ALBERT

Description: Abstract 4471 Background: Patient-Reported Outcome (PRO) measures help clinicians and researchers monitor symptoms, HRQOL, satisfaction, and adherence related to cancer treatment. Symptoms affect HRQOL, and when both are reported frequently and longitudinally, a patient-reported data stream emerges that reflects physiological functioning and complements traditional laboratory and clinician-based assessments. Such data could significantly enhance risk prediction and safety monitoring in patients undergoing HCT. This study evaluates the feasibility of collecting daily and weekly PRO measurements to inform our ability to capture variation in patient experiences over time. Patients and methods: We enrolled 32 patients undergoing planned HCT (10 autologous, 11 myeloablative allogeneic, 11 reduced intensity allogeneic) in a feasibility study of frequent HRQOL and symptom surveillance following HCT. All surveys were administered electronically though patients could opt for pen and paper. PRO measures were derived from the NIH PROMIS and PRO-CTCAE measures, which have not been previously used extensively or at all in HCT patients. All patients completed a 10-question HRQOL measure (PROMIS-Global Health) and a 34-question symptom measure (a pre-selected subset of the 83-question PRO-CTCAE, with 7-day recall period) prior to HCT and weekly until D+100. Auto patients completed a daily 21-question symptom measure (a pre-selected subset of the weekly symptom surveys, with 24-hour recall period) until hospital discharge, and allo patients completed daily symptom surveys until 100 days after stem cell infusion (D+100). Kruskal-Wallis tests were used to compare groups. Median age of the sample was 55 years (range 18–70). 16 patients (50%) were female. Most auto patients had myeloma (N=8, 80%) and most allo patients had acute leukemia (16, 72%); other diagnoses included NHL (4), CML, MDS and AA. Twenty-six (81%) patients were Caucasian, 4 (12.5%) were African American, 2 were other (6.2%). Thirteen (41%) had a high school education or lower. Results: Median daily survey completion percentages prior to hospital discharge for surviving patients were 94% among auto patients, 90% among reduced intensity allo patients and 70% among myeloablative allo patients (p=0.07). Prior to D+100, median daily survey completion percentages were 87% among reduced intensity allo patients and 58% among myeloablative allo patients (p=0.004). Median weekly survey completion percentages prior to hospital discharge were 100% in all cohorts. Prior to D+100, these were 100% in auto and reduced intensity allo cohorts, and 80% among myeloablative allo patients (p=0.002). Daily surveys were completed in a median of 3 minutes, and longer weekly surveys in a median of 4.3 minutes. 93% of respondents were satisfied with survey length and 85% of respondents were satisfied with the electronic self-report system. Median weekly total symptom scores (higher scores indicated greater symptom severity) prior to conditioning were 16 in autos, 12 in myeloablative allos, and 5 in reduced intensity allos (p=0.3) and at D+7 were 23 in autos, 40 in myeloablative allos and 18 in reduced intensity allos (p=0.01). For the physical health subscale of the PROMIS measure (lower scores indicated greater impairment), baseline mean weekly HRQOL scores were 47.7 in autos, 50.8 in myeloablative allos and 50.8 in reduced intensity allos (p=0.9). By D+7, mean HRQOL scores were 37.4 in autos, 37.4 in myeloablative allos and 52.5 in reduced intensity allos (p=0.005). Conclusion: Frequent symptom and HRQOL surveillance is feasible and acceptable to HCT patients, and survey data correlates with toxicity and physiological function after transplant. Compliance rates were lower in myeloablative allo patients, especially for daily surveys, perhaps reflecting the higher burden of critical illness in this population. Future studies may be enhanced by caregiver-reported proxy data. Analyses of weekly symptom and HRQOL surveys beyond D+7, daily surveys, symptom clusters, biologic correlates and individualized profiles are ongoing. Larger studies are warranted to explore and develop risk prediction models based on this technique. Disclosures: No relevant conflicts of interest to declare.

