Impact of TP53 on outcome of patients with myelofibrosis undergoing hematopoietic stem cell transplantation.

TP53 mutations (TP53MTs) have been associated with poor outcomes in various hematologic malignancies, but no data exist regarding its role in patients with myelofibrosis undergoing hematopoietic stem cell transplantation (HSCT). Here, we took advantage of a large international multicenter cohort to evaluate the role of TP53MT in this setting. Among 349 included patients, 49 (13%) had detectable TP53MT, of whom 30 showed a multihit configuration. Median variant allele frequency was 20.3%. Cytogenetic risk was favorable (71%), unfavorable (23%), and very high (6%), with complex karyotype present in 36 patients (10%). Median survival of patients with TP53MT was 1.5 vs 13.5 years for those with wild-type TP53 (TP53WT; P < .001). Outcome was driven by multihit TP53MT constellation (P < .001), showing 6-year survival of 56% for individuals with single-hit vs 25% for those with multihit TP53MT vs 64% for those with TP53WT. Outcome was independent of current transplantation-specific risk factors and conditioning intensity. Similarly, cumulative incidence of relapse was 17% for single-hit vs 52% for multihit vs 21% for TP53WT. Ten patients with TP53MT (20%) presented as leukemic transformation vs only 7 (2%) in the TP53WT group (P < .001). Out of the 10 patients with TP53MT, 8 showed multihit constellation. Median time to leukemic transformation was shorter for multihit and single-hit TP53MT (0.7 and 0.5 years, respectively) vs 2.5 years for TP53WT. In summary, multihit TP53MT represents a very high-risk group in patients with myelofibrosis who are undergoing HSCT, whereas single-hit TP53MT alone showed similar outcome to patients with nonmutated TP53, informing prognostication for survival and relapse together with current transplantation-specific tools.

High Incidence of Herpes Zoster After Cord Blood Hematopoietic Cell Transplant Despite Longer Duration of Antiviral Prophylaxis.

BACKGROUND: Cord blood transplant (CBT) recipients have a high incidence of herpes zoster (HZ) in the context of short-term peritransplant antiviral prophylaxis. In 2009, international guidelines recommended HZ prophylaxis for at least 1 year after hematopoietic cell transplant. The impact of longer-term antiviral prophylaxis on HZ incidence after CBT is unknown. METHODS: We retrospectively analyzed varicella zoster virus (VZV)-seropositive CBT recipients who were transplanted between 2006 and 2016. We abstracted HZ events and other variables for up to 5 years post-CBT. We calculated the cumulative incidence of HZ and used Cox proportional hazards regression to identify variables associated with HZ. RESULTS: The study cohort consisted of 227 patients. Among 1-year survivors, 91% were still receiving prophylaxis, for a median duration of 20.6 months. HZ occurred in 44 patients (19%) at a median of 23.6 months. The cumulative incidence of HZ by 1 year after CBT was 1.8% (95% confidence interval [CI], .1%-4%), but increased to 26% (95% CI, 19%-33%) by 5 years. In a multivariable analysis, acute graft-vs-host disease was associated with increased risk, whereas antiviral prophylaxis was associated with reduced risk for HZ (adjusted hazard ratio, 0.19 [95% CI, .09-.4]). There was no association between CD4+ T-cell counts at 1 year post-CBT and subsequent risk for HZ. CONCLUSIONS: We found a high incidence of HZ after CBT despite antiviral prophylaxis for > 1 year. Based on these findings, we suggest longer duration of prophylaxis for HZ after CBT. Compliance with antiviral prophylaxis, VZV-specific immune monitoring, and vaccination to mitigate HZ after CBT also require further study.

Early Mixed Lymphoid Donor/Host Chimerism is Associated with Improved Transplant Outcome in Patients with Primary or Secondary Myelofibrosis.

