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

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

Germ line predisposition variants occur in myelodysplastic syndrome patients of all ages.

The frequency of pathogenic/likely pathogenic (P/LP) germ line variants in patients with myelodysplastic syndrome (MDS) diagnosed at age 40 years or less is 15% to 20%. However, there are no comprehensive studies assessing the frequency of such variants across the age spectrum. We performed augmented whole-exome sequencing of peripheral blood samples from 404 patients with MDS and their related donors before allogeneic hematopoietic stem cell transplantation. Single-nucleotide and copy number variants in 233 genes were analyzed and interpreted. Germ line status was established by the presence of a variant in the patient and related donor or for those seen previously only as germ line alleles. We identified P/LP germ line variants in 28 of 404 patients with MDS (7%), present within all age deciles. Patients with P/LP variants were more likely to develop higher-grade MDS than those without (43% vs 25%; P = .04). There was no statistically significant difference in outcome parameters between patients with and without a germ line variant, but the analysis was underpowered. P/LP variants in bone marrow failure syndrome genes were found in 5 patients aged less than 40 years, whereas variants in DDX41 (n = 4), telomere biology disorder genes (n = 2), and general tumor predisposition genes (n = 17) were found in patients aged more than 40 years. If presumed germ line variants were included, the yield of P/LP variants would increase to 11%, and by adding suspicious variants of unknown significance, it would rise further to 12%. The high frequency of P/LP germ line variants in our study supports comprehensive germ line genetic testing for all patients with MDS regardless of their age at diagnosis.

Relative prognostic value of flow cytometric measurable residual disease before allogeneic hematopoietic cell transplantation for adults with MDS/AML or AML.

Multiparameter flow cytometry (MFC) measurable residual disease (MRD) before allogeneic hematopoietic cell transplantation (HCT) independently predicts poor outcomes in acute myeloid leukemia (AML). Conversely, its prognostic value in the newly defined disease entity, myelodysplastic neoplasm (MDS)/AML is unknown. To assess the relationship between disease type, pre-HCT MRD, and post-HCT outcomes, we retrospectively analyzed 1265 adults with MDS/AML (n = 151) or AML (n = 1114) who received a first allograft in first or second morphologic remission at a single institution between April 2006 and March 2023. At 3 years, relapse rates (29% for MDS/AML vs. 29% for AML, p = .98), relapse-free survival (RFS; 50% vs. 55%, p = .22), overall survival (OS; 52% vs. 60%, p = .073), and non-relapse mortality (22% vs. 16%, p = .14) were not statistically significantly different. However, a significant interaction was found between pre-HCT MFC MRD and disease type (MDS/AML vs. AML) for relapse (p = .009), RFS (p = .011), and OS (p = .039). The interaction models indicated that the hazard ratios (HRs) for the association between pre-HCT MRD and post-HCT outcomes were lower in patients with MDS/AML (for relapse: HR = 1.75 [0.97-3.15] in MDS/AML vs. 4.13 [3.31-5.16] in AML; for RFS: HR = 1.58 [1.02-2.45] vs. 2.98 [2.48-3.58]; for OS: HR = 1.50 [0.96-2.35] vs. 2.52 [2.09-3.06]). On the other hand, residual cytogenetic abnormalities at the time of HCT were equally informative in MDS/AML as in AML patients. Our data indicate that MFC-based pre-HCT MRD testing, but not testing for residual cytogenetic abnormalities, is less informative for MDS/AML than AML patients when used for prognostication of post-HCT outcomes.

Splenic irradiation for myelofibrosis prior to hematopoietic cell transplantation: A global collaborative analysis.

