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Abstract 218 Background: Overall survival (OS) for acute leukemia in relapse (RL) or induction failure (IF) treated with HCT is 16–19% (Duval et al., JCO 2010). While randomized studies have shown a dose response relationship, with higher doses of radiation resulting in decreased relapse, this benefit is offset by increased treatment related mortality. Patients and Methods: To explore the safety and tolerability of targeted radiation treatment in the context of HCT, a phase I trial is being conducted in which escalated doses of targeted whole body radiation is delivered to marrow bearing and lymphoid areas, while sparing non hematopoietic (vital) organs. The transplant preparative regimen is as follows: tomotherapy on days −10 to −6; etoposide 60mg/kg [adj bw] on day −5 with cyclophosphamide 100mg/kg [ideal bw] on day −3. The radiation dose was started at 1200cGy delivered in 150 cGy fractions twice a day. As part of the design, the dose of radiation was escalated in increments of 150 cGy until 1500 cGy and then 100 cGy incrementally using cohorts of three until ultimately dose limiting toxicity is reached according to the Bearman and CTCAE 3.0 (for hematologic toxicity) scales. Liver and brain dose was kept at 1200 cGy. Normal organs received 17–62% of the marrow dose (lung 47%, esophagus 35% and oral cavity 28%). All patients received peripheral blood stem cells on day 0. GVHD prophylaxis consisted of tacrolimus and sirolimus. Results: To date, a total of 26 patients have been transplanted; from 3/14/2008 to 2/9/2012. Additional patient characteristics are as follows: Age median 33y (20–54y) AML n=12, ALL Ph- n=10, ALL Ph+ n=2, Biphenotypic n=2 Disease status at HCT, 1RL n=9, 2RL n=2, IF n=15 Cytogenetic risk: intermediate n=13, unfavorable n=8 and information not available n=5 KPS at HCT median 80 (70–100) Donor source sibling n=13, HLA matched related n=6, mismatched (1 allele) unrelated n=7 WBC at HCT median 1.9 (0.1–14.9) blasts (blood) at HCT median 0.5% (0–85%) blasts (marrow) at HCT median 46% (10–85%) Two patients presented with extramedullary disease at time of HCT. With a median follow-up for alive patients of 16.1 months (5.3–47.7), the OS and cumulative incidence of relapse/progression at 1 year are 55% (95%CI: 44–65) and 34.6% (95%CI: 17.1–52.9) respectively. Five patients have been treated at 1600 cGy, the current dose level being tested, without reaching DLT. Twenty-two patients (85%) achieved CR at their day 30 post transplant evaluation. Twelve (46%) of patients developed acute GvHD; 5(42%) of these developed grades 3–4. The day 30 and day 100 NRM was 0% and 8% respectively. The most common toxicity across the dose levels tested is grade 2 stomatitis (Bearman Scale). Causes of death were disease progression/persistent disease n=10, GvHD n=2 and infection n=1. Conclusion: These results are encouraging and suggest that 1) doses of targeted whole body, marrow and lymphoid radiation delivered by Tomotherapy can be safely escalated to 1600 cGy in combination with etoposide and cyclophosphamide (DLT not reached and dose escalation continues); and that 2) a reduction in relapse/progression compared to published reports can be achieved without increasing NRM in this high risk population. Disclosures: No relevant conflicts of interest to declare.

Abstract 606 Background: alloHCT is offered with curative intent to patients with hematologic malignancies, and conventionally-computed survival estimates are offered for prognosticating outcomes. However, conventionally-computed survival estimates do not take into account elapsed time (and changing hazards with time survived); conditional survival overcomes these limitations, by calculating the probability of survival after having already survived a certain period of time – such data are unavailable for alloHCT recipients. We describe cause-specific (relapse-, GvHD-, treatment-related) conditional survival after alloHCT, providing clinically relevant information for patients who have survived 6 mos, 1, 2, and 5y after alloHCT. Methods: From 1976 to 2006, 2,427 consecutive patients received alloHCT for a hematologic malignancy at a single institution (median age: 34.7y [0.6–72.5]). Vital status and cause of death were determined using National Death Index, Social Security Death Index and medical records. Results: As of 12/31/2007, a total of 1413 deaths (58% of the cohort) were observed; 39% attributed to recurrent disease; 34% to GvHD; 12% to infection; 5% to cardiopulmonary disease; 2% to subsequent malignant neoplasm (SMNs); and 8% to other causes. Conventionally-computed probability of survival was 44.6% at 5y and 41.2% at 10y from alloHCT. On the other hand, conditional on survival for 6 mo, 1, 2, and 5y after alloHCT, 5-y survival rates were 62%, 75%, 83%, and 93%, respectively (Figure A). The cohort was at a 40-fold increased risk of any death compared with the general population (95%CI=38.2–42.4); at a 25.6-fold increased risk of death due to pulmonary complications, 3.3-fold risk due to SMNs, and 2.3-fold risk due to cardiovascular complications. Among patients followed for 15+y after HCT, the risk of all-cause mortality was 2.6-fold that of the general population (95%CI=1.8–3.7). Standardized mortality ratios (SMR) and cause-specific conditional mortality rates by primary diagnosis are summarized in the Table. Individuals who survived the first 5y had negligible (≤5%) risk of relapse- and GvHD-related mortality over the subsequent 5y. Treatment-related mortality increased over time; among those who survived 5y, treatment-related mortality rates exceeded relapse-related mortality (Figure B). After adjustment for demographics, underlying diagnosis and treatment era, individuals with chronic GVHD (cGVHD) had a significantly lower risk of relapse-related mortality (RR=0.43, 95%CI=0.4–0.5) compared to those without cGVHD. Conclusions: The projected 5-y survival rates improve conditional on time survived from alloHCT; 5-y survival exceeds 93% for those who have already survived 5y. However, alloHCT recipients who have survived 15+y continue to remain at increased risk of death compared to the general population. cGVHD is associated with decreased risk of relapse-related mortality. Both relapse-related and GvHD-related mortality rates decline with time, such that, among those who have survived 5y, treatment-related mortality exceeds relapse-related mortality. Conditional survival estimates provide clinically relevant prognostic information, helping inform preventive and interventional strategies. Disclosures: No relevant conflicts of interest to declare.

