ALBERT

Description: Background We hypothesized lenalidomide (len) related diarrhea (LRD) may correlate with activation of an immune response against multiple myeloma (MM) based on colon biopsies that showed crypt apoptosis reminiscent of GVHD in 3 MM patients with severe LRD but without prior allogeneic stem cell transplantation or gastrointestinal disorder. To investigate whether survival may be influenced by the presence of LRD we performed a retrospective chart review. Methods Patients who developed symptomatic MM on or after 1/1/2005 as defined by the start of anti-MM therapy and had been on len for at least 6 consecutive months by 12/31/2010 were included in the analysis. Significant LRD was considered present if the treating physician attributed the diarrhea to len and recommended supportive therapy in at least two clinic notes.  The first time treatment for LRD was recommended was used as the date of onset of LRD. As possible confounding factors age at the start of len therapy, number of prior regimens, prior high dose chemotherapy with autologous stem cell transplant (ASCT), and use of antineoplastic agents other than corticosteroids at any time during the continuous len therapy were collected. The primary outcome was overall survival (OS), which was calculated from the start of len. Fisher’s exact test, Mann-Whitney test, and the logrank test were used to compare characteristics and duration of len between patients with and without LRD. Proportional hazards models were used to assess the impact of LRD on OS. The lag between the start of len and development of LRD was accounted for by treating LRD as a time-varying covariate in these models. Results 161 patients were identified, 47 (29%) had LRD, and 59 (37%) died during follow up. LRD and no LRD groups were balanced for gender, age, number of prior regimens, prior transplant, and use of antineoplastic agents other than corticosteroids with len, but len treatment duration differed; LRD patients had received a median of  43.4 consecutive months of len (range 5.8-82.9) compared to 14.6 (range 5.9-89) for patients without LRD (p=0.001). Onset of LRD occurred after a median of 17.7 months (range 0.3-75.4) of len therapy. In multivariable analyses, development of LRD (HR 0.46, 95% C.I. 0.21-1.00, p=0.05) was associated with improved OS as were the number of prior therapies (0-2, vs 〉2, HR 0.16, 95% C.I. 0.08-0.32, p

Description: Although outcomes after allogeneic hematopoietic cell transplantation (alloHCT) for AML have improved, this has mainly been attributed to a reduction in transplant-related mortality rather than reduced leukemia relapse. NK cell alloreactivity is regulated by inhibitory and activating signals mediated through cell-surface receptors including the killer immunoglobulin-like receptors (KIRs). Group A and B KIR haplotypes have distinct centromeric (Cen) and telomeric (Tel) gene-content motifs and donor Cen group B KIR haplotypes have been reported to be associated with decreased relapse and improved survival in AML patients undergoing unrelated donor alloHCT. We hypothesized that donor KIR genotype may also be predictive of outcomes after matched related donor (MRD) alloHCT. We evaluated 93 AML patients in CR1/CR2 who underwent T-cell replete alloHCT using HLA- matched related donors at our institution from 1/2000-3/2013. Sixty-six had myeloablative conditioning (MAC) that that was busulfan/cyclophosphamide-based and 27 had reduced-intensity conditioning (RIC) with fludarabine/total body irradiation or busulfan/fludarabine. Donors were KIR genotyped to assign haplotypes A/A vs. B/X and the distinctive Cen and Tel gene-content motifs of group A and B KIR haplotypes according to the presence or absence of one or more B haplotype-defining KIR genes. KIR B–content score for each KIR genotype was defined as the number of Cen and Tel gene-content motifs containing B haplotype–defining genes (range, 0-4). As compared to those with haplotypes B/X (n=40; B content scores of 1-4) those with haplotype A/A (n=25; B content score of 0) undergoing MAC had significantly lower 100-day, 6-, 12- and 24-month non-relapse mortality (NRM) (8% vs. 0%, 13% vs. 0%, 15% vs. 0%, 25% vs. 0%, respectively, Figure 1) which was confirmed on multivariable analysis (HR 9.19, p=0.03). There were no differences between these groups regarding patient and transplant-related characteristics, or for acute or chronic GVHD, relapse, or survival. The causes of death in the group with haplotypes B/X were most commonly attributed to infection and then GVHD. However, within the group with B/X haplotypes, the B motif content score (1-4) was not associated with significant differences in NRM (HR 0.79, p=0.56). No difference in outcomes was observed for those undergoing RIC. The number of donor activating KIR genes (2SD1, 2DS2, 2DS3, 2DS4, 2DS5, and 3DS1) was then assessed. As compared to those with 3-6 activating KIR genes (n=20) those with 0-2 (n=41) undergoing MAC had significantly lower 100-day, 6-, 12- and 24-month non-relapse mortality (NRM) (15% vs. 0%, 15% vs. 5%, 15% vs. 5%, 29% vs. 8%, respectively, Figure 2) which was confirmed on multivariable analysis (HR 4.07, p=0.01). There were no differences in other post-transplant outcomes when comparing these groups or when considering those undergoing RIC. An increase of 1 donor activating KIR also was highly associated with NRM (HR 1.37, p=0.008). Overall, these results suggest that in the MRD MAC alloHCT setting donor KIR genotype may be predictive of increased NRM risk, particularly for those with B/X haplotypes and greater numbers donor activating KIRs. No comparable effects were observed in the RIC setting. Future strategies to further enhance immune reconstitution post-transplant may be appropriate to pursue for these higher risk patients. These results may have potential implications to improve donor selection for those AML patients with multiple HLA-matched related donors and need to be validated in larger cohorts. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.

