bluuebunny/crossref_metadata_2025 huggingface dataset:
Association of intensive chemotherapy with the rate of pathogenic driver mutation clearance in acute myeloid leukemia.
Authors: Maini Ruby , Olet Susan , Hillis Emma , Saxena Raina , Haupt Carl , Philon Ernest , Davis Carter Thomas
Published: June 2023

7040

Background: Identification of pathogenic molecular mutations (PMM) as drivers in the development of acute myeloid leukemia (AML) and in initial prognostic assessment has become clinical practice. Persistence of PMM in a morphologic leukemia free state is correlated with high risk of relapse and poor prognosis. Therapy for induction of remission and elimination of all markers of residual disease remains controversial, especially with the addition of venetoclax to hypomethylating agents (HMA). Here we compare the rates of PMM clearance between intensive chemotherapy (IC) and less intensive chemotherapy (LIC) regimens. Secondary, we assessed differences in ethnicity between white and black patients (pts). Methods: Retrospective study from a leukemia treatment center in Louisiana. De-identified pt records from 2018-2022 assessed for demographics: race, age, sex and diagnosis: AML, ELN 2017 staging, and mortality by IC vs. LIC regimen. IC included anthracycline and cytarabine containing regimens. LIC included HMA, with or without venetoclax. Chi-Squared analysis preformed, threshold for significance at p < 0.05. Results: 408 pts with non-M3 AML who underwent treatment, 180(44.1%) were female, 91(22.3%) were black, 303(74.3%) were white, 273(66.9%) received IC while 135(33.1%) received LIC. NGS found a total of 280 pre-treatment PMM. Among 217 pts who received treatment, the rate of mutation clearance with IC was 55.2%, compared with 50.8% LIC(p = 0.55). Stratifying by race, black pts had a twofold mutation clearance compared to white pts OR = 1.76, 95% CL (0.91 – 3.44). Similar proportions of pts received LIC vs IC among both white (74.1% vs 74.4%) and black (22.2% vs 22.3). There was no statistically significant difference for overall survival on chemotherapy regimen intensity (p = 0.1991), race (p = 0.2736), or gender (p = 0.6912). Conclusions: In our study, PMM clearance was similar between IC and LIC inductions. Although these findings are from a single center, the ability to clear driver mutations at a similar rate to IC may offer a significant advantage of LIC with venetoclax. Mutation clearance is often used as a surrogate marker for residual disease, it may be reasonably inferred that these regimens serve as suitable induction regimens for pts who may be considered for allogeneic stem cell transplantation. Blacks make up a greater proportion of the population in Louisiana (~33%) as compared to the national average (~13%). Often underrepresented in prospective clinical trials, blacks made up 22.7% of subjects providing increased insight to clinical responses. No difference in mortality based on race and a trend toward greater mutational clearance in blacks. Emphasizing the importance of standardizing care in treatment centers and the need for greater representation in prospective clinical trials to understand better how differences in race may impact treatment outcomes.
Capped F10, a novel DNA directed fluoropyrimidine, in TP53 mutated acute myeloid leukemia (AML).
Authors: Pardee Timothy S. , Okechukwu Charles , Pladna Kristin , Gmeiner William
Published: June 2023

7046

Background: Acute myeloid leukemia (AML) is an aggressive malignancy characterized by resistance to treatment and poor outcomes. One of the most devastating mutations in AML involves loss of the tumor suppressor TP53. AML harboring this loss carries a dismal prognosis and there is a clear need for new approaches. Methods: To identify new therapeutics, a TP53 null and WT isogenic cell line pair was generated using CRISPR/CAS9 using a murine AML cell line. Clonal isolates were obtained and loss of detectable TP53 was confirmed by Western Blotting. A high throughput screen of currently FDA approved anticancer agents was performed. Results: When agents were ranked by equal cytotoxicity against TP53 null and WT AML cells 20% (6/30) of the top 30 agents targeted the folate/thymidylate synthase axis. This suggests that thymidylate synthase (TS) is a vulnerability in TP53 null AML cells. To confirm TS as a target in TP53 null AML an additional murine AML TP53 null/WT cell line pair was generated using CRISPR/CAS9. When these cell lines were treated with doxorubicin the TP53 null cells were significantly more resistant (p≤0.001 at 10nM). Capped F10 (CF10) is a second generation fluoropyrimidine oligonucleotide that has been shown to be a highly potent inhibitor of TS. In contrast to doxorubicin, CF10 treatment resulted in significant cell death when dosed in the low picomolar range with minimal differences between the null and WT cell lines (p = 0.31 at 50pM). To extend this result TP53 WT or null cells were injected into syngeneic recipients and upon engraftment mice were treated with CF10 at 300mg/kg twice weekly. CF10 provided a significant survival benefit in the TP53 null but not WT injected mice consistent with CF10 having activity against TP53 null AML (p = 0.035 vs 0.13). To confirm a TP53 independent mechanism, competition assays were performed with CAS9 expressing AML cells partially infected with a vector expressing an sgRNA targeting TP53 and a GFP reporter. When the mixed population was treated with the IC90 concentration of 5-fluorouracil there was a highly significant increase in GFP+ cells indicating a TP53 mediated cell death (p = < 0.001). In contrast when cells were treated with the IC90 concentration of CF10 there was a non-significant increase in GFP+ population (p = 0.074) consistent with a mainly TP53 independent mechanism. Fluoropyrimidine based therapy can be myelosuppressive especially in patients with low dihydropyrimidine dehydrogenase (DPD) activity. To assess the tolerability of CF10, healthy WAG/RAJ rats were treated with the DPD inhibitor ethynyl uracil at 2mg/kg alone or in combination with either 141 mg/kg CF10 or the molar equivalent of 50 mg/kg 5-flurouracil (5-FU) and weight determined. In contrast to 5-FU, CF10 treated animals did not have a significant change in weight compared to controls. Conclusions: Taken together these data suggest that CF10 is a promising new agent for TP53 null AML.
Effect of disease status prior to T-cell depleted allogeneic stem cell transplantation on relapse-free and overall survival in patients with adverse-risk acute myeloid leukemia (AML).
Authors: Rojek Alexandra Ewa , Mortel Mylove , Artz Andrew S. , Larson Richard A. , Liu Hongtao , Nawas Mariam , Odenike Olatoyosi , Stock Wendy , Bishop Michael Russell , Kosuri Satyajit
Published: June 2023

