Clinical and Cytogenetic Characterization of Early and Late Relapses in Patients Allografted for Myeloid Neoplasms with a Myelodysplastic Component.

An improved understanding of relapse kinetics is required to optimize detection and treatment strategies for the post-transplant relapse of myeloid neoplasms. Therefore, we retrospectively analyzed data from 91 patients allografted for MDS (n = 54), AML-MRC (n = 29) and chronic myelomonocytic leukemia (CMML, n = 8), who relapsed after transplant. Patients with early (<12 months, n = 56) and late relapse (>12 months, n = 35) were compared regarding patient-, disease- and transplant-related factors, including karyotype analyses at diagnosis and relapse. After a median follow-up of 17.4 months after relapse, late relapses showed improved outcomes compared with early relapses (2-yr OS 67% vs. 32%, p = 0.0048). Comparing frequency of distinct patient-, disease- and transplant-related factors among early and late relapses, complex karyotype (p = 0.0004) and unfavorable disease risk at diagnosis (p = 0.0008) as well as clonal evolution at relapse (p = 0.03) were more common in early than in late relapses. Furthermore, patients receiving transplant without prior cytoreduction or in complete remission were more frequently present in the group of late relapses. These data suggest that cytogenetics rather than disease burden at diagnosis and transplant-related factors determine the timepoint of post-transplant relapse and that upfront transplantation may be favored in order to delay relapse.

The importance of the Peritoneal Cancer Index (PCI) to predict surgical outcome after neoadjuvant chemotherapy in advanced ovarian cancer.

PURPOSE: Achieving complete cytoreduction (CCR) is crucial for a patient's prognosis with advanced epithelial ovarian cancer (EOC). So far, prognostic predictors have failed to predict surgical outcome after neoadjuvant chemotherapy (NACT). In clinical trials, scores were used to predict operability in recurrent ovarian cancer (Harter et al. in N Engl J Med 385(23):2123-2131, 2021) but there is no known prediction score for CCR after NACT. The Peritoneal Cancer Index (PCI) is an established tool to predict surgical outcome in primary setting (Lampe et al. in 25:135-144, 2015). We now examined the predictive power of the PCI to achieve CCR after NACT. METHODS: In this single-center study, the data of patients with advanced stage EOC (FIGO > IIIb) treated between 01/2015 and 12/2020 were analyzed retrospectively. Inclusion criteria were a mandatory staging laparoscopy, a PCI score > 25, and NACT. CT scans were analyzed in blinded fashion according to RECIST criteria (Borgani et al. in 237; 93-99, 2019) Reaction of PCI after NACT was compared with the analysis of radiologic imaging and CA-125 levels. RESULTS: Three hundred and sixteen patients were screened, 62 were treated with NACT, and 23 were included in our analysis. 87% of cases presented with an FIGO IIIc stadium. The reduction of PCI itself after NACT showed to be the most powerful predictor for achieving CCR. The reduction of the initial PCI score by minimum of 8.5 points was a better predictor for CCR than reaching a PCI < 25. In contrast to data deriving from patients undergoing primary debulking surgery (PDS), we found a PCI of 17, rather than 25, to be a more valuable cut-off for CCR in neoadjuvant-treated patients. CONCLUSION: The extend of PCI reduction after NACT is a better predictor for achieving CCR compared with CA125 levels and radiologic imaging. The PCI must be assessed differently in neoadjuvant setting than in a primary situation. CCR was most likely for a post-NACT PCI < 17.

Opportunities and Limitations of Pelvic Exenteration Surgery.

