Search

The treatment and evolution of B-cell non-Hodgkin lymphoma (B-NHL) has undergone important changes in the last years with the emergence of targeted therapies, such as monoclonal antibodies, small molecules, antibody-drug conjugates, and bispecific antibodies. Nevertheless, a significant portion of patients remains refractory or relapsed (R/R) to the new therapeutic modalities, representing thus an unmet medical need. The use of CAR-T cells for the treatment of B-NHL patients has shown to be a promising therapy with impressive results in patients with R/R disease. The expectations are as high as the imminent approval of CAR-T cell therapy in Brazil, which it is expected to impact the prognosis of R/R B-NHL. The aim of this manuscript is to offer a consensus of specialists in the field of onco-hematology and cellular therapy, working in Brazil and United States, in order to discuss and offer recommendations in the present setting of the use of CAR-T cells for patients with B-NHL.

We present long-term combined results of two clinical trials implementing R-MACLO-IVAM induction followed by thalidomide or rituximab maintenance in 44 patients with untreated mantle cell lymphoma (MCL). The first 22 patients (UM-MCL1 ClinicalTrials.gov identifier NCT00450801) received maintenance with thalidomide (200 mg daily until relapse/intolerable toxicity) and a subsequent cohort of 22 patients (UM-MCL2 ClinicalTrials.gov identifier NCT00878254) received rituximab (375 mg/m2 IV weekly × 4, repeated every 6 months for 3 years). Considering all 44 patients, 41 (93.2%) achieved complete response (CR), two (4.5%) partial response (PR), and one (2.3%) was not evaluated for response. With a median follow up of 7.2 years (range < 1 month to 16 years), the 5-year progression-free survival (PFS) was 55.6% (95% CI: 38.9%-69.4%) and median PFS 7.9 years (95% CI: 3.7-11 years). The 5-year OS was 83.3% (95% CI: 68.1%-91.7%) and median OS was not reached. Patients with blastic variant (n = 6) had a 5-year PFS and OS of 20.8% and 60%, respectively. Myelosuppression was the most common adverse event during immunochemotherapy. Long-term treatment-related mortality was 6.8%. Note, R-MACLO-IVAM followed by maintenance therapy is an effective regimen to induce long-term remission in MCL without need for consolidation with ASCT.

Chimeric antigen receptor T-cells (CAR-T cells) are a new modality of oncological treatment which has demonstrated impressive response in refractory or relapsed diseases, such as acute lymphoblastic leukemia (ALL), lymphomas, and myeloma but is also associated with unique and potentially life-threatening toxicities. The most common adverse events (AEs) include cytokine release syndrome (CRS), neurological toxicities, such as the immune effector cell-associated neurotoxicity syndrome (ICANS), cytopenias, infections, and hypogammaglobulinemia. These may be severe and require admission of the patient to an intensive care unit. However, these AEs are manageable when recognized early and treated by a duly trained team. The objective of this article is to report a consensus compiled by specialists in the fields of oncohematology, bone marrow transplantation, and cellular therapy describing recommendations on the Clinical Centers preparation, training of teams that will use CAR-T cells, and leading clinical questions as to their use and the management of potential complications.