7049

Background: Patients (pts) with adverse risk AML experience poor long term disease control. Some of these pts can be rescued with allogeneic stem cell transplantation (SCT). Adverse risk was defined by high risk cytogenetic and molecular markers (2017 European Leukemia Network criteria) and by disease status prior to SCT. We investigated outcomes of pts receiving in vivo T-cell depleted allogeneic SCT (TCD-SCT) at our center. Methods: We retrospectively analyzed 200 adverse-risk AML pts who received TCD-SCT from 2002-19. Pts were categorized into groups: untreated first relapse at SCT, primary induction failure with active disease at SCT, resistant to first induction but achieving morphologic complete remission (CR) by SCT, and induction sensitive CR with high-risk disease by ELN criteria. Outcomes were evaluated by 1-year (yr) and 3-yr relapse-free survival (RFS), overall survival (OS), and non-relapse mortality (NRM), and compared with log-rank tests of significance. Results: Baseline pt characteristics included a median age of 54 years (IQR, 44-61) with 62 (31%) pts older than 60, and 81 (41%) with HCT-CI score 3 or greater. All pts underwent in vivo TCD with alemtuzumab or ATG; 153 (77%) received reduced-intensity conditioning; 142 (71%) had 8/8 or 7/8 matched donors. Fourteen (7%) pts developed grade III-IV acute graft versus host disease (GVHD), and 25 (13%) developed chronic GVHD. With a median follow up of 14.3 months, cumulative incidence of relapse was 59% and NRM was 27%. Outcomes are summarized in the table. There was a statistically significant difference between categorized groups by RFS (p<0.01) and OS (p<0.01). Conclusions: We conclude that among adverse-risk AML pts, those in CR at time of TCD-SCT have superior survival outcomes to those with active disease. For those in CR at TCD-SCT, prior resistance to frontline induction was associated with inferior survival, suggesting that AML biology, treatment sensitivity, and remission status are important factors for TCD-SCT outcomes. The inferior outcomes observed for those with primary refractory disease suggest that while TCD-SCT can be effective with acceptable NRM, more work is needed to identify which pts can benefit from future transplant strategies. Better post-SCT therapy is needed to prevent relapses. [Table: see text]
Myeloablative fractionated busulfan-based conditioning regimen in patients with AML and MDS: Results of a randomized clinical trial comparing 2 fractionation schedules.
Authors: Popat Uday R. , Lontos Konstantinos , Bassett Roland L. , Alousi Amin Majid , Alatrash Gheath , Bashir Qaiser , Hosing Chitra M. , Im Jin Seon , Kebriaei Partow , Marin David , Mehta Rohtesh S. , Nieto Yago , Oran Betul , Olson Amanda Leigh , Qazilbash Muzaffar H. , Ramdial Jeremy L , Srour Samer Ali , Shpall Elizabeth J. , Champlin Richard E. , Andersson Borje S
Published: June 2023

7051

Background: Hematopoietic stem cell transplantation (HSCT) cures leukemias, but comes at a cost of higher toxicity and non-relapse mortality (NRM). We previously showed that fractionating the busulfan (Bu) dose and starting it on day -13 instead of day -6, leads to lower toxicity and permits delivery of a myeloablative regimen, even to older patients. We designed a single institution randomized trial to validate the concept of fractionation and to test the hypothesis that further fractionation by starting chemotherapy on day -20 further reduces toxicity and lowers NRM without increasing relapse risk. Methods: Patients with AML or MDS, 18 to 70 years old, with a matched related or unrelated donor were eligible if they had adequate organ function. Patients were randomized to one of two arms: The shorter arm consisted of outpatient Bu 80mg/m2 on days -13 and -12, while the longer arm consisted of outpatient Bu 80mg/m2 on days -20 and -13. The rest of the regimen and GVHD prophylaxis were similar in both arms: On days -6 to -3, fludarabine 10mg/m2, cladribine 10mg/m2 and Bu dosed to achieve total Bu exposure of 20,000 ± 12% µMol-min for the whole course, including outpatient doses. Additionally, the last 33 patients received venetoclax from days -22 to -3 in both arms. The GVHD prophylaxis was tacrolimus and mini-methotrexate in the first 29 patients and tacrolimus and cyclophosphamide in the remainder. The only difference between the two arms was if busulfan was started on day -20 or not. Results: A total of 116 patients were randomized, 59 to the shorter day -13 arm and 57 to the longer day -20 arm. Median age was 59 in the day -13 arm and 57 in the -20 arm. 70.7% had AML. 41.4% were transplanted in first complete remission. The characteristics of the two groups were well-balanced. The median follow-up in the 67 surviving patients was 48.9 months. More patients in the day -13 group experienced grade ≥3 toxicities than in the day -20 group (93.2% vs. 73.7%, p = 0.005). The difference in toxicity led to a reduction of the 3-year NRM (19% vs. 7%, p = 0.067). There was no difference in relapse rate (p = 0.99) (Table). Conclusions: Further fractionating busulfan and moving just one dose of busulfan 1 week earlier reduces toxicities and may lower NRM, without increasing relapse rate. Clinical trial information: NCT02250937 . [Table: see text]
Financial toxicity and quality of life in patients undergoing bone marrow transplant evaluation: A single center analysis.
Authors: Hussaini S. M. Qasim , Ren Yi , Racioppi Alessandro , Lew Meagan , Bohannon Lauren M. , Johnson Ernaya , Thompson Jillian , Henshall Bethany , Darby Maurisa , Choi Taewoong , Lopez Richard D , Sarantopoulos Stefanie , Gasparetto Cristina J. , Long Gwynn Douglas , Horwitz Mitchell , Chao Nelson Jen An , Zafar Yousuf , Sung Anthony Derek
Published: June 2023

