Peripheral T/NK-Cell Lymphomas: Survival with Current Treatment Strategies. La Princesa University Hospital Single Experience

Abstract BACKGROUND: Peripheral T/NK–cell lymphomas (PTCL) are a heterogeneous group of neoplasms with a median survival of 2-3 years. Currently, there is not standard treatment although consolidation of response with autologous stem cell transplantation (ASCT) is recommended as front line therapy, except in anaplastic ALK+ and T/NK nasal localized lymphomas. AIM: To analyze the outcome of patients with PTCL diagnosed and treated in our center between 2000 and 2012. METHODS: An Intention to treat analysis has been performed to assess the response rate, progression-free survival (PFS) and overall survival (OS). RESULTS: Thirty eight patients were identified in this period, 2 were excluded, 1 due to misdiagnosis and the other was not treated in our Department. There were 28 men and 8 women with a median age of 62 years (20-85 y), ECOG ≥ 2: 19%, B symptoms: 61%, IPI ≥ 2: 56% and PIT ≥2: 47%. The histological subtypes are described in Table 1. Five patients died during diagnosis (aspergillosis, septic shock, intestinal perforation, Evans syndrome and hemophagocytic syndrome) and 2 rejected treatment. We treated 29 patients (80.5%) mainly with CHOP-like chemotherapy (77%) adding other schemas in order to achieve best response if needed. In 15 patients ASCT was not indicated (9 due to age and 6 due to histological subtype). After induction, 4 patients achieved complete remission (CR), 3 partial response (PR) and 8 progressed (NR / P). Median number of treatments was 1 (range 1 to 3). Fourteen patients were candidates for transplant but 4 of them could not receive it due to progression, early death, lost to follow-up and medical decision. Finally, 10 patients (71%) proceeded to transplant: 9 ASCT and 1 allo-SCT. The median number of treatments was 2 (1 - 3). Three patients were transplanted in CR, 6 PR and 1 NR/P; no patient improved the response. Three patients died during the procedure (RSV pneumonia, CMV and gram positive sepsis). The allo-SCT patient died of grade IV acute GVHD. Currently, 7 out of 36 patients are alive in CR, 24 have died and in 5 were lost to follow-up. Causes of death were: lymphoma (58%), infection (25%), toxicity (4%) and unknown (13%). With a median follow-up for alive patients was 72 months, OS was 15.34 months (95% CI, 3.98-26.71) and PFS 13.61 months (95% CI, 10.15-17.07). In Table 2 and figure 1 we show the median PFS and OS obtained in transplant- eligible and non-eligible patients. CONCLUSIONS: We confirm the difficulty of long-term control of PTCL with current first-line treatments recommended by guidelines. Even in those patients receiving more intensive treatment with SCT, no improvement in PFS or OS was observed. New drugs and strategies are needed to improve the prognosis of these patients. Table 1. HISTOLOGICAL SUBTYPES N= 36 Peripheral T-cell lymphoma NOS 12 (33%) Angioimmunoblastic T-cell lymphoma 7 (19%) Anaplastic large T-cell lymphoma, ALK+ 6 (17%) Anaplastic large T-cell lymphoma, ALK- 5 (14%) T/NK-cell lymphoma, nasal type 4 (11%) Intestinal T-cell lymphoma 1 (3%) Hepatosplenic γ/d T-cell lymphoma 1 (3%) Table 2. SCT candidates No SCT candidates OS months (CI 95%) 13.97 (6.40-21.53) 11.67 (2.86-20.48) PFS months (CI 95%) 13.61 (7.09-20.12) 11.51 (4.76-18.25) Figure 1. Figure 1. Disclosures Alegre: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jansen: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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A Phase 2 Study of Panobinostat (PAN) in Combination with Bortezomib (BTZ) in Patients with Relapsed/Refractory Peripheral T-Cell Lymphoma (PTCL) or NK/T-Cell Lymphoma (NKL)

Blood ◽

10.1182/blood.v124.21.503.503 ◽

2014 ◽

Vol 124 (21) ◽

pp. 503-503 ◽

Cited By ~ 3

Author(s):

Yeow-Tee Goh ◽

William YK Hwang ◽

Colin Phipps Diong ◽

Yap chun Hsien ◽

Kevin Tay ◽

...

Keyword(s):

T Cell ◽

Board Of Directors ◽

Research Funding ◽

Nk Cell ◽

Cell Lymphoma ◽

Performance Status ◽

Objective Response ◽

T Cell Lymphoma ◽

Conventional Chemotherapy ◽

Advisory Committees

Abstract Background Relapsed/refractory PTCL and NKL after conventional chemotherapy carry a poor prognosis and there is currently no proven salvage treatment available. Numerous preclinical studies have demonstrated synergistic interactions between proteasome and histone deacetylase (HDAC) inhibitors. PAN inhibits the aggresome pathway of protein degradation, which is upregulated when the proteasome pathway is inhibited by BTZ. Primary end point of this phase II multi-center open-label clinical study (NCT00901147) is the objective response rate (ORR) according to the Revised Response Criteria (Cheson 2007) among eligible patients (pts) treated with this novel combination of BTZ and PAN. Secondary end points include the evaluation of the progression-free survival (PFS) and the assessment of the safety and tolerability of the combination. We report the final clinical results of our study exploring this novel combination. Methods Pts with histologically confirmed PTCL or NKL who failed or were refractory to 1 or more prior systemic therapy, and had measurable disease and ECOG performance status 0–2 were eligible. Pts were accrued according to a 2-stage Gehan design. Pts receive thrice weekly oral PAN (20 mg) and twice weekly BTZ (IV 1.3 mg/m2), both for 2 of 3 weeks for up to 8 cycles. CT scanning and/or FDG-PET were performed after every two cycles. Results: Among 25 pts enrolled, histologies included: angioimmunoblastic T-cell lymphoma (AITL) n=8, PTCL (unspecified) n=11, Anaplastic large cell lymphoma, ALK+ and ALK- n=1 and 2 respectively, NKL, nasal type n=2 and subcutaneous panniculitis-like T-cell lymphoma n=1. The median age was 59 (35-79) years, and 64% were male. Outcomes are available on 23 patients as 2 patients withdrew consent before any response assessment could be made. The ORR (CR+PR) was 43% (10/23) with 22% (5/23) attaining a CR. Median time to response was 6 weeks. Five pts (22%) had stable disease while 8 pts developed progressive disease (35%) while on study. Pts received a median of 2 prior therapies (range 1-4); 28% had prior autologous stem cell transplantation (SCT). Common treatment-related grade 3/4 adverse events included thrombocytopenia (68%), neutropenia (36%), diarrhoea (28%) and asthenia/fatigue (16%). Peripheral neuropathy of any grade was observed in 40%. 5 pts successfully underwent subsequent allogeneic SCT. Updated survival analysis will be presented. Conclusions The study regimen is generally well tolerated and shows encouraging activity across different T/NK-cell lymphomas. The novel combination could successfully serve as a bridge to allogeneic SCT for many transplant-eligible patients who have failed conventional chemotherapy. These results form the basis for further validation studies on proteasome and HDAC inhibition in PTCL or NKL. Ongoing correlative studies are designed to determine if the study regimen is more active in diseases with up-regulation of NF-kappa B activity or transcription factors/ co-regulators known to be modified by acetylation. Disclosures Goh: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Jannsen Pharmaceuticals: Honoraria, Research Funding, Speakers Bureau; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead Sciences: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Kim:Novartis, Celgene, Takeda: Research Funding. Tan:JANSEN: Honoraria, Research Funding; NOVARTIS: Research Funding.

