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This cohort study of data from 39 patients assesses whether the presence of a dominant T-cell receptor clone in peripheral blood is associated with time to systemic treatment in patients with stage IB mycosis fungoides.

Table S1, S2, S3, S4 Fig. S1, S2

Purpose:The histone deacetylase (HDAC) inhibitor romidepsin and the anthracycline liposomal doxorubicin (LD) have modest single-agent activity in cutaneous T-cell lymphoma (CTCL) and peripheral T-cell lymphoma (PTCL). We investigated the safety and efficacy of the combination of these two agents in CTCL and PTCL.Patients and Methods:Using CTCL cell lines and primary CTCL tumor cells, we demonstrated synergistic antitumor activity with romidepsin plus doxorubicin. We then conducted a phase I dose-escalation study of the romidepsin/LD combination in relapsed/refractory CTCL and PTCL. The primary objective was to determine the MTD of romidepsin in combination with LD at 20 mg/m2 i.v., once every 28 days.Results:Eleven patients with CTCL and 12 patients with PTCL were treated. The MTD of romidepsin was determined to be 12 mg/m2. Grade 3/4 hematologic toxicities included thrombocytopenia (17%), anemia (13%), and neutropenia (9%). The most frequent treatment-related nonhematologic adverse events were fatigue (48%), nausea (48%), vomiting (35%), and anorexia (30%). Among 21 evaluable patients, the overall response rate was 70% [1 complete response (CR), 6 partial responses (PR)] in CTCL and 27% (3 CR, 0 PR) in PTCL. Of the patients with CTCL, 8 of 10 had skin response, including 6 patients (60%) achieving skin involvement less than 10% of their body surface area at time of best response.Conclusions:Romidepsin plus LD demonstrated an acceptable safety profile and promising clinical efficacy with deep skin responses in relapsed/refractory CTCL. Thus, this combination could be considered as a bridge to skin-directed treatment or allogeneic hematopoietic cell transplantation in patients with aggressive CTCL.

Hodgkin lymphoma (HL) is an uncommon malignancy of B-cell origin. Classical HL (cHL) and nodular lymphocyte–predominant HL are the 2 main types of HL. The cure rates for HL have increased so markedly with the advent of modern treatment options that overriding treatment considerations often relate to long-term toxicity. These NCCN Guidelines Insights discuss the recent updates to the NCCN Guidelines for HL focusing on (1) radiation therapy dose constraints in the management of patients with HL, and (2) the management of advanced-stage and relapsed or refractory cHL.

Peripheral T-cell lymphomas (PTCLs) are a heterogeneous group of lymphoproliferative disorders arising from mature T cells, accounting for about 10% of non-Hodgkin lymphomas. PTCL-not otherwise specified is the most common subtype, followed by angioimmunoblastic T-cell lymphoma, anaplastic large cell lymphoma, anaplastic lymphoma kinase–positive, anaplastic large cell lymphoma, anaplastic lymphoma kinase–negative, and enteropathy-associated T-cell lymphoma. This discussion section focuses on the diagnosis and treatment of PTCLs as outlined in the NCCN Guidelines for T-Cell Lymphomas.

Clinical Practice Points • Aggressive NK-cell leukemia/lymphoma (ANKL) is a rare natural killer (NK)-cell malignancy, and although it typically presents as rapidly progressive disease, cases may present more indolently, progressing over months rather than weeks. • Unlike the more common extranodal NK-cell leukemia/lymphoma, ANKL may not involve the nasopharynx and can be Epstein-Barr virus (EBV) negative. • Diagnosing ANKL can be challenging. Although not yet standard of care, next-generation sequencing and digital image analysis can be used to clarify this rare diagnosis and confirm EBV negativity. • Treatment of ANKL utilizes asparaginase-based regimens, unlike the anthracycline-based regimens used in peripheral T-cell lymphomas or myeloid disorders. Ensuring the correct diagnosis is crucial in determining the appropriate treatment regimen for this uncommon disease.

The number of patients with primary cutaneous lymphoma (PCL) relative to other non-Hodgkin lymphomas (NHLs) is small and the number of subtypes large. Although clinical trial guidelines have been published for mycosis fungoides/Sézary syndrome, the most common type of PCL, none exist for the other PCLs. In addition, staging of the PCLs has been evolving based on new data on potential prognostic factors, diagnosis, and assessment methods of both skin and extracutaneous disease and a desire to align the latter with the Lugano guidelines for all NHLs. The International Society for Cutaneous Lymphomas (ISCL), the United States Cutaneous LymphomaConsortium (USCLC), and the Cutaneous Lymphoma Task Force of the European Organization for the Research and Treatment of Cancer (EORTC) now propose updated staging and guidelines for the study design, assessment, endpoints, and response criteria in clinical trials for all the PCLs in alignment with that of the Lugano guidelines. These recommendations provide standardized methodology that should facilitate planning and regulatory approval of new treatments for these lymphomas worldwide, encourage cooperative investigator-initiated trials, and help to assess the comparative efficacy of therapeutic agents tested across sites and studies.

Context.— Evidence of T-cell clonality is often critical in supporting a T-cell lymphoma. Objectives.— To retrospectively explore the significance of copy number losses at the 14q11.2 T-cell receptor α locus in relation to the presence of a T-cell neoplasm and proportion of T cells by targeted next-generation sequencing. Design.— Targeted next-generation sequencing data from 139 tissue biopsies including T-cell lymphomas, B-cell lymphomas, classic Hodgkin lymphomas, nonhematopoietic malignancies, and normal samples were reviewed for copy number losses involving the T-cell receptor α gene segments at chr14q11.2. Results.— We found that biallelic or homozygous deletion of 14q11.2 was found in most (28 of 33, 84.8%) T-cell lymphomas. The magnitude of 14q11.2 loss showed a statistically significant correlation with the proportion of T cells in lymphoma tissue samples. Copy number losses could also be detected in other lymphomas with high number of T cells (8 of 32, 25% of B-cell lymphomas, 4 of 4 classical Hodgkin lymphomas), though biallelic/homozygous deletion of 14q11.2 was not significantly observed outside of T-cell lymphomas. Most nonhematopoietic neoplasms and normal tissues (59 of 64, 92.2%) showed no significant copy number losses involving the T-cell receptor α locus at chr14q11.2. Conclusions.— Analysis of copy number losses at the T-cell receptor α locus chr14q11.2 with targeted next-generation sequencing can potentially be used to estimate the proportion of T cells and detect T-cell neoplasms.

CD70 is a member of the tumor necrosis factor receptor superfamily. Emerging data indicate that CD70 may be a suitable target for various malignancies. We investigated the expression of CD70 in cutaneous and systemic T-cell lymphomas and conducted preclinical studies of SGN-CD70A, a CD70-directed antibody-drug conjugate (ADC), using patient-derived xenograft cutaneous T-cell lymphoma (CTCL PDX) models. CD70 expression was examined by immunohistochemical (IHC) stains in 49 diagnostic specimens of T-cell lymphomas. The activities of SGN-CD70A in growth inhibition and apoptosis induction were examined in CTCL cell lines and primary CTCL tumor cells. Using previously established CTCL PDXs, we conducted a dose-finding trial followed by a phase 2-like trial to evaluate the optimal dosing and the efficacy of SGN-CD70A in tumor-bearing PDX animals. The therapeutic efficacy of SGN-CD70A was measured by tumor-associated cell-free DNA (cfDNA) and survival of treated PDXs. We found that CD70 is highly expressed in T-cell lymphomas, especially in CTCL. SGN-CD70A inhibited cell growth and induced apoptosis in CD70-expressing CTCL cell lines and primary tumors cells. Additionally, SGN-CD70A at 100 μg/kg and 300 μg/kg prolonged the survival of PDXs in a dose-dependent manner. Finally, treatment with 3 doses of SGN-CD70A at 300 μg/kg was superior to a single-dose treatment in survival prolongation (median survival: 111 days vs 39 days; P = .017). Most importantly, multiple dosing of SGN-CD70A induced complete eradication of established tumors in PDXs measured by cfDNA. Our results demonstrated marked antitumor activity of SGN-CD70A in CTCL PDXs, providing compelling support for its clinical investigation.

Hepatosplenic T-cell lymphoma (HSTCL) is a rare subtype of T-cell lymphoma associated with an aggressive clinical course and a worse prognosis. HSTCL develops in the setting of chronic immune suppression or immune dysregulation in up to 20% of cases and is most often characterized by spleen, liver, and bone marrow involvement. Diagnosis and management of HSTCL pose significant challenges given the rarity of the disease along with the absence of lymphadenopathy and poor outcome with conventional chemotherapy regimens. These Guidelines Insights focus on the diagnosis and treatment of HSTCL as outlined in the NCCN Guidelines for T-Cell Lymphomas.

The NCCN Clinical Practice Guidelines in Oncology for Hodgkin Lymphoma (HL) provide recommendations for the management of adult patients with HL. The NCCN panel meets at least annually to review comments from reviewers within their institutions, examine relevant data, and reevaluate and update their recommendations. Current management of classic HL involves initial treatment with chemotherapy alone or combined modality therapy followed by restaging with PET/CT to assess treatment response. Overall, the introduction of less toxic and more effective regimens has significantly advanced HL cure rates. This portion of the NCCN Guidelines focuses on the management of classic HL.

Mycosis fungoides (MF) is the most common subtype of cutaneous T-cell lymphoma (CTCL), and Sézary syndrome (SS) is a rare erythrodermic and leukemic subtype of CTCL characterized by significant blood involvement. Although early-stage disease can be effectively treated predominantly with skin-directed therapies, systemic therapy is often necessary for the treatment of advanced-stage disease. Systemic therapy options have evolved in recent years with the approval of novel agents such as romidepsin, brentuximab vedotin, and mogamulizumab. These NCCN Guidelines Insights discuss the diagnosis and management of MF and SS (with a focus on systemic therapy).

