Showing papers by "Vinod Pullarkat published in 2019"
University of Texas MD Anderson Cancer Center1, Johns Hopkins University2, City of Hope National Medical Center3, University of California, Davis4, Emory University5, University of Washington6, Fred Hutchinson Cancer Research Center7, Northwestern University8, Monash University9, AbbVie10, Genentech11, University of Colorado Denver12, Harvard University13
TL;DR: The novel combination of venetoclax with decitabine or azacitidine was effective and well tolerated in elderly patients with AML and achieved complete remission (CR) + CR with incomplete count recovery (CRi).
1,153 citations
TL;DR: This work has shown that TTP disease course is independent of myeloma treatment and response, and the evaluation of monoclonal gammopathy of renal significance: a consensus report of the International Kidney and Monoclonals Gammopathy Research Group.
Abstract: REFERENCES 1. George JN. Systemic malignancies as a cause of unexpected microangiopathic hemolytic anemia and thrombocytopenia. Oncology (Williston Park). 2011;25:908-914. 2. Ravindran A, Go RS, Fervenza FC, Sethi S. Thrombotic microangiopathy associated with monoclonal gammopathy. Kidney Int. 2017;91:691-698. 3. Chang JC, Naqvi T. Thrombotic thrombocytopenic purpura associated with bone marrow metastasis and secondary myelofibrosis in cancer. Oncologist. 2003;8:375-380. 4. Hofmeister CC, Jin M, Catalano SR, et al. TTP disease course is independent of myeloma treatment and response. Am J Hematol. 2010;85: 304-306. 5. Schurder J, Rafat C, Vigneron C. Complement-dependent, monoclonal gammapathy-associated thrombotic microangiopathy. Kidney Int. 2017; 92:516-516. 6. Leung N, Bridoux F, Batuman V, et al. The evaluation of monoclonal gammopathy of renal significance: a consensus report of the International Kidney and Monoclonal Gammopathy Research Group. Nat Rev Nephrol. 2019;15:45-59.
50 citations
TL;DR: Several promising studies tailored specifically toward older adults with ALL are ongoing, with the majority of them incorporating novel immunotherapies, targeted therapies, or third-generation tyrosine kinase inhibitors into the front-line treatment regimen.
Abstract: Acute lymphoblastic leukemia (ALL) in older adults presents a real challenge as a result of adverse disease biology and comorbidities that preclude delivering curative regimens. Conventional chemotherapy approaches have generally yielded unsatisfactory results in older patients with ALL as a result of excessive induction mortality, chemotherapy resistance of the leukemia, and the need to omit or dose reduce key drugs during the course of therapy because of adverse effects. Philadelphia chromosome-positive ALL represents about a quarter of newly diagnosed older adults, and the striking single-agent activity and excellent safety profile of tyrosine kinase inhibitors has allowed incorporation of these agents into therapy, significantly improving the outcome of older adults with Philadelphia chromosome-positive ALL. Allogeneic hematopoietic cell transplantation using reduced-intensity conditioning is a potentially curative approach in the older adult with ALL, and ironically, it may be better tolerated than intensive combination chemotherapy in a subset of older patients with ALL. Immunotherapies such as chimeric antigen receptor-modified T-cells, the bispecific T-cell-engaging antibody targeting CD19 (blinatumomab), and the antibody-drug conjugate targeting CD22 (inotuzumab) have shown safety and exceptional activity even in advanced ALL, and the efficacy of these agents has been observed irrespective of patient age. Several promising studies tailored specifically toward older adults with ALL are ongoing, with the majority of them incorporating novel immunotherapies, targeted therapies, or third-generation tyrosine kinase inhibitors into the front-line treatment regimen.
45 citations
TL;DR: A retrospective analysis of AML patients treated with the combination of VEN/HMA using an in-house next generation sequencing panel found the combination is welltolerated even in frail patients and is associated with low treatment-related mortality (TRM) (DiNardo et al, 2019).
