Publications by authors named "Mohammad Hussaini"

30 Publications

  • Page 1 of 1

Post-transplant relapse of therapy-related MDS as gastric myeloid sarcoma: Case report and review of literature.

Leuk Res Rep 2021 14;15:100244. Epub 2021 May 14.

Department of Hematopathology and Lab Medicine, Moffitt Cancer Center, Tampa, FL, USA.

Introduction: Myelodysplastic syndrome (MDS) are hematologic neoplasms characterized by morphologic dysplasia and ineffective hematopoiesis in the bone marrow. The only potentially curative therapy is stem cell transplant. However, relapse remains a major challenge and is seen in about 25-40% of cases. Myeloid sarcoma presenting as relapse post allogeneic transplant for myeloid neoplasms is rare. We report the sentinel case of a patient with MDS who relapsed as gastric myeloid sarcoma 1 ½ years after allogeneic stem cell transplant.

Case Presentation: Sixty-nine-year-old male who was diagnosed with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) in 2006 and transitional cell bladder carcinoma in 2008. In 2011, he developed therapy-related myeloid neoplasm t(7;22) and no excess blasts. He was treated with Vidaza followed by a MUD hematopoietic stem cell transplant on 8/24/2012. In 2013 the patient developed anorexia and gastric biopsies showed severe gastritis. Repeat gastric biopsy on 02/05/2014 showed an extensive mononuclear infiltrate which could easily be confused with lymphocytes but staining showed myeloid sarcoma. Marrow was negative. The patient remained refractory to therapy and expired 08/10/2016.

Conclusion: In summary, we report the first case of GI relapse of MDS as a myeloid sarcoma post-transplant. We seek to alert our audience of this potentially serious diagnostic pitfall, particularly one that can be relatively easily resolved on the basis of immunohistochemical profiling.
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http://dx.doi.org/10.1016/j.lrr.2021.100244DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8170141PMC
May 2021

ELN 2017 Genetic Risk Stratification Predicts Survival of Acute Myeloid Leukemia Patients Receiving Allogeneic Hematopoietic Stem Cell Transplantation.

Transplant Cell Ther 2021 03 2;27(3):256.e1-256.e7. Epub 2021 Feb 2.

Blood and Marrow Transplantation and Cellular Immunotherapy, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida. Electronic address:

European LeukemiaNet (ELN) 2017 risk stratification by genetics is prognostic of outcomes in patients with acute myeloid leukemia (AML). However, the prognostic impact of the 2017 ELN genetic risk stratification after allogeneic hematopoietic cell transplantation (alloHCT) is not well established. We examined the effect of 2017 ELN genetic risk stratification on alloHCT outcomes of AML. We included 500 adult (≥18 years) AML patients in first (n = 370) or second (n = 130) complete remission receiving alloHCT from 2005 to 2016. Patients were classified into favorable (12%), intermediate (57%), and adverse (32%) 2017 ELN risk groups. The Cox proportional hazard model was used to conduct the multivariable analyses of leukemia-free survival (LFS) and overall survival (OS). Relapse and nonrelapse mortality were analyzed by the Fine-Gray regression model. OS at 2 years was 72% in the favorable versus 60% in the intermediate versus 45% in the adverse risk groups (P < .001). In multivariable analyses, the 2017 ELN classifier was an independent predictor of OS after alloHCT with significantly higher overall mortality in the intermediate (hazard ratio [HR] = 1.68, 95% confidence interval [CI], 1.06-2.68; P = .03) and adverse (HR = 2.50, 95% CI, 1.54-4.06; P < .001) risk groups compared to the favorable risk group. Similarly, LFS was worse in the intermediate (HR = 1.63, 95%, CI 1.06-2.53; P = .03) and adverse (HR 2.23, 95% CI, 1.41-3.54; P < .001) risk groups while relapse was higher in the adverse risk group (HR = 2.36, 95% CI, 1.28-4.35; P = .006) as compared to the favorable risk group. These data highlight the prognostic impact of the 2017 ELN genetic risk stratification on the survival of AML patients after alloHCT. Patients in the adverse risk group had the highest risk of relapse and worst survival. Thus the 2017 ELN prognostic system can help identify AML patients who may benefit from clinical trials offering relapse mitigation strategies to improve transplant outcomes.
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http://dx.doi.org/10.1016/j.jtct.2020.12.021DOI Listing
March 2021

Baseline and serial molecular profiling predicts outcomes with hypomethylating agents in myelodysplastic syndromes.

Blood Adv 2021 02;5(4):1017-1028

Malignant Hematology Department and.

Hypomethylating agents (HMAs) are widely used in the treatment of myelodysplastic syndromes (MDSs), yet identifying those patients unlikely to benefit remains challenging. We assessed response and overall survival (OS) in 247 patients molecularly profiled by next-generation sequencing (NGS) before first-line HMA therapy, and a subset of 108 patients were sequenced serially during treatment. The most common mutations included TP53 (33.1%), ASXL1 (19%), TET2 (16.5%), DNMT3A (14.1%), and SRSF2 (12.1%). The overall response rate was 42.1%, with the composite TET2-mutant/ASXL1 wild-type genotype representing the strongest predictor of response (overall response rate, 62.1%; complete remission rate, 34.5%). The median OS for the cohort was 15 months, and the number of mutations detected by NGS (hazard ratio [HR], 1.22; P = .02), as well as mutations in TP53 (HR, 2.33; P = .001) and EZH2 (HR, 2.41; P = .04) were identified as independent covariates associated with inferior OS in multivariable analysis. Serial molecular profiling revealed that clearance of TP53 mutations during HMA therapy was associated with superior OS (HR, 0.28; P = .001) and improved outcome in patients proceeding to allogeneic hematopoietic cell transplantation. These data support baseline molecular profiling by NGS in MDS patients treated with HMAs and provide novel observations of sequential profiling during therapy that provide particular value in TP53-mutated disease.
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http://dx.doi.org/10.1182/bloodadvances.2020003508DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7903224PMC
February 2021

Genomic characteristics and prognostic significance of co-mutated ASXL1/SRSF2 acute myeloid leukemia.

