Publications by authors named "Eric D Jacobsen"

46 Publications

Phase II biomarker-driven study of ruxolitinib demonstrates effectiveness of JAK/STAT targeting in T-cell lymphomas.

Blood 2021 Oct 15. Epub 2021 Oct 15.

Memorial Sloan-Kettering Cancer Center, New York, New York, United States.

Signaling through JAK1 and/or JAK2 is common among tumor and non-tumor cells within peripheral T-cell lymphoma (PTCL). No oral therapies are approved for PTCL and better treatments for relapsed/refractory disease are urgently needed. We conducted a phase II study of the JAK1/2 inhibitor, ruxolitinib, for patients with relapsed/refractory PTCL (n=45) or mycosis fungoides (MF) (n=7). Patients enrolled onto one of three biomarker-defined cohorts: 1) activating JAK and/or STAT mutations; 2) ≥30% pSTAT3 expression among tumor cells by immunohistochemistry; or 3) neither or insufficient tissue to assess. Patients received ruxolitinib 20 mg PO BID until progression and were assessed for response after cycles 2, 5 and every three cycles thereafter. The primary endpoint was clinical benefit rate (CBR) defined as the combination of complete response (CR), partial response (PR), and stable disease lasting at least 6 months. Only one of 7 patients with MF had CBR (ongoing PR>18 months). CBR among the PTCL cases (n=45) in cohorts 1, 2 and 3 were 53%, 45%, and 13% (cohorts 1&2 vs. 3, p=0.02). Eight patients had CBR>12 months (5 ongoing), including 4 of 5 patients with T-cell large granular lymphocytic leukemia. In an exploratory analysis using multiplex immunofluorescence, expression of phosphorylated S6 (pS6), a marker of PI3 kinase or MAP kinase activation, in <25% of tumor cells was associated with response to ruxolitinib (p=0.05). We conclude that ruxolitinib is active across various PTCL subtypes and support a precision therapy approach to JAK/STAT inhibition in patients with PTCL. (Registered at clincialtrials.gov, #NCT02974647).
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http://dx.doi.org/10.1182/blood.2021013379DOI Listing
October 2021

Autologous EBV-specific T cell treatment results in sustained responses in patients with advanced extranodal NK/T lymphoma: results of a multicenter study.

Ann Hematol 2021 Oct 24;100(10):2529-2539. Epub 2021 Jul 24.

Center for Cell and Gene Therapy, Baylor College of Medicine, Houston Methodist Hospital and Texas Children's Hospital, Houston, TX, USA.

We conducted a phase II clinical trial to develop an autologous EBV-specific T cell product (baltaleucel T) for advanced, relapsed ENKTL. Among 47 patients who provided whole blood starting material for manufacturing the product, 15 patients received a median of 4 doses of baltaleucel T. Thirty-two (68%) patients did not receive baltaleucel-T due to manufacturing failure, rapid disease progression, and death. Of the 15 patients, 10 patients had measurable disease at baseline (salvage cohort), and 5 patients had no disease at baseline assessment (adjuvant cohort). In the 15 patients, the median follow-up duration was 10.2 months (range 2.0-23.5 months), median progression-free survival (PFS) was 3.9 months, and the median overall survival (OS) was not reached. Patients in the salvage cohort achieved a 30% complete response (CR) and a 50% overall response rate (ORR). In the adjuvant cohort, disease progression was reported in three patients and two patients did not relapse during study follow-up. When we compared survival outcomes of seven responders and eight non-responders, the PFS (P = 0.001) and OS (P = 0.014) of responders proved statistically superior to that of non-responders. Baltaleucel-T was well tolerated. We have performed a phase II clinical trial of autologous EBV-specific T cell treatment (baltaleucel-T) in R/R ENKTL. Autologous EBV-specific T cells were well tolerated and demonstrated single-agent activity in R/R ENTKL.
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http://dx.doi.org/10.1007/s00277-021-04558-0DOI Listing
October 2021

High-grade heart block associated with ibrutinib therapy.

HeartRhythm Case Rep 2021 Jun 19;7(6):391-394. Epub 2021 Mar 19.

Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.

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http://dx.doi.org/10.1016/j.hrcr.2021.03.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8226304PMC
June 2021

Cutaneous Langerhans cell histiocytosis in adults: A retrospective cohort study of adult patients presenting to a single academic cancer center between 2003 and 2017.

J Am Acad Dermatol 2021 Jun 11. Epub 2021 Jun 11.

Harvard Medical School, Boston, Massachusetts; Department of Dermatology, Brigham and Women's Hospital, Boston, Massachusetts; Center for Cutaneous Oncology, Department of Dermatology, Dana-Farber/Brigham and Women's Cancer Center, Boston, Massachusetts. Electronic address:

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http://dx.doi.org/10.1016/j.jaad.2021.06.016DOI Listing
June 2021

Spatial signatures identify immune escape via PD-1 as a defining feature of T-cell/histiocyte-rich large B-cell lymphoma.

