Cripe, Larry D.

Bruton tyrosine kinase inhibitors (BTKis) and BCL2 inhibitor (BCL2i)–containing regimens significantly improve survival outcomes in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Results from randomized clinical trials have demonstrated that time-limited treatment with BCL2i-containing regimens resulted in higher rates of undetectable measurable residual disease (uMRD) than BTKi monotherapy or chemoimmunotherapy (CIT). Pirtobrutinib (a noncovalent BTKi) and lisocabtagene maraleucel (CD19-directed CAR T-cell therapy) are newer options for relapsed or refractory disease after prior therapy with BTKi and BCL2i-contining regimens. Histologic transformation of CLL/SLL to diffuse large B-cell lymphoma (Richter transformation) is associated with a poor prognosis. Molecular analysis to determine whether there is clonal relationship between CLL/SLL and transformed diffuse large B-cell lymphoma is useful to select an appropriate treatment option. These NCCN Guideline Insights highlight significant updates to the NCCN Guidelines for the treatment of CLL/SLL and Richter transformation.

Abstract Copy Number Alterations (CNAs), including chromosomal gains and losses, shape the genetics and clinical management of acute myeloid leukemia (AML), particularly in complex karyotypes (e.g. CK-AML). Traditionally, AML associated CNAs have been studied using cytogenetic approaches, i.e., karyotyping, that are limited in resolution and sensitivity. Here, low-coverage, sparse whole genome sequencing followed by machine learning applied to over 600 AML patient samples (ECOG-ARCIN trials: E1900, E3999) reveals novel genetic, biologic, and clinical correlates in AML disease. We find that multi-variate Cox-regression analysis applied to the data identifies select patients exhibiting focal and cryptic hemizygous deletions at 17q, 21q, and 3p, in otherwise diploid genomes, associate with inferior survival compared to other patients (median overall survival; OS = 65.5 compared to 421 days, Chi-square test pval=6x10-11), independent of factors such as age, treatment, and karyotype complexity status. In addition, we confirm that amplifications at 11q23, encoding the KM2TA gene, are associated with inferior outcome, and further identify unique breakpoint event features as well as transcriptional signatures suggestive of distinctive KM2TA-translocation independent biology. Applying machine learning approaches to the data, more specifically Non-negative Matrix Factorization (NMF), we develop a prognostic model that captures clinically adverse, cryptic variation such as focal 5q deletions, missed by conventional chromosome analysis and thereby, adds novel, complementary information to traditional, cytogenetic based risk-stratification (e.g. ELN). The model also associates gain of chromosome 8 in Intermediate risk patients with worse outcome compared to other Intermediate risk patients (median OS = 186 compared to 446 days, Chi-square test pval=0.005) and identifies a subgroup of patients within the adverse risk category that lack deletions on chromosomes 5, 7, and 17, and that fare better than the rest of the adverse risk patients (median OS = 188 compared to 97.5 days, Chi-square test pval=0.02), likely reflecting previously identified “atypical” CK-AML patients. Last, we develop a prognostic classifier based on a combination of Neural-Network and Random-Forest based learning, that predicts disease outcome with high accuracy and is based on a three genomic feature list on chromosome bands 5q31.2, 7q31.33, and 8q24, suggesting potential for clinical implementation. Altogether, our results show that low coverage, sparse whole genome sequencing combined with advanced learning methods can be applied clinically to support the diagnosis and clinical management of AML disease as well as serve as a powerful tool to further a basic understanding of the genetics and biology of CNAs in myeloid neoplasms and other cancers.

