Abstract: Background: Patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) often have a poor prognosis despite therapies using second-line chemoimmunotherapy (CIT). Achievement of complete response (CR) with second-line therapy is associated with improved long-term outcomes. Unfortunately, only 25-35% of patients achieve CR with standard CIT regimens alone. The addition of novel targeted agents such as Bruton Tyrosine Kinase inhibitors (BTKi) to second-line therapy may offer improved treatment responses given the importance of B-cell receptor (BCR) signaling in DLBCL. BTK has been shown to be essential for BCR-mediated activation of the NF- κB/Rel family of transcription factors and BCR signaling has been recognized as a key pathway in the pathogenesis of DLBCL. Moreover, NF-κB activity relies upon chronic active BCR signaling in activated B-cell-like DLBCL, which can be potentially blocked by kinase inhibitors targeting BTK. In this study we examine the feasibility and efficacy of adding the BTKi, acalabrutinib (A), to standard second-line therapy to improve disease response in patients with R/R DLBCL. Here we present initial safety and tolerability data for the ongoing study. Study Design and Methods: This is an open-label, prospective phase II trial (NCT03736616). Cohort A is open to R/R DLBCL patients eligible for autologous hematopoietic transplantation (HCT). Cohort B is open to R/R DLBCL patients considered ineligible for autologous HCT. The primary endpoint for cohort A is to estimate the confirmed CR rate (RECIL 2017 criteria) prior to autologous HCT in patients undergoing second-line CIT. The primary endpoint for cohort B is defined as the estimate of one-year progression-free survival in patients undergoing second-line induction and maintenance acalabrutinib therapy. Cohort A receive 2 cycles of standard RICE salvage CIT in combination with acalabrutinib, 100mg BID days 1-21 of a 21-day cycle (RICE+A). After 2 cycles of therapy, patients undergo autologous stem cell mobilization and collection. Patients then receive a 3 rd cycle of RICE in combination with acalabrutinib. PET-CT (PET3) is to be performed on day 15 of cycle 3 to assess response. Patients with CR or partial response (PR) after PET3 proceed to autologous HCT with BEAM conditioning within 28-42 days of PET3. Post-HCT CR patients receive acalabrutinib 100mg BID as maintenance therapy for 12 additional months. Protocol amendment in May 2021 allows for PET assessment (C2D15) prior to autologous stem cell collection (after cycle 3). Cohort B receive 3 cycles of RICE+A in 21-day cycles followed by PET-CT (PET3) on day 15 of cycle 3. Patients without progressive disease at PET3 continue with acalabrutinib maintenance up to 12 additional cycles until disease progression or unacceptable toxicity. Patients demonstrating progressive disease are withdrawn from study treatment but followed for outcomes. Results: Here we report initial safety and tolerability data for the ongoing study with data cutoff July 28, 2021. Twenty-two patients have been screened and 20 patients have received at least 1 cycle of RICE+A. Patient characteristics are shown in Table 1. Fifteen patients (79%) have completed 3 cycles of RICE+A. One patient (5%) discontinued due to an adverse event (AE; recurrent appendicitis), 3 patients (16%) discontinued due to progressive disease, and 1 patient is receiving ongoing RICE+A as of data cutoff. Hematologic AE have been observed in 17 patients (89%) with 74% being Grade 3/4. Amongst these, neutropenia was the most common AE occurring in 47% with all being Grade 3/4, and thrombocytopenia occurring in 32% with all being Grade 3/4. All hematologic AE recovered to baseline or grade 1 in median 7 days. Amongst non-hematologic AE, diarrhea occurred in 21% and 0% were Grade 3/4, nausea 16% with 0% Grade 3/4, and headache in 16% with 0% Grade 3/4. Discontinuation of therapy due to AE occurred in 1 patient (recurrent appendicitis) and dose reduction occurred in 1 patient (Gr 4 neutropenia). Temporary (per protocol) dose holds of A occurred in 9 patients (45%), primarily for cytopenias during concurrent