Stem Cell Transplant Experiences Among Hispanic/Latinx Patients: A Qualitative Analysis.

BACKGROUND: Hispanic/Latinx (H/L) patients with cancer treated with stem cell transplant are vulnerable to adverse outcomes, including higher mortality. This study explored their unmet transplant needs, barriers, and facilitators. METHODS: Eighteen English- or Spanish-speaking H/L patients (M age = 59.2) who had a transplant in the past year were interviewed about their transplant experience and rated their interest in receiving information about transplant topics (0 = not at all to 10 = extremely). RESULTS: Content analysis revealed five main themes: (1) pre-transplant barriers and concerns; (2) complex relationships with medical teams; (3) informational mismatch; (4) impacts on daily life after transplant; and (5) methods of coping. Participants were most interested in information about ways of coping with transplant (M = 9.11, SD = 1.45) and words of hope and encouragement (M = 9.05, SD = 1.80). At just above the scale's midpoint, they were least interested in information about side effects and unintended consequences of transplant (M = 5.61, SD = 3.85). CONCLUSIONS: Cultural factors, social determinants, and structural inequalities give rise to unique needs in this growing patient population. Healthcare team members and researchers can better meet the needs of H/L transplant recipients through attention to described considerations, such as financial barriers, communication difficulties, family dynamics, and coping styles.

Greater Social Isolation and Social Constraints Prior to Hematopoietic Stem Cell Transplant Are Associated with Greater Anxiety and Depressive Symptoms.

BACKGROUND: Hematopoietic stem cell transplantation (hereafter "HCT") is a physically and psychologically difficult treatment for patients with hematological cancers. This study examined relationships among patients' reports of pre-transplant social isolation, social constraints, and psychological distress. METHOD: We used baseline data from a multisite randomized controlled trial evaluating the effects of expressive helping writing to reduce physical and emotional symptoms in HCT patients. We collected data prior to randomization and before either allogenic or autologous HCT using validated scales to assess social constraints, social isolation, anxiety, and depressive symptoms. We analyzed data using bivariate analysis and multivariate linear regression. We also explored whether social isolation mediated the effect of social constraints on both of our outcomes: anxiety and depressive symptoms. RESULTS: Among 259 adults recruited prior to transplant, 43.6% were women (mean age = 57.42 years, SD = 12.34 years). In multivariate analysis controlling for relevant covariates, both social isolation (ß = 0.24, p < 0.001) and social constraints (ß = 0.28, p < 0.001) were associated with anxiety. When both social constraints and social isolation were in the model, only greater social isolation (ß = 0.79, p < 0.001) was associated with depressive symptoms. Social isolation fully mediated the association between social constraints and anxiety and depressive symptoms. CONCLUSION: For patients awaiting either allogenic or autologous HCT, the negative association between social constraints and anxiety and depressive symptoms may be related, in part, to the mechanism of perceived social isolation. Interventions prior to and during HCT are needed to support patients' psychological health and sense of social connectedness.

Optimizing use of written peer support as a supportive resource in cancer: Focus group insights.

PURPOSE: Cancer survivors frequently describe wanting to learn from others who have had similar diagnoses or treatments (peer support). We conducted focus groups to investigate hematopoietic stem cell transplant survivors' attitudes and preferences regarding accessing written peer support through a website. Although written peer support does not allow for interpersonal interactions with peers, it could increase transplant recipients' access to evidence-based benefits of informational and emotional peer support. METHODS: We conducted four videoconference focus groups with 34 adult transplant survivors who were diverse in their medical and sociodemographic characteristics and geographic location. Discussions were recorded, transcribed, and content analyzed. RESULTS: Many participants reported need for information about transplant beyond what they received from their healthcare providers. Needs varied across participants, as did preferences for characteristics and timing of information optimally provided through peer support. Participants were enthusiastic about the value of written peer support but emphasized that it should be delivered in a way that accommodates variation in transplant experiences, underscores its trustworthiness, and pairs it with useful psychoeducational content. CONCLUSIONS: Findings provide guidance for making written peer support an accessible, supportive resource for transplant survivors. Future research should evaluate personalized online delivery of written peer support paired with psychoeducational content that enhances its benefits. IMPLICATIONS FOR CANCER SURVIVORS: Written peer support delivered online could be a useful, valued resource for transplant survivors.