Background: Covalent BTK inhibitors (BTKi) have transformed the management of MCL, WM, and MZL. Despite the marked efficacy of covalent BTKi, treatment failure can occur through the development of resistance and discontinuation for adverse events. Covalent BTKi also share pharmacologic liabilities (e.g. low oral bioavailability, short half-life) that may lead to suboptimal BTK target coverage, for example in rapidly proliferating tumors with high BTK protein turnover, ultimately manifesting as acquired resistance in some patients (pts). To address these limitations, LOXO-305, a highly selective, non-covalent BTKi that inhibits both wild type (WT) and C481-mutated BTK with equal low nM potency was developed. The aim of the BRUIN trial was to define the safety and early efficacy of LOXO-305 in pts with B-cell malignancies. Here we report these data in pts with previously treated MCL, WM, and other NHLs. Methods: BRUIN is a multicenter phase 1/2 trial (NCT 03740529) enrolling pts with advanced B-cell malignancies who have received >2 prior therapies. Dose was escalated according to a standard 3+3 design with LOXO-305 dosed orally in 28-day cycles. The primary endpoint was MTD/RP2D identification. Intra-patient dose-escalation to previously cleared dose levels was permitted. Efficacy evaluable pts included all dosed pts who underwent their first response evaluation or discontinued therapy. Response was assessed every 8 weeks from cycle 3, and every 12 weeks from cycle 13 and was measured according to Lugano Classification or iWWM. Safety was assessed in all pts (CLL/SLL and NHL, n=186). Results: As of 30 April 2020, 186 pts with B-cell malignancies (94 CLL/SLL, 38 MCL, 19 DLBCL, 17 WM, 6 FL, 5 MZL, and 7 Other [B-PLL and Richter's transformation]) were treated on 7 dose levels (25mg to 300mg QD). Among the 92 pts with NHL, the median age was 68 (range 27-87) years. Median number of prior lines of therapy was 2 for MCL (range 2-8), and 3 for other NHLs (range 2-11). 92% of MCL pts had received a prior BTKi; 87% received at least an anti-CD20 antibody, chemotherapy, and BTKi; 10 pts had received SCT/CAR-T; 71% of WM pts had received a prior BTKi. LOXO-305 demonstrated high oral exposures, with doses ≥100mg QD exceeding the BTK IC90 for the entirety of the dosing interval. There were no DLTs or dose reductions. Consistent with LOXO-305's selectivity, the only treatment emergent adverse events regardless of attribution or grade seen in >10% of pts (n=186) were fatigue (n=29, 16%) and diarrhea (n=28, 15%). Responses were observed at the first dose level of 25mg QD. A RP2D of 200mg QD was selected for future studies. At the efficacy cutoff date, 24 MCL pts (63%) and 35 other NHL pts (65%) remained on therapy. Among the 35 efficacy-evaluable MCL pts treated across all dose levels, the ORR was 51% including 9 CRs, 9 PRs, 7 SDs, 8 PDs, and 2 NEs. An additional 3 MCL pts were awaiting initial radiologic assessment. Among the subset of 20 efficacy evaluable MCL pts who started at the RP2D (200mg QD), the ORR was 65% including 7 CRs, 6 PR, 4 SDs, 1 PD and 2 NEs. Of the 18 responding pts treated at any dose, all except 2 remain on therapy, with the longest followed responding pt on treatment for 14 months and ongoing. Of the 2 responding pts who have discontinued treatment, 1 progressed and 1 achieved a CR and electively discontinued treatment to undergo allogeneic stem cell transplant. Responses in MCL have been observed in pts who received prior cell therapy, including 3 of 7 patents with prior SCT, and 1 of 2 with prior CAR-T. Among the 15 efficacy-evaluable pts with WM, the ORR was 60% (1 VGPR, 4 PRs, 4 MRs, 5 SDs, 1 NE), and also 60% in the subset with prior BTKi treatment. 8 of 9 WM responders were ongoing (follow-up time from initial response: 0.1-4.8 months). For the remaining 29 efficacy-evaluable other NHL pts, best response was as follows: DLBCL (3 CRs, 1 SD, 6 PDs, 5 NEs), FL (3 PRs, 1 SD, 1 PD), MZL (2 PRs, 1 SD) and Other [5 Richter's transformation, 1 B-PLL] (2 PRs, 2 SDs, 2 NEs). Conclusion: LOXO-305 demonstrated promising efficacy in heavily pretreated, poor-prognosis MCL pts following multiple prior lines of therapy, including covalent BTKi. Early efficacy was also observed in BTK-treated WM, as well as heavily pretreated other NHLs. LOXO-305 was well tolerated and exhibited a wide therapeutic index. Disclosures Wang: Kite Pharma: Consultancy, Other: Travel, accommodation, expenses, Research Funding; Loxo Oncology: Consultancy, Research Funding; Verastem: Research Funding; Molecular Templates: Research Funding; Dava Oncology: Honoraria; InnoCare: Consultancy; Oncternal: Consultancy, Research Funding; Nobel Insights: Consultancy; VelosBio: Research Funding; OMI: Honoraria, Other: Travel, accommodation, expenses; Celgene: Consultancy, Other: Travel, accommodation, expenses, Research Funding; AstraZeneca: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Pharmacyclics: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Targeted Oncology: Honoraria; Juno: Consultancy, Research Funding; BioInvent: Research Funding; Lu Daopei Medical Group: Honoraria; OncLive: Honoraria; Beijing Medical Award Foundation: Honoraria; MoreHealth: Consultancy; Guidepoint Global: Consultancy; Acerta Pharma: Research Funding; Pulse Biosciences: Consultancy. Shah:Cell Vault: Research Funding; Miltenyi Biotec: Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Incyte: Consultancy; Lily: Consultancy, Honoraria; Kite Pharma: Consultancy, Honoraria; Verastim: Consultancy; TG Therapeutics: Consultancy. Alencar:Genentech, Celgene, KITE, Loxo Oncology at Lilly: Consultancy. Gerson:Loxo: Research Funding; Pharmacyclics: Consultancy; Abbvie: Consultancy; Genentech: Consultancy. Fakhri:University of California San Francisco: Current Employment. Jurczak:MeiPharma: Research Funding; Roche: Research Funding; Takeda: Research Funding; Jagiellonian University, Krakow, Poland: Ended employment in the past 24 months; Pharmacyclics: Research Funding; Bayer: Research Funding; Janssen: Research Funding; Acerta: Research Funding; TG Therapeutics: Research Funding; Maria Sklodowska-Curie National Research Institute of Oncology, Krakow, Poland: Current Employment. Tan:Sir Charles Gairdner Hospital and Linear Clinical Research: Current Employment. Lewis:Sir Charles Gairdner Hospital and Linear Clinical Research: Current Employment. Fenske:Medical College of Wisconsin: Current Employment. Coombs:Novartis: Honoraria; Octapharma: Honoraria; LOXO Oncology: Honoraria; MEI Pharma: Honoraria; AstraZeneca: Honoraria; Genentech: Honoraria; Abbvie: Consultancy, Honoraria. Flinn:Calithera Biosciences: Research Funding; Loxo: Research Funding; IGM Biosciences: Research Funding; Takeda: Consultancy, Research Funding; Genentech, Inc.: Research Funding; F. Hoffmann-La Roche: Research Funding; Gilead Sciences: Consultancy, Research Funding; Agios: Research Funding; Karyopharm Therapeutics: Research Funding; Incyte: Research Funding; BeiGene: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; Curio Science: Consultancy; MorphoSys: Consultancy, Research Funding; Curis: Research Funding; Nurix Therapeutics: Consultancy; Novartis: Research Funding; Pfizer: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Portola Pharmaceuticals: Research Funding; Seattle Genetics: Consultancy, Research Funding; Teva: Research Funding; Constellation Pharmaceuticals: Research Funding; Great Point Partners: Consultancy; Forma Therapeutics: Research Funding; Iksuda Therapeutics: Consultancy; Unum Therapeutics: Consultancy, Research Funding; Juno Therapeutics: Consultancy, Research Funding; Infinity Pharmaceuticals: Research Funding; Acerta Pharma: Research Funding; AbbVie: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Trillium Therapeutics: Research Funding; Triphase Research & Development Corp.: Research Funding; Verastem: Consultancy, Research Funding; Yingli Pharmaceuticals ≠: Consultancy, Research Funding; Rhizen Pharmaceuticals: Research Funding; Johnson & Johnson: Other; Roche: Consultancy, Research Funding; Vincera Pharma: Consultancy; Merck: Research Funding; Celgene: Research Funding; ArQule: Research Funding; Kite Pharma: Consultancy, Research Funding; Forty Seven: Research Funding. Le Gouill:Loxo Oncology at Lilly: Consultancy; Roche Genentech, Janssen-Cilag and Abbvie, Celgene, Jazz pharmaceutical, Gilead-kite, Loxo, Daiichi-Sankyo and Servier: Honoraria. Palomba:Celgene: Honoraria; Pharmacyclics: Honoraria; Genentech: Research Funding; Novartis: Honoraria; Merck: Honoraria; Juno Therapeutics, a Bristol-Meyers Squibb Company: Honoraria, Research Funding; Regeneron: Research Funding. Woyach:Janssen, Pharmacyclics, AstraZeneca, Abbvie, Arqule: Consultancy; Pharmacyclics, Janssen, Morphosys, Karyopharm, Verastem, Abbvie, Lox: Research Funding; Pharmacyclics LLC, an AbbVie Company, AbbVie, Janssen, AstraZeneca, ArQule: Honoraria. Lamanna:Columbia University Medical Center: Current Employment; MingSight: Other: Institutional research grants, Research Funding; Octapharma: Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bei-Gene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional research grants, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional research grants, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional research grants, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Juno: Other: Institutional research grants, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional research grants, Research Funding; Loxo: Research Funding; Oncternal, Verastem, TG Therapeutics: Other: Institutional research grants, Research Funding. Cohen:Genentech, BMS, Novartis, LAM, BioInvent, LRF, ASH, Astra Zeneca, Seattle Genetics: Research Funding; Janssen, Adicet, Astra Zeneca, Genentech, Aptitude Health, Cellectar, Kite/Gilead, Loxo: Consultancy. Ghia:Gilead: Consultancy, Honoraria, Research Funding; ArQule: Consultancy, Honoraria; Acerta/AstraZeneca: Consultancy, Honoraria; BeiGene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Celgene/Juno: Consultancy, Honoraria; Lilly: Consultancy, Honoraria; MEI: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria, Research Funding; Adaptive, Dynamo: Consultancy, Honoraria; Novartis: Research Funding; AbbVie: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding. Eyre:KITE, AZ, Loxo Oncology at Lilly: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Other: travel support; AbbVie: Consultancy, Honoraria, Other: travel support; Gilead: Consultancy, Honoraria, Other: travel support. Yin:Loxo Oncology at Lilly: Current Employment. Nair:Loxo Oncology at Lilly: Current Employment. Tsai:Loxo Oncology at Lilly: Current Employment. Ku:Loxo Oncology at Lilly: Current Employment. Mato:Pharmacyclics: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Loxo: Consultancy, Research Funding; Genentech: Consultancy, Research Funding. Cheah:Celgene, F. Hoffmann-La Roche, MSD, Janssen, Gilead, Ascentage Pharma, Acerta, Loxo Oncology, TG therapeutics: Honoraria; Celgene, F. Hoffmann-La Roche, Abbvie, MSD: Research Funding.

The dermatologic manifestations of Waldenstrom macroglobulinemia (WM) are typically categorized as disease specific or non–disease specific.1 Non–disease-specific findings are related to hyperviscosity or cryoglobulinemia, including mucosal bleeding, purpura, livedo reticularis, and Raynaud phenomenon. Two rare types of specific skin findings have been identified: cutaneous infiltrates of mature B-cell neoplasms, specifically heavy-chain or malignant immunoproliferative diseases, and deposits of monoclonal immunoglobulin (Ig) M, referred to as cutaneous macroglobulinosis (CM). Although classically described in patients with WM, cutaneous deposition could develop in any condition associated with IgM paraproteinemia. First documented in 1978 by Tichenor et al,2 CM is remarkable for its association with underlying plasma cell dyscrasias and its ability to mimic other depositional disorders. Here, we report a patient initially diagnosed with lymphoplasmacytic lymphoma (LPL) whose subsequent development of neuropathy and hyperviscosity syndrome due to elevated serum IgM led to a diagnosis of WM. The patient then developed a disseminated cutaneous presentation of CM, with minimal residual WM disease and cryoglobulinemia.

Context: Despite the marked efficacy of covalent BTK inhibitors (BTKi) in CLL/SLL, the development of resistance and discontinuation for adverse events can lead to treatment failure. Low oral bioavailability or short half-life of these agents can lead to suboptimal BTK target coverage and ultimately result in acquired resistance in some patients (pts). Pirtobrutinib (LOXO-305) is a highly selective, non-covalent BTKi that inhibits both WT and C481-mutated BTK with equal, low nM potency. Objective: To evaluate pirtobrutinib safety and efficacy in pts with CLL/SLL. Design: BRUIN is an ongoing multi-center phase 1/2 trial (NCT03740529). Enrollment was initiated 21 March 2019. Setting: Global: community hospitals, and academic medical centers. Patients: As of 27 September 2020, 323 previously treated pts with B-cell malignancies (170 CLL/SLL, 61 MCL, 26 WM, and 66 other B-cell lymphomas) were enrolled. Interventions: Oral pirtobrutinib (7 dose escalation levels: 25–300mg once daily) in 28-day cycles. Main Outcomes Measures: Determining the maximum tolerated dose/recommended phase 2 dose (RP2D), safety profile, and efficacy based on response assessment using disease-specific criteria (iwCLL2018 for CLL/SLL) per protocol. Results: Pirtobrutinib demonstrated high oral exposures, with doses ≥100mg QD exceeding BTK IC90 for the entirety of the dosing interval. No DLTs occurred. The only treatment-emergent adverse events, regardless of attribution or grade seen in ≥10% of pts (n=323), were fatigue (20%), diarrhea (17%), and contusion (13%). An RP2D of 200 mg QD was selected for future studies. The ORR (per iwCLL 2018) was 63%, with 69 PRs, 19 PR-Ls, 45 SDs, 1 PD, and 5 discontinued prior to first response assessment. Responses deepened over time among pts with ≥10 months of follow-up (n=29; 86% ORR). ORR was not influenced by the reason for prior BTKi discontinuation (i.e., progression vs intolerance) or other classes of prior therapy received (including a covalent BTK and a BCL2 inhibitor). The longest followed responding pt continues on treatment for 17.8+ months. Conclusions: Pirtobrutinib showed promising efficacy in pre-treated CLL/SLL pts, was well-tolerated, and exhibited a wide therapeutic index.

