Incidence, risk factors, and outcomes of second neoplasms in patients with acute promyelocytic leukemia: the PETHEMA-PALG experience.

The most important challenges in acute promyelocytic leukemia (APL) is preventing early death and reducing long-term events, such as second neoplasms (s-NPLs). We performed a retrospective analysis of 2670 unselected APL patients, treated with PETHEMA "chemotherapy based" and "chemotherapy free" protocols. Only de novo APL patients who achieved complete remission (CR) and completed the three consolidation cycles were enrolled into the analysis. Out of 2670 APL patients, there were 118 (4.4%) who developed s-NPLs with the median latency period (between first CR and diagnosis of s-NPL) of 48.0 months (range 2.8-231.1): 43.3 (range: 2.8-113.9) for s-MDS/AML and 61.7 (range: 7.1-231.1) for solid tumour. The 5-year CI of all s-NPLs was of 4.43% and 10 years of 7.92%. Among s-NPLs, there were 58 cases of s-MDS/AML, 3 cases of other hematological neoplasms, 57 solid tumours and 1 non-identified neoplasm. The most frequent solid tumour was colorectal, lung and breast cancer. Overall, the 2-year OS from diagnosis of s-NPLs was 40.6%, with a median OS of 11.1 months. Multivariate analysis identified age of 35 years (hazard ratio = 0.2584; p < 0.0001) as an independent prognostic factor for s-NPLs. There were no significant differences in CI of s-NPLs at 5 years between chemotherapy-based vs chemotherapy-free regimens (hazard ratio = 1.09; p = 0.932). Larger series with longer follow-up are required to confirm the potential impact of ATO+ATRA regimens to reduce the incidence of s-NPLs after front-line therapy for APL.

Research on the Pathogenesis of Cognitive and Neurofunctional Impairments in Patients with Noonan Syndrome: The Role of Rat Sarcoma-Mitogen Activated Protein Kinase Signaling Pathway Gene Disturbances.

Noonan syndrome (NS) is one of the most common genetic conditions inherited mostly in an autosomal dominant manner with vast heterogeneity in clinical and genetic features. Patients with NS might have speech disturbances, memory and attention deficits, limitations in daily functioning, and decreased overall intelligence. Here, 34 patients with Noonan syndrome and 23 healthy controls were enrolled in a study involving gray and white matter volume evaluation using voxel-based morphometry (VBM), white matter connectivity measurements using diffusion tensor imaging (DTI), and resting-state functional magnetic resonance imaging (rs-fMRI). Fractional anisotropy (FA) and mean diffusivity (MD) probability distributions were calculated. Cognitive abilities were assessed using the Stanford Binet Intelligence Scales. Reductions in white matter connectivity were detected using DTI in NS patients. The rs-fMRI revealed hyper-connectivity in NS patients between the sensorimotor network and language network and between the sensorimotor network and salience network in comparison to healthy controls. NS patients exhibited decreased verbal and nonverbal IQ compared to healthy controls. The assessment of the microstructural alterations of white matter as well as the resting-state functional connectivity (rsFC) analysis in patients with NS may shed light on the mechanisms responsible for cognitive and neurofunctional impairments.

Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) in Poland: analysis of patient series and practical guidelines for breast surgeons.

Introduction: Although breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is infrequent, with less than 1000 noted cases worldwide, patients consenting for breast implant surgery should be aware of its risk. We describe the first Polish multicenter case-series data on BIA-ALCL patients and present diagnostic and treatment recommendation for breast surgeons. Material and methods: In cooperation with the Polish Society of Surgical Oncology and Polish Lymphoma Research Group, we collected BIA-ALCL cases in Poland. Results: We retrospectively reviewed clinical data of seven BIA-ALCL patients, diagnosed between July 2013 and November 2019. The median time from implant placement to the first BIA-ALCL symptoms was 65 months (range: 33-96 months). All the patients were exposed to textured implants at presentation. Capsulectomy with implant removal was performed in all the patients with immediate reimplantation in 2 cases. In a median follow-up of 19 months (range 5-81 months), there was no recurrence and all the patients stayed alive. Between 2013 and 2019, the incidence of BIA-ALCL in Polish female population age 30 and above ranged from 0 to 0.021/100 000/year. Conclusions: BIA-ALCL is scarce in the Polish population. In a short-term follow-up, patients' prognosis remains excellent. Due to the withdrawal of roughly textured implants from the market and the exclusion of likely the most potent etiologic factor, it might be expected that the incidence of BIA-ALCL will become even rarer.

