Publications by authors named "Rachel B Salit"

38 Publications

The role of JAK inhibitors in hematopoietic cell transplantation.

Authors:
Rachel B Salit

Bone Marrow Transplant 2022 Apr 6. Epub 2022 Apr 6.

Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.

The Janus Kinase (JAK)/Signal Transducers and Activators of Transcription (STAT) pathway is essential for both the regulation of hematopoiesis and the control of inflammation. Disruption of this pathway can lead to inflammatory and malignant disease processes. JAK inhibitors, designed to control the downstream effects of pro-inflammatory and pro-angiogenic cytokines, have been successfully used in pre-clinical models and clinical studies of patients with autoimmune diseases, hematologic malignancies, and the hematopoietic cell transplantation (HCT) complication graft versus host disease (GVHD). In the last decade, JAK inhibitors Ruxolitinib, Fedratinib, and most recently Pacritinib have been United States Federal Drug Administration (FDA) approved for the treatment of myelofibrosis (MF). Ruxolitinib was also recently approved for the treatment of steroid refractory acute as well as chronic GVHD; JAK inhibitors are currently under evaluation in the pre-HCT setting in MF and for the prevention of GVHD. This review will focus on the role of JAK inhibitors in the treatment of hematologic malignancies, the potential function of pre-HCT JAK inhibitors in patients with MF, and the role of JAK inhibitors in the prevention and treatment of acute and chronic GVHD.
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http://dx.doi.org/10.1038/s41409-022-01649-yDOI Listing
April 2022

Outcomes after hematopoietic cell transplantation among non-English- compared to English-speaking recipients.

Bone Marrow Transplant 2022 03 31;57(3):440-444. Epub 2022 Jan 31.

Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.

Multiple studies have documented that racial/ethnic minority patients are less likely to undergo hematopoietic cell transplantation (HCT) in the United States (US), and if they do, they often have worse outcomes. No studies to our knowledge have compared the outcomes of English-speakers to non-English speakers undergoing HCT in the US. To test our hypothesis that non-English speakers have worse outcomes than English speakers after HCT, all transplants performed between 2015 and 2019 at Fred Hutchinson Cancer Research Center in Seattle, WA, USA were analyzed. Cox proportional hazards models were used to test our hypothesis, adjusting for significant clinical covariates. Out of 2051 patients, 106 (5%) were documented to be non-English speakers. Mortality for non-English speakers was not different than English speakers (adjusted HR 1.02, 95% CI 0.63-1.63, p = 0.95). When the analysis was limited to the allogeneic population, the results were similar to the total population (adjusted HR 1.10, 0.64-1.88, p = 0.73). The risk of grade II-IV acute graft-versus-host disease (GVHD) was higher in the non-English speaking subset: adjusted OR 2.01, 95% CI, 1.02-3.98, p = 0.04. These data suggest that non-English speakers have similar survival compared to English speakers following HCT although they have more acute GVHD.
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http://dx.doi.org/10.1038/s41409-021-01557-7DOI Listing
March 2022

Reduced intensity hematopoietic stem cell transplantation for accelerated-phase myelofibrosis.

Blood Adv 2022 02;6(4):1222-1231

Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Accelerated-phase myelofibrosis, currently defined by circulating blasts 10% to 19%, usually confers very high risk for progression and poor outcome. The outcome of hematopoietic stem cell transplantation for accelerated-phase myelofibrosis has not been evaluated yet. We analyzed the outcome of 349 clinically and genetically annotated patients with primary or secondary myelofibrosis undergoing reduced intensity transplantation, of whom 35 had accelerated-phase myelofibrosis. In comparison with chronic-phase (<10% blasts) myelofibrosis, median leukocyte counts were higher, more patients had constitutional symptoms, and RAS mutations were detected more frequently in the accelerated-phase group. After a median follow-up of 5.9 years, estimated 5-year overall survival was 65% (95% confidence interval [CI], 49% to 81%) vs 64% (95% CI, 59% to 69%) for the chronic-phase group (P = .91), and median overall survival was not reached. In terms of relapse-free survival, estimated 5-year outcome for the accelerated-phase group was 49% (95% CI, 32% to 67%) vs 55% (95% CI, 50% to 61%) for the chronic-phase group (P = .65). Estimated 5-year nonrelapse mortality was 20% (95% CI, 8% to 33%) for the accelerated-phase group vs 30% (95% CI, 24% to 35%; P = .25) for the chronic-phase group. In terms of relapse, 5-year incidence was 30% (95% CI, 14% to 46%) for the accelerated-phase group vs 15% (95% CI, 11% to 19%) for the chronic-phase group (P = .02). Results were confirmed in multivariable analysis and propensity score matching. In conclusion, reduced intensity transplantation showed excellent survival but higher relapse for accelerated-phase myelofibrosis.
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http://dx.doi.org/10.1182/bloodadvances.2021006827DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8864646PMC
February 2022