Abstract 3151 Background: Ablative dose total body irradiation (TBI) of 800 cGy in combination with high-dose melphalan (MEL) as part of single cycle autologous transplantation (AT) was found to be too toxic, and therefore inferior, in comparison to MEL. We set out to test total marrow irradiation, (TMI), a “sculpted” form of targeted total body irradiation using image-guided intensity modulated helical tomotherapy, given as the sole ablative regimen during the second cycle of tandem AT (TAT) as consolidation in patients with stable/responsive myeloma. Patients and Methods: Patients with Durie-Salmon stages I-III multiple myeloma in response or with stable disease, who were ≤ 70 years old and within 18 months from diagnosis, were enrolled. Patients received MEL 200 mg/m2 and AT (cycle 1), and, following recovery, TMI and AT were administered (cycle 2) at a median of approximately 2 months after the first AT. During the phase I part, TMI was tested between 1000 cGy and 1800 cGy given twice daily × 5 days. The maximum tolerated dose (MTD) –as previously reported- was established at 1600 cGy [Somlo et al. Clin Cancer Res. 2011; 17 (1):174–82]. Following cycle 2 of TAT, maintenance therapy consisted of dexamethasone 40 mg/day × 4 days and an IMiD (first thalidomide, and during the phase II portion, lenalidomide) in a 28-day cycle, administered for 6 cycles for patients in complete response (CR), or for a minimum of 12 cycles for pts not in CR. Results: 54 patients were enrolled (23 females, 31 males). The median age was 54.2 years (range 31.5–66.9). All patients with stage I (7), II (14), III (n=33) multiple myeloma received MEL. Forty-three patients (79.6%) received TMI, 30 at the MTD (6 enrolled at the MTD did not receive TMI). Reversible grade 3 non-hematologic toxicities following TMI at the MTD included febrile neutropenia (5/30), electrolyte abnormalities (7/30), sepsis/infection (5/30), anorexia (2/30), nausea/vomiting (2), fatigue (1), syncope (1). Grade 3 late toxicities include 1 case each of fatigue, nausea, 1 myositis and transaminitis. There were no primary or secondary graft failures, or second malignancies. Of the entire cohort of 54 patients, by intent to treat analysis best responses following TAT included CR (n: 20), very good partial response (VGPR, n:11), partial response (PR, n:16). At a median follow-up of 39 months from first AT, progression-free survival is 55% (95% CI 42–73%) and overall survival is 81% (95% CI 70–94%). For patients treated at the MTD of TMI 1600 cGy, at a median follow-up of 39 months from the first AT, progression-free survival (PFS) is 66% (50–88%), and overall survival (OS) is 80% (65–99%). Conclusion: TMI of 1600 cGy is feasible as ablative therapy following recovery from high-dose melphalan and AT. CR and VGPR rates are expected to improve with time on maintenance therapy and such data as well as progresion-free and overall survival will be updated. Safety and progression-free and overall survival data are encouraging, and further assessment of the role of TMI is warranted in combination with MEL as part of either single AT, part of TAT, or in comparison of tandem versus single ablative therapy, both in the upfront, and salvage settings. Disclosures: Off Label Use: IMiDs as maintenance.

Abstract 2399 The quality and depth of response particularly achievement of complete remission (CR) have been associated with significant improvement in progression free survival (PFS) and overall survival in multiple myeloma patients undergoing autologous stem cell transplant. Achievement of CR is considered a valid surrogate endpoint for survival in clinical trials for patients with multiple myeloma. We performed a phase II study investigating the role of sequential bortezomib/dexamethasone followed by thalidomide/dexamethasone as maintenance therapy post single autologous PSCT. The objectives were to examine the feasibility, toxicities, CR, PFS and overall survival rates. Within 4–8 weeks of autologous PSCT using melphalan 200mg/m2, pts received weekly bortezomib (bor) at 1.3mg/m2 /wk × 3 weeks with 1 week rest and dexamethasone (dex) at 40mg/d × 4 d for 6 months, followed by thalidomide (thal) at 50 –200mg/d and dexamethasone (dex) at 40mg/dx4 d for 6 more months. Single agent thalidomide was then continued until disease progression. Between March 2008 and June 2010, forty-five pts were enrolled. Median age was 54 years (29-71). Median time from diagnosis was 6.1 mo. (3.5 – 145.9). Disease stage at diagnosis; by Salmon-Durie (I/II/III 2/8/34/1 not available) and by ISS (I/II/III 18/14/8/ 5 not available). Pts received prior induction treatment with thal/dex (15), bortezomib based (27) and lenalidomide based regimens (10). Median B2M at enrollment was 1.8 mg/L (1.05 -5.3). Disease status at enrollment included complete remission (CR) (11), very good partial response (VGPR) (11), partial response (PR) (23). Six pts had chromosome 13 abnormalities (1 pt by karyotype and 5 pts by FISH), 2 pts had t 4;14 (one with concurrent ch 17 p del) and 3 pts had complex cytogenetic abnormalities. Results: Forty-five pts have been enrolled and undergone transplant. Five pts were unable to start planned maintenance therapy due to development of grade II or more neuro toxicities (4), and persistent thrombocytopenia (1) after PSCT. Thirty nine pts started maintenance bor/dex within 4–8 weeks of PSCT. One pt is too early for maintenance therapy. Twenty-five pts have completed the planned 6 months of bor/dex. Ten pts stopped bor/dex because of low WBC (2), PN (4), diagnosis of adrenal cancer (1), myocardial infarction (MI) (1), and relapse (2). Six pts are still receiving maintenance bortezomib. With a median F/U of 8.5 mo. (0.2 -24.0) twelve of 44 evaluable pts (27%) have achieved CR post PSCT and 17 of 33 evaluable pts (51%) have achieved CR after bor/dex on an intention to treat (ITT) analysis. Fifteen of 25 pts (60%) who have completed 6 months of bor/dex have achieved CR. Nine of 25 pts (36%) have upgraded their response with bor/dex. Eight pts (24%) could not complete bortezomib due to toxicities. At one year post PSCT fourteen of 28 evaluable pts (50%) remain in CR. Six pts have relapsed of whom 2 died of relapsed myeloma (leptomeningeal disease 1 pt). One pt experienced MI while receiving bortezomib (grade IV). Grade III toxicities have occurred in 17 pts; low platelet (1), asthenia (2), mood alteration (1), GI (severe constipation due to partial bowel obstruction on thalidomide) (1), skin rash (1), hyperglycemia (1), lymphopenia (10), sinus bradycardia (1), elevated triglyceride (1), DVT (1), low phosphate (3), leukopenia (1), edema (1). Sixteen pts had peripheral neuropathy (PN) grade I prior to start of bortezomib. Only 8 pts have developed new PN on the study and all are grade I-II. No patient has experienced grade III-IV PN. Median bortezomib dose is 1.3 mg /m2 per week. Conclusion: Prolonged weekly bortezomib maintenance therapy is well tolerated and can upgrade response post single autologous PSCT with no severe peripheral neuropathy. Fifty one percent of pts have achieved CR and 36% have upgraded their response after six months of bortezomib/dexamethasone therapy suggesting this is an active maintenance strategy post PSCT. Disclosures: No relevant conflicts of interest to declare.

