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PURPOSE Burkitt lymphoma is an aggressive B-cell lymphoma curable with dose-intensive chemotherapy derived from pediatric leukemia regimens. Treatment is acutely toxic with late sequelae. We hypothesized that dose-adjusted etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone, and rituximab (DA-EPOCH-R) may obviate the need for highly dose-intensive chemotherapy in adults with Burkitt lymphoma. METHODS We conducted a multicenter risk-adapted study of DA-EPOCH-R in untreated adult Burkitt lymphoma. Low-risk patients received three cycles without CNS prophylaxis, and high-risk patients received six cycles with intrathecal CNS prophylaxis or extended intrathecal treatment if leptomeninges were involved. The primary endpoint was event-free survival (EFS), and secondary endpoints were toxicity and predictors of EFS and overall survival (OS). RESULTS Between 2010 and 2017, 113 patients were enrolled across 22 centers, and 98 (87%) were high risk. The median age was 49 (range, 18-86) years, and 62% were ≥ 40 years. Bone marrow and/or CSF was involved in 29 (26%) of patients, and 28 (25%) were HIV positive. At a median follow-up of 58.7 months, EFS and OS were 84.5% and 87.0%, respectively, and EFS was 100% and 82.1% in low- and high-risk patients. Therapy was equally effective across age groups, HIV status, and International Prognostic Index risk groups. Involvement of the CSF identified the group at greatest risk for early toxicity-related death or treatment failure. Five treatment-related deaths (4%) occurred during therapy. Febrile neutropenia occurred in 16% of cycles, and tumor lysis syndrome was rare. CONCLUSION Risk-adapted DA-EPOCH-R therapy is effective in adult Burkitt lymphoma regardless of age or HIV status and was well tolerated. Improved therapeutic strategies for adults with CSF involvement are needed (funded by the National Cancer Institute; ClinicalTrials.gov identifier: NCT01092182 ).

Mantle cell lymphoma (MCL) is biologically and clinically heterogeneous and would benefit from prognostic biomarkers to guide management. Circulating tumor DNA (ctDNA) is a novel prognostic biomarker in diffuse large B-cell lymphoma that may have applicability in MCL. We analyzed ctDNA dynamics in previously untreated patients with MCL who received induction therapy with bortezomib and DA-EPOCH-R for 6 cycles followed by random assignment to observation or bortezomib maintenance in responding patients in a prospective phase 2 study. Most patients also underwent initial treatment window of bortezomib alone prior to induction. Serum was collected pretreatment, after the window, after cycles 1 and 2, at the end of induction, and at each follow-up visit along with restaging computed tomography scans. Next-generation sequencing was used to identify and quantify ctDNA encoding the immunoglobulin receptor sequences in serum as markers of minimal residual disease. Fifty-three patients were enrolled, with a median follow-up of 12.7 years. Patients without detectable ctDNA after 2 cycles of induction had longer progression-free survival (PFS) and overall survival (OS) compared with those with detectable ctDNA (median PFS, 2.7 vs 1.8 years; overall P = .005; median OS, 13.8 vs 7.4 years; overall P = .03). Notably, in vivo assessment of ctDNA dynamics during the bortezomib window was not prognostic, and there was no difference in PFS or OS with bortezomib maintenance. ctDNA monitoring after induction showed that molecular relapse preceded clinical relapse in some cases. In conclusion, interim ctDNA negativity strongly correlates with improved survival and supports the investigation of response-adapted strategies. This trial was registered at www.clinicaltrials.gov as #NCT00114738.

To evaluate the feasibility and clinical efficacy of the combination of alemtuzumab with dose-adjusted etoposide/cyclophosphamide/doxorubicin/vincristine/prednisone (DA-EPOCH) as upfront therapy for untreated aggressive T and NK cell lymphomas, a phase 1/2 trial was conducted. Thirty patients were treated with the study regimen, consisting of alemtuzumab on day 1 of a 21 day cycle with standard dosing of DA-EPOCH for 6-8 cycles. Alemtuzumab 30 mg IV was used for the phase 2 component. Of 30 treated patients, 17 had a complete response (CR) and eight had a partial response (83.3% overall response rate). The median overall survival and progression-free survival were 20.2 and 6.6 months, respectively. There were five treatment-related deaths on study mainly due to infectious complications, including one case each of disseminated toxoplasmosis and pneumonia and two cases of sepsis. Alemtuzumab with DA-EPOCH is of limited clinical utility due to unacceptable toxicity, despite the high rate of CR.

Summary Background MYC gene rearrangement is present in approximately 10% of aggressive B-cell lymphomas, with half also harbouring a BCL2 gene rearrangement. Multiple retrospective studies of R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone or prednisolone) have shown a worse outcome in patients with MYC rearrangement (alone or with rearrangement of BCL2 or BCL6, or both) than in patients without MYC rearrangement, and suggest improved outcomes after more intensive treatment. We aimed to determine the outcome of dose-adjusted EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab; DA-EPOCH-R), an intensive infusional treatment regimen, in untreated aggressive B-cell lymphoma with MYC rearrangement. Methods We present the final analysis of a prospective, multicentre, single-arm, phase 2 study of DA-EPOCH-R in patients with untreated aggressive B-cell lymphoma with MYC rearrangement. DA-EPOCH-R was scheduled to be administered with CNS prophylaxis for six cycles. Primary endpoints included event-free and overall survival. This study is registered with ClinicalTrials.gov ( NCT01092182 ). Findings 53 patients were enrolled, with median age of 61 years (range 29–80; IQR 50–70); 43 (81%) patients had stage III–IV disease and 26 (49%) had high-intermediate or high international prognostic index (IPI) scores. 19 patients had confirmed MYC rearrangement alone (single-hit) and 24 also had rearrangement of BCL2, BCL6, or both (double-hit), with similar characteristics between these two groups. After a median follow-up of 55·6 months (IQR 50·5–61·1), 48-month event-free survival was 71·0% (95% CI 56·5–81·4) and 48-month overall survival was 76·7% (95% CI 62·6–86·1) for all patients. Toxicity included grade 4 neutropenia in 160 (53%) of 301 cycles, grade 4 thrombocytopenia in 40 (13%) cycles, and any grade of fever with neutropenia in 56 (19%) cycles. There were three treatment-related deaths (all infections). Interpretation In this study, DA-EPOCH-R produced durable remission in patients with MYC-rearranged aggressive B-cell lymphomas and should be considered for the treatment of these diseases. Funding Cancer Trials Support Unit and Center for Cancer Research of the National Cancer Institute and Genentech.

