Cytogenetic Risk Factors Research Articles

CLEC11A methylation is correlated to AML subtypes and cytogenetic risk factors but not patient demographics.

Acute myeloid leukemia (AML) is an aggressive and lethal cancer of the blood, which leads to the death of over 11,000 patients in the United States each year. Research on identifying, characterizing, and treating AML is crucial in the fight against this deadly disease. Recent studies have examined the role of CLEC11A in cancer, including AML. However, there have been conflicting reports related to tumor progression and survival. Because survival is based on a variety of factors, including classification of the tumor, genetic risk factors, and demographics, it is imperative that we determine what role CLEC11A may have in cancer survival. Therefore, utilizing data from the Genomic Data Commons, we analyzed CLEC11A methylation in 108 AML patients compared to FAB classification, cytogenetic risk factors, age, race, and gender. Our results show statistically significant correlations between methylation of CLEC11A and FAB classification as well as poor genetic risk factors. However, no difference was observed in CLEC11A methylation when compared to demographic data. Our results, matched with a known biological function of CLEC11A in early hematopoiesis, indicate that CLEC11A may be an important marker for AML diagnosis and prognosis and provide relevant data in the ongoing search for novel therapeutics to improve AML survival.

A Risk Stratification System in Myeloma Patients with Autologous Stem Cell Transplantation.

Autologous stem cell transplantation (ASCT) has been a mainstay in myeloma treatment for over three decades, but patient prognosis post-ASCT varies significantly. In a retrospective study of 5259 patients with multiple myeloma (MM) at the University of Arkansas for Medical Sciences undergoing ASCT with a median 57-month follow-up, we divided the dataset into training (70%) and validation (30%) subsets. Employing univariable and multivariable Cox analyses, we systematically assessed 29 clinical variables, identifying crucial adverse prognostic factors, such as extended duration between MM diagnosis and ASCT, elevated serum ferritin, and reduced transferrin levels. These factors could enhance existing prognostic models. Additionally, we pinpointed significant poor prognosis markers like high serum calcium and low platelet counts, though they are applicable to a smaller patient population. Utilizing seven easily accessible high-risk variables, we devised a four-stage system (ATM4S) with primary stage borders determined through K-adaptive partitioning. This staging system underwent validation in both the training dataset and an independent cohort of 514 ASCT-treated MM patients from the University of Iowa. We also explored cytogenetic risk factors within this staging system, emphasizing its potential clinical utility for refining prognostic assessments and guiding personalized treatment approaches.

Assessment of Cytogenetic Findings and Risk Factors in Females with Primary Amenorrhea

Assessment of Cytogenetic Findings and Risk Factors in Females with Primary Amenorrhea

Complex karyotype but not other cytogenetic abnormalities is associated with worse posttransplant survival of patients with nucleophosmin 1-mutated acute myeloid leukemia: A study from the European Society for Blood and Marrow Transplantation Acute Leukemia Working Party.

In the 2022 European LeukemiaNet classification, patients with nucleophosmin 1 (NPM1)-mutated acute myeloid leukemia (AML) were classified in the adverse-risk category in the presence of high-risk cytogenetics (CG). Nonetheless, the impact of various CG aberrations on posttransplant outcomes remains to be unraveled. This registry study analyzed adult patients with NPM1-mutated de novo AML who underwent their first allogeneic hematopoietic cell transplantation in the first complete remission from 2005 to 2021. A total of 3275 patients were identified, 2782 had normal karyotype, 493 had chromosomal aberrations including 160 with adverse-risk CG, 72 patients had complex karyotype (CK), and 66 monosomal karyotype (MK). Overall, 2377 (73%) patients had FLT3-ITD. On univariate analysis, only FLT3-ITD, minimal/measurable residual disease (MRD) positivity and CK, but not abnormal CG, affected posttransplant outcomes. On multivariable analysis, CK was associated with lower overall survival (OS) (hazard ratio [HR] 1.72, p = .009). In the subgroup of 493 patients with aberrant CG, the 2-year leukemia-free survival (LFS) and OS were around 61% and 68%, respectively. On multivariable analysis for this subgroup, CK and MRD positivity were associated with increased risk of relapse (HR 1.7, p = .025; and 1.99, p = .003 respectively) and worse LFS (HR 1.62, p = .018; and 1.64, p = .011 respectively) while FLT3-ITD, MK, or other CG abnormalities had no significant effect. Importantly, CK negatively affected OS (HR 1.91, p = .002). In the first complete remission transplant setting, CK was found as the only cytogenetic risk factor for worse outcomes in NPM1-mutated AML. Nevertheless, even for this subgroup, a significant proportion of patients can achieve long-term posttransplant survival.

Evaluating the Effectiveness of Risk Adjustment Using Dynamic Frailty Assessment in Treating Newly Diagnosed Multiple Myeloma in Elderly Patients

