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Nodal peripheral T-cell lymphomas (PTCL), the most common PTCLs, are generally treated with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone)-based curative-intent chemotherapy. Recent molecular data have assisted in prognosticating these PTCLs, but most reports lack detailed baseline clinical characteristics and treatment courses. We retrospectively evaluated cases of PTCL treated with CHOP-based chemotherapy that had tumors sequenced by the Memorial Sloan Kettering Integrated Mutational Profiling of Actionable Cancer Targets (MSK-IMPACT) next-generation sequencing (NGS) panel to identify variables correlating with inferior survival. We identified 132 patients who met these criteria. Clinical factors correlating with increased risk of progression (by multivariate analysis) were advanced-stage disease (HR, 5.1; 95% CI, 1.1-22.5, P=.03) and bone marrow involvement (HR, 3.0; 95% CI, 1.1-8.4; P=.04). The only somatic genetic aberrancies correlating with inferior progression-free survival (PFS) were TP53 mutations (HR, 3.1; 95% CI, 1.4-6.8; P=.005) and TP53/17p deletions (HR, 4.1; 95% CI, 1.1-15.0, P=.03). PFS remained inferior when stratifying by TP53 mutation status, with a median PFS of 4.5 months (95% CI, 3.8-13.9) for PTCL with a TP53 mutation (n=21) vs 10.5 months (95% CI, 7.8-18.1; P

BACKGROUND: Accurate Sezary cell detection in peripheral blood of mycosis fungoides/Sezary syndrome (MF/SS) patients by flow cytometry can be difficult due to overlapping immunophenotypes with normal T cells using standard markers. We assessed the utility of programmed death-1 (PD-1/CD279), a transmembrane protein expressed in some hematopoietic cells, for identification and quantitation of circulating Sezary cells among established markers using flow cytometry. METHODS: 50 MF/SS and 20 control blood samples were immunophenotyped by flow cytometry. Principal component analysis (PCA) assessed contributions of antigens to separation of abnormal from normal T cell populations. PD-1 was assessed over time in blood and bone marrow of available MF/SS cases. RESULTS: Normal CD4+ T cells showed dim/intermediate to absent PD-1 expression. PD-1 in Sezary cells was informatively brighter (≥1/3 log) than internal normal CD4+ T cells in 39/50 (78%) cases. By PCA, PD-1 ranked 3(rd) behind CD7 and CD26 in population separation as a whole; it ranked in the top 3 markers in 32/50 (64%) cases and 1(st) in 4/50 (8%) cases when individual abnormal populations were compared to total normal CD4+ T cells. PD-1 clearly separated Sezary from normal CD4+ T cells in 15/26 (58%, 30% of total) cases with few and subtle alterations of pan T-cell antigens/CD26 and was critical in 6 (12% of total), without which identification and quantification were significantly affected or nearly impossible. PD-1 remained informative in blood/bone marrow over time in most patients. CONCLUSIONS: PD-1 significantly contributes to accurate flow cytometric Sezary cell assessment in a routine Sezary panel.

CONSORT Diagram.

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Purpose: The PARP inhibitor veliparib enhances the cytotoxicity of alkylating agents. This phase I study evaluated veliparib with the bifunctional alkylator bendamustine (VB) in patients with relapsed/refractory lymphoma, multiple myeloma, and solid malignancies, with a cohort expansion of VB with rituximab (VBR) in patients with B-cell lymphomas.Experimental Design: This dose-escalation study evaluated safety, pharmacokinetics, and preliminary efficacy of veliparib (20–400 mg twice a day, days 1–7 of 28-day cycle) and bendamustine (70 and 90 mg/m2 intravenously, days 1 and 2). A cohort expansion was conducted, which combined veliparib and bendamustine at the maximum tolerated dose (MTD) with rituximab (375 mg/m2, day 1) in patients with B-cell lymphomas. Thirty-four patients were treated in seven dose-escalation cohorts and seven patients in the dose-expansion cohort.Results: The MTD was veliparib 300 mg twice daily plus bendamustine 90 mg/m2. Dose-limiting toxicities (DLT) were anemia, nausea, hypertension, and hyperhidrosis. Grade ≥3 toxicities included lymphopenia (87.8%), anemia (19.5%), neutropenia (12.2%), thrombocytopenia (9.8%), leukopenia (9.8%), nausea (7.3%), and hypophosphatemia (7.3%). Apparent veliparib clearance was slightly lower than previously reported. Of 14 patients with lymphoma evaluable for response, five of seven (71%) on VB and six of seven (86%) on VBR achieved objective response. One patient with multiple myeloma achieved partial response.Conclusions: VB and VBR were generally well-tolerated. VBR had preliminary clinical activity in patients with B-cell lymphoma, which warrants further investigation in a phase II trial. This trial was registered at www.clinicaltrials.gov as NCT01326702. Clin Cancer Res; 23(15); 4119–26. ©2017 AACR.

PTCL with T-follicular helper phenotype (PTCL-TFH) has recurrent mutations affecting epigenetic regulators, which may contribute to aberrant DNA methylation and chemoresistance. This phase 2 study evaluated oral azacitidine (CC-486), a DNA methyltransferase inhibitor, plus CHOP as initial treatment for PTCL (ClinicalTrials.gov - NCT03542266). CC-486 at 300 mg daily was administered for 7 days prior to C1 of CHOP, and for 14 days before CHOP C2-6. The primary endpoint was end-of-treatment CR. Secondary endpoints included ORR, safety and survival. Correlative studies assessed mutations, gene expression and methylation in tumor samples. Grade 3-4 hematologic toxicities were mostly neutropenia (71%), with febrile neutropenia uncommon (14%). Non-hematologic toxicities included fatigue (14%) and GI symptoms (5%). In 20 evaluable patients, CR was 75%, including 88.2% for PTCL-TFH (n=17). At a median follow-up of 21 months, 2-yr PFS was 65.8% for all and 69.2% for PTCL-TFH, while 2-yr OS was 68.4% for all and 76.1% for PTCL-TFH. The frequencies of the TET2, RHOA, DNMT3A, and IDH2 mutations were 76.5%, 41.1%, 23.5% and 23.5%, respectively, with TET2 mutations significantly associated with CR (p=0.007), favorable PFS (p=0.004) and OS (p=0.015), and DNMT3A mutations associated with adverse PFS (p=0.016). CC-486 priming contributed to the reprograming of the tumor microenvironment by upregulation of genes related to apoptosis (p

