ALBERT

Description: Backgound Venetoclax (V) plus obinutuzumab (O) regimen is active as frontline CLL treatment; a little over half of patients (pts) will achieve undetectable minimal residual disease in the bone marrow (BM-uMRD) with one year of time-limited therapy (Fischer et al. NEJM 2019). Novel strategies may further augment the efficacy of VO. Ibrutinib was previously combined with VO, but relatively high rates of infusion reactions and neutropenia were observed, as were the characteristic toxicities of ibrutinib including diarrhea and bruising (Rogers et al. Blood 2018). Acalabrutinib (A), a more selective BTK inhibitor, is well-tolerated and active as monotherapy or with O, and we previously found that it sensitizes CLL cells to V (Deng et al. Leukemia 2017). We hypothesized that a time-limited triplet combination of A, V, and O (AVO) could achieve a high rate of BM-uMRD with good tolerability. For the first time we now report on the safety and preliminary efficacy data of AVO in previously untreated CLL pts. Methods This ongoing open-label, single arm, phase 2 investigator-initiated study (NCT03580928) enrolled pts with previously untreated CLL without restriction by prognostic marker status. Eligibility: requiring treatment by iwCLL criteria, ECOG PS ≤ 2, creatinine clearance ≥50ml/min, absolute neutrophil count ≥500/mm3, and platelets ≥30,000/mm3. A, V, and O are started sequentially (see figure), with one 28-day cycle lead-in with A at 100 mg bid, then 2 cycles of AO (with O at standard dosing), then V ramp-up beginning at C4, followed by 3 more cycles of triplet AVO therapy. After 6 months of O, the AV doublet continues through C15; pts with BM-uMRD-negative CR after C15 may discontinue therapy, while all others continue AV until completing C24, with the option to discontinue therapy if in BM-uMRD CR at that time. Response is assessed by 2018 iwCLL criteria, including bone marrow biopsy with MRD testing in the BM and peripheral blood (PB) by 8-color flow cytometry at a sensitivity of at least 10-4. The primary endpoint is the rate of BM-uMRD CR after 15 cycles. Non-hematologic adverse events (AEs) are assessed by CTCAE v5.0, with hematologic toxicity determined by iwCLL criteria. Results The data cut for this interim analysis was July 11, 2019. The study is fully accrued at 37 pts. Median age: 63 years (range: 41-78), 73% male. Baseline prognostic features: unmutated IGHV in 23 (62%) pts, TP53 aberrant disease (defined as either del(17p) and/or TP53 mutation) in 10 (27%) pts, del(11q) in 10 (27%) pts, and complex karyotype in 7 (19%) pts. Thirty-six pts remain on study drugs with a median time on therapy of 8 months (range: 2-11). One pt withdrew consent after 6 cycles due to gastrointestinal symptoms. The overall response rate for the 24 pts who have completed re-staging at C8 is 100%, 18 (75%) PR and 5 (25%) CR. At C8 restaging, 65% of pts were PB-uMRD, 50% of pts were BM-uMRD, and 3 pts (13%) had BM-uMRD CRs. In 8 pts with TP53-aberrant disease who have reached C8, 6 had PR and 2 had CR, with 3 pts BM-uMRD. The most frequent AEs have been fatigue (81% total, 78% gr 1+2, 3% gr ≥3) and headache (76% total, 73% gr 1+2, 3% gr ≥3). Bruising was reported by 16 pts (43%, all gr 1+2). The most frequent gr 3/4 AE has been neutropenia (68% total, 32% gr ≥3). Infusion-related reactions were seen in 8 pts (22%, 19% gr 1+2, 3% gr ≥3). Laboratory tumor lysis syndrome (TLS) occurred in 2 pts (5%), both gr 3 immediately after starting O and prior to any V; both pts continued O. Out of 32 pts, 31 (97%) were medium-to-high risk for TLS on C1D1 but only 3 (9%) were medium-to-high risk at V initiation on C4D1, with 4 medium-to-low risk pts electively admitted for V initiation. One case of gr 3 atrial fibrillation and no cases of hemorrhage or febrile neutropenia were observed. Conclusion Our preliminary data suggest that even at an early response evaluation after 8 cycles of therapy (including only 4 months of V), AVO as frontline CLL therapy leads to a high proportion of pts achieving BM-uMRD and CR, including pts with TP53-aberrant disease. The AE profile is favorable, with a low rate of infusion reactions and no significant cardiac or bleeding toxicities. Updated data will be presented at the meeting for this ongoing study. Based on our initial results we have opened an expansion cohort to further characterize the efficacy and safety of AVO. AVO will also be studied head-to-head against chemoimmunotherapy and the AV doublet in the phase 3 trial CL-311 (NCT03836261), which is currently enrolling. Figure Disclosures Montegaard: Pharmacyclics: Consultancy; Janssen: Consultancy. Jacobson:Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Novartis: Consultancy, Honoraria, Other: Travel Expenses; Pfizer: Consultancy, Research Funding; Humanigen: Consultancy, Other: Travel Expenses; Bayer: Consultancy, Other: Travel Expenses; Precision Biosciences: Consultancy, Other: Travel Expenses; Celgene: Consultancy, Other: Travel Expenses. Jacobsen:Astra-Zeneca: Consultancy; Novartis: Research Funding; F. Hoffmann-LaRoche: Research Funding; Takeda: Honoraria; Pharmacyclics: Research Funding; Merck: Consultancy, Research Funding; Acerta: Consultancy. LaCasce:Seattle Genetics: Consultancy, Research Funding; BMS: Consultancy; Research to Practice: Speakers Bureau; Humanigen: Consultancy. Arnason:Regeneron Pharmaceuticals, Inc.: Consultancy; Celgene/Juno: Consultancy. Armand:Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Affimed: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Research Funding; Otsuka: Research Funding; Sigma Tau: Research Funding; Infinity: Consultancy; Genentech: Research Funding; Pfizer: Consultancy; ADC Therapeutics: Consultancy; Tensha: Research Funding. Brown:BeiGene: Consultancy; AbbVie: Consultancy; Catapult Therapeutics: Consultancy; Dynamo Therapeutics: Consultancy; Genentech/Roche: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; Loxo: Consultancy, Research Funding; Novartis: Consultancy; Juno/Celgene: Consultancy; Acerta Pharma: Consultancy; AstraZeneca: Consultancy; Gilead: Consultancy, Research Funding; Pfizer: Consultancy; Pharmacyclics: Consultancy; Sunesis: Consultancy; TG Therapeutics: Consultancy; Verastem: Consultancy, Research Funding; Sun Pharmaceuticals: Research Funding; Janssen: Honoraria; Teva: Honoraria; Morphosys: Other: Data safety monitoring board; Invectys: Other: Data safety monitoring board; Octapharma: Consultancy. Davids:AbbVie, Acerta Pharma, Adaptive, Biotechnologies, Astra-Zeneca, Genentech, Gilead Sciences, Janssen, Pharmacyclics, TG therapeutics: Membership on an entity's Board of Directors or advisory committees; AbbVie, Astra-Zeneca, Genentech, Janssen, MEI, Pharmacyclics, Syros Pharmaceuticals, Verastem: Consultancy; Acerta Pharma, Ascentage Pharma, Genentech, MEI pharma, Pharmacyclics, Surface Oncology, TG Therapeutics, Verastem: Research Funding; Research to Practice: Honoraria. OffLabel Disclosure: Acalabrutinib, venetoclax, obinutuzumab - combination therapy for previously untreated CLL

Description: Background: Induction chemoimmunotherapy followed by autologous stem cell transplantation (ASCT) is a standard of care for transplant eligible (TE) patients (pts) with untreated mantle cell lymphoma (uMCL); however, there is no consensus on the optimal induction regimen. The addition of rituximab + high-dose cytarabine (RC) to an RCHOP-like regimen is associated with better outcomes. In addition, two randomized trials have demonstrated superior efficacy and tolerability for rituximab/bendamustine (RB) compared to RCHOP for uMCL. Based on this, we conducted a phase 2 trial of 3 cycles of RB followed by 3 cycles of RC in 23 TE pts with uMCL, with encouraging preliminary results (Armand, BJH 2016). Pts continued to be followed for relapse and survival. Meanwhile, RB/RC became the standard frontline regimen at Dana-Farber Cancer Institute (DFCI). Simultaneously, investigators at Washington University in St. Louis (WUSTL) initiated a similar study of alternating cycles of RB/RC for uMCL. Herein, we report the results of both phase 2 trials as well as the off-trial experience. Methods: In the DFCI trial, TE pts (age 18-69) with uMCL were treated with 3 cycles of RB (R 375 mg/m2 d1, B 90 mg/m2 d1-2) followed by 3 cycles of RC (R 375 mg/m2 d1, C 3gm/m2 BID d1-2 with dose reductions for age, renal dysfunction, or pre-existing neurotoxicity). Off-trial pts treated with RB/RC at DFCI or in consulting community practices were retrospectively identified using clinical and pharmacy databases. In the WUSTL trial, TE pts (age 18-65) received alternating cycles of RB (cycles 1, 3, 5) and RC (cycles 2, 4, 6) (same dosing as above). Response assessments were made using CT scans for the DFCI trial and PET/CT for the WUSTL trial and DFCI off-trial pts. Results: In total, 86 pts (23 DFCI trial, 49 DFCI off-trial, 14 WUSTL trial) were treated with RB/RC. The median age was 57 (range 30-72). Pts in the WUSTL cohort were more likely to be male, have a high MIPI score, and have blastoid variant (Table). 94% of pts completed 6 cycles of RB/RC therapy. Off-trial pts were more likely to receive a lower starting dose (≤ 2gm/m2) of cytarabine (76%) compared to trial pts (38%). At the EOI, the overall response rate and CRR were 98% and 92%, respectively, with similar response rates across cohorts (Table). 73 pts (85%) subsequently underwent ASCT and 4 additional pts (5%) have ASCTs planned. 9 pts did not undergo ASCT because of persistent or PD (n=3), prolonged cytopenias (n=3), an incidentally identified ASXL1 mutation without cytopenias (n=1), pt preference (n=1), and inadequate stem cell collection (n=1). Delayed platelet engraftment after ASCT was seen for pts receiving alternating cycles of RB/RC compared to sequential RB/RC at day 30 (plts