Splenomegaly is the clinical hallmark of myelofibrosis. Splenomegaly at the time of allogeneic hematopoietic cell transplantation (HCT) is associated with graft failure and poor graft function. Strategies to reduce spleen size before HCT especially after failure to Janus kinase (JAK) inhibition represent unmet clinical needs in the field. Here, we leveraged a global collaboration to investigate the safety and efficacy of splenic irradiation as part of the HCT platform for patients with myelofibrosis. We included 59 patients, receiving irradiation within a median of 2 weeks (range, 0.9-12 weeks) before HCT. Overall, the median spleen size prior to irradiation was 23 cm (range, 14-35). Splenic irradiation resulted in a significant and rapid spleen size reduction in 97% of patients (57/59), with a median decrease of 5.0 cm (95% confidence interval, 4.1-6.3 cm). The most frequent adverse event was thrombocytopenia, with no correlation between irradiation dose and hematological toxicities. The 3-year overall survival was 62% (95% CI, 48%-76%) and 1-year non-relapse mortality was 26% (95% CI, 14%-38%). Independent predictors for survival were severe thrombocytopenia and anemia before irradiation, transplant-specific risk score, higher-intensity conditioning, and present portal vein thrombosis. When using a propensity score matching adjusted for common confounders, splenic irradiation was associated with significantly reduced relapse (p = .01), showing a 3-year incidence of 12% for splenic irradiation versus 29% for patients with immediate HCT and 38% for patients receiving splenectomy. In conclusion, splenic irradiation immediately before HCT is a reasonable approach in patients experiencing JAK inhibition failure and is associated with a low incidence of relapse.

The mutational landscape in chronic myelomonocytic leukemia and its impact on allogeneic hematopoietic cell transplantation outcomes: a Center for Blood and Marrow Transplantation Research (CIBMTR) analysis.

Somatic mutations are recognized as an important prognostic factor in chronic myelomonocytic leukemia (CMML). However, limited data are available regarding their impact on outcomes after allogeneic hematopoietic cell transplantation (HCT). In this registry analysis conducted in collaboration with the Center for International Blood and Marrow Transplantation Registry database/sample repository, we identified 313 adult patients with CMML (median age: 64 years, range, 28- 77) who underwent allogeneic HCT during 2001-2017 and had an available biospecimen in the form of a peripheral blood sample obtained prior to the start of conditioning. In multivariate analysis, a CMML-specific prognostic scoring system (CPSS) score of intermediate-2 (HR=1.46, P=0.049) or high (HR=3.22, P=0.0004) correlated significantly with overall survival. When the molecularly informed CPSS-Mol prognostic model was applied, a high CPSS-Mol score (HR=2 P=0.0079) correlated significantly with overall survival. The most common somatic mutations were in ASXL1 (62%), TET2 (35%), KRAS/NRAS (33% combined), and SRSF2 (31%). DNMT3A and TP53 mutations were associated with decreased overall survival (HR=1.70 [95% CI: 1.11-2.60], P=0.0147 and HR=2.72 [95% CI: 1.37-5.39], P=0.0042, respectively) while DNMT3A, JAK2, and TP53 mutations were associated with decreased disease-free survival (HR=1.66 [95% CI: 1.11-2.49], P=0.0138, HR=1.79 [95% CI: 1.06-3.03], P=0.0293, and HR=2.94 [95% CI: 1.50-5.79], P=0.0018, respectively). The only mutation associated with increased relapse was TP53 (HR=2.94, P=0.0201). Nonetheless, the impact of TP53 mutations specifically should be interpreted cautiously given their rarity in CMML. We calculated the goodness of fit measured by Harrell's C-index for both the CPSS and CPSS-Mol, which were very similar. In summary, via registry data we have determined the mutational landscape in patients with CMML who underwent allogeneic HCT, and demonstrated an association between CPSS-Mol and transplant outcomes although without major improvement in the risk prediction beyond that provided by the CPSS.

Retrospective analysis of pacritinib in patients with myelofibrosis and severe thrombocytopenia.

Thrombocytopenia is common in patients with myelofibrosis (MF) and is a well-established adverse prognostic factor. Both of the approved Janus kinase (JAK) inhibitors, ruxolitinib and fedratinib, can worsen thrombocytopenia and have not been evaluated in patients with severe thrombocytopenia (platelet counts <50×109/L). Pacritinib, a novel JAK2/interleukin-1 receptor-associated kinase 1 inhibitor, has been studied in two phase III trials (PERSIST-1 and PERSIST- 2), both of which enrolled patients with MF and severe thrombocytopenia. In order to better characterize treatment outcomes for this population with advanced disease, we present a retrospective analysis of efficacy and safety data in the 189 patients with severe thrombocytopenia treated in the PERSIST studies. The proportion of patients in the pacritinib group meeting efficacy endpoints was greater than in the BAT group for ≥35% spleen volume reduction (23% vs. 2%, P=0.0007), ≥50% modified Total Symptom Score reduction (25% vs. 8%, P=0.044), and self-reported symptom benefit ("much" or "very much" improved; 25% vs. 8%, P=0.016) at the primary analysis time point (week 24). The adverse event profile of pacritinib was manageable, and dose modification was rarely required. There was no excess in bleeding or death in pacritinib-treated patients. These results indicate that pacritinib is a promising treatment for patients with MF who lack safe and effective therapeutic options due to severe thrombocytopenia.