7052

Background: The impact of pre-transplant financial toxicity on quality of life (QOL) outcomes following bone marrow transplant (BMT) is unknown. We investigated the prevalence of financial toxicity in a population undergoing evaluation for BMT and its impact on post-transplant clinical and health-related QOL outcomes. Methods: This is a cross-sectional study in patients undergoing evaluation for allogeneic BMT between 1/1/2018 and 9/23/2020 at a large academic medical center. Financial health at baseline was measured via the comprehensive score for financial toxicity (COST) survey. The cohort was divided into three groups: none, mild, and moderate-high financial toxicity. QOL was measured using Functional Assessment of Cancer Therapy (FACT)-based questionnaires at multiple timepoints. Multivariate logistic regression analysis evaluated factors associated with financial toxicity. Kaplan-Meier curves and log-rank tests evaluated overall survival and non-relapse survival. Results: Of 245 patients evaluated for BMT, 176 (71.8%) completed both questionnaires with 63.1% male, 72.2% white, and median age 57 years. Common diagnoses were myelodysplastic syndrome (39.2%), leukemia (38.1%), and lymphoma (13.6%). Overall, 83 (47.2%) patients reported no financial toxicity, 51 (29.0%) mild, and 42 (23.9%) with moderate-high financial toxicity at initial evaluation for BMT. Compared to those with no financial toxicity, those with mild or moderate-high financial toxicity reported significantly reduced spending on leisure, food/clothing, used all or a portion of savings, borrowed money or accumulated debt using a credit card, and did not fill a prescription due to costs (p < 0.0001 for all). In patients with baseline moderate-high financial toxicity, FACT-BMT scores were lower at 6 months (126 none vs 122 mild vs 92 moderate-high; p = 0.0007) and 1 year (133 none vs 117 mild vs 112 moderate-high; p = 0.0075) following BMT. Older age (>62) (OR 0.4; 95% CI [0.17 – 0.94], p = 0.03) and income equal or greater than $60,000 (OR 0.16; 95% CI [0.07 – 0.36], p = < 0.001) were associated with lower odds of financial toxicity. No association was noted between financial toxicity and selection for BMT, overall survival, or non-relapse mortality. Conclusions: Financial toxicity was highly correlated with patient-reported changes in behavior affecting their daily activities and transplant care, with notable impact on QOL following transplant for up to 1 year. Early interventions by physician and social work-led teams may benefit patients who are at risk for financial toxicity. [Table: see text]
Report of a chronic myeloid leukemia registry in a low-and middle-income setting.
Authors: Othieno-Abinya Nicolas Anthony , Mwanda Walter , Mutebi Miriam Claire , Nyangasi Mary Flaviane , Mwenda Valerian , Oyiro Peter Omondi , Mcligeyo Angela Awino , Ezzi Mohammed Shabbir , Odhiambo Andrew Oluoch , Ong'ondi Matilda , Mwanzi Sitna Ali , Adamjee Ebrahim , Induli Magdalene
Published: June 2023

7054

Background: Treatment of chronic myeloid leukaemia (CML) in Kenya has been supported since the year 2002 by a collaboration between the Max Foundation and Novartis Pharmaceuticals in the Glivec International Patient Assistance Program (GIPAP). In November 2020 this was transitioned to Max Access Solutions (MAS) that brought in the Ministry of Health as a partner. A broad range of BCR-ABL tyrosine kinase inhibitors are available. We wanted to describe epidemiology, treatment and outcome of CML in the country. Methods: Patients’ records were reviewed and data entered in a database. Key variables included age, sex, BMI, diet, disease phase at diagnosis, treatment, and outcome. Continuous variables were summarized using mean (standard deviation) or median (interquartile range). Categorical variables were summarized using counts and percentages. Bivariate comparisons of treatment outcome were done using chi-square or Fisher’s exact test. Analysis of variance (ANOVA) or Kruskal-Wallis test was used for continuous variables. Results: 1347 patients-males 748 (55.5%), females 599 (44.5%). Mean age was 44.5 years. Seventy (9.0%) were underweight, 88 (11.4%) obese. Mean body surface area (BSA) was 1.75m2. Chronic phase cases were 1177 (96.2%), accelerated phase 46 (3.8%), blastic phase 1 (0.1%). Mean bone marrow blast count was 5.25%, BCR-ABL/ABL was 63.7%, haemoglobin 10.8g/dl, total wbc count 225 x 109/litre, platelets 392.5 x 109/litre. Imatinib was administered upfront to 1319 patients (99.8%). Two hundred and six (15.3%) were switched to second line; 100 (48.8%) to dasatinib, 50 (24.4%) to bosutinib. Transformation was registered in 26 cases (1.9%) - accelerated in 13 (72.2%), blastic in 5 (27.8%), 4 (80.0%) being myeloid and 1 (20%) lymphoblastic. Those alive are 1151 (85.4%) and 185 (13.7%) lost to follow-up. Deaths were recorded in 11 (0.8%). Those with lower BSA were more likely to die (p = 0.01). Conclusions: CML in Kenya occurs at a younger age-group with a slight male preponderance. With availability of a range of BCR-ABL tyrosine kinase inhibitors, treatment outcome is close to what is documented in high-income settings.
Methylation-based prediction of myelodysplastic syndrome survival outcomes.
Authors: Shi Alvin , Ali Abdullah , Cann Gordon , Shaknovich Rita , Venn Oliver , Raza Azra , Liu Qinwen
Published: June 2023

