Yasenchak, Christopher A.

TPS7571 Background: The majority of patients (pts) with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) who relapse after HSCT, or who are not candidates for HSCT have poor outcomes and are in need of novel therapies. Brentuximab vedotin (BV) is a CD30-directed ADC and preclinical data provide a strong rationale for combining BV, lenalidomide, and rituximab in the treatment of R/R DLBCL. In addition, in a phase 1 trial in which 37 pts with R/R DLBCL were treated with BV + lenalidomide, the ORR was 56.7% (73.3% in CD30+ pts; manuscript in preparation). The median duration of remission was 13.2 months in pts with a CR or PR and 11.7 months in pts with CR, PR, or stable disease > 6 months. The PFS and median OS were 11.2 months and 14.3 months, respectively and results were similar in the CD30+ and CD30 < 1% groups. The clinical activity and manageable safety profiles of BV, lenalidomide, and rituximab as single agents, make the combination a viable option in multiply relapsed and heavily pretreated pts. Methods: This is a randomized, double-blind, placebo-controlled, active-comparator, multicenter phase 3 study designed to evaluate the efficacy of BV vs placebo, in combination with lenalidomide + rituximab, in subjects with R/R DLBCL (NCT04404283). Prior to randomization, there will be a safety and PK run-in period where 6 pts will receive BV, lenalidomide + rituximab, and safety and PK will be evaluated after the first cycle of treatment; 6/6 subjects have been enrolled. Key eligibility criteria include: pts aged ≥18 with R/R DLBCL with an eligible subtype; ≥2 prior lines of therapy and must be ineligible for, or have declined, stem cell transplant, and chimeric antigen receptor T-cell (CAR-T) therapy; ECOG 0 to 2; fluorodeoxyglucose-avid disease by PET and bidimensional measurable disease of at least 1.5 cm by CT. Patients (n = 400) will be randomized 1:1 to receive either BV or placebo in combination with lenalidomide + rituximab and will be stratified by CD30 expression (positive [ ≥1%] versus < 1%), prior allogeneic or autologous stem cell transplant therapy (received or not), prior CAR-T therapy (received or not), and cell of origin (GCB or non-GCB). The primary endpoints are PFS per BICR in the ITT and CD30+ populations. Key secondary endpoints are OS in the ITT and CD30+ populations, and ORR per BICR. Other secondary endpoints include CR rate, duration of response, and safety and tolerability of the combination. Disease response will be assessed by BICR and the investigator according to the Lugano Classification Revised Staging System. Radiographic disease evaluations, including contrast-enhanced CT scans and PET, will be assessed at baseline, then every 6 weeks from randomization until Week 48, then every 12 weeks. PET is not required after CR is achieved. The trial is currently enrolling and will be open in 16 countries. Clinical trial information: NCT04404283.

Background Majority of patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) who relapse after HSCT, or who are not candidates for HSCT have poor outcomes and are in need of novel therapies. Preclinical data provides a strong rationale for combining brentuximab vedotin, lenalidomide, and rituximab in the treatment of R/R DLBCL. In a phase 1 trial, 37 subjects with R/R DLBCL were treated with brentuximab vedotin in combination with lenalidomide. The objective response rate (ORR) (proportion of subjects with complete response [CR] or partial response [PR]) for all subjects was 56.7% (21 of 37 subjects). For the CD30-positive population, the ORR was 73.3% (11 of 15 subjects), whereas the ORR for the CD30 &lt;1% population was 45.6% (10/22). The median follow-up time was 14.3 months (range: 1 to 56.7 months). The median duration of remission for subjects with CR or PR was 13.2 months (range: 3.2 to 55.2 months). For subjects with CR, PR, or stable disease (SD) &gt;6 months, the median duration of remission was 11.70 months (range: 3.2 to 55.2 months). The progression-free survival (PFS) and overall survival (OS) results appear similar in both the CD30-positive and CD30 &lt;1% groups. The PFS in the combined population is 10.2 months and the median OS is 14.2 months (manuscript in preparation). Study Design and Methods This is a randomized, double-blind, placebo-controlled, active-comparator, multicenter phase 3 study designed to evaluate the efficacy of brentuximab vedotin in combination with lenalidomide and rituximab versus placebo in combination with lenalidomide and rituximab for the treatment of subjects with R/R DLBCL (NCT04404283). Key eligibility criteria include the following: subjects aged 18 and older with R/R DLBCL with an eligible subtype; subjects must have ≥2 prior lines of therapy and must be ineligible for, or have declined, stem cell