Consensus about a standard segmentation method to derive metabolic tumor volume (MTV) in classical Hodgkin lymphoma (cHL) is lacking, and it is unknown how different segmentation methods influence quantitative PET features. Therefore, we aimed to evaluate the delineation and completeness of lesion selection and the need for manual adaptation with different segmentation methods, and to assess the influence of segmentation methods on the prognostic value of MTV, intensity, and dissemination radiomics features in cHL patients. Methods: We analyzed a total of 105 18F-FDG PET/CT scans from patients with newly diagnosed (n = 35) and relapsed/refractory (n = 70) cHL with 6 segmentation methods: 2 fixed thresholds on SUV4.0 and SUV2.5, 2 relative methods of 41% of SUVmax (41max) and a contrast-corrected 50% of SUVpeak (A50P), and 2 combination majority vote (MV) methods (MV2, MV3). Segmentation quality was assessed by 2 reviewers on the basis of predefined quality criteria: completeness of selection, the need for manual adaptation, and delineation of lesion borders. Correlations and prognostic performance of resulting radiomics features were compared among the methods. Results: SUV4.0 required the least manual adaptation but tended to underestimate MTV and often missed small lesions with low 18F-FDG uptake. SUV2.5 most frequently included all lesions but required minor manual adaptations and generally overestimated MTV. In contrast, few lesions were missed when using 41max, A50P, MV2, and MV3, but these segmentation methods required extensive manual adaptation and overestimated MTV in most cases. MTV and dissemination features significantly differed among the methods. However, correlations among methods were high for MTV and most intensity and dissemination features. There were no significant differences in prognostic performance for all features among the methods. Conclusion: A high correlation existed between MTV, intensity, and most dissemination features derived with the different segmentation methods, and the prognostic performance is similar. Despite frequently missing small lesions with low 18F-FDG avidity, segmentation with a fixed threshold of SUV4.0 required the least manual adaptation, which is critical for future research and implementation in clinical practice. However, the importance of small, low 18F-FDG-avidity lesions should be addressed in a larger cohort of cHL patients.

Purpose: Activation of Bruton tyrosine kinase (BTK) and phosphatidylinositol-3-kinase (PI3K) represent parallel, synergistic pathways in lymphoma pathogenesis. As predominant PI3Kδ inhibition is a possible mechanism of tumor escape, we proposed a clinical trial of dual BTK and pan-PI3K inhibition. Patients and Methods: We conducted a single-center phase I/Ib trial combining a BTK inhibitor (ibrutinib) and a pan-PI3K inhibitor (buparlisib) in 37 patients with relapsed/refractory (R/R) B-cell lymphoma. Buparlisib and ibrutinib were administered orally, once daily in 28-day cycles until progression or unacceptable toxicity. The clinical trial is registered with clinicaltrials.gov, NCT02756247. Results: Patients with mantle cell lymphoma (MCL) receiving the combination had a 94% overall response rate (ORR) and 33-month median progression-free survival; ORR of 31% and 20% were observed in patients with diffuse large B-cell lymphoma and follicular lymphoma, respectively. The maximum tolerated dose was ibrutinib 560 mg plus buparlisib 100 mg and the recommended phase II dose was ibrutinib 560 mg plus buparlisib 80 mg. The most common grade 3 adverse events were rash/pruritis/dermatitis (19%), diarrhea (11%), hyperglycemia (11%), and hypertension (11%). All grade mood disturbances ranging from anxiety, depression, to agitation were observed in 22% of patients. Results from serial monitoring of cell-free DNA samples corresponded to radiographic resolution of disease and tracked the emergence of mutations known to promote BTK inhibitor resistance. Conclusions: BTK and pan-PI3K inhibition in mantle cell lymphoma demonstrates a promising efficacy signal. Addition of BCL2 inhibitors to a BTK and pan-PI3K combination remain suitable for further development in mantle cell lymphoma.

R ± DHAX has been traditionally administered to inpatient due to the timing of chemotherapy administration and the perceived need for close monitoring of adverse effects. To administer R ± DHAX outpatient, a multidisciplinary task force created clinical and educational guidelines which were implemented through two phases: pilot and expansion. The pilot program determined the feasibility of transitioning R ± DHAX outpatient at a single infusion site. The expansion phase led to a service-wide implementation across all outpatient sites. A total of 40 patients were included, of which 23 patients completed all cycles, outpatient, 12 transitioned inpatient to outpatient administration, and 5 transitioned outpatient to inpatient administration. The success rate of outpatient R ± DHAX administration was 90% (36 patients successfully completed outpatient administration/40 total patients). No cytarabine-related cerebellar or ophthalmic toxicity was reported. Outpatient R ± DHAX saved 192 hospital days. R ± DHAX could be successfully administered outpatient with minimal safety concerns and reduced hospital bed utilization.

PURPOSE To improve curability and limit long-term adverse effects for newly diagnosed early-stage (ES), unfavorable-risk Hodgkin lymphoma. METHODS In this multicenter study with four sequential cohorts, patients received four cycles of brentuximab vedotin (BV) and doxorubicin, vinblastine, and dacarbazine (AVD). If positron emission tomography (PET)-4–negative, patients received 30-Gy involved-site radiotherapy in cohort 1, 20-Gy involved-site radiotherapy in cohort 2, 30-Gy consolidation-volume radiotherapy in cohort 3, and no radiotherapy in cohort 4. Eligible patients had ES, unfavorable-risk disease. Bulk disease defined by Memorial Sloan Kettering criteria (> 7 cm in maximal transverse or coronal diameter on computed tomography) was not required for cohorts 1 and 2 but was for cohorts 3 and 4. The primary end point was to evaluate safety for cohort 1 and to evaluate complete response rate by PET for cohorts 2-4. RESULTS Of the 117 patients enrolled, 116 completed chemotherapy, with the median age of 32 years: 50% men, 98% stage II, 86% Memorial Sloan Kettering–defined disease bulk, 27% traditional bulk (> 10 cm), 52% elevated erythrocyte sedimentation rate, 21% extranodal involvement, and 56% > 2 involved lymph node sites. The complete response rate in cohorts 1-4 was 93%, 100%, 93%, and 97%, respectively. With median follow-up of 3.8 years (5.9, 4.5, 2.5, and 2.2 years for cohorts 1-4), the overall 2-year progression-free and overall survival were 94% and 99%, respectively. In cohorts 1-4, the 2-year progression-free survival was 93%, 97%, 90%, and 97%, respectively. Adverse events included neutropenia (44%), febrile neutropenia (8%), and peripheral neuropathy (54%), which was largely reversible. CONCLUSION BV + AVD × four cycles is a highly active and well-tolerated treatment program for ES, unfavorable-risk Hodgkin lymphoma, including bulky disease. The efficacy of BV + AVD supports the safe reduction or elimination of consolidative radiation among PET-4–negative patients.