We investigated risk factors for the development of mixed chimerism in 131 patients who underwent transplantation for myelofibrosis and determined the impact of lymphoid (CD3+) and myeloid (CD33+) chimerism on transplant outcome. Disease risk included DIPSS plus categories low to high. The median patient age was 58 years. Patients were conditioned with high-intensity (myeloablative) or low/reduced-intensity (nonmyeloablative) regimens and received a transplant from a related or unrelated donor. Mixed CD3+ chimerism was observed earlier after HCT, whereas CD33+ chimerism occurred later. Mixed chimerism was more frequent with low-intensity regimens than with high- intensity regimens. Mixed CD3+ chimerism did not lead to graft failure and was associated with a reduced incidence of acute GVHD and improved overall survival (OS) and relapse-free survival, whereas mixed CD33+ chimerism was associated with an increased incidence of relapse and reduced OS and relapse-free survival, independent of the CD34+ cell dose transplanted. Thus, mixed CD3+ chimerism in patients with myelofibrosis had a favorable impact on transplantation outcome and does not require therapeutic interventions.

Return-to-Work Guidelines and Programs for Post-Hematopoietic Cell Transplantation Survivors: An Initial Survey.

Hematopoietic cell transplantation (HCT) requires absence from work, with potential consequences of unemployment and early retirement. Risk factors for failure to return to work (RTW) following HCT have been reported, but there is little information about how transplant centers facilitate the RTW transition for their post-HCT patients. In the present study, we aimed to determine (1) whether transplant centers have guidelines for RTW post-HCT and the consistency of these guidelines and (2) whether centers have RTW programs for their patients, and the characteristics of these programs. We surveyed representatives from 150 adult transplant centers regarding their RTW guidelines and RTW programs. Centers were selected if they performed at least 50 HCTs (autologous [auto] and/or allogeneic [allo]) annually. The online survey contained 32 open-ended and closed-ended questions and 3 questions each eliciting respondents' demographic and transplant centers information. We received completed surveys from 45 centers (30% response rate). Forty-four percent of centers reported having RTW guidelines. All centers recommend RTW at 6 months or less after HCT for their auto-HCT recipients; recommendations for allo-HCT recipients ranged from 4 months to >1 year after HCT having jobs involving interactions with children, sick people, and animals was considered a reason to delay RTW by most centers. Although 87% of centers endorsed that RTW is a problem for post-HCT recipients, only 36% reported having an RTW program for their patients. The majority validated that RTW programs would be either somewhat helpful (36%) or very helpful (51%) for their patients. The majority of responding HCT centers believe that RTW is a problem for patients after HCT; however, consistent guidelines and RTW programs are lacking. With increasing numbers of HCT survivors, efforts to create standardized guidelines and to develop RTW programs are needed.

Impact of clinical, cytogenetic, and molecular profiles on long-term survival after transplantation in patients with chronic myelomonocytic leukemia.

Chronic myelomonocytic leukemia (CMML) is a heterogeneous group of clonal hematopoietic malignancies with variable clinical and molecular features. We analyzed long-term results of allogeneic hematopoietic cell transplantation in patients with CMML and determined clinical and molecular risk factors associated with outcomes. Data from 129 patients, aged 7-74 (median 55) years, at various stages of the disease and transplanted from related or unrelated donors were analyzed. Using a panel of 75 genes somatic mutations present before hematopoietic cell transplantation were identified In 52 patients. The progression-free survival rate at 10 years was 29%. The major cause of death was relapse (32%), which was significantly associated with adverse cytogenetics (hazard ratio, 3.77; P=0.0002), CMML Prognostic Scoring System (hazard ratio, 14.3, P=0.01), and MD Anderson prognostic scores (hazard ratio, 9.4; P=0.005). Mortality was associated with high-risk cytogenetics (hazard ratio, 1.88; P=0.01) and high Hematopoietic Cell Transplantation Comorbidity Index (score ≥4: hazard ratio, 1.99; P=0.01). High overall mutation burden (≥10 mutations: hazard ratio, 3.4; P=0.02), and ≥4 mutated epigenetic regulatory genes (hazard ratio 5.4; P=0.003) were linked to relapse. Unsupervised clustering of the correlation matrix revealed distinct high-risk groups with unique associations of mutations and clinical features. CMML with a high mutation burden appeared to be distinct from high-risk groups defined by complex cytogenetics. New transplant strategies must be developed to target specific disease subgroups, stratified by molecular profiling and clinical risk factors.

Prognostic Performance of the Augmented Hematopoietic Cell Transplantation-Specific Comorbidity/Age Index in Recipients of Allogeneic Hematopoietic Stem Cell Transplantation from Alternative Graft Sources.

