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.

Primary graft failure after myeloablative allogeneic hematopoietic cell transplantation for hematologic malignancies.

Clinical outcomes after primary graft failure (PGF) remain poor. Here we present a large retrospective analysis (n=23,272) which investigates means to prevent PGF and early detection of patients at high risk. In patients with hematologic malignancies, who underwent their first myeloablative allogeneic hematopoietic cell transplantation, PGF was reported in 1278 (5.5%), and there was a marked difference in PGFs using peripheral blood stem cell compared with bone marrow grafts (2.5 vs 7.3%; P<0.001). A fourfold increase of PGF was observed in myeloproliferative disorders compared with acute leukemia (P<0.001). Other risk factors for PGF included recipient age <30, HLA mismatch, male recipients of female donor grafts, ABO incompatibility, busulfan/cyclophosphamide conditioning and cryopreservation. In bone marrow transplants, total nucleated cell doses ⩽2.4 × 10(8) per kg were associated with PGF (odds ratio 1.39; P<0.001). The use of tacrolimus-based immunosuppression and granulocyte colony-stimulating factor were associated with decreased PGF risk. These data, allow clinicians to do more informed choices with respect to graft source, donor selection, conditioning and immunosuppressive regimens to reduce the risk of PGF. Moreover, a novel risk score determined on day 21 post transplant may provide the rationale for an early request for additional hematopoietic stem cells.

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.

Physician perceptions and practice patterns regarding fertility preservation in hematopoietic cell transplant recipients.

Physician practice variation may be a barrier to informing hematopoietic cell transplant (HCT) recipients about fertility preservation (FP) options. We surveyed HCT physicians in the United States to evaluate FP knowledge, practices, perceptions and barriers. Of the 1035 physicians invited, 185 completed a 29-item web-survey. Most respondents demonstrated knowledge of FP issues and discussed and felt comfortable discussing FP. However, only 55% referred patients to an infertility specialist. Most did not provide educational materials to patients and only 35% felt that available materials were relevant for HCT. Notable barriers to discussing FP included perception that patients were too ill to delay transplant (63%), patients were already infertile from prior therapy (92%) and time constraints (41%). Pediatric HCT physicians and physicians with access to an infertility specialist were more likely to discuss FP and to discuss FP even when prognosis was poor. On analyses that considered physician demographics, knowledge and perceptions as predictors of referral for FP, access to an infertility specialist and belief that patients were interested in FP were observed to be significant. We highlight variation in HCT physician perceptions and practices regarding FP. Physicians are generally interested in discussing fertility issues with their patients but lack educational materials.

Effects of spleen status on early outcomes after hematopoietic cell transplantation.

To assess the impact of spleen status on engraftment, and early morbidity and mortality after allogeneic hematopoietic cell transplantation (HCT), we analyzed 9,683 myeloablative allograft recipients from 1990 to 2006; 472 had prior splenectomy (SP), 300 splenic irradiation (SI), 1,471 with splenomegaly (SM), and 7,440 with normal spleen (NS). Median times to neutrophil engraftment (NE) and platelet engraftment (PE) were 15 vs 18 days and 22 vs 24 days for the SP and NS groups, respectively (P<0.001). Hematopoietic recovery at day +100 was not different across all groups, however the odds ratio of days +14 and +21 NE and day +28 PE were 3.26, 2.25 and 1.28 for SP, and 0.56, 0.55, and 0.82 for SM groups compared to NS (P<0.001), respectively. Among patients with SM, use of peripheral blood grafts improved NE at day +21, and CD34+ cell dose >5.7 × 10(6)/kg improved PE at day+28. After adjusting variables by Cox regression, the incidence of GVHD and OS were not different among groups. SM is associated with delayed engraftment, whereas SP prior to HCT facilitates early engraftment without having an impact on survival.

No increased mortality from donor or recipient hepatitis B- and/or hepatitis C-positive serostatus after related-donor allogeneic hematopoietic cell transplantation.