Cytomegalovirus (CMV) Cell-Mediated Immunity and CMV Infection After Allogeneic Hematopoietic Cell Transplantation: The REACT Study.

BACKGROUND: Cytomegalovirus (CMV) infection remains an important cause of morbidity and mortality in allogeneic hematopoietic cell transplant (allo-HCT) recipients. CMV cell-mediated immunity (CMV-CMI) as determined by a peptide-based enzyme-linked immunospot (ELISPOT) CMV assay may identify patients at risk for clinically significant CMV infection (CS-CMVi). METHODS: The CS-CMVi was defined as CMV viremia and/or disease necessitating antiviral therapy. CMV-CMI was characterized as high when the intermediate-early 1 (IE-1) antigen spot counts (SPCs) were >100 (cutoff 1) or when the IE-1 and phosphoprotein 65 antigen SPCs were both >100 SPCs per 250 000 cells (cutoff 2), and a low CMV-CMI when SPCs were below these thresholds. In this prospective multicenter study, we evaluated CMV-CMI every 2 weeks from the pretransplant period until 6 months posttransplantation in 241 allo-HCT recipients with positive CMV serostatus. The primary endpoint was CS-CMVi occurring within 2 weeks of the last measurement of CMV-CMI. RESULTS: CS-CMVi occurred in 70 allo-HCT recipients (29%). CMV-CMI was low in patients who experienced CS-CMVi (94%), whereas those who had a high CMV-CMI were less likely to have CS-CMVi (P < .0001). Patients with CS-CMVi had higher all-cause mortality (P = .007), especially those with low CMV-CMI (P = .035). On multivariable analysis, CMV-CMI, sex, race, antithymocyte globulin, and steroid use were independent predictors of CS-CMVi, and the time from transplant to engraftment was the only predictor of mortality. CONCLUSIONS: Measurement of CMV-CMI using a novel ELISPOT assay would be useful clinically to monitor allo-HCT recipients and distinguish between those at risk of developing CS-CMVi and requiring antiviral prophylaxis or therapy and those who are protected.

Health-Related Quality-of-Life Comparison of Adult Related and Unrelated HSC Donors: An RDSafe Study.

Multiple investigations have documented the health-related quality-of-life (HRQoL) and donation-related experiences of unrelated donors (URDs), but similar investigations of the related donor (RD) experience have been less common. The central goal of this study was to longitudinally examine and compare HRQoL of RD and URD hematopoietic stem cell (HSC) donors from predonation through 1 year postdonation. This prospective investigation included adult HSC donors ages 18 to 60 years who donated bone marrow or peripheral blood stem cells at one of 48 geographically diverse US transplant/donor centers and completed HRQoL interviews at predonation and 4 weeks and 1 year postdonation. At predonation, related donors were less ambivalent about donation (t = -3.30; P = .001), more satisfied with their decision to donate (t = 2.65; P = .009), and more likely to define themselves as donors (t = 2.94; P = .004) than were URDs. However, related donors were more concerned about the use of needles (odds ratio [OR] = 2.19; P = .012), about who would pay for the procedure (OR = 2.80; P = .011), and the possibility that they would feel responsible if the transplant failed (t = 2.31; P = .022). Shortly postdonation, related donors were more likely to report donation-related pain (t = 2.50; P = .013) and lightheadedness (OR = 3.63; P = .028). At 1 year postdonation, related donors were less likely to be fully recovered from donation (OR = 0.10; P = .010) and more likely to report a longer recovery period following donation (t = 2.57; P = .011), although this latter finding was primarily due to the percentage of related versus unrelated donors not fully recovered at 1 year postdonation (10% versus 1%). Taken together, these findings suggest that current related donor management practices may be sufficient in preparing related donors for the psychological aspects of donation but that there may be more to do in terms of calibrating the description of donation-related experiences and recovery time to the related donor group (i.e., descriptions of donation experiences based on unrelated donation may not provide best estimates of experience for this group).

