Publications by authors named "Mark Litzow"

419 Publications

A novel Iowa-Mayo validated composite risk assessment tool for allogeneic stem cell transplantation survival outcome prediction.

Blood Cancer J 2021 Nov 20;11(11):183. Epub 2021 Nov 20.

Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA, 52242, USA.

Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative option for many hematologic conditions and is associated with considerable morbidity and mortality. Therefore, prognostic tools are essential to navigate the complex patient, disease, donor, and transplant characteristics that differentially influence outcomes. We developed a novel, comprehensive composite prognostic tool. Using a lasso-penalized Cox regression model (n = 273), performance status, HCT-CI, refined disease-risk index (rDRI), donor and recipient CMV status, and donor age were identified as predictors of disease-free survival (DFS). The results for overall survival (OS) were similar except for recipient CMV status not being included in the model. Models were validated in an external dataset (n = 378) and resulted in a c-statistic of 0.61 and 0.62 for DFS and OS, respectively. Importantly, this tool incorporates donor age as a variable, which has an important role in HSCT outcomes. This needs to be further studied in prospective models. An easy-to-use and a web-based nomogram can be accessed here: https://allohsctsurvivalcalc.iowa.uiowa.edu/ .
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http://dx.doi.org/10.1038/s41408-021-00573-6DOI Listing
November 2021

Tipifarnib as maintenance therapy did not improve disease-free survival in patients with acute myelogenous leukemia at high risk of relapse: Results of the phase III randomized E2902 trial.

Leuk Res 2021 Oct 28;111:106736. Epub 2021 Oct 28.

Northwestern University, Chicago, IL, United States(1); Memorial Sloan Kettering Cancer Center, NY, NY, United States(2).

Purpose: Despite the achievement of complete remission with chemotherapy in patients with acute myeloid leukemia (AML), relapse is common and the majority of patients will die of their disease. Patients who achieve a remission after refractory or relapsed disease as well as elderly patients have a very high rate of relapse even if they achieve a complete remission. A phase 3 randomized ECOG-ACRIN-led intergroup study was conducted to determine whether post-remission therapy with the farnesyl transferase inhibitor, tipifarnib (R115777), improved the disease-free survival (DFS) of adult patients with AML in complete remission (CR), at high risk for relapse.

Patients And Methods: Adult patients with AML in remission after salvage therapy and/or over age 60 in first remission were enrolled in this study. They were randomly assigned to treatment with tipifarnib or observation (control). The primary objective was to compare the disease-free survival (DFS) between the two arms based on intention to treat, which includes all randomized patients.

Results: One hundred and forty-four patients were enrolled on the study. Median DFS was 8.9 vs 5.3 months, for tipifarnib vs observation (one-sided p = 0.026) and did not cross the pre-specified boundary to call the study positive. For the 134 eligible patients, median DFS was 10.8 vs 5.3 months for those randomized to tipifarnib vs observation (one-sided p = 0.008). Moreover in an ad hoc evaluation of all women (n = 71) median DFS was 12.1 vs 3.9 months for tipifarnib vs observation (one-sided p = 0.0004) while median OS was 26.5 vs 8.4 months respectively (one-sided p = 0.001).

Conclusion: This study was not able to demonstrate a benefit to tipifarnib as maintenance therapy in patients with AML in remission. While subsets of patients may indeed benefit, additional studies would be needed to elucidate that benefit which is unlikely given that other seemingly better options have since become available.
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http://dx.doi.org/10.1016/j.leukres.2021.106736DOI Listing
October 2021

Intracellular cholesterol pools regulate oncogenic signaling and epigenetic circuitries in Early T-cell Precursor Acute Lymphoblastic Leukemia.

Cancer Discov 2021 Oct 28. Epub 2021 Oct 28.