Abstract 32 Background: RIT based conditioning offers the potential of combining the efficacy of radiation with decreased toxicity over traditional TBI. In pilot trials we demonstrated that combining Yttrium 90 (ibritumomab tiuxetan) with high-dose BEAM (ZBEAM) is feasible and has a toxicity profile similar to high-dose BEAM. Herein we report the results of a comparative analysis designed to evaluate transplant outcomes among DLCL patients who were conditioned with either ZBEAM or a TBI-based conditioning regimen. Patients were matched on age (+/− 5 years), disease status, number of prior regimens, year of diagnosis (+/− 5 years), and year of transplant (+/− 5 years). There was a total of 92 DLCL patients treated from 01/1997-01/2009; 46 patients in each treatment group. The median patient age was 56.5 years (range: 19–78) for the ZBEAM group, and 53 years (range: 21–62) for the TBI group. Both groups had a median of two prior regimens, with 13% (ZBEAM) and 15% (TBI) considered high-risk first remission, 65% beyond 1st CR and 22% induction failures in each cohort. The median length of follow-up for surviving patients was 51–83 months. There was a trend toward improved PFS in the RIT group: 2 year PFS for ZBEAM group 66% (95%CI: 56–74) vs. 50% (95%CI: 43–57) for TBI group (p4 years post transplant. Similarly the OS estimate was significantly higher for ZBEAM compared to TBI controls: 84% vs. 59 % (p Conclusions: RIT based conditioning demonstrated improved survival when compared to traditional radiation based regimens in the treatment of DLCL due to a more favorable toxicity profile, while maintaining potent anti-lymphoma effects. Disclosures: No relevant conflicts of interest to declare.

Abstract 902 Background: HCT is a curative option for patients with hematologic malignancies. However, the procedure carries a high risk of death in the immediate post-HCT period in part due to disease recurrence (relapse-related mortality [RM]), but also due to treatment-related mortality (TRM) resulting from the following: i) toxicity due to high intensity treatment; ii) graft vs. host disease (GvHD) and its management; and iii) infections. Previous studies utilizing data from HCTs performed in 1980s and 1990s indicate that the 1-yr cumulative incidence of TRM exceeds 20% for related donor and 30% for unrelated donor HCTs. However, gaps in knowledge remain related to the cause-specific cumulative incidence of TRM and RM after autologous and allogeneic HCT performed in the more recent eras. Methods: Between 2005 and 2008, a total of 1,673 consecutive patients received HCT at City of Hope at a median age of 50 years for AML (n=433), NHL (n=428), MM (n=369), ALL (n=176), and HL (n=154); 913 patients received autologous HCT; 382 allogeneic related donor; and 378 unrelated donor HCT. Reduced intensity conditioning was used for 268 patients. Early mortality was defined as death in the first year after HCT due to disease (RM) or treatment (TRM). Information regarding vital status and cause of death were obtained from medical records, supplemented with Social Security Death Index. Overall survival (OS) and cumulative incidence of TRM and RM were calculated for 30 d, 6 mo and 1 yr after HCT for i) the entire cohort, and by ii) diagnosis and iii) type of HCT. Multivariable models identified predictors of TRM and RM. Results: A total of 323 deaths (19.3% of the entire cohort) were observed within the first year after HCT; 55.5% attributed to TRM and 44.5% to RM. Among deaths due to TRM, 59% were attributed to infections, 12.9% to acute or chronic GvHD, and 9.5% to organ toxicity. Among autologous, related and unrelated donor HCT recipients, overall survival (OS) was 87.2%, 76.6% and 63.5% at 1 yr (p Conclusion: For patients with NHL and AML, cumulative incidence of RM does not differ by HCT type. Unrelated donor HCT continues to be associated with the highest risk of TRM. Infection is the most frequent cause of TRM, accounting for 62% of deaths due to TRM in unrelated donor, 52% in related donor, and 46% in autologous HCT recipients – reinforcing the need for aggressive measures for prevention and treatment of infections in this immune compromised population. Disclosures: No relevant conflicts of interest to declare.