Context Despite the marked efficacy of covalent BTK inhibitors (BTKi) in MCL, WM, and MZL, the development of resistance and discontinuation for adverse events can lead to treatment failure. Low oral bioavailability or short half-life of these agents can lead to suboptimal BTK target coverage and ultimately result in acquired resistance in some patients (pts). Pirtobrutinib (LOXO-305) is a highly selective, non-covalent BTKi that inhibits both WT and C481-mutated BTK with equal, low nM potency. Objective To evaluate safety and efficacy of pirtobrutinib in pts with MCL/NHLs. Design BRUIN is an ongoing multi-center phase 1/2 trial (NCT03740529). Enrollment was initiated 21 March 2019. Setting Global: community hospitals, academic medical centers. Patients Previously treated pts with advanced B-cell malignancies. Interventions Oral pirtobrutinib (7 dose escalation levels: 25–300mg once daily) in 28-day cycles. Main Outcomes Measures Determining the maximum tolerated dose/recommended phase 2 dose (RP2D), safety profile, and efficacy based on response assessment using disease-specific criteria per protocol. Results As of 27 September 2020, 323 pts with B-cell malignancies (170 CLL/SLL, 61 MCL, 26 WM, and 66 other B-cell lymphomas) were treated on 7 dose levels (25–300mg QD). Pirtobrutinib demonstrated high oral exposures, with doses ≥100 mg QD exceeding the BTK IC90 for the entirety of the dosing interval. No DLTs occurred. The only TEAEs, regardless of attribution or grade in ≥10% of pts (n=323), were fatigue (20%), diarrhea (17%) and contusion (13%). A RP2D of 200mg QD was selected. At the efficacy cutoff date, 35 (57%) MCL pts, 18 (69%) WM pts, and 34 (52%) other NHL pts remained on therapy. Among the 52 efficacy evaluable prior BTKi treated MCL pts, the ORR was 52%. Among the 19 efficacy evaluable pts with WM, the ORR was 68%. For the other 55 efficacy evaluable NHL pts, ORR was 24% (DLBCL), 50% (FL), 22% (MZL), and 75% (Richter's transformation). Conclusion Pirtobrutinib demonstrated promising efficacy in MCL and other NHL pts, was well-tolerated and exhibited a wide therapeutic index.

International audience; Background: Covalent Bruton's tyrosine kinase (BTK) inhibitors are efficacious in multiple B-cell malignancies, but patients discontinue these agents due to resistance and intolerance. We evaluated the safety and efficacy of pirtobrutinib (working name; formerly known as LOXO-305), a highly selective, reversible BTK inhibitor, in these patients.Methods: Patients with previously treated B-cell malignancies were enrolled in a first-in-human, multicentre, open-label, phase 1/2 trial of the BTK inhibitor pirtobrutinib. The primary endpoint was the maximum tolerated dose (phase 1) and overall response rate (ORR; phase 2). This trial is registered with ClinicalTrials.gov, NCT03740529.Findings: 323 patients were treated with pirtobrutinib across seven dose levels (25 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, and 300 mg once per day) with linear dose-proportional exposures. No dose-limiting toxicities were observed and the maximum tolerated dose was not reached. The recommended phase 2 dose was 200 mg daily. Adverse events in at least 10% of 323 patients were fatigue (65 [20%]), diarrhoea (55 [17%]), and contusion (42 [13%]). The most common adverse event of grade 3 or higher was neutropenia (32 [10%]). There was no correlation between pirtobrutinib exposure and the frequency of grade 3 treatment-related adverse events. Grade 3 atrial fibrillation or flutter was not observed, and grade 3 haemorrhage was observed in one patient in the setting of mechanical trauma. Five (1%) patients discontinued treatment due to a treatment-related adverse event. In 121 efficacy evaluable patients with chronic lymphocytic leukaemia (CLL) or small lymphocytic lymphoma (SLL) treated with a previous covalent BTK inhibitor (median previous lines of treatment 4), the ORR with pirtobrutinib was 62% (95% CI 53-71). The ORR was similar in CLL patients with previous covalent BTK inhibitor resistance (53 [67%] of 79), covalent BTK inhibitor intolerance (22 [52%] of 42), BTK C481-mutant (17 [71%] of 24) and BTK wild-type (43 [66%] of 65) disease. In 52 efficacy evaluable patients with mantle cell lymphoma (MCL) previously treated with covalent BTK inhibitors, the ORR was 52% (95% CI 38-66). Of 117 patients with CLL, SLL, or MCL who responded, all but eight remain progression-free to date.Interpretation: Pirtobrutinib was safe and active in multiple B-cell malignancies, including patients previously treated with covalent BTK inhibitors. Pirtobrutinib might address a growing unmet need for alternative therapies for these patients.Funding: Loxo Oncology.

Background Langerhans cell tumors are rare clonal disorders characterized by neoplastic proliferation of dendritic cells that can be further classified into the subtypes Langerhans cell histiocytosis and Langerhans cell sarcoma, which are rare neoplasms exhibiting aggressive features and a poor prognosis. In addition to illustrating the refractoriness and poor outcomes of multisystem Langerhans cell histiocytosis in adults, specific events in this case highlight important characteristics of disease biology that warrant detailed discussion and exposition to a wider audience. Case presentation We describe the case of a 42-year-old Caucasian man with Langerhans cell histiocytosis diagnosed from a lesion on the left arm that presented with constitutional symptoms, early satiety, and weight loss. Esophagogastroduodenoscopy showed extensive esophageal and duodenal involvement by Langerhans cell histiocytosis with features of Langerhans cell sarcoma. He was initially treated for Langerhans cell histiocytosis with low doses of cytarabine until he eventually presented clear transformation to acute monoblastic leukemia with complex karyotype that could not be properly controlled, leading eventually to death. Conclusions Langerhans cell histiocytosis remains an exceedingly rare entity in adults, frequently presenting as multisystem disease with risk organ involvement. Langerhans cell sarcoma represents an aggressive subtype with extremely poor prognosis for which intensive acute myeloid leukemia induction should be strongly considered.

When South Florida became a hotspot for COVID-19 disease in March 2020, we faced an urgent need to develop test capability to detect SARS-CoV-2 infection. We assembled a transdisciplinary team of knowledgeable and dedicated physicians, scientists, technologists and administrators, who rapidly built a multi-platform, PCR- and serology-based detection program, established drive-thru facilities and drafted and implemented guidelines that enabled efficient testing of our patients and employees. This process was extremely complex, due to the limited availability of needed reagents, but outreach to our research scientists and to multiple diagnostic laboratory companies and government officials enabled us to implement both FDA authorized and laboratory developed testing (LDT)-based testing protocols. We analyzed our workforce needs and created teams of appropriately skilled and certified workers, to safely process patient samples and conduct SARS-CoV-2 testing and contact tracing. We initiated smart test ordering, interfaced all testing platforms with our electronic medical record, and went from zero testing capacity, to testing hundreds of healthcare workers and patients daily, within three weeks. We believe our experience can inform the efforts of others, when faced with a crisis situation.

When South Florida became a hot spot for COVID-19 disease in March 2020, we faced an urgent need to develop test capability to detect SARS-CoV-2 infection. We assembled a transdisciplinary team of knowledgeable and dedicated physicians, scientists, technologists, and administrators who rapidly built a multiplatform, polymerase chain reaction- and serology-based detection program, established drive-through facilities, and drafted and implemented guidelines that enabled efficient testing of our patients and employees. This process was extremely complex, due to the limited availability of needed reagents, but outreach to our research scientists and multiple diagnostic laboratory companies, and government officials enabled us to implement both Food and Drug Administration authorized and laboratory-developed testing-based testing protocols. We analyzed our workforce needs and created teams of appropriately skilled and certified workers to safely process patient samples and conduct SARS-CoV-2 testing and contact tracing. We initiated smart test ordering, interfaced all testing platforms with our electronic medical record, and went from zero testing capacity to testing hundreds of health care workers and patients daily, within 3 weeks. We believe our experience can inform the efforts of others when faced with a crisis situation.

