Long-term survival is now an expected outcome after hematopoietic cell transplantation (HCT). However, the burden of morbidity long-term after HCT remains unknown. We examined the magnitude of risk ...of chronic health conditions reported by 1022 HCT survivors and their siblings (n = 309). A severity score (grades 1 mild through 4 life-threatening) was assigned to each health condition using the Common Terminology Criteria for Adverse Events, Version 3. Sixty-six percent of the HCT survivors reported at least one chronic condition; 18% reported severe/life-threatening conditions; comparable values in siblings were 39% and 8%, respectively (P < .001). The cumulative incidence of a chronic health condition among HCT survivors was 59% (95% confidence interval CI, 56%-62%) at 10 years after HCT; for severe/life-threatening conditions or death from chronic health conditions, the 10-year cumulative incidence approached 35% (95% CI, 32%-39%). HCT survivors were twice as likely as siblings to develop a chronic condition (95% CI, 1.6-2.1), and 3.5 times to develop severe/life-threatening conditions (95% CI, 2.3-5.4). HCT survivors with chronic graft-versus-host disease were 4.7 times as likely to develop severe/life-threatening conditions (95% CI, 3.0-7.2). The burden of long-term morbidity borne by HCT survivors is substantial, and long-term follow-up of patients who received transplantation is recommended.
Effectiveness of double umbilical cord blood (dUCB) grafts relative to conventional marrow and mobilized peripheral blood from related and unrelated donors has yet to be established. We studied 536 ...patients at the Fred Hutchinson Cancer Research Center and University of Minnesota with malignant disease who underwent transplantation with an human leukocyte antigen (HLA)–matched related donor (MRD, n = 204), HLA allele–matched unrelated donor (MUD, n = 152) or 1-antigen–mismatched unrelated adult donor (MMUD, n = 52) or 4-6/6 HLA matched dUCB (n = 128) graft after myeloablative conditioning. Leukemia-free survival at 5 years was similar for each donor type (dUCB 51% 95% confidence interval (CI), 41%-59%; MRD 33% 95% CI, 26%-41%; MUD 48% 40%-56%; MMUD 38% 95% CI, 25%-51%). The risk of relapse was lower in recipients of dUCB (15%, 95% CI, 9%-22%) compared with MRD (43%, 95% CI, 35%-52%), MUD (37%, 95% CI, 29%-46%) and MMUD (35%, 95% CI, 21%-48%), yet nonrelapse mortality was higher for dUCB (34%, 95% CI, 25%-42%), MRD (24% (95% CI, 17%-39%), and MUD (14%, 95% CI, 9%-20%). We conclude that leukemia-free survival after dUCB transplantation is comparable with that observed after MRD and MUD transplantation. For patients without an available HLA matched donor, the use of 2 partially HLA-matched UCB units is a suitable alternative.
Graft-versus-host disease (GVHD) is the major cause of non-relapse mortality after allogeneic haemopoietic stem-cell transplantation (SCT). The severity of symptoms at the onset of GVHD does not ...accurately define risk, and thus most patients are treated alike with high dose systemic corticosteroids. We aimed to define clinically meaningful risk strata for patients with newly diagnosed acute GVHD using plasma biomarkers.
Between April 13, 2000, and May 7, 2013, we prospectively collected plasma from 492 SCT patients with newly diagnosed acute GVHD and randomly assigned (2:1) using a random number generator, conditional on the final two datasets having the same median day of onset, into training (n=328) and test (n=164) sets. We used the concentrations of three recently validated biomarkers (TNFR1, ST2, and Reg3α) to create an algorithm that computed the probability of non-relapse mortality 6 months after GVHD onset for individual patients in the training set alone. We rank ordered the probabilities and identified thresholds that created three distinct non-relapse mortality scores. We evaluated the algorithm in the test set, and again in an independent validation set of an additional 300 patients who underwent stem cell transplant and were enrolled on multicentre clinical trials of primary therapy for acute GVHD.
