Background:
There is no standard of care treatment for Acute Myeloid Leukemia (AML) in relapse post-allogeneic hematopoietic stem cell transplant (post-HSCT), with overall 5-year survival about ...5-10%. Venetoclax (Ven) is a novel BCL2 inhibitor approved by the FDA for treatment of newly diagnosed AML in combination with hypomethylating agents (HMA) or low dose cytarabine for patients unfit for intensive induction. However, data in relapsed/refractory AML are limited, especially in the post-HSCT setting. In this retrospective study, we reviewed outcomes of patients with AML relapse post-HSCT who received Ven in combination with HMA in a single center.
Methods:
Charts of 17 patients who had AML relapse post-HSCT treated with combination of Ven and HMA between November 2018 - March 2020 at the University of Kansas Medical Center were reviewed. We utilized descriptive statistics for baseline characteristics and outcomes, and Kaplan-Meier log-rank test for calculating overall survival.
Results
Seventeen patients received Ven+HMA for AML relapse post-HSCT in our center. At the time of SCT, patients were in first complete remission (CR) (n=15); second CR (n=1) and primary failure induction (1). Median age was 62 at time of relapse (31-71) years, and 8 patients were female (47%). 9 patients (53%) had adverse risk AML (ELN 2017) 8 of them were in CR1 and 1 with primary induction failure. Common mutations included DNMT3a, ASLX-1, TET2 (3); TP53 (2); IDH1/2 (2); NPM1/FLT3 (1); NPM1/IDH2 (1); NPM1 (1 transplanted in CR2); FLT3 (1). 2/17 had received Ven+HMA prior to SCT; 4 patients received HMA alone prior to SCT. 11 patients (65%) were naïve to either Ven or HMA prior to relapse. Median time to relapse was 181 (44-851) days post-HSCT. 9 (53%) patients received Azacitidine+Ven and 8 (47%) received Decitabine+Ven. HMA+Ven was the first line of therapy post-HSCT relapse in 14 patients. 2 had donor lymphocyte infusion (DLI) after either MEC or dacogen but relapsed prior to Ven+HMA. 1 had IDH (2) inhibitor. Patients received median of 2 (1-10) cycles of HMA+Ven. Six (35%) patients achieved complete remission/complete remission with incomplete hematologic recovery (CR/CRi), and 2/6 patients had negative measurable residual disease by multiparameter flow cytometry. Median overall survival was 361 days from relapse (Figure 1). 3/14 patients received subsequent DLI with Ven+HMA. Disease progression was the most common cause of death in 8/9 of patients who died during the follow up period. Most common side effects included neutropenic fever (n=8, 47%) and acute graft versus host disease (aGVHD) (n=5, 30%). 2/5 developed new aGVHD on HMA+Ven with no prior history of aGVHD. However, aGVHD was mainly grade I-II and responsive to therapy.
Discussion
HMA+Venetoclax demonstrates potential activity in patients with AML relapse post-HSCT with a CR/CRi rate of 35%, comparable to other salvage therapies. There were no unexpected side effect in this high-risk population. Larger studies are needed to confirm efficacy and toxicity in this setting.
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McGuirk:Pluristem Ltd: Research Funding; Kite Pharmaceuticals: Consultancy, Honoraria, Research Funding, Speakers Bureau; Gamida Cell: Research Funding; Bellicum Pharmaceutical: Research Funding; Allo Vir: Consultancy, Honoraria, Research Funding; Juno Therapeutics: Consultancy, Honoraria, Research Funding; Astellas: Research Funding; Fresenius Biotech: Research Funding; Novartis: Research Funding. Lin:Aptevo: Research Funding; Abbvie: Research Funding; Bio-Path Holdings: Research Funding; Celgene: Research Funding; Gilead Sciences: Research Funding; Incyte: Research Funding; Jazz: Research Funding; Mateon Therapeutics: Research Funding; Ono Pharmaceutical: Research Funding; Pfizer: Research Funding; Prescient Therapeutics: Research Funding; Seattle Genetics: Research Funding; Tolero Pharmaceuticals: Research Funding; Trovagene: Research Funding; Genetech-Roche: Research Funding; Celyad: Research Funding; Astellas Pharma: Research Funding.