Background: The treatment of newly diagnosed multiple myeloma (NDMM) in elderly patients is challenging due to various problems. To address these challenges, the European Myeloma Network (EMN) recommends conducting a frailty assessment before NDMM treatment in elderly patients. If the assessment identifies an intermediate fit or frail group, dosage reduction is recommended to avoid excessive treatment. However, as frailty status improves, there may be a risk of insufficient treatment leading to poor outcomes. In order to explore the optimal treatment approach for elderly NDMM patients in real-world settings, a retrospective analysis was conducted on the effectiveness of dynamically adjusting treatments based on frailty assessment in intermediate-fit and frail groups of elderly NDMM patients. Methods: Patients who were initially diagnosed with multiple myeloma and assessed as intermediate fit or frail patients by IMWG-GA frailty assessment at the Department of Hematology, Affiliated Hospital of Hebei University from January 1, 2018 to April 1, 2023 were included in this study.The initial treatment regimen for all patients in this group consisted of a combination of Bortezomib with dexamethasone (BD) or Ixazomib with dexamethasone (ID) .Frailty assessment and efficacy evaluation were conducted every 2-3 courses during the treatment period. In the frail group, treatment in those frailty status improved was adjusted based on prognosis stratification by adding a third drug to high-risk R-ISS patients and subsequently adjusting it according to efficacy evaluation; additionally, a third drug was added to patients who did not reach partial response (<PR). For the intermediate fit group, sequential addition of a third drug occurred during courses 2-3.The options for the third drug included cyclophosphamide, lenalidomide, and thalidomide，and common regimens used were ICD, IRD, VRD, VCD, and VTD.The response rate, discontinuation rate, early death, and adverse drug reactions were observed. Results: A total of 45 patients with newly diagnosed NDMM were included in this study. Among them, 37 patients were assessed as frail .24 /45 patients were treated with the BD regimen and 21/45 patients with the ID regimen. During treatment, dynamic frailty assessment showed significant improvement in frail status during courses 3-4 (see Table 1). Following dynamically adjusted principles, additional drugs were administered to certain patients: 24 /37 frail patients received a third drug; among the intermediate fit patients, all received a third drug. The best ORR achieved throughout the study was at an impressive rate of 82.2% (37/45), with a corresponding best efficacy above VGPR seen in 51.1% (23/45) of cases. Twenty-one patients experienced disease progression for various reasons during treatment, with a median PFS of 14.0 (3.0-96.0) months. During the follow-up period, a total of 17 patients died, while none died within 6 months. The median overall survival (OS) was found to be 18.0 months (ranging from 3.0 to 115.5 months). Safety evaluation was conducted on all 45 patients within the first year and they tolerated the treatment well. Most adverse reactions reported were of grade 1-2 according to CTCAE version 5.0. Conclusion: This study is a retrospective study that the initial treatment involved administering a low-intensity regimen consisting of either BD or ID two-drug combination. Serious adverse reactions, drug withdrawal, and early death decreased in both groups. The treatment intensity was increased for high-risk patients or those with poor efficacy in the frail group after the improvement of frailty status. This new therapeutic strategy which integrates dynamic changes of frailty status, cytogenetic risk factors, efficacy evaluation and dynamic adjustment of treatment, has shown improved efficacy for patients with two different levels of frailty. Additionally, it has been found to reduce early mortality rates. These promising results warrant further investigation through prospective studies.

Sequential Imaging with Diffusion-Weighted Whole-Body MRI (DW-MRI) and PET-CT Identifies Patients at High Risk of Relapse in Multiple Myeloma

Introduction: Although the vast majority of patients with newly diagnosed multiple myeloma (NDMM) achieve deep responses during first-line therapy, most of them face relapse over time. Focal lesions, which are seen in up to 80% of NDMM, play a crucial role in MM evolution and can act as reservoirs for relapse disease. As a consequence, the combination of imaging- and minimal residual disease (MRD) negativity has been defined as a new response category. However, the dynamics and location of focal lesions during the treatment course remains poorly characterized and the answer to what imaging modality should be used to visualize focal residual disease remains elusive. In this study, we employed two techniques, PET-CT and DW-MRI, at multiple pre-defined time points to longitudinally track resistant lesions and investigate the combined prognostic value of these imaging modalities with other prognostic markers. Methods: We included 170 NDMM patients who were diagnosed between the years of 2010-2015 to ensure sufficient median follow-up time, which was 10 years. Median age of the study cohort was 60 years (range: 34-76), 104 were male (61%), and 31 patients (18%) had high-risk according to gene-expression profiles. All patients underwent PET-CT and DW-MRI evaluation at three pre-defined timepoints: baseline, post autologous stem-cell transplantation (ASCT) and at relapse. Minimal residual disease testing (MRD) by 8 color flow cytometry at a sensitivity level of 10 -5 post ASCT was available for 70 patients. Results: At baseline, 144/170 patients (85%) presented with focal lesions. Both imaging modalities, PET-CT and DW-MRI, showed positive results in 116 patients (68%). However, 21 patients (12%) had focal lesions detectable only by DW-MRI, while 7 patients (4%) showed focal lesions solely in PET-CT. After ASCT, only 12 patients had PET-CT positive lesions, whereas DW-MRI detected focal lesions in 53 patients, indicating a much higher detection rate with DW-MRI. Overall, 55 out of 170 patients (32%) showed residual lesions at this time point. The 26 patients w/o focal lesions in both PET-CT and DW-MRI at baseline remained negative post ASCT. Except for one patient, focal lesions after ASCT were persistent from initial diagnosis. Of note, two-thirds of the patients had residual focal lesions in the humeri and/or femora, which is surprising given that myeloma is considered a disease of the axial skeleton. Next, we correlated the presence of residual lesions with baseline patient characteristics, including age, gender, stage, and cytogenetic risk factors. Compared to patients w/o residual lesions, PET-positive patients showed an enrichment of rISS stage III (7 vs 50%, p<0.001) and deletion 17p (10 vs 33%, p=0.04). In contrast, patients who were DW-MRI positive only showed no significant association with any of the investigated variables. Both PET- and DW-MRI positive lesions post ASCT were associated with poor PFS (median 1.5 and 2.4 years, respectively vs. 9.4 years in imaging-negative patients, p<0.001) and OS (median 3.7 and 5.7 years, respectively vs. 11.3 years, p<0.001). Importantly, in a multivariate model the adverse prognostic effect of residual lesions was independent of baseline risk factors. To increase the power of the following combined imaging/MRD analysis, we defined an “Imaging+” group, which included the patients with PET+ and/or DW-MRI+ focal lesions. Among the 20 patients who achieved MRD-negative and imaging-negative status, an excellent PFS was observed, with only three events occurring in an 8-year follow-up. Residual lesions despite MRD negativity were only seen in two patients, and one of them progressed after 1.5 years. Dismal PFS was seen for double-positive patients (median 1.4 years), significantly worse compared to patients with MRD positivity only (8.9 years). Conclusion: Taken together, DW-MRI captures more patients with prognostically relevant residual focal lesions compared to PET-CT and should therefore be considered as a preferable imaging modality post ASCT. The high number of residual lesions in the extremities suggests a role of humeri and femora as reservoirs for treatment-resistant cells, deserving further investigation. For patients with MRD and imaging double positivity post ASCT, prognosis is dismal and alternate therapeutic approaches should be considered.