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Survival Analysis of Patients with T-Cell Lymphoma or T-Cell Large Granular Leukemia and Concomitant Plasma Cell Dyscrasias

Blood ◽

10.1182/blood-2021-152556 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 2449-2449

Author(s):

Zachary Braunstein ◽

Miguel Ruiz ◽

Eric McLaughlin ◽

Naresh Bumma ◽

Don M Benson ◽

...

Keyword(s):

T Cell ◽

Board Of Directors ◽

Research Funding ◽

Cell Lymphoma ◽

T Cell Lymphoma ◽

Survival Outcomes ◽

Advisory Committees ◽

T Cell Malignancies ◽

Cell Malignancy

Abstract Introduction: Sporadic cases of patients with a combined T-cell malignancy and plasma cell dyscrasia (PCD) have been reported in the literature. While the most commonly observed association is with T-cell large granular lymphocytic leukemia (T-LGLL) and PCD, there are case reports of other T-cell malignancies and PCD, such as peripheral T-cell lymphoma (PTCL) and angioimmunoblastic T-cell lymphoma (AITL) with multiple myeloma (MM). Nearly one-third of MM patients develop clonal T-cell populations that share a similar immunophenotype to T-LGLL, suggesting likely under diagnosis of concomitant T-cell malignancies in patients with PCD. However, with the limited data available regarding the overlap between PCD and T-cell malignancy, the significance, associated pathogenesis, and impact on survival outcomes is unknown. The purpose of this study is to describe the outcomes of patients with overlapping T-cell malignancies and PCD in order to determine the survival outcomes and ultimately make management/diagnostic recommendations. Methods: In this IRB approved study, we retrospectively evaluated patients with concomitant T-cell malignancy and PCD at Ohio State University from 2010-2020. Patients were identified using a database search for T-cell malignancies as well as PCD. All patients that were included met the 2016 World Health Organization diagnostic criteria for their respective T-cell malignancy and PCD. Progression-free survival (PFS) was measured as time from the start of treatment until first progression, death, or last follow-up according to the Kaplan-Meier method with median survival times and 95% confidence intervals reported. Results: A total of 21 patients, with a median follow-up time of 22 months (range 1-153), were included in this analysis. Baseline demographics are in table 1. The most common T-cell malignancy was T-LGLL (11/21; 52%) and the most common PCD were MGUS (8/21; 38%) and MM (8/21; 38%). Ten (48%) patients presented with a T-cell malignancy as their primary malignancy, 9 (43%) presented with a PCD as their primary malignancy, 1 (5%) patient was diagnosed with both at the same time, and for 1 (5%) patient it is unknown. Within the cohort, 62% (13/21) of patients received primary treatment for their T-cell malignancy and 38% (8/21) of patients received primary treatment for their PCD. Of the 7 patients that had their PCD clone 4 were treated concomitantly and 3 were treated for only their T-cell malignancy. Overall, 9/21 (42.9%) of patients had progression of their T-cell malignancy. A summary of outcomes is provided in Table 2. 54.6% of patients with T-LGLL and 60% of patients with AITL/PTCL experienced progressive T-cell disease and no patients with CTCL had progressive T-cell disease. The median overall survival (OS) across all patients was 4.1 years. Median OS was not reached for patients with T-LGLL, 1.7 years for AITL/PTCL, and 12.4 years for CTCL. PFS was 11 months for patients with T-LGLL, 1 year for AITL/PTCL, and 12.37 years for CTCL. Survival probability is shown in Figure 1. The rates of progression, OS, and PFS were consistent with previously published data for patients with these T-cell malignancies. Conclusions: Herein, we characterize a cohort of patients with concomitant T-cell malignancies and PCD with an emphasis on survival outcomes. Our data suggests that there is no PFS or OS difference for patients with T-cell malignancies and concomitant PCD when treated with standard T-cell directed therapy. There is the potential that treating a patient's T-cell malignancy may lead to resolution of their PCD clone, even without therapy directed at the PCD. While our data is limited by small sample size, this report represents the largest data set available in this rarely described patient population. Larger retrospective cohort studies are needed to further characterize this population and validate these findings. For patients with T-cell malignancies as the primary diagnosis with concomitant PCD, treatment with standard T-cell directed therapies is recommended with continued follow-up and monitoring of the concomitant PCD. Figure 1 Figure 1. Disclosures Bumma: Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees. Porcu: Viracta: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Innate Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BeiGene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; Daiichi: Honoraria, Research Funding; Kiowa: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Spectrum: Consultancy; DrenBio: Consultancy. Brammer: Seattle Genetics: Speakers Bureau; Celgene: Research Funding; Kymera Therapeutics: Consultancy.