Introduction Adults with Burkitt lymphoma (BL) are at risk for both early toxic death and disease progression. Age is associated with a poor prognosis with highly dose-intensive regimens, but it is unclear if this is driven by disease biology or treatment intolerance. We previously reported that survival for adult BL patients treated with DA-EPOCH-R were poorest with CNS, bone marrow (BM) and/or peripheral blood (PB) involvement, but age was not prognostic (Roschewski et al J Clin Oncol 2020). A retrospective study of patients treated with standard regimens outside of clinical trials identified the Burkitt Lymphoma International Prognostic Index (BL-IPI) which stratified patients into risk categories based on 4 variables: age ≥40y, ECOG ≥2, serum LDH >3x ULN, and CNS involvement (Olszewski J Clin Oncol 2021). We analyzed the prognostic utility of BL-IPI to predict time to progression (TTP) and event-free survival (EFS) for adult patients with BL treated on a prospective multicenter study of risk-adapted DA-EPOCH-R. Methods NCI 9177 was a multicenter study that included pts ≥ age 18 with any HIV status. Treatment was risk-adapted based on LDH, ECOG status, stage, and largest tumor lesion. Low-risk patients received 3 cycles of DA-EPOCH-RR and high-risk patients received 6 cycles of DA-EPOCH-R with either IT chemo prophylaxis or extended IT treatment for active CNS disease. Event-free survival (EFS) was calculated from study entry until progression, last documentation of active disease, death, or last follow-up. Time to progression (TTP) was calculated from study entry until date of progression. Kaplan-Meier estimation and log-tank tests were used to determine the prognostic utility of the BL-IPI including individual factors. Receiver operating characteristic curves were plotted to determine the c-index which measures the predictive ability of a survival model. Results 113 patients were enrolled including 31 (27%) low-risk, 55 (49%) intermediate-risk, and 27 (24%) high-risk by BL-IPI. With a median follow up of living patients of 3.3y, the 5-year TTP for pts with high-risk BL-IPI was 78.3% (95% CI: 55-90) compared to 95.2% (95% CI: 88-98)(p=0.022) for pts with low/intermediate IPI (Figure 1A). Pts with high-risk BL-IPI had a lower 5-year EFS of 66.7% (95% CI: 46-81) compared to 94.2% (95% CI: 83-98) for intermediate-risk and 83.6% (95% CI: 65-93) for low-risk, respectively (p=0.004)(Table 1). Pts aged ≥40y had a similar 5-year TTP and EFS of 93.6% (95% CI: 84-98) versus 88.4% (95% CI: 74-95)(p=0.32) and 86.7% (95% CI: 76-93) versus 81.1% (95% CI: 66-90)(p=0.50) compared to pts under 40y. Pts with ECOG PS ≥2 had a worse 5-year TTP and EFS of 76.5% (95% CI: 49-90) versus 94.4% (95% CI: 87-98)(p=0.01) and 61.9% (95% CI: 38-79) versus 89.8% (95% CI: 81-95)(p=0.0004) compared to pts with ECOG PS 3x ULN. Pts with CNS involvement had worse 5-year TTP and EFS of 62.5% (95% CI: 23-86) versus 93.9% (95% CI: 87-97)(p=0.002) and 45.5% (95% CI: 17-71) versus 88.8% (95% CI: 81-94)(p=0.0001) compared to pts without CNS involvement. Nineteen (70%) pts high-risk by BL-IPI had CNS/BM/PB involvement while 8 (30%) had no CNS/BM/PB involvement. Ten (12%) pts with low/intermediate-risk by BL-IPI had CNS/BM/PB involvement and 76 (88%) had no CNS/BM/PB involvement. Pts without involvement of CNS/BM/PB had an excellent prognosis across BL-IPI groups with 5-year TTP of 97.3% (95% CI: 90-99) for low/intermediate-risk by BL-IPI and 100% for high-risk by BL-IPI. Patient with CNS/BM/PB involvement had 5-year TTP of 80.0% (95% CI: 41-95) for low/intermediate-risk by BL-IPI and 66.7% (95% CI: 38-85) for high-risk by BL-IPI (global p=0.006)(Figure 1B). Compared to BL-IPI (C-index 0.62 p=0.13), CNS/BM/PB involvement had better discrimination between prognostic groups (C-index 0.76, p=0.0005). Conclusion Patients with low-or intermediate risk BL-IPI scores had an excellent 5-year TTP and EFS of 95% and 94% in NCI 9177. Age is not prognostic with DA-EPOCH-R but CNS/BM/PB involvement is prognostic across BL-IPI groups. Future studies in adults with BL should focus on high-risk disease including younger patients. Figure 1 Figure 1. Disclosures Dunleavy: Gebmab: Honoraria; Beigene: Honoraria; Morphosys: Honoraria; Bayer: Honoraria; Pharmacyclics: Honoraria; Genetech: Honoraria; Idec: Honoraria. Abramson: C4 Therapeutics: Consultancy; Allogene Therapeutics: Consultancy; Kymera: Consultancy; Bluebird Bio: Consultancy; BeiGene: Consultancy; Incyte Corporation: Consultancy; Astra-Zeneca: Consultancy; Novartis: Consultancy; Kite Pharma: Consultancy; Genmab: Consultancy; EMD Serono: Consultancy; Bristol-Myers Squibb Company: Consultancy, Research Funding; Morphosys: Consultancy; Seagen Inc.: Research Funding; AbbVie: Consultancy; Karyopharm: Consultancy; Genentech: Consultancy. Link: MEI: Consultancy; Genentech/Roche: Consultancy, Research Funding; Novartis, Jannsen: Research Funding. Friedberg: Novartis: Other: DSMC ; Acerta: Other: DSMC ; Bayer: Other: DSMC . Kahl: AbbVie, Adaptive, ADCT, AstraZeneca, Bayer, BeiGene, Bristol-Myers Squibb, Celgene, Genentech, Incyte, Janssen, Karyopharm, Kite, MEI, Pharmacyclics, Roche, TG Therapeutics, and Teva: Consultancy; AbbVie, Acerta, ADCT, AstraZeneca, BeiGene, Genentech: Research Funding. Bartlett: Pharmacyclics: Research Funding; Millennium: Research Funding; Merck: Research Funding; Kite, a Gilead Company: Research Funding; Janssen: Research Funding; Genentech: Research Funding; Forty Seven: Research Funding; Celgene: Research Funding; Bristol Myers Squibb: Research Funding; Autolus: Research Funding; Seagen: Consultancy, Research Funding; Roche/Genentech: Consultancy; ADC Therapeutics: Consultancy, Research Funding. Noy: Epizyme: Consultancy; Rafael Parhma: Research Funding; Morphosys: Consultancy; Targeted Oncology: Consultancy; Medscape: Consultancy; Pharmacyclics: Consultancy, Research Funding; Janssen: Consultancy, Honoraria.