7058

Background: Myelodysplastic syndromes (MDS) are a heterogeneous group of myeloid malignancies associated with a myriad of deleterious outcomes and a 5-year relative survival of 37%. MDS risk stratification is key for optimal treatment decisions. DNA methylation is associated with MDS biology due to frequent somatic mutations in genes (i.e. TET2, DNMT3A, IDH1, IDH2, and WT1) that affect DNA methylation. We hypothesized that methylation-based markers may help stratify risk and improve IPSS-R (the Revised International Prognostic Scoring System). Here, we evaluated the potential of both Bone Marrow (BM) Whole-genome Bisulfite Sequencing (WGBS) and Serum-based Targeted Methylation (TM) Sequencing to predict survival of MDS patients. Methods: We conducted paired BM WGBS and Serum-based TM sequencing on a cohort of 127 patients with MDS (N = 104) and secondary AML (N = 23) treated at the Columbia University Medical Center. We categorized patients based on an overall survival of > 3 (“long”, N = 50) or < 3 years (“short”, N = 77). We then identified differentially methylated regions (DMRs) differing between long and short survivor groups, and analyzed the biological pathways and functions enriched in these regions. To assess survival association, we trained a random forest classifier on principal components (“methylation classifier”) on the methylation fractions from a subset of 96 Serum and 98 BM MDS patient samples to predict long vs. short survival, and compared this against a logistic regression IPSS-R model. We optimized the hyperparameters and assessed classifier performance using six-fold nested cross-validation. Finally, we conducted a multivariable cox regression with predicted scores from the methylation classifier, IPSS-R scores (recalculated at sample collection), age, and gender. Results: We identified a total of 7,742 DMRs in the BM WGBS and 14,093 DMRs in the Serum TM as significantly different between long and short survivor groups. Signaling pathways for calcium, cAMP, MAPK, Rap1, and PI3K-Akt were significantly enriched in DMRs. We also identified a previously-reported CpG island hypermethylation signature associated with AML progression in BM and Serum. The methylation classifier achieved a comparable AUROC compared to IPSS-R logistic regression for both BM WGBS (0.80 vs 0.78) and Serum TM (0.77 vs 0.73) samples. Multivariable Cox regression demonstrated that both predicted scores from the methylation classifier (Serum p =0.002; BM p =0.016) and IPSS-R scores (Serum p =0.003; BM p =0.004) are significant predictors of survival. Conclusions: We demonstrated methylation-based sequencing represents a promising new tool for MDS patient risk stratification. As IPSS-R relies on bone marrow aspirates, the Serum-based TM assay offers a less-invasive method for MDS risk stratification.
Outcome of TP53-mutated CCUS and the risk of progression to myeloid neoplasms.
Authors: Shah Syed Naseem , Li Marissa , Baranwal Anmol , Chen Dong , He Rong , Alkhateeb Hassan B. , Tefferi Ayalew , Mangaonkar Abhishek A , Al-Kali Aref , Patnaik Mrinal S , Shah Mithun Vinod
Published: June 2023

7059

Background: TP53-mutated ( TP53mut) myeloid neoplasms (MN) are aggressive leukemia with poor survival. A subset of TP53mut MN is preceded by TP53mut CCUS that is conventionally considered to be high-risk premalignant condition, though evidence supporting the notion is lacking. We studied outcomes of TP53mut CCUS compared to TP53 wild-type ( TP53wt) CCUS. Methods: Mayo Clinic Molecular Hematology Database (N=7593) was queried to identify patients (pts) harboring pathogenic variant(s) in exons 4-11 of the TP53 gene with ≥2% variance allele frequency (VAF). CCUS was defined using the 5th edition of the WHO Classification for MN. Results: Of 457 pts with TP53mut, 29 (5.9%) had TP53mut CCUS. The median age at diagnosis was 67 years, 17 (59%) were female, and 20 (69%) had received cytotoxic therapies. One and ≥2 TP53mut were seen in 26 (89.6%) and 3 (10.3%) pts, respectively. Median TP53mut VAF was 9% (range 3-42), 3 had TP53mut VAF ≥20%, and 4 (14%) had non-MDS defining cytogenetic anomalies. Of 16 pts with available follow up evaluation (median interval 22 months, Table), 3 (10.3%) progressed to TP53mut MN at 5, 13, and 14 months from diagnosis. We next compared outcomes of TP53mut CCUS to TP53wt CCUS (n=138). The proportion of pts developing MN was not different between TP53wt and TP53mut CCUS (18.1 vs 10.3%, P= .42). Progression free survival of TP53mut CCUS was comparable to TP53wt CCUS at 1- (77 vs 83%), 2- (67 vs 67%), and 5-years (67 vs 59%, P=.9). Similarly, overall survival of TP53mut vs TP53wt CCUS at 1- (81 vs 89%), 2- (76 vs 76%), and 5-years (76 vs 67%) was comparable ( P= .94). Conclusions: In contrast to the prevalent notion, TP53mut was not associated with a higher risk of MN progression or mortality compared to TP53wt CCUS. Majority of TP53mut clones showed remarkable stability over years. [Table: see text]
Indirect treatment comparison (ITC) of momelotinib (MMB) vs fedratinib (FED) safety in patients (pts) with myelofibrosis (MF).
Authors: Masarova Lucia , Verstovsek Srdan , Palandri Francesca , Mesa Ruben A. , Harrison Claire , Sajeev Gautam , Gorsh Boris , Simpson Ryan , Cho Sang Kyu , Wang Zhaohui , Ellis Catherine Elizabeth , Conlon Seán , Signorovitch James
Published: June 2023