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Case of Primary Breast and Ipsilateral Axillary T-Cell Lymphoma: a Rare Occurrence

Case Reports in Surgery ◽

10.1155/2020/6927835 ◽

2020 ◽

Vol 2020 ◽

pp. 1-6

Author(s):

Faryal Afridi ◽

Garry D. Ruben ◽

Eric Oristian

Keyword(s):

T Cell ◽

Cell Lymphoma ◽

T Cell Lymphoma ◽

Non Hodgkin Lymphoma ◽

T Cell Lymphomas ◽

Lost To Follow Up ◽

Ipsilateral Axilla ◽

Rare Diagnosis ◽

Breast Malignancies

Background. Malignant lymphomas of the breast are rare and can be primary or secondary. Non-Hodgkin Lymphoma involving the breast is even rarer comprising 0.04-0.5% of all breast malignancies (Takemura). The incidence is even lower for T-cell lymphomas compared with B-cell subtype. We report the rare incidence of primary T-cell lymphoma involving both breast and ipsilateral axilla. Case. This is the case of an 80-year-old female who initially presented with asymmetry of her right breast. Initial mammograms were inconclusive. MRI could not be performed due to the patient’s severe claustrophobia. The patient was then lost to follow-up but re-presented with a new palpable density in the same breast. Subsequent mammogram showed a suspicious lesion with suspicious right axillary lymphadenopathy. Core biopsy was consistent with T-cell lymphoproliferative disorder involving both the breast and the axilla. She was then referred to medical oncology for management. Conclusion. Although rare, lymphoproliferative disorders of the breast can be encountered during workup for suspicious breast lesions. It is imperative that the surgeon is aware of this rare diagnosis to facilitate appropriate therapeutic intervention.

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Final Results From a Pivotal, Multicenter, International, Open-Label, Phase 2 Study of Romidepsin In Progressive or Relapsed Peripheral T-Cell Lymphoma (PTCL) Following Prior Systemic Therapy

Blood ◽

10.1182/blood.v116.21.114.114 ◽

2010 ◽

Vol 116 (21) ◽

pp. 114-114 ◽

Cited By ~ 7

Author(s):

Bertrand Coiffier ◽

Barbara Pro ◽

H. Miles Prince ◽

Francine M Foss ◽

Lubomir Sokol ◽

...

Keyword(s):

T Cell ◽

Board Of Directors ◽

Systemic Therapy ◽

Research Funding ◽

Cell Lymphoma ◽

T Cell Lymphoma ◽

Phase 2 ◽

Open Label ◽

Advisory Committees ◽

Prior Systemic Therapy

Abstract Abstract 114 Background: Romidepsin is a potent HDAC inhibitor approved by the FDA for patients (pts) with cutaneous T-cell lymphoma who have received at least 1 prior systemic therapy. Durable clinical benefit and tolerability of romidepsin in pts with recurrent or refractory PTCL have been previously observed in a phase 2 trial conducted by the National Cancer Institute. The aim of this phase 2, single-arm, open-label registration study was to evaluate the activity of romidepsin in a larger number of pts with progressive or relapsed PTCL. Methods: Pts with histologically confirmed PTCL (PTCL NOS, angioimmunoblastic T-cell lymphoma, ALCL [ALK-1 negative], other subtypes) who failed or were refractory to ≥ 1 prior systemic therapy, and had measurable disease and ECOG performance status 0–2 were eligible. Exclusions included inadequate bone marrow or other organ function and significant cardiovascular abnormalities. Pts received romidepsin 14 mg/m2 as a 4-h IV infusion on days 1, 8, and 15 every 28 days for up to 6 cycles; treatment could be extended for stable disease (SD) or response. The primary endpoint was rate of complete response (CR + CRu) as evaluated by a central Independent Review Committee (IRC) using International Working Criteria for non-Hodgkin's lymphoma. IRC assessment consisted of a 2-step process, with initial radiographic review of images (CT, MRI) followed by an overall clinical assessment based on the radiology evaluations, photographs, and relevant clinical parameters. Secondary endpoints included objective response rate (ORR): CR + CRu + partial response (PR), investigator-assessed responses, duration of response, time to response, and safety. Results: 131 pts from 48 US, European, and Australian sites were enrolled and received at least 1 dose of romidepsin (as-treated population); 130 patients had histologically confirmed PTCL by central review. Mean age of all pts was 59.4 y (range, 20–83) and median time since diagnosis was 1.25 y (range, 0–17). Median number of prior systemic therapies was 2 (range, 1–8). 21 pts (16%) had failed a prior stem cell transplant. Responses assessed by the IRC are noted in the table below. Longest duration of response is 26+ mo and 16 (94%) of the 17 pts with a CR had not progressed as of the data cutoff (March 31, 2010). Investigator-assessed responses included 21 pts (16%) with CR + CRu, 18 pts (14%) with PR for an ORR of 30%. Currently, 13 pts continue to receive treatment (range, 10–36 cycles). Adverse events (AEs) were reported in 126 of 131 pts (96%). AEs reported in ≥ 20% of pts were nausea (59%), fatigue (41%), vomiting (38%), thrombocytopenia (38%), diarrhea (35%), pyrexia (34%), neutropenia (30%), anorexia (28%), constipation (28%), anemia (23%), and dysgeusia (21%). AEs ≥ grade 3 were reported for 86 pts (66%), with the most common (≥ 5%) being pneumonia (5%), pyrexia (5%), sepsis (5%), and vomiting (5%). 60 pts (46%) had at least 1 serious AE: the most frequently reported (≥ 5%) were pyrexia (7%), pneumonia (5%), vomiting (5%), and sepsis (5%). 22 pts (17%) withdrew due to AEs. 8 pts (6%) died within 30 days of the last dose of romidepsin; 1 death, due to sepsis, was assessed as possibly related to treatment. Conclusions: Complete and durable responses were observed with single agent romidepsin in pts with relapsed PTCL. These data support the therapeutic potential for romidepsin in relapsed PTCL and suggest that romidepsin is a strong candidate for inclusion in future novel regimens for these diseases. As of the data cutoff (March 31, 2010), the median duration of follow-up for CR is 8.2 mo. Disclosures: Coiffier: Gloucester: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau. Off Label Use: Romidepsin is indicated for the treatment of cutaneous T-cell lymphoma (CTCL) in patients who have received at least one prior systemic therapy. Romidepsin is not currently approved for the treatment of peripheral T-cell lymphoma (PTCL). Pro:Celgene: Research Funding. Prince:Celgene: Consultancy, Honoraria, Research Funding. Foss:Celgene: Consultancy; Eisai: Consultancy, Speakers Bureau; Merck: Speakers Bureau; Allos: Consultancy, Speakers Bureau; Cephalon: Speakers Bureau. Sokol:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Caballero:Celgene: Membership on an entity's Board of Directors or advisory committees. Morschhauser:Roche: Consultancy, Honoraria; Bayer: Honoraria. Padmanabhan:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Shustov:Celgene: Research Funding. Nichols:Celgene: Employment. Carroll:Celgene: Employment. Balser:Gloucester Pharmaceutical: Consultancy. Horwitz:Celgene: Consultancy, Honoraria.