Tandem Autologous-Autologous versus Autologous-Allogeneic Hematopoietic Stem Cell Transplant for Patients with Multiple Myeloma: Long-Term Follow-Up Results from the Blood and Marrow Transplant Clinical Trials Network 0102 Trial.

Allogeneic hematopoietic cell transplant (HCT) may improve long-term multiple myeloma (MM) control through the graft-versus-myeloma effect. The Blood and Marrow Transplant Clinical Trials Network 0102 trial was a biologic assignment trial comparing tandem autologous transplant (auto-auto) versus autologous followed by reduced-intensity allogeneic (auto-allo) transplant in patients with newly diagnosed MM with standard-risk (n = 625) or high-risk (n = 85; ß2-microglobulin at diagnosis ≥ 4 mg/dL or deletion of chromosome 13 by conventional karyotyping) disease. Although the initial 3-year analysis showed no difference in progression-free survival (PFS) between arms in either risk group, we hypothesized that long-term follow-up may better capture the impact of the graft-versus-myeloma effect. Median follow-up of survivors was over 10 years. Among standard-risk patients there was no difference in PFS (hazard ratio [HR], 1.11; 95% confidence interval [CI], .93 to 1.35; P = .25) or OS (HR, 1.03; 95% CI, .82 to 1.28; P = .82). The 6-year PFS was 25% in the auto-auto arm versus 22% in the auto-allo arm (P = .32), and 6-year overall survival (OS) was 60% and 59%, respectively (P = .85). In the high-risk group, although there was no statistically significant difference in PFS (HR, .66; 95% CI, .41 to 1.07; P = .07) and OS (HR, 1.01; 95% CI, .60 to 1.71; P = .96), a reduction in 6-year risk of relapse of 77% versus 47% (P = .005) was reflected in better PFS of 13% versus 31% (P = .05) but similar OS, at 47% versus 51% (P = .69). Allogeneic HCT can lead to long-term disease control in patients with high-risk MM and needs to be explored in the context of modern therapy.

Recombinant Zoster Vaccine Significantly Reduces the Impact on Quality of Life Caused by Herpes Zoster in Adult Autologous Hematopoietic Stem Cell Transplant Recipients: A Randomized Placebo-Controlled Trial (ZOE-HSCT).

Herpes zoster (HZ) can have a substantial impact on quality of life (QoL). The vaccine efficacy (VE) of a recombinant zoster vaccine (RZV) was 68.2% (95% confidence interval [CI], 55.6% to 77.5%) in a phase 3 study in adult autologous hematopoietic stem cell transplant (HSCT) recipients (NCT01610414). Herein, we report the impact of RZV on patients' QoL. Autologous HSCT recipients were randomized 1:1 to receive 2 doses of RZV or placebo, given 1 to 2 months apart. QoL was measured by the Short Form Survey-36 and Euro-QoL-5 Dimension at baseline, 1 month, and 1 year postdose 2 and during suspected HZ episodes with the Zoster Brief Pain Inventory (ZBPI). The RZV impact on ZBPI burden of illness and burden of interference scores was estimated. The 2 scores were calculated from the area under the curve (days 0 to 182) of the ZBPI worst pain and ZBPI activities of daily living scores, respectively, assuming a score of 0 for patients not having a confirmed HZ episode. The ZBPI maximum worst pain score was significantly lower in the RZV than placebo group (mean: 5.8 versus 7.1, P = .011). Consequently, the VE estimates for HZ burden of illness (82.5%; 95% CI, 73.6 to 91.4) and burden of interference (82.8%; 95% CI, 73.3 to 92.3) were higher than the HZ VE estimate (ie, 68.2%). RZV showed significantly better QoL scores than placebo 1 week following rash onset among patients with confirmed HZ. In addition to reducing the risk of HZ and its complications, RZV significantly reduced the impact of HZ on patients' QoL in those who developed breakthrough disease.