The Hematopoietic Cell Transplantation-Specific Comorbidity Index (HCT-CI) was developed and validated to weigh the burden of pretransplantation comorbidities and estimate their impact on post-transplantation risks of nonrelapse mortality (NRM). Recently, the HCT-CI was augmented by the addition of both age and the values of 3 markers: ferritin, albumin, and platelet count. So far, research involving The HCT-CI has been limited almost exclusively to recipients of allogeneic hematopoietic cell transplantation (HCT) from HLA-matched grafts. To this end, we sought to investigate the discriminative capacity of an augmented comorbidity/age index among 724 recipients of allogeneic HCT from HLA-mismatched (n = 345), haploidentical (n = 117), and umbilical cord blood (UCB; n = 262) grafts between 2000 and 2013. In the overall cohort, the augmented comorbidity/age index had a higher c-statistic estimate for prediction of NRM compared with the original HCT-CI (.63 versus .59). Findings were similar for recipients of HLA-mismatched (.62 versus .59), haploidentical (.60 versus .54), or UCB grafts (.65 versus .61). Compared with patients with an HCT-CI score ≥4, those with a score <4 had a higher survival rate among recipients of HLA-mismatched (55% versus 39%; P < .0008), HLA-haploidentical (58% versus 38%; P = .01), or UCB (67% versus 48%; P = .004) grafts. Our results demonstrate the utility of the augmented comorbidity/age index as a valid prognostic tool among recipients of allogeneic HCT from alternative graft sources.

Rates and Risk Factors for Post-Traumatic Stress Disorder Symptomatology among Adult Hematopoietic Cell Transplant Recipients and Their Informal Caregivers.

Hematopoietic cell transplant (HCT) can cause significant distress in patients and their informal caregivers. Despite advances in reduced-intensity conditioning and supportive care, few recent studies have reported rates of clinically significant post-traumatic stress disorder (PTSD) symptomatology. Goals of the current study were to examine rates of PTSD and distress in patients and caregivers and to identify sociodemographic and clinical risk factors for PTSD. As part of an annual survivorship survey, 2157 HCT recipients and their caregivers were mailed self-report measures of PTSD and distress. Patients also completed self-report measures of sociodemographic information (eg, age, sex, employment status). Clinical variables (eg, time since transplant, transplant type) were captured in the transplant database. A total of 691 recipients (56% age 60 or above at the time of survey, 47% women, median 10.1 years post-HCT) and 333 caregivers provided PTSD data and were included in the current analyses. More caregivers reported PTSD (6.6%) than patients (3.3%; P = .02). Patients or caregivers who had PTSD reported significantly higher distress related to uncertainty, family strain, medical demands, finances, identity, and health burden (P < .0001) compared with those without PTSD. Patient but not caregiver PTSD was associated with more recent transplant (P = .01 and P = .16, respectively). Rates of PTSD are relatively low in long-term survivors of HCT and their caregivers. Nevertheless, results are consistent with other studies of cancer caregiving suggesting that caregivers often experience greater distress than patients. Timely referral to psychosocial services should be offered to both HCT recipients and caregivers reporting symptoms of PTSD.

Post-transplantation employment status of adult survivors of childhood allogeneic hematopoietic cell transplant: A report from the Center for International Blood and Marrow Transplant Research (CIBMTR).

BACKGROUND: Data are scarce regarding employment outcomes of survivors of childhood allogeneic hematopoietic cell transplantation (alloHCT) and the factors that affect their employment status. METHODS: By using the Center for International Blood and Marrow Transplant Research database, the authors studied employment outcomes of ≥1-year survivors of childhood alloHCT who were age ≥18 years at their most recent assessment (year of transplantation, 1985-2010). Employment status was assessed at their attained ages (ages 18-22, 23-27, and 28-32 years) and according to transplantation center (TC) location (United States or International). A multivariable analysis assessing the factors that affected employed status (full-time/part-time work or student) was performed. RESULTS: Unemployment rates among 2844 survivors were persistently high at all attained ages (United States TCs: ages 18-22 [14%], 23-27 [15%], and 28-32 [13%] years; International TCs: ages 18-22 [56%], 23-27 [53%], and 28-32 [68%] years). The factors associated a with higher likelihood of employment included: older age at alloHCT (ages 5-9-years: hazard ratio [HR], 2.07; 95% confidence interval [CI], 1.65-2.6; ages 10-14 years: HR, 4.43; 95% CI, 3.58-5.47; ages 15-18-years: HR, 7.13; 95% CI, 5.72-8.88), myeloablative conditioning without total body irradiation (TBI) (HR, 1.56; 95% CI, 1.38-1.77), reduced-intensity conditioning with TBI (HR, 1.47; 95% CI, 1.19-1.8) or without TBI (HR, 2.51; 95% CI, 2.15-2.92), and US-based TC (HR, 1.84; 95% CI, 1.62-2.08). CONCLUSIONS: Young adult survivors of childhood alloHCT have high unemployment rates at all studied attained ages after HCT. Future efforts should be directed toward understanding the causes of unemployment their and relation to quality of life using patient-reported outcome measures.

