Publications by authors named "Neha Mehta-Shah"

33 Publications

An Update on the Current Genomic Landscape of Breast Implant-Associated Anaplastic Large Cell Lymphoma.

Cancers (Basel) 2021 Sep 30;13(19). Epub 2021 Sep 30.

Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia.

Breast implant-associated lymphoma (BIA-ALCL) is a rare subtype of anaplastic large-cell lymphoma associated with breast prostheses. Most patients present with a localised periprosthetic effusion and are managed with removal of the implant and surrounding capsule. Less commonly, the lymphoma can form a mass associated with the capsule and rarely can present with disseminated disease. Recent series characterising the genomic landscape of BIA-ALCL have led to insights into the mechanisms of lymphomagenesis. Constitutive JAK/STAT pathway activation has emerged as a likely key component while, more recently, aberrancies in epigenetic regulators have been reported. This review describes the genomic characterisation reported to date and the insight these findings have provided into this rare entity.
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http://dx.doi.org/10.3390/cancers13194921DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8508182PMC
September 2021

Romidepsin and lenalidomide-based regimens have efficacy in relapsed/refractory lymphoma: Combined analysis of two phase I studies with expansion cohorts.

Am J Hematol 2021 10 29;96(10):1211-1222. Epub 2021 Jul 29.

Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

Romidepsin (histone deacetylase inhibitor), lenalidomide (immunomodulatory agent), and carfilzomib (proteasome inhibitor), have efficacy and lack cumulative toxicity in relapsed/refractory lymphoma. We performed two investigator initiated sequential phase I studies to evaluate the maximum tolerated dose (MTD) of romidepsin and lenalidomide (regimen A) and romidepsin, lenalidomide, and carfilzomib (regimen B) in relapsed/refractory lymphoma. Cohorts in T-cell lymphoma (TCL), B-cell lymphoma (BCL) were enrolled at the MTD. Forty-nine patients were treated in study A (27 TCL, 17 BCL, 5 Hodgkin lymphoma (HL)) and 27 (16 TCL, 11 BCL) in study B. The MTD of regimen A was romidepsin 14 mg/m IV on days 1, 8, and 15 and lenalidomide 25 mg oral on days 1-21 of a 28-day cycle. The MTD of regimen B was romidepsin 8 mg/m on days 1 and 8, lenalidomide 10 mg oral on days 1-14 and carfilzomib 36 mg/m IV on days 1 and 8 of a 21-day cycle. In study A, 94% had AEs ≥Grade 3, most commonly neutropenia (49%), thrombocytopenia (53%), and electrolyte abnormalities (49%). In study B 59% had AEs ≥Grade 3, including thrombocytopenia (30%) and neutropenia (26%). In study A the ORR was 49% (50% TCL, 47% BCL, 50% HL). In study B the ORR was 48% (50% TCL, 50% BCL). For study A and B the median progression free survival (PFS) was 5.7 months and 3.4 months respectively with 11 patients proceeding to allogeneic transplant. The combinations of romidepsin and lenalidomide and of romidepsin, lenalidomide and carfilzomib showed activity in relapsed/refractory lymphoma with an acceptable safety profile.
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http://dx.doi.org/10.1002/ajh.26288DOI Listing
October 2021

Prognosis and risk stratification of peripheral T-cell lymphomas.

Semin Hematol 2021 Apr 11;58(2):70-77. Epub 2021 Feb 11.

Washington University in St. Louis, St. Louis, MO. Electronic address:

Peripheral T-cell lymphomas represent a rare heterogeneous group of non-Hodgkin lymphomas with generally worse outcomes with standard chemotherapy compared to B-cell lymphomas. Clinical risk prediction tools at baseline have been shown to be prognostic but generally do not impact clinical decision making. However, improving understanding of the prognostic implications of histology and its molecular underpinnings as well as strategies surrounding the use of CD30 as a predictive biomarker for brentuximab vedotin have led to better understanding of how to risk stratify patients. Baseline, interim, and end of treatment PET/CT as evaluated by the Lugano criteria as well as by baseline metabolic tumor volume have also been shown to be prognostic. The role of minimal residual disease tools such as cell free DNA and T-cell gene receptor sequencing remain active areas of investigation in hopes to develop predictive biomarkers in these rare diseases. This review focuses on strategies used to prognosticate in more common forms of peripheral T-cell lymphoma as well as in extranodal NK/T-cell lymphoma.
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http://dx.doi.org/10.1053/j.seminhematol.2021.02.001DOI Listing
April 2021

Phase I Trial of N-803, an IL15 Receptor Agonist, with Rituximab in Patients with Indolent Non-Hodgkin Lymphoma.