Purpose: The histone deacetylase (HDAC) inhibitor romidepsin and the anthracycline liposomal doxorubicin (LD) have modest single-agent activity in cutaneous T-cell lymphoma (CTCL) and peripheral T-cell lymphoma (PTCL). We investigated the safety and efficacy of the combination of these two agents in CTCL and PTCL. Patients and Methods: Using CTCL cell lines and primary CTCL tumor cells, we demonstrated synergistic antitumor activity with romidepsin plus doxorubicin. We then conducted a phase I dose-escalation study of the romidepsin/LD combination in relapsed/refractory CTCL and PTCL. The primary objective was to determine the MTD of romidepsin in combination with LD at 20 mg/m2 i.v., once every 28 days. Results: Eleven patients with CTCL and 12 patients with PTCL were treated. The MTD of romidepsin was determined to be 12 mg/m2. Grade 3/4 hematologic toxicities included thrombocytopenia (17%), anemia (13%), and neutropenia (9%). The most frequent treatment-related nonhematologic adverse events were fatigue (48%), nausea (48%), vomiting (35%), and anorexia (30%). Among 21 evaluable patients, the overall response rate was 70% [1 complete response (CR), 6 partial responses (PR)] in CTCL and 27% (3 CR, 0 PR) in PTCL. Of the patients with CTCL, 8 of 10 had skin response, including 6 patients (60%) achieving skin involvement less than 10% of their body surface area at time of best response. Conclusions: Romidepsin plus LD demonstrated an acceptable safety profile and promising clinical efficacy with deep skin responses in relapsed/refractory CTCL. Thus, this combination could be considered as a bridge to skin-directed treatment or allogeneic hematopoietic cell transplantation in patients with aggressive CTCL.

Background Anti-CD19 chimeric antigen receptor (CAR) T-cell therapy leads to high overall response rates of ∼80% even in heavily pre-treated diffuse large B-cell lymphoma (DLBCL), though relapse-free survival drops to ∼40% within the first 12 months. There are early data suggesting that inhibiting the programmed cell death protein 1: programmed cell death ligand 1 (PD-1: PD-L1) checkpoint axis may decrease T cell exhaustion and improve CAR T-cell function. However, there is limited data regarding the toxicity of sequencing these two modalities. This case series of three patients with relapsed/refractory DLBCL treated sequentially with CAR T and checkpoint inhibitor explores the immune-related adverse events (irAEs) with this approach. Case Presentation Case 1 is a 47-year-old male with refractory T-cell/Histiocyte-Rich Large B-Cell Lymphoma who was treated initially with pembrolizumab followed by CAR T-cell therapy and developed autoimmune thyroiditis. Case 2 is a 67-year-old male with refractory DLBCL who was treated with CAR T and subsequently pembrolizumab and developed pneumonitis and respiratory failure. Case 3 is a 22-year-old female with primary refractory mediastinal DLBCL who was treated with pembrolizumab following CAR T therapy and subsequently developed a T-cell mediated autoimmune skin reaction. Conclusions T cell exhaustion has been suspected to contribute to poor persistence of CAR T-cells and clinical relapse, which may be overcome by checkpoint inhibition. While the synergy between CAR T-cell therapy and checkpoint inhibition is promising, the interaction may also lead to off-target irAEs. Prospective trials exploring the safety and efficacy of this combination in relapsed/refractory DLBCL are under way.

Previously considered a subtype of diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBCL) is now recognized by the World Health Organization as an independent entity. PMBCL has clinicopathologic features that are separate from systemic DLBCL and harbors some biologic characteristics which overlap with nodular sclerosing classic Hodgkin’s lymphoma (cHL). Similar to cHL, copy number alterations of 9p24.1 are frequently seen in PMBCL, which leads to increased expression of key genes in the region, including programmed death-ligand 1( PD-L1), PD-L2, and JAK2. In addition, PMBCL cells express CD30 in a mostly patchy fashion. In the upfront setting, dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (i.e., DA-EPOCH-R) is the only regimen that has been shown in a prospective setting to result in outstanding outcomes without consolidative radiation to the mediastinum, with a 5-year event-free survival rate of 93% and overall survival rate of 97%. Thus, in recent years, DA-EPOCH-R has been recognized as the preferred frontline regimen. Despite the encouraging results in the frontline setting, the outcomes in the relapsed/refractory setting remain poor. The current approach of salvage chemotherapy followed by autologous stem cell transplantation, as used in patients with DLBCL, does not result in high rates of cure in patients with rrPMBCL. In recent years, the characteristic molecular features identified in PMBCL have provided more treatment opportunities for this patient population. In the relapsed setting, single-agent PD-1 inhibitor pembrolizumab have demonstrated high and durable remission rates. Despite the expression of CD30, the CD30 antibody drug-conjugate brentuximab vedotin (BV) as a single agent has been deemed inactive in this disease. On the contrary, the combinations of BV and PD-1 inhibitor have shown higher response rates than PD-1 inhibitor alone. Moreover, anti-CD19 chimeric antigen receptor T-cell (CAR T-cell) therapy has been positioned as another successful strategy for patients with rrPMBCL. Axicabtagene ciloleucel and lisocabtagene maraleucel are two products used in rrPMBCL.

Background: T cell lymphomas (TCL) have been known to exhibit epigenetic dysregulation and aberrant cell signaling. Tenalisib (RP6530), a highly selective PI3K δ/γ+SIK3 inhibitor has shown clinically promising activity as a single agent in TCL with a differentiated and favorable safety profile. In vitro studies in TCL cell lines showed increased apoptosis when tenalisib was combined with romidepsin (Rhizen data on file). A Phase I/II study of tenalisib in combination with romidepsin was designed to assess safety, pharmacokinetics and efficacy in relapsed/refractory TCL (NCT03770000). Methods: This is a multi-center, open label, Phase I/II study in patients with T cell lymphoma (PTCL and CTCL). The Phase I is a 3+3 dose escalation study to determine the MTD/optimal dose. The Phase II is an expansion cohort at the MTD/optimal dose of the combination. Tenalisib was administered orally at doses of 400, 600 and 800 mg BID in combination with romidepsin (12 &14 mg/m2, Q3W). The objectives of the study are to establish safety, MTD/optimal dose, pharmacokinetics and anti-tumor activity of the combination. We report the dose escalation results and preliminary data from the expansion cohorts. Results: A total 15 patients were enrolled between July 24, 2019 and July 20, 2020. Baseline demographics are presented in Table 1. Patients had a median of 3 (range; 1-17) prior treatments and 11 (73%) were refractory to their last therapy. About 67% (6/9) of CTCL patients had prior mogamulizumab therapy. No DLT was reported in the dose escalation phase and Tenalisib 800 mg BID+ Romidepsin 14 mg/m2, Q3W was considered as the optimal dose for expansion cohorts. PK analysis showed linear and dose-dependent kinetics for tenalisib. Co-administration of romidepsin along with tenalisib did not significantly alter the mutual PK of either agents. Fifteen patients were assessed for safety. Most common treatment emergent adverse events of any grade were nausea (33%), thrombocytopenia (33%) and fatigue (27%). Related ≥ Grade 3 AEs were seen in 5 (33%) patients. These included thrombocytopenia (7%), atrial fibrillation (7%) and pyrexia (7%) which were related to romidepsin while anemia (7%) neutropenia (7%) and rash (7%) were considered related to the combination. There were no instances of transaminitis or colitis. None of the TEAEs led to study discontinuation. Patients from the dose escalation cohorts (n=9) were evaluated for response. Three patients (3/9) showed complete response (CR), 4 patients (4/9) showed stable disease (SD) while 2 patients (2/9) had progressive disease (PD). Out of the three responders, two were PTCL (AITL) patients, one of which is planned for transplantation, while the third patient was a CTCL (Sezary syndrome) patient who had progressed on prior mogamulizumab therapy. This patient showed rapid reduction of Sezary cell count after 2 cycles of treatment. Three patients (2 CR, 1 SD) are currently ongoing with a median duration of response being 9.0 (range; 7.6-10.5+) months. The expansion cohort has 6 patients and is currently enrolling. Conclusions: The combination of tenalisib and romidepsin demonstrates a favorable safety profile and promising indicators of combined anti-tumour activity in patients with R/R TCL. The expansion cohort in CTCL and PTCL is currently underway to validate these encouraging early results. Updated results will be presented during the ASH meeting. Disclosures Iyer: Afffimed: Research Funding; Rhizen: Research Funding; Seattle Genetics, Inc.: Research Funding; Curio Biosciences: Honoraria; Trillium: Research Funding; Daiichi Sankyo: Consultancy; Legend Biotech: Consultancy; Target Oncology: Honoraria; Spectrum: Research Funding; Merck: Research Funding; CRISPR: Research Funding. Huen:Seattle Genetics: Consultancy, Research Funding; Kyowa Kirin: Consultancy, Research Funding; Rhizen: Research Funding; Glaxo Smith Kline: Research Funding; Galderma: Research Funding; Miragen: Research Funding; Helsinn: Consultancy; Medivir: Research Funding. Haverkos:Viracta THerapeutics: Consultancy. Ai:ADC Therapeutics, Kymera: Membership on an entity's Board of Directors or advisory committees; Nurix Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kuzel:Eselixis, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genomic Health: Honoraria; Sanofi/Genzyme: Honoraria; Bioarray: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Marck: Membership on an entity's Board of Directors or advisory committees; Tyme: Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cardinal Health: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Alderuccio:ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Inovio Pharmaceuticals: Other: Family member; Foundation Medicine: Other: Family member; Puma Biotechnology: Other: Family member; Forma Therapeutics: Other: Family member; Agios Pharmaceuticals: Other: Family member; Oncinfo: Honoraria; OncLive: Honoraria. Stevens:Amgen, MorphoSys: Consultancy. Feldman:Viracta: Research Funding; Portola: Research Funding; Janssen: Speakers Bureau; AstraZeneca: Consultancy; Trillium: Research Funding; Amgen: Research Funding; Pfizer: Research Funding; Kyowa Kirin: Consultancy, Research Funding; Cell Medica: Research Funding; Rhizen: Research Funding; Corvus: Research Funding; BMS: Consultancy, Honoraria, Research Funding; Kite: Honoraria, Other: Travel expenses, Speakers Bureau; Celgene: Honoraria, Research Funding; Seattle Genetics, Inc.: Consultancy, Honoraria, Other: Travel expenses, Research Funding, Speakers Bureau; Takeda: Honoraria, Other: Travel expenses; Pharmacyclics: Honoraria, Other, Speakers Bureau; Abbvie: Honoraria; Bayer: Consultancy, Honoraria; Eisai: Research Funding. Jagadeesh:Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Regeneron: Research Funding; Verastem: Membership on an entity's Board of Directors or advisory committees; Debiopharm Group: Research Funding; MEI Pharma: Research Funding. Reddy:KITE Pharma, Abbvie, BMS, Celgene: Consultancy; Genentech, BMS: Research Funding. Routhu:Rhizen Pharmaceuticals S.A>.: Current Employment. Barde:Rhizen Pharmaceuticals S.A: Current Employment. Nair:Rhizen Pharmaceuticals S.A.: Current Employment.