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Comprehensive Oncology Measures for Peripheral T-Cell Lymphoma Treatment (COMPLETE): First Detailed Report of Primary Treatment

Blood ◽

10.1182/blood.v120.21.1614.1614 ◽

2012 ◽

Vol 120 (21) ◽

pp. 1614-1614 ◽

Cited By ~ 5

Author(s):

Francine M. Foss ◽

Kenneth R. Carson ◽

Lauren Pinter-Brown ◽

Steven M. Horwitz ◽

Steven T. Rosen ◽

...

Keyword(s):

T Cell ◽

B Cell ◽

Board Of Directors ◽

Initial Treatment ◽

Research Funding ◽

Cell Lymphoma ◽

Primary Treatment ◽

T Cell Lymphoma ◽

Peripheral T Cell Lymphoma ◽

Advisory Committees

Abstract 1614 Background: Registries can be invaluable for describing patterns of care for a population of patients. COMPLETE is a registry of peripheral T-cell lymphoma (PTCL) patients designed to identify the lymphoma-directed treatments and supportive care measures that PTCL patients receive. We report here the first detailed findings of initial therapy. Methods: This is a prospective, longitudinal, observational registry that is led by a global steering committee. Patients with newly diagnosed PTCL and providing written informed consent are eligible. Patients are entered into the registry from time of initial diagnosis and followed for up to 5 years. Only locked records are reported. Results: As of July 2012, 330 patients have been enrolled from the United States. The first patient was enrolled in February 2010. Locked baseline and treatment records are available for 124 and 81 patients, respectively. Of the 124 patients with locked baseline records, 67 patients (54%) were male, the mean age was 59 (range: 19–89), and race/ethnicity was recorded as: White (87 patients; 70%), Black (19; 15%), Asian (5; 4%) and other/unknown (13; 11%). Histology was reported as follows: PTCL-not otherwise specified (27%), anaplastic large cell lymphoma-primary systemic type (18%), angioimmunoblastic T-cell lymphoma (17%), transformed mycosis fungoides (7%), T/NK-cell lymphoma-nasal and nasal type (6%), adult T-cell leukemia/lymphoma, HTLV 1+ (6%) and other (19%). 25 patients (20%) had received another diagnosis, including B-cell lymphoma, Hodgkin's disease and other T-cell lymphomas, prior to their current diagnosis of PTCL. 49 patients (40%) had B symptoms, 102 patients (82%) had an Ann Arbor stage of III/IV, 116 patients (94%) had ECOG performance status of 0–1, and international prognostic index (IPI) score was distributed as follows: IPI 0 (7% of patients), 1 (15%), 2 (43%), 3 (26%), and 4 (9%). Of the 81 patients with locked treatment records, details on initial treatment can be found in table below. Conclusions: This first detailed analysis of primary treatment of PTCL indicates that this disease is still largely being treated with regimens derived primarily from studies of B-cell lymphomas and that a single standard of care does not exist. The fact that a meaningful proportion of patients were initially diagnosed with something other than their current diagnosis of PTCL points out the challenges of diagnosing the disease. While the intent of initial treatment for most patients is to affect a cure, more than 20% of patients were noted as deceased at the end of initial treatment, underscoring the need for more effective, disease-specific therapy. Disclosures: Foss: Merck: Study Grant, Study Grant Other; Celgene: Study Grant, Study Grant Other; Eisai: Consultancy; Seattle Genetics: Consultancy; Celgene: Consultancy; Allos: Consultancy. Carson:Allos: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau. Pinter-Brown:Allos: Consultancy, Membership on an entity's Board of Directors or advisory committees. Horwitz:Allos: Consultancy, Research Funding. Rosen:Allos: Consultancy, Honoraria. Pro:Celgene: Honoraria, Research Funding; Spectrum: Honoraria; Allos: Honoraria; Seattle Genetics: Research Funding. Gisselbrecht:Allos: Consultancy, Membership on an entity's Board of Directors or advisory committees. Hsi:Allos: Research Funding; Eli Lilly: Research Funding; Abbott: Research Funding; Cellerant Therapeutics: Research Funding; BD Biosciences: Research Funding; Millenium: Research Funding.

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Long-Term Responders after Brentuximab Vedotin: Experience on 57 Patients with Relapsed and Refractory Hodgkin and Anaplastic Large Cell Lymphoma

Blood ◽

10.1182/blood.v126.23.2725.2725 ◽

2015 ◽

Vol 126 (23) ◽

pp. 2725-2725 ◽

Cited By ~ 1

Author(s):

Pier Luigi Zinzani ◽

Letizia Gandolfi ◽

Beatrice Casadei ◽

Cinzia Pellegrini ◽

Alessandro Broccoli ◽

...