Am J Hematol 2021 04 15;96(4):462-470. Epub 2021 Feb 15.

Lineberger Comprehensive Cancer Center, The University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA.

The ASXL1 and SRSF2 mutations in AML are frequently found in patients with preexisting myeloid malignancies and are individually associated with poor outcomes. In this multi-institutional retrospective analysis, we assessed the genetic features and clinical outcomes of 43 patients with ASXL1 SRSF2 AML and compared outcomes to patients with either ASXL1 (n = 57) or SRSF2 (n = 70) mutations. Twenty-six (60%) had secondary-AML (s-AML). Variant allele fractions suggested that SRSF2 mutations preceded ASXL1 mutational events. Median overall survival (OS) was 7.0 months (95% CI:3.8,15.3) and was significantly longer in patients with de novo vs s-AML (15.3 vs 6.4 months, respectively; P = .04 on adjusted analysis). Compared to ASXL1 SRSF2 and ASXL1 SRSF2 , co-mutated patients had a 1.4 and 1.6 times increase in the probability of death, respectively (P = .049), with a trend towards inferior OS (median OS = 7.0 vs 11.5 vs 10.9 months, respectively; P = .10). Multivariable analysis suggests this difference in OS is attributable to the high proportion of s-AML patients in the co-mutated cohort (60% vs 32% and 23%, respectively). Although this study is limited by the retrospective data collection and the relatively small sample size, these data suggest that ASXL1 SRSF2 AML is a distinct subgroup of AML frequently associated with s-AML and differs from ASXL1 SRSF2 /ASXL1 SRSF2 with respect to etiology and leukemogenesis.
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http://dx.doi.org/10.1002/ajh.26110DOI Listing
April 2021

Prognostic significance of serial molecular annotation in myelodysplastic syndromes (MDS) and secondary acute myeloid leukemia (sAML).

Leukemia 2021 04 29;35(4):1145-1155. Epub 2020 Jul 29.

Malignant Hematology Department, H. Lee Moffitt Cancer Center, Tampa, FL, USA.

The implementation of next-generation sequencing (NGS) has influenced diagnostic, prognostic, and therapeutic decisions in myeloid malignancies. However, the clinical relevance of serial molecular annotation in patients with myelodysplastic syndrome (MDS) undergoing active treatment is unknown. MDS or secondary acute myeloid leukemia (sAML) patients who had at least two NGS assessments were identified. Outcomes according to mutation clearance (NGS-) on serial assessment were investigated. Univariate and multivariate Cox regression models were used to evaluate the prognostic impact of NGS trajectory on overall survival (OS). A total of 157 patients (MDS [n = 95]; sAML [n = 52]; CMML [n = 10]) were identified, with 93% of patients receiving treatment between NGS assessments. Magnitude of VAF delta from baseline was significantly associated with quality of response to treatment. Patients achieving NGS- had significantly improved OS compared to patients with mutation persistence (median OS not reached vs. 18.5 months; P = 0.002), which was confirmed in multivariate analysis (HR,0.14; 95%CI = 0.03-0.56; P = 0.0064). Serial TP53 VAF evaluation predicts outcomes with TP53 clearance representing an independent covariate for superior OS (HR,0.22; 95%CI = 0.05-0.99; P = 0.048). Collectively, our study highlights the clinical value of serial NGS during treatment and warrants prospective validation of NGS negativity as a biomarker for treatment outcome.
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http://dx.doi.org/10.1038/s41375-020-0997-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7854836PMC
April 2021

Tumor Microenvironment Composition and Severe Cytokine Release Syndrome (CRS) Influence Toxicity in Patients with Large B-Cell Lymphoma Treated with Axicabtagene Ciloleucel.

Clin Cancer Res 2020 09 15;26(18):4823-4831. Epub 2020 Jul 15.

Department of Blood and Marrow Transplantation and Cellular Immunotherapy, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.

Purpose: One of the challenges of adoptive T-cell therapy is the development of immune-mediated toxicities including cytokine release syndrome (CRS) and neurotoxicity (NT). We aimed to identify factors that place patients at high risk of severe toxicity or treatment-related death in a cohort of 75 patients with large B-cell lymphoma treated with a standard of care CD19 targeted CAR T-cell product (axicabtagene ciloleucel).

Experimental Design: Serum cytokine and catecholamine levels were measured prior to lymphodepleting chemotherapy, on the day of CAR T infusion and daily thereafter while patients remained hospitalized. Tumor biopsies were taken within 1 month prior to CAR T infusion for evaluation of gene expression.

Results: We identified an association between pretreatment levels of IL6 and life-threatening CRS and NT. Because the risk of toxicity was related to pretreatment factors, we hypothesized that the tumor microenvironment (TME) may influence CAR T-cell toxicity. In pretreatment patient tumor biopsies, gene expression of myeloid markers was associated with higher toxicity.

