Source of hematopoietic progenitor cells determines their capacity to generate innate lymphoid cells ex vivo.

BACKGROUND AIMS: The success of allogeneic hematopoietic cell transplantation (HCT) as therapy for hematologic conditions is negatively impacted by the occurrence of graft-versus-host disease (GVHD). Tissue damage, caused, for example, by chemotherapy and radiotherapy, is a key factor in GVHD pathogenesis. Innate lymphoid cells (ILCs) are important mediators of tissue repair and homeostasis. The presence of ILCs before, and enhanced ILC reconstitution after, allogeneic HCT is associated with a reduced risk to develop mucositis and GVHD. However, ILC reconstitution after allogeneic HCT is slow and often incomplete. A way to replenish the pool of ILC relies on the differentiation of hematopoietic progenitor cells (HPCs) into ILC. METHODS: We developed an ex vivo stromal cell-containing culture system to study the capacity of HPCs to differentiate into all mature helper ILC subsets. RESULTS: ILC development depended on the source of HPCs. ILCs developed at high frequencies from umbilical cord blood- and fetal liver-derived HPC and at low frequencies when HPCs were obtained from allogeneic or autologous adult HCT grafts or healthy adult bone marrow. Although all helper ILC subsets could be generated from adult HPC sources, development of tissue protective ILC2 and NKp44+ ILC3 was notoriously difficult. CONCLUSIONS: Our data suggest that slow ILC recovery after allogeneic HCT may be related to an intrinsic incapability of adult HPC to develop into ILC.

Gut microbiome in allogeneic HCT survivors: The insults are gone but the damage lingers.

The gut microbiome is an important regulator of health and disease. The report by Hino et al. suggests that damage to the microbiome, inflicted before and soon after allogeneic haematopoietic progenitor cell transplantation, does not heal by itself, most likely with consequences for late transplantation outcomes. Commentary on: Hino et al. Prolonged gut microbial alterations in post-transplant survivors of allogeneic haematopoietic stem cell transplantation. Br J Haematol 2023;200:725-737.

Economic and clinical burden associated with respiratory viral infections after allogeneic hematopoietic cell transplant in the United States.

BACKGROUND: Allogeneic hematopoietic cell transplant (allo-HCT) recipients are at increased risk for respiratory viral infections (RVIs), which invoke substantial morbidity and mortality. Limited effective antiviral options and drug resistance often hamper successful RVI treatment, creating additional burden for patients and the health care system. METHODS: Using an open-source health care claims database, we examined differences in clinical outcomes, health resource utilization, and total reimbursements during the 1-year period following allo-HCT in patients with and without any RVI infection (respiratory syncytial virus, influenza, parainfluenza virus, and human metapneumovirus). RVIs were diagnosed at any time ≤1 year after allo-HCT and identified by International Classification of Disease codes. Analyses were stratified by the presence or absence of acute or chronic graft-versus-host disease (GVHD). RESULTS: The study included 13 363 allo-HCT patients, 1368 (10.2%) of whom had a diagnostic code for any RVI. A higher proportion of patients with any RVI had pneumonia ≤1 year after allo-HCT compared to patients without any RVI, with or without GVHD. Patients with any RVI had higher all-cause mortality risk, longer length of post-allo-HCT hospital stay, higher readmission rate, and higher number of hospital days after allo-HCT compared to patients without the infection (all p < .05). Total unadjusted median reimbursements were higher for those with any RVI and each specific RVI assessed than those without the specific infection, with or without GVHD. CONCLUSION: Allo-HCT patients with RVIs had significantly worse clinical outcomes and increased health resource utilization and reimbursements during the year following allo-HCT, with or without GVHD.

Experience with a Reduced Toxicity Allogeneic Transplant Regimen for Non-CGD Primary Immune Deficiencies Requiring Myeloablation.

