Unfavorable Cytogenetic Abnormalities Research Articles

Refining High-Risk Multiple Myeloma: Advancements in Genomic, Clinical, and Prognostic Criteria.

Multiple myeloma (MM) is a heterogeneous disease, with MM patients experiencing different clinical outcomes depending on the disease's biological features. Novel insights into the molecular mechanisms of MM have led to the introduction of sophisticated drugs, which dramatically improved patient treatment and survival. To date, young patients with newly diagnosed MM could experience a median overall survival (OS) of 10 years. Nevertheless, a small proportion of patients still undergoes early disease progression and death. Indeed, cases defined as ultra-high-risk MM (uHRMM) and high-risk MM (HRMM) are destined for a worse outcome, with an OS of 2-3 and 3-5 years, respectively. In this regard, current risk stratification systems failed to identify this subset of patients better. The application of existing risk models has led to the identification of extremely heterogeneous categories of patients, and they have not taken into account biological and clinical differences. The concept of HRMM was initially formalised in 2015. Since then, a great effort has been made to identify those parameters whose presence pone MM patients at higher risk of developing an early relapse. The simultaneous presence of 2 or more unfavourable cytogenetic abnormalities, the identification of an extramedullary disease or the detection of circulating plasma cells, as well as high-risk gene expression profiling (GEP) signature, have shown to be well related to a worse outcome and are going to be incorporated into new prognostic systems. The introduction of the Individualised Risk Model for Multiple Myeloma (IRMMa) marks a significant advancement in the management of HRMM by integrating genomic and clinical data to tailor treatment strategies. This model demonstrates improved prognostic accuracy compared to traditional staging systems and emphasises the importance of personalised treatment approaches. The implementation of these advanced tools is essential for enhancing precision medicine in MM and improving outcomes for patients in high-risk categories.

Эффективность ибрутиниба в первой линии терапии у пациентов из группы высокого риска и во второй, третьей линиях при резистентном течении хронического лимфоцитарного лейкоза

Risk stratification appears to be the most valid criterion in decision-making regarding optimal specific therapy in chronic lymphocytic leukemia (CLL). The CLL International Prognostic Index takes account of unfavorable cytogenetic abnormalities (del(17p)/del(11q) and/or TP53 gene mutations) as well as the mutation status of immunoglobulin heavy chain variable (IGHV) region genes. Unmutated V(H)-status is commonly associated with such prognostically unfavorable genetic markers as del(17p)/del(11q), trisomy 12, and TP53 mutation. The combination of unmutated V(H)-status with unfavorable karyotype abnormalities (del(17p)/del(11q)) negatively affects the prognosis and overall survival rate. Besides, in high-risk CLL, the efficacy of therapy is rather low, and the development of refractoriness is possible. Targeted therapy (Bruton tyrosine kinase inhibitors) both in first line and in resistant CLL considerably increases the probability of achieving long-term remission. The present paper provides the comparative analysis of clinical and hematological efficacy and tolerability of ibrutinib in first-line CLL therapy of high-risk patients as well as second- and third-line therapies of resistant CLL. Ibrutinib shows high efficacy and low toxicity. First-line ibrutinib treatment results in a faster response and effectively reduces the probability of CLL progression. Second- and third-line ibrutinib treatment allows to overcome CLL resistance without impairing patients’ quality of life.

Outcome Disparities Among Hispanic and Non-Hispanic Patients with Acute Lymphoblastic Leukemia

Introduction: Acute lymphoblastic leukemia (ALL) is the predominant type of leukemia diagnosed in children and accounts for approximately 20% of all cases of acute leukemia in adults. In pediatric cases, ALL generally exhibits a favorable prognosis and outcome. Unfortunately, this optimistic scenario does not extend to adults, as the majority of deaths related to ALL occur in this age group. The outcomes observed in children with ALL are linked to the favorable cytogenetic profile of their leukemia. However, as individuals age, the cytogenetic profile progressively shifts towards high-risk groups. Furthermore, several epidemiologic studies have identified ethnicity, specifically Hispanic and African American backgrounds, as independent factors associated with worse outcomes. The factors contributing to these outcomes are diverse and include limited healthcare access, insurance coverage, immigration status, treatment adherence, socioeconomic status, and timeliness of treatment initiation, among others. Additionally, individuals of Hispanic ethnicity are more prone to complex cytogenetics and Central Nervous System involvement, both of which are commonly associated with a poor prognosis. Our study aimed to assess the differences in treatment outcomes among adults diagnosed with ALL by conducting a specific comparison between non-Hispanic and Hispanic individuals. Methods: In this retrospective observational study, we collected data from the electronic medical records (EMR) of patients aged 18 years and older who received a diagnosis of Acute Lymphoblastic Leukemia between February 1, 2011, and February 28, 2020 at Ascension Seton Hospitals in Texas. The collected data included sociodemographic factors such as gender, ethnicity, and age at diagnosis, as well as clinical characteristics such as cytogenetics, immunophenotype, treatment, and overall survival. Bivariate and multivariate analyses were conducted using a chi-squared test. Statistical significance was defined as a P-value less than 0.05. Results: A total of 56 patients with ALL were identified, with 45% being non-Hispanic and 55% being Hispanic. The incidence of ALL did not show significant variation based on gender or age, but it exhibited a significant difference depending on insurance status. The analysis revealed that Hispanic patients had a significantly higher likelihood of lacking insurance coverage (75%) compared to non-Hispanic patients (25%), with a statistically significant p-value of 0.001. With the exception of one non-Hispanic patient diagnosed with T-cell ALL, almost all participants in the study had B-cell ALL. Among the patients who received chemotherapy, 44% were non-Hispanic, while 56% were Hispanic. Among patients with t(9;22)/BCR-ABL1 positive ALL, non-Hispanics represented 76% and Hispanics represented 23%. Other cytogenetic abnormalities, including CRLF2-IGH fusion, IgH rearrangement, CRLF2 rearrangement, PBX1/TCF3 fusion, t(1;19) with PBX1/TCF3 fusion, ETV6 deletion, near haploidy, and 9p deletion, were more prevalent in Hispanic patients (79%) compared to non-Hispanic patients (21%). The overall survival rates at 1 year were 64% for non-Hispanic patients and 67.7% for Hispanic patients. However, at 3 years, the overall survival rates decreased to 32% for non-Hispanic patients and 25.8% for Hispanic patients. Conclusions: Our study provides important insights into the demographic and clinical characteristics of patients with ALL and highlights notable disparities between non-Hispanic and Hispanic patients. A higher proportion of Hispanic patients lacked any form of health insurance coverage at the time of diagnosis. Interestingly, the incidence of Philadelphia-positive ALL was found to be higher among non-Hispanic patients, whereas other cytogenetic abnormalities were more prevalent among Hispanic patients. Additionally, Hispanic patients experienced lower rates of overall survival at 3 years, suggesting potential disparities in outcomes. The differences observed between Hispanic and non-Hispanic patients highlight the necessity for additional investigation and tailored interventions to address the specific challenges faced by Hispanic patients, including access to healthcare, insurance coverage, and the prevalence of unfavorable cytogenetic abnormalities.

