Publications by authors named "Lubomir Sokol"

161 Publications

Clinical characteristics and prognostic factors of 70 patients with Sézary syndrome: a single-institutional experience at Moffitt cancer center.

Leuk Lymphoma 2021 Sep 1:1-8. Epub 2021 Sep 1.

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

Sézary syndrome (SS) is a rare and aggressive leukemic variant of cutaneous T-cell lymphoma, with a median overall survival (OS) rate of 2-4 years. Few studies have described the clinical outcome of SS patients since 2012. We retrospectively analyzed 70 patients diagnosed with SS treated at a high-volume tertiary cancer center between 2000 and 2018. Overall survival at 1 and 5 years was 84.1% and 50.7%, respectively. Univariate analyses identified older age (>65 years) and male sex as poor prognostic factors. Five patients presented with circulating large granular lymphocytic proliferation and had a favorable prognosis. Targeted therapies were effective in treating refractory/relapsed SS patients with a durable response. Therapeutic advancements and the comprehensive treatments used in a multidisciplinary clinic improved OS rates.
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http://dx.doi.org/10.1080/10428194.2021.1971218DOI Listing
September 2021

Aggressive natural killer cell leukemia: diagnosis, treatment recommendations, and emerging therapies.

Expert Rev Hematol 2021 Aug 20;14(8):731-740. Epub 2021 Jul 20.

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

Introduction: Aggressive natural killer cell leukemia (ANKL) is a rare hematologic malignancy characterized by the EBV-driven proliferation of mature natural killer cells. It mostly frequently affects younger adults and has a fulminant course with a median overall survival of 2 months. Challenges in managing this disease include an aggressive clinical course, hematologic complications, limited clinical evidence, and a lack of consensus on therapeutic strategies.

Areas Covered: Here, authors reviewed the key aspects of the epidemiology and current understandings of the molecular pathogenesis of ANKL. The available clinical evidence and proposed diagnostic and therapeutic algorithms in treating ANKL are discussed. Currently, the only potential cure is induction therapy with L-asparaginase-based combined chemotherapy regimens, followed by allogeneic hematologic stem transplant. However, options are extremely limited in the relapsed/refractory setting. Recently, international efforts have been made to understand the aberrant molecular pathways of ANKL and identify potential drug targets for this disease; PD-1 inhibitors, EBV-specific cytotoxic lymphocyte therapy, BCL-2 inhibitors, and JAK2 inhibitors in combination with other agents have been shown to have promising potential in treating this aggressive disease.

Expert Opinion: When clinical trials are not available, a personalized approach using next-generation sequencing results should be encouraged in the relapse/refractory setting.
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http://dx.doi.org/10.1080/17474086.2021.1955345DOI Listing
August 2021

Targeting CD22 for the Treatment of B-Cell Malignancies.

Immunotargets Ther 2021 6;10:225-236. Epub 2021 Jul 6.

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

Immunotherapeutic agents play an increasingly important role in the treatment of B-cell malignancies. CD19 and CD20 are common targets for lymphoid malignancies, though patients who relapse have few therapeutic options remaining. CD22 is a cell surface sialoglycoprotein uniquely present on B-cells and regulates B-cell function and proliferation. Thus, it is an appealing therapeutic target for autoimmune disorders and B-cell malignancies. A variety of therapies targeting CD22 have been developed, including monoclonal antibodies, antibody-drug conjugates, radioimmunoconjugates, chimeric antigen receptor T cells, and bispecific antibodies. Here, we review the biology of CD22 and key therapies targeting CD22 in lymphoid malignancies.
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http://dx.doi.org/10.2147/ITT.S288546DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8275043PMC
July 2021

Long-Term Remission After Matched Sibling Donor Hematopoietic Cell Transplantation in a Patient With Primary Cutaneous CD8+ Aggressive Epidermotropic Cytotoxic T-Cell Lymphoma.

Cureus 2021 May 20;13(5):e15132. Epub 2021 May 20.

Hematology and Oncology, Moffitt Cancer Center, Tampa, USA.

Primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma (CD8+ PCAECTL) is an extremely rare neoplasm with a poor prognosis. Chemotherapy typically does not result in a sustained response, and hematopoietic stem cell transplant (HSCT) is the only therapy that has been shown to produce a durable response of any kind. Here, we report a case of a 25-year-old previously healthy male who presented with a painful ulcerative lesion on the bottom of his right great toe and local lymphadenopathy. The biopsy of the lesion was consistent with CD8+ PCAECTL. He received immediate chemotherapy followed by matched related donor HSCT (MRD-HSCT) and remained in complete remission (CR) for eight years post-transplant, longer than any CR reported in the literature. In conclusion, our report provides clinical evidence that early transplant consult and donor search is one of the key factors in the management of CD8+ PCAECTL.
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http://dx.doi.org/10.7759/cureus.15132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8214246PMC
May 2021

Large granular lymphocytic leukemia - A retrospective study of 319 cases.

Am J Hematol 2021 07 24;96(7):772-780. Epub 2021 Apr 24.

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

Large granular lymphocytic leukemia (LGLL) is a rare hematological malignancy that arises from cytotoxic T lymphocytes (T-LGLL) in 85% of cases and natural killer (NK) cells in the rest. A significant knowledge gap exists regarding the pathogenesis, treatment choices, and prognostic factors of LGLL. We report a cohort of 319 consecutive LGLL patients who presented to our cancer center between 2001 and 2020. A total of 295 patients with T-LGLL and 24 with chronic NK-cell lymphoproliferative disorder (CLPD-NK) were identified. The median age was 65 years (range, 17-90 years). Eighty-three patients (26.0%) had autoimmune diseases. A total of 119 patients (37.3%) had coexisting malignancies, 66 (20.7%) had solid tumors, and 59 (18.5%) had hematological malignancies. Most coexisting malignancies were diagnosed before the diagnosis of LGLL. Treatment was needed for 57% of patients. Methotrexate (MTX), cyclophosphamide (Cy), and cyclosporine A (CSA) were most used and had similar response rates between 61.5%-74.4%. Cy produced more complete responses (32.3%) compared to MTX and CSA (15.7% and 23.1%, respectively). Thrombocytopenia, splenomegaly, and female gender (after controlling for autoimmune diseases) were associated with decreased response rates to MTX, CSA, or Cy. Autoimmune diseases were associated with increased response rates. Thrombocytopenia was an independent risk factor for worse survival.
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http://dx.doi.org/10.1002/ajh.26183DOI Listing
July 2021

Mapping cutaneous T-cell lymphoma in the state of Florida: A retrospective exploratory spatial analysis of incidence patterns.

J Am Acad Dermatol 2021 Jan 19. Epub 2021 Jan 19.

Department of Dermatology and Cutaneous Surgery, University of South Florida (USF), Tampa, Florida; Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center, Tampa, Florida. Electronic address:

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http://dx.doi.org/10.1016/j.jaad.2021.01.041DOI Listing
January 2021

Should we integrate viscoelastic assays with standard coagulation screening?

J Clin Pathol 2021 Mar 12;74(3):141-143. Epub 2021 Jan 12.

Department of Malignant Hematology, Moffitt Cancer Center, Tampa, Florida, USA.

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http://dx.doi.org/10.1136/jclinpath-2020-207099DOI Listing
March 2021

Utility of flow cytometry and gene rearrangement analysis in tissue and blood of patients with suspected cutaneous T‑cell lymphoma.

Oncol Rep 2021 01 23;45(1):349-358. Epub 2020 Nov 23.

Department of Anatomic Pathology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.