Mature T- and natural killer (NK)-cell neoplasms are a heterogeneous group of diseases, accounting for roughly 10% of non-Hodgkin lymphomas in the United States management. Compared to mature, aggr...

Background: Secondary CNS B-cell lymphomas (SCNSL) are aggressive lymphomas with a very poor prognosis. Genetic subtypes of DLBCL with CNS tropism are enriched for chronic active B-cell receptor signaling and may respond to BTK inhibition (BTKi). CLL, MCL, and transformed lymphomas can also involve the CNS and are BTKi responsive. TEDDI-R achieves durable remissions in relapsed/refractory primary DLBCL of the CNS (PCNSL) but the profile of SCNSL tumors that are ibrutinib-responsive is unknown. We present preliminary results from a response-adapted trial of ibrutinib with TEDD-R in SCNSL. Methods: Pts with aggressive B-cell lymphomas with secondary CNS involvement are eligible if age ≥18 and adequate organ function. Pts must have relapsed after frontline therapy or can be untreated if brain parenchyma involved. Prior BTKi is allowed, but HIVinfection and EBV+ lymphomas are excluded. Baseline tests include brain MRI, FDG-PET brain and body, CSF with flow cytometry, Ommaya, and eye exam. Pts receive isavuconazole starting at 200mg BID x 3d prior to ibrutinib to prevent fungal infections associated with TEDDI-R and then 200mg daily unless ibrutinib stopped. Pts first receive ibrutinib 560mg daily x 14d in a window. If ≥20% reduction after ibrutinib, pts receive TEDDI-R for 4 cycles every 21d with IT cytarabine. Pts with Results: 16 pts with a median age 67 (range 40-79) enrolled between June 2019 and July 2020. 15 (94%) pts had DLBCL comprising 9 (60%) non-GCB, 5 (33%) GCB, and 1 (7%) transformed from MZL. One pt had plasmablastic lymphoma. Eight (50%) pts had a MYC-rearrangement including 4 (25%) with both MYC and BCL2 or BCL6 rearrangements. Eight (50%) pts had isolated CNS disease and 8 (50%) had synchronous CNS and peripheral disease. All pts relapsed after a median of 2 (range 1-4) prior therapies and all (100%) pts received prior anthracycline. Seven pts (44%) had prior CNS prophylaxis and 8 pts (50%) had prior HD-MTX based salvage therapy. Toxicity was evaluated across 35 cycles. G3 and G4 neutropenia occurred in 49% and 29% of cycles, respectively, while febrile neutropenia occurred in 9% of cycles. The median (range) duration of neutropenia was 6 (1-13) days. Five (14%) cycles were complicated by ≥G3 infection, but no opportunistic infections (including Aspergillus) were observed. One pt developed a bacterial infection during cycle 1 and died. G3 and G4 thrombocytopenia occurred in 34% and 23% of cycles, respectively, and 1 pt developed G3 hematuria. G3 mucositis occurred in 9% of cycles and palmar-plantar-erythrodysesthesia led to dose reductions of liposomal doxorubicin in 5 (36%) pts. Of 15 pts who completed the 14d ibrutinib window and were evaluable, 8 (53%) were ibrutinib-responsive and 7 (47%) were ibrutinib-resistant (Figure 1). Clinical responses were concordant across anatomic compartments; of 8 pts with both CNS and peripheral disease, 5 (63%) responded to ibrutinib in both compartments while 3 (37%) did not respond in either compartment. All 8 ibrutinib responders had a non-GCB phenotype and six (75%) achieved CR. One died of treatment-related toxicity after a PR and 1 is still on therapy. Only two (29%) pts with ibrutinib-resistant tumors achieved PR and none have achieved CR. After a median follow-up of 5.1m, a landmark analysis starting after the ibrutinib window demonstrated the PFS for pts with ibrutinib-responsive compared to ibrutinib-resistant tumors was not reached vs. 0.9m (95% CI: 0.1-2m)(p=0.002)(Figure 2). Conclusions: Patients with SCNSL tumors that are ibrutinib-responsive achieve a high rate of complete response to TEDDI-R in both CNS and peripheral disease. Patients with tumors that are ibrutinib-resistant also respond poorly to TEDD-R. Toxicity is mainly hematologic, and no Aspergillus infections have occurred with the use of isavuconazole prophylaxis. Updated clinical results from this ongoing study (NCT03964090) and will be presented at the meeting. Disclosures No relevant conflicts of interest to declare. OffLabel Disclosure: ibrutinib for use in secondary cns lymphoma as part of a clinical trial

