Morbidity and Mortality Differences Between Hematopoietic Cell Transplantation Survivors and Other Cancer Survivors.

Purpose To compare the risks of serious health outcomes among hematopoietic cell transplantation (HCT) survivors versus a matched population of patients with cancer who did not undergo HCT, where the primary difference may be exposure to HCT. Methods Two-year HCT survivors treated at a comprehensive cancer center from 1992 through 2009 who were Washington State residents (n = 1,792; 52% allogeneic and 90% hematologic malignancies) were frequency matched by demographic characteristics and underlying cancer diagnosis (as applicable) to non-HCT 2-year cancer survivors, using the state cancer registry (n = 5,455) and the general population (n = 16,340) using driver's license files. Late outcomes for all three cohorts were ascertained from the state hospital discharge and death registries; subsequent cancers were ascertained from the state cancer registry. Results After median follow-up of 7.1 years, HCT survivors experienced significantly greater rates of hospitalization compared with matched non-HCT cancer survivors (280 v 173 episodes per 1,000 person-years, P < .001) and greater all-cause mortality (hazard ratio [HR], 1.1; 95% CI, 1.01 to 1.3). HCT survivors had more hospitalizations or death with infections (10-year cumulative incidence, 31% v 22%; HR, 1.4; 95% CI, 1.3 to 1.6) and respiratory complications (cumulative incidence, 27% v 20%; HR, 1.4; 95% CI, 1.2 to 1.5). Risks of digestive, skin, and musculoskeletal complications also were greater among HCT versus non-HCT cancer survivors. The two groups had similar risks of circulatory complications and second cancers. Both HCT and non-HCT cancer survivors had significantly greater 10-year cumulative incidences of all major organ-system outcomes versus the general population. Conclusion History of HCT was associated with late morbidity and mortality among cancer survivors. In particular, clinicians who care for HCT survivors should be aware of their high rates of late respiratory and infectious complications.

'Open Window': a randomized trial of the effect of new media art using a virtual window on quality of life in patients' experiencing stem cell transplantation.

OBJECTIVES: To measure the psychological effect of an art intervention on hospitalized patients and explore benefits to their quality of life. METHODS: We conducted a large prospective randomized trial between July 2006 and August 2009 of an art intervention, Open Window (OW), in patients undergoing stem cell transplantation for a hematological malignancy compared with a control group. The primary endpoint measured the effect of an art intervention on levels of anxiety, depression, and stress using the Hospital Anxiety and Depression Scale and the Distress Thermometer. The secondary endpoint measured the influence of OW on patients' experiences of stem cell transplantation using the OW survey and expectations questionnaires. RESULTS: Of the 199 patients in the study, 96 were randomized to the intervention group and 103 to the control group. Participants in the intervention group had significantly reduced levels of anxiety on the day before transplant (p = 0.001), at day 7 (p = 0.041), and day 60 (p = 0.035). There was a significant reduction in depression before transplant (p = 0.022). Participants in the intervention group reported better experiences (p < 0.005). Qualitative data showed that those in the intervention group commented freely on their likes and dislikes about OW and how it made them feel. CONCLUSION: An art intervention, OW, had a positive influence on health-related quality of life and patients' experiences of having a stem cell transplant.

The effect of zinc sulfate in the prevention of high-dose chemotherapy-induced mucositis: a double-blind, randomized, placebo-controlled study.

The purpose of this study was to evaluate the effect of oral zinc sulfate in the prevention of chemotherapy-induced mucositis in patients undergoing hematopoietic stem-cell transplantation (HSCT). This study was a double-blind, randomized, placebo-controlled design, with 60 patients undergoing HSCT, divided proportionally in experimental group who received zinc sulfate, and in placebo group. They all had received high-dose chemotherapy conditioning regimen for allogenic transplantation. Oral mucositis assessed was based on World Health Organization (WHO) oral mucositis scale. There were no significant differences in the development of mucositis between the two groups. Severity of mucositis was not significantly different between the two groups either. The same result was obtained regarding the duration of mucositis. Zinc sulfate did not show any significant adverse effects in experimental group. In conclusion, Zinc sulfate did not have any clinical benefits in prevention or reduction of severity, and duration of high-dose chemotherapy-induced mucositis in patients undergoing HSCT.

Efficacy and safety of ciprofloxacin for prophylaxis of polyomavirus BK virus-associated hemorrhagic cystitis in allogeneic hematopoietic stem cell transplantation recipients.