Abstract 3467 Background: In recent studies, the incidence of extramedullary (EM) relapse post full-intensity allogeneic hematopoietic cell transplantation (AlloHCT) for AML has been reported to be approximately 5–15%. However, the incidence and clinical significance of EM relapse following reduced-intensity (RI) AlloHCT has not been studied. To better understand the incidence and predictors of EM relapse following RI-AlloHCT for AML, a consecutive case-series of 246 adult AML patients who underwent RI-AlloHCT from (inception) February 2000 through December 2008 at City of Hope were identified and selected for analysis from a prospective observational research database. Patient Characteristics: The median patient age was 55 years (range: 19–71) with a fairly balanced gender distribution (male=125, 51%; female=121, 49%). There were 108 (44%) matched related donors and 138 (56%) matched unrelated donors. 221 (90%) of patients received peripheral blood stem cells. The median time from diagnosis to RI-AlloHCT was 6.4 months (range: 0.5–124.8). Disease status at HCT: 1CR/2CR=137(56%), induction failure=40 (16%), relapse=69 (28%). Nine percent (n=22) of patients had a history of EM relapse prior to RI-AlloHCT. Twenty-eight percent of patients (n=68) received a prior auto (n=50) or allo (n=18) HCT. The majority of patients received fludarabine/melphalan conditioning n=227, 92%. GVHD prophylaxis consisted of CSA/MMF=113, 46% or Tacro/Siro=135, 54%. A total of 205 patients were evaluable for cytogenetics. Based on SWOG criteria (2000), there were 10 (5%) favorable, 118 (57.5%) intermediate and 77 (37.5%) unfavorable cytogenetics. Results: Initial relapse occurred in the BM in 72 (29%) patients and EM sites in 16 (6.5%) patients. The sites were: brain/CSF 5, breast 3, multiple sites 2, spine 1, liver 1, ascites 1, soft tissue 1, testes 1, and bone 1. Three (1%) had concurrent bone marrow/EM relapse. In addition, 6 (2.4%) patients had a second relapse in an EM site. The sites of second or subsequent relapse were: CSF 2, multiple sites 2, spine 1, parietal mass 1. The two-year cumulative incidence of EM relapse was 10.4% (6.8%-15.7%). Treatment for EM relapse included: combined chemo-RT 11, RT and/or chemotherapy followed by second allo/DLI 4, chemotherapy 3, palliative care 3, and RT 1. Time from Allo-HCT to initial EM relapse was 12.2 months (range: 2.8–42.9) and time from HCT to initial BM relapse 6.5 months (range: 1.0–33.3). Overall survival after initial EM relapse was 68.8% (50.3% - 81.5%) at 1-year and 50.0% (37.3% - 61.5%) at 2 years. Risk Factors: Of the risk factors studied (prior EM disease, prior HCT, disease status, cytogenetic risk, and age (=55)), advanced disease status (IF/RL/>3CR) (HR: 2.8, p=0.04) and unfavorable cytogenetics (HR: 5.2, p Conclusion: This is the first report to analyze specifically the incidence of EM relapse of AML post RI-AlloHCT. Our data show that the incidence of incidence EM relapse following RI-AlloHCT is similar to rates reported following ablative AlloHCT. By multivariable analysis, advanced disease and unfavorable cytogenetics were associated with increased risk for EM relapse, also similar to findings in the ablative setting. In conclusion, reduced-intensity conditioning does not appear to be associated with an increased risk of EM relapse. Furthermore, the median time to EM relapse exceeds median time to BM relapse and long-term survival is possible following EM relapse. Disclosures: No relevant conflicts of interest to declare.

Abstract 933 Background: aHCT is offered with curative intent to patients with hematologic malignancies. However, survival estimates are conventionally computed from time of transplantation. These estimates provide initial prognosis, but do not reflect how prognosis changes with changing hazard rates over time. Conditional survival accounts for elapsed time since diagnosis, describing the probability of survival after having already survived a certain period of time after aHCT. We describe cause-specific conditional survival, providing clinically relevant information to inform preventive and interventional strategies for patients alive for differing lengths of time from aHCT. Methods: From 1986 to 2006, a total of 2,603 consecutive patients received aHCT at City of Hope at a median age of 48 yrs (NHL: n=1063; MM: n=625; HL: n=475; AML: n=330; other: n=110). Information regarding vital status and cause of death were determined using National Death Index Plus and medical records. Survival probabilities and standardized mortality ratios (SMRs) were calculated for the entire cohort as well as by diagnosis, conditional on survival for 1, 2, 5, and 10 yrs after aHCT. Results: A total of 1135 deaths (representing 44% of the cohort) were observed by December, 2007; 79% of deaths were attributed to recurrent disease (range: 88% after MM to 71% after HL); 8% to subsequent neoplasm (SMN: range: 4% after MM to 13% after HL); 6% to cardiopulmonary disease (range: 2% after MM to 10% after HL); and 7% to other causes. Using conventional survival estimates, overall survival (OS) was 60% at 5 yr and 48% at 10 yr from aHCT; and the cohort was at a 15.6-fold increased risk of premature death compared with the general population (95%CI=14.7-16.6). Females were at a higher risk of premature death (SMR=19.1) than males (SMR=12.3). The cohort was at a 4.9-fold (95%CI=3.9-5.9) increased risk of death due to SMNs, and at a 2.3-fold (1.5-3.2) increased risk of deaths due to late cardiac complications. Conditional survival estimates demonstrated that every additional yr survived was associated with an increase in the probability of surviving the subsequent 5 yrs. Thus, the 5-yr survival rate was 68% after surviving 1 yr, 73% after surviving 2 yr, 80% after 5 yr; and approaching 88% after having survived 10 yrs from aHCT (Figure). Cause-specific conditional survival rates and SMRs by primary diagnosis are summarized in the Table. The risk of premature death (due to any cause) was comparable to the general population for 10-yr survivors, with the exception of HL survivors (2.6-fold increased). With the exception of MM, individuals who had survived 10 years were projected to have a Conclusion: This study demonstrates that the projected 5-yr survival rates improve conditional on previous time survived from aHCT, and that the 10-year survivors of aHCT for AML, NHL, and MM have mortality rates that are comparable to the general population. HL survivors continue to experience a 2.6-fold increased risk of premature death, primarily because of the excess risk of non-relapse mortality (due to SMN and cardiac causes). Conditional survival estimates provide clinically relevant prognostic information and an accurate estimate of cause-specific survival, helping inform preventive and interventional strategies. Disclosures: Nademanee: Genzyme: Consultancy, Research Funding; Allos Therapeutics: Membership on an entity's Board of Directors or advisory committees; Spectrum Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees.