RICE+A. Median duration for dose holds of A was 5.5 days. Conclusion: RICE+A is feasible with manageable primarily hematologic AEs similar to those reported for RICE alone. Enrollment and follow up is ongoing for efficacy endpoints and further toxicity assessment. Figure 1 Figure 1. Disclosures Bensinger: BMS, Janssen, Poseida, Regeneron, Trillium: Research Funding; Amgen, BMS, Janssen, Sanofi: Speakers Bureau. Glennie: Pharmacyclics/Janssen: Speakers Bureau. Pagel: Pharmacyclics/AbbVie: Consultancy; Incyte/MorphoSys: Consultancy; MEI Pharma: Consultancy; Gilead: Consultancy; Actinium Pharmaceuticals: Consultancy; AstraZeneca: Consultancy; BeiGene: Consultancy; Kite, a Gilead Company: Consultancy; Epizyme: Consultancy. Patel: Bristol Myers Squibb: Consultancy, Speakers Bureau; Janssen: Consultancy; Genentech: Consultancy; BeiGene: Consultancy; TG Therapeutics: Consultancy, Speakers Bureau; Abbvie: Consultancy; Pharmacyclics: Consultancy; Morphosys: Consultancy; Kite Pharma: Consultancy, Speakers Bureau; AstraZeneca: Consultancy, Research Funding, Speakers Bureau; MEI Pharma: Consultancy; ADC Therapeutics: Consultancy; Lilly: Consultancy. OffLabel Disclosure: Acalabrutinib is not FDA approved for treatment of DLBCL and is discussed in the context of an ongoing clinical trial only.

Abstract: High-dose therapy (HDT) with autologous stem cell transplantation (ASCT) is the standard treatment for patients (pts) with chemosensitive relapsed or refractory Hodgkins lymphoma (HL). Unfortunately, there are few established options for HL pts with chemoresistant disease and data regarding the efficacy of HDT and ASCT in this setting are limited. One hundred and seventy-two patients underwent HDT followed by ASCT for HL at our centers between 1971 and 2005. Of these, 66 pts (38.6%) had chemoresistant disease defined as 〈 50% reduction in the size of the tumor with the chemotherapy regimen immediately preceding HDT. The baseline characteristics of these pts included: median age = 34 years (yrs) (range, 14–59 yrs), male = 39 (59%), stage I/II= 15 (23%), stage III = 17 (26%), Stage IV = 34 (51.5%), ≥ 5cm tumor bulk = 23 (35%), 〉 1 extranodal site of disease (ENS) = 13 (20%), median # of prior regimens = 2 (range 1–5), and prior radiation (RT) = 34 (52%). Histologies included nodular sclerosis (NS) in 53 (80%), mixed-cellularity in 11 (17%), and lymphocyte predominant in 2 (2%). Twenty-seven pts (41%) received TBI-based preparative regimens and 39 (59%) underwent non-TBI conditioning with the most common chemo-only regimen of bulsulfan, melphalan, thiotepa used in 19 pts.The estimated 5-year overall (OS) and progression-free survival (PFS) of this cohort was 31% and 18%, respectively with a median follow-up of 2.6 yrs among surviving pts (Figure). Twenty-two (56%) of the 39 deaths were due to relapse and 17 (44%) resulted from non-relapse causes including: 7 infections, 5 pulmonary, 1 cardiac, 1 hepatic, 1 renal, and 2 (5%) unknown causes. Multivariable modeling utilizing the above baseline criteria identified factors that were statistically significantly associated with inferior OS and PFS. These included: NS histology (OS: HR=3.8, p=0.03; PFS: HR=2.5, p=.03), non-TBI conditioning (OS: HR=2.6, p=0.009; PFS: HR=2.1, p=.02), 2 or more ENS (OS: HR=4.1, p=.0005; PFS: HR=3.7, p=0.0008); and male gender (OS: HR=2.0, p=.05; PFS: HR=2.0, p=.03) These data suggest that HDT and ASCT may result in prolonged remissions and survival for a significant minority of chemoresistant HD pts, with improved outcomes observed in those treated with TBI-based regimens, non-NS histology, female gender, and fewer ENS, though novel improved therapies for these patients are still required. Figure Figure