Polyoma virus BK-induced hemorrhagic cystitis is an important cause of morbidity after hematopoietic stem cell transplantation (HSCT). Fluoroquinolones have been shown in vitro to inhibit BK viral replication by direct inhibition of the BK-encoded DNA gyrase. We hypothesized that extended prophylaxis with ciprofloxacin may decrease the incidence of severe (grades 3 and 4) BK virus-associated hemorrhagic cystitis (sBKHC) after HSCT. We retrospectively collected patient and transplant data, as well as incidence of sBKHC, for all consecutive patients undergoing allogeneic HSCT between June 2006 and August 2010 at our institution. Prophylaxis for sBKHC with ciprofloxacin 500 mg orally twice daily from day 0 until day 60 had been instituted in March 2009, delimiting a group receiving ciprofloxacin prophylaxis (CP) or no prophylaxis (NP). We compared the cumulative incidence of sBKHC in CP and NP, including death in absence of sBKHC as a competing risk. Ninety-two consecutive patients were included in the analysis, 44 in CP and 48 in NP. Median age of patients was 50 years (range: 19-70), and 47% received a myeloablative conditioning regimen. The cumulative incidence of sBKHC was significantly reduced in CP (2.6% versus 20.9%, P = .01). Multivariate Cox regression analysis revealed that assignment to CP and concomitant acute graft-versus-host disease (GVHD) were the only factors independently associated with the occurrence of sBKHC. Patients in CP did not experience a higher risk of Clostridium difficile diarrhea and were less likely to develop episodes of bacteremia. Ciprofloxacin prophylaxis appears safe and effective in reducing the incidence of severe BKHC after allogeneic HSCT.

Phase I study of high-stringency CD8 depletion of donor leukocyte infusions after allogeneic hematopoietic stem cell transplantation.

BACKGROUND: Donor leukocyte infusions (DLI) are given after hematopoietic stem-cell transplantation to eradicate persistent tumor or correct mixed chimerism (MC). The drawback of DLI is the risk of graft-versus-host disease (GVHD). In this phase I study, we examined the potential of highly extensive CD8 depletion of DLI as a means of improving its safety profile. METHODS: High-stringency immunomagnetic CD8 depletion of DLI was performed after steady state donor apheresis. Patients with persistent disease or MC received escalated dose CD8-depleted DLI at 3-month intervals starting from 6 months posttransplantation. The starting dose was 1 x 10(6) CD4 cells/kg in recipients of unrelated and 3 x 10(6) CD4 cells/kg in recipients of related donor transplantations. RESULTS: Twenty-eight patients received CD8-depleted DLI (n=16 unrelated or mismatched, n=12 human leukocyte antigen-identical sibling). Median CD8 depletion was more than 4 log. The median overall dose of CD4+ cells/kg given was 4 x 10(6) (range 1 x 10(6)-43 x 10(6)). Conversion from MC to full donor chimerism was observed in 8 of 16 evaluable patients, and disease responses occurred in 5 of 11 patients (complete response in four and partial response in one). Five of 28 patients developed severe acute pattern (grade II-IV) GVHD. Two patients died as a result of complications relating to GVHD. CONCLUSIONS: Graft-versus-tumor effects can be observed after high-stringency CD8-depleted DLI, although the major toxicity remains GVHD in this high-risk patient group. The safety and efficacy profile of this approach will require testing in a randomized controlled study.

Novel antifungal agents as salvage therapy for invasive aspergillosis in patients with hematologic malignancies: posaconazole compared with high-dose lipid formulations of amphotericin B alone or in combination with caspofungin.

In patients with hematologic malignancy, invasive aspergillosis continues to be associated with high mortality even when treated with conventional antifungal therapy. To investigate novel antifungal agents, we compared 53 patients who received posaconazole salvage therapy to 52 contemporary control patients who received high-dose lipid formulation of amphotericin B (HD-LPD/AMB at > or = 7.5 mg kg(-1) per day) and 38 other control patients who received caspofungin plus HD-LPD/AMB. Patients in the three groups had similar. The overall response rate to salvage therapy was 40% for posaconazole, 8% for HD-LPD/AMB (P < or = 0.001) and 11% for combination therapy (P < 0.002). Aspergillosis contributed to the death of 40% of posaconazole group, 65% of the HD-LPD/AMB group and 68% of the combination group (P < or = 0.008). By multivariate analysis, posaconazole therapy independently improved response (9.5; 95% confidence interval, 2.8-32.5; P < 0.001). HD-LPD/AMB alone or in combination was associated with a significantly higher rate of nephrotoxicity (P < or = 0.02) and hepatotoxicity (P < 0.03). In conclusion, posaconazole salvage therapy demonstrated greater efficacy and safety than HD-LPD/AMB alone or in combination with caspofungin in the salvage therapy of invasive aspergillosis in hematologic malignancy.