Blood 2021 03;137(10):1353-1364

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

T-cell/histiocyte-rich large B-cell lymphoma (TCRLBCL) is an aggressive variant of diffuse large B-cell lymphoma (DLBCL) characterized by rare malignant B cells within a robust but ineffective immune cell infiltrate. The mechanistic basis of immune escape in TCRLBCL is poorly defined and not targeted therapeutically. We performed a genetic and quantitative spatial analysis of the PD-1/PD-L1 pathway in a multi-institutional cohort of TCRLBCLs and found that malignant B cells harbored PD-L1/PD-L2 copy gain or amplification in 64% of cases, which was associated with increased PD-L1 expression (P = .0111). By directed and unsupervised spatial analyses of multiparametric cell phenotypic data within the tumor microenvironment, we found that TCRLBCL is characterized by tumor-immune "neighborhoods" in which malignant B cells are surrounded by exceptionally high numbers of PD-L1-expressing TAMs and PD-1+ T cells. Furthermore, unbiased clustering of spatially resolved immune signatures distinguished TCRLBCL from related subtypes of B-cell lymphoma, including classic Hodgkin lymphoma (cHL) and DLBCL-NOS. Finally, we observed clinical responses to PD-1 blockade in 3 of 5 patients with relapsed/refractory TCRLBCL who were enrolled in clinical trials for refractory hematologic malignancies (NCT03316573; NCT01953692), including 2 complete responses and 1 partial response. Taken together, these data implicate PD-1 signaling as an immune escape pathway in TCRLBCL and also support the potential utility of spatially resolved immune signatures to aid the diagnostic classification and immunotherapeutic prioritization of diverse tumor types.
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http://dx.doi.org/10.1182/blood.2020006464DOI Listing
March 2021

Cutaneous Langerhans Cell Histiocytosis Responsive to Topical Nitrogen Mustard.

J Drugs Dermatol 2020 Aug;19(8):803-805

Langerhans cell histiocytosis (LCH) limited to the skin is rare in adult patients. Given the challenges of prospective clinical trials for this rare disease, there is paucity in data to guide the management of cutaneous LCH. Topical nitrogen mustard is a possible treatment for cutaneous LCH with positive responses in five known adult cases in the literature. In this report, we present two adult patients with recalcitrant cutaneous LCH and no evidence of systemic involvement who had rapid and complete response on topical nitrogen mustard therapy. We provide support for topical nitrogen mustard as a treatment option for primary cutaneous LCH which may spare patients from requiring systemic immunosuppressive treatments. J Drugs Dermatol. 2020;19(8):803-805. doi:10.36849/JDD.2020.4943.
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http://dx.doi.org/10.36849/JDD.2020.4943DOI Listing
August 2020

Erdheim-Chester disease: consensus recommendations for evaluation, diagnosis, and treatment in the molecular era.

Blood 2020 05;135(22):1929-1945

Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, NY.

Erdheim-Chester disease (ECD) is a rare histiocytosis that was recently recognized as a neoplastic disorder owing to the discovery of recurrent activating MAPK (RAS-RAF-MEK-ERK) pathway mutations. Typical findings of ECD include central diabetes insipidus, restrictive pericarditis, perinephric fibrosis, and sclerotic bone lesions. The histopathologic diagnosis of ECD is often challenging due to nonspecific inflammatory and fibrotic findings on histopathologic review of tissue specimens. Additionally, the association of ECD with unusual tissue tropism and an insidious onset often results in diagnostic errors and delays. Most patients with ECD require treatment, except for a minority of patients with minimally symptomatic single-organ disease. The first ECD consensus guidelines were published in 2014 on behalf of the physicians and researchers within the Erdheim-Chester Disease Global Alliance. With the recent molecular discoveries and the approval of the first targeted therapy (vemurafenib) for BRAF-V600-mutant ECD, there is a need for updated clinical practice guidelines to optimize the diagnosis and treatment of this disease. This document presents consensus recommendations that resulted from the International Medical Symposia on ECD in 2017 and 2019. Herein, we include the guidelines for the clinical, laboratory, histologic, and radiographic evaluation of ECD patients along with treatment recommendations based on our clinical experience and review of literature in the molecular era.
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http://dx.doi.org/10.1182/blood.2019003507DOI Listing
May 2020

PD-1 blockade for diffuse large B-cell lymphoma after autologous stem cell transplantation.

Blood Adv 2020 01;4(1):122-126

Department of Hematology and Oncology, Beth Israel Deaconess Medical Center, Boston, MA.

Disease relapse remains the leading cause of failure after autologous stem cell transplantation (ASCT) for patients with relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL). We conducted a phase 2, multicenter, single-arm study of the anti-PD-1 monoclonal antibody pembrolizumab given after ASCT in patients with chemosensitive DLBCL, hypothesizing that it would improve the progression-free survival (PFS) at 18 months after ASCT (primary endpoint) from 60% to 80%. Pembrolizumab was administered at 200 mg IV every 3 weeks for up to 8 cycles, starting within 21 days of post-ASCT discharge. Twenty-nine patients were treated on this study; 62% completed all 8 cycles. Seventy-nine percent of patients experienced at least one grade 3 or higher adverse event, and 34% experienced at least one grade 2 or higher immune-related adverse event. Overall, 59% of patients were alive and progression free at 18 months, which did not meet the primary endpoint. The 18-month overall survival was 93%. In conclusion, pembrolizumab was successfully administered as post-ASCT consolidation in patients with R/R DLBCL, but the PFS did not meet the protocol-specific primary objective and therefore does not support a larger confirmatory study. This trial was registered at www.clinicaltrials.gov as #NCT02362997.
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http://dx.doi.org/10.1182/bloodadvances.2019000784DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6960482PMC
January 2020

Consensus criteria for diagnosis, staging, and treatment response assessment of T-cell prolymphocytic leukemia.

Blood 2019 10 10;134(14):1132-1143. Epub 2019 Jul 10.

The Royal Marsden Hospital, NHS Foundation Trust, London, United Kingdom.

