Improved Outcome of Allogeneic Transplantation in Older Patients Treated for Myeloid Malignancies Using Post-Transplantation Cyclophosphamide and Reduced Duration of Immune Suppression.

Allogeneic stem cell transplantation (alloSCT) offers curative potential for older patients with myeloid malignancies. We evaluated the efficacy and safety of alloSCT using post-transplantation cyclophosphamide (PTCy) in combination with a very short duration of immune suppression (IS) in this population. We retrospectively analyzed 92 consecutive patients aged 65 years and older who underwent an alloSCT for myeloid malignancies between February 2018 and December 2022 at our institution. Data on patient characteristics, treatment modalities, and outcomes were collected. Ninety-two patients received an alloSCT with PTCy-based graft versus host disease (GVHD) prophylaxis. The majority had minimal comorbidities and were diagnosed with acute myeloid leukemia. Patients mostly received conditioning regimens with low to intermediate transplant conditioning intensity scores. In 43% of patients, IS could be permanently stopped at day +90, resulting in a median time of IS of 2.93 months in high-risk patients. At a median follow-up of 21.3 months, the 1- and 2-year overall survival rates were 89% and 87%, respectively. Relapse-free survival rates were 88% and 84% at 1 and 2 years, respectively. The 1- and 2-year cumulative incidences of relapse were 8% and 13%, while treatment-related mortality (TRM) estimates were 9% at both time points. Acute GVHD grade 3 to 4 occurred in 7% within the first 180 days and severe chronic GVHD in 6% of patients. This all resulted in a 1- and 2-year graft versus host and relapse-free survival of 74% and 70%, respectively. AlloSCT using PTCy in combination with a short duration of IS in older patients with myeloid malignancies demonstrates favorable survival outcomes due to low relapse rates and a low TRM. The low incidence of relapse and acceptable rates of graft-versus-host disease suggest the efficacy and safety of this approach. Further studies are warranted to validate these findings and optimize transplant strategies for older patients with myeloid malignancies.

Younger unrelated donors may be preferable over HLA match in the PTCy era: A study from the ALWP of the EBMT.

There is a paucity of information on how to select the most appropriate unrelated donor (UD) in hematopoietic stem cell transplant (HSCT) using post-transplant cyclophosphamide (PTCy). We retrospectively analyzed the characteristics of 10/10 matched unrelated donors (MUD) and 9/10 mismatched unrelated donors (MMUD) that may affect transplant outcomes in patients with acute myeloid leukemia (AML) in first or second complete remission (CR1 or CR2). The primary endpoint was leukemia-free survival (LFS). Overall, 1011 patients were included with a median age of 54 years (range, 18-77). Donors had a median age of 29 years (range, 18-64); 304 (30%) were females of which 150 (15% of whole group) were donors to male recipients, and 621 (61%) were MUDs; 522 (52%) had negative cytomegalovirus (CMV-neg) serostatus of which 189 (19%) were used for CMV-neg recipients. Donor age older than 30 years had a negative impact on relapse (HR 1.38; 95% CI 1.06-1.8), LFS (HR 1.4; 95% CI 1.12-1.74), overall survival (HR 1.45; 95% CI 1.14-1.85) and GVHD-free, relapse-free survival (HR 1.29; 95% CI 1.07-1.56). Additionally, CMV-neg donor for CMV-neg recipient was associated with improved LFS (HR 0.74; 95% CI 0.55-0.99). The use of MMUD and female donors for male recipients did not significantly impact any transplant outcomes. For patients undergoing HSCT from an UD with PTCy for AML, donor age < 30 years significantly improves survival. In this context, donor age might be prioritized over HLA match considerations. In addition, CMV neg donors are preferable for CMV neg recipients. However, further research is needed to validate and refine these recommendations.

Donor KIR genotype based outcome prediction after allogeneic stem cell transplantation: no land in sight.