BOREAS: a global, phase III study of the MDM2 inhibitor navtemadlin (KRT-232) in relapsed/refractory myelofibrosis.

Patients with myelofibrosis (MF) who discontinue ruxolitinib due to progression/resistance have poor prognoses. JAK inhibitors control symptoms and reduce spleen volumes with limited impact on underlying disease pathophysiology. Murine double minute 2 (MDM2), a negative regulator of p53, is overexpressed in circulating malignant CD34+ MF cells. The oral MDM2 inhibitor navtemadlin (KRT-232) restores p53 activity to drive apoptosis of wild-type TP53 tumor cells by inducing expression of pro-apoptotic Bcl-2 family proteins. Navtemadlin demonstrated promising clinical and disease-modifying activity and acceptable safety in a phase II study in patients with relapsed/refractory MF. The randomized phase III BOREAS study compares the efficacy and safety of navtemadlin to best available therapy in patients with MF that is relapsed/refractory to JAK inhibitor treatment.

Myelofibrosis (MF) is a rare blood cancer that disrupts normal blood cell production and causes fibrosis (tissue thickening/scarring) in bone marrow, reduced red blood cells in the circulation, and an enlarged spleen. Although currently approved treatments can help relieve some effects, they have limited impact on the underlying cause of the disease. Navtemadlin is a new therapy that inhibits a protein frequently overexpressed in cancer cells found in MF patients called murine double minute 2 (MDM2), which regulates a common tumor suppressor protein called p53. By inhibiting MDM2, navtemadlin restores normal p53 function and its ability to kill MF cancer cells. BOREAS is a large clinical study of navtemadlin for MF patients whose disease is not responding to current therapy.

Allogeneic hematopoietic cell transplantation with non-myeloablative conditioning for patients with hematologic malignancies: Improved outcomes over two decades.

We have used a non-myeloablative conditioning regimen for allogeneic hematopoietic cell transplantation for the past twenty years. During that period, changes in clinical practice have been aimed at reducing morbidity and mortality from infections, organ toxicity, and graft-versus-host disease. We hypothesized that improvements in clinical practice led to better transplantation outcomes over time. From 1997-2017, 1,720 patients with hematologic malignancies received low-dose total body irradiation +/- fludarabine or clofarabine before transplantation from HLA-matched sibling or unrelated donors, followed by mycophenolate mofetil and a calcineurin inhibitor ± sirolimus. We compared outcomes in three cohorts by year of transplantation: 1997 +/- 2003 (n=562), 2004 +/- 2009 (n=594), and 2010 +/- 2017 (n=564). The proportion of patients ≥60 years old increased from 27% in 1997 +/- 2003 to 56% in 2010-2017, and with scores from the Hematopoietic Cell Transplantation Comborbidity Index of ≥3 increased from 25% in 1997 +/- 2003 to 45% in 2010 +/- 2017. Use of unrelated donors increased from 34% in 1997 +/- 2003 to 65% in 2010-2017. When outcomes from 2004 +/- 2009 and 2010-2017 were compared to 1997 +/- 2003, improvements were noted in overall survival (P=.0001 for 2004-2009 and P <.0001 for 2010-2017), profression-free survival (P=.002 for 2004-2009 and P <.0001 for 2010 +/- 2017), non-relapse mortality (P<.0001 for 2004 +/- 2009 and P <.0001 for 2010 +/- 2017), and in rates of grades 2 +/- 4 acute and chronic graft-vs.-host disease. For patients with hematologic malignancies who underwent transplantation with non-myeloablative conditioning, outcomes have improved during the past two decades. Trials reported are registered under ClinicalTrials.gov identifiers: NCT00003145, NCT00003196, NCT00003954, NCT00005799, NCT00005801, NCT00005803, NCT00006251, NCT00014235, NCT00027820, NCT00031655, NCT00036738, NCT00045435, NCT00052546, NCT00060424, NCT00075478, NCT00078858, NCT00089011, NCT00104858, NCT00105001, NCT00110058, NCT00397813, NCT00793572, NCT01231412, NCT01252667, NCT01527045.