Keyword(s):

Overall Survival ◽

Board Of Directors ◽

Cell Lymphoma ◽

Large Cell ◽

Median Number ◽

Brentuximab Vedotin ◽

Advisory Committees ◽

Large Cell Lymphoma

Abstract Brentuximab vedotin (BV) is an antibody drug-conjugate targeting CD30 linked to monomethyl auristatin E. Several studies have shown the efficacy of BV in patients with refractory or relapsed Hodgkin lymphoma (HL) and systemic anaplastic large cell lymphoma (sALCL). We reviewed our clinical database to evaluate the long-term efficacy of this treatment. From July 2009 to February 2015, 57 patients were treated with BV in our Institute: 43 with a diagnosis of HL and 14 with sALCL. Thirty-six were males and 21 were females, with a median age of 33 years (range 16-77). All of them had been heavily pretreated before BV with a median number of previous therapies of 3 (range 2-10). Thirty-nine had refractory disease and 18 were relapsed. Autologous stem cells transplantation had failed in 30 patients. BV was administered at a dosage of 1.8 mg/mq, every 21 days, for a maximum of 16 cycles. The median number of cycles was 8 (range 2-16); 13 patients completed the entire schedule. The best overall response rate was globally 57,8% (33 of 57 patients), including 25 (43.8%) complete responses (CR): 18 with HL and 7 with sALCL. At present, 20/25 (80%) patients are still in continuous CR (CCR) with a median follow up of 9 months (range 3-41): 10 of them have consolidated the response with a stem cell transplantation (SCT) (4 auto-SCT and 6 allo-SCT) and 10 patients have remained in CR without any other therapy after BV. Among these long-term responders without any consolidation (7 patients with HL and 3 with sALCL), the median follow-up is 12 months (range 3-37); in particular there are 3 patients in CCR after at least 24 months. The global overall survival rate at 68 months is 71% (no patients with sALCL dead) and the median overall survival has not been reached yet. The global progression-free survival rate at 48 months is 30%, the median is achieved at 11,7 months. Toxicity was primarily neurological with peripheral sensory symptoms (30%) and motor neuropathy (5%); the majority was grade 3 in severity (8 patients). This study confirms the safety and the high efficacy of BV that can be considered an effective treatment in patients with relapsed or refractory HL or sALCL. This drug can induce a durable complete response representing a "bridge" to auto-SCT or allo-SCT. However our data show a subset of patients that can be considered "long-term responders", who have remained in CCR without any consolidation after BV. Disclosures Zinzani: Celgene: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; J&J: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Cavo:Janssen: Honoraria; Celgene: Honoraria, Speakers Bureau; Amgen: Honoraria; Bristol Myers Squibb: Honoraria; Novartis: Honoraria.

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Utility of Interim and Post-Therapy PET/CT in T-Cell and NK-Cell Lymphoma: A Single Institutional Analysis over 9 Years

Blood ◽

10.1182/blood.v126.23.3915.3915 ◽

2015 ◽

Vol 126 (23) ◽

pp. 3915-3915

Author(s):

Kota Fukumoto ◽

Manabu Fujisawa ◽

Yasuhito Suehara ◽

Yoshiaki Usui ◽

Kentaro Narita ◽

...

Keyword(s):

T Cell ◽

Nk Cell ◽

Cell Lymphoma ◽

T Cell Lymphoma ◽

Peripheral T Cell Lymphoma ◽

Index Lesion ◽

Pet Ct ◽

Post Therapy ◽

Initial Staging

Abstract Introduction: Positron emission tomography combined with computed tomography (PET-CT) is functional imaging test and has been widely used in malignant lymphoma (ML) for initial staging and monitoring response to treatment. Interim PET-CT (iPET) and post-therapy PET-CT (ePET) is also used to assess the early response and guide subsequent treatment, although its role is still controversial other than in Hodgkin's disease and diffuse large B cell lymphoma. Peripheral T cell lymphoma (PTCL) and natural killer (NK) cell lymphomas are relatively rare and heterogeneous types of ML. The prognosis of T and NK (T/NK) cell lymphoma is poor and no standard treatment is available. Therefore, there is a need to find better prognostic factors or tools for these patients. PET-CT is both sensitive and specific for initial staging of T/NK cell lymphoma, although there have been few studies using i- and ePET in these lymphomas. We investigated the prognostic value of i- and ePET in T/NK cell lymphoma in a retrospective single-center study. Methods: Between June 2006 and June 2015, 79 patients with T/NK cell lymphomas had iPET after 2 to 4 courses of treatment and at the end of treatment at Kameda Medical Center, Japan. iPET was performed just before the next cycle of treatment. Treatment responses were scored according to the Deauville score using a 5-point scale (DS). We defined DS scores 1 - 3 as complete metabolic response (CMR). Standardized uptake value (SUV) measurement was normalized relative to the injected dose and lean body mass. The SUV was measured for all lesions and the highest value for each scan was recorded as maximum SUV (SUVmax). These lesions were identified as indicator lesions. For mid- and end-treatment scans, we recorded the change in SUVmax (DSUV), comparing the index lesion and the highest SUVmax in the scan regardless of the index lesion. Differences in overall survival (OS) and progression-free survival (PFS) were calculated by two-sided log-rank test. PET-CT status was assessed for its ability to predict PFS and OS. Results: The study population consisted of 48 men and 31 women with a median age of 70 years. The most frequent lymphoma diagnoses were peripheral T cell lymphoma-not otherwise specified (PTCL-NOS) (n = 29), angioimmunoblastic T cell lymphoma (AITL) (n = 21), anaplastic large cell lymphoma (ALCL) (n = 6), adult T cell leukemia/lymphoma (ATLL) (n = 12), enteropathy-associated T cell lymphoma (EATL) (n = 2), and NK/T cell lymphoma (NKTCL) (n = 9). Most patients except for ATLL and NK cell lymphoma were instituted with the CHOP-like regimen. Baseline PET scan was positive in all cases and median SUVmax was 13.7 (range, 2.6 - 37.4). iPET results were negative in 17 cases (26%), and ePET results were negative in 22 of 46 (48%) cases. With a median follow up of 30 months, 5-year PFS rate was 66% for obtaining CMR vs. 9.2% for not obtaining CMR (P < 0.001). The percentages of patients that obtained CMR were 48% (14/29), 62% (13/21), 67% (4/6), 33% (3/9), 50% (1/2), and 56% (5/9) for those with PTCL-NOS, AITL, ALCL, ATLL, EATL, and NKTCL, respectively. The patients who obtained CMR showed significantly longer PFS and OS compared to those who did not. We also analyzed DSUVmax. Using the ROC curve, DSUVmax values between baseline and iPET of > 62% and > 85% were predictive of better PFS and OS (sensitivity 96%, specificity 67%, area under the curve (AUC) 0.89, 95% confidence interval (CI) = 0.82 - 0.97 and sensitivity 49%, specificity 97%, AUC 0.80, 95% CI = 0.70 - 0.90, respectively). We examined the positive and negative predictive values (PPV and NPV) and accuracy in predicting PFS and OS in 66 patients who underwent iPET. Of 35 iPET-positive patients, 31 (89%) showed progression, and 26 (74%) died during the follow-up. On multivariate Cox regression analysis, obtaining CMR at iPET emerged as an independent prognostic factor for PFS and OS (P<0.001 and P<0.001, respectively). Conclusions: Our data suggest that patients with positive results on i- or ePET should be considered candidates for intensive therapeutic strategies to improve their clinical outcome. Large prospective studies of patients with tumors of a homogeneous histological subtype within the T/NK cell lymphoma, treated with a uniform protocol, and evaluated on the basis of standardized criteria are warranted. Figure 1. Figure 1. Disclosures No relevant conflicts of interest to declare.