T-cell prolymphocytic leukemia (T-PLL) is a rare, mature T-cell neoplasm with a heterogeneous clinical course. With the advent of novel treatment options that will potentially change the management of patients with T-PLL, it has become necessary to produce consensus guidelines for the design and conduct of clinical trials. The T-PLL International Study group (TPLL-ISG) set out to define standardized criteria for diagnosis, treatment indication, and evaluation of response. These criteria will facilitate comparison of results from clinical trials in T-PLL, and will thus support clinical decision making, as well as the approval of new therapeutics by healthcare authorities.
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http://dx.doi.org/10.1182/blood.2019000402DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7042666PMC
October 2019

Peripheral T-Cell Lymphoma: Moving Toward Targeted Therapies.

Hematol Oncol Clin North Am 2019 08 18;33(4):657-668. Epub 2019 May 18.

Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA.

Therapeutic advances for peripheral T-cell non-Hodgkin lymphoma (PTCL) have lagged behind their B-cell NHL counterparts in part because novel agents to treat PTCL have been developed empirically. The recent clinical success of brentuximab-vedotin suggests that novel therapies for PTCL can significantly improve outcomes when properly targeted. Aberrancies in T-cell receptor, Jak/STAT, and DNA methylation pathways play critical roles in T-NHL pathogenesis based on genomic studies and preclinical experimental validation. New strategies targeting these pathways in patients with PTCL are underway, and this clinical trial experience will possibly contribute to additional improvements in outcome for patients with these diseases.
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http://dx.doi.org/10.1016/j.hoc.2019.04.002DOI Listing
August 2019

PD-1 blockade with pembrolizumab for classical Hodgkin lymphoma after autologous stem cell transplantation.

Blood 2019 07 5;134(1):22-29. Epub 2019 Apr 5.

Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, CA.

Autologous stem cell transplantation (ASCT) remains the standard of care for patients with relapsed/refractory (RR) classical Hodgkin lymphoma (cHL) who respond to salvage chemotherapy. However, relapse after ASCT remains a frequent cause of treatment failure, with poor subsequent prognosis. Because cHL is uniquely vulnerable to programmed cell death-1 (PD-1) blockade, PD-1 blockade given as consolidation after ASCT could improve ASCT outcomes. We therefore conducted a multicohort phase 2 study of pembrolizumab in patients with RR cHL after ASCT, hypothesizing that it would improve the progression-free survival (PFS) at 18 months after ASCT (primary end point) from 60% to 80%. Pembrolizumab was administered at 200 mg IV every 3 weeks for up to 8 cycles, starting within 21 days of post-ASCT discharge. Thirty patients were treated on this study. The median age was 33 years, and 90% were high-risk by clinical criteria. Seventy-seven percent completed all 8 cycles. Toxicity was manageable, with 30% of patients experiencing at least 1 grade 3 or higher adverse event (AE), and 40% at least 1 grade 2 or higher immune-related AE. Two patients were lost to follow-up in complete remission at 12 months. The PFS at 18 months for the 28 evaluable patients was 82%, meeting the primary end point. The 18-month overall survival was 100%. In conclusion, pembrolizumab was successfully administered as post-ASCT consolidation in patients with RR cHL, and resulted in a promising PFS in a high-risk patient cohort, supporting the testing of this strategy in a randomized trial. This trial was registered at www.clinicaltrials.gov as #NCT02362997.
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http://dx.doi.org/10.1182/blood.2019000215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6609955PMC
July 2019

DYNAMO: A Phase II Study of Duvelisib (IPI-145) in Patients With Refractory Indolent Non-Hodgkin Lymphoma.

J Clin Oncol 2019 04 11;37(11):912-922. Epub 2019 Feb 11.

19 University of Bologna, Bologna, Italy.

Purpose: Indolent non-Hodgkin lymphoma (iNHL) remains largely incurable and often requires multiple lines of treatment after becoming refractory to standard therapies. Duvelisib was approved by the Food and Drug Administration for relapsed or refractory (RR) chronic lymphocytic leukemia or small lymphocytic lymphoma (SLL) and RR follicular lymphoma (FL) after two or more prior systemic therapies. On the basis of the activity of duvelisib, a first-in-class oral dual inhibitor of phosphoinositide 3-kinase-δ,-γ, in RR iNHL in a phase I study, the safety and efficacy of duvelisib monotherapy was evaluated in iNHL refractory to rituximab and either chemotherapy or radioimmunotherapy.

Patients And Methods: Eligible patients had measurable iNHL (FL, SLL, or marginal zone B-cell lymphoma) double refractory to rituximab (monotherapy or in combination) and to either chemotherapy or radioimmunotherapy. All were treated with duvelisib 25 mg orally twice daily in 28-day cycles until progression, unacceptable toxicity, or death. The primary end point was overall response rate (ORR) using the revised International Working Group criteria for malignant lymphoma.

Results: This open-label, global phase II trial enrolled 129 patients (median age, 65 years; median of three prior lines of therapy) with an ORR of 47.3% (SLL, 67.9%; FL, 42.2%; MZL, 38.9%). The estimated median duration of response was 10 months, and the estimated median progression-free survival was 9.5 months. The most frequent any-grade treatment-emergent adverse events (TEAEs) were diarrhea (48.8%), nausea (29.5%), neutropenia (28.7%), fatigue (27.9%), and cough (27.1%). Among the 88.4% of patients with at least one grade 3 or greater TEAE, the most common TEAEs were neutropenia (24.8%), diarrhea (14.7%), anemia (14.7%), and thrombocytopenia (11.6%).

Conclusion: In the DYNAMO study, oral duvelisib monotherapy demonstrated clinically meaningful activity and a manageable safety profile in heavily pretreated, double-refractory iNHL, consistent with previous observations. Duvelisib may provide a new oral treatment option for this patient population of which many are elderly and in need of additional therapies.
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http://dx.doi.org/10.1200/JCO.18.00915DOI Listing
April 2019

2019 NCCN Consensus Guidelines on the Diagnosis and Treatment of Breast Implant-Associated Anaplastic Large Cell Lymphoma (BIA-ALCL).