Disability related to chronic graft -versus-host disease after alternative donor hematopoietic cell transplantation.

We determined the incidence of disability related to chronic graft-versus-host disease (bronchiolitis obliterans, grade ≥2 keratoconjunctivitis sicca, sclerotic features or esophageal stricture) for three categories of alternative donor: cord blood, haplorelated marrow or peripheral blood with post-transplant cyclophosphamide, and unrelated single HLA-allele mismatched peripheral blood. Among 396 consecutive hematopoietic cell transplant recipients, 129 developed chronic graft-versus-host disease with 3-year cumulative incidences of 8% for cord blood, 24% for haplorelated grafts, and 55% for unrelated single HLA-allele mismatched peripheral blood. Disability rates were significantly lower for cord blood [hazard ratio (HR) 0.13; 95% confidence interval (CI): 0.1-0.4] and for the haplorelated group (HR 0.31; 95% CI: 0.1-0.7) compared to the rate in the group transplanted with unrelated single HLA-allele mismatched peripheral blood. Cord blood recipients were also >2-fold more likely to return to work/school within 3 years from the onset of chronic graft-versus-host disease (HR 2.54; 95% CI: 1.1-5.7, P=0.02), and the haplorelated group trended similarly (HR 2.38; 95% CI: 1.0-5.9, P=0.06). Cord blood recipients were more likely to discontinue immunosuppression than were recipients of unrelated single HLA-allele mismatched peripheral blood (HR 3.96; 95% CI: 1.9-8.4, P=0.0003), similarly to the haplorelated group (HR 4.93; 95% CI: 2.2-11.1, P=0.0001). Progression-free survival and non-relapse mortality did not differ between groups grafted from different types of donors. Our observations that, compared to recipients of unrelated single HLA-allele mismatched peripheral blood, recipients of cord blood and haplorelated grafts less often developed disability related to chronic graft-versus-host disease, and were more likely to resume work/school, should help better counseling of pre-hematopoietic cell transplant candidates.

Transplant Decisions in Patients with Myelofibrosis: Should Mutations Be the Judge?

The prognosis of myeloproliferative neoplasms, including primary myelofibrosis (PMF), polycythemia vera, and essential thrombocythemia varies considerably, between these disorders as well as within each diagnosis. Molecular studies have identified "driver mutations" in JAK2, MPL1, and CALR and additional somatic DNA mutations, including ASXL1, EZH2, IDH1/2, and SRSF2, that affect prognosis differentially. Patients with mutations in CALR (type1) have a better outlook than patients with mutations in JAK2 or MPL, whereas patients without any of the driver mutations (triple negative) have the shortest life expectancy. Mutations in ASXL1, EZH2, and SRSF2 may be associated with shortened survival, and IDH mutations carry a higher risk of leukemic transformation. The combination and number of mutations are more important than a given single mutation. Mutations also appear to impact the outcome of hematopoietic cell transplantation (HCT), currently the only treatment with curative potential. Based on available data, the best post-HCT outcome is observed with CALR mutations. Triple negativity has a negative impact. The data on JAK2 are controversial. Mutations in ASXL1 or IDH1/2 reduce the probability of progression-free survival after HCT, although the impact of ASXL1 differs between patients with primary and secondary myelofibrosis. Although it is not clear to what extent HCT can overcome the risks associated with a given mutational pattern, at present, early HCT should be considered in triple-negative patients and patients with PMF who harbor mutations in ASXL1. Mutations in EZH2, SRSF2, or IDH, particularly if combined with other mutations, should also lead to consideration of HCT. Further studies are needed to validate the present observations and determine the impact of additional mutations that have been identified.