Introduction: Patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) who fail multi-agent chemoimmunotherapy have a poor prognosis and a need for more treatment options. Loncastuximab tesirine (Lonca) comprises a humanized anti-CD19 antibody conjugated to a potent pyrrolobenzodiazepine dimer toxin. We present updated results from a phase 2 study of Lonca in patients with R/R DLBCL who had failed established therapies, including analysis of response in high-risk DLBCL subgroups. Methods: Patients aged ≥18 years with R/R DLBCL who had failed ≥2 prior therapies were enrolled in this single-arm open-label phase 2 study (NCT03589469). Overall response rate (ORR) was assessed by independent reviewer according to the Lugano response criteria and duration of response (DoR) was defined as the time from earliest date of first response until the first date of either disease progression or death due to any cause. Pre-specified analyses of ORR and DoR by demographic and clinical characteristics were performed. Treatment-emergent adverse events (TEAEs) were reported for the all-treated population and by age group. Results: In this study, 145 patients with DLBCL received Lonca (mean 4.3 cycles [range: 1-15]) and were evaluable for safety and efficacy. As of data cutoff (April 6, 2020), follow-up was ≥6 months since first dose. The ORR was 48.3%, and complete response rate (CRR) was 24.1%. Median DoR (mDoR) for the 70 responders was 10.3 months. For patients with a CR, mDoR was 13.4 months (Figure 1). Most patients responded after 2 treatment cycles; median time to first response was 41.0 days. Responses, including CRs, were observed in several subgroups with higher-risk characteristics (Figure 2). ORR was 44.8% in patients with transformed disease, 45.8% in patients aged 65-74 years, and 52.4% in patients aged ≥75 years. For patients with double- or triple-hit DLBCL, ORR was 33.3% (notably all CRs). Patients who were refractory (no response) to first-line therapy, most recent therapy, or any prior therapy had ORRs of 37.9%, 36.9%, and 36.0%, respectively. Patients who had received a prior stem cell transplant (SCT) had a notable ORR of 58.3%. Lonca was also effective in patients who had received prior CD19-directed chimeric antigen receptor T-cell (CAR-T) therapy (ORR 46.2%). Durable responses were noted in patients with high-risk characteristics. mDoR was not reached for patients with transformed disease. Older patients had a longer mDoR than younger patients ( Following Lonca treatment, 15 patients received CD19-directed CAR-T therapy with an investigator-assessed ORR of 46.7% (6 CR; 1 partial response), and 9 patients proceeded to SCT as consolidation after responding to Lonca. Overall, 143 (98.6%) patients had ≥1 TEAE and 105 (72.4%) patients had grade ≥3 TEAEs. The most common (≥25%) all-grade TEAEs were gamma-glutamyltransferase (GGT) increased (40.7%), neutropenia (39.3%), thrombocytopenia (33.1%), fatigue (27.6%), and anemia (26.2%). The most common (≥10%) grade ≥3 TEAEs were neutropenia (25.5%), thrombocytopenia (17.9%), GGT increased (16.6%), and anemia (10.3%). Treatment-related TEAEs leading to treatment discontinuation occurred in 24 patients (16.6%), most commonly GGT increased (14 patients; 9.7%). No increase in toxicity was seen in patients aged ≥65 years compared with younger patients. Conclusions: Lonca had substantial single-agent antitumor activity in patients with R/R DLBCL. No new safety concerns were identified and no increase in toxicity was observed for patients aged ≥65 years. Encouraging and durable responses were observed in high-risk patient groups, including double- or triple-hit, transformed or refractory DLBCL, and notably in those who had progressed after prior CAR-T cell therapy. In addition, investigator-reported ORR indicates that many patients also respond to CAR-T therapy given after Lonca. Updated DoR data will be presented at the meeting. Funding: This study is sponsored by ADC Therapeutics SA; clinicaltrials.gov/ct2/show/NCT03589469. Disclosures Caimi: Celgene: Speakers Bureau; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Genentech, ADC Therapeutics: Research Funding; ADCT, Kite Therapeutics, Genentech, Amgen, Verastem, TG Therapeutics, Bayer: Consultancy. Ai:ADC Therapeutics, Kymera: Membership on an entity's Board of Directors or advisory committees; Nurix Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding. Alderuccio:ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; OncLive: Honoraria; Puma Biotechnology: Other: Family member; Foundation Medicine: Other: Family member; Inovio Pharmaceuticals: Other: Family member; Oncinfo: Honoraria; Forma Therapeutics: Other: Family member; Agios Pharmaceuticals: Other: Family member. Ardeshna:Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi, Genzyme, AstraZeneca: Speakers Bureau; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; University College London (UCL)/UCL Hospitals (UCLH) Biomedical Research Unit: Other: Supported by this organisation; Beigene: Membership on an entity's Board of Directors or advisory committees. Hamadani:Takeda Pharmaceutical Company; Spectrum Pharmaceuticals; Astellas Pharma: Research Funding; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Janssen R&D; Incyte Corporation; ADC Therapeutics; Celgene Corporation; Pharmacyclics, Omeros, AbGenomics, Verastem, TeneoBio: Consultancy; Sanofi Genzyme, AstraZeneca: Speakers Bureau. Hess:ADC Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS, AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Kahl:Roche Laboratories Inc: Consultancy; Genentech: Consultancy; ADC Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene Corporation: Consultancy; AstraZeneca Pharmaceuticals LP: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Acerta: Consultancy, Research Funding; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics LLC: Consultancy. Radford:GlaxoSmithKline: Current equity holder in publicly-traded company, Other: Spouse; AstraZeneca: Current equity holder in publicly-traded company, Other: Spouse; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Research Funding; ADCT: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Stathis:Member of the steering committee of the trial of this abstract: Other; Loxo: Honoraria, Other, Research Funding; Cellestia: Research Funding; PharmaMar: Other: Travel Grant; Abbvie: Other: Travel Grant; ADC Therapeutcis: Other, Research Funding; MEI Pharma: Other, Research Funding; Novartis: Other, Research Funding; Bayer: Other, Research Funding; Merck: Other, Research Funding; Roche: Other, Research Funding; Pfizer: Other, Research Funding. Zinzani:Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: 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; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Immune Design: 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; MSD: 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; Celltrion: 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; 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; TG Therapeutics, Inc.: Honoraria, 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; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Honoraria, 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; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, 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; Kyowa Kirin: Consultancy, Speakers Bureau; Eusapharma: Consultancy, Speakers Bureau. Feingold:ADC Therapeutics: Current Employment, Current equity holder in publicly-traded company. Ungar:ADC Therapeutics: Current Employment, Current equity holder in publicly-traded company. Qin:ADC Therapeutics: Current Employment, Current equity holder in publicly-traded company. He:ADC Therapeutics: Current Employment, Current equity holder in publicly-traded company. Carlo-Stella:Servier, Novartis, Genenta Science srl, ADC Therapeutics, F. Hoffmann-La Roche, Karyopharm, Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics and Rhizen Pharmaceuticals: Research Funding; Bristol-Myers Squibb, Merck Sharp & Dohme, Janssen Oncology, AstraZeneca: Honoraria; Boehringer Ingelheim and Sanofi: Consultancy.

TPS7581 Background: Bruton’s tyrosine kinase inhibitors (BTKi) have received regulatory approvals and are standard of care for patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), and WaldenstrÖm macroglobulinemia (WM). However, BTKi-resistant disease remains a clinical challenge with limited options for subsequent therapy. Immunomodulatory drugs (IMiDs, e.g., lenalidomide) are approved as monotherapy for follicular lymphoma (FL), MZL, and MCL, in combination with other therapies for diffuse large B-cell lymphoma (DLBCL) and have shown synergy with BTK-targeted therapy. Dual activity of BTK protein degradation with IMiD-like activity offers a unique approach to overcome known resistance to BTKi. NX-2127 is an oral small molecule that induces BTK degradation via recruitment of cereblon, an adaptor protein of the E3 ubiquitin ligase complex. NX-2127 has shown preclinical activity similar to IMiDs by catalyzing the ubiquitination of Ikaros (IKZF1) and Aiolos (IKZF3), ultimately leading to increased T-cell activation. NX-2127 was shown to degrade both wild-type (WT) and C481-mutated (ibrutinib-resistant) BTK protein in vitro. Robust BTK degradation was also shown in non-human primate studies. Further, NX-2127 demonstrates potent tumor growth inhibition in BTK-dependent mouse xenograft tumor models expressing either WT or ibrutinib-resistant C481S BTK-mutant protein. This dual activity of BTK degradation and IMiD-like activity offers a promising treatment for patients who have failed prior therapy. Methods: NX-2127-001 is a first-in-human, dose escalation (Phase 1a) and cohort expansion (Phase 1b) study designed to evaluate the safety, tolerability, and preliminary efficacy of NX-2127 in adult patients with relapsed/refractory B-cell malignancies with once daily oral dosing. Dose escalation will proceed using a modified Fibonacci design with 1 patient per cohort, proceeding to a standard 3 + 3 design based on protocol specified criteria. There will be up to 5 expansion cohorts in Phase 1b enrolling patients with CLL/SLL, DLBCL, FL, MCL, MZL, and WM. Key eligibility criteria include >2 two prior lines of therapy (>1 prior for WM); measurable disease; and an Eastern Cooperative Oncology Group performance status of 0 or 1. Approximately 130 patients (30 in Phase 1a, 100 in Phase 1b) will be enrolled and treated until disease progression or unacceptable toxicity. The primary objectives are to evaluate safety and tolerability and to determine the maximum tolerated dose (Phase 1a), and to evaluate the early clinical activity of NX-2127 in expansion cohorts (Phase 1b). The Phase 1a part of this study is currently enrolling in the United States. Clinical trial information: NCT04830137.