Abstract Background: Population registries and the Alliance co-operative group database have highlighted racial disparities in AML survival attributed to differential prevalence and impact of oncogenic drivers on disease biology. However, the small number of Black patients with well-annotated genomic profiles limits the validity of these findings. The current study leverages ECOG-ACRIN cytogenetic and outcomes data from newly diagnosed adult AML patients treated on intensive chemotherapy-based clinical trials over three decades. Methods: Self-reported race was categorized as White, Black or Other. Descriptive statistics were used to summarize baseline characteristics using the Wilcoxon rank-sum and Fisher's exact tests. Multivariable Cox proportional hazards regression models evaluated the association between race and survival outcomes adjusting for age, hemoglobin, platelet count, white blood cell count, blast percentage, performance status and ELN cytogenetic risk score (RS). All Cox models were stratified by protocol. Subgroup analyses of overall survival (OS) and disease-free survival (DFS) were performed using Kaplan-Meier curves stratified by race using log-rank tests. All statistical tests were two-sided. Analyses included only patients with complete data for the variables of interest. Results: Data was collected across 10 phase II and III interventional trials for newly diagnosed adult AML that accrued patients between 1984 and 2019. The study population included 3469 White, 184 Black, and 156 Other patients with a Black representation of 1.1-11% across trials. Blacks were significantly younger at diagnosis with a median age of 47.9 years compared to 53.5 years in Whites (p<0.001). Racial groups were well matched for gender and performance status. Black race was an independent prognostic factor for inferior OS (HR 1.212, CI 1.01 – 1.453; p = 0.0383) and DFS (HR 1.313, CI 1.05-1.641; p = 0.017). Complete cytogenetic results were available for 117 Black and 2162 White patients and revealed no significant racial differences in the distribution of ELN 2017 cytogenetic RS, although core binding factor AML was non-significantly enriched in Black patients (12.8% vs 8.3%). No difference was observed between Blacks and Whites in the prevalence of complex karyotype (CK), CK with -5/del(5q), -7/del(7q), or -17/del(17p), and AML-MRC including +8 and del(20q). Notably, the ELN 2017 cytogenetic RS effectively predicted OS in Black (57.8 vs 14.2 vs 5.8 months in favorable, intermediate and adverse RS, p = 0.018), and White patients (60.1 vs 15.2 vs 7.1 months, p < 0.0004 for Whites) but only predicted DFS for White AML patients (p < 0.0001 for Whites, p=0.48 for Blacks). In patients with molecular data for FLT3-ITD (n=1218), CEBPA (n=576), TP53 (n=572), or NPM1(n=683), no racial difference in the prevalence of these mutations was observed. However, NPM1 mutations were associated with inferior OS in Blacks compared to Whites (19.1 vs 8.9 months; p = 0.0095). Black and White AML patients had similar responses with complete remission rates of 58.2% vs 57.5%, p=0.55, and treatment tolerability with 30-day mortality of 7.1% vs 8.9%, p=0.50. However, consolidation approaches differed significantly. Among patients that underwent stem cell transplant (SCT), a significantly higher percentage of White patients received allogenic SCT compared to Blacks (48.5% versus 37.1%, p <0.01). Conclusions: This study represents one of the largest race-based comparisons of cytogenetic abnormalities and clinical outcomes in prospective trials of intensive chemotherapy in AML . Our data confirms the independent prognostic relevance of race in AML survival and validates the predictive ability of the ELN 2017 cytogenetic RS for OS across racial groups. There is ancestry-based attenuation of the survival benefit of NPM1 mutations as previously reported, underscoring the need to tailor the current treatment approach to NPM1 mutated AML based on race. The availability of NGS data limited the genomic analysis to a subset of patients. Future studies should examine the depth of treatment response incorporating MRD biomarkers and explore the effect of race on co-occurring mutations and the leukemic stem cell transcriptome to better explain the observed disparities. Finally, persistent disparities in access to allo-SCT even within the context of clinical trials reinforces the need to address diversity in the stem cell donor pool and social barriers to transplant.

Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are essentially different manifestations of the same disease that are similarly managed. A number of molecular and cytogenetic variables with prognostic implications have been identified. Undetectable minimal residual disease at the end of treatment with chemoimmunotherapy or venetoclax-based combination regimens is an independent predictor of improved survival among patients with previously untreated or relapsed/refractory CLL/SLL. The selection of treatment is based on the disease stage, presence or absence of del(17p) or TP53 mutation, immunoglobulin heavy chain variable region mutation status, patient age, performance status, comorbid conditions, and the agent’s toxicity profile. This manuscript discusses the recommendations outlined in the NCCN Guidelines for the diagnosis and management of patients with CLL/SLL.

AbstractBackgroundObesity (body mass index [BMI] ≥30 kg/m2) is an important epidemiological risk factor for developing acute myeloid leukemia (AML). Therefore, the authors studied the association of obesity with clinical and genetic phenotype and its impact on outcome in adults with AML.MethodsThe authors analyzed BMI in 1088 adults who were receiving intensive remission induction and consolidation therapy in two prospective, randomized therapeutic clinical trials of the Eastern Cooperative Oncology Group‐American College of Radiology Imaging Network: E1900 (ClinicalTrials.gov identifier NCT00049517; patients younger than 60 years) and E3999 (ClinicalTrials.gov identifier NCT00046930; patients aged 60 years or older).ResultsObesity was prevalent at diagnosis (33%) and, compared with nonobesity, was associated with intermediate‐risk cytogenetics group (p = .008), poorer performance status (p = .01), and a trend toward older age (p = .06). Obesity was not associated with somatic mutations among a selected 18‐gene panel that was tested in a subset of younger patients. Obesity was not associated with clinical outcome (including complete remission, early death, or overall survival), and the authors did not identify any patient subgroup that had inferior outcomes based on BMI. Obese patients were significantly more likely to receive <90% of the intended daunorubicin dose despite protocol specification, particularly in the E1900 high‐dose (90 mg/m2) daunorubicin arm (p = .002); however, this did not correlate with inferior overall survival on multivariate analysis (hazard ratio, 1.39; 95% confidence interval, 0.90–2.13; p = .14).ConclusionsObesity is associated with unique clinical and disease‐related phenotypic features in AML and may influence physician treatment decisions regarding daunorubicin dosing. However, the current study demonstrates that obesity is not a factor in survival, and strict adherence to body surface area‐based dosing is not necessary because dose adjustments do not affect outcomes.