Institute for Cancer Genetics, Columbia University Medical Center

Early T-cell acute lymphoblastic leukemia (ETP-ALL) is an aggressive hematologic malignancy associated with early relapse and poor prognosis that is genetically, immunophenotypically and transcriptionally distinct from more mature T-cell acute lymphoblastic (T-ALL) tumors. Here, we leveraged global metabolomic and transcriptomic profiling of primary ETP and T-ALL leukemia samples to identify specific metabolic circuitries differentially active in this high-risk leukemia group. ETP-ALLs showed increased biosynthesis of phospholipids and sphingolipids, and were specifically sensitive to inhibition of 3-hydroxy-3-methylglutaryl-CoA Reductase (HMGCR), the rate-limiting enzyme in the mevalonate pathway. Mechanistically, inhibition of cholesterol synthesis inhibited oncogenic AKT1 signaling and suppressed MYC expression via loss of chromatin accessibility at a leukemia stem cell-specific long range MYC enhancer. In all, these results identify the mevalonate pathway as a druggable novel vulnerability in high-risk ETP-ALL cells and uncover an unanticipated critical role for cholesterol biosynthesis in signal transduction and epigenetic circuitries driving leukemia cell growth and survival.
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http://dx.doi.org/10.1158/2159-8290.CD-21-0551DOI Listing
October 2021

Comparative study of therapy-related and de novo adult b-cell acute lymphoblastic leukaemia.

Br J Haematol 2021 Oct 25. Epub 2021 Oct 25.

Division of Hematology and Medical Oncology, Mayo Clinic, USA.

We report a comparative analysis of patients with therapy-related acute lymphoblastic leukaemia (tr-ALL) vs de novo ALL. We identified 331 patients with B-ALL; 69 (21%) were classified as tr-ALL. The most common prior malignancies were breast (23·2%) and plasma cell disorders (20·3%). Patients with tr-ALL were older (median 63·2 vs. 46·2 years, P < 0.001), more often female (66·7% vs. 43·5%, P < 0·001), and more likely to have hypodiploid cytogenetics (18·8% vs. 5·0%, P < 0·001). In multivariable analysis, patients with tr-ALL were less likely to achieve complete remission [odds ratio (OR) = 0·16, P < 0·001] and more likely to be minimal residual disease-positive (OR = 4·86, P = 0·01) but had similar OS after diagnosis and allo-haematopoietic cell transplantation.
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http://dx.doi.org/10.1111/bjh.17906DOI Listing
October 2021

Genetic features and clinical outcomes of patients with isolated and comutated DDX41-mutated myeloid neoplasms.

Blood Adv 2021 Oct 13. Epub 2021 Oct 13.

Mayo Clinic, Rochester, Minnesota, United States.

DDX41 mutations (germline and somatic) are associated with late onset myelodysplastic syndromes/acute myeloid leukemia (MDS/AML). Myeloid neoplasms (MN) with germline predisposition was identified as a distinct category in the 2016 WHO classification revision, including MN with germline DDX41 mutation. We retrospectively analyzed the molecular findings and clinical characteristics of thirty-three DDX41-mutated (mDDX41) patients at our institution. We identified 14 distinct pathogenic DDX41 variants in 32 patients and 8 DDX41 variants of unknown significance (VUS) in 9 patients. Five (16%) patients had a second DDX41 somatic mutation p.R525H and 13 (40%) had at least one additional oncogenic co-mutation in other genes. The median age at the time of diagnosis was 66 years, with male predominance (72%) and the majority of patients had normal cytogenetics (91%). Two-year overall survival (OS) was 86% and 6 (21%) MDS/AML patients with relatively preserved hematopoietic function were observed without further intervention. In comparison to AML patients with prognostically more favorable subtypes [t(8;21), n=27 and inv(16), n=40], mDDX41 patients in our cohort showed similarly favorable OS. Our study highlights that mDDX41-MN patients often have an indolent course and mDDX41-AML has comparable OS to favorable-risk AML.
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http://dx.doi.org/10.1182/bloodadvances.2021005738DOI Listing
October 2021

CNS involvement in AML at diagnosis is rare and does not affect response or survival: data from 11 ECOG-ACRIN trials.

Blood Adv 2021 11;5(22):4560-4568

Mayo Clinic, Rochester, MN.

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.
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http://dx.doi.org/10.1182/bloodadvances.2021004999DOI Listing
November 2021

An adapted European LeukemiaNet genetic risk stratification for acute myeloid leukemia patients undergoing allogeneic hematopoietic cell transplant. A CIBMTR analysis.