e19551 Background: Loncastuximab tesirine (loncastuximab tesirine-lpyl; Lonca) is an FDA approved CD19-directed antibody-drug conjugate for R/R DLBCL. From the LOTIS-2 trial primary data cut (April 6, 2020), overall response rate was 48.3% and median overall survival (OS) was 9.9 months. The OS Kaplan-Meier (KM) plot displayed a survival plateau suggesting the presence of long-term survivors (LTS). Survival analyses were conducted on a more mature data cut (March 1, 2021; median follow-up = 1.7 years, follow-up completeness at median = 81%) to estimate the percentage of LTS and expected lifetime survival (mean OS) for lonca-treated patients. Methods: Consistent with studies of other R/R DLBCL treatments, identified through a literature review, parametric and mixture cure models were fit utilizing multiple distributions. Flexible cubic spline (hazard scale 1-3 knots) and non-mixture cure analyses were also conducted. Age- and gender-matched United States life table hazards were used in projections for LTS and to ensure modeled hazards were not less than the general population. Best-fit models were determined through fit statistics, KM and fitted curve overlays, and clinical plausibility. The best-fit model from each method was a candidate for overall best fit. A hybrid model following the best-fit parametric/spline model to a defined time point and switching to general population mortality was also constructed. Results: Mixture and non-mixture cure models fit best (individual best fits gamma and Weibull, respectively). Parametric and spline models (individual best fits log-normal and 2 knot models, respectively) did not fit the observed data well nor fit the clinical expectation of long-term survival. Due to better fit, spline models were used in the hybrid model. LTS from the mixture cure and non-mixture cure models were 24-26%. Mixture cure, non-mixture cure, and hybrid model with a 2-year switch point were consistent in survival predictions (6.11-6.23 years). In a sensitivity analysis with 3-year switch point in the hybrid model, the estimated survival was shorter due to the switch point being below the observed survival plateau. Table presents full survival results and fit statistics. Conclusions: The observed survival plateau suggests lonca-treated patients may include LTS. Mixture cure, non-mixture cure, and hybrid models fit the trial data well and align on survival projections (6.11-6.23 years). Additional follow-up may help refine the switch point of the hybrid model and confirm presence of LTS.[Table: see text]

Context Patients with relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL) who are ineligible for, or relapse after, salvage chemotherapy/stem cell transplant (SCT) have a poor prognosis. Lonca comprises a humanized anti-CD19 antibody conjugated to a potent pyrrolobenzodiazepine dimer toxin. Objective To assess updated efficacy and safety findings from a Phase 2 study evaluating Lonca in patients with R/R DLBCL (LOTIS-2; NCT03589469). Design Multicenter, open-label, single-arm Phase 2 study in adult patients (≥18 years) with pathologically defined R/R DLBCL and ≥2 prior systemic treatments. Intervention Lonca (150 µg/kg every 3 weeks [Q3W] for 2 cycles; 75 µg/kg Q3W thereafter). Main Outcomes Measures Primary efficacy endpoint: Overall response rate (ORR), assessed by central review. Secondary efficacy endpoints: Duration of response (DoR), progression-free survival (PFS), and overall survival (OS). Safety analyses: Treatment-emergent adverse events (TEAEs). Follow-up period: Q12W for ≤3 years after end of treatment. Results 145 patients with R/R DLBCL received ≥1 Lonca dose. Median age was 66 years (range 23–94). Patients received a median of 3 prior therapies (range 2–7). At data cut-off (October 26, 2020, ≥12 months since first dose), 2 patients continued treatment. Patients received a mean of 4.6 Lonca cycles (std 4.1; range 1–22). ORR was 48.3% (complete response [CR]: 24.8%; partial response [PR]: 23.4%). Median DoR was 12.6 months for patients with CR or PR (n=70); not reached for patients with CR. Median PFS and OS were 4.9 and 9.5 months, respectively. Post-Lonca treatment, 15 patients received CD19-directed chimeric antigen receptor T-cell therapy with an investigator-assessed ORR of 46.7%, and 11 patients proceeded to SCT as consolidation after Lonca response. Most common (≥25.0%) all-grade TEAEs were increased gamma-glutamyltransferase (41.4%), neutropenia (40.0%), thrombocytopenia (33.1%), fatigue (27.6%), and anemia (26.2%). Grade ≥3 TEAEs occurred in 107 (73.8%) patients. Treatment-related TEAEs leading to treatment discontinuation and dose delays occurred in 26 (17.9%) and 62 (42.8%) patients, respectively. Conclusions After longer follow-up of patients in LOTIS-2, durable responses to Lonca continue to be observed in heavily pre-treated patients with R/R DLBCL. No new safety concerns occurred. Research funding ADC Therapeutics SA.

Cutaneous T-cell lymphoma is a form of non-Hodgkin lymphoma that manifests initially in the skin and disseminates systemically as the disease progresses. Mycosis fungoides and Sézary syndrome are the most common subtypes of cutaneous T-cell lymphoma. Advanced mycosis fungoides and Sézary syndrome are life threatening with few treatment options. We searched for new agents by high-throughput screening of selected targeted compounds and identified high-value targets, including phosphatidylinositol 3-kinase (PI3K) and cyclin-dependent kinases. To validate these hits from the screen, we developed patient-derived xenograft mouse models that recapitulated the cardinal features of mycosis fungoides and Sézary syndrome and maintained histologic and molecular characteristics of their clinical counterparts. Importantly, we established a blood-based biomarker assay using tumor cell-free DNA to measure systemic tumor burden longitudinally in living mice during drug therapy. A PI3K inhibitor, BKM120, was tested in our patient-derived xenograft model leading to disease attenuation and prolonged survival. Isoform-specific small interfering RNA knockdowns and isoform-selective PI3K inhibitors identified PI3K-δ as required for tumor proliferation. Additional studies showed a synergistic combination of PI3K-α/δ inhibitors with histone deacetylase inhibitors. The strong preclinical efficacy of this potent combination against multiple patient-derived xenograft models makes it an excellent candidate for further clinical development.

Summary Background Patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who do not respond to or who have progressive disease after salvage therapies have a poor prognosis. Loncastuximab tesirine is a CD19-directed antibody–drug conjugate with encouraging phase 1 single-agent antitumour activity and acceptable safety in non-Hodgkin lymphoma. We aimed to evaluate the antitumour activity and safety of loncastuximab tesirine in patients with relapsed or refractory DLBCL. Methods We did a multicentre (28 hospital sites in the USA, UK, Italy, and Switzerland), open-label, single-arm, phase 2 trial (LOTIS-2) in patients aged 18 years or older with relapsed or refractory DLBCL after two or more multiagent systemic treatments, who had measurable disease and Eastern Cooperative Oncology Group performance status 0–2. Eligible patients received loncastuximab tesirine intravenously on day 1 of each 21-day cycle, at 150 μg/kg for two cycles, then 75 μg/kg thereafter, for up to 1 year or until disease relapse or progression, unacceptable toxicity, death, major protocol deviation, pregnancy, or patient, investigator, or sponsor decision. The primary endpoint was overall response rate assessed by central review. Primary antitumour activity and safety analyses were done in the as-treated population (patients who received at least one dose of loncastuximab tesirine), when all responding patients had at least 6 months of follow-up after initial documented response. Enrolment is complete. This trial is registered with ClinicalTrials.gov , NCT03589469 . Findings Between Aug 1, 2018, and Sept 24, 2019, 184 patients were assessed for eligibility and 145 (79%) were enrolled and received at least one dose of loncastuximab tesirine, including patients with high-risk characteristics for poor prognosis, such as double-hit, triple-hit, transformed, or primary refractory DLBCL. 70 of 145 patients had complete or partial response (overall response rate 48·3% [95% CI 39·9–56·7]); 35 had complete response and 35 had partial response. The most common grade 3 or higher treatment-emergent adverse events were neutropenia (37 [26%] of 145 patients), thrombocytopenia (26 [18%]), and increased gamma-glutamyltransferase (24 [17%]). Serious adverse events were reported in 57 (39%) of 145 patients. Treatment-emergent adverse events with a fatal outcome occurred in eight (6%) of 145 patients; none were considered related to loncastuximab tesirine. Interpretation Loncastuximab tesirine has substantial single-agent antitumour activity and produces durable responses with an acceptable safety profile, potentially offering a new therapeutic option for heavily pretreated patients with relapsed or refractory DLBCL. Funding ADC Therapeutics.

Introduction We designed a multicenter, phase Ib dose-escalation trial of carfilzomib with bendamustine and rituximab in patients with relapsed/refractory non-Hodgkin lymphoma ( NCT02187133 ) in order to improve the response rates of this difficult-to-treat population. Chemoimmunotherapy with bendamustine and rituximab has shown activity in a variety of lymphomas, and proteasome inhibitors have demonstrated pre-clinical synergy and early clinical activity in this population. The objectives were to determine the maximum tolerated dose of carfilzomib and the preliminary efficacy of this combination. Patients and Methods The protocol followed a 3+3 design of carfilzomib dose escalation combined with standard doses of bendamustine and rituximab. Patients were treated for up to 6 cycles with an interim positron emission tomography/computed tomography after cycle 3. Results Ten patients were treated on the dose-escalation phase. The study was terminated at a carfilzomib dose of 56 mg/m2, and the maximum tolerated dose was not reached. The most common grade 3/4 adverse event was thrombocytopenia. There was 1 dose-limiting toxicity observed, grade 3 febrile neutropenia, and there were no treatment-related deaths. The overall response rate was 40% (complete response rate, 30%), with a median duration of response of 12 months and a median progression-free survival of 2.1 months. Conclusion Carfilzomib in combination with bendamustine and rituximab is a safe and well-tolerated treatment for patients with relapsed/refractory non-Hodgkin lymphoma. Preliminary data indicate that this combination may have efficacy with an acceptable side effect profile in this heavily pre-treated patient population with limited treatment options.

Background More than one-half of high-risk patients with relapsed/refractory (rr) diffuse large B-cell lymphoma (DLBCL) relapse after autologous hematopoietic cell transplantation (auto-HCT). In this phase II study, we investigate the long-term outcomes of high-risk patients with rrDLBCL receiving intensive consolidation therapy (ICT) with OVA (ofatumumab, etoposide, and high-dose cytarabine) prior to auto-HCT. Patients and Methods The primary endpoints were the ability of OVA to mobilize peripheral stem cells and the 2-year progression-free survival (PFS) rate following OVA. Secondary endpoints included safety, 2-year overall survival (OS), impact of cell of origin (COO), and the prognostic utility of next-generation sequencing minimal residual disease (MRD) testing. We simultaneously retrospectively assessed the outcomes of DLBCL patients who underwent ICT with a similar regimen at our institution. Results Twenty-seven patients received salvage chemotherapy, with a response rate of 25% in patients with germinal center B-cell (GCB)-DLBCL versus 92% in patients with non-GCB-DLBCL (P = .003). Nineteen responding patients underwent ICT with OVA (100% successful stem cell mobilization). The 2-year PFS and OS rate was 47% and 59%, respectively, with no difference based on COO. Similar findings were observed when the study and retrospective cohorts were combined. Neutropenia was the most common toxicity (47%). MRD-negative patients at the completion of salvage had a median OS of not reached versus 3.5 months in MRD-positive patients (P = .02). Conclusions OVA followed by auto-HCT is effective and safe for high-risk rrDLBCL. Patients with GCB-DLBCL had a lower response to salvage chemotherapy, but no difference in outcomes based on COO was seen after auto-HCT. MRD testing in the relapsed setting was predictive of long-term survival.

