ALBERT

Description: Abstract 3453 Individuals undergoing allogeneic transplantation receive multiple red blood cell transfusions both as part of the transplant procedure and as part of the pre-transplant care of the underlying disease. Therefore these patients may be at risk for complications of transfusional iron overload. Several studies have noted that individuals entering the transplant with baseline elevated serum ferritin values have decreased overall survival and higher rates of disease relapse. Whether the iron is a direct contributor to inferior outcomes or is a marker of more advanced disease (thereby requiring greater transfusions) is unclear. Little is known about the incidence and consequences of iron overload among long-term survivors of allogeneic transplantation. Methods: Using Kaplan-Meier and Cox regression analyses, we performed a single center, retrospective cohort study of consecutive allogeneic transplants performed at Hackensack University Medical Center from January 2002 through June 30, 2009 to determine the association between serum ferritin (measured approximately 1 yr post allogeneic transplant) and overall survival. Results: During the study time frame, 637 allogeneic transplants (Donor Lymphocyte Infusion procedures excluded) were performed at our center and 342 (54%) survived ≥ one year. Among 1-year survivors 240 (70%) had post-transplant serum ferritin values available for review, including 132 (55%) allogeneic sibling, 68 (28%) matched unrelated, and 40 (17%) mismatched unrelated donor transplants. The median post-transplant ferritin value among 1-year survivors of allogeneic transplant was 628 ng/ml (95% CI 17, 5010), with 93 (39%) above 1000 ng/ml and 40 (17%) above 2500 ng/ml. The median post-transplant ferritin levels varied by underlying hematologic disease (aplastic anemia = 1147, acute leukemia = 1067, MDS = 944, CLL = 297, CML = 219, lymphoma = 123, multiple myeloma = 90). The Kaplan-Meier projected 5-year survival rate was 76% for the cohort that had survived one year and had available ferritin values. Fifty late deaths have occurred; causes of late death were disease relapse (n=37, 74%), GVHD (n=7, 14%), infection (n=4, 8%), cardiac (n=1, 2%) and second malignancy (n=1, 2%). The 1-year post-transplant serum ferritin value was a significant predictor of long term survival. Using a cut-off ferritin value of 1000 ng/ml, the 5-year projected survivals were 85% (95 CI 75%-91%) and 64% (95% CI 52–73%) for the low and high ferritin cohorts respectively (Figure, log-rank p

Description: Abstract LBA-3 Mutations in the transcription factor genes, RUNX1 and CEBPA, can lead to an autosomal dominant familial predisposition to MDS/AML. Using a candidate gene approach, we have detected domain specific heterozygous mutations in the GATA2 gene in 4 MDS/AML families which predispose to MDS/AML. The same novel heterozygous T354M missense mutation was observed in 3 families and a 355delT mutation in 1 family, all with multigenerational transmission of MDS and/or MDS/AML. Importantly, these genetic variants segregate with all affected members in each of the families. The 2 mutated threonine residues are in 5 consecutive highly conserved threonine residues at the DNA-binding, protein-protein interacting second zinc finger (ZF2) of GATA2. Neither these mutations, nor any other variants in the GATA2 coding sequence, were seen in a population screen of 695 normal individuals. Haplotype analysis suggests that the T354M mutation has multiple ancestral origins. While mutations in RUNX1 and CEBPA, can also lead to familial predisposition to MDS/AML, these patients with GATA2 mutations are unique in that there is no obvious pre-MDS or pre-leukaemic phenotype such as thrombocytopenia (RUNX1) and eosinophilia (CEBPA) in predisposed carriers. Most patients in these families have had a rapid disease course “appearing out of the blue” leading to death, with a variety of ages of onset from teenagers to early 40s. Yet remarkably, there are still asymptomatic carriers in their 60s. One of these carriers, and his 2 children, has had bone marrow prophylactically stored over 15 years ago in case of disease onset. No pathogenic GATA2 coding sequence changes were found in 268 sporadic MDS/AML patient samples. Additionally, GATA2 