Abstract: TP53 mutations occur in nearly 10% of adults with de novo acute myeloid leukaemia (AML); however, these mutations are encountered at higher frequency in therapy-related AML (t-AML) (~35%) and AML with complex cytogenetics (50– 60%) (Rucker et al, 2012; Ok et al, 2015). The presence of the TP53 mutation (TP53m) conveys an extremely poor prognosis (Grossmann et al, 2012; Rucker et al, 2012). Patients with TP53m AML are generally older in age (Rucker et al, 2012), and their physical fitness, especially in those with t-AML, is poor (Granfeldt Ostgard et al, 2015). The clinical response of TP53m AML to standard induction regimens has been disappointing, and if achieved, is usually short-lived (Grossmann et al, 2012; Rucker et al, 2012). Venetoclax (VEN) has shown encouraging activity when combined with hypomethylating agents (HMAs) in both newly diagnosed and relapsed/refractory (r/r) AML (Aldoss et al, 2018; DiNardo et al, 2019). The combination is welltolerated even in frail patients and is associated with low treatment-related mortality (TRM) (DiNardo et al, 2019). Apoptosis mediated by venetoclax appears to be TP53-independent (Anderson et al, 2016), and VEN/HMA activity was observed across various high-risk leukaemia genetics (Aldoss et al, 2018; DiNardo et al, 2019). We conducted a retrospective analysis of AML patients treated with the combination of VEN/HMA at our institution between June 2016 and April 2019. We identified TP53m utilizing an in-house next generation sequencing panel. The study was approved by the City of Hope Institutional Review Board. Response was defined as either complete remission (CR) or CR with incomplete count recovery (CRi). In univariate analysis, descriptive statistics were used to summarize the covariates for both response and non-response groups. The correlations between response to VEN/ HMA and these covariates were assessed by the Pearson Chisquare test for categorical variables. A logistic multivariable regression model was applied to the three covariates with P values not exceeding 0 1; odds ratios and 95% confidence intervals (CI) are listed in Table S1. The median leukaemiafree survival (LFS) and overall survival (OS) were summarized for the response group only. All analyses were performed with R 3.5.1 (http://www.R-project.org) or SAS 9.4 (SAS Institute Inc, Cary, NC). We identified 32 adults with TP53m AML who were treated with VEN/HMA. One patient with r/r AML was unevaluable for response because of death from sepsis 10 days after initiating therapy. The median age was 68 years (22–85). Sixteen (52%) patients had r/r AML while 15 (48%) patients were newly diagnosed. The majority of patients had complex cytogenetics (n = 24, 77%). The median variant allele frequency (VAF) for TP53m was 56% (range, 3–95%), and 9 (29%) patients had more than one TP53 mutation. Nineteen (61%) patients had additional somatic mutations. Decitabine was the HMA used in the majority of cases (90%) and was more frequently given as a 5-day schedule rather than a 10day schedule (52% vs. 39%). Among the 31 evaluable patients, 16 (52%) experienced a response, including 7 CR and 9 CRi. Response was achieved after a median of 2 (range, 1–3) cycles. Minimal residual disease (MRD), defined as >0 01% by multiparameter flow cytometry in a reference laboratory, was evaluated in 10 of the responders, and 7 (70%) achieved MRD negativity. Prior HMA monotherapy was the only factor observed to be associated with a lower response compared to that in patients who were HMA-naive (14% vs. 63%, P = 0 025). There was a trend toward a higher CR/CRi rate in patients with more than one TP53 mutation (78% vs. 41%, P = 0 062) and in those who were treated with VEN/HMA in the frontline setting (67% vs. 38%, P = 0 1). Response was comparable across patient age, sex, AML type, receipt of prior allogeneic haematopoietic cell transplantation (alloHCT), cytogenetics, presence of additional mutations and type and duration of HMA therapy. Table I depicts patient characteristics and response rates. In multivariate analysis of response, prior exposure to HMA was associated with a non-significant trend toward lower response (odds ratio = 0 12; 95%CI: 1 69 to 1 27; P = 0 092) (Table S2). Response to VEN/HMA in TP53m AML according to associated additional mutations is shown in Table S1. The location and pattern of TP53 mutations for responders and non-responders is depicted in Fig 1. The median TP53 VAF was comparable for responders and non-responders (56% vs. 52%). The median LFS and OS for responders was 234 days (95% CI: 101–329) and 329 days (95% CI: 284–not reached), respectively. Five responders (31%) underwent alloHCT in CR. Consistent with previous reports (DiNardo et al, 2019), we illustrate that the response to this regimen in the frontline setting is encouraging for this high-risk group, especially considering the fact that the majority of patients with TP53m AML carried complex cytogenetics. Furthermore, we Correspondence
44 citations
TL;DR: The overall risk of IFIs during VEN-HMA therapy is low, but the risk is higher in nonresponders and in those who were treated in the r/r setting; these patients need reevaluation of their antifungal prophylaxis to minimize the risk ofIFIs during therapy.