Objectives We sought to examine the natural history of geriatric assessment (GA) and quality of life (QOL) domains among adults age ≥ 50 years undergoing autologous hematopoietic cell transplantation (autoHCT). Materials and Methods A QOL tool and cancer-specific GA were completed before autoHCT in patients ≥50 years, and at 100 days, six months, and one year post-transplant. Results One hundred eighty-four patients completed the pre-transplant QOL/GA assessment, 169 (92%) completed the 100-day assessment, 162 (88%) completed the six-month assessment, and 145 (79%) completed the twelve-month assessment. Functional status, as measured by instrumental activities of daily living (IADL), decreased from baseline to day 101 (mean change −0.42 points, 95% CI, −0.75 to −0.09, p = 0.01) but returned to baseline by one year. Physical function as measured by Medical Outcomes Study-Physical Health (MOS-PH) increased by mean of 3.27 points (95% CI, −0.02 to 6.56, p = 0.05) by one year. Physician-rated KPS improved by one year, but patient-rated KPS did not. No QOL metric deteriorated from baseline. Baseline factors predictive of IADL and MOS-PH as measured over time included comorbidities and disease status at transplant. IADL and MOS-PH as measured over time were not significantly associated with age. Conclusions AutoHCT for adults age ≥ 50 years resulted in an initial decrease in functional status, with subsequent improvement back to baseline by one year. Physical health and QOL measures were improved or unchanged over time. AutoHCT is well tolerated in well selected older patients, using patient reported geriatric metrics as outcomes.

Mycosis fungoides (MF) is the most common subtype of cutaneous T-cell lymphoma (CTCL), and Sézary syndrome (SS) is a rare erythrodermic and leukemic subtype of CTCL characterized by significant blood involvement. Although early-stage disease can be effectively treated predominantly with skin-directed therapies, systemic therapy is often necessary for the treatment of advanced-stage disease. Systemic therapy options have evolved in recent years with the approval of novel agents such as romidepsin, brentuximab vedotin, and mogamulizumab. These NCCN Guidelines Insights discuss the diagnosis and management of MF and SS (with a focus on systemic therapy).

Given the rarity of anaplastic large cell lymphoma (ALCL), studies evaluating new therapies have typically grouped ALCL together with other peripheral T cell lymphomas (PTCL). Thus, the treatment paradigm for ALCL largely mirrors that of PTCL in general. In this review, we discuss the current standard of care as well as emerging therapies, including antibody-based drugs, in systemic ALCL as well as primary cutaneous and breast implant-associated ALCL. High CD30 expression in ALCL has allowed the use of brentuximab vedotin, an anti-CD30 antibody-drug conjugate, in both systemic and primary cutaneous ALCL. Recent clinical trials with brentuximab have shown substantial activity in the relapsed/refractory setting. A randomized phase III study is ongoing comparing brentuximab plus CHP (cyclophosphamide, doxorubicin, prednisone) with standard CHOP in the front-line setting. The use of targeted therapies and other novel agents have improved outcomes for ALCL patients and in the future can complement or even replace the current standard of care and front-line treatment options.

The NCCN Clinical Practice Guidelines in Oncology for Hodgkin Lymphoma (HL) provide recommendations for the management of adult patients with HL. The NCCN Guidelines Panel meets at least annually to review comments from reviewers within the NCCN Member Institutions, examine relevant data, and reevaluate and update the recommendations. These NCCN Guidelines Insights summarize recent updates centered on treatment considerations for relapsed/refractory classic HL.

Background: Brentuximab vedotin (Bv) is an anti-CD30 antibody conjugated via a protease-cleavable linker to the anti-microtubule agent monomethyl auristatin E (MMAE). It is FDA approved for the treatment of classic Hodgkin lymphoma (cHL) and CD30-expressing T-cell lymphomas in both upfront and relapsed/refractory (R/R) settings. The most common side effects in the original registration trials (ECHELON-1, ECHELON-2, AETHERA) include peripheral neuropathy and cytopenias. With its expanded use in real world settings, it is imperative to identify less-established adverse events which may also result in dose delays or reductions. Pulmonary toxicity is a rare but potentially life-threatening side effect of Bv, but few studies have characterized this toxicity in the adult and pediatric populations. Here, we characterize the incidence and risk factors of developing Bv-associated pulmonary toxicity in patients with lymphoma. Methods: We conducted a multicenter, retrospective, descriptive study of patients receiving Bv at University of California San Francisco Health in San Francisco, CA and Community Medical Center in Fresno, CA. Adult and pediatric patients were included if they received at least one dose of Bv between June 1, 2015 and September 30, 2020. Retrospective chart review was conducted to identify patients who developed respiratory symptoms concerning for Bv-induced pneumonitis. Past medical history, smoking history, and prior administration of pulmonary toxic agents were collected to assess for risk factors contributing to Bv-associated pulmonary toxicity. Respiratory symptoms were classified as likely related, possibly related, or not related to Bv. Patients were identified to have pulmonary toxicities likely related to Bv if they satisfied the following criteria: development of respiratory symptoms with a temporal relation to Bv, suggestive chest imaging or pulmonary function tests (PFTs), rule out of other etiologies including infectious causes, and relief of symptoms with steroid treatment and/or Bv discontinuation at the physician's discretion. Patients were identified to have pulmonary toxicities possibly related to Bv if they satisfied the following criteria: development of respiratory symptoms with a temporal relation to Bv, equivocal chest imaging or PFTs, inability to fully rule out other etiologies, and relief of symptoms with steroid treatment or Bv discontinuation at the physician's discretion. Data is reported using descriptive statistics. A consort flow diagram of the selection process is depicted in Figure 1. Results: A total of 123 patients were reviewed, of whom 27 were excluded due to pregnancy, prisoner status, or not having received Bv during the study period. 96 patients were included in the final analysis. Baseline characteristics are captured in Table 1. Following Bv administration, 19 of the 96 patients developed pulmonary symptoms (dry cough, shortness of breath, dyspnea on exertion, chest pain, or hypoxic respiratory failure not justified by a competing process). Based on the prespecified definitions, we identified four patients (4.2%) who developed respiratory symptoms concerning for Bv-induced toxicity. The mean age of the four patients was 51 (range 28-76) and one patient was female. One patient received Bv in the upfront setting for cHL, one had R/R cHL, and the remaining two had anaplastic large cell lymphoma (ALCL). One patient previously received pulmonary toxic agents (gemcitabine and carmustine) and two patients had a history of tobacco use. The cumulative doses of Bv the four patients received prior to developing respiratory symptoms ranged from 8.8 to 30.4 mg/kg (6-21 cycles). Three patients were classified as likely related based on supportive findings on chest imaging or PFTs and one patient was classified as possibly related given lack of definitive evidence to differentiate between pneumonitis and disease progression. Three of the four patients developed symptoms requiring steroid treatment and two required Bv dose reduction and/or discontinuation. Conclusions: This study is an effort to raise awareness of the incidence of Bv-induced pulmonary toxicity and describe the potential risk factors associated with this adverse event. Further real world studies in larger and diverse patient populations are necessary to better characterize the incidence and risk factors associated with Bv-associated pulmonary toxicities. Figure 1 Figure 1. Disclosures Lo: EUSA Pharma: Consultancy; Oncopeptides: Consultancy. Ai: Kymria, Kite, ADC Therapeutics, BeiGene: Consultancy. Abdulhaq: BMS, Alexion, Oncopeptides, Morphosys, Pfizer, Norvartis: Honoraria; Oncopeptides, Alexion, Amgen: Speakers Bureau; Morphosys, BMS, Amgen: Membership on an entity's Board of Directors or advisory committees. Fakhri: Loxo/Lilly: Research Funding.