mutations were not found in germline samples from 35 other families predisposed to AML and various other hematological malignancies. Both the T354M and 355delT mutants appear to localize appropriately to the nucleus and maintain at least some DNA binding in electrophoretic mobility shift assays. We used the known murine Gata3 ZF2 structure bound to DNA to model the effects of the observed mutations and demonstrated that the T354 residue does not contact DNA but makes polar contact with the adjacent threonines, and via its amino group, with C349 which coordinates the zinc atom. Replacement of the T354 side-chain with the bulky methionine moiety may affect the zinc contacts and is predicted to alter the overall structure of this ZF2. In contrast, 355delT will shorten the conserved threonine string which is predicted to impact on the orientation and position of L359 which directly contacts DNA. Thus, 355delT is likely to have an effect on DNA binding. Luciferase reporter assays indicate that T354M and 355delT greatly reduce the transactivation ability of GATA2 on multiple response elements, impacting on downstream target genes such as RUNX1 and CD34. Of note, T354M shows a markedly lesser synergistic effect than wildtype (WT) GATA2 with PU.1 on the CSF1R promoter. Competition assays show that these mutations may be acting in a dominant negative fashion in some biological contexts. In stable promyelocytic HL-60 cell lines expressing regulatable GATA2 (WT or T354M), T354M allows proliferation to proceed even under stimulus to differentiate with all-trans retinoic acid. Microarray studies indicated that the down regulation of proapoptotic BCL-xS by T354M, but not WT, may be responsible for this phenotype. GATA2 is considered to be a hematopoietic “stemness” gene, highly expressed in haematopoietic stem cells and is required for megakaryocyte and mast cell production. GATA2 is down regulated during myeloid differentiation and forced overexpression prevents such differentiation. Discovery of GATA2 mutants in MDS/AML predisposed families provides new tools for probing the mechanism of GATA2 induced leukemogenesis, and possibly also for clarifying its role in maintenance of stemness. Our findings highlight the power of investigating familial predispositions to cancer identifying specific mutations with unique biological effects. They have immediate implications for diagnostic genetic testing, and longer term therapeutic implications through identification of drugable biological pathways such as apoptosis. The poor outcome associated with these mutations may suggest that an aggressive strategy is appropriate in the treatment of affected individuals in families found to be carrying GATA2 mutations. Disclosures: No relevant conflicts of interest to declare.

Description: Abstract 2752 Introduction: We recently identified a poor prognostic subgroup of pediatric BCR-ABL1 negative ALL patients characterized by deletion of IKZF1 (encoding the lymphoid transcription factor IKAROS) and a gene expression signature similar to BCR-ABL1 positive ALL, raising the possibility of activated tyrosine kinase signaling within this leukemia subtype. Targeted sequencing revealed activating sequence mutations in the Janus tyrosine kinases (JAK1 (N=3), JAK2 (N=17) and JAK3 (N=1)) in 21 of 187 (11.2%) BCR-ABL1 negative, high-risk pediatric ALL cases. All 21 cases with JAK mutations had the BCR-ABL1-like expression profile, accounting for about 50% of the cases with this phenotype, suggesting that mutations in JAK kinases account for some, but not all, cases with this distinctive profile. To determine whether mutations in other kinases might also be associated with this distinctive gene expression profile, we sequenced 126 genes encoding tyrosine kinases and mediators of kinase signaling in an additional 46 high-risk ALL cases with a BCR-ABL1-like expression profile. The genes sequenced included the entire tyrosine kinome. Methods: The 46 leukemia specimens studied were from patients enrolled on COG clinical trials for high risk ALL (P9906, n=23 and AALL0232, n=23), with risk defined primarily by elevated WBC and/or age 〉 10 years. All 46 cases had a BCR-ABL1 like expression profile. The 23 P9906 cases all lacked JAK mutations, while 3 of the 23 AALL0232 cases were found