Association of socioeconomic status with autologous hematopoietic cell transplantation outcomes for lymphoma.

Socioeconomic status (SES) is an important determinant of disparities in health care. The association of SES with outcomes in autologous hematopoietic cell transplantation (AHCT) has not been described previously. We conducted a retrospective cohort study of 687 AHCT recipients with lymphoma transplanted between 2003 and 2013. Patients were categorized into low (<$50 000/year) and high SES (⩾$50 000/year). A greater proportion of low SES patients lived farther away from our center (median 54 vs 28 miles), belonged to a racial minority (12 vs 3%), had poorer performance status (4 vs 1%) and had high-risk disease at AHCT (9 vs 5%). Median follow-up was 53 months. In univariable analysis, low SES patients had significantly higher relapse mortality and lower OS and PFS. This was confirmed on multivariable analysis for relapse mortality (HR for high vs low SES: 0.74 (95% confidence interval (CI), 0.54-0.99), P=0.05), OS (HR 0.74 (0.58-0.95), P=0.02) and PFS (HR 0.77 (0.63-0.95), P=0.02). In multivariable analysis of ⩾1-year progression-free survivors, high SES patients had better OS (HR 0.73, P=0.05 vs low SES) that was primarily driven by a trend toward lower risk of non-relapse mortality (HR 0.62, P=0.06). SES is associated with outcomes of AHCT in patients with lymphoma.

Association of socioeconomic status with long-term outcomes in 1-year survivors of allogeneic hematopoietic cell transplantation.

The relationship of socioeconomic status (SES) with long-term outcomes in allogeneic hematopoietic cell transplantation (HCT) survivors has not been well described. We studied the association of SES with the outcomes of 283 consecutive allogeneic HCT recipients transplanted between 2003 and 2012 who had survived for at least 1 year in remission. Median annual household income was estimated using Census tract data and from ZIP code of residence. SES categories were determined by recursive partitioning analysis (low SES (<$51 000/year), N=203; high SES (⩾$51 000/year), N=80). In multivariable analyses, low SES patients had higher risks of all-cause mortality (hazard ratio (HR) 1.98, P=0.012) and non-relapse mortality (NRM) (HR 2.22, P=0.028), but similar risks of relapse mortality (HR 1.01, P=0.97) compared with high SES patients. A trend toward better survival and lower NRM for high SES patients with no chronic GVHD was observed; low SES patients without GVHD had similar survival as patients with chronic GVHD. In allogeneic HCT survivors who survive in remission for at least 1 year, SES is associated with long-term survival that is primarily mediated through higher risks of NRM. More research is needed to understand the mechanisms of health-care disparities and interventions to mitigate them.

Prognostic significance of pre-transplant quality of life in allogeneic hematopoietic cell transplantation recipients.

Quality of life (QOL) is an important outcome for hematopoietic cell transplantation (HCT) recipients. Whether pre-HCT QOL adds prognostic information to patient and disease related risk factors has not been well described. We investigated the association of pre-HCT QOL with relapse, non-relapse mortality (NRM), and overall mortality after allogeneic HCT. From 2003 to 2012, the Functional Assessment of Cancer Therapy-Bone Marrow Transplant Scale instrument was administered before transplantation to 409 first allogeneic HCT recipients. We examined the association of the three outcomes with (1) individual QOL domains, (2) trial outcome index (TOI) and (3) total score. In multivariable models with individual domains, functional well-being (hazard ratio (HR) 0.95, P=0.025) and additional concerns (HR 1.39, P=0.002) were associated with reduced risk of relapse, no domain was associated with NRM, and better physical well-being was associated with reduced risk of overall mortality (HR 0.97, P=0.04). TOI was not associated with relapse or NRM but was associated with reduced risk of overall mortality (HR 0.93, P=0.05). Total score was not associated with any of the three outcomes. HCT-comorbidity index score was prognostic for greater risk of relapse and mortality but not NRM. QOL assessments, particularly physical functioning and functional well-being, may provide independent prognostic information beyond standard clinical measures in allogeneic HCT recipients.

