Haberman, Thomas M

Abstract The International Prognostic Index at the time of relapse (IPI-R) has been reported to predict clinical outcome in patients with relapsed diffuse large B-cell lymphoma (DLBCL) undergoing autologous stem cell transplantation (ASCT) [Jabbour et al, Leukemia & Lymphoma2005;46(6):861–867; Lerner et al, Biology of Blood and Marrow Transplant2006;13:486–492; and Costa et al, Bone Marrow Transplant2008;41:715–720]. The absolute lymphocyte count (ALC) has been reported as a prognostic factor for survival at diagnosis, during standard chemotherapy and at day 15 post-ASCT for multiple hematological malignancies; however, no reports have addressed whether ALC at the time of relapse (ALC-R) predicts survival. Thus, we assessed the prognostic significance of ALC-R in patients with relapsed DLBCL. To be included in the study, patients were required to have been diagnosed with relapsed DLBCL, have ALC values available from the time of relapse, and to be followed at Mayo Clinic, Rochester. From Feb 2,1987 until March 6, 2006, 121 DLBCL patients qualified for the study. The overall survival (OS) was measured from the time of relapse to the date of death or last follow-up and progression-free survival (PFS) was defined as the time from relapse to the time of progression, relapse, death, or last follow-up. The median age at relapse was 68 years (range:25–88 years) and the median ALC-R was 1.21 x 109/L (range: 0.33–5.99 x 109/L). The value of ALC-R ≥ 1.0 x 109/L was used for the analysis based on previous publications. The groups (ALC-R ≥ 1 or < 1 x 109/L) were balanced for the IPI-R (p=0.1), as well as for undergoing ASCT (p=0.4). Superior OS was observed in patients with an ALC-R ≥ 1.0 x 109/L (N = 76) [median OS: 27.5 months, 3 years OS rates of 42%] compared with patient with an ALC-R < 1.0 x 109/L (N =45) [median OS: 9.4 months, 3 years OS rates of 13%] (p <0.0001). Superior PFS was also observed in patients with an ALC-R ≥ 1.0 x 109/L (N = 76) [median PFS: 14.8 months, 3 years PFS rates of 30%] compared with patient with an ALC-R < 1.0 x 109/L (N =45) [median PFS: 6.2 months, 3 years PFS rates of 11%] (p <0.001). ALC-R was an independent prognostic factor for OS [RR = 0.551, p < 0.009] and PFS [RR = 0.674, p < 0.02] in the multivariate analysis when compared with the IPI-R and whether patients underwent ASCT or not. Our study supports the hypothesis that ALC at relapse predicts clinical outcome in DLBCL and suggests that patient host immunity is an important variable predicting survival in relapsed DLBCL.

Abstract Introduction New treatment strategies are improving outcomes for patients with Hodgkin (HL) and non-Hodgkin lymphoma (NHL) but achieving durable responses and cure in the relapsed patient remain a challenge. Both the mTORC1 inhibitor everolimus (RAD001) and the IMiD, lenalidomide (LEN) have efficacy as single agents in patients with relapsed and refractory (R/R) HL and NHL. Individually, LEN and RAD present a low toxicity profile and in combination may offer synergistic therapeutic efficacy by unique mechanisms of action. A phase I/II clinical trial of RAD and LEN was designed to explore the tolerability, toxicity and to determine the maximum tolerated dose (MTD) of this combination for the Phase II study. The results of phase I/II data are reported here. Methods MC0981 was activated on January 10, 2011. In phase I, the study enrolled a total of 25 patients and RAD 5 mg daily + LEN 10 mg/d X 21d in a 28-day cycle was defined as the MTD. The phase II opened on May 14, 2013, and closed on Feb 19, 2014, during which 33 patients were enrolled and were treated until progression of disease. Eligibility required age ≥18, biopsy proven relapsed or refractory NHL or HL, ECOG PS 0- 2, measurable disease, Hb >9g/dl, ANC ≥1200/uL, platelet ≥ 50,000/uL, creatinine ≤1.5xULN