Reduced-Dose Chemotherapy Followed By Blinatumomab As Induction Therapy in Treatment of Newly Diagnosed Philadelphia Chromosome-Negative B-Cell Precursor Acute Lymphoblastic Leukemia - Interim Results from a Multicenter, Single-Arm, Phase 2 Study

Introduction: Although intensive pediatric chemotherapeutic regimens have shown good efficacy in the treatment of Philadelphia Chromosome-negative (Ph-negative) B-cell precursor acute lymphoblastic leukemia (BCP-ALL) in adults, the high incidence of chemotherapy-related toxicities limits their use. Blinatumomab, a CD3/CD19 bispecific T-cell antibody, has shown high efficacy in relapsed/refractory or minimal residual disease (MRD) positive BCP-ALL; however, the efficacy of single-agent blinatumomab does not meet the treatment needs of adult patients. Therefore, combining low-intensity chemotherapy with blinatumomab could be a better induction regimen for newly diagnosed adult patients with BCP-ALL. Methods: This multicenter, single-arm, phase 2 trial (NCT05557110) enrolled adult patients (aged 15-59 years) with newly diagnosed Ph-negative BCP-ALL. The induction regimen comprised reduced intensity chemotherapy (idarubicin 8 mg/m 2 on day 1, vindesine 4 mg on day 1, and dexamethasone 9 mg/m 2/day from day 1-7) followed by 2 weeks of blinatumomab (9 ug/day from day 8-14, 28 ug/day from day 15-21). The primary endpoint was to assess the overall response rate (ORR=complete remission [CR] + CR with partial hematologic recovery [CRh] + CR with incomplete hematologic recovery [CRi]) of this induction regimen. Secondary endpoints were MRD negativity (<1x10 -4 by flow cytometry), event-free survival (EFS), overall survival (OS) and safety. Bone marrow evaluation and one intrathecal injection chemotherapy were performed on day 22±2. Patients not achieving ORR continued blinatumomab for another 2 weeks (28 ug/day from day 1-14), followed by bone marrow re-evaluation. Consolidation therapy was given after achieving ORR with recommended multidrug combination chemotherapy (including high-dose methotrexate or cytarabine combined with asparaginase) or alternating with blinatumomab (28 ug/day for 28 days). If allogeneic hematopoietic stem cell transplantation (allo-HSCT) is not performed, consolidation therapy needs at least 4 courses before 2 years of maintenance therapy. Results: Interim results are presented here.By July 6, 2023 (data cut-off), 25 patients were enrolled with a median age of 42 years (range: 15-53); 68% were females. The Eastern Cooperative Oncology Group Performance Status score ranged from 0-1. Eight (32.0%) patients had poor cytogenetic risk factors, including 3 with P2RY8::CRLF2, 2 with hypodiploidy, 2 with KMT2A rearranged and 1 with alterations of IKZF1 (Table 1). The bone marrow evaluation done in 19 patients on day 8 prior to blinatumomab treatment showed that none of the patients had got ORR. All 21 (100%) patients evaluable for the primary endpoint attained CR/Cri - 19 at the end of 2 weeks of blinatumomab and the remaining 2 after another 2 weeks of blinatumomab (Table 2). The MRD negativity rate was 90.5% (19/21) after 2 weeks of blinatumomab which increased to 95.5% (20/21) after another 2 weeks of treatment with blinatumomab. In 21 patients evaluated for safety, blinatumomab-related cytokine release syndrome was reported in 10 (47.6%) patients (grade 1: n=6, grade 2: n=3 and grade 3: n=1). No incidence of neurotoxicity was reported. Febrile neutropenia was reported in 4 (19%) patients (all ≥grade 3). The non-hematological AEs reported were fever in 7 (33.3%) patients (any grade), increased ALT in 10 (47.6%) patients (any grade) and infections in 4 (19%) patients, including pneumonia in 2 and sepsis in 2 (all ≥grade 3). The median duration of neutrophil deficiency (<0.5×10 9/L) and platelet deficiency (<20×10 9/L) during induction therapy was 9 days (range: 0-20) and 1 day (range: 0-18), respectively. The median follow-up time was 4 months and no relapse or leukemia-related deaths were observed. The median EFS and OS were not yet reached. All enrolled patients are alive except one who died of infection after multidrug combination consolidation chemotherapy. The median cycles for consolidation were 2 (range: 1-5) with 3 patients undergoing allo-HSCT. Conclusion: Thesepreliminary results indicate that the reduced intensity chemotherapy followed by blinatumomab is an effective regimen in adults with newly diagnosed Ph-negative BCP-ALL, resulting in favorable response rates, deep remission, and low-grade treatment-related AEs. These promising findings may provide a rationale for integrating blinatumomab into future induction therapy recommendations.

The prognostic significance of circulating plasma cells in newly diagnosed multiple myeloma patients.