Prognostic value of XIAP and survivin expression in locally advanced breast cancer patients treated with anthracycline-based neoadjuvant chemotherapy.

Introduction: Neoadjuvant treatment in locally advanced breast cancer (LABC) is intended to decrease the cancer mass, increase the likelihood of radical resection and improve survival. Resistance to chemotherapy may depend on cellular expression of anti-apoptotic proteins. XIAP and survivin are the most potent inhibitors of apoptosis (IAP), but their role in drug-induced cancer cell apoptosis remains unclear. This study was designed to evaluate the impact of pre-treatment expression of XIAP and survivin on pathological complete response and survival in LABC patients. Material and methods: The study included 60 LABC patients treated with anthracycline-based chemotherapy. XIAP and survivin expression was assessed immunohistochemically in pre-treatment core biopsy specimens. Results: Pathological complete response was achieved in 33% of the LABC patients. Low/intermediate expression of both XIAP and survivin was significantly associated with pathological complete response (p ≤ 0.04 and p < 0.001, respectively) and positively correlated with disease-free survival (p = 0.017 and p < 0.001) and overall survival (p = 0.052 and p < 0.001). The area under receiver operating characteristics curves (AUC) revealed predictive value of survivin expression for relapse and death in breast cancer patients (AUC = 0.63, p = 0.001 and AUC = 0.8, p < 0.001, respectively). Conclusions: Our findings suggest that downregulation of XIAP and survivin in LABC patients might predict better treatment outcomes after anthracycline-based chemotherapy. This, in turn, may indicate XIAP and survivin proteins as potential targets for innovative anticancer therapies.

Targeting Apoptosis in AML: Where Do We Stand?

More than 97% of patients with acute myeloid leukemia (AML) demonstrate genetic mutations leading to excessive proliferation combined with the evasion of regulated cell death (RCD). The most prominent and well-defined form of RCD is apoptosis, which serves as a defense mechanism against the emergence of cancer cells. Apoptosis is regulated in part by the BCL-2 family of pro- and anti-apoptotic proteins, whose balance can significantly determine cell survival. Apoptosis evasion plays a key role in tumorigenesis and drug resistance, and thus in the development and progression of AML. Research on the structural and biochemical aspects of apoptosis proteins and their regulators offers promise for new classes of targeted therapies and strategies for therapeutic intervention. This review provides a comprehensive overview of current AML treatment options related to the mechanism of apoptosis, particularly its mitochondrial pathway, and other promising concepts such as neddylation. It pays particular attention to clinically-relevant aspects of current and future AML treatment approaches, highlighting the molecular basis of individual therapies.

Cladribine Combined with Low-Dose Cytarabine as Frontline Treatment for Unfit Elderly Acute Myeloid Leukemia Patients: Results from a Prospective Multicenter Study of Polish Adult Leukemia Group (PALG).

Acute myeloid leukemia (AML) in older unfit patients is a therapeutic challenge for clinical hematologists. We evaluated the efficacy and safety of a novel low-intensity regimen consisting of low-dose cytarabine and cladribine (LD-AC+cladribine) in first-line treatment of elderly (≥60 years) AML patients not eligible for intensive chemotherapy (IC) who had either the Eastern Cooperative Oncology Group performance status (ECOG PS) ≥2 or the hematopoietic cell transplantation comorbidity index (HCT-CI) score ≥3. The induction phase included two cycles of LD-AC+cladribine. Patients who achieved at least partial remission (PR) received maintenance treatment with LD-AC alone. Overall, 117 patients with a median age of 70 years were enrolled. Adverse cytogenetics, ECOG PS ≥2 and HCT-CI score ≥3 was observed in 43.5%, 60%, and 58% of patients, respectively. The response rate (≥PR) was 54% (complete remission [CR], 32%; CR with incomplete hematologic recovery [CRi], 5%). A median overall survival (OS) was 21 and 8.8 months in CR/CRi and PR group, respectively. Advanced age (≥75 years) and adverse cytogenetics had a negative impact on OS. The 56-day mortality rate was 20.5%. In conclusion, LD-AC+cladribine is a beneficial therapeutic option with a predictable safety profile in elderly AML patients not eligible for IC.