Cutaneous T‑cell lymphoma (CTCL) is difficult to diagnose at an early stage. Current diagnostic tools include clinical examination, histomorphologic analysis, immunohistochemistry, flow cytometry of peripheral blood and/or lesional tissue, and evaluation of T‑cell receptor (TCR) clonality by gene rearrangement analysis (TCRGR). Advances in genomic sequencing, including high‑throughput sequencing (HTS), can be used to identify specific clones of rearranged TCR genes. Even with all of these tools, CTCL can take as long as a decade to definitively diagnose, potentially delaying treatment options and causing patient anxiety. This study aimed to evaluate the performance of the various ancillary testing modalities used to diagnose early‑stage CTCL. In a subset of patients the performance of HTS was compared to flow cytometry and conventional TCRGR analysis via polymerase chain reaction (PCR). Fifty‑five patients, with a total of 68 skin biopsies and peripheral blood draws, were evaluated using flow cytometry, PCR‑TCRGR, and HTS‑TCRGR to determine the sensitivity and specificity of each ancillary test. In tissue biopsies, flow cytometry (64%), PCR (71%) and HTS (69%) shared similar sensitivities; flow cytometry had the highest specificity (93%), followed by HTS (86%) and PCR (76.9%). However, flow cytometry and PCR had insufficient DNA quantities in 29 and 15% of the specimens, respectively. Peripheral blood testing was less sensitive than tissue testing (flow cytometry 14%, PCR 41%, HTS 33%); in peripheral blood, HTS was the most specific test (flow cytometry, 70%; PCR, 62.5%; and HTS, 100%). HTS is a highly specific molecular test for identifying CTCL in peripheral blood and skin biopsy specimens; however, our findings suggest a need for a continued search for more sensitive tests for early‑stage CTCL.
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http://dx.doi.org/10.3892/or.2020.7865DOI Listing
January 2021

Methyltransferase inhibitors restore SATB1 protective activity against cutaneous T cell lymphoma in mice.

J Clin Invest 2021 02;131(3)

Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, USA.

Cutaneous T cell lymphoma (CTCL) has a poorly understood etiology and no known cure. Using conditional knockout mice, we found that ablation of the genomic organizer special AT-rich sequence-binding protein 1 (Satb1) caused malignant transformation of mature, skin-homing, Notch-activated CD4+ and CD8+ T cells into progressively fatal lymphoma. Mechanistically, Satb1 restrained Stat5 phosphorylation and the expression of skin-homing chemokine receptors in mature T cells. Notably, methyltransferase-dependent epigenetic repression of SATB1 was universally found in human Sézary syndrome, but not in other peripheral T cell malignancies. H3K27 and H3K9 trimethylation occluded the SATB1 promoter in Sézary cells, while inhibition of SUV39H1/2 methyltransferases (unlike EZH2 inhibition) restored protective SATB1 expression and selectively abrogated the growth of primary Sézary cells more effectively than romidepsin. Therefore, inhibition of methyltransferases that silence SATB1 could address an unmet need for patients with mycosis fungoides/Sézary syndrome, a set of incurable diseases.
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http://dx.doi.org/10.1172/JCI135711DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7843215PMC
February 2021

Combined oral 5-azacytidine and romidepsin are highly effective in patients with PTCL: a multicenter phase 2 study.

Blood 2021 04;137(16):2161-2170

Division of Hematology and Oncology, Program for T-Cell Lymphoma Research, University of Virginia Cancer Center, Charlottesville, VA.

Peripheral T-cell lymphomas (PTCLs) are uniquely vulnerable to epigenetic modifiers. We demonstrated in vitro synergism between histone deacetylase inhibitors and DNA methyltransferase inhibitors in preclinical models of T-cell lymphoma. In a phase 1 trial, we found oral 5-azacytidine and romidepsin to be safe and effective, with lineage-selective activity among patients with relapsed/refractory (R/R) PTCL. Patients who were treatment naïve or who had R/R PTCL received azacytidine 300 mg once per day on days 1 to 14, and romidepsin 14 mg/m2 on days 8, 15, and 22 every 35 days. The primary objective was overall response rate (ORR). Targeted next-generation sequencing was performed on tumor samples to correlate mutational profiles and response. Among 25 enrolled patients, the ORR and complete response rates were 61% and 48%, respectively. However, patients with T-follicular helper cell (tTFH) phenotype exhibited higher ORR (80%) and complete remission rate (67%). The most frequent grade 3 to 4 adverse events were thrombocytopenia (48%), neutropenia (40%), lymphopenia (32%), and anemia (16%). At a median follow-up of 13.5 months, the median progression-free survival, duration of response, and overall survival were 8.0 months, 20.3 months, and not reached, respectively. The median progression-free survival and overall survival were 8.0 months and 20.6 months, respectively, in patients with R/R disease. Patients with tTFH enjoyed a particularly long median survival (median not reached). Responders harbored a higher average number of mutations in genes involved in DNA methylation and histone deacetylation. Combined azacytidine and romidepsin are highly active in PTCL patients and could serve as a platform for novel regimens in this disease. This trial was registered at www.clinicaltrials.gov as #NCT01998035.
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http://dx.doi.org/10.1182/blood.2020009004DOI Listing
April 2021

NCCN Guidelines Insights: T-Cell Lymphomas, Version 1.2021.

