Publications by authors named "Animesh Pardanani"

282 Publications

Venetoclax with azacitidine or decitabine in blast-phase myeloproliferative neoplasm: A multicenter series of 32 consecutive cases.

Am J Hematol 2021 Apr 12. Epub 2021 Apr 12.

Division of Hematology, Mayo Clinic, Rochester, Minnesota, USA.

Venetoclax (Ven) combined with a hypomethylating agent (HMA) has now emerged as an effective treatment regimen for acute myeloid leukemia, in both de novo and relapsed/refractory setting. The current multicenter study retrospectively examined Ven + HMA treatment outcome among 32 patients (median age 69 years; 59% males) with blast-phase myeloproliferative neoplasm (MPN-BP). Pre-leukemic phenotype included essential thrombocythemia (ET)/post-ET myelofibrosis (34%), polycythemia vera (PV)/post-PV myelofibrosis (38%) and primary myelofibrosis (28%). Twenty-nine study patients were fully annotated cytogenetically and molecularly (NGS): 69% harbored complex karyotype and/or mutations, including TP53 (41%), IDH1/2 (21%), ASXL1 (21%), N/KRAS (14%), SRSF2 (10%), EZH2 (10%) and U2AF1 (7%). All patients received Ven combined with either azacitidine (n = 12) or decitabine (n = 20); either up front (n = 23) or after failing another induction therapy (n = 9). Complete remission with (CR) or without (CRi) count recovery was achieved in 14 (44%) patients and was more likely to occur in the absence of pre-leukemic PV/post-PV myelofibrosis phenotype (p < .01), complex karyotype (p < .01) or K/NRAS (p = .03) mutations; seven of eight patients (88%) without vs four of 21 (19%) with complex karyotype or K/NRAS mutation achieved CR/CRi (p < .01); all 11 informative patients with pre-leukemic PV/post-PV myelofibrosis phenotype displayed complex karyotype (p < .01). In contrast, neither TP53 (p = .45) nor IDH1/2 (p = .63) mutations affected response. Compared to historical controls treated with HMA alone (n = 26), the CR/CRi rate (44% vs 4%) and median survival (8 vs 5.5 months) were more favorable with Ven + HMA, but without significant difference in overall survival. Importantly, six patients with CR/CRi subsequently received allogeneic hematopoietic stem cell transplant (AHSCT). Note, Ven + HMA produces robust CR/CRi rates in MPN-BP, especially in the absence of RAS mutations and complex karyotype, thus enabling AHSCT, in some patients.
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http://dx.doi.org/10.1002/ajh.26186DOI Listing
April 2021

Mayo Clinic experience with 1123 adults with acute myeloid leukemia.

Blood Cancer J 2021 Mar 2;11(3):46. Epub 2021 Mar 2.

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

Between 2004 and 2017, a total of 1123 adult patients (median age 65 years; 61% males) with newly diagnosed acute myeloid leukemia (AML), not including acute promyelocytic leukemia, were seen at the Mayo Clinic. Treatment included intensive (n = 766) or lower intensity (n = 144) chemotherapy or supportive care (n = 213), with respective median survivals of 22, 9, and 2 months (p < 0.01). Intensive chemotherapy resulted in complete remission (CR) and CR with incomplete count recovery (CRi) rates of 44 and 33%, respectively, with no difference in survival outcome between the two (p = 0.4). Allogeneic hematopoietic stem cell transplant (AHSCT) was documented in 259 patients and provided the best survival rate (median 55 months; p < 0.01). After a median follow-up of 13 months, 841 (75%) deaths were recorded. Multivariate analysis identified age >60 years (HR 2.2, 1.9-2.6), adverse karyotype (HR 2.9, 1.9-4.9), intermediate-risk karyotype (HR 1.6, 1.02-2.6), post-myeloproliferative neoplasm AML (HR 1.9, 1.5-2.4), and other secondary AML (HR 1.3 (1.1-1.6) as risk factors for shortened survival. These risk factors retained their significance after inclusion of FLT3/NPM1 mutational status in 392 informative cases: FLT3+NPM1- (HR 2.8, 1.4-5.6), FLT3+/NPM+ (HR 2.6 (1.3-5.2), and FLT3-NPM1- (HR 1.8, 1.0-3.0).
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http://dx.doi.org/10.1038/s41408-021-00435-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7925511PMC
March 2021

Extreme thrombocytosis in low-risk essential thrombocythemia: Retrospective review of vascular events and treatment strategies.