PURPOSE: A need exists for reduced toxicity conditioning regimens that offer less toxicity while maintaining myeloablation, especially for primary immune deficiencies where myeloablation or high donor myeloid chimerism is required to achieve cure. We adapted a busulfan and fludarabine regimen by Gungor et al. for children and young adults undergoing allogeneic HCT for non-CGD primary immune deficiencies requiring myeloablation or high donor myeloid chimerism, and herein report our experience. METHODS: We retrospectively reviewed records of 41 consecutive patients who underwent allogeneic HCT for Wiskott-Aldrich syndrome (n = 12), primary HLH/XLP (n = 10), CD40L deficiency (n = 7), or other (n = 12) primary immune deficiencies with a conditioning regimen containing pharmacokinetic-guided busulfan dosing which achieved a cumulative AUC between 57 and 74 mg/L × h (65-80% of conventional myeloablative exposure), along with fludarabine and alemtuzumab or anti-thymocyte globulin at 3 transplant centers between 2014 and 2019. RESULTS: Forty-one patients underwent a first (n = 33) or second (n = 8) allogeneic HCT. Median age was 2.3 years (range, 0.3 years-19.8 years). All but one patient (97.5%) achieved neutrophil recovery at a median of 14 days (range, 11-34 days). One patient developed sinusoidal obstruction syndrome and two patients developed diffuse alveolar hemorrhage. Four patients developed grades II-IV acute GVHD. Three patients developed chronic GVHD. One-year overall survival was 90% (95% confidence interval [CI] 81-99%) and event-free survival was 83% (95% CI 71-94%). CONCLUSIONS: Our experience suggests that a reduced toxicity busulfan-fludarabine regimen offers low toxicity, low incidence of grades 2-4 GVHD, durable myeloid engraftment, and excellent survival, and may be considered for a variety of primary immune deficiencies where myeloablative HCT is desired.

A biomarker-guided, prospective, phase 2 trial of pre-emptive graft-versus-host disease therapy using anti-thymocyte globulin.

BACKGROUND AIMS: Intensified immunosuppressive prophylaxis for graft-versus-host disease (GVHD) may be toxic and therefore warranted only in patients at high risk of developing GVHD. In patients who underwent allogeneic hematopoietic cell transplant at the authors' center, high serum soluble IL-2 receptor alpha (sIL-2Rα) and low IL-15 levels on day 7 post-transplant were found to predict a high risk of developing clinically significant GVHD (sGVHD), defined as grade 2-4 acute GVHD or moderate to severe chronic GVHD. METHODS: This was a prospective, phase 2 trial in which high-risk patients (serum sIL-2Rα >4500 ng/L or IL-15 <31 ng/L) received rabbit anti-thymocyte globulin (ATG) 3 mg/kg on day 8 post-transplant. Controls consisted of patients who had their sIL-2Rα/IL-15 levels measured but did not participate in the trial. A total of 68 trial patients and 143 controls were accrued to this study. The primary endpoint was incidence of sGVHD. RESULTS: There was a reduction in sGVHD in high-risk trial patients (received day 8 ATG) compared with high-risk controls (did not receive day 8 ATG) (sub-hazard ratio [SHR] = 0.48, P < 0.05). There was no significant difference between the groups in overall survival or relapse; however, there was a greater incidence of non-GVHD-associated non-relapse mortality in high-risk trial patients (SHR = 3.73, P < 0.05), mostly related to infections. This may be due in part to the biomarkers ineffectively stratifying GVHD risk. CONCLUSIONS: Pre-emptive ATG therapy is both feasible and effective at reducing sGVHD without increasing relapse. Further mitigation strategies are needed to reduce the risk of infection associated with intensified GVHD prophylaxis. This study was registered at ClinicalTrials.gov (NCT01994824).

Venetoclax and donor lymphocyte infusion for early relapsed acute myeloid leukemia after allogeneic hematopoietic cell transplantation. A retrospective multicenter trial.

Prognosis in patients with post allogeneic HCT-early relapse of acute myeloid leukemia (<6 months post HCT) is dismal and response to salvage treatment is < 20%. In addition, majority of patients at this early point are unable to withstand intensive salvage chemotherapy. We hypothesized that the combination of donor lymphocyte infusion (DLI) and venetoclax may result in increased response in this difficult to treat patient group. We retrospectively analyzed 22 patients from February 2017-December 2019, who were given the Venetoclax/DLI combination. Median age was 65 (43-75) years. There were no cases of tumor lysis syndrome. Microbiology documented infections occurred in 8 patients (36%). Majority were able to tolerate the protocol without admissions. Acute GVHD was observed in 4 (18%) patients and cGVHD was observed in 6 (27%) patients. Overall response was observed in 11 (50%) patients (CR, n = 4; CRi, n = 1; CRp, n = 4; MLFS n = 2). Median time to response was 28 (18-67) days and median cycles of venetoclax 2 [1-8] and duration of response were 135 (31-564) days. Median survival was 6.1 months (95% CI .73-11.4). Cox regression model for survival showed decreased WBC at relapse, GVHD and better performance status were associated with better survival. These results may endorse the hypothesis that enhancing alloreactivity combined with venetoclax is safe and efficacious and should be further investigated in prospective trials.