Bone Marrow Transplant 2021 Sep 28. Epub 2021 Sep 28.

Division of Hematology/BMT, Mayo Clinic, Rochester, MN, USA.

Cytogenetic and molecular abnormalities are known to influence post-transplant outcomes in acute myeloid leukemia (AML) but data assessing the prognostic value of combined genetic models in the HCT setting are limited. We developed an adapted European LeukemiaNet (aELN) risk classification based on available genetic data reported to the Center for International Blood and Marrow Transplant Research, to predict post-transplant outcomes in 2289 adult AML patients transplanted in first remission, between 2013 and 2017. Patients were stratified according to aELN into three groups: favorable (Fav, N = 181), intermediate (IM, N = 1185), and adverse (Adv, N = 923). Univariate analysis demonstrated significant differences in 2-year overall survival (OS) (Fav: 67.7%, IM: 64.9% and Adv: 53.9%; p < 0.001); disease-free survival (DFS) (Fav: 57.8%, IM: 55.5% and Adv: 45.3; p < 0.001) and relapse (Fav: 28%, IM: 27.5% and Adv: 37.5%; p < 0.001). Multivariate analysis (MVA) revealed no differences in outcomes between the Fav and IM groups, thus they were combined. On MVA, patients in the Adv risk group had the highest risk of relapse (HR 1.47 p ≤ 0.001) and inferior DFS (HR 1.35 p < 0.001) and OS (HR 1.39 p < 0.001), even using myeloablative conditioning or in those without the pre-HCT measurable-residual disease. Novel approaches to mitigate relapse in this high-risk group are urgently needed.
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http://dx.doi.org/10.1038/s41409-021-01450-3DOI Listing
September 2021

Acute Lymphoblastic Leukemia, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology.

J Natl Compr Canc Netw 2021 09 20;19(9):1079-1109. Epub 2021 Sep 20.

National Comprehensive Cancer Network.

The NCCN Guidelines for Acute Lymphoblastic Leukemia (ALL) focus on the classification of ALL subtypes based on immunophenotype and cytogenetic/molecular markers; risk assessment and stratification for risk-adapted therapy; treatment strategies for Philadelphia chromosome (Ph)-positive and Ph-negative ALL for both adolescent and young adult and adult patients; and supportive care considerations. Given the complexity of ALL treatment regimens and the required supportive care measures, the NCCN ALL Panel recommends that patients be treated at a specialized cancer center with expertise in the management of ALL This portion of the Guidelines focuses on the management of Ph-positive and Ph-negative ALL in adolescents and young adults, and management in relapsed settings.
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http://dx.doi.org/10.6004/jnccn.2021.0042DOI Listing
September 2021

Risk classification at diagnosis predicts post-HCT outcomes in intermediate-, adverse-risk, and KMT2A-rearranged AML.

Blood Adv 2021 Sep 22. Epub 2021 Sep 22.

University of Texas Southwestern Medical Center, Dallas, Texas, United States.

Little is known about whether risk classification at diagnosis predicts post-hematopoietic cell transplantation (HCT) outcomes for acute myeloid leukemia (AML) patients. We evaluated 8709 AML patients from the CIBMTR database and, after selection and manual curation of cytogenetics data, 3779 patients in CR1 were included in the final analysis: 2384 with intermediate-risk, 969 with adverse-risk, and 426 with KMT2A-rearranged disease. An adjusted multivariable analysis compared to intermediate-risk patients detected an increased risk of relapse for KMT2A-rearranged and adverse-risk patients (HR 1.27, p = 0.01 and HR 1.71, p < 0.001, respectively). Leukemia-free survival (LFS) was similar for KMT2A and adverse-risk patients (HR 1.26, p = 0.002 and HR 1.47, p < 0.001), as was overall survival (OS) (HR 1.32, p < 0.001 and HR 1.45, p < 0.001). No differences in outcome could be detected when patients were stratified by KMT2A fusion partner. This is the largest study conducted to date on post-HCT outcomes in AML using manually curated cytogenetics for risk stratification. Our work demonstrates that risk classification at diagnosis remains predictive of post-HCT outcomes in AML. It also highlights the critical need to develop novel treatment strategies for patients with KMT2A rearrangements and adverse-risk disease.
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http://dx.doi.org/10.1182/bloodadvances.2021004881DOI Listing
September 2021

Haploidentical vs. sibling, unrelated, or cord blood hematopoietic cell transplantation for acute lymphoblastic leukemia.