J Natl Compr Canc Netw 2020 11 2;18(11):1460-1467. Epub 2020 Nov 2.

26The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute.

Hepatosplenic T-cell lymphoma (HSTCL) is a rare subtype of T-cell lymphoma associated with an aggressive clinical course and a worse prognosis. HSTCL develops in the setting of chronic immune suppression or immune dysregulation in up to 20% of cases and is most often characterized by spleen, liver, and bone marrow involvement. Diagnosis and management of HSTCL pose significant challenges given the rarity of the disease along with the absence of lymphadenopathy and poor outcome with conventional chemotherapy regimens. These Guidelines Insights focus on the diagnosis and treatment of HSTCL as outlined in the NCCN Guidelines for T-Cell Lymphomas.
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http://dx.doi.org/10.6004/jnccn.2020.0053DOI Listing
November 2020

Extranodal NK/T Cell Lymphoma: Evidence-based Review of Safety and Toxicity of the Available Regimens.

Clin Lymphoma Myeloma Leuk 2021 04 8;21(4):199-204. Epub 2020 Oct 8.

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

Extranodal natural killer/T cell lymphoma (ENKTL) is a rare type of mature T and NK neoplasm. It is more prevalent in Asia and Latin America where the Epstein-Barr virus is endemic and has been linked to the disease. Most studies have emerged from those 2 regions to evaluate best management options. There are no standards of care in the management owing to the lack of unified approach depending on the treatment region and availability of different therapy options. Several reviews have focused on the outcome of the different chemotherapy combinations. There are no systematic reviews of the toxicity of those regimens despite the fact that many of them incorporate the use of asparaginase and/or radiation in combination with chemotherapy. We have found that although integration of asparaginase and/or radiation have led to improved outcome, it was done at the expense of increased toxicity. The most recent studies are showing promising outcomes while decreasing toxicity.
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http://dx.doi.org/10.1016/j.clml.2020.10.006DOI Listing
April 2021

Myasthenia Gravis and Large Granular Lymphocytic Leukemia: a rare association.

Leuk Res Rep 2020 6;14:100226. Epub 2020 Oct 6.

Moffitt Cancer Center, Tampa FL 33612.

Myasthenia gravis (MG) is an autoimmune neuromuscular junction disorder sometimes observed in hematologic malignancies as a paraneoplastic syndrome. T-cell Large Granular Lymphocytic Leukemia (T-LGLL) is a rare lymphoproliferative clonal frequently associated with autoimmune disorders. Here we report two patients with T-LGLL who developed MG. In both patients the MG was bulbar without generalized weakness and did not involve the thymus. The treatment of T-LGLL led to the resolution of MG symptoms and decrease in acetylcholine receptor antibody titers in both patients suggesting a causative association.
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http://dx.doi.org/10.1016/j.lrr.2020.100226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7568180PMC
October 2020

Primary Cutaneous Gamma/Delta T-cell Lymphoma and Hemophagocytic Lymphohistiocytosis Associated With AIDS.

Cureus 2020 Sep 11;12(9):e10386. Epub 2020 Sep 11.

Hematology and Oncology, Moffitt Cancer Center, Tampa, USA.