Function of the hypothalamic-pituitary-gonadal axis in long-term survivors of hematopoietic stem cell transplantation for hematological diseases.

Gonadal dysfunction in adult long-term survivors of hematopoietic stem cell transplantation (HSCT) is an adverse effect of conditioning regimens consisting of chemotherapy and total body irradiation (TBI). The impact of conditioning regimens consisting of chemotherapy alone on the function of the hypothalamic-pituitary-gonadal (HPG) axis was evaluated in a series of 41 female and 31 male patients who had undergone either autologous or allogeneic bone marrow/peripheral blood stem cell transplantation; mean age at transplantation was 32.6 years and mean time interval from transplantation was 1.5 years (range 0.2-9.8 years). Provocative testing of the HPG axis by administration of luteinizing hormone-releasing hormone was included in the first endocrinological evaluation. The follow-up period extended to three consecutive years. Gonadal dysfunction was not reported by any of the patients prior to their underlying illness. Hypergonadotrophic hypogonadism was observed in 97% of female and 19% of male patients. Leydig cell strain (normal testosterone, high luteinizing hormone levels) was evident in 32% and spermatogenesis damage (high follicle-stimulating hormone levels) in 68% of the male population. At the conclusion of the study four women (10%) had regained spontaneous menses and all hypogonadal men had resumed normal testosterone levels. Our results indicate a high incidence of gonadal dysfunction due to target organ failure in HSCT recipients not treated by TBI.

CD34+-enriched peripheral blood progenitor cells from unrelated donors for allografting of adult patients: high risk of graft failure, infection and relapse despite donor lymphocyte add-back.

Fifty-one adults with haematological malignancies were transplanted with CD34+-selected peripheral blood progenitor cells (PBPC) from unrelated donors. The conditioning protocol contained total body irradiation (n = 17) or combinations of busulphan and other alkylating agents (n = 34). Antithymocyte globulin was infused in all patients. The median number of CD3+ T cells infused with the graft after purification with the Isolex 300 system in the first cohort of 18 patients was 2.1 x 10(5)/kg. Prophylactic donor lymphocyte infusion (DLI) containing 1 x 10(5) CD3+ T cells was performed on d 21 in the following 33 patients who had received PBPC purified by the CliniMACS system. Early graft failure occurred in 8/51 patients (16%). After a median follow-up of 31 months (range 8-60), the probability of disease-free survival (DFS) was 36% for the whole group. Reasons for death were opportunistic infections (n = 15), graft-versus-host disease (GvHD, n = 7) and relapse (n = 4). Pre-transplant factors with significant impact on DFS were cytomegalovirus status and risk category of underlying disease. The occurrence of graft failure or GvHD was associated with poor outcome. Recipients of CD34+-selected PBPC from unrelated donors are at high risk of infectious complications, relapse and graft failure which cannot be prevented by early reinfusion of unmodified donor lymphocytes.

A prospective analysis of the pattern of immune reconstitution in a paediatric cohort following transplantation of positively selected human leucocyte antigen-disparate haematopoietic stem cells from parental donors.

Transplantation of haematopoietic stem cells from human leucocyte antigen (HLA)-disparate parental donors presents a promising new approach for the treatment of patients lacking a HLA-matched donor. Success against major obstacles such as graft-versus-host disease (GvHD) and graft rejection has recently been demonstrated, so that immune reconstitution is one of the prime factors that determines the long-term prognosis following transplantation. Twenty children transplanted with megadoses of highly purified CD34(+) haematopoietic stem cells after rigorous T-cell depletion were prospectively monitored for their immune reconstitution during the first post-transplant year. Natural killer (NK) cells showed a marked increase on d +30. T and B cells began to reconstitute on d +72 and +68 respectively. During extended follow-up, their numbers and proliferative capacity upon mitogen stimulation continually increased. Early reconstituting T cells were predominantly of a primed, activated phenotype with severely skewed T-cell receptor (TCR)-repertoire complexity. Naive T cells emerged 6 months post transplantation, paralleled by an increase in TCR-repertoire diversity. All patients self-maintained sufficient immunoglobulin levels after d +200. This study demonstrates that paediatric recipients of highly purified, haploidentical stem cells are able to reconstitute functioning T-, B- and NK-cell compartments within the first post-transplant year. This, together with the absence of significant GvHD, provides a strong indication for this approach to be considered in children who lack a HLA-matched donor.