Optimizing natural killer (NK) cell alloreactivity could further improve outcome after allogeneic hematopoietic cell transplantation (alloHCT). The donor's Killer-cell Immunoglobulin-like Receptor (KIR) genotype may provide important information in this regard. In the past decade, different models have been proposed aiming at maximizing NK cell activation by activating KIR-ligand interactions or minimizing inhibitory KIR-ligand interactions. Alternative classifications intended predicting outcome after alloHCT by donor KIR-haplotypes. In the present study, we aimed at validating proposed models and exploring more classification approaches. To this end, we analyzed samples stored at the Collaborative Biobank from HLA-compatible unrelated stem cell donors who had donated for patients with acute myeloid leukemia (AML) or myelodysplastic neoplasm (MDS) and whose outcome data had been reported to EBMT or CIBMTR. The donor KIR genotype was determined by high resolution amplicon-based next generation sequencing. We analyzed data from 5,017 transplants. The median patient age at alloHCT was 56 years. Patients were transplanted for AML between 2013 and 2018. Donor-recipient pairs were matched for HLA-A, -B, -C, -DRB1, and -DQB1 (79%) or had single HLA mismatches. Myeloablative conditioning was given to 56% of patients. Fifty-two percent of patients received anti-thymocyte-globulin-based graft-versus-host disease prophylaxis, 32% calcineurin-inhibitor-based prophylaxis, and 7% post-transplant cyclophosphamide-based prophylaxis. We tested several previously reported classifications in multivariable regression analyses but could not confirm outcome associations. Exploratory analyses in 1,939 patients (39%) who were transplanted from donors with homozygous centromeric (cen) or telomeric (tel) A or B motifs, showed that the donor cen B/B-tel A/A diplotype was associated with a trend to better event-free survival (HR 0.84, p=.08) and reduced risk of non-relapse mortality (NRM) (HR 0.65, p=.01). When we further dissected the contribution of B subtypes, we found that only the cen B01/B01-telA/A diplotype was associated with a reduced risk of relapse (HR 0.40, p=.04) while all subtype combinations contributed to a reduced risk of NRM. This exploratory finding has to be validated in an independent data set. In summary, the existing body of evidence is not (yet) consistent enough to recommend use of donor KIR genotype information for donor selection in routine clinical practice.

Role of knowledge and reasoning processes as predictors of resident physicians' susceptibility to anchoring bias in diagnostic reasoning: a randomised controlled experiment.

BACKGROUND: Diagnostic errors have been attributed to reasoning flaws caused by cognitive biases. While experiments have shown bias to cause errors, physicians of similar expertise differed in susceptibility to bias. Resisting bias is often said to depend on engaging analytical reasoning, disregarding the influence of knowledge. We examined the role of knowledge and reasoning mode, indicated by diagnosis time and confidence, as predictors of susceptibility to anchoring bias. Anchoring bias occurs when physicians stick to an incorrect diagnosis triggered by early salient distracting features (SDF) despite subsequent conflicting information. METHODS: Sixty-eight internal medicine residents from two Dutch university hospitals participated in a two-phase experiment. Phase 1: assessment of knowledge of discriminating features (ie, clinical findings that discriminate between lookalike diseases) for six diseases. Phase 2 (1 week later): diagnosis of six cases of these diseases. Each case had two versions differing exclusively in the presence/absence of SDF. Each participant diagnosed three cases with SDF (SDF+) and three without (SDF-). Participants were randomly allocated to case versions. Based on phase 1 assessment, participants were split into higher knowledge or lower knowledge groups. MAIN OUTCOME MEASUREMENTS: frequency of diagnoses associated with SDF; time to diagnose; and confidence in diagnosis. RESULTS: While both knowledge groups performed similarly on SDF- cases, higher knowledge physicians succumbed to anchoring bias less frequently than their lower knowledge counterparts on SDF+ cases (p=0.02). Overall, physicians spent more time (p<0.001) and had lower confidence (p=0.02) on SDF+ than SDF- cases (p<0.001). However, when diagnosing SDF+ cases, the groups did not differ in time (p=0.88) nor in confidence (p=0.96). CONCLUSIONS: Physicians apparently adopted a more analytical reasoning approach when presented with distracting features, indicated by increased time and lower confidence, trying to combat bias. Yet, extended deliberation alone did not explain the observed performance differences between knowledge groups. Success in mitigating anchoring bias was primarily predicted by knowledge of discriminating features of diagnoses.