Abstract 3423 Poster Board III-311 Long term survival for patients with chemo-refractory non-Hodgkin lymphoma (NHL) is poor even with high dose chemotherapy (HDC) and autologous stem cell transplantation (ASCT). Strategies such as novel transplant conditioning regimens and post transplant maintenance therapy are being evaluated to improve outcomes. Herein we report on the results of a phase II study designed to assess the impact of a novel radioimmunotherapy (RIT) based conditioning regimen of Y90 ibritumomab tiuxetan in conjunction with high dose BEAM (BCNU, Etoposide, Ara–C, Melphalan) in patients with poor risk NHL. Between May 2002 and Jan 2009, 31 patients who were either primary induction failure (n=18) or in partial remission (n=13) underwent HDC with Y90 plus BEAM. Patients received an imaging dose of Indium 111 on day -21 followed by a treatment dose of Y90 (0.4mCi/kg) on day-14. HDC with BEAM was started on day -7. The median age at ASCT was 57 (range: 19–70). The majority of patients were male (n=23, 74%) and had advanced stage disease (III or IV) at the time of diagnosis, (n=23, 74%). The histologies included Follicular n=6, Diffuse Large B-cell n=13, Mantle cell n=8, and Transformed n=4. The median number of prior regimens was 2 (range: 1-5). All patients engrafted at a median of 11 days. At the time of analysis, 23 (74%) patients were alive, and eight had expired (seven due to relapse/progressive disease, one due to COPD). The non-relapse mortality was 3.2%. The median length of follow-up for surviving patients is 46.9 months (range: 3.3-75.0). The two-year overall survival and disease-free survival was 77.9% (95%CI: 62.7-87.6%) and 50.9% (95%CI: 40.5-60.3%) respectively for the entire cohort. However, the relapse rate in the subset of MCL pts was strikingly high and approached 80% at 4 yrs. The other subgroups had a stable DFS (figure 1). In conclusion in this poor risk group of patients Y90 plus high dose BEAM can induce responses and long term remissions, however, for patients with chemorefractory MCL other treatment approaches may be warranted. Disclosures Off Label Use: yttrium 90 in combination with high dose BEAM chemotherapy.

Abstract 3403 Poster Board III-291 Autologous PSCT remains standard treatment in younger patients (pts) with multiple myeloma. However, relapse is the major cause of treatment failure. Several studies have reported improved progression-free survival (PFS) and possibly overall survival with thalidomide alone or in combination with steroid and chemotherapy as maintenance/consolidation therapy post autologous PSCT. We performed a phase II study investigating the role of sequential velcade/thalidomide/dexamethasone (VTD) as maintenance therapy post single PSCT. The objectives were to examine the toxicities of prolonged course of sequential VTD, CR rate, PFS and overall survival following single autologous PSCT. Within 4-8 weeks of autologous PSCT using melphalan 200mg/m2, pts received weekly velcade (vel) at 1.3mg/m2 /wk x 3 weeks with 1 week rest and dexamethasone (dex) at 40mg/d x 4 d for 6 months, followed by thalidomide (thal) at 50 -200mg/d and dexamethasone (dex) at 40mg/dx4 d for 6 more months. Single agent thalidomide was then continued until disease progression. Twenty-eight pts have been enrolled. Median age is 54 years (29-66). Median time from diagnosis is 7.9 mo. (4.2 – 145). Disease stage at diagnosis; by Salmon-Durie (II/III 6/22) and by ISS (I/II/III 11/9/7/missing data in 1 pt). Pts received induction treatment with thal/dex (14), velcade based (15) and revlimid based regimens (7). Median B2M at enrollment is 1.75 mg/L (1.14 -5.3). Disease status at enrollment; CR (7) VGPR (9), PR (11), SD (1). Three pts have chromosome 13 abnormalities (1 pt by karyotype and 2 pts by FISH). Results: All pts have undergone transplant. Four pts were unable to start planned maintenance therapy due to development of grade II or more neuro toxicities (3), and persistent thrombocytopenia (1) after PSCT. Twenty-four pts started maintenance vel/dex within 4-8 weeks of PSCT. Nine pts have completed 6 months of vel/dex. Two pts stopped vel/dex because of low WBC (1) or PN (1). With a median F/U of 5.2 mo. (1.2 -17.3) nine of 28 pts (33%) have achieved CR post PSCT and six out of 11 evaluable pts (55%) have achieved CR after vel/dex. Six out of 9 pts (66%) who have completed 6 mo. of vel/dex achieved CR. Two out of 9 pts (22%) have upgraded their response with vel/dex. Four pts have completed 6 month of thal/dex and are beyond 1 year post PSCT. Two out of 4 pts remain in CR at one year post PSCT. One pt is in PR and 1 pt has progressed. Two pts could not complete thal/dex phase of therapy because of relapse (1) and grade III GI toxicity (1). Three pts have relapsed of whom 1 pt died of relapsed myeloma (leptomeningeal disease). No grade IV toxicity has been noted. Grade III toxicities have occurred in 4 pts; low platelet (1), fatigue (1), mood alteration (1), GI (severe constipation) (1). Thirteen pts have peripheral neuropathy (PN). Ten pts had PN grade I at enrollment. Only 3 pts have developed PN on the study and all are grade I - II. Median velcade dose is 1.3 mg /m2/wk and thalidomide dose is 100mg /d. Conclusion: Prolonged sequential velcade/thalidomide/dexamethasone maintenance therapy post single autologous PSCT is well tolerated with no severe peripheral neuropathy. Fifty-five percent of pts have achieved CR and 22% have upgraded their response after six months of velcade/dexamethasone therapy suggesting this is an active and well tolerated maintenance strategy post PSCT. Disclosures: Sahebi: Celgene: Honoraria; Millennium Pharmaceutical: Research Funding. Off Label Use: The use of bortezomib(Velcade)in combination with thalidomide and dexamethasone is investigated as maintenance therapy post autologuous stem cell transplant in patients with multiple myeloma.