Clin Cancer Res 2021 Jun 8;27(12):3339-3350. Epub 2021 Apr 8.

Washington University School of Medicine, St. Louis, Missouri.

Purpose: N-803 is an IL15 receptor superagonist complex, designed to optimize persistence and trans-presentation, thereby activating and expanding natural killer (NK) cells and CD8 T cells. Monoclonal antibodies (mAbs) direct Fc receptor-bearing immune cells, including NK cells, to recognize and eliminate cancer targets. The ability of IL15R agonists to enhance tumor-targeting mAbs in patients has not been reported previously.

Patients And Methods: Relapsed/refractory patients with indolent non-Hodgkin lymphoma were treated with rituximab and intravenous or subcutaneous N-803 on an open-label, dose-escalation phase I study using a 3+3 design (NCT02384954). Primary endpoint was maximum tolerated dose. Immune correlates were performed using multidimensional analysis via mass cytometry and cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) which simultaneously measures protein and single-cell RNA expression.

Results: This immunotherapy combination was safe and well tolerated and resulted in durable clinical responses including in rituximab-refractory patients. Subcutaneous N-803 plus rituximab induced sustained proliferation, expansion, and activation of peripheral blood NK cells and CD8 T cells, with increased NK cell and T cells present 8 weeks following last N-803 treatment. CITE-seq revealed a therapy-altered NK cell molecular program, including enhancement of AP-1 transcription factor. Furthermore, the monocyte transcriptional program was remodeled with enhanced MHC expression and antigen-presentation genes.

Conclusions: N-803 combines with mAbs to enhance tumor targeting in patients, and warrants further investigation in combination with immunotherapies.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-4575DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8197753PMC
June 2021

Clinical Trial of High-Dose Pegylated-Interferon-Alfa-2b Combined With Phototherapy in Advanced Stage Mycosis Fungoides.

J Drugs Dermatol 2021 03;20(3):349-350

The combination of Interferon-α-2b (IFN-α-2b) and phototherapy is highly effective in treating mycosis fungoides (MF) but side effects often lead to discontinuation of therapy.1.
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http://dx.doi.org/10.36849/JDD.5756DOI Listing
March 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

T follicular helper phenotype predicts response to histone deacetylase inhibitors in relapsed/refractory peripheral T-cell lymphoma.

Blood Adv 2020 10;4(19):4640-4647

Lymphoma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.

Histone deacetylase inhibitors (HDACi) are active agents for peripheral T-cell lymphoma (PTCL). Anecdotally angioimmunoblastic T-cell lymphoma (AITL) appears to respond better than PTCL-not otherwise specified (NOS) to HDACi. The new World Health Organization classification shows that a subgroup of PTCL carries similarities in phenotype and gene expression profiling to AITL, comparable to T follicular helper (TFH) cells. The disease might behave similarly to AITL when treated with HDACi. We analyzed 127 patients with AITL or PTCL-NOS treated with HDACi at relapse as a single agent or in combination. We re-reviewed the pathology of all PTCL-NOS to identify the TFH phenotype. Patients received HDACi at relapse as a single agent in 97 cases (76%, 59 TFH, 38 non-TFH) or in combination in 30 cases (24%, 18 TFH, 12 non-TFH) including duvelisib, lenalidomide, lenalidomide plus carfilzomib, and pralatrexate. Seven PTCL-NOS had TFH phenotype; 2 PTCL-NOS were reclassified as AITL. Overall response rate (ORR) was 56.5% (28.9% complete response [CR]) in TFH and 29.4% (19.6% CR) in non-TFH phenotype patients (P = .0035), with TFH phenotype being an independent predictor of ORR (P = .009). Sixteen patients sufficiently responded to HDACi or HDACi in combination with another agent to proceed directly to allogeneic transplantation; 1 of 16 responded to donor lymphocyte infusion (12 TFH, 4 non-TFH). Our results, although retrospective, support that HDACi, as a single agent or in combination, may have superior activity in TFH-PTCL compared with non-TFH PTCL. This differential efficacy could help inform subtype-specific therapy and guide interpretation of HDACi trials.
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http://dx.doi.org/10.1182/bloodadvances.2020002396DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7556143PMC
October 2020

Lenalidomide demonstrates clinical activity in anaplastic lymphoma kinase-positive large B-cell lymphoma.

BMJ Case Rep 2020 Aug 25;13(8). Epub 2020 Aug 25.

Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, Missouri, USA

Anaplastic lymphoma kinase-positive large B-cell lymphoma (ALK+ LBCL) is known to be a rare and aggressive form of lymphoma that relapses quickly after both conventional chemotherapy and more targeted therapy. Lenalidomide is an immunomodulator that has shown safety and efficacy in multiple myeloma and is also approved for use in several types of lymphoma. In the case described here, the patient had a significant partial response to lenalidomide, which has not previously been described in this type of lymphoma. Given how aggressive and difficult to treat ALK+ LBCL is, further research is warranted to more completely elucidate the mechanism of action of lenalidomide in ALK+ LBCL and its role in treatment.
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http://dx.doi.org/10.1136/bcr-2020-235578DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7449333PMC
August 2020

CAR-modified memory-like NK cells exhibit potent responses to NK-resistant lymphomas.

Blood 2020 11;136(20):2308-2318

Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO.

Natural killer (NK) cells are a promising cellular immunotherapy for cancer. Cytokine-induced memory-like (ML) NK cells differentiate after activation with interleukin-12 (IL-12), IL-15, and IL-18, exhibit potent antitumor responses, and safely induce complete remissions in patients with leukemia. However, many cancers are not fully recognized via NK cell receptors. Chimeric antigen receptors (CARs) have been used to enhance tumor-specific recognition by effector lymphocytes. We hypothesized that ML differentiation and CAR engineering would result in complementary improvements in NK cell responses against NK-resistant cancers. To test this idea, peripheral blood ML NK cells were modified to express an anti-CD19 CAR (19-CAR-ML), which displayed significantly increased interferon γ production, degranulation, and specific killing against NK-resistant lymphoma lines and primary targets compared with nonspecific control CAR-ML NK cells or conventional CAR NK cells. The 19-CAR and ML responses were synergistic and CAR specific and required immunoreceptor tyrosine-based activation motif signaling. Furthermore, 19-CAR-ML NK cells generated from lymphoma patients exhibited improved responses against their autologous lymphomas. 19-CAR-ML NK cells controlled lymphoma burden in vivo and improved survival in human xenograft models. Thus, CAR engineering of ML NK cells enhanced responses against resistant cancers and warrants further investigation, with the potential to broaden ML NK cell recognition against a variety of NK cell-resistant tumors.
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http://dx.doi.org/10.1182/blood.2020006619DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7702478PMC
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

Rituximab/bendamustine and rituximab/cytarabine induction therapy for transplant-eligible mantle cell lymphoma.

Blood Adv 2020 03;4(5):858-867

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.

The addition of high-dose cytarabine to rituximab/bendamustine (RB) induction could improve outcomes for transplant-eligible patients with mantle cell lymphoma (MCL). We conducted a pooled analysis of 2 phase 2 trials and an off-trial cohort each testing 3 cycles of RB and 3 cycles of rituximab/high-dose cytarabine (RC) followed by autologous stem cell transplantation (ASCT) among untreated, transplant-eligible patients with MCL. Dana-Farber Cancer Institute (DFCI) and Washington University in St. Louis (WUSTL) led separate phase 2 trials testing sequential and alternating cycles of RB/RC, respectively. Patients treated at DFCI with sequential RB/RC off trial were retrospectively identified. Minimal residual disease (MRD) was assessed in the DFCI trial. A total of 88 patients (23 DFCI trial, 18 WUSTL trial, and 47 off trial) received RB/RC; 92% of patients completed induction, and 84% underwent planned consolidative ASCT. Grade 3 or 4 adverse events among trial patients included lymphopenia (88%), thrombocytopenia (85%), neutropenia (83%), and febrile neutropenia (15%). There were no treatment-related deaths during induction and 2 following ASCT. Among 87 response-evaluable patients, the end-of-induction overall and complete response rates were 97% and 90%, respectively. After a median follow-up of 33 months, 3-year progression-free survival and overall survival were 83% and 92%, respectively. Patients undergoing MRD testing experienced prolonged MRD negativity after ASCT with emergence of MRD occurring in only 1 patient who subsequently relapsed. RB/RC followed by ASCT achieves high rates of durable remissions in transplant-eligible patients with MCL. These trials were registered at www.clinicaltrials.gov as #NCT01661881 (DFCI trial) and #NCT02728531 (WUSTL trial).
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http://dx.doi.org/10.1182/bloodadvances.2019001355DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7065472PMC
March 2020

Brentuximab Vedotin in the Treatment of Peripheral T Cell Lymphoma and Cutaneous T Cell Lymphoma.

Curr Hematol Malig Rep 2020 02;15(1):9-19

Division of Oncology, Department of Medicine, Washington University School of Medicine, 660 S. Euclid, Box 8056, St. Louis, MO, 63110, USA.