Abstract: Background High dose chemotherapy followed by autologous stem cell transplantation (ASCT) is a standard of care for patients with advanced or treatment refractory multiple myeloma (MM) and non-Hodgkin lymphoma (NHL). Stem cell proliferation and mobilization can be enhanced though the addition of myelosuppressive chemotherapy prior to GCSF administration. Chemotherapeutic agents without cross resistance to prior therapies may support peripheral blood stem cell (PBSC) collection and improve patient outcomes by exacting a more potent direct anti-tumor effect prior to ASCT. Bendamustine (Treanda®) is a synthetic chemotherapeutic agent that shares structural similarities to both purine analog and alkylating agents without significant cross resistance to other compounds in either drug class. Bendamustine appears to have low stem cell toxicity in vitro, is well tolerated, and has activity in MM and NHL, but the potential for the purine moiety to adversely impact stem cell reserve is unknown. We hypothesized that bendamustine’s activity in patients with disease resistant to first line therapies makes it a logical candidate for chemotherapy based PBSC mobilization and tested its impact on stem cell yield. Methods Patients were eligible if they had relapsed or refractory MM, B-cell NHL or T-cell NHL and were candidates for ASCT. Other criteria included: age 〉 18 years, ANC 〉 1,500/mm3, platelets 〉 100,000/mm3, adequate renal and hepatic function, 〈 3 prior myelotoxic regimens, 〈 6 cycles of lenalidomide, no failed mobilization attempt, and no prior pelvic/spinal irradiation. Patients received 1 cycle of BED therapy [bendamustine (120 mg/m2 IV d 1, 2 - provided along with financial support for this study by Teva Pharmaceuticals), etoposide (200 mg/m2 IV d 1- 3), dexamethasone (40 mg PO d 1- 4), delivered as an outpatient, followed by filgrastim (initially 10 mcg/kg/d sc; starting on d 5 through end of collection)]. Apheresis was initiated when peripheral blood CD34 cell counts were 〉 5/µL. The primary endpoint was successful mobilization, defined as collection of 〉 2.0 x 106CD34 cells/kg. AEs were graded using the CTCAE v4.0. Results Thirty-seven patients (32 MM, 4B-cell NHL, 1 NK/T-cell NHL) were treated. The median age was 60 years (range 43-70). The median number of prior therapies was 1 (range 1-3) for MM and 2 (range 1-3) for NHL patients. All patients (37/37) were successfully mobilized. The median number of CD34+ cells collected was 19.43 x 106/kg (range 4.35 to 55.51 x 106). All MM patients collected 〉 10 x 106 CD34+cells/kg. The median time from the start of BED mobilization therapy to the first day of CD34 stem cell collection was 12 days (range 9 to 20 days). The median number of apheresis days was 1 (range 1 to 4). A predictable pattern of leucocyte nadir and recovery was demonstrated (95% of patients started apheresis between days 9-13). Two patients (5%) were given plerixafor and for 2 patients (5%) GCSF was increased to 16 mcg/kg twice daily. Among the 37 patients mobilized and collected, 31 have thus far undergone ASCT and 100% (31/31) achieved an unsupported neutrophil count 〉 500/µL at a median of 15 days (range 7-19) after PBSC infusion and a platelet count 〉 20K/µL at a median of 11 days (range 8-14). Ten SAEs were observed in 8 patients and 1 patient died due to disease progression prior to ASCT. SAEs include: neutropenic fever (1, grade [GR] 3), bone pain (2, GR 3), renal insufficiency (1, GR 1), atrial fibrillation (1, GR 2), hypotension (1, GR 3), stroke (1, GR 2), and one patient accounted for 3 SAEs including GR 3 tumor lysis syndrome and sepsis and GR 5 disease progression. Among twenty-nine evaluable patients to date, responses include: CR= 4 PR=2, SD=19 and PD=4. The ORR to this single cycle of therapy was 21%. Conclusions PBSC mobilization with BED is safe and effective. BED is not an acute stem cell toxin. Large numbers of stem cells were rapidly mobilized and resulted in short durations of apheresis. No patient with MM collected 〈 10 x 106 CD34+ cells/kg (sufficient for 2 ASCTs). Twenty-one percent of patients demonstrated a measurable response to a single cycle of BED therapy and an additional 65% of patients had stable disease. In patients who were transplanted, the time to neutrophil and platelet engraftment was comparable to other chemotherapy based mobilization regimens. The BED regimen was well tolerated and these findings suggest that the role of BED in PBSC mobilization should be further explored. Disclosures: No relevant conflicts of interest to declare.