and willingness to sign informed consent. Women of child bearing potential had pregnancy testing and all patients followed recommendations for contraception. Follow up data was analyzed as of July 2014. Results A total of 58 patients were enrolled to this study and fifty five are evaluable for analysis (2 never started therapy, 1 deemed ineligible). The median age was 62 years (21-82) and 38 (69.1%) were male. Sixty-five percent had stage IV disease and 42% had 4 or more prior treatments including stem cell transplantation in 49%. Histologies included HL (n=10) and NHL (n=45 with 23 DLBCL, 2 FL-III, 5 LPL, 3 MCL, 2 MF, and 3 other). At least 1 Gr≥3 adverse event was seen in 74.5% of patients. The most common Gr≥3 toxicities were hematologic - neutropenia (30.9%), and thrombocytopenia (21.8%), and anemia (10.9%). Nine of 55 patients (16%) had Gr≥3 infection; 2 with skin infection, 1 with cholecystitis, 1 with lung infection, 1 with pharyngitis 1 with otitis externa, 1 with otitis media, and 1 with pleural infection and 1 with upper respiratory tract infection. Seven patients discontinued treatment due to adverse events. At this time, 44% (25/55) remain progression-free. A documented tumor response, as overall response rate (ORR) was seen in 20% (11/55) with 1CR, 8PR, and 2MR; 17 remain on therapy; and 22 deaths have occurred with a median survival of 15.0 months (95% CI 7.5-NR). Median follow up time was 5.5 (range, 0.7- 41.0) months. The median duration of response (DOR) in those responding is 19.4 months. Conclusions In a heavily pretreated population with baseline compromised bone marrow function, the combination of everolimus and lenalidomide is feasible with a modest ORR and a surprisingly long DOR. Future studies in more defined groups of NHL or HL are necessary to better predict which patients will be long-term responders. This trial is sponsored by Novartis and Celgene Disclosures Off Label Use: mTORC1 inhibitor (Everolimus) and the Immunomodulatory (IMiD) drug Lenalidomide for patients with Heavily Pretreated Relapsed Lymphoma . Mikhael:Onyx: Research Funding; Celgene: Research Funding; Sanofi: Research Funding; Novartis: Research Funding. Nowakowski:Celgene, Morphosis: Consultancy. Witzig:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding. Reeder:Millennium, Celgene, Novartis: Research Funding.

Abstract Peripheral blood absolute lymphocyte count (ALC) at diagnosis is a predictor of survival in B-cell lymphomas. The role of ALC at diagnosis on survival in T-cell lymphoma has not been studied. Thus, we studied the role of ALC at diagnosis on clinical outcome in adult patients with primary anaplastic large cell lymphoma (PALCL) that were diagnosed, treated, and followed at the Mayo Clinic, Rochester. Between 1985 and 2006, 50 patients with PALCL qualified for the study. ALC was identified to be a strong predictor for complete response (CR), area under the curve (AUC = 0.83, p < 0.002). The median follow-up was 31.8 months (range: 1–212.6 months). ALC, as a continuous variable was a predictor for overall survival (OS) (HR = 0.143; 95%CI = 0.042–0.416; p < 0.0001) and progression-free survival (PFS) (HR = 0.150; 95%CI = 0.047–0.415; p < 0.0001) .Superior OS and PFS (Figure 1) were observed with an ALC ≥ 1.0 x 109/L (N = 31) versus an ALC < 1.0 x 109/L (N=19) (median OS: not reached vs 7.5 months, OS rates at 5 years, 81% vs 36%, p < 0.0006, respectively; and median PFS: not reached vs 6.3 months; PFS rates at 5 years, 77% vs 37%, p < 0.0007, respectively). Multivariate analysis demonstrated ALC to be an independent prognostic indicator for OS (HR = 0.196; 95%CI = 0.125–0.693; p < 0.002) and PFS (HR = 0.191; 95%CI = 0.053–0.559; p < 0.0008) when compared to anaplastic lymphoma kinase, international prognostic index, and cutaneous versus systemic presentation. Figure 1 Figure 1.