41 citations
TL;DR: An undiscovered mechanism underlying synergistic effect of decitabine and venetoclax in AML cells is demonstrated, elucidating for impressive results in antileukemic activity against AML in preclinical and early clinical studies by combined treatment of these drugs.
Abstract: Induction of reactive oxygen species (ROS), an important process for the cytotoxicity of various acute myeloid leukemia (AML) therapies including hypomethylating agents (HMAs), concurrently activates the NF-E2-related factor 2 (Nrf2) antioxidant response pathway which in turn results in induction of antioxidant enzymes that neutralize ROS. In this study, we demonstrated that Nrf2 inhibition is an additional mechanism responsible for the marked antileukemic activity in AML seen with the combination of HMAs and venetoclax (ABT-199). HMA and venetoclax combined treatment augmented mitochondrial ROS induction and apoptosis compared with treatment HMA alone. Treatment of AML cell lines as well as primary AML cells with venetoclax disrupted HMA decitabine-increased nuclear translocation of Nrf2 and induction of downstream antioxidant enzymes including heme oxygenase-1 and NADP-quinone oxidoreductase-1. Venetoclax treatment also leads to dissociation of B-cell lymphoma 2 from the Nrf2/Keap-1 complex and targets Nrf2 to ubiquitination and proteasomal degradation. Thus, our results here demonstrated an undiscovered mechanism underlying synergistic effect of decitabine and venetoclax in AML cells, elucidating for impressive results in antileukemic activity against AML in preclinical and early clinical studies by combined treatment of these drugs.
38 citations
TL;DR: One of the largest single-center experiences of Flu/Mel-based allo-HCT is presented, demonstrating that revised cytogenetic changes and MIPSS70+ v2.0 score predict transplantation outcomes, and thus can better inform physicians and patients in making decisions about allo -HCT.
38 citations
TL;DR: The increasing amount of empirical information on the epidemiology, outcomes and genomics of Latinos with ALL is critically examined, and an association between polymorphisms that are commonly found in indigenous Americans and high rates of ALL is suggested.
33 citations
Stanford University1, City of Hope National Medical Center2, University of Chicago3, University of Texas MD Anderson Cancer Center4, Royal Melbourne Hospital5, St. Jude Children's Research Hospital6, Oregon Health & Science University7, Royal Children's Hospital8, Nationwide Children's Hospital9, AbbVie10, Cincinnati Children's Hospital Medical Center11, University of North Carolina at Chapel Hill12
TL;DR: Venetoclax (Ven) is a highly selective BCL-2 inhibitor with established efficacy in adults with hematologic malignancies as discussed by the authors, but prolonged thrombocytopenia limits its continuous use at higher doses.
24 citations
TL;DR: Pegylated asparaginase (PEG-Asp), a key component in the treatment of acute lymphoblastic leukemia (ALL), is associated with coagulopathy and an increased risk of venous thromboembolism (VTE), which lowers antithrombin (AT) levels.
Abstract: Pegylated asparaginase (PEG-Asp), a key component in the treatment of acute lymphoblastic leukemia (ALL), is associated with coagulopathy and an increased risk of venous thromboembolism (VTE). PEG-...
19 citations
Johns Hopkins University1, University of Texas MD Anderson Cancer Center2, Emory University3, Harvard University4, University of Chicago5, City of Hope National Medical Center6, NewYork–Presbyterian Hospital7, Fred Hutchinson Cancer Research Center8, University of Washington9, Genentech10, AbbVie11, University of Colorado Denver12
TL;DR: Venetoclax in combination with either HMAs or LDAC has led to high rates of early, deep and durable responses in untreated AML patients ineligible for standard induction chemotherapy, suggesting that prior to SCT in patients deemed ineligible for intensive chemotherapy may provide a durable remissions.
TL;DR: The fundamental question of whether all adults with Ph-like ALL require an allogeneic hematopoietic cell transplantation (HCT) in first complete remission (CR1) regardless of other presenting features and treatment response parameters is raised.
TL;DR: Combined treatment of NSG mice engrafted withFLT3‐ITD + MV4−11 AML cells with 8‐Cl‐Ado and the FLT3 inhibitor AC220 (quizartinib) synergistically enhanced survival, compared with that of mice treated with the individual drugs, suggesting a potentially effective approach for FLT 3‐ITd AML patients.