Description: Background: Hemorrhagic cystitis (HC) is a known complication of high-dose cyclophosphamide, which is part of the conditioning regimen for stem cell transplantation, and is associated with significant morbidity. Treatment of HC is frequently unsatisfactory, leading to prolonged hospitalization and utilization of health care resources. High-dose recombinant factor VIIa (rFVIIa) is used as a hemostatic agent in patients with hemophilia with inhibitors. As rFVIIa enhances the generation of thrombin on activated platelets and facilitates the formation of a stable fibrin plug that is resistant to premature lysis, we conducted a pilot study to assess its efficacy and safety in the treatment of HC. Methods: Subjects between 18–65 years with severe HC that was judged unresponsive to (a) optimization of hemostatic parameters, and (b) a trial of at least 24-hours of continuous bladder irrigation using a standardized protocol were eligible. Consented subjects were administered 80 μg/kg of rFVIIa for the first dose, and 120 μg/kg every 3 hours for up to 2 additional doses if hematuria was persistent. Response was evaluated by monitoring urine color photographically and by measuring urine hemoglobin content, using spectrophotometer. Subjects were followed for 24 hours. Complete response was defined as complete clearing of the color of urine at any time point in the 24-hour study period, and partial response was defined as slowing of hematuria, as evidenced by lightening of the color of urine. Results: Of the 7 subjects who participated in the study, 4 had a complete response, 2 had a partial response, and 1 had no response. The response duration was temporary, and all the subjects required the administration of the three doses of rFVIIa. No major adverse effects were encountered. Conclusion: rFVIIa appears to be effective in temporarily abating bleeding in HC. Further trials should include multiple dosing and/or addition of antifibrinolytic agents for a more durable effect.

Description: Background: A major advance in allogeneic stem cell transplant (SCT) has been the establishment of effective and less toxic reduced intensity regimens as alternative therapeutic approaches for patients with certain hematologic malignancies. The focus of these approaches has been to reduce treatment related mortality (TRM) while providing sufficient host immunosuppression to permit the achievement of complete donor chimerism that leads to a graft versus tumor effect, resulting in long-term disease control and cure. In this study we report overall survival (OS), relapse rate (RR), and non-relapse mortality (NRM) in patients receiving reduced intensity conditioning (RIC) with a 48 hour continuous infusion of busulfan with fludarabine followed by methotrexate (MTX) alone or with lympho-depleting anti-CD52 monoclonal antibody (mAb), alemtuzumab, or T cell depleting immunoglobulins, anti-thymocyte globulin (ATG) given as graft versus host disease (GVHD) prophylaxis. Methods: Patients with histologically confirmed hematologic malignancies, who were over the age of 55, or otherwise ineligible for more intensive busulfan-based therapy were enrolled on a Phase II protocol, LCCC 0306, at the University of North Carolina. All patients received IV fludarabine 30 mg/m2/day on days-7 through-3; busulfan 6.4 mg/kg by continuous infusion over 48 hours on days-6 through-5 and tacrolimus from day-1 plus either MTX alone, ATG or alemtuzumab alone, or a combination of these agents depending on disease risk and donor status. Results: 71 patients were enrolled. The median age was 58 (range 28 - 69). 58% were men and 42% women. 