic RDW in AML patients. Patients with a secondary AML or secondary AML-associated gene mutations had higher diagnostic RDW levels. The presence of a high diagnostic RDW identifies patients with worse outcomes, irrespective of the ELN2017 risk classification and the applied consolidation therapy. This cost-effective and fast to assess parameter may help to personalize AML patient treatment. [Display omitted] DisclosuresVucinic: Gilead: Honoraria, Other: Travel Sponsoring; Novartis: Honoraria; MSD: Honoraria; Abbvie: Honoraria, Other: Travel Sponsoring; Janssen: Honoraria, Other: Travel Sponsoring. Backhaus: Bayer: Other: Current Employment of Family Member. Franke: BMS: Honoraria; Pfizer: Honoraria; Novartis: Honoraria; MSD: Honoraria; Jazz Pharmaceuticals: Honoraria, Other: Travel Sponsoring; Gilead: Honoraria, Other: Travel Sponsoring. Platzbecker: Janssen: Honoraria; Celgene/BMS: Honoraria; AbbVie: Honoraria; Novartis: Honoraria; Takeda: Honoraria; Geron: Honoraria. Schwind: Novartis: Honoraria, Research Funding; Pfizer: Honoraria. Jentzsch: Astellas: Honoraria; Jazz Pharmaceuticals: Honoraria; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees.

CPX-351 Exposure-Response Based on Cumulative Dose of Cytarabine and Daunorubicin in Patients with Newly Diagnosed, Treatment-Related Acute Myeloid Leukemia (AML) or AML with Myelodysplasia-Related Changes

▪CPX-351 is a dual-drug liposomal encapsulation of cytarabine and daunorubicin at a synergistic ratio. Intact CPX-351 liposomes containing the synergistic ratio are taken up by leukemia cells to a greater extent versus normal bone marrow cells, have a high retention of drug cargo, and have a long plasma half-life. In a phase 3 study in older adults with newly diagnosed, treatment-related AML or AML with myelodysplasia-related changes, CPX-351 demonstrated significantly improved overall survival and response rates compared with conventional 7+3 chemotherapy and a safety profile consistent with that of 7+3. Cumulative lifetime exposure to daunorubicin is associated with risks of cardiotoxicity. Therefore, it was of interest to determine if the superior efficacy observed with CPX-351 versus 7+3 was achieved with lower cumulative doses of cytarabine and daunorubicin relative to 7+3. An exposure-response analysis was conducted to document the relationships of cumulative doses of cytarabine and daunorubicin with efficacy outcomes for CPX-351 versus 7+3 therapy.Efficacy and cumulative exposure data were obtained from the phase 3 study CLTR0310-301 (NCT01696084), in which patients were randomized 1:1 to receive CPX-351 or 7+3 induction therapy. Cumulative dose corresponded to the total amount of drug (mg of cytarabine or daunorubicin) administered to an individual patient during the entire time that patient remained on the study. The clinical endpoints for efficacy were overall survival, complete remission (CR), and CR + CR with incomplete hematologic recovery (CR+CRi).A total of 309 patients were enrolled in the study; the exposure-response analysis for cumulative dose included 153 patients treated with CPX-351 and 149 patients treated with 7+3. Baseline characteristics were generally similar between the CPX-351 and 7+3 cohorts. In the overall study population, median duration of the treatment was 62 days in the CPX-351 arm and 41 days in the 7+3 arm. The most common reason for discontinuation among patients included in this analysis was lack of efficacy, but the incidence was lower for the CPX-351 cohort (34.6%) than for the 7+3 cohort (49.0%). In the exposure-response analysis for overall survival, patients treated with CPX-351 who were alive at the data cut-off time for the primary endpoint analysis (n = 47) tended to have received less cytarabine and daunorubicin than those treated with 7+3 (n = 23). The mean cumulative doses of cytarabine and daunorubicin for patients alive in the CPX-351 cohort were 61.9% and 76.8%, respectively, of cumulative doses for patients alive in the 7+3 cohort (Table). Among responders classified as achieving a CR or CR+CRi, those treated with CPX-351 tended to receive less cytarabine and daunorubicin than those treated with 7+3 chemotherapy. The mean cumulative doses of cytarabine and daunorubicin for patients who achieved a CR in the CPX-351 cohort were 26.5% and 63.2%, respectively, of cumulative doses for patient with CR in the 7+3 cohort, and the mean cumulative doses for patients who achieved a CR+CRi in the CPX-351 cohort were 36.2% and 65.1%, respectively, of those with CR+CRi in the 7+3 cohort (Table). For non-responders or deceased patients, the mean cumulative doses of cytarabine and daunorubicin similarly tended to be lower in patients who received CPX-351 than in those who received 7+3 therapy. The finding that a lower cumulative dose of cytarabine and daunorubicin in CPX-351 relative to standard 7+3 therapy led to improved efficacy and increased on-target myelosuppression supports the observation in animal models that CPX-351 is taken up in the bone marrow by leukemia cells to a greater extent than normal cells.Taken together, the results of this exposure-response analysis show that the mean cumulative doses of cytarabine and daunorubicin associated with an overall survival benefit were lower with CPX-351 than with 7+3, as were the mean cumulative doses associated with achieving a CR or CR+CRi. Thus, compared with 7+3, CPX-351 was associated with improved efficacy at a reduced total drug burden in this population of older adults with newly diagnosed, treatment-related AML or AML with myelodysplasia-related changes. [Display omitted] DisclosuresBanerjee:Celator/Jazz: Employment, Equity Ownership. Wang:Celator/Jazz: Employment, Equity Ownership. Wang:Celator/Jazz: Consultancy. Gibbons:Celator/Jazz: Employment, Equity Ownership.