Multiple myeloma (MM) is a highly characteristic tumor that is influenced by numerous factors that determine its prognosis. Studies indicate that the presence of circulating plasma cells (cPCs) is a detrimental factor that significantly impacts the prognosis of patients with MM. This study retrospectively analyzed the prognostic value of cPCs quantified by 10-color flow cytometry in 145 newly diagnosed MM (NDMM) cases in the First Affiliated Hospital of Soochow University from November 2018 to February 2021. The study was approved by the Ethics Committee of the hospital (2021 No. 93). Of the 145 patients, 99 (68.2%) were detected cPCs. Through receiver operating characteristics (ROC) analysis, an optimal threshold of 0.165% was identified as a predictor for overall survival (OS). The median progression-free survival (PFS) was 33 months in patients with cPCs ≥0.165%, whereas those with cPCs <0.165% had a PFS of <33 months (p=0.001). The median OS was not reached for two groups; the 3-year OS for patients with cPCs ≥0.165% was 71% compared with 87% for those with cPCs <0.165% (p=0.003). In transplant patients, cPCs ≥0.165% also predicted worse prognosis. Similarly, when considering cytogenetic risk factors in conjunction with cPC levels, comparable results were obtained. To evaluate whether the Revised International Staging System (R-ISS) groups could be further stratified based on different prognostic factors related to cPCs, our study revealed similar median PFS and OS rates in R-ISS II stage patients with cPCs ≥0.165% compared to those in the III stage (p=0.659 and 0.249, respectively). This study demonstrates that a high ratio of cPCs serves as a reliable indicator for predicting a poorer prognosis in MM cases. Furthermore, incorporating the R-ISS system and cytogenetic risk factors alongside the level of cPCs enhances the accuracy of prognostic predictions for patients with MM.

Evaluation of 5-Day Vs. 10-Day Decitabine in Combination with Venetoclax in Newly Diagnosed AML Patients Ineligible for Induction Chemotherapy

BACKGROUND. Standard dosing of decitabine 20mg/m 2 daily given over 5 days in combination with the Bcl-2 inhibitor venetoclax (5-day DEC/VEN), in elderly or chemotherapy ineligible patients with Acute Myeloid Leukemia (AML), induces both a high rate of complete remission (CR/CRi rate 71%) and prolonged survival (median OS 14.2 months). (DiNardo CD et al. Blood. 2019) Extending the duration of decitabine treatment to 10-days (10-day DEC/VEN) may increase efficacy of the combination. In a phase 2 study of newly diagnosed chemotherapy ineligible AML patients aged ≥ 60 years, 10-day DEC/VEN led to a high CR/CRi rate of 89%, with 67% of these being negative for measurable residual disease and a median OS of 18 months. (DiNardo, CD et al. Leukemia. 2020). As a prospective clinical trial comparing efficacy of the different dosing schedule of decitabine in combination with venetoclax is unlikely to be performed, we conducted a single center retrospective analysis comparing 5-day and 10-day DEC/VEN outcomes. METHODS. We retrospectively studied patients with newly diagnosed AML receiving either 5-day or 10-day DEC/VEN between January 2016 to May 2022 at City of Hope National Medical Center. Patients receiving prior AML therapies including hypomethylating agents were excluded. Responses were evaluated per the ELN criteria (Dohner, H et al. Blood. 2017) Measurable residual disease (MRD) flow cytometry was performed at the University of Washington. Patient characteristics were summarized by frequency and associations between overall response and patient and disease characteristics were tested by Fisher's exact test. Overall Survival (OS) was evaluated by the Kaplan-Meier method and the difference between groups was determined by log-rank test. All statistical analyses were performed using R software. RESULTS. 139 patients were included: 48% (n=67) treated with 5-day decitabine and 52% (n=72) treated with 10-day decitabine. The baseline characteristics of the patients are summarized in table 1. At baseline, 5-day decitabine + venetoclax treated patients were older with a median of age of 73 vs. 70 years (p=0.01). The 5-day and 10-day groups were otherwise well balanced with no significant difference in AML type, ELN risk or adverse molecular features. Rates of CR/CRi, CR/CRi, MRD negativity, and the percentage of responders proceeding to allogeneic stem cell transplant were similar between regimens (Table 1). There was also no difference in 8-week mortality (p = 0.44). With a median follow-up of 12 months for responding patients, the median OS (figure 1) and RFS for 5-day and 10-day DEC/VEN were 14 vs. 27 months, p=0.091 and 12.9 vs. 14.3 months, p= 0.75 respectively. In subgroup analysis, patients without therapy- related AML (non-tAML) receiving the 10-day-regimen had a longer median OS (42.5 vs. 14.6 months, p= 0.03). No other subgroups, including those with high-risk molecular (eg.TP53) or cytogenetic risk factors (e.g. complex karyotype) demonstrated a significant difference between the 5 and 10-day DEC/VEN regimen. CONCLUSION. Among newly diagnosed AML patients receiving venetoclax in combination with either 5-day or 10-day decitabine, there was no significant difference in response (CR/CRi or MRD negativity) or survival outcomes (OS or RFS). Although a significant difference was not observed, 10-day DEC/VEN led to an increased median OS, which may reach significance with more patients and longer follow-up. Additionally, the 10-day DEC/VEN regimen may benefit certain subpopulations; it demonstrated longer median OS in patients without t-AML. Further analysis to confirm a survival benefit among patients without t-AML receiving either 5-day or 10-day DEC/ VEN is needed and will be presented at ASH. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Old and New Drugs for Chronic Lymphocytic Leukemia: Lights and Shadows of Real-World Evidence.