Ocular Graft-versus-Host Disease after Hematopoietic Cell Transplantation: Expert Review from the Late Effects and Quality of Life Working Committee of the Center for International Blood and Marrow Transplant Research and Transplant Complications Working Party of the European Society of Blood and Marrow Transplantation.

Ocular graft-versus-host disease (GVHD) occurs in more than one-half of patients who develop chronic GVHD after allogeneic hematopoietic cell transplantation (HCT), causing prolonged morbidity that affects activities of daily living and quality of life. Here we provide an expert review of ocular GVHD in a collaboration between transplantation physicians and ophthalmologists through the Late Effects and Quality of Life Working Committee of the Center for International Blood and Marrow Transplant Research and the Transplant Complications Working Party of the European Society of Blood and Marrow Transplantation. Recent updates in ocular GVHD regarding pathophysiology, preclinical models, risk factors, prevention, screening, diagnosis, response criteria, evaluation measures, and treatment are discussed. Ocular GVHD involves at least 3 biological processes: lacrimal gland dysfunction, meibomian gland dysfunction, and corneoconjunctival inflammation. Preclinical models have identified several novel pathogenic mechanisms, including the renin angiotensin system and endoplasmic reticulum stress signaling, which can be targeted by therapeutic agents. Numerous studies have identified reliable tests for establishing diagnosis and response assessment of ocular GVHD. The efficacy of systemic and topical treatment for ocular GVHD is summarized. It is important that all health professionals caring for HCT recipients have adequate knowledge of ocular GVHD to provide optimal care.

Effect of Aging and Predonation Comorbidities on the Related Peripheral Blood Stem Cell Donor Experience: Report from the Related Donor Safety Study.

The development of reduced-intensity approaches for allogeneic hematopoietic cell transplantation has resulted in growing numbers of older related donors (RDs) of peripheral blood stem cells (PBSCs). The effects of age on donation efficacy, toxicity, and long-term recovery in RDs are poorly understood. To address this we analyzed hematologic variables, pain, donation-related symptoms, and recovery in 1211 PBSC RDs aged 18 to 79 enrolled in the Related Donor Safety Study. RDs aged > 60 had a lower median CD34+ level before apheresis compared with younger RDs (age > 60, 59 × 106/L; age 41 to 60, 81 × 106/L; age 18 to 40, 121 × 106/L; P < .001). This resulted in older donors undergoing more apheresis procedures (49% versus 30% ≥ 2 collections, P < .001) and higher collection volumes (52% versus 32% > 24 L, P < .001), leading to high percentages of donors aged > 60 with postcollection thrombocytopenia <50 × 109/L (26% and 57% after 2 and 3days of collection, respectively). RDs aged 18 to 40 had a higher risk of grades 2 to 4 pain and symptoms pericollection, but donors over age 40 had more persistent pain at 1, 6, and 12 months (odds ratio [OR], 1.7; P = 0.02) and a higher rate of nonrecovery to predonation levels (OR, 1.7; P = .01). Donors reporting comorbidities increased significantly with age, and those with comorbidities that would have led to deferral by National Marrow Donor Program unrelated donor standards had an increased risk for persistent grades 2 to 4 pain (OR, 2.41; P < .001) and failure to recover to predonation baseline for other symptoms (OR, 2.34; P = .004). This information should be used in counseling RDs regarding risk and can assist in developing practice approaches aimed at improving the RD experience for high-risk individuals.

Related peripheral blood stem cell donors experience more severe symptoms and less complete recovery at one year compared to unrelated donors.