Blood Adv 2021 Sep 21. Epub 2021 Sep 21.

University of Virginia, Charlottesville, Virginia, United States.

The role of haploidentical hematopoietic cell transplantation (HCT) using post-transplant cyclophosphamide (PTCy) for acute lymphoblastic leukemia (ALL) is being defined. We performed a retrospective, multivariate analysis comparing outcomes of HCT approaches by donor for adults with ALL in remission. The primary objective was to compare overall survival (OS) between haploidentical HCT using PTCy and HLA-matched sibling donor (MSD), 8/8 HLA-matched unrelated donor (MUD) , 7/8 HLA-matched UD, or umbilical cord blood (UCB) HCT. Comparing haploidentical to MSD HCT, OS, leukemia-free survival (LFS), non-relapse mortality (NRM), relapse, and acute graft-versus-host disease (aGVHD) were not different but chronic GVHD (cGVHD) was higher with MSD HCT. Compared to MUD HCT, OS, LFS, and relapse were not different but MUD HCT had increased NRM (HR 1.42, P=0.02), grade 3-4 aGVHD (HR 1.59, P=0.005), and cGVHD. Compared to 7/8 UD HCT, LFS and relapse were not different, but 7/8 UD HCT had worse OS (HR 1.38, P=0.01) and increased NRM (HR 2.13, P=<0.001), grade 3-4 aGVHD (HR 1.86, P=0.003), and cGVHD (HR 1.72, P=<0.001). Compared to UCB HCT, late OS , late LFS, relapse, and cGVHD were not different but UCB HCT had worse early OS (≤18 months, HR 1.93, P<0.001), worse early LFS (HR 1.40, P=0.007) and increased incidences of NRM (HR 2.08, P<0.001) and grade 3-4 aGVHD (HR 1.97, P<0.001). Haploidentical HCT using PTCy showed no difference in survival but less GVHD compared to traditional MSD and MUD HCT and is the preferred alternative donor HCT option for adults with ALL in CR.
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http://dx.doi.org/10.1182/bloodadvances.2021004916DOI Listing
September 2021

Allogeneic Transplantation to Treat Therapy-Related Myelodysplastic Syndrome and Acute Myelogenous Leukemia in Adults.

Transplant Cell Ther 2021 Nov 21;27(11):923.e1-923.e12. Epub 2021 Aug 21.

Section of Bone Marrow Transplant and Cell Therapy, Rush University Medical Center, Chicago, Illinois.

Patients who develop therapy-related myeloid neoplasm, either myelodysplastic syndrome (t-MDS) or acute myelogenous leukemia (t-AML), have a poor prognosis. An earlier Center for International Blood and Marrow Transplant Research (CIBMTR) analysis of 868 allogeneic hematopoietic cell transplantations (allo-HCTs) performed between 1990 and 2004 showed a 5-year overall survival (OS) and disease-free survival (DFS) of 22% and 21%, respectively. Modern supportive care, graft-versus-host disease prophylaxis, and reduced-intensity conditioning (RIC) regimens have led to improved outcomes. Therefore, the CIBMTR analyzed 1531 allo-HCTs performed in adults with t-MDS (n = 759) or t-AML (n = 772) between and 2000 and 2014. The median age was 59 years (range, 18 to 74 years) for the patients with t-MDS and 52 years (range, 18 to 77 years) for those with t-AML. Twenty-four percent of patients with t-MDS and 11% of those with t-AML had undergone a previous autologous (auto-) HCT. A myeloablative conditioning (MAC) regimen was used in 49% of patients with t-MDS and 61% of patients with t-AML. Nonrelapse mortality at 5 years was 34% (95% confidence interval [CI], 30% to 37%) for patients with t-MDS and 34% (95% CI, 30% to 37%) for those with t-AML. Relapse rates at 5 years in the 2 groups were 46% (95% CI, 43% to 50%) and 43% (95% CI, 40% to 47%). Five-year OS and DFS were 27% (95% CI, 23% to 31%) and 19% (95% CI, 16% to 23%), respectively, for patients with t-MDS and 25% (95% CI, 22% to 28%) and 23% (95% CI, 20% to 26%), respectively, for those with t-AML. In multivariate analysis, OS and DFS were significantly better in young patients with low-risk t-MDS and those with t-AML undergoing HCT with MAC while in first complete remission, but worse for those with previous auto-HCT, higher-risk cytogenetics or Revised International Prognostic Scoring System score, and a partially matched unrelated donor. Relapse remains the major cause of treatment failure, with little improvement seen over the past 2 decades. These data mandate caution when recommending allo-HCT in these conditions and indicate the need for more effective antineoplastic approaches before and after allo-HCT.
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http://dx.doi.org/10.1016/j.jtct.2021.08.010DOI Listing
November 2021