Introduction: Patients with diffuse large B-cell lymphoma (DLBCL) that is resistant to chimeric antigen receptor T-cell (CAR-T) therapy have poor outcomes (Chow VA, et al. Am J Hematol. 2019;94:E209-E13). The majority of patients with DLBCL who relapse after CAR-T therapy do so with disease that continues to express CD19 surface antigen (Shah NN, Fry TJ. Nat Rev Clin Oncol. 2019;16:372-85); however, it is unknown whether treatment with CD19-targeted agents is an effective strategy for patients with prior failure of anti-CD19 CAR-T therapy. Loncastuximab tesirine (loncastuximab tesirine-lpyl; Lonca) is an FDA-approved CD19-directed antibody-drug conjugate (ADC) which had encouraging phase 1 antitumor activity and acceptable safety in non-Hodgkin lymphoma (Hamadani M, et al. Blood. 2021;137:2634-2645). In the Phase 2 LOTIS-2 trial (NCT03589469) the efficacy and safety of Lonca was evaluated in patients with relapsed or refractory (R/R) DLBCL after ≥2 lines of systemic treatments (Caimi PF, et al. Lancet Oncol. 2021;22:790-800). The overall response rate (ORR) was 48.3%. The aim of this post-hoc analysis of the LOTIS-2 trial was to investigate the antitumor activity of Lonca in patients with DLBCL relapsed or refractory after CAR-T therapy. Methods: The methodology of the LOTIS-2 trial has been published. Briefly, patients were treated with Lonca (0.15 mg/kg for the first 2 cycles then 0.075 mg/kg for subsequent cycles) administered as a single 30-minute infusion, once every 3 weeks for up to 1 year, or until progressive disease or unacceptable toxicity. Patients with previous anti-CD19 CAR-T therapy were required to have persistent CD19 expression, evaluated by local review of immunohistochemistry of a post-CAR-T biopsy. The primary endpoint was ORR, defined as the proportion of patients with best overall response of complete response (CR) or partial response (PR), determined by independent review. Secondary endpoints included overall survival (OS), progression free survival (PFS), and duration of response (DOR). PET/CT imaging was performed 6 and 12 weeks after the first Lonca dose and every 9 weeks thereafter. Response was assessed using the Lugano 2014 criteria. Kaplan Meier survival analysis was performed from initiation of Lonca treatment. Results: The characteristics of 13 patients with DLBCL with disease relapse or progression after anti-CD19 CAR-T therapy are shown in table 1. The median time interval between CAR-T infusion and Lonca treatment was 7 months (range, 45-400 days). Ten (77%) patients received Lonca as the first therapy after CAR-T failure, 3 patients received other treatments prior to Lonca (chemoimmunotherapy [R-GemOx], n = 1; allogenic stem cell transplant, n = 1; chemoimmunotherapy [R-GemOx] followed by venetoclax + bromodomain inhibitor, n =1). The ORR to Lonca was 46.2% (n=6; CR, 15.4% [n = 2]; PR, 30.8% [n = 4]) after a median of 2 cycles (range, 1-9). Of the 6 patients who achieved a response to Lonca, 5 had a previous response to CAR-T and 1 had prolonged, stable disease for >1 year after CAR-T. With a median follow-up of 8 months, the median OS and PFS were 8.2 and 1.4 months, respectively (Figure 1); the 1-year OS estimate was 33.3%. The median DOR to Lonca was 8 months. Conclusions: Lonca achieved a response in 6 out of 13 patients who had failed prior CAR-T therapy. Five out of 6 responding patients had previously presented at least a partial response after CAR-T therapy. These data suggest that in patients without CD19 antigen loss, repeat therapy with another agent targeting this antigen can result in disease control. Prior response to anti-CD19 therapy may be associated with subsequent response to a second anti-CD19 treatment. Further studies are needed to confirm the feasibility and value of repeated anti-CD19 treatments in patients with B-cell non-Hodgkin lymphoma. Funding: This study was funded by ADC Therapeutics; medical writing support was provided by CiTRUS Health Group. Figure 1 Figure 1. Disclosures Caimi: Amgen Therapeutics.: Consultancy; XaTek: Patents & Royalties: Royalties from patents (wife); ADC Theraputics: Consultancy, Research Funding; Genentech: Research Funding; Kite Pharmaceuticals: Consultancy; Verastem: Consultancy; Seattle Genetics: Consultancy; TG Therapeutics: Honoraria. Ardeshna: Gilead, Beigene, Celegene, Novartis and Roche: Honoraria; Norvartis, BMS, Autolus, ADCT, Pharmocyclics and Jansen: Research Funding; Gilead, Beigene, Celegene, Novartis and Roche: Membership on an entity's Board of Directors or advisory committees. Reid: Aptose Biosciences: Other: Serves as Principle Investigator, Research Funding; ADC Therapeutics: Other: Serves as Principle Investigator, Research Funding; Millennium Pharmaceuticals: Other: Serves as Principle Investigator, Research Funding; Xencor: Other: Serves as Principle Investigator, Research Funding. Ai: Kymria, Kite, ADC Therapeutics, BeiGene: Consultancy. Lunning: Myeloid Therapeutics: Consultancy; Spectrum: Consultancy; Daiichi-Sankyo: Consultancy; Verastem: Consultancy; Janssen: Consultancy; AstraZeneca: Consultancy; Morphosys: Consultancy; Beigene: Consultancy; Legend: Consultancy; ADC Therapeutics: Consultancy; Acrotech: Consultancy; Celgene, a Bristol Myers Squibb Co.: Consultancy; AbbVie: Consultancy; Kite, a Gilead Company: Consultancy; TG Therapeutics: Consultancy; Novartis: Consultancy; Kyowa Kirin: Consultancy; Karyopharm: Consultancy. Zain: Secura Bio, DaichiSankyo, Abbvie: Research Funding; Kiyoaw Kirin, Secura Bio, Seattle Genetics: Honoraria; Secura Bio, Ono , Legend, Kiyowa Kirin, Myeloid Therapeutics Verastem Daichi Sankyo: Consultancy. Solh: ADCT Therapeutics: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy; BMS: Consultancy; Partner Therapeutics: Research Funding. Kahl: AbbVie, Acerta, ADCT, AstraZeneca, BeiGene, Genentech: Research Funding; AbbVie, Adaptive, ADCT, AstraZeneca, Bayer, BeiGene, Bristol-Myers Squibb, Celgene, Genentech, Incyte, Janssen, Karyopharm, Kite, MEI, Pharmacyclics, Roche, TG Therapeutics, and Teva: Consultancy. Hamadani: Takeda, Spectrum Pharmaceuticals and Astellas Pharma: Research Funding; Janssen, Incyte, ADC Therapeutics, Omeros, Morphosys, Kite: Consultancy; Sanofi, Genzyme, AstraZeneca, BeiGene: Speakers Bureau.

Introduction: Loncastuximab tesirine (loncastuximab tesirine-lpyl; Lonca) is an FDA-approved CD19-directed antibody-drug conjugate (ADC) indicated for the treatment of adult patients with relapsed or refractory (R/R) large B-cell lymphoma after ≥2 lines of systemic therapy, including patients with high-grade B-cell lymphoma. In the Phase 2 LOTIS-2 trial (NCT03589469), Lonca was evaluated as a single agent in patients with R/R diffuse large B-cell lymphoma (DLBCL) and the overall response rate (ORR) was 48.3% (Caimi PF, et al. Lancet Oncol. 2021; 22:790-800). In an analysis of the 11 patients from the LOTIS-2 clinical trial with high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements (HGBCL; data cutoff: April 6, 2020), 45.5% (n=5) achieved an overall response. In this patient subgroup, the median duration of response was 13.37 months, and the median progression-free survival was 9.13 months. The aim of this analysis (data cut off: March 1, 2021) was to further characterize the clinical characteristics and efficacy of Lonca in patients with HGBCL enrolled in the LOTIS-2 clinical trial. Methods: The methodology for the LOTIS-2 trial has been published. Briefly, Lonca (0.15 mg/kg for the first 2 cycles followed by 0.075 mg/kg for subsequent cycles) was administered as a single 30-minute infusion, once every 3 weeks for up to 1 year, until progressive disease or unacceptable toxicity. The primary outcome was ORR defined as the proportion of patients with best overall response of complete response (CR) or partial response (PR), assessed by independent review. Investigator assessment of histopathology according to the 2016 WHO classification was used to define HGBCL. Results: The demographics and disease characteristics of the 11 patients with HGBCL are shown in Table 1. The median age was 74 years; 5 patients (45.5%) were age ≥75 years. The majority of patients received ≥3 prior lines of therapy (n = 8; 72.7%). One patient had a prior stem cell transplant (autologous; 9.1%). Of the 11 patients with HGBCL, the overall response rate was 45.5%, with all 5 patients achieving CR. The median (min, max) time to first CR or PR response was 43.0 (38, 148) days and the median time to first CR response was 79.0 (38, 148) days. All five responding patients (45.5%) had a duration of response ≥1 year; median duration of response has not been reached at the time of data cutoff. Conclusions: Efficacy data from this small subgroup of patients with HGBCL enrolled in the LOTIS-2 clinical trial are consistent with the overall trial population. These results suggest that Lonca is active in the treatment of this high-risk lymphoma subgroup, achieving comparable response rates with other risk groups and with long-term disease control in responding patients. Funding: This study was funded by ADC Therapeutics; medical writing support was provided by CiTRUS Health Group. Figure 1 Figure 1. Disclosures Alderuccio: Inovio Pharmaceuticals: Other: Family member; Agios Pharmaceuticals: Other: Family member; Puma Biotechnology: Other: Family member; ADC Therapeutics: Consultancy, Research Funding; Oncinfo / OncLive: Honoraria; Forma Therapeutics: Other: Family member. Ai: Kymria, Kite, ADC Therapeutics, BeiGene: Consultancy. Radford: ADC Therapeutics: Consultancy, Current holder of individual stocks in a privately-held company, Honoraria, Speakers Bureau; BMS: Honoraria; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; AstraZeneca: Current holder of individual stocks in a privately-held company. Solh: Jazz Pharmaceuticals: Consultancy; BMS: Consultancy; Partner Therapeutics: Research Funding; ADCT Therapeutics: Consultancy, Research Funding. Ardeshna: Gilead, Beigene, Celegene, Novartis and Roche: Honoraria; Norvartis, BMS, Autolus, ADCT, Pharmocyclics and Jansen: Research Funding; Gilead, Beigene, Celegene, Novartis and Roche: Membership on an entity's Board of Directors or advisory committees. Lunning: AbbVie: Consultancy; Novartis: Consultancy; Beigene: Consultancy; ADC Therapeutics: Consultancy; Daiichi-Sankyo: Consultancy; Spectrum: Consultancy; Acrotech: Consultancy; AstraZeneca: Consultancy; Myeloid Therapeutics: Consultancy; Janssen: Consultancy; Verastem: Consultancy; Celgene, a Bristol Myers Squibb Co.: Consultancy; Kite, a Gilead Company: Consultancy; Kyowa Kirin: Consultancy; Karyopharm: Consultancy; TG Therapeutics: Consultancy; Morphosys: Consultancy; Legend: Consultancy. Hess: BMS: Speakers Bureau; ADC Therapeutics: Consultancy. Zinzani: EUSAPHARMA: Consultancy, Other, Speakers Bureau; SANDOZ: Other: Advisory board; ROCHE: Other, Speakers Bureau; MSD: Consultancy, Other: Advisory board, Speakers Bureau; NOVARTIS: Consultancy, Other, Speakers Bureau; TG Therapeutics: Other: Advisory board, Speakers Bureau; KYOWA KIRIN: Other, Speakers Bureau; TAKEDA: Other: Advisory board, Speakers Bureau; Beigene: Other, Speakers Bureau; Incyte: Other, Speakers Bureau; ADC Therap.: Other; SERVIER: Other: Advisory board, Speakers Bureau; BMS: Other: Advisory board, Speakers Bureau; JANSSEN-CILAG: Other: Advisory board, Speakers Bureau; GILEAD: Other: Advisory board, Speakers Bureau; CELLTRION: Other: Advisory board, Speakers Bureau; VERASTEM: Consultancy, Other: Advisory board, Speakers Bureau. Stathis: Abbvie and PharmaMar: Other: travel grant; Pfizer, ADC Therapeutics, Bayer, Roche, Merck, Novartis, MEI Therapeutics and Abbvie: Research Funding; Bayer / Eli Lilly: Consultancy. Carlo-Stella: Sanofi: Consultancy, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Honoraria; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria; Janssen Oncology: Honoraria; Celgene: Membership on an entity's Board of Directors or advisory committees; Karyopharm Therapeutics: Membership on an entity's Board of Directors or advisory committees. Hamadani: Sanofi, Genzyme, AstraZeneca, BeiGene: Speakers Bureau; Janssen, Incyte, ADC Therapeutics, Omeros, Morphosys, Kite: Consultancy; Takeda, Spectrum Pharmaceuticals and Astellas Pharma: Research Funding. Kahl: AbbVie, Acerta, ADCT, AstraZeneca, BeiGene, Genentech: Research Funding; AbbVie, Adaptive, ADCT, AstraZeneca, Bayer, BeiGene, Bristol-Myers Squibb, Celgene, Genentech, Incyte, Janssen, Karyopharm, Kite, MEI, Pharmacyclics, Roche, TG Therapeutics, and Teva: Consultancy. Ungar: ADC Therapeutics: Current Employment, Current equity holder in publicly-traded company. Kilavuz: ADC Therapeutics: Current Employment, Current equity holder in publicly-traded company. Yu: ADC Therapeutics: Current Employment. Qin: ADC Therapeutics: Current Employment, Current equity holder in publicly-traded company. Caimi: TG Therapeutics: Honoraria; Amgen Therapeutics.: Consultancy; XaTek: Patents & Royalties: Royalties from patents (wife); ADC Theraputics: Consultancy, Research Funding; Seattle Genetics: Consultancy; Verastem: Consultancy; Genentech: Research Funding; Kite Pharmaceuticals: Consultancy.