Purpose Of Review: The recent development of brentuximab vedotin (BV), an antibody-drug conjugate targeting CD30-positive cells, has led to therapeutic advances in the treatment of T cell lymphomas. In this review, we discuss key studies of BV in peripheral T cell lymphoma (PTCL) and cutaneous T cell lymphoma (CTCL) and highlight important questions for further investigation.

Recent Findings: Monotherapy with BV has proven to be effective and well tolerated in patients with relapsed/refractory (R/R) CD30-positive CTCL. BV has shown significant activity in R/R PTCL as well, with particularly durable responses in patients with anaplastic large cell lymphoma (ALCL). In a landmark phase III study (ECHELON-2), BV + CHP demonstrated superior progression-free and overall survival relative to CHOP as frontline therapy for patients with CD30-expressing PTCL, representing the first randomized trial demonstrating an overall survival benefit in PTCL. Though BV is overall well tolerated, peripheral neuropathy remains a clinically significant adverse effect. BV is a major therapeutic advance in the treatment of patients with R/R CTCL and of those with PTCL in both the R/R and frontline settings. Key ongoing areas of investigation include optimization of CD30 expression as a predictive biomarker as well as the role of BV in consolidation therapy.
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http://dx.doi.org/10.1007/s11899-020-00561-wDOI Listing
February 2020

Lymphomatoid Papulosis.

JAMA Dermatol 2020 03;156(3):360

Division of Dermatology, Department of Medicine, Washington University School of Medicine, St Louis, Missouri.

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http://dx.doi.org/10.1001/jamadermatol.2019.4513DOI Listing
March 2020

A Cautionary Tale and Update on Breast Implant-Associated Anaplastic Large Cell Lymphoma (BIA-ALCL).

Aesthet Surg J 2020 11;40(12):1288-1300

Division of Plastic and Reconstructive Surgery, Washington University in St Louis School of Medicine, St Louis, MO.

Breast implant-associated anaplastic large T-cell lymphoma (BIA-ALCL) was first recognized by the World Health Organization in 2016. The total number of cases worldwide continues to increase, with >800 cases confirmed through a combination of Food and Drug Administration data, verified reports, and registries. To date, 33 deaths have been reported. Typical presentation includes a late seroma containing monoclonal T cells that are CD30 positive and anaplastic lymphoma kinase negative. We present a review of the current literature and report on 3 cases of BIA-ALCL at our institution, which serve to illustrate our approach to diagnosis and management of this disease. In 2 cases, the diagnosis of BIA-ALCL was not initially confirmed due to an incomplete workup but was recognized upon explantation. The seroma fluid was sent for flow cytometry. Initially, the cells were reported as morphologically suspicious for malignancy with phenotypically normal T cells based on standard CD3+ T-cell gating. Subsequent cytology specimens were reported as consistent with recurrent adenocarcinoma. However, upon regating of flow-cytometry data, a population of CD30+, CD3- T cells was noted and the diagnosis of BIA-ALCL was confirmed by immunohistochemical stains of the excised breast capsule specimen. Given the increasing incidence of this disease, as plastic surgeons we must stay informed to order the correct workup to avoid misdiagnosis and be prepared to appropriately refer affected patients to centers with multidisciplinary teams experienced in the management of BIA-ALCL.

Level Of Evidence: 4:
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http://dx.doi.org/10.1093/asj/sjz377DOI Listing
November 2020

Emerging strategies in peripheral T-cell lymphoma.

Authors:
Neha Mehta-Shah

Hematology Am Soc Hematol Educ Program 2019 12;2019(1):41-46

Washington University in St. Louis, St. Louis, MO.

Peripheral T-cell lymphomas (PTCLs) are a heterogenous group of aggressive non-Hodgkin lymphomas that are less chemosensitive than their B-cell counterparts. Until recently, standard therapy did not distinguish between subtypes, and deeper understanding of the biology of these diseases was lacking. The availability of targeted therapy and more sophisticated subtype classification has translated into the development of novel treatment options for these rare diseases. This includes the development of a brentuximab vedotin-based upfront chemotherapy regimen that confers an overall survival benefit for a subset of patients. Clinical trials of targeted agents, as well as development of better preclinical models of PTCL, are leading to therapeutic advances in the field, including the development of phosphoinositide-3-kinase inhibitors, histone deacetylase inhibitor-based strategies, CD30-directed strategies, Janus kinase inhibitors, and spleen-associated tyrosine kinase inhibitors. Better understanding of the biology of these diseases based on gene expression profiling, minimal residual disease evaluation, and modeling in patient-derived xenografts should help define mechanisms of response and resistance to therapy. Given the complex biology of these heterogeneous lymphomas, well-tolerated combination strategies targeted toward specific subtypes of PTCL can lead to advances in the field. Similar to the story of brentuximab vedotin, development of effective therapies in the salvage setting will likely lead to improved upfront strategies in PTCLs, and ultimately a more personalized approach.
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http://dx.doi.org/10.1182/hematology.2019000012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6913433PMC
December 2019

Breast Implant-Associated Anaplastic Large Cell Lymphoma: Real, Rare, but Avoidable.