PURPOSE: The practice of exenterative surgery is sometimes controversial and has garnered a certain scepticism. Surgical studies are difficult to conduct due to insufficient data. The aim of this review is to present the current standing of pelvic exenteration from a surgical, gynaecological and urological point of view. METHODS: This review is based upon a literature review (MEDLINE (PubMed), CENTRAL (Cochrane) and EMBASE (Elsevier)) of retrospective studies on exenterative surgery from 1993-2020. Using MeSH (Medical Subject Headings) search terms, 1572 publications were found. These were evaluated and screened with respect to their eligibility using algorithms and well-defined inclusion and exclusion criteria. Therefore, the guidelines for systematic reviews (PRISMA) were used. RESULTS: A complete tumour resection (R0) often represents the only curative option for advanced pelvic carcinomas and their recurrences. A recent systematic review showed significant symptom relief in 80% of palliative patients after pelvic exenteration. Surgical limitations (distant metastases, involvement of the pelvic wall, etc.) are diminished by adequate surgical expertise and close interdisciplinary cooperation. While the mortality rate is low (2-5%), the still relatively high morbidity rate (32-84%) can be minimized by optimizing the perioperative setting. Following exenterations, roughly 79-82% of patients report satisfying results according to PROs (patient-reported outcomes). CONCLUSION: Due to multimodality treatment strategies combined with extended surgical expertise and patients' preferences, pelvic exenteration can be offered nowadays with low mortality and acceptable postoperative quality of life. The possibilities of surgical treatment are often underestimated. A multi-centre database (PelvEx Collaborative) was established to collect data and experiences to optimize the research in this field.

Role of the Cardiophrenic Lymph Node Status After Neoadjuvant Chemotherapy in Primary Advanced Ovarian Cancer.

BACKGROUND/AIM: This study investigated the cardiophrenic lymph node (CPLN) status before and after neoadjuvant chemotherapy (NACT), as its presence seems to have a rather prognostic significance in patients with advanced ovarian cancer. PATIENTS AND METHODS: The baseline computed tomography scans of 66 patients with advanced ovarian cancer primary treated with NACT between March 2015 and June 2020 were reviewed. A CPLN enlargement was defined as ≥5 mm. RESULTS: 44% (n=29) of the patients had enlarged CPLNs; 10.7% (n=3) showed a complete response, 71.4% (n=20) a partial response, and 17.9% (n=5) a stable disease after NACT. There was no significant difference between the response to NACT measured according to the status of CPLN compared to other biomarkers in the CPLN group. CONCLUSION: Patients with CPLN enlargement have a tendency to an impaired prognosis. The response of CPLN to NACT was comparable to the response of established biomarkers, adding a monitoring function to the CPLN.

Eligibility for clinical trials is unsatisfactory for patients with myelodysplastic syndromes, even at a tertiary referral center.

Participation in clinical trials may allow patients with MDS to gain access to therapies not otherwise available. However, access is limited by strict inclusion and exclusion criteria, reflecting academic or regulatory questions addressed by the respective studies. We performed a simulation in order to estimate the average proportion of MDS patients eligible for participation in a clinical trial. The simulation drew upon 1809 patients in the Düsseldorf MDS Registry whose clinical data allowed eligibility screening for a wide range of clinical trials. This cohort was assumed to be alive and available for study participation. The simulation also posited that all MDS trials (n = 47) conducted in our center between 1987 and 2016 were open for recruitment. In addition, study activities in the year 2016 were analyzed to determine the proportion of patients eligible for at least one of the 9 MDS trials open at that time. On average, each clinical trial was suitable for about 18 % of patients in the simulation cohort. Conversely, 34 % of the patients were eligible for at least one of the 9 clinical studies in 2016. Inclusion/exclusion criteria of studies initiated by the pharmaceutical industry excluded more than twice the fraction of patients compared with investigator initiated trials (potential inclusion of 10 % vs. 21 %, respectively). Karyotype (average exclusion rate 58 %), comorbidities (40 %), and prior therapies (55 %) were the main reasons for exclusion. We suggest that in- and exclusion criteria should be less restrictive, in order to meet the needs of the real-life population of elderly MDS patients.

Genome-wide DNA methylation analysis pre- and post-lenalidomide treatment in patients with myelodysplastic syndrome with isolated deletion (5q).