37 patients received HLA-matched related donor (MRD) stem cell grafts, and 34 patients received either matched unrelated donor (MUD) or HLA-mismatched grafts. The median HCT-Comorbidity Index (CI) score was 3 (range 0 - 8, HCT-CI score: 0 = 12 pts, 1 - 2 = 22 pts, ⪴ 3 = 36 pts). The majority of pts were intermediate risk by Disease Risk Index (DRI) score (9 low, 40 int, 19 high, 1 very high, 2 undetermined). The DRI low/int group had an estimated 18 month OS of 65% (CI 0.50 - 0.77), and DRI high/very high OS was 35% (CI 0.16 - 0.55). Estimated median survival time based on DRI for low/int was 1674 days (CI 646 - 2920) versus 375.5 days (CI 136 - 1018) (p = 0.003) for DRI high/very high pts. OS at 18 months in the MTX alone arm (n = 20) was 70% (CI 0.45 - 0.83), ATG (+/- MTX, n = 27) was 52% (CI 0.32 - 0.69), and alemtuzumab (+/- MTX, n = 24) was 46% (CI 0.26 - 0.64); (p = 0.17). The 18 month relapse rate for the MTX alone arm was 50% (CI 0.27 - 0.69), 41% in ATG (CI 0.37 - 0.76), and 41% in alemtuzumab (CI 0.36 - 0.77); (p = 0.85). The 18 month NRM in the MTX alone arm was 7% (CI 0.61 - 0.99), alemtuzumab (+/- MTX) was 32% (CI 0.42 - 0.85), and ATG (+/- MTX) was 27% (CI 0.52 - 0.86); (p = 0.05). Much of the increased NRM in the alemtuzumab and ATG arms was attributable to increased rates of fatal infectious complications: 1 in the MTX arm, 3 in the ATG arm and 8 in the alemtuzumab arm. No patients receiving MTX alone, 3 receiving alemtuzumab and 6 receiving ATG developed grade 3-4 acute GVHD. 5 of the 20 surviving patients have extensive chronic GVHD. Conclusion: Continuous infusion, reduced dose, busulfan and fludarabine can be safely administered to patients who are ineligible for myeloablative conditioning either because of age or comorbidities. The use of MTX alone with this regimen results in a median survival of over 4 years. Patients with high DRI or who received treatment with alemtuzumab or ATG had higher NRM and poorer OS irrespective of donor status. Disclosures Wood: Best Doctors: Consultancy; Inform Genomics: Consultancy.

Description: High dose Melphalan (Mel) has demonstrated efficacy in the treatment of multiple myeloma (MM). Mitoxantrone (Mit), in combination with vincristine and prednisone, also has demonstrated activity in MM with the benefit of less cardiac toxicity than other standard regimens. In this trial Mel and Mit were combined as a transplant preparative regimen. Mit was given as a prolonged 6 hour infusion on 2 separate days to increase intracellular drug levels and decrease cardiac toxicity (Kaminer et al. Cancer1990; 65, 2619–2623; Koc et al. Hematol Oncol2004;22:43–53). PATIENTS: 35 patients with a diagnosis of MM were enrolled between 9/98–6/02. Median age was 59 (range, 38–69); 60% had received ≥ 2 previous regimens (range, 1–6). The median time from diagnosis to transplant was 9 months (95% CI, 8–12 months). 57% had stage III disease and 26% stage II at diagnosis; median Beta-2 microglobulin was 3.6 mg/L (available in only 13 patients). All patients completed therapy with Mit 30mg/m2/day infused over 6 hours on days -6 and -5 and Mel 180mg/m2 on day -1. RESULTS: The median follow-up for survivors was approximately 45 months (range, 3–84 months). The median times to granulocyte and platelet engraftment were 11 days and 14 days respectively. 2 patients failed to engraft; 1 proceeded to allogeneic transplant, the other died on day 28 secondary to sepsis. The 100-day TRM was 2.9%. The median progression free survival (PFS) was 20 months (95% CI, 13–31) (Figure 1) with a median overall survival (OS) of 57 months (Figure 2). 4 patients are alive and progression free more than 48 months out from transplant. 8/35 (23%) of patients achieved a complete response (CR). Of the 8 patients who had a CR, 7 (20% of total patients) are still alive and progression free with a median follow-up of 39 months after transplant (range, 12 to 80 months). The achievement of a CR was significantly associated with longer PFS but not with OS. The mean CD34 count of infused cells was 4.92 ×106/kg and did not appear to be significantly associated with CR rate, OS, or time to engraftment of platelets or granulocytes. Overall, therapy was well tolerated with a median of 8 days (range, 0–15) of any grade of mucositis and a median of 3 days of fever. The mean LVEF on MUGA was 64% pre-transplant and decreased to 58% post-transplant. 1 patient with diabetes and hypertension developed congestive heart failure after discharge from the hospital but with therapy the LVEF returned to normal. CONCLUSION: The combination of Mel and infusional Mit is an effective regimen with 23% CR rate despite multiple previous therapies. The median OS of 57 months compares well to other transplant trials and patients who achieved a CR demonstrated better long-term PFS. Figure Figure Figure Figure

