ALBERT

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: Abstract 4481 Patients undergoing hematopoietic cell transplantation (HCT) require central venous access during treatment, predisposing this inherently susceptible population to infection. Central line-associated blood stream infection (CLABSI) is defined by the National Healthcare Safety Network as a primary bloodstream infection (BSI) in a patient with a central line within the 48-hour period before the development of the BSI. CLABSI surveillance is being increasingly used as an objective measure of quality of care delivered at individual hospitals. The Centers for Disease Control and Prevention have developed guidelines for the insertion, surveillance, and timely removal of these lines to prevent CLABSI, of which approximately 10% are fatal, and the Centers for Medicare & Medicaid will adjust reimbursement for CLABSI. The incidence, risk factors, and impact on survival of CLABSI in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) patients undergoing HCT has not been reported. AML or MDS patients undergoing HCT between August 2009 and December 2011 were identified from the Cleveland Clinic Unified Transplant Database, and occurrence of CLABSI was determined from the infection control database. Variables analyzed included occurrence of CLABSI, as well as patient demographics, disease type, prior treatment, HCT comorbidity index, transplant type/HLA-match, CD34+ count, and time to neutrophil recovery (absolute neutrophil count 〉500). CLABSI incidence was estimated using Kaplan-Meier method, and univariable and multivariable risk factors were identified by Cox proportional hazards analyses. Of the 73 patients identified, 48 were male; 68 were Caucasian; 44 had AML, and 29 MDS. The median age at transplant was 52 (range 16–70), and 39 had a low to intermediate HCT comorbidity index (0–2), while 34 had a high index (≥3). Patients received a median of 2 prior chemotherapy regimens (range 0–6), 3 had prior radiation, and 6 had prior transplant. Preparative regimen was myeloablative (n=54) or reduced-intensity (n=19); 34 received bone marrow (BM), 24 peripheral stem cells (PSC), and 15 cord blood cells (CBC). The median CD34+ count was 2.42 × 106/kg and median time to neutrophil recovery was 14 days (range 6–24) with BM/PSC compared to 28 days with CBC (range 19–77). Among these 73 patients, 23 (31.5%) developed CLABSI, of whom 16 (69.6%) died. The majority (16/23) of CLABSI occurred within 14 days (median 9 days, range 2–211 days) from HCT (Figure 1), but timing of CLABSI was highly associated with cell source: median of 5 days (range 2–12 days) for CBC and 78 days (range 7–211 days) for BM/PSC (p

Description: Abstract 2015 Allogeneic hematopoietic stem cell transplantation (AlloSCT) remains the only curative option for MDS. Several retrospective studies evaluated the impact of various prognostic factors (i.e. cytogenetic risk group, WHO classification, ferritin level etc.) on post-transplant outcomes of pts with MDS, however comprehensive analyses including a cytogenetic abnormalities detected by SNP array (SNP-A) karyotyping method have not been performed. We have analyzed prognostic factors of post-AlloSCT outcomes among 74 pts with MDS (2000–2010) including the predictive value of SNP-A abnormalities. Cox proportional hazards analysis was used to identify univariable prognostic factors for acute GVHD (aGVHD), chronic GVHD (cGVHD), disease relapse, relapse free (RFS) and overall survival (OS). Multivariable prognostic factors were identified by stepwise Cox proportional hazards analysis. The median time from MDS diagnosis to transplant for all pts was 6 mos (range, 0.2– 141 mos). The median age at transplant was 51 yrs; 32% of the pts had a hematopoietic cell transplant co-morbidity index (HCT-CI) score ≥ 3; 69% had ≥1 prior chemotherapies; and only 30% were in remission prior to their transplant. 27 pts (37%) had RAEB-2, 11 (15%) had RAEB-1, and 9 (12%) had treatment-related MDS. 42 pts (58%) belonged to an intermediate-2 or higher IPSS risk category. 23 pts (31%) had adverse karyotype (complex or monosomy 7) detected by metaphase cytogenetics (MC). SNP abnormalities were identified in 58% of patients; 79% of all patients with SNP abnormalities had lesions not previously detected by traditional cytogenetic techniques. Median pre-transplant ferritin level was 1127 (range, 9–5201). 73% of the pts received myeloablative conditioning. In 61% of cases stem cells were harvested from the bone marrow. Matched related donors accounted for half of the cases. Twelve pts (16%) died within 100 days of transplant and 39 pts (53%) within the median follow up of 36 mos (range, 5–114). MDS relapse occurred in 22 pts (30%). The rates of grade II-IV aGVHD and extensive cGVHD were 49% and 24% respectively. Disease relapse was the most common cause of death (31%) followed by aGVHD (18%) and cGVHD (13%). In univariate analysis, aGVHD was associated with myeloablative (p