Racial differences in allogeneic hematopoietic cell transplantation outcomes among African Americans and whites.

The impact of race on outcome has been identified in a number of cancers, with African Americans having poorer survival compared with whites. We conducted a study to investigate the association of race with allogeneic hematopoietic cell transplant (HCT) outcomes. We identified 789 patients (58 African Americans and 731 whites) who underwent allogeneic HCT for hematologic disorders. There were no significant differences between African Americans and white patients in gender, performance status or comorbidity score. However, African Americans were younger than whites (median 40 years versus 47 years, P=0.003) and were more likely to be in remission at HCT (74% versus 57%, P=0.011), to have an HLA-mismatched donor (36% versus 14%, P<0.001), to have positive donor or recipient CMV serostatus (90% versus 69%, P<0.001) and to have received a cord blood transplant (21% versus 6%, P<0.001). In univariate analysis, African Americans had worse overall survival (OS) (HR 1.41, P=0.026) compared with whites, with no significant differences in acute or chronic GvHD, non-CMV infection or relapse. However, after adjusting for several transplant and disease-related factors in multivariate analysis, the OS difference between African Americans and whites became nonsignificant (HR 1.27, P=0.18). These results suggest that race in and of itself does not lead to worse survival post HCT.

Risk factors for vancomycin-resistant enterococcus bacteremia and its influence on survival after allogeneic hematopoietic cell transplantation.

Vancomycin-resistant enterococcus (VRE) is a well-known infectious complication among immunocompromised patients. We performed a retrospective analysis to identify risk factors for the development of VRE bacteremia (VRE-B) within 15 months after allogeneic hematopoietic cell transplantation (alloHCT) and to determine its prognostic importance for other post-transplant outcomes. Eight hundred consecutive adult patients who underwent alloHCT for hematologic diseases from 1997 to 2011 were included. Seventy-six (10%) developed VRE-B at a median of 46 days post transplant. Year of transplant, higher HCT comorbidity score, a diagnosis of ALL, unrelated donor and umbilical cord blood donor were all significant risk factors on multivariable analysis for the development of VRE-B. Sixty-seven (88%) died within a median of 1.1 months after VRE-B, but only four (6%) of these deaths were attributable to VRE. VRE-B was significantly associated with worse OS (hazard ratio 4.28, 95% confidence interval 3.23-5.66, P<0.001) in multivariable analysis. We conclude that the incidence of VRE-B after alloHCT has increased over time and is highly associated with mortality, although not usually attributable to VRE infection. Rather than being the cause, this may be a marker for a complicated post-transplant course. Strategies to further enhance immune reconstitution post transplant and strict adherence to infection prevention measures are warranted.

Quality of life and outcomes in patients⩾60 years of age after allogeneic hematopoietic cell transplantation.

Hematopoietic cell transplantation (HCT) has become an established standard of care for many older patients with hematologic malignancies. The effect of transplantation on the quality of life (QOL) of older patients, however, has not been well studied. We thus analyzed QOL in patients ⩾60 undergoing an allogeneic HCT compared with patients <60 years. Prospective psychometric instruments were administered to 351 patients who underwent HCT from 2003 to 2010. Psychometric data were assessed longitudinally by validated questionnaires: Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT), Coping Inventory and the Profile of Mood State-Short Form. Patients ⩾60 reported better social (P=0.006) and functional well-being (P=0.05) with FACT assessment, and had better total scores, (P=0.043) across all time points. When adjusted for baseline QOL scores as a covariate, social well-being remained significantly better, whereas the other scores became non-significant. With a median follow-up of 49 months, there were no significant differences in OS, relapse-free survival, relapse or chronic GVHD. This study provides further evidence that advanced age should not be a barrier in the decision to pursue allogeneic HCT. Older patients achieved comparable QOL when compared with younger patients.