Limited data exist on allogeneic transplant outcomes in recipients receiving hematopoietic cells from donors with prior or current hepatitis B (HBV) or C virus (HCV) infection (seropositive donors), or for recipients with prior or current HBV or HCV infection (seropositive recipients). Transplant outcomes are reported for 416 recipients from 121 centers, who received a human leukocyte antigen-identical related-donor allogeneic transplant for hematologic malignancies between 1995 and 2003. Of these, 33 seronegative recipients received grafts from seropositive donors and 128 recipients were seropositive. The remaining 256 patients served as controls. With comparable median follow-up (cases, 5.9 years; controls, 6.7 years), the incidence of treatment-related mortality, survival, graft-versus-host disease, and hepatic toxicity, appears similar in all cohorts. The frequencies of hepatic toxicities as well as causes of death between cases and controls were similar. Prior exposure to HBV or HCV in either the donor or the recipient should not be considered an absolute contraindication to transplant.

Palifermin for the reduction of acute GVHD: a randomized, double-blind, placebo-controlled trial.

This prospective, randomized, double-blind, placebo-controlled study evaluated the efficacy of palifermin to reduce the incidence of severe (grade 3-4) acute GVHD after myeloablation and allo-SCT. Adults who received allo-SCT for hematologic malignancies received placebo or palifermin 60 µg/kg daily on three consecutive days before conditioning and a single dose of 180 µg/kg after conditioning, but often 1 or 2 days before allo-SCT. Subjects received MTX (plus CYA or tacrolimus) on days 1, 3, 6 and 11. Acute GVHD was evaluated once weekly and oral mucositis was evaluated daily. Subjects were randomly assigned to placebo (n=78) or palifermin (n=77). Conditioning included TBI in approximately half of the subjects (48% placebo, 51% palifermin). The primary efficacy end point, subject incidence of grade 3-4 acute GVHD, was similar between treatment groups (17% placebo, 16% palifermin). Grade 3-4 oral mucositis (73% placebo, 81% palifermin) and other secondary efficacy end points were similar between treatment groups. The most commonly reported treatment-related adverse events were skin/s.c. events such as rash, pruritus, and erythema. This exploratory study of acute GVHD after myeloablation and allo-SCT did not provide evidence of a treatment effect with this dosing regimen of palifermin.

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.

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.

Comparative analysis of BU and CY versus CY and TBI in full intensity unrelated marrow donor transplantation for AML, CML and myelodysplasia.

We retrospectively compared clinical outcomes in 1593 T-replete unrelated donor (URD) marrow transplant recipients with AML, MDS and CML who received myeloablative conditioning regimens of either BU and CY (BuCy), standard-dose Cy/TBI (1000-1260 cGy) or high-dose Cy/TBI (1320-1500 cGy). Subjects were drawn from patients transplanted between 1991 and 1999 facilitated by the National Marrow Donor Program. Patients who received high-dose Cy/TBI regimens were slightly younger, more likely to receive a mismatched transplant and to have intermediate or advanced disease compared with patients in the BuCy or standard-dose TBI group. Neutrophil recovery was significantly higher in the standard-dose CY/TBI group compared with the high-dose Cy/TBI or BuCy group. Patients who received the high-dose Cy/TBI regimen had an increased risk of developing grades III-IV aGVHD when compared with the control group who received BuCy (P = 0.011). OS, disease-free survival (DFS), TRM and relapse were not significantly different between any of the regimens. We conclude that BuCy, standard-dose and high-dose Cy/TBI regimens have equivalent efficacy profiles for OS, DFS, TRM and relapse risk in patients undergoing T-replete URD marrow transplantation for AML, CML and MDS.

Extracorporeal photopheresis for the prevention of acute GVHD in patients undergoing standard myeloablative conditioning and allogeneic hematopoietic stem cell transplantation.