Abstract: Mantle cell lymphoma (MCL) has one of the worst prognoses of any subtype of non-Hodgkin’s lymphoma (NHL), with a median survival of 3–4 years in most series. High-dose therapy followed by autologous stem cell transplantation (ASCT) is an increasingly common treatment approach for MCL, and some ASCT studies suggest that less heavily pre-treated patients have a longer duration of progression-free survival (PFS), suggesting that ASCT may lead to more favorable outcomes if used earlier in the course of therapy. We analyzed the outcomes of ASCT with respect to remission status at the time of transplantation and induction regimen used in 56 consecutive transplanted patients with MCL. Twenty-one patients received induction chemotherapy with HyperCVAD with or without rituximab (±R) followed by ASCT in first complete or partial remission (CR1/PR1), 15 received CHOP (±R) followed by ASCT in CR1/PR1, and 20 received ASCT following disease progression. A variety of conditioning regimens were used for ASCT in all 3 groups. Estimates of overall (OS) and progression-free survival (PFS) at 3 years among patients transplanted in CR1/PR1 were 93% and 63%, compared with 46% and 36% for patients transplanted with relapsed or refractory disease, respectively (Figure 1). The hazard of mortality among patients transplanted with relapsed or refractory disease was 6.09 times that of patients transplanted in CR1/PR1 (P=.006). Patients in the CHOP (±R) group appeared to have a higher risk of failure for PFS compared to patients in the HyperCVAD (±R) group, though the difference did not reach statistical significance (hazard ratio [HR] 3.67, P=.11) with the small sample size available. The estimated 3-year PFS was 81% for patients in the HyperCVAD group and 44% for patients in the CHOP group. Patients who received R with induction therapy had a reduced risk of mortality (HR 0.33, P=.05) and failure for PFS (HR 0.28, P=.005) compared to those who did not. In summary, these results sug gest that ASCT in first remission leads to improved survival outcomes for patients with MCL compared to ASCT with relapsed or refractory disease, and a HyperCVAD (±R) induction regimen may be associated with an improved PFS among patients transplanted in CR1/PR1. Figure 1. Kaplan-Meier estimates of overall survival from the time of ASCT, with respect to remission status at ASCT. Figure 1. Kaplan-Meier estimates of overall survival from the time of ASCT, with respect to remission status at ASCT.

Abstract: Background: The selective HDAC6 inhibitor ACY-241, a tablet, is structurally related to ricolinostat (ACY-1215), the first agent in this class in the clinic.Ricolinostat, an oral liquid, demonstrated clinical efficacy in a Phase 2 combination with pomalidomide (Pom) and dexamethasone (Dex) in patients (pts) with relapsed or relapsed-and-refractory multiple myeloma (RRMM) without toxicities greater than those reported with Pom and Dex alone (Raje et al., EHA 2016, S813). Preclinical data demonstrate synergistic activity of ACY-241 with Pom and lenalidomide (Len) in induction of cell cycle arrest and apoptosis in MM cells as well as significant extension of survival in a mouse xenograft model (Niesvizky et al., Blood 2015, 126: 3040). We present updated data on safety and efficacy of the ACY-241/Pom/Dex combination in pts with relapsed or RRMM (ACE-MM-200, NCT02400242). Aims:Determine the safety, tolerability, and preliminary efficacy of ACY-241 monotherapy and combination with Pom and Dex and the recommended dose for further development. Methods:Based on clinical experience with ricolinostat and non-clinical pharmacokinetics (PK) of ACY-241, we designed a first-in-human phase 1a/1b clinical trial of a single-cycle of ACY-241 monotherapy followed by ACY-241 in combination with Pom (4mg) and low-dose Dex in pts with relapsed or RRMM. The starting dose of ACY-241 was chosen to give similar exposure to the therapeutic dose of ricolinostat (160 mg QD). The trial design was chosen to grant pts access to combination therapy with an active regimen while exploring the safety, PK, and pharmacodynamic profile of ACY-241 alone and in combination with Pom/Dex. The PK of Pom and Dex was also assessed. Pts with relapsed or RRMM previously treated with ≥ 2 cycles of Len and a proteasome inhibitor were eligible. Cohorts of 3 pts had ACY-241 PO QD as monotherapy (180, 360 and 480 mg) on days 1-21 of a 28 day cycle. If no DLT was noted in cycle 1 with ACY-241, pts continued to cycle 2 of combo therapy with ACY-241/Pom/Dex. Pharmacodynamic assessments were acetylated tubulin (HDAC6 marker) and acetylated histones (Class 1 HDAC marker) in peripheral blood mononuclear cells. Results: Since June 2015, 40 pts have enrolled (34 safety-evaluable, 6 had no dosing information in the database). Median age was 62 (34-84) years and median number of prior regimens was 3 (1-7). 