Alterations in microRNA Expression during Hematopoietic Stem Cell Mobilization.

microRNAs play an important role in the regulation of gene expression, cell fate, hematopoiesis, and may influence the efficacy of CD34+ cell mobilization. The present study examines the role of hsa-miR-15a-5p, hsa-miR-16-5p, hsa-miR-34a-5p, hsa-miR-126-3p, hsa-miR-146a-5p, hsa-miR-155-5p, and hsa-miR-223-3p in the course of hematopoietic stem cell mobilization. The numbers of CD34+ cells collected in patients with hematological malignancies (39 multiple myelomas, 11 lymphomas) were determined during mobilization for an autologous hematopoietic stem cell transplantation. The miRNA level was evaluated by RT-PCR. Compared to baseline, a significant decline in hsa-miR-15a-5p, hsa-miR-16-5p, hsa-miR-126-3p, hsa-miR-146a-5p, and hsa-miR-155-5p was observed on the day of the first apheresis (day A). An increase was observed only in the expression of hsa-miR-34a-5p. On day A, a negative correlation was found between hsa-miR-15a-5p and hsa-miR-146a-5p levels and the number of CD34+ cells in peripheral blood. A negative correlation was observed between hsa-miR-146a-5p and the number of collected CD34+ cells after the first apheresis. Good mobilizers, defined according to GITMO criteria, demonstrated a lower hsa-miR-146a-5p level on day A than poor mobilizers. Patients from the hsa-miR-146a-5p "low expressors" collected more CD34+ cells than "high expressors". Our results suggest that the investigated miRNAs, especially hsa-miR-146a-5p, may influence the efficacy of HSC mobilization.

The role of NF-κB and Smac/DIABLO proteins in the treatment response and survival of acute myeloid leukemia patients.

INTRODUCTION: The misbalance between a family of inhibitor of apoptosis proteins (IAP), regulated by the nuclear factor kappa B (NF-κB) and their natural antagonist second mitochondrial-derived activator of caspases/direct IAP binding protein with low pI (Smac/DIABLO) are important to biology of acute myeloid leukemia (AML). MATERIAL AND METHODS: The aim of the study was to assess NF-κB and Smac/DIABLO proteins expression in blasts of 109 newly diagnosed AML patients using the multicolor flow cytometry and evaluate their influence on AML patients outcome. RESULTS: Expression of NF-κB and of Smac/DIABLO proteins were found in 95% and 98% of the patients, respectively. A negative correlation between Smac/DIABLO and NF-κB was observed. Age < 60 years old as well as higher Smac/DIABLO expression were associated with a higher probability of complete response achievement in the multivariate analysis. Longer overall survival (OS) in the univariate and multivariate analyses was influenced by age < 60 years old, a favorable or intermediate-risk karyotype and high Smac/DIABLO expression. Additionally, in the survival analysis of the subgroups, the patients aged < 60 years old, with high Smac/DIABLO expression, lower NF-κB expression and < 50% of bone marrow blasts who were treated with standard treatment had better OS. CONCLUSIONS: Lower NF-κB and higher Smac/DIABLO expression may influence AML patients outcome.

IDH2 mutations in patients with normal karyotype AML predict favorable responses to daunorubicin, cytarabine and cladribine regimen.

Mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2) genes occur in about 20% patients with acute myeloid leukemia (AML), leading to DNA hypermethylation and epigenetic deregulation. We assessed the prognostic significance of IDH1/2 mutations (IDH1/2+) in 398 AML patients with normal karyotype (NK-AML), treated with daunorubicine + cytarabine (DA), DA + cladribine (DAC), or DA + fludarabine. IDH2 mutation was an independent favorable prognostic factor for 4-year overall survival (OS) in total NK-AML population (p = 0.03, censoring at allotransplant). We next evaluated the effect of addition of cladribine to induction regimen on the patients' outcome according to IDH1/2 mutation status. In DAC group, 4-year OS was increased in IDH2+ patients, compared to IDH-wild type group (54% vs 33%; p = 0.0087, censoring at allotransplant), while no difference was observed for DA-treated subjects. In multivariate analysis, DAC independently improved the survival of IDH2+ patients (HR = 0.6 [0.37-0.93]; p = 0.024; censored at transplant), indicating that this group specifically benefits from cladribine-containing therapy. In AML cells with R140Q or R172K IDH2 mutations, cladribine restrained mutations-related DNA hypermethylation. Altogether, DAC regimen produces better outcomes in IDH2+ NK-AML patients than DA, and this likely results from the hypomethylating activity of cladribine. Our observations warrant further investigations of induction protocols combining cladribine with IDH1/2 inhibitors in IDH2-mutant.

Early induction intensification with cladribine, cytarabine, and mitoxantrone (CLAM) in AML patients treated with the DAC induction regimen: a prospective, non-randomized, phase II study of the Polish Adult Leukemia Group (PALG).

We present the results of a prospective, non-randomized phase 2 trial in which 253 AML patients (pts) under 60 years old received DAC (Daunorubicin + AraC + Cladribine) as first induction followed by CLAM (Cladribine + AraC + Mitoxantrone) as early second induction on day 16 based on bone marrow (BM) blasts on day 14 (D14). The CR/CRi rate after a single course of DAC was 83% for pts with D14 BM blasts less than 10%. Forty-six pts had >10% BM blasts on D14, of whom 35 received CLAM with rates of CR/CRi 60% and early death (ED) 23%. The remaining 11 pts were not fit to receive CLAM, with rates of CR/CRi 28%, PR 18%, and ED 18%. Median OS was 7.2 versus 7.5 months, respectively. The overall CR/CRi rate was 77% after the first induction, with final CR/CRi rate 80% after DAC reinduction for pts who achieved PR with initial DAC course. CLAM used as early second induction might improve CR/CRi rates for younger AML pts with poor early response to DAC induction, but may be associated with higher mortality.

Outcome of a Real-Life Population of Patients With Acute Promyelocytic Leukemia Treated According to the PETHEMA Guidelines: The Polish Adult Leukemia Group (PALG) Experience.

BACKGROUND: Acute promyelocytic leukemia (APL) has a favorable prognosis. However, results of randomized studies do not necessarily reflect the outcomes of a real-life population. PATIENTS AND METHODS: We analyzed 283 unselected APL patients treated in 20 Polish hospitals between 2005 and 2017. All patients were intended to be treated with PETHEMA (Programa Español para el Tratamiento de las Hemopatías Malignas) protocols based on all-trans retinoic acid plus chemotherapy. RESULTS: The probability of overall survival at 4 years was 67%, while event-free survival was 64%. The early death (ED) rate was 20.1% (n = 57), while 3.5% (n = 10) patients died before induction therapy was started. The main causes of ED included hemorrhage (45.6%), infections (17.5%), and differentiation syndrome (14.5%). Of 273 treated patients, 214 (78.4%) experienced hematologic morphologic remission, 2 (0.7%) were found to have resistant disease, 47 (17.2%) could not be evaluated for response because of ED, and in 6 (3.7%) no data concerning the response were available. Multivariate analyses showed that predictors of ED and overall survival were Eastern Cooperative Oncology Group performance status > 2, age > 60 years, and all types of bleeding episodes that occurred before starting therapy, while an additional predictor of event-free survival was high white blood cell count (> 10 109/L). CONCLUSION: ED remains a major problem in APL patients, especially in a real-life population. Shortening of the time between the initial contact with a health care professional, and all-trans retinoic acid administration and the use of appropriate supportive care could improve the outcome of unselected APL population, mainly by reducing the ED rate.