Comorbidity profile of adult survivors at 20 years following allogeneic hematopoietic cell transplantation.

Numerous chronic medical conditions and complications can arise following allogeneic hematopoietic cell transplantation (HCT) that may have a negative impact on survival and quality of life. OBJECTIVE: The purpose of the present study was to review the comorbidities of a single-center cohort of allogeneic HCT recipients that survived 20 years postallogeneic transplantation. METHODS: We retrospectively investigated 172 patients that underwent allogeneic HCT at the Princess Margaret Cancer Centre between 1979 and 1998 and who survived at least 20 years post-HCT. RESULTS: The most frequent individual comorbidities documented were dyslipidemia (29%), hypertension (31%), osteoporosis (15%), hypothyroidism (15%), and depression/anxiety (13%). Follow-up data following the 20-year mark were available for 135 patients, overall survival (OS) of that group at 5 and 10 years was 94% and 90%, respectively. When grouped by the number of concurrent comorbidities, there was a significant difference in OS between the groups with 0-1, 2-3, and ≥4 comorbidities (P = .01). CONCLUSIONS: Evidently, long-term allogeneic HCT recipients may develop a number of comorbidities that negatively influence survival even past the 20-year post-transplant mark. These findings warrant the continuous long-term medical follow-up of allogeneic transplant patients, regardless of age or time that has lapsed post-HCT.

Antipneumococcal Seroprotection Years After Vaccination in Allogeneic Hematopoietic Cell Transplant Recipients.

BACKGROUND: International guidelines recommend vaccinating allogeneic hematopoietic cell transplant (HCT) recipients at 3 months after transplant, giving 3 doses of pneumococcal conjugate vaccine (PCV) followed by either a dose of 23-valent pneumococcal polysaccharide vaccine (PSV23) or a fourth PCV dose in the case of graft-versus-host disease (GvHD). However, the long-term immunity after this regimen is unknown, and there is no recommendation from 24 months after transplant regarding boosts. Our objective was to assess the antipneumococcal antibody titers and seroprotection rates of allogeneic HCT recipients years after different schedules of vaccination. METHODS: We assessed 100 adult HCT recipients a median of 9.3 years (range: 1.7-40) after transplant. All patients had received at least one dose of PCV and were assessed for antipneumococcal immunoglobulin G (IgG) antibody titers against the 7 serotypes shared by PCV7, PCV13, and PSV23. Sixty-six percent of the patients had been vaccinated according to the current guidelines. RESULTS: Considering an IgG titer ≥ 0.35 µg/mL as protective for each serotype, the seroprotection rate was 50% for 7/7 serotypes and 70% for 5/7 serotypes, with no differences between the different vaccination schedules. The lack of seroprotection was associated with a transplant performed not in complete remission or from a cord-blood unit, a relapse after transplant, or chronic GvHD at assessment. CONCLUSION: Because only half of the vaccinated patients had long-term protection, pending prospective studies defining the best boost program after the initial one, we recommend the assessment of specific IgG titers starting from 24 months to decide for further doses.

Postremission Consolidation by Autologous Hematopoietic Cell Transplantation (HCT) for Acute Myeloid Leukemia in First Complete Remission (CR) and Negative Implications for Subsequent Allogeneic HCT in Second CR: A Study by the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation (EBMT).