Several novel treatments for chronic lymphocytic leukemia (CLL) have been recently approved based on the results of randomized clinical trials. However, real-world evidence (RWE) is also requested before and after drug authorization in order to confirm safety and to provide data for health technology assessments. We conducted a scoping review of the available RWE for targeted treatments of CLL, namely ibrutinib, acalabrutinib, idelalisib, and venetoclax, as well as for chemoimmunotherapy (CIT). In particular, we searched studies published since 1 January 2010 and reported outcomes of the above treatments based on health databases, registries, or phase IV studies, including named-patient programs. We included both full papers and abstracts of studies presented at major meetings. Overall, 110 studies were selected and analyzed: 28,880 patients were treated with ibrutinib, 1424 with idelalisib, 751 with venetoclax, 496 with acalabrutinib, and 14,896 with CIT. Reported discontinuation rates were higher than in clinical trials, while effectiveness could not be indirectly compared with clinical trials since a detailed case mix, including cytogenetic risk factors, was partially available and propensity scores rarely applied. RWE on CLL can help to set realistic outcomes with novel treatments, however, real-world studies should be fostered, and available data shared.

MECOM gene overexpression in pediatric patients with acute myeloid leukemia

Background Acute myeloid leukemia (AML) is characterized by blocked or aberrant differentiation of hematopoietic stem cells. The MECOM gene overexpression in hematopoietic progenitors induces myeloid differentiation block, resulting in increased self-renewal and survival of these transformed progenitors. However, its exact role in AML remains unclear. We aimed to estimate the prevalence of MECOM overexpression among pediatric AML patients, and assess its impact on clinical outcome. Patients and Methods Real-time quantitative polymerase chain reaction and Livak method (2ΔΔCt) were used to determine relative MECOM expression level among 243 pediatric patients with AML. MECOM overexpression was considered if the cumulative relative expression was above 1 (2-ΔΔCt) and was designated as MECOMpos . Results Of 243 AML patients tested 57(23.5%) demonstrated MECOMpos . Patients with MECOMpos had significantly lower median age. The frequency of MECOMpos was significantly higher among AML patients with 11q23 abnormalities, complex karyotypes and among high- and intermediate-risk groups compared to low-risk group (p = .014). MECOMpos patients had significantly lower overall survival (OS) (38.7 vs. 78.9%, p < .001), event-free survival (EFS) (37.3% vs. 68.4%, p < .001), and had higher cumulative incidence of relapse (49.5% vs. 23.5%, p = .002) at 36 months compared to MECOMneg patients. Multivariate analysis revealed that MECOMpos was an adverse prognostic factor for OS (hazards ratio (HR) = 2.11, 95% confidence interval (CI) 1.24–3.60, p = .006) and EFS (HR= 1.71, 95% CI 1.07–2.75, p = .025). The logistic regression model showed that MECOMpos was an independent prognostic factor regardless of minimal residual disease status post first induction therapy in the intermediate-risk group (odds ratio 2.89; 95% CI 1.19–6.57, p = .018). Conclusion The aberrant MECOM gene expression is an adverse prognostic factor, especially in patients without previously known cytogenetic risk factors. Our results suggest the potential benefit from pretreatment screening for MECOM gene overexpression in newly diagnosed AML patients for better risk stratification and treatment adjustment.

Autologous and allogeneic hematopoietic cell transplantation for diffuse large B-cell lymphoma–type Richter syndrome

Richter syndrome (RS) represents a transformation from chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) to aggressive lymphoma, most commonly diffuse large B-cell lymphoma (DLBCL), which is associated with a dismal prognosis. Patients with DLBCL-RS have poor outcomes with DLBCL-directed therapy; thus, consolidation with hematopoietic cell transplantation (HCT) has been used, with durable remissions observed. Studies reporting HCT outcomes in patients with DLBCL-RS have been small, have not evaluated the prognostic impact of cytogenetic risk factors, and were conducted prior to the era of novel targeted therapy of CLL/SLL. We performed a Center for International Blood and Transplant Research registry study evaluating outcomes after autologous HCT (auto-HCT; n = 53) and allogeneic HCT (allo-HCT; n = 118) in patients with DLBCL-RS treated in the modern era. More auto-HCT recipients were in complete response (CR) at HCT relative to allo-HCT recipients (66% vs 34%), whereas a higher proportion of allo-HCT recipients had 17p deletion (33% vs 7%) and had previously received novel agents (39% vs 10%). In the auto-HCT cohort, the 3-year relapse incidence, progression-free survival (PFS), and overall survival (OS) were 37%, 48%, and 57%, respectively. Among allo-HCT recipients, the 3-year relapse incidence, PFS, and OS were 30%, 43%, and 52%, respectively. In the allo-HCT cohort, deeper response at HCT was associated with outcomes (3-year PFS/OS, 66%/77% CR vs 43%/57% partial response vs 5%/15% resistant; P < .0001 for both), whereas cytogenetic abnormalities and prior novel therapy did not impact outcomes. In our study, HCT resulted in durable remissions in therapy-sensitive patients with DLBCL-RS treated in the era of targeted CLL/SLL therapy, including patients with high-risk features.

