Publications by authors named "Ann S LaCasce"

106 Publications

Brentuximab vedotin in combination with nivolumab in relapsed or refractory Hodgkin lymphoma: 3-year study results.

Blood 2021 Apr 7. Epub 2021 Apr 7.

City of Hope National Medical Center, Duarte, California, United States.

This phase 1-2 study evaluated brentuximab vedotin (BV) combined with nivolumab (Nivo) as first salvage therapy in patients with relapsed or refractory classical Hodgkin lymphoma. In parts 1 and 2, patients received staggered dosing of BV and Nivo in cycle 1, followed by same-day dosing in cycles 2-4. In part 3, both study drugs were dosed same day for all 4 cycles. At end of study treatment, patients could undergo autologous stem cell transplantation (ASCT) per investigator discretion. The objective response rate (N=91) was 85%, with 67% achieving a complete response. At a median follow-up of 34.3 months, the estimated progression-free survival (PFS) rate at 3 years was 77% (95% confidence interval [CI]: 65% to 86%) and 91% (95% CI, 79% to 96%) for patients undergoing ASCT directly after study treatment. Overall survival at 3 years was 93% (95% CI, 85% to 97%). The most common adverse events (AEs) prior to ASCT were nausea (52%) and infusion-related reactions (43%), all grade 1 or 2. A total of 16 patients (18%) had immune-related AEs that required systemic corticosteroid treatment. Peripheral blood immune signatures were consistent with an activated T-cell response. Median gene expression of CD30 in tumors was higher in patients who responded compared with those who did not. Longer-term follow up of BV and Nivo as a first salvage regimen shows durable efficacy and impressive PFS, especially in patients who proceeded directly to transplant, without additional toxicity concerns.
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http://dx.doi.org/10.1182/blood.2020009178DOI Listing
April 2021

Dana-Farber Cancer Institute/Mass General Brigham Fellowship Response to the COVID-19 Pandemic.

JCO Oncol Pract 2021 Feb 2:OP2000894. Epub 2021 Feb 2.

Division of Hematology and Oncology, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA.

The coronavirus disease (COVID)-19 pandemic has affected graduate medical education training programs, including hematology-oncology fellowship programs, both across the United States and abroad. Within the Dana-Farber Cancer Institute/Mass General Brigham hematology-oncology fellowship program, fellowship leadership had to quickly reorganize the program's clinical, educational, and research structure to minimize the risk of COVID-19 spread to our patients and staff, allow fellows to assist in the care of patients with COVID-19, maintain formal didactics despite physical distancing, and ensure the mental and physical well-being of fellows. Following the first wave of patients with COVID-19, we anonymously surveyed the Dana-Farber Cancer Institute/Mass General Brigham first-year fellows to explore their perceptions regarding what the program did well and what could have been improved in the COVID-19 response. In this article, we present the feedback from our fellows and the lessons we learned as a program from this feedback. To our knowledge, this represents the first effort in the hematology-oncology literature to directly assess a hematology-oncology program's overall response to COVID-19 through direct feedback from fellows.
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http://dx.doi.org/10.1200/OP.20.00894DOI Listing
February 2021

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

Blood 2021 Mar;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

Bortezomib consolidation or maintenance following immunochemotherapy and autologous stem cell transplantation for mantle cell lymphoma: CALGB/Alliance 50403.

Am J Hematol 2020 06 6;95(6):583-593. Epub 2020 Apr 6.

Hematology-Oncology, MedStar Georgetown University Hospital, Washington, District of Columbia, USA.

Immunochemotherapy followed by autologous transplant (ASCT) in CALGB/Alliance 59909 achieved a median progression-free survival (PFS) in mantle cell lymphoma (MCL) of 5 years, but late recurrences occurred. We evaluated tolerability and efficacy of adding post-transplant bortezomib consolidation (BC) or maintenance (BM) to this regimen in CALGB/Alliance 50403, a randomized phase II trial. Following augmented-dose R-CHOP/ methotrexate, high-dose cytarabine-based stem cell mobilization, cyclophosphamide/carmustine/etoposide (CBV) autotransplant, and rituximab, patients were randomized to BC (1.3 mg/m IV days 1, 4, 8, 11 of a 3-week cycle for four cycles) or BM (1.6 mg/m IV once weekly × 4 every 8 weeks for 18 months) beginning day 90. The primary endpoint was PFS, measured from randomization for each arm. Proliferation signature, Ki67, and postinduction minimal residual disease (MRD) in bone marrow were assessed. Of 151 patients enrolled; 118 (80%) underwent ASCT, and 102 (68%) were randomized. Both arms met the primary endpoint, with median PFS significantly greater than 4 years (P < .001). The 8-year PFS estimates in the BC and BM arms were 54.1% (95% CI 40.9%-71.5%) and 64.4% (95% 51.8%-79.0%), respectively. Progression-free survival was significantly longer for transplanted patients on 50403 compared with those on 59909. Both the PFS and OS were significantly better for those who were MRD-negative post-induction. The high risk proliferation signature was associated with adverse outcome. Both BM and BC were efficacious and tolerable, although toxicity was significant. The comparison between studies 50403 and 59909 with long-term follow up suggests a PFS benefit from the addition of BC or BM post- transplant.
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http://dx.doi.org/10.1002/ajh.25783DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7486983PMC
June 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