7065

Background: JAK inhibitors (JAKi) are a mainstay of MF treatment, with proven ability to improve symptoms and spleen volume for most pts; although safety profiles vary, some approved JAKi have associated hematologic toxicity. The JAK1/JAK2/ACVR1 inhibitor MMB has shown consistent benefit in improving anemia, symptoms, and spleen volume in pts with MF. Clinical trials have directly compared MMB with ruxolitinib, with MMB showing a more favorable hematologic toxicity profile. However, there are limited data comparing MMB vs other JAKi such as FED. We performed an ITC of safety outcomes between MMB and FED in pts with MF. Methods: A matching-adjusted indirect comparison (MAIC) was undertaken to compare outcomes from phase 2 and/or 3 MMB and FED trials. Adverse events (AEs) occurring in > 10% of a treatment arm over 24 weeks were evaluated; primary outcomes were grade 3/4 anemia and thrombocytopenia. Separate analyses were performed in JAKi-naive (SIMPLIFY-1 [S1] vs JAKARTA) and JAKi-experienced (pooled SIMPLIFY-2 [S2], MOMENTUM vs JAKARTA2) pts. Evaluable outcomes were limited by published aggregate data, so not all were feasible to compare. MAIC involved reweighting MMB pt data by matching baseline characteristics prioritized by expert clinical input (DIPSS/IPSS, Total Symptom Score, platelet counts, spleen volume/length, and/or hemoglobin levels) between trial arms, and determining odds ratios (ORs), risk ratios, and risk differences (RDs) between outcomes in resulting balanced populations. As nonrandomized groups were compared, results may be biased due to unmeasured/residual confounding, despite adjusting for prognostic factors/effect modifiers. Results: Effective MMB sample sizes after adjustment were 151.1 JAKi-naive and 79.4 JAKi-experienced pts. Risk of any or grade 3/4 anemia, diarrhea, nausea, and serious AEs leading to dose reductions were statistically less likely with MMB vs FED in both populations; any or grade 3/4 thrombocytopenia was also less likely with MMB vs FED, significantly so in JAKi-naive pts. Odds/risk of other outcomes assessed varied in significance (key OR/RD results presented in the Table). No identified outcomes were statistically less likely with FED. Conclusions: MMB showed a favorable safety profile vs FED in both JAKi-naive and experienced pts, including a significantly lower risk of key hematologic AEs, diarrhea, and nausea over 24 weeks. Clinical trial information: NCT04173494 ; NCT01969838 ; NCT02101268 ; NCT01523171 ; NCT01437787 . [Table: see text]
Bromodomain and extra-terminal (BET) inhibitor INCB057643 (LIMBER-103) in patients (pts) with relapsed or refractory myelofibrosis (R/R MF) and other advanced myeloid neoplasms: A phase 1 study.
Authors: Watts Justin M. , Hunter Anthony , Iurlo Alessandra , Xicoy Blanca , Palandri Francesca , Reeves Brandi , Vannucchi Alessandro M. , Bose Prithviraj , Diaz Rosa Ayala , Halpern Anna B. , Chen Xuejun , Seguy Francis , Zhou Feng , Zheng Fred , Vachhani Pankit
Published: June 2023

7069

Background: BET proteins are epigenetic readers that regulate expression of critical oncoproteins involved in the pathophysiology of hematologic malignancies, including MF. INCB057643 is a small-molecule BET inhibitor evaluated as monotherapy and in combination with ruxolitinib (RUX) in pts with advanced malignancies in 2 previous phase 1/2 clinical trials. Methods: This ongoing phase 1, 3+3 dose-escalation/expansion study (NCT04279847) evaluates safety and tolerability of INCB057643 (4 mg once daily [qd]; escalation up to 12 mg qd) in pts aged ≥18 years as (1) monotherapy (part 1) in R/R MF, myelodysplastic syndromes (MDS), or MDS/myeloproliferative neoplasm (MPN) overlap syndromes (MDS/MPN) or (2) added to RUX (part 2) in pts with MF and suboptimal response to RUX. The primary endpoint is safety and tolerability, including identification of dose-limiting toxicities (DLTs). Results: 13 pts have been treated in part 1 (4 mg, n=6; 8 mg, n=4; 10 mg, n=1; 12 mg, n=2), and 3 pts received 4 mg + RUX in part 2 (overall age range, 50–79 years; men, n=9; study treatment duration range, 15–314 days). 12 pts had MF, and 4 had MDS/MPN. All 6 pts in the 4-mg cohort discontinued treatment (3 for progressive disease [PD]; MF, n=2; MDS/MPN, n=1); 1 pt with MF in the 12-mg cohort discontinued for thrombocytopenia. The other 9 pts remain on treatment. Thrombocytopenia was the most common treatment-emergent adverse event (TEAE; n=9; Table) and the only TEAE leading to discontinuation (n=3). Grade ≥3 TEAEs occurring in ≥1 pt were thrombocytopenia (n=4), anemia (n=3), and hypokalemia (n=2). There were 8 serious AEs across 4 pts, with only COVID-19 occurring in >1 pt (n=2); all but one (pneumonia) were considered unrelated to study treatment. There were 2 DLTs (thrombocytopenia [MDS/MPN pt] and hyperbilirubinemia [MF pt]; both 12-mg cohort) and 2 deaths (both 4-mg cohort due to PD [MF, n=1; MDS/MPN, n=1]). Conclusions: Treatment with INCB057643 monotherapy (4 and 8 mg qd) and in combination (4 mg qd) with RUX was generally well tolerated in this pt population. The 12-mg qd monotherapy dose was not tolerated and caused 2 DLTs. There were no treatment-related fatal events. Dose finding in part 1 is ongoing with 10 mg qd, after which a recommended phase 2 dose will be declared. Combination dose escalation is also ongoing. Preliminary efficacy including spleen size and symptoms will be available for presentation. Clinical trial information: NCT04279847 . [Table: see text]
Clinical outcomes by SF3B1 mutation status in patients (pts) with lower-risk myelodysplastic syndrome (LR-MDS) retreated with erythropoiesis-stimulating agents (ESAs).
Authors: Makinde Adeola Y. , Garcia-Manero Guillermo , Matsuno Rayna K. , McBride Ali , Brown Thomas D. , Idryo Danny , Broome Ronda , Herriman Autumn , Wilkinson Kristiana , Walters Sheetal , Schrag Andrew , Mohammed Hina , Izano Monika A. , Mukherjee Sudipto
Published: June 2023