to have activating JAK mutations (JAK1 (N=1), JAK2 (N=2)). The entire coding region and UTRs of each gene was amplified by PCR of whole genome amplified genomic DNA, and subjected to Sanger sequencing. A CEPH sample (NA19085) was also included as a normal control DNA. Results: A total of 1,149,117 bases were sequenced bi-directionally for each sample; 96% of the targeted bases were covered with high-quality sequencing data. We identified a total of 2,302 variations predicted to change protein sequences, 173 of which are novel, putative variations after removing germline variations found in dbSNP, The Cancer Genome Atlas Project (TCGA) and the normal CEPH sample NA19085 in this study. For each novel variation, the tumor DNA was resequenced and matching normal DNA was sequenced to validate the original observation and to distinguish somatic from inherited variants. The results show that 105 variations are germline, 20 are false positives while the remaining markers failed in validation assay. Aside from 1 FLT3 mutation (23aainsN609), there are no confirmed somatic mutations in any other tyrosine kinase genes. Conclusion: Aside from JAK mutations, somatically acquired sequence mutations in tyrosine kinase genes are rare in children with high risk ALL and BCR-ABL1 like gene expression profiles. We are pursuing the identification of alternative mechanisms for kinase activation that might explain the distinctive expression profile observed in these cases. Disclosures: Relling: St. Jude Children's Research Hospital: Employment, Patents & Royalties; Enzon Pharmaceuticals: Research Funding. Hunger:bristol myers squibb: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; eisai: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Description: We evaluated the efficacy and safety of romiplostim, a thrombopoietin mimetic, in patients with low- or intermediate-risk myelodysplastic syndromes (MDS) receiving azacitidine therapy. Forty patients with low- or intermediate-risk MDS were stratified by baseline platelet counts (〈 50 vs ≥ 50 × 109/L) and randomized to romiplostim 500 μg or 750 μg or placebo subcutaneously once weekly during 4 cycles of azacitidine. The primary endpoint was the incidence of clinically significant thrombocytopenic events, defined by grade 3 or 4 thrombocytopenia starting on day 15 of the first cycle or platelet transfusion at any time during the 4-cycle treatment period. No formal hypothesis testing was planned. The incidence of clinically significant thrombocytopenic events in patients receiving romiplostim 500 μg, romiplostim 750 μg, or placebo was 62%, 71%, and 85%, respectively. The incidence of platelet transfusions was 46%, 36%, and 69%, respectively. These differences were not statistically significant with the small numbers in each group. Romiplostim 750 μg significantly raised median platelet counts during cycle 3 on day 1 (P = .0373) and at the nadir (P = .0035) compared with placebo. Grade 3 rash and arthralgia each were reported in 1 romiplostim-treated patient (4%). This study suggests romiplostim may provide clinical benefits in MDS patients during azacitidine therapy. This study was registered at www.clinicaltrials.gov as #NCT00321711.

Description: Abstract 1937 Background: Three-drug combinations with bortezomib (Bz) and/or either thalidomide or lenalidomide (Len) are highly active in frontline MM and appear superior to at least some 2-drug combinations with these agents. In an attempt to further improve treatment outcomes, we developed the 4-drug RVDD regimen of lenalidomide (Revlimid®, Len), Bz (Velcade®), pegylated liposomal doxorubicin (Doxil®, PLD), and dexamethasone (Dex), which demonstrates high activity in newly diagnosed MM. Here we present final results of this Phase I/II trial. Methods: Patients (Pts) received eight 3-week cycles with Len 15–25 mg (days 1–14), Bz 1.3 mg/m2 (days 1, 4, 8, 11), Dex 20/10 mg (cycles 1–4/5-8; days of and after Bz), PLD 20 or 30 mg/m2 (day 4) at 4 dose levels and the maximum tolerated dose (MTD; Phase II). Responses were assessed by modified EBMT and IMWG criteria with the addition of nCR. Pts could proceed to autologous stem cell transplant (ASCT) or continue treatment, which after 8 cycles consisted of 21-day maintenance cycles with Len (days 1–14), Bz (day 1 and 