Quality of Life of Caregivers of Hematopoietic Cell Transplant Recipients.

Caregivers are critical to recipient recovery after hematopoietic cell transplant (HCT); however, little is known about their long-term health and quality of life (QoL). In this study we surveyed 4446 caregiver-recipient pairs in the post-HCT period to describe their QoL and its determinants. In total, 849 caregiver-recipient pairs at a median of 6 years after autologous or allogeneic HCT responded. Among 849 responding caregivers at a median of 6 years post-HCT, 67% of caregivers were women and 68% indicated they were still providing care to the recipient. Mean and median QoL measures of caregivers were at or above general population norms; however, approximately 20% of caregivers reported poor QoL relative to general population norms. Multivariate analysis revealed that caregiver characteristics, including age, gender, and educational attainment, were important determinants of caregiver QoL. Additional determinants of caregiver QoL included recipient QoL, relapse after autologous HCT, and ongoing use of immunosuppression after allogeneic HCT. Additionally, the prevalence of depression and sleep disorders appear to be higher in caregivers than in the general population. We have identified a population of caregivers who may benefit from interventions aimed at improving QoL and health outcomes. HCT clinical practice should also consider caregiver well-being.

Hematopoietic Cell Transplantation for Myelofibrosis: the Dynamic International Prognostic Scoring System Plus Risk Predicts Post-Transplant Outcomes.

Hematopoietic cell transplantation (HCT) provides potentially curative treatment for patients with myelofibrosis (MF). HCT outcomes are associated with the Dynamic International Prognostic Scoring System (DIPSS) risk scores. In the present study we analyzed results in 233 patients to determine if the DIPSS plus classification, which adds cytogenetics, thrombocytopenia, and RBC transfusion dependence as risk factors, would better predict post-HCT outcomes than the original DIPSS. Multivariate analysis showed that each risk parameter incorporated into the DIPPS plus model contributed to its predictive power of overall mortality, relapse-free survival, and nonrelapse mortality. The 5-year overall survival (OS), relapse, and treatment-related mortality (TRM) rates for patients with low/intermediate-1 risk MF were 78%, 5%, and 20%, respectively. The 5-year OS, relapse, and TRM rates for patients with high-risk MF were 35%, 28%, and 40%, respectively. The HCT-specific comorbidity index of 3 or greater was associated with higher nonrelapse and overall mortality and reduced relapse-free survival. The relapse incidence was significantly increased in older patients (HR, 3.02; P = .0007). With a median follow-up of 8 years 124 patients (53%) were surviving. The components of the DIPSS plus classification still have prognostic relevance after adjustment by the DIPSS classification. This information should enhance our ability to advise patients when making decisions regarding timing of transplant.

Success of Immunosuppressive Treatments in Patients with Chronic Graft-versus-Host Disease.

Moderate to severe chronic graft-versus-host disease (GVHD) is treated with potent immunosuppressive therapy (IST) to modulate the allo-immune response, control symptoms, and prevent further organ damage. We sought to understand the types of treatments used in clinical practice and the likelihood of successful treatment associated with each. A chart review was performed for 250 adult patients at Fred Hutchinson Cancer Research Center enrolled in a prospective observational study. After a median follow-up of 5.6 years for survivors, approximately one-third were still on IST (of whom half were on fourth or greater line of therapy), one-third were alive and off IST, and one-third had relapsed or died. Approximately half of survivors stopped all IST at least once, although half of these restarted IST after a median of 3.4 months (interquartile range, 2.3 to 8.0) off therapy. Successful discontinuation of IST for at least 9 months was associated with myeloablative conditioning (P = .04), more years since transplant (P = .009), and lack of oral (P < .001) and skin (P = .049) involvement compared with those who had to restart IST. We conclude that patients with chronic GVHD usually receive multiple lines and years of IST, with only a third off IST, alive, and free of malignancy at 5 years after chronic GVHD diagnosis. Patients stopping IST should be cautioned to self-monitor and continue close medical follow-up, especially for 3 to 6 months after stopping IST.

Transplant Conditioning with Treosulfan/Fludarabine with or without Total Body Irradiation: A Randomized Phase II Trial in Patients with Myelodysplastic Syndrome and Acute Myeloid Leukemia.