Donor T-cell chimerism and early post-transplant cytomegalovirus viremia in patients treated with myeloablative allogeneic hematopoietic stem cell transplant.

BACKGROUND: Cytomegalovirus (CMV) is a common infection after myeloablative allogeneic hematopoietic stem cell transplant (M-alloHSCT). Achievement of complete donor T-cell chimerism (CDC-T) post transplant is a measure of immune reconstitution. We investigated the association between CDC-T post M-alloHSCT and the incidence of CMV viremia. METHODS: We retrospectively reviewed all CMV and chimerism results of 47 patients for the first 6 months post M-alloHSCT. CDC-T was analyzed as a time-varying covariate for association with post M-alloHSCT CMV viremia. RESULTS: CMV viremia occurred in 15 (32%) and CDC-T was achieved in 38 (81%) recipients within the first 6 months post M-alloHSCT. On univariable analysis, increased CMV viremia was seen among patients with CDC-T (hazard ratio 2.81 [P = 0.07, 95% confidence interval = 0.93-8.52]). A 30-day landmark analysis showed that the incidence of CMV viremia at 6 months (regardless of recipient CMV serostatus) was 50% among those who had achieved CDC-T by day 30, and 23% among those who had not (P = 0.06). CONCLUSION: We conclude that shorter time to CDC-T may be associated with higher risk of CMV viremia. If confirmed in a larger cohort, this might be a marker for risk stratification in the management of CMV in this population.

Fludarabine as a risk factor for poor stem cell harvest, treatment-related MDS and AML in follicular lymphoma patients after autologous hematopoietic cell transplantation.

Fludarabine is an effective treatment for follicular lymphoma (FL), but exposure to it negatively impacts stem cell mobilization and may increase the risk of subsequent myelodysplastic syndrome and acute myelogenous leukemia (t-MDS/AML). We hypothesized that the risk that fludarabine imparts to stem cell mobilization and t-MDS/AML would be affected by dose or timing. All patients with FL treated at Cleveland Clinic from 1991 to 2007 with autologous hematopoietic cell transplantation were evaluated. Recursive partitioning analysis was used to explore associations of fludarabine and mitoxantrone dose and timing with poor stem cell harvest and t-MDS/AML. We identified 171 patients, of whom 52 previously received fludarabine. Patients exposed to fludarabine prior to auto-HCT were more likely to require >5 days of leukapheresis (P<0.001) and second stem cell mobilization (P<0.001), especially at a cumulative dose >150 mg/m(2). Univariable risk factors for t-MDS/AML included the number of chemotherapy regimens before auto-HCT, the need for >5 days of leukapheresis to collect CD34+ cells and fludarabine exposure in a dose-dependent manner, particularly when >500 mg/m(2). A cumulative dose of fludarabine >150 mg/m(2) increases the risk for poor stem cell harvests and any exposure increases the risk of t-MDS/AML, with the greatest risk being at doses >500 mg/m(2).

Etoposide plus G-CSF priming compared with G-CSF alone in patients with lymphoma improves mobilization without an increased risk of secondary myelodysplasia and leukemia.

The use of etoposide (VP-16) for stem cell mobilization has been reported as a significant risk factor for the development of therapy-related myelodysplasia/therapy-related AML (tMDS/tAML) after transplantation. We compared the safety and effectiveness of VP-16+G-CSF (VP+G) to G-CSF alone for PBPC mobilization in patients with non-Hodgkin's lymphoma and Hodgkin's lymphoma who underwent autologous transplantation at the Cleveland Clinic and Ohio State University. In the VP+G group, median total CD34+ cells collected were 9.34 × 10(6) per kg (range 0.97-180.89), with 42% of all patients having adequate (2 × 10(6) cells per kg) CD 34+ collection after 2 days of apheresis compared with a median in the G-CSF group of 3.83 × 10(6) per kg (range, 0.72-50.38), with only 16% patients having adequate collection after 2 days (P<0.001). tMDS/tAML occurred in 15 patients (2.3%) in the VP+G and in 12 patients (3.8%) receiving G-CSF alone. (P=0.62). Increased number of days of apheresis was associated with the risk of tMDS/tAML (hazard ratio (HR) 1.19, 95% confidence interval (CI) 1.08-1.30, P<0.001). Priming regimen was not a significant variable for relapse-free survival or OS. The addition of etoposide significantly improves the effectiveness of mobilization at the cost of an increased incidence of neutropenic fever though with no mortalities. There is no evidence of increased incidence of tMDS/tAML in patients receiving VP+G compared with those mobilized with G-CSF alone.