Cutaneous Eruptions from Ibrutinib Resembling EGFR Inhibitor-Induced Dermatologic Adverse Events.

J Am Acad Dermatol 2019 Dec 20. Epub 2019 Dec 20.

Center for Cutaneous Oncology, Department of Dermatology, Dana-Farber/Brigham & Women's Cancer Center, Boston, MA. Electronic address:

Background: Ibrutinib is an oral inhibitor of Bruton's tyrosine kinase (BTK) that is FDA-approved for several lymphoproliferative disorders and chronic GVHD.

Objective: To characterize cutaneous eruptions arising from ibrutinib and highlight overlap with epidermal growth factor receptor inhibitor (EGFRi)-induced dermatologic adverse events (dAEs).

Methods: Single-center retrospective cohort of patients referred to the Skin Toxicities Program for management of cutaneous eruptions while taking ibrutinib.

Results: Among 19 patients, cutaneous eruptions manifested as facial-predominant papulopustular eruptions, petechiae or ecchymoses, photosensitivity, panniculitis, xerosis, and clinical staphylococcal overgrowth. The majority of patients were able to continue ibrutinib therapy with focused management of their cutaneous toxicities.

Limitations: This study represents cases at a single tertiary care center and is limited to patients referred for toxicity.

Conclusions: With the exception of petechiae, the cutaneous toxicities of ibrutinib overlap with those associated with selective EGFR inhibitors. We observed that these reactions can be successfully managed using approaches for EGFR inhibitor-induced cutaneous adverse events.
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http://dx.doi.org/10.1016/j.jaad.2019.12.031DOI Listing
December 2019

Evidence-Based Minireview: What is the optimal timing of anti-PD-1 antibodies in relapsed classical Hodgkin lymphoma?

Hematology Am Soc Hematol Educ Program 2019 12;2019(1):249-251

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

A 26-year-old woman was initially diagnosed with stage III classical Hodgkin lymphoma (HL) treated with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) for 6 cycles and relapsed 9 months after completing therapy. She was treated with salvage chemotherapy followed by an autologous transplantation and 1 year of brentuximab vedotin (BV) maintenance therapy. She now presents 1 year later with relapsed disease above and below the diaphragm. What treatment would you recommend for this patient?
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http://dx.doi.org/10.1182/hematology.2019000077DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6913434PMC
December 2019

Evidence-Based Minireview: What is the optimal timing of anti-PD-1 antibodies in relapsed classical Hodgkin lymphoma?

Hematology Am Soc Hematol Educ Program 2019 12;2019(1):249-251

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

A 26-year-old woman was initially diagnosed with stage III classical Hodgkin lymphoma (HL) treated with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) for 6 cycles and relapsed 9 months after completing therapy. She was treated with salvage chemotherapy followed by an autologous transplantation and 1 year of brentuximab vedotin (BV) maintenance therapy. She now presents 1 year later with relapsed disease above and below the diaphragm. What treatment would you recommend for this patient?
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http://dx.doi.org/10.1182/hematology.2019000077DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6913434PMC
December 2019

Cancer Treatment-Related Infertility: A Critical Review of the Evidence.

JNCI Cancer Spectr 2019 Mar 9;3(1):pkz008. Epub 2019 Apr 9.