Description: Objective 18F-fluorodeoxyglucose (FDG)-positron emission tomography (PET) is used routinely for response assessment and treatment decision making in Hodgkin lymphoma and B cell non-Hodgkin lymphoma. The predictive value of PET/CT in patients with peripheral T-cell lymphomas (PTCL) is not well defined. We performed a retrospective single institution analysis to determine the utility of pre-transplant PET/CT to predict outcomes following autologous stem cell transplant (ASCT) for PTCL. Materials and Methods PET/CT patient population We screened the Dana-Farber Cancer Institute database for patients undergoing ASCT between 2005 and 2015 and identified 109 PTCL patients. Patients had PET/CT performed within 3 months prior to transplant and follow up PET/CT within one year of ASCT. 38 patients met the inclusion criteria (17 women, 21 men, mean age at transplant 56 years, SD ±14.6, range 22-73). Image interpretation The FDG-PET/CT images were reviewed on HERMES GOLD (Hermes Medical Solutions AB, Stockholm, Sweden) workstation by a radiologist (AON) blinded to clinical details. Pre-transplant PET/CT images were read initially and then one week later the post-transplant PET/CT images were read with the reader blinded to the pre-transplant PET/CT findings. The Deauville five-point scale was used for staging and assessment of treatment response and recurrence. A Deauville score of 3 or less was considered a complete response (CR). Results There was mean of 1.3 months between the initial PET/CT and transplant. Mean of 5 months between transplant and follow up PET/CT. A total of 30 patients had a CR on pre-transplant PET/CT. There were 8 patients with persistent sites of FDG uptake on PET/CT with Deauville 4 (n=4), Deauville 5 (n=2) consistent with partial response to treatment. Pre-transplant PET/CT did not correlate with long term survival outcomes including 3-year PFS in our data; a negative pre-transplant PET/CT was not associated with improved 3-year PFS as compared to a positive pre-transplant PET/CT. A total of 26 patients (68%) had no evidence of disease on post-transplant PET or negative post treatment PET/CT. Of those, 23 (88%) had a 3 -year progression free survival, 13 (50%) had a 5-year progression free survival, and 5 (19%) had died of recurrent disease at the time of our analysis. On post-transplant, a total of 12 patients had positive PET/CT with 6 achieving partial remission and 6 having progressive disease on post-transplant PET/CT. In terms of outcome, the 3-year PFS for the PET positive group was 42% (5/12). Of those, 2 (17%) had durable 5-year PFS with treatment after transplant while the other 10 (83%) eventually died of their disease. The 3-year PFS rate in the PET negative group was 88% (23/26) (95% CI: 70 - 98%) and 42% (5/12) (95% CI: 15 - 72%%) for PET positive group. The difference in the 3-year PFS in the PET negative group is significantly larger than that of the PET negative group (p

Description: Burkitt lymphoma (BL) is a highly aggressive B-cell non-Hodgkin lymphoma (NHL) accounting for nearly 3% of all newly diagnosed NHLs. Treatment of adult non-HIV-related BL with the intensive CODOX-M/IVAC regimen (modified Magrath regimen) produces complete responses (CR) in 75 to 86% of patients, with lower CR rates reported in HIV-related BL. The CD20-directed monoclonal antibody rituximab has never been reported in combination with CODOX-M/IVAC, and here we report the first series in BL patients, with or without HIV infection. A total of 24 patients were identified at our institutions who received rituximab plus CODOX-M/IVAC with curative intent. Rituximab was administered at 375mg/m2 on day 3 of cycle 1, and then on day 1 of subsequent cycles. Twenty-three patients received 4 alternating cycles of R-CODOX-M/R-IVAC for high risk disease, while 1 patient received 3 cycles of R-CODOX-M alone for low risk disease, defined as a single focus less than 10cm with a normal LDH. All patients received white cell growth factor support, and pneumocystis prophylaxis was included for all HIV+ patients. The median age was 45 years (17–67), advanced Ann Arbor stage 80%, LDH 〉 upper limit of normal 80%, extra nodal involvement 80% and ECOG PS

Description: BACKGROUND: ABVD with or without radiation is standard therapy for limited stage HL, but carries risks of bleomycin-lung injury and radiation toxicity. Brentuximab vedotin (BV) is an anti-CD30 antibody drug conjugate which is highly active in relapsed classical HL. We previously combined BV with AVD in limited stage non-bulky classical HL which resulted in a high CR rate, but at the cost of increased neutropenia, neutropenic fever, and neuropathy, likely related to the overlapping toxicity profile with vinblastine. Similar toxicity findings were also observed with BV-AVD in advanced stage classical Hodgkin lymphoma. We therefore evaluated BV plus AD (BV-AD) without radiation therapy for non-bulky stage I-II classical HL with the goal of reducing toxicity and maintaining high rates of inducing CR. METHODS: This is a multicenter single arm open label phase 2 study. Patients received BV 1.2 mg/kg plus standard dose adriamycin and dacarbazine on days 1 and 15 of each 28 day cycle. GCSF prophylaxis was not included. Patients received 4 or 6 cycles of BV-AD based on the results of an interim PETCT scan performed following cycle 2. PET negativity was defined as Deauville scores 1-3. Patients in CR on interim PETCT received 4 total cycles of therapy; patients in PR completed 6 cycles. The primary endpoint is complete response rate (CRR) at end of treatment. A sample size of 34 was required to detect an end of treatment CRR