transplant, and chimeric antigen receptor T-cell (CAR-T) therapy; subjects must have an ECOG performance status score of 0 to 2; subjects must have a fluorodeoxyglucose-avid disease by PET and bidimensional measurable disease of at least 1.5 cm by CT, as assessed by the site radiologist. Subjects (n=400) will be randomized 1:1 to receive either brentuximab vedotin or placebo in combination with lenalidomide and rituximab and will be stratified by CD30 expression (positive [≥1%] versus &lt;1%), prior allogeneic or autologous stem cell transplant therapy (received or not), prior CAR-T therapy (received or not), and cell of origin (germinal-center B-cell-like (GCB) or non-GCB). Cell of origin (GCB or non-GCB) will be histologically determined by local pathology assessment. Disease response will be assessed by a blinded independent central review (BICR) and the investigator according to the Lugano Classification Revised Staging System. Radiographic disease evaluations, including contrast-enhanced CT scans and PET/CT, will be assessed at baseline, then every 6 weeks from randomization for 12 months, then every 12 weeks (±3 days). PET/CTs will be discontinued if negative. For the primary efficacy analyses of PFS per BICR in the intent-to-treat population and in CD30-positive subjects, the stratified log-rank test will be used to compare PFS between the 2 treatment groups. The hazard ratio will be estimated using a stratified Cox regression model. PFS will also be summarized using the Kaplan-Meier method. Similar methods will be used for the secondary efficacy endpoint of OS, and other time-to-event efficacy endpoints. The trial will have sites open in the US and multiple countries in Europe and Asia, with enrollment planning to begin in the second half of 2020. Disclosures Bartlett: Roche/Genentech: Consultancy, Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium: Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Seattle Genetics: Consultancy, Research Funding; Janssen: Research Funding; Kite, a Gilead Company: Research Funding; Merck: Research Funding; BTG: Consultancy; Acerta: Consultancy; Affimed Therapeutics: Research Funding; Immune Design: Research Funding; Forty Seven: Research Funding; BMS/Celgene: Research Funding; ADC Therapeutics: Consultancy; Autolus: Research Funding. Yasenchak:Takeda: Honoraria; BeiGene: Speakers Bureau; Seattle Genetics: Honoraria, Research Funding. Sims:Seattle Genetics, Inc.: Current Employment, Current equity holder in publicly-traded company, Other: Travel expenses. Nowakowski:Roche: Consultancy, Research Funding; Celgene/BMS: Consultancy, Research Funding; Kite: Consultancy; Denovo: Consultancy; Kymera: Consultancy; Ryvu: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other; Curis: Consultancy; Seattle Genetics: Consultancy; Nanostrings: Research Funding; MorphoSys: Consultancy, Research Funding.

Abstract Introduction: Type II Cryoglobulinemia (CG) is a heterogeneous disorder caused by a monoclonal antibody with activity against polyclonal antibodies. No standard therapy exists, but two small recent studies have suggested a role for rituximab. We describe our experience with 8 patients with Type II CG who were treated with Rituximab. Methods: The data was obtained from a prospectively held dysproteinemia database and by directly reviewing patient records. Follow up time ranged from 7 to 63 months. All patients had symptomatic disease with a monoclonal IgMκ Type II cryoglobulin and had undergone previous therapy for CG. Results: Six of the patients had an underlying lymphoproliferative disorder (LPD), with two of these also having hepatitis C, and two others having Sjogren syndrome. One patient had essential CG and one had Gaucher disease with hyperslpenism. A total of 14 courses of treatment were given, as some patients received rituximab on multiple occasions. Five patients received rituximab either alone or with low dose prednisone initially, with one of these later receiving rituximab with cyclophosphamide and prednisone. One patient was treated initially with R-CHOP and subsequently with rituximab alone, one received rituximab with chlorambucil and prednisone, and one received rituximab with plasma exchange and prednisone. The patients were treated for a variety of indications including cutaneous ulcers, progressive renal failure, the underlying LPD, and biochemical recurrence of disease. Six of 8 patients experienced an improvement in their clinical status. Of the two patients who did not improve, one had end stage liver disease at the time of rituximab and died 2 years later, and the other had a progressive chronic B cell lymphoproliferative disorder leading to sepsis and death. Though lab values were not available on one patient, 4 of the remaining 7 demonstrated improvement in cryocrit, total