Measurable Residual Disease Does Not Preclude Prolonged Progression-free Survival in CLL Treated with Ibrutinib.

Blood 2021 Aug 18. Epub 2021 Aug 18.

Mayo Clinic, Rochester, Minnesota, United States.

E1912 was a randomized phase 3 trial comparing indefinite ibrutinib plus six cycles of rituximab (IR) to six cycles of fludarabine, cyclophosphamide and rituximab (FCR) in untreated younger patients with CLL. We describe measurable residual disease (MRD) levels in E1912 over time and correlate them with clinical outcome. Undetectable MRD rates (< 1 CLL cell per 104 leukocytes) were 29.1%, 30.3%, 23.4% and 8.6% at 3, 12, 24 and 36 months for FCR, and significantly lower at 7.9%, 4.2% and 3.7% at 12, 24 and 36 months for IR, respectively. Undetectable MRD at 3, 12, 24 and 36 months was associated with longer progression-free survival (PFS) for the FCR arm with hazard ratios (MRD detectable / MRD undetectable) of 4.29 (95% CI 1.89 - 9.71), 3.91 (95% CI 1.39 - 11.03), 14.12 (95% CI 1.78 - 111.73), and not estimable (no events among those with undetectable MRD), respectively. For the IR arm, patients with detectable MRD did not have significantly worse PFS compared to those in whom MRD was undetectable; however, PFS was longer for those with MRD levels of less than 10-1 compared to those with MRD levels above this threshold. Our observations provide additional support for the use of MRD as a surrogate endpoint for PFS in patients receiving FCR. For patients on indefinite ibrutinib-based therapy, PFS did not differ significantly by undetectable MRD status, while those with MRD less than 10-1 tend to have longer PFS, although continuation of ibrutinib is very likely required to maintain treatment efficacy.
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http://dx.doi.org/10.1182/blood.2020010146DOI Listing
August 2021

Fludarabine and Melphalan Compared with Reduced Doses of Busulfan and Fludarabine Improve Transplantation Outcomes in Older Patients with Myelodysplastic Syndromes.

Transplant Cell Ther 2021 Nov 14;27(11):921.e1-921.e10. Epub 2021 Aug 14.

Department of Hematology/Oncology, Hospital Infantil Universitario Nino Jesus, Madrid, Spain.