In this prospective, randomized, phase II "pick the winner" trial we assessed the efficacy of transplant conditioning with treosulfan/fludarabine ± 2 Gy total body irradiation (TBI) in reducing post-transplant relapse in 100 patients, aged 2 to 70 years (median, 57), with myelodysplastic syndrome (MDS)/chronic myelomonocytic leukemia (n = 51) or acute myeloid leukemia (AML; n = 49). Patients received i.v. treosulfan, 14 g/m2/day on days -6 to -4 and i.v. fludarabine, 30 mg/m2/day on days -6 to -2, alone or combined with 2 Gy TBI (day 0). Donors were related (n = 43) or unrelated (n = 57). When a planned interim analysis showed superior progression-free survival in the TBI arm (P = .04), all subsequent patients received TBI. With a follow-up of 12 to 40 months (median, 20), the 1-year overall survival was 80% for the TBI arm and 69% for the non-TBI arm. The 1-year cumulative incidence of relapse was 22% and 34%, respectively (P = .06). Among patients with low-risk disease the 1-year relapse incidence was 15% and 31% (P = .20) and for patients with high-risk disease, 26% and 36% (P = .18), respectively. Among MDS patients the 1-year relapse incidence was 27% versus 33% (P = .49) and among AML patients 16% versus 35% (P = .05), respectively. The largest difference was among patients with unfavorable cytogenetics, with 1-year relapse incidences of 31% and 63% (P = .18), respectively. Nonrelapse mortality in this high-risk patient population was 9% at 6 months and did not differ between arms. Thus, treosulfan/fludarabine/low-dose TBI provided effective conditioning for allogeneic hematopoietic cell transplantation in high-risk patients up to 70 years of age. The addition of TBI had a more profound effect in patients with AML than in those with MDS. High-risk disease features were associated with a lower overall success rate. Further studies are warranted.

Prognostic Value of the Hematopoietic Cell Transplantation Comorbidity Index for Patients Undergoing Reduced-Intensity Conditioning Cord Blood Transplantation.

The Hematopoietic Cell Transplantation Comorbidity Index (HCT-CI) has been validated as a tool for evaluating the risk of treatment-related mortality (TRM) in HLA-matched sibling and matched unrelated donor bone marrow and peripheral blood stem cell transplantation patients. However, the role of the HCT-CI after cord blood transplantation (CBT) has not been fully investigated. In this analysis, we sought to evaluate the predictive value of the HCT-CI in patients undergoing reduced-intensity conditioning (RIC) CBT. Between 2006 and 2013, HCT-CI scores were prospectively tabulated for patients with hematologic malignancies sequentially enrolled on multicenter RIC CBT studies coordinated by the Fred Hutchinson Cancer Research Center: 151 patients with acute myeloid leukemia/myelodysplastic syndrome (n = 101), chronic myeloid leukemia (n = 3), acute lymphocytic leukemia (n = 24), non-Hodgkin lymphoma (n = 8), Hodgkin lymphoma (n = 3), and other hematologic malignancies (n = 12) underwent RIC CBT and were included. Two patients received a single CBT and the remaining 149 received a double CBT. All patients received cyclosporine and mycophenolate mofetil for graft-versus-host disease prophylaxis. Median HCT-CI for the whole group was 3 (range, 0 to 8). Using the HCT-CI categories of low (0), intermediate (1 or 2), and high risk (>3), there was no significant difference in TRM between the 3 groups. However, when the patients were divided into 2 groups, HCT-CI ≤ 3 or > 3, the incidence of TRM at 3 years after transplantation was 26% (95% confidence interval [CI], 17 to 36) in the HCT-CI ≤ 3 group versus 50% (95% CI, 30 to 67) in the HCT-CI > 3 group (P = .01). Overall survival for patients with HCT-CI ≤ 3 was 40% (95% CI, 27 to 51) versus 29% in patients with HCT-CI >3 (95% CI, 12 to 48) (P = .08). Our study demonstrates that HCT-CI score > 3 is associated with an increased risk of TRM at 3 years after transplantation in patients undergoing RIC CBT. Because of the significant risk of TRM in patients with HCT-CI > 3 compared with risk for those with HCT-CI ≤ 3, patients with an HCT-CI score >3 should be counseled before undergoing RIC CBT.

Outcomes of Cord Blood Transplantation as Salvage Therapy after Graft Failure or Relapse after Prior Allogeneic Transplantation.