Upper and/or Lower Respiratory Tract Infection Caused by Human Metapneumovirus After Allogeneic Hematopoietic Stem Cell Transplantation.

BACKGROUND: Human metapneumovirus (hMPV) epidemiology, clinical characteristics and risk factors for poor outcome after allogeneic stem cell transplantation (allo-HCT) remain a poorly investigated area. METHODS: This retrospective multicenter cohort study examined the epidemiology, clinical characteristics, and risk factors for poor outcomes associated with human metapneumovirus (hMPV) infections in recipients of allo-HCT. RESULTS: We included 428 allo-HCT recipients who developed 438 hMPV infection episodes between January 2012 and January 2019. Most recipients were adults (93%). hMPV infections were diagnosed at a median of 373 days after allo-HCT. The infections were categorized as upper respiratory tract disease (URTD) or lower respiratory tract disease (LRTD), with 60% and 40% of cases, respectively. Patients with hMPV LRTD experienced the infection earlier in the transplant course and had higher rates of lymphopenia, neutropenia, corticosteroid use, and ribavirin therapy. Multivariate analysis identified lymphopenia and corticosteroid use (>30 mg/d) as independent risk factors for LRTD occurrence. The overall mortality at day 30 after hMPV detection was 2% for URTD, 12% for possible LRTD, and 21% for proven LRTD. Lymphopenia was the only independent risk factor associated with day 30 mortality in LRTD cases. CONCLUSIONS: These findings highlight the significance of lymphopenia and corticosteroid use in the development and severity of hMPV infections after allo-HCT, with lymphopenia being a predictor of higher mortality in LRTD cases.

Comparison of patellofemoral contact pressure after semi-cylindrical recession trochleoplasty and trochlear block recession in feline cadavers.

Introduction: The purpose of this study was to compare the changes in the patellofemoral joint (PFJ) contact mechanisms of the normal state, trochlear hypoplasia model and after performing trochleoplasty on the hypoplasia model in feline cadavers. Methods: Twenty normal pelvic limbs were acquired from the 10 feline cadavers. First, the PFJ contact mechanisms were measured in normal state, then trochlear hypoplasia models were created using customized trochlear ridge cutting guides. After measuring PFJ contact mechanisms in the trochlear hypoplasia models, they were divided into two groups and performed semi-cylindrical recession trochleoplasty (SCRT) and trochlear block recession (TBR) were performed, respectively. After that, the PFJ contact mechanisms were measured and the values of the 4 groups (normal state, trochlear hypoplasia, SCRT, TBR) were compared. Results: The trochlear hypoplasia group showed increased contact pressure and decreased contact areas compared to the normal state group. In the groups that underwent tracheoplasty (SCRT and TBR), PFJ contact mechanisms were recovered similarly to that of the normal state group. The PFJ of the SCRP group was measured similar to that of the normal group than that of the TBR group. Discussion: Tracheoplasty can be useful in restoring PFJ contact mechanisms and SCRT can be considered as a good alternative to the conventional methods of trochleoplasty.

Allogeneic hematopoietic cell transplantation for patients with AML aged 70 years or older in first remission. A study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation (EBMT).

Accessibility to allogeneic hematopoietic cell transplantation (HCT) programs for older patients is growing constantly. We report on the clinical outcomes of a group of 701 adults aged ≥70 years, with acute myeloid leukemia (AML) in first complete remission (CR1), who received a first HCT, from HLA-matched sibling donors (MSD), 10/10 HLA-matched unrelated donors (UD), 9/10 HLA-mismatched unrelated donors (mUD) or haploidentical (Haplo) donors. The 2-year overall survival (OS) was 48.1%, leukemia-free survival (LFS) 45.3%, relapse incidence (RI) 25.2%, non-relapse mortality (NRM) 29.5% and GVHD-free, relapse-free survival (GRFS), 33.4%. Compared to MSD, patients transplanted from Haplo and UD presented lower RI (HR 0.46, 95% CI 0.25-0.8, p = 0.02 and HR 0.44, 95% CI: 0.28-0.69, p = 0.001, respectively); this translated into prolonged LFS for Haplo (HR 0.62, 95% CI: 0.39-0.99, p = 0.04). Patients transplanted from mUD exhibited the highest NRM incidence (HR 2.33, 95% CI: 1.26-4.31, p = 0.007). HCT in selected adult CR1 AML patients >70 years is feasible and could be associated with good clinical outcomes. Prospective clinical trials are warranted.