Reduced-intensity conditioning (RIC) regimens developed to extend the use of allogeneic hematopoietic stem cell transplantation (HSCT) to older patients have resulted in encouraging outcomes. We aimed to compare the 2 most commonly used RIC regimens, i.v. fludarabine with busulfan (FluBu) and fludarabine with melphalan (FluMel), in patients with myelodysplastic syndrome (MDS). Through the Center for International Blood and Marrow Transplant Research (CIBMTR), we identified 1045 MDS patients age ≥60 years who underwent first HSCT with a matched related or matched (8/8) unrelated donor using an RIC regimen. The CIBMTR's definition of RIC was used: a regimen that incorporated an i.v. busulfan total dose ≤7.2 mg/kg or a low-dose melphalan total dose ≤150 mg/m. The 2 groups, recipients of FluBu (n = 697) and recipients of FluMel (n = 448), were comparable in terms of disease- and transplantation-related characteristics except for the more frequent use of antithymocyte globulin or alemtuzumab in the FluBu group (39% versus 31%). The median age was 67 years in both groups. FluMel was associated with a reduced relapse incidence (RI) compared with FluBu, with a 1-year adjusted incidence of 26% versus 44% (P ≤ .0001). Transplantation-related mortality (TRM) was higher in the FluMel group (26% versus 16%; P ≤ .0001). Because the magnitude of improvement with FluMel in RI was greater than the improvement in TRM with FluBu, disease-free survival (DFS) was better at 1 year and beyond with FluMel compared with FluBu (48% versus 40% at 1 year [P = .02] and 35% versus 27% at 3 years [P = .01]). Overall survival was comparable in the 2 groups at 1 year (63% versus 61%; P = .4) but was significantly improved with FluMel compared with FluBu at 3 years (46% versus 39%; P = .03). Our results suggest that FluMel is associated with superior DFS compared with FluBu owing to reduced RI in older patients with MDS patients. © 2021 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.
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http://dx.doi.org/10.1016/j.jtct.2021.08.007DOI Listing
November 2021

De novo isolated myeloid sarcoma: comparative analysis of survival in 19 consecutive cases.

Br J Haematol 2021 Nov 3;195(3):413-416. Epub 2021 Aug 3.

Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA.

Institutional database search (1999-2020) for acute myeloid leukaemia (AML) identified 109 cases of myeloid sarcoma (MS), of which 19 were isolated and presented de novo. The latter displayed longer survival (median 78 months), compared to MS with synchronous intramedullary AML (n = 32; median 16 months) and de novo AML without MS (n = 729; median 22 months; P = 0·13). However, the difference in survival was no longer apparent after accounting for bone marrow cytogenetic risk status (P = 0·67). Treatment-induced MS tumour resolution was not affected by the presence of intramedullary disease (P = 0·61). The current study clarifies the prognosis of de novo isolated MS, in the context of AML.
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http://dx.doi.org/10.1111/bjh.17742DOI Listing
November 2021

Adverse event burden in older patients with CLL receiving bendamustine plus rituximab or ibrutinib regimens: Alliance A041202.

Leukemia 2021 Oct 17;35(10):2854-2861. Epub 2021 Jul 17.

Division of Hematology, The Ohio State University, Columbus, OH, USA.

Ibrutinib has superior progression-free survival compared with bendamustine plus rituximab (BR) in older CLL patients, however, differences in treatment duration, six monthly BR cycles versus continuous ibrutinib, complicate adverse event (AE) comparisons. We introduce the AE burden score (AE) to compare AEs, calculated for each patient by summing over products of reporting period length and grade for each all-cause grade 1-4 AE and dividing by the length of time over which AEs are assessed. A total of 176 patients received BR and 361 ibrutinib alone or with six cycles of rituximab. At 38 months median follow-up, 64% remained on ibrutinib. Median AE was higher with BR versus ibrutinib in the first six cycles (7.2 versus 4.9, p < 0.0001). Within ibrutinib arms, median AE decreased significantly to 3.7 after six cycles (p < 0.0001). 10% and 14% of BR and ibrutinib patients discontinued treatment for AEs. In ibrutinib arms, cumulative incidence of grade 3 or higher atrial fibrillation, hypertension, and infection (AEs of clinical interest) at 12 months was 4.5%, 17.5%, and 12.8%, respectively, and increased more slowly thereafter to 7.7%, 25.4%, and 20.5% at 36 months. Analytical tools including the AE and cumulative incidence of AEs can help to better characterize AE burden over time. ClinicalTrials.gov identifier: NCT01886872.
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http://dx.doi.org/10.1038/s41375-021-01342-xDOI Listing
October 2021

and Mutations Exert Divergent Effects on DNA Repair and Sensitivity of Leukemia Cells to PARP Inhibitors.

Cancer Res 2021 Oct 2;81(19):5089-5101. Epub 2021 Jul 2.

Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, United Kingdom.