Unlike unrelated donor registries, transplant centers lack uniform approaches to related donor assessment and deferral. To test whether related donors are at increased risk for donation-related toxicities, we conducted a prospective observational trial of 11,942 related and unrelated donors aged 18-60 years. Bone marrow (BM) was collected at 37 transplant and 78 National Marrow Donor Program centers, and peripheral blood stem cells (PBSC) were collected at 42 transplant and 87 unrelated donor centers in North America. Possible presence of medical comorbidities was verified prior to donation, and standardized pain and toxicity measures were assessed pre-donation, peri-donation, and one year following. Multivariate analyses showed similar experiences for BM collection in related and unrelated donors; however, related stem cell donors had increased risk of moderate [odds ratios (ORs) 1.42; P<0.001] and severe (OR 8.91; P<0.001) pain and toxicities (OR 1.84; P<0.001) with collection. Related stem cell donors were at increased risk of persistent toxicities (OR 1.56; P=0.021) and non-recovery from pain (OR 1.42; P=0.001) at one year. Related donors with more significant comorbidities were at especially high risk for grade 2-4 pain (OR 3.43; P<0.001) and non-recovery from toxicities (OR 3.71; P<0.001) at one year. Related donors with more significant comorbidities were at especially high risk for grade 2-4 pain (OR 3.43; P<0.001) and non-recovery from toxicities (OR 3.71; P<0.001) at one year. Related donors reporting grade ≥2 pain had significant decreases in Health-Related Quality of Life (HR-QoL) scores at one month and one year post donation (P=0.004). In conclusion, related PBSC donors with comorbidities are at increased risk for pain, toxicity, and non-recovery at one year after donation. Risk profiles described in this study should be used for donor education, planning studies to improve the related donor experience, and decisions regarding donor deferral. Registered at clinicaltrials.gov identifier:00948636.

Effects of Social Support Source and Effectiveness on Stress Buffering After Stem Cell Transplant.

BACKGROUND: This study used the social support effectiveness framework to examine whether effective social support buffered the relationship between stressful life events and distress among hematopoietic stem cell transplant (HSCT) survivors and whether that buffering effect depended on the type of caregiver who provided it (partner versus non-partner caregivers). METHODS: A total of 275 HSCT survivors completed measures of the effectiveness of their caregiver's support-social support effectiveness (SSE)-distress, and stressful life events. Hierarchical linear regression was used to analyze a three-way interaction between stressful life events, caregiver SSE, and caregiver type on distress. RESULTS: After controlling for covariates, the three-way interaction of stressful life events, caregiver SSE, and caregiver type was significant (b = - 0.21, SE = 0.00, p < 0.001). Among partnered survivors, more stressful life events were associated with greater distress (B = 0.03, SE = 0.01, p = 0.045) when caregiver SSE was low. There was no association between stressful life events and distress when caregiver SSE was average (B = 0.01, SE = 0.01, p = 0.50) or high (B = - 0.01, SE = 0.02, p = 0.61). Among non-partnered survivors, there was a positive association between stressful life events and distress regardless of caregiver SSE. CONCLUSIONS: Average or highly effective caregiver support buffered effects of stressful life events on distress among partnered survivors. There was no evidence that support at any level of effectiveness buffered stressful life events among non-partnered survivors. Findings highlight the importance of measuring social support effectiveness and source of support among HSCT survivors.

Health-Related Quality of Life among Older Related Hematopoietic Stem Cell Donors (>60 Years) Is Equivalent to That of Younger Related Donors (18 to 60 Years): A Related Donor Safety Study.

The increasing number of older adults with blood-related disorders and the introduction of reduced-intensity conditioning regimens has led to increases in hematopoietic stem cell (HSC) transplantation among older adults and a corresponding increase in the age of siblings who donate HSCs to these patients. Data regarding the donation-related experiences of older donors are lacking. The Related Donor Safety Study aimed to examine/compare health-related quality of life (HRQoL) of older versus younger HSC donors. Sixty peripheral blood stem cell (PBSC) donors ages 18 to 60 years and 104 PBSC donors age >60 years completed validated questionnaires before donation and 4 weeks and 1 year after donation. Before donation, older donors had poorer general physical health (t = -3.27; P = .001) but better mental health (t = 2.11; P < .05). There were no age differences in multiple other donation-related factors. At 4 weeks after donation, there were no group differences in general physical/mental health, but older donors were less likely to report donation-related pain (t = -2.26; P < .05) and concerns (t = -3.38; P = .001). At both 4 weeks and 1 year after donation, there were no significant differences in the percentage of each age group feeling physically back to normal or in the number of days it took donors to feel completely well. There was no evidence that increasing age within the older donor group was associated with poorer donation-related HRQoL. Taken together, these data support the current practice of HSC donation by sibling donors above age 60, providing no evidence of worsening HRQoL up to 1 year after donation in individuals up to age 76.