Multivariate Efficacy Analysis of a Randomized, Phase 3 Study of CPX-351 Versus 7+3 in Older Adults with Treatment-Related Acute Myeloid Leukemia (AML) or AML with Myelodysplasia-Related Changes

Multivariate Efficacy Analysis of a Randomized, Phase 3 Study of CPX-351 Versus 7+3 in Older Adults with Treatment-Related Acute Myeloid Leukemia (AML) or AML with Myelodysplasia-Related Changes

Clinical and Molecular Characteristics of Therapy-Related Acute Lymphoblastic Leukemia

Background: Therapy-related acute lymphoblastic leukemia (t-ALL) represents <7% of all ALL cases (Ganzel C, et al. 2015; 170:50-5). While treatment-related acute myeloid leukemia is more common and better described, our knowledge on t-ALL is limited. Furthermore, “secondary ALL” has been used as a broad term, combining patients with t-ALL and ALL patients with antecedent malignancy who did not receive chemotherapy or radiotherapy for the first malignancy (am-ALL). We investigated the clinical and molecular characteristics, as well as prognostic predictors of outcomes in t-ALL patients, while comparing t-ALL to am-ALL.Methods: ALL patients treated at the Cleveland Clinic, University of Washington, University of Chicago, and Stanford University during the years 1997-2016 were screened for eligibility. Patients with a history of another malignancy prior to ALL diagnosis were included, and further categorized as t-ALL and am-ALL based on the administration of chemotherapy or radiotherapy for first malignancy. Patients with mixed lineage leukemia and CML in blast crisis were excluded. Complete response (CR) was defined as <5% blasts with an absolute neutrophil count (ANC) of >1000/uL and platelets >100,000/uL; CRi: same as CR without count recovery. Cytogenetic risk was ascribed by CALGB criteria. A subset of diagnostic samples were sequenced with libraries prepared according to Illumina's Nextera Rapid Capture Custom Enrichment Kit and subjected to massive parallel sequencing using the HiSeq 2000. Our panel consisted of 170 genes highly prevalent in hematologic cancers or associated with congenital blood disorders.Results: A total of 82 patients with t-ALL, and 16 with am-ALL were identified. In the t-ALL group, 56.1% were female, 70.7% were Caucasian, 92.7% had B-ALL, and 47.3% had poor risk cytogenetics. The median age at ALL diagnosis was higher in the am-ALL group as compared to t-ALL (65 vs 58.5, respectively, p= 0.03), however the interval between the diagnosis of first malignancy and ALL was similar between the groups (7.5 vs 6.3 years, respectively, p= 0.34) (Table). In the t-ALL group, treatment for the first malignancy included alkylators in 64%, topoisomerase II inhibitors in 33%, and radiotherapy in 63%. The CR rate was significantly lower in patients with a history of radiotherapy (80% vs 100%, p= 0.003). Patients with t-ALL had a shorter median overall survival (OS) (23 vs 38 months, p= 0.33) and relapse-free survival (RFS) (11 vs 27 months, p=0.28) than patients with am-ALL, but the difference did not reach statistical significance (Figure). In univariable analysis, factors