complement, C4, and/or rheumatoid factor. The lab values correlated well with the clinical response, as treatment failures showed no laboratory changes. Cutaneous manifestations including rash and ulceration were the most responsive to treatment. Renal disease generally failed to improve, and the response of LPDs were variable. No adverse events associated with rituximab were reported, including no flares of hepatitis. Conclusion: The high prevalence of LPD associated cryoglobulinemia distinguishes our results from the previous studies which had focused on patients with hepatitis C. Given the lack of any cryoglobulinemia specific therapy, and the potential toxicity of other immunosuppressive or anti viral therapies, rituximab remains a reasonable, safe, and effective therapeutic choice. Treatment Regimens and Responses Patient Comorbid Condition Symptom Regimen Response: Clinical/Lab LPD= lymphoproliferative disorder; HCV= Hepatitis C Virus; ESRD= End Stage Renal Disease; Y=Yes; N= No; U= Unknown 1 B Cell LPD Leg Ulcers Rituxan Prednisone Y/Y 1 Leg Ulcers Rituxan Prednisone Y/U 2 None Rash, Paresthesia Rituxan Prednisone Y/Y 2 Pupura Rituxan Prednisone Y/Y 2 Pupura Rituxan Prednisone Y/Y 2 Pupura Rituxan Prednisone Cytoxan Y/Y 3 HCV, low grade NHL Renal Failure Rituxan N/N 4 MALToma, Sjogren Disease MALToma R-CHOP Y/U 4 MALToma Rituxan N/U 5 Gaucher with hypersplenia Renal Failure Rituxan Y/Y 6 Lymphoplasmacytic Lymphoma, HCV, ESRD Lymphoma Rituxan Y/U 6 Lymphoma Rituxan N/N 7 B Cell LPD Renal Failure, ulcers, rash, LPD Rituxan chlorambucil prednisone N/N 8 MALToma Sjogren Disease Rash, Fatigue Rituxan Prednisone Y/Y

Abstract Intravascular lymphoma is a rare subtype of extranodal DLBCL characterized by the proliferation of malignant B-cells within the lumina of blood vessels. Organ involvement is variable and diffuse. Making the diagnosis can be challenging with symptoms persisting for months prior to definitive diagnosis. Treatment to date with standard anthracycline containing chemotherapy regimens has been disappointing with variable response rates, high relapse rates, and median survival times typically measured in months. We report diagnostic, treatment, and follow-up information regarding a group of patients with intravascular lymphoma evaluated at the Mayo Clinic with special attention to those receiving rituximab and/or high dose chemotherapy with or without peripheral blood autologous stem cell rescue. Methods: The medical records of patients with intravascular lymphoma seen at the Mayo Clinic between January 1970 and May 2005 were reviewed. Patients were included if they had evidence of intravascular lymphoma at the time of diagnosis of lymphoma. Pathologic specimens were reviewed for confirmation of diagnosis. Results: Twenty patients with a diagnosis of intravascular lymphoma were identified. Their median age was 66.5 years. Thirteen (65%) had B symptoms at the time of diagnosis and 13 had a performance status ≥ 3. Nine (45%) had an IPI ≥ 4. The median time to diagnosis from the onset of symptoms was 5.5 months. All had stage IV disease with biopsy proven involvement of at least one organ. The sites of disease involvement were CNS (10), marrow (7), lung (5), adrenal (3), kidney (2), lymph node, seminal vesicle, and skin (1). Two patients had involvement of three organs, six had involvement of two organs, and twelve had involvement of one organ. Nineteen patients received chemotherapy: ProMACE/CytaBOM (3), CHOP (6), RCHOP (6), DHAP (1), high dose methotrexate (1), methylprednisolone, nitrogen mustard, rituximab (1), and hyperCVAD (1). Three patients underwent peripheral blood autologous stem cell rescue after conditioning with BEAM. With a median follow-up of 60 months for all patients, the median overall survival was 8 months. No difference in outcome was seen with regard to site of organ involvement, number of organs involved, presence of B symptoms, or IPI. With a median follow-up for those receiving rituximab of 26 months, the median survival has not yet been reached while the median survival for those receiving non-rituximab containing regimens was 6.5 months. Similarly, with a median follow-up for those receiving high dose chemotherapy (hyperCVAD or BEAM) of 9.3 months, the median survival has not yet been reached while the median survival for those not receiving high dose therapy was 7 months. Conclusion: Intravascular lymphoma is a unique and aggressive subtype of DLBCL. The clinical presentation and sites of organ involvement are variable and the time from onset of symptoms to diagnosis can be prolonged. Standard chemotherapeutic treatment leads to poor outcomes. However, survival may be improved upon with newer strategies such as the use of rituximab and/or high dose chemotherapy with or without peripheral blood autologous stem cell rescue.