Description: Background Information is limited on the efficacy and long-term tolerability of weekly ubcutaneous (SC) bortezomib (BTZ), especially when given alone or combined only with glucocorticoids. We implemented use of SC BTZ in 12/2010 and based on equal AUC and efficacy with twice a week SC as IV BTZ (Moreau et al. Lancet Oncology 2011) at reduced but still significant neurotoxicity allowed weekly SC, maintaining the BTZ starting dose at 1.3mg/m2. Methods Multiple myeloma (MM) and AL amyloidosis (ALA) patients (pts) who had received SC BTZ by February 2013 were identified from our plasma cell disorder registry. After IRB approval, their electronic medical records were reviewed for occurrence, severity, and evolution of PNP with each BTZ containing regimen, administration schedule of BTZ, presence of underlying PNP and neuropathy risk factors (diabetes mellitus, ESRD, spinal cord compression/disease, vitamin B12 deficiency, alcoholism, chronic liver disease, hyperlipidemia, hypothyroidism), concurrently used antineoplastic agents, physician assigned responses, and reasons for BTZ dose reductions or discontinuation. To compare first BTZ regimen administration schedules Fisher’s exact test and chi-square tests were used for categorical data, Kruskal-Wallis and Wilcoxon rank sum test for age and interval from diagnosis to treatment, and logrank test for treatment duration. Proportional hazards models were used to assess the impact of BTZ administration schedule on neuropathy and response. The impact of prior regimens before first BTZ administration on response was estimated by logistic regression models. Results 136 patients were identified, 12 were excluded due to insufficient data (not followed at our Center). The remaining 124 pts began their first BTZ regimen between 02/2005 and 02/2013. 81% had MM, 12 % ALA, and 7% both MM and amyloidosis. Patients received a median of 2 BTZ containing regimens (range 1-9); overall 312 BTZ regimens were analyzed. In 114 SC weekly, 32 SC twice a week, 59 IV weekly, 62 IV twice a week, and 11 twice a week SC/IV followed by weekly BTZ regimens, neuropathy led to BTZ discontinuation in 7.9% (n=9), 9.4% (n=3), 13.6% (n=8), 22.6% (n=14), 9.1% (n=1), respectively, and to dose reduction in 5.3% (n=6), 3.2% (n=1), 6.8% (n=4), 6.5% (n=4), 9.1% (n=1), respectively. Patients who received weekly SC BTZ as their first BTZ containing regimen (n=37) had received a median of 0 prior regimens (range 0-10), 27% (n=10) had mild (n=8) or severe (n=2) underlying neuropathy, and most (68%) received BTZ with only glucocorticoids (n=23) or alone (n=2), while lenalidomide (n=8) or other agents (n=4) were added to 32%. After a median treatment duration of 4.3 months (0.2-23.3+), 26 of these 37 pts (70%) developed no neuropathy (n=20) or no worsening of pre-existing neuropathy (n=6), but 7 (19%) required BTZ dose reduction (n=2) or supportive medications (n=5) for neuropathy and in 4 (11%) BTZ was discontinued because of neuropathy. In multivariable analyses for neurotoxicity and lack of response, use of schedules other than weekly SC as the first BTZ administration schedule caused more neuropathy (HR 2.3, 95% C.I. 1.0-5.3, p=0.05), while age and underlying disease associated with neuropathy had no impact (p=0.57 and 0.61, respectively); lack of response tended to be more common with schedules other than weekly SC (HR 2.0, 95% C.I. 0.9-4.5, p=0.09) but age and disease (MM vs. AL amyloid) did not affect response (p=0.33 and 0.32, respectively). A response rate of 71% (n=22) to the first SC weekly bortezomib containing regimen in 37 pts who had received a median of 0 (range 0-10) previous regimens was within the expected range for standard administration schedules; of 8 pts who received weekly SC BTZ with not more than a total of 40mg dexamethasone per week as upfront therapy for myeloma, 5 achieved VGPR, 1 PR, and one MR; in 6 evaluable AL amyloid patients this upfront treatment led to VGPR in 3 and PR in 1 patient. Conclusions Weekly SC BTZ, even if administered only with glucocorticoids, is effective and better tolerated than other BTZ administration schedules. However, neuropathy continues to impact therapy, affecting about a third of patients in our series who received BTZ for the first time. Disclosures: Off Label Use: Upfront weekly SC bortezomib. Faiman:Onyx: Consultancy, Speakers Bureau; Millennium: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau. Valent:Millennium: Speakers Bureau; Clegene: Speakers Bureau. Duong:Celgene: Honoraria, Research Funding. Reu:Onyx: Speakers Bureau; Celgene: Research Funding.