Primary cutaneous gamma delta T-cell lymphoma (PCGD-TCL) is a rare lymphoma that makes up less than 1% of all cutaneous T-cell lymphomas. Patients with PCGD-TCL typically present with rapidly progressing plaques and ulceronecrotic nodules most frequently located on extremities without lymph node or bone marrow involvement. The overall prognosis is poor with a median overall survival of approximately 15 months. This case highlights a patient with concomitant PCGD-TCL, hemophagocytic lymphohistiocytosis, and human immunodeficiency virus-1-acquired immunodeficiency syndrome. There is a paucity of case reports describing PCGD-TCL and there are no evidence-based treatment recommendations. Further studies are needed to optimize strategies to treat patients with these diseases.
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http://dx.doi.org/10.7759/cureus.10386DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7549995PMC
September 2020

Classical Hodgkin Lymphoma: Clinicopathologic Features, Prognostic Factors, and Outcomes From a 28-Year Single Institutional Experience.

Clin Lymphoma Myeloma Leuk 2021 02 27;21(2):132-138. Epub 2020 Aug 27.

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

Introduction: Classical Hodgkin lymphoma (cHL) is a curable malignancy, with a complete remission rate of approximately 90%. However, relapse remains a significant cause of mortality. Prognostic factors are useful in guiding therapy. This is a large, single-institution study defining the clinicopathologic features, prognostic factors, and treatment outcomes of patients with cHL.

Patients And Methods: We reviewed 727 patients with cHL treated at H. Lee Moffitt Cancer Center and Research Institute from 1990 to 2017. Data on demographics, laboratory studies, and disease statuses were collected from the institutional database and electronic medical records. Statistical analyses, overall survival (OS), progression-free survival (PFS), and multivariate analyses were performed.

Results: The median age was 35 years. Fifty-four percent of patients were men; 45.6% had advanced stage disease; 82% were treated with ABVD (doxorubicin hydrochloride [adriamycin], bleomycin sulfate, vincristine, and dacarbazine) as frontline therapy; and 70% achieved complete response. The median PFS after first-line treatment was 16.8 years. The median OS of patients with early stage and advanced stage cHL was 19 and 12.9 years, respectively. Poor prognostic factors for OS included older age, advanced stage disease, presence of B symptoms, and a higher International Prognostic Score.

Conclusion: Despite high cure rates, cHL accounted for the cause of death in 47% of patients who died during follow-up. Prognostic factors, such as age, stage at diagnosis, International Prognostic Score, and B symptoms, are helpful to guide treatment. Outcomes observed in this study are comparable with those reported in previously published studies.
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http://dx.doi.org/10.1016/j.clml.2020.08.018DOI Listing
February 2021

CD8-positive cutaneous lymphoproliferation associated with large granular lymphocyte leukemia in a patient with X-linked agammaglobulinemia.

J Cutan Pathol 2021 Apr 30;48(4):567-571. Epub 2020 Sep 30.

Department of Dermatology, Morsani College of Medicine, University of South Florida, Tampa, Florida, USA.

Patients with primary immunodeficiency are at increased risk for malignancy, especially hematologic neoplasms. This paper reports a unique case of a 47-year-old man with X-linked agammaglobulinemia who presented with progressive asymptomatic violaceous papules and plaques on his face, hands, and trunk for 1 year. Skin biopsies revealed deep, nodular infiltrates of histiocytes and CD8-positive lymphocytes, with a CD4:CD8 ratio of 1:10. Laboratory studies showed cytopenias. Flow cytometry in the skin, blood, and bone marrow (BM) showed a CD3+/CD8+/CD57+ large granular lymphocyte population. BM biopsy showed 30% involvement with these atypical T-cells. T-cell gene rearrangement studies of skin, blood, and BM revealed identical T-cell clones. He was diagnosed with T-large granular lymphocyte leukemia (T-LGLL) with an associated CD8+ cutaneous lymphoproliferation. Skin involvement was suspected to represent infiltration by T-LGLL. However, co-existence of two lymphoproliferative disorders (LPDs), T-LGLL and CD8+ granulomatous LPD, remains a possibility. In general, cutaneous infiltrates associated with LGLL are rare and poorly understood. It has been suggested that they are markers of poor prognosis. Our case report describes skin, blood, and BM findings in an immunosuppressed patient with T-LGLL in detail. These findings have not yet been reported and their significance requires further investigation.
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http://dx.doi.org/10.1111/cup.13860DOI Listing
April 2021

Durable Complete Response to AMG 655 (Conatumumab) and Vorinostat in a Patient With Relapsed Classical Hodgkin Lymphoma: Extraordinary Response from a Phase 1b Clinical Protocol.