Therapy Related Myeloid Neoplasms Following PARP Inhibitors : Real-Life Experience

Purpose: To assess the hematologic toxicity of PARP inhibitors (PARPi) treatment, and provide insights into the diagnosis and management of therapy-related myeloid neoplasms (t-MN) following PARPi. Experimental Design: In a leading cancer center, we compared the profile of 13 t-MN diagnosis among 37 ovarian cancer (OC) patients treated with PARPi referred for hematological consultation. Next, we compared these 13 t-MN post PARPi among 37 t-MN post OC. Finally, we described the specificities of 69 t-MN post PARPi treated for gynecologic cancer (breast and/or ovarian cancer) in a national observatory. Results: From 2016 to 2021, cumulative incidence of t-MNs was 3.5% (13/373) among OC patients treated with a PARPi. At the time of referral for hematological consultation, patients who developed t-MNs had a longer PARPi exposure (9 months vs. 3, p= 0.01), lower platelet count (74 vs. 173 G/L, p=0.0005), and more cytopenias (2 vs 1, p=0.0005). After NGS evaluation of patients without t-MN, 5 patients (13.5%) were finally classified as CHIP (clonal hematopoiesis of indeterminate potential), 7 (18.9%) as CCUS (clonal cytopenia of undetermined significance) and 2 (5%) as ICUS (idiopathic cytopenia of undetermined significance). Compared to t-MN not exposed to PARPi, t-MN-PARPi patients had more BRCA1/2 germline mutation (61.5% vs 0% p=0.03) but similar OS [8.2 (95% CI: 2.03-18.7) months in the t-MN-PARPi group compared to 6.1 (95% CI: 3-12.2) months in the t-MN-non-PARPi group; p=0.8]. In the national observatory, t-MN post PARPi had mostly a complex karyotype (61%) associated with a high rate of TP53 mutation (71%) with a median VAF of 41% (IQR, 17-67) and 75% of multi-hit mutations (Figure 1). IPSS score was "Low and Intermediate-1" and "Intermediate-2 and High" MDS groups for 50% of patients, respectively. AMLs were mainly considered as adverse (75%) according to the ELN 2017 classification. Median OS from t-MN diagnosis was 9.7 months (95% CI: 5.3-13.9). In multivariate analysis, a longer time between the end of PARPi and t-NM (HR 1.046, p=0.02), olaparib treatment compared to others PARPi (HR 5.82, p=0.003) and AML (HR 2.485, p=0.01) were associated with shorter OS independently of the BRCA1/2 status (Figure 2). Conclusions: In a large series, we described a high incidence of t-MN post PARPi associated with unfavorable cytogenetic and molecular abnormalities leading to poor OS. Time to diagnose t-MN after PARPi interruption seems to influence OS, suggesting the importance of early diagnosis. Particular consideration should be done on BRCA1/2 patients, and in case of thrombocytopenia or more than one cytopenia and relatively long PARPi exposure. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Dual Negativity of CD56 and CD117 Links to Unfavorable Cytogenetic Abnormalities and Predicts Poor Prognosis in Multiple Myeloma.

The prognostic value of CD56 and CD117 expression on myeloma cells is controversial. This study aims to analyze the correlation of CD56 and CD117 expression with cytogenetic abnormalities and survival. A total of 128 patients with newly diagnosed multiple myeloma (NDMM) were recruited in this single-center retrospective study. Flow cytometry and FISH tests of marrow cells were performed for all of the subjects. The statistical methods included a chi-squared test, univariate and multivariate