Abstract Abstract 2802 Background: Redundancy of pro-survival signaling pathways promotes survival and drug resistance in lymphoid and plasma cell malignancies. In particular, the PI3K-Akt and the MEK-ERK pathways have been shown to play an important role in the proliferation and survival of these malignant cells induced by various cytokines in the tumor microenvironment. Sorafenib, a Raf kinase and VEGF receptor inhibitor, and everolimus, an mTOR inhibitor, have synergistic cytotoxicity in myeloma and lymphoma cells due to inhibition of multiple signaling pathways. Methods: We designed a Phase 1/2 clinical trial to identify the maximum tolerated doses of the two drugs used in combination and the efficacy of the combination. Patients (Pts) with relapsed myeloma or lymphoma were eligible for enrollment. Pts were required to have an absolute neutrophil count ≥1500 × 10(6)/L, a platelet count ≥75,000, and a serum creatinine 21.5 mg/dL. The study utilized the classic 3+3 design. Extensive pharmacokinetic studies were performed to better delineate potential drug interactions. Results: Twenty-six pts were accrued from August 2007 to February 2009. Four pts discontinued sorafenib during cycle 1 for various reasons (2 patient refusal, 1 unrelated medical condition and 1 physician discretion) and were excluded from MTD determination. An additional pt did not have measurable disease and was ineligible, leaving 19 pts with lymphoma (including 6 with Hodgkin lymphoma) and 2 with myeloma for phase I analysis. The pts had a median age of 56 years (range, 22, 69) and were heavily pretreated with a median of 4 prior therapies (range, 1–10). Eighteen (86%) had received a prior stem cell transplant. Four dose limiting toxicities were seen across all dose levels (Table). These included grade 3 vomiting (level 1), grade 4 thrombocytopenia (level 2 and 3, one each) and grade 2 hand and foot rash leading to treatment delay (level 3). Overall, 13 pts experienced a grade 3 or 4 hematologic toxicity. Grade 3 or 4 anemia, neutropenia, and thrombocytopenia occurred in 19%, 43%, and 38% of pts, respectively. Four pts have experienced a grade 3 non-hematologic toxicity; no grade 4 non-hematologic toxicities were seen. Grade 3 non-hematologic toxicities included hypokalemia, weight loss, vomiting, hand-foot skin reaction, fatigue, and elevated alkaline phosphatase. Dose level 1 (sorafenib 200 mg and everolimus 5 mg daily) was best tolerated and was selected for phase 2 evaluation. The ORR was 33% (7/21;95% CI: 15–57%, Table) with 3 pts at dose level 0 (2 PR, 1 CR), one at level 2 (1 PR) and three at level 3 (2 PR, 1 CR) responding. The responders included 5 pts with Hodgkin's disease and one each with an NK cell and T-cell lymphoma. Pts have received a median of 6 cycles (range: 1–19) of treatment. 16 pts have discontinued treatment due to disease progression (13 pts), non-resolution of cytopenias (1 pt), physician discretion (1 pt), and death on study due to lymphoma (1 pt). Disease progression has been seen in 16 pts; 9 pts have died. Median follow-up for pts still alive is 18.7 months (range: 11.5–29.4). 6 pts died from disease progression, one each due to sepsis unlikely related to treatment, cholecystitis, and unknown causes. Sorafenib is metabolized by the cytochrome P450 CYP3A enzyme and RAD-001 mainly by the CYP3A4 system in the liver, hence there is a potential for interactions. The detailed PK analyses performed as part of this trial showed a decrease in the RAD001 levels following initiation of sorafenib on day 8 of cycle 1 (Figure). Conclusion: The combination of sorafenib and everolimus is safe at a recommended phase 2 dose of sorafenib 200 mg and everolimus 5 mg daily. There is no significant drug interaction seen. Activity has been observed, especially in the setting of Hodgkins Disease. Disclosures: Kumar: Celgene: Consultancy, Research Funding; Millennium: Research Funding; Merck: Consultancy, Research Funding; Novartis: Research Funding; Genzyme: Consultancy, Research Funding; Cephalon: Research Funding. Off Label Use: Lenalidomide for treatment of newly diagnosed myeloma. Witzig:Novartis and Celgene: Patents & Royalties, Research Funding, Served on advisory boards with Novartis and Celgene – both uncompensated with compensation to Mayo Clinic.