Return to Work Among Young Adult Survivors of Allogeneic Hematopoietic Cell Transplantation in the United States.

Transplant Cell Ther 2021 08 22;27(8):679.e1-679.e8. Epub 2021 Apr 22.

Center for International Blood and Marrow Transplant Research), National Marrow Donor Program/Be The Match, Minneapolis, Minnesota.

Young adult (YA) survivors of allogeneic hematopoietic cell transplantation (HCT) are at risk for late psychosocial challenges, including the inability to return to work post-HCT. Work-related outcomes in this population remain understudied, however. We conducted this study to assess the post-HCT work status of survivors of allogeneic HCT who underwent HCT as YAs and to analyze the patient-, disease-, and HCT-related factors associated with their work status at 1 year post-HCT. Using Center for International Blood and Marrow Transplant Research data, we evaluated the post-HCT work status (full-time, part-time work, unemployed, or medical disability) of 1365 YA HCT survivors who underwent HCT between 2008 and 2015. Percentages of work status categories were reported at 4 time points: 6 months, 1 year, 2 years, and 3 years post-HCT. Percentages of post-HCT work status categories at the 1-year time point were also described in relation to survivors' pre-HCT work status categories. Factors associated with 1-year post-HCT work status (full-time or part-time work) were examined using logistic regression. From 6 months to 3 years post-HCT, the percentage of survivors working full-time increased from 18.3% to 50.7% and the percentage working part-time increased from 6.9% to 10.5%. Of patients in full-time work pre-HCT, 50% were unemployed or on medical disability at 1 year post-HCT. Female sex (odds ratio [OR], 0.55; 95% confidence interval [CI], 0.40 to 0.77), HCT Comorbidity Index score ≥3 (OR, 0.57; 95% CI, 0.39 to 0.82), pre-HCT unemployment (OR, 0.37; 95% CI, 0.24 to 0.56), medical disability (OR, 0.44; 95% CI, 0.28 to 0.70), development of grade III-IV acute graft-versus-host disease (OR, 0.52; 95% CI, 0.34 to 0.80), and relapse within 1 year post-HCT (OR, 0.34; 95% CI, 0.21 to 0.56) were associated with a lower likelihood of employment at 1 year post-HCT. Compared with myeloablative conditioning (MAC) with total body irradiation (TBI), MAC without TBI (OR, 1.71; 95% CI, 1.16 to 2.53) was associated with a greater likelihood of employment at 1 year post-HCT. Graduate school-level education (OR, 2.47; 95% CI, 1.49 to 4.10) was also associated with a greater likelihood of employment at 1 year post-HCT. Although the work status among YA HCT survivors continued to improve over time, a substantial subset became or remained unemployed or on medical disability. These findings underscore the need for effective interventions to support return to work in this population.
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http://dx.doi.org/10.1016/j.jtct.2021.04.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8425287PMC
August 2021

A prognostic score including mutation profile and clinical features for patients with CMML undergoing stem cell transplantation.