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

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

The Role of Donor Lymphocyte Infusion (DLI) in Post-Hematopoietic Cell Transplant (HCT) Relapse for Chronic Myeloid Leukemia (CML) in the Tyrosine Kinase Inhibitor (TKI) Era.

Treatment for relapse of chronic myeloid leukemia (CML) following hematopoietic cell transplantation (HCT) includes tyrosine kinase inhibitors (TKIs) with or without donor lymphocyte infusions (DLIs), but the most effective treatment strategy is unknown. This study was performed through the Center for International Blood and Marrow Transplant Research (CIBMTR) database. We retrospectively reviewed all patients reported to the CIBMTR registry from 2002 to 2014 who underwent HCT for CML and were alive 30 days postrelapse. A total of 215 HCT recipients relapsed and were analyzed in the following groups: (1) TKI alone (n = 128), (2) TKI with DLI (n = 48), and (3) DLI without TKI (n = 39). In multivariate analysis, disease status prior to HCT had a significant effect on overall survival (OS). Patients who received a DLI alone compared with a TKI with a DLI had inferior survival (hazard ratio, 2.28; 95% confidence interval, 1.23 to 4.24; P= .009). Those who received a TKI alone had similar survival compared with those who received a TKI with a DLI (P = .81). These data support that despite use of TKIs pretransplantation, TKI salvage therapy continues to provide significant survival following relapse in patients with CML following HCT. These data do not suggest that adding a DLI to a TKI adds an improvement in OS.

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

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

Hematopoietic Cell Transplantation for Paroxysmal Nocturnal Hemoglobinuria in the Age of Eculizumab.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired clonal hematopoietic cell disease characterized by the destruction of hematopoietic cells through activation of the complement system with manifestations that can be life-threatening including hemolysis, thrombosis, and marrow failure. Allogeneic hematopoietic cell transplantation (HCT) remains the sole cure for PNH, but eculizumab, a terminal complement inhibitor of C5, has been used to prevent complement-mediated hemolysis in patients with PNH since its approval by the Food and Drug Administration in 2007. We examined outcomes of HCT in patients with PNH to evaluate the effects of disease subtype, conditioning intensity, and eculizumab use either pre-HCT or post-HCT. Fifty-five patients with a diagnosis of PNH underwent at least 1 HCT, with 4 patients requiring a second HCT for graft failure. The median age at the time of first HCT was 30.0 years (range, 4.2 to 66.9 years). Seventeen patients (30.9%) had classical PNH, and the remaining 38 patients had PNH associated with another marrow disorder (aplastic anemia in 26 of the 38). Indications for HCT included pancytopenia in 47.3% of the patients, myeloid malignancy (myelodysplastic syndrome, myeloproliferative neoplasm, or acute myelogenous leukemia) in 21.8%, recurrent hemolysis in 20.0%, and thrombosis in 10.9%. Of the 55 first HCTs, 26 were performed with myeloablative conditioning, 27 were performed with reduced-intensity conditioning, and 2 sets of identical twins underwent HCT without any conditioning. Donor types included HLA-matched related in 38.2%, HLA-matched unrelated in 34.5%, single HLA-allele mismatched unrelated in 16.4%, umbilical cord blood in 5.5%, syngeneic in 3.6%, and HLA-haploidentical in 1.8%. The median duration of follow-up in surviving patients was 6.1 years (range, 2.1 to 46.1 years) after first HCT. The median time to neutrophil and platelet engraftment was 17 days and 19 days, respectively; all but 2 patients (96.3%) had sustained engraftment. Overall survival was 70% at 5 years. Neither the choice of conditioning intensity nor PNH subtype affected survival. Nineteen patients died during follow-up, including 12 patients before day +365. Six patients received treatment with eculizumab before HCT, and 2 were treated after HCT. All patients treated with eculizumab were alive at a median follow-up of 2.3 years (range, .2 to 6.9 years). Both patients treated with eculizumab after HCT had minimal to no acute GVHD (aGVHD), with grade I skin aGVHD in 1 patient and no aGVHD in the other patient, and no chronic GVHD at 2.1 and 4.1 years post-HCT, respectively. With the approval of eculizumab, the indications for HCT include persistent hemolysis, persistent thrombosis, and associated marrow failure. Administration of eculizumab before and after HCT warrants further study, particularly considering our observation of minimal to no GVHD in 2 patients who received eculizumab after HCT.