After autologous hematopoietic cell transplantation (HCT) in the first complete remission (CR1), patients with acute myeloid leukemia (AML) may relapse and undergo allogeneic HCT in the second complete remission (CR2). The aim of this study was to analyze the outcome of allogeneic HCT performed in CR2 comparing patients with prior consolidation by autologous HCT versus patients with chemotherapy consolidation. Included were 2619 adults with allogeneic HCT in CR2 from 2000 to 2017 with (n = 417) or without (n = 2202) prior autologous HCT. Patient groups were not entirely comparable; patients with prior autologous HCT were younger, had less often a favorable cytogenetic profile, had more commonly donors other than matched siblings, and more often received reduced-intensity conditioning. In multivariate analysis, nonrelapse mortality risks in patients with prior autologous HCT were 1.34 (1.07 to 1.67; P = .01) after adjustment for age, cytogenetic risk, transplant year, donor, conditioning intensity, sex matching, interval diagnosis-relapse, and relapse-allogeneic HCT as compared with chemotherapy consolidation. Similarly, risks of events in leukemia-free survival and graft-versus-host disease, relapse-free survival were higher with prior autologous HCT, 1.17 (1.01 to 1.35), P = .03 and 1.18 (1.03 to 1.35), P = .02, respectively. Risk of death was also higher, 1.13 (0.97 to 1.32), P = .1, but this was not significant. Postremission consolidation with autologous HCT for AML in CR1 increases toxicity of subsequent allogeneic HCT in CR2.

Hematopoietic Stem Cell Transplant Recipients Surviving at Least 2 Years from Transplant Have Survival Rates Approaching Population Levels in the Modern Era of Transplantation.

The health and outcomes of long-term survivors after hematopoietic cell transplant (HCT) are areas of evolving interest as short-term transplant outcomes improve. Because recent changes in transplant practice have likely changed the survivor population, we sought to assess the survival of a contemporary cohort of patients who were alive and free of disease 2 years after HCT. Data were extracted from first transplants documented between 2002 and 2011 in the Australasian Bone Marrow Transplant Recipient Registry on patients who received an allogeneic HCT for acute myeloid leukemia (AML), acute lymphoblastic leukemia, chronic myeloid leukemia (CML), non-Hodgkin lymphoma, and myelodysplastic syndromes or an autologous HCT for myeloma or lymphoma. Patients were included if they had survived at least 2 years without disease relapse or progression. Mortality rates were compared with standard Australian and New Zealand populations using relative-survival analysis. A total of 1562 allogeneic and 3822 autologous HCT patients were included, with a median follow-up of 5.6 years. Compared with a matched group of patients from our previous study from 1992 to 2001, the contemporary cohort of allogeneic HCT recipients was older and more likely to receive peripheral blood stem cells and from unrelated donors. Allogeneic HCT for AML increased, wheresa transplants for CML fell from 32% to 8%. Increasing use of reduced-intensity conditioning and unrelated donors was also seen. Long-term survival after allogeneic and autologous HCT were very similar to the previous 1992 to 2001 cohort despite changes in practice over time. Recipients of autologous HCT for myeloma demonstrated substantially lower overall survival than HCT for other indications with no clear plateau. Annual relative survival for survivors of allogeneic HCT was 96% to 99% of the general population but only 89% to 96% of the general population for recipients of autologous HCT. Late deaths were primarily due to nonrelapse causes after allogeneic HCT, but relapse or disease progression remained prominent for recipients of autologous HCT, particularly for myeloma. The management of late HCT effects is important to improve long-term survival of transplant recipients but should be tailored to the risks specific to the primary disease and transplant type. Future planning should account for the impact of the expected increase in transplant activity and number of survivors on resource utilization.

Utilization and Outcomes of Fertility Preservation Techniques in Women Undergoing Allogeneic Hematopoietic Cell Transplant.