Blood Adv 2021 03;5(6):1760-1769

Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

The inclusion of mutation status improved risk stratification for newly diagnosed patients with chronic myelomonocytic leukemia (CMML). Stem cell transplantation is a potentially curative treatment option, and patient selection is critical because of relevant transplant-related morbidity and mortality. We aimed to evaluate the impact of mutation status together with clinical presentations on posttransplant outcome. Our study included 240 patients with a median follow-up of 5.5 years. A significant association with worse survival was identified for the presence of mutations in ASXL1 and/or NRAS. In multivariable analysis, ASXL1- and/or NRAS-mutated genotype (hazard ratio [HR], 1.63), marrow blasts >2% (HR, 1.70), and increasing comorbidity index (continuous HR, 1.16) were independently associated with worse survival. A prognostic score (CMML transplant score) was developed, and the following points were assigned: 4 points for an ASXL1- and/or NRAS-mutated genotype or blasts >2% and 1 point each for an increase of 1 in the comorbidity index. The CMML transplant score (range, 0-20) was predictive of survival and nonrelapse mortality (P < .001 for both). Up to 5 risk groups were identified, showing 5-year survival of 81% for a score of 0 to 1, 49% for a score of 2 to 4, 43% for a score of 5 to 7, 31% for a score of 8 to 10, and 19% for a score >10. The score retained performance after validation (concordance index, 0.68) and good accuracy after calibration. Predictions were superior compared with existing scores designed for the nontransplant setting, which resulted in significant risk reclassification. This CMML transplant score, which incorporated mutation and clinical information, was prognostic in patients specifically undergoing transplantation and may facilitate personalized counseling.
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http://dx.doi.org/10.1182/bloodadvances.2020003600DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7993107PMC
March 2021

Genetic factors rather than blast reduction determine outcomes of allogeneic HCT in BCR-ABL-negative MPN in blast phase.

Blood Adv 2020 11;4(21):5562-5573

Center for International Blood and Marrow Transplant Research (CIBMTR), Department of Medicine, Medical College of Wisconsin, Milwaukee, WI.

There is a limited understanding of the clinical and molecular factors associated with outcomes of hematopoietic cell transplantation (HCT) in patients with BCR-ABL-negative myeloproliferative neoplasms in blast phase (MPN-BP). Using the Center for International Blood and Marrow Transplant Research database, we evaluated HCT outcomes in 177 patients with MPN-BP. Ninety-five (54%) had sufficient DNA for targeted next-generation sequencing of 49 genes clinically relevant in hematologic malignancies. At 5 years, overall survival (OS), cumulative incidence of relapse, and nonrelapse mortality of the study cohort was 18%, 61%, and 25%, respectively. In a multivariable model, poor-risk cytogenetics was associated with inferior OS (hazard ratio [HR], 1.71; 95% CI, 1.21-2.41) due to increased relapse (HR, 1.93; 95% CI, 1.32-2.82). Transplants using mobilized peripheral blood (PB) were associated with better OS (HR, 0.60; 95% CI, 0.38-0.96). No difference in outcomes was observed in patients undergoing HCT with PB/BM blasts <5% vs those with active leukemia. Among the 95 patients with molecular data, mutation of TP53, present in 23%, was the only genetic alteration associated with outcomes. In a multivariate model, TP53-mutant patients had inferior OS (HR, 1.99; 95% CI, 1.14-3.49) and increased incidence of relapse (HR, 2.59; 95% CI, 1.41-4.74). There were no differences in the spectrum of gene mutations, number of mutations, or variant allele frequency between patients undergoing HCT with PB/BM blasts <5% vs those with active leukemia. Genetic factors, namely cytogenetic alterations and TP53 mutation status, rather than degree of cytoreduction predict outcomes of HCT in MPN-BP. No meaningful benefit of conventional HCT was observed in patients with MPN-BP and mutated TP53.
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http://dx.doi.org/10.1182/bloodadvances.2020002727DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7656913PMC
November 2020

Treosulfan-based conditioning is feasible and effective for cord blood recipients: a phase 2 multicenter study.

Blood Adv 2020 07;4(14):3302-3310

Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA.