8), and Dex (days of and after Bz) at the doses tolerated by the end of initial treatment. The primary objectives were to evaluate MTD and VGPR rate at the end of 4 and 8 cycles. Results: The study enrolled 72 pts with a median age 60 (range 29–77); 53% ISS II/III; 46% any of the del 13q, t(4;14), t(14;16), or del 17p, of which 37 were treated at the MTD (including 6 in Phase I). Pts received a median of 4.5 cycles (range 2–31); 70 pts completed at least 4 cycles and 20 at least 8 cycles. Five pts developed DLTs, including 2 pts grade (G) 3 asymptomatic neutropenia, 1 G3 elevation of transaminases, 1 G3 drug fever, and 1 G3 hypophosphatemia. Based on the pre-determined definition of MTD, the maximum planned doses of Len 25 mg, Bz 1.3 mg/m2, PLD 30 mg/m2, and Dex 20/10 mg were selected as the maximum tolerated dose (MTD) for the Phase II portion of the study as the closest to, but not exceeding, a target rate of 20% DLTs. The most common toxicities (all grades) were fatigue (83%), infections (72%), constipation (69%), and sensory neuropathy (65%) of which 8%, 14%, 1%, and 6% were G3, respectively. Other G3/4 toxicities included neutropenia (19%), infections (16 %), thrombocytopenia (11%), hyperglycemia (10%), and DVT/PE (3%). There was 25% G1/2 palmar-plantar erythrodysesthesia and 1 pt experienced G1 asymptomatic and reversible decrease in ejection fraction attributed to PLD. Importantly, there was no treatment-related mortality. The best response rates for all pts were as follows: 96% ≥ PR, 66% ≥ VGPR, and 38% CR/nCR. At the end of 4 and 8 cycles, defined in the protocol for efficacy assessment, response rates were: 96% and 95% ≥ PR, 57% and 65% ≥VGPR and 29% and 35% CR/nCR; at the MTD ≥PR was 96%, ≥VGPR 66%, and CR/nCR 34%. Response rates were not statistically different in a subset of pts with any of del 13q, t(4;14), t(14;16), or del 17p. Forty-seven (65%) pts proceeded to ASCT, after collection of a median 6.7 × 106 CD34+ cells/kg (range 1.9–17.7). At 3 months post ASCT, ≥ VGPR and CR/nCR rates improved in 45 evaluable pts from 64% to 84% and from 38% to 60%, respectively. After a median of 15.5 months of follow-up, the estimated 18-month PFS for all pts is 84% and overall survival 99%. Conclusion: RVDD is generally well tolerated and highly active with rapid reduction of MM tumor burden seen (≥ PR 96%, ≥VGPR 57% and CR/nCR rate 29% at the completion of 4 cycles). Response rates further improved after additional treatment, both in pts who continued RVDD treatment (’VGPR 65%, CR/nCR 35%) and pts who proceeded to ASCT (≥VGPR 84%, and CR/nCR 60%), although some additional toxicity was noted. Whether the incorporation of a 4th agent in the form of PLD has made an impact in this pt population remains to be defined. At equivalent time points (i.e. at the completion of 4 and 8 cycles), the ≥VGPR and CR/nCR rates as well as the current estimated PFS appear to compare favorably to RVD, which provides the rationale for consideration of further studies with this regimen, including potential randomized trials in this setting. Disclosures: Jakubowiak: Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Exelixis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Centocor OrthoBiotech: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Off Label Use: Lenalidomide for newly diagnosed multiple myeloma. Reece:Celgene: Unrestricted educational lectures, research funding, ad hoc advisory boards. Lonial:Millennium: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; BMS: Consultancy, Speakers Bureau. Zimmerman:Celgene: Speakers Bureau; Millennium: Speakers Bureau. Campagnaro:NIH: Research funding for NIH K12 CA076917. Raje:Celgene: Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Research Funding; Acetylon: Research Funding. Anderson:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees. Barrickman:Celgene: Employment, Equity Ownership. Tendler:Johnson & Johnson Pharmaceutical Services: Employment, Equity Ownership. Esseltine:Millennium: The Takeda Oncology Company: Employment; Johnson & Johnson: Equity Ownership. Anderson:Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Onyx: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Acetylon: Equity Ownership. Richardson:Millennium: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees.