Iatrogenic menopause with consequent infertility is a major complication in reproductive-age women undergoing hematopoietic cell transplantation (HCT). Recent guidelines recommend a discussion of the possibility of infertility and the options for fertility preservation as part of informed consent before initiation of any cancer-directed therapy, including HCT. Women age 15 to 49 years at the time of allogeneic HCT, between the years 2001 and 2017, were identified from the Mayo Clinic Rochester institutional HCT database. One hundred seventy-seven women were eligible, of whom 49 (28%) were excluded due to documented postmenopausal state or prior hysterectomy. The median age of the cohort was 31 years (range, 15 to 49 years) with median gravidity and parity being G1P1 (range, G0 to G8, P0 to P6). Fifty-four (42%) women were nulligravid at the time of HCT. Eighty-two percent underwent myeloablative conditioning (MAC), whereas 18% underwent reduced-intensity conditioning (RIC). Only 34 women (27%) had documented fertility counseling within 72 hours of diagnosis, and a total of 61 (48%) received fertility counseling prior to HCT. Thirty-eight women (30%) were referred to a reproductive endocrinologist, of whom 13 (10%) underwent assisted reproductive technologies (ART; nine oocyte cryopreservation, four embryo cryopreservation). Of these, nine procedures yielded successful cryopreserved tissue (two completed at outside institutions). The median time to completion of the seven successful ART procedures at Mayo Clinic was 13 days (range, 9 to 15 days). The remainder of women referred to reproductive endocrinology did not undergo ART due to disease severity (68%), financial barriers (20%), and/or low antral follicle count (12%). Ninety-three women (73%) received leuprolide for ovarian suppression prior to conditioning. Three (4%) of 75 women who underwent MAC and were alive >365 days after HCT had spontaneous menstrual recovery after HCT (median time, 14 months; range, 6 to 21 months), in comparison to 10 (50%) of 20 women who underwent RIC and were alive >365 days after HCT (P < .01) (median, 21.5 months; range, 5 to 83 months). In the latter cohort, there were two spontaneous pregnancies, occurring at 71 and 72 months after HCT, respectively. Oncofertility is an emerging field due to an increasing number of young cancer survivors. Herein, we document that even at a large tertiary HCT center, the rate of documented fertility counseling and reproductive endocrinology referrals was low and the rate of ART was even lower. Spontaneous menstrual recovery was rare but more likely in the setting of nonmalignant disease and RIC HCT. A concerted multidisciplinary effort is needed to understand parenthood goals and to explore the impact of HCT on decision making about fertility preservation and parenthood. These efforts could improve oncofertility referral, ART utilization, and reproductive outcomes.

Cognitive Function and Quality of Life in Vorinostat-Treated Patients after Matched Unrelated Donor Myeloablative Conditioning Hematopoietic Cell Transplantation.

Myeloablative conditioning allogeneic hematopoietic cell transplantation (HCT) puts patients at greater risk for significant cognitive and quality of life decline compared with recipients of reduced-intensity conditioning or autologous HCT. Vorinostat, a histone deacetylase inhibitor, has been shown to have neuroprotective and neurorestorative effects in preclinical models of neurologic diseases. Thus, within the context of a myeloablative conditioning phase II clinical trial of vorinostat combined with tacrolimus and methotrexate for graft-versus-host disease prophylaxis, we conducted an ancillary study to evaluate feasibility of assessing associations between vorinostat and neurocognitive function and quality of life (ClinicalTrials.gov NCT02409134). Nine patients (mean age, 53 years; range, 36 to 66) underwent computerized neuropsychological testing (Cogstate) and completed surveys of mood (Patient Health Questionnaire-9), anxiety (General Anxiety Disorder-7), and quality of life (Functional Assessment of Cancer Therapy-General). Control cohorts from a separate concurrent longitudinal study (19 autologous and 18 allogeneic HCT patients, who matched the vorinostat patients on relevant medical and demographic variables) completed the same test battery. All allogeneic patients received busulfan-based myeloablative conditioning and were transplanted with HLA-matched unrelated donors. The total neurocognitive performance score of vorinostat patients did not change significantly across the study duration (ie, baseline, day 30, day 100, and day 160). Depression, anxiety, and quality of life also did not differ significantly across time. In univariate analyses (analysis of variance), vorinostat-treated patients showed no difference in neurocognitive function or quality of life compared with autologous and allogeneic control subjects. However, when medical variables were accounted for in a linear mixed effects regression model, the total neurocognitive performance of vorinostat-treated patients was comparable with autologous control subjects. Notably, autologous control subjects performed significantly better than allogeneic control subjects (estimate, .64; standard error, .23; P ≤ .01). Moreover, a smaller percentage of vorinostat-treated patients were classified as mildly, moderately, or severely impaired across neurocognitive domains as well as time points compared with both control cohorts. Thus, vorinostat may have neurorestorative or neuroprotective effects in the HCT setting. Accordingly, we recognize the need for a future, full-scale randomized controlled trial to further examine this hypothesis.

Fludarabine and Busulfan versus Fludarabine, Cyclophosphamide, and Rituximab as Reduced-Intensity Conditioning for Allogeneic Transplantation in Follicular Lymphoma.