Am J Hematol 2021 Jun 11;96(6):E182-E184. Epub 2021 Mar 11.

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

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http://dx.doi.org/10.1002/ajh.26137DOI Listing
June 2021

Young platelet millionaires with essential thrombocythemia.

Am J Hematol 2021 04 18;96(4):E93-E95. Epub 2021 Feb 18.

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

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http://dx.doi.org/10.1002/ajh.26114DOI Listing
April 2021

Systemic mastocytosis in adults: 2021 Update on diagnosis, risk stratification and management.

Am J Hematol 2021 04 21;96(4):508-525. Epub 2021 Feb 21.

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

Overview: Systemic mastocytosis (SM) results from a clonal proliferation of abnormal mast cells (MC) in extra-cutaneous organs.

Diagnosis: The major criterion is presence of multifocal clusters of spindled MC in the bone marrow. Minor diagnostic criteria include elevated serum tryptase level, abnormal MC CD25 expression, and presence of KITD816V mutation.

Risk Stratification: Establishing SM subtype as per the World Health Organization classification system is an important first step. Broadly, patients either have indolent/smoldering SM (ISM/SSM) or advanced SM, the latter includes aggressive SM (ASM), SM with associated hematological neoplasm (SM-AHN), and mast cell leukemia (MCL). Identification of poor-risk mutations (ie, ASXL1, RUNX1, SRSF2, NRAS) further refines the risk stratification. Recently, clinical and hybrid clinical-molecular risk models have been developed to more accurately assign prognosis in SM patients.

Management: Treatment goals for ISM patients are primarily directed towards anaphylaxis prevention/symptom control/osteoporosis treatment. Patients with advanced SM frequently need MC cytoreductive therapy to ameliorate disease-related organ dysfunction. High response rates have been seen with small-molecule inhibitors that target mutant-KIT, including midostaurin (Food and Drug Administration approved) or avapritinib (investigational). Other options for MC cytoreduction include cladribine or interferon-α, although head-to-head comparisons are lacking. Treatment of SM-AHN primarily targets the AHN component, particularly if an aggressive disease such as acute myeloid leukemia is present. Allogeneic stem cell transplant can be considered in such patients, or in those with relapsed/refractory advanced SM. Imatinib has a limited therapeutic role in SM; effective cytoreduction is limited to those with imatinib-sensitive KIT mutations.
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http://dx.doi.org/10.1002/ajh.26118DOI Listing
April 2021

The Impact of Obesity on the Outcomes of Adult Patients with Acute Lymphoblastic Leukemia - A Single Center Retrospective Study.

Blood Lymphat Cancer 2021 22;11:1-9. Epub 2021 Jan 22.

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

Introduction: Obesity is a worldwide problem that is related to cardiac disease, thrombosis and cancer. However, little is known about the impact of obesity on the outcomes of adult acute lymphoblastic leukemia (ALL) patients.

Methods: We retrospectively evaluated a cohort of 154 newly diagnosed adult ALL patients between 1994 and 2011 at Mayo Clinic (Rochester). According to the World Health Organization (WHO) international BMI classification, patients were stratified as underweight, normal weight, overweight, and obese. For some analyses, patients were also stratified according to a two-sided non-obese or obese classification.

Results: The median follow-up time was 8.37 years. Obese patients were more likely to be women (p=0.024) and ≥60 years old (p=0.003). Five-year mortality rates were higher in obese patients than non-obese [HR 95% CI: 1.60 (1.03-2.50) p=0.035]. This was also the case in subgroup analysis among T-cell patients although the number of patients was small [HR 95% CI: 5.42 (1.84-15.98) p<0.001]. There was no difference in mortality among the B-cell patients. After adjusting for baseline variables, the difference in mortality remained in several models. There was no difference in EFS or cumulative incidence of relapse rates between obese and non-obese patients among the overall population.

Discussion: In conclusion, our study suggests that adult ALL patients with obesity have lower survival rates, especially in T-cell ALL.
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http://dx.doi.org/10.2147/BLCTT.S269748DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7837742PMC
January 2021

Myeloid/Lymphoid Neoplasms with Eosinophilia and TK Fusion Genes, Version 3.2021, NCCN Clinical Practice Guidelines in Oncology.

J Natl Compr Canc Netw 2020 09;18(9):1248-1269

The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute.