The peripheral T-cell lymphomas (PTCLs) are a notoriously diverse family of non-Hodgkin lymphomas with generally aggressive biology. Clinical management is challenging given a largely inadequate literature base comprised of few randomized trials and heterogeneous observational reports. Herein, we provide an account of our practice in the treatment of the 3 most common nodal PTCLs: PTCL, not otherwise specified, angioimmunoblastic T-cell lymphoma, and anaplastic large cell lymphoma (ALCL). In the up-front setting, we employ anthracycline-based induction, with the incorporation of brentuximab vedotin for all those with ALCL and consideration in those with other CD30-expressing PTCLs based on improved progression-free and overall survival in the absence of additional toxicity in the ECHELON-2 trial. We strongly consider high-dose therapy with autologous stem cell rescue in first complete remission. In the relapsed or refractory (R/R) setting, we often look to clinical trials or choose from 4 FDA-approved single agents-belinostat, brentuximab vedotin, romidepsin, and pralatrexate-based on tumor phenotype and side-effect profiles. Our goal in the R/R setting is achievement of complete remission followed by allogeneic transplant with curative intent in appropriate candidates or long-term disease control in others. Numerous investigational agents are advancing through trials and have potential to alter standards of care in the near future.

Although patients with bronchus-associated lymphoid tissue (BALT) lymphoma show an indolent clinical course, appropriate disease management at diagnosis is not well defined. This study aimed to compare 3 treatment strategies for patients with BALT lymphoma: active surveillance, systemic chemotherapy or immunotherapy at diagnosis, or complete surgical resection at diagnosis. We conducted a retrospective study of all patients with new diagnoses of marginal zone lymphoma (MZL) involving the lung who were treated at the Memorial Sloan Kettering Cancer Center between 1995 and 2017. Primary BALT lymphoma was defined as disease confined to the lungs and adjacent lymph nodes. Active surveillance was defined as a documented observation plan and ≥3 months of follow-up before initiating treatment. Overall survival (OS) and event-free survival (EFS) were compared between treatment groups. We reviewed 200 consecutive patients with MZL involving the lung; 123 met the inclusion criteria and were managed by active surveillance (47%), complete surgical resection (41%), or systemic chemotherapy or immunotherapy (11%). With a median follow-up of >60 months, surgical resection was associated with a superior EFS compared with active surveillance and systemic treatment (6-year EFS: 74% vs 65% vs 62%, respectively; P = .013). Larger lesions and thrombocytopenia were associated with shorter EFS. All groups had excellent OS at 6 years (93%), albeit with a slight superiority for surgical resection (100%) over active surveillance (91%) and systemic treatment (76%) (P = .024). BALT lymphoma is an indolent disease that can often be managed expectantly and not require therapy for many years.

The prognosis of patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) is poor. Chimeric antigen receptor (CAR) T-cell therapy has been approved for R/R DLBCL after 2 prior lines of therapy based on data from single-arm phase 2 trials, with complete responses (CRs) in 40% to 60% of patients. However, a direct comparison with other treatments is not available and, moreover, its true efficacy in real-world patients is unknown. In this single center, retrospective, observational study of 215 patients, we compared outcomes in patients treated with CAR T-cell therapy (n = 69) with a historical population treated with alternate therapies (n = 146). Patients treated with CAR T cell vs alternate therapies demonstrated a CR rate of 52% vs 22% (P < .001), median progression-free survival (PFS) of 5.2 vs 2.3 months (P = .01), and median overall survival (OS) of 19.3 vs 6.5 months (P = .006), and this advantage appeared to persist irrespective of the number of lines of prior therapy. After adjusting for unfavorable pretreatment disease characteristics, superior overall response rate in the CAR T cohort remained significant; however, differences in PFS and OS between cohorts did not. In addition, patients who responded to alternate therapies demonstrated prolonged remissions comparable to those who responded to CAR T therapy. We contend that in select clinical scenarios alternate therapies may be as efficacious as CAR T therapy; thus, additional study is warranted, ideally with randomized prospective trials.

A modification of the SMILE regimen with dexamethasone, methotrexate, ifosfamide, L-asparaginase, etoposide (mSMILE) followed by Intensity-Modulated Radiotherapy (IMRT) at lower than usual dose, has been adopted as standard of care for extranodal NK/T cell lymphoma (ENKL) at our institution. mSMILE is a short course, intensive regimen incorporating pegylated asparaginase. Here we describe clinical details, outcome and safety of patients receiving mSMILE. Among 28 patients with ENKL treated, response post mSMILE was 93% (CR 68%), response post IMRT was 95% (CR 87.5%). Among early-stage patients/low PINK-E (n=13), overall survival (OS) was 100% at the median follow up of 31 months; progression-free survival (PFS) was 92%. Advanced-stage and intermediate/high PINK-E patients fared similarly (OS 43%, PFS 33.3% at the median follow-up). 32% of the patients experienced G3–4 non-hematologic toxicity, all experienced hematologic toxicity. Most localized-stage patients achieved long-term disease control. Despite high response rates, most of the advanced stage patients relapsed quickly.

Background The prevalence of mycosis fungoides/Sezary syndrome (MF/SS) is higher in the black population than in the white population in the United States and worse outcomes have been observed in black patients. Objective To describe the outcomes and to identify prognostic factors in African American and black patients with MF/SS. Methods Clinical features and follow-up data were analyzed in 157 self-identified African American or black patients seen during 1994-2018. Results We included 122 patients with early stage MF and 35 patients with advanced-stage disease (median follow-up of 25 months). Overall, >80% of the patients who died from disease or progressed had erythema or hyperpigmentation without hypopigmentation. Patients with hypopigmentation, either as the sole manifestation or in combination with other lesions, had better overall survival (P = .002) and progression-free survival (P = .014). Clinical stage, TNMB classification, plaque disease, and elevated serum lactate dehydrogenase were also significantly associated with outcomes. Demographic and socioeconomic parameters were not associated with prognosis. Limitations A retrospective study at a single cancer center. Conclusion MF/SS manifestations and outcomes in African American and black patients are heterogeneous. Demographic and socioeconomic factors do not seem to have a prognostic role, while clinical characteristics might help in the stratification of risk of progression and shorter survival, allowing for individually tailored therapeutic interventions.