Impact of disease burden on clinical outcomes of AML patients receiving allogeneic hematopoietic cell transplantation: a study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation.

Pre-transplant detectable measurable residual disease (MRD) is still associated with high risk of relapse and poor outcomes in acute myeloid leukemia (AML). We aimed at evaluating the impact of disease burden on prediction of relapse and survival in patients receiving allogeneic hematopoietic cell transplantation (allo-HCT) in first remission (CR1). We identified a total of 3202 adult AML patients, of these 1776 patients were in CR1 and MRD positive and 1426 patients were primary refractory at time of transplant. After a median follow-up of 24.4 months, non-relapse mortality and relapse rate were significantly higher in the primary refractory group compared to the CR1 MRD positive group (Hazards Ratio (HR) = 1.82 (95% CI: 1.47-2.24) p < 0.001 and HR = 1.54 (95% CI: 1.34-1.77), p < 0.001), respectively. Leukemia-free survival (LFS) and overall survival (OS) were significantly worse in the primary refractory group (HR = 1.61 (95% CI: 1.44-1.81), p < 0.001 and HR = 1.71 (95% CI: 1.51-1.94), p < 0.001, respectively). Our real-life data suggest that patients in CR1 and MRD positive at time of transplant could still be salvaged by allo-HCT with a 2-year OS of 63%, if negative MRD cannot be obtained and their outcomes are significantly better than patients transplanted with active disease.

Impact of measurable residual disease on outcomes of unrelated donor haematopoietic cell transplantation with post-transplant cyclophosphamide in AML in first complete remission.

Pre-transplant measurable residual disease (MRD) predicts relapse and outcome of allogeneic haematopoietic cell transplantation (allo-HCT). The impact of MRD on the outcomes of post-transplant cyclophosphamide (PTCy)-based allo-HCT from a matched unrelated donor (UD) is unknown. This study assessed the impact of MRD in acute myeloid leukaemia (AML) in the first complete remission (CR1). A total of 272 patients (MRD negative [MRD-], n = 165; MRD positive [MRD+], n = 107) with a median follow-up of 19 (range: 16-24) months were studied. The incidence of grades II-IV and grades III-IV acute GVHD at day 180 was 25.2% and 25% (p = 0.99), and 10.6% and 6.8% (p = 0.29), respectively, and 2-year chronic GVHD was 35% and 30.4% (p = 0.96) in MRD+ and MRD- cohorts, respectively. In multivariate analysis, MRD+ status was associated with a higher incidence of relapse (RI) (hazard ratio [HR] = 2.56, 95% CI: 1.39-4.72), lower leukaemia-free survival (LFS) (HR = 2.04, 95% CI: 1.23-3.39), overall survival (OS) (HR = 1.83, 95% CI: 1.04-3.25) and GVHD-free, relapse-free survival (GRFS) (HR = 1.69, 95% CI: 1.10-2.58). MRD status did not have a significant impact on non-relapse mortality (NRM), or acute or chronic GVHD risk. Among patients with AML undergoing UD allo-HCT with PTCy, pre-transplant MRD+ status predicted a higher relapse rate, lower LFS, OS and GRFS.

Prediction of Nonrelapse Mortality in Patients With Acute Myeloid Leukemia and Acute Lymphoblastic Leukemia Receiving Allogeneic Stem Cell Transplantation With Posttransplantation Cyclophosphamide-based Graft Versus Host Disease Prophylaxis.