Myelodysplastic syndrome (MDS) with isolated deletion of chromosome 5q (MDS del5q) is a distinct subtype of MDS with quite favorable prognosis and excellent response to treatment with lenalidomide. Still, a relevant percentage of patients do not respond to lenalidomide and even experience progression to acute myeloid leukemia (AML). In this study, we aimed to investigate whether global DNA methylation patterns could predict response to lenalidomide. Genome-wide DNA methylation analysis using Illumina 450k methylation arrays was performed on n=51 patients with MDS del5q who were uniformly treated with lenalidomide in a prospective multicenter trial of the German MDS study group. To study potential direct effects of lenalidomide on DNA methylation, 17 paired samples pre- and post-treatment were analyzed. Our results revealed no relevant effect of lenalidomide on methylation status. Furthermore, methylation patterns prior to therapy could not predict lenalidomide response. However, methylation clustering identified a group of patients with a trend towards inferior overall survival. These patients showed hypermethylation of several interesting target genes, including genes of relevant signaling pathways, potentially indicating the evaluation of novel therapeutic targets.

Treatment of myeloid malignancies relapsing after allogeneic hematopoietic stem cell transplantation with venetoclax and hypomethylating agents-a retrospective multicenter analysis on behalf of the German Cooperative Transplant Study Group.

Treatment of relapse after allogeneic hematopoietic stem cell transplantation (alloHSCT) remains a great challenge. Aiming to evaluate the combination of venetoclax and hypomethylating agents (HMAClax) for the treatment of relapse of myeloid malignancies after alloHSCT, we retrospectively collected data from 32 patients treated at 11 German centers. Venetoclax was applied with azacitidine (n = 13) or decitabine (n = 19); 11 patients received DLI in addition. HMAClax was the first salvage therapy in 8 patients. The median number of cycles per patient was 2 (1-19). All but 1 patient had grade 3/4 neutropenia. Hospital admission for grade 3/4 infections was necessary in 23 patients (72%); 5 of these were fatal. In 30 evaluable patients, overall response rate (ORR) was 47% (14/30, 3 CR MRDneg, 5 CR, 2 CRi, 1 MLFS, 3 PR). ORR was 86% in first salvage patients versus 35% in later salvage patients (p = 0.03). In 6 patients with molecular relapse (MR), ORR was 67% versus 42% in patients with hematological relapse (HR) (n = 24, p = n.s.). After a median follow-up of 8.4 months, 25 patients (78%) had died and 7 were alive. Estimated median overall survival was 3.7 months. Median survival of patients with HMAClax for first versus later salvage therapy was 5.7 and 3.4 months (p = n.s.) and for patients with MR (not reached) compared to HR (3.4 months, p = 0.024). This retrospective case series shows that venetoclax is utilized in various different combinations, schedules, and doses. Toxicity is substantial and patients who receive venetoclax/HMA combinations for MR or as first salvage therapy derive the greatest benefit.

Prediction of Response and Survival Following Treatment with Azacitidine for Relapse of Acute Myeloid Leukemia and Myelodysplastic Syndromes after Allogeneic Hematopoietic Stem Cell Transplantation.

To provide long-term outcome data and predictors for response and survival, we retrospectively analyzed all 151 patients with relapse of myeloid neoplasms after allogeneic hematopoietic stem cell transplantation (allo-HSCT) who were uniformly treated with first-line azacitidine (Aza) salvage therapy at our center. Patients were treated for molecular (39%) or hematologic relapse (61%), with a median of 5 cycles of Aza and at least one donor lymphocyte infusion in 70% of patients. Overall response was 46%, with 41% achieving complete (CR) and 5% achieving partial remission. CR was achieved after a median of 4 cycles and lasted for a median of 11 months (range 0.9 to 120 months). With a median follow-up of 22 months (range: 1 to 122 months), the 2-year survival rate was 38% ± 9%, including 17 patients with ongoing remission for >5 years. Based on results from multivariate analyses, molecular relapse and time to relapse were integrated into a score, clearly dividing patients into 3 subgroups with CR rates of 71%, 39%, and 29%; and 2-year survival rates of 64%, 38%, and 27%, respectively. In the subgroup of MDS and secondary AML, receiving upfront transplantation was associated with superior response and survival, and therefore pretransplant strategy was integrated together with relapse type into a MDS-sAML-specific score. Overall, Aza enables meaningful responses and long-term survival, which is a predictable with a simple-to-use scoring system.