Conclusions: These results suggest that a proinflammatory state and an unfavorable TME preemptively put patients at risk for toxicity after CAR T-cell therapy. Tailoring toxicity management strategies to patient risk may reduce morbidity and mortality.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-1434DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7501265PMC
September 2020

Genomics of Peripheral T-Cell Lymphoma and Its Implications for Personalized Medicine.

Front Oncol 2020 19;10:898. Epub 2020 Jun 19.

Department of Malignant Hematology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, United States.

Peripheral T-cell lymphoma (PTCL) is a rare, heterogenous group of mature T-cell neoplasms that comprise 10-15% of non-Hodgkin lymphoma cases in the United States. All subtypes of PTCL, except for ALK anaplastic T-cell lymphoma, are associated with poor prognosis, with median overall survival (OS) rates of 1-3 years. The diagnosis of PTCL is mainly based on clinical presentation, morphologic features, and immunophenotypes. Recent advances in genome sequencing and gene expression profiling have given new insights into the pathogenesis and molecular biology of PTCL. An enhanced understanding of its genomic landscape holds the promise of refining the diagnosis, prognosis, and management of PTCL. In this review, we examine recently discovered genetic abnormalities identified by molecular profiling in 3 of the most common types of PTCL: and epigenetic regulator mutations in angioimmunoblastic T-cell lymphoma, ALK expression and JAK/STAT3 pathway mutations in anaplastic T-cell lymphoma, and T-follicular helper phenotype and GATA3/TBX21 expression in PTCL-not otherwise specified. We also discuss the implications of these abnormalities for clinical practice, new/potential targeted therapies, and the role of personalized medicine in the management of PTCL.
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http://dx.doi.org/10.3389/fonc.2020.00898DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7317006PMC
June 2020

New Insights Into the Complex Mutational Landscape of Sézary Syndrome.

Front Oncol 2020 21;10:514. Epub 2020 Apr 21.

Department of Malignant Hematology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, United States.

Sézary syndrome (SS) is a genetically and clinically distinct entity among cutaneous T-cell lymphomas (CTCL). SS is characterized by more aggressive disease compared to the most common indolent type of CTCL, mycosis fungoides. However, there are limited available genomic data regarding SS. To characterize and expand current mappings of the genomic landscape of CTCL, whole exome sequencing (WES) was performed on peripheral blood samples from seven patients with SS. We detected 21,784 variants, of which 21,140 were novel and 644 were previously described. Filtering revealed 551 nonsynonymous variants among 525 mutated genes-25 recurrent mutations and 1 recurrent variant. Several recurrently mutated genes crucial to pathogenesis pathways, including Janus kinase (JAK)/signal transducers and activators of transcription (STAT), peroxisome proliferator-activated receptors (PPAR), PI3K-serine/threonine protein kinases (AKT), and fibroblast growth factor receptors (FGFR), were identified. Furthermore, genetic mutations spanned both known and novel genes, supporting the idea of a long-tail distribution of mutations in lymphoma. Acknowledging these genetic variants and their affected pathways may inspire future targeted therapies. WES of a limited number of SS patients revealed both novel findings and corroborated complexities of the "long-tail" distribution of previously reported mutations.
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http://dx.doi.org/10.3389/fonc.2020.00514DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7186303PMC
April 2020

Comparison of SF3B1/DNMT3A Comutations With DNMT3A or SF3B1 Mutation Alone in Myelodysplastic Syndrome and Clonal Cytopenia of Undetermined Significance.

Am J Clin Pathol 2020 06;154(1):48-56

Department of Hematopathology and Lab Medicine, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL.

Objectives: To compare the clinical significance of SF3B1/DNMT3A Comutations with SF3B1 or DNMT3A mutation alone in myelodysplastic syndrome (MDS) and clonal cytopenia of undetermined significance (CCUS).

Methods: We identified and compared 31 patients with only DNMT3A mutation, 48 patients with only SF3B1 mutation, and 16 patients with only SF3B1/DNMT3A comutations.

Results: SF3B1/DNMT3A comutations were found to be more common in MDS, whereas DNMT3A mutation alone was more common in CCUS. The patients with SF3B1/DNMT3A comutations were less likely to have poor cytogenetics than patients with DNMT3A mutation alone. Patients with SF3B1/DNMT3A comutations showed significantly longer median survival time and better overall survival than patients with DNMT3A mutation alone.

Conclusions: Patients with SF3B1/DNMT3A comutations appear to have better clinical outcomes than patients with isolated DNMT3A mutation. These findings suggest that the favorable prognosis of SF3B1 mutation in is not abrogated by the concurrent presence of a DNMT3A mutation.
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http://dx.doi.org/10.1093/ajcp/aqaa016DOI Listing
June 2020

Adopting solutions for annotation and reporting of next generation sequencing in clinical practice.

Pract Lab Med 2020 Mar 10;19:e00154. Epub 2020 Feb 10.

Department of Hematopathology and Lab Medicine, Moffitt Cancer Center, Tampa, FL, 33612, USA.