Abstract Diffuse large B-cell lymphoma (DLBCL) is a genetically heterogeneous disease characterized by multiple low-frequency alterations including somatic mutations, copy number alterations (CNAs) and chromosomal rearrangements. We sought to identify previously unrecognized low-frequency genetic events, integrate recurrent alterations into comprehensive signatures and associate these signatures with clinical parameters. For these reasons, our multi-institutional international group assembled a cohort of 304 primary DLBCLs from newly diagnosed patients, 87% of whom were uniformly treated with state-of-the-art therapy (rituximab-containing CHOP regimen) and had long term followup. Tumors were subjected to whole exome sequencing with an extended bait set that included custom probes designed to capture recurrent chromosomal rearrangements. In this cohort, 47% of samples had available transcriptional profiling and assignment to associated disease subtypes. Analytical pipelines developed at the Broad Institute were used to detect mutations (MuTect), CNAs (Recapseq+Allelic Capseq) and chromosomal rearrangements (dRanger+Breakpointer) and assess clonality (Absolute). To analyze formalin-fixed paraffin-embedded tumors without paired normals we developed a method which utilized 8334 unrelated normal samples to stringently filter recurrent germline events and artifacts. Significant mutational drivers were identified using the MutSig2CV algorithm and recurrent CNAs were assessed with GISTIC2.0. In addition, we utilized a recently developed algorithm, CLUMPS2, to prioritize somatic mutations which cluster in 3-dimensional protein structure. With this approach, we identified > 90 recurrently mutated genes, 34 focal amplifications and 41 focal deletions, 20 arm-level events and > 200 chromosomal rearrangements in the DLBCL series. Of note, 33% of the mutational drivers were also perturbed by chromosomal rearrangements or CNAs, underscoring the importance of a comprehensive genetic analysis. In the large DLBCL series, we identified several previously unrecognized but potentially targetable alterations including mutations in NOTCH2 (8%) and TET2 (5%). The majority of identified chromosomal rearrangements involved translocations of potent regulatory regions to intact gene coding sequences. The most frequently rearrangements involved Ig regulatory elements which were translocated to BCL2, MYC, BCL6 and several additional genes with known roles in germinal center B-cell biology. After identifying recurrent somatic mutations, CNAs and chromosomal rearrangements, we performed hierarchical clustering and identified subsets of DLBCLs with comprehensive signatures comprised of specific alterations. A large subset of tumors shared recurrent alterations previously associated with follicular lymphoma including mutations of chromatin modifiers such as CREBBP, MLL2, and EZH2 in association with alterations of TNFRSF14 and GNA13 and translocations of BCL2. This cluster was enriched in GCB-type DLBCLs and contained a subset with select genetic alterations associated with an unfavorable outcome. An additional cohort of tumors was characterized by alterations perturbing B-cell differentiation including recurrent BCL6 translocations or alterations of PRDM1. A subset of these DLBCLs had alterations of NOTCH2 and additional pathway components or mutations of MYD88 in association with TNFAIP3, CD70 and EBF1, a master regulator of B-cell differentiation. An additional group of DLBCLs exhibited frequent MYD88 mutations in association with alterations of CD79B, PIM1, TBL1XR1 and ETV6 and BCL2 copy gain; these tumors were highly enriched for ABC-type DLBCLs. This coordinate signature and additional alterations of p53 pathway components were associated with outcome. We explored bases for the identified genetic alterations in DLBCL by performing an in silico mutational signature analysis. The most frequent mutational signatures were those of spontaneous deamination (aging) and AID with rare cases of microsatellite instability. We also assessed the clonality of identified genetic features to define cancer cell fraction and establish the timing of specific genetic events. The comprehensive genetic signatures of clinically annotated DLBCLs provide new insights regarding approaches to targeted therapy. Disclosures Link: Kite Pharma: Research Funding; Genentech: Consultancy, Research Funding. Rodig:Perkin Elmer: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding. Pfreundschuh:Boehringer Ingelheim, Celegene, Roche, Spectrum: Other: Advisory board; Roche: Honoraria; Amgen, Roche, Spectrum: Research Funding. Shipp:Gilead: Consultancy; Sanofi: Research Funding; BMS: 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; Bayer: Membership on an entity's Board of Directors or advisory committees, Research Funding.