Eosinophilic disorders and related syndromes represent a heterogeneous group of neoplastic and nonneoplastic conditions, characterized by more eosinophils in the peripheral blood, and may involve eosinophil-induced organ damage. In the WHO classification of myeloid and lymphoid neoplasms, eosinophilic disorders characterized by dysregulated tyrosine kinase (TK) fusion genes are recognized as a new category termed, myeloid/lymphoid neoplasms with eosinophilia and rearrangement of PDGFRA, PDGFRB or FGFR1 or with PCM1-JAK2. In addition to these aforementioned TK fusion genes, rearrangements involving FLT3 and ABL1 genes have also been described. These new NCCN Guidelines include recommendations for the diagnosis, staging, and treatment of any one of the myeloid/lymphoid neoplasms with eosinophilia (MLN-Eo) and a TK fusion gene included in the 2017 WHO Classification, as well as MLN-Eo and a FLT3 or ABL1 rearrangement.
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http://dx.doi.org/10.6004/jnccn.2020.0042DOI Listing
September 2020

Venetoclax and hypomethylating agents in acute myeloid leukemia: Mayo Clinic series on 86 patients.

Am J Hematol 2020 12 16;95(12):1511-1521. Epub 2020 Sep 16.

Division of Hematology, Mayo Clinic, Rochester, Minnesota, USA.

Venetoclax and hypomethylating agent (HMA) combination therapy is FDA-approved for elderly or unfit acute myeloid leukemia (AML) patients unable to withstand intensive chemotherapy. The primary objective of the current study was to impart our institutional experience with the above regimen, outlining response, survival outcomes, and its determinants amongst 86 treatment- naïve and relapsed/refractory AML patients. A total of 44 treatment-naïve AML patients, median age 73.5 years, enriched with secondary, therapy related and ELN adverse risk disease (n = 27) were studied. The CR/CRi rates of 50% (22 of 44 patients) were superior to 23% in a matched AML cohort treated with HMA alone (P = .005). Response rates were similar with TP53, FLT3, NPM1 and IDH mutations (P = .31). Moreover, CEPBA mutations (P = .03) and neutropenia (P = .05) emerged as predictors of complete response. Survivalwas prolonged in patients achieving CR/CRi (17 vs 3 months without CR/CRi, P < .001; conversely adverse ELN risk portended inferior survival. Amongst 42 relapsed/refractory AML patients, half received ≥2 prior therapies excluding transplant, and 15 (35.7%) had received HMA. A group of 14 patients (33.3%) attained CR/CRi; age > 65 years, AML with myelodysplasia, JAK2, DNMT3A, and BCOR mutations predicted complete response. Survival distinctions were based on CR/CRi (median survival 15 vs 3 months with/without CR/CRi; P < .001), and TP53 mutation status (P = .04). In summary, we corroborate existing reports demonstrating superior response and prolonged survival with venetoclax and HMA in treatment -naïve and relapsed/refractory AML patients regardless of genotype. Additionally, we identify unique predictors of response to therapy which require validation.
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http://dx.doi.org/10.1002/ajh.25978DOI Listing
December 2020

Erythrocytosis associated with cerebral hemangiomas and multiple venous anomalies.

Am J Hematol 2020 Jun 29. Epub 2020 Jun 29.

Division of Hematology, Mayo Clinic, Rochester, Minnesota, USA.

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http://dx.doi.org/10.1002/ajh.25913DOI Listing
June 2020

81-Year-Old Man With Insomnia and Pruritus.

Mayo Clin Proc 2020 06;95(6):e59-e64

Advisor to residents and Consultant in Hematology, Mayo Clinic, Rochester, MN. Electronic address:

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http://dx.doi.org/10.1016/j.mayocp.2019.10.044DOI Listing
June 2020

Phase 1 study of CWP232291 in patients with relapsed or refractory acute myeloid leukemia and myelodysplastic syndrome.

Blood Adv 2020 05;4(9):2032-2043

MD Anderson Cancer Center, Houston, TX.