Although the use of treosulfan (TREO) in conventional donor hematopoietic cell transplantation (HCT) has been extensively evaluated, its use in cord blood transplantation (CBT) for hematologic malignancies has not been reported. Between March 2009 and October 2019, 130 CBT recipients were enrolled in this prospective multicenter phase 2 study. The conditioning regimen consisted of TREO, fludarabine, and a single fraction of 2 Gy total-body irradiation. Cyclosporine and mycophenolate mofetil were used for graft-versus-host disease prophylaxis. The primary end point was incidence of graft failure (GF), and based on risk of GF, patients were classified as low risk (arm 1, n = 66) and high risk (arm 2, n = 64). The median age was 45 years (range, 0.6-65 years). Disease status included acute leukemias in first complete remission (CR; n = 56), in ≥2 CRs (n = 46), and myelodysplastic (n = 25) and myeloproliferative syndromes (n = 3). Thirty-five patients (27%) had received a prior HCT. One hundred twenty-three patients (95%) engrafted, with neutrophil recovery occurring at a median of 19 days for patients on arm 1 and 20 days for patients on arm 2. The 3-year overall survival, relapse-free survival (RFS), transplant-related mortality, and relapse for the combined groups were 66%, 57%, 18%, and 24%, respectively. Among patients who had a prior HCT, RFS at 3 years was 48%. No significant differences in clinical outcomes were seen between the 2 arms. Our results demonstrate that TREO-based conditioning for CBT recipients is safe and effective in promoting CB engraftment with favorable clinical outcomes. This trial was registered at www.clinicaltrials.gov as #NCT00796068.
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http://dx.doi.org/10.1182/bloodadvances.2020002222DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7391133PMC
July 2020

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

Biol Blood Marrow Transplant 2020 12 18;26(12):2197-2203. Epub 2020 Jul 18.

Fred Hutchinson Cancer Research Center, Seattle, Washington; University of Washington School of Medicine, Seattle, Washington.

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.
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http://dx.doi.org/10.1016/j.bbmt.2020.07.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8816377PMC
December 2020

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

Biol Blood Marrow Transplant 2020 08 29;26(8):1520-1526. Epub 2020 Apr 29.

Fred Hutchinson Cancer Research Center, Seattle, Washington; University of Washington School of Medicine, Seattle, Washington.

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.
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http://dx.doi.org/10.1016/j.bbmt.2020.04.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7546432PMC
August 2020

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

Clin Infect Dis 2021 04;72(8):1350-1357

Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.

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.
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http://dx.doi.org/10.1093/cid/ciaa222DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8075034PMC
April 2021

Diagnosis of pulmonary hypertension by noninvasive methods in hematopoietic cell transplant patients with myelofibrosis.

Bone Marrow Transplant 2020 08 12;55(8):1681-1683. Epub 2019 Dec 12.

Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.

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http://dx.doi.org/10.1038/s41409-019-0769-9DOI Listing
August 2020

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

Haematologica 2020 03 9;105(3):652-660. Epub 2019 Jul 9.

Fred Hutchinson Cancer Research Center

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; =0.0002), CMML Prognostic Scoring System (hazard ratio, 14.3, =0.01), and MD Anderson prognostic scores (hazard ratio, 9.4; =0.005). Mortality was associated with high-risk cytogenetics (hazard ratio, 1.88; =0.01) and high Hematopoietic Cell Transplantation Comorbidity Index (score ≥4: hazard ratio, 1.99; =0.01). High overall mutation burden (≥10 mutations: hazard ratio, 3.4; =0.02), and ≥4 mutated epigenetic regulatory genes (hazard ratio 5.4; =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.
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http://dx.doi.org/10.3324/haematol.2019.218677DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7049334PMC
March 2020

Pre-hematopoietic cell transplant Ruxolitinib in patients with primary and secondary myelofibrosis.

Bone Marrow Transplant 2020 01 8;55(1):70-76. Epub 2019 Apr 8.

Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.