Large, multicenter studies comparing commonly used reduced-intensity conditioning (RIC) approaches in follicular lymphoma (FL) have not been performed. Using the Center for International Blood and Marrow Transplant Research database, we report the outcomes of the 2 most commonly used RIC approaches, fludarabine and busulfan (Flu/Bu) versus fludarabine, cyclophosphamide, and rituximab (FCR) in FL patients. We evaluated 200 FL patients undergoing allogeneic hematopoietic cell transplantation (allo-HCT) who received RIC with either Flu/Bu (n = 98) or FCR (n = 102) during 2008 to 2014. All patients received peripheral blood grafts, and graft-versus-host disease (GVHD) prophylaxis was limited to calcineurin inhibitor-based approaches. Median follow-up of survivors in the Flu/Bu and FCR groups was 48 months and 46 months, respectively. On univariate analysis in the Flu/Bu and FCR groups, the 3-year rates of nonrelapse mortality (11% versus 11%, P = .94), relapse/progression (18% versus 15%, P = .54), progression-free survival (PFS) (71% versus 74%, P = .65), and overall survival (OS) (73% versus 81%, P = .18) were not significantly different. On multivariate analysis no difference was seen between the FCR and Flu/Bu cohorts in terms of grades II to IV (relative risk [RR], 1.06; 95% confidence interval [CI], .59 to 1.93; P = .84) or grades III to IV (RR, 1.18; 95% CI, .47 to 2.99; P = .72) acute GVHD, nonrelapse mortality (RR, .83; 95% CI, .38 to 1.82; P = .64), relapse/progression (RR, .99; 95% CI, .49 to 1.98; P = .97), PFS (RR, .92; 95% CI, .55 to 1.54; P = .76), or OS (RR, .70; 95% CI, .40 to 1.23; P = .21) risk. However, RIC with FCR was associated with a significantly reduced chronic GVHD risk (RR, .52; 95% CI, .36 to .77; P = .001). RIC with either Flu/Bu or FCR in patients with FL undergoing allo-HCT provides excellent 3-year OS, with acceptable rates of nonrelapse mortality. FCR-based conditioning was associated with a lower risk of chronic GVHD.

Outcome following second allogeneic hematopoietic cell transplantation: A single-center experience.

OBJECTIVE: Second allogeneic hematopoietic cell transplantation (HCT) may be indicated following relapse or graft failure following first HCT. Our retrospective single-center study sought to investigate parameters that influence post-second allogeneic HCT survival. METHOD: We investigated 92 patients who underwent second allogeneic HCT between 1980 and 2016 for relapse or graft failure following first HCT. Median age at second HCT was 41 years (range 16-68), performed for relapse in 59 patients (64%) and for graft failure in 33 patients (36%). RESULTS: On univariate analysis, 3-year OS of the entire cohort was 35% (95% CI=25-45). Eastern Cooperative Oncology Group (ECOG) score (3-year OS 48% for ECOG 0-1, 18% for ECOG 2-3, P=.0006), second HCT indication (3-year OS 43% for relapse, 20% for graft failure, P=.02), time from first HCT to relapse/graft failure (3-year OS for <12months 21%, for ≥12months 46%, P=.009), and conditioning intensity (3-year OS for MA 42% vs other regimens 23%, P=.08) significantly influenced OS. Multivariable analysis confirmed ECOG score (HR=2.15 for ECOG 2-3, 95% CI=1.32-3.51, P=.002) and second HCT indication (HR=1.67 for graft failure, 95% CI=1.02-2.75, P=.04) to independently influence survival. CONCLUSION: Second HCT may offer long-term survival particularly to patients with good performance status who relapse post-first HCT.

High expression of ETS2 predicts poor prognosis in acute myeloid leukemia and may guide treatment decisions.