Graft versus host disease (GVHD) prophylaxis with posttransplantation cyclophosphamide (PTCY) has been established to reduce severe GVHD, and thereby potentially reducing nonrelapse mortality (NRM) after allogeneic stem cell transplantation (alloSCT). We evaluated the predictive capacity of established NRM-risk scores in patients receiving PTCY-based GVHD prophylaxis, and subsequently developed and validated a novel PTCY-specific NRM-risk model. Adult patients (n = 1861) with AML or ALL in first complete remission who received alloSCT with PTCY-based GVHD prophylaxis were included. The PTCY-risk score was developed using multivariable Fine and Gray regression, selecting parameters from the hematopoietic cell transplantation-comorbidity index (HCT-CI) and European Group for Blood and Marrow Transplantation (EBMT) score with a subdistribution hazard ratio (SHR) of ≥1.2 for 2-year NRM in the training set (70% split), which was validated in the test set (30%). The performance of the EBMT score, HCT-CI, and integrated EBMT score was relatively poor for discriminating 2-year NRM (c-statistic 51.7%, 56.6%, and 59.2%, respectively). The PTCY-risk score included 10 variables which were collapsed in 3 risk groups estimating 2-year NRM of 11% ± 2%, 19% ± 2%, and 36% ± 3% (training set, c-statistic 64%), and 11% ± 2%, 18% ± 3%, and 31% ± 5% (test set, c-statistic 63%), which also translated into different overall survival. Collectively, we developed an NRM-risk score for acute leukemia patients receiving PTCY that better predicted 2-year NRM compared with existing models, which might be applicable to the specific toxicities of high-dose cyclophosphamide.

Allogeneic stem cell transplantation for patients with acute myeloid leukemia (AML) in second complete remission (CR2) transplanted from unrelated donors with post-transplant cyclophosphamide (PTCy). A study on behalf of the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation.

Post-transplant cyclophosphamide (PTCy) is being increasingly used as graft-versus-host disease (GVHD) prophylaxis post allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients with acute myeloid leukemia (AML) transplanted in first complete remission (CR1). However, results may differ in patients transplanted in CR2. We retrospectively evaluated transplant outcomes of adult AML patients transplanted between 2010-2019 from 9-10/10 human leukocyte antigen (HLA)-matched unrelated donor (UD) in CR2. In total, 127 patients were included (median age 45.5 years, 54% male). Median follow-up was 19.2 months. Conditioning was myeloablative (MAC) in 50.4% and the graft source was peripheral blood in 93.7% of the transplants. Incidence of acute (a)GVHD II-IV and III-IV was 26.2% and 9.2%. Two-year total and extensive chronic (c)GVHD were 34.3% and 13.8 %, respectively. Two-year non-relapse mortality (NRM), relapse incidence (RI), leukemia-free survival (LFS), overall survival (OS), and GVHD-free, relapse-free survival (GRFS) were 17.2%, 21.1%, 61.7, %, 65.2%, and 49.3%, respectively. Time from diagnosis to transplant (>18 months) was a favorable prognostic factor for RI, LFS, OS, and GRFS while favorable risk cytogenetics was a positive prognostic factor for OS. The patient's age was a poor prognostic factor for NRM and cGVHD. Finally, the female-to-male combination and reduced intensity conditioning (RIC) were poor and favorable prognostic factors for cGVHD, respectively. We conclude that PTCy is an effective method for GVHD prophylaxis in AML patients undergoing allo-HCT in CR2 from UD.

Clonal hematopoiesis in patients with stem cell mobilization failure: a nested case-control study.