Description: Abstract 2356 Introduction: Allogeneic stem cell transplantation (SCT) is commonly offered to patients with acute myeloid leukemia (AML) over the age of 55 with good performance status. For this patient population, potential sibling donors are necessarily older and have more comorbidities than siblings of younger patients. It is not known whether the advanced donor age of older patients outweighs the beneficial effect of having a sibling donor. To address this question, we retrospectively analyzed data from 62 consecutive patients who received allogeneic SCT at the Cleveland Clinic from 1990–2009. Methods: Inclusion criteria were: age ≥ 55 years, diagnosis of AML, and history of myeloablative or nonmyeloablative allogeneic SCT from related or unrelated adult donors. 31 patients underwent transplantation from matched related donors (30 siblings, 1 cousin). 31 patients received unrelated donor transplants. The median age was 59 for patients with related and unrelated donors (P=0.89). There was an equal percentage of males (64.5%) in both groups (P=1.0). There was an equivalent distribution hematopoietic cell transplant comorbidity index scores of low, intermediate and high for patients with related and unrelated donors (38.7%, 37.1% and 24.2% vs. 38.7%, 32.3%, and 29.0% P = 0.65). 45.2% of patients with related donors underwent myeloablative conditioning vs. 54.8% for patients with unrelated donors (P =0.61). Results: Sibling donors were significantly older than unrelated donors [median 59 years (range 41–75) vs. 36 (range 24–58), P 〈 0.001]. The incidence of acute and chronic graft-versus-host disease (GVHD) was similar in both groups. At five years, the cumulative incidence of relapse (43.2% vs. 38.7%, P = 0.88), non-relapse mortality (48.1% vs. 48.8%, P =0.91) and overall survival (17.2% vs. 24.1%, P =0.88) were similar for recipients of matched related and unrelated donor transplants. Older donor age was not predictive of death in univariate or multivariate analysis. Kaplan-Meier estimates of overall survival for recipients of related and unrelated donor transplants are shown. Conclusion: Patients with AML 55 years or older who underwent related donor transplantation had significantly older donors but equivalent survival when compared to patient who underwent unrelated donor transplantation. Advanced donor age should not be a contraindication to allogeneic SCT for older patients with AML. Disclosures: No relevant conflicts of interest to declare.