Background: Primary DLBCL of the CNS (PCNSL) relies on chronic active B-cell receptor (BCR) signaling. Ibrutinib targets BCR signaling through BTK inhibition (BTKi), which may also impair innate immunity. We showed that ibrutinib and temozolomide, etoposide, liposomal doxorubicin, dexamethasone, rituximab (TEDDI-R) induces durable remissions in relapsed/refractory PCNSL but 7 (39%) pts developed Aspergillus infections without fungal prophylaxis. Newer triazoles are effective against Aspergillus but inhibit ibrutinib clearance through CYP3A4. Isavuconazole has less effect on CYP3A4 and less hepatotoxicity than voriconazole. We hypothesized that ibrutinib and isavuconazole could be safely co-administered in TEDDI-R and ameliorate the risk of Aspergillus while maintaining efficacy. We studied escalating doses of ibrutinib in TEDDI-R with isavuconazole to determine the safety profile, ibrutinib PK, and clinical activity in relapsed/refractory PCNSL. Methods: Pts with relapsed/refractory PCNSL, age ≥18, ECOG PS ≤2, and adequate organ function were enrolled. Previous BTKi, HIV, EBV+, and pregnancy were excluded. Pts had baseline MRI brain, FDG-PET brain and body, Ommaya placed, CSF with flow cytometry, and eye exam. Isavuconazole 200mg BID x 3d started prior to ibrutinib then 200mg daily. Three dose levels of ibrutinib (280mg, 420mg, 560mg) were given continuously through each cycle. Pts received up to 6 cycles of TEDDI-R with IT cytarabine. No one received maintenance or consolidation. If a DLT occurred in the first 3 pts at a given ibrutinib dose level, 3 more pts were treated before escalating. Full safety and PK data was reviewed after two dose levels prior to escalating. An expansion of 10 pts was planned at the highest ibrutinib dose level to confirm safety and clinical activity. Surveillance for fungal infections included chest CT mid-cycle 1 and after each cycle along with Beta-D glucan and aspergillus galactomannan in blood and CSF. Brain MRI was performed after cycles 1, 2, 4, and 6 to determine response and screen for CNS Aspergillus. All remissions by MRI were confirmed with FDG-PET and CSF analysis. Surveillance brain MRI were q3m for 1y, q4m x 1y, q6m x 1y, then annually. Primary objective was to identify the highest dose of ibrutinib safely co-administered with isavuconazole in TEDDI-R that achieves adequate PK concentrations. Results: 13 relapsed/refractory PCNSL pts enrolled between 11/2018 and 06/2020. 10 (77%) pts were male and the median age was 65 (range 46-77), including 3 pts ≥age 70. 13 (100%) pts had prior high-dose MTX, and 2 (15%) pts had prior autologous stem cell transplant (ASCT). Three evaluable pts received ibrutinib 280mg, 3 pts received ibrutinib 420mg, and 6 pts received ibrutinib 560mg. One pt in the 280mg cohort was not evaluable. Toxicity was evaluated in 13 pts across 49 cycles and the toxicity was mainly hematologic. G3 and G4 neutropenia occurred in 45% and 37% of cycles, respectively, while febrile neutropenia occurred in 8% of cycles. The median (range) duration of neutropenia was 4.5 (1-12) days. One pt with prior ASCT stopped after 4 cycles due to myelosuppression. Four (8%) cycles were complicated by ≥G3 infection, but no opportunistic infections (including Aspergillus) were observed. G3 and G4 thrombocytopenia occurred in 22% and 8% of cycles, respectively, and 1 pt developed melena with no overt GI bleeding. ≥G3 mucositis occurred in 6% of cycles and 1 patient stopped therapy after 5 cycles due to recurrent mucositis. Palmar-plantar-erythrodysesthesia led to dose reductions of liposomal doxorubicin in 9 (69%) pts, but only 1 G3 event occurred. Twelve pts were evaluable for response, and 11 (92%) pts have responded and all after receiving only 1 cycle (Figure 1). All 8 (100%) pts who have completed at least 4 cycles have achieved CR and the other 4 remain on therapy. Six (75%) pts who achieved CR remain in remission while 2 (25%) pts relapsed within 3 months of stopping therapy. After a median potential f/u of 5.2 months, the 1-year PFS is estimated at 60.0% (95% CI, 12.6-88.2) and the OS is 100%. Conclusions: Ibrutinib 560mg was safely co-administered with isavuconazole in TEDDI-R for relapsed/refractory PCNSL. No DLTs were observed, no cases of Aspergillus occurred, and no new safety signals. The first 8 (100%) patients who have completed therapy achieved complete response. Updated clinical results from this ongoing study (NCT02203526) will be presented at the meeting. Disclosures Lai: Abbvie: Consultancy; Agios: Consultancy; Jazz: Speakers Bureau; Macrogenics: Consultancy; Astellas: Speakers Bureau.