The involvement of microRNAs in malignant transformation and cancer progression was previously grounded. The observations made by multiple published studies led to the conclusion that some of these small sequences could be eventually used as biomarkers for diagnosis/prognosis. This meta-analysis investigated whether microRNA-181 family members could predict the outcome of patients carrying different types of cancer. We searched the PubMed and Embase databases for studies evaluating the expression levels of miR-181a/b/c/d in patients with cancer, selecting the publications that assessed the relation between low and high levels of one of these four microRNAs and patients’ outcome. Hazard ratios (HRs) or risk ratios (RRs) were extracted from the studies, and random-effect model was performed to investigate the role of miR-181 in the outcome of these patients. The meta-analysis comprised 26 studies including 2653 cancer patients from 6 countries. The results showed significant association between the expression of miR-181 family members and colorectal cancer. Considering the heterogeneity of the pathologies, the analysis, including all types of cancer and the expression of all the miR-181 family members together, showed no association with distinct outcome (HR = 1.099, p = 0.435). When the analysis was performed on each microRNA separately, the expression of miR-181c was significantly associated with the outcome of patients with cancer (HR = 2.356, p = 0.011) and miR-181a expression levels significantly correlated with survival in patients with non-small-cell lung cancer (HR = 0.177, p

Introduction FCR remains the only therapy other than allo transplant proven to provide a significant chance of functional cure with very long term follow-up for young, fit patients with mutated IGHV CLL. Given the excellent efficacy and tolerability of ibrutinib in a broad population of young, fit CLL patients, we designed the frontline iFCR study to investigate whether time-limited novel agent plus chemoimmunotherapy could provide durable remission for CLL patients irrespective of IGHV status. We previously reported that with a median follow-up of 16.5 months, the rate of CR with bone marrow undetectable minimal residual disease (BM-uMRD) 2 months post-FCR (primary endpoint) was 33%, and that 84% of patients achieved BM-uMRD as best response (Davids et al., Lancet Haem, 2019). Here, we report updated data with longer follow-up, with all patients having had the opportunity to complete 2 years of ibrutinib maintenance following iFCR. Methods This is a multicenter, single arm, phase 2 investigator sponsored trial (NCT02251548) which enrolled CLL patients age ≤65 years without restriction by IGHV mutation status, all of whom met iwCLL treatment criteria. Ibrutinib 420 mg daily was given for 7 days, then combination ibrutinib with FCR for up to 6 cycles. Responders continued on ibrutinib maintenance, and patients with BM-uMRD after 2 years of maintenance discontinued therapy. Response was assessed by 2008 iwCLL criteria, and toxicity by CTCAE v4.03 and iwCLL criteria. The primary objective was to determine the rate of CR/CRi with BM-uMRD 2 months after iFCR combination. Secondary objectives were to assess response rates, PFS/OS, rates of BM-uMRD after 2 years of ibrutinib maintenance, and safety/tolerability. Results Between October, 2014, and April, 2018, 85 patients were enrolled at 9 US sites.As previously reported, the median age was 55 years (range 38-65). IGHV was unmutated in 46/79 patients (58.2%). Deletion of 17p and TP53 mutation were present in 4/83 (4.8%) and 3/81 (3.7%) patients, respectively; 2 of these patients had both. The median number of FCR cycles completed was 6 (range 1-6). Median follow-up is now 40.3 months (range 3.1-76). Median number of ibrutinib maintenance cycles is 24 (range 0-81). By ITT analysis, the rate of CR with BM-uMRD at any point on study is now 55% (47/85 patients), and best rate of BM-uMRD remained 84% (71/85). After 2 years of ibrutinib maintenance, the rates of CR/CRi, BM-uMRD, and PB-uMRD in patients with available data were 77% (44/57), 81% (50/62), and 81% (55/68), respectively, with no differences based on IGHV status. At the median follow-up time of 40 months, PFS and OS for all patients were 97% and 99%, respectively (see Figure, below). Thirteen of 61 patients (21.3%) who completed iFCR and started ibrutinib maintenance in a BM-uMRD state have had recurrent BM-MRD, with median time to MRD recurrence not yet reached. Seven patients underwent retreatment with ibrutinib monotherapy (5 due to clinical progression and 2 due to recurrent BM-MRD without clinical progression), and all 7 achieved PR with re-treatment. Median time on re-treatment is 12.8 months (range 4.2-26.2), and none of these 7 patients have progressed on re-treatment. One patient died 17 months into ibrutinib maintenance due to presumed sudden cardiac death. In the updated safety analysis, the most common treatment-emergent Gr 3/4 adverse events were hematologic, including neutropenia 40% (up from 35%), thrombocytopenia 32% (unchanged), and anemia 11% (unchanged). Ten patients (12%, up from 9%) experienced Gr ≥3 febrile neutropenia, and 20 patients (24%, up from 11%) had Gr ≥3 infection. Any Gr atrial fibrillation was observed in 8%, and ventricular arrhythmia in 1 patient. No major bleeding events occurred. Two patients developed MDS, and both are now in CR for CLL and MDS after undergoing allo transplant. No patients developed Richter's syndrome. Conclusions With longer term follow-up (median of 40.3 months), most patients treated with iFCR have continued to maintain deep responses, including patients with unmutated IGHV. The safety profile remains consistent with the individual toxicities of ibrutinib and FCR. Among the few patients with recurrence after this time-limited therapy, all have responded to re-treatment with ibrutinib monotherapy. iFCR is worthy of exploring in comparative studies in younger, fit CLL patients who desire the possibility of functional cure with time-limited therapy. Figure 1 Figure 1. Disclosures Davids: Ascentage Pharma: Consultancy, Research Funding; Celgene: Consultancy; Eli Lilly and Company: Consultancy; Janssen: Consultancy; MEI Pharma: Consultancy; Merck: Consultancy; Research to Practice: Consultancy; Takeda: Consultancy; Novartis: Consultancy, Research Funding; BeiGene: Consultancy; Adaptive Biotechnologies: Consultancy; Astra-Zeneca: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; MEI Pharma: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; Verastem: Consultancy, Research Funding; Surface Oncology: Research Funding; AbbVie: Consultancy. Brander: NCCN: Other: panel member; Verastem: Consultancy; MEI Pharma: Research Funding; Juno Therapeutics/Celgene/Bristol Myers Squibb: Research Funding; ArQule: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Pfizer: Consultancy, Other: Biosimilars outcomes research panel; DTRM: Research Funding; ArQule/Merck: Consultancy; LOXO: Research Funding; AbbVie: Consultancy, Other: informCLL registry steering committee, Research Funding; TG Therapeutics: Consultancy, Research Funding; AstraZeneca: Research Funding; Novartis: Research Funding; Genentech: Consultancy, Research Funding; Ascentage: Research Funding; BeiGene: Research Funding. Montegaard: AbbVie: Consultancy; AstraZeneca*-: Consultancy; Janssen: Consultancy; Pharmacyclics: Consultancy. Alencar: Seattle Genetics: Consultancy; Kite Pharma: Consultancy; Karyopharm: Consultancy; Janssen: Consultancy; Incyte: Consultancy; Epizyme: Consultancy; Celgene: Consultancy; BeiGene: Consultancy; Amgen: Consultancy. Jacobson: Humanigen: Consultancy, Honoraria, Other: Travel support; Pfizer: Consultancy, Honoraria, Other: Travel support, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel support; Novartis Pharmaceuticals Corporation: Consultancy, Honoraria, Other: Travel support; Celgene: Consultancy, Honoraria, Other: Travel support; AbbVie: Consultancy, Honoraria; Axis: Speakers Bureau; Lonza: Consultancy, Honoraria, Other: Travel support; Clinical Care Options: Speakers Bureau; Precision Biosciences: Consultancy, Honoraria, Other: Travel support; Nkarta: Consultancy, Honoraria. Armand: Infinity: Consultancy; Pfizer: Consultancy; Kite: Research Funding; Tensha: Research Funding; IGM: Research Funding; Roche: Research Funding; Genentech: Consultancy, Research Funding; AstraZeneca: Consultancy; Epizyme: Consultancy; Enterome: Consultancy; Regeneron: Consultancy; C4: Consultancy; GenMab: Consultancy; Tessa Therapeutics: Consultancy; Miltenyi: Consultancy; Morphosys: Consultancy; Daiichi Sankyo: Consultancy; Otsuka: Research Funding; Sigma Tau: Research Funding; Celgene: Consultancy; ADC Therapeutics: Consultancy; Adaptive: Consultancy, Research Funding; Affimed: Consultancy, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding. Crombie: Roche: Research Funding; Merck: Research Funding; Abbvie: Research Funding; Bayer: Research Funding; Karyopharm: Consultancy; Incyte: Consultancy. LaCasce: Bristol-Myers Squibb Company.: Other: Data Safetly and Monitoring. Arnason: Juno/BMS: Honoraria. Hochberg: Trapelo Health: Consultancy; Leuko: Consultancy. Abramson: Bristol-Myers Squibb Company: Consultancy, Research Funding; Kite Pharma: Consultancy; Novartis: Consultancy; Morphosys: Consultancy; C4 Therapeutics: Consultancy; EMD Serono: Consultancy; Genmab: Consultancy; Bluebird Bio: Consultancy; Kymera: Consultancy; BeiGene: Consultancy; Incyte Corporation: Consultancy; Astra-Zeneca: Consultancy; Allogene Therapeutics: Consultancy; Seagen Inc.: Research Funding; AbbVie: Consultancy; Karyopharm: Consultancy; Genentech: Consultancy. Brown: Gilead, Loxo/Lilly, SecuraBio, Sun, TG Therapeutics: Research Funding; Invectys: Other: Data Safety Monitoring Committee Service; Abbvie, Acerta/Astra-Zeneca, Beigene, Bristol-Myers Squibb/Juno/Celgene, Catapult, Eli Lilly, Genentech/Roche, Janssen, MEI Pharma, Morphosys AG, Nextcea, Novartis, Pfizer, Rigel: Consultancy. OffLabel Disclosure: Ibrutinib being used to enhance the efficacy of FCR