Aesthet Surg J 2019 01;39(Suppl_1):S3-S13

Department of Hematology, Memorial Sloan Kettering Cancer Center, New York, NY.

National Comprehensive Cancer Network (NCCN) guidelines represent the consensus standard of care for diagnosis and management of the majority of known cancers. NCCN guidelines on breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) have been recognized by the US Food and Drug Administration and widely advocated by national specialty societies. Consensus guidelines have helped create a treatment standardization for BIA-ALCL at all stages of disease. NCCN guidelines are evidence-based where possible and utilize expert consensus opinion to fill in gaps that may exist. NCCN undergoes annual panel review by multidisciplinary faculty members, and this article represents the most up-to-date 2019 guidelines. Recommendations focus on parameters for achieving reliable diagnosis and disease management and emphasize the critical role for complete surgical ablation. Suggestions for adjunct treatments and chemotherapy regimens are included for advanced BIA-ALCL with lymph node involvement. BIA-ALCL recurrence and management of unresectable disease, and organ metastasis are addressed. Adherence to recognized BIA-ALCL guidelines ensures patients receive the most current efficacious treatment available.
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http://dx.doi.org/10.1093/asj/sjy331DOI Listing
January 2019

Randomized Phase III Study of Alisertib or Investigator's Choice (Selected Single Agent) in Patients With Relapsed or Refractory Peripheral T-Cell Lymphoma.

J Clin Oncol 2019 03 1;37(8):613-623. Epub 2019 Feb 1.

27 University of Washington, Seattle Cancer Care Alliance, Seattle, WA.

Purpose: The aim of this open-label, first-in-setting, randomized phase III trial was to evaluate the efficacy of alisertib, an investigational Aurora A kinase inhibitor, in patients with relapsed/refractory peripheral T-cell lymphoma (PTCL).

Patients And Methods: Adult patients with relapsed/refractory PTCL-one or more prior therapy-were randomly assigned 1:1 to receive oral alisertib 50 mg two times per day (days 1 to 7; 21-day cycle) or investigator-selected single-agent comparator, including intravenous pralatrexate 30 mg/m (once per week for 6 weeks; 7-week cycle), or intravenous gemcitabine 1,000 mg/m or intravenous romidepsin 14 mg/m (days 1, 8, and 15; 28-day cycle). Tumor tissue (disease subtype) and imaging were assessed by independent central review. Primary outcomes were overall response rate and progression-free survival (PFS). Two interim analyses and one final analysis were planned.

Results: Between May 2012 and October 2014, 271 patients were randomly assigned (alisertib, n = 138; comparator, n = 133). Enrollment was stopped early on the recommendation of the independent data monitoring committee as a result of the low probability of alisertib achieving PFS superiority with full enrollment. Centrally assessed overall response rate was 33% for alisertib and 45% for the comparator arm (odds ratio, 0.60; 95% CI, 0.33 to 1.08). Median PFS was 115 days for alisertib and 104 days for the comparator arm (hazard ratio, 0.87; 95% CI, 0.637 to 1.178). The most common adverse events were anemia (53% of alisertib-treated patients v 34% of comparator-treated patients) and neutropenia (47% v 31%, respectively). A lower percentage of patients who received alisertib (9%) compared with the comparator (14%) experienced events that led to study drug discontinuation. Of 26 on-study deaths, five were considered treatment related (alisertib, n = 3 of 11; comparator, n = 2 of 15). Two-year overall survival was 35% for each arm.

Conclusion: In patients with relapsed/refractory PTCL, alisertib was not statistically significantly superior to the comparator arm.
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http://dx.doi.org/10.1200/JCO.18.00899DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6494247PMC
March 2019

Identification of diverse activating mutations of the RAS-MAPK pathway in histiocytic sarcoma.

Mod Pathol 2019 06 9;32(6):830-843. Epub 2019 Jan 9.

Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA.

Recent studies have demonstrated recurrent activating mutations involving the classical MAPK and PI3K signaling pathways in a large proportion of histiocytic neoplasms, such as Langerhans cell histiocytosis. However, very little is known about the molecular genetics of histiocytic sarcoma, a rare aggressive malignant neoplasm that shows pathologic characteristics of mature macrophages. Here we report the genomic characteristics of a large cohort of histiocytic sarcomas (n = 28) using a targeted next-generation sequencing approach to identify driver alterations. We identified recurrent mutations involving the RAS-MAPK signaling pathway (MAP2K1, KRAS, NRAS, BRAF, PTPN11, NF1, CBL) in a majority (57%) of histiocytic sarcoma cases and report a clinical response to a MEK inhibitor (Cobimetinib) in a patient with a NF1-mutated histiocytic sarcoma. A smaller subset of cases (21%) also showed mutations resulting in activation of the PI3K signaling pathway (PTEN, MTOR, PIK3R1, PIK3CA). In addition, the tumor-suppressor gene CDKN2A was the most frequently altered gene (46%). Further, a subset of histiocytic sarcoma cases shows striking molecular genetic similarities to B cell lymphomas, supporting a clonal relationship between B cell neoplasms and a subset of histiocytic sarcomas. These findings support a cooperative role for MAPK, PI3K, and cyclin-CDK4/6-INK4 signaling in the pathogenesis of histiocytic sarcoma and provide a rational basis for targeting these pathways.
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http://dx.doi.org/10.1038/s41379-018-0200-xDOI Listing
June 2019

Umbralisib in combination with ibrutinib in patients with relapsed or refractory chronic lymphocytic leukaemia or mantle cell lymphoma: a multicentre phase 1-1b study.