In follicular lymphoma (FL), detection of bone marrow (BM) involvement (BMI) by 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) improves the accuracy of staging vs BM biopsy (BMB) alone. Our objective was to determine the diagnostic utility of PET for BMI FL and the prognostic value of BMI by PET (positive PET result [PET+]). Records of patients (2002-2016) with PET and BMB at the time of initial treatment were reviewed. BMI was identified by positive BMB result (BMB+) and/or unifocal or multifocal BM FDG uptake on blindly reviewed PET scans with no corresponding CT abnormality (PET+). Among 261 patients, BMI was diagnosed in 78 patients (29.9%) by PET+, in 81 patients (31.0%) by BMB+, and in 113 patients (43.3%) by either PET+ or BMB+. PET+ upstaged 24 patients to stage IV, including 10 from stages I or II to stage IV. Median duration of follow-up was 6.0 years (range, 0-16.6 years). In univariate analysis, a high Follicular Lymphoma International Prognosis Index (FLIPI) score, PET+, and BMB+ correlated with shorter progression-free survival (PFS; all P ≤ .03), and high FLIPI, PET+, and combined PET+ and BMB+ with shorter overall survival (OS; all P ≤ .01). In multivariate analysis, PET+ was the only independent predictor of PFS, whereas high FLIPI score and PET+ predicted OS (P ≤ .03). Combined PET and BMB identify BMI more accurately than either BMB or PET alone, but BMB rarely adds critical information. For patients initiating treatment of FL, identification of BMI by PET is predictive of PFS and OS.

PURPOSE To assess the efficacy of pembrolizumab in patients with advanced relapsed or refractory mycosis fungoides (MF) or Sézary syndrome (SS). PATIENTS AND METHODS CITN-10 is a single-arm, multicenter phase II trial of 24 patients with advanced MF or SS. Patients were treated with pembrolizumab 2 mg/kg every 3 weeks for up to 24 months. The primary end point was overall response rate by consensus global response criteria. RESULTS Patients had advanced-stage disease (23 of 24 with stage IIB to IV MF/SS) and were heavily pretreated with a median of four prior systemic therapies. The overall response rate was 38% with two complete responses and seven partial responses. Of the nine responding patients, six had 90% or more improvement in skin disease by modified Severity Weighted Assessment Tool, and eight had ongoing responses at last follow-up. The median duration of response was not reached, with a median response follow-up time of 58 weeks. Immune-related adverse events led to treatment discontinuation in four patients. A transient worsening of erythroderma and pruritus occurred in 53% of patients with SS. This cutaneous flare reaction did not result in treatment discontinuation for any patient. The flare reaction correlated with high PD-1 expression on Sézary cells but did not associate with subsequent clinical responses or lack of response. Treatment responses did not correlate with expression of PD-L1, total mutation burden, or an interferon-γ gene expression signature. CONCLUSION Pembrolizumab demonstrated significant antitumor activity with durable responses and a favorable safety profile in patients with advanced MF/SS.

The T Cell Project was the largest prospective trial to explore the incidence, treatment patterns, and outcomes for T cell lymphomas. The rare subtypes of T cell lymphomas, including hepatosplenic T cell lymphoma (HSTCL), enteropathy associated T cell lymphoma (EATL), and peripheral gamma delta T cell lymphomas (PGDTCLs) are poorly represented in most studies and there is little data regarding treatment patterns. We report results from 115 patients with hepatosplenic (n = 31), enteropathy associated (n = 65), and PGDTCLs (n = 19). While anthracycline regimens were most commonly used as first line therapy, response rates ranged from 20%−40% and were suboptimal for all groups. Autologous stem cell transplantation was performed as a consolidation in first remission in a small number of patients (33% of HSTCL, 7% of EATL, and 12% of PGDTCL), and four patients with HSTCL underwent allogeneic stem cell transplantation in first remission. The progression free survival at 3 years ranged from 28%−40% for these rare subtypes, and the overall survival at 3 years was most favorable for PGDTCL (70%). These data highlight the need for novel treatment approaches for rare subtypes of T cell lymphomas and for their inclusion in clinical trials.

Approximately 10% to 30% of patients with classical Hodgkin lymphoma (cHL) develop relapsed or refractory (R/R) disease. Of those patients, 50% to 60% show long-term progression-free survival after standard salvage chemotherapy followed by high-dose chemotherapy (HDCT) and autologous stem cell transplant (ASCT). In the past decade, novel therapies have been developed, such as the CD30-directed antibody–drug conjugate brentuximab vedotin and immune checkpoint inhibitors, which have greatly extended the treatment possibilities for patients with R/R cHL. Several phase 1/2 clinical trials have shown promising results of these new drugs as monotherapy or in combination with chemotherapy, but unfortunately, very few randomized phase 3 trials have been performed in this setting, making it difficult to give evidence-based recommendations for optimal treatment sequencing. Two important goals for the improvement in the treatment of R/R cHL can be identified: (1) increasing long-term progression-free and overall survival by optimizing risk-adapted treatment and (2) decreasing toxicity in patients with a low risk of relapse of disease by evaluating the need for HDCT/ASCT in these patients. In this review, we discuss treatment options for patients with R/R cHL in different settings: patients with a first relapse, primary refractory disease, and in patients who are ineligible or unfit for ASCT. Results of clinical trials investigating novel therapies or strategies published over the past 5 years are summarized.