Inadequate mobilization of peripheral blood progenitor cells (PBPCs) is a limiting factor to proceeding with autologous hematopoietic cell transplantation (auto-HCT). To assess the impact of clonal hematopoiesis (CH) on mobilization failure of PBPC for auto-HCT, we investigated the characteristics of poor mobilizers (with a total PBPC collection <2 × 106 CD34+ cells per kg) in a consecutive single-center cohort of 776 patients. Targeted error-corrected next-generation sequencing of 28 genes was performed in a nested case-control cohort of 90 poor mobilizers and 89 matched controls. CH was detected in 48 out of 179 patients (27%), with most patients carrying a single mutation. The presence of CH (detected at variant allele frequency [VAF] ≥ 1%) did not associate with poor mobilization potential (31% vs 22% in controls, odds ratio, 1.55; 95% confidence interval, 0.76-3.23; P = .238). PPM1D mutations were detected more often in poor mobilizers (P = .005). In addition, TP53 mutations in this cohort were detected exclusively in patients with poor mobilization potential (P = .06). The incidence of therapy-related myeloid neoplasms (t-MN) was higher among patients with mobilization failure (P = .014). Although poor mobilizers experienced worse overall survival (P = .019), this was not affected by the presence of CH. We conclude that CH at low VAF (1%-10%) is common at the time of stem cell mobilization. TP53 mutations and PPM1D mutations are associated with poor mobilization potential and their role in subsequent development of t-MN in these individuals should be established.

Allogeneic hematopoietic cell transplantation in patients with chronic phase chronic myeloid leukemia in the era of third generation tyrosine kinase inhibitors: A retrospective study by the chronic malignancies working party of the EBMT.

Following the introduction of tyrosine kinase inhibitors (TKI), the number of patients undergoing allogeneic hematopoietic cell transplantation (allo-HCT) for chronic phase (CP) chronic myeloid leukemia (CML) has dramatically decreased. Imatinib was the first TKI introduced to the clinical arena, predominantly utilized in the first line setting. In cases of insufficient response, resistance, or intolerance, CML patients can subsequently be treated with either a second or third generation TKI. Between 2006 and 2016, we analyzed the impact of the use of 1, 2, or 3 TKI prior to allo-HCT for CP CML in 904 patients. A total of 323-, 371-, and 210 patients had 1, 2, or 3 TKI prior to transplant, respectively; imatinib (n = 778), dasatinib (n = 508), nilotinib (n = 353), bosutinib (n = 12), and ponatinib (n = 44). The majority had imatinib as first TKI (n = 747, 96%). Transplants were performed in CP1, n = 549, CP2, n = 306, and CP3, n = 49. With a median follow-up of 52 months, 5-year OS for the entire population was 64.4% (95% CI 60.9-67.9%), PFS 50% (95% CI 46.3-53.7%), RI 28.7% (95% CI 25.4-32.0%), and NRM 21.3% (95% CI 18.3-24.2%). No difference in OS, PFS, RI, or NRM was evident related to the number of TKI prior to allo-HCT or to the type of TKI (p = ns). Significant factors influencing OS and PFS were > CP1 versus CP1 and Karnofsky performance (KPS) score > 80 versus ≤80, highlighting CP1 patients undergoing allo-HCT have improved survival compared to >CP1 and the importance of careful allo-HCT candidate selection.

Should anti-thymocyte globulin be added in post-transplant cyclophosphamide based matched unrelated donor peripheral blood stem cell transplantation for acute myeloid leukemia? A study on behalf of the Acute Leukemia Working Party of the EBMT.

In this registry-based study which includes acute myeloid leukemia patients who underwent a matched unrelated donor allogeneic peripheral-blood stem cell transplantation in complete remission and received post-transplant cyclophosphamide (PTCY) as graft-versus-host disease (GvHD) prophylaxis, we compared 421 recipients without anti-thymocyte globulin (ATG) with 151 patients with ATG. The only significant differences between PTCY and PTCY + ATG cohorts were the median year of transplant and the follow-up period (2017 vs 2015 and 19.6 vs 31.1 months, respectively, p < 0.0001). Overall, 2-year survival was 69.9% vs 67.1% in PTCY and PTCY + ATG, respectively, with deaths related to relapse (39% vs 43.5%), infection (21.9% vs 23.9%) or GvHD (17.1% vs 17.4%) not differing between groups. On univariate comparison, a significantly lower rate of extensive chronic GvHD was found when ATG was added (9.9% vs 21%, p = 0.029), a finding which was not confirmed in the multivariate analysis. The Cox-model showed no difference between PTCY + ATG and PTCY alone with respect to acute and chronic GvHD of all grades, non-relapse mortality, relapse, leukemia-free survival, overall survival, and GvHD-free-relapse-free survival between study cohorts. Our results highlight that the addition of ATG in PTCY does not provide any extra benefit in terms of further GvHD reduction, better GRFS or better survival.