Cancer treatments may compromise the fertility of children, adolescents, and young adults, and treatment-related infertility represents an important survivorship issue that should be addressed at diagnosis and in follow-up to ensure optimal decision-making, including consideration of pursuing fertility preservation. Risk of infertility varies substantially with patient and treatment factors. The ability to accurately assess fertility risk for many patients is hampered by limitations of the current literature, including heterogeneity in patient populations, treatments, and outcome measures. In this article, we review and synthesize the available data to estimate fertility risks from modern cancer treatments for both children and adult cancer survivors to enable clinicians to counsel patients about future fertility.
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http://dx.doi.org/10.1093/jncics/pkz008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6649805PMC
March 2019

Five-year follow-up of SWOG S0816: limitations and values of a PET-adapted approach with stage III/IV Hodgkin lymphoma.

Blood 2019 10;134(15):1238-1246

Division of Hematology/Oncology, University of Rochester, Rochester NY.

Patients with advanced-stage Hodgkin lymphoma (HL) demonstrated excellent 2-year progression-free survival (PFS) after receiving positron emission tomography (PET)-adapted therapy on SWOG S0816. Patients received 2 cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). Patients achieving complete response (CR) on PET scan following cycle 2 of ABVD (PET2) continued 4 additional cycles of ABVD. Patients not achieving CR on PET2 were switched to escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (eBEACOPP) for 6 cycles. After a median follow-up of 5.9 years, a subset of 331 eligible patients with central review of PET2 was analyzed. PET2 was negative in 82% and positive in 18%. For all patients, the estimated 5-year PFS and OS was 74% (95% confidence interval [CI], 69%-79%) and 94% (95% CI, 91%-96%), respectively. For PET2- and PET2+ patients, the 5-year PFS was 76% (95% CI, 70%-81%) and 66% (95% CI, 52%-76%), respectively. Seven (14%) and 6 (2%) patients reported second cancers after treatment with eBEACOPP and ABVD, respectively (P = .001). Long-term OS of HL patients treated on S0816 remains high. Nearly 25% of PET2- patients experienced relapse events, demonstrating limitations ABVD therapy and of the negative predictive value of PET2. In PET2+ patients who received eBEACOPP, PFS was favorable, but was associated with a high rate of second malignancies compared with historical controls. Our results emphasize the importance of long-term follow-up, and the need for more efficacious and less toxic therapeutic approaches for advanced-stage HL patients. This trial was registered at www.clinicaltrials.gov as #NCT00822120.
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http://dx.doi.org/10.1182/blood.2019000719DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6788007PMC
October 2019

Ibrutinib plus fludarabine, cyclophosphamide, and rituximab as initial treatment for younger patients with chronic lymphocytic leukaemia: a single-arm, multicentre, phase 2 trial.

Lancet Haematol 2019 Aug 14;6(8):e419-e428. Epub 2019 Jun 14.

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

Background: Fludarabine, cyclophosphamide, and rituximab (FCR) can improve disease-free survival for younger (age ≤65 years) fit patients with chronic lymphocytic leukaemia with mutated IGHV. However, patients with unmutated IGHV rarely have durable responses. Ibrutinib is active for patients with chronic lymphocytic leukaemia irrespective of IGHV mutation status but requires continuous treatment. We postulated that time-limited ibrutinib plus FCR would induce durable responses in younger fit patients with chronic lymphocytic leukaemia.

Methods: We did a multicentre, open-label, non-randomised, single-arm phase 2 trial at seven sites in the USA. We enrolled patients aged 65 years or younger with previously untreated chronic lymphocytic leukaemia. Our initial cohort (original cohort) was not restricted by prognostic marker status and included patients who had del(17p) or TP53 aberrations. After a protocol amendment (on March 21, 2017), we enrolled an additional cohort (expansion cohort) that included patients without del(17p). Ibrutinib was given orally (420 mg/day) for 7 days, then up to six 28-day cycles were administered intravenously of fludarabine (25 mg/m, days 1-3), cyclophosphamide (250 mg/m, days 1-3), and rituximab (375 mg/m day 1 of cycle 1; 500 mg/m day 1 of cycles 2-6) with continuous oral ibrutinib (420 mg/day). Responders continued on ibrutinib maintenance for up to 2 years, and patients with undetectable minimal residual disease in bone marrow after 2 years were able to discontinue treatment. The primary endpoint was the proportion of patients who achieved a complete response with undetectable minimal residual disease in bone marrow 2 months after the last cycle of ibrutinib plus FCR. Analyses were done per-protocol in all patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov (NCT02251548) and is ongoing.