Description: Regulation of topoisomerase II (TOPO II) isozymes  and β is influenced by the growth and transformation state of cells. Using HL-60 cells induced to differentiate by all-trans retinoic acid (RA), we have investigated the expression and regulation of TOPO II isozymes as well as the levels of topoisomerase I (TOPO I). During RA-induced differentiation of human leukemia HL-60 cells, levels of TOPO I remained unchanged, whereas the levels and phosphorylation of TOPO II and TOPO IIβ proteins were increased twofold to fourfold and fourfold to eightfold, respectively. The elevation of TOPO II ( and β) protein levels and phosphorylation was apparent at 48 hours of treatment with RA and persisted through 96 hours. The increased level of TOPO IIβ protein was also detected in differentiated cells subsequently cultured for 96 hours in RA-free medium. Pulse chase experiments in cells labeled with 35S-methionine showed that the rate of degradation of TOPO IIβ protein in control cells was about twofold faster than that in the differentiated RA-treated cells. The level of decatenation activity of kDNA was comparable in nuclear extracts from control or RA-treated cells. Whereas etoposide (1 to 10 μmol/L) -induced DNA cleavage was not significantly different, apoptosis was significantly lower (P = .012) in RA-treated versus control cells after exposure to 10 μmol/L etoposide. Consistent with unaltered levels of TOPO I, camptothecin (CPT) -induced DNA cleavage was similar in control or RA-treated cells. However, apoptosis after exposure to 1 to 10 μmol/L CPT was significantly lower (P = .003 to P 〈 .001) in RA-treated versus control cells. Results suggest that TOPO IIβ protein levels are posttranscriptionally regulated and that degradation of TOPO IIβ is decreased during RA-induced differentiation. Furthermore, whereas the total level of TOPO II ( + β) is increased with RA, the level of TOPO II catalytic activity and etoposide-stabilized DNA cleavage activity remains unaltered. Thus, TOPO IIβ may have a specific role in transcription of genes involved in differentiation with RA treatment. © 1998 by The American Society of Hematology.

Description: Skin toxicity is a known but understudied complication of autologous stem cell transplantation (ASCT). Its assessment is complicated by the development of graft-vs-host disease following allogeneic transplantation. We chose therefore to study skin toxicity following autologous transplantation. We retrospectively reviewed the records of 392 patients undergoing ASCT to analyze risk factors for skin toxicity, its association with mucositis and its effect on survival. Skin toxicity was assessed three times a week during the transplant admission and was classified as none, mild, moderate, severe or life threatening. The most severe skin toxicity is used in this analysis. Mucositis was assessed using the modified oral mucositis assessment scale (OMAS). Median patient age was 53 years; 63% of patients had non-Hodgkin s lymphoma (NHL), 17.6% multiple myeloma, 13.5% Hodgkin disease (HD) and 5.9% acute leukemia. Peripheral blood progenitor cells were mobilized with G-CSF alone (36%) or the combination of etoposide plus G-CSF (64%). The preparative regimen was busulfan (Bu)/cyclophosphamide (Cy) /etoposide in 82% and Bu/Cy alone in 18%. Two hundred and sixty patients (67%) developed skin toxicity of which 143 patients (36.5%) had mild, 105 (26.8%) had moderate and 16 (3.9%) had severe skin toxicity. Factors associated with the development of any skin toxicity in univariable analysis were male gender (p=0.028), diagnosis of NHL (p

Description: Despite the fact that autologous bone marrow/stem cell transplantation (ABMT) has been successfully used to treat patients with relapsed Non Hodgkin’s Lymphoma (NHL) for over 25 years, few series report follow-up beyond 10 years. We have followed a cohort of 110 NHL patients who underwent ABMT from 9/1988 through 12/1993, all treated with a uniform preparative regimen of CBV (Cyclophosphamide, BCNU, Etoposide (VP-16)). At the present time, 38 (35%) are alive and 72 patients have expired. Among the 38 living patients, the median follow-up is 15 years. NHL histology for all transplanted patients was based on the Working Formulation, and 21% had low grade, 54% intermediate grade, 25% high grade (the majority of the high grade group had diffuse immunoblastic large cell lymphoma). Median age at transplant was 47 years; 85% were sensitive to salvage chemotherapy; 31% had elevated LDH at the time of diagnosis; age adjusted IPI at ABMT was 0 (7%), 1 (56%), 2 (29%), 3 (7%). Multivariable analysis analyzing prognostic factors for survival predictably revealed that sensitivity to chemotherapy, and LDH status at the time of transplant, had significant impact on survival. Additionally, age at transplant was also highly significant (p=0.002). This is shown graphically below: Figure Figure The incidence of low grade histologies was similar for all three groups. The younger group had a lower incidence of relapse mortality, as shown below: Figure Figure It is commonly believed that age is of limited importance with respect to survival after ABMT. However, this data suggests that age may play a very important prognostic role. The causes are not well defined, but the continued relapse and mortality risk may warrant surveillance indefinitely for patients undergoing ABMT for NHL.

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