Consensus about a standard segmentation method to derive metabolic tumor volume (MTV) in classical Hodgkin lymphoma (cHL) is lacking, and it is unknown how different segmentation methods influence quantitative PET features. Therefore, we aimed to evaluate the delineation and completeness of lesion selection and the need for manual adaptation with different segmentation methods, and to assess the influence of segmentation methods on the prognostic value of MTV, intensity, and dissemination radiomics features in cHL patients. Methods: We analyzed a total of 105 (18)F-FDG PET/CT scans from patients with newly diagnosed (n = 35) and relapsed/refractory (n = 70) cHL with 6 segmentation methods: 2 fixed thresholds on SUV4.0 and SUV2.5, 2 relative methods of 41% of SUV(max) (41max) and a contrast-corrected 50% of SUV(peak) (A50P), and 2 combination majority vote (MV) methods (MV2, MV3). Segmentation quality was assessed by 2 reviewers on the basis of predefined quality criteria: completeness of selection, the need for manual adaptation, and delineation of lesion borders. Correlations and prognostic performance of resulting radiomics features were compared among the methods. Results: SUV4.0 required the least manual adaptation but tended to underestimate MTV and often missed small lesions with low (18)F-FDG uptake. SUV2.5 most frequently included all lesions but required minor manual adaptations and generally overestimated MTV. In contrast, few lesions were missed when using 41max, A50P, MV2, and MV3, but these segmentation methods required extensive manual adaptation and overestimated MTV in most cases. MTV and dissemination features significantly differed among the methods. However, correlations among methods were high for MTV and most intensity and dissemination features. There were no significant differences in prognostic performance for all features among the methods. Conclusion: A high correlation existed between MTV, intensity, and most dissemination features derived with the different segmentation methods, and the prognostic performance is similar. Despite frequently missing small lesions with low (18)F-FDG avidity, segmentation with a fixed threshold of SUV4.0 required the least manual adaptation, which is critical for future research and implementation in clinical practice. However, the importance of small, low (18)F-FDG–avidity lesions should be addressed in a larger cohort of cHL patients.

Signaling through JAK1 and/or JAK2 is common among tumor and nontumor 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 2 study of the JAK1/2 inhibitor ruxolitinib for patients with relapsed/refractory PTCL (n = 45) or mycosis fungoides (MF) (n = 7). Patients enrolled onto 1 of 3 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 twice daily until progression and were assessed for response after cycles 2 and 5 and every 3 cycles thereafter. The primary endpoint was clinical benefit rate (CBR), defined as the combination of complete response, partial response (PR), and stable disease lasting at least 6 months. Only 1 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 = .02), respectively. 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, a marker of PI3 kinase or mitogen-activated protein kinase activation, in

Patients with mycosis fungoides (MF) and Sezary syndrome (SS) often require multiple lines of systemic therapy. In the phase 3 MAVORIC study (NCT01728805), mogamulizumab demonstrated superiority to vorinostat in median progression-free survival (PFS) and confirmed overall response rate (ORR) in patients with MF/SS. This post hoc analysis examined the effects of number and type of prior systemic therapies on mogamulizumab response. MAVORIC patients randomized to mogamulizumab (1.0 mg/kg intravenously weekly) or vorinostat (400 mg orally daily) were grouped by number of prior therapies and immunomodulatory activity of immediate prior systemic therapy while also considering time elapsed since treatment. ORR, PFS, and duration of response (DOR) did not vary with number of prior therapies. ORR and DOR remained consistent regardless of immediate prior therapy type. Additionally, immunomodulatory activity of the last prior therapy and time from prior treatment generally did not affect the ORR or PFS observed in response to mogamulizumab.