Description: Abstract 4517 Oral mucositis is a common toxicity associated with many cancer therapies and has been correlated with risk for infection, mortality, and extended hospital stay. Prophylactic use of a supersaturated calcium phosphate mouth rinse (SSCPR, Caphosol..) was found in a phase III study to reduce the frequency, intensity, and duration of oral mucositis in patients (pts) undergoing allogeneic or autologous hematopoietic stem cell transplantation (Papas, et al. Bone Marrow Transpl 2003;31:705). That study also found a faster time to recovery of an absolute neutrophil count (ANC) ≥0.2×109/l, but not for other engraftment endpoints, possibly a result of the mixed pt population studied. We performed a single-center retrospective review of a uniform population of pts

Description: Regulated vascular endothelial growth factor (VEGF) signaling is required for proper angiogenesis, and excess VEGF signaling results in aberrantly formed vessels that do not function properly. Tumor endothelial cells have excess centrosomes and are aneuploid, properties that probably contribute to the morphologic and functional abnormalities of tumor vessels. We hypothesized that endothelial cell centrosome number is regulated by signaling via angiogenic factors, such as VEGF. We found that endothelial cells in developing vessels exposed to elevated VEGF signaling display centrosome overduplication. Signaling from VEGF, through either MEK/ERK or AKT to cyclin E/Cdk2, is amplified in association with centrosome overduplication, and blockade of relevant pathway components rescued the centrosome overduplication defect. Endothelial cells exposed to elevated FGF also had excess centrosomes, suggesting that multiple angiogenic factors regulate centrosome number. Endothelial cells with excess centrosomes survived and formed aberrant spindles at mitosis. Developing vessels exposed to elevated VEGF signaling also exhibited increased aneuploidy of endothelial cells, which is associated with cellular dysfunction. These results provide the first link between VEGF signaling and regulation of the centrosome duplication cycle, and suggest that endothelial cell centrosome overduplication contributes to aberrant angiogenesis in developing vessel networks exposed to excess angiogenic factors.

Description: Recent studies of WT1 mutations in acute myeloid leukemia (AML) mostly report an association with unfavorable clinical outcome. We screened 842 patients treated on 3 consecutive pediatric AML trials for WT1 zinc-finger mutations. Eighty-five mutations were detected in 70 of 842 patients (8.3%). Mutations occurred predominantly in exon 7 (n = 74) but were also found in exons 8 (n = 5) and 9 (n = 6). Normal karyotype was observed in 35.3% of WT1mut patients, whereas 27.5% WT1mut patients harbored favorable risk cytogenetics. Patients with or without mutations had similar rates of complete remission after one course of induction chemotherapy. Overall survival (OS) for patients with WT1 mutations was 41% versus 54% for those without mutations (P = .016). Corresponding event-free survival (EFS) was also significantly worse for those with WT1 mutations (28% vs 42%; P = .01). However, FLT3/ITD was present in 36% of the WT1mut cohort; WT1mut patients without FLT3/ITD had similar OS (56% vs 56%, respectively; P = .8) and EFS (35% and 44%, respectively; P = .34) to patients who were wild type for both mutations. In current risk stratification schemes incorporating cytogenetics and FLT3/ITD status, the presence of WT1 mutations has no independent prognostic significance in predicting outcome in pediatric AML. The clinical trials are registered at www.clinicaltrials.gov as #NCT00002798 and #NCT00070174.

Description: 8-Aminoadenosine (8-NH2-Ado), a ribosyl nucleoside analog, in preclinical models of multiple myeloma inhibits phosphorylation of proteins in multiple growth and survival pathways, including Akt. Given that Akt controls the activity of mammalian target of rapamycin (mTOR), we hypothesized that 8-NH2-Ado would be active in mantle cell lymphoma (MCL), a hematological malignancy clinically responsive to mTOR inhibitors. In the current study, the preclinical efficacy of 8-NH2-Ado and its resulting effects on Akt/mTOR and extracellular-signal–regulated kinase signaling were evaluated using 4 MCL cell lines, primary MCL cells, and normal lymphocytes from healthy donors. For all MCL cell lines, 8-NH2-Ado inhibited growth and promoted cell death as shown by reduction of thymidine incorporation, loss of mitochondrial membrane potential, and poly (adenosine diphosphate-ribose) polymerase cleavage. The efficacy of 8-NH2-Ado was highly associated with intracellular accumulation of 8-NH2-adenosine triphosphate (ATP) and loss of endogenous ATP. Formation of 8-NH2-ATP was also associated with inhibition of transcription and translation accompanied by loss of phosphorylated (p-)Akt, p-mTOR, p-Erk1/2, p-phosphoprotein (p)38, p-S6, and p-4E-binding protein 1. While normal lymphocytes accumulated 8-NH2-ATP but maintained their viability with 8-NH2-Ado treatment, primary lymphoma cells accumulated higher concentrations of 8-NH2-ATP, had increased loss of ATP, and underwent apoptosis. We conclude that 8-NH2-Ado is efficacious in preclinical models of MCL and inhibits signaling of Akt/mTOR and Erk pathways.