JAMA Surg 2020 01;155(1):3-4

Department of Pathology and Immunology, Washington University School of Medicine in St Louis, St Louis, Missouri.

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http://dx.doi.org/10.1001/jamasurg.2019.3154DOI Listing
January 2020

Nivolumab Combined With Brentuximab Vedotin for Relapsed/Refractory Primary Mediastinal Large B-Cell Lymphoma: Efficacy and Safety From the Phase II CheckMate 436 Study.

J Clin Oncol 2019 11 9;37(33):3081-3089. Epub 2019 Aug 9.

Memorial Sloan Kettering Cancer Center, New York, NY.

Purpose: Primary mediastinal B-cell lymphoma (PMBL) is a rare but aggressive non-Hodgkin lymphoma with poor outcomes in patients with relapsed/refractory (R/R) disease. PMBL is characterized by high expression of programmed death-1 ligand and variable expression of CD30. Nivolumab, an anti-programmed death-1 immune checkpoint inhibitor, and brentuximab vedotin (BV), an anti-CD30 antibody-drug conjugate, may have synergistic activity in R/R PMBL.

Methods: The expansion cohort of the open-label, phase I/II CheckMate 436 study enrolled patients with confirmed R/R PMBL who were previously treated with either autologous hematopoietic cell transplantation or two or more prior chemotherapy regimens if ineligible for autologous hematopoietic cell transplantation. Patients received nivolumab (240 mg intravenously) and BV (1.8 mg/kg intravenously) every 3 weeks until disease progression or unacceptable toxicity. Primary end points were investigator-assessed objective response rate (ORR) per the Lugano 2014 criteria and safety.

Results: Thirty patients with PMBL were treated and evaluable. At a median follow-up of 11.1 months, ORR (95% CI) was 73% (54% to 88%), with a 37% complete remission rate per investigator, and ORR of 70% (51% to 85%), with a 43% complete metabolic response rate per independent review. Median duration of response, median progression-free survival, and median overall survival have not been reached. Eleven responders had consolidation with autologous (n = 5) or allogeneic (n = 6) transplantation. Treatment-related adverse events were reported in 25 patients (83%). Sixteen patients (53%) had grade 3 to 4 treatment-related adverse events; the most common were neutropenia (n = 9), thrombocytopenia (n = 3), and peripheral neuropathy (n = 3). There were no treatment-related deaths.

Conclusion: In patients with R/R PMBL, the combination of nivolumab plus BV represents a promising option, with high antitumor activity and a manageable safety profile.
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http://dx.doi.org/10.1200/JCO.19.01492DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6864847PMC
November 2019

Novel cell adhesion/migration pathways are predictive markers of HDAC inhibitor resistance in cutaneous T cell lymphoma.

EBioMedicine 2019 Aug 26;46:170-183. Epub 2019 Jul 26.

Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA. Electronic address:

Background: Treatment for Cutaneous T Cell Lymphoma (CTCL) is generally not curative. Therefore, selecting therapy that is effective and tolerable is critical to clinical decision-making. Histone deacetylase inhibitors (HDACi), epigenetic modifier drugs, are commonly used but effective in only ~30% of patients. There are no predictive markers of HDACi response and the CTCL histone acetylation landscape remains unmapped. We sought to identify pre-treatment molecular markers of resistance in CTCL that progressed on HDACi therapy.

Methods: Purified T cells from 39 pre/post-treatment peripheral blood samples and skin biopsies from 20 patients were subjected to RNA-seq and ChIP-seq for histone acetylation marks (H3K14/9 ac, H3K27ac). We correlated significant differences in histone acetylation with gene expression in HDACi-resistant/sensitive CTCL. We extended these findings in additional CTCL patient cohorts (RNA-seq, microarray) and using ELISA in matched CTCL patient plasma.