CWP232291 (CWP291) is a small-molecule inhibitor of Wnt signaling that causes degradation of β-catenin via apoptosis induction through endoplasmic reticulum stress activation. This first-in-human, open-label, dose-escalation study to evaluate the safety, maximum tolerated dose (MTD), and preliminary efficacy of CWP291 enrolled 69 patients with hematologic malignancies (acute myeloid leukemia [AML], n = 64; myelodysplastic syndrome, n = 5) in 15 dose-escalation cohorts of 4 to 334 mg/m2 using a modified 3+3 design and 1 dose-expansion cohort. CWP291 was administered IV daily for 7 days every 21 days. The most common treatment-emergent adverse events (TEAEs) were nausea (n = 44, 64%), vomiting (n = 32, 46%), diarrhea (n = 25, 36%), and infusion-related reactions (n = 20, 29%). Grade ≥3 TEAEs in >3 patients (5%) were pneumonia (n = 8, 12%); hypophosphatemia (n = 6, 8%); leukocytosis, nausea, cellulitis, sepsis, and hypokalemia (n = 5 each, 7% each); and hypertension (n = 4, 6%). Dose-limiting toxicities included nausea (n = 3) and abdominal pain, anaphylactic reaction, myalgia, and rash (n = 1, each); the MTD was defined at 257 mg/m2. CWP232204, the active metabolite of CWP291, showed pharmacokinetic linearity on both days 1 and 7, and a terminal half-life of ∼12 hours. Among 54 response-evaluable AML patients, there was one complete response at a dose of 153 mg/m2 and one partial response at 198 mg/m2; bone marrow blast percentage reduced from a median of 58.3% to 3.5% and 15.0% to 4.2%, respectively. Future studies will explore CWP291, with a mechanism of action aimed at eradication of earlier progenitors via Wnt pathway blockade, as combination therapy. This trial was registered at www.clinicaltrials.gov as #NCT01398462.
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http://dx.doi.org/10.1182/bloodadvances.2019000757DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7218422PMC
May 2020

WHO defined chronic eosinophilic leukemia, not otherwise specified (CEL, NOS): A contemporary series from the Mayo Clinic.

Am J Hematol 2020 07 17;95(7):E172-E174. Epub 2020 Apr 17.

Division of Hematology, Mayo Clinic, Rochester, Minnesota, USA.

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http://dx.doi.org/10.1002/ajh.25811DOI Listing
July 2020

Essential Thrombocythemia. Reply.

N Engl J Med 2020 03;382(12):e21

Mayo Clinic, Rochester, MN

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http://dx.doi.org/10.1056/NEJMc1917586DOI Listing
March 2020

Clinical outcomes of adults with hemophagocytic lymphohistiocytosis treated with the HLH-04 protocol: a retrospective analysis.

Leuk Lymphoma 2020 07 11;61(7):1592-1600. Epub 2020 Mar 11.

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

Hemophagocytic lymphohistiocytosis (HLH) is a rare syndrome of pathologic immune activation in children that is increasingly being recognized in adults. Efficacy data for the HLH-04 protocol in adults is lacking. This study retrospectively analyzed 31 adult patients, median age 46 years, who received HLH-04 from 1/1/2004 to 5/1/2018. HLH etiology included malignancy ( = 9), autoimmune ( = 8), infection ( = 8), and idiopathic ( = 6). Eighteen patients were evaluable for response at week 4 with 7 having no response, 11 reaching partial response, and 0 reaching complete response (CR). Six patients eventually achieved CR at a median 195 days. The 1-year overall survival (OS) was 35% and median OS was 3.2 months. Univariate analysis showed shorter survival for hemoglobin <9 g/dL (HR 4.29,  = 0.003), platelets <100 × 10/L (HR 4.06,  = 0.027), ANC <1 × 10/L (HR 5.24,  = 0.001), and total bilirubin >1.2 mg/dL (HR 3.30,  = 0.022). Outcomes of adults treated with HLH-04 remain dismal and newer treatment modalities are needed.
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http://dx.doi.org/10.1080/10428194.2020.1737684DOI Listing
July 2020

Mutation-enhanced international prognostic systems for essential thrombocythaemia and polycythaemia vera.

Br J Haematol 2020 04 16;189(2):291-302. Epub 2020 Jan 16.

Department of Experimental and Clinical Medicine, CRIMM, Center of Research and Innovation of Myeloproliferative Neoplasms, Azienda Ospedaliera Universitaria Careggi, University of Florence, and Denothe Excellence Center, Florence, Italy.