Background: Acute myeloid leukemia (AML) with germline DDX41 mutation is implicated in 2-5% of AML patients (pts). Unlike other genetic predispositions in AML, germline DDX41 mutations are associated ...with later-onset myeloid malignancies (median age 69 years), making it difficult to distinguish clinically from sporadic AML. Data suggests that pts with germline DDX41-mutated AML have more favorable outcomes compared to sporadic AML. However, data regarding optimal treatment and long-term prognosis remains limited. Methods: Pts treated for AML at The University of Kansas Medical Center between 2015 and 2022 with at least one DDX41 variant were identified via retrospective search. Demographics, disease characteristics, treatments, and vital status were analyzed. DDX41 and other co-occurring mutations included for analysis were pathogenic, likely pathogenic, or variants of uncertain significance. Mutations were considered germline in origin if the variant allele frequency (VAF) exceeded 40% or via search of ClinVar repository in borderline cases (VAF 35-40%, n=2) or if VAF was not reported (n=3). Pts suspected to have germline DDX41 mutations were included in the primary analysis. Results: We identified 42 pts with AML with at least one DDX41 variant. Two cases had donor-derived leukemia after prior related donor allogeneic stem cell transplant (SCT) and two cases only had somatic DDX41 p.R525H mutations. These were excluded from primary analysis. 36 pts had suspected germline DDX41 mutations and were included for analysis. 28 (78%) had DDX41 mutations at diagnosis and 8 were found later with a broader next-generation sequencing (NGS) panel (in 6, after induction and in 2, after relapse). Average age of pts with germline DDX41-mutated AML was 67 years, with 3:1 male predominance. Most had preceding cytopenias, and 12 (33%) had antecedent myelodysplastic syndrome (MDS). Family history of malignancy was common (Table 1). 27 (77%) of the available 35 karyotypes at diagnosis were normal. One patient did not have an available karyotype due to lack of records. 28 pts had testing at diagnosis that included DDX41 in the NGS panel. Of these, 57% (n=16) had two DDX41 mutations, with one germline and one somatic mutation. The most common germline DDX41 mutations were p.M1I (14.3%) and p.D140fs*2 (10.7%), and the most common somatic mutation was p.R525H (39.3%). Other commonly concomitant mutations were in ASXL1 (36.1%), CUX1 (22.2%), and KMT2C (13.9%). Mutations such as NPM1 (5.6%), TP53 (5.6%), and FLT3 (2.8%) were uncommon. Germline testing was performed in 5 (13.9%) pts, confirming germline variants. 39% (n=14) were treated with a 7+3-based regimen (average age 60 years) with a 71% response rate. 36% (n=13) were treated with venetoclax/hypomethylating agent (Ven/HMA) (average age 72 years) with a 69% response rate (Figure 1). Two pts receiving Ven/HMA died during the first cycle (one from myocardial infarction, one from pneumonia). 18 pts (50%) received SCT, and 50% of those (n=9) had a related donor. 33% of related donors (n=3) were tested for a germline DDX41 mutation prior to transplant. At last follow-up, 44% were alive in CR (n=16), 5.5% alive with disease (n=2), 14% deceased in CR (n=5), 25% deceased with disease (n=9), and 11% deceased with unknown status (n=4). Median survival was 12.8 months (average 19.6 months in pts with SCT vs. 8.3 in those without, p = 0.012). 11 pts died from AML (33.3%) or complications (22% infection, 6% bleeding). Two pts with only somatic DDX41 mutations were adverse risk (with ASXL1 mutation) and intermediate risk per 2022 ELN risk stratification, both deceased but in CR at time of death. The adverse-risk patient underwent SCT with unrelated donor (survival 7.3 months). The intermediate-risk patient was re-induced after PIF and died from aortic stenosis (survival 2.2 months). Conclusions: In our cohort of germline DDX41-mutated AML, responses to a 7+3- or Ven/HMA-based regimen were similar. SCT evaluation remains crucial with improved overall survival in pts receiving SCT. Our study highlights the importance of comprehensive genetic testing that includes DDX41 at diagnosis, along with testing of related donors and children of pts with a germline DDX41 mutation due to the impact of positive testing on donor selection and to identify pts at risk of AML. The presence of only somatic DDX41 mutations was rare, and further research is needed on the impact of somatic DDX41 mutations alone.