Abstract 1192 Poster Board I-214 Background: Even though Hodgkin lymphoma (HL) is a curable disease, about, 20-30% patients are either refractory to induction chemotherapy or relapse post treatment. High dose chemotherapy and autologous HCT has been shown to be an effective salvage therapy for patients with relapsed HL. However, relapse continues to occur after auto-HCT, especially in patients with chemoresistant or poor-risk features at relapse. The prognosis of these patients is poor with limited options of treatment. Although allo-HCT offers both cytoreduction and potential graft-versus-tumor effect, its use in relapsed HL has been limited by non-relapse mortality (NRM) and patient co-morbidities induced by numerous prior treatments. To examine the potential impact of allo-HCT on survival and disease outcomes, we performed retrospective analysis of allo-HCT in relapsed/refractory HL to determine if allo-HCT can induce long-term remission in heavily pretreated relapsed HL. Results: Between January 2003 and December 2008, 29 patients with relapsed HL underwent allo-HCT at City of Hope National Medical Center. The median age was 37 (range: 14-63). 20 (69%) patients were chemosensitive at time of allo-HCT. 17 (59%) patients had prior auto-HCT. 16 (55%) patients received matched siblings and 13 (45%) received unrelated donor cells. 20 (69%) patients had prior radiation treatments. The median number of prior regimens was 5 (range: 2-8). 23 (79%) patients underwent a non-myeloablative conditioning regimen while 6 (21%) patients had a myeloablative regimen. 14 (48%) patients received Tacrolimus/Sirolimus as graft versus host disease prophylaxis and 15 (52%) patients received a combination of Cellcept/CsA, Cellcept/CsA/MTX, Tacrolimus/MTX, or Tacrolimus/Sirolimus/MTX. With a median follow up of 31.9 months (range: 9.7-69.1) for surviving patients, the results show: 1) OS 1 year 75.8% (95% CI 61.5, 85.5), 2 year 60.8% (95% CI 48.8, 70.8), Figure 1 2) DFS 1 year 41.4% (95% CI 33.9, 48.7), 2 year 33.9% (95% CI 28.0, 39.8), Figure 2 3) Relapse rate 1 year 50.0% (95% CI 40.8, 60.0), 2 year 59.1% (95% CI 51.2, 67.1) 4) Non-relapse mortality 100 days 6.9% (95% CI 1.9, 22.8), 1 year 14.2% (95% CI 6.4, 29.9), 2 years 16.3% (95% CI 6.4, 29.9) 5) GVHD Grade II-IV aGVHD 51.6%, cGVHD 58.6% 6) Prior radiation showed a trend toward adversely affects OS with a hazard ratio of 4.45 (CI 0.97, 20.47), p=0.056 7) Chemoresistant disease at allo-HCT adversely affecting DFS with a hazard ratio of 2.3 (95% CI 0.9, 5.91), p=0.083 8) The only difference between relapsed group and non-relapse group was the type of donor. Relapse rate is 75% for matched related donor versus 23% for unrelated donor (P=0.005). Conclusion: Allogeneic hematopoietic cell transplantation in heavily pretreated relapsed Hodgkin's lymphoma is feasible, tolerable, and can induce durable clinical remissions. Download : Download high-res image (82KB) Download : Download full-size image Download : Download high-res image (82KB) Download : Download full-size image Disclosures: No relevant conflicts of interest to declare.

Abstract 2323 Poster Board II-300 Introduction: High dose chemotherapy with ASCT can increase overall survival (OS) in patients with poor risk or relapsed Non- Hodgkin lymphoma (NHL). Novel conditioning regimens combining radioimmunotherapy (RIT) with high dose chemotherapy have demonstrated favorable toxicity profiles and potentially improved response rates. Herein we report on 84 patients who underwent conditioning with Y90 Ibritumomab plus high dose BEAM (BCNU VP16 AraC Melphalan) and the effects of pretreatment rituximab levels on relapse. On day-23 and day-16 of conditioning pts had a blood draw for rituximab levels. If levels were &10ug/ml, pts received rituximab 250mg/m2. This was followed by pretherapy imaging with Indium 111 on day -21 and Y90 treatment on day -14. High dose BEAM chemotherapy started on day-7and all pts received rituximab 250mg/m2 at day+8. Results: The median age at ASCT was 58.5 years (range 19-78). Histologies included DLC n=36, Mantle Cell n=27, Follicular n=11, Transformed NHL n=10. Disease status at ASCT was 1st or 2nd CR n=35, 1stPR n=13, 1st or 2nd rel n=18, induction failure (IF) n=18. Median length of f/u for living pts was 34 months. All patients engrafted at a median of 11 days (anc>500) Transplant related mortality was 2.3 %. Two year OS/PFS for the entire cohort was 85.62% (77-91) and 66% (58-73). There was no significant difference in either DFS or OS based on histology (figure 1)Rituximab levels were available in a subset of 18 pts. and of note there was a trend towards higher relapse rates in patients with higher day-23 rituximab levels (35% vs. 0) (see figure 2). Conclusions. Y90 BEAM conditioning is well tolerated. Short term outcome is similar among different histologic types of NHL. The true effects of rituximab levels may not yet be fully appreciated due to small patient numbers. However, the trend towards higher relapse rates in the cohort with high circulating pre RIT rituximab levels suggests that titration of rituximab dosing pre RIT may be another strategy in which to improve transplant outcomes by optimizing targeting of the RIT. Disclosures: Off Label Use: yttrium 90 in combination with high dose BEAM chemotherapy.

Although treatment outcomes for adult ALL remain stagnant at 35–40% 5 yr event free survival (EFS), allogeneic transplant particularly from unrelated donors has frequently been reserved for patient beyond first complete remission (CR1) with the exception of patients with a t(9;22) or Philadelphia (Ph+) cytogenetic abnormality. Between 4/1/2001 and 11/14/2007, 67 patients with ALL received URD-HCT; disease status at HCT was (CR1) in 27 pts (40%), CR2 in 20 pts (30%) and advanced disease (AD) which included induction failure, relapse or CR3 in 20 pts (30%). Age ranged from 2–58 yrs with median age of 29.5 yr. One third of the patients were Ph+. An additional 18 pts had high or very high risk cytogenetics abnormalities. The majority (≥75%) of Ph+ patients had received Gleevec prior to HCT. The conditioning regimen was FTBI 1320 Gy given as 11 fractions over four days followed by VP-16 60 mg/kg. Graft vs. host disease (GVHD) prophylaxis was tacrolimus (FK) and methotrexate (MTX) in 20 pts; sirolimus (Siro) was added to this regimen in 15 pts. Other GVHD regimens used were FK, MTX and Cellcept (12 pts) FK and siro (4 pts) and anti thymocyte globulin was added in 11 pts. Graft source was marrow in 12 pts and peripheral blood stem cells in 55 pts. Median time to ANC > 500 was 17 days (range 11–36d) and for platelets was 24 days (range 15–218d). Three patients died prior to day 18 of infectious complications and were considered unevaluable for engraftment. The incidence of acute GVHD Grade II-IV was 57% with Grade III-IV in 18%. Chronic GVHD occurred in 52% of 56 patients at risk. Treatment related mortality was 16% at 100 days and 28% at 1yr. At two years the event free survival (EFS) was 58% for CR1 pts vs 23% for CR2 and 17% for AD. Relapse rates were 18%, 24% and 40% respectively EFS was 62% at 2 yrs for Ph- pts and 50% for Ph+ in CR1 vs 19% for pt > CR1 who were Ph-and 40% for Ph+ (p=0.31). Remission status (CR1 vs > CR1) was a significant predictor of survival (p=0.01) and EFS (p=0.03) in multivariate analysis while age and Ph+ status had no impact on survival end points. Conclusion: The preparative regimen of FTBI and VP16 offers 2 yr EFS rates of 50–60% in patients receiving URD-HCT in CR1, including patients with Ph+ and other high risk cytogenetic risk groups. These results are comparable to those reported with sibling donor transplants and provide a curative option for patients in CR1 lacking a family donor. Figure Figure