Abstract Introduction DLBCL is the most common lymphoid neoplasm in adults (Swerdlow 2016). While durable CRs are achieved in approximately 70% of patients (pts) with frontline RCHOP therapy (Pfreundschuh 2008), pts with high-risk features often experience disease resistance or relapse. In Part 1 of an ongoing study, pts with high-intermediate or high risk DLBCL by international prognostic index (IPI) scores, regardless of CD30 expression by IHC, were treated with 1.2 or 1.8 mg/kg brentuximab vedotin (BV) combined with RCHOP. After 3 of the first 10 pts treated at 1.8 mg/kg BV+RCHOP developed Grade 3 peripheral neuropathy (per Standardized MedDRA Query [SMQ]), all pts enrolled subsequently received treatment with 1.2 mg/kg BV+RCHOP. Following completion of enrollment in Part 1, the protocol was amended to enroll a non-randomized portion of the study (Part 2) evaluating the safety and efficacy of 1.8 mg/kg BV+RCHP (Yasenchak 2015), followed by an open-label, randomized portion comparing BV+RCHP to RCHOP (Part 3). Initial results from Part 2 and updated results from Part 1 are reported here. Methods For Part 2 of the study, pts with CD30-expressing high-intermediate and high-risk DLBCL were treated with up to 6 cycles of 1.8 mg/kg BV+RCHP (NCT01925612). Key inclusion criteria were CD30 expression by IHC performed by a local pathology lab and standard IPI scores of 3-5 or age-adjusted IPI (aaIPI) scores of 2-3 (high-intermediate/high risk). CD30 expression was confirmed by a central pathology lab, although CD30 expression by local pathology lab was required for eligibility. Disease response was evaluated with PET/CT per Cheson 2007. Results At the time of analysis for this ongoing study, 11 pts in Part 2 were treated with BV+RCHP (7 male, 4 female; 22-78 yrs). Of these pts, 9 had high-intermediate risk (IPI 3, aaIPI 2) and 2 had high risk disease (IPI 4-5, aaIPI 3), 6 had Stage IV disease, and 6 had an ECOG score of 2. At the end of treatment, the overall response rate was 91% (9 CR, 1 PR); 1 pt had PD after Cycle 4. The most frequent (>20%) treatment-emergent adverse events (AEs) were alopecia and nausea (73% each); fatigue (64%); constipation and peripheral sensory neuropathy (55% each); neutropenia and throat irritation (36% each); and chills, diarrhea, headache, and stomatitis (27% each). Grade 3 or 4 AEs occurred in 8 pts and 5 pts had serious AEs, which included febrile neutropenia, bacteremia, nausea, pneumocystis jiroveci pneumonia, pulmonary embolism, and vomiting. Peripheral sensory neuropathy occurred in 6 pts and all were Grade 1 or 2 events; no peripheral motor neuropathy AEs were reported. No AEs were fatal or led to discontinuation. One pt discontinued treatment after Cycle 4 due to disease progression. For the first 51 pts in Part 1, the progression-free survival (PFS) at 18 months for pts with CD30 expression (25 pts) or without detectable CD30 expression (24 pts) by IHC was 79% (95% CI: 57%, 91%) versus 58% (95% CI: 36%, 75%), respectively. Overall survival for pts was 92% (95% CI: 71%, 98%) versus 71% (95% CI: 48%, 85%), respectively. Ten pts had pre-existing peripheral neuropathy (per SMQ) at study entry. Treatment-emergent peripheral neuropathy (per SMQ) was observed in 75% of pts (38/51) who received BV+RCHOP; 55% of these pts (21/38) had resolution of all or some peripheral neuropathy events. Conclusions 1.8 mg/kg BV+RCHP is active as frontline treatment in CD30-expressing, high-intermediate/high risk DLBCL. When combined with RCHP, 1.8 mg/kg BV appears to be well-tolerated. The PFS and OS for pts with CD30-expression who received BV+RCHOP appear promising. The study is currently ongoing in pts with CD30-expressing high-intermediate/high risk DLBCL to assess the safety and activity of 1.8 mg/kg BV+RCHP versus standard RCHOP. Disclosures Halwani: Bristol Myers-Squibb: Research Funding; Kyowa Hakko Kirin: Research Funding; Takeda: Research Funding; Genentech: Research Funding; AbbVie: Consultancy, Other: Travel Expenses, Research Funding; Seattle Genetics: Consultancy, Research Funding; Immune Design: Research Funding; Miragen: Research Funding; Pharmacyclics: Consultancy; Amgen: Research Funding. Yasenchak:Seattle Genetics: Research Funding. Farber:Seattle Genetics: Research Funding. Burke:Pfizer: Consultancy; Janssen: Consultancy; Incyte: Consultancy; TG Therapeutics: Other: Travel Expenses; Millenium: Consultancy. Fayad:Seattle Genetics: Consultancy, Research Funding. Holkova:Seattle Genetics: Research Funding. Knapp:Insys Therapeutics, Inc.: Consultancy, Other: Travel, Accommodations, Expenses; Pharmacyclics, LLC, an AbbVie Company: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding. Kolibaba:Gilead: Consultancy, Research Funding; Celgene: Research Funding; TG Therapeutics: Research Funding; Takeda Pharmaceuticals International Co.: Research Funding; Seattle Genetics: Research Funding; Pharmacyclics: Research Funding; janssen: Research Funding; GSK: Research Funding; Genentech: Research Funding; Acerta: Research Funding. Patel-Donnelly:Seattle Genetics: Research Funding. Yimer:Ariad Pharmaceuticals: Consultancy; Biotheranostics: Consultancy; Bluebird Bio: Equity Ownership; Kite Pharma: Equity Ownership; Clovis Oncology: Equity Ownership; Juno Therpeutics: Equity Ownership; Seattle Genetics: Research Funding. Smith:Celgene: Consultancy, Speakers Bureau; Seattle Genetics: Research Funding. Levy:Janssen: Speakers Bureau; Amgen: Speakers Bureau; Takeda Pharmaceuticals International Co.: Speakers Bureau; Seattle Genetics: Research Funding; Actinium Pharmaceuticals, Inc.: Research Funding. Seetharam:Seattle Genetics: Research Funding. Belada:Seattle Genetics: Research Funding. Brooks:Seattle Genetics: Research Funding. Kingsley:Gilead: Equity Ownership; Pharmacyclics LLC, an AbbVie Company: Equity Ownership. Wagner-Johnston:Seattle Genetics: Research Funding. Ruffner:Forma Therapeutics: Consultancy; Sydnax: Consultancy; Seattle Genetics: Employment, Equity Ownership; Array Biopharma: Employment; Medivation: Employment. Bartlett:Gilead: Consultancy.

Abstract Introduction RCHOP is the standard frontline treatment for patients with DLBCL. However, for patients with high-intermediate or high-risk disease (IPI 3-5), outcomes are suboptimal, with an estimated 3-year PFS of about 55%. In addition to IPI, an additional factor associated with an increased risk include non-GCB cell of origin. Brentuximab vedotin, an ADC targeting CD30, has demonstrated single-agent activity in relapsed/refractory DLBCL patients. Of note, higher ORR and CR, as well as longer duration of PFS, were observed in those patients with CD30 detected on tumor cells by routine IHC. Methods This phase 2 study was designed to evaluate combination therapy using brentuximab vedotin (BV) and standard RCHOP chemotherapy as frontline treatment in patients with high-intermediate/high risk (standard IPI score 3-5 or age-adjusted IPI [aaIPI] score 2-3) DLBCL, regardless of CD30 expression (ClinicalTrials.gov NCT01925612). Patients were randomized to receive either 1.2 mg/kg BV+RCHOP or 1.8 mg/kg BV+RCHOP for up to 6 cycles of treatment. BV was given on Day 1 of every 21-day cycle. Response was assessed per investigator using Cheson 2007. AEs, physical examination findings, and laboratory testing were utilized to characterize safety. Tumor cell CD30 expression was measured by IHC and gene expression analysis; soluble CD30 was measured in plasma. Tumor microenvironment was also evaluated for frequency of immune-infiltrating cells. The primary endpoints for this study were the tolerability of each regimen and the CR rate at the end of treatment (EOT). Key secondary endpoints included progression-free survival (PFS). Additional exploratory endpoints included CD30 expression on tumor specimens (CD30- defined as <1% per IHC) and correlation of CD30 expression and response. Results Twenty-nine patients were treated with 1.2 mg/kg BV+RCHOP and 22 patients were treated with 1.8 mg/kg BV+RCHOP. Over half (63%) were high-intermediate risk (IPI 3, aaIPI 2) and 37% were high risk (IPI 4-5, aaIPI 3). Most had Stage IV disease (71%) and 27% had an ECOG score of 2. AEs in ≥50% of patients included peripheral sensory neuropathy (63%), fatigue (61%), nausea (55%), and diarrhea (53%). Grade 3 or higher events occurred in 76% of patients; the most frequent were neutropenia (33%) and febrile neutropenia (31%). The PET-negative CR rate was 69% overall; CD30+ patients had a CR rate of 76% (19/25) compared with 63% (12/19) in CD30- patients by IHC. Although PFS data are still immature (median follow up of 8 months), the estimated PFS rate at 12 months was 82% (95% CI: 58, 93) in CD30+ patients and 56% (95% CI: 32, 75) in CD30- patients. 