Multiple myeloma (MM) outcomes have consistently shown survival improvement of almost 2- to 3-fold in the last decade. Lenalidomide constitutes an important part of effective MM therapy; however, it ...has been associated with a higher incidence of second primary malignancies. Secondary acute lymphoblastic leukemia (sALL) has been reported in 1.5% of treated patients with MM.
To evaluate the incidence and outcomes of sALL in patients with MM.
Single-center retrospective analysis. We identified patients with MM treated between January 2009 and April 2023.
735 patients with MM were reviewed, and 7 patients with a confirmed diagnosis of sALL were identified.
Descriptive analysis was performed on available data for patient characteristics, disease course, and outcomes.
The overall incidence of sALL was 0.95%. The median age was 65 years; 4 patients (57%) were men. Five patients (71%) had the immunoglobulin G (IgG) isotype, 2 patients (28%) had Revised International Staging System (R-ISS) stage III disease, and 3 patients (42%) had normal cytogenetics on diagnosis of MM. MM was in complete remission at the time of ALL diagnosis in 6 of 7 patients (85%); they were on lenalidomide maintenance therapy. Five patients (71%) received high-dose chemotherapy with melphalan 200 mg/m2 followed by autologous stem cell transplantation for MM treatment. The median time from starting lenalidomide therapy until diagnosis of sALL was 113 months (range, 35–146 months). Cytogenetics at the time of diagnosis of sALL was normal in 3 of the patients (42%); all patients (100%) were t(9;22)-negative. Six patients (85%) received treatment for sALL. Five patients achieved a complete response after therapy, while 1 patient is on active treatment for ALL. One patient died from relapsed MM, diagnosed after consolidation chemotherapy for B-cell ALL. Four patients (57%) are in remission after treatment for both MM and sALL.
Based on these observations, we conclude that the low incidence of sALL in patients with MM, and the high efficacy of immunomodulatory agents, should not alter physicians’ current practice or preclude the use of these agents.
e19003 Background: Since the approvals of chimeric antigen receptor T-cell (CAR T) therapy in acute lymphoblastic leukemia (ALL), non-Hodgkin lymphoma (NHL), and multiple myeloma (MM), it has been ...increasingly offered in centers nationwide. Immune effector cell-associated neurotoxicity syndrome (ICANS) poses a potentially fatal risk with CAR-T. Identifying patients at risk of having high grade ICANS is a thus a priority. Scoring systems such as the EASIX scores have accounted for disease and comorbidity factors but haven’t addressed neurocognitive function. The St. Louis University Mental Status (SLUMS) Exam and the Montreal Cognitive Assessment (MoCA) have not been examined for validity and reliability in this population, so we performed a retrospective review of CAR T patients at the University of Kansas Medical Center to identify if incidence or severity of ICANS could be correlated with neurocognitive testing performed in the pre-infusion period. Methods: Patients receiving CAR T targeting CD19 or BCMA between December 2017 and December 2023 were included. Neurocognitive testing was performed by trained onco-psychology, neurology, or hematology-oncology staff. The SLUMS exam is an 11 question exam scored on a 30 point scale to predict normal neurocognitive function (27-30 points), mild neurocognitive disorders (21-26 points), and dementia (0-20 points). The MoCA is an 11 question exam scored on a 30 point scale to predict normal cognition (26-30 points), mild cognitive impairment (18-25 points), moderate cognitive impairment (10-17 points), and severe cognitive impairment (<10 points). Incidence of ICANS and severity of ICANS were compared between patients who had any detected cognitive dysfunction and those who had none, as well as between the tiered result system unique to each test. Results: We included 360 patients in this analysis, (257 NHL, 84 MM and 19 ALL) leading to comparisons of 276 CD19-directed CAR T patients and 84 BCMA-directed CAR T patients. In CD19-directed patients, there were no differences in ICANS incidence according to the SLUMS scores. There was a significant increase in ICANS incidence for patients who had a positive MoCA exam, p=0.006. Additionally, ICANS incidence was correlated with more severe MoCA results, p=0.01. No differences in ICANS severity were observed using any neurocognitive test. In BCMA-directed patients, no differences in ICANS were observed using the SLUMS or MoCA. Conclusions: Our results suggest that while the SLUMS exam does not predict ICANS, the MoCA may independently predict incidence of ICANS. Patients with a higher score correlating with normal cognition are less likely to develop ICANS and may be appropriate for outpatient therapy. For those with lower scores correlating with more severe neurocognitive disorders, inpatient monitoring and early intervention will continue to be important.