Improving the accuracy of prognostication in chronic myelomonocytic leukemia.

INTRODUCTION: Chronic myelomonocytic leukemia (CMML) is a hematological malignancy that is extremely variable regarding its clinical course. It may present either as a chronic disorder with mild symptoms and low disease burden for several years, thereby justifying a watch-and-wait-strategy, or may soon progress to acute myeloid leukemia (AML) leaving allogeneic stem cell transplantation as the only curative treatment option. AREAS COVERED: Attempts have been made to integrate clinical, cytogenetic, and molecular parameters into scoring systems aiming at providing reliable prognostic information. In this article, we discuss several prognostic parameters and validate prognostic scores in a cohort of 645 patients with CMML. EXPERT OPINION: We show that the CPSS (CMML prognostic scoring system) is a useful prognostic tool. The integration of molecular data into the new CPSS-mol will further improve prognostic accuracy, primarily by identifying an increased proportion of higher-risk patients.

The Value of Torque Teno Virus (TTV) as a Marker for the Degree of Immunosuppression in Adult Patients after Hematopoietic Stem Cell Transplantation (HSCT).

Torque teno virus (TTV) is a nonenveloped, single-stranded, circular DNA virus of the family of Anelloviridae. The first contact with TTV usually occurs in early childhood, followed by persistent infection in bone marrow and lymphocytes. Increased levels of TTV-DNA are found in the serum in various states of immune deficiency. The objective of this study was to assess if monitoring of TTV viremia after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a predictive marker for immune-related clinical complications. In a retrospective study, 2054 whole-blood samples from 123 patients were tested for viral loads of TTV-DNA by real-time PCR within 345 days after allo-HSCT. We enrolled all patients who underwent allo-HSCT between September 2015 and April 2018. Clinical and laboratory data were collected and statistically analyzed. Patients with an underlying lymphatic malignancy had significantly higher torque teno (TT) viral loads compared with patients with an underlying malignant myeloid disease (P < .05). Complete remission before allo-HSCT correlated significantly with higher TT viral loads after allo-HSCT (P < .05). Myeloablative conditioning regimens led to significantly higher TT viral loads than reduced-intensity conditioning regimens (P < .05). A higher anti-thymocyte globulin (ATG) dose was associated with a significantly higher TT viral load. We did not observe any significant differences of TT viral load correlating with accompanying clinically relevant events such as virus reactivations (cytomegalovirus, Epstein-Barr virus, Adenovirus), acute graft-versus-host disease (aGVHD), relapse, or death. TT viral load after allo-HSCT did weakly correlate with T cell, T suppressor cell, T helper cell, and natural killer and B cell count. Although statistically significant differences between study groups were observed, virus reactivations, aGVHD, and clinical outcomes could not be predicted by monitoring TTV viremia. Therefore, TTV seems not to be suitable as a marker for the degree of immunosuppression or as a prognostic marker for clinically critical events in patients after allo-HSCT.

Lymphopenia at diagnosis is highly prevalent in myelodysplastic syndromes and has an independent negative prognostic value in IPSS-R-low-risk patients.

Lymphopenia is associated with an increased mortality in several medical conditions. Its prognostic impact in myelodysplastic syndromes (MDS) is less well studied. Hence, we analyzed 1023 patients from the Düsseldorf MDS-registry with regard to the absolute lymphocyte count (ALC) at diagnosis. An ALC below the median of the population (1.2 × 109/l) was associated with lower counts of neutrophils (median 1.35 vs. 1.92 × 109/l, p < 0.001) and platelets (median 100 vs. 138 × 109/l, p < 0.001) and with a significant lower overall survival in univariate analysis (whole cohort: median 36 vs. 46 months, p = 0.016; 721 patients without hematopoietic stem cell transplantation or induction chemotherapy: median 36 vs. 56 months, p = 0.001). For low-risk MDS according to IPSS-R, an ALC < 1.2 × 109/l was of additional prognostic value in a multivariate Cox regression model together with age (< or ≥65 years) and LDH (< or ≥normal value of 240 U/l; HR 1.46, 95% CI: 1.03-2.08, p = 0.033). These data support the hypothesis of subtle but clinical relevant changes of the adaptive immune system in MDS. Further studies are necessary to identify the ALC cut-off best suitable for prognostication and the mechanisms responsible for the impairment of lymphoid homeostasis in MDS.