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Tolinapant (ASTX660), a Non-Peptidomimetic Antagonist of cIAP1/2 and XIAP, and the HDAC Inhibitor Romidepsin Are Synergistic in in Vitro Models of T Cell Lymphoma

Blood ◽

10.1182/blood-2021-153451 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 4356-4356

Author(s):

John S Manavalan ◽

Ipsita Pal ◽

Aidan Pursley ◽

George A. Ward ◽

Tomoko Smyth ◽

...

Keyword(s):

T Cell ◽

Cell Line ◽

Board Of Directors ◽

Cell Lines ◽

Research Funding ◽

Cell Lymphoma ◽

T Cell Lymphoma ◽

Tnf Alpha ◽

Sensitive Cell ◽

Advisory Committees

Abstract Background: The PTCL are a heterogeneous group of non-Hodgkin lymphomas originating from mature T-lymphocytes. They are aggressive diseases, often resistant to conventional chemotherapy. Despite the fact that a number of new agents have been approved, treatment paradigms tailored to the biology of the disease have yet to emerge. Tolinapant (ASTX660) is a potent antagonist of both cellular and X-linked inhibitors of apoptosis proteins (cIAP1/2 and XIAP), and is presently in phase I/II trials in patients with advanced solid tumors and lymphomas (NCT02503423). IAP antagonists enhance tumor necrosis factor (TNF) receptor superfamily mediated apoptosis (Ward GA, et al. Mol Cancer Ther. 2018), are potent anti-tumor immune enhancers and induce markers of immunogenic cell death such as damage associated molecular patterns (DAMPs; Ye W, et al, Oncoimmunology, 2020). Objectives: We explored the sensitivity of a range of T-cell lymphoma (TCL) cell lines to tolinapant. We establish the synergy coefficient between tolinapant and the HDAC inhibitor, romidepsin, and interrogated the molecular basis of their synergistic interaction. Methods: A panel of human T-cell lymphoma cell lines were tested in proliferation assays (CellTiterGlo) for sensitivity to tolinapant in the presence or absence of 10ng/ml of TNF alpha. For combination studies, with tolinapant and romidepsin, each drug was tested at the IC10 and IC40 concentrations in the presence or absence of TNF alpha. Synergy scores using the Excess over Bliss (EOB) model were calculated using SynergyFinder (Aleksandr Ianevski et al; Nucleic Acids Research, 2020). Additionally, the effects of tolinapant and romidepsin on the IAPs and caspases were analyzed by western blots. TNFR1 receptor expression and induction of DAMPs were also analyzed by flow cytometry. Results: TCL Lines demonstrated varying sensitivities to tolinapant in the presence or absence of TNF alpha. The most sensitive cell lines, ALK+ ALCL and SUP-M2, had IC50 concentrations ranging from 200nM ± 100nM to 20nM ± 1nM in the absence or presence of TNF alpha, respectively, at 24, 48 and 72hrs, while a resistant CTCL cell line HH had an IC50 concentration of over 20mM, even in the presence of TNF alpha. Interestingly, using western blot analysis, we found that the presence of TNF alpha increased the levels of cIAP1 in the tolinapant sensitive SUP-M2 cell line, but not in the resistant HH cell line. However, there was a concentration dependent decrease in cIAP1 but not in XIAP in both cell lines treated with tolinapant. Flow cytometry analysis demonstrated that tolinapant increases the expression of TNFR1 and DAMPs in a dose dependent manner on the sensitive SUP-M2, but not in the resistant HH cells. In combination experiments, using the EOB model, tolinapant plus romidepsin was found to be synergistic in the absence of TNF alpha, at 36hrs, in both the sensitive cell line SUP-M2 and the resistant cell line HH. In the presence of TNF alpha, synergism was seen only in the sensitive cell line SUP-M2 and antagonistic in the HH cell line (Fig. 3). In the tolinapant plus romidepsin treated samples, cIAP1 levels decreased in the SUP-M2 cell line, in the absence of TNF alpha, however, addition of TNF alpha did not alter the levels of cIAP1 in the SUP-M2 cells. The cIAP1 levels decreased in the HH cells treated with the combination, in both the presence or absence of TNF alpha (Figure). Our findings indicate that the synergy of the tolinapant plus romidepsin is not dependent on the presence of TNF alpha. Conclusion: Tolinapant has demonstrated potent cytotoxic effects against a broad range of TCL lines both as a monotherapy and in combination with the HDAC Inhibitor, romidepsin. In in vitro studies, T cell lymphoma cell lines demonstrated varying sensitivity to tolinapant with certain cell lines being more resistant, even in the presence of TNF alpha. Interestingly, the addition of romidepsin appeared to overcome the intrinsic resistance to tolinapant in the absence of TNF alpha. These data provide the rationale to continue to explore the combination of tolinapant and romidepsin in vivo and to investigate additional combinations with T-cell specific agents (e.g. pralatrexate, belinostat, azacitidine and decitabine). Figure 1 Figure 1. Disclosures Smyth: Astex Pharmaceuticals: Current Employment. Sims: Astex Pharmaceuticals: Current Employment. Loughran: Kymera Therapeutics: Membership on an entity's Board of Directors or advisory committees; Bioniz Therapeutics: Membership on an entity's Board of Directors or advisory committees; Keystone Nano: Membership on an entity's Board of Directors or advisory committees; Dren Bio: Membership on an entity's Board of Directors or advisory committees. Marchi: Kyowa Kirin: Honoraria; Myeloid Therapeutics: Honoraria; Astex: Research Funding; BMS: Research Funding; Merck: Research Funding; Kymera Therapeutics: Other: Scientific Advisor.