Background:
Mutations in the nucleophosmin (NPM1) gene are associated with better responses to chemotherapy and improved survival among acute myeloid leukemia (AML) patients. However, older AML ...patients (≥ 60 years old) with NPM1 mutation have worse survival outcomes than younger patients (<60 years old). This may be attributed to more adverse biologic features (frequent complex karyotype, FLT3 mutations) in addition to lower odds to receive intensive curative chemotherapy due to co-morbidities. We sought to compare the outcomes of older NPM1 mutated AML patients with younger NPM1 mutated patients after exclusions of patients with adverse-risk per ELN 2017 criteria. We also compared their genomic mutation profile and gene expression utilizing the Beat AML dataset.
Methods:
We queried the Beat AML dataset, supported in part by the Leukemia & Lymphoma Society and the OHSU Knight Cancer Institute, for pts with NPM1 gene mutations who did not have adverse-risk ELN 2017 (poor cytogenetic profile or mutations in FLT3, TP53 or ASXL1). Descriptive statistics described baseline characteristics and responses. Kaplan-Meier with log-rank test was used for survival analysis. DNA mutation data were obtained from the exome sequencing and analyzed using the beat AML data viewer (Vizome). RNA exome sequencing data were downloaded. Differential expression of raw count RNA-Seq and gene set enrichment was done using R via limma and ClusterProfiler packages.
Results:
Among 562 unique patients in the Beat AML umbrella trial, there were 81 patients with newly diagnosed NPM1 mutated AML after exclusion of patients with ELN 2017 adverse-risk category. Among these patients there was 49 older patients (≥ 60 years old) and 32 younger patients (<60 years old). 39 (77.6%) in the older group received intensive induction chemotherapy and 30 patients (93.7%) in the younger group. 29 (59.1%) patients achieved complete morphologic responses in the older patient group compared to 28 (84.4%) in the younger patient group (OR 0.2, P=0.009). Median overall survival in the older patient group was 20.1 months compared to 25.4 months in the younger group (HR 0.52, P=0.08).
Exome sequencing data were available for 43 and 30 patients from the older and younger group respectively. There was a median of 6.5 (2-20) and 7 (2-19) mutations in the older and younger group respectively (P=0.78). After exclusion of the benign mutations and variant of unknown significance, the median number of mutations was 4 in both group (P=0.28). Both groups shared only 24 (3.9%) of the gene mutations while there were 334 unique gene mutations in the older group and 262 in the younger group. Most common gene mutations were DNMT3a, TET2, NRAS, WT1, and PTPN11 with frequencies are shown (Figure 1). RNA sequencing data was available for 26 patients from the older group and 18 patients from the younger group. We explored the gene expression profile of the top 1000 differentially expressed genes in both groups after adjustment. There was distinctive clustering of the gene expression profile between the two groups (Figure 2). Gene set enrichment analysis identified multiple immune-related pathways among the highly enriched gene sets in both groups but with different functions in the two groups. There was significant gene set enrichment in the TGFβ signaling in the older patient group which is associated with immune suppression and microenvironment modulation. While the younger group showed significant enrichment in the TNFa, IL17, PI3K-AKT signaling which are associated with inflammation.
Conclusion:
Older AML patients with NPM1 mutations, and no adverse risk features, had lower rate of complete responses and a trend towards a worse survival compared to younger patients. Whole exome sequencing did not show increased mutational burden. However, 96% of the mutated genes were different between the two groups as were the gene expression profiles. Gene set enrichment analysis showed contrasting enriched immune-related pathways between both groups. The immunosuppressive TGFβ signaling gene set were significantly enriched in the older group while the inflammatory TNFa, IL17, PI3K-AKT signaling gene sets were significantly enriched in the younger group. Older AML patient with NPM1 mutations have distinctive genomic landscape compared to the younger patient which may explain in part the worse clinical outcomes in the absence of other adverse risk features.
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Lin:Jazz Pharmaceuticals: Honoraria; Pfizer: Membership on an entity's Board of Directors or advisory committees.