associated with worse outcomes in t-ALL patients included male sex (HR, 2.24; p= 0.009 for OS, and HR, 2.16; p=0.008 for RFS) and hematologic cancer history (HR, 2.14; p=0.03 for OS, and HR, 1.8; p= 0.06 for RFS), while Asian race (HR, 0.21; p= 0.04 for OS, and HR, 0.17; p= 0.01 for RFS) and performance of hematopoietic cell transplant (HCT) after ALL diagnosis (HR, 0.53; p= 0.04 for OS, and HR, 0.65; p= 0.15 for RFS) were associated with better survival. Other clinical factors analyzed, including age at ALL diagnosis, type of treatment for first malignancy, immunophenotype, and cytogenetics for ALL did not have a significant impact on survival. In multivariable analysis, longer interval between the first malignancy and ALL (HR, 0.93; p= 0.05 for OS, and HR, 0.94; p= 0.05 for RFS) and performance of HCT for ALL (HR, 0.44; p= 0.02 for OS, and HR, 0.61; p= 0.14 for RFS) were independent predictors of better outcomes in t-ALL. An expanded mutation panel was performed in 9 t-ALL and 3 am-ALL patients, for whom samples were available for sequencing. In the t-ALL group, all patients had at least one mutation: 3 patients had KDM6B , 2 patients had TP53 , and 2 patients had BRCA2 mutations. In am-ALL, 1 patient had JAK2 , and 1 patient had an NBN mutation.Conclusion: Therapy-related ALL is a rare complication of treatment for previous malignancies. While there is no significant difference in clinical features of t-ALL vs am-ALL, our observation on genomic characteristics of a small cohort of patients suggest that they might be biologically different. Longer interval between two diagnoses and performance of HCT after ALL were associated with better outcomes. We believe that our results improve our knowledge on this rare entity, and should be further validated through larger prospective studies utilizing comprehensive lymphoid mutation panels. [Display omitted] DisclosuresStock:Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees. Larson:Novartis: Consultancy, Research Funding; Amgen Inc.: Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Astellas: Consultancy, Research Funding. Sekeres:Celgene: Membership on an entity's Board of Directors or advisory committees. Gerds:Incyte: Consultancy; CTI BioPharma: Consultancy. Maciejewski:Alexion Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Speaker Fees; Apellis Pharmaceuticals: Consultancy; Ra Pharma: Consultancy. Advani:Takeda/ Millenium: Research Funding; Pfizer: Consultancy.

Rates of Adverse Events per Patient-Year in a Randomized, Phase 3 Study of CPX-351 Versus 7+3 in Older Adults with Newly Diagnosed, Treatment-Related Acute Myeloid Leukemia (AML) or AML with Myelodysplasia-Related Changes

Rates of Adverse Events per Patient-Year in a Randomized, Phase 3 Study of CPX-351 Versus 7+3 in Older Adults with Newly Diagnosed, Treatment-Related Acute Myeloid Leukemia (AML) or AML with Myelodysplasia-Related Changes

Budget Impact Analysis of CPX-351 in the Treatment of Patients with Treatment-Related Acute Myeloid Leukemia (tAML) or AML with Myelodysplasia-Related Changes (MRC) from a US Payer Perspective