In all three datasets (training, test, and validation), the cumulative incidence of 6-month non-relapse mortality significantly increased as the Ann Arbor GVHD score increased. In the multicentre validation set, scores were 8% (95% CI 3-16) for score 1, 27% (20-34) for score 2, and 46% (33-58) for score 3 (p<0·0001). Conversely, the response to primary GVHD treatment within 28 days decreased as the GVHD score increased 86% for score 1, 67% for score 2, and 46% for score 3 in the multicentre validation set, p<0·0001).
Biomarker-based scores can be used to guide risk-adapted therapy at the onset of acute GVHD. High risk patients with a score of 3 are candidates for intensive primary therapy, while low risk patients with a score of 1 are candidates for rapid tapers of systemic steroid therapy.
The National Cancer Institute, the National Heart, Lung, and Blood Institute, the National Institute of Allergy and Infectious Diseases, the Doris Duke Charitable Fund, the American Cancer Society, and the Judith Devries Fund.
PURPOSE Acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) primarily afflict older individuals. Hematopoietic cell transplantation (HCT) is generally not offered because of concerns ...of excess morbidity and mortality. Reduced-intensity conditioning (RIC) regimens allow increased use of allogeneic HCT for older patients. To define prognostic factors impacting long-term outcomes of RIC regimens in patients older than age 40 years with AML in first complete remission or MDS and to determine the impact of age, we analyzed data from the Center for International Blood and Marrow Transplant Research (CIBMTR). PATIENTS AND METHODS We reviewed data reported to the CIBMTR (1995 to 2005) on 1,080 patients undergoing RIC HCT. Outcomes analyzed included neutrophil recovery, incidence of acute or chronic graft-versus-host disease (GVHD), nonrelapse mortality (NRM), relapse, disease-free survival (DFS), and overall survival (OS). RESULTS Univariate analyses demonstrated no age group differences in NRM, grade 2 to 4 acute GVHD, chronic GVHD, or relapse. Patients age 40 to 54, 55 to 59, 60 to 64, and > or = 65 years had 2-year survival rates as follows: 44% (95% CI, 37% to 52%), 50% (95% CI, 41% to 59%), 34% (95% CI, 25% to 43%), and 36% (95% CI, 24% to 49%), respectively, for patients with AML (P = .06); and 42% (95% CI, 35% to 49%), 35% (95% CI, 27% to 43%), 45% (95% CI, 36% to 54%), and 38% (95% CI, 25% to 51%), respectively, for patients with MDS (P = .37). Multivariate analysis revealed no significant impact of age on NRM, relapse, DFS, or OS (all P > .3). Greater HLA disparity adversely affected 2-year NRM, DFS, and OS. Unfavorable cytogenetics adversely impacted relapse, DFS, and OS. Better pre-HCT performance status predicted improved 2-year OS. CONCLUSION With these similar outcomes observed in older patients, we conclude that older age alone should not be considered a contraindication to HCT.
In vivo expansion of haploidentical natural killer (NK) cell infusions with interleukin-2 (IL-2) can induce remission of refractory acute myeloid leukemia, but efficacy may be hampered by concurrent ...stimulation of host regulatory T cells. To overcome this limitation, we substituted the NK homeostatic factor IL-15 in 2 phase 1/2 trials. Forty-two patients received either intravenous (IV) (NCT01385423) or subcutaneous (SC) (NCT02395822) recombinant human IL-15 (rhIL-15) after lymphodepleting chemotherapy and haploidentical NK cells. Escalating doses of rhIL-15 (0.3-1.0 μg/kg) were given on 12 consecutive days in a phase 1 trial. Of 26 patients, 36% had robust in vivo NK-cell expansion at day 14, and 32% achieved complete remission. Hypothesizing that SC dosing of rhIL-15 would be safer and better tolerated, 16 patients received 10 once per day doses of SC rhIL-15 at 2.0 μg/kg on a phase 2 trial. NK-cell expansion at day 14 was seen in 27% of the patients, and 40% achieved remission. rhIL-15 induced better rates of in vivo NK-cell expansion and remission compared with previous trials with IL-2, but it was associated with previously unreported cytokine release syndrome (CRS) after SC but not IV dosing. CRS was observed in 56% of patients given SC rhIL-15 (with concurrent neurologic toxicity in 5 of 9 patients) and was responsive to steroids and tocilizumab. SC administration was associated with slower pharmacokinetic clearance and higher levels of IL-6 than IV dosing. These novel trials testing the use of IL-15 to potentiate cell therapy suggest that dosing schedules based on pharmacokinetics and pharmacodynamics will preserve the therapeutic benefits of IL-15 and minimize CRS. These trials were registered at www.clinicaltrials.gov as #NCT01385423 and #NCT02395822.