Intravenous compared with oral busulfan as preparation for allogeneic hematopoietic progenitor cell transplantation for AML and MDS.

BU and CY is a common conditioning regimen for allogeneic hematopoietic progenitor cell transplantation (HPCT). I.v. BU is increasingly used in place of the oral formulation for conditioning. We compared the outcomes of 135 consecutively treated AML and myelodysplastic syndrome patients who underwent allogeneic HPCT at our institution with BUCY2 using oral (n=93) or i.v. (n=42) BU, without dose adjustment. The i.v. BU patients had a lower incidence of any severity of oral mucositis (3 versus 55%, P=0.002) and severe mucositis (3 versus 24%, P=0.005). Other post transplant outcomes were comparable between the groups. In all 26 i.v. BU and 33 oral BU patients are alive; however, the median follow-up was significantly longer for the oral BU group. One- and two-year non-relapse mortality for the i.v. BU patients was 21% for both, and for the oral BU group was 23% and 29%, respectively. One- and two-year relapse mortality for the i.v. BU patients was 21% for both, and for the oral BU group was 24% and 29%, respectively. Substituting i.v. for oral BU reduces variability in drug exposure and potentially improves toxicity as suggested by our finding of significantly less oral mucositis and decreased severity with i.v. BU.

p53 independent epigenetic-differentiation treatment in xenotransplant models of acute myeloid leukemia.

Suppression of apoptosis by TP53 mutation contributes to resistance of acute myeloid leukemia (AML) to conventional cytotoxic treatment. Using differentiation to induce irreversible cell cycle exit in AML cells could be a p53-independent treatment alternative, however, this possibility requires evaluation. In vitro and in vivo regimens of the deoxycytidine analogue decitabine that deplete the chromatin-modifying enzyme DNA methyl-transferase 1 without phosphorylating p53 or inducing early apoptosis were determined. These decitabine regimens but not equimolar DNA-damaging cytarabine upregulated the key late differentiation factors CCAAT enhancer-binding protein ɛ and p27/cyclin dependent kinase inhibitor 1B (CDKN1B), induced cellular differentiation and terminated AML cell cycle, even in cytarabine-resistant p53- and p16/CDKN2A-null AML cells. Leukemia initiation by xenotransplanted AML cells was abrogated but normal hematopoietic stem cell engraftment was preserved. In vivo, the low toxicity allowed frequent drug administration to increase exposure, an important consideration for S phase specific decitabine therapy. In xenotransplant models of p53-null and relapsed/refractory AML, the non-cytotoxic regimen significantly extended survival compared with conventional cytotoxic cytarabine. Modifying in vivo dose and schedule to emphasize this pathway of decitabine action can bypass a mechanism of resistance to standard therapy.

Apheresis days required for harvesting CD34+ cells predicts hematopoietic recovery and survival following autologous transplantation.

