High-dose chemotherapy with autologous stem cell transplantation (ASCT) remains the standard of care for patients with multiple myeloma. Outpatient ASCT can be an attractive option given wait times and costs associated with inpatient procedures. We initiated an outpatient transplantation protocol in 2006. Patients were treated at a university hospital outpatient clinic that was open 5 days a week. The present study investigated safety and cost-effectiveness of the outpatient program. Ninety-one patients underwent ASCT between 2006 and 2010. The majority of patients (77%) had Durie-Salmon stage III disease; 38% had 1 or more comorbidities. Seventy-six patients (84%) were hospitalized during the first 100 days, mainly for febrile neutropenia (n = 71). Overall survival at day 100 was 100%. No patient was admitted to an intensive care unit. Risk factors for prolonged hospitalization (longer than 7 days) were disease stage IIB or higher and age >60 years. The cost savings was $19,522 (Canadian dollars) per patient compared with inpatient ASCT, for an annual savings of approximately $740,000. In summary, outpatient ASCT performed in a weekday clinic for patients with multiple myeloma appears to be safe and cost-effective, but is associated with a relatively high hospitalization rate.

Invasive aspergillosis (IA) remains a major complication following allogeneic hematopoietic stem cell transplant (HSCT). In contrast to conventional HSCT, few investigators have examined risk factors of IA associated with nonmyeloablative (NMA) regimens characterized by outpatient administration, immunosuppression rather than cytoreduction, and short duration of neutropenia posttransplant. We report our results on a cohort of 125 patients treated homogenously who received a 6/6 matched sibling NMA HSCT designed to be performed on an outpatient basis. Conditioning regimen included fludarabine (30 mg/m(2) x 5 days) and cyclophosphamide (300 mg/m(2) x 5 days) followed by reinfusion of a minimum of 4 x 10(6) CD34(+) cells/kg. Acute graft-versus-host disease (aGVHD) prophylaxis consisted of tacrolimus and mycophenolate mofetil (MMF). Overall, 13 patients developed IA (5 proved, 6 probable, 2 possible) 44-791 days (median 229) after NMA HSCT, with a risk of 7% at 1, 11% at 2, and 15% at 3 years. Patients who suffered from IA had poorer overall survival (crude hazard ratio 2.3; 95% confidence interval [CI] 1.0-5.4; P = .045). Intestinal aGVHD or chronic GVHD (cGVHD) was significantly associated with IA at 1 (27% versus 3%, P = .003), 2 (27% versus 8%, P = .01), and 3 years (37% versus 10%, P = .005). The use of daclizumab was also significantly associated with IA at 3 years (47% versus 12%, P = .02). Age, sex, diagnosis, previous autologous transplant, duration of neutropenia, occurrence of cytomegalovirus viremia, duration of steroids or MMF intake, aGVHD, cGVHD, and cumulative number of days spent in hospital were not associated with IA. After multivariate analysis, intestinal GVHD remained the only statistically significant risk factor for IA at 1 (P = .003), 2 (P = .01), and 3 years (P = .005). We conclude that in NMA HSCT, the risk of IA increases over time and is significantly associated with intestinal GVHD. Because there is currently no surrogate in vitro markers of immunocompetence following NMA HSCT, this clinical finding is of particular importance to identify a population at higher risk who should be targeted for antimold prophylaxis.

Graft-versus-host disease (GVHD) remains a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). Measures developed that have significantly reduced GVHD were also frequently associated with an increased risk of relapse. GVHD and graft-versus-tumor (GVT) effects are tightly linked, and balance between both reactions is difficult to achieve. To have an impact on the outcome and quality of life after HSCT, improvements in current strategies to prevent and treat GVHD while preserving the GVT effect are clearly needed. Sirolimus (rapamycin) is a lipophilic macrocytic lactone with immunosuppressive, antitumor, and antiviral properties. Because of its multiple modes of activities, it is being increasingly used in the management of GVHD. This review aims to summarize its mechanisms of action and potential advantages over other immunosuppressors and to analyze the most relevant studies investigating its role in both prevention and treatment of GVHD.