•Haploidentical NK-cell infusions given with rhIL-15 achieved remission in 35% of patients with refractory acute myeloid leukemia.•SC dosing of rhIL-15 after lymphodepletion prolongs drug exposure leading to cytokine release syndrome and neurotoxicity.
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In 2005, the National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic GVHD proposed a new scoring system for individual organs and an algorithm for ...calculating global severity (mild, moderate, severe). The Chronic GVHD Consortium was established to test these new criteria. This report includes the first 298 adult patients enrolled at 5 centers of the Consortium. Patients were assessed every 3-6 months using standardized forms recommended by the Consensus Conference. At the time of study enrollment, global chronic GVHD severity was mild in 10% (n = 32), moderate in 59% (n = 175), and severe in 31% (n = 91). Skin, lung, or eye scores determined the global severity score in the majority of cases, with the other 5 organs determining 16% of the global severity scores. Conventional risk factors predictive for onset of chronic GVHD and nonrelapse mortality in people with chronic GVHD were not associated with NIH global severity scores. Global severity scores at enrollment were associated with nonrelapse mortality (P < .0001) and survival (P < .0001); 2-year overall survival was 62% (severe), 86% (moderate), and 97% (mild). Patients with mild chronic GVHD have a good prognosis, while patients with severe chronic GVHD have a poor prognosis. This study was registered at www.clinicaltrials.gov as no. NCT00637689.
Killer cell Ig-like receptors (KIRs) interact with HLA class I ligands to regulate NK cell development and function. These interactions affect the outcome of unrelated donor hematopoietic cell ...transplantation (HCT). We have shown previously that donors with KIR B versus KIR A haplotypes improve the clinical outcome for patients with acute myelogenous leukemia by reducing the incidence of leukemic relapse and improving leukemia-free survival (LFS). Both centromeric and telomeric KIR B genes contribute to the effect, but the centromeric genes are dominant. They include the genes encoding inhibitory KIRs that are specific for the C1 and C2 epitopes of HLA-C. We used an expanded cohort of 1532 T cell-replete transplants to examine the interaction between donor KIR B genes and recipient class I HLA KIR ligands. The relapse protection associated with donor KIR B is enhanced in recipients who have one or two C1-bearing HLA-C allotypes, compared with C2 homozygous recipients, with no effect due to donor HLA. The protective interaction between donors with two or more, versus none or one, KIR B motifs and recipient C1 was specific to transplants with class I mismatch at HLA-C (RR of leukemia-free survival, 0.57 0.40-0.79; p = 0.001) irrespective of the KIR ligand mismatch status of the transplant. The survival advantage and relapse protection in C1/x recipients compared with C2/C2 recipients was similar irrespective of the particular donor KIR B genes. Understanding the interactions between donor KIR and recipient HLA class I can be used to inform donor selection to improve outcome of unrelated donor hematopoietic cell transplantation for acute myelogenous leukemia.