Oral ixazomib maintenance following autologous stem cell transplantation (TOURMALINE-MM3): a double-blind, randomised, placebo-controlled phase 3 trial.

BACKGROUND: Maintenance therapy following autologous stem cell transplantation (ASCT) can delay disease progression and prolong survival in patients with multiple myeloma. Ixazomib is ideally suited for maintenance therapy given its convenient once-weekly oral dosing and low toxicity profile. In this study, we aimed to determine the safety and efficacy of ixazomib as maintenance therapy following ASCT. METHODS: The phase 3, double-blind, placebo-controlled TOURMALINE-MM3 study took place in 167 clinical or hospital sites in 30 countries in Europe, the Middle East, Africa, Asia, and North and South America. Eligible participants were adults with a confirmed diagnosis of symptomatic multiple myeloma according to International Myeloma Working Group criteria who had achieved at least a partial response after undergoing standard-of-care induction therapy followed by high-dose melphalan (200 mg/m2) conditioning and single ASCT within 12 months of diagnosis. Patients were randomly assigned in a 3:2 ratio to oral ixazomib or matching placebo on days 1, 8, and 15 in 28-day cycles for 2 years following induction, high-dose therapy, and transplantation. The initial 3 mg dose was increased to 4 mg from cycle 5 if tolerated during cycles 1-4. Randomisation was stratified by induction regimen, pre-induction disease stage, and response post-transplantation. The primary endpoint was progression-free survival (PFS) by intention-to-treat analysis. Safety was assessed in all patients who received at least one dose of ixazomib or placebo, according to treatment actually received. This trial is registered with ClinicalTrials.gov, number NCT02181413, and follow-up is ongoing. FINDINGS: Between July 31, 2014, and March 14, 2016, 656 patients were enrolled and randomly assigned to receive ixazomib maintenance therapy (n=395) or placebo (n=261). With a median follow-up of 31 months (IQR 27·3-35·7), we observed a 28% reduction in the risk of progression or death with ixazomib versus placebo (median PFS 26·5 months [95% CI 23·7-33·8] vs 21·3 months [18·0-24·7]; hazard ratio 0·72, 95% CI 0·58-0·89; p=0·0023). No increase in second malignancies was noted with ixazomib therapy (12 [3%] patients) compared with placebo (eight [3%] patients) at the time of this analysis. 108 (27%) of 394 patients in the ixazomib group and 51 (20%) of 259 patients in the placebo group experienced serious adverse events. During the treatment period, one patient died in the ixazomib group and none died in the placebo group. INTERPRETATION: Ixazomib maintenance prolongs PFS and represents an additional option for post-transplant maintenance therapy in patients with newly diagnosed multiple myeloma. FUNDING: Millennium Pharmaceuticals, a wholly owned subsidiary of Takeda Pharmaceutical Company.

SMAC protein expression as a potent favorable prognostic factor in locally advanced breast cancer.

Preoperative systemic therapy including neoadjuvant chemotherapy (NCT) is standard treatment in locally advanced breast cancer (LABC), the aim of which is to enable a radical surgery and to reduce the risk of local and distant recurrence. It has been established that NCT in LABC may effectively induce apoptosis. The study objective was to assess the role of a proapoptotic second mitochondria-derived activator of apoptosis (SMAC) in LABC. The study group comprised 56 patients with advanced non-metastatic breast cancer (stage IIB -node positive and III), who received NCT followed by surgery and adjuvant treatment. Expression of SMAC protein was analysed using the immunohistochemistry technique in core biopsies sampled from the patients' breasts before NCT and in surgical specimens collected after completion of NCT. Expression of SMAC was significantly higher in the breast cancer specimens after NCT (p < 0.01). High expression of SMAC in the core biopsy before NCT correlated with a pathological complete remission (pCR, p < 0.01). The patients with a high expression of SMAC in the surgical specimens after NCT had longer DFS. Our study proves a potential role of SMAC expression in LABC as a novel favourable prognostic factor in LABC for pCR and disease-free survival (DFS).

miRNA-15a, miRNA-16, miRNA-126, miRNA-146a, and miRNA-223 expressions in autologous hematopoietic stem cell transplantation and their impact on engraftment.