of 95% with 91% power and alpha error of 0.09. RESULTS: 34 patients were enrolled. Median age is 36 (range 18-63). Stage is IA (3), IB (1), IIA (29) and IIB (1). Risk is classified per the GHSG criteria as early unfavorable in 47%, and favorable in 53%. The interim CR rate is 94%. Accordingly, 32 interim PET negative patients (94%) received 4 total cycles of therapy, and 2 interim PET positive patients (6%) received 6 total cycles of therapy. No patients received consolidative radiation therapy, per protocol. The primary endpoint of end of treatment CR rate is 100%. At a median follow-up of 15 months, the FFS, PFS and OS are all 100%. The most common adverse events of any grade are nausea (79%), peripheral sensory neuropathy (56%), fatigue (50%), constipation (38%), alopecia (35%) and neutropenia (24%). Most toxicities were low grade, with only 15% of subjects experiencing any grade 3 toxicity, and there were no grade 4 or 5 toxicities. Specifically, 2 patients had grade 3 neutropenia, and 1 patient each had grade 3 nausea/vomiting, pneumonia and thromboembolic event. Peripheral sensory neuropathy was grade 1 in 17 patients, and grade 2 in 2 patients. There were no cases of neutropenic fever. CONCLUSIONS: BV-AD for 4-6 cycles induces high interim and end of treatment CR rates of 94% and 100%, respectively, allowing 4 total cycles of therapy in most patients. The PFS, FFS and OS are all 100% at last follow up. Toxicity appears mild and notable for a low incidence of neutropenia, alopecia, and moderate peripheral neuropathy. This promising regimen avoids bleomycin, vinblastine, radiation and primary GCSF prophylaxis with resultant low toxicity and preserved high efficacy rates in patients with early favorable and early unfavorable non-bulky limited stage classical Hodgkin lymphoma. Follow up for this trial is ongoing. Figure. Figure. Disclosures Abramson: Merck: Consultancy; Seattle Genetics: Consultancy; Karyopharm: Consultancy; Verastem: Consultancy; Amgen: Consultancy; Humanigen: Consultancy; Juno Therapeutics: Consultancy; Gilead: Consultancy; Novartis: Consultancy; Bayer: Consultancy; Celgene: Consultancy. Sokol:Mallinckrodt Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy; Spectrum Pharmaceuticals: Consultancy. Jacobsen:Merck: Consultancy; Seattle Genetics: Consultancy. LaCasce:Seattle Genetics: Consultancy, Honoraria; Research to Practice: Speakers Bureau; Humanigen: Consultancy, Honoraria; Bristol-Myers Squibb: Other: Data safety and monitoring board.

Description: Background Langerhans cell histiocytosis (LCH) is a heterogeneous disease whose myriad manifestations result from accumulation of Langerhans cells in a variety of organs most commonly including skin, bone, central nervous system, liver, lymph nodes, and bone marrow. The disease can affect people of any age. Treatment is primarily driven by disease extent and organ involvement and can range from focused radiation or surgery to multi-agent chemotherapy. There is a relatively high recurrence rate following complete remissions with conventional chemotherapy. In the first-time-in-human (FTIH) study of the oral pan-AKT inhibitor afuresertib (GSK2110183), in patients with hematologic malignancies, a patient with refractory multi-system LCH experienced a prolonged period (〉 3 years) of clinical benefit on 125mg oral once daily afuresertib. This observation led to the evaluation of the use of afuresertib in patients with LCH. Methods This single-arm, open-label trial was designed to evaluate the efficacy and safety of afuresertib, administered at 125 mg once daily, in adults and adolescents with relapsed/refractory LCH and adults with treatment-naïve LCH. Secondary objectives included pharmacokinetics. Diagnosis of LCH was confirmed by pathology review of archival tissue. The Histiocyte Society criteria were used for response evaluation at three and six months with safety and pharmacokinetic assessments performed at pre-specified intervals. BRAF status from archival tissue was evaluated by Sanger sequencing. Results 17 patients (16 adults, 10 females) were enrolled; median age was 38 years (15-75). 3/17 patients had isolated pulmonary disease, 1/17 had single-system multifocal-bone disease, 1/17 had single-system skin disease, and 12/17 had multi-system disease. Seven patients were treatment-naïve; 10 had relapsed/refractory disease, including the one adolescent. The most frequent (〉20% of patients) adverse events (AEs), regardless of causality, were nausea (59%), fatigue (59%), upper respiratory infection (47%), diarrhea (47%), dyspepsia (35%), bone pain (39%), asthenia (24%), memory impairment (24%), decreased appetite (24%) and vomiting (24%). Most AEs were Grade 1 or 2 in severity; no Grade 4 AEs were reported and no Grade 3 AEs occurring in more than 1 subject were reported. 6/17 (35%) had afuresertib dose modifications (interruption or reduction). Afuresertib plasma concentrations in the adult patients were similar to values seen in adult patients with other hematologic malignancies in the FTIH study. Following a single dose, the concentration-time profile in the adolescent patient was similar to adults in the FTIH study (Tmax = 3h: Cmax 229 ng/ml: AUC24 = 3893 ng*h/mL). 