With advancements in the understanding of human cancers (carcinomas, sarcomas, and hematopoietic malignancies), molecular profiling, especially by Next Generation Sequencing (NGS), is playing an increasingly important role in the diagnosis, prognostication, and therapeutic management of cancer patients. The final and critical step in NGS is the annotation of detected variants and reporting of their clinical significance. Automated bioinformatics tools are available to assist with annotation, but the final responsibility for interpretation and validation of the annotation rests with the pathologist who may be constrained by the pressures of clinical sign-out and limited training in NGS. In this manuscript, we detail our experience in outsourcing variant annotation to a high-quality vendor to improve quality, standardize reporting, and decrease turn-around time of NGS reporting in clinical practice. We describe the composition of the evaluation team, steps that should be taken to evaluate potential annotation vendors, and detailed parameters that should be addressed before contracting with a vendor to guarantee the clinical reliability of the reported annotations.
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http://dx.doi.org/10.1016/j.plabm.2020.e00154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7031307PMC
March 2020

Interrogation of molecular profiles can help in differentiating between MDS and AML with MDS-related changes.

Leuk Lymphoma 2020 06 4;61(6):1418-1427. Epub 2020 Feb 4.

Department of Hematopathology and Laboratory Medicine, Moffitt Cancer Center, Tampa, FL, USA.

A subset of AML with myelodysplastic syndrome (MDS)-related changes (MRCs) occurs without a documented MDS phase. We studied genomic profile of 646 patients: 310 with MDS, 167 with AML without (w/o) MRC, 99 with primary (p) AML-MRC, and 70 with secondary (s) AML-MRC and sought to find differences in mutational patterns. Among the 32-myeloid associated genes studied, ( ≤ .001) was significantly mutated in higher proportion of patients with MDS, compared to other categories. ( < .001), ( = .08), and ( = .02) mutations showed trend toward significance for AML w/o MRC, compared to other categories. In pAML-MRC, ( < .001) was significantly mutated in higher proportion of patients. Similarly, ( = .001), ( = .004), and ( = .04) mutations were more commonly seen in sAML-MRC. While these signatures may not be diagnostically discriminatory, they may help in disease categorization when other data are absent or in challenging cases.
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http://dx.doi.org/10.1080/10428194.2020.1719089DOI Listing
June 2020

Concurrent mutations in other epigenetic modulators portend better prognosis in BCOR-mutated myelodysplastic syndrome.

J Clin Pathol 2020 Apr 26;73(4):209-212. Epub 2019 Nov 26.

Hematopathology, H Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA.

Introduction: The role of single mutations has been extensively studied myelodysplastic syndromes (MDS), but the impact of genetic aberrations in the context of other mutations is less well understood. is an epigenetic transcriptional corepressor. In MDS, mutations are rare and certain mutations are associated with poor prognosis. Our aim was to investigate the role of concurrent mutations in epigenetic MDS-driver genes in -mutated MDS. We hypothesised that these would be redundant and would not contribute to worse prognosis.

Methods: Internal Next Generation Sequencing (NGS) database with targeted genetic profiling of >4000 tumor cases was queried to locate cases of MDS with BCL6 Corepressor protein () mutations only (pBCOR) and cBCOR (comutated epigenetic modulators: , , , , , , , ). Overall survival was determined by chart review. Fischer's exact test and unpaired t-test was performed for statistical analysis.

Results: 25 patients with cBCOR were detected. Only five MDS patients with pBCOR were found. The number of patients with comutations (cBCOR) in epigenetic modulators comprised (n=5), (n=9), (n=11), (n=2), (n=4), IDH1 (n=1), (n=3), (n=1). cBCOR overall survival was 23.8 months versus 11.8 months for pBCOR group.

Conclusions: In this study, we confirm the rarity of mutations. Our results show that there is a trend towards poorer prognosis in patient with pBCOR versus cBCOR although statistical significance was not reached. This may be due to enrichment of poor cytogenetics in pBCOR or increased responsiveness to hypomethylating agents in cBCOR. Larger studies are needed to validate our data.
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http://dx.doi.org/10.1136/jclinpath-2019-206132DOI Listing
April 2020

Haemophagocytic lymphohistiocytosis has variable time to onset following CD19 chimeric antigen receptor T cell therapy.

Br J Haematol 2019 10 13;187(2):e35-e38. Epub 2019 Aug 13.

Department of Blood & Marrow Transplant and Cellular Immunotherapy, Moffitt Cancer Center, Tampa, FL, USA.

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http://dx.doi.org/10.1111/bjh.16155DOI Listing
October 2019

High-dose Therapy and Autologous Hematopoietic Cell Transplantation as Consolidation Treatment for Primary Effusion Lymphoma.

Clin Lymphoma Myeloma Leuk 2019 09 29;19(9):e513-e520. Epub 2019 Mar 29.

Department of Malignant Hematology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL.

Background: Primary effusion lymphoma (PEL) is a rare type of non-Hodgkin lymphoma. The limited disease-free survival after chemotherapy has resulted in a poor prognosis. The outcomes data for high-dose therapy followed by autologous hematopoietic cell transplantation (auto-HCT) for PEL are limited owing to the rarity of the disease.

Patients And Methods: The present study included 9 patients with PEL from 2 major academic centers. Of these patients, 4 had received auto-HCT after high-dose therapy. Of the 9 patients, 8 (89%) had immunodeficiency (7 with human immunodeficiency virus seropositivity; 1, a solid organ transplant recipient) at the diagnosis. Human herpesvirus-8 by immunohistochemistry was positive in 8 patients. Anthracycline-based combination chemotherapy was used as first-line treatment in 7 patients; 4 underwent auto-HCT after attaining first complete remission.