Ruxolitinib (Rux), a Jak1/2 inhibitor, results in reduced spleen size and improvement in constitutional symptoms in the majority of patients with myelofibrosis (MF). Therefore Rux, when given prior to hematopoietic cell transplantation (HCT) in patients with MF was hypothesized to improve engraftment, decrease incidence and severity of graft-versus-host disease, and lower non-relapse mortality (NRM). We conducted a phase II prospective trial to assess the effects of pre-HCT Rux on post-HCT outcomes in patients with MF. The primary endpoint was 2-year overall survival. To date, 28 patients (median age 56 years) have been transplanted. The median time on Rux pre-HCT was 7 months. Twenty-three patients received myeloablative and five reduced intensity conditioning. Donors included 14 HLA-matched siblings, 11 matched unrelated, 1 allele mismatched unrelated, and 3 umbilical cord blood. There have been no episodes of cytokine release syndrome and all patients achieved sustained engraftment. Two patients died from NRM and two patients relapsed. With a median follow-up of 13 months, overall survival is 93% (95% CI: 0.73, 0.98) at 1 year and 86% (95% CI: 0.61, 0.96) at 2 years post-HCT. This study demonstrates that pre-HCT Rux is well tolerated and suggests that pre-HCT Rux may improve post-HCT outcome.
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http://dx.doi.org/10.1038/s41409-019-0523-3DOI Listing
January 2020

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

Biol Blood Marrow Transplant 2019 05 28;25(5):1045-1052. Epub 2018 Nov 28.

Clinical Research Division, Fred Hutchinson Cancer Research Center; Seattle, Washington; Division of Medical Oncology, Department of Medicine, University of Washington School of Medicine; Seattle, Washington. Electronic address:

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.
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http://dx.doi.org/10.1016/j.bbmt.2018.11.030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6511303PMC
May 2019

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

Haematologica 2019 04 15;104(4):835-843. Epub 2018 Nov 15.

Fred Hutchinson Cancer Research Center, Clinical Research Division, Seattle, WA, USA

We determined the incidence of disability related to chronic graft--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--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--host disease (HR 2.54; 95% CI: 1.1-5.7, =0.02), and the haplorelated group trended similarly (HR 2.38; 95% CI: 1.0-5.9, =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, =0.0003), similarly to the haplorelated group (HR 4.93; 95% CI: 2.2-11.1, =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--host disease, and were more likely to resume work/school, should help better counseling of pre-hematopoietic cell transplant candidates.
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http://dx.doi.org/10.3324/haematol.2018.202754DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6442956PMC
April 2019

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).

Cancer 2019 01 12;125(1):144-152. Epub 2018 Oct 12.

Center for International Blood and Marrow Transplant Research (CIBMTR), Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin.

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.
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http://dx.doi.org/10.1002/cncr.31781DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6310211PMC
January 2019

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

Biol Blood Marrow Transplant 2019 01 9;25(1):145-150. Epub 2018 Aug 9.

Department of Health Outcomes and Behavior, Moffitt Cancer Center, Tampa, Florida. Electronic address:

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.
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http://dx.doi.org/10.1016/j.bbmt.2018.08.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6310630PMC
January 2019

Quality of Life of Caregivers of Hematopoietic Cell Transplant Recipients.

Biol Blood Marrow Transplant 2018 11 21;24(11):2271-2276. Epub 2018 Jun 21.

Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.

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.
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http://dx.doi.org/10.1016/j.bbmt.2018.06.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6242735PMC
November 2018

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.

Biol Blood Marrow Transplant 2018 05 20;24(5):956-963. Epub 2017 Dec 20.

Fred Hutchinson Cancer Research Center, Seattle, Washington; University of Washington School of Medicine, Seattle, Washington.

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/m/day on days -6 to -4 and i.v. fludarabine, 30 mg/m/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.
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http://dx.doi.org/10.1016/j.bbmt.2017.12.785DOI Listing
May 2018

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

Biol Blood Marrow Transplant 2018 03 10;24(3):555-562. Epub 2017 Nov 10.

Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; Department of Medical Oncology, University of Washington, Seattle, Washington.

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.
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http://dx.doi.org/10.1016/j.bbmt.2017.10.042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5826880PMC
March 2018

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

Biol Blood Marrow Transplant 2018 04 8;24(4):649-658. Epub 2017 Nov 8.

Fred Hutchinson Cancer Research Center, University of Washington, Seattle, Washington. Electronic address:

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.
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http://dx.doi.org/10.1016/j.bbmt.2017.10.037DOI Listing
April 2018

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

Biol Blood Marrow Transplant 2018 02 29;24(2):386-392. Epub 2017 Sep 29.