15 patients had archival tissues collected for BRAF testing; 13 had DNA suitable for analysis. 2/13 was BRAF V600E mutant and 11/13 were BRAF wild type. Upon evaluation of the all-treated patient population, 5/17 (29%) patients were reported as better at the three and/or six month disease assessment. Among the 5 responders, three were treatment-naïve and two had relapsed/refractory disease. The median duration on study for all patients was 214 (44-426) days. For the 5 patients who responded, the median duration on study was 372 (255-426) days. Conclusion The pharmacokinetic and safety profile of afuresertib in patients with LCH was consistent with that observed in patients with other hematologic malignancies evaluated in the FTIH study. Afuresertib was active in patients with both treatment-naïve and relapsed/refractory disease. Additional evaluation, including molecular profiling, may be warranted alone or in combination with BRAF inhibitors or established therapies for LCH to determine the optimal population of patients with LCH who might benefit from afuresertib Disclosures: Vassallo: GlaxoSmithKline: Research Funding. Oliff:GlaxoSmithKline: Employment. Morris:GlaxoSMithKline: Employment. Reedy:GlaxoSmithKline: Employment. Portnoy:GlaxoSmithKline: Stock, prior employee Other. Smith:GlaxoSmithKline: Employment, Equity Ownership. Noble:GlaxoSmithKline: Employment, stock Other. Murnane:GlaxoSmithKline: Employment, stock Other. Szabo:GlaxoSmithKline: Employment. Heaney:Novartis: Research Funding; Sanofi-Aventis: Consultancy, Research Funding; Onconova: Research Funding; Incyte: Consultancy, Research Funding.

Description: Abstract 4881 Background: In a wide range of malignancies, including nonHodgkin lymphoma (NHL), treatment-naive patients generally show a greater response to chemotherapy than patients receiving second-line or subsequent therapy. Furthermore, objective response rate (ORR) and progression-free survival (PFS) generally decrease with each subsequent line of therapy, the hallmark of acquired drug resistance. This trend would also be expected for PTCL, although there are no published studies or retrospective data analyses specifically in PTCL describing the pattern of response to successive treatments. The goal of the analysis presented here was to determine whether a trend of progressive resistance is observed in relapsed or refractory PTCL, and to identify the efficacy (PFS and ORR) of pralatrexate (FOLOTYN®) as a subsequent therapy relative to previous treatments. The PROPEL (Pralatrexate in Patients with Relapsed Or Refractory Peripheral T-cell Lymphoma) study is the largest data set published for relapsed or refractory PTCL to date. As a part of the patients' medical history, data were collected on response and PFS in previous lines of therapy. Patients had a median of 3 prior systemic therapies (range 1 to 12). Overall in the PROPEL study, pralatrexate demonstrated a 39% ORR by investigator assessment and a 29% ORR by central review. The median duration of response was 8.1 months by investigator assessment and 10.1 months by central review. The median duration of PFS was 4.0 months by investigator assessment and 3.5 months by central review. Median overall survival was 14.5 months. Methods: Analyses were conducted on patients according to the number of prior systemic therapies. PFS and ORR of the third therapy prior to pralatrexate (-3) were compared with those of the second prior therapy (-2); PFS and ORR of second prior therapy (-2) were compared with those of the last (most recent) line of therapy (-1) prior to pralatrexate; and PFS and ORR of last line of therapy (-1) were compared with pralatrexate therapy for these patients. These analyses utilized investigator assessment of PFS and response since review of tumor assessments on prior therapies was based on investigator assessment. Results: 57 patients had undergone at least 3 prior systemic therapies before entry into PROPEL. Of these 57 patients, 34 had 〉 3 previous treatments and 23 had exactly 3 previous treatments. As presented in the table below, a trend of reduced PFS and ORR with successive lines of therapy was observed. The hazard ratio (HR) for outcomes worsens with successive lines of therapy [-3 vs -2: HR 0.660 (0.450, 0.967); -2 vs -1: HR 0.823 (0.566, 1.195)]. Thus, patients with ≥3 prior lines of therapy (-3) had higher response rates and PFS vs the RR and PFS in the same patients with later lines of therapy (-2 or -1). According to this analysis, this trend was reversed with pralatrexate treatment demonstrated by a higher response rate (40%) and longer PFS (median =134 days) than the previous line of therapy. The only HR 〉1 in this analysis, indicating a longer PFS for a more recent line of therapy vs the most recent prior line of therapy, is for pralatrexate vs -1. The same analyses were performed on the 86 patients who had undergone at least 2 previous treatments. The trend for PFS and response rate to decrease with each subsequent treatment was again demonstrated and was again reversed with pralatrexate (HR for PFS = 1.201 [-1 vs -0] vs 