Findings: Resistant CTCL exhibited high levels of histone acetylation, which correlated with increased expression of 338 genes (FDR < 0·05), including some novel to CTCL: BIRC5 (anti-apoptotic); RRM2 (cell cycle); TXNDC5, GSTM1 (redox); and CXCR4, LAIR2 (cell adhesion/migration). Several of these, including LAIR2, were elevated pre-treatment in HDACi-resistant CTCL. In CTCL patient plasma (n = 6), LAIR2 protein was also elevated (p < 0·01) compared to controls.

Interpretation: This study is the first to connect genome-wide differences in chromatin acetylation and gene expression to HDACi-resistance in primary CTCL. Our results identify novel markers with high pre-treatment expression, such as LAIR2, as potential prognostic and/or predictors of HDACi-resistance in CTCL.

Funding: NIH:CA156690, CA188286; NCATS: WU-ICTS UL1 TR000448; Siteman Cancer Center: CA091842.
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http://dx.doi.org/10.1016/j.ebiom.2019.07.053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6711861PMC
August 2019

Multicenter analysis of outcomes in blastic plasmacytoid dendritic cell neoplasm offers a pretargeted therapy benchmark.

Blood 2019 08 26;134(8):678-687. Epub 2019 Jun 26.

Dana-Farber Cancer Institute, and.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an uncommon hematologic malignancy with poor outcomes. Existing data on the clinical behavior of BPDCN are limited because reported outcomes are from small retrospective series, and standardized treatment guidelines are lacking. The interleukin-3 cytotoxin conjugate tagraxofusp was recently tested in phase 1/2 trials that led to US Food and Drug Administration approval, the first ever for BPDCN. However, because there was no matched internal comparator in this or any clinical study to date, results of BPDCN trials testing new drugs are difficult to compare with alternative therapies. We therefore sought to define the clinical characteristics and outcomes of a group of patients with BPDCN treated at 3 US cancer centers in the modern era but before tagraxofusp was available. In 59 studied patients with BPDCN, the median overall survival from diagnosis was 24 months, and outcomes were similar in patients with "skin only" or with systemic disease at presentation. Intensive first-line therapy and "lymphoid-type" chemotherapy regimens were associated with better outcomes. Only 55% of patients received intensive chemotherapy, and 42% of patients underwent stem cell transplantation. Clinical characteristics at diagnosis associated with poorer outcomes included age >60 years, abnormal karyotype, and terminal deoxynucleotidyltransferase (TdT) negativity in the BPDCN cells. We also identified disease responses to pralatrexate and enasidenib in some patients. This study highlights poor outcomes for patients with BPDCN in the modern era and the need for new treatments. Outcomes from ongoing clinical trials for BPDCN can be evaluated relative to this contemporary cohort.
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http://dx.doi.org/10.1182/blood.2019001144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6706810PMC
August 2019

Baseline and interim functional imaging with PET effectively risk stratifies patients with peripheral T-cell lymphoma.

Blood Adv 2019 01;3(2):187-197

Molecular Imaging and Therapy Service, Department of Radiology, and.

The prognosis of peripheral T-cell lymphoma (PTCL) is heterogenous. Baseline or interim imaging characteristics may inform risk-adapted treatment paradigms. We identified 112 patients with PTCL who were consecutively treated with cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP)/CHOP-like regimens with the intent to consolidate with an autologous transplant. Baseline (n = 93) and interim (after 4 cycles, n = 99) positron emission tomography (PET) images were reevaluated, and we calculated baseline total metabolic tumor volume (TMTV). Interim PET (iPET) responses were graded visually by 5-point score (i5PS) and by percentage change of standardized uptake value. By univariate analysis, predictors of event-free survival (EFS) included Prognostic Index for Peripheral TCL (PIT) higher than 1 (hazard ratio [HR], 1.83; = .021), International Prognostic Index (IPI) higher than 3 (HR, 2.01; = .021), high TMTV (>125 cm; HR, 3.92; = .003), and positive iPET (HR, 3.57; < .001). By multivariate analysis, high baseline TMTV predicted worse overall survival (OS; HR, 6.025; = .022) and EFS (HR, 3.861; = .005). Patients with i5PS of 1 to 3 had a longer median OS and EFS (104 months, 64 months) than those with i5PS of 4 to 5 (19 months, 11 months; < .001). Four-year OS and EFS for patients with i5PS of 1 to 3 and PIT of 1 or less were 85% and 62%, respectively. However, 4-year OS and EFS for those with i5PS of 4 to 5 and PIT higher than 1 were both 0% ( < .001). In multivariate analysis, after controlling for IPI and PIT, i5PS was independently prognostic for EFS (HR, 3.400 95% confidence interval, 1.750-6.750; < .001) and OS (HR, 10.243; 95% confidence interval, 4.052-25.891; < .001). In conjunction with clinical parameters, iPET helps risk stratify patients with PTCL and could inform risk-adapted treatment strategies. Prospective studies are needed to confirm these findings.
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http://dx.doi.org/10.1182/bloodadvances.2018024075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6341183PMC
January 2019

How I treat breast implant-associated anaplastic large cell lymphoma.