7071

Background: Pts with SF3B1-mutated LR-MDS often have a more favorable prognosis versus those with SF3B1 wildtype. A sizeable number of pts with LR-MDS undergo ESA treatment even after experiencing ESA failure in first line. This study evaluated the outcomes of pts with LR-MDS retreated with ESAs in routine clinical practice, stratified by SF3B1 status. Methods: This retrospective cohort study included pts with LR-MDS in the US community setting who initiated ESAs as first-line therapy between January 1, 2016 and June 30, 2019, and were followed through June 30, 2021. Eligible pts discontinued ESAs (treatment gap ≥ 3 wk for epoetin alfa or ≥ 6 wk for darbepoetin alfa) and subsequently reinitiated ESA therapy at least once during follow-up. Ring sideroblasts (RS) ≥ 15% served as a surrogate for pts with unknown SF3B1 mutation status. Outcomes included ESA switches, dose reductions and escalations, ESA failure, and overall survival (OS). Primary ESA failure was defined as no rise in hemoglobin (Hb) ≥ 1.5 g/dL or no decrease in RBC transfusion requirement by 8 wk of treatment. Transfusion-dependent (TD) status was evaluated for pts who were transfusion independent (TI) at baseline. Results: A total of 82 pts with LR-MDS and repeat ESA treatment were included. Median age at start of ESA treatment was 79 y (interquartile range [IQR], 72–85). Diagnosis of MDS-RS, MDS with isolated del(5q), MDS with multilineage dysplasia, and MDS with single lineage dysplasia was reported in 30 (36%), 7 (9%), 9 (11%), and 9 (11%) pts, respectively; 27 (33%) had unknown classification. Median follow-up was 26 mo (IQR, 13–38) with 65% failing ESA therapy by 8 wk. Table shows pts’ SF3B1 mutation status, median OS, pts who had an ESA switch, dose reduction or escalation, experienced ESA failure, and pts who were TI at baseline and became TD during follow-up. Results were similar when RS was not used as a surrogate, and when analyses were limited to pts who were treated with ESAs only throughout follow-up. Conclusions: In this study of pts with LR-MDS retreated with ESAs, primary ESA failure was high with nearly half of TI pts becoming TD during follow-up. OS was poor regardless of SF3B1 status – 2–4 times lower than the remaining life expectancy for a 79-y-old (108 mo for men; 125 mo for women). Although treatment options were limited during the study period, the high primary failure rate suggests that pts with LR-MDS may benefit from alternatives to ESAs. [Table: see text]
SAVE (Safe Accelerated Venetoclax Escalation): Initial results of a prospective, phase Ib study of venetoclax with an accelerated dose ramp-up in patients with CLL.
Authors: Crombie Jennifer Leigh , Ahn Inhye E , Tyekucheva Svitlana , Merryman Reid , Fisher David Christopher , Armand Philippe , Montegaard Josie , Kilcommons Marykate , Carey Celeste , Black Robert , Brown Jennifer R. , Davids Matthew Steven
Published: June 2023

7512

Background: Venetoclax (VEN)-based regimens are highly effective for patients (pts) with treatment naïve (TN) and relapsed/refractory (R/R) CLL. Despite high rates of undetectable minimal residual disease (uMRD) and durable responses even with time-limited therapy, uptake of VEN in routine clinical practice has been relatively low, in part due to the inconvenient 5-week dose ramp-up used to reduce the risk of tumor lysis syndrome (TLS). Accelerated ramp-up schedules have been evaluated in retrospective studies (Davids et al., AJH, 2022), but prospective studies are lacking. Here we present initial results of SAVE: Safe Accelerated Venetoclax Escalation, a phase Ib study of VEN with an accelerated dose ramp-up in pts with CLL. Methods: This is an ongoing phase Ib investigator-sponsored trial for pts with TN and R/R CLL (NCT04843904). Key eligibility include CLL requiring therapy per 2018 iwCLL criteria and adequate renal function. The primary endpoint is the highest risk TLS group that can safely tolerate an accelerated VEN ramp-up. Secondary endpoints include safety and tolerability and rates of ORR/CR/uMRD after 3 months of VEN-based therapy. Patients are treated inpatient with a 5-day daily VEN ramp-up schedule (20-50-100-200-400 mg). TLS labs are monitored pre-dose and at 4, 8, 12, and 24 hours following each dose. Anti-CD20 antibody is given per SOC. At least 5 pts from cohort A (low TLS risk using standard assessment) were required to enroll prior to opening cohort B (medium and high TLS risk). Efficacy is assessed using 2018 iwCLL criteria, toxicity using iwCLL and CTCAE v5, and MRD using central 8-color flow at 10-4. Results: As of 2/2/2023, 20 pts have been treated (10 each from cohort A and B) (Table). 19 pts received obinutuzumab with VEN, and 1 pt received VEN monotherapy. All pts completed an accelerated VEN ramp-up without any clinical TLS. One pt with medium TLS risk had lab TLS (phos and uric acid peaked at 8.7 mg/dL) after the first VEN 400 mg dose, which resolved with sevelamer and rasburicase, thereby prolonging the ramp-up to 6 days. Median inpatient time was 6 days (range 5-8). All grade heme tox: neutropenia (45%; 20% G3/4), thrombocytopenia (35%; 10% G3/4). One pt died 2 months into treatment due to complications of a bowel obstruction unrelated to study treatment. ORR after 3 mo. was 89% in 19 evaluable pts including 2 CRs. Among 19 evaluable patients after 3 mo., 74% and 42% had uMRD in PB and BM, respectively. Conclusions: Our early data suggest that an inpatient, accelerated 5-day VEN ramp-up is feasible in CLL, with a low rate of TLS, even among patients with medium or high risk of TLS. The study is currently ongoing. Clinical trial information: NCT04843904 . [Table: see text]
Long-term safety with ≥12 months of pirtobrutinib in relapsed/refractory (R/R) B-cell malignancies.
Authors: Coombs Catherine Callaghan , Shah Nirav Niranjan , Jurczak Wojciech , Woyach Jennifer Ann , Cheah Chan , Patel Krish , Maddocks Kami J. , Wang Yucai , Muehlenbein Catherine E. , Wang Chunxiao , Abhyankar Sarang , Tsai Donald Edward , Eyre Toby A.
Published: June 2023