Description: Background: HuLuc63 is a humanized monoclonal antibody directed against CS1 that has demonstrated potent in vivo and in vitro activity against myeloma cells in pre-clinical models. CS1 is a cell surface glycoprotein expressed at high levels on myeloma cells, plasma cells and to a lesser extent on a subset of CD8 + lymphocytes and natural killer (NK) cells. A Phase I study was initiated to evaluate the maximum tolerated dose (MTD) of HuLuc63 in a population of relapsed refractory multiple myeloma patients who have been exposed to at least two prior therapies. In a traditional phase 1 design, six potential dosing cohorts are planned with 3 to 6 patients enrolled per cohort to evaluate safety, pharmacokinetics (PK), biologic activity and clinical response. Each course of HuLuc63 is given IV at the same dose every 2 weeks for a total of 4 doses at a level of 0.5, 1, 2.5, 5, 10, 20 mg/kg. An additional 4 doses may be administered if the patient has demonstrated at least stable disease during the initial course of therapy. To date, a total of 7 patients have been treated at 2 dose levels; 3 in the 0.5 mg/kg cohort and 4 in the 1.0 mg/kg cohort. Median patient age is 64 years and the median number of prior therapies is five. An additional patient was enrolled in the 1.0 mg/kg cohort as a patient in that cohort had a 2-week delay in receiving his second dose due to worsening pain at the site of a pre-existing lytic bone lesion. No dose-limiting toxicities have occurred. Infusions were well tolerated, with grade 1 and 2 toxicities occurring during or after the first dose including chills (2 patients), flushing, pyrexia, rigors, dyspnea and fatigue. Patients who reported first dose reactions were pretreated with acetaminophen and diphenhydramine prior to subsequent doses and only one patient reported fatigue after the second dose. Four serious adverse events have occurred in 2 patients which were considered unrelated to HuLuc63. These include migraine headache (twice in the same patient), congestive heart failure and hypercalcemia. Two patients discontinued therapy prematurely due to progressive disease but all other patients have received 4 doses of HuLuc63. No clinical responses have been observed. In xenograft mouse models, a consistent drug level of 10 mcg / mL was required to show minimal biologic activity. Preliminary PK data reveals that peak serum drug levels for the 0.5 mg/kg dosing cohort reached 10 mcg / mL, which was sufficient to achieve CS 1 saturation of at least 70% on the antigen rich NK cell subset. Drug levels dropped below 1 mcg/mL by day 7, however, coinciding with a decrease in saturation. This indicates that the higher doses to be used in subsequent cohorts may achieve and surpass sustained concentrations in patients above this level. Thus far, HuLuc63 appears to be well tolerated in patients with multiple myeloma. Enrollment is continuing to determine the MTD.