Effect of ruxolitinib on the oral mucosa of patients with steroid-refractory chronic Graft-versus-Host disease and oral involvement.

BACKGROUND: Chronic Graft-versus-Host Disease (cGVHD) can impact quality of life, especially in patients with oral involvement. Half of the patients with cGVHD do not respond to first-line therapy with corticosteroids and calcineurin inhibitors. Ruxolitinib is effective in steroid-refractory (SR)-cGVHD cases, but the long-term effects of ruxolitinib on the oral mucosa are unknown. OBJECTIVE(S): This study aims to assess the effect of ruxolitinib on the oral mucosa of SR-cGVHD patients with oral involvement. MATERIALS AND METHODS: An observational longitudinal patient study was conducted in 53 patients with SR-cGVHD and oral involvement who were treated with ruxolitinib. The baseline condition of the oral mucosa was compared to its condition at 4 and 12 weeks after starting ruxolitinib. RESULTS: The overall response was 81% (43/53), with a complete response in 53% (28/53) and partial response in 28% (15/53) after 12 weeks (p < 0.001). Men and patients concurrently using immunosuppressive therapy responded better than women (p = 0.005) and patients with ruxolitinib monotherapy (p = 0.02), respectively. At a longer follow-up (median 20 months), oral symptoms were comparable to the 12-week symptoms (p = 0.78), regardless of ruxolitinib use (p = 0.83). CONCLUSION: Ruxolitinib treatment of SR-cGVHD patients with oral involvement was associated with a significant response of the oral manifestations at 12 weeks. CLINICAL RELEVANCE: The oral mucosa of SR-cGVHD patients is likely to improve after 4 and 12 weeks of ruxolitinib treatment. Symptom severity at baseline does not affect the response of the oral mucosa.

Measurable residual disease, FLT3-ITD mutation, and disease status have independent prognostic influence on outcome of allogeneic stem cell transplantation in NPM1-mutated acute myeloid leukemia.

Nucleophosmin-1 (NPM1) mutations in acute myeloid leukemia (AML) confer a survival advantage in the absence of FLT3-internal tandem duplication (FLT3-ITD). Here, we investigated the main predictors of outcome after allogeneic hematopoietic stem cell transplantation (allo-HCT). We identified 1572 adult (age ≥ 18 year) patients with NPM1-mutated AML in first complete remission (CR1:78%) or second complete remission (CR2:22%) who were transplanted from matched sibling donors (30.8%) or unrelated donors (57.4%) between 2007 and 2019 at EBMT participating centers. Median follow-up for survivors was 23.7 months. FLT3-ITD was present in 69.3% of patients and 39.2% had detectable minimal/measurable residual disease (MRD) at transplant. In multivariate analysis, relapse incidence (RI) and leukemia-free survival (LFS) were negatively affected by concomitant FLT3-ITD mutation (HR 1.66 p = 0.0001, and HR 1.53, p < 0.0001, respectively), MRD positivity at transplant (HR 2.18, p < 10-5 and HR 1.71, p < 10-5 , respectively), and transplant in CR2 (HR 1.36, p = 0.026, and HR 1.26, p = 0.033, respectively), but positively affected by Karnofsky score ≥90 (HR 0.74, p = 0.012, and HR 0.7, p = 0.0002, respectively). Overall survival (OS) was also negatively influenced by concomitant FLT3-ITD (HR 1.6, p = 0.0001), MRD positivity at transplant (HR 1.61, p < 10-5 ), and older age (HR 1.22 per 10 years, p < 0.0001), but positively affected by matched sibling donor (unrelated donor: HR 1.35, p = 0.012; haploidentical donor: HR 1.45, p = 0.037) and Karnofsky score ≥90 (HR 0.73, p = 0.004). These results highlight the independent and significant role of FLT3-ITD, MRD status, and disease status on posttransplant outcomes in patients with NPM1-mutated AML allowing physicians to identify patients at risk of relapse who may benefit from posttransplant prophylactic interventions.