Comparative Outcomes after Haploidentical or Unrelated Donor Bone Marrow or Blood Stem Cell Transplantation in Adult Patients with Hematological Malignancies.

Most patients eligible for allogeneic hematopoietic stem cell transplantation will require identification of an alternate (unrelated or mismatched related) donor. We explored the transplantation outcomes for a sequential series of 54 patients undergoing haploidentical donor transplantation (HAPLO) compared to those from a control group of patients receiving cells from matched or mismatched unrelated donors (URD) selected by diagnosis and stem cell source. Patients undergoing HAPLO transplantations received graft-versus-host disease (GVHD) prophylaxis with post-transplantation cyclophosphamide (Cy). Day 15 neutrophil recovery was lower after HAPLO than in URD recipients (43% versus 77%, P < .001), as was day 30 platelet recovery (67% versus 84%, P = .043). HAPLO patients receiving bone marrow achieved neutrophil engraftment at a median of 17 days and platelet engraftment at a median of 29 days, compared with 16 days and 24 days, respectively, for recipients of peripheral blood stem cells. The incidence of graft failure was similar for both HAPLO and URD recipients (P = .42). HAPLO recipients were more likely to reach donor CD3 chimerism >95% by day 28 after transplantation (88% versus 62%, P = .003). The cumulative incidence of grades II to IV acute GVHD (aGVHD) at 6 months after transplantation did not differ for these 2 groups (63% for HAPLO and 53% for URD recipients; P = .269), nor did the cumulative incidence of severe grade III/IV aGVHD (13% for HAPLO and 8% for URD recipients; P = .44). The cumulative incidence of moderate or severe chronic GVHD at 2 years did not differ, with probabilities of 24% for HAPLO and 18% for URD recipients (P = .43). The cumulative incidence of cytomegalovirus reactivation by day 100 after transplantation did not differ (45% for HAPLO and 46% for URD recipients; P = .96). The HAPLO recipients experienced a lower incidence of Epstein-Barr virus reactivation by day 100 (6% versus 32%, P < .001) but a higher incidence of Human Herpesvirus-6 reactivation (35% versus 10%, P = .001). Relapse risk, regimen-related mortality, progression-free survival, and overall survival probabilities did not differ between these 2 groups. These data support the use of HAPLO transplantation with post-transplantation Cy as an alternate transplantation technique for patients lacking HLA-matched sibling donors. Transplantation of peripheral blood stem cells does not appear to enhance the speed of neutrophil recovery. The different patterns of viral reactivation require additional studies to explain.

A Phase I/II Study of Escalating Doses of Bortezomib in Conjunction with High-Dose Melphalan as a Conditioning Regimen for Salvage Autologous Peripheral Blood Stem Cell Transplantation in Patients with Multiple Myeloma.

Escalating doses of bortezomib with high-dose melphalan was evaluated as as a conditioning regimen for autologous stem cell transplantation (ASCT) in patients with relapsed or refractory multiple myeloma (MM). MM patients with less than a partial remission (PR) (or 50% reduction) compared to their pretransplantation paraprotein parameters after a prior ASCT with melphalan conditioning, or who were in relapse after a prior autologous transplantation, were eligible for study. Bortezomib was dose escalated in steps of 1, 1.3, and 1.6 mg/m2 (3 × 3 design) on days -4 and -1 before transplantation with melphalan 200 mg/m2 given on day -2. Thirty-two patients were enrolled: 12 in the phase I dose escalation phase and an additional 20 in phase II to gain additional experience with the regimen. Twenty-four (75%) patients were Durie Salmon stage III, and 12 (37.5%) had >2 prior lines of therapy. The overall response rate (≥PR) was 44% with 22% complete remission. Two-year overall survival and progression-free survival were 76% and 39%, respectively, with a median follow-up of 31.7 months. The most common grade 3 and 4 nonhematologic adverse events were neutropenic fever (25%), nausea (18.8%), and mucositis (9.4%). Serious adverse events included intensive care unit admission (9.4%), seizure (3.1%), prolonged diarrhea (3.1%), and Guillain-Barre syndrome (3.1%). Two patients (6%) died of sepsis. There was no emergent peripheral neuropathy nor increase in any pre-existing peripheral neuropathy. The addition of bortezomib to melphalan as conditioning for salvage ASCT was well tolerated. More importantly, it can provide durable remission for patients who have a suboptimal response to prior single-agent melphalan conditioning for ASCT, without requiring a reduction in the dose of melphalan. Larger randomized prospective studies to determine the effect of combination conditioning are being conducted.