0.785 [-2 vs -1]). Conclusions: This is the first analysis to demonstrate that patients with PTCL exhibit the same pattern of progressive resistance as seen in most other tumor types. It is also the first to demonstrate that a drug, pralatrexate, can reverse the pattern of progressive resistance in patients with drug-resistant PTCL. Pralatrexate demonstrated higher responses and longer PFS than would be expected in a later line of therapy setting, thus reversing the trend of progressive resistance. Disclosures: O'Connor: Allos Therapeutics, Inc.: Research Funding. Haouin: GlaxoSmithKline: Consultancy; Amgen Inc.: Consultancy. Gisselbrecht: Allos Therapeutics, Inc.: Research Funding. Foss: Allos Therapeutics, Inc.: Consultancy, Speaker. Savage: Allos Therapeutics, Inc.: Consultancy, Honoraria. Pro: Allos Therapeutics, Inc.: Research Funding. Pinter-Brown: Allos Therapeutics, Inc.: Consultancy. Horwitz: Allos Therapeutics, Inc.: Consultancy, Research Funding. Jacobsen: Allos Therapeutics, Inc.: Consultancy. Koutsoukos: Allos Therapeutics, Inc.: Employment. Fruchtman: Allos Therapeutics, Inc.: Employment.

Description: Lymphomas represent nearly 70 distinct diseases with unique clinical presentations, therapeutic responses and underlying biology. There is a pressing shortage of publically available cell line and in vivo models of nearly all of these diseases, which has severely hampered efforts to understand and target their biology. To address this issue, we have established a repository of patient-derived xenografts (PDX) of lymphomas by engrafting human tumors into immunodeficient NOD/SCID/IL2rgnull (NSG) mice. These lymphomas, along with a spectrum of other PDXs of hematologic malignancies, are available to collaborators through the online portal PRoXe (Public Repository of Xenografts) at http://PRoXe.org. Blood and bone marrow specimens involved with tumor are injected by tail vein (IV) injection. Lymph node and extranodal biopsy specimens are implanted under the renal capsule as a 1x1x2mm tumor seed (renal), which maintains the in situ microarchitecture. A full description of xenografted lymphomas is included in the Table. Table 1.DiseaseType of implant# in 1st passage# in 2nd passage or higherT-cell prolymphocytic leukemiaIV1Angioimmunoblastic T-cell lymphomaIV11Mantle cell lymphomaIV12Double-hit DLBCLIV2Sézary SyndromeIV1Adult T-cell Leukemia/LymphomaIV1Diffuse large B cell lymphomaIV2Diffuse large B cell lymphomarenal2Marginal zone lymphomarenal11NK/T-cell lymphomarenal1Peripheral T-cell lymphoma-NOSrenal1Breast implant-associated anaplastic large cell lymphomarenal1 Engrafted PDXs have been extensively characterized by immunohistochemistry, flow cytometry, transcriptome sequencing and targeted DNA sequencing. Flow cytometric analysis of patient tumors and their respective xenografts consistently revealed highly concordant immunophenotypes compared to the original tumors. Similarly, immunohistochemistry of involved tissues confirmed retention of tumor immunophenotypes, architecture, and even tissue tropism in the PDXs. Examples include a Sézary syndrome PDX that was injected by tail vein and trafficked to spleen, bone marrow, blood and skin, a diffuse large B-cell lymphoma (DLBCL) PDX that infiltrated the CNS, and a second DLBCL PDX that was implanted into the renal capsule of the left kidney and progressed within 8 weeks to bilateral renal involvement. Other notable models include a breast implant-associated, ALK-negative anaplastic large cell lymphoma implanted under the renal capsule that metastasized to the liver and spleen while uniformly retaining CD30 positivity. Two double-hit lymphoma (DHL) PDXs maintained their CD20-negative phenotype through serial passage to P1. A peripheral T-cell lymphoma-NOS (PTCL) specimen implanted under the renal capsule engrafted in the spleen, with a notable admixture of nonmalignant T cells and scattered EBV-positive B cells. T-cell receptor gene rearrangement PCR performed on this PTCL demonstrated an identical rearrangement pattern in the primary tumor and the PDX. Luciferized mantle cell lymphoma and DHL PDXs clearly home to bone marrow, lymph nodes, spleen, and liver as early as two weeks after injection. These findings support the utility of these PDX lines as in vivo models that more accurately recapitulate the human disease than commonly used subcutaneous cell line models. In addition to generating PDXs that remain faithful to their source tumors, we have witnessed interesting examples of in vivo histologic transformation, opening the door to studies of disease progression. One primary follicular lymphoma specimen injected into a cohort of mice transformed to DLBCL in one mouse and a lymphoblastic lymphoma-like disease in another mouse, as confirmed by IHC and flow cytometry. Further xenografting of primary tumors is underway with the goal of establishing a large repository of lymphoma PDXs useful for biologic interrogation and preclinical trials. Disclosures Davids: Genentech: Other: ad board; Pharmacyclics: Consultancy; Janssen: Consultancy. Shipp:Gilead: Consultancy; Sanofi: Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees.