Somatic variants in and are founding mutations in hematological malignancies that affect the epigenetic regulation of DNA methylation. Mutations in both genes often co-occur with activating mutations in genes encoding oncogenic tyrosine kinases such as , and , or with mutations affecting related signaling pathways such as and . Here, we show that and mutations exert divergent roles in regulating DNA repair activities in leukemia cells expressing these oncogenes. Malignant TET2-deficient cells displayed downregulation of BRCA1 and LIG4, resulting in reduced activity of BRCA1/2-mediated homologous recombination (HR) and DNA-PK-mediated non-homologous end-joining (D-NHEJ), respectively. TET2-deficient cells relied on PARP1-mediated alternative NHEJ (Alt-NHEJ) for protection from the toxic effects of spontaneous and drug-induced DNA double-strand breaks. Conversely, DNMT3A-deficient cells favored HR/D-NHEJ owing to downregulation of PARP1 and reduction of Alt-NHEJ. Consequently, malignant TET2-deficient cells were sensitive to PARP inhibitor (PARPi) treatment and , whereas DNMT3A-deficient cells were resistant. Disruption of TET2 dioxygenase activity or TET2-Wilms' tumor 1 (WT1)-binding ability was responsible for DNA repair defects and sensitivity to PARPi associated with TET2 deficiency. Moreover, mutation or deletion of mimicked the effect of mutation on DSB repair activity and sensitivity to PARPi. Collectively, these findings reveal that and mutations may serve as biomarkers of synthetic lethality triggered by PARPi, which should be explored therapeutically. SIGNIFICANCE: and mutations affect distinct DNA repair mechanisms and govern the differential sensitivities of oncogenic tyrosine kinase-positive malignant hematopoietic cells to PARP inhibitors.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-3761DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8487956PMC
October 2021

Targeted and cytotoxic therapies as maintenance treatment for non-transplant eligible patients with acute myeloid leukemia.

Blood Rev 2021 Nov 21;50:100863. Epub 2021 Jun 21.

Deparment of Medicine, Division of Hematology/Oncology, UMass Memorial Medical Center, University of Massachusetts Medical School, Worcester, MA, USA. Electronic address:

In the recent years, there have been multiple approvals by the Food and Drug Administration (FDA) for therapeutics for acute myeloid leukemia (AML). The role of maintenance therapy in AML has been rather unrealized mostly due to lack of efficacy and increased toxicity of classical chemotherapy agents. Many clinical trials have demonstrated a disease-free survival benefit for various therapeutics in the maintenance setting for patients with AML who are ineligible for stem cell transplant. Notably, oral hypomethylating agent therapy has recently shown an overall survival and disease-free survival benefit in the maintenance setting for AML. In this review, we summarize the relevant data on maintenance therapy with a specific focus on cytotoxic antimetabolite chemotherapeutics, hypomethylating agents, targeted agents, and immunotherapeutics. We discuss our approach to maintenance therapy in AML in 2021 and propose a measurable residual disease (MRD)-adapted, personalized approach based on the best available evidence.
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http://dx.doi.org/10.1016/j.blre.2021.100863DOI Listing
November 2021

Network-based systems pharmacology reveals heterogeneity in LCK and BCL2 signaling and therapeutic sensitivity of T-cell acute lymphoblastic leukemia.

Nat Cancer 2021 Mar 21;2(3):284-299. Epub 2021 Jan 21.

Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, USA.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy, and novel therapeutics are much needed. Profiling patient leukemia' drug sensitivities , we discovered that 44.4% of childhood and 16.7% of adult T-ALL cases exquisitely respond to dasatinib. Applying network-based systems pharmacology analyses to examine signal circuitry, we identified preTCR-LCK activation as the driver of dasatinib sensitivity, and T-ALL-specific LCK dependency was confirmed in genome-wide CRISPR-Cas9 screens. Dasatinib-sensitive T-ALLs exhibited high BCL-XL and low BCL2 activity and venetoclax resistance. Discordant sensitivity of T-ALL to dasatinib and venetoclax is strongly correlated with T-cell differentiation, particularly with the dynamic shift in LCK vs. BCL2 activation. Finally, single-cell analysis identified leukemia heterogeneity in LCK and BCL2 signaling and T-cell maturation stage, consistent with dasatinib response. In conclusion, our results indicate that developmental arrest in T-ALL drives differential activation of preTCR-LCK and BCL2 signaling in this leukemia, providing unique opportunities for targeted therapy.
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http://dx.doi.org/10.1038/s43018-020-00167-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8208590PMC
March 2021

Prognostic effect of gender on outcome of treatment for adults with acute myeloid leukaemia.