Description: Abstract 3131 Introduction: Although MCL is reported to be an FDG-avid NHL subtype, PET-CT is not currently recommended in the modified IWG criteria (Chesen et al, JCO 2007) to stage, survey and assess treatment response in MCL. PET-CT is however frequently used for these purposes in clinical practice in MCL. Although convincing data exists regarding the prognostic utility of PET-CT imaging in Hodgkin Lymphoma (interim & post treatment) and DLBCL (post treatment), its prognostic utility both during treatment and immediately following treatment have not systematically been evaluated in a large MCL patient cohort to support its use in clinical practice. Methods: We conducted a two-center (JTCC & UPenn), retrospective cohort study to examine the prognostic utility of pre-treatment (PET-1), interim-treatment (PET-2 after 2–3 treatment cycles) and post-treatment PET-CT (PET-3) imaging in a uniform MCL patient cohort undergoing dose-intensive chemotherapy (R-HCVAD) or high-dose chemotherapy followed by autologous stem (ASCT) cell rescue in the 1st line setting. The primary study endpoints were PFS and OS. PET-CT images were centrally reviewed for the purposes of this study using standardized response criteria proposed by the Imaging Subcommittee of International Harmonization Project in Lymphoma (Juweid et al, JCO 2007). Radiologists were blinded to clinical outcomes at the time of PET-CT review and results were dichotomized at each time point and their concomitant SUV max at a suspected site of disease was recorded. Result: 82 pts (median age 61, range 35–95) with advanced stage (98% stage IV) MCL with PET-CT data were identified for this analysis. Of these, 57 pts were treated with R-HCVAD (50) or ASCT (7) in the first-line setting. 154 PET-CT scans were reviewed. Overall treatment response rate (IWG) was 93% (76% CR + 17%PR). With median follow-up of 23 months (disease progression) and 27 months (overall survival), 3 year PFS and OS estimates were 70% (CI 53–82%) and 82% (CI 65–91%) respectively. Median baseline characteristics: WBC 7.4, ECOG PS 1, LDH/ULN .82, Ki-67 (MIB-1) 28% (range 10–90%), MIPI 3.5 (31% intermediate risk, 19% high risk). 20% and 30% of pts were blastoid variant and leukemic phase at diagnosis respectively. Pre-treatment PET-CTs were FDG-avid in 92% of MCL patients with a median SUV max of 7.8 (range 2.4–36.7) at a suspected site of disease. Pre-treatment PET-CT SUV max was positively associated with high Ki-67 (variance-weighted least-squares regression, p=.01). PET-2 and PET-3 were positive in 34% and 18% of patients respectively. Kaplan Meier and Cox regression survival analyses were used to test the association between PET-CT and survival. Interim PET-CT status was not associated with PFS (HR 1.1, CI .4-3.6, p=.8) or OS (HR .8, CI .15-4.6, p=.8). Post treatment PET-CT status was statistically significantly associated with PFS (HR 5.4, CI 2.0–14.5, p=.001, Harrell's C =.70, Figure) and trended towards significant for OS (HR 3.2, CI .8-11.9, p=.1). Post treatment PET-CT status remained an independent predictor of PFS in multivariate analysis which included MIPI score, blastoid variant and Ki-67. Conclusion: Our cohort is the first large series of MCL patients treated essentially with R-HCVAD examining the correlation between PET-CT and outcome in the front-line setting. A positive PET-CT following the completion of therapy identifies patients with an inferior PFS and a trend towards inferior OS. These data do not support the prognostic utility of PET-CT in pre-treatment (no upstaging) and interim treatment settings. This information should be incorporated into the design of future prospective clinical trials. We are currently examining the relationship of novel computer-assisted quantitative FDG-PET/CT measures of total tumor volume and total tumor metabolic burden with clinical outcome in patients with mantle cell lymphoma. Disclosures: No relevant conflicts of interest to declare.