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Nanatinostat (Nstat) and Valganciclovir (VGCV) in Relapsed/Refractory (R/R) Epstein-Barr Virus-Positive (EBV +) Lymphomas: Final Results from the Phase 1b/2 VT3996-201 Study

Blood ◽

10.1182/blood-2021-152603 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 623-623

Author(s):

Bradley M. Haverkos ◽

Onder Alpdogan ◽

Robert Baiocchi ◽

Jonathan E Brammer ◽

Tatyana A. Feldman ◽

...

Keyword(s):

T Cell ◽

B Cell ◽

Board Of Directors ◽

Research Funding ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

T Cell Lymphoma ◽

Phase 2 ◽

Advisory Committees ◽

Phase 1B

Abstract Introduction: EBV can be associated with several types of lymphomas, with reported frequencies of up to 8-10% in diffuse large B cell lymphoma (DLBCL), 30-100% in peripheral T cell lymphoma (PTCL) subtypes, 80% in post-transplant lymphoproliferative disease (PTLD), and 15-30% in classical Hodgkin lymphoma (HL), with adverse impact on outcomes. Nanatinostat (Nstat) is a Class-I selective oral HDAC inhibitor that induces the expression of the lytic BGLF4 EBV protein kinase in EBV + tumor cells, activating ganciclovir (GCV) via phosphorylation. This results in GCV-induced inhibition of viral and cellular DNA synthesis and apoptosis. Herein we report the final results from this exploratory study for patients with R/R EBV + lymphomas (NCT03397706). Methods: Patients aged ≥18 with histologically confirmed EBV + lymphomas (defined as any degree of EBER-ISH positivity), R/R to ≥1 prior systemic therapies with an absolute neutrophil count ≥1.0×10 9/L, platelet count ≥50×10 9/L, and no curative treatment options per investigator were enrolled into 5 dose escalation cohorts to determine the recommended phase 2 doses (RP2D) of Nstat + VGCV for phase 2 expansion. Phase 2 patients received the RP2D (Nstat 20 mg daily, 4 days per week + VGCV 900 mg orally daily) in 28-day cycles until disease progression or withdrawal. Primary endpoints were safety/RP2D (phase 1b) and overall response rate (ORR) (phase 2); secondary endpoints were pharmacokinetics, duration of response (DoR), time to response, progression free survival and overall survival. Responses were assessed using Lugano 2014 response criteria beginning at week 8. Results: As of 18 June 2021, 55 patients were enrolled (phase 1b: 25; phase 2: 30). Lymphoma subtypes were DLBCL (n=7), extranodal NK/T-cell (ENKTL) (n=9), PTCL, not otherwise specified (PTCL-NOS) (n=5), angioimmunoblastic T cell lymphoma (n=6), cutaneous T cell (n=1), HL (n=11), other B cell (n=3), and immunodeficiency-associated lymphoproliferative disorders (IA-LPD) (n=13), including PTLD (n=4), HIV-associated (n=5), and other [n=4: systemic lupus erythematosus (SLE) (n=2), common variable/primary immunodeficiency (n=2)]. Median age was 60 years (range 19-84), M/F 35/20, median number of prior therapies was 2 (range 1-11), 76% had ≥2 prior therapies, 78% were refractory to their most recent prior therapy, and 84% had exhausted standard therapies. EBER positivity ranged from <1 to 90% in 42 tumor biopsies with central lab review. The most common treatment-emergent adverse events (TEAEs) of all grades were nausea (38%), neutropenia (34%), thrombocytopenia (34%), and constipation (31%). Grade 3/4 TEAEs in >10% of patients included neutropenia (27%), thrombocytopenia (20%), anemia (20%), and lymphopenia (14%). Dose reductions and interruptions due to treatment-related AEs were reported in 14 (25%) and 16 (29%) patients, respectively. Only 1 patient had to discontinue therapy. There were no cases of CMV reactivation. For 43 evaluable patients (EBER-ISH + with ≥ 1 post-treatment response assessment) across all histologies, the investigator-assessed ORR and complete response (CR) rates were 40% (17/43) and 19% (8/43) respectively. Patients with T/NK-NHL (n=15; all refractory to their last therapy) had an ORR of 60% (n=9) with 27% (n=4) CRs. Two patients (ENKTL and PTCL-NOS) in PR and CR respectively were withdrawn at 6.7 and 6.6 months (m) respectively for autologous stem cell transplantation. For DLBCL (n=6), ORR/CR was 67%/33% (both CRs were in patients refractory to first-line R-CHOP). For IA-LPD (n=13), ORR/CR was 30%/20% (PTLD: 1 CR, other: 1 CR, 1 PR). For HL (n=10), there was 1 PR (4 SD). The median DoR for all responders was 10.4 m, with a median follow-up from response of 5.7 m (range 1.9-34.1 m). For the 17 responders, 8 lasted ≥ 6 months. Conclusions: The combination of Nstat and VGCV was well-tolerated with a manageable toxicity profile and shows promising efficacy in patients with R/R EBV + lymphomas, particularly in refractory T/NK-NHL, a heterogeneous group of aggressive lymphomas with dismal outcomes, with multiple durable responses. Further evaluation of this novel combination therapy for the treatment of recurrent EBV + lymphomas is ongoing in the phase 2 VT3996-202 trial. Disclosures Haverkos: Viracta Therapeutics, Inc.: Honoraria, Research Funding. Baiocchi: Prelude Therapeutics: Consultancy; viracta: Consultancy, Current holder of stock options in a privately-held company; Codiak Biosciences: Research Funding; Atara Biotherapeutics: Consultancy. Brammer: Seattle Genetics: Speakers Bureau; Celgene: Research Funding; Kymera Therapeutics: Consultancy. Feldman: Alexion, AstraZeneca Rare Disease: Honoraria, Other: Study investigator. Brem: Karyopharm: Membership on an entity's Board of Directors or advisory committees; SeaGen: Speakers Bureau; BeiGene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees; KiTE Pharma: Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Consultancy; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics/Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Morphosys/Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Scheinberg: Roche: Consultancy; Abbvie: Consultancy; BioCryst Pharmaceuticals: Consultancy; Alexion pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau. Joffe: AstraZeneca: Consultancy; Epizyme: Consultancy. Katkov: Viracta Therapeutics, Inc.: Current Employment. McRae: Viracta Therapeutics, Inc.: Current Employment. Royston: Viracta Therapeutics, Inc.: Current Employment. Rojkjaer: Viracta Therapeutics, Inc.: Current Employment. Porcu: Viracta: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Innate Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BeiGene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; Daiichi: Honoraria, Research Funding; Kiowa: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Spectrum: Consultancy; DrenBio: Consultancy.