90% of pts were refractory to last treatment. 83% were refractory to Len and 50% to both bortezomib and Len. 20% of pts had high risk cytogenetics. No monotherapy DLTs were observed at the highest dose explored (480 mg). Common toxicities in the monotherapy safety population (N=15) were all grade 1/2, except 1 pt with grade 3 anemia at the 480 mg dose level. Toxicities included nausea (4 pts, 27%), anemia (3 pts, 20%), dizziness, fatigue, leukopenia and thrombocytopenia (2 pts each, 13%). Doses of 180 mg and 360 mg were explored in combination; one DLT (grade 4 thrombocytopenia) occurred at 360 mg. Common toxicities in the combination therapy safety population (N=33) included neutropenia (13 pts, 40%), fatigue (9 pts, 27%), anemia, leukopenia (6 pts each, 18%), cough, insomnia, rash (4 pts each, 12%), and hyperglycemia (3 pts, 9%). Grade 3/4 toxicities included neutropenia (10 pts, 30%), leukopenia (3 pts, 9%) and anemia (2 pts, 6%). PK results showed a dose-linear increase in exposure with increasing dose, no accumulation and no drug-drug interaction with Pom and Dex. Selective increase in acetylated tubulin was seen at 180 mg with increasing levels of acetylated tubulin and histones at higher doses. Confirmed efficacy data (median follow-up 3.5 months) for combination treatment (N=22, all refractory to last treatment regimen) shows 1 VGPR, 10 PR, 2 MR and 8 SD and 1 PD. Median PFS and duration of response were not reached at time of the data cut. Given the safety profile, PK exposure (Cmax~6 µM) and PD profile, the 360 mg QD dose level was recommended for further clinical exploration of ACY-241 in combination with Pom/Dex. Summary/Conclusion:ACY-241 is well tolerated in combination with Pom/Dex with dose proportional increase in drug exposure. Early response data to combination treatment parallel those observed with ricolinostat/Pom/Dex and compare favorably to historic controls of Pom/Dex. Cohort expansion at 360 mg ACY-241 with Pom/Dex is ongoing to confirm the dose and schedule for a planned pivotal trial of Pom/Dex +/- ACY-241 and to explore selected biomarkers. Disclosures Richardson: Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees. Nooka:Amgen: Consultancy; Spectrum: Consultancy; Novartis: Consultancy. Raab:Amgen: Consultancy, Research Funding; BMS: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Research Funding. Shain:Takeda/Millennium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Speakers Bureau; Amgen/Onyx: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Signal Genetics: Research Funding. Matous:Celgene: Consultancy, Speakers Bureau; Takeda Pharmaceuticals International Co.: Speakers Bureau; Seattle Genetics: Research Funding, Speakers Bureau. Agarwal:Celgene: Speakers Bureau; Onyx: Speakers Bureau; Janssen: Speakers Bureau; Amgen: Consultancy; Millennium: Consultancy; AbbVie: Honoraria, Research Funding. Madan:Amgen: Speakers Bureau; Onyx: Speakers Bureau; Takeda: Speakers Bureau; Celgene: Speakers Bureau. Moreau:Novartis: Honoraria; Takeda: Honoraria; Janssen: Honoraria, Speakers Bureau; Celgene: Honoraria; Amgen: Honoraria; Bristol-Myers Squibb: Honoraria. Mateos:Janssen: Honoraria; Celgene: Honoraria; Amgen: Honoraria; Takeda: Honoraria. Facon:Acetylon Pharmaceuticals Inc: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Tamang:Acetylon Pharmaceutical Inc.: Employment. Jones:Acetylon Pharmaceuticals, Inc.: Employment, Equity Ownership. Markelewicz:Acetylon Pharmaceutical Inc.: Employment. Wheeler:Acetylon Pharmaceuticals Inc.: Employment. Trede:Acetylon Pharmaceutials Inc: Employment. Raje:Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Research Funding; Eli Lilly: Research Funding. Terpos:Amgen: Consultancy, Honoraria, Other: Travel expenses, Research Funding; Genesis: Consultancy, Honoraria, Other: Travel expenses, Research Funding; Novartis: Honoraria; BMS: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: Travel expenses, Research Funding; Takeda: Consultancy, Honoraria; Celgene: Honoraria. Bensinger:Amgen: Honoraria; Celgene: Honoraria; Acetylon Pharmaceuticals Inc.: Honoraria; Amgen: Consultancy; Celgene: Consultancy; Sanofi: Consultancy; Merck: Consultancy; Bristol-Meyers Squibb: Consultancy; Celgene: Speakers Bureau; Takeda: Speakers Bureau; Amgen: Speakers Bureau; Acetylon Pharmaceuticals Inc: Research Funding; Bristol-Meyers Squibb: Research Funding; Celgene: Research Funding; Karyopharm Therapeutics: Research Funding; Merck: Research Funding; Amgen: Research Funding; Sanofi: Research Funding; Takeda: Consultancy.