Blood 2018 11 12;132(18):1889-1898. Epub 2018 Sep 12.

Department of Medicine, Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York, NY.

Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is a recently described form of T-cell non-Hodgkin lymphoma now formally recognized by the World Health Organization classification of lymphoid neoplasms. The disease most often presents with a delayed seroma around the breast implant, almost exclusively with a textured surface, and manifests with breast pain, swelling or asymmetry, capsular contracture, but can also present with a breast mass, and lymph node involvement. The prognosis of BIA-ALCL is favorable compared with many other subtypes of systemic T-cell lymphoma; however, unlike other non-Hodgkin lymphomas, complete surgical excision for localized disease is an important part of the management of these patients. In this paper, we share our recommendations for a multidisciplinary team approach to the diagnosis, workup, and treatment of BIA-ALCL in line with consensus guidelines by the National Comprehensive Cancer Network.
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http://dx.doi.org/10.1182/blood-2018-03-785972DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6536699PMC
November 2018

Management of relapsed/refractory classical Hodgkin lymphoma in transplant-ineligible patients.

Blood 2018 04 2;131(15):1698-1703. Epub 2018 Mar 2.

Division of Medical Oncology, Department of Medicine, Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO.

Addition of brentuximab vedotin, a CD30-targeted antibody-drug conjugate, and the programmed death 1 (PD-1) inhibitors nivolumab and pembrolizumab to the armamentarium for transplant-ineligible relapsed/refractory classical Hodgkin lymphoma has resulted in improved outcomes, including the potential for cure in a small minority of patients. For patients who have failed prior transplant or are unsuitable for dose-intense approaches based on age or comorbidities, an individualized approach with sequential use of single agents such as brentuximab vedotin, PD-1 inhibitors, everolimus, lenalidomide, or conventional agents such as gemcitabine or vinorelbine may result in prolonged survival with a minimal or modest effect on quality of life. Participation in clinical trials evaluating new approaches such as combination immune checkpoint inhibition, novel antibody-drug conjugates, or cellular therapies such as Epstein-Barr virus-directed cytotoxic T lymphocytes and chimeric antigen receptor T cells offer additional options for eligible patients.
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http://dx.doi.org/10.1182/blood-2017-09-772681DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6536701PMC
April 2018

NCCN Guidelines Insights: T-Cell Lymphomas, Version 2.2018.

J Natl Compr Canc Netw 2018 Feb;16(2):123-135

Natural killer (NK)/T-cell lymphomas are a rare and distinct subtype of non-Hodgkin's lymphomas. NK/T-cell lymphomas are predominantly extranodal and most of these are nasal type, often localized to the upper aerodigestive tract. Because extranodal NK/T-cell lymphomas (ENKL) are rare malignancies, randomized trials comparing different regimens have not been conducted to date and standard therapy has not yet been established for these patients. These NCCN Guidelines Insights discuss the recommendations for the diagnosis and management of patients with ENKL as outlined in the NCCN Guidelines for T-Cell Lymphomas.
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http://dx.doi.org/10.6004/jnccn.2018.0007DOI Listing
February 2018

Adult T-Cell Leukemia/Lymphoma.

J Oncol Pract 2017 08;13(8):487-492

Washington University, St Louis, MO; and Memorial Sloan Kettering Cancer Center, New York, NY.

Adult T-cell lymphoma/leukemia (ATL) is a rare T-cell lymphoproliferative neoplasm caused by human T-lymphotrophic virus 1. In its more common, aggressive forms, ATL carries one of the poorest prognoses of the non-Hodgkin lymphomas. The disease has clinical subtypes (ie, acute, lymphoma, chronic, and smoldering forms) defined by the presenting features, and therefore, the clinical course can vary. For the smoldering and lower-risk chronic forms, combinations involving antiviral therapies have shown some success. However, in many patients, the more indolent forms will evolve into the more aggressive subtypes. In the more aggressive acute, lymphoma, and higher-risk chronic forms, the literature supports initial treatment with combination chemotherapy followed by allogeneic transplantation as a potentially curative approach. Recently, mogamulizumab and lenalidomide have shown promise in the treatment of ATL. With better understanding of the molecular drivers of this disease, we hope that the therapeutic landscape will continue to expand.
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http://dx.doi.org/10.1200/JOP.2017.021907DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6366298PMC
August 2017

Uncommon Variants of T-Cell Lymphomas.