Br J Haematol 2021 Jul 17;194(2):309-318. Epub 2021 Jun 17.

Mayo Clinic, Rochester, MN, USA.

There 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.
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http://dx.doi.org/10.1111/bjh.17523DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8532194PMC
July 2021

Degradation of Janus kinases in CRLF2-rearranged acute lymphoblastic leukemia.

Blood 2021 Jun 10. Epub 2021 Jun 10.

St Jude Children's Research Hospital, Memphis, Tennessee, United States.

CRLF2-rearranged (CRLF2r) acute lymphoblastic leukemia (ALL) comprises over half of Philadelphia chromosome-like (Ph-like) ALL, is associated with poor outcome in children and adults. Overexpression of CRLF2 results in activation of JAK-STAT and parallel signaling pathways in experimental models, but existing small molecule inhibitors of Janus kinases show variable and limited efficacy. Here we evaluated the efficacy of proteolysis-targeting chimeras (PROTACs) directed against Janus kinases. Solving the structure of type I JAK inhibitors ruxolitinib and baricitinib bound to the JAK2 tyrosine kinase domain enabled the rational design and optimization of multiple series of cereblon (CRBN)-directed JAK PROTACs utilizing derivatives of JAK inhibitors, linkers and CRBN-specific molecular glues. The resulting JAK PROTACs were evaluated for target degradation, and activity tested in a panel of leukemia/lymphoma cell lines and xenograft models of kinase-driven ALL. Multiple PROTACs were developed that degraded Janus kinases and potently killed CRLF2--rearranged cell lines, the most active of which also degraded the known CRBN neosubstrate GSPT1, and suppressed proliferation of CRLF2-rearranged ALL in vivo. While dual JAK/GSPT1-degrading PROTACs were most potent, development and evaluation of multiple PROTACs in an extended panel of xenografts identified a potent JAK2-degrading GSPT1-sparing PROTAC that demonstrated efficacy in the majority of the kinase-driven xenografts which were otherwise unresponsive to type I JAK inhibitors. Together, these data show the potential of JAK-directed protein degradation as a therapeutic approach in JAK-STAT-driven ALL, and highlight the interplay of Janus kinase and GSPT1 degradation activity in this context.
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http://dx.doi.org/10.1182/blood.2020006846DOI Listing
June 2021

Enhancer Hijacking Drives Oncogenic Expression in Lineage-Ambiguous Stem Cell Leukemia.

Cancer Discov 2021 Nov 8;11(11):2846-2867. Epub 2021 Jun 8.

Department of Data Science, Dana-Farber Cancer Institute, Boston, Massachusetts.

Lineage-ambiguous leukemias are high-risk malignancies of poorly understood genetic basis. Here, we describe a distinct subgroup of acute leukemia with expression of myeloid, T lymphoid, and stem cell markers driven by aberrant allele-specific deregulation of , a master transcription factor responsible for thymic T-lineage commitment and specification. Mechanistically, this deregulation was driven by chromosomal rearrangements that juxtapose to superenhancers active in hematopoietic progenitors, or focal amplifications that generate a superenhancer from a noncoding element distal to . Chromatin conformation analyses demonstrated long-range interactions of rearranged enhancers with the expressed allele and association of with activated hematopoietic progenitor cell -regulatory elements, suggesting BCL11B is aberrantly co-opted into a gene regulatory network that drives transformation by maintaining a progenitor state. These data support a role for ectopic expression in primitive hematopoietic cells mediated by enhancer hijacking as an oncogenic driver of human lineage-ambiguous leukemia. SIGNIFICANCE: Lineage-ambiguous leukemias pose significant diagnostic and therapeutic challenges due to a poorly understood molecular and cellular basis. We identify oncogenic deregulation of driven by diverse structural alterations, including superenhancer generation, as the driving feature of a subset of lineage-ambiguous leukemias that transcend current diagnostic boundaries..
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http://dx.doi.org/10.1158/2159-8290.CD-21-0145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8563395PMC
November 2021
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