Description: Abstract 306 Introduction: Histone deacetylase inhibitors potentiate the efficacy of anthracyclines and proteasome inhibitors in preclinical models of multiple myeloma (MM). We therefore conducted a phase I clinical trial to evaluate the safety of the histone deacetylase inhibitor, vorinostat, in combination with pegylated liposomal doxorubicin (PLD) and bortezomib for patients with relapsed/refractory MM. Patients and Methods: Patients received bortezomib at 1.3mg/m2 on days 1, 4, 8, and 11; PLD at 30mg/m2 on day 4, and escalating doses of vorinostat (200 to 400mg once daily) on days 4 through 11 of a 3-week cycle. Dose escalation followed a standard “3 + 3” design. Patients remained on therapy until disease progression or unacceptable toxicity. Eligibility criteria included an ANC of ≥1.0×109/L, platelets of ≥100×109/L, a CrCl of ≥30 mL/min., and adequate hepatic and cardiac function. The primary objectives of the study were to establish dose limiting toxicities (DLTs) in cycle 1 and the maximum tolerated dose (MTD) for future phase II testing. Results: Nine patients have enrolled thus far at vorinostat dose levels of 200mg (n=3), 300mg (n=4), and 400mg (n=2). Six patients had relapsed disease, while 3 had relapsed disease that was refractory to their last prior therapy. The median age was 56 (range 44–73), median time from diagnosis was 66 months (range 28 to 117), and median prior number of lines of therapy was 2 (1 to 7). Six of 9 patients received prior bortezomib, 3 of whom were refractory, 7 of 9 had received anthracyclines, 9 of 9 were treated with corticosteroids, 8 of 9 were treated with immunomodulatory agents, and 7 of 9 had undergone autologous stem cell transplantation. One patient was removed from the study at the 300mg vorinostat dose level due to a grade 3 infusion reaction with the first dose of PLD and was not evaluable for DLT or response. Otherwise, there have been no DLTs, serious adverse events, or deaths to date. Common non-hematologic toxicities of all grades have included fatigue (44%), constipation (67%), diarrhea (67%), nausea (56%), vomiting (33%), and peripheral neuropathy (56%), the majority of which were grade 1 and 2 in severity. Grade 3 sensory neuropathy was seen in 2 patients. Common hematologic toxicities of all grades have included neutropenia (44%), lymphopenia (44%), and thrombocytopenia (67%). Grade 3/4 neutropenia, lymphopenia and thrombocytopenia were seen in 2, 3, and 2 patients, respectively. Dose reductions for non-hematologic toxicities have been necessary for 3 patients thus far. Using International Myeloma Working Group criteria, 6 out of 7 evaluable patients have responded to treatment, including 1 complete remission (CR), 1 very good partial remission, and 4 partial remissions (PRs). The only non-responder was assigned to the 200mg vorinostat dose level. PRs were seen in 2 of 3 patients with bortezomib-refractory disease. Conclusions: At the dose levels tested thus far, the addition of vorinostat to the PLD/bortezomib backbone is safe and efficacious in relapsed/refractory MM patients, including those with bortezomib-refractory disease. Cumulative constitutional, gastrointestinal, and neurologic toxicities are common but manageable, and will need to be considered when determining the optimal phase II dose moving forward. Enrollment into the 400mg dose cohort continues. Disclosures: Voorhees: Celgene: Speakers Bureau; Millennium Pharmaceuticals, Inc.: Speakers Bureau. Off Label Use: Vorinostat for the treatment of multiple myeloma. Gasparetto:Millennium Pharmaceuticals: Consultancy, Speakers Bureau. Richards:Cephalon, Inc.: Speakers Bureau. Garcia:Millennium Pharmaceuticals: Speakers Bureau; Celgene: Speakers Bureau. MacLean:Novartis: Speakers Bureau. Foster:Genzyme: Consultancy, Research Funding. Shea:Otsuka: Research Funding; Novartis: Consultancy, Research Funding; Millennium Pharmaceuticals: Research Funding; Genzyme: Consultancy, Research Funding; Genetech: Consultancy. Rizvi:Merck: Employment.