Incidence of grade II-IV acute graft-versus-host disease (aGVHD) in nonmyeloablative (NMA) transplant recipients remains high. To date, the ideal prophylaxis regimen, which minimizes aGVHD and chronic GVHD (cGVHD), but does not abrogate graft-versus-tumor (GVT) response, has not been described. Because tacrolimus is more potent than cyclosporine (CSA), and because mycophenolate mofetil (MMF) is an effective immunosuppressant that does not lead to mucositis, we hypothesized that a combination of these 2 oral agents may be an effective GVHD prophylactic strategy. We, therefore, designed an outpatient prospective cohort study with a conditioning regimen consisting of fludarabine (Flu) 30 mg/m2 daily and cyclophosphamide (Cy) 300 mg/m2 daily for 5 days followed by infusion of blood stem cells. Tacrolimus 3mg twice a day was started on day (D) -8, adjusted to achieve levels 10-15 nmol/L, continued until D +50 and then tapered by D +100 or +180 according to estimated risk of relapse. MMF 1000 mg twice a day was started on D +1 and discontinued on D +50. To date, 131 patients (males/females: 75/56) with a median age of 54 years have received a 6/6 matched sibling transplant using this protocol. Indication for NMA transplant included age >55 years (24%), expected increased risk of toxicity (28%), or participation in a multiple myeloma (MM) sequential protocol (48%). Most common diagnoses included MM (N = 62), non-Hodgkin lymphoma (NHL, N = 46), and acute leukemia (N = 10). Following infusion of 6.8 x 10(6) CD34+ cells/kg (range: 0.30-22.3), neutrophil and lymphocyte engraftment occurred in 95% of patients by D +180. The estimated cumulative incidence of classical grade I-IV aGVHD by D +120 was 11.6% (95% confidence interval [CI]: 7.1-18.5). No grade IV aGVHD was observed. In addition, 15 patients (12%: CI: 7.4-19.2; median D +140) developed an overlap syndrome consisting of clinical and histologic features of both aGVHD and cGVHD simultaneously. The estimated cumulative incidence of extensive cGVHD was 76.1% (95% CI: 67.4-83.9) at 2 years, with clinical features at presentation similar to other reported series. In patients developing extensive cGVHD, the probability of remaining on immunosuppression at 5 years was 34.8% (95% CI: 16.4-57.3). With a median follow-up of 982 days, the estimated probabilities of nonrelapse mortality (NRM) and overall survival (OS) were 15.5% (95% CI: 9.0-26.1) and 62.7% (95% CI: 51.4-72.1). The cumulative incidence of relapse was 30% at 7 years. Following NMA transplant, disease-free survival (DFS) was highest in recipients with follicular NHL (79.8%: 95% CI: 57.6-91.2) and lowest in large cell NHLs (34.3%: 95% CI: 1.6-75.9). From this large group of patients treated with a uniform conditioning and GVHD prophylaxis regimen, we conclude that aGVHD prophylaxis with early use of tacrolimus and MMF is safe, effective, and associated with low NRM. Future strategies will need to focus on decreasing the incidence of extensive cGVHD without increasing the risk of relapse.

Although the use of nonmyeloablative (NMA) hematopoietic stem cell transplantation (HSCT) regimens has expanded in the past decade, little data exist to support antiviral prophylaxis to prevent herpes zoster (HZ) in recipients who are seropositive for varicella-zoster virus in this population. The present study examined the clinical features, incidence, and risk factors for HZ in a homogeneous cohort of NMA allogeneic HSCT recipients. We conducted a retrospective cohort study assessing all patients who underwent sibling NMA HSCT at Maisonneuve-Rosemont Hospital (Montreal) between July 2000 and December 2008. All patients received the same conditioning regimen, immunoprophylaxis, and graft-versus-host disease therapy. The diagnosis of HZ was defined clinically. Factors associated with HZ were identified using a Cox proportional hazards model. A total of 179 patients were followed for a median of 33 months (interquartile range, 21-59). HZ developed in 66 patients (37%) at a median of 8.3 months post-HSCT; the incidence rate was 175 cases/1000 person-years. The estimated cumulative HZ incidence was 27% at 1 year, 36% at 2 years, and 44% at 3 years. Thoracic dermatomes were most frequently involved (30%); dissemination occurred in 5 patients. No deaths resulted from HZ, but 23% of patients developed postherpetic neuralgia. In multivariate analysis, reactivation of cytomegalovirus and herpes simplex virus was associated with a reduced likelihood of HZ (hazard ratio, 0.54 and 0.33, respectively). Antiviral prophylaxis or treatment for cytomegalovirus and herpes simplex virus reactivations were protective against HZ. The incidence of HZ in our cohort of NMA HSCT recipients is similar to the incidence reported in HSCT recipients who received a myeloablative conditioning regimen. Given the observed high risk, we conclude that recommendations for antiviral prophylaxis should apply, at least for the first year, to the NMA HSCT population as well.

Infections are a major cause of morbidity and mortality in patients with chronic lymphocytic leukemia (CLL), who typically have increased susceptibility because of hypogammaglobulinemia (HGG) related to their disease and its treatment. Immunoglobulin replacement therapy (IGRT) has been shown to reduce the frequency of bacterial infections and associated hospitalizations in patients with HGG or a history of infection, or both. However, use of IGRT in CLL is contentious. Studies examining such treatment were conducted largely before the use of newer chemoimmunotherapies, which can extend lifespan, but do not correct the HGG inherent to the disease. Thus, the utility of IGRT has to be re-evaluated in the current setting. Here, we discuss the evidence for the use of IGRT in CLL and provide a practical approach to its use in the prevention and management of infections.