Findings: Between Oct 23, 2014, and April 23, 2018, 85 patients with chronic lymphocytic leukaemia were enrolled. del(17p) was detected in four (5%) of 83 patients and TP53 mutations were noted in three (4%) of 81 patients; two patients had both del(17p) and TP53 mutations. Median patients' age was 55 years (IQR 50-58). At data cutoff, median follow-up was 16·5 months (IQR 10·6-34·1). A complete response and undetectable minimal residual disease in bone marrow 2 months after the last cycle of ibrutinib plus FCR was achieved by 28 (33%, 95% CI 0·23-0·44) of 85 patients (p=0·0035 compared with a 20% historical value with FCR alone). A best response of undetectable minimal residual disease in bone marrow was achieved by 71 (84%) of 85 patients during the study. One patient had disease progression and one patient died (sudden cardiac death after 17 months of ibrutinib maintenance, assessed as possibly related to ibrutinib). The most common all-grade toxic effects were haematological, including thrombocytopenia in 63 (74%) patients, neutropenia in 53 (62%), and anaemia in 41 (49%). Grade 3 or 4 non-haematological serious adverse events included grade 3 atrial fibrillation in three (4%) patients and grade 3 Pneumocystis jirovecii pneumonia in two (2%).

Interpretation: The proportion of patients who achieved undetectable minimal residual disease in bone marrow with ibrutinib plus FCR is, to our knowledge, the highest ever published in patients with chronic lymphocytic leukaemia unrestricted by prognostic marker status. Ibrutinib plus FCR is promising as a time-limited combination regimen for frontline chronic lymphocytic leukaemia treatment in younger fit patients.

Funding: Pharmacyclics and the Leukemia & Lymphoma Society.
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http://dx.doi.org/10.1016/S2352-3026(19)30104-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7036668PMC
August 2019

NCCN Guidelines Insights: B-Cell Lymphomas, Version 3.2019.

J Natl Compr Canc Netw 2019 06;17(6):650-661

National Comprehensive Cancer Network.

Diffuse large B-cell lymphomas (DLBCLs) and follicular lymphoma (FL) are the most common subtypes of B-cell non-Hodgkin's lymphomas in adults. Histologic transformation of FL to DLBCL (TFL) occurs in approximately 15% of patients and is generally associated with a poor clinical outcome. Phosphatidylinositol 3-kinase (PI3K) inhibitors have shown promising results in the treatment of relapsed/refractory FL. CAR T-cell therapy (axicabtagene ciloleucel and tisagenlecleucel) has emerged as a novel treatment option for relapsed/refractory DLBCL and TFL. These NCCN Guidelines Insights highlight important updates to the NCCN Guidelines for B-Cell Lymphomas regarding the treatment of TFL and relapsed/refractory FL and DLBCL.
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http://dx.doi.org/10.6004/jnccn.2019.0029DOI Listing
June 2019

Treating Hodgkin lymphoma in the new millennium: Relapsed and refractory disease.

Authors:
Ann S LaCasce

Hematol Oncol 2019 Jun;37 Suppl 1:87-91

Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States.

Although the majority of patients with Hodgkin lymphoma are cured with initial therapy, 10% to 15% of patients with early stage disease and 15% to 30% of patients with advanced disease have primary refractory or relapsed lymphoma. For younger patients whose disease is sensitive to second-line therapy, more than half of patients will experience long-term disease control with high-dose chemotherapy/autologous stem cell rescue (ASCT). For those patients who are chemotherapy refractory, relapse after, or are ineligible for ASCT, brentuximab vedotin, and checkpoint, inhibitors are highly active, although the majority of patients will ultimately experience recurrent lymphoma. Allogeneic transplant is curative in a subset of patients but may be associated with significant toxicity. Novel targeted and immunotherapy approaches, including chimeric antigen receptor T-cell therapy, are currently being studied in clinical trials with promising early results.
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http://dx.doi.org/10.1002/hon.2589DOI Listing
June 2019

Brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine for nonbulky limited-stage classical Hodgkin lymphoma.

Blood 2019 08 11;134(7):606-613. Epub 2019 Jun 11.

Moffitt Cancer Center, Tampa, FL.

Doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) with or without radiation is standard therapy for limited-stage Hodgkin lymphoma (HL) but carries risks of bleomycin-induced lung injury and radiation toxicity. Brentuximab vedotin is highly active in relapsed HL and was recently approved with doxorubicin, vinblastine, and dacarbazine (AVD) for previously untreated stage III/IV HL. We evaluated brentuximab-AVD for nonbulky stage I/II HL in a multicenter phase 2 study. Patients received a lead-in cycle of brentuximab vedotin monotherapy on days 1 and 15, followed by an exploratory positron emission tomography/computed tomography scan. Patients then received brentuximab-AVD for 4 to 6 cycles based on interim positron emission tomography/computed tomography scanning after cycle 2. Thirty-four patients were enrolled with a median age of 36 years (range, 20-75 years). Risk was early favorable in 62% and unfavorable in 38%. The best complete response rate was 100%. At a median follow-up of 38 months, the progression-free survival and overall survival were 94% and 97%, respectively. The most common adverse events were peripheral sensory neuropathy (79%), neutropenia (76%), fatigue (74%), and nausea (71%). The most common grade 3/4 toxicities were neutropenia (62%), febrile neutropenia (35%), and peripheral sensory neuropathy (24%). One elderly patient died of neutropenic sepsis in the first brentuximab-AVD cycle. Brentuximab dose reductions were required in 38% of patients, most for peripheral neuropathy. In conclusion, brentuximab-AVD without bleomycin or radiation produced a high complete response rate, with most patients requiring only 4 total cycles of therapy. Because toxicity was higher than would be expected from AVD alone, this method may not be appropriate for early-stage patients with a highly favorable prognosis. This trial was registered at www.clinicaltrials.gov as #NCT01534078.
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http://dx.doi.org/10.1182/blood.2019001272DOI 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

Epstein Barr Virus Associated B-Cell Lymphomas and Iatrogenic Lymphoproliferative Disorders.

Front Oncol 2019 7;9:109. Epub 2019 Mar 7.

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

Epstein-Barr virus (EBV) is a ubiquitous herpesvirus, affecting up to 90% of the population. EBV was first identified as an oncogenic virus in a Burkitt lymphoma cell line, though subsequently has been found to drive a variety of malignancies, including diffuse large B-cell lymphoma (DLBCL) and other lymphoma subtypes. EBV has a tropism for B-lymphocytes and has the unique ability to exist in a latent state, evading the host immune response. In cases of impaired cell mediated immunity, as in patients with advanced age or iatrogenic immune suppression, the virus is able to proliferate in an unregulated fashion, expressing viral antigens that predispose to transformation. EBV-positive DLBCL not otherwise specified, which has been included as a revised provisional entity in the 2016 WHO classification of lymphoid malignancies, is thought to commonly occur in older patients with immunosenescence. Similarly, it is well-established that iatrogenic immune suppression, occurring in both transplant and non-transplant settings, can predispose to EBV-driven lymphoproliferative disorders. EBV-positive lymphoproliferative disorders are heterogeneous, with variable clinical features and prognoses depending on the context in which they arise. While DLBCL is the most common subtype, other histologic variants, including Burkitt lymphoma, NK/T-cell lymphoma, and Hodgkin lymphoma can occur. Research aimed at understanding the underlying biology and disease prevention strategies in EBV-associated lymphoproliferative diseases are ongoing. Additionally, personalized treatment approaches, such as immunotherapy and adoptive T-cell therapies, have yielded encouraging results, though randomized trials are needed to further define optimal management.
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http://dx.doi.org/10.3389/fonc.2019.00109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6416204PMC
March 2019

AIDS-Related Kaposi Sarcoma, Version 2.2019, NCCN Clinical Practice Guidelines in Oncology.

J Natl Compr Canc Netw 2019 02;17(2):171-189

27Roswell Park Comprehensive Cancer Center; and.

As treatment of HIV has improved, people living with HIV (PLWH) have experienced a decreased risk of AIDS and AIDS-defining cancers (non-Hodgkin's lymphoma, Kaposi sarcoma, and cervical cancer), but the risk of Kaposi sarcoma in PLWH is still elevated about 500-fold compared with the general population in the United States. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for AIDS-Related Kaposi Sarcoma provide diagnosis, treatment, and surveillance recommendations for PLWH who develop limited cutaneous Kaposi sarcoma and for those with advanced cutaneous, oral, visceral, or nodal disease.
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http://dx.doi.org/10.6004/jnccn.2019.0008DOI Listing
February 2019

Current considerations in AYA Hodgkin lymphoma.

Br J Haematol 2019 01 20;184(1):72-81. Epub 2018 Nov 20.