Background: B-cell lymphoma 2 (BCL2) is a key regulator of apoptosis and provides protection from cell death in many hematological malignancies. The BCL2 inhibitor venetoclax is approved for the treatment of CLL/SLL and acute myeloid leukemia and has activity in other lymphoid malignancies. LOXO-338 is a novel, orally bioavailable small molecule inhibitor of BCL2, designed to achieve selectivity over BCL-xL and thus avoid dose-limiting thrombocytopenia associated with BCL-xL inhibition. In preclinical studies, LOXO-338 showed a favorable pharmacological profile, selectively inhibited BCL2, and was well-tolerated in vivo. LOXO-338 also demonstrated dose-dependent tumor growth inhibition in various murine xenograft models, and showed improved efficacy in combination with pirtobrutinib, a highly selective, non-covalent BTK inhibitor (Brandhuber et al. Cancer Res 2021; 81, 13 Supplement, 1258). Study Design and Methods: LOXO-BCL-20001 is an open-label, multi-center, first-in-human Phase 1 study of oral LOXO-338 in patients with advanced hematologic malignancies who have received standard therapy. The study will be conducted in 2 parts. Part 1 will evaluate LOXO-338 as monotherapy, and will explore different dosing strategies. Part 2 will evaluate LOXO-338 in combination with pirtobrutinib. The dose escalation portion of the study in Part 1 will follow an i3+3 design. Each cycle will be 28 days (4 weeks). Eligible patients include those with CLL/SLL, mantle cell lymphoma (MCL), and Waldenstrӧm macroglobulinemia (WM) who have already received standard therapy. Patients with other B-cell non-Hodgkin lymphomas (NHLs) who failed standard therapy or, in the opinion of the investigator, have no known available options to provide benefit for the patient's condition, are also eligible. Patients must have recovered from prior treatment-related adverse events. Patients with active or suspected Richter transformation, transformed low grade lymphoma, Burkitt or Burkitt-like lymphoma, and multiple myeloma (MM) are eligible in dose-expansion. Key exclusion criteria include history of CNS involvement, stem cell transplant or CAR-T therapy The primary objective of Part 1 is to determine the maximum tolerated dose (MTD)/ recommended Phase 2 dose (RP2D) of oral LOXO-338 in patients who were previously treated for CLL/SLL and other B-cell NHLs. Key secondary objectives include determining the safety and tolerability, and pharmacokinetic properties of LOXO-338. Antitumor activity will be evaluated based on overall response rate (ORR), progression-free survival (PFS), time to progression (TTP) and duration of response (DOR) based on disease-specific response criteria per investigator assessment. Key objectives of part 2 are to determine the safety profile and tolerability, PK properties, and anti-tumor activity of LOXO-338 in combination with pirtobrutinib. Disclosures Alencar: Seattle Genetics: Consultancy; Kite Pharma: Consultancy; Karyopharm: Consultancy; Janssen: Consultancy; Incyte: Consultancy; Epizyme: Consultancy; Celgene: Consultancy; BeiGene: Consultancy; Amgen: Consultancy. Roeker: AbbVie, AstraZeneca, Janssen, LOXO, Pharmacyclics, TG Therapeutics, Vaniam Group, Verastem: Consultancy; Pharmacyclics: Consultancy; Pfizer: Consultancy, Research Funding; Loxo Oncology: Consultancy; TG Therapeutics: Consultancy; Abbot Laboratories: Current equity holder in publicly-traded company. Hoffmann: TG Therapeutics: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pharmcyclics: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; celgene: Consultancy, Honoraria. Guru Murthy: Cancerexpertnow: Honoraria; Guidepoint: Consultancy; Techspert: Consultancy; Qessential: Consultancy; Cardinal Health Inc.: Honoraria; TG therapeutics: Other: Advisory board. Patel: Loxo Oncology at Lilly: Current Employment, Current equity holder in publicly-traded company. Ku: Loxo Oncology at Lilly: Current Employment, Current holder of stock options in a privately-held company. Pauff: Loxo Oncology at Lilly: Current Employment, Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company. Eyre: Incyte: Consultancy; Loxo Oncology: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Beigene: Honoraria, Research Funding; Roche: Consultancy, Honoraria; Gilead/KITE: Honoraria, Other: Travel support for conferences, Research Funding, Speakers Bureau; Secura Bio: Consultancy, Honoraria; Janssen: Honoraria; Abbvie: Consultancy, Honoraria, Other: Travel to conferences; AstraZeneca: Honoraria, Research Funding. Jurczak: Celtrion: Research Funding; Celgene: Research Funding; Debbiopharm: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Loxo Oncology: Membership on an entity's Board of Directors or advisory committees; Sandoz: Membership on an entity's Board of Directors or advisory committees; BeiGene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Research Funding; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Epizyme: Research Funding; Incyte: Research Funding; Merck: Research Funding; Takeda: Research Funding; TG Therapeutics: Research Funding. OffLabel Disclosure: LOXO-338 is a novel, orally bioavailable small molecule inhibitor of BCL2 for advanced hematologic malignancies.

PURPOSE: Nivolumab, an anti–programmed death-1 monoclonal antibody, has demonstrated frequent and durable responses in relapsed/refractory classic Hodgkin lymphoma (cHL). We report results from Cohort D of the CheckMate 205 trial, which assessed nivolumab monotherapy followed by nivolumab plus doxorubicin, vinblastine, and dacarbazine (N-AVD) for newly diagnosed cHL. METHODS: Patients 18 years of age or older with untreated, advanced-stage (defined as III to IV and IIB with unfavorable risk factors) cHL were eligible for Cohort D of this multicenter, noncomparative, phase II trial. Patients received nivolumab monotherapy for four doses, followed by 12 doses of N-AVD; all doses were every 2 weeks, and nivolumab was administered at 240 mg intravenously. The primary end point was safety. Efficacy end points included objective response rate and modified progression-free survival, defined as time to disease progression/relapse, death, or next therapy. Chromosome 9p24.1 alterations and programmed death-ligand 1 expression were assessed in Hodgkin Reed-Sternberg cells in evaluable patients. RESULTS: A total of 51 patients were enrolled and treated. At diagnosis, 49% of patients had an International Prognostic Score of 3 or greater. Overall, 59% experienced a grade 3 to 4 treatment-related adverse event. Treatment-related febrile neutropenia was reported in 10% of patients. Endocrine immune-mediated adverse events were all grade 1 to 2 and did not require high-dose corticosteroids; all nonendocrine immune-mediated adverse events resolved (most commonly, rash; 5.9%). At the end of therapy, the objective response rate (95% CI) per independent radiology review committee was 84% (71% to 93%), with 67% (52% to 79%), achieving complete remission (five patients [10%] were nonevaluable and counted as nonresponders). With a minimum follow-up of 9.4 months, 9-month modified progression-free survival was 92%. Patients with higher-level Hodgkin Reed-Sternberg programmed death-ligand 1 expression had more favorable responses to N-AVD (P = .041). CONCLUSION: Nivolumab followed by N-AVD was associated with promising efficacy and safety profiles for newly diagnosed, advanced-stage cHL.