Description: Background: Clofarabine is a second-generation purine analogue FDA-approved as an intravenous formulation for relapsed/refractory pediatric ALL. Purine analogues demonstrate significant clinical activity in non-Hodgkin lymphomas (NHL). Clofarabine may offer pharmacologic advantages over other nucleoside analogues including being a more efficient substrate for deoxycytidine kinase, more completely inhibiting ribonucleotide reductase and DNA polymerase α, and demonstrating improved activity in cells that are non-dividing or have a low proliferation rate. This phase 1-2 trial studied an oral formulation of clofarabine in relapsed or refractory NHL. Methods: Patients were eligible if they had relapsed or refractory NHL of any histologic subtype. All pts were required to have adequate organ function and performance status ≤2 as well as absence of CNS involvement. Patients were treated at 4 dose levels (1mg, 2mg, 4mg and ultimately 3mg) with oral clofarabine administered once daily on days 1-21 of a 28 day cycle for up to 6 cycles. Three to 6 pts were treated at each dose level in a traditional 3+3 design followed by a 10 patient dose expansion at the recommended phase 2 dose (RP2D). The phase 1 portion of this study has been published (Leuk Lymph 2013; 45:1915-1920). Phase 2 was designed to enroll 24 additional subjects. The primary endpoint in phase 2 was overall response rate (ORR). Secondary endpoints were progression-free survival (PFS), overall survival (OS), and safety. A total of 50 patients were accrued on the phase 1-2 trial; 31 subjects were treated in phase 1 and 19 in phase 2. Phase 2 accrual was stopped prematurely due to discontinuation of the drug formulation used in the study. All patients treated at the RP2D (n=36) are included in the phase 2 efficacy analysis since there were no differences in treatment or follow-up for these patients. Results: The median age for all patients was 69 years (range 45-92). Eighty-two percent had advanced stage at study entry. The median number of prior regimens was 2 (range 1-7) and 4 patients had prior auto stem cell transplant. Histologies included follicular lymphoma (FL, 13 pts), small lymphocytic lymphoma (SLL, 8 pts), diffuse large B-cell lymphoma (DLBCL, 6 pts), marginal zone lymphoma (MZL, 11 pts), mantle cell lymphoma (MCL, 9 pts), T-cell lymphoma (TCL, 2 pts) and lymphoplasmacytic lymphoma (LPL 1 pt). The 3mg dose was declared the RP2D, as previously reported. The most common toxicities were anemia (78%), leukopenia (66%), neutropenia (64%), thrombocytopenia (62%) and fatigue (60%). Twenty-nine patients (58%) experienced at least one grade 3-4 toxicity. The most common grade 3-4 toxicities were leukopenia and neutropenia (48%), thrombocytopenia (30%), anemia (14%) and fatigue (6%). There were 2 deaths on study, both considered unrelated to study drug (cardiac arrest, progressive disease). The median number of cycles administered was 4, and 18 patients (36%) completed all 6 cycles of therapy. The most common reasons for discontinuing therapy were progressive disease (34%) and toxicity (16%). Of 50 patients on study, the ORR was 28% (95% CI: 16 - 42%) with complete response rate (CRR) of 10% (95% CI: 3 - 22%). An additional 36% had stable disease (SD). By histology, responses were seen in 5/11 MZL, 4/9 MCL, 3/8 SLL, 3/13 FL, and 1/1 LPL. No responses were observed in DLBCL or TCL, although an angioimmunoblastic T-cell lymphoma patient had SD with a 42% reduction in tumor volume, and a mycosis fungoides patient had significant reduction in cutaneous disease burden. Among 36 patients treated at the RP2D and included in the phase 2 analysis, the ORR was 28% (95% CI: 14 - 45%) with CRR of 8% (95% CI: 2 - 22%), and 44% of patients with SD. A higher proportion of patients treated at a non-RP2D experienced progressive disease on study (43% vs. 28% in the RP2D cohort). The median PFS was 5.5 months, and the one- and two- year PFS were 32% (95% CI: 20%, 45%) and 16% (95% CI: 7.5%, 27%), respectively. The median duration of follow-up was 3.8 years, with 26 patients alive and 22 deceased at last follow-up; two patients were lost to follow-up. The median OS was not reached, and the 3 year OS was 58% (95% CI: 43%, 71%). Conclusion: Oral clofarabine is generally well tolerated and produces disease control in a substantial proportion of patients with relapsed/refractory NHL, particularly in indolent histologies and MCL. Disclosures Abramson: Sanofi: Consultancy. Off Label Use: Clofarabine is not FDA-approved for non-Hodgkin lymphoma. Brown:Sanofi: Consultancy.