BACKGROUND: ETS2 is a downstream effector of the RAS/RAF/ERK pathway, which plays a critical role in the development of malignant tumor. However, the clinical impact of ETS2 expression in AML remains unknown. METHODS: In this study, we evaluated the prognostic significance of ETS2 expression using two relatively large cohorts of AML patients. RESULTS: In the first cohort, compared to low expression of ETS2 (ETS2 low), high expression of ETS2 (ETS2 high) showed significant shorter OS, EFS and RFS in the current treatments including the allogeneic HCT group (n = 72) and the chemotherapy group (n = 100). Notably, among ETS2 high patients, those received allogeneic HCT had longer OS, EFS and RFS than those with chemotherapy alone (allogeneic HCT, n = 39 vs. chemotherapy, n = 47), but treatment modules play insignificant role in the survival of ETS2 low patients (allogeneic HCT, n = 33 vs. chemotherapy, n = 53). Moreover, gene/microRNA expression data provides insights into the biological changes associated with varying ETS2 expression levels in AML. The prognostic value of ETS2 was further validated in the second AML cohort (n = 329). CONCLUSIONS: Our results indicate that ETS2 high is a poor prognostic factor in AML and may guide treatment decisions towards allogeneic HCT.

Individual outcome prediction for myelodysplastic syndrome (MDS) and secondary acute myeloid leukemia from MDS after allogeneic hematopoietic cell transplantation.

We integrated molecular data with available prognostic factors in patients undergoing allogeneic hematopoietic cell transplantation (alloHCT) for myelodysplastic syndrome (MDS) or secondary acute myeloid leukemia (sAML) from MDS to evaluate their impact on prognosis. Three hundred four patients were sequenced for mutations in 54 genes. We used a Cox multivariate model and competing risk analysis with internal and cross validation to identify factors prognostic of overall survival (OS), cumulative incidence of relapse (CIR), and non-relapse mortality (NRM). In multivariate analysis, mutated NRAS, U2AF1, IDH2, and TP53 and/or a complex karyotype were significant prognostic markers for OS besides age above 60 years, remission status, IPSS-R cytogenetic risk, HCT-CI > 2 and female donor sex. Mutated NRAS, IDH1, EZH2, and TP53 and/or a complex karyotype were genetic aberrations with prognostic impact on CIR. No molecular markers were associated with the risk of NRM. The inclusion of molecular information results in better risk prediction models for OS and CIR when assessed by the Akaike information criterion. Internal cross validation confirmed the robustness of our comprehensive risk model. In summary, we propose to combine molecular, cytogenetic, and patient- and transplantation-associated risk factors into a comprehensive risk model to provide personalized predictions of outcome after alloHCT.

Follow-up of patients with refractory or relapsed multiple myeloma after allogeneic hematopoietic cell transplantation.

BACKGROUND: The role of allogeneic hematopoietic cell transplantation (HCT) for the treatment of multiple myeloma is controversial. However, the introduction of proteasome inhibitors and immunomodulatory drugs might influence outcomes in case of relapse or refractory disease after allogeneic HCT. METHODS: We report 41 consecutive patients that underwent allogeneic HCT for the treatment of relapsed or refractory multiple myeloma. RESULTS: Three-year event-free survival (EFS) and overall survival (OS) of the whole cohort were 15% and 51%, respectively. In a subgroup analysis, allogeneic HCT after a second high-dose chemotherapy with autologous stem cell support was associated with a decreased 3-year EFS (6% vs 24%, P=.04) and OS (35% vs 64%, P=.09). In case of relapse or refractory disease after allogeneic HCT, the treatment with proteasome inhibitors or immunomodulatory drugs significantly improved survival (1-year OS 79% vs 29%, P=.001). CONCLUSION: The incorporation of proteasome inhibitors and immunomodulatory drugs into transplant protocols has the potential to improve outcomes and refine the role of allogeneic HCT for the treatment of multiple myeloma as a platform for long-term disease control.

Improved Treatment-Related Mortality and Overall Survival of Patients with Grade IV Acute GVHD in the Modern Years.