Fred Hutchinson Cancer Research Center, the University of Washington Medical Center/Seattle Cancer Care Alliance, Seattle, Washington. Electronic address:

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.
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http://dx.doi.org/10.1016/j.bbmt.2017.09.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6481667PMC
February 2018

Mobilized Peripheral Blood Stem Cells Versus Unstimulated Bone Marrow As a Graft Source for T-Cell-Replete Haploidentical Donor Transplantation Using Post-Transplant Cyclophosphamide.

J Clin Oncol 2017 Sep 23;35(26):3002-3009. Epub 2017 Jun 23.

Asad Bashey, Melhem Solh, The Blood and Marrow Transplant Program at Northside Hospital, Atlanta, GA; Mei-Jie Zhang, Andrew St. Martin, Trevor Argall, Mehdi Hamadani, and Mary Eapen, Medical College of Wisconsin, Milwaukee, WI; Shannon R. McCurdy and Ephraim Joseph Fuchs, The Johns Hopkins Hospital, Baltimore, MD; Claudio Anasetti, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL; Stefan O. Ciurea, MD Anderson Cancer Center, Houston, TX; Omotayo Fasan, The Center for Bone Marrow Transplantation at Geisinger Medical Center, Danville; Sameh Gaballa, Thomas Jefferson University Hospital, Philadelphia, PA; Pashna Munshi and Scott Rowley, MedStar Georgetown University Hospital, Washington, DC; Monzr M. Al Malki and Ryotaro Nakamura, City of Hope National Medical Center, Duarte, CA; Paul V. O'Donnell, Massachusetts General Hospital; Robert J. Soiffer, Dana-Farber Cancer Institute, Boston, MA; Miguel-Angel Perales, Memorial Sloan Kettering Cancer Center, New York, NY; Kavita Raj, King's College Hospital, London; Vanderson Rocha, Churchill Hospital, Oxford, United Kingdom; Rizwan Romee, Barnes Jewish Hospital, St Louis, MO; Scott Rowley, Hackensack University Medical Center, Hackensack, NJ; and Rachel B. Salit, Fred Hutchinson Cancer Research Center, Seattle, WA.

Purpose T-cell-replete HLA-haploidentical donor hematopoietic transplantation using post-transplant cyclophosphamide was originally described using bone marrow (BM). With increasing use of mobilized peripheral blood (PB), we compared transplant outcomes after PB and BM transplants. Patients and Methods A total of 681 patients with hematologic malignancy who underwent transplantation in the United States between 2009 and 2014 received BM (n = 481) or PB (n = 190) grafts. Cox regression models were built to examine differences in transplant outcomes by graft type, adjusting for patient, disease, and transplant characteristics. Results Hematopoietic recovery was similar after transplantation of BM and PB (28-day neutrophil recovery, 88% v 93%, P = .07; 100-day platelet recovery, 88% v 85%, P = .33). Risks of grade 2 to 4 acute (hazard ratio [HR], 0.45; P < .001) and chronic (HR, 0.35; P < .001) graft-versus-host disease were lower with transplantation of BM compared with PB. There were no significant differences in overall survival by graft type (HR, 0.99; P = .98), with rates of 54% and 57% at 2 years after transplantation of BM and PB, respectively. There were no differences in nonrelapse mortality risks (HR, 0.92; P = .74) but relapse risks were higher after transplantation of BM (HR, 1.49; P = .009). Additional exploration confirmed that the higher relapse risks after transplantation of BM were limited to patients with leukemia (HR, 1.73; P = .002) and not lymphoma (HR, 0.87; P = .64). Conclusion PB and BM grafts are suitable for haploidentical transplantation with the post-transplant cyclophosphamide approach but with differing patterns of treatment failure. Although, to our knowledge, this is the most comprehensive comparison, these findings must be validated in a randomized prospective comparison with adequate follow-up.
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http://dx.doi.org/10.1200/JCO.2017.72.8428DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5590802PMC
September 2017

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

Biol Blood Marrow Transplant 2017 Apr 9;23(4):654-658. Epub 2017 Feb 9.

Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; Department of Medicine, University of Washington Medical Center, Seattle, Washington.