AML is a rapidly progressing and life-threatening blood cancer that disproportionately affects older adults. The treatment paradigm in AML has seen little change in the past 4 decades, with intensive chemotherapy with a 7-day continuous infusion of cytarabine plus an anthracycline such as daunorubicin on Days 1-3 (ie, “7+3” regimen) remaining the standard-of-care induction therapy for AML. CPX-351 is a dual-drug liposomal encapsulation of cytarabine and daunorubicin that delivers a synergistic drug ratio into leukemia cells. In a phase 3 study (NCT01696084), CPX-351 demonstrated superior overall survival (9.56 vs 5.95 months; HR = 0.69; P= 0.005) and significantly improved complete remission rate (38% vs 26%; P= 0.040) compared with 7+3 in the treatment of elderly patients with newly diagnosed tAML or AML-MRC (Lancet JE, et al. ASCO 2016. Abstr 7000). Additionally, CPX-351 is administered as a 90-minute infusion on Days 1, 3, and 5 (induction cycle 1 only), and offers the potential for outpatient administration. The aim of this study was to estimate the budget impact associated with the introduction of CPX-351 for the treatment of patients with tAML or AML-MRC from a US payer perspective.A decision analytic model was developed to estimate the budget impact of using CPX-351 compared with 7+3 for induction and consolidation treatment of AML patients with tAML and AML-MRC. The decision algorithm was developed based on clinical practice guidelines from the National Comprehensive Cancer Network and validated by an oncologist. Epidemiology estimates were from SEER 2017. Clinical outcomes (response rate and incidence of adverse events [AE]) and site of care were from the CPX-351 phase 3 pivotal trial. In that study, CPX-351 was administered in the outpatient setting for 51% of patients in consolidation cycle 1 and 61% in cycle 2, compared with 6% and 0% of 7+3 patients in consolidation cycles 1 and 2 (Kolitz JE, et al. ASCO 2017. Abstr 7036). Administration costs were from CMS for Medicare and InGauge Healthcare Solutions for commercial costs. Hospital costs were from the CMS Limited Data Set. H-CUP National Inpatient Sample was used to estimate the AE costs by payer type. Drug costs were wholesale acquisition costs. The model did not include costs for hematopoietic cell transplant.For a hypothetical 1 million-member plan, it is estimated that there are approximately 12 patients with tAML and AML-MRC each year. Increasing the use of CPX-351 from year 1 to 3 (assumption of year 1 = 20%, year 2 = 50%, and year 3 = 80%) resulted in cost increases compared with 7+3 (year 1 = $7,471 to year 3 = $29,884, or <$0.01 per member per month increase in each year). Over the same time period, the estimated number of responders increased from 3.06 with 7+3 to 4.19 with CPX-351. The increased level of responses with CPX-351 reduced the cost/responder from $358,695 with 7+3 to $269,106 by year 3 following introduction of CPX-351. Of note, outcomes are derived from a phase 3 randomized, controlled trial of CPX-351 versus 7+3, the model did not account for potential regimen changes, and costs may not be generalizable across all settingsThis model predicted that the use of CPX-351 may be associated with improved patient outcomes and limited budget impact from the payer perspective. DisclosuresJensen:Celator/Jazz: Consultancy. Wu:Celator/Jazz: Consultancy. Sacks:Celator/Jazz: Consultancy. Cyr:Celator/Jazz: Consultancy. Chung:Baxter: Equity Ownership; Shire: Equity Ownership; Baxalta: Equity Ownership; Amgen: Equity Ownership; Gilead: Equity Ownership; Bayer: Equity Ownership; Gilead: Employment; Jazz Pharmaceuticals: Employment, Equity Ownership.