Abstract: Background: Aggressive B-cell non-Hodgkin lymphomas (B-NHL) harboring MYC oncogene abnormalities carry a poor prognosis and frequently relapse after standard front-line therapy. However, little is known about the outcomes following these relapses. Multiple series have suggested that survival is very poor, but detailed descriptions are generally lacking. We sought to examine this under-described yet frequent scenario. Methods: We performed a retrospective analysis of our center’s experience under an IRB-approved protocol. Patients included those with MYC copy number alteration (CN) or gene rearrangement (GR) as detected by fluorescence in situ hybridization and/or metaphase cytogenetics that did not meet diagnostic criteria for Burkitt lymphoma and who experienced initial treatment failure (ITF): relapse after or unable to achieve complete remission (CR) following upfront therapy. Frequencies of characteristics between groups were compared using a chi-square test. Kaplan-Meier plots and Cox proportional hazard models were used to investigate associations between variables. Clinical follow-up was updated as of June 2014. Results: We identified 43 pts with relapsed/refractory B-NHL and a MYC gene abnormality, 31 (72%) of which were MYC GR. Of these 31, 18 (64%) were “double-hit” lymphomas with concurrent BCL2 GR, plus another 2 (7%) that also possessed BCL6 GR (“triple-hit”; BCL2/BCL6 data missing from 3). There were no significant differences in overall survival (OS) from ITF between MYC CN, MYC-only GR, and double-/triple-hit (p = 0.73). Additional clinical features at initial diagnosis included median age of 60 years (yrs) (range: 19-72 yrs), stage III-IV disease in 84% (n = 36), elevated LDH in 83% (n = 24; missing data from 14), and B symptoms in 42% (n = 18). Median time from diagnosis until ITF was 6 months (mo) (range: 1-41 mo). Median follow-up from ITF of surviving pts was 8 mo (range: 2-66 mo). Initial chemotherapy consisted of CHOP in 56% (n = 24), while 35% (n = 15) received a more intense regimen: hyperCVAD (n = 7), dose-adjusted EPOCH (n = 6), or CODOX-M/IVAC (n = 2); all but 1 pt received rituximab (R) with initial therapy. There was no significant difference in the use of CHOP vs intensified regimens with regard to the presence of MYC CN (33% vs 20%, respectively) or MYC GR (67% vs 80%, respectively; p = 0.37). However, 1-yr OS from ITF among those who received CHOP upfront was significantly higher than those who received intensified upfront therapy (34% vs 0%, p = 0.01; Figure 1). CHOP was used more frequently among those who later received ICE salvage (n = 21) than cytarabine (Ara-C)-based salvage (n = 10; 71% vs 40%, respectively; p = 0.09). The rates of subsequent stem cell transplantation (SCT) following ICE and Ara-C were comparable (57% vs 40%, respectively; p = 0.37). R was included in all but 1 pt who received Ara-C. Pts who received ICE had a significantly higher 1-yr OS from ITF than those treated with Ara-C (28% vs 8%, p = 0.01; not shown). 1-yr OS from ITF was significantly better among the 17 pts (40%) who were able to undergo autologous (auto) SCT than the 22 (51%) who did not (38% vs 7%, respectively; p = 0.02; Figure 2). Four pts (9%) received an allogeneic (allo) SCT for their initial salvage SCT and were analyzed separately: Three pts relapsed at 1, 4, and 8 mo post-SCT, while the fourth died in CR 3 yrs later. Rates of SCT use were comparable for pts who initially received CHOP (50%) and those treated with intensified initial therapy (60%; p = 0.54). All but 1 pt in this cohort were treated with the intent of undergoing SCT. Six pts (14%) had confirmed central nervous system (CNS) relapse, 1 of whom received CNS prophylaxis during initial therapy. Among these, 4 died within 6 mo of ITF and 1 was lost to follow-up with progressive disease only 2 mo after ITF. The remaining pt underwent auto SCT in CR and is alive but with only 1 mo of follow-up. Conclusions: We have described the outcomes of one of the largest cohorts of relapsed/refractory MYC+ B-NHL reported to date. Though intensified initial therapy may improve outcomes upfront, pts for whom these regimens fail do exceedingly poorly. Pts unable to undergo SCT also have exceptionally dismal outcomes. These subsets of pts in particular should be offered novel therapies in the context of clinical trials. Further, more aggressive initial therapies including consolidative SCT are worth studying since the outcomes after ITF are so poor. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Gopal: Seattle Genetics: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda/Millennium: Honoraria, Research Funding, Speakers Bureau; Gilead: Research Funding; Janssen: Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; BMS: Research Funding; Piramal: Research Funding; Teva: Research Funding; Spectrum: Research Funding; BioMarin: Research Funding; Merck: Research Funding; Emergent: Research Funding.

Abstract: High-dose therapy (HDT) with autologous stem cell transplantation (ASCT) is the standard treatment for patients with chemosensitive relapsed or refractory diffuse large B cell lymphoma (DLBCL). Unfortunately, there are few established options for DLBCL patients with chemoresistant disease and data regarding the efficacy of ASCT in this setting are limited. We conducted a retrospective review of patients with chemoresistant DLCBL undergoing ASCT at our Center with the goal of identifying variables associated with better outcomes. Between March 1990 and September 2004, 40 pts underwent ASCT for chemoresistant DLBCL, defined as 〈 50% reduction in the size of the tumor with the chemotherapy regimen immediately preceding ASCT. The median age of these pts was 44 years (range 17–69). The number of prior chemotherapies was 2 (n=21), 3 (n=15), or 4 (n=4). Twenty-two (55%) patients had progressive disease (PD) following their pre-transplant salvage therapy and 18 (45%) patients had stable disease (SD). Sixteen patients (40%) had never achieved at least a partial response (PR) to any previous chemotherapy. Median time from diagnosis to ASCT was 13 months (range 6–98). The international prognostic index (IPI) at time of ASCT was available for 33 patients and was 0–1 for 10 patients and 2–4 for 23 patients. Twenty-four patients (60%) underwent conditioning with combined chemotherapy and radiation and 16 patients (40%) received chemotherapy only. All patients received mobilized peripheral blood stem cells. Thirty-three patients have died as of last contact, with an estimated 3-year overall survival (OS) of 21% and a median follow-up of 4.0 years among the 7 survivors. Among 34 patients who did not have refractory disease following transplant, estimated 3-year progression free survival (PFS) was 12%. Causes of death include PD (n=24), ASCT toxicity (n=3), and late infection (n=2). After adjusting for year of transplant, patients with a remission duration of less than one year following initial treatment and patients whose remission duration exceeded one year had a reduced, but not statistically significant, hazard of mortality compared to patients that never responded (remission 〈 1 year: HR=0.28, p=0.21; 〉 1 year: HR=0.14, p=0.08) (Figure 1). The hazard of death decreased with transplants performed more recently (p=0.03). There was no statistically significant association between outcomes and age at transplant, number of prior chemotherapy regimens, conditioning regimen (radiation vs non-radiation based), disease status at ASCT (progressive vs stable), or pre-ASCT IPI (available for 33 patients). Though outcomes following ASCT for chemoresistant DLBCL are poor, a minority of patients with prolonged remission prior to initial relapse may achieve long term survival following HDT. Additional strategies are needed to treat this disease. Figure Figure