Intravenous Once-Daily BuCy 2 With Pharmacokinetic (PK)-Guided Dose Adjustment As Conditioning Regimen For AML Patients In First Complete Remission

Introduction Busulfan (Bu) represents a backbone as conditioning prior to hematopoietic stem cell transplantation (HSCT). The intravenous (IV) form of Busulfan allows 100% bioavaibility and a limited inter- and intra-patient (pt) variability compared to the oral form. In Europe, IV Bu (Busilvex® fixed dose of 0.8 mg/kg x 16 doses) in combination with Cyclophosphamide (60 mg/kg/d x 2) is indicated prior to conventional HSCT in adults when the combination is the best available option. IV BuCy2 allows a precise delivery with 80% of adult pts within the defined therapeutic window [900 μmol/L x min-100 μmol/L x min] without dose-adjustments. Despite major advances in the risk-stratification and management of acute myelogenous leukaemia (AML) based on cytogenetics and molecular biology, the relapse rate remains high. Several published experiences suggested that Bu exposure may have an impact on the clinical outcomes after allogeneic HSCT. Study Objective The study was implemented to explore the use of a narrow range and high values of Bu exposure [4400 µmol/Lx min to 6000 µmol/Lx min] with a PK-guided dose adjustments and once-daily administration x 4 days. Methods The study was a prospective non-randomized multicentric phase II. The eligible pts were required to have AML in first complete (CR1, cytological remission) and to be eligible allogeneic HSCT following a myeloablative regimen. On the first day of the conditioning regimen IV Bu was administered as a single dose of 3.2 mg/kg; further daily dose of IV Bu were determined based on the previous Bu AUC exposure. The graft-versus-host disease (GVHD) prophylaxis consisted of calcineurin inhibitor, IV methotrexate post-transplant. The addition of antithymoglobulin (ATG) for unrelated donors was decided by each center based on their institutional guidelines. Pts could either receive related or unrelated bone marrow or peripheral blood stem cells. Nine centres with laboratory facilities for the pharmacokinetics analysis entered the study. Patient and transplant characteristics Thirty AML pts in CR1 (21 males, 70%) were treated between may 2010 and may 2012, 87% of pts had de novo AML. Twenty pts (67%) had matched sibling donor, the remaining pts received allograft from an unrelated donor. The median age of the cohort was 43.5 years [19.3-55.5]. The performance status score was comprised between 90 and 100. The majority of the cohort (83%) had an intermediate or unfavorable cytogenetic risk-factors. In 3 cases (10%) the karyotyping analyses could not be performed; 1 pt (3%) did not have cytogenetic test performed. Results Thirty pts were treated and analyzed. The expected cumulative AUC over 4 days [17600 µmol/Lxmin -24000 µmol/Lxmin] was reached in 90% of pts. The mean dose of IV Bu administered was 3.51 mg/kg/day. The mean total cumulative dose of IV Bu over 4 days was 13.25 mg/kg [8-21.3]. All pts engrafted. For the entire cohort, the neutrophil engraftment [absolute neutrophil count (ANC) > 0.5 x 10 9/L] occured at a median time of 17.5 d (11-35). Overall, 3 episodes (10%) of sinusoidal obstruction syndrome (S.O.S) occured (one mild, two severe, all resolved) in two patients. One pt developed 2 severe episodes of S.O.S and received defibrotide. Overall, 12 pts out of 30 (40%) developed acute GVHD between day 0 and day +100 after transplant (4 pts had grade III, 6 pts had grade II and 2 pts developed grade III, no patient developed grade IV). The median follow-up was 12 months [95% CI (11.9-12.2)] After day +100, 4 pts died of non-relapse causes ; one death from pulmonary fibrosis was related to the conditioning regimen. The cumulative incidence of TRM was 13.3% [95% CI (11.1%-15.6%)]. Five pts relapsed at a median time of 3.3 months [2-5.6] and 4 pts died of relapse. The cumulative incidence of one-year survival was 73.3% [95% CI (53.7%-85.7%)]. Conclusion The AUC intensification with once-daily IV BuCy2 is effective and yields an acceptable one year TRM for pts with high-risk AML in CR1. However, longer follow-up is needed in order to assess the impact of AUC intensification on the relapse rate and survivals. Disclosures: Suarez:Laboratoires Pierre Fabre: Travel grant Other. Off Label Use: IV Busulfan was administered in once-daily in this study. In Europe, IV Busulfan combined to cyclophosphamide is registered with a different schedule (infusion of IV Busulfan four times a day). IV Busulfan (Busilvex(r)) is an alkylating agent used as a conditioning regimen prior to hematopoietic stem cell transplantation. Socie:Laboratoires Pierre Fabre: Speakers Bureau. Michallet:Genzyme, MSD, BMS, Novartis, TEVA, Pfizer: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Paci:Laboratoires Pierre Fabre: Honoraria. Blaise:Laboratoires Pierre Fabre: Speakers Bureau, travel grant Other. Marcais:Laboratoires Pierre Fabre: travel grant Other. Xhaard:Laboratoires Pierre Fabre: Honoraria. Nicolini:BMS, Teva, Ariad, Pfizer, Novartis: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau. Furst:Laboratoires Pierre Fabre: travel grant Other. Levrault:Laboratoires Pierre Fabre: Employment. Riggi:Laboratoires Pierre Fabre: Employment. Ta Thanh Minh:Laboratoires Pierre Fabre: Employment.

Pre-Transplant Minimal Residual Disease Evaluation Performed By Molecular WT1-Based or Multicolor Flow Cytometry Assessment Overcomes the Prognostic Value of Cytogenetic and Molecular Risk Factors at Diagnosis in Advanced Acute Myeloid Leukemia Patients