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Brentuximab Vedotin As Single Agent in the Treatment of Relapsed/Refractory CD30 Positive Peripheral T-Cell Lymphoma Patients: A Phase 2 Study of the Fondazione Italiana Linfomi

Blood ◽

10.1182/blood-2020-136917 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 21-21

Author(s):

Vittorio Stefoni ◽

Paolo Corradini ◽

Lorella Orsucci ◽

Stefano Volpetti ◽

Lisa Argnani ◽

...

Keyword(s):

T Cell ◽

Board Of Directors ◽

Cell Lymphoma ◽

Single Agent ◽

Progression Free Survival ◽

T Cell Lymphoma ◽

Phase 2 ◽

Advisory Committees ◽

Not Otherwise Specified ◽

Phase 2 Study

Options are limited for patients with relapsed or refractory (R/R) peripheral T-cell lymphoma (PTCL) for whom the median overall survival (OS) and progression free survival (PFS) are less than 6 months. Patients who are candidates for allogeneic stem cell transplantation can be cured should they achieve adequate response to salvage therapy prior to transplant. Patients who relapse after transplant or who are not transplant candidates are often treated with sequential single-agent therapies with non-curative intent. Only four agents are FDA-approved for the treatment of R/R PTCL including pralatrexate, romidepsin and belinostat. The objective response rate to each of these agents is only 25-30% and duration of response (DOR) is limited. For a specific subtype of PTCL, namely systemic anaplastic large-cell lymphoma, single-agent brentuximab vedotin (BV) treatment resulted in an 86% overall response rate (ORR) and a 57% complete response (CR) rate in R/R disease. A phase 2 study evaluated the efficacy and safety of BV in angioimmunoblastic T-cell lymphoma (AITL) and PTCL not otherwise specified reporting an ORR of 41% (Horwitz et al, Blood. 2014). We conducted a phase 2 study to determine the antitumor efficacy of single-agent BV (1.8 mg/kg administered intravenously every 3 weeks for a maximum of 16 cycles) as measured by the ORR in R/R CD30+ PTCL patients (PTCL not otherwise specified, AITL and transformed mycosis fungoides). Secondary objectives were to assess duration of tumor control, including duration of response and progression-free survival, overall survival and the safety and tolerability of BV in this setting. ClinicalTrials.gov Identifier: NCT02497131. From September 2015 and September 2019, 25 patients were enrolled and 23 (population for the final analysis) received at least one BV infusion (median 5, range 2-16). There were 10 females, 18 patients were in stage IV and 16 subjects were refractory to the last therapy. Median number of therapies received prior to BV was 2 (range 1-6). Final ORR was 30.4%, with 4 CR. CR patients were 3 PTCL not otherwise specified and 1 AITL with response duration of 2.8, 3.3, 4.5 and 10.7 months, respectively. Best response was achieved at the III cycle. PFS was 4.3% at 12 months (median reached at 4.4 months), OS at 12 months was 49.8% (median reached at 11.4 months) and median DOR was 3.4 months. No correlation between CD30 expression per central review and response was observed. Twenty-one hematological toxicities occurred, 14 of them were grade ≥3 (10 thrombocytopenia and 4 neutropenia, all resolved or improved during BV therapy). Among extra-hematological toxicities (n=26, 3.5% grade ≥3), 7 were serious adverse events. To note, 6 of them (23.1%) were lung infection/pneumonia. Only one peripheral neuropathy (grade 1) occurred. In terms of response, the ORR and PFS in this trial are comparable to those in similar populations studied with both other recently approved agents, such as pralatrexate and romidepsin, and with the other phase 2 study on BV. The ORR of 30% and the OS of in the present study places BV among the active agents for PTCL. Safety concerns emerged about infections, claiming for a strict monitoring for these toxicities. Disclosures Corradini: Gilead: Consultancy, Honoraria, Other: Travel and accommodations paid by for; Kite: Consultancy, Honoraria; KiowaKirin: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Incyte: Consultancy; Servier: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Other; BMS: Other; Daiichi Sankyo: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Other: Travel and accommodations paid by for; F. Hoffman-La Roche Ltd: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Other: Travel and accommodations paid by for; AbbVie: Consultancy, Honoraria, Other: Travel and accommodations paid by for; Amgen: Consultancy, Honoraria, Other: Travel and accommodations paid by for. Zinzani:Immune Design: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Consultancy, Honoraria, 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, Speakers Bureau; Eusapharma: Consultancy, Speakers Bureau; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; EUSA Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kirin Kyowa: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; TG Therapeutics, Inc.: Honoraria, Speakers Bureau; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kyowa Kirin: Consultancy, Speakers Bureau; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Immune Design: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

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