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

Hodgkin lymphoma (HL) commonly occurs in adolescents and young adults (AYA), defined by the National Cancer Institute as people diagnosed with cancer between the ages of 15 and 39 years. Despite therapeutic advances, the AYA population has derived less incremental benefit compared to both paediatric and adult counterparts. Although the exact aetiology is unclear, contributing factors probably include differences in disease biology, delayed diagnosis, decreased participation in clinical trials and treatment adherence secondary to complex social factors. As such, while HL remains highly curable, there is not a clear consensus regarding the management of patients within this age range, specifically whether paediatric or adult regimens are preferred or how best to incorporate emerging therapeutic advancements. Ongoing clinical trials, as well as continued collaborative efforts are required to address the needs of this population, investigate the potential for unique biological factors and allow for optimization of treatment. Here we review current prognostic and treatment strategies for paediatric and adult patients with HL and highlight complexities around the management of this patient population.
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http://dx.doi.org/10.1111/bjh.15640DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6310106PMC
January 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

Cancer in People Living With HIV, Version 1.2018, NCCN Clinical Practice Guidelines in Oncology.

J Natl Compr Canc Netw 2018 08;16(8):986-1017

People living with HIV (PLWH) are diagnosed with cancer at an increased rate over the general population and generally have a higher mortality due to delayed diagnoses, advanced cancer stage, comorbidities, immunosuppression, and cancer treatment disparities. Lack of guidelines and provider education has led to substandard cancer care being offered to PLWH. To fill that gap, the NCCN Guidelines for Cancer in PLWH were developed; they provide treatment recommendations for PLWH who develop non-small cell lung cancer, anal cancer, Hodgkin lymphoma, and cervical cancer. In addition, the NCCN Guidelines outline advice regarding HIV management during cancer therapy; drug-drug interactions between antiretroviral treatments and cancer therapies; and workup, radiation therapy, surgical management, and supportive care in PLWH who have cancer.
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http://dx.doi.org/10.6004/jnccn.2018.0066DOI Listing
August 2018

Assessment of CD52 expression in "double-hit" and "double-expressor" lymphomas: Implications for clinical trial eligibility.

PLoS One 2018 18;13(7):e0199708. Epub 2018 Jul 18.

Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, United States of America.

"Double-hit" and "double-expressor" lymphomas represent distinct but overlapping subsets of aggressive B-cell non-Hodgkin lymphoma. The high rates of bone marrow involvement by these lymphomas pose a major therapeutic challenge due to the chemotherapy-resistant nature of the bone marrow microenvironment and the limited utility of rituximab-based salvage regimens in patients with relapsed/refractory disease. Preclinical studies utilizing high-dose cyclophosphamide in combination with the anti-CD52 monoclonal antibody alemtuzumab have recently shown promise in the treatment of intramedullary disease, and a Phase I human trial is now underway. In support of such efforts, here we perform CD52 target validation on a series of double-hit (n = 40) and double-expressor (n = 58) lymphomas using immunohistochemistry. CD52 expression levels varied considerably across samples, however positive staining was observed in 75% of both double-hit and double-expressor lymphomas. Similarly, high levels of CD52 expression were seen in patients whose disease was associated with high-risk clinical features, including primary refractory status (73%), higher IPI score (76%), and bone marrow involvement (74%). CD52 expression was not significantly correlated with diagnostically relevant pathologic features such as morphology, cytogenetic findings or other immunophenotypic features, but was notably present in all cases lacking CD20 expression (n = 6). We propose that CD52 expression status be evaluated on a case-by-case basis to guide eligibility for clinical trial enrollment.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0199708PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6051601PMC
December 2018

Positron emission tomography-computed tomography predictors of progression after DA-R-EPOCH for PMBCL.

Blood Adv 2018 06;2(11):1334-1343

Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX.

Dose-adjusted rituximab plus etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (DA-R-EPOCH) has produced good outcomes in primary mediastinal B-cell lymphoma (PMBCL), but predictors of resistance to this treatment are unclear. We investigated whether [F]fluorodeoxyglucose positron emission tomography-computed tomography (PET-CT) findings could identify patients with PMBCL who would not respond completely to DA-R-EPOCH. We performed a retrospective analysis of 65 patients with newly diagnosed stage I to IV PMBCL treated at 2 tertiary cancer centers who had PET-CT scans available before and after frontline therapy with DA-R-EPOCH. Pretreatment variables assessed included metabolic tumor volume (MTV) and total lesion glycolysis (TLG). Optimal cutoff points for progression-free survival (PFS) were determined by a machine learning approach. Univariate and multivariable models were constructed to assess associations between radiographic variables and PFS. At a median follow-up of 36.6 months (95% confidence interval, 28.1-45.1), 2-year PFS and overall survival rates for the 65 patients were 81.4% and 98.4%, respectively. Machine learning-derived thresholds for baseline MTV and TLG were associated with inferior PFS (elevated MTV: hazard ratio [HR], 11.5; = .019; elevated TLG: HR, 8.99; = .005); other pretreatment clinical factors, including International Prognostic Index and bulky (>10 cm) disease, were not. On multivariable analysis, only TLG retained statistical significance ( = .049). Univariate analysis of posttreatment variables revealed that residual CT tumor volume, maximum standardized uptake value, and Deauville score were associated with PFS; a Deauville score of 5 remained significant on multivariable analysis ( = .006). A model combining baseline TLG and end-of-therapy Deauville score identified patients at increased risk of progression.
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http://dx.doi.org/10.1182/bloodadvances.2018017681DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5998935PMC
June 2018