Randomized trials have demonstrated superior progression free (PFS)and overall survival (OS) with autologous stem cell transplant (ASCT) for patients with relapsed chemosensitive non-Hodgkin lymphoma (NHL) compared with conventional dose salvage chemotherapy. More recent trials have proven that ASCT is also feasible in pts with AIDS associated NHL (ARL). However, the impact of the HIV infection on long term outcome is unknown. We therefore, undertook a retrospective case control analysis of ASCT for high risk B cell NHL in HIV positive (HIV Pos) and HIV negative (HIV Neg) pts. Twenty-nine pts with ARL who underwent ASCT between 1998 and 2007 were matched with HIV Neg controls. Pts were matched for gender, time from NHL dx to ASCT, age at ASCT, dz status at ASCT, number of prior regimens, conditioning regimen (chemo vs. FTBI). Histology was matched as closely as possible with the exception that there were more high-grade NHL pts in the HIV Pos group. Patient HIV Pos HIV Neg P value* Age at ASCT 42 (11–68) 48(21–65) .06 HISTOLOGY Large cell 19 25 Burkitts 10 0 Follicular gr 3 0 3 Marginal zone 0 1 Disease status 1CR/PR 16 16 IF 2 2 1.0 Relapse 11 11 Prior regimens 2(1–4) 2(1–4) .33 Conditioning - - FTBI 4 4 1.0 Non TBI 25 25 (* P value by Fishers exact test or Wilson signed rank sum test) Median followup for HIV Pos pts is 46.7 months and 43.3 months for HIV neg controls (NS). Pts engrafted WBC at a median of 10 days (HIV Pos) and 11 days (HIV Neg) (NS) respectively. Non-relapse mortality (NRM) was 8% (95% CI 2–26) in HIV Pos pts and 4% (95%CI 0.7–25)in HIV Neg controls (NS). Two year PFS for the HIV Pos cohort was 76% (95% CI 62–85) and 56% (95% CI 45–66) for the controls (NS). OS was also similar at 75% (95% CI 61–85) versus 75% (95% CI 60–85)respectively{ see figure }. In conclusion, despite the inclusion of more poor risk pts by histology in the HIV Pos cohort, our series demonstrated matching OS for HIV Pos and HIV Neg pts undergoing ASCT for NHL The equivalent NRM also provides further evidence that HIV status does not affect the outcome of ASCT for NHL and therefore, should be considered a standard approach for select pts with ARL. Download : Download high-res image (77KB) Download : Download full-size image

Acute lymphoblastic leukemia has a poor prognosis in adults, with a two-year survival rate of 35–40% despite aggressive therapy (American Cancer Society: Cancer Facts and Figures 2008 Atlanta, GA: American Cancer Society, 2008). Reduced-intensity allogeneic stem cell transplantation (SCT) relies mainly on graft versus leukemia (GVL) for its efficacy; however, the role of GVL in ALL is less well-defined. Between 5/7/02 and 6/15/07, 25 adult ALL patients were uniformly treated with fludarabine 25mg/m2 daily for 5 days and melphalan 140mg/m2 followed by ALLO-SCT using peripheral blood stem cells. The indications for the reduced intensity regimen were: ≥ 50 years (10 pts) (40%), decreased organ function (9 pts) (36%) and previous ALLO-SCT (6 pts) (24%). Patient demographics include: median age, 47 years (range, 23–68 yrs.), remission status at ALLO-SCT: first complete remission (CR) (12 pts) (48%), first relapse (3 pts) (12%), second CR (5 pts) (20%), >second CR (4 pts) (16%), induction failure (one pt) (4%), t(9;22) or Philadelphia positive (Ph+) ALL(9 pts) (36%). Donor source was matched sibling in 9 pts (36%), and matched unrelated in 16 pts (64%). Graft versus host disease (GVHD) prophylaxis: was cyclosporine (CSA)/+ mycophenylate (MMF) (3 pts) (12%), CSA/MMF/methotrexate (MTX) (8 pts) (32%), CSA/MMF/ATG (one pt) (4%), tacrolimus/sirolimus (7 pts) (28%) and tacrolimus/sirolimus/MTX (6 pts) (24%). With a median follow-up for surviving patients of 28.5 months (range: 12.8–72.5 months), the two year cumulative probability of overall survival and disease-free survival were both 59% (95% CI: 46–69.2%). The relapse rate was 16% (95% CI: 6.4,–37.4%),. Incidence of acute GVHD was 60% for grade II–IV and 20% for grade III–IV. Of the patients at risk for chronic GVHD, 8% developed limited chronic GVHD and 60% developed extensive chronic GVHD. The 100-day, one year and two year non-relapse mortality rates were 12% (CI: 4.6–29.3%), 24.2% (CI: 14–39.9%) and 29.3% (CI: 18.4–44.6%), respectively. There was no difference in survival outcomes based on donor source. The results of this study show that reduced intensity ALLO-SCT using fludarabine/melphalan based conditioning with primed peripheral stem cells from a matched related or unrelated donor provides a curative option for patients with high risk ALL who are not eligible for full intensity transplant. Figure Figure