Lancet Haematol 2019 Jan 14;6(1):e38-e47. Epub 2018 Dec 14.

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

Background: Patients with relapsed or refractory high-risk chronic lymphocytic leukaemia or mantle cell lymphoma often do not derive durable benefit from ibrutinib monotherapy. We hypothesised that dual B-cell receptor pathway blockade would be tolerable and efficacious. We investigated a next-generation phosphoinositide-3-kinase-δ inhibitor (PI3K-δi), umbralisib, plus a Bruton tyrosine kinase inhibitor (BTKi), ibrutinib, in relapsed or refractory chronic lymphocytic leukaemia and mantle cell lymphoma.

Methods: We did an investigator-initiated, multicentre, phase 1-1b study of patients from five sites in the USA (academic and community sites). Patients were 18 years and older with relapsed or refractory chronic lymphocytic leukaemia or mantle cell lymphoma, with an Eastern Cooperative Oncology Group performance status of 2 or less, and were given umbralisib orally once daily (400 mg, 600 mg, or 800 mg) and ibrutinib orally once daily (420 mg for chronic lymphocytic leukaemia or 560 mg for mantle cell lymphoma) until disease progression or unacceptable toxicity. The phase 1 dose-escalation cohorts for each histology escalated independently in a standard 3 × 3 design. The primary endpoints were intention-to-treat assessment of maximum-tolerated dose, safety, and dose-limiting toxicities. This trial is ongoing and is registered with ClinicalTrials.gov, number NCT02268851.

Findings: Between Dec 5, 2014, and March 7, 2018, we enrolled 44 patients, of which 42 were given at least one dose of study drug (chronic lymphocytic leukaemia, n=21; mantle cell lymphoma, n=21). Patients had a median age of 68 years (range 48-85) and had a median of two (IQR 1-3) previous therapies. No dose-limiting toxicities were observed and the maximum-tolerated dose of umbralisib was not reached. The recommended phase 2 dose of umbralisib when given in combination with ibrutinib was 800 mg once daily. The most frequent adverse events included diarrhoea (22 [52%] patients, 10% of whom had grade 3), infection (21 [50%], 17% grade 3-4), and transaminitis (ten [24%], 2% grade 3). Serious adverse events occurred in 12 (29%) patients and included lipase elevation, atrial fibrillation, hypophosphataemia, adrenal insufficiency, transaminitis, and infections.

Interpretation: Umbralisib plus ibrutinib is well tolerated and active in relapsed or refractory chronic lymphocytic leukaemia and mantle cell lymphoma, with a recommended phase 2 dose of umbralisib 800 mg once daily. To the best of our knowledge, these are the first clinical data on a BTKi and PI3K-δi doublet in B-cell malignancies, and the results suggest that this approach is feasible and worthy of further study.

Funding: TG Therapeutics, Leukemia and Lymphoma Society Therapy Accelerator Program.
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http://dx.doi.org/10.1016/S2352-3026(18)30196-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7132223PMC
January 2019

Challenges and implications of genomics for T-cell lymphomas.

Hematology Am Soc Hematol Educ Program 2018 11;2018(1):63-68

Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA; and.

Treatment outcomes for patients with peripheral T-cell lymphomas (PTCLs) and advanced-stage cutaneous T-cell lymphomas (CTCLs) remain poor. The past few years have witnessed an explosion in our understanding of the genetics of these diverse malignancies. Many subtypes harbor highly recurrent mutations, including single-nucleotide variants, insertions/deletions, and chromosomal rearrangements, that affect T-cell receptor signaling, costimulatory molecules, JAK/STAT and phosphatidylinositol 3-kinase pathways, transcription factors, and epigenetic modifiers. An important subset of these mutations is included within commercially available, multigene panels and, in rare circumstances, indicate therapeutic targets. However, current preclinical and clinical evidence suggests that only a minority of mutations identified in TCLs indicate biologic dependence. With a few exceptions that we highlight, mutations identified in TCLs should not be routinely used to select targeted therapies outside of a clinical trial. Participation in trials and publication of both positive and negative results remain the most important mechanisms for improving patient outcomes.
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http://dx.doi.org/10.1182/asheducation-2018.1.63DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6246015PMC
November 2018

Imaging of Histiocytosis in the Era of Genomic Medicine.

Radiographics 2019 Jan-Feb;39(1):95-114. Epub 2018 Nov 30.

From the Departments of Radiology (H.P., M.N.), Pathology (J.L.H.), and Medical Oncology (E.D.J.), Brigham and Women's Hospital and Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, MA 02215.

Histiocytosis describes a group of diseases that have long been considered enigmatic in the history of medicine. Recently, novel genomic analyses have identified somatic oncogenic driver mutations responsible for the pathogenesis of these entities. These discoveries have led to the recharacterization of histiocytoses as neoplastic diseases and have opened a new era of precision medicine approaches for treatment. The histiocytic disorders demonstrate a variety of imaging manifestations involving multiple organ systems, and radiologists play a major role in diagnosis and monitoring. An up-to-date knowledge of the novel genomic discoveries and their implications is essential for radiologists to understand the new approaches to treating histiocytic disorders and to contribute as key members of the multidisciplinary treatment team. This article provides a cutting-edge review of the novel concepts in histiocytosis, with a focus on recent genomic discoveries and precision medicine approaches to treating the disease, and describes imaging manifestations with correlative histologic and genomic findings, with an emphasis on adult-onset cases and uncommon subtypes. RSNA, 2018.
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http://dx.doi.org/10.1148/rg.2019180054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6357950PMC
March 2020

Cutaneous Involvement of Hematologic Malignancies.