Background: Patients who do not have a human leukocyte antigen (HLA)-matched donor can undergo hematopoietic stem cell transplantation (HSCT) by utilizing haploidentical (haplo) family donors and ...post-transplant cyclophosphamide (PTCy) for Graft-versus-host disease (GVHD) prophylaxis. Originally, Haplo transplants utilized a bone marrow (BM) source because of concern of higher incidence of GVHD with peripheral blood stem cells (PBSC) graft. Recent years have seen an increase in PBSC graft utilization. Some published studies have reported comparable survival between the two graft sources. These studies also reported lower rate of chronic GVHD and higher quality of life with BM and a lower relapse rate and faster engraftment with PBSCs. We aimed to investigate the outcomes following BM versus PBSC haplo HSCT using (PT-Cy)-based GVHD prophylaxis. Methods: In this single-center retrospective study, we included all (n=176) adult patients who underwent haplo HSCT from August 2016 to July 2021 and had at least one year of follow-up. Bivariate analyses, using the chi-square and t-test, were performed. Kaplan-Meier and regression analyses were conducted. Data were analyzed using SPSS version 28. Statistical significance was considered at p<0.05. Results: The study included 176 haplo transplants including 65% peripheral blood and 35% bone marrow grafts. The median age was 54 (18-74) years and 68% of recipients were males. Ethnic minorities comprised 30% of recipients. Hematologic diagnoses included myeloid disease (65%), lymphoid disease (29%), and others (6%). 31 % of the patients underwent a Myeloablative transplant. Hematopoietic cell transplantation comorbidity index of 3 or higher was noted in 53% of patients. With a Median follow-up 21 (0-73) months, Overall survival (OS) and disease-free survival (DFS) was not reached in either BM or PBSC haplo HSCT group. 1-year OS of 75% and 74% (p-0.898) and 1-year DFS of 63% and 63% (p-0.994) were noted in BM and PBSC group respectively. In PBSC versus BM haplo recipients, an earlier neutrophil engraftment (17 days vs 18 days, p=0.022) was seen. Similar incidences of grade II-IV acute GVHD (50% vs 51%, p=0.875), relapse (22% vs 26%, p=0.579), non-relapse mortality (NRM, 17% vs 20%, p=0.682), platelet engraftment (28 vs 31 days, p<0.092) and 1- year chronic GVHD (35% vs 38%, p=0.410) were noted. Conclusions: In this study, Haploidentical allogeneic hematopoietic stem cell transplant recipients demonstrated similar rates of overall and disease-free survival, relapse, non-relapse mortality, acute and chronic GVHD, and platelet engraftment regardless of graft source. Neutrophil engraftment was observed one day earlier in peripheral stem cell recipients. This supports the use of either PBSC or Bone marrow as the preferred source of Haploidentical transplants.
Background: Matched unrelated donors (MUD) have become an acceptable alternative donor for patients requiring potentially curative hematopoietic stem cell transplantation (HSCT) and lacking a matched ...sibling donor. Patients may undergo a bone marrow (BM) or peripheral blood stem cell (PBSC) graft, with previous studies showing similar survival outcomes. However, BM grafts have shown a lower incidence of chronic graft-versus-host disease (GVHD) but a higher relapse rate and slower engraftment. We aimed to compare the outcomes of BM versus PBSC in patients undergoing MUD HSCT. Methods: For this retrospective single-center study, we included all (n=276) adult MUD HSCT recipients at the University of Kansas Medical Center who had at least one year of follow-up (August 2016 to July 2021). We conducted a bivariate analysis using chi-squared and ANOVA tests. The Kaplan-Meier and regression analyses were also performed. Data analyses were conducted using SPSS version 28. Statistical significance was considered at p<0.05. Results: Our study included 276 MUD patients including 110 PBSC (40%) and 166 BM (60%) grafts. The median age was 55 (range 21-77) years, and 158 patients (57%) were males. Eighteen patients (6%) were ethnic minorities, and 89 (32%) patients had a Karnofsky performance status of ≥90%. 