Results: The median follow-up of the surviving patients was 25 months (95% confidence interval [CI], 8%-29%). The 2-year progression-free and overall survival for the 8 patients who had received treatment was 58% (95% CI, 22%-95%) and 73% (95% CI, 41%-100%), respectively. The 2-year progression-free and overall survival for the patients who had received auto-HCT was 50% (95% CI, 1%-99%) and 75% (95% CI, 33%-100%), respectively. Of the 4 auto-HCT recipients, all had been in first complete remission at the time of autografting. The cumulative incidence of relapse was 50% (95% CI, 19%-100%). No deaths were attributable to auto-HCT at 2 years after autografting.

Conclusion: Despite the small sample size, our data have shown that consolidative auto-HCT is safe and effective and should be considered for eligible patients with PEL after demonstration of an objective response to induction chemotherapy. However, the high relapse rate remains a concern and warrants the development of new strategies to mitigate post-transplantation relapse.
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http://dx.doi.org/10.1016/j.clml.2019.03.021DOI Listing
September 2019

Does Double Mutation Portend Better or Worse Prognosis Than Isolated or Mutation?

Cancer Genomics Proteomics 2019 Jan-Feb;16(1):91-98

Department of Hematopathology and Lab Medicine, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, U.S.A.

Background: Mutations in splicing factor 3b subunit 1 (SF3B1) have been reported to be associated with a favorable prognosis, while the prognostic impact of tet methylcytosine dioxygenase 2 (TET2) mutations is still controversial. The clinical significance of combined SF3B1 and TET2 mutation is even more uncertain. In this study, the clinical consequences of concurrent double SF3B1/TET2 mutation were compared with isolated SF3B1 or TET2 mutation.

Materials And Methods: The demographics, diagnosis, cytogenetic abnormalities, and overall survival time of 130 patients with isolated SF3B1 (n=48) or TET2 mutation (n=54), or double SF3B1/TET2 mutation (n=28) were compared by next-generation sequencing.

Results: Patients with double mutation were found to be significantly older than patients with isolated TET2 mutation. Patients with double mutation or isolated SF3B1 mutation were less likely to be diagnosed with acute myeloid leukemia than patients with isolated TET2 mutation. Patients with myelodysplasia had a higher percentage of double or isolated SF3B1 mutation, while patients with myeloproliferative neoplasms had a higher percentage of isolated TET2 mutation. Patients with double mutation more frequently had increased ring sideroblasts similarly to patients with isolated SF3B1 mutation. The percentage of patients with normal cytogenetics or good cytogenetic abnormalities was significantly higher in patients with double mutation than those with isolated mutation. Finally, in patients with myelodysplasia and normal cytogenetics, the median survival time in those with double mutation was significantly longer than in those with isolated SF3B1 mutation, even though the overall survival curve was not statistically significant.

Conclusion: TET2 mutation appeared not to have additional effects when combined with SF3B1, and patients with double mutation appeared to have at least as, good as or even better prognosis than patients with isolated mutation.
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http://dx.doi.org/10.21873/cgp.20115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6348401PMC
April 2019

Principles for the Oncologist in Caring for Muslim Patients.

J Oncol Pract 2018 09 23;14(9):521-524. Epub 2018 Aug 23.

University of Florida College of Medicine; Gainesville; and H Lee Moffitt Cancer Center, Tampa, FL.

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http://dx.doi.org/10.1200/JOP.18.00116DOI Listing
September 2018

Transformation of T-Cell Acute Lymphoblastic Lymphoma to Peripheral T-Cell Lymphoma: A Report of Two Cases.

Case Rep Hematol 2018 28;2018:9191582. Epub 2018 Feb 28.

Moffitt Cancer Center, Tampa, FL, USA.

Nonhepatosplenic/noncutaneous peripheral T-cell lymphoma (NHNC PTCL) represents a miscellaneous group of unrelated T-cell lymphomas of which only isolated cases have been reported. We describe two cases of transformation from T-lymphoblastic leukemia/lymphoma to NHNC PTCL. Transformation into more aggressive disease is a rare event in T-cell lineage-derived hematologic malignancies compared to B-cell neoplasms. Nevertheless, both of our cases involved relapse as PTCL manifested with skin involvement and an overt shift from blastic morphology to large granular leukemia-like mature T cells. Among other notable molecular characteristics, expression of immature markers such as TdT was lost in both cases. Based on cytogenetics, phenotype, and morphology, both patients represent a novel phenomenon of clonal transformation from T-ALL to PTCL which has rarely been reported in the literature. Such transformation may carry important diagnostic and biological implications.
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http://dx.doi.org/10.1155/2018/9191582DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5850893PMC
February 2018

Genetic Landscape of Acute Myeloid Leukemia Interrogated by Next-generation Sequencing: A Large Cancer Center Experience.

Cancer Genomics Proteomics 2018 Mar-Apr;15(2):121-126

Department of Hematopathology, Moffitt Cancer Center, Tampa, FL, U.S.A.

Background/aim: Acute myeloid leukemia (AML) represents a heterogeneous disease with varying morphologic, immunophenotypic, and genetic features, along with varying patient outcomes. The genomic tractability of AML makes it amenable for targeted next-generation sequencing (NGS) testing clinically.

Materials And Methods: One hundred eights-seven unique patients with a diagnosis of acute myeloid leukemia between May 2011 and Oct 2014 and with mutational analysis by NGS were included in this study. The distribution of gene mutations was investigated in different subcategories of AML.