Hematol Oncol Clin North Am 2019 02;33(1):163-172

Lymphoma Clinic, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA. Electronic address:

In reviewing cutaneous manifestations of various hematologic malignancies, the authors focus on secondary cutaneous lymphomas and cutaneous manifestations of histiocyte disorders. Secondary cutaneous lymphomas are defined as skin lesions that develop secondary to infiltration by systemic lymphomas with predominantly extracutaneous involvement. In their review of histiocytic disorders with skin involvement, the authors focus on Langerhans cell histiocytosis and Rosai-Dorfman disease. Their review emphasizes the histology, pathophysiology, clinical presentation, prognosis, and treatments available for these diseases.
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http://dx.doi.org/10.1016/j.hoc.2018.08.005DOI Listing
February 2019

Ofatumumab plus high dose methylprednisolone followed by ofatumumab plus alemtuzumab to achieve maximal cytoreduction prior to allogeneic transplantation for 17p deleted or TP53 mutated chronic lymphocytic leukemia

Leuk Lymphoma 2019 05 15;60(5):1312-1315. Epub 2018 Oct 15.

a Departments of Medical Oncology , Dana-Farber Cancer Institute, Harvard Medical School , Boston , MA , USA.

We hypothesized that ofatumumab with sequential methylprednisolone - alemtuzumab would be an effective and tolerable regimen for patients with high-risk chronic lymphocytic leukemia (CLL) with TP53 dysfunction. Thirty CLL patients with TP53 dysfunction (15 treatment naive (TN), 15 relapsed/refractory (R/R)) were enrolled in this phase II study. Therapy included ofatumumab with methylprednisolone for 2-4 monthly cycles, then ofatumumab with alemtuzumab for 4-24 weeks, then allogeneic transplantation or maintenance. The rate of overall response, complete response, marrow minimal residual disease (MRD) negativity, 3-year progression-free survival and overall survival were 80, 13, 80, 53, and 66%, respectively, in TN patients and 68, 0, 54, 25, and 53%, respectively, in R/R patients. Notable grade 3/4 toxicities included neutropenia and infection in 43 and 40% of patients, respectively. At median follow-up of 45 months, 13 patients died, and 10 patients are alive posttransplant. Overall, we observed high rates of MRD-negativity and acceptable tolerability in high-risk CLL.
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http://dx.doi.org/10.1080/10428194.2018.1519814DOI Listing
May 2019

Targetable vulnerabilities in T- and NK-cell lymphomas identified through preclinical models.

Nat Commun 2018 05 22;9(1):2024. Epub 2018 May 22.

Department of Pathology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA.

T- and NK-cell lymphomas (TCL) are a heterogenous group of lymphoid malignancies with poor prognosis. In contrast to B-cell and myeloid malignancies, there are few preclinical models of TCLs, which has hampered the development of effective therapeutics. Here we establish and characterize preclinical models of TCL. We identify multiple vulnerabilities that are targetable with currently available agents (e.g., inhibitors of JAK2 or IKZF1) and demonstrate proof-of-principle for biomarker-driven therapies using patient-derived xenografts (PDXs). We show that MDM2 and MDMX are targetable vulnerabilities within TP53-wild-type TCLs. ALRN-6924, a stapled peptide that blocks interactions between p53 and both MDM2 and MDMX has potent in vitro activity and superior in vivo activity across 8 different PDX models compared to the standard-of-care agent romidepsin. ALRN-6924 induced a complete remission in a patient with TP53-wild-type angioimmunoblastic T-cell lymphoma, demonstrating the potential for rapid translation of discoveries from subtype-specific preclinical models.
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http://dx.doi.org/10.1038/s41467-018-04356-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5964252PMC
May 2018

Autologous Stem Cell Transplantation in Elderly Lymphoma Patients in Their 70s: Outcomes and Analysis.

Oncologist 2018 05 28;23(5):624-630. Epub 2017 Dec 28.

Blood and Marrow Transplant Program, Massachusetts General Hospital, Boston, Massachusetts, USA

Background: High-dose chemotherapy and autologous stem cell transplantation (ASCT) can offer durable remission in many patients with relapsed or high-risk lymphoma. However, elderly patients are often not considered ASCT candidates based on age alone.

Subjects, Materials, And Methods: A retrospective analysis of patients ≥70 years of age with a diagnosis of Hodgkin or non-Hodgkin lymphoma receiving ASCT between 2000 and 2016 at two partner institutions was performed. Clinical data were extracted from institutional databases and individual medical records. Multivariate analysis was performed to examine the association of clinical variables with transplant outcomes.

Results: One hundred seven patients were identified. Median age at transplant was 72 years (range, 70-79). The most common lymphoma subtype was diffuse large B-cell ( = 63, 59%). Median time to neutrophil and platelet engraftment were 10 and 12 days, respectively. With a median follow-up for survivors of 20 months following ASCT (range, 6 months to 13.1 years), estimates for 2-year progression-free survival and overall survival were 58% (95% confidence interval [CI], 48%-67%) and 65% (95% CI, 55%-74%), respectively. Two-year estimate for relapse was 34% (95% CI, 25%-44%) and nonrelapse mortality (NRM) was 7% (95% CI, 3%-14%). Multivariate analysis showed that more recent date of transplant was associated with lower NRM. The Hematopoietic Cell Transplantation-Comorbidity Index score was not predictive of NRM in this data set (high-risk vs. low-risk, hazard ratio 3.45,  = .065).