118 (43%) patients had a hematopoietic cell transplantation-specific comorbidity index of 3 or higher. Hematologic diseases included acute myeloid leukemia (n=119, 43%), myeloid disorders (n=77, 28%), acute lymphoblastic leukemia (ALL) (n=35, 13%), Lymphoma (n=15, 5%), and others (n=30, 11%). Sixty-two percent of patients were in complete remission at the time of transplantation, and patients not in remission included myelodysplastic syndrome, myelofibrosis, and lymphoma patients. Reduced-intensity conditioning (RIC, n=162, 58%) and myeloablative conditioning (MAC) (n=114, 41%) were used. The median follow-up was 55 (21-73) months. Overall survival (OS) was not reached in either BM or PBSC MUD HSCT group, while a median disease-free survival of 45 and 49 months was noted in PBSC and BM groups respectively (p=0.915). We observed similar rates of relapse (25% vs 27%, p=0.413), one-year overall survival (75% vs 72%, p=0.679), one-year disease-free survival (63% vs 62%, p=1.00), and one-year non-relapsed morality (NRM, 23% vs 21%, p=0.779) after PBSC or BM graft. Bone marrow graft recipients had delayed engraftment of neutrophils (20 days vs 16 days, p<0.001) and platelets (>20 K/uL: 24 days vs 16 days, p<0.001; >50 K/uL: 28 days vs 18 days, p=0.006) compared to PBSC recipients. Bone marrow graft recipients had similar rates of grade II-IV acute GVHD (50% vs 52%, p=0.714) and grade III-IV GVHD (12% vs 11%, p=0.847), but lower rates of 1-year chronic GVHD (39 % vs 55%, p=0.014) compared to PBSC recipients. In the subgroup analysis stratified by conditioning intensity, faster engraftment of neutrophils (median 16 vs 21 days, p<0.001) and platelets (>20 K/uL: 18 days vs 27 days, p<0.001; >50 K/uL: 18 days vs 33 days, p<0.001) was observed with PBSC as compared to BM graft in myeloablative transplant recipients, while there was no statistically significant association with the rates of acute or chronic GVHD, NRM, Relapse, DFS, and OS after a PBSC or BM graft. Among the RIC transplant recipients, faster neutrophil engraftment (mean 17 vs 20 days, p<0.001) and higher 1-year extensive chronic GVHD (52% vs 32%, p=0.015) were observed with PBSC compared to BM graft whereas no statistically significant difference was noted in platelet engraftment, acute GVHD, NRM, Relapse, DFS, and OS after a BM or PBSC graft. Conclusions: Allogeneic matched unrelated donor hematopoietic stem cell transplant recipients had similar rates of overall and disease-free survival, relapse, non-relapse mortality, and acute GVHD after a bone marrow or peripheral blood stem cell graft; however, delayed neutrophil and platelet engraftment with a lower incidence of chronic GVHD was noted after a bone marrow graft compared to peripheral blood stem cell graft.
Melanoma treatment has been revolutionized over the past decade. Long-term results with immuno-oncology (I-O) agents and targeted therapies are providing evidence of durable survival for a ...substantial number of patients. These results have prompted consideration of how best to define long-term benefit and cure. Now more than ever, oncologists should be aware of the long-term outcomes demonstrated with these newer agents and their relevance to treatment decision-making. As the first tumor type for which I-O agents were approved, melanoma has served as a model for other diseases. Accordingly, discussions regarding the value and impact of long-term survival data in patients with melanoma may be relevant in the future to other tumor types. Current findings indicate that, depending on the treatment, over 50% of patients with melanoma may gain durable survival benefit. The best survival outcomes are generally observed in patients with favorable prognostic factors, particularly normal baseline lactate dehydrogenase and/or a low volume of disease. Survival curves from melanoma clinical studies show a plateau at 3 to 4 years, suggesting that patients who are alive at the 3-year landmark (especially in cases in which treatment had been stopped) will likely experience prolonged cancer remission. Quality-of-life and mixture-cure modeling data, as well as metrics such as treatment-free survival, are helping to define the value of this long-term survival. In this review, we describe the current treatment landscape for melanoma and discuss the long-term survival data with immunotherapies and targeted therapies, discussing how to best evaluate the value of long-term survival. We propose that some patients might be considered functionally cured if they have responded to treatment and remained treatment-free for at least 2 years without disease progression. Finally, we consider that, while there have been major advances in the treatment of melanoma in the past decade, there remains a need to improve outcomes for the patients with melanoma who do not experience durable survival.
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