BACKGROUND AND AIMSAllogeneic stem cell transplantation (HSCT) offers the only chance of cure for patients with advanced acute myeloid leukemia (AML). High levels of pre-HSCT minimal residual disease (MRD) have been reported to predict relapse risk after HSCT even in patient transplanted in first complete remission (CR). WT1 expression levels and multicolor flow cytometry (MFC) are the most common tools to evaluate MRD. The aim of this study was to analyze the role of pre-HSCT combined MRD assessment as predictor for the post-transplant relapse risk in patient transplanted beyond first CR.MATERIALS AND METHODSWe retrospectively analyzed the outcome of 92 consecutive AML patients receiving HSCT in 2nd or 3rd CR. Pre-HSCT marrow samples were analyzed for WT1 expression and MFC as MRD evaluation. Median age at transplant was 45 years. Disease phase was CR2 in 63 (68%) and CR3 in 29 patients (32%). ELN risk category at diagnosis was low in 28 (30%), intermediate in 44 (48%) and high in 20 (22%) patients. Sixty-six (71%) patients received myeloablative conditioning, whereas 26 patients (29%) received reduced intensity conditioning. Stem cell source was bone marrow in most cases and donor was an HLA-identical sibling in 18 (20%), haploidentical sibling (HAPLO) in 24 (26%) and unrelated donor in 50 (54%). Median follow-up was 64 months (95% CI 39.8 - 88.2 months).A positive MFC MRD was defined by the presence of at least 1x10-3 residual leukemic cells by 4 or 8 (since 2011) color flow-cytometry. WT1 copy number/Abl copy number 250x104 was used as cut-off value for abnormal WT1 expression.RESULTSRelapse occurred in 30 patients (33%) and two years non-relapse mortality was 29%. Three-year estimate of OS was 47.9% (median 19 months). The survival probability was significantly affected by donor source (better for HAPLO, p<0.05), ELN risk at diagnosis (better for ELN low risk, p<0.01), MRD status before HSCT measured with any method (p <0.01 for WT1-based MRD, p<0.03 for MFC based MRD) and CR status at HSCT (better for CR2, p<0.05).Specifically, among MRD negative patient a relatively low rate of relapse was observed regardless of risk at diagnosis (2-years OS of 62.2% and 52.7% among MFC MRD negative patient with ELN risk low or intermediate/high, respectively, Fig.1).The predictive value of MRD resulted independent from all other analyzed variables. However, patients with positive MRD did slightly better when undergoing HAPLO HSCT. Multivariate OS analysis revealed that the MRD evaluation by any method was the only independent predictor of OS (p <0.05 for both methods of analysis).MRD evaluation was also a strong predictor of cumulative incidence (CI) of relapse in competitive risk analysis (p<0.01 and p<0.03, respectively, for WT1 and MFC MRD). Multivariate CI of relapse analysis showed that donor source and MRD evaluation significantly influenced relapse risk (p <0.05 and <0.01, respectively).CONCLUSIONSPre transplant MRD evaluation by both WT1 and MFCon bone marrow samples is a reliable predictor of relapse risk which may overcome the prediction based on ELN risk at diagnosis. Both methods were able to efficiently predict post-transplant disease reoccurrence risk: patients with negative pre-HSCT MRD markers have a significantly better OS, while patients with positive MRD markers show an higher risk of relapse, irrespective of lower or higher ELN risk at diagnosis.Furthermore, our results seem to suggest that HAPLO donor may have a positive impact in reducing relapse rate in advanced AML patients, in particular in patients with positive MRD.Refining the baseline risk assessment based on ELN risk in patient undergoing HSCT beyond CR1 who have an higher risk of relapse is very important when evaluating optimal stem cell source and conditioning intensity and could allow to apply pre-emptive therapeutic strategies to prevent AML relapse, from donor lymphocyte infusion to other innovative approaches. [Display omitted] DisclosuresAngelucci:Roche: Other: Advisory board: biosimilars; Novartis Oncology: Other: Protocol Telesto: sterring committee Chair; Bluebird Bio: Other: Advisory board: Gene therapy in Thalassemia; Jazz: Other: Advisory board: AML; Celgene: Other: protocoll ACE 536 B-Thal 001: DMC Chair; Novartis Oncology: Other: Advisory board: iron toxicity; Novartis Oncology Swiss: Other: Invited speakers sponsored satellite meeting during ; Celgene: Honoraria, Other: Advisory: research project .

Clinico-Hematological and cytogenetic spectrum of adult myelodysplastic syndrome: The first retrospective cross-sectional study in Iranian patients

BackgroundMyelodysplastic syndrome (MDS), a heterogeneous group of hematopoietic malignancy, has been shown to present different cytogenetic abnormalities, risk factors, and clinico-hematological features in different populations and geographic areas. Herein, we determined the cytogenetic spectrum and clinico-hematological features of Iranian MDS patients for the first time.MethodsThis prospective cross-sectional study was conducted on 103 patients with MDS in Ahvaz, southwest of Iran, from 2014 to 2018. Clinical presentations, complete blood counts (CBC), and bone marrow (BM) biopsy samples were assessed. Perls' staining was used to evaluate BM iron storage. The cytogenetic evaluation was performed using the conventional G banding method on the BM.ResultsPatients’ median age was 62.3 (ranged from 50–76), and the majority were male (72.8%). The most common clinical symptom at the time of admission was fatigue (n = 33) followed by pallor (n = 27). The most common subgroup was MDS-Multi Lineage Dysplasia (MDS-MLD) (n = 38, 36.8%), followed by MDS-Single Lineage Dysplasia (MDS-SLD) (n = 28, 18.4%). A normal karyotype was observed in 59 patients (57.3%), while 44 patients (42.7%) had cytogenetic abnormalities. Trisomy 8 (+ 8) was the most common cytogenetic abnormality (n = 14) followed by del 17p (n = 9) and monosomy 7 (− 7) (n = 7). Twelve patients (11.65%) were transformed to AML.ConclusionOur data betokened that among our MDS patients, Trisomy 8 is the predominant cytogenetic abnormality, and MDS-MLD and MDS-SLD are the most common of subtypes. Noteworthy, the male: female ratio was slightly higher in Iran than in previous reports from other parts of the world. Our study is the first report of the clinical, hematological, and cytogenetic spectrum of MDS patients in Iran

Development of new therapeutic options for the treatment of uveal melanoma.