GVHD is partly mediated by host APCs that activate donor T cells. Extracorporeal photopheresis (ECP) can modulate APC function and benefit some patients with GVHD. We report the results of a study using ECP administered before a standard myeloablative preparative regimen intended to prevent GVHD. Grades II-IV acute GVHD developed in 9 (30%) of 30 recipients of HLA-matched related transplants and 13 (41%) of 32 recipients of HLA-matched unrelated or HLA-mismatched related donor transplants. Actuarial estimates of overall survival (OS) at day 100 and 1-year post transplant were 89% (95% CI, 78-94%) and 77% (95% CI, 64-86%), respectively. There were no unexpected adverse effects of ECP. Historical controls receiving similar conditioning and GVHD prophylaxis regimens but no ECP were identified from the database of the Center for International Blood and Marrow Transplant Research and multivariate analysis indicated a lower risk of grades II-IV acute GVHD in patients receiving ECP (P=0.04). Adjusted OS at 1 year was 83% in the ECP study group and 67% in the historical control group (relative risk 0.44; 95% CI, 0.24-0.80) (P=0.007). These preliminary data may indicate a potential survival advantage with ECP for transplant recipients undergoing standard myeloablative hematopoietic cell transplantation.

Ethical reasoning about patient eligibility in allogeneic BMT based on psychosocial criteria.

Chairpersons of the hospital ethics committees (HECs) and BMT clinicians were compared with regard to their willingness to proceed with allogeneic BMT given select psychosocial risk factors. A self-administered questionnaire was sent to 62 HEC chairpersons at hospitals with an accredited BMT program; the response rate was 37%. Items included background information, followed by six case vignettes from a 2006 national survey on which BMT physicians, nurses and social workers agreed not to proceed with allogeneic BMT on the basis of the following risk factors: suicidal ideation; use of addictive, illicit drugs; history of non-compliance; absence of a caregiver; alcoholism; and mild dementia from early onset of Alzheimer's disease. Opinions regarding transplant differed in one case only, in a patient with mild dementia; 27% of HEC chairpersons recommended not proceeding with BMT, which was significantly lower than that of nurses (68%, P<0.001), physicians (63.5%, P<0.001) and social workers (51.9%, P=0.05). Qualitative data show patterns of informal reasoning, linking transplant decisions to patient's responsibility for their psychosocial risk factor(s), as well as to medical benefit and outcome.

400 cGy TBI with fludarabine for reduced-intensity conditioning allogeneic hematopoietic stem cell transplantation.

Fludarabine and 200 cGy TBI are commonly used for reduced-intensity conditioning preceding allogeneic hematopoietic SCT (HSCT). However, graft rejection and disease relapse are significant causes of treatment failure with this regimen. We modified this regimen by escalating the TBI dose to 400 cGy in 40 patients with hematologic malignancies. Thirty-four patients achieved complete donor T-cell chimerism at a median of 40 days following HSCT. The incidences of grades II-IV and III-IV acute GVHD were 40 and 15%, respectively, whereas that of limited and extensive chronic GVHD were 12 and 20%, respectively. Two patients rejected their grafts and 12 relapsed. The 100-day mortality was 18%, 2-year transplant-related mortality 20% and overall survival was 58% at a median follow-up of 16 months. There were no significant survival differences between patients with lymphoid compared to myeloid malignancies. A dose of 400 cGy TBI administered with fludarabine is well tolerated and further study is needed to determine whether outcomes are superior to those with 200 cGy TBI.

Influence of killer immunoglobulin-like receptor/HLA ligand matching on achievement of T-cell complete donor chimerism in related donor nonmyeloablative allogeneic hematopoietic stem cell transplantation.

Achievement of complete donor chimerism (CDC) after allogeneic nonmyeloablative hematopoietic stem cell transplantation (NMHSCT) is important for preventing graft rejection and for generating a graft-vs-malignancy effect. The alloreactivity of NK cells and some T-cell subsets is mediated through the interaction of their killer immunoglobulin-like receptors (KIRs) with target cell HLA/KIR ligands. The influence of KIR matching on the achievement of T-cell CDC after NMHSCT has not been previously described. We analyzed 31 patients undergoing T-cell replete related donor NMHSCT following fludarabine and 200 cGy TBI. Recipient inhibitory KIR genotype and donor HLA/KIR ligand matches were used to generate an inhibitory KIR score from 1 to 4 based upon the potential number of recipient inhibitory KIRs that could be engaged with donor HLA/KIR ligands. Patients with a score of 1 were less likely to achieve T-cell CDC (P=0.016) and more likely to develop graft rejection (P=0.011) than those with scores greater than 1. Thus, patients with lower inhibitory KIR scores may have more active anti-donor immune effector cells that may reduce donor chimerism. Conversely, patients with greater inhibitory KIR scores may have less active NK cell and T-cell populations, which may make them more likely to achieve CDC.