Description: Advances in supportive care have reduced early treatment related mortality with ASCT to approximately 1%. Registry data has shown that relapse is the cause of treatment failure in approximately 80% of patients. However, non-relapse mortality (NRM), over time, affects 20% of transplant recipients. Delayed NRM is poorly studied. To characterize the factors associated with NRM, we reviewed 1573 consecutive autologous transplants performed at the Cleveland Clinic from 1/1992 through 12/2005. This analysis included only adult patients (pts) receiving peripheral stem cells, busulfan based preparative regimens, single transplants, and diagnoses of NHL, HD and MM (n = 856). The median age was 49, 62% were male, and 30% received prior radiation therapy. The most common number of prior chemotherapy regimens was 2 (48%); the primary diagnosis was NHL (67%), HD (18%), MM (15%); and 90% had sensitive disease at the time of transplant. 471 (55%) are alive and 385 (45%) have died. Relapse was the most common cause of death, occurring in 303 (79%) patients. Non-relapse mortality occurred in 82 patients (21% of deaths). The most common cause of NRM was pulmonary toxicity, occurring in 26 patients, followed by secondary malignancy in 19 pts, infection (12 pts), cardiac toxicity (7 pts), other organ failure (7 pts), and other causes (11 pts). Patients who died from secondary malignancy were significantly more likely to have received prior radiation therapy (p = 0.004), to require more days of pheresis to collect stem cells (p

Description: Despite successful outcomes for many patients (pts) with relapsed or refractory Hodgkin lymphoma, disease recurrence leads to a significant number of treatment failures after high-dose chemotherapy with autologous stem cell transplantation (ASCT). Using a prospectively maintained database, a retrospective analysis was conducted in 245 consecutive pts who underwent ASCT for Hodgkin lymphoma from 1985 through 2005 at the Cleveland Clinic Foundation. Objectives were to identify risk factors and outcomes associated with early relapse (within 1 year post ASCT) versus late relapse (over 1 year post ASCT). Patient characteristics: male gender in 64%; median age, 34 years (range, 18–70); median time from diagnosis to transplant, 22 months (4–327); Karnofsky score 〉 80 in 89%; median 2 prior regimens (1–4); prior XRT in 52%; bulky disease 〉 10 cm in 20%; stage III-IV in 62%; disease status of CR1/PR1 in 8%, CR2/PR2 in 69%, refractory in 11%, other in 12%; preparative regimen of BuCyVP in 65%, CBV in 26%, TBI/others in 9%. Median follow-up after ASCT for all pts was 35 months (0–223); for surviving pts, 74 months (3–223). Relapse occurred in 115 pts; 5-year estimated relapse-free survival was 36%, and 5-year estimated relapse rate was 44%. Early relapse occurred in 72 pts and was associated with poor survival (median 13.8 months), with only 5 of these pts surviving at least 5 years. Late relapse occurred in 43 pts and was characterized by markedly better median survival of 57.9 months. Among these pts, 20 survived for 5 or more years post ASCT, and 2 survived more than 10 years. Survival after Early versus Late Relapse Following ASCT Survival Rate 1-Year 2-Year 3-Year 5-Year 10-Year Median Survival P Kaplan-Meier estimates of survival following ASCT. Early Relapse 56% 40% 21% 9% 0% 13.8 months