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.
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http://dx.doi.org/10.1016/j.bbmt.2017.01.084DOI Listing
April 2017

Reduced-Intensity Transplantation for Lymphomas Using Haploidentical Related Donors Versus HLA-Matched Sibling Donors: A Center for International Blood and Marrow Transplant Research Analysis.

J Clin Oncol 2016 09 6;34(26):3141-9. Epub 2016 Jun 6.

Nilanjan Ghosh, Levine Cancer Institute, Carolinas Healthcare System, Charlotte, NC; Reem Karmali, Rush University Medical Center; Sonali M. Smith, The University of Chicago, Chicago, IL; Vanderson Rocha, Churchill Hospital, Oxford, United Kingdom; Kwang Woo Ahn, Alyssa DiGilio, and Mehdi Hamadani, Medical College of Wisconsin & Center for International Blood and Marrow Transplant Research; Parameswaran N. Hari and Anita D'Souza, Medical College of Wisconsin; Timothy S. Fenske, Froedtert Memorial Lutheran Hospital, Milwaukee, WI; Veronika Bachanova, University of Minnesota Medical Center, Minneapolis, MN; Ulrike Bacher, University Medicine Goettingen and University Cancer Center Hamburg, Hamburg, Germany; Parastoo Dahi, Memorial Sloan Kettering Cancer Center-Adults, New York, NY; Marcos de Lima, University Hospitals Case Medical Center, Cleveland; Samantha Jaglowski, The Ohio State University Medical Center, Columbus, OH; Siddhartha Ganguly, University of Kansas Medical Center, Kansas City, KS; Mohamed A. Kharfan-Dabaja, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL; Tim D. Prestidge, Blood and Cancer Centre, Starship Children's Hospital, Auckland, New Zealand; Bipin N. Savani, Vanderbilt University Medical Center, Nashville, TN; Anna M. Sureda, European Group for Blood and Marrow Transplantation and Hospital Duran I Reynals, Barcelona, Spain; Edmund K. Waller, Winship Cancer Institute, Emory University, Atlanta, GA; Alex F. Herrera, City of Hope National Medical Center, Duarte, CA; Philippe Armand, Dana-Farber Cancer Institute, Boston, MA; Rachel B. Salit, Fred Hutchinson Cancer Research Center, Seattle, WA; and Nina D. Wagner-Johnston, Ephraim Fuchs, and Javier Bolaños-Meade, Johns Hopkins University Sidney Kimmel Cancer Center, Baltimore, MD.

Purpose: Related donor haploidentical hematopoietic cell transplantation (Haplo-HCT) using post-transplantation cyclophosphamide (PT-Cy) is increasingly used in patients lacking HLA-matched sibling donors (MSD). We compared outcomes after Haplo-HCT using PT-Cy with MSD-HCT in patients with lymphoma, using the Center for International Blood and Marrow Transplant Research registry.

Materials And Methods: We evaluated 987 adult patients undergoing either Haplo-HCT (n = 180) or MSD-HCT (n = 807) following reduced-intensity conditioning regimens. The haploidentical group received graft-versus-host disease (GVHD) prophylaxis with PT-Cy with or without a calcineurin inhibitor and mycophenolate. The MSD group received calcineurin inhibitor-based GVHD prophylaxis.

Results: Median follow-up of survivors was 3 years. The 28-day neutrophil recovery was similar in the two groups (95% v 97%; P = .31). The 28-day platelet recovery was delayed in the haploidentical group compared with the MSD group (63% v 91%; P = .001). Cumulative incidence of grade II to IV acute GVHD at day 100 was similar between the two groups (27% v 25%; P = .84). Cumulative incidence of chronic GVHD at 1 year was significantly lower after Haplo-HCT (12% v 45%; P < .001), and this benefit was confirmed on multivariate analysis (relative risk, 0.21; 95% CI, 0.14 to 0.31; P < .001). For Haplo-HCT v MSD-HCT, 3-year rates of nonrelapse mortality (15% v 13%; P = .41), relapse/progression (37% v 40%; P = .51), progression-free survival (48% v 48%; P = .96), and overall survival (61% v 62%; P = .82) were similar. Multivariate analysis showed no significant difference between Haplo-HCT and MSD-HCT in terms of nonrelapse mortality (P = .06), progression/relapse (P = .10), progression-free survival (P = .83), and overall survival (P = .34).