Summary Background Fludarabine, cyclophosphamide, and rituximab (FCR) can improve disease-free survival for younger (age ≤65 years) fit patients with chronic lymphocytic leukaemia with mutated IGHV. However, patients with unmutated IGHV rarely have durable responses. Ibrutinib is active for patients with chronic lymphocytic leukaemia irrespective of IGHV mutation status but requires continuous treatment. We postulated that time-limited ibrutinib plus FCR would induce durable responses in younger fit patients with chronic lymphocytic leukaemia. Methods We did a multicentre, open-label, non-randomised, single-arm phase 2 trial at seven sites in the USA. We enrolled patients aged 65 years or younger with previously untreated chronic lymphocytic leukaemia. Our initial cohort (original cohort) was not restricted by prognostic marker status and included patients who had del(17p) or TP53 aberrations. After a protocol amendment (on March 21, 2017), we enrolled an additional cohort (expansion cohort) that included patients without del(17p). Ibrutinib was given orally (420 mg/day) for 7 days, then up to six 28-day cycles were administered intravenously of fludarabine (25 mg/m2, days 1–3), cyclophosphamide (250 mg/m2, days 1–3), and rituximab (375 mg/m2 day 1 of cycle 1; 500 mg/m2 day 1 of cycles 2–6) with continuous oral ibrutinib (420 mg/day). Responders continued on ibrutinib maintenance for up to 2 years, and patients with undetectable minimal residual disease in bone marrow after 2 years were able to discontinue treatment. The primary endpoint was the proportion of patients who achieved a complete response with undetectable minimal residual disease in bone marrow 2 months after the last cycle of ibrutinib plus FCR. Analyses were done per-protocol in all patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov ( NCT02251548 ) and is ongoing. Findings Between Oct 23, 2014, and April 23, 2018, 85 patients with chronic lymphocytic leukaemia were enrolled. del(17p) was detected in four (5%) of 83 patients and TP53 mutations were noted in three (4%) of 81 patients; two patients had both del(17p) and TP53 mutations. Median patients' age was 55 years (IQR 50–58). At data cutoff, median follow-up was 16·5 months (IQR 10·6–34·1). A complete response and undetectable minimal residual disease in bone marrow 2 months after the last cycle of ibrutinib plus FCR was achieved by 28 (33%, 95% CI 0·23–0·44) of 85 patients (p=0·0035 compared with a 20% historical value with FCR alone). A best response of undetectable minimal residual disease in bone marrow was achieved by 71 (84%) of 85 patients during the study. One patient had disease progression and one patient died (sudden cardiac death after 17 months of ibrutinib maintenance, assessed as possibly related to ibrutinib). The most common all-grade toxic effects were haematological, including thrombocytopenia in 63 (74%) patients, neutropenia in 53 (62%), and anaemia in 41 (49%). Grade 3 or 4 non-haematological serious adverse events included grade 3 atrial fibrillation in three (4%) patients and grade 3 Pneumocystis jirovecii pneumonia in two (2%). Interpretation The proportion of patients who achieved undetectable minimal residual disease in bone marrow with ibrutinib plus FCR is, to our knowledge, the highest ever published in patients with chronic lymphocytic leukaemia unrestricted by prognostic marker status. Ibrutinib plus FCR is promising as a time-limited combination regimen for frontline chronic lymphocytic leukaemia treatment in younger fit patients. Funding Pharmacyclics and the Leukemia & Lymphoma Society.

Between 11 and 37% of extranodal marginal zone lymphoma (EMZL) patients present with disease involvement in multiple mucosal sites (MMS). We analyzed 405 EMZL patients seen between 1995 and 2017: 265 (65.4%) patients presented with stage I disease, 49 of 309 (15.8%) patients with bone marrow involvement, and 35 of 328 (10.7%) patients with monoclonal gammopathy (MG). Forty-three (10.6%) patients had MMS presentation, which was more frequently seen in patients aged >60 years (55.8%). Five (17.9%) of 28 MMS patients had MG. MMS patients commonly exhibited the International Prognostic Index (IPI) >2 (79.1%), Follicular Lymphoma International Prognostic Index (FLIPI) >2 (39.5%), and Mucosa-Associated Lymphoid Tissue Lymphoma International Prognostic Index (MALT-IPI) 2-3 (60.5%). Both MMS presentation and MG were associated with shorter survival univariately. In multivariable Cox regression models, shorter progression-free survival (PFS) and overall survival (OS) were observed in patients with MMS (hazard ratio [HR] = 3.08 and 2.92, respectively), age ≥60 years (HR = 1.52 and 2.45, respectively), and in patients who failed to attain a complete remission following initial therapy (HR = 3.27 and 2.13, respectively). Elevated lactate dehydrogenase was associated with shorter PFS (HR = 1.92), while anemia (HR = 2.46) was associated with shortened OS. MALT-IPI ≥2 (HR = 2.47 and 4.75), FLIPI >2 (HR = 1.65 and 2.09), and IPI >2 (HR = 2.09 and 1.73) were associated with shorter PFS and OS, respectively. Higher grade transformation (HGT) occurred in 11 (25.6%) MMS patients with a 5-year cumulative incidence of 13.2% (95% CI 4.7-26.1%). EMZL patients with MMS presentation represent a novel clinical subset associated with shorter PFS, OS, and higher incidence of HGT that needs novel therapeutic approaches.

BACKGROUND: Mantle cell lymphoma is characterized by short remissions and a median overall survival (OS) of less than 6 years with standard chemotherapy. We previously reported results of a single-arm phase II clinical trial of intensive chemotherapy induction with R-MACLO-IVAM followed by thalidomide maintenance with promising progression-free survival (PFS) and OS (Lossos et al. Leuk Lymph 2010). A subsequent single-arm phase II clinical trial assessing rituximab (R) rather than thalidomide maintenance was conducted and preliminary data communicated (Hosein et al. Am J Hematol 2015). We now present the final results of these studies. METHODS: Two prospective single-arm phase II clinical trials conducted at the University of Miami were IRB approved. Eligible patients were chemotherapy-naïve with confirmed diagnosis of MCL using WHO criteria, age 18-75 years, ECOG PS: 0-2, adequate organ function and no history of HIV or prior cancer. Pretreatment staging included CT and PET scans, colonoscopy and bone marrow biopsy. The chemotherapy regimen has been previously described (Lossos et al. Leuk Lymph 2010). Patients who achieved complete responses (both radiologically and pathologically) were eligible for the maintenance phase. Between June 2004 and 2019, 44 patients were enrolled; the first 22 patients received maintenance therapy with thalidomide (200 mg daily until relapse/intolerable toxicity) and a subsequent cohort of 22 patients received R (375mg/m2 IV weekly x 4 weeks, repeated every 6 months for 3 years). OS was calculated from date of diagnosis to date of death or last follow up, and PFS from date of diagnosis to the date of pathological evidence of recurrence or death. Analysis was performed using the Kaplan-Meier method, and the log-rank or Wilcoxon test for group comparison. RESULTS: Median PFS in thalidomide and R cohorts were 7.8 and 8.1 years, and 10-year OS 63.6% and 57.8%, respectively. There was no statistically significant PFS or OS difference between patients treated with thalidomide or R maintenance (Wilcoxon p= 0.988 and p= 0.564, respectively). Therefore, all 44 patients were evaluable together for toxicity and 43 for response. Median age was 58 (range 39-73 years), most patients were males (35, 79.5%) and ECOG PS ≤ 1 (42, 95.5%). All patients had at least stage III disease, with bone marrow involvement in 38 (86.4%), gastrointestinal involvement in 23 out of 39 (59%), and elevated LDH in 14 (68.2%) patients. Ki67 was >30% in 20 (54.1%) and blastic variant in 6 (13.6%) patients. Most patients presented with IPI ≥ 3 (23, 52.3%) and intermediate-high MIPI (30, 68.1%) scores. 36 completed all 4 cycles of therapy, treatment was stopped in 6 after 3 cycles, and in 1 after 2 cycles. 1 patient died during the first cycle. Of the 43 patients completing 2 cycles of chemotherapy 41 (95.3%) achieved complete response (CR) and 2 (4.7%) partial response (PR). There were 23 (52.3%) events for PFS (19 relapses, 4 deaths without documented progression/relapse), and 14 (31.8%) total deaths over a median follow up of 6.7 years (range 1-15). The 5 and 10-year PFS were 54.9% (95%CI: 37.6-69.2%) and 39.2% (95%CI: 22.3-55.8%), respectively; median PFS 8 years (95%CI: 3.9-12.5 years). 5 and 10-year OS were 84.4% (95%CI: 68.4-92.7%) and 60.4% (95%CI: 41.2-75.1%), respectively; and median OS was not reached. PFS and OS were statistically significant shorter in the high-risk MIPI group than intermediate and low groups (5-year PFS rates: 23.1% vs. 53.8% vs. 92.9%, respectively, p CONCLUSIONS: These phase II clinical trials implementing frontline R-MACLO-IVAM in MCL demonstrate high overall response rates (95.3% CR and 4.7% PR) with encouraging PFS and OS. Notably, high risk patients such as those with blastic variant and high-risk MIPI score also demonstrated favorable outcomes compared to historical controls. Results demonstrate that R-MACLO-IVAM is an effective regimen to induce long-term remission and survival in MCL, without need for consolidation with stem-cell transplant. Disclosures Alderuccio: OncLive: Consultancy; Puma Biotechnology: Other: Immediate family member; Agios: Other: Immediate family member; Foundation Medicine: Other: Immediate family member; Inovio Pharmaceuticals: Other: Immediate family member; Targeted Oncology: Honoraria. Alencar:Celgene: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees. Rosenblatt:Mologen AG: Employment; Kite Pharma: Employment; Synergys Technologies: Employment; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Merck: Employment. Lossos:Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Janssen Scientific: Membership on an entity's Board of Directors or advisory committees; NIH: Research Funding.