Response-Adapted Therapy in Aggressive Lymphoma: Not Yet Ready for Clinical Care.

J Clin Oncol 2018 07 22;36(20):2009-2011. Epub 2018 May 22.

Reid W. Merryman and Ann S. LaCasce, Dana-Farber Cancer Institute, Boston, MA.

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http://dx.doi.org/10.1200/JCO.2018.78.9362DOI Listing
July 2018

Brentuximab vedotin plus bendamustine: a highly active first salvage regimen for relapsed or refractory Hodgkin lymphoma.

Blood 2018 07 27;132(1):40-48. Epub 2018 Apr 27.

Stanford Cancer Institute, Stanford, CA.

Autologous stem cell transplantation (ASCT) is standard of care for patients with Hodgkin lymphoma (HL) who have relapsed/refractory disease after frontline chemotherapy. Achievement of complete remission (CR) with pre-ASCT salvage chemotherapy predicts favorable outcomes post-ASCT. This phase 1/2 study evaluated the combination of brentuximab vedotin (BV) plus bendamustine as a first salvage regimen in relapsed/refractory HL. A total of 55 patients (28 primary refractory and 27 relapsed) were enrolled. Patients received BV (1.8 mg/kg) on day 1 and bendamustine (90 mg/m) on days 1 and 2 of a 21-day cycle for up to 6 cycles. Patients could undergo ASCT any time after cycle 2. Following ASCT or completion of combination therapy if not proceeding to ASCT, patients could receive BV monotherapy for up to 16 cycles of total therapy. After a median of 2 cycles of combination therapy (range, 1-6), the objective response rate among 53 efficacy-evaluable patients was 92.5%, with 39 patients (73.6%) achieving CR. Forty patients underwent ASCT. Thirty-one patients (25 of whom underwent ASCT) received BV monotherapy (median, 10 cycles; range, 1-14). After a median of 20.9 months of follow-up, the estimated 2-year progression-free survival was 69.8% and 62.6% for patients who received ASCT and all patients, respectively. Thirty-one patients (56.4%) experienced infusion-related reactions (IRRs), with a majority occurring during cycle 2 of combination therapy. A protocol amendment requiring premedication reduced IRR severity. BV plus bendamustine as first salvage therapy in relapsed/refractory HL is highly active with a manageable toxicity profile. This trial was registered at www.clinicaltrials.gov as #NCT01874054.
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http://dx.doi.org/10.1182/blood-2017-11-815183DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6073588PMC
July 2018

Brentuximab Vedotin for Stage III or IV Hodgkin’s Lymphoma.

N Engl J Med 2018 04;378(16):1560

Dana–Farber Cancer Institute, Boston, MA

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http://dx.doi.org/10.1056/NEJMc1802363DOI Listing
April 2018

Excellent Outcomes Following Response-based Omission of Radiotherapy in Children and Adolescents With Intermediate or High-risk Hodgkin Lymphoma.

J Pediatr Hematol Oncol 2018 08;40(6):e338-e342

Departments of Pediatric Oncology.