Clin Lymphoma Myeloma Leuk 2020 12 25;20(12):e944-e946. Epub 2020 Jul 25.

Division of Medical Oncology, H. Lee Moffitt Cancer Center and Research Institute, University of South Florida, Tampa, FL. Electronic address:

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http://dx.doi.org/10.1016/j.clml.2020.07.012DOI Listing
December 2020

Survival outcomes in blastic plasmacytoid dendritic cell neoplasm by first-line treatment and stem cell transplant.

Blood Adv 2020 07;4(14):3435-3442

Department of Malignant Hematology and.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematologic malignancy with dismal clinical outcomes. Conventional chemotherapies such cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) and hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone alternating with high-dose cytarabine and methotrexate (CVAD) have been commonly used for the BPDCN treatment until a recent study showed promising outcomes in patients treated with SL-401 (Tagraxofusp). In this single-institution retrospective study, we identified a total of 49 consecutive BPDCN patients. Among 42 patients who received treatment, hyper-CVAD regimen was associated with higher complete response rate compared with CHOP-based regimens or SL-401 (91% vs 50% vs 50%), although the difference did not achieve statistical significance. Furthermore, there was no significant overall survival (OS) difference between patients treated with SL-401 vs other chemotherapies as their first-line treatment (hazard ratio = 1.597; 95% CI, 0.460-5.548; P = .431). Of note, patients who received allogeneic stem cell transplant (allo-SCT) had significantly longer OS (hazard ratio = 0.160; 95% CI, 0.0453-0.56; P = .041). Extent of disease (skin vs bone marrow vs both) or younger age (<60 years old) did not have significant prognostic impact on OS. Collectively, our study confirmed the survival benefit of allo-SCT and suggests that conventional and intensive chemotherapies such as CHOP and hyper-CVAD as well as SL-401 would be comparable first-line choice for the BPDCN patients.
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http://dx.doi.org/10.1182/bloodadvances.2020001875DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7391135PMC
July 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

Characterization of myelodysplastic syndromes (MDS) with T-cell large granular lymphocyte proliferations (LGL).

Leukemia 2020 11 21;34(11):3097-3099. Epub 2020 Jun 21.

Formerly Department of Malignant Hematology, H. Lee Moffitt Cancer center, Tampa, FL, USA.

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http://dx.doi.org/10.1038/s41375-020-0928-4DOI Listing
November 2020

NCCN Guidelines Insights: Primary Cutaneous Lymphomas, Version 2.2020.

J Natl Compr Canc Netw 2020 05;18(5):522-536

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

Mycosis fungoides (MF) is the most common subtype of cutaneous T-cell lymphoma (CTCL), and Sézary syndrome (SS) is a rare erythrodermic and leukemic subtype of CTCL characterized by significant blood involvement. Although early-stage disease can be effectively treated predominantly with skin-directed therapies, systemic therapy is often necessary for the treatment of advanced-stage disease. Systemic therapy options have evolved in recent years with the approval of novel agents such as romidepsin, brentuximab vedotin, and mogamulizumab. These NCCN Guidelines Insights discuss the diagnosis and management of MF and SS (with a focus on systemic therapy).
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http://dx.doi.org/10.6004/jnccn.2020.0022DOI Listing
May 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

Hepatic Infiltration with Malignant T-cells Manifesting as Impending Acute Liver Failure in Sezary Syndrome.

Mediterr J Hematol Infect Dis 2020 1;12(1):e2020007. Epub 2020 Jan 1.

Moffitt Cancer Center, Tampa, FL 33612.