Survival prediction in essential thrombocythaemia (ET) and polycythaemia vera (PV) is currently based on clinically-derived variables; we examined the possibility of integrating genetic information for predicting survival. To this end, 906 molecularly-annotated patients (416 Mayo Clinic; 490 University of Florence, Italy), including 502 ET and 404 PV, were recruited. Multivariable analysis identified spliceosome mutations to adversely affect overall (SF3B1, SRSF2 in ET and SRSF2 in PV) and myelofibrosis-free (U2AF1, SF3B1 in ET) survival; TP53 mutations predicted leukaemic transformation in ET; "adverse" mutations occurred in 51 (10%) ET and 8 (2%) PV patients. We confirmed the independent survival effect of adverse mutations [hazard ratio (HR) 2·4, 95% CI 1·6-3·5], age >60 years (6·6, 4·6-9·7), male sex (1·8, 1·3-2·4) and leukocytosis ≥11 × 10 /l (1·6, 1·1-2·2), in ET, and adverse mutations (7·8, 3·1-17·0), age >67 years (5·4, 3·6-8·1), leukocytosis ≥15 × 10 /l (2·8, 1·8-4·2) and thrombosis history (2·0, 1·4-2·9), in PV. HR-based risk point allocation allowed development of three-tiered mutation-enhanced international prognostic systems (MIPSS) which were validated in both cohorts and performance was shown to be superior to conventional scoring systems. Spliceosome mutations enhance survival prediction in ET and PV and identify patients at risk for fibrotic progression. TP53 mutations predict leukaemic transformation in ET.
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http://dx.doi.org/10.1111/bjh.16380DOI Listing
April 2020

Clinical, molecular, and prognostic correlates of number, type, and functional localization of TET2 mutations in chronic myelomonocytic leukemia (CMML)-a study of 1084 patients.

Leukemia 2020 05 13;34(5):1407-1421. Epub 2019 Dec 13.

Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN, USA.

Loss-of-function TET2 mutations (TET2) are frequent early clonal events in myeloid neoplasms and are thought to confer a fitness advantage to hematopoietic precursors. This large, multi-institutional study (n = 1084), investigated the TET2 mutational landscape and prognostic implications of the number, type, and location of TET2 and the epistatic relationship with other somatic events in chronic myelomonocytic leukemia (CMML). Nine hundred and forty-two TET2 were identified in 604 (56%) patients, of which 710 (75%) were predicted to be truncating (involving the catalytic domain). Three hundred and sixteen (29%) patients had ≥1 TET2, with 28%, 1%, and 0.2% harboring 2, 3, and 5 mutations, respectively. In comparison to TET2, TET2 patients were older in age, more likely to have dysplastic CMML, a higher number of co-occurring mutations, and lower-risk stratification. Importantly, TET2 were associated with a survival advantage (49 vs. 30 months, p < 0.0001), especially in the context of multiple TET2 (≥2; 57 months, p < 0.001), and truncating TET2 (51 months, p < 0.001). In addition, the adverse prognostic impact of ASXL1 was partially mitigated by concurrent TET2, with the ASXL1/TET2 genotype having better outcomes and resulting in further risk stratification of ASXL1 inclusive CMML prognostic models, in comparison to ASXL1 alone.
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http://dx.doi.org/10.1038/s41375-019-0690-7DOI Listing
May 2020

Prevalence and spectrum of T-cell lymphoproliferative disorders in patients with Hypereosinophilia: A reference laboratory experience.

Ann Diagn Pathol 2020 Feb 18;44:151412. Epub 2019 Oct 18.

Division of Hematopathology, Mayo Clinic, Rochester, MN, United States of America. Electronic address:

Hypereosinophilia (HE) is defined as persistently elevated absolute eosinophil count (AEC) ≥ 1.5 × 10/L, which can be due to a variety of underlying causes. In this study, we investigated the prevalence and spectrum of T-cell lymphoproliferative disorders in 124 consecutive patients with HE by flow cytometric immunophenotyping. Available medical records, pathology reports and T-cell receptor (TCR) gene rearrangement were reviewed. Fifteen patients (12%) with HE had abnormal T-cell populations that were initially detected by flow cytometry. The presence of immunophenotypically abnormal T cells was not associated with higher AEC or higher absolute lymphocyte count levels, in comparison to those without abnormal T cells. Molecular studies concordantly identified a clonal TCR gene rearrangement in 8 of 10 cases tested. Based on the combination of clinical presentation, morphologic findings and laboratory studies, seven patients were diagnosed with the lymphocytic variant of hypereosinophilic syndrome and five with overt T-cell lymphoma (4 peripheral T-cell lymphoma NOS, 1 primary cutaneous T-cell lymphoma). The remaining three had an unknown diagnosis due to lack of information and additional workup would be warranted. These findings underscore the importance of flow cytometry as a screening tool to identify T-cell lymphoproliferative disorders in patients with HE.
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http://dx.doi.org/10.1016/j.anndiagpath.2019.151412DOI Listing
February 2020