Total body irradiation dose escalation decreases risk of progression and graft rejection after hematopoietic cell transplantation for myelodysplastic syndromes or myeloproliferative neoplasms.

A non-myeloablative regimen of fludarabine and 200 cGy total body irradiation combined with post-grafting immunosuppression with mycophenolate mofetil and a calcineurin inhibitor facilitates allogeneic hematopoietic cell transplantation from HLA-matched related or unrelated donors in older patients and/or those with comorbidities. However, outcomes of prior studies have been disappointing in patients with myelodysplastic syndromes or myeloproliferative neoplasms due to high incidences of progression or graft failure (together termed hematopoietic cell transplantation-failure). We hypothesized that escalating the total body irradiation dose may improve the outcomes and subsequently performed a phase II total body irradiation dose-escalation trial. Patients with median age 66 years were enrolled in two arms to receive non-myeloablative conditioning followed by hematopoietic cell transplantation with total body irradiation dose escalation for excessive hematopoietic cell transplantation-failure: Arm A: myeloproliferative neoplasm/myelodysplastic syndrome low risk (n=36); and Arm B: myelodysplastic syndrome high-risk/chronic myelomonocytic leukemia (n=41). Total body irradiation dose levels were: Level-1 (300 cGy), Level-2 (400 cGy), or Level-3 (450 cGy). Patients received intravenous fludarabine 30 mg/m2 for three days. Total body irradiation was administered on day 0 followed by infusion of peripheral blood stem cells from HLA-matched related (n=30) or unrelated (n=47) donors. Post-grafting immunosuppression with mycophenolate mofetil and cyclosporine was administered. The primary end point was day 200 hematopoietic cell transplant failure, with the objective of reducing the incidence to <20%. The primary end point was reached on Arm A at dose Level-1 (300 cGy total body irradiation) with a cumulative incidence of day 200 hematopoietic cell transplant failure of 11%, and on Arm B at dose Level-3 (450 cGy) with a cumulative incidence of day 200 hematopoietic cell transplant failure of 9%. Increasing the total body irradiation dose leads to a higher success rate with non-myeloablative conditioning by reducing relapse and rejection. Further studies are necessary to decrease non-relapse mortality, especially among patients with high-risk disease. Trial registered under clinicaltrials.gov identifier: NCT00397813.

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

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

CC-486 Maintenance after Stem Cell Transplantation in Patients with Acute Myeloid Leukemia or Myelodysplastic Syndromes.

Relapse is the main cause of treatment failure after allogeneic stem cell transplant (alloSCT) in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). Injectable azacitidine can improve post-transplant outcomes but presents challenges with exposure and compliance. Oral CC-486 allows extended dosing to prolong azacitidine activity. We investigated use of CC-486 maintenance therapy after alloSCT. Adults with MDS or AML in morphologic complete remission at CC-486 initiation (42 to 84 days after alloSCT) were included. Patients received 1 of 4 CC-486 dosing schedules per 28-day cycle for up to 12 cycles. Endpoints included safety, pharmacokinetics, graft-versus-host disease (GVHD) incidence, relapse/progression rate, and survival. Of 30 patients, 7 received CC-486 once daily for 7 days per cycle (200 mg, n = 3; 300 mg, n = 4) and 23 for 14 days per cycle (150 mg, n = 4; 200 mg, n = 19 [expansion cohort]). Grades 3 to 4 adverse events were infrequent and occurred with similar frequency across regimens. Standard concomitant medications did not alter CC-486 pharmacokinetic parameters. Three patients (10%) experienced grade III acute GVHD and 9 experienced chronic GVHD. Of 28 evaluable patients, 6 (21%) relapsed or had progressive disease: 3 of 7 patients (43%) who had received 7-day dosing and 3 of 23 (13%) who had received 14-day dosing. Transplant-related mortality was 3%. At 19 months of follow-up, median overall survival was not reached. Estimated 1-year survival rates were 86% and 81% in the 7-day and 14-day dosing cohorts, respectively. CC-486 maintenance was generally well tolerated, with low rates of relapse, disease progression, and GVHD. CC-486 maintenance may permit epigenetic manipulation of the alloreactive response postallograft. Findings require confirmation in randomized trials. (ClinicalTrials.gov NCT01835587.).