Results: Most patients in this study (n=182) received Genoptix testing (either 5-gene panel or 21-gene panel). In 130/187 (70%) cases, there was an average of 2.3 mutations per case (range=0-7 mutations). We specifically mention mutations in 32 genes, their significance and co-occurrence as detected in different types of AML.

Conclusion: The genetic heterogeneity of AML signifies the importance of taking a personalized-medicine approach to the management of patients with AML.
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http://dx.doi.org/10.21873/cgp.20070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5892606PMC
August 2018

Allogeneic hematopoietic cell transplantation in T-cell prolymphocytic leukemia: A single-center experience.

Leuk Res 2018 04 31;67:1-5. Epub 2018 Jan 31.

Department of Blood & Marrow Transplant and Cellular Immunotherapy, Moffitt Cancer Center, Tampa, FL, USA.

Background: T- cell prolymphocytic leukemia (T- PLL) is a rare aggressive hematological malignancy. Alemtuzumab, an anti-CD52 humanized monoclonal antibody, is the treatment of choice for remission induction. Allogeneic hematopoietic cell transplantation (allo-HCT) has been described to induce durable remissions and improve survival, but data is limited.

Patients And Methods: We evaluated clinical outcomes of 11 patients, median age of 56 (range, 43-71) years who underwent allo-HCT for T-PLL. The majority of cases were in the first complete remission (CR1 = 9, CR2 = 1, second partial response PR2 = 1) at time of allo-HCT. Myeloablative conditioning was the most commonly prescribed preparative regimen (n = 8, 73%) and tacrolimus plus sirolimus was most commonly prescribed regimen for graft-versus-host disease prophylaxis (n = 5, 46%).

Results: The median follow-up for surviving patients was 48 (range, 6-123) months. The 4-year progression-free survival (PFS) and overall survival (OS) were 45% (95% confidence interval (CI) = 13-78%) and 56% (95% CI = 24-89%), respectively. Cumulative incidence of non-relapse mortality (NRM) at 4-year post-transplantation was 34% (95%CI = 14-85%). The 4-year cumulative incidence of relapse/progression was 21% (95% CI = 6-71%).

Conclusion: Allo-HCT is an effective treatment for T-PLL. Patients must be evaluated for their candidacy for allo-HCT as soon as the diagnosis is confirmed. Efforts are needed to decrease NRM and relapse.
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http://dx.doi.org/10.1016/j.leukres.2018.01.009DOI Listing
April 2018

Allogeneic Hematopoietic Cell Transplantation for Richter Syndrome: A Single-Center Experience.

Clin Lymphoma Myeloma Leuk 2018 01 12;18(1):e35-e39. Epub 2017 Oct 12.

Department of Malignant Hematology, Moffitt Cancer Center, Tampa, FL.

Background: Recent studies have shown dismal outcomes when chronic lymphocytic leukemia progresses to Richter syndrome after patients receive ibrutinib, with a median overall survival ranging from 2.6 to 3.5 months. Published data on efficacy of allogeneic hematopoietic cell transplantation in Richter syndrome are limited to single-center case series and registry data.

Patients And Methods: We evaluated the efficacy of allogeneic transplantation in 10 patients, median age of 63 (range, 50-74) years, allografted at a median of 5 (range, 4-25) months from diagnosis of Richter syndrome. All showed an objective response to therapy before transplantation (first complete remission = 7 [70%], first partial response = 2 [20%], second partial response = 1 [10%]). Most received a myeloablative conditioning regimen (n = 7, 70%). Filgrastim-mobilized peripheral blood stem cells was the preferred cell source (n = 10, 100%).

Results: Median follow-up of surviving patients was 46 (range, 15-82) months. The 4-year overall survival was 50% (95% confidence interval [CI], 19%-81%). Nonrelapse mortality at 1 year and 4 years post-transplantation were 40% (95% CI, 19%-85%) for both time points. The 4-year incidence of relapse/progression was 10% (95% CI, 2%-64%).

Conclusion: Allogeneic hematopoietic cell transplantation is an effective treatment for patients with Richter syndrome who show an objective response before allografting. Patients must be referred to transplant centers as soon as the diagnosis is confirmed to evaluate candidacy for the procedure and identify a suitable donor in a timely manner.
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http://dx.doi.org/10.1016/j.clml.2017.10.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6716154PMC
January 2018

Myeloid/lymphoid neoplasms with FGFR1 rearrangement.

Leuk Lymphoma 2018 07 9;59(7):1672-1676. Epub 2017 Nov 9.

a Department of Leukemia , The University of Texas MD Anderson Cancer Center , Houston , TX , USA.

Myeloid/lymphoid neoplasms with FGFR1 rearrangement are a rare entity. We present a multicenter experience of 17 patients with FISH-confirmed FGFR1 rearrangement. The clinical presentation at diagnosis included myeloproliferative neoplasm (MPN) in 4 (24%) patients, acute leukemia (AL) in 7 (41%), and concomitant MPN with AL in 6 (35%). The two most frequently observed cytogenetic abnormalities were t(8;13)(p11.2;q12)(partner gene ZMYM2) and t(8;22)(p11.2; q11.2)(BCR). Seventy-eight percent of tested patients had a RUNX1 mutation, of whom all had AL. Overall response rate to frontline therapy was 69%, and 76% of patients subsequently received allogeneic stem cell transplant (ASCT). After a median follow-up of 11 months, median progression-free survival was 15 months and median overall survival was not reached. In conclusion, FGFR1-rearranged hematologic malignancies present with features of MPN and/or AL. FGFR1 and RUNX1 are therapeutic targets for ongoing and future clinical trials.
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http://dx.doi.org/10.1080/10428194.2017.1397663DOI Listing
July 2018

PRDM1 expression levels in marginal zone lymphoma and lymphoplasmacytic lymphoma.