We describe a case of impending acute liver failure in a patient with Sézary syndrome (SS). The three-phase computed tomography (CT) of the liver showed neither mass nor hepatomegaly. Liver biopsy confirmed infiltration with malignant CD4+ clonal T-cells. Prompt administration of combination chemotherapy, consisting of gemcitabine, dexamethasone, and cisplatin (GDP), resulted in full recovery of liver function. To the best of our knowledge, this is the first report of liver failure from SS. Commercial next-generation sequencing panel identified 11 clinically relevant mutations. Interestingly, the identified ARID2 mutation, frequently observed in hepatocellular carcinoma, rarely occurs in hematologic malignancies. Further studies are necessary to elucidate the role of ARID2 mutations in the biological behavior of Sezary cells, such as a propensity to infiltrate liver parenchyma.
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http://dx.doi.org/10.4084/MJHID.2020.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6951350PMC
January 2020

Pembrolizumab-associated tumor development in a patient with Sézary syndrome.

JAAD Case Rep 2020 Jan 24;6(1):16-18. Epub 2019 Dec 24.

Department of Dermatology, Morsani College of Medicine, University of South Florida, Tampa, Florida.

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http://dx.doi.org/10.1016/j.jdcr.2019.11.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6938917PMC
January 2020

Hematological Malignancies and Arterial Thromboembolism.

Indian J Hematol Blood Transfus 2019 Oct 28;35(4):611-624. Epub 2019 Jan 28.

3Division of Medical Oncology, City of Hope Cancer Center, Duarte, CA 91010 USA.

Established guidelines exist for prevention and treatment of venous thromboembolism in hematological malignancies, but none for arterial thromboembolism. However, arterial and venous thromboembolism share the same provoking features-including altered procoagulant factors and defective fibrinolytic system. The morbidity for arterial thromboembolism is increasing in hematological malignancies, with the advent of immunomodulatory and targeted therapy. However, survival rate for hematological malignancy is improving. Consequently, as patients with hematological malignancies live longer, comorbidities including diabetes, hypertension and dyslipidemia, may accentuate arterial thrombosis. Thus far, the scientific literature on prophylaxis and treatment for arterial thromboembolism in hematological malignancies is limited. This review highlights the pathogenesis, incidence and clinical features of arterial thromboembolism in hematological malignancies.
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http://dx.doi.org/10.1007/s12288-019-01085-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6825093PMC
October 2019

Non-del(5q) myelodysplastic syndromes-associated loci detected by SNP-array genome-wide association meta-analysis.

Blood Adv 2019 11;3(22):3579-3589

Department of Malignant Hematology and.

Myelodysplastic syndromes (MDS) are hematopoietic stem cell malignancies. Known predisposing factors to adult MDS include rare germline mutations, cytotoxic therapy, age-related clonal hematopoiesis, and autoimmune or chronic inflammatory disorders. To date, no published studies characterizing MDS-associated germline susceptibility polymorphisms exist. We performed a genome-wide association study of 2 sample sets (555 MDS cases vs 2964 control subjects; 352 MDS cases vs 2640 control subjects) in non-del(5q) MDS cases of European genomic ancestry. Meta-analysis identified 8 MDS-associated loci at 1q31.1 (PLA2G4A), 3p14.1 (FAM19A4), 5q21.3 (EFNA5), 6p21.33, 10q23.1 (GRID1), 12q24.32, 15q26.1, and 20q13.12 (EYA2) that approached genome-wide significance. Gene expression for 5 loci that mapped within or near genes was significantly upregulated in MDS bone marrow cells compared with those of control subjects (P < .01). Higher PLA2G4A expression and lower EYA2 expression were associated with poorer overall survival (P = .039 and P = .037, respectively). Higher PLA2G4A expression is associated with mutations in NRAS (P < .001), RUNX1 (P = .012), ASXL1 (P = .007), and EZH2 (P = .038), all of which are known to contribute to MDS development. EYA2 expression was an independently favorable risk factor irrespective of age, sex, and Revised International Scoring System score (relative risk, 0.67; P = .048). Notably, these genes have regulatory roles in innate immunity, a critical driver of MDS pathogenesis. EYA2 overexpression induced innate immune activation, whereas EYA2 inhibition restored colony-forming potential in primary MDS cells indicative of hematopoietic restoration and possible clinical relevance. In conclusion, among 8 suggestive MDS-associated loci, 5 map to genes upregulated in MDS with functional roles in innate immunity and potential biological relevance to MDS.
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http://dx.doi.org/10.1182/bloodadvances.2019000922DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6880887PMC
November 2019

Pembrolizumab in Relapsed and Refractory Mycosis Fungoides and Sézary Syndrome: A Multicenter Phase II Study.