Post-transplant cyclophosphamide in one-antigen mismatched unrelated donor transplantation versus haploidentical transplantation in acute myeloid leukemia: a study from the Acute Leukemia Working Party of the EBMT.

Whether to choose Haploidentical (Haplo) or one-antigen mismatched unrelated donor (1Ag-MMUD) hematopoietic cell transplantation (HCT) with post-transplant cyclophosphamide (PTCy) remains an unanswered question. We compared PTCy- Haplo-HCT to PTCy-1Ag-MMUD-HCT for acute myeloid leukemia (AML) in complete remission (three groups: 1Ag-MMUD using peripheral blood (1Ag-MMUD-PB; n = 155); Haplo using bone marrow (Haplo-BM; n = 647) or peripheral blood (Haplo-PB; n = 949)). Haplo-BM and Haplo-PB had a higher non-relapse mortality (NRM) compared to 1Ag-MMUD-PB (HR 2.28, 95% CI 1.23-4.24, p < 0.01; HR 2.65, 95% CI 1.46-4.81, p < 0.01, respectively). Haplo groups experienced a lower leukemia-free survival (LFS) compared to 1Ag-MMUD-PB (Haplo-BM: HR 1.51, 95% CI 1.06-2.14, p = 0.02; Haplo-PB: 1.47, 95% CI 1.05-2.05, p = 0.02); overall survival (OS) was also lower in Haplo-HCT (Haplo-BM: HR 1.50, 95% CI 1.02-2.21, p = 0.04; Haplo-PB: HR 1.51, 95% CI 1.05-2.19, p = 0.03). No differences were observed for graft-versus-host/relapse-free survival (GRFS) and relapse incidence (RI). Haplo-BM was associated with a lower risk of grade III-IV acute graft-versus-host disease (GVHD) (HR 0.44, 95% CI 0.24-0.81; p < 0.01), while no statistical differences were observed between groups for grade II-IV aGVHD and for cGVHD. Use of PTCy in 1Ag-MMUD-HCT is a valid alternative to consider when using alternative donors. Larger analysis of 1Ag-MMUD versus Haplo-HCT are warranted.

Graft-versus-Host Disease Prophylaxis with Post-Transplantation Cyclophosphamide versus Cyclosporine A and Methotrexate in Matched Sibling Donor Transplantation.

Cyclosporine A (CSA) and methotrexate (MTX) is the standard graft-versus-host disease (GVHD) prophylaxis regimen for matched sibling donor (MSD) allogeneic hematopoietic cell transplantation (allo-HCT). Recently, post-transplantation cyclophosphamide (PTCy) has been shown to be effective in GVHD prevention. In this registry-based study, we compared outcomes of 118 patients treated with PTCy and 1202 patients with CSA/MTX who underwent MSD allo-HCT for acute myelogenous leukemia. In a matched-pair analysis, PTCy was associated with a higher incidence of relapse at 2 years compared with CSA/MTX (41.1% versus 21.3%; P = .039). The incidences of day +180 grade II-IV acute GVHD and 2-year chronic GVHD were comparable in the PTCy and CSA/MTX arms (25.2% versus 25.4% [P = .90] and 42.6% versus 42.6% [P = .84], respectively). Similarly, 2-year leukemia-free survival (LFS; 54.4% versus 74.32%; P = .052), overall survival (OS; 70.6% versus 79.7%; P = .15), and GVHD-free relapse-free survival (GRFS; 38.1% versus 52.5%; P = .49) were not statistically different in the 2 arms. Our data show that GVHD prophylaxis with PTCy is feasible, resulting in similar incidences of GVHD, GRFS, LFS, and OS as seen with conventional CSA/MTX in patients undergoing allo-HCT from an MSD. The higher rate of relapse observed with PTCy needs further evaluation in a prospective study. © 2021 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.