7513

Background: While Bruton tyrosine kinase inhibitors (BTKi) can induce sustained remissions, ongoing response requires continuous treatment and thus long-term safety/tolerability is critical for adherence, maintaining dose intensity, and delivering maximum efficacy. Pirtobrutinib is a highly selective, non-covalent (reversible) BTKi approved by the FDA in January 2023 for R/R mantle cell lymphoma after 2 prior lines of therapy including a BTKi. Pirtobrutinib has demonstrated promising efficacy with low discontinuation and dose reduction rates in patients (pts) with multiple subtypes of R/R B-cell malignancies. However, the long-term safety and tolerability of pirtobrutinib has not yet been reported. Here we report the clinical safety in pts with long-term (≥12 months) pirtobrutinib treatment from the phase 1/2 BRUIN trial. Methods: Pts with R/R B-cell malignancies who received ≥12 months of pirtobrutinib were included. Median time to onset, dose reduction, discontinuation, and cumulative incidence rates were determined for treatment emergent adverse event (TEAE) that occurred in ≥20% of pts and select AE of interest associated with BTKi. Results: As of 29 July 2022, 773 pts were enrolled, and 326 (42%) pts received treatment for ≥12 months. Among these 326 pts, median time on treatment was 19 months (IQR: 16,25), with 231 (71%) remaining on pirtobrutinib. The most common TEAE (all grade, regardless of attribution) in this long-term 326 pt cohort were fatigue (32%), diarrhea (31%), Covid-19 (29%), contusion (26%), cough (25%), and back pain (21%). TEAE leading to dose reduction or discontinuation occurred in 23 (7%) and 11 (3%) pts, respectively. Four (1%) pts discontinued due to a treatment-related AE, and 1 pt had a fatal treatment-related AE (Covid-19 pneumonia). Select AE of interest for the long-term pts are shown in the Table. Comprehensive safety analyses describing the frequency of TEAE over time will be presented. Conclusions: Prolonged pirtobrutinib therapy continues to demonstrate a safety profile amenable to long-term administration at the recommended dose without evidence of new or worsening toxicity signals. The safety and tolerability observed in pts on therapy for ≥12 months was similar to previously published safety analyses on all pts enrolled regardless of follow-up. Clinical trial information: NCT03740529 . [Table: see text]
Efficacy and safety of pembrolizumab every six weeks in relapsed/refractory classical Hodgkin lymphoma or primary mediastinal B-cell lymphoma: The phase 2 KEYNOTE-B68 trial.
Authors: McDonald Andrew Bruce , Verburgh Estelle , Gotti Manuel , Pinto Antonio , Zaucha Jan , Ivanov Vladimir , Melnichenko Vladimir , Mocikova Heidi , Ozcan Muhit , Patti Caterina , Farias Joao , Goncalves Iara , Mayer Jiří , Saydam Guray , Tomassetti Sarah , Pathiraja Kumudu , Ryland Katherine , Chakraborty Samhita , Jurczak Wojciech
Published: June 2023

7517

Background: Pembrolizumab (pembro) 200 mg Q3W demonstrated robust antitumor activity and manageable safety in relapsed/refractory (R/R) classical Hodgkin lymphoma (cHL) and R/R primary mediastinal B-cell lymphoma (PMBCL), resulting in FDA approval. Recently, the FDA granted accelerated approval of pembro 400 mg Q6W in all approved indications based on data from solid tumor trials in solid tumors. The global Phase 2 trial (NCT04875195) evaluates the efficacy and safety of pembro 400 mg Q6W in R/R cHL and R/R PMBCL. We present, for the first time, data from 66 patients (pts) with approximately 9 months (mo) of follow up. Methods: In this nonrandomized, open-label trial, pts aged ≥18 years with PD-1 inhibitor naïve R/R cHL or PMBCL received 400 mg pembro Q6W for ≤ 18 cycles, until progression, unacceptable toxicity, or withdrawal. Eligible pts with cHL must have relapsed or failed to respond after ≥1 prior lines of therapy (LOT) or relapsed or failed to respond after ≥1 prior multiagent LOT or autologous stem cell transplant (ASCT). Eligible pts with PMBCL must have relapsed or failed to respond after ≥2 prior LOT including rituximab and relapsed or failed to respond to or were ineligible for ASCT. The primary endpoint was ORR per Lugano criteria by investigator (Lugano, INV). Secondary endpoints were DOR (Lugano, INV) and safety. Exploratory endpoints were PFS (Lugano, INV) and OS. Data cut-off date was October 18, 2022. Results: At data cut-off, 66 pts (60 R/R cHL, 6 R/R PMBCL) were enrolled. Median follow-up (range) was 8.9 mo (1 – 15.9) for pts with R/R cHL and 10.6 mo (5.1 – 15.4) with R/R PMBCL. The ORR was 65% (95% CI, 51.6 – 76.9 [33.3% CR; 31.7% PR]) for pts with R/R cHL, and 50% (95% CI, 11.8 – 88.2 [33.3% CR; 16.7% PR]) for R/R PMBCL. Drug-related adverse events (AE) occurred in 24 pts (40%) with R/R cHL and 2 pts (33.3%) with R/R PMBCL. Grade ≥3 drug-related AEs occurred in 3 pts (5%) with R/R cHL and 1 pt (16.7%) with R/R PMBCL. Immune-mediated AEs occurred in 13 pts (21.7%) with R/R cHL and 1 pt (16.7%) with R/R PMBCL. Grade ≥3 immune-mediated AEs occurred in 2 pts (3.3%) with R/R cHL. Antitumor activity is summarized in the Table. Conclusions: With approximately 9 mo of follow up, pembro 400 mg Q6W demonstrates robust antitumor activity in pts with R/R cHL and R/R PMBCL. The ORR observed is similar to pembro 200 mg Q3W in R/R cHL and R/R PMBCL. Pembro 400 mg Q6W had no new safety concerns, confirming Q6W dosing in hematologic indications. Clinical trial information: NCT04875195 . [Table: see text]
Subgroup analysis of elderly patients (pts) with diffuse large B-cell lymphoma (DLBCL) in the phase 3 POLARIX study.
Authors: Hu Bei , Reagan Patrick Michael , Sehn Laurie Helen , Sharman Jeff Porter , Hertzberg Mark , Zhang Huilai , Kim Austin Injae , Herbaux Charles , Molina Lysiane , Maruyama Dai , Smolewski Piotr , Stenner Frank , Craine Veronica , Kothari Rucha , Hirata Jamie H. , Sahin Deniz , Sugidono Matthew Dean Sei , Lee Calvin , Tilly Herve
Published: June 2023