Topic Significance & Study Purpose/Background/Rationale Inconsistencies on the nurses’ interpretation of neutropenic diet can lead to patients obtaining misinformation on food safety standards and foods permitted on the diet. The purpose of this quality improvement project (QIP) is to identify University of Miami Hospital and Clinic's (UMHC) nurses’ understanding of the neutropenic diet, safe food handling, and to provide cohesive education to the nurses. Methods, Intervention, & Analysis Identical, 17-question pre and post surveys were created to ascertain nurse's knowledge on foods allowed on the facility's neutropenic diet and USDA's food safety standards. The pre-survey was administered to 46 UMHC oncology nurses from inpatient stem cell transplant and hematology/oncology. Subsequent education was provided by the nurse practitioner and dieticians on both topics, followed by a post-survey. Findings & Interpretation Among the UMHC's oncology nurses the averaged overall pre-survey's score revealed that 56.3% of questions were answered correctly based on the facility's neutropenic diet and national standards of food safety, compared to the post survey's 85.2% (Figure 1). Nurses had more difficulty correctly answering which foods are allowed on neutropenic diet, general food safety and temperature control questions versus cross contamination and preparation/wash questions (Table 1). Discussion & Implications Inconsistencies of UMHC nurse's knowledge regarding foods allowed on neutropenic diets and food safety standards were identified. Providing education improved nurses’ knowledge which could decrease patient misinformation and potentially minimize patient's risk. It is important to implement routine education to nurses to decrease risk of food borne illnesses to this vulnerable population.

Invasive fusariosis (IF) most commonly occurs in patients with hematologic malignancies and severe neutropenia, particularly during concomitant corticosteroid use. Breakthrough infections can occur in high-risk patients despite Aspergillus-active antifungal prophylaxis. We describe a patient with rapid acute lymphoblastic leukemia (ALL) progression who presented with multifocal skin nodules thought to be choloromatous disease. These lesions were ultimately diagnosed as IF and the patient had two simultaneously active disease processes. This case highlights the importance of pathologic diagnosis of new skin lesions in ALL patients, even during leukemia progression, and demonstrates that IF can occur despite normal neutrophil counts and Aspergillus-active prophylaxis.

e19526Background: Diffuse large B cell lymphoma (DLBCL) has subtypes with different biological features and outcomes. Cell of origin classification (COO) represents 2 biologic entities - germinal c...

Background:Racial disparities in multiple myeloma (MM) outcomes are well established. Clinical characteristics and cytogenetic abnormalities dictate outcomes in MM but historically they have been mostly defined in White patients with paucity of information regarding racial-ethnic minorities. Hispanics are the fastest growing racial-ethnic subgroup in United States and have the worst overall survival (OS) in MM but differences in disease presentation among Hispanics compared to Whites, the historical control, are undefined. Methods: MM patients seen at Mayo Clinic in Florida (MCF) and Arizona (MCA) between 1/1/2000-06/15/2017 were included. Patient and disease characteristics including gender, age at diagnosis, bone marrow (BM) plasmacytosis, laboratory data [M spike, creatinine (Cr), beta-2-microglobulin (B2M), Hemoglobin (Hb), calcium (Ca)], MM subtype [IgG, IgA, light chain (LC), other], LC subtype (κ, λ, biclonal), presence of lytic bone lesions, disease stage (DS, ISS, R-ISS), mSMRT cytogenetic risk category, presence of individual cytogenetic mutations (deletions, translocations, gains, trisomy/hyperdiploidy) was collected. Comparisons between Hispanic study cohort characteristics and historical control were made by Chi-square, Fischer's exact and Signed rank tests, where applicable, using data from previous publications [Kyle et al, 2003 (n=1027) and Fonseca et al, 2003 (n=351)]. Patients with missing data on a certain clinical or disease feature were not included in the statistical analysis of that specific characteristic. Results: A total of 1705 MM patients were screened and 266 Hispanic patients seen at either site between the specified dates were identified for the analysis. These included equal number of males and females (n=133 each) with a median age of 58 years (range 25-87). IgG disease was seen in 52% with IgA and LC subtypes in 23% each. LC subtype was κ in 67%, λ in 31% and biclonal in 2% cases. Lytic and extramedullary disease were noted in 71% and 44% patients, respectively. DS and R-ISS stage at the time of MM diagnosis was not available in most patients while ISS stage among 150 patients showed stage 1, 2 and 3 in 48%, 28% and 24% patients, respectively. mSMART risk categories were present in 226 patients and included high, intermediate and standard risk in 12%, 11% and 77% patients, respectively. Of these 226 patients, cytogenetic disease prior to starting any MM treatment was available in 153 patients with similar risk category distribution. Median follow up for the whole Hispanic cohort was 38.6 months with a median OS 10.7 years (Figure 1). Comparison with historical control datasets which were 97% or greater comprised of White patients showed some significant differences for the Hispanic cohort including gender distribution, median age, BM plasmacytosis at the time of diagnosis, median Hb, Cr or M spike at presentation, light chain subtype, presence of lytic bone disease and certain cytogenetic alterations including t(4;14) and del13q/monosomy (Table 1). We did not note differences in high-risk cytogenetics between Hispanics and historical White controls. Conclusions: We report the first description of clinical and cytogenetic characteristics of Hispanic MM patients. The current and historical datasets that we have used are all from Mayo Clinic experience, thus making reasonable comparisons possible. We were able to confirm previous reports of demographic differences in Hispanics e.g., younger age at diagnosis. While some characteristics were significantly different, the clinical and cytogenetic differences we note do not clearly explain the inferior OS noted for Hispanics in population-based studies. Significant differences that we report warrant continued exploration in larger institutional and public databases in addition to a continued look into healthcare access and utilization. An ongoing collaborative analysis with data from Mayo Clinic, University of Miami and University of Southern California, Los Angeles is ongoing. Disclosures Fonseca: AMGEN: Consultancy; Jansen: Consultancy; Mayo Clinic & Dr Fonseca: Patents & Royalties: Prognostication of myeloma via FISH, ~$2000/year; Celgene Corporation: Consultancy, Research Funding; Merck: Consultancy; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy; Bristol-Myers Squibb: Consultancy; Takeda: Consultancy; Sanofi: Consultancy; Pharmacyclics: Consultancy; Novartis: Consultancy. Kelly: Pharmacyclics: Honoraria; Abbvie: Honoraria; Amgen: Honoraria; Jannsen: Honoraria. Sher: LAM Therapeutics, Inc: Research Funding. Ailawadhi: Pharmacyclics: Research Funding; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria.

51 Background: Overutilization of emergency room services by oncology patients is a known problem associated with increased admission rates and health care expenditure. A review of our oncology patients’ emergency room (ER) visits from January to May 2015 demonstrated that 48% of ER visits happened during office hours. Consequently a rapid cycle quality improvement project was developed with an aim to decrease ER visits by 30% by September 2015. Methods: A multidisciplinary team completed an action plan, starting with a project charter and definition of aim statement. A process map for patient scheduling/triage was created. A cause and effect diagram helped identify potential causes patient utilization of the ER. Diagnostic data were obtained querying our EMR (EPIC) for ER visits from January to May 2015. A Pareto chart identified Breast, Hematology and GI malignancies as main diagnosis utilizing the ER. Plan-do-study-act (PDSA) #1 began with development of a protocol to guide the handling of patients' calls that could previously resulted in an ER visit. Staff from the patient access center (PAC), a telephone operator service, and physicians’ offices were trained on its application. PDSA #2 focused on patient education to the importance of contacting the PAC for any concern or symptom related to active chemotherapy treatment. Results: The implementation of a triage system at our PAC resulted in a 60% decrease in the number of patients utilizing the ER, which met our goal. Patients’ calls to the PAC have increased. Two new materials were developed: a telephone triage form categorizing the patient’s complaint and the resulting action by our PAC center staff, and a patient Clinical Intervention Triage Tracking Log which allowed for the tracking of all patients triaged, their data, and the responsible team member. Conclusions: This study suggests that the development of a tool to properly identify and address emergent chemotherapy symptoms without utilizing the ER during working hours resulted in an intervention that positively affected the pre-specified endpoint.