60% (3/5) of patients with CD30- ABC-DLBCL progressed versus 27% (3/11) of CD30+ ABC-DLBCL patients. Four patients with EBV+ DLBCL were treated and all achieved CR; 3 EBV+ patients remain in remission after a median follow-up of 12 months. Within the microenvironment, a higher percentage of CD3+ T-cells was observed in patients with CR (23%; range, 4-80%) than in those with PR (14%; range, 10-15%) or PD (11%; range, 5-15%). Of the 32 patients who have not yet progressed, 50% had ≥20% CD3+ cells compared to 18% of patients with PD (2/11). Other factors, including soluble CD30 levels and infiltrating CD68+ cells, were not associated with clinical outcomes. Conclusions Interim results demonstrate that adding BV to RCHOP results in a high rate of CR in this population of IPI 3-5 DLBCL. Patients with CD30-expression in the tumor appear to have a higher CR rate and fewer early progression events than patients with CD30- DLBCL. Furthermore, subsets of patients who have a particularly poor prognosis (CD30+ ABC subtype and EBV+ DLBCL) appeared to have a favorable outcome with BV+RCHOP. Evaluation of the tumor microenvironment showed that higher frequencies of infiltrating CD3+ cells were observed in the CR group, suggesting possible immunologic correlates of response. However, CD30 expression appears to have greater prognostic significance in this study despite the relatively small sample size. These results are intriguing and merit further testing in a randomized trial. Disclosures Yasenchak: Seattle Genetics, Inc.: Research Funding. Off Label Use: Brentuximab vedotin is indicated in the US for treatment of patients with Hodgkin lymphoma after failure of autologous stem cell transplant or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not ASCT candidates and for the treatment of patients with systemic anaplastic large cell lymphoma after failure of at least one prior multi-agent chemotherapy regimen. The drug is being evaluated in this study for use as frontline treatment in patients with high-intermediate/high risk DLBCL in combination with multiagent chemotherapy. . Halwani:Abbvie: Research Funding; Pharmacyclics: Other: Travel expenses, Research Funding; Takeda/Millenium: Research Funding; BMS: Research Funding; Seattle Genetics, Inc.: Other: Travel expenses, Research Funding; Roche/Genentech: Research Funding; Kyowa Hakko Kirin: Research Funding; Amgen: Research Funding. Advani:Seattle Genetics, Inc.: Research Funding; Genetech: Consultancy. Ansell:Bristol-Myers Squibb: Research Funding; Celldex: Research Funding. Budde:Merck: Research Funding; Ikara Inc: Patents & Royalties; Atara Biotherapeutics: Consultancy; Seattle Genetics, Inc.: Research Funding. Burke:Millenium/Takeda: Consultancy; Incyte: Consultancy; TG Therapeutics: Other: Travel expenses; Gilead: Consultancy; Janssen: Consultancy; Seattle Genetics, Inc.: Research Funding. Farber:Seattle Genetics, Inc.: Research Funding. Holkova:Seattle Genetics, Inc.: Research Funding. Kolibaba:GSK: Research Funding; Seattle Genetics, Inc.: Research Funding; Acerta: Research Funding; Celgene: Research Funding; Gilead: Consultancy, Research Funding; Takeda Pharmaceuticals International Co.: Research Funding; Genentech: Research Funding; Pharmacyclics: Research Funding; Janssen: Research Funding; TG Therapeutics: Research Funding. Knapp:Celgene: Research Funding; Heron Pharmaceuticals: Other: Travel expenses, Research Funding; Merck: Research Funding; Seattle Genetics, Inc.: Research Funding; Takeda Pharmaceuticals International Co.: Research Funding; Brystol-Myers Squibb: Research Funding; Genentech: Honoraria, Other: Travel expenses, Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; EMD Serono: Research Funding. Li:Seattle Genetics, Inc.: Employment, Equity Ownership. Manley:Seattle Genetics, Inc.: Employment, Equity Ownership. Patel-Donnelly:Seattle Genetics, Inc.: Research Funding. Seetharam:Seattle Genetics, Inc.: Research Funding. Yimer:Seattle Genetics, Inc.: Research Funding. Bartlett:Gilead: Consultancy, Research Funding; Janssen: Research Funding; Pharmacyclics: Research Funding; Genentech: Research Funding; Pfizer: Research Funding; Novartis: Research Funding; Millennium: Research Funding; Colgene: Research Funding; Medimmune: Research Funding; Kite: Research Funding; Insight: Research Funding; Seattle Genetics: Consultancy, Research Funding; MERC: Research Funding; Dynavax: Research Funding; Idera: Research Funding; Portola: Research Funding; Bristol Meyers Squibb: Research Funding; Infinity: Research Funding; LAM Theapeutics: Research Funding.