Abstract Introduction Several studies reported that AML patients who remain in long-term remission after allogeneic transplant (allo-HCT) or autologous transplant (auto-HCT) have a shorter life expectancy, compared to the general population. However, little is known about the life expectancy of adult long-term survivors of AML who were treated with chemotherapy without HCT and, there have been no comparisons with survival among the general population. The current study reports on the life expectancy of AML patients who survived 3 years in complete remission (CR) after treatment without HCT, and compared this to the gender- and age-matched normal population. At 3 years in CR, the incidence of recurrence is exceedingly low (3%; Watts JM, Leuk Res 2014) minimizing the impact of relapse on the long-term survival. Methods Between 1984 and 2008, 3,012 patients, aged 15 years and older, with untreated AML entered 9 consecutive, phase II and III, ECOG-ACRIN trials (E3483, PC486, E3489, E1490, E3993, E4995, E3997, E3999, E1900). Patients in CR and relapse-free at 3 years are included in the analysis . Minimal cytogenetic information was available in the early protocols (E1490, E3483, PC486). A Kaplan-Meier plot was generated for the three groups, allo, auto and no HCT, censoring for patients alive at last contact. Univariate and multivariate cox proportional hazard regression models were generated, considering death as an event. For comparison of long-term outcomes, patients were grouped together by age and matched to a normative population mortality rate. Subjects were also grouped by gender and treatment allowing for separate analysis of these groups with the no HCT group as the main group of interest. The normative population comparator of expected deaths was derived using mortality rates from United State CDC life table data. The median year was derived by calculating the person-years for each calendar year that patients were followed. To calculate the expected deaths for each age group, person-years was calculated by tabulating the years lived in each age group for all subjects. Each year of follow-up for AML patient was counted as one person year, and the tabulated bin corresponded with their age at the time. Person-years was then multiplied by the matching mortality rate. Chi-square statistics were derived using expected and observed deaths and then summed for each gender and treatment. The final comparison was of mortality rates since diagnosis in the 3-year alive and relapse-free AML patient population vs the normative population. To produce plots of mortality from diagnosis, person-years was tabulated for every year since diagnosis by treatment. The person-years were tabulated into 2-year bins. The US life tables from the CDC were used to generate a population mortality rate from diagnosis. Results A total of 503 adult AML patients in 3 year CR with a mean age of 42.9 years (15-79) were identified; 78 underwent allo, 110 auto and 315 did not undergo transplantation. The patients in the groups differed in age (p&lt;.001) and cytogenetics (p=.01). The multivariate model showed equivalent hazards of death to the 3 groups. Observed deaths and person-years were given by age group, gender, and treatment group and each were matched to a mortality rate from the United State CDC life table data that matched the median year of each treatment group. A chi square test for each group compared the derived expected to observed deaths. In every treatment group, patients had a shorter survival compared to their age- and gender- matched general population (p-value of 0.004 for the auto-HCT and &lt;0.001 for both allo-HSCT and no transplant groups). Table 1, selected only for the no HCT group, demonstrates the mortality rates by age and gender. Figure 1 indicates that AML patients who have survived relapse-free for at least 3 years continue to have higher mortality rates compared to the normative population for up to 14 years. This finding is not altered even if the very small number of patients who die from late relapse (&gt;3 years from diagnosis) are removed from the analysis (data not shown) Conclusions Patients with AML who remain in CR at 3 years, do not have a normal life expectancy, even if they do not undergo HCT. The shorter life expectancy observed following an HCT may, at least in part, be related to the prior intensive therapy or other predisposing factors (e.g. CHIP) of the leukemia, rather than the transplant procedure itself. Figure 1 Figure 1. Disclosures Luger: Syros: Honoraria; Agios: Honoraria; Daiichi Sankyo: Honoraria; Jazz Pharmaceuticals: Honoraria; Brystol Myers Squibb: Honoraria; Acceleron: Honoraria; Astellas: Honoraria; Pfizer: Honoraria; Onconova: Research Funding; Celgene: Research Funding; Biosight: Research Funding; Hoffman LaRoche: Research Funding; Kura: Research Funding. Lazarus: Bristol Myer Squibb: Membership on an entity's Board of Directors or advisory committees. Douer: Amgen: Consultancy, Speakers Bureau; Servier: Consultancy, Speakers Bureau; Adaptive: Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company, Speakers Bureau; Jazz: Consultancy. Tallman: Syros: Membership on an entity's Board of Directors or advisory committees; Kura: Membership on an entity's Board of Directors or advisory committees; Innate Pharma: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Biosight: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Membership on an entity's Board of Directors or advisory committees; Oncolyze: Membership on an entity's Board of Directors or advisory committees; KAHR: Membership on an entity's Board of Directors or advisory committees; Orsenix: Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Rafael Pharmaceuticals: Research Funding; Glycomimetics: Research Funding; Biosight: Research Funding; Orsenix: Research Funding; Abbvie: Research Funding; NYU Grand Rounds: Honoraria; Mayo Clinic: Honoraria; UC DAVIS: Honoraria; Northwell Grand Rounds: Honoraria; NYU Grand Rounds: Honoraria; Danbury Hospital Tumor Board: Honoraria; Acute Leukemia Forum: Honoraria; Miami Leukemia Symposium: Honoraria; New Orleans Cancer Symposium: Honoraria; ASH: Honoraria; NCCN: Honoraria. Litzow: Pluristem: Research Funding; Biosight: Other: Data monitoring committee; AbbVie: Research Funding; Actinium: Research Funding; Astellas: Research Funding; Omeros: Other: Advisory Board; Jazz: Other: Advisory Board; Amgen: Research Funding.