7518

Background: In the Phase 3 POLARIX study (NCT03274492), polatuzumab vedotin with rituximab, cyclophosphamide, doxorubicin, and prednisone (Pola-R-CHP) significantly improved progression-free survival (PFS) compared with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP), with a similar safety profile in pts aged 18–80 years with previously untreated DLBCL (Tilly et al. 2022). Combination regimens may be associated with higher rates of toxicity in elderly pts. We report the efficacy and safety of Pola-R-CHP vs R-CHOP in pts aged ≥70 years enrolled in POLARIX. Methods: POLARIX methods were described by Tilly et al. (2022). Pts with previously untreated DLBCL were randomized 1:1 to receive 6 cycles of Pola-R-CHP or R-CHOP, plus 2 cycles of rituximab. This analysis focused on pts aged ≥70 years at enrollment. Results: Overall, 284 pts were analyzed for efficacy (Pola-R-CHP, n=141; R-CHOP, n=143) and 280 pts were analyzed for safety (Pola-R-CHP, n=137; R-CHOP, n=143). Median age was 74 years (range 70–80), and 69.7% had an International Prognostic Index score of 3–5. Most pts in either arm received all 6 doses of polatuzumab vedotin or vincristine (88.3% and 91.6% in the Pola-R-CHP and R-CHOP arms, respectively). At data cutoff (June 28, 2021; median follow-up: 24.2 months), the risk of progression, relapse or death was lower with Pola-R-CHP vs R-CHOP (hazard ratio [HR] 0.64; 95% confidence interval [CI]: 0.41–0.99) (Table). Death by any cause occurred in 14.2% and 19.6% of pts treated with Pola-R-CHP and R-CHOP, respectively. Overall survival (OS) and disease-free survival (DFS) results are presented in the Table. Safety profiles were generally comparable for Pola-R-CHP vs R-CHOP, including rates of Grade 3–5 adverse events (AEs), Grade 5 AEs, serious AEs, peripheral neuropathy (any grade), neutropenia (Grade 3–4), and infection (Grade 3–4) (Table). Conclusions: Pola-R-CHP and R-CHOP demonstrated similar safety profiles in pts aged ≥70 years with previously untreated DLBCL. The risk-benefit profile favored Pola-R-CHP vs R-CHOP. Clinical trial information: NCT03274492 . [Table: see text]
Metabolic response rates of epcoritamab + R-CHOP in patients with previously untreated (1L) high-risk diffuse large B-cell lymphoma, including double-hit/triple-hit lymphoma: Updated EPCORE NHL-2 data.
Authors: Falchi Lorenzo , Clausen Michael , Offner Fritz , de Vos Sven , Brody Joshua , Linton Kim M. , Snauwaert Sylvia , Cordoba Raul , Wu Jun , Bykhovski Irina , Wang Liwei , Rana Ali , Belada David
Published: June 2023

7519

Background: Patients (pts) with 1L diffuse large B-cell lymphoma (DLBCL) typically receive rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP); however, around 40% relapse. Complete response rates and long-term outcomes are worse for high-risk pts with International Prognostic Index (IPI) 3–5 or double-hit/triple-hit lymphoma, representing an underserved pt population requiring better curative options. Data from the pivotal study of single-agent epcoritamab, a T-cell–engaging bispecific antibody, demonstrated impressive efficacy and a manageable safety profile (Thieblemont et al, JCO 2022). Preliminary data for epcoritamab + R-CHOP in 1L DLBCL (NCT04663347) showed encouraging efficacy. Here we present results for a larger cohort with longer follow-up. Methods: Pts with 1L CD20+ DLBCL and IPI ≥3 received subcutaneous epcoritamab (cycle [C] 1–4, QW; C5–6, Q3W) + R-CHOP for 6 Cs (21 d each) followed by epcoritamab monotherapy Q4W (28-d Cs) up to a total of 1 y. Results: As of Oct 31, 2022, 47 pts (median age, 64 y) had received epcoritamab 48 mg + R-CHOP with a median follow-up of 11.5 mo (range, 0.8–15.5). All pts had IPI 3–5, 37 (79%) had stage IV disease, and of 25 pts with FISH data available, 11 (44%) had double-hit/triple-hit DLBCL. Median time from diagnosis to first dose was 28 d (range, 3–423). Median dose intensity for R-CHOP was ≥95%. The most common treatment-emergent AEs (TEAEs) of any grade (G) were neutropenia (64%), anemia (62%), CRS (60%), fatigue (40%), pyrexia (40%), injection-site reactions (38%), and nausea (38%). TEAEs led to epcoritamab discontinuation in 3 pts; 1 pt had a G5 TEAE (COVID-19, unrelated to treatment). CRS was predominantly low grade (57% G1–2, 2% G3) and occurred mostly after the first full dose (C1D15); all cases resolved. One pt experienced G2 ICANS, which resolved. All response-evaluable pts (100%) had a response, and 76% had a complete metabolic response (CMR; Table). Notably, response rates were similar for double-hit/triple-hit pts (CMR rate, 82% [9/11]). The median durations of response, progression-free survival, and overall survival were not reached. Responses were durable; at 9 mo, an estimated 96% of pts with CMR remained in CMR. Updated data will be presented. Conclusions: Subcutaneous epcoritamab + R-CHOP induces high CMR rates with a manageable safety profile in pts with 1L high-risk DLBCL, including double-hit/triple-hit pts. These results support the ongoing phase 3 study of epcoritamab + R-CHOP in 1L pts (NCT05578976). Clinical trial information: NCT04663347 . [Table: see text]