Background: Response-adapted therapy aims to minimize toxicity while maintaining efficacy. Patients with HIV-associated lymphomas are at increased risk for complications and minimizing treatment is advantageous. In 33 patients with HIV-associated diffuse large B-cell lymphoma (DLBCL), we previously reported a 5-year freedom from progression (FFP) and overall survival (OS) rate of 84% and 68%, respectively, with 79% of patients receiving only 3 cycles of short course EPOCH-RR (Dunleavy, 2010). In that study, treatment duration was based on an interim FDG PET-CT scan comparing global reduction of SUV to baseline. Herein, we report an updated analysis including an additional 22 patients and investigate the predictive value of interim PET scans using modern Lugano response criteria. Methods: Eligible patients had untreated HIV-associated DLBCL with adequate organ function. All performance status and stages were eligible, including CNS involvement. Pre-treatment evaluation included bone marrow biopsy, lumbar puncture, CT and PET scan, and brain MRI/CT if indicated. Infusional EPOCH was delivered every 21 days with rituximab on days 1 and 5 (SC-EPOCH-RR) without dose-adjustment for a minimum of 3 and maximum of 6 cycles. HIV antiretroviral therapy (ART) was held until completion of systemic chemotherapy. Treatment response was determined by CT and PET imaging after 2 cycles, with restaging imaging performed consecutively after each cycle. Patients that had a global PET decrease > 50% compared to pre-treatment PET, were treated with only 1 additional cycle. Patients who did not decrease > 50% on PET, continued treatment until there was < 25% reduction in bidimensional products on serial CT imaging. Active CNS disease was treated with twice weekly intrathecal (IT) methotrexate until CSF clearance followed by maintenance IT therapy. All other patients received prophylactic IT methotrexate starting on cycle 3 for 8 doses. The primary endpoint of the study was progression-free survival (PFS). Independent and blinded review of PET scans using Lugano response criteria (Deauville score 1-3 = negative, score 4-5 = positive) was performed by a nuclear medicine specialist (M.A.). Results: Fifty-five patients were enrolled between March 2001 and February 2019. Median age was 42 (range, 9-60) and 85% were male. Ann Arbor stage was III/IV in 84% and 71% had a high-intermediate or high IPI score. Six (11%) patients had CNS involvement, and 6 (11%) had bone marrow involvement. Median CD4 count was 210 cell/m3 (range 0-1192). Cell-of-origin by Hans classified 69% as GCB and 22% were EBV positive. 31 patients were tested for MYC rearrangement by FISH and 5 (16%) were positive. Patients received a median of 3 cycles of therapy; 1 (2%) patient received only 1 cycle, 2 patients (4%) received 2 cycles, 45 patients (82%) received 3 cycles, 3 (5%) patients received 4 cycles, and 4 (7%) patients received 5 cycles. After a median potential follow-up of 12.6 years, 5-year FFP, PFS and OS were 76.0%, 64.3% and 71.8%, respectively [Figures 1, 2]. Two patients progressed during therapy, while 11 patients relapsed after therapy - all within 12 months of treatment completion. Of 18 deaths on study, 6 were due to disease progression and 12 died from causes unrelated to lymphoma or treatment. Of forty-seven patients with interim (post-cycle 2) PET scans, 30 (64%) became PET negative after 2 cycles. The 5-year PFS was not different in patients who achieved interim PET negativity: 73.4% versus 62.7% (p = 0.14 for comparison of entire PFS curves) [Figure 4]. Of the 13 total patients who progressed or relapsed, 5 were negative on interim PET. Conclusion:Response-adapted SC-EPOCH-RR therapy is effective for HIV-associated DLBCL and many patients are cured with only 3 cycles of therapy. Interim PET scans after 2 cycles using Lugano criteria did not reliably predict clinical outcomes. Further studies investigating the role of circulating tumor DNA (ctDNA) for genotyping and predicting clinical outcomes are planned. This work was supported by the Intramural Research Program of NCI. Disclosures Dunleavy: Pharmacyclics: Membership on an entity's Board of Directors or advisory committees.

Introduction: Relapsed and refractory aggressive B-cell lymphomas can be cured with hematopoietic stem cell transplant (HSCT), but effective salvage regimens are required. Anthracyclines are the most effective agents in lymphoma and dose-adjusted doxorubicin, etoposide, vincristine, cyclophosphamide, prednisone with rituximab (DA-EPOCH-R) was originally developed in relapsed/refractory lymphomas. Gene-expression profiling of diffuse large B-cell lymphoma (DLBCL) identified stromal signatures associated with inferior survival and targeting the tumor microenvironment may block important survival signals. Alemtuzumab is a humanized monoclonal antibody targeting CD52, present on both B and T-cells. We hypothesized that targeting CD52 could overcome treatment resistance. We report the safety and activity of alemtuzumab added to DA-EPOCH-R in relapsed/refractory aggressive B-cell lymphomas, including Hodgkin lymphoma (HL). Methods: Adult pts with relapsed/refractory aggressive B cell lymphomas and adequate organ function were eligible. Pts with HIV or CNS involvement were ineligible. Pre-treatment evaluation included laboratory investigations, computed tomography (CT) scans, bone marrow aspirate/biopsy, and brain MRI/CT if indicated. Alemtuzumab 30 mg was infused first on day 1 over 12 hours before rituximab. EPOCH was infused over 5 days and dose-adjusted based on neutrophil nadir for up to 6 cycles. Responding pts were allowed to receive consolidation. Infective prophylaxis included trimethoprim-sulfamethoxazole, acyclovir, and fluconazole in all pts, and lamivudine for pts at risk of HBV reactivation. PCR for cytomegalovirus (CMV) was done at baseline and with every cycle. Tumor response was assessed per the revised 2014 International Working Group guidelines. CT scans were performed after cycles 4 and 6, and every 3 months for year 1, 4 months for year 2 and 6 months for years 3-5. Positron-emission tomography scans were performed after cycle 4 and 6. The primary endpoint of the study was overall response rate. Results: 50 pts were enrolled from November 2009 to March 2014. Two pts did not receive any chemotherapy due to congestive heart failure and rapid disease. 