OBJECTIVE: MicroRNAs engaged in angiogenesis and hematopoiesis can influence hematopoietic stem cells (HSCs) homing after transplantation by targeting bone marrow niche microenvironment. This study aimed to examine the kinetics of miRNA-15a, miRNA-16, miRNA-126, miRNA-146a, and miRNA-223 in autologous HSC transplantation settings. METHODS: The study comprised of 51 patients with hematological malignancies (42 multiple myeloma, 9 lymphoma). Samples were taken at four time points: before conditioning, after chemotherapy but prior to autologous HSC transplantation (day 0), on day +7, and +14 days after HSCT. The miRNA levels were evaluated by the real-time PCR method. RESULTS: A significant, steady decline of all tested microRNAs in the course of transplantation, as compared to the baseline, was found. The study revealed that higher levels of miRNA-15a, miRNA-16, miRNA-126, and miRNA-146a on day 0 correlated with longer time to engraftment. Additionally, a positive correlation between the levels of miRNA-15a, miRNA-146a, and miRNA-223 assessed on day +7 and the time to engraftment was observed. CONCLUSIONS: In conclusion, all investigated microRNAs changed significantly in the course of transplantation. Our results suggest that the miRNAs may participate in hematopoietic recovery in the early post-transplant period and influence engraftment efficiency after HSCT.

VEGF, ANGPT1, ANGPT2, and MMP-9 expression in the autologous hematopoietic stem cell transplantation and its impact on the time to engraftment.

As a site of complicated interactions among cytokines, bone marrow niche has been the subject of many scientific studies, mainly in the context of the proteins influencing damage or recovery of endothelium after allogeneic hematopoietic stem cell transplantation (HSCT). In this study, we aimed at exploring mutual correlations of bone marrow niche cytokines involved in the homing and mobilization of hematopoietic stem cells, as well as in angiogenesis. The aim of our study was to evaluate levels of cytokines: VEGF, angiopoietin-1 (ANGPT1), angiopoietin-2 (ANGPT2), and matrix metalloproteinase 9 (MMP-9) during autologous HSCT and to examine their influence on hematological recovery. Forty-three patients with hematological malignancies (33 multiple myeloma, 10 lymphoma) were enrolled in the study. Plasma samples were taken at five time points: before conditioning treatment (BC), on transplantation day (0) and 7 (+7), 14 (+14), and 21 (+21) days after HSCT. The cytokine levels were evaluated by ELISA method. Our study revealed decreased levels of VEGF, ANGPT1, and MMP-9 in the early post-transplant period as compared to the baseline (BC). ANGPT2 was decreased after conditioning treatment, but tended to increase from day +7. On day +7, positive correlations between ANGPT1 level as well as MMP-9 and the time to engraftment were observed. As opposite to ANGPT1, negative correlation between ANGPT2 level on day +7 after HSCT and the time to hematological recovery was noticed. Our study suggests that investigated cytokines are an important part of bone marrow environment and significantly influence the time to engraftment after HSCT.

Addition of cladribine to the standard induction treatment improves outcomes in a subset of elderly acute myeloid leukemia patients. Results of a randomized Polish Adult Leukemia Group (PALG) phase II trial.