Hematol Oncol Clin North Am 2017 04;31(2):285-295

Department of Medicine, Memorial Sloan Kettering Cancer Center, Weill-Cornell Medical College, 1233 York Avenue, New York, NY 10022, USA. Electronic address:

Peripheral T-cell lymphomas represent 10% to 15% of non-Hodgkin lymphomas and comprise more than 20 different entities. Treatment of very rare T-cell lymphomas can be challenging because there are no large or randomized studies to guide clinical decision making, and treatment paradigms are often based on small series or imperfect data. Although a strict algorithm cannot be written with certainty, through the literature that exists and clinical experience, themes and principles of approaches do emerge that when coupled with clinical judgment allow reasonable and logical decisions.
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http://dx.doi.org/10.1016/j.hoc.2016.11.004DOI Listing
April 2017

The Genetic Basis of Hepatosplenic T-cell Lymphoma.

Cancer Discov 2017 04 25;7(4):369-379. Epub 2017 Jan 25.

Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina.

Hepatosplenic T-cell lymphoma (HSTL) is a rare and lethal lymphoma; the genetic drivers of this disease are unknown. Through whole-exome sequencing of 68 HSTLs, we define recurrently mutated driver genes and copy-number alterations in the disease. Chromatin-modifying genes, including , and , were commonly mutated in HSTL, affecting 62% of cases. HSTLs manifest frequent mutations in (31%), (9%), and (9%), for which there currently exist potential targeted therapies. In addition, we noted less frequent events in , and was the most frequently silenced gene in HSTL. We experimentally demonstrated that acts as a tumor suppressor gene. In addition, we found that mutations in and activate critical signaling pathways important to cell survival in HSTL. Our work thus defines the genetic landscape of HSTL and implicates gene mutations linked to HSTL pathogenesis and potential treatment targets. We report the first systematic application of whole-exome sequencing to define the genetic basis of HSTL, a rare but lethal disease. Our work defines as a tumor suppressor gene in HSTL and implicates genes including and in the disease. .
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http://dx.doi.org/10.1158/2159-8290.CD-16-0330DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5402251PMC
April 2017

Lenalidomide in Adult T-Cell Leukemia/Lymphoma.

J Clin Oncol 2016 12 31;34(34):4066-4067. Epub 2016 Oct 31.

Neha Mehta-Shah, Washington University, St Louis, MO; and Steven M. Horwitz, Memorial Sloan-Kettering Cancer Center, New York, NY.

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http://dx.doi.org/10.1200/JCO.2016.69.4505DOI Listing
December 2016

Managing Patients with Cutaneous B-Cell and T-Cell Lymphomas Other Than Mycosis Fungoides.

Curr Hematol Malig Rep 2016 06;11(3):224-33

Department of Medicine, Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Cutaneous lymphomas (CL) are a heterogeneous group of neoplasms characterized with clinical and histopathological variation, as well as overlap with benign dermatoses. Diagnosis and treatment of CLs is challenging and often requires a multidisciplinary approach. However, prognostic knowledge of these conditions and awareness of treatment options can help optimize appropriate use of available regimens, thereby improving care for patients. Here, we review the most recent literature and outline treatment themes for managing patients with cutaneous B-cell and T-cell lymphomas other than mycosis fungoides.
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http://dx.doi.org/10.1007/s11899-016-0322-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5611851PMC
June 2016

Zebras and hen's teeth: recognition and management of rare T and NK lymphomas.

Hematology Am Soc Hematol Educ Program 2015 ;2015:545-9

Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY; and Department of Medicine, Weill-Cornell Medical College, New York, NY.

Although all the peripheral T-cell lymphomas are uncommon, there are some entities that are truly rare. Subtypes, such as enteropathy-associated T-cell lymphoma, hepatosplenic T-cell lymphoma, extranodal NK/T-cell lymphoma, and subcutaneous panniculitis-like T-cell lymphoma, have an approximate annual incidence in United States of <500 each. In these very rare subtypes, there is limited data to guide clinical decision-making. As such, our treatment decisions are often based on extrapolation, case series, personal experience, and biases. We summarize the existing data regarding initial management of these entities and compare how that management follows paradigms established for the more common T-cell lymphomas.
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http://dx.doi.org/10.1182/asheducation-2015.1.545DOI Listing
October 2016
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