For patients with disease relapse or graft failure after allogeneic hematopoietic cell transplantation (HCT), there are few treatment options and survival rates are exceedingly low. Because of the unacceptably high risk of transplantation-related mortality, second allogeneic HCTs are often not considered. Herein, we report the outcomes of 23 patients (median age, 33 years) undergoing a second allogeneic transplantation with unrelated cord blood donor grafts between 2006 and 2013. Indications for second HCT were relapse (n = 19), graft failure (n = 3), and donor-derived myelodysplastic syndrome (n = 1). Ten patients received reduced-intensity conditioning and 13 patients received either myeloablative (MAC) or middle-intensity (MIDI) conditioning. Twenty patients received a double cord blood transplantation. All patients engrafted at a median of 22 days (range, day 6 to 49). Death before day 100 occurred in 5 patients. Overall disease-free survival (DFS), treatment-related mortality, and relapse at 2 years were 31%, 33%, and 35%, respectively. Two-year DFS in the 13 patients receiving MAC or MIDI conditioning was slightly higher at 46%. Our results demonstrate that second allogeneic HCT using cord blood as the graft source should be considered in patients who have relapsed or experience graft failure after an allogeneic HCT.

Resilience, health, and quality of life among long-term survivors of hematopoietic cell transplantation.

BACKGROUND: Low patient-reported resilience is associated with an ongoing risk of poor health and psychosocial outcomes. Using a large cross-sectional sample of survivors of hematopoietic cell transplantation (HCT), this study explored associations between patient-reported resilience, psychological distress, posttraumatic growth, and health-related quality of life. METHODS: Between July 1, 2013 and June 30, 2014, the annual Fred Hutchinson Cancer Research Center (FHCRC) posttransplant survivorship survey queried patient-reported health and functional status and included instruments assessing psychosocial outcomes: the 10-item Connor-Davidson Resilience Scale, the Posttraumatic Growth Inventory, the Cancer and Treatment Distress measure, and the 12-item Medical Outcomes Study Short Form quality-of-life scale. Multivariate linear and logistic regression models included demographic and health covariates extracted from the FHCRC research database. RESULTS: Among 4643 adult survivors of HCT, 1823 (39%) responded after a single mailing and subsequent reminder letter. The participants' median age was 59 years (interquartile range [IQR], 50-66 years); 52.5% were male, and most were non-Hispanic white. The median time since HCT was 9 years (IQR, 3-18 years). Lower patient-reported resilience was associated with chronic graft-versus-host disease of higher severity, lower performance scores, missing work because of health, and permanent disability (all P < .0001). After adjustments for demographic and health characteristics, patients reporting low resilience scores had higher odds of having psychological distress (odds ratio [OR], 3.0; 95% confidence interval [CI], 2.1-4.3) and being in the lowest quartile for mental health-related quality of life (OR, 5.9; 95% CI, 4.4-8.0). CONCLUSIONS: Patient-reported resilience is independently associated with health and psychosocial outcomes. Future studies must determine whether interventions can bolster resilience and improve survivorship outcomes.

Recombinant human factor VIIa for alveolar hemorrhage following allogeneic stem cell transplantation.

The mortality rate of alveolar hemorrhage (AH) after allogeneic hematopoietic stem cell transplantation is greater than 60% with supportive care and high-dose steroid therapy. We performed a retrospective cohort analysis to assess the benefits and risks of recombinant human factor VIIa (rFVIIa) as a therapeutic adjunct for AH. Between 2005 and 2012, 57 episodes of AH occurred in 37 patients. Fourteen episodes (in 14 patients) were treated with steroids alone, and 43 episodes (in 23 patients) were treated with steroids and rFVIIa. The median steroid dose was 1.9 mg/kg/d (interquartile range [IQR], 0.8 to 3.5 mg/kg/d; methylprednisolone equivalents) and did not differ statistically between the 2 groups. The median rFVIIa dose was 41 µg/kg (IQR, 39 to 62 µg/kg), and a median of 3 doses (IQR, 2 to 17) was administered per episode. Concurrent infection was diagnosed in 65% of the episodes. Patients had moderately severe hypoxia (median PaO2/FiO2, 193 [IQR, 141 to 262]); 72% required mechanical ventilation, and 42% survived to extubation. The addition of rFVIIa did not alter time to resolution of AH (P = .50), duration of mechanical ventilation (P = .89), duration of oxygen supplementation (P = .55), or hospital mortality (P = .27). Four possible thrombotic events (9% of 43 episodes) occurred with rFVIIa. rFVIIa in combination with corticosteroids did not confer clear clinical advantages compared with corticosteroids alone. In patients with AH following hematopoietic stem cell transplantation, clinical factors (ie, worsening infection, multiple organ failure, or recrudescence of primary disease) may be more important than the benefit of enhanced hemostasis from rFVIIa.