48 pts received 1 cycle and were included in the analysis. Median age was 45 years (range, 18-72) and 29 (60%) pts were male. Twenty-one (44%) pts had DLBCL (T-cell-histiocyte rich DLBCL (THRLBCL) in 4), 16 (33%) HL, 6 (13%) primary mediastinal B-cell lymphoma, 4 (8%) mediastinal grey zone lymphoma and 1 (2%) B-cell lymphoma NOS. Median lines of prior treatment was 2 (range 1-10). All pts received prior anthracycline and 10 (20%) received prior ASCT. Thirty-five (72%) were primary refractory to chemotherapy. In 46 pts evaluable for response, overall response rate (ORR) was 65% including a complete response (CR) rate of 33%. Of 30 responding pts, 13 (44%) received consolidation therapy (5 allogeneic HSCT, 7 radiation, 1 ASCT) and 17 received no further therapy with 7 long-term remissions. In 20 evaluable DLBCL pts, the ORR was 65% including a 30% rate of CR. All 4 THRLBCL responded and 3 had durable remissions after consolidative XRT (2) and allogeneic HSCT (1). In 15 evaluable HL pts, the ORR was 80% including a CR rate of 60%. After a median potential follow up of 84.6 months, median PFS and OS were 6.7 months (CI95: 4.1 - 10.4) and 18.1 months (CI95: 11.5 - not estimable), respectively. In DLBCL, the 2-year PFS and OS were 23% (CI95 9%-47%) (Figure 1A) and 41% (CI95 19%-66%), respectively, while in HL, the 2-year PFS and OS were 36% (CI95 15%-63%) (Figure 1B) and 60% (CI95 33%-82%), respectively. Febrile neutropenia, grade 4 thrombocytopenia, and CMV reactivation without infection occurred in 18%, 26%, and 53% of cycles, respectively. Grade 3 infection occurred in 18% of pts and included BK (3), HSV (1), and CMV (1). Overall, 27 deaths occurred, 3 during therapy (2 of sepsis, 1 of congestive heart failure) and 24 post-therapy (9 of PD, 5 of sepsis, 1 of hemorrhage, 1 of PTLD, and 8 of unknown causes). Conclusion: Alemtuzumab can safely be added to DA-EPOCH-R in relapsed/refractory aggressive B-cell lymphomas without a significant increase risk of opportunistic infections or unexpected toxicity. Nearly half of patients were successfully bridged to consolidation therapy; however, selected pts, particularly those with significant T-cell infiltration, experience long-term durable remission. Figure 1 Disclosures Dunleavy: Pharmacyclics: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Alemtuzumab is not standard of care treatment of lymphoma. We have studied Alemtuzumab in combination with EPOCH in this study

Background: Lymphomatoid granulomatosis (LYG) is a rare EBV-driven B-cell lymphoproliferative disorder characterized by a reactive T-cell infiltrate that is angioinvasive and angiodestructive. Dysregulated immune surveillance of EBV is thought to contribute to the pathogenesis of LYG and grading of disease is based on the density and number of EBV+ large atypical B-cells. Grade I-II (low-grade) disease is typically polyclonal/oligoclonal and immune-dependent whereas grade III (high-grade) disease is typically monoclonal and immune-independent. Herein, we report additional and extended results from an on-going prospective study at the National Cancer Institute on the treatment of patients with low and high-grade LYG using Interferon-α (INF-α) and/or DA-EPOCH+/-R, respectively. Methods: Pts with histologically confirmed LYG by the Laboratory of Pathology, NCI, were eligible. LYG of any grade or stage was included as were pts with untreated or previously treated disease. Baseline tests included laboratory studies, body CT and FDG-PET, CT or MRI brain, echocardiogram, LP with flow cytometry/cytopathology, and bone marrow aspiration/biopsy. Grade 1-2 LYG pts received primary therapy with INF-α initially at 7.5 MIU TIW which was dose-escalated every 1-2 wks. as tolerated until best response and then continued for 1 yr. Pts with grade 3 LYG received combination chemotherapy with DA-EPOCH+/-R for up to 6 cycles. Pts with progression after primary INF-α therapy and those who progressed after or failed to achieve CR after DA-EPOCH+/-R could cross over to the other treatment. Restaging CT was performed every 4 wks. until stable dose of INF-α and then every 3 mos. and after cycles 4 and 6 of DA-EPOCH+/-R. Surveillance CT was performed every 3, 4, 6 and 12 mos. for post-treatment yrs. 1, 2, 3, and 4-5, respectively, and then as clinically indicated. Results: 70 LYG pts were enrolled between Jan. 1991 and Feb. 2018. Characteristics included; male sex in 45 (64%) pts, median (range) age of 46.2 yrs. (14.9-67) and histologic grade I in 19 (27%), II in 24 (34%), and III in 27 (39%) pts. Twenty-three (33%) pts were untreated, and 32 (46%) and 21 (30%), respectively, had received steroids and/or chemotherapy+/-R. The most common disease sites included lung (100%), CNS (37%), skin (33%), kidney (17%), and liver (17%). Peripheral blood at baseline showed median (range) CD4, CD8 and NK-cell counts of 510 (80-1864; Normal: 359-1565), 138 (8-1245; Normal: 178-853), and 96 (25-1567; Normal: 126-729) cells/uL, respectively, and a median (range) EBV viral load of 100 (1-13,950) copies/mL and 3.48 (0-4.48) Log 10 IU/mL. With a median potential follow-up of 12.9 yrs., 5-yr. PFS and OS for all 67 treated pts was 41% and 70.8%, respectively (Fig.1). There was no significant difference in PFS or OS associated with baseline histologic grade (p=0.47 and p=0.23, respectively) or CNS involvement (p=0.67 and p=0.98, respectively). Of 49 INF-α treated pts, 47 were evaluable for response with an ORR of 60% (CR 55%) and a median (range) TTR of 6.7 mo. (1.4-40) and 5-yr. DOR of 66.6% (95% CI: 45.4-81.1%). ORR was similar [60% (CR 55%)] in the 20 INF-α treated pts with baseline CNS involvement. Overall, in 49 INF-α treated pts, 5-yr. PFS and OS were 46.2% and 72.5%, respectively (Fig.1). Median (range) dose and duration of INF-α was 20 MIU (7.5-40) and 7.9 mo. (0.5-48.6), respectively. Nineteen pts received secondary therapy with DA-EPOCH+/-R for progression during/after INF-α with an ORR of 72% (CR/CRu 56%) in 18 evaluable pts. In 13 evaluable pts refractory to INF-α, ORR was 92% (CR/CRu 69%) with DA-EPOCH+/-R. Of 18 DA-EPOCH+/-R treated pts, 17 were evaluable for response with an ORR of 76% (CR/CRu 41%) and a median (range) TTR of 4.1 mo. (2.6-7.4) and median DOR of 1.5 yrs. (95% CI: 0.3-9.2). Overall, in 18 DA-EPOCH+/-R treated pts, 5-yr. PFS and OS were 27.8% and 66.2%, respectively (Fig.1). Eight pts received secondary INF-α therapy for progression during/after or failure to achieve CR after DA-EPOCH+/-R with an ORR of 75% (CR/CRu 63%). Conclusion: INF-α and DA-EPOCH+/-R result in prolonged remissions in a significant subset of pts with low and high-grade LYG, respectively. Progression to high-grade disease and relapse with low-grade disease following INF-α and DA-EPOCH+/-R treatment, respectively, occurs frequently due to the continued immune dysregulation of EBV and can be successfully treated through cross over to the alternative treatment modality. Disclosures No relevant conflicts of interest to declare.