Int J Clin Exp Pathol 2017 1;10(8):8610-8618. Epub 2017 Aug 1.

Department of Pathology and Immunology, Washington University St. Louis, MO, USA.

PRDM1 (BLIMP1) is a transcription repressor protein shown to be involved in B-cell differentiation into plasma cells. Marginal zone lymphomas (MZL) and lymphoplasmacytic lymphomas (LPL) are B cell lymphomas that both show some degree of plasmacytic differentiation and thus can sometimes constitute a difficult differential diagnosis. In this study, we investigated if MZL and LPL have abnormalities in the expression of PRDM1 beta and if there are any differences in expression between these two entities. After interrogating 42 samples (15 marginal zone lymphomas, 9 lymphoplasmacytic lymphomas, 3 follicular lymphomas, and 13 normal/control samples), we have found that a significant percentage of MZL and LPL cases harbor abnormalities (67% and 44%, respectively) involving the PRDM1-β transcript (P=0.004). By immunohistochemistry, PRDM1 positive staining (>5%) was more common in MZL. We conclude that PRDM1-β may play a role in the pathogenesis of these low-grade lymphomas with plasmacytic differentiation.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6965379PMC
August 2017

Comparison of the Mutational Profiles of Primary Myelofibrosis, Polycythemia Vera, and Essential Thrombocytosis.

Am J Clin Pathol 2017 May;147(5):444-452

Departments of Hematopathology and Laboratory Medicine.

Objectives: To compare the mutational profiles of patients with primary myelofibrosis (PMF), polycythemia vera (PV), and essential thrombocytosis (ET).

Methods: Next-generation sequencing results of 75 cases of PMF, 33 cases of PV, and 27 cases of ET were compared.

Results: Mutation rates of ASXL1 and SRSF2 were significantly higher in PMF than in PV or ET. ASXL1 mutations appeared to be more frequently associated with risk of transformation to acute myeloid leukemia than JAK2 or TET2 mutations. The most common mutation-cytogenetic combinations in myeloproliferative neoplasm (MPN) were mutations of JAK2 or ASXL1 with del(20q) and were more common in patients with PMF and PV than in patients with ET. Differences were also found between patients with PMF and PV.

Conclusions: PMF, PV, and ET show different mutational profiles, which may be helpful in resolving the differential diagnosis between MPNs. Due to the relatively small number of cases and variable testing over time, larger controlled studies are necessary to confirm the findings.
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http://dx.doi.org/10.1093/ajcp/aqw222DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5402718PMC
May 2017

Detection of Novel t(12;17)(p12;p13) in Relapsed Refractory Acute Myeloid Leukemia by Anchored Multiplex PCR(AMP)-based Next-Generation Sequencing.

Appl Immunohistochem Mol Morphol 2019 03;27(3):e28-e31

Department of Hematopathology and Laboratory Medicine, Moffitt Cancer Center, Tampa, FL.

Although several technologies can be used to detect gene fusions, anchored multiplex PCR next-generation sequencing (AMP-NGS) offers the advantage of novel fusion detection and the ability to multiplex multitudinous genes. We applied AMP-NGS technology in the evaluation of a 56-year-old gentleman with myelodysplastic syndrome transformed acute myeloid leukemia (AML). Patient was initially diagnosed with low-risk myelodysplastic syndrome-refractory cytopenias and multilineage dysplasia (MDS-RCMD), progressed to AML after failing hypomethylating agent therapy. At progression patients had normal cytogenetics but NGS profiling showed ETV6 c.416_417del CT frame shift and U2AF1 S34F mutations. Patient attains brief remission of 2 months after induction chemotherapy and then he was refractory to 2 salvage chemotherapy regimens. Reassessment after failing second salvage, identified t(12;17)(p13;p13)[20] by karyotype. It was postulated that the 12p13 locus might represent a new rearrangement of ETV6. AMP-NGS confirmed involvement of the ETV6 with discovery of a novel fusion partner, HIC1. The detection of the novel fusion partners was supported by the breakpoints originally observed by karyotype. This discovery of ETV6-HIC1 gene fusion by AMP-NGS technology provided new insight into a leukemogenic pathway in AML. Future use of this technology can serve as an adjunct tool in workup of patients with AML and can also help in formulating therapeutic strategies.
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http://dx.doi.org/10.1097/PAI.0000000000000477DOI Listing
March 2019

Sentinel case of Richter transformation from chronic lymphocytic leukaemia/small lymphocytic lymphoma to CD3+ diffuse large B-cell lymphoma.

J Clin Pathol 2017 Jul 29;70(7):575-578. Epub 2016 Nov 29.

Moffitt Cancer Center, Tampa, Florida, USA.

Aim: To report the first case of a Richter syndrome where small lymphocytic lymphoma (SLL) progressed to a CD3+ diffuse large B-cell lymphoma (DLBCL).

Methods: Macrodissection of small and large cell lymphomatous components was performed. This was followed by flow cytometric analysis along with molecular B-cell immunoglobulin (heavy and light chains) and T-cell receptor (γ and β chains) gene rearrangement studies to investigate a clonal relationship between the components.