Background T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL) is an uncommon variant of diffuse large B cell lymphoma (DLBCL), characterized by low content of lymphoma cells in a background of extensive infiltrate of T-cells and histiocytes. Historically, THRLBCL was considered an aggressive variant of DLBCL with poorer outcomes and a 3-year OS We aimed to describe the clinical characteristics, prognostic factors, response to treatment, and outcome among pts diagnosed with THRLBCL at Memorial Sloan Kettering Cancer Center (MSKCC) in the rituximab era. Patients and Methods We retrospectively reviewed all cases of THRLBCL who were diagnosed in our center from January 2000 to October 2019. We collected data for demographic and clinical characteristics, pathology results, disease stage and sites of involvement, treatment regimen, and outcome. Fisher's exact test was used to assess associations between patient characteristics and treatment regimen. Fisher's exact test and Wilcoxon test were used to assess associations between categorical or continuous characteristics and response to treatment, respectively. The likelihood ratio test was used to assess significance of Cox regression univariate models. Overall survival (OS) was measured from date of diagnosis until last follow up or death. Event-free survival (EFS) was measured from end of treatment to last follow up or pathology proven relapse or disease progression. Survival curves were estimated using the Kaplan Meier method. Results A total of 100 pts were diagnosed with THRLBCL at our center during the study period. We excluded 33 pts who had missing data regarding stage, frontline treatment, or response. A total of 67 pts were included for analysis in our cohort. Median follow up duration among survivors was 3.4 years (range 0.4-10.8 years). Baseline characteristics are summarized in table 1. Forty-eight were males (72%). Median age at diagnosis was 41 years (range 19-86). Fifty-three (72%) pts were diagnosed at stage IV. Thirty-five (52%) pts had involvement of more than 1 extra-nodal site. The most common extranodal site was bone (60%). Fourteen pts had a positive bone marrow biopsy (26% of those evaluated). Univariate analysis was performed for age, gender, ethnicity, stage, extra-nodal sites, presence of B symptoms, performance status, elevated LDH, IPI score>=3, and history of NLPHL. None of these factors were found significantly associated with response rate, EFS, or OS. Frontline treatment is shown in table 2 and included R-CHOP or R-CHOP based treatment in 48% (n=32), R-EPOCH in 12% (n=8), R-CHOP/R-ICE (4 cycles of R-CHOP-14 followed by 3 cycles of R-ICE, Moskowitz CH, et al. JCO 2010) in 33% (n=22) and other regimens in 7.5% (n=5). CNS prophylactic treatment was given in 19 pts. One pt had an autologous stem cell transplant and 1 pt had an allogeneic stem cell transplant as part of frontline treatment. Fifty-one (76%) pts had a complete response (CR) to frontline treatment. Among these pts, 6 relapsed. Sixteen (24%) pts had refractory disease. Among pts with relapsed or refractory disease, 18 received additional therapy. In the whole cohort, 3-year EFS was 68% and 3-year OS was 85%. In a sub-group analysis of pts who received R-CHOP/R-ICE compared to pts who were treated with R-CHOP or R-EPOCH, CR rates were 95% and 70% respectively (p=0.014). The R-CHOP/R-ICE regimen was also associated with higher 3-year EFS of 86% compared to 62% (p=0.049) and a better 3-year OS of 100% compared with 79% (p=0.016). See figures 1-2. The 2 treatment groups were not significantly different with regards to baseline characteristics. Conclusions Our study demonstrates better outcomes among pts with THRLBCL compared to available historical data from the pre-rituximab era. In addition, with the limitation of a retrospective, single-center study, our data suggests that for newly diagnosed THRLBCL, treatment with a higher intensity regimen, such as R-CHOP/R-ICE, may be associated with favorable outcome. Disclosures Batlevi: Life Sci, GLG, Juno/Celgene, Seattle Genetics, Kite: Consultancy; Janssen, Novartis, Epizyme, Xynomics, Bayer, Autolus, Roche/Genentech: Research Funding. Falchi:Roche: Research Funding; Genmab: Research Funding. Hamlin:Molecular Templates: Research Funding; Portola Pharmaceutics: Consultancy; J&J Pharmaceuticals: Research Funding; Incyte: Research Funding; Celgene: Consultancy; Juno Therapeutics: Consultancy; Karyopharm: Consultancy; Portola: Research Funding. Horwitz:Forty Seven: Consultancy, Research Funding; ADCT Therapeutics: Consultancy, Research Funding; ASTEX: Consultancy; Beigene: Consultancy; Portola: Consultancy, Research Funding; Mundipharma: Consultancy; Innate Pharma: Consultancy; Corvus: Consultancy; Trillium: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Millenium/Takeda: Consultancy, Research Funding; Verastem: Consultancy, Research Funding; GlaxoSmithKline: Consultancy; Infinity/Verastem: Research Funding; Kyowa Hakka Kirin: Consultancy, Research Funding; Aileron: Consultancy, Research Funding; Vividion Therapeutics: Consultancy; Affirmed: Consultancy; Janssen: Consultancy; Kura Oncology: Consultancy; Miragen: Consultancy; Myeloid Therapeutics: Consultancy; Celgene: Consultancy, Research Funding; C4 Therapeutics: Consultancy; Daiichi Sankyo: Research Funding. Joffe:AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Epizyme: Membership on an entity's Board of Directors or advisory committees. Kumar:AbbVie: Research Funding; Astra Zeneca: Honoraria, Other: Honoraria for Advisory Board; Celgene: Honoraria, Other: Honoraria for Advisory Board; Seattle Genetics: Research Funding; Pharmacyclics: Research Funding; Celgene: Research Funding; Adaptive Biotechnologies,: Research Funding; Kite Pharmaceuticals: Honoraria, Other: Honoraria for Advisory Board. Matasar:Pharmacyclics: Honoraria, Research Funding; Immunovaccine Technologies: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; IGM Biosciences: Research Funding; GlaxoSmithKline: Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Daiichi Sankyo: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Rocket Medical: Consultancy, Research Funding; Teva: Consultancy; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; Juno Therapeutics: Consultancy; Genentech, Inc.: Consultancy, Honoraria, Research Funding; Merck: Consultancy; Bayer: Consultancy, Honoraria, Research Funding. Noy:Pharmacyclics: Research Funding; Medscape: Consultancy; NIH: Research Funding; Rafael Pharma: Research Funding; Janssen: Consultancy; Pharmacyclics: Consultancy; Morphosys: Consultancy; Targeted Oncology: Consultancy. Palomba:Genentech: Research Funding; Juno: Research Funding; Regeneron: Research Funding; Novartis: Honoraria; Merck: Honoraria; Celgene: Honoraria; Juno: Honoraria; Pharmacyclics: Honoraria. Straus:Karyopharm Therapeutics: Membership on an entity's Board of Directors or advisory committees; Targeted Oncology: Consultancy, Speakers Bureau; NY Lymphoma Rounds: Consultancy; Takeda Pharmaceuticals: Research Funding, Speakers Bureau; OncLive: Speakers Bureau; Elsevier: Membership on an entity's Board of Directors or advisory committees, Other: CME writer; ASH: Other: Conference in December 2019 on HL to other physicians during ASH; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Imedex, Inc.: Speakers Bureau. Vardhana:Other: Other: SAV has received honoraria from Agios Pharmaceuticals and Rheos Pharmaceuticals, is an advisor for Immunai and has consulted for ADC Therapeutics. von Keudell:Bayer: Research Funding; Genentech: Research Funding; Pharmacyclics: Research Funding. Zelenetz:Celgene: Consultancy; Gilead: Consultancy; Genentech/Roche: Consultancy; Gilead: Research Funding; Adaptive Biotechnology: Consultancy; Sandoz: Research Funding; MorphoSys: Research Funding; Celgene: Research Funding; MEI Pharma: Research Funding; Roche: Research Funding; BeiGene: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy; Novartis: Consultancy; Amgen: Consultancy. Moskowitz:Incyte: Research Funding; Merck: Consultancy; Seattle Genetics: Consultancy; Miragen Therapeutics: Consultancy; Imbrium Therapeutics, L.P.: Consultancy; Merck: Research Funding; Bristol-Myers Squibb: Research Funding; Seattle Genetics: Research Funding.