Relapse patterns and treatment strategies in patients receiving allogeneic hematopoietic stem cell transplantation for myeloid malignancies.

Allogeneic hematopoietic stem cell transplantation (aHSCT) cures a considerable number of patients with myeloid malignancies, but relapse is the most frequent cause of death. We retrospectively studied relapse rate, kinetics, treatment, and outcome after first aHSCT in 446 patients during a 13-year period. Relapse occurred in 167 patients after a median of 4.6 months (116 hematologic (HR), 38 molecular (MR), and 13 extramedullary relapses (XR)). Median survival after relapse was 8.4 months and 2-year overall survival was 25%. Regarding survival after relapse, type (MR/HR/XR) and timepoint of relapse ( 12 months), age ( 50), diagnosis (MDS/AML and sAML), and remission status at transplant (CR and untreated MDS vs. refractory disease) were relevant in univariate analyses, in multivariate analyses timepoint, and type of relapse, age, and diagnosis. One hundred fifty-six patients were treated, most frequently with hypomethylating agents (HMA, n = 109) or intensive chemotherapy (n = 12). Donor lymphocyte infusion (DLI) was administered to 99 patients. Second aHSCT was performed in three patients as first and in 21 as higher salvage treatment. A complete remission (CR) was achieved in 46 patients (30%). Among CR patients, 65% had received HMA and DLI. Median survival of patients achieving CR was 105 months and 2-year overall survival was 80%. We conclude that with HMA and DLI or second aHSCT, a substantial number of patients, who relapse after aHSCT, can re-achieve remission and long-term survival. Techniques to further improve the detection of minimal residual disease are urgently needed because early treatment of MR results in significantly better survival.

Comparison between Upfront Transplantation and different Pretransplant Cytoreductive Treatment Approaches in Patients with High-Risk Myelodysplastic Syndrome and Secondary Acute Myelogenous Leukemia.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative treatment for patients with advanced myelodysplastic syndrome (MDS) and secondary acute myelogenous leukemia (sAML), but in the absence of prospective trials the impact of pretransplant cytoreduction is controversially discussed. We retrospectively analyzed the outcome of 165 patients with MDS and excess blasts (n = 126, 76%) and sAML (n = 39, 24%) according to a pretransplant strategy. Sixty-seven patients (41%) were directly transplanted (upfront group), whereas 98 patients (59%) had received pretransplant cytoreductive treatment (induction chemotherapy [CTX], n = 64; hypomethylating agents [HMAs], n = 34) resulting in a significantly higher complete remission rate in the CTX group (59% versus HMA 18%, P < .0001). Estimated rates of 5-year overall survival (OS) and relapse-free survival (RFS) for the entire group were 54% and 39%, respectively. The 5-year OS rates of the upfront, CTX, and HMA groups were 61%, 50%, and 45%, respectively (P = .116), whereas RFS rates were 38%, 41%, and 38% (P = .926). Cumulative incidence of relapse (CIR) and nonrelapse mortality (NRM) did not differ between treatment groups. In the upfront group no difference regarding OS and RFS was seen with respect to pretransplant blast count (>10% versus <10%). In multivariate analyses type of pretransplant strategy did not have an effect on OS, RFS, CIR, and NRM, whereas cytogenetics (OS, RFS, CIR), reduced-intensity conditioning (OS, RFS, CIR), and an unrelated donor (RFS, CIR) were identified as negative predictors. When compared with the upfront group, 5-year OS was significantly lower in patients with CTX-refractory disease (34% versus 64%, P = .0346) and by clear trend in HMA nonresponders (42% versus 61%, P = .073), whereas RFS did not differ significantly. In further support of the concept, that pretransplant therapy may favor the selection of resistant clones, patients in the upfront group had a higher likelihood to respond to HMAs as salvage therapy for relapse in comparison with pretreated patients (complete remission, 58% versus 10%; P = .0005) and a higher 2-year OS rate after relapse (59% versus 19%, P = .0001). These data suggest that an upfront transplant strategy is at least not inferior to pretransplant cytoreduction and may be augmented by HMAs + donor lymphocyte infusion salvage therapy in case of relapse after allo-HSCT.