Cutaneous T cell lymphoma (CTCL) is a type of non-Hodgkin's lymphoma in which malignant T cells initially home to the skin followed by systemic dissemination as the disease progresses. CD70 is rarely expressed in normal tissues but is overexpressed in activated T and B lymphocytes. From archival diagnostic specimens of 37 patients, we demonstrate that CD70 is highly expressed in subtypes of mature TCL, especially CTCL. SGNCD70A is a new anti-CD70 antibody-drug conjugate combining a monoclonal antibody to CD70 with a DNA-damaging agent. SGNCD70A inhibited cell growth and induced apoptosis of CD70+ CTCL cell lines and primary tumors from patient-derived xenograft (PDX) mice, but had no inhibitory effect on CD70- lymphoblastic TCL cells and normal T cells. Next, we examined the anti-tumor activity of SGNCD70A in CTCL PDX model. One week after tumor inoculation, mice were treated intraperitoneally with single-dosing of PBS, 100 μg/kg (SGN70A100) or 300 μg/kg (SGN70A300) of SGN-CD70A. SGN-CD70A prolonged survival of treated mice in a dose-dependent fashion compared to untreated mice. Median survival was 21 days, 27.5 days (P=0.041), and 57 days (p85 days), resulting in markedly prolonged survival compared to the single-dose- and PBS-treated mice with a median survival of 39 days, (P Citation Format: Chi-Heng Wu, Chen-Yen Yang, Linlin Wang, Ryan Gill, Frank McCormick, Weiyun Z. Ai. A CD70 antibody-drug conjugate is highly active and induces long term remission in patient-derived xenograft mouse models of cutaneous T cell lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1844.

Lonca (ADCT-402) is an antibody (Ab) drug conjugate comprising a humanized anti-CD19 monoclonal Ab, conjugated with a pyrrolobenzodiazepine (PBD) dimer toxin. Lonca showed antitumor activity in a dose-finding Phase 1 study in relapsed/refractory (R/R) B-NHL (NCT02669017), and an open-label Phase 2 (NCT03589469) study in R/R diffuse large B-cell lymphoma (DLBCL), where patients received 150 µg/kg every 3 weeks (Q3W) for two doses, followed by 75 µg/kg Q3W thereafter until disease progression or unacceptable toxicity. Here, we evaluated the efficacy, safety, tolerability, and tolerable doses of Lonca PBD-conjugated Ab (cAb). A pooled Phase 1 and 2 population pharmacokinetics model of total Ab and cAb data was used to generate individual cAb exposure metrics (patients with DLBCL [n=284] for efficacy; all patients [N=328] for safety), including average cAb concentration (Cavg). SAS© v9.4 and R statistical software v4.0.1 were used for the exposure-response analysis. Efficacy endpoints included overall response rate (ORR), overall survival (OS), and duration of response (DoR); selected treatment-emergent adverse events (TEAEs) were used as safety endpoints. Univariate and multivariate logistic regression models were used to analyze ORR and safety endpoints. Time-to-event Kaplan-Meier and a Cox proportional hazards model were used to analyze OS and DoR, as applicable. Significant relationships between exposure and response (ORR and OS) were observed. ORR was 64.8% for patients in the highest quartile (Q4) of Cycle 1 Cavg compared with 23.9% for patients with drug exposure in Q1. The odds of response increased 1.2-fold for each 0.1 µg/kg increase in Cycle 1 Cavg (p Significant positive relationships were found between exposure and increased gamma-glutamyltransferase (GGT), skin and nail disorder, and liver function test abnormalities (but no evidence of hepatotoxicity). The odds of Grade ≥2 GGT occurrence increased with Cavg in Cycle 1 (p=0.000669). Higher Lonca exposure resulted in improved response. As expected, probability of Grade ≥2 TEAEs overall increased with exposure. The dosing regimen using initial dose of 150 µg/kg with dose reduction after two cycles resulted in rapid attainment and maintenance of high steady-state levels, and is anticipated to aid in response durability while minimizing toxicity. Citation Format: Brian Hess, Weiyun Ai, William Townsend, David Ungar, Sam Liao, Lori Liao, Xiaoyan Zhang, Joseph Boni. Relationship between exposure and safety/efficacy of loncastuximab tesirine (Lonca) in B-cell non-Hodgkin lymphoma (B-NHL) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1367.

This portion of the NCCN Guidelines for Hodgkin lymphoma (HL) focuses on the management of classical HL. Current management of classical HL involves initial treatment with chemotherapy or combined modality therapy followed by restaging with PET/CT to assess treatment response using the Deauville criteria (5-point scale). The introduction of less toxic and more effective regimens has significantly advanced HL cure rates. However, long-term follow-up after completion of treatment is essential to determine potential long-term effects.

Background: Chimeric antigen receptor T-cell (CAR T) immunotherapy is an evolving treatment for relapsed/ refractory non-Hodgkin lymphoma (NHL) and multiple myeloma (MM). There is a growing need to elucidate the infectious complications of BCMA- and CD19-directed CAR T therapy. We performed a single-center retrospective analysis of infection outcomes up to 1-year post BCMA and CD19-directed CAR T treatment. Methods: All patients treated at our institution with a BCMA-directed CAR T therapy for MM or with a CD19-directed CAR T for NHL from 2018-2020 were analyzed for risk factors for infection and infectious complications. Bacterial, viral and fungal infections were recorded if there was a microbiologic or histopathologic diagnosis or if clinical suspicion for infection required empiric treatment. Infection severity was classified as mild, moderate, severe, life-threatening, or fatal as previously described (Young et al. 2016, van Burnik et al. 2007). Infections were identified from the day of the first CAR T-cell infusion up to 1 year after infusion. Observation of infections was terminated at the time of disease progression, initiation of next therapy, or death, whichever occurred first. Fisher's exact test and Wilcoxon rank-sum test were used to compare between cohorts. Poisson mixed effects model with a subject-specific random intercept and an offset to account for the duration at risk was used to identify risk factors for infections. Results: Of the 104 subjects in this study, 55 patients (53%) had MM treated with BCMA CAR T and 49 patients (47%) had NHL treated with CD19 CAR T. Median number of prior therapies was 6 (4 - 9) in the BCMA cohort and 3 (2-4) in the CD19 cohort (Table 1). Prior to starting lymphodepleting (LD) chemotherapy, most patients did not have IgG< 400, ALC< 200, or ANC< 500. Almost all the patients were on antibacterial (99%), antiviral (99%) and antifungal (92%) prophylaxis (ppx), with 18%, 90% and 9% of patients starting this before LD chemotherapy, respectively. Median follow-up time was 5.8 months (95% CI: 4.2-6.4). In total, there were 87 infection events (48 bacterial, 33 viral, and 6 fungal) observed in 56 patients (54%), with 47 infections in 29 (53%) patients in the BCMA CAR T cohort and 40 infections in 27 (55%) patients in the CD19 CAR T cohort (p =0.9). The BCMA cohort had 19 bacterial (40%) vs 29 bacterial (73%) in CD19 cohort (p=0.005), while BCMA cohort had 25 viral (53%) vs 8 viral (20%) in CD19 cohort (p=0.002). Fungal infection rates were comparable between BCMA and CD19 cohorts, 3 (6%) vs 3 (8%) respectively (p=1). Among the infections that occurred, 20 (23%) were high severity occurring in 16 patients (15%) of the overall cohort. Four high severity infections (5%) occurred in 3 patients (5%) in the BCMA cohort while 16 high severity infections (18%) occurred in 13 patients (27%) in the CD19 cohort (p < 0.001) (Figure 1). The BCMA cohort had higher rates of respiratory infections (68% vs 50%, p=0.1), while the CD19 cohort had higher rates of bloodstream infections (15% vs 2%, p=0.05) and gastrointestinal infections (10% vs 0%, p=0.04). The rates of grade (Gr) 3-4 neutropenia and IgG < 300 in both the cohorts at various time points post CAR T were comparable. At 9-12 months, Gr 3-4 neutropenia was 7% vs 8% (p=1) and IgG < 300 was 7% vs 33% (p=0.1) for the BCMA and CD19 cohorts respectively. Adjusting for time periods, risk factors for development of infections were use of steroids (incidence rate ratio [IRR] 1.6, 95% CI: 1.1-2.5, p=0.03) and post CAR T hypogammaglobulinemia (IgG < 600) (IRR =2.1, 95% CI: 1.2-3.9, p=0.02). Conclusions: This retrospective study is one of the largest studies to date comparing the post CAR T infections rates between BCMA and CD19 directed CAR T treated patients. While the incidence of infection, use of antimicrobial ppx, and rates of Gr 3-4 neutropenia and hypogammaglobulinemia were comparable between BCMA and CD19 CAR T cohorts, viral infections were more common post BCMA CAR T while bacterial infections were more frequent post CD19 CAR T. Use of steroids as well as post CAR T hypogammaglobulinemia are possible risk factors for development of infections. Further studies are needed to examine the infectious complications post-CAR T treatment, characterize the underlying risk factors, and to establish appropriate prophylactic approaches in patients undergoing CD19- and BCMA-directed CAR T therapy. Disclosures Fakhri: University of California San Francisco: Current Employment. Ai:Nurix Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics, Kymera: Membership on an entity's Board of Directors or advisory committees. Martin:Seattle Genetics: Research Funding; GSK: Consultancy; Sanofi: Research Funding; AMGEN: Research Funding; Janssen: Research Funding. Wolf:Adaptive: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Shah:BMS, Janssen, Bluebird Bio, Sutro Biopharma, Teneobio, Poseida, Nektar: Research Funding; GSK, Amgen, Indapta Therapeutics, Sanofi, BMS, CareDx, Kite, Karyopharm: Consultancy. Andreadis:Genentech: Other: Spouse Employee (salary and stock); Novartis: Research Funding; Celgene/Juno: Research Funding; Amgen: Research Funding; Merck: Research Funding; Gilead/Kite: Other: Advisor; Jazz Pharmaceuticals: Other: Advisor; Astellas: Other: Advisor; Seattle Genetics: Other: Advisor; Karyopharm: Other: Advisor; Incyte: Other. Wong:GSK: Research Funding; Amgen: Consultancy; Sanofi: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Research Funding; Roche: Research Funding; Janssen: Research Funding; Fortis: Research Funding.