Conclusion: Haplo-HCT with PT-Cy provides survival outcomes comparable to MSD-HCT, with a significantly lower risk of chronic GVHD.
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http://dx.doi.org/10.1200/JCO.2015.66.3476DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5012706PMC
September 2016

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

Biol Blood Marrow Transplant 2016 Feb 17;22(2):339-343. Epub 2015 Oct 17.

Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; Department of Pediatrics, Seattle Children's Medical Center, Seattle, Washington.

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.
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http://dx.doi.org/10.1016/j.bbmt.2015.10.013DOI Listing
February 2016

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

Cancer 2015 Dec 19;121(23):4250-7. Epub 2015 Aug 19.

Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.

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.
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http://dx.doi.org/10.1002/cncr.29651DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4666727PMC
December 2015

Role of hematopoietic stem cell transplantation in patients with myeloproliferative disease.

Hematol Oncol Clin North Am 2014 Dec 3;28(6):1023-35. Epub 2014 Oct 3.

Clinical Research Division, Cord Blood Transplant Research Program, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; University of Washington Medical Center, Seattle, WA 98195, USA. Electronic address:

Myeloproliferative neoplasms (MPN) are clonal hematopoietic stem cell disorders. While some MPN patients have an indolent course, all are at risk of progressing to severe marrow failure or transforming into acute leukemia. Allogeneic hematopoietic cell transplantation (allo-HCT) is the only potential curative therapy. Major pre-transplant risk factors are disease stage of the MPN, the presence of comorbid conditions and the use of HLA non-identical donors. The development of reduced-intensity conditioning regimens has allowed for successful allo-HCT even for older patients and patients with comorbid conditions. The pre-transplant use of JAK2 inhibitors, which may be effective in down staging a patient's disease, may improve the outcomes following allo-HCT.
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http://dx.doi.org/10.1016/j.hoc.2014.08.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4254532PMC
December 2014

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

Biol Blood Marrow Transplant 2014 Jul 20;20(7):969-78. Epub 2014 Mar 20.

Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, Maryland.

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.
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http://dx.doi.org/10.1016/j.bbmt.2014.03.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4057942PMC
July 2014

Host lymphocyte depletion as a strategy to facilitate early full donor chimerism after reduced-intensity allogeneic stem cell transplantation.

Biol Blood Marrow Transplant 2013 Oct 13;19(10):1509-13. Epub 2013 Aug 13.

Experimental Transplantation and Immunology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland; Fred Hutchinson Cancer Research Center, Clinical Research Division, Seattle, Washington. Electronic address:

Reduced-intensity conditioning (RIC) allogeneic hematopoietic stem cell transplantation (RIC-alloHSCT) is associated with lower toxicity but higher rates of prolonged mixed chimerism than myeloablative conditioning. Decreased pretransplantation host T cell numbers are associated with less graft rejection and early full donor chimerism. To compensate for variability in pretransplantation host lymphocyte numbers and facilitate the achievement of rapid full donor chimerism, we tested a strategy of targeted lymphocyte depletion (TLD) using chemotherapy at conventional doses to provide cytoreduction and lymphocyte depletion before RIC-alloHSCT. In our study, 111 patients with advanced hematologic malignancies received 1 to 3 cycles of conventional-dose chemotherapy to reduce circulating lymphocytes to a predetermined level. Patients then underwent RIC-alloHSCT from HLA-matched siblings. Patients received a median of 2 cycles of TLD chemotherapy, resulting in a median 71% decline in CD4(+) count. All patients engrafted; there were no late graft failures. By day +14, median CD3(+) chimerism was 99% donor and was significantly associated with lower post-TLD CD4(+) counts (P = .012). One- and 5-year treatment-related mortality were 15% and 21%, respectively. At 1-year follow-up, 66% of patients had achieved complete remission (CR) of which 92% were not in CR at the time of transplantation. Overall survival at 1 and 5 years post transplantation were 66% and 47%, respectively.
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http://dx.doi.org/10.1016/j.bbmt.2013.08.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7511977PMC
October 2013
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