Abstract Background: Absolute lymphocyte count (ALC) recovery is an independent prognostic factor for survival for different hematological malignancies treated with autologous stem cell transplantation. Recently, we reported superior overall survival (OS) in patients with follicular lymphomas that presented with a higher ALC (ALC ≥ 1 x 109/L) at diagnosis. The role of ALC at diagnosis on survival in T cell lymphomas is not known. Methods: All patients evaluated at the Mayo Clinic for T cell lymphomas from October 1984 until April 2005 were analyzed in the study. The primary objective of the study was to assess the role of ALC at diagnosis and survival in T cell lymphomas. ALC at diagnosis was obtained from the standard complete blood cell count (CBC). Results: 223 patients with T cell lymphomas were included in the study. The histology included: peripheral T-cell lymphoma-unspecified (40%), anaplastic large cell (13%), angioimmunoblastic (10%), angiocentric (4%), intestinal T-cell (2%), and other (31%). The median follow-up was 18.6 months (range: 1 month – 229 months [19 years]). The sample population included 60% male and 40% females with a median age of 60 years (15–90 years). The median ALC at diagnosis was 1.2 x 109/L (range: 0.04–6.7 x 109/L). ALC as a continuous variable was identified as predictor for OS in the univariate analysis (HR= 0.690, 95%CI: 0.542–0.862, p < 0.0006). ALC ≥ 1 x 109/L was selected as the dichotomized value because it yielded the maximum difference in survival by c2 analysis looking at different cut-point from 0.6 to 1.7 x 109/L that were included between the 25% and 75% quartiles. Univariately, ALC ≥ 1 x 109/L was also identified as a predictor for OS (HR = 0.682, 95%CL= 0.578–0.804, p < 0.0001). Patients (N = 122) with an ALC ≥ 1 x 109/L experienced superior survival compared to patients (N = 101) with an ALC < 1 x 109/L [median OS: 76.3 vs 10.6 months, respectively; and 5 years OS estimates of 53% vs 23%, respectively, p < 0.0001]. When ALC ≥ 1 x 109/L was compared to the international prognostic index (IPI), ALC ≥ 1 x 109/L remained an independent predictor for survival in the multivariate analysis (HR = 0.779, 95%CL: 0.655–0.925, p < 0.004). Conclusion: This study demonstrates ALC as an independent predictor for OS in T cell lymphomas, suggesting that the host immune system affects survival in this group of patients.

Abstract Background Outcomes for patients with DLBCL have improved over the past decade, with the addition of rituximab to CHOP or CHOP-like multi-agent chemotherapy regimens improving the 3-year overall survival (OS) of patients by 10-16% compared to multi-agent chemotherapy alone (Coiffier 2002; Pfreundschuh 2010). However, patients with high-intermediate or high-risk disease have relatively poor outcomes with the standard RCHOP regimen (Ziepert 2010); in a recent prospective trial of intermediate- and high-risk DLBCL patients, complete response (CR) rate for RCHOP alone was 26% (Hainsworth 2011). Brentuximab vedotin (ADCETRIS®) is an antibody-drug conjugate comprising the antibody cAC10, specific for human CD30, covalently attached to the microtubule-disrupting agent monomethyl auristatin E (MMAE) via a protease-cleavable linker. Brentuximab vedotin has demonstrated compelling activity as a single agent in patients with relapsed or refractory DLBCL, even those with low CD30 expression (Bartlett 2013). This phase 2, randomized, open label study is designed to evaluate the antitumor activity and safety of brentuximab vedotin (1.2 or 1.8 mg/kg) when administered in combination with standard RCHOP chemotherapy (A+RCHOP) for the front-line treatment of patients with CD30-unselected high-intermediate/high-risk (standard IPI score 3–5 or age-adjusted IPI [aaIPI] score 2–3) DLBCL (ClinicalTrials.gov NCT01925612). Methods Patients were randomized to receive up to 6 cycles of either 1.2 or 1.8 mg/kg brentuximab vedotin administered IV on Day 1 of every 21-day cycle in combination with RCHOP; prednisone was administered orally on Days 1-5 of every 21-day cycle. Assessments included disease response per Cheson 2007, as evaluated by the investigator, surveillance of adverse events (AEs), physical examination findings, and laboratory testing. The primary endpoints for this study are the CR rate at the end of treatment (EOT) and the type, incidence, and