Background: Burkitt lymphoma (BL) is a highly aggressive B-cell lymphoma that is largely curable with intensive therapy. Previously, a single-center study of 30 patients demonstrated that DA-EPOCH-R based therapy was highly effective in adults with BL (N Engl J Med 2013; 369:1915-1925). We set out to validate these results in a multi-center study and assess if a risk-adapted approach using DA-EPOCH-R is effective. Methods: Patients had newly diagnosed BL, age 18 years or older and HIV negative or positive. Low-risk (LR) patients (normal LDH, ECOG P.S. 0-1, stage I or II disease and a maximum tumor size < 7cm) received 3 cycles of DA-EPOCH-R (with no intrathecal prophylaxis) and all other patients (classified as high risk (HR)) received 6 cycles (with IT prophylaxis days 1 and 5 on cycles 3-6). Results: 77 patients were enrolled. Characteristics include median (range) age 45 (19-78) years; male sex 63 (82%); stage III or IV disease 49 (64%); elevated LDH 41 (53%); CNS involvement 7 (10%); HIV positive 20 (26%). Eleven (14%) and 66 (86%) were classified as LR and HR respectively. There were 2 deaths on treatment in the HR arm secondary to infection. Other toxicities were similar to previous reports of DA-EPOCH-R. At a median follow-up time of 25 months, time to progression (TTP), progression-free survival (PFS) and overall survival (OS) were 92% (95% CI: 82.9-96.8%), 87% (95% CI: 76.2-93%) and 88% (95% CI: 77.1-93.8%) respectively for all patients. TTP, PFS and OS were not significantly different for HR versus LR disease, HIV positive versus negative and age over versus under 40y. Conclusions: In a multicenter setting, both LR and HR patients have excellent outcomes with 3 and 6 cycles of therapy respectively. Risk group, HIV status and age are not associated with outcome (see table). Accrual to this study continues ([NCT01092182][1]). | | | TTP | PFS | OS | | ------------------------------------------- | ------------- | ------------------------------ | ------------------------------ | ------------------------------ | | Patients | N=77 | 92% | 87% | 88% | | LR HR p | 11 66 | 100% 91% 0.35 | 100% 85% 0.22 | 100% 86% 0.24 | | HIV - HIV + p | 57 20 | 96% 84% 0.1 | 88% 84% 0.66 | 90% 83% 0.53 | | Age under 40 Age over 40 p | 35 42 | 94% 91% 0.83 | 90% 84% 0.45 | 93% 83% 0.24 | Table. ![Figure 1.][2] Figure 1. Disclosures Link: Genentech: Consultancy, Research Funding; Kite Pharma: Research Funding. Kahl: Roche/Genentech: Consultancy; Seattle Genetics: Consultancy; Millennium: Consultancy; Cell Therapeutics: Consultancy; Celgene: Consultancy; Infinity: Consultancy; Pharmacyclics: Consultancy; Juno: Consultancy. Bartlett: Gilead: Consultancy, Research Funding; Janssen: Research Funding; Pharmacyclics: Research Funding; Genentech: Research Funding; Pfizer: Research Funding; Novartis: Research Funding; Millennium: Research Funding; Colgene: Research Funding; Medimmune: Research Funding; Kite: Research Funding; Insight: Research Funding; Seattle Genetics: Consultancy, Research Funding; MERC: Research Funding; Dynavax: Research Funding; Idera: Research Funding; Portola: Research Funding; Bristol Meyers Squibb: Research Funding; Infinity: Research Funding; LAM Theapeutics: Research Funding. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01092182&atom=%2Fbloodjournal%2F126%2F23%2F342.atom [2]: pending:yes

Introduction: Primary central nervous system lymphoma (PCNSL) is a rare type of diffuse large B-cell lymphoma (DLBCL). It closely resembles activated B-cell (ABC) DLBCL and most cases have B cell receptor (BCR) and MyD88 mutations. Ibrutinib is an inhibitor of BTK that targets BCR signaling and is active in patients with relapsed/refractory (R/R) ABC DLBCL. Methods: Ibrutinib was incorporated into a novel regimen called DA-TEDDI-R (temozolomide, etoposide, doxil, dexamethasone, ibrutinib and rituximab) (with intraventricular cytarabine). DA-TEDDI-R was designed around therapeutic principles for systemic DLBCL and CNS penetration. Methotrexate was excluded due to potential antagonism with ibrutinib based on preliminary in vitro experiments. Untreated or R/R PCNSL patients were eligible and received ibrutinib in cohorts (560-1120 mg/day PO) for 14-days in a "window" prior to cycle 1 of DA-TEDDI-R (with pre and post-brain MRI/FDG-PET), followed by DA-TEDDI-R with ibrutinib (days 1-10) q21 days x 6. Plasma and CSF PKs of ibrutinib and its metabolite PCI-45227 were analyzed. CSF penetration (AUCCSF: AUCPLASMA) was corrected for human plasma protein binding: parent: 97.3%, metabolite: 91%. CSF PKs of TEDDI drugs and molecular analysis of FFPE biopsies are ongoing. Results: Eleven patients have enrolled; 6 were R/R (median 3 (1-5) prior treatments) and 5 were previously untreated. Eleven completed the ibrutinib window and 5 patients completed and 2 remain on DA-TEDDI-R; Ibrutinib dosing was 560 mg in patients 1-6; 700 