Long-term outcomes of adults with acute lymphoblastic leukemia after autologous or unrelated donor bone marrow transplantation: a comparative analysis by the National Marrow Donor Program and Center for International Blood and Marrow Transplant Research.

For adults with high-risk or recurrent ALL who lack a suitable sibling donor, the decision between autologous (Auto) and unrelated donor (URD) hematopoietic stem cell transplantation (HSCT) is difficult due to variable risks of relapse and treatment-related mortality (TRM). We analysed data from two transplant registries to determine outcomes between Auto and URD HSCT for 260 adult ALL patients in first (CR1) or second (CR2) CR. All patients received a myeloablative conditioning regimen. The median follow-up was 77 (range 12-170) months. TRM at 1 year post transplant was significantly higher with URD HSCT; however, there were minimal differences in TRM according to disease status. Relapse was higher with Auto HSCT and was increased in patients transplanted in CR2. Five-year leukemia-free (37 vs 39%) and overall survival (OS) rates (38 vs 39%) were similar for Auto HSCT vs URD HSCT in CR1. There were trends favoring URD HSCT in CR2. The long-term follow-up in this analysis demonstrated that either Auto or URD HSCT could result in long-term leukaemia-free survival and OS for adult ALL patients. The optimal time (CR1 vs CR2) and technique to perform HSCT remains an important clinical question for adult ALL patients.

Allogeneic hematopoietic cell transplantation for metastatic breast cancer.

We reviewed 66 women with poor-risk metastatic breast cancer from 15 centers to describe the efficacy of allogeneic hematopoietic cell transplantation (HCT). Median follow-up for survivors was 40 months (range, 3-64). A total of 39 patients (59%) received myeloablative and 27 (41%) reduced-intensity conditioning (RIC) regimens. More patients in the RIC group had poor pretransplant performance status (63 vs 26%, P=0.002). RIC group developed less chronic GVHD (8 vs 36% at 1 year, P=0.003). Treatment-related mortality rates were lower with RIC (7 vs 29% at 100 days, P=0.03). A total of 9 of 33 patients (27%) who underwent immune manipulation for persistent or progressive disease had disease control, suggesting a graft-vs-tumor (GVT) effect. Progression-free survival (PFS) at 1 year was 23% with myeloablative conditioning and 8% with RIC (P=0.09). Women who developed acute GVHD after an RIC regimen had lower risks of relapse or progression than those who did not (relative risk, 3.05: P=0.03), consistent with a GVT effect, but this did not affect PFS. These findings support the need for preclinical and clinical studies that facilitate targeted adoptive immunotherapy for breast cancer to explore the benefit of a GVT effect in breast cancer.

Effect of prior rituximab on high-dose therapy and autologous stem cell transplantation in follicular lymphoma.

Autologous stem-cell transplantation (ASCT) has been used in follicular lymphoma (FL) to achieve durable responses in first remission or in the relapsed or refractory settings. Addition of rituximab to chemotherapy for FL has been shown to improve survival. The impact of prior therapy with rituximab upon the effectiveness of high-dose therapy (HDT) and ASCT in patients with FL is unknown. We retrospectively reviewed consecutive patients with FL who underwent HDT and ASCT. Patients were categorized according to prior therapy with rituximab. Outcomes were compared between groups in all patients and in a well-matched subset. In all 35 patients received prior rituximab and 71 rituximab-naive patients were analyzed. The rituximab-naive group had a median overall survival (OS) that was not reached during follow-up, with a median relapse-free (RFS) survival of 49.9 months. The prior rituximab group also did not reach median OS and had a median RFS of 24.6 months. Survivals were not significantly different in this group or in the well-matched subset. In conclusion, these results suggest that the use of rituximab-based regimens for the treatment of FL does not compromise the effectiveness of HDT and ASCT as a salvage strategy in patients with FL.