Primary bone lymphoma (PBL) is a rare disease. There has been paucity of studies addressing its therapy and prognosis. We retrospectively examined PBL cases seen at the University of Miami from June 2000 to August 2007 to describe our single institution experience and review the literature. Fifty-three patients were identified with a median age of 52 (18-87) and a median follow-up of 40 months (0-106). The most common histologic type was diffuse large B-cell lymphoma (83%). Forty-one patients (77%) presented with localized disease and 48 were treated at our institution. Forty-six patients underwent chemotherapy (40 patients) and/or radiation (36 patients). Forty-four patients achieved a complete response and all patients were alive at last follow-up. The progression-free survival (PFS) was 83% at 4 years. No difference in PFS was observed between patients treated with chemotherapy or combined chemotherapy plus radiation. There was a trend toward improvement in PFS (p = 0.062) of patients with DLBCL treated with rituximab plus chemotherapy. Our single institutional experience demonstrates that the outcome of patients with PBL is excellent. Although the current data support the use of combined modality treatment for localized PBL, randomized controlled trials are needed especially now, when rituximab is routinely added to chemotherapy regimens.

Denileukin diftitox (Ontak), a recombinant fusion protein of diphtheria toxin and ligand, IL-2, binds to the IL-2 receptor, is internalized, and causes cell death. Denileukin diftitox was approved for the treatment of cutaneous T-cell lymphomas (CTCLs) with CD25+ expression. We prospectively stained lesional skin biopsy specimens from 113 mycosis fungoides and Sézary Syndrome patients for activation markers CD25 and CD30 to correlate expression with clinical tumor-node metastasis (TNM) stage, histologic grade, and response to denileukin diftitox. High expression was defined as positivity ofor =20% of lesional T-cells using immunohistochemistry (IHC). CD25 and CD30 expression was more common in lesions from advanced patients (P = 0.04 and 0.002, respectively). Advanced TNM (T3 or T4) was significantly associated with intermediate-grade (P = 0.002) and large-cell transformation histology (P = 0.04). Of interest, clinical responses were observed in 78.5% of patients with high CD25 expression versus 20% with low to undetectable CD25 expression (P = 0.01) among 24 patients receiving standard 5-day infusions of denileukin diftitox at 18 microg/kg/day. These data suggest that high CD25 expression by IHC is associated with advanced CTCL and with clinical response to denileukin diftitox therapy.

Alemtuzumab is a monoclonal antibody to CD52 that has activity in T-cell leukemia and lymphoma. This study aims to describe the complications and outcomes of a subset of patients with mycosis fungoides/Sézary syndrome who were treated with alemtuzumab. Four of 8 patients, with no prior history of cardiac problems, developed significant cardiac toxicity (congestive heart failure or arrhythmia) that mostly improved after alemtuzumab discontinuation. The role of this agent in potentially inducing important cardiac side effects is suggested and argues for further investigation.

Several gene expression signatures are predictive of prognosis in diffuse large B cell lymphoma (DLBCL), but the lack of practical methods for a genome scale analysis has restricted their clinical applicability. Towards construction of a molecular predictor amenable to rapid testing on routinely obtained diagnostic clinical specimens, we studied genes previously reported to be associated with survival in DLBCL, testing and validating risk scoring models with robust survival associations in the current therapeutic era. We identified LMO2 expression as a robust univariate predictor of survival and cell of origin classification of DLBCL, with independent prognostic value. We examined bivariate models combining expression of LMO2 with other genes, and identified TNFRSF9 as a tumor microenvironment gene with independent prognostic influence. A combined model integrating both LMO2 and TNFRSF9 expression was independent of “cell of origin” classification, “stromal signatures,” International Prognostic Index (IPI), and added to the predictive power of IPI. A composite model was validated in multiple independent patient cohorts using public microarray data. Using routinely obtained formalin fixed, paraffin embedded diagnostic specimens from an independent cohort, we developed a simple assay validating the clinical utility of this 2-gene model, as well as a composite model integrating the IPI. In conclusion, measurement of a single gene expressed by tumor cells and a single gene expressed by the immune microenvironment is sufficient to predict overall survival in patients with DLBCL treated with R-CHOP. A combined model serves as a robust clinical risk assessment tool. This talk is also presented as Poster A27. Citation Information: Clin Cancer Res 2010;16(14 Suppl):PR5.

Abstract 622 Background: Several gene-expression signatures are predictive of prognosis in diffuse large-B-cell lymphoma (DLBCL), but the lack of practical methods for a genome-scale analysis has restricted their routine clinical applicability. Methods: We studied genes whose expression had been reported to predict survival in DLBCL, attempting to validate genes and prognostic models with robust survival associations that are amenable to rapid diagnostic testing. Results: Among a previously described set of 6-genes shown to predict survival independent of measurement platform or therapy era (Lossos, et al. 2004 NEJM 350:1828), we identified LMO2 as the single gene with strongest independent prognostic value in 3 independent cohorts of patients with DLBCL. To assess the independent contribution of other genes in predicting survival, using existing microarray gene expression data (Lenz, et al. 2008 NEJM 359:2313), we evaluated all pairwise models that included LMO2 toward construction of a robust bivariate survival predictor. Among 54674 possible models, one combining expression of LMO2 with TNFRSF9 (encoding 4-1BB, also known as CD137) emerged as among the best in cross-validation when assessed in training (n=233) and test (n=181) cohorts. This bivariate predictor remained prognostic in both CHOP (p=1.7e-6) and R-CHOP (p=6.5e-8) therapy eras, was highly independent of the International Prognostic Index, Cell-of-Origin classification, 6-gene predictive model, ‘stromal' model, and added significantly to their prognostic power. While LMO2 expression was highly restricted to tumor cells and was linked to Cell-of-Origin (GCB, p=2.2e-16), TNFRSF9 expression was highest in non-tumor cells (P=0.02), particularly in an activated subset of infiltrating CD8 T-cells. To validate this bivariate model and devise a practical diagnostic assay, we used quantitative real-time polymerase-chain-reaction to measure the expression of LMO2 and TNFRSF9 as well as other components of the 6-gene model (BCL2, BCL6, FN1, CCL3, and CCND2) in diagnostic formalin fixed and paraffin-embedded samples of lymphoma from an independent set of 147 patients with de novo DLBCL treated with R-CHOP. The IPI distribution for these patients was: 0-1 factor (n=70), 2 factors (n=40), 3 factors (n=26), ≥4 factors (n=11). In univariate and multivariate analyses of this independent cohort, LMO2 and TNFRSF9 expression remained individually prognostic of both progression free and overall survival. The bivariate model combining LMO2/TNFRSF9 could be used to stratify distinct risk groups for overall survival (p=0.004), and remained independent of IPI. Conclusion: Measurement of the expression of two genes integrating contributions of tumor cells and the tumor microenvironment is sufficient to predict overall survival in patients with DLBCL treated with R-CHOP. Disclosures: Advani: Seattle Genetics, Inc.: Research Funding.

18157 Background: Single agent gemcitabine is active as second line therapy in NSCLC. Oxaliplatin may be non-cross resistant with the other platinum-containing agents used as first-line therapy in NSCLC. The combination of gemcitabine and oxaliplatin (GEMOX) is synergistic in pre-clinical models. Methods: A phase II, non-randomized trial was designed to assess the efficacy and tolerability of gemcitabine 1,000 mg/m2 over 100 min in combination with oxaliplatin 100 mg/m2 over 2 hours both given on days 1 and 15 of each 28-day cycle. Patients with NSCLC were eligible if they had progressed after first line treatment. Primary endpoint was tumor response rate. Planned sample size is 30 patients over a period of 2 years. Functional Assessment of Cancer Therapy- Lung (FACT-L) v.4 questionaire was used to assess quality of life of patients on therapy. Results: Twenty-two patients have been enrolled. 13 males (59%) and 9 females (41%). 15 Hispanic (68%), 4 Caucasian (18%), and 3 African-American (13%). Median age is 55 yrs. Histologic subtypes are as follows: adenocarcinoma, 12; NSCLC not otherwise specified 7; squamous cell carcinoma, 3. Nine patients had an ECOG performance status (PS) of 0 (41%) and 13 had a PS of 1 (59%). Two patients were never smokers. A total of 56 cycles have been administered (median 2, range 1 to 6). GEMOX as second-line therapy was given to 18 patients (81%), third-line to 4 patients (18%). Two patients died on study from disease progression leading to respiratory and multi-organ failure. The following Grade 3 and 4 adverse events were seen in 2 patients each: fatigue, dyspnea, anemia, and multi-organ failure. Cancer pain was seen in 1 patient. Twenty patients are available for assessment of response. Two patients had a confirmed partial response (10%) and another eight had stable disease (40%). Preliminary results of FACT-L analysis in 19 pts shows improvement in Lung Cancer Subscale (LCS) score in 25% of the patients after 2 cycles of therapy. Conclusions: Combination gemcitabine and oxaliplatin is active and well tolerated as second line treatment for NSCLC. Improvement of LCS score after 2 cycles suggests a clinical benefit that is beyond the observed response rate of 10%. No significant financial relationships to disclose.