CMX001 to prevent cytomegalovirus disease in hematopoietic-cell transplantation.

BACKGROUND: The use of available antiviral agents for the prevention of cytomegalovirus (CMV) disease is limited by frequent toxic effects and the emergence of resistance. CMX001 has potent in vitro activity against CMV and other double-stranded DNA viruses. We evaluated the safety and anti-CMV activity of CMX001 in patients who had undergone allogeneic hematopoietic-cell transplantation. METHODS: From December 2009 through June 2011, a total of 230 patients with data that could be evaluated were enrolled in the study. We randomly assigned these adult CMV-seropositive transplant recipients from 27 centers to oral administration of CMX001 or placebo. Patients were assigned in a 3:1 ratio to five sequential study cohorts according to a dose-escalating, double-blind design. Randomization was stratified according to the presence or absence of acute graft-versus-host disease and CMV DNA in plasma. Patients received the study drug after engraftment for 9 to 11 weeks, until week 13 after transplantation. Polymerase-chain-reaction analysis of CMV DNA in plasma was performed weekly. Patients in whom CMV DNA was detected at a level that required treatment discontinued the study drug and received preemptive treatment against CMV infection. The primary end point was a CMV event, defined as CMV disease or a plasma CMV DNA level greater than 200 copies per milliliter when the study drug was discontinued. The analysis was conducted in the intention-to-treat population. RESULTS: The incidence of CMV events was significantly lower among patients who received CMX001 at a dose of 100 mg twice weekly than among patients who received placebo (10% vs. 37%; risk difference, -27 percentage points; 95% confidence interval, -42 to -12; P=0.002). Diarrhea was the most common adverse event in patients receiving CMX001 at doses of 200 mg weekly or higher and was dose-limiting at 200 mg twice weekly. Myelosuppression and nephrotoxicity were not observed. CONCLUSIONS: Treatment with oral CMX001 at a dose of 100 mg twice weekly significantly reduced the incidence of CMV events in recipients of hematopoietic-cell transplants. Diarrhea was dose-limiting in this population at a dose of 200 mg twice weekly. (Funded by Chimerix; CMX001-201 ClinicalTrials.gov number, NCT00942305.).

Peripheral-blood stem cells versus bone marrow from unrelated donors.

BACKGROUND: Randomized trials have shown that the transplantation of filgrastim-mobilized peripheral-blood stem cells from HLA-identical siblings accelerates engraftment but increases the risks of acute and chronic graft-versus-host disease (GVHD), as compared with the transplantation of bone marrow. Some studies have also shown that peripheral-blood stem cells are associated with a decreased rate of relapse and improved survival among recipients with high-risk leukemia. METHODS: We conducted a phase 3, multicenter, randomized trial of transplantation of peripheral-blood stem cells versus bone marrow from unrelated donors to compare 2-year survival probabilities with the use of an intention-to-treat analysis. Between March 2004 and September 2009, we enrolled 551 patients at 48 centers. Patients were randomly assigned in a 1:1 ratio to peripheral-blood stem-cell or bone marrow transplantation, stratified according to transplantation center and disease risk. The median follow-up of surviving patients was 36 months (interquartile range, 30 to 37). RESULTS: The overall survival rate at 2 years in the peripheral-blood group was 51% (95% confidence interval [CI], 45 to 57), as compared with 46% (95% CI, 40 to 52) in the bone marrow group (P=0.29), with an absolute difference of 5 percentage points (95% CI, -3 to 14). The overall incidence of graft failure in the peripheral-blood group was 3% (95% CI, 1 to 5), versus 9% (95% CI, 6 to 13) in the bone marrow group (P=0.002). The incidence of chronic GVHD at 2 years in the peripheral-blood group was 53% (95% CI, 45 to 61), as compared with 41% (95% CI, 34 to 48) in the bone marrow group (P=0.01). There were no significant between-group differences in the incidence of acute GVHD or relapse. CONCLUSIONS: We did not detect significant survival differences between peripheral-blood stem-cell and bone marrow transplantation from unrelated donors. Exploratory analyses of secondary end points indicated that peripheral-blood stem cells may reduce the risk of graft failure, whereas bone marrow may reduce the risk of chronic GVHD. (Funded by the National Heart, Lung, and Blood Institute-National Cancer Institute and others; ClinicalTrials.gov number, NCT00075816.).