Returning to Work Following Hematopoietic Cell Transplantation: The Survivor's Perspective.

While curing a patient's underlying disease is the primary goal of physicians performing hematopoietic cell transplantation (HCT), the ultimate objective is to provide patients with optimal post-HCT quality of life. For many survivors, this includes returning to work (RTW). We conducted a survey of 1- to 5-yr post-HCT survivors at our center to evaluate their perspective on facilitators and barriers to RTW as well as to gauge interest in potentially useful RTW support interventions. Survivors aged 18 to 65 yrs (n = 994) were sent an annual survey that included 36 supplementary questions about post-HCT RTW. Survey questions were selected from published national cancer survivor surveys and then modified specifically for HCT survivors. Three hundred forty-four (35%) survivors with a mean age of 53 yrs completed the survey, of whom 272 (79%) had worked prior to their diagnosis. Of those 272 patients, 145 (53%) were working currently and another 22 (8%) had attempted to go back to work following HCT but were not presently working. We found that having had an allogeneic versus autologous HCT (P = .006) was associated with a decreased likelihood of currently working, whereas frequent employer communication (>once a month) (P = .070) and having a more supportive employer (P = .036) were associated with a greater chance of currently working. Of survivors currently working, 45% reported that they had made one or more changes to their work schedule (e.g., flexible schedule or part-time work) or environment (e.g., work from home) upon RTW. Ninety-five percent of responders reported that they could have benefited from RTW support provided by the transplant center, but only 13% indicated that they had received it. Education on RTW challenges, information on disability benefits, and access to physical therapy were among the most requested support interventions. To improve post-HCT quality of life for survivors open to assistance, providers should address work status and goals, recognize barriers to successful return, and offer RTW support including working directly with employers. Allogeneic HCT survivors are particularly vulnerable to failing attempts to RTW and should be the target of retention interventions. A previously published manuscript on RTW guidance for providers of stem cell transplant patients endorsed by the American Society of Transplant and Cellular Therapy is available in Open Access and can be used as a tool to counsel and support these patients.

Financial Toxicity, Time Toxicity, and Quality of Life in Multiple Myeloma.

BACKGROUND: Patients with multiple myeloma (MM) may be on therapy for years, which can lead to financial toxicity (FinTox) or time toxicity (TimeTox). The prevalence, predictors, and quality of life (QOL) impacts of FinTox and TimeTox during different phases of MM treatment have not been characterized. PATIENTS AND METHODS: We conducted a single-center cross-sectional survey of patients with MM who had undergone transplantation. FinTox+ was defined as a COST-FACIT score <23, TimeTox+ as MM-related interactions (including phone calls) ≥1x weekly or ≥1x monthly in-person among far-residing patients, QOL using PROMIS Global Health, and functional status using patient-reported Karnofsky performance status (KPS). RESULTS: Of 252 patients, 22% and 40% met FinTox+ and TimeTox+ criteria respectively. Respective FinTox+ and TimeTox+ proportions were 22%/37% for patients on maintenance, 22%/82% with active therapy, and 20%/14% with observation. FinTox+ predictors included annual income (P < .01) and out-of-pocket costs (P < .01). TimeTox+ predictors included disease status (P < .001), caregiver status (P = .01), far-residing status (P < .001), and out-of-pocket costs (P = .03). FinTox+ was associated with a clinically meaningful decrease in mental QOL, while TimeTox+ patients were more likely to have KPS ≤ 80. CONCLUSIONS: In our large study, monetary status but not disease status predicted FinTox. Over a third of patients on maintenance reported TimeTox. FinTox+ was associated with decreased mental health, while TimeTox+ was associated with worse performance status. These two toxicities may negatively impact patient wellbeing, and studies of strategies to mitigate their impact are in development.