Abstract: Nucleoside analogs represent the backbone of several distinct chemotherapy regimens for acute myeloid leukemia (AML) and combination with tyrosine kinase inhibitors has improved survival of AML patients, including those harboring the poor-risk FLT3-ITD mutation. Although these compounds are effective in killing proliferating blasts, they lack activity against quiescent leukemia stem cells (LSCs), which contributes to initial treatment refractoriness or subsequent disease relapse. The reagent 8-chloro-adenosine (8-Cl-Ado) is a ribose-containing, RNA-directed nucleoside analog that is incorporated into newly transcribed RNA rather than in DNA, causing inhibition of RNA transcription. In this report, we demonstrate antileukemic activities of 8-Cl-Ado in vitro and in vivo and provide mechanistic insight into the mode of action of 8-Cl-Ado in AML. 8-Cl-Ado markedly induced apoptosis in LSC, with negligible effects on normal stem cells. 8-Cl-Ado was particularly effective against AML cell lines and primary AML blast cells harboring the FLT3-ITD mutation. FLT3-ITD is associated with high expression of miR-155. Furthermore, we demonstrate that 8-Cl-Ado inhibits miR-155 expression levels accompanied by induction of DNA-damage and suppression of cell proliferation, through regulation of miR-155/ErbB3 binding protein 1(Ebp1)/p53/PCNA signaling. Finally, we determined that combined treatment of NSG mice engrafted with FLT3-ITD + MV4-11 AML cells with 8-Cl-Ado and the FLT3 inhibitor AC220 (quizartinib) synergistically enhanced survival, compared with that of mice treated with the individual drugs, suggesting a potentially effective approach for FLT3-ITD AML patients.
TL;DR: The results, despite low patient numbers, indicate that IDH mutations are associated with higher relapse rate after alloHCT, and further prospective studies on post transplantation IDH inhibition is required to improve outcomes in AML patients who carry IDh mutations.
Abstract: Background Mutations in isocitrate dehydrogenase (IDH)1/2 genes result in nicotinamide adenine dinucleotide phosphate-dependent reduction of α-ketoglutarate and formation of 2-hydroxyglutarate, which blocks normal cellular differentiation and promotes leukemogenesis. Nearly 20% of acute myeloid leukemia (AML) patients carry IDH1/2 mutations. Although multiple investigators have described the prognostic implications of IDH mutations in AML patients receiving chemotherapy, the effect of these mutations on outcomes after allogeneic (allo) hematopoietic cell transplantation (HCT) is unknown. Patients and Methods We report on the clinical outcome of a cohort of AML patients, who were tested for IDH mutations and underwent alloHCT at City of Hope (2015-2017). Of a total of 317 screened patients, 99 (31%) underwent alloHCT, of whom 23 carried and 76 did not carry IDH mutations (control). Results No statistical significance was detected in patient’s overall survival (P = .84). With a median follow-up of 7.8 months, 1-year relapse rate of 29% and 13% was seen in the IDH-mutated and control group, respectively (P = .033). IDH1/2 mutation status remained significantly associated with relapse (hazard ratio, 2.8; P = .046) after inclusion of pre-HCT disease status in a multivariable model. Conclusion Our results, despite low patient numbers, indicate that IDH mutations are associated with higher relapse rate after alloHCT. Further prospective studies on post transplantation IDH inhibition is required to improve outcomes in AML patients who carry IDH mutations.
TL;DR: This is a 26-year-old Latino female with B-cell ALL who underwent allogeneic hematopoietic cell transplantation (alloHCT) following total body irradiation and etoposide conditioning from her HLA-matched brother and remains on dasatinib at 140mg daily.
Abstract: Trial registration: ClinicalTrials.gov identifier: NCT02420717.Trial registration: ClinicalTrials.gov identifier: NCT02883049.The majority of Philadelphia-like (Ph-like) acute lymphoblastic leukemi...
TL;DR: All related to prior cytotoxic therapy (t-ALL) appears to be a distinct entity when compared to the de novo ALL, with characteristics including older age at the time of onset, female predominance and leukemia genetics enriched with KMT2A (MLL) gene rearrangement and chromosomes 5/7 abnormalities.
TL;DR: The role of allogeneic HCT consolidation must be re-examined in the context of some key advances in ALL management, including the introduction of minimal residual disease (MRD) monitoring and classifying ALL using nextgeneration sequencing approaches in addition to cytogenetics.