Historically, alternative donor hematopoietic cell transplantation (HCT) for Fanconi anemia (FA) patients resulted in excessive morbidity and mortality. To improve outcomes, we made sequential ...changes to the HCT conditioning regimen. A total of 130 FA patients (median age, 9.0 years; range, 1-48) underwent alternative donor HCT at the University of Minnesota between 1995 and 2012. All patients received cyclophosphamide (CY), single fraction total body irradiation (TBI), and antithymocyte globulin (ATG) with or without fludarabine (FLU), followed by T-cell–depleted bone marrow or unmanipulated umbilical cord blood transplantation. The addition of FLU enhanced engraftment 3-fold. The incidence of grades 2-4 acute and chronic graft-versus-host disease was 20% and 10%, respectively. Severe toxicity was highest in patients >10 years of age or those with a history of opportunistic infections or transfusions before HCT. Mortality was lowest in patients without a history of opportunistic infection or transfusions and who received conditioning with TBI 300 cGy, CY, FLU, and ATG. These patients had a probability of survival of 94% at 5 years. Alternative donor HCT is now associated with excellent survival for patients without prior opportunistic infections or transfusions and should be considered for all FA patients after the onset of marrow failure. These studies were registered at http://www.clinicaltrials.gov as NCT00005898, NCT00167206, and NCT00352976.
•With no prior opportunistic infections/transfusions, 5-year survival after alternative donor HCT with TBI 300 cGy, CY, FLU, and ATG was 94%.•Today, most FA patients with standard risk disease are cured of their bone marrow failure by HCT even without an HLA-matched sibling donor.
Quality of life (QOL) after hematopoietic cell transplantation (HCT) is compromised by chronic GVHD. In a prospectively assembled multicenter cohort of adults with chronic GVHD (n = 298), we examined ...the relationship between chronic GVHD severity defined by National Institutes of Health (NIH) criteria and QOL as measured by the SF-36 and FACT-BMT instruments at time of enrollment. Chronic GVHD severity was independently associated with QOL, adjusting for age. Compared with population normative data, SF-36 scores were more than a SD (10 points) lower on average for the summary physical component score (PCS) and role-physical subscale, and significantly lower (with magnitude 4-10 points) for several other subscales. Patients with moderate and severe cGVHD had PCS scores comparable with scores reported for systemic sclerosis, systemic lupus erythematosus, and multiple sclerosis, and greater impairment compared with common chronic conditions including diabetes, hypertension, and chronic lung disease. Moderate to severe cGVHD as defined by NIH criteria is associated with significant compromise in multiple QOL domains, with PCS scores in the range of other systemic autoimmune diseases. Compromised QOL provides a functional assessment of the effects of chronic GVHD, and may be measured in cGVHD clinical studies using either the SF-36 or the FACT-BMT.
We assessed late mortality in 1479 individuals who had survived 2 or more years after allogeneic hematopoietic cell transplantation (HCT). Median age at HCT was 25.9 years and median length of ...follow-up was 9.5 years. The conditional survival probability at 15 years from HCT was 80.2% (SE = 1.9%) for those who were disease-free at entry into the cohort, and the relative mortality was 9.9 (95% confidence interval, 8.7-11.2). Relative mortality decreased with time from HCT, but remained significantly elevated at 15 years after HCT (standardized mortality ratio = 2.2). Relapse of primary disease (29%) and chronic graft-versus-host disease (cGVHD: 22%) were the leading causes of premature death. Nonrelapse-related mortality was increased among patients older than 18 years at HCT (18-45 years: relative risk RR = 1.7; 46+ years: RR = 3.7) and among those with cGVHD (RR = 2.7), and was lower among patients who received methotrexate for GVHD prophylaxis (RR = 0.5). HCT survivors were more likely to report difficulty in holding jobs (odds ratio OR = 13.9), and in obtaining health (OR = 7.1) or life (OR = 9.9) insurance compared with siblings. This study demonstrates that mortality rates remain twice as high as that of the general population among 15-year survivors of HCT, and that the survivors face challenges affecting their health and well-being.
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