The impact of advances in supportive care and hematopoietic stem cell transplantation (HSCT) practices on the outcomes of patients who develop grade III or IV acute graft-versus-host disease (GVHD) is unknown. We performed a retrospective analysis of 427 patients with overall grade III or IV acute GVHD treated at 2 partner institutions between 1997 and 2012. We compared treatment-related mortality (TRM) and overall survival (OS) in 2 cohorts based on the year of transplantation, 1997 to 2006 (n = 222) and 2007 to 2012 (n = 205), using multivariate analysis, adjusting for significant patient-, disease-, and transplantation-related factors. Recipient age, reduced-intensity conditioning, unrelated donor, and peripheral blood stem cell grafts in the patients with grade III or IV acute GVHD increased over time. In the unadjusted analysis, 12-month OS increased over time (30% in 1997 to 2006 versus 42% in 2007 to 2012; P = .003) reflecting a decrease in TRM (58% in 1997 to 2006 versus 38% in 2007 to 2012; P = .0002), and an increase in PFS (29% in 1997 to 2006 versus 43% in 2007 to 2012; P = .002). On multivariate analysis, the period of transplantation remained a significant predictor for OS (hazard ratio [HR], 0.71; 95% confidence interval [CI], 0.54 to 0.94; P = .02), progression-free survival (PFS) (HR, 0.70; 95% CI, 0.52 to 0.94; P = .02), and TRM (HR, 0.57; 95% CI, 0.39 to 0.82; P = .002). In subgroup analysis, these differences were observed mainly in patients with grade IV acute GVHD. The outcomes of patients who develop overall grade III or IV acute GVHD after allogeneic HSCT has improved over time, with lower TRM and improved OS. This improvement in outcomes was seen primarily in patients with grade IV acute GVHD.

Analysis of the efficiency and costs of antifungal prophylaxis and mycological diagnostics in patients undergoing allogeneic haematopoietic cell transplantation: "real life" evaluation.

Antifungal prophylaxis/therapy (AP/AT) raises the cost of allogeneic haematopoietic cell transplantation (alloHCT). Its efficacy, different approaches for AP/AT, diagnostic measures and cost-effectiveness must still be evaluated. In 2010, we conducted a prospective study with 106 consecutive patients receiving an alloHCT analysing AP/AT, choice and costs of diagnostics applied including CT scans, galactomannan (Gal) and ß-D-glucan (ß-D) testing. Antifungal prophylaxis in 91 patients consisted of fluconazole (FLU) or L-AMB (AmBisome™ 1 or 3 mg/kg/day b.w.), and antifungal therapy had to be initiated in 38 % of the FLU/L-AMB-1-mg patients but in none with L-AMB 3 mg. Empirical AT consisted of L-AMB 1 mg/kg (n = 12) and preemptive AT of L-AMB 3 mg/kg (n = 17) and proved very efficacious with no further antifungal drug escalation in 89.6 %. Mean costs of diagnostic measures were 402 €/alloHCT; however, only 22 % of the CT scans, 4 % of ß-D and 3 % of galactomannan testing were positive. We detected one proven, 17 probable and 14 possible fungal infections. Due to the German diagnosis-related group system with additional compensation, all our AP/AT strategies were adequately reimbursed. While clinical symptoms and CT scans are the most commonly used, inexpensive decision-making tools for starting AT, the expensive laboratory diagnostic procedures are ineffective; we have therefore discontinued regular GAL/ß-D testing and changed our AP in patients at risk.

Reduced-intensity conditioning with fludarabine and busulfan for allogeneic hematopoietic cell transplantation in elderly or infirm patients with advanced myeloid malignancies.

We report a retrospective single-center analysis of 112 consecutive patients that underwent allogeneic hematopoietic cell transplantation (HCT) after reduced-intensity conditioning (RIC) with fludarabine (FLU) and busulfan (BU) for the treatment of acute myeloid leukemia (AML), myelodysplastic syndrome (MDS) and myeloproliferative syndrome (MPS) from 2005 to 2014. Three-year event-free survival (EFS) and overall survival (OS) were 46 and 58 %, respectively. Patients ≥60 years of age showed a similar outcome compared to younger patients (3-year OS 55 vs. 61 %, p = 0.96; 3-year EFS 46 vs. 46 %, p = 0.82). Cumulative incidence of non-relapse mortality (NRM) at 3 years adjusted for relapse as competing risk was 25 % for patients aged <60 years and 15 % for older patients (p = 0.15). Infusions of higher CD34(+) blood stem cell doses were associated with a significantly better outcome in the elderly subgroup (3-year OS 82 vs. 39 %, p = 0.007). Moreover, complete donor chimerism at day +100 was associated with a significantly improved survival (3-year OS 69 vs. 23 %, p = 0.003). In conclusion, our data suggest that RIC with FLU/BU enables long-term disease-free survival even in an elderly patient population. Age has no negative impact on the outcome of allogeneic HCT, and decision for transplant should be based on disease risk and performance status rather than age alone.