BACKGROUND: Treatment of chronic lymphocytic leukemia (CLL) with a fixed-duration venetoclax (Ven)-based regimen is now a standard of care (SOC) option for both frontline and relapsed refractory (R/R) disease based on results of the CLL14 and MURANO trials (Fischer et al NEJM 2019, Seymour et al NEJM 2018). As fixed-duration Ven regimens are now a SOC, it is expected that an increasing number of patients (pts) will ultimately progress after Ven exposure and require additional CLL-directed therapy. While many discuss re-treatment with Ven as a subsequent treatment option, the current literature contains response data on an extremely limited number of evaluable pts (11 pts MURANO, overall response rate (ORR) 55%; 3 pts VEN 365, ORR 100%). Whether re-treatment with Ven is an acceptable option remains an important unanswered clinical question. METHODS: We conducted a multicenter, retrospective study of CLL pts treated with a Ven-based regimen (Ven1) and then re-treated with a second Ven-based regimen (Ven2) in a later line of therapy (LOT). Data were collected from 13 centers and the CLL Collaborative Study of Real-World Evidence database. CLL pts were eligible for inclusion if they were treated with a Ven-based regimen in any LOT and then re-treated with a Ven-based regimen as a later LOT. Collected data included demographics, prognostic disease characteristics, tumor lysis syndrome (TLS) risk and incidence, clinical response and reasons for treatment discontinuation (dc). The primary study endpoint was investigator-assessed ORR (CR: complete response, PR: partial response, SD: stable disease, PD: progression of disease, iwCLL 2018). Kaplan-Meier method was used to estimate progression free survival (PFS). All other analyses were descriptive. RESULTS: We identified 25 pts who were re-treated with Ven. Pt characteristics prior to treatment with Ven1 are summarized in Table 1. In 24% of pts (n=6), Ven1 was administered as part of a clinical trial. Median prior LOT was 2 (range 0-10) with 12.0% treatment naïve and 60% with prior BTKi exposure. The majority of pts had ≥1 high-risk prognostic marker: del17p (39%), TP53 mut (27%), complex karyotype ≥5 abnormalities (30%) and unmutated IGHV (84%). For Ven1, treatment regimens, TLS risk, and dose are summarized in Table 2. With a median duration of exposure of 15 months (mos) (64% pts > 12 mos) for Ven1, the ORR was 88% (CR: 48%, PR: 40%, Figure 1A). Ten pts had minimal residual disease (MRD) assessments by flow cytometry; 8 pts (80%) achieved undetectable MRD (10^-4). Most common reasons for Ven1 dc included: toxicity (28%), completion of planned therapy (24%), MD/pt preference (24%), other (12%), alloHSCT (4%) and cost (4%). There was a median of 8.7 mos (36% > 12 mos) between Ven1 and the initiation of Ven2, and 88% did not receive another LOT between Ven1 and Ven2. Reasons for Ven2 initiation were either CLL progression (87.5%) or MRD-positive relapse (12.5%). For Ven2, TLS risk, TLS incidence and dose information are outlined in Table 2. TLS was a rare event during Ven re-treatment (4.5%, lab only). For Ven2, Ven monotherapy was the most common regimen (52%). Standard Ven dose-escalation was used for re-initiation in 17 of 19 pts with available data, however 1 pt started Ven2 at 400 mg daily (no TLS) and another underwent a prolonged ramp-up period. At the time of this analysis, 18 pts had available response assessments for Ven2: ORR is 72.2% (CR: 4, PR: 9, SD: 4 and PD: 1, Figure 1B). Median time from Ven2 to progression or last follow up is 8 mos (0.2-29 mos). Median PFS has not been reached. Estimated 12-month PFS is 69.1%. For pts with a CR to Ven2, median follow up time is 14.5 mos vs 7 mos for pts with PR or SD. Of 25 pts re-treated with Ven, 68% remain on Ven2 presently and 32% have discontinued Ven2, including due to CLL progression (n=4), completion of planned therapy (n=1), unrelated death (n=1), MD/pt preference (n=1). CONCLUSIONS: To our knowledge, this is the largest reported cohort of CLL pts re-treated with Ven after a prior Ven-based regimen. The high ORR in this pt population (median 2 prior therapies) suggests that re-treatment is a promising strategy and should be considered in treatment sequencing algorithms. Notably, pts with a CR to Ven2 had a longer median follow up than those with a PR or SD, suggesting a likelihood of deeper responses with time. Given the promising ORR, further research to prospectively validate Ven re-treatment is warranted. Updated data will be presented. Disclosures Allan: Celgene, Genentech, Janssen, TG Therapeutics: Research Funding; Abbvie, Janssen, AstraZeneca, Pharmacyclics: Honoraria; Acerta, Genentech, Abbvie, Sunesis, Ascentage, Pharmacyclics, Janssen, AstraZeneca, BeiGene: Consultancy. Sail:AbbVie Inc.: Current Employment, Current equity holder in publicly-traded company. Manzoor:Abbvie: Current Employment, Other: may hold stock or stock options. Pu:Takeda Pharmaceuticals: Consultancy. Barr:Gilead: Consultancy; Janssen: Consultancy; AstraZeneca: Consultancy, Research Funding; Abbvie/Pharmacyclics: Consultancy, Research Funding; Verastem: Consultancy; Morphosys: Consultancy; TG therapeutics: Consultancy, Research Funding; Seattle Genetics: Consultancy; Celgene: Consultancy; Merck: Consultancy; Genentech: Consultancy. Coombs:LOXO Oncology: Honoraria; MEI Pharma: Honoraria; Abbvie: Consultancy, Honoraria; Genentech: Honoraria; AstraZeneca: Honoraria; Octapharma: Honoraria; Novartis: Honoraria. Schuster:AlloGene, AstraZeneca, BeiGene, Genentech, Inc./ F. Hoffmann-La Roche, Juno/Celgene, Loxo Oncology, Nordic Nanovector, Novartis, Tessa Therapeutics: Consultancy, Honoraria; Novartis, Genentech, Inc./ F. Hoffmann-La Roche: Research Funding. Skarbnik:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Alexion: Consultancy; Beigene: Speakers Bureau; Verastem: Speakers Bureau; Novartis: Speakers Bureau; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CLL Society: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kite Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Rhodes:Verastem: Consultancy; Abbvie/Genentech: Consultancy; Pharmacyclics: Consultancy; AstraZeneca: Consultancy. Barrientos:Janssen: Honoraria; Sandoz: Consultancy; Oncternal Therapeutics: Research Funding; Bayer: Consultancy; Genentech: Consultancy; Gilead: Consultancy; AstraZeneca: Consultancy. Roeker:American Society of Hematology: Research Funding; Abbott Laboratories: Other: spouse with minority ownership interest ; AbbVie: Other: spouse with minority ownership interest . Leslie:Celgene: Speakers Bureau; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Speakers Bureau; KitePharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BeiGene: Honoraria, Speakers Bureau; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Epizyme: Honoraria, Speakers Bureau; Karyopharm: Honoraria, Speakers Bureau; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADC therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Kamdar:Roche: Research Funding. Choi:Pharmacyclics/Abbvie: Research Funding; Genentech: Consultancy. Simkovic:Abbvie: Consultancy, Other: travel expenses. Lansigan:Seattle Genetics: Consultancy; BMS: Consultancy; BMS Steering Committee for MAGNIFY Program: Membership on an entity's Board of Directors or advisory committees; Spectrum Pharma: Consultancy, Research Funding. Zelenetz:Novartis: Consultancy; Gilead: Research Funding; Janssen: Consultancy; Celgene: Consultancy; Gilead: Consultancy; Genentech/Roche: Consultancy; Roche: Research Funding; BeiGene: Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnology: Consultancy; MorphoSys: Research Funding; Amgen: Consultancy; Sandoz: Research Funding; Celgene: Research Funding; MEI Pharma: Research Funding. Moskowitz:Merck: Research Funding; Seattle Genetics: Research Funding; Bristol-Myers Squibb: Research Funding; Miragen Therapeutics: Consultancy; Incyte: Research Funding; Merck: Consultancy; Imbrium Therapeutics, L.P.: Consultancy; Seattle Genetics: Consultancy. Goy:Morphosys: Research Funding; AbbVie: Research Funding; MD Anderson: Research Funding; Regional Cancer Care Associates/OMI: Current Employment; Infinity Verastem: Research Funding; Infinity: Research Funding; Karyopharm: Research Funding; Genentech/Roche: Research Funding; CALBG: Research Funding; Constellation: Research Funding; Bayer: Research Funding; PracticeUpdate Oncology: Consultancy; RCCA/OMI: Current Employment; Acerta: Consultancy, Honoraria, Other: leadership role, Research Funding; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: leadership role, Research Funding; Celgene: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Other: leadership role, Research Funding; COTA: Consultancy, Current equity holder in publicly-traded company, Other: leadership role; Kite, a Gilead Company: Consultancy, Current equity holder in publicly-traded company, Honoraria, Other: leadership role, Research Funding; Xcenda: Consultancy; Hackensack UMC and University of Nebraska: Research Funding. Feldman:Pfizer: Research Funding; Kyowa Kirin: Consultancy, Research Funding; Eisai: Research Funding; Cell Medica: Research Funding; Amgen: Research Funding; Pharmacyclics: Honoraria, Other, Speakers Bureau; Abbvie: Honoraria; Bayer: Consultancy, Honoraria; Trillium: Research Funding; Portola: Research Funding; Janssen: Speakers Bureau; AstraZeneca: Consultancy; Viracta: Research Funding; Rhizen: Research Funding; Corvus: Research Funding; BMS: Consultancy, Honoraria, Research Funding; Kite: Honoraria, Other: Travel expenses, Speakers Bureau; Celgene: Honoraria, Research Funding; Takeda: Honoraria, Other: Travel expenses; Seattle Genetics, Inc.: Consultancy, Honoraria, Other: Travel expenses, Research Funding, Speakers Bureau. Furman:Verastem: Consultancy; Genentech: Consultancy; Beigene: Consultancy; AstraZeneca: Consultancy, Research Funding; Acerta: Consultancy; Abbvie: Consultancy; TG Therapeutics: Consultancy, Research Funding; Sunesis: Consultancy; Pharmacyclics: Consultancy; Oncotarget: Consultancy; Loxo Oncology: Consultancy; Janssen: Consultancy, Speakers Bureau; Incyte: Consultancy. Mato:Genentech: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; BeiGene: Consultancy; LOXO: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; TG Therapeutics: Consultancy, Other: DSMB, Research Funding; Adaptive: Consultancy, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding.