mg in patients 7-10; and 840 mg in patient 11. No patient had dose limiting toxicity determined on cycle 1 of DA-TEDDI-R. There were 3 on-study deaths: from progressive disease, infection and ventricular arrhythmia. Ibrutinib PK was completed in patients 1-10 (Table). When corrected for protein binding, CSF penetration was 21.4-100% for ibrutinib and 48-120% for its metabolite. CSF concentrations > IC50were maintained for a median of 4 hours and 8.5 hours at the 560 mg and 700 mg doses, respectively. With ibrutinib alone, 7 of 8 evaluable patients achieved partial responses, and 1 patient had a mixed response. After DA-TEDDI-R, all 5 patients achieved complete remission of which 4 (all R/R) are in remission at 1+, 2+, 3+, and 6+ months, and 1 (previously untreated) patient relapsed at 3 months. Conclusions: Ibrutinib is active in PCNSL and achieves meaningful CSF concentrations. DA-TEDDI-R is a novel treatment for PCNSL and leverages molecular and therapeutic principles developed for the curative treatment of ABC DLBCL. Accrual continues. | | Plasma Ibrutinib PK | CSF Ibrutinib PK | CSF penetration | Hours above IC50(0.5nM) | | ------------------- | ------------------- | ---------------- | --------------- | ------------------------------- | ---------------- | | Dose 560 mg | Cmax (nM) | Tmax (h) | AUC0-10 (nM•h) | T½ (h) | Cmax (nM) | Tmax (h) | AUC0-last (nM•h) | AUCCSF : AUCPlasma (%) | AUCCSF : AUCPlasma Corrected (%) | Plasma | CSF | | 1 | 502 | 1 | 1232 | 10.2 | 1.99 | 2 | 7.7 (10h) | 0.6 | 23.7 | 24 | 4 | | 2 | 145 | 2 | 471 | 4.6 | 0.69 | 2 | 2.4 (6h) | 0.5 | 21.4 | 24 | 2 | | 3 | 77 | 2 | 347 | 3.1 | 1.28 | 2 | 4.4(6hr) | 1.3 | 55.8 | 24 | 4 | | 4 | 72 | 1 | 202 | 2.6 | 1.54 | 4 | 5.5 (10hr) | 2.7 | 100 | 24 | 8 | | 5 | 162 | 2 | 624 | 8.5 | 2.0 | 2 | 9.2 (10hr) | 1.5 | 54.9 | 24 | 10 | | 6 | 99 | 1 | 404 | 6.3 | 0.71 | 2 | 3.4 (4hr) | 1.2 | 45 | 24 | 4 | | Median | 122 | 1.5 | 437 | 5.5 | 1.4 | 2 | 5 | 1.3 | 50 | 24 | 4 | | Range | 75-502 | 1-2 | 202-1232 | 2.6-10.2 | 0.7-2 | 2-4 | 2.4 | 9.2 | 21.4-100 | 24 | 2-10 | | Dose 700mg | | | | | | | | | | | | | 7 | 581 | 1 | 2340 | 5.3 | 11.1 | 2 | 48.6 (24) | 1.7 (10) | 63 (10) | 24 | 10 | | 8 | 411 | 2 | 1565 | 2.4 | 1.63 | 2 | 11.9 (10) | 0.8 | 28.1 | 10 | 10 | | 9 | 164 | 2 | 865 | 3.8 | 0.69 | 4 | 3.9(10) | 0.45 | 16.7 | 24 | 3 | | 10 | 577 | 2 | 1648 | 5.4 | 2.36 | 2 | 11.0(10) | 0.67 | 24.8 | 24 | 7 | | Median | 494 | 2 | 1606 | 4.6 | 1.98 | 2 | 11.5(10) | 0.74 | 26.5 | 24 | 8.5 | | Range | 164-581 | 1-2 | 865-2340 | 2.4-5.4 | 0.69-11.1 | 2-4 | 3.9-48.6 | 0.45-1.7 | 16.7-63 | 10-24 | 3-10 | Table. Disclosures Staudt: Pharmacyclics LLC, an AbbVie Company: Patents & Royalties, Research Funding; NIH: Patents & Royalties.

Background: In diffuse large B-cell lymphoma (DLBCL), a MYC-rearrangement (MYC-R) is present in approximately 10% of cases and has been associated with an inferior outcome following R-CHOP chemotherapy. In a previous report that retrospectively analyzed the prognostic impact of a MYC-R on survival following DA-EPOCH-R, patients with a MYC-R had a similar outcome to MYC negative cases (4 year EFS of 83% versus 76% respectively: p=0.46 Ann Oncol 2011 (22) Suppl 4 # 71). We set out to prospectively validate these results in a multicenter study. Methods: Patients were newly diagnosed with DLBCL or B-cell lymphoma unclassifiable (BCL-U) with features intermediate between DLBCL and Burkitt lymphoma (BL). Only cases that harbored a MYC translocation by fluorescent in-situ hybridization (FISH) or conventional cytogenetic testing were included in this report. Treatment consisted of 6 cycles of DA-EPOCH-R. R esults: 52 patients were included in this preliminary analysis. Characteristics were median (range) age 61 (29-80) years; male sex 37 (71%); stage III or IV disease 38 (73%); IPI score 0-2 in 35% versus 3-5 in 65%; HIV positive 4 (7%). Histologic diagnosis was DLBCL in 45 (86%) and BCL-U in 7 (14%). All cases had a MYC-rearrangement. BCL2 was rearranged in 14/31 (45%) and overexpressed by IHC in 24/43 (56%) cases tested. There were 3 deaths secondary to infectious complications and otherwise toxicities were similar to previous reports of the regimen. At a median follow-up time of 14 months, progression-free survival (PFS), time to progression (TTP) and overall survival (OS) were 79%, 86% and 77% respectively for all patients. PFS was 87% and 64% in cases that were FISH positive (double-hit) and IHC positive for BCL2 respectively. Conclusions: Albeit short follow-up, DA-EPOCH-R in MYC-R DLBCL demonstrates promising activity in a multicenter prospective setting. Further analysis of this data is planned with central pathology review of cases and longer follow-up. The principal arm of this study testing the regimen in BL remains open to accrual (NCT01092182). Figure 1 Figure 1. Disclosures LaCasce: Seattle Genetics, Inc.: Research Funding.