J Clin Oncol 2020 01 18;38(1):20-28. Epub 2019 Sep 18.

National Cancer Institute, Bethesda, MD.

Purpose: To assess the efficacy of pembrolizumab in patients with advanced relapsed or refractory mycosis fungoides (MF) or Sézary syndrome (SS).

Patients And Methods: CITN-10 is a single-arm, multicenter phase II trial of 24 patients with advanced MF or SS. Patients were treated with pembrolizumab 2 mg/kg every 3 weeks for up to 24 months. The primary end point was overall response rate by consensus global response criteria.

Results: Patients had advanced-stage disease (23 of 24 with stage IIB to IV MF/SS) and were heavily pretreated with a median of four prior systemic therapies. The overall response rate was 38% with two complete responses and seven partial responses. Of the nine responding patients, six had 90% or more improvement in skin disease by modified Severity Weighted Assessment Tool, and eight had ongoing responses at last follow-up. The median duration of response was not reached, with a median response follow-up time of 58 weeks. Immune-related adverse events led to treatment discontinuation in four patients. A transient worsening of erythroderma and pruritus occurred in 53% of patients with SS. This cutaneous flare reaction did not result in treatment discontinuation for any patient. The flare reaction correlated with high PD-1 expression on Sézary cells but did not associate with subsequent clinical responses or lack of response. Treatment responses did not correlate with expression of PD-L1, total mutation burden, or an interferon-γ gene expression signature.

Conclusion: Pembrolizumab demonstrated significant antitumor activity with durable responses and a favorable safety profile in patients with advanced MF/SS.
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http://dx.doi.org/10.1200/JCO.19.01056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6943974PMC
January 2020

Oral 5-azacytidine and romidepsin exhibit marked activity in patients with PTCL: a multicenter phase 1 study.

Blood 2019 10;134(17):1395-1405

Center for Lymphoid Malignancies, Department of Medicine.

The peripheral T-cell lymphomas (PTCLs) are uniquely sensitive to epigenetic modifiers. Based on the synergism between histone deacetylase inhibitors and hypomethylating agents that we established in preclinical PTCL models, we conducted a phase 1 study of oral 5-azacytidine (AZA) and romidepsin (ROMI) in patients with advanced lymphoid malignancies, with emphasis on PTCL. According to a 3 + 3 design, patients were assigned to 1 of 7 cohorts with AZA doses ranging from 100 mg daily on days 1 to 14 to 300 mg daily on days 1 to 21, ROMI doses ranging from 10 mg/m2 on days 8 and 15 to 14 mg/m2 on days 8, 15, and 22, with cycles of 21 to 35 days. Coprimary end points included maximum tolerated dose (MTD) and dose-limiting toxicity (DLT). We treated a total of 31 patients. The MTD was AZA 300 mg on days 1 to 14 and ROMI 14 mg/m2 on days 8, 15, and 22 on a 35-day cycle. DLTs included grade 4 thrombocytopenia, prolonged grade 3 thrombocytopenia, grade 4 neutropenia, and pleural effusion. There were no treatment-related deaths. The combination was substantially more active in patients with PTCL than in those with non-T-cell lymphoma. The overall response rate in all, non-T-cell, and T-cell lymphoma patients was 32%, 10%, and 73%, respectively, and the complete response rates were 23%, 5%, and 55%, respectively. We did not find an association between response and level of demethylation or tumor mutational profile. This study establishes that combined epigenetic modifiers are potently active in PTCL patients. This trial was registered at www.clinicaltrials.gov as NCT01998035.
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http://dx.doi.org/10.1182/blood.2019001285DOI Listing
October 2019

Skin-first nodulotumoral adult T-cell lymphoma mimicking cutaneous T-cell lymphoma.

JAAD Case Rep 2019 Aug 31;5(8):650-652. Epub 2019 Jul 31.

Department of Cutaneous Oncology, Moffitt Cancer Center, Tampa, Florida.

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http://dx.doi.org/10.1016/j.jdcr.2019.05.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6677771PMC
August 2019
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