We sought to determine whether patients requiring more aphereses to obtain adequate numbers of CD34+ cells had delayed hematopoietic recovery following autologous transplantation. We identified 496 consecutive individuals with lymphoma who underwent hematopoietic stem cell mobilization using etoposide and G-CSF and first autologous transplantation. In multivariate analysis, increased apheresis days as a continuous and as a categorical variable at ≥5/<5 days significantly predicted neutrophil recovery. Apheresis days fell just short of significance (P=0.06) as a predictor of platelet recovery in multivariate analysis. Increased apheresis days (as both continuous and categorical variables) were also predictive of treatment-related myelodysplastic syndrome/AML. Patients who underwent ≥5 days of pheresis had significantly worse survival (P=0.001) than patients with less pheresis days owing to significantly higher relapse mortality (P=0.001).

BU- vs TBI-based conditioning for adult patients with ALL.

Evidence suggests an advantage for TBI over BU as a component of conditioning regimens for allogeneic hematopoietic cell transplant in patients with ALL. We have employed both TBI and BU for conditioning in ALL and reviewed our experience to compare outcomes. From July 1989 to June 2008, we identified 86-adult ALL patients treated with either a TBI- or BU-based regimen and transplanted with either a well-matched sibling or unrelated donor. Data including demographics, immunophenotype, disease status and cytogenetic risk were examined by Cox proportional hazards analysis. Patients treated with TBI were older (median age 40 vs 33 years; P=0.018), had a higher-risk cytogenetic profile (P=0.010), were more often transplanted using an unrelated donor (P=0.038) and were treated more recently (P<0.001). There was a significant improvement in EFS (P=0.046), and a trend to improved OS (P=0.08) in patients treated with TBI compared with those treated with BU. However, the advantage for TBI could not be confirmed by multivariable analysis where only disease status retained statistical significance.

Comparison of donor chimerism following myeloablative and nonmyeloablative allogeneic hematopoietic SCT.

Surveillance of hematopoietic chimerism following hematopoietic SCT (HSCT) with nonmyeloablative (NMA) preparative regimens is standard to assess the need for clinical intervention. Monitoring of donor chimerism following HSCT with myeloablative (MA) preparative regimens is, however, not considered useful because engraftment is thought to occur rapidly and consistently. This study compares the timing of donor hematopoietic cell engraftment in patients undergoing NMA conditioning with fludarabine and TBI with those receiving MA conditioning with BU- or TBI-based regimens. Achievement of ≥ 90% donor leukocyte chimerism occurred rapidly and consistently in all three groups and time to achievement of ≥ 90% donor T cells was similar among the three groups (P = 0.57). Achievement of ≥ 90% donor leukocyte chimerism was not associated with risk of acute or chronic GVHD, graft rejection, relapse or all cause mortality in multivariate analyses. Donor T-cell chimerism of ≥ 90% was significantly associated with development of extensive chronic GVHD. The value of routine surveillance of chimerism following any of the preparative regimens used in this study should be reevaluated.

Comparison of outcomes after auto-SCT for patients with relapsed diffuse large B-cell lymphoma according to previous therapy with rituximab.

The standard approach for relapsed diffuse large B-cell lymphoma (DLBCL) involves auto-SCT. However, studies that established this approach were conducted before the inclusion of rituximab (R) with first-line therapy became routine. Whether DLBCL patients (pts) relapsing after first-line chemoimmunotherapy including R derive a comparable benefit from auto-SCT to pts in the pre-R era is unknown. We analyzed outcomes after auto-SCT for relapsed DLBCL among pts receiving initial R and those who did not. We reviewed 257 consecutive pts with relapsed DLBCL treated at our institution with auto-SCT. In all, 226 pts were included in the analysis, of whom 161 had received no R and 65 received R as part of first-line therapy (Planned R). Median OS and relapse-free survival, measured from transplant, were similar between No R vs Planned R groups: 67 vs 44 months (P=0.3) and 25 vs 27 months (P=0.8), respectively. A further analysis was carried out between two cohorts matched by propensity analysis. Again, no differences in outcomes were observed. This suggests that auto-SCT may be equally effective in pts relapsing after first-line therapy including R, and should remain the standard of care for relapsed DLBCL.