severity of AEs. Key secondary endpoints include objective response rate (ORR), progression-free survival (PFS), and OS. Results At the time of the planned interim analysis, 33 patients were enrolled (17 patients, 1.2 mg/kg A+RCHOP; 16 patients, 1.8 mg/kg A+RCHOP). Median age for all patients was 66 years (range, 21 to 81). At baseline, 36% were high-risk (IPI 4-5, aaIPI 3) and 64% were high-intermediate risk (IPI 3, aaIPI 2). The majority of patients (73%) had Stage IV disease and 33% had an ECOG status of 2. At the time of interim analysis, a total of 12 patients (6 patients in each arm) had completed EOT. Across both dose levels, ORR was 92% (11/12), with 7 CRs (58%), 4 PRs (33%), and 1 PD. The patient with PD subsequently died. Patients with PR had a median reduction of baseline tumor size of 84% (range, 92% to 83%), as measured by SPD. The only patient with follow-up after EOT converted from PR to CR without subsequent therapy. Treatment-emergent AEs occurring in ≥30% of patients treated (26/33) were nausea, diarrhea, peripheral sensory neuropathy, fatigue, and decreased appetite. Grade 3 or higher events occurring in more than 2 patients were febrile neutropenia and neutropenia. Events of peripheral neuropathy occurred equally per arm (46%, 1.2 mg/kg A+RCHOP; 46% 1.8 mg/kg A+RCHOP) and were generally Grade 1 or 2 (15% and 23%, respectively); events were of similar grade across dose levels. The median time to onset of any grade of peripheral neuropathy was 6 weeks (range, 2 to 10 weeks). Five patients (19%) had dose reductions due to peripheral neuropathy and 3 patients (12%) had dose reductions due to febrile neutropenia. One patient who received 1.2 mg/kg A+RCHOP discontinued study drug due to an AE (thrombocytopenia). Conclusions At doses of 1.2 or 1.8 mg/kg, A+RCHOP exhibited manageable toxicity in the treatment of newly-diagnosed DLBCL; the incidence of peripheral neuropathy was similar to single-agent administration of brentuximab vedotin (Pro 2012, Younes 2012) and RCHOP alone (Rummel 2013, Flinn 2014). In 12 patients with response-assessable, high-intermediate and high-risk DLBCL, A+RCHOP showed encouraging antitumor activity, with an ORR of 92% and a CR rate of 58%. Disclosures Yasenchak: Seattle Genetics, Inc.: Research Funding. Off Label Use: Brentuximab vedotin is indicated in the US for treatment of patients with Hodgkin lymphoma after failure of autologous stem cell transplant or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not ASCT candidates and for the treatment of patients with systemic anaplastic large cell lymphoma after failure of at least one prior multi-agent chemotherapy regimen. . Farber:Seattle Genetics, Inc.: Research Funding. Budde:Seattle Genetics, Inc.: Research Funding. Ansell:Seattle Genetics, Inc.: Research Funding. Advani:Takeda Pharmaceuticals International Co.: Research Funding; Celgene: Research Funding; Pharmacyclics: Research Funding; Jansseen Pharmaceuticals: Research Funding; Genentech: Research Funding; Seattle Genetics, Inc.: Research Funding, Travel expenses Other. Holkova:Seattle Genetics, Inc.: Research Funding. Halwani:Seattle Genetics, Inc.: Research Funding. Knapp:Takeda Pharmaceuticals International Co.: Research Funding; EMD Serono: Research Funding; Bristol Myers Squibb: Research Funding; Celgene: Research Funding; Merck: Research Funding; Heron Pharmaceuticals: Research Funding, Travel expenses, Travel expenses Other; Genentech: Research Funding, Travel expenses, Travel expenses Other; Seattle Genetics, Inc.: Research Funding; Pharmacyclics: Research Funding. Fayad:Seattle Genetics, Inc.: Consultancy, Research Funding. Kolibaba:Genentech: Research Funding; Takeda Pharmaceuticals International Co.: Research Funding; Seattle Genetics, Inc.: Research Funding. Patel-Donnelly:Seattle Genetics, Inc.: Research Funding. Seetharam:Seattle Genetics, Inc.: Research Funding. Manley:Seattle Genetics, Inc.: Employment, Equity Ownership. Bartlett:Genentech: Research Funding; ImaginAb: Research Funding; Celgene: Research Funding; MedImmune: Research Funding; Novartis: Research Funding; Pharmacyclics: Research Funding; Pfizer: Research Funding; Takeda Pharmaceuticals International Co.: Research Funding; Seattle Genetics, Inc.: Research Funding, Travel expenses Other; Janssen: Research Funding; Astra Zeneca: Research Funding.