Conclusion: Eligibility for ASCT should be an individualized decision, and age should not be an absolute contraindication to ASCT in healthy elderly patients with lymphoma.

Implications For Practice: Although high-dose chemotherapy and autologous stem cell transplantation (ASCT) can offer durable remission in many patients with relapsed or high-risk lymphoma, elderly patients are often not considered candidates due to concern for excess toxicity and mortality. This retrospective study showed favorable transplant outcomes, including survival and toxicity, in a large cohort of lymphoma patients over 70 years of age who underwent ASCT. Eligibility for ASCT should be an individualized decision, and age should not be an absolute contraindication to ASCT in healthy elderly patients with lymphoma.
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http://dx.doi.org/10.1634/theoncologist.2017-0499DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5947447PMC
May 2018

Axicabtagene Ciloleucel CAR T-Cell Therapy in Refractory Large B-Cell Lymphoma.

N Engl J Med 2017 12 10;377(26):2531-2544. Epub 2017 Dec 10.

From the University of Texas M.D. Anderson Cancer Center, Houston (S.S.N., J.R.W.); H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL (F.L.L., J.C.C.); Washington University and Siteman Cancer Center, St. Louis (N.L.B., A. Ghobadi); University of Miami, Miami (L.J.L., K.V.K.); Stanford University, Stanford (D.B.M., R.L.), City of Hope National Medical Center, Duarte (T.S.), University of California at Los Angeles, Los Angeles (J.M.T.), University of California at San Diego, San Diego (J.E.C.), and Kite Pharma, Santa Monica (A.B., J.R., L.N., Y.J., J.A., M.E., D.C., J.W., W.Y.G.) - all in California; Dana-Farber Cancer Institute, Boston (C.A.J., E.D.J.); Montefiore Medical Center, Bronx (I.B.), and the University of Rochester School of Medicine, Rochester (J.W.F., P.R.) - both in New York; Vanderbilt University Medical Center (O.O.O.) and the Sarah Cannon Research Institute and Tennessee Oncology (I.W.F.), Nashville; Mayo Clinic, Rochester, MN (Y.L., T.E.W.); Loyola University Medical Center, Maywood, IL (P.J.S.); John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, NJ (A. Goy); Cleveland Clinic, Cleveland (B.T.H., M.R.S.); Karmanos Cancer Center, Wayne State University, Detroit (A.D.); University of Iowa Carver College of Medicine, Iowa City (U.F.); Colorado Blood Cancer Institute, Denver (P.M.S.); Banner M.D. Anderson Cancer Center, Gilbert, AZ (J.M.); and Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel (I.A.).

Background: In a phase 1 trial, axicabtagene ciloleucel (axi-cel), an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, showed efficacy in patients with refractory large B-cell lymphoma after the failure of conventional therapy.

Methods: In this multicenter, phase 2 trial, we enrolled 111 patients with diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma, or transformed follicular lymphoma who had refractory disease despite undergoing recommended prior therapy. Patients received a target dose of 2×10 anti-CD19 CAR T cells per kilogram of body weight after receiving a conditioning regimen of low-dose cyclophosphamide and fludarabine. The primary end point was the rate of objective response (calculated as the combined rates of complete response and partial response). Secondary end points included overall survival, safety, and biomarker assessments.

Results: Among the 111 patients who were enrolled, axi-cel was successfully manufactured for 110 (99%) and administered to 101 (91%). The objective response rate was 82%, and the complete response rate was 54%.With a median follow-up of 15.4 months, 42% of the patients continued to have a response, with 40% continuing to have a complete response. The overall rate of survival at 18 months was 52%. The most common adverse events of grade 3 or higher during treatment were neutropenia (in 78% of the patients), anemia (in 43%), and thrombocytopenia (in 38%). Grade 3 or higher cytokine release syndrome and neurologic events occurred in 13% and 28% of the patients, respectively. Three of the patients died during treatment. Higher CAR T-cell levels in blood were associated with response.

Conclusions: In this multicenter study, patients with refractory large B-cell lymphoma who received CAR T-cell therapy with axi-cel had high levels of durable response, with a safety profile that included myelosuppression, the cytokine release syndrome, and neurologic events. (Funded by Kite Pharma and the Leukemia and Lymphoma Society Therapy Acceleration Program; ZUMA-1 ClinicalTrials.gov number, NCT02348216 .).
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http://dx.doi.org/10.1056/NEJMoa1707447DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5882485PMC
December 2017

Developing a Novel Model to Improve Research and care for Cancer Survivors: a Feasibility Study.

J Cancer Educ 2019 04;34(2):229-233

Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, MA, 02215, USA.

Despite a growing number of clinical trials and supportive care programs for cancer survivors, recruitment of patients for these opportunities during the survivorship phase of care is challenging. We piloted a novel process to systematically educate patients about available research studies and supportive care programs as part of a survivorship care visit. Between 3/2015 and 8/2015, patients seen in the Adult Survivorship Program who had not previously received a treatment summary and survivorship care plan (TS/SCP) were provided with one accompanied by a list of survivorship research studies and care programs tailored to their diagnosis. Survivorship providers discussed the opportunities and recorded whether the patient was interested in relevant studies and placed referrals to study staff. Following the visit, we tracked study enrollment and surveyed patients about their experience. Fifty of 56 (89%) pilot participants completed the survey. Almost all (98%) reported that the TS/SCP visit and document helped with knowledge of research opportunities and supportive care interventions. Following receipt of the TS/SCP, 44% were interested in at least one study and in further follow-up with research staff. Of the 30 survivors eligible for at least one study, 6 (20%) have enrolled in at least one study to date. This pilot program demonstrates that the systematic sharing of available clinical studies and supportive care programming as part of a survivorship care plan visit is feasible and well received by cancer survivors and may facilitate and enhance accrual to clinical trials in the survivorship phase of care.
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http://dx.doi.org/10.1007/s13187-017-1291-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5910291PMC
April 2019

Peripheral T-Cell Lymphoma: The Beginning of the End of the Beginning.