Role of Donor Clonal Hematopoiesis in Allogeneic Hematopoietic Stem-Cell Transplantation.

PURPOSE: Clonal hematopoiesis of indeterminate potential (CHIP) occurs in the blood of approximately 20% of older persons. CHIP is linked to an increased risk of hematologic malignancies and of all-cause mortality; thus, the eligibility of stem-cell donors with CHIP is questionable. We comprehensively investigated how donor CHIP affects outcome of allogeneic hematopoietic stem-cell transplantation (HSCT). METHODS: We collected blood samples from 500 healthy, related HSCT donors (age ≥ 55 years) at the time of stem-cell donation for targeted sequencing with a 66-gene panel. The effect of donor CHIP was assessed on recipient outcomes, including graft-versus-host disease (GVHD), cumulative incidence of relapse/progression (CIR/P), and overall survival (OS). RESULTS: A total of 92 clonal mutations with a median variant allele frequency of 5.9% were identified in 80 (16.0%) of 500 donors. CHIP prevalence was higher in donors related to patients with myeloid compared with lymphoid malignancies (19.2% v 6.3%; P ≤ .001). In recipients allografted with donor CHIP, we found a high cumulative incidence of chronic GVHD (cGVHD; hazard ratio [HR], 1.73; 95% CI, 1.21 to 2.49; P = .003) and lower CIR/P (univariate: HR, 0.62; 95% CI, 0.40 to 0.97; P = .027; multivariate: HR, 0.63; 95% CI, 0.41 to 0.98; P = .042) but no effect on nonrelapse mortality. Serial quantification of 25 mutations showed engraftment of 24 of 25 clones and disproportionate expansion in half of them. Donor-cell leukemia was observed in two recipients. OS was not affected by donor CHIP status (HR, 0.88; 95% CI, 0.65 to 1.321; P = .434). CONCLUSION: Allogeneic HSCT from donors with CHIP seems safe and results in similar survival in the setting of older, related donors. Future studies in younger and unrelated donors are warranted to extend these results. Confirmatory studies and mechanistic experiments are warranted to challenge the hypothesis that donor CHIP might foster cGVHD development and reduce relapse/progression risk.

Long-term outcome of high risk patients with myelodysplastic syndromes or secondary acute myeloid leukemia receiving intensive chemotherapy.

Intensive chemotherapy (IC) used to be a common treatment approach for patients with higher-risk myelodysplastic syndromes (MDS) or acute myeloid leukemia after MDS (sAML). We conducted a retrospective analysis of 299 patients, including a matched pair analysis comparing 96 patients receiving IC with 96 patients not undergoing IC, in order to evaluate the impact of IC on overall survival (OS) and to identify factors that influence remission rates and OS. Complete remission (CR) after first induction chemotherapy was reached in 50% of patients. Parameters influencing the probability of achieving CR were blast count in the bone marrow (< 30%), age < 65 years, presence of Auer rods, duration of antecedent MDS shorter than 6 months, and timing of IC in relation to first diagnosis. The difference in survival time was not significantly better for patients receiving IC (median OS 12.7 months vs. 7 months). Parameters favorably influencing survival were the presence of Auer rods, age below 60 years, blast count below 30%, IC given shortly after first diagnosis, and achievement of CR. On multivariate analysis, achieving CR, presence of Auer rods, and percentage of blasts below or above 30% significantly influenced median survival. Relapse occurred in 63% of patients after a median of 9.9 months with a median survival of 7.6 months. Considering the high relapse rate and short survival, we conclude that intensive chemotherapy is not promising for high-risk MDS or sAML.

Peripheral blood cytogenetics allows treatment monitoring and early identification of treatment failure to lenalidomide in MDS patients: results of the LE-MON-5 trial.

Transfusion-dependent patients with low- or intermediate-1-risk myelodysplastic syndrome, <5% bone marrow (BM) blasts and isolated 5q-deletion received lenalidomide within the German MDS study group phase-II clinical trial LE-MON-5 (EudraCT:2008-001866-10) of the University of Duesseldorf, Germany. Cytogenetic monitoring was performed by chromosome banding analyses (CBA) of BM cells and fluorescence in situ hybridization (FISH) analyses of peripheral blood (PB) mononuclear CD34+ cells using extended probe panels. Out of 144 patients screened for study enrollment, 24% failed to meet inclusion criteria due to cytogenetic findings. Eighty-seven patients were followed with a median observation time of 30 months. Cytogenetic response detected by FISH and CBA in 74 and 66% of patients, respectively, was predictive for hematologic response as well as of high prognostic relevance. After 2 years, AML rate was 8% for all patients. Karyotype evolution was detected in 21 (FISH)-34% (CBA) of patients associated with significantly shorter AML-free survival. Disease progression was first detectable on the cytogenetic level on average 5-6 months before recurrence of transfusion dependence. Our data show for the first time in a prospective setting that a cytogenetic monitoring from the PB helps to early identify treatment failure and progressive disease in lenalidomide-treated patients to improve clinical management. TRIAL REGISTRATION: EudraCT:2008-001866-10.

Integrating clinical features and genetic lesions in the risk assessment of patients with chronic myelomonocytic leukemia.

Chronic myelomonocytic leukemia (CMML) is a myelodysplastic/myeloproliferative neoplasm with variable clinical course. To predict the clinical outcome, we previously developed a CMML-specific prognostic scoring system (CPSS) based on clinical parameters and cytogenetics. In this work, we tested the hypothesis that accounting for gene mutations would further improve risk stratification of CMML patients. We therefore sequenced 38 genes to explore the role of somatic mutations in disease phenotype and clinical outcome. Overall, 199 of 214 (93%) CMML patients carried at least 1 somatic mutation. Stepwise linear regression models showed that these mutations accounted for 15% to 24% of variability of clinical phenotype. Based on multivariable Cox regression analyses, cytogenetic abnormalities and mutations in RUNX1, NRAS, SETBP1, and ASXL1 were independently associated with overall survival (OS). Using these parameters, we defined a genetic score that identified 4 categories with significantly different OS and cumulative incidence of leukemic evolution. In multivariable analyses, genetic score, red blood cell transfusion dependency, white blood cell count, and marrow blasts retained independent prognostic value. These parameters were included into a clinical/molecular CPSS (CPSS-Mol) model that identified 4 risk groups with markedly different median OS (from >144 to 18 months, hazard ratio [HR] = 2.69) and cumulative incidence of leukemic evolution (from 0% to 48% at 4 years, HR = 3.84) (P < .001). The CPSS-Mol fully retained its ability to risk stratify in an independent validation cohort of 260 CMML patients. In conclusion, integrating conventional parameters and gene mutations significantly improves risk stratification of CMML patients, providing a robust basis for clinical decision-making and a reliable tool for clinical trials.

Complete genome sequence of Desulfohalobium retbaense type strain (HR(100)).

Desulfohalobium retbaense (Ollivier et al. 1991) is the type species of the polyphyletic genus Desulfohalobium, which comprises, at the time of writing, two species and represents the family Desulfohalobiaceae within the Deltaproteobacteria. D. retbaense is a moderately halophilic sulfate-reducing bacterium, which can utilize H(2) and a limited range of organic substrates, which are incompletely oxidized to acetate and CO(2), for growth. The type strain HR(100) (T) was isolated from sediments of the hypersaline Retba Lake in Senegal. Here we describe the features of this organism, together with the complete genome sequence and annotation. This is the first completed genome sequence of a member of the family Desulfohalobiaceae. The 2,909,567 bp genome (one chromosome and a 45,263 bp plasmid) with its 2,552 protein-coding and 57 RNA genes is a part of the Genomic Encyclopedia of Bacteria and Archaea project.