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

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

Recipient single nucleotide polymorphisms in Paneth cell antimicrobial peptide genes and acute graft-versus-host disease: analysis of BMT CTN-0201 and -0901 samples.

Host genetics shape the gut microbiota, and gut dysbiosis increases the risk of acute graft-versus-host disease (aGVHD). Paneth cells and microbiota have interactions that contribute to immune regulation. α-defensin-5 (HD5) and regenerating islet-derived protein 3 alpha (Reg3A) are the most abundant Paneth cell antimicrobial peptides (AMPs). We hypothesized that single nucleotide polymorphisms (SNPs) in the genes for HD5 (DEFA5) and Reg3A (REG3A) predict aGVHD risk. We analysed pre-transplant recipient peripheral blood mononuclear cell samples from randomized Blood and Marrow Transplant Clinical Trials Network (BMT CTN) studies 0201 (94 patients with bone marrow and 93 with peripheral blood grafts) and 0901 (86 patients with myeloablative and 77 with reduced-intensity conditioning; all using peripheral blood grafts). In multivariable analysis (with a SNP × graft source interaction term in CTN-0201 and a SNP × conditioning intensity term in CTN-0901), DEFA5 rs4415345 and rs4610776 were associated with altered incidence of aGVHD grade II-IV [rs4415345 G vs. C: hazard ratio (HR) 0·58, 95% confidence interval (95% CI) 0·37-0·92, P = 0·02; rs4610776 T vs. A: HR 1·53, 95% CI 1·01-2·32, P = 0·05] in CTN-0201, but not CTN-0901, suggesting a stronger effect in bone marrow allografts. REG3A SNP was not associated with aGVHD. Host genetics may influence aGVHD risk by modulating Paneth cell function.

Hematopoietic Cell Transplantation in Myelodysplastic Syndromes after Treatment with Hypomethylating Agents.

The prognosis of patients with myelodysplastic syndromes (MDS) after failure of hypomethylating agent (HMA) therapy is poor. Allogeneic hematopoietic cell transplantation (HCT) can be effective in curing patients who have failed therapy with HMA. However, published results have not addressed the outcomes with HCT in this setting. We identified 125 MDS patients who had been treated with HMA and underwent subsequent HCT. Among these, 68 were considered HMA failures and 57 responders. Failure was defined as progression to higher grade MDS or acute myeloid leukemia, lack of hematologic improvement after at least 4 HMA cycles, or loss of response after initial improvement. Response was defined as showing at least hematologic improvement. Outcomes were compared using Cox regression. Overall, 73 of 125 HMA-treated patients (58%) had died by the time of last contact. Median follow-up of survivors, measured from HCT, was 41.9 months (range, 2.7 to 98.5). The estimated probability of relapse at 3 years was 56.6% and 34.2% among failing and responding patients, respectively (hazard ratio [HR], 2.1; 95% confidence interval [CI], 1.2 to 3.66; P < .01). The estimated probability of relapse-free survival at 3 years was 23.8% and 42% in failing and responding patients, respectively (HR for relapse/death, 1.88; 95% CI, 1.19 to 2.95; P < .01). The risk of nonrelapse mortality was similar for both groups (HR, 1.12; 95% CI, .52 to 2.39; P = .77). Failure of treatment with HMA was associated with higher risk of post-HCT relapse than observed in patients responding to HMA. Prospective trials are needed to evaluate the efficacy of novel conditioning regimens and post-HCT maintenance strategies in patients who have failed HMA pre-HCT.