Abstract Central nervous system (CNS) involvement in patients with newly diagnosed acute myeloid leukemia (AML) is rare, and systematic data regarding outcome are scarce. This retrospective study summarized data from 11 consecutive Eastern Cooperative Oncology Group-American College of Radiology Imaging Network (ECOG-ACRIN) clinical trials for patients with newly diagnosed AML. In all, 3240 patients with AML were analyzed, and 36 (1.11%) were found to have CNS involvement at diagnosis. The incidence of CNS disease among the 5 studies with per protocol mandatory lumbar puncture (LP) was similar to the incidence among studies in which LP was performed at the discretion of the investigator (0.86% vs 1.41%; P = .18). There was no significant difference in the rate of complete remission (CR) among patients with CNS involvement and those with other extramedullary disease (EMD) sites or those with no EMD (52.8% vs 59.3%-60%). The median overall survival (OS) for patients who were CNS positive, who had other EMD, or who had no EMD was 11.4, 11.3, and 12.7 months, respectively. There was no difference in OS among patients with CNS involvement, those with other EMD (hazard ratio [HR], 0.96; adjusted P = .84), and those with no EMD (HR, 1.19; adjusted P = .44). In conclusion, the reported incidence of CNS involvement in patients with newly diagnosed AML is low (1.1%), irrespective of whether an LP is mandatory or not. The presence of CNS disease at diagnosis in and of itself does not seem to portend a poor prognosis for achieving an initial CR or for OS.

SummaryThere are conflicting reports in the literature suggesting that one gender or the other has a better survival with acute myeloid leukaemia (AML). The present study was done in an attempt to resolve the issue. The effect of gender was examined on 3546 newly diagnosed patients with AML, including 548 patients with acute promyelocytic leukaemia (APL) enrolled in 10 multi‐institutional treatment studies from March 1984 to November 2008. Kaplan–Meier estimates were used to estimate event‐time distributions for survival and multivariate models were used to examine the gender effect after adjusting for multiple risk factors. P values were based on two‐sided tests. Non‐APL female patients had a significantly better overall (OS) but not disease‐free survival (DFS) than males, irrespective of age, initial white blood cell count, or dose of daunorubicin. No differences were observed for obese or FMS‐like tyrosine kinase 3‐internal tandem duplication (FLT3‐ITD)‐positive patients. Female patients with APL had a significantly better OS and DFS than male patients with APL, and differences in survival were greater for patients with t(15;17) + other cytogenetic abnormalities compared with those with t(15;17) only. Gender is an independent prognostic variable in patients with AML. Whether these survival differences are due to hormonal, genetic or pharmacokinetic differences between the sexes or differential toxin exposure such as smoking is unknown. However, the former seems less likely as patient age did not influence the survival advantage for female patients.