Description: Patients who undergo high-dose chemotherapy with autologous stem cell transplantation (ASCT) for Hodgkin lymphoma routinely undergo surveillance for post-transplant recurrence. Follow-up schedules after ASCT are based largely upon expert opinion rather than data. To formally describe the evolution of recurrence risk over time for Hodgkin lymphoma after ASCT, we used a prospectively maintained database to retrospectively evaluate the outcomes of 245 patients who underwent ASCT for Hodgkin lymphoma at the Cleveland Clinic Foundation from 1985 through 2005. Patient characteristics: male gender in 64%; median age, 34 years (range, 18–70); median time from diagnosis to transplant, 22 months (4–327); Karnofsky score 〉 80 in 89%; median 2 prior regimens (1–4); prior XRT in 52%; bulky disease 〉 10 cm in 20%; stage III-IV in 62%; disease status of CR1/PR1 in 8%, CR2/PR2 in 69%, refractory in 11%, other in 12%; preparative regimen of BuCyVP in 65%, CBV in 26%, TBI/others in 9%. Median follow-up after ASCT for all pts was 35 months (0–223); for surviving pts, 74 months (3–223). At 5 years, estimated overall survival and relapse-free survival were 47% and 36%, respectively. Relapse occurred in 115 pts, with 5-year relapse rate estimated at 44% (Figure). Figure Figure Landmark analyses were conducted to estimate long-term outcomes for patients in remission at various times after ASCT, as shown in the Table: Duration of Remission after ASCT Long-Term Likelihood of Continued Remission 1 year 63.8% 2 years 78,8% 3 years 83.0% 5 years 97.0% These data illustrate the declining threat of relapse that faces patients who achieve remission following ASCT for Hodgkin lymphoma. Most patients who are destined to experience disease recurrence after ASCT do so within the first 2 years post-transplant. Patients who remain in remission 5 years after ASCT are at extremely low risk for subsequent relapse and can be reassured that they are likely cured. This analysis provides a factual basis to support gradually decreasing the frequency of surveillance visits and to discontinue routine monitoring for relapse at 5 years after ASCT.

Description: Broad spectrum antibiotics are sometimes used prophylactically during the neutropenic phase of stem cell transplantation, but this practice is controversial. Possible benefits include the prevention of fever and infectious episodes. Possible disadvantages include increased usage of antibiotics with associated increases in cost, toxicities and development of antibiotic resistance. OBJECTIVE: To compare prophylactic (PRO) administration of ceftazidime at the beginning of neutropenia (ANC

Description: The addition of R to first line chemotherapy regimens for DLBCL has resulted in improvements in DFS and OS. HDT and ASCT have been shown to improve outcome for pts with relapsed DLBCL compared with conventional dose salvage regimens. The effectiveness of HDT and ASCT in pts with DLBCL who have received prior therapy including R is unknown. We reviewed 257 consecutive pts with DLBCL treated with ASCT from 1/94–12/02. Of these, 161 (63%) had received R as part of their initial therapy and 65 (25%) had not received prior R. A third group (N = 31, 12%) who had been treated with R as part of salvage therapy prior to ASCT were excluded from further analysis. Patient characteristics are shown in Table 1. All patients received a preparative regimen of Busulfan, Cyclophosphamide, and Etoposide. Greater than 75% of patients in both groups had evidence of disease at time of transplant. Univariable and multivariable analyses demonstrated no difference between the pts previously treated with R and those not treated with R. After median follow up of 76 months (13–142) no statistical difference in DFS or OS was observed between the two groups. Patients were then adjusted for age, gender, stage, prior chemotherapy/radiation, time from diagnosis to CR, IPI, and disease status and compared again. The matched propensity analysis also showed no significant difference in DFS (p=0.87) and OS (p=0.22) (Figures 1 and 2). Despite concerns that pts with DLBCL previously treated with regimens containing R may have more resistant disease at relapse, our results suggest that HDT and ASCT is equally effective for these pts compared with those who have not received prior R. A prospective analysis is needed to confirm these results. Table 1. Patient Characteristics Categories No Rituximab (n=65) Rituximab (n=161) Age-median (range) 48 (19–70) 53 (23–72) Gender (M/F) 42/23 93/68 Stage IV (n) 75% (49) 61% (98) Prior Chemo Regimens-median (range) 2 (1–4) 2 (1–6) Prior Radiation (n) 25% (16) 32% (51) IPI (Low/Low-Intermediate vs High-Intermediate/High) 66% vs 34% 55% vs 45% CD34 collection (x 10^6)-median (range) 8.3 (2.9–39.2) 4.4 (0–52.8) Time to Transplant (mos)-median (range) 14.7 (2.8–274.3) 14.5 (5.1–192.6) Diffuse Large B-cell Lymphoma - Matched Groups Diffuse Large B-cell Lymphoma - Matched Groups Diffuse Large B-cell Lymphoma - Matched Groups Diffuse Large B-cell Lymphoma - Matched Groups