Multicenter study of banked third-party virus-specific T cells to treat severe viral infections after hematopoietic stem cell transplantation.

Virus-specific T cell (VST) lines could provide useful antiviral prophylaxis and treatment of immune-deficient patients if it were possible to avoid the necessity of generating a separate line for each patient, often on an emergency basis. We prepared a bank of 32 virus-specific lines from individuals with common HLA polymorphisms who were immune to Epstein-Barr virus (EBV), cytomegalovirus, or adenovirus. A total of 18 lines were administered to 50 patients with severe, refractory illness because of infection with one of these viruses after hematopoietic stem cell transplant. The cumulative rates of complete or partial responses at 6 weeks postinfusion were 74.0% (95% CI, 58.5%-89.5%) for the entire group (n = 50), 73.9% (95% CI, 51.2% -96.6%) for cytomegalovirus (n = 23), 77.8% for adenovirus (n = 18), and 66.7% (95% CI, 36.9%-96.5%) for EBV (n = 9). Only 4 responders had a recurrence or progression. There were no immediate infusion-related adverse events, and de novo graft-versus-host disease developed in only 2 patients. Despite the disparity between the lines and their recipients, the mean frequency of VSTs increased significantly postinfusion, coincident with striking decreases in viral DNA and resolution of clinical symptoms. The use of banked third-party VSTs is a feasible and safe approach to rapidly treat severe or intractable viral infections after stem cell transplantation. This study is registered at www.clinicaltrials.gov as NCT00711035.

Phase 2 clinical trial of rapamycin-resistant donor CD4+ Th2/Th1 (T-Rapa) cells after low-intensity allogeneic hematopoietic cell transplantation.

In experimental models, ex vivo induced T-cell rapamycin resistance occurred independent of T helper 1 (Th1)/T helper 2 (Th2) differentiation and yielded allogeneic CD4(+) T cells of increased in vivo efficacy that facilitated engraftment and permitted graft-versus-tumor effects while minimizing graft-versus-host disease (GVHD). To translate these findings, we performed a phase 2 multicenter clinical trial of rapamycin-resistant donor CD4(+) Th2/Th1 (T-Rapa) cells after allogeneic-matched sibling donor hematopoietic cell transplantation (HCT) for therapy of refractory hematologic malignancy. T-Rapa cell products, which expressed a balanced Th2/Th1 phenotype, were administered as a preemptive donor lymphocyte infusion at day 14 post-HCT. After T-Rapa cell infusion, mixed donor/host chimerism rapidly converted, and there was preferential immune reconstitution with donor CD4(+) Th2 and Th1 cells relative to regulatory T cells and CD8(+) T cells. The cumulative incidence probability of acute GVHD was 20% and 40% at days 100 and 180 post-HCT, respectively. There was no transplant-related mortality. Eighteen of 40 patients (45%) remain in sustained complete remission (range of follow-up: 42-84 months). These results demonstrate the safety of this low-intensity transplant approach and the feasibility of subsequent randomized studies to compare T-Rapa cell-based therapy with standard transplantation regimens.