7546 Background: Outcomes for patients with refractory/relapsed diffuse large B-cell lymphoma (R/R DLBCL) are poor, particularly for those with high-risk clinical characteristics. There remains an unmet need for new treatment options for these patients. Loncastuximab tesirine (Lonca) is an antibody-drug conjugate comprising a humanized anti-CD19 antibody conjugated to a potent pyrrolobenzodiazepine dimer toxin. LOTIS 2 was a pivotal Phase 2 study that demonstrated substantial single-agent anti-cancer activity of Lonca in patients with R/R DLBCL. Efficacy and safety data were presented at ASH 2020 (Caimi et al, ASH 2020; abstract 1183). Here we present subgroup analyses of duration of response (DoR) to Lonca by demographic and clinical characteristics. Methods: Adult patients with R/R DLBCL who had received ≥2 prior therapies were enrolled in this Phase 2, multicenter, single-arm, open-label study of single-agent Lonca (150 µg/kg every 3 weeks for 2 doses, followed by 75 µg/kg thereafter for up to 1 year). The primary analysis has previously been reported, with a primary endpoint of overall response rate (ORR). Patients are being followed-up every 12 weeks for up to 3 years. DoR was a key secondary efficacy endpoint, defined as time from the first documentation of response (central review) to disease progression or death. We analyzed pre-specified demographic and clinical characteristic subgroups for DoR. Results: As of data cut-off (August 6, 2020), ORR in the total population (N = 145) was 48.3% (24.8% had complete response [CR] and 23.4% had partial response [PR]). Median DoR (mDoR) for the 70 responders was 12.58 months. mDoR for patients with CR and PR was 13.37 months and 5.68 months, respectively. Overall, subgroups with high-risk characteristics for poor prognosis had a DoR comparable to the whole study population. mDoR for patients with double-/triple-hit DLBCL was 13.37 months, with advanced stage disease was 12.58 months, and with transformed disease was 12.58 months. The mDoR for older patients was longer than for younger patients (≥75 years, 13.37 months; 65 to < 75 years, 12.58 months; < 65 years, 9.26 months). Patients with DLBCL refractory (defined as no response to therapy) to first-line, most recent line, and all prior lines of therapy had mDoRs of 9.63 months, 9.26 months, and 9.63 months, respectively. Conclusions: Durable responses were observed with the recommended Phase 2 dose regimen of Lonca in heavily pre-treated patients and those at high risk of poor prognosis, including older patients and those with double-/triple-hit, advanced stage, transformed, and primary refractory DLBCL. Updated DoR data will be presented at the meeting. Clinical trial information: NCT03589469.

e19538 Background: A major unmet clinical need in the care of early-stage MF patients is the identification of those with a high risk of failing skin directed therapy or progressing to advanced disease. Herein, we inquired if the identification of a clonal T-cell receptor (TCR) gene rearrangement by PCR in peripheral blood could predict the clinical outcome, particularly the need for systemic treatment, in patients with stage IB MF. Methods: This is a retrospective cohort study of patients with stage IB MF who underwent peripheral blood TCR clonality analysis by PCR. The primary outcome of the study was time from diagnosis to initiation of systemic treatment. Secondary outcomes were: (1) time to progression to advanced-stage disease (stages IIB-IV) and (2) overall survival. Patients were censored at time of last clinical follow up. Log rank test was used to compare the survival distributions of the two groups; p value < 0.05 was considered significant. Results: From May 2014 to October 2019, 56 consecutive stage IB pts with > 6 months follow up were included in this analysis. Peripheral blood TCR clonality status was available in 42 patients: 18 pts had a positive TCR clone and 24 did not. Median follow up time was 36 months (range 8.5 – 198 months). At 3 years, 39% of patients with peripheral clone had progressed to systemic treatment versus 8% of those without a peripheral clone (log rank test, p-value = 0.003). For the secondary outcomes, at 3 years 17% of patients with peripheral clone had progressed to advanced stage versus 4% of those without (log rank test, p-value = 0.10); 5% of patients with peripheral clone had died versus 0% of those without (log rank test, p-value = 0.03). Conclusions: Detection of a predominant TCR clone by PCR in the peripheral blood is an important prognostic marker in the initial workup of MF, as its presence is highly correlated with subsequent progression to systemic treatment and death. If this finding is validated, it can be used to risk stratify and individualize therapy for MF patients.[Table: see text]

Importance A new cutaneous staging system for folliculotropic mycosis fungoides (FMF) has been purported to better estimate survival compared with the staging system for conventional mycosis fungoides. Objective To analyze predictive variables associated with survival and evaluate the effectiveness of the newly proposed staging system for estimating overall survival and disease-specific survival (DSS) in a US cohort. Design, Setting, and Participants This cohort study assessed 195 patients with FMF in the dermatopathology database of the University of California, San Francisco from January 1, 1990, to April 31, 2012, for eligibility. A total of 153 patients were excluded for the following reasons: (1) alternative diagnoses were favored ranging from benign dermatitides to other forms of cutaneous lymphoma; (2) technical problems with slides; and (3) lack of follow-up information. Data were analyzed from January 1, 2018, to August 31, 2020. Main Outcomes and Measures Kaplan-Meier curves were used to estimate overall survival and DSS for the entire cohort. Possible predictive variables associated with survival were evaluated using Cox proportional hazards regression modeling. Each variable was examined separately, followed by a multiple-variable model. Kaplan-Meier curves were used to estimate overall survival and DSS by subdividing the cohort into early- and advanced-stage cutaneous disease. Results Forty-two patients were included in the analysis (mean age at diagnosis, 55 [range, 8-89] years; 31 men [74%]). For the entire cohort, the estimated 5-year overall survival rate was 89% (95% CI, 79%-99%); 10-year rate, 78% (95% CI, 63%-92%); and 15-year rate, 58% (95% CI, 31%-85%). Estimated 5- and 10-year DSS rates were 89% (95% CI, 79%-99%); 15-year rate, 80% (95% CI, 61%-99%). For overall survival in the multiple-variable Cox proportional hazards regression model, only age was statistically significant (hazard ratio [HR] per 10-year age increase, 3.1; 95% CI, 1.4-7.2;P = .008), whereas for DSS, only cutaneous disease was statistically significant (HR, 11.4; 95% CI, 1.3-103.0;P = .03). When stage stratified, the 5-year estimated overall survival rate for early-stage disease was 96% (95% CI, 89%-103%); 10-year rate, 82% (95% CI, 65%-98%); and 15-year rate, 65% (95% CI, 33%-97%). For advanced-stage disease, the estimated 5- and 10-year overall survival rates were 70% (95% CI, 41%-98%); the 15-year rate, 53% (95% CI, 16%-89%). For early-stage cutaneous disease, the estimated 5-, 10- and 15-year DSS rates were all 96% (95% CI, 89%-103%). For advanced-stage cutaneous disease, the estimated 5- and 10-year DSS rates were 70% (95% CI, 41%-98%); the 15-year rate, 53% (95% CI, 16%-89%). Conclusions and Relevance Cox proportional hazards regression modeling demonstrated cutaneous stage to be the only statistically significant predictive variable associated with DSS. Subdividing FMF into early and advanced cutaneous stages was associated with effective estimation of survival in this cohort. Thus, findings suggest that FMF is a heterogeneous disease with early and advanced cutaneous stages; that the new staging system is effective in estimating survival in a US cohort; and that the poor prognosis initially associated with FMF only applies to the advanced cutaneous stage.

In 2014, autologous hematopoietic cell transplant (autoHCT) was removed from the National Comprehensive Cancer Network guidelines as a recommended treatment for patients with intermediate-risk AML in first complete remission (CR1). We reviewed the outcomes of all patients with intermediate-risk AML treated with autoHCT in CR1 at our institution. Of 334 patients who underwent autoHCT for AML between 1988 and 2013, 133 patients with intermediate-risk AML in CR1 were identified. Cytogenetics were diploid in 97 (73%). With a median follow-up of 4.1 years (range 0.1-17), median overall survival (OS) is 6.7 years; at 5 years post-transplant, 59% of patients remain alive and 43% remain relapse-free. Forty-eight percent of relapsing patients proceeded to salvage alloHCT. Our findings demonstrate that nearly half of patients with intermediate-risk AML in CR1 achieve sustained remissions, and that salvage alloHCT is feasible in those who relapse. AutoHCT therefore remains a reasonable option for intermediate-risk patients with AML in CR1.

Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is a rare form of cutaneous T-cell lymphoma characterized by neoplastic α/β T cells infiltrating subcutaneous tissues in a lobular pattern. Few data support the optimal treatment regimen for patients, given the rarity of this condition, and even fewer data describe treatment when diagnosed during pregnancy. We describe a case of SPTCL in a pregnant patient who achieved clinical remission after treatment with corticosteroid monotherapy. Our case suggests that corticosteroids should be considered as first-line treatment in pregnant patients with SPTCL.