Several pediatric Hodgkin lymphoma (HL) consortia have demonstrated safe omission of radiotherapy (RT) in early stage HL, whereas feasibility of omitting RT in advanced HL is still under investigation. This is a single institution retrospective analysis of 27 patients with intermediate-risk or high-risk HL (age 22 y and younger), treated with a modification of the dose-intensive OEPA-COPDAC (vincristine, etoposide, prednisone, doxorubicin-cyclophosphamide, vincristine, prednisone, dacarbazine) regimen, with radiation restricted to only sites of inadequate early response (Deauville ≥3 and/or ≤75% tumor shrinkage). Their outcome was compared with a historical cohort (n=42) treated with Stanford V or ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine), who received consolidative involved-field RT. RT was omitted in 15 of 27 (56%) of patients treated with OEPA-COPDAC, majority of whom (67%) had high-risk disease. At a median follow-up of 3.1 years, the 3-year progression-free survival was 100% in patients who received OEPA-COPDAC, versus 83.3% (95% confidence interval, 68.2%-91.7%) in the historical cohort, P=0.03. Our analysis demonstrates excellent survival with omission of RT in more than 50% of patients with pediatric advanced HL, treated with a dose-intensive chemotherapy regimen. When administered, RT was restricted to only sites of inadequate early response. Results of large prospective studies are needed to validate these findings.
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http://dx.doi.org/10.1097/MPH.0000000000001076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6026082PMC
August 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

Interim results of brentuximab vedotin in combination with nivolumab in patients with relapsed or refractory Hodgkin lymphoma.

Blood 2018 03 11;131(11):1183-1194. Epub 2017 Dec 11.

Stanford University Medical Center, Palo Alto, CA.

In this phase 1/2 study, brentuximab vedotin (BV) and nivolumab (Nivo) administered in combination were evaluated as initial salvage therapy in patients with relapsed or refractory (R/R) classical Hodgkin lymphoma (HL). Patients received up to 4 cycles of combination treatment, with BV administered on day 1 and Nivo on day 8 of the first cycle. For cycles 2 to 4, BV and Nivo were both administered on day 1. After study treatment, responses were evaluated by investigators per the 2014 Lugano classification, and patients could proceed to autologous stem cell transplantation (ASCT). Sixty-two patients were enrolled; the complete response rate among all treated patients (n = 61) was 61%, with an objective response rate of 82%. Before ASCT, adverse events (AEs) occurred in 98% of patients, mostly grades 1 and 2. Infusion-related reactions (IRRs) occurred in 44% of patients overall, with 41% of patients experiencing an IRR during at least 1 infusion of BV. Five patients (8%) were treated with systemic steroids for immune-related AEs. A reduction of peripheral T-cell subsets including regulatory T cells was observed after the first dose of BV, and reduced serum levels of thymus- and activation-regulated chemokine concurrent with an increase in proinflammatory cytokines and chemokines were seen after the first BV plus Nivo infusions. The combination of BV plus Nivo was an active and well-tolerated first salvage regimen, potentially providing patients with R/R HL an alternative to traditional chemotherapy. This trial was registered at www.clinicaltrials.gov as #NCT02572167.
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http://dx.doi.org/10.1182/blood-2017-10-811224DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5855021PMC
March 2018

Human Immunodeficiency Virus Type 1 Persistence Following Systemic Chemotherapy for Malignancy.

J Infect Dis 2017 07;216(2):254-262

Division of Infectious Diseases, Brigham and Women's Hospital.

Background: Systemic chemotherapies for various malignancies have been shown to significantly, yet transiently, decrease numbers of CD4+ T lymphocytes, a major reservoir for human immunodeficiency virus type 1 (HIV-1) infection. However, little is known about the impact of cytoreductive chemotherapy on HIV-1 reservoir dynamics, persistence, and immune responses.

Methods: We investigated the changes in peripheral CD4+ T-cell-associated HIV-1 DNA and RNA levels, lymphocyte activation, viral population structure, and virus-specific immune responses in a longitudinal cohort of 15 HIV-1-infected individuals receiving systemic chemotherapy or subsequent autologous stem cell transplantation for treatment of hematological malignancies and solid tumors.

Results: Despite a transient reduction in CD4+ T cells capable of harboring HIV-1, a 1.7- and 3.3-fold increase in mean CD4+ T-cell-associated HIV-1 RNA and DNA, respectively, were observed months following completion of chemotherapy in individuals on antiretroviral therapy. We also observed changes in CD4+ T-cell population diversity and clonal viral sequence expansion during CD4+ T-cell reconstitution following chemotherapy cessation. Finally, HIV-1 DNA was preferentially, and in some cases exclusively, detected in cytomegalovirus (CMV)- and Epstein-Barr virus (EBV)-responsive CD4+ T cells following chemotherapy.

Conclusions: Expansion of HIV-infected CMV/EBV-specific CD4 + T cells may contribute to maintenance of the HIV DNA reservoir following chemotherapy.
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http://dx.doi.org/10.1093/infdis/jix265DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5853412PMC
July 2017