Cost-Effectiveness of CPX-351 Versus 7+3 Regimen in the Treatment of Treatment-Related Acute Myeloid Leukemia (tAML) or AML with Myelodysplasia-Related Changes (MRC)

CPX-351 is a dual-drug liposomal encapsulation of cytarabine and daunorubicin that delivers a synergistic drug ratio. In a phase 3 trial (NCT01696084) in elderly patients with newly diagnosed tAML or AML-MRC, CPX-351 demonstrated superior overall survival (9.56 vs 5.95 months; HR = 0.69; P= 0.005) and significantly improved complete remission rate (38% vs 26%; P= 0.040) compared to the 7+3 regimen of cytarabine and daunorubicin, the current standard of care for remission induction. These clinical improvements may increase the cost of caring for patients with AML through higher drug costs, increased numbers of patients receiving hematopoietic cell transplant (HCT), and the costs of disease management during extended survival. In an era of increased scrutiny of drug costs and health care budgets, it is essential to understand the balance of clinical benefits and costs associated with treatment of AML using CPX-351.A health economic model with a lifetime time horizon was developed comparing the costs and outcomes of CPX-351 to those of 7+3 in the treatment of AML from the perspective of a US commercial payer. The model was developed in accordance with good modeling practice guidelines and recommendations of the US Second Panel on Cost-Effectiveness in Health and Medicine. The model considered a patient population stratified by age and AML subtype based on the CPX-351 phase 3 clinical trial design. Within each subpopulation, patients were distributed among potential treatment pathways in accordance with observed trial data. Treatment pathways in the model were defined in terms of whether or not patients responded following induction and whether or not patients received an HCT. The numbers of induction and consolidation cycles were also tracked. The model then projected overall and event-free survival over patients' lifetimes based on the patients' characteristics and treatment pathways using statistical extrapolation of observed data from the clinical trial. Specifically, for each treatment pathway, a parametric survival function was fit to the observed data with patient characteristics, treatment arm, cycles of induction, and cycles of consolidation included as risk factors. These survival functions were then applied in the model for each subpopulation and summed to estimate the overall clinical outcomes for the full population. Costs of drugs were assigned based on published sources for 7+3 and manufacturers' estimates for CPX-351. Costs of non-pharmaceutical management were estimated based on DRG coding and published literature. Quality of life at different disease stages was assessed using the time trade-off method in vignette-based interviews.We found that treatment with CPX-351 was projected to provide an additional 1.9 years of life compared to 7+3 (2.8 vs 0.9 years, respectively). These gains reflected shifts among the treatment pathways, particularly a larger fraction of patients receiving HCT with CPX-351 than with 7+3, and longer survival within pathways among patients who responded to induction therapy. While the CPX-351 treatment arm demonstrated increased numbers of responders, non-responders had no difference in outcomes between the arms in the model. When accounting for the quality of life of patients with different stages of AML, the additional life years were equivalent to an incremental increase of 1.02 quality-adjusted life years (QALYs) compared to 7+3. Patients in the CPX-351 arm incurred a total incremental cost of $113,658 compared to 7+3, primarily due to pharmacy costs and costs associated with the larger number of HCTs. Taken together, these costs and improved clinical outcomes yield an incremental cost-effectiveness ratio (ICER) of $111,385/QALY gained over 7+3.These results suggest a favorable balance between the clinical gains and incremental costs of treatment with CPX-351 versus the 7+3 standard of care and demonstrate that CPX-351 is a cost-effective option in the treatment of patients with tAML or AML-MRC. DisclosuresKansal:Celator/Jazz: Consultancy. Du:Celator/Jazz: Consultancy. Herrera-Restrepo:Celator/Jazz: Consultancy. Leipold:Celator/Jazz: Consultancy. Ryan:Celator/Jazz: Employment, Equity Ownership. Louie:Celator/Jazz Pharmaceuticals, Inc.: Employment, Equity Ownership, Patents & Royalties. Chung:Bayer: Equity Ownership; Amgen: Equity Ownership; Baxalta: Equity Ownership; Gilead: Employment; Shire: Equity Ownership; Baxter: Equity Ownership; Gilead: Equity Ownership; Jazz Pharmaceuticals: Employment, Equity Ownership.