Results: The immunophenotypic profile was similar between small and large cell components of the lymphoma by flow cytometry. Furthermore, shared clonal peaks were observed between both components based on molecular B-cell and T-cell receptor gene rearrangement studies, confirming a clonal relationship.

Conclusions: Chronic lymphocytic leukaemia/SLL may rarely undergo Richter transformation to a DLBCL demonstrating lineage infidelity. This is a potentially important diagnostic pitfall and such cases should not be confused with a de novo T-cell lymphoma.
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http://dx.doi.org/10.1136/jclinpath-2016-204024DOI Listing
July 2017

EBV-positive Richter's syndrome with laboratory features of Burkitt's lymphoma, in Ibrutinib-treated chronic lymphocytic leukemia.

Leuk Lymphoma 2017 07 16;58(7):1753-1756. Epub 2016 Nov 16.

d Division of Hematopathology , Mayo Clinic , Rochester , MN , USA.

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http://dx.doi.org/10.1080/10428194.2016.1256482DOI Listing
July 2017

CD4-positive diffuse large B-cell lymphoma: A variant with aggressive clinical potential.

World J Methodol 2016 Sep 26;6(3):181-6. Epub 2016 Sep 26.

Mohammad O Hussaini, Division of Molecular Pathology, Department of Pathology and Immunology, Washington University in St. Louis School of Medicine, St. Louis, MO 63110, United States.

CD4 expression is rare in diffuse large B-cell lymphoma (DLBCL), with 4 previously reported cases. Its significance is uncertain. We report five patients with CD4(+) DLBCL and one CD4(+) primary mediastinal large B-cell lymphoma. Cases were identified by searching the electronic database of the department; each was reviewed. Average age was 56 years. Neoplastic cells expressed CD20 (5/6 tested cases). BCL2/BCL6 expression were seen in 3/3 tested cases, suggesting a germinal center origin. Additionally, expression of T-cell antigens CD2 and CD5 was noted in 2/2 and CD7 in 1/1 tested case. CD3 was negative in all. Lymph nodes were commonly involved (67%). Patients received chemotherapy +/- radiation (6/6) and bone marrow transplant (2/6). Average survival was 44.2 mo. CD4 expression in DLBCL raises questions of lineage commitment. CD4(+) DLBCL is rare; care should be exercised not to diagnose these as T-cell lymphomas. A subset behaves aggressively.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5031925PMC
http://dx.doi.org/10.5662/wjm.v6.i3.181DOI Listing
September 2016

Biomarkers in Hematological Malignancies: A Review of Molecular Testing in Hematopathology.

Cancer Control 2015 Apr;22(2):158-66

Department of Hematopathology and Laboratory Medicine, Moffitt Cancer Center, Tampa, FL 33612, USA.

Background: Molecular interrogation of genetic information has transformed our understanding of disease and is now routinely integrated into the workup and monitoring of hematological malignancies. In this article, a brief but comprehensive review is presented of state-of-the-art testing in hematological disease.

Methods: The primary medical literature and standard textbooks in the field were queried and reviewed to assess current practices and trends for molecular testing in hematopathology by disease.

Results: Pertinent materials were summarized under appropriate disease categories.

Conclusion: Molecular testing is well entrenched in the diagnostic and therapeutic pathways for hematological malignancies, with rapid growth and insights emerging following the integration of next-generation sequencing into the clinical workflow.
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http://dx.doi.org/10.1177/107327481502200206DOI Listing
April 2015

Frozen section analysis of margins for head and neck tumor resections: reduction of sampling errors with a third histologic level.

Mod Pathol 2011 May 7;24(5):665-70. Epub 2011 Jan 7.

Department of Pathology and Immunology, Washington University in St Louis, 660 South Euclid Avenue,St Louis, MO 63110, USA.

Frozen section analysis is an essential tool for assessing margins intra-operatively to assure complete resection. Many institutions evaluate surgical defect edge tissue provided by the surgeon after the main lesion has been removed. With the increasing use of transoral laser microsurgery, this method is becoming even more prevalent. We sought to evaluate error rates at our large academic institution and to see if sampling errors could be reduced by the simple method change of taking an additional third section on these specimens. All head and neck tumor resection cases from January 2005 through August 2008 with margins evaluated by frozen section were identified by database search. These cases were analyzed by cutting two levels during frozen section and a third permanent section later. All resection cases from August 2008 through July 2009 were identified as well. These were analyzed by cutting three levels during frozen section (the third a 'much deeper' level) and a fourth permanent section later. Error rates for both of these periods were determined. Errors were separated into sampling and interpretation types. There were 4976 total frozen section specimens from 848 patients. The overall error rate was 2.4% for all frozen sections where just two levels were evaluated and was 2.5% when three levels were evaluated (P=0.67). The sampling error rate was 1.6% for two-level sectioning and 1.2% for three-level sectioning (P=0.42). However, when considering only the frozen section cases where tumor was ultimately identified (either at the time of frozen section or on permanent sections) the sampling error rate for two-level sectioning was 15.3 versus 7.4% for three-level sectioning. This difference was statistically significant (P=0.006). Cutting a single additional 'deeper' level at the time of frozen section identifies more tumor-bearing specimens and may reduce the number of sampling errors.
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http://dx.doi.org/10.1038/modpathol.2010.233DOI Listing
May 2011
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