Authors:
Eric D Jacobsen

Hematol Oncol Clin North Am 2017 04;31(2):xiii-xiv

Department of Medical Oncology, Dana-Farber Cancer Institute, Assistant Professor in Medicine, Harvard Medical School, Mayer 219, 450 Brookline Avenue, Boston, MA 02215, USA. Electronic address:

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http://dx.doi.org/10.1016/j.hoc.2017.01.001DOI Listing
April 2017

Relapsed or Refractory Double-Expressor and Double-Hit Lymphomas Have Inferior Progression-Free Survival After Autologous Stem-Cell Transplantation.

J Clin Oncol 2017 Jan 24;35(1):24-31. Epub 2016 Oct 24.

Alex F. Herrera, Matthew Mei, Lawrence Low, Joo Y. Song, Victoria Bedell, Lithua Budde, Wing C. Chan, Robert Chen, Joyce Murata-Collins, Auayporn P. Nademanee, Raju Pillai, Leslie Popplewell, Tanya Siddiqi, Jasmine Zain, Steven T. Rosen, Larry W. Kwak, Stephen J. Forman, Dennis D. Weisenburger, Young Kim, Amrita Krishnan, Tanya Paris, Tracey Stiller, Joycelynne M. Palmer, City of Hope National Medical Center, Duarte, CA; Haesook T. Kim, Jennifer R. Brown, Matthew S. Davids, Arnold S. Freedman, David C. Fisher, Eric D. Jacobsen, Caron A. Jacobson, Ann S. LaCasce, David M. Weinstock, Scott J. Rodig, Philippe Armand, Dana-Farber Cancer Institute; Gabriel K. Griffin, Reid W. Merryman, Christine Pak, Heather Sun, Brigham and Women's Hospital; German A. Pihan, Beth Israel Deaconess Medical Center; and Aliyah R. Sohani, Massachusetts General Hospital, Boston, MA.

Purpose Double-hit lymphomas (DHLs) and double-expressor lymphomas (DELs) are subtypes of diffuse large B-cell lymphoma (DLBCL) associated with poor outcomes after standard chemoimmunotherapy. Data are limited regarding outcomes of patients with relapsed or refractory (rel/ref) DEL or DHL who undergo autologous stem-cell transplantation (ASCT). We retrospectively studied the prognostic impact of DEL and DHL status on ASCT outcomes in patients with rel/ref DLBCL. Methods Patients with chemotherapy-sensitive rel/ref DLBCL who underwent ASCT at two institutions and in whom archival tumor material was available were enrolled. Immunohistochemistry for MYC, BCL2, and BCL6 and fluorescence in situ hybridization (FISH) for MYC were performed. In cases with MYC rearrangement or copy gain, FISH for BCL2 and BCL6 was also performed. Results A total of 117 patients were included; 44% had DEL and 10% had DHL. DEL and DHL were associated with inferior progression-free survival (PFS), and DHL was associated with poorer overall survival (OS). The 4-year PFS in patients with DEL compared with those with non-DEL was 48% versus 59% ( P = .049), and the 4-year OS was 56% versus 67% ( P = .10); 4-year PFS in patients with DHL compared with those with non-DHL was 28% versus 57% ( P = .013), and 4-year OS was 25% versus 61% ( P = .002). The few patients with concurrent DEL and DHL had a poor outcome (4-year PFS, 0%). In multivariable models, DEL and DHL were independently associated with inferior PFS, whereas DHL and partial response ( v complete response) at transplant were associated with inferior OS. Conclusion DEL and DHL are both associated with inferior outcomes after ASCT in patients with rel/ref DLBCL. Although ASCT remains a potentially curative approach, these patients, particularly those with DHL, are a high-risk subset who should be targeted for investigational strategies other than standard ASCT.
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http://dx.doi.org/10.1200/JCO.2016.68.2740DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5455688PMC
January 2017

Brentuximab vedotin activity in diffuse large B-cell lymphoma with CD30 undetectable by visual assessment of conventional immunohistochemistry.

Leuk Lymphoma 2017 07 20;58(7):1607-1616. Epub 2016 Nov 20.

p Hematologic Oncology, Dana-Farber Cancer Institute , Boston , MA , USA.

This phase 2 study evaluated brentuximab vedotin monotherapy in CD30-expressing DLBCL; after several patients with little to no CD30 achieved a complete remission (CR), the study evaluated treatment of DLBCL with undetectable CD30 (CD30u) by local visual immunohistochemistry (vIHC). Sixteen of 52 CD30u DLBCL patients (31%) had an objective response (6 CRs [12%]). Median progression-free survival (PFS) was 1.4 months (range, 0.4-15.6) and median overall survival (OS) was 7.5 months (range, 0.7-18.6+). Subsequent CD30 expression quantitated by computer-assisted digital image analysis (cIHC) showed that 11 of 16 CD30u DLBCL responders had ≥1% CD30. Correlative analyses of CD30u and CD30-expressing DLBCL combined demonstrated that ≥1% CD30 expression by cIHC resulted in a trend toward a higher response rate and significantly longer median PFS and OS. A minimum CD30 expression threshold appears to be required for antitumor activity in DLBCL; however, other factors also likely contribute to activity. (NCT01421667).
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http://dx.doi.org/10.1080/10428194.2016.1256481DOI Listing
July 2017
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