Description: Introduction: High dose chemotherapy followed by autologous stem cell transplantation (ASCT) cures a subset of patients with chemosensitive relapsed or refractory (rel/ref) diffuse large B-cell lymphoma (DLBCL). Several factors associated with post-ASCT outcome have been identified, including pre-ASCT PET status, but better biomarkers are needed in order to optimally select candidates for the procedure. In other lymphoma subtypes with defining chromosomal translocations, PCR detection of pre- and post-ASCT minimal residual disease (MRD) in peripheral blood and of tumor contamination in the stem cell product is associated with inferior outcome. Until recently, MRD detection in DLBCL was limited by the rarity of detectable circulating disease using conventional techniques. The immunosequencing platform (Adaptive Biotechnologies, Corp.) is a next-generation-sequencing (NGS)-based MRD assay that detects small amounts of circulating tumor DNA (CTD) in patients with lymphoid malignancies. The assay detects CTD at diagnosis in most DLBCL patients and CTD levels track with response to induction therapy (Armand, 2013). Persistence of CTD or recurrence of CTD after completion of therapy is highly associated with DLBCL relapse (Kurtz, 2015; Roschewski, 2015). We evaluated whether CTD in autologous stem cell grafts was predictive of outcome in patients with rel/ref DLBCL undergoing ASCT. Methods: We retrospectively studied patients with rel/ref DLBCL, including transformed indolent lymphoma (TIL), who had paired archival tumor and autologous stem cell specimens and underwent ASCT at Brigham and Women's Hospital/Dana-Farber Cancer Institute from 2003-2013. Genomic tumor DNA was extracted from archival formalin-fixed paraffin-embedded (FFPE) tissue and analyzed using the NGS-based MRD assay. PCR amplification of IGH-VDJ, IGH-DJ,and IGK regions using universal consensus primers was performed followed by NGS to determine the tumor clonotype(s), defined as having a frequency 〉 5% in the tumor specimen. DNA from all available autologous peripheral blood or bone marrow stem cell specimens from each patient was amplified using universal consensus primers and sequenced to determine the level of CTD, defined as the number of lymphoma molecules per diploid genome. Results: We identified 98 eligible patients with rel/ref DLBCL/TIL. The median age was 60 (range 22-77) years; 63% were male; 65% had DLBCL, 29% had TIL, and 5% had primary mediastinal DLBCL; the median number of prior lines of therapy was 2 (range 2-5); all had received prior rituximab; 38% had primary refractory disease; 60% were in complete remission at ASCT; 96% received CBV conditioning. Median follow-up was 56 (range 19-123) months. The 4y progression-free survival (PFS) and overall survival (OS) in the entire cohort were 46% and 64%, respectively. Among 83 patients (85%) with sufficient DNA for clonotype determination, a clonotype was identified in 59 (71%). CTD data was complete in 53 patients (52 received peripheral blood stem cells (PBSC) and 1 received bone marrow). Eight patients (15%) had detectable CTD (CTD+) in the stem cell autografts (all PBSC) and 6/8 relapsed after ASCT. One CTD+ patient had early non-relapse mortality less than 1 month after ASCT and was never restaged. Seven of 8 CTD+ patients had TIL histology, 5 of whom relapsed (4 with aggressive lymphoma). The 4y PFS and OS in CTD+ v CTD- patients were 13% v 48% (p=0.01), and 38% v 67% (p=0.013), respectively [Figure 1]. In multivariable models including CTD status and pre-ASCT characteristics, CTD+ was the only factor associated with OS (HR 3.1, p=0.018), but was not significantly associated with PFS. Discussion: In patients with rel/ref DLBCL undergoing ASCT, the presence of CTD in the autologous stem cell graft is associated with inferior survival. CTD detection in the autograft may be more common in patients with TIL. In studies evaluating CTD detection in DLBCL, the plasma compartment has been more sensitive for detecting CTD than mononuclear cells. The use of concentrated cell specimens in this study may have decreased the sensitivity of the assay. Nevertheless, if the present findings are confirmed in a larger population, CTD detection may permit the identification of a subgroup of patients with a particularly poor outcome after ASCT, for whom alternative approaches could be considered. Figure 1. Overall (A) and Progression-Free (B) Survival in CTD+ vs CTD- Patients Figure 1. Overall (A) and Progression-Free (B) Survival in CTD+ vs CTD- Patients Figure 2. Figure 2. Disclosures Herrera: Sequenta, Inc.: Research Funding; Pharmacyclics: Research Funding; Genentech: Research Funding. Kong:Adaptive Biotechnologies, Corp.: Employment, Other: Stockholder. Davids:Genentech: Other: ad board; Pharmacyclics: Consultancy; Janssen: Consultancy. Rodig:Perkin Elmer: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Research Funding. Faham:Adaptive Biotechnologies Corp.: Employment, Other: Stockholder. Armand:BMS: Research Funding; Infinity: Consultancy, Research Funding; Merck: Consultancy, Research Funding; Sequenta, Inc.: Research Funding.