PURPOSE We conducted a phase II study evaluating pembrolizumab plus gemcitabine, vinorelbine, and liposomal doxorubicin (pembro-GVD) as second-line therapy for relapsed or refractory (rel/ref) classical Hodgkin lymphoma (cHL) (ClinicalTrials.gov identifier: NCT03618550 ). METHODS Transplant eligible patients with rel/ref cHL following first-line therapy were treated with two to four cycles of pembrolizumab (200 mg intravenous [IV], day 1), gemcitabine (1,000 mg/m2 IV, days 1 and 8), vinorelbine (20 mg/m2 IV, days 1 and 8), and liposomal doxorubicin (15 mg/m2, days 1 and 8), given on 21-day cycles. The primary end point was complete response (CR) following up to four cycles of pembro-GVD. Patients who achieved CR by labeled fluorodeoxyglucose-positron emission tomography (Deauville ≤ 3) after two or four cycles proceeded to high-dose therapy and autologous hematopoietic cell transplantation (HDT/AHCT). HDT/AHCT was carried out according to institutional standards, and brentuximab vedotin maintenance was allowed following HDT/AHCT. RESULTS Of 39 patients enrolled, 41% had primary ref disease and 38% relapsed within 1 year of frontline treatment. 31 patients received two cycles of pembro-GVD, and eight received four cycles. Most adverse events were grade 1 or two, whereas few were grade 3 and included transaminitis (n = 4), neutropenia (n = 4), mucositis (n = 2), thyroiditis (n = 1), and rash (n = 1). Of 38 evaluable patients, overall and CR rates after pembro-GVD were 100% and 95%, respectively. Thirty-six (95%) patients proceeded to HDT/AHCT, two received pre-HDT/AHCT involved site radiation, and 13 (33%) received post-HDT/AHCT brentuximab vedotin maintenance. All 36 transplanted patients are in remission at a median post-transplant follow-up of 13.5 months (range: 2.66-27.06 months). CONCLUSION Second-line therapy with pembro-GVD is a highly effective and well-tolerated regimen that can efficiently bridge patients with rel/ref cHL to HDT/AHCT.

Romidepsin (histone deacetylase inhibitor), lenalidomide (immunomodulatory agent), and carfilzomib (proteasome inhibitor), have efficacy and lack cumulative toxicity in relapsed/refractory lymphoma. We performed two investigator initiated sequential phase I studies to evaluate the maximum tolerated dose (MTD) of romidepsin and lenalidomide (regimen A) and romidepsin, lenalidomide, and carfilzomib (regimen B) in relapsed/refractory lymphoma. Cohorts in T-cell lymphoma (TCL), B-cell lymphoma (BCL) were enrolled at the MTD. 49 patients were treated in study A (27 TCL, 17 BCL, 5 HL) and 27 (16 TCL, 11 BCL) in study B. The MTD of regimen A was romidepsin 14 mg/m2 IV on days 1, 8, and 15 and lenalidomide 25 mg oral on days 1-21 of a 28-day cycle. The MTD of regimen B was romidepsin 8mg/m2 on days 1 and 8, lenalidomide 10mg oral on days 1-14 and carfilzomib 36mg/m2 IV on days 1 and 8 of a 21-day cycle. In study A, 94% had AEs ≥Grade 3, most commonly neutropenia (49%), thrombocytopenia (53%), and electrolyte abnormalities (49%). In study B 59% had AEs ≥Grade 3, including thrombocytopenia (30%) and neutropenia (26%). In study A the ORR was 49% (50% TCL, 47% BCL, 50% HL). In study B the ORR was 48% (50% TCL, 50% BCL). For study A and B the median progression free survival (PFS) was 5.7 months and 3.4 months respectively with 11 patients proceeding to allogeneic transplant. The combinations of romidepsin and lenalidomide and of romidepsin, lenalidomide and carfilzomib showed activity in relapsed/refractory lymphoma with an acceptable safety profile. This article is protected by copyright. All rights reserved.