Abstract: Allogeneic hematopoietic cell transplantation (HCT) consolidation has an established record of curing acute lymphoblastic leukemia (ALL) in a subset of adult patients. Historically, the majority of adults with ALL were deemed high-risk, and thus, allogeneic HCT was offered more broadly as a consolidation in suitable candidates at a time when effective salvage regimens for relapsed ALL were lacking. Allogeneic HCT was particularly recommended to consolidate high-risk adult ALL defined based on traditional risk factors such as cytogenetics, older age, and elevated initial white blood cell count. Several prospective studies were conducted that utilized biological randomization to examine the benefit of allogeneic HCT in adults with ALL who attained first complete remission (CR1). The majority of these studies illustrated superiority of HCT over chemotherapy consolidation in reducing leukemia relapse, and several of those studies even demonstrated survival advantage with the transplantation approach [1–3]. Nevertheless, who attains the most benefit from early allogeneic HCT was and still remains a matter of debate. More recently, the management of adult ALL has witnessed changes at an unprecedented pace, and this may impact and alter the indications for allogeneic HCT for adults with Philadelphia-chromosome negative (Ph−) ALL in CR1. Hence, the role of allogeneic HCT consolidation must be re-examined in the context of some key advances in ALL management. First, contemporary pediatric-inspired regimens have been safely administered to fit adults at least until 50 years of age [4–7], and these regimens have yielded long-term outcomes that appear similar to results of allogeneic HCT consolidation in CR1 [8]. Secondly, the introduction of minimal residual disease (MRD) monitoring, a sensitive and reliable biological marker of leukemia chemosensitivity has refined the management of ALL with frontline regimens [4, 9, 10]. The routine application of MRD has led to better stratifying ALL patients as well as identifying patients who have better chances of cure with chemotherapy only approach. Thus, MRD has emerged as a very powerful and dynamic prognostic tool that has to a large extent replaced traditional risk factors in guiding the decision to transplant. Finally, classifying ALL using nextgeneration sequencing approaches in addition to cytogenetics has led to discovery of high-risk genomic features that were previously undefined and has refined our ability to identify new high-risk prognostic subgroups that would previously have been considered standard-risk. The key example is ALL with Philadelphia-like (Ph-like) gene signature, a high-risk subset that responds poorly to traditional chemotherapy regimens and may require novel treatment approaches possibly in conjunction with allogeneic HCT for cure [11]. A compelling argument in the past for performing allogeneic HCT in CR1 has been the poor outcome of relapsed/ refractory ALL primarily due inability to achieve a second CR (CR2) in many patients. This precluded many patients from eventually undergoing allogeneic HCT. Also, allogenic HCT outcomes are poor in patients who fail to respond to salvage therapy at the time of relapse and/or undergo transplant with active leukemia or positive MRD. Moreover, salvage conventional chemotherapies have additive toxicities when done before HCT. Hence, the concept of “delaying allogeneic HCT until leukemia relapses and then the patient can be rescued and transplanted in CR2” was unrealistic and can lead to missing the “cure window” with frontline transplant. Recently, the development of novel highly active immune-based and * Ibrahim Aldoss ialdoss@coh.org
TL;DR: Outcomes of the single arm, single center pilot study investigating the safety and efficacy of Rux administration in patients with primary or secondary MF undergoing HCT, finding the maximum tolerated dose and recommended phase II dose was safety was reported.
TL;DR: This is the first case of successful management of major non-ABO incompatibility caused by anti-Jk(a) in a patient receiving an allogeneic HSCT reported in the literature.
Abstract: A 49-year-old white man with blood group AB, D+ was found to have alloanti-Jk(a) and -K when he developed a delayed hemolytic transfusion reaction before allogeneic hematopoietic stem cell transplant (HSCT). Given that his stem cell donor was blood group O, D+, Jk(a+), K-, rituximab was added to his conditioning regimen of fludarabine and melphalan to prevent hemolysis of engrafting Jk(a+) donor red blood cells. The patient proceeded to receive a peripheral blood stem cell transplant from a matched unrelated donor with no adverse events. To our knowledge, this is the first case of successful management of major non-ABO incompatibility caused by anti-Jk(a) in a patient receiving an allogeneic HSCT reported in the literature.
TL;DR: Administration of Venetoclax-based salvage regimen as a bridge to HCT is safe with no added immediate toxicities post-HCT, and early outcome data are promising for this otherwise high-risk population.
TL;DR: The overall survival (OS), progression-free survival (PFS), relapse rate, non-relapse mortality (NRM), cumulative incidence of Grade 2-4 acute GvHD and chronic GVHD between the two groups by univariate and multivariate analysis was analyzed.