Background: Radiation therapy has been used primarily for palliation in pts with MM. Ablative dose total body irradiation (TBI) of 800 cGy in combination with high-dose melphalan (MEL) as part of single cycle AT was found to be too toxic, and therefore inferior, in comparison to MEL. TMI, a form of image-guided targeted TBI using intensity modulated helical tomotherapy, when given as the sole ablative regimen during the second cycle of TAT, may improve the efficacy of MEL without unacceptable toxicities. Patients and Methods: We designed a phase I-II TAT study in pts with Durie-Salmon stages I–III MM in response or with stable disease (SD), who were ≤ 70 years old. Pts received MEL 200 mg/m2 and AT (cycle 1), and, following recovery, TMI and AT was administered (cycle 2). The dose of TMI started at 1000 cGy, and was to be escalated by an increment of 200 cGy per cohort, up to 200 cGy twice daily x 5 days. Following cycle 2 of TAT, maintenance therapy consisted of dexamethasone 40 mg/day x 4 days and thalidomide (Thal) 50–200 mg daily on a 28-day cycle, administered for 6 cycles for pts in complete response (CR), or for a minimum of 12 cycles for pts not in CR. Results: The median age was 53.5 years (35–66). Twenty three pts (13 female, 10 male) with stages I (1), II (6), III (16) MM received MEL at a median time of 10 mos (7–18) from diagnosis; 22 pts received TMI (1000 cGy through 1800 cGy); 1 pt did not receive TMI due to post-MEL toxicities. The median time between MEL and TMI was 63.5 days (range, 44–119). Granulocyte recovery to >1000/microliter following Mel was 14 days (13–15) versus 15 days after TMI (range; 13–19). Platelet recovery to >20,000/microliter was identical: 13 days (range: 0–16 versus 0–17). Reversible grade 3 non-hematologic toxicities by TMI dose levels included febrile neutropenia (levels 1 and 2: 1 pt each); none (level 3); fatigue (level 4: 1 pt). Dose limiting toxicities (DLT) at level 5 (1800 cGy) were reversible, and included grade 3 radiation pneumonitis/congestive heart failure necessitating administration of oxygen, steroids, and oral cardiac medications, and abdominal pain/enteritis requiring parenteral feeding (n: 1), and grade 3 hypotension requiring pressor support (n: 1), defining the maximum tolerated dose (MTD) at 1600 cGy (200 cGy twice daily x 4 days). The estimated median radiation dose to normal organs was 14–64% of the targeted bone marrow dose in the 6 pts each treated at doses 1600 and 1800 cGy. Late toxicities included reversible enteritis in the pt previously experiencing the same symptom as DLT after receiving 1800 cGy of TMI, and lower extremity deep venous thrombosis (DVT) during maintenance therapy in 2 pts. We observed neither primary nor secondary engraftment failure. Best responses included CR (n: 12), very good partial response (VGPR, n: 4) PR or stable disease (n: 6). At a median follow-up of 22 months (range, 10–39+ months) 5 pts progressed (at 7.5, 8, 16, 21, and 22 months) and 8 pts continue on maintenance. Conclusion: We defined the MTD of TMI as 1600 cGy. Delayed toxicities are limited so far, but underline the need for careful long-term monitoring and DVT prophylaxis during Thal-based maintenance. Phase II of this trial at the MTD of 1600 cGy of TMI is ongoing.

Although autologous transplant remains standard of care for patients with multiple myeloma, it is rarely curative. Allogeneic peripheral stem cell transplant (PSCT) using reduced intensity conditioning (RIC) or non-myeloablative conditioning following autologous PSCT (auto-allo) have been used in an attempt to improve survival. Although the graft vs. myeloma effect is an important therapeutic aspect of these approaches higher relapse rates have been reported using reduced intensity regimens suggesting that cytoreduction with auto PSCT (auto-allo) is required for optimal disease control. To examine the differences between RIC and auto-allo PSCT we performed a retrospective analysis of 49 patients who underwent auto-allo and RIC transplants. Thirty-seven patients received an auto-allo PSCT using melphalan (200mg/m2) prior to auto PSCT and TBI (200 cGy) prior to allograft PSCT and twelve patients underwent RIC allograft PSCT following fludarabine (125mg/m2) and melphalan (140mg/m2), between Feb 2000 to April 2005. Donors included HLA matched siblings (47) or matched unrelated donors (2 in the RIC group). Median follow up for the alive patients is 4.5 and 5.4 years for the auto-allo and the RIC groups, respectively. Median age was 51 years in the auto-allo group (range 38–66) and 48 years in the RIC group (range 42–62). Patients in the auto-allo group received their allograft within 60–120 days following autologous PSCT. In the RIC group, 7 patients failed a previous single (1) or tandem (6) auto PSCT. Cytogenetic data were available in 47 patients prior to transplant, with chromosome 13 deletion present in 2 patients in the auto-allo group and in 4 patients in the RIC group. Median B2-microglobulin was 1.8 in the auto-allo group and 2.1 in the RIC group. There were more patients in complete remission (CR)/partial remission (PR) in the auto-allo group (76%) than in the RIC group (17%, P= 0.0005), and there were more patients who received early transplant (< one yr) in the auto-allo group (68%) than the RIC group (8%, P= 0.0005). There was no difference in 1 year non-relapse mortality between the two groups (5% auto-allo vs. 8% RIC, P=1.00. Three year overall survival (OS) was statistically superior in the auto-allo group (81%) versus the RIC group (35%, P=0.02). Three year PFS was 54% in the auto-allo group and 21% in the RIC groups (P=0.11). However, when Cox regression analysis was performed adjusting for the disease status and time from diagnosis, there was no statistically difference in the OS between the 2 groups (P=0.27). Conclusion: Our data suggest that RIC allograft and auto-allo PSCT-associated treatment related mortality is similar, and RIC allograft when administered earlier during the disease course may result in similar outcome. However whether using early reduced intensity allogeneic transplant could eliminate the need for cytoreductive auto-PSCT needs to be addressed in prospective clinical trial.