Intensive induction chemotherapy using anthracycline and cytarabine backbone is considered the most effective upfront therapy in physically fit older patients with acute myeloid leukemia (AML). However, outcomes of the standard induction in elderly AML are inferior to those observed in younger patients, and they are still unsatisfactory. As addition of cladribine to the standard induction therapy is known to improve outcome in younger AML patients. The present randomized phase II study compares efficacy and toxicity of the DAC (daunorubicin plus cytarabine plus cladribine) regimen with the standard DA (daunorubicin plus cytarabine) regimen in the newly diagnosed AML patients over 60 years of age. A total of 171 patients were enrolled in the study (DA, 86; DAC, 85). A trend toward higher complete remission (CR) was observed in the DAC arm compared to the DA arm (44% vs. 34%; P = .19), which did not lead to improved median overall survival, which in the case of the DAC group was 8.6 months compared to in 9.1 months in the DA group (P = .64). However, DAC appeared to be superior in the group of patients aged 60-65 (CR rate: DAC 51% vs. DA 29%; P = .02). What is more, a subgroup of patients, with good and intermediate karyotypes, benefited from addition of cladribine also in terms of overall survival (P = .02). No differences in hematological and nonhematological toxicity between the DA and DAC regimens were observed.

Concomitance of monosomal karyotype with at least 5 chromosomal abnormalities is associated with dismal treatment outcome of AML patients with complex karyotype - retrospective analysis of Polish Adult Leukemia Group (PALG).

Monosomal karyotype (MK) and complex karyotype (CK) are poor prognostic factors in acute myeloid leukemia (AML). A comprehensive analysis of cytogenetic and clinical factors influencing an outcome of AML-CK+ was performed. The impact of cladribine containing induction on treatment results was also evaluated. We analyzed 125 patients with AML-CK+ treated within PALG protocols. MK was found in 75 (60%) individuals. The overall complete remission (CR) rate of 66 intensively treated patients was 62% vs. 28% in CK+ MK- and CK+ MK+ group (p = .01). No difference in CR rate was observed between DA and DAC arms. The overall survival (OS) in intensively treated patients was negatively influenced by MK, karyotype complexity (≥5 abnormalities), and WBC >20 G/L in multivariate analysis. The addition of cladribine to DA regimen improved OS only in MK- but not in MK+ group. In conclusion, concomitance of MK with ≥5 chromosomal abnormalities is associated with dismal treatment outcome in AMK-CK+.

Erratum to: Donor age and C1orf132/MIR29B2C determine age-related methylation signature of blood after allogeneic hematopoietic stem cell transplantation.

[This corrects the article DOI: 10.1186/s13148-016-0257-7.].

Donor age and C1orf132/MIR29B2C determine age-related methylation signature of blood after allogeneic hematopoietic stem cell transplantation.

BACKGROUND: Our recent study demonstrated that DNA methylation status in a set of CpGs located in ELOVL2, C1orf132, TRIM59, KLF14, and FHL2 can accurately predict calendar age in blood. In the present work, we used these markers to evaluate the effect of allogeneic hematopoietic stem cell transplantation (HSCT) on the age-related methylation signature of human blood. METHODS: DNA methylation in 32 CpGs was investigated in 16 donor-recipient pairs using pyrosequencing. DNA was isolated from the whole blood collected from recipients 27-360 days (mean 126) after HSCT and from the donors shortly before the HSCT. RESULTS: It was found that in the recipients, the predicted age did not correlate with their calendar age but was correlated with the calendar age (r = 0.94, p = 4 × 10(-8)) and predicted age (r = 0.97, p = 5 × 10(-10)) of a respective donor. Despite this strong correlation, the predicted age of a recipient was consistently lower than the predicted age of a donor by 3.7 years (p = 7.8 × 10(-4)). This shift was caused by hypermethylation of the C1orf132 CpGs, for C1orf132 CpG_1. Intriguingly, the recipient-donor methylation difference correlated with calendar age of the donor (r = 0.76, p = 6 × 10(-4)). This finding could not trivially be explained by shifts of the major cellular factions of blood. CONCLUSIONS: We confirm the single previous report that after HSCT, the age of the donor is the major determinant of age-specific methylation signature in recipient's blood. A novel finding is the unique methylation dynamics of C1orf132 which encodes MIR29B2C implicated in the self-renewing of hematopoietic stem cells. This observation suggests that C1orf132 could influence graft function after HSCT.