Uveal melanoma (UM) is the most common primary intraocular malignancy in adults. Important cytogenetic and genetic risk factors for the development of UM include chromosome 3 monosomy, mutations in the guanine nucleotide-binding proteins GNAQ/GNA11, and loss of the BRACA1-associated protein 1 (BAP 1). Most primary UMs are treated conservatively with radiotherapy, but enucleation is necessary for large tumours. Despite the effectiveness of local control, up to 50% of UM patients develop metastasis for which there are no effective therapies. Attempts to utilise the targeted therapies that have been developed for the treatment of other cancers, including a range of signal transduction pathway inhibitors, have rarely produced significant outcomes in UM. Similarly, the application of immunotherapies that are effective in cutaneous melanoma to treat UM have also been disappointing. Other approaches that have been initiated involve proteasomal inhibitors and histone deacetylase inhibitors which are approved for the treatment of other cancers. Nevertheless, there have been occasional positive outcomes from these treatments in UM. Moreover, combination approaches in UM have also yielded some positive developments. It would be valuable to identify how to apply such therapies efficiently in UM, potentially via individualised tumour profiling. It would also be important to characterise UM tumours to differentiate the potential drivers of progression from those in other types of cancers. The recent identification of novel kinases and metastatic genes in UM tumours makes the development of new UM-specific treatments feasible.

Pharmacologic Therapies to Prevent Relapse of Acute Myeloid Leukemia After Allogeneic Hematopoietic Stem Cell Transplantation.

Relapse is the main cause of mortality in patients with acute myeloid leukemia (AML) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Adverse cytogenetic or molecular risk factors, as well as refractory disease or persistent measurable residual disease (MRD) at the time of transplantation are associated with an increased risk of recurrence. Salvage therapy for AML relapse after allo-HSCT is often limited to chemotherapy, donor lymphocyte infusions and/or second transplants and is rarely successful. Effective post-transplant preventive intervention in high risk AML may be crucial. The most frequent and promising approach is the use of post-transplant maintenance with hypomethylating agents or with FLT3 tyrosine kinase inhibitors when the target is present. Moreover, IDH1/IDH2 inhibitors and BCL-2 inhibitors in combination with other strategies are promising approaches in the maintenance setting. Here we summarize the current knowledge about the preemptive and prophylactic use of pharmacologic agents after allo-HSCT to prevent relapse of AML.

Chronische lymphatische Leukämie

Chronic lymphocytic leukemia (CLL) is one of the most common hematological neoplasms and is the most common leukemia in western industrial nations. According to the World Health Organization classification, CLL is an indolent B‑cell non-Hodgkin's lymphoma (NHL). Diagnosis requires an increase of B‑lymphocytes to more than 5.0 G/l as well as detection of CD5- and CD19-positive B‑lymphocytes. Symptoms can be B symptoms, fatigue or frequent infections. Therapy is only required if there are pronounced symptoms or changes in the blood count, such as a relevant drop in hemoglobin and/or platelets. The prognosis strongly depends on the individual molecular and cytogenetic risk factors. For a long time, the first-line treatment was characterized by chemotherapy in combination with CD20 antibodies. In recent years, the approval of new targeted drugs has changed the treatment landscape significantly and has led to a shift towards chemotherapy-free regimens.

UGT1A1 genotype influences clinical outcome in patients with intermediate-risk acute myeloid leukemia treated with cytarabine-based chemotherapy.

The treatment of acute myeloid leukemia (AML) is adjusted according to cytogenetic risk factors and molecular markers. Cytarabine remains the main drug to treat AML, and several studies have explored the prognostic relevance of the genotype of cytarabine metabolizing enzymes in AML. Glucuronidation has been identified to be relevant in the cytarabine clearance, but there are still few data concerning the clinical impact of genetic polymorphisms known to condition the activity of UDP-glucuronosyl transferases in AML patients. Here we report the association between the UGT1A1 rs8175347 genotype and the clinical outcome of 455 intermediate-risk cytogenetic AML patients receiving cytarabine-based chemotherapy. Patients with the UGT1A1*28 homozygous variant (associated to a lower UGT1A1 activity) had a lower overall survival (OS) (25.8% vs. 45.5%; p: 0.004). Multivariate analysis confirmed this association (p: 0.008; HR: 1.79; 95% CI: 1.16-2.76). Subgroup analysis showed the negative effect of the UGT1A1*28 homozygous genotype on OS in women (14.8% vs. 52.7%; p: 0.001) but not in men. This lower OS was associated with longer neutropenia after consolidation chemotherapy and with higher mortality without previous relapse, suggesting an association between a low glucuronidation activity and mortal toxic events.

Chronic lymphocytic leukemia

Chronic lymphocytic leukemia (CLL) is one of the most common hematological neoplasms and is the most common leukemia in western industrial nations. According to the World Health Organization classification, CLL is an indolent B‑cell non-Hodgkin's lymphoma (NHL). Diagnosis requires an increase of B‑lymphocytes to more than 5.0 G/l as well as detection of CD5- and CD19-positive B‑lymphocytes. Symptoms can be B symptoms, fatigue or frequent infections. Therapy is only required if there are pronounced symptoms or changes in the blood count, such as arelevant drop in hemoglobin and/or platelets. The prognosis strongly depends on the individual molecular and cytogenetic risk factors. For along time, the first-line treatment was characterized by chemotherapy in combination with CD20 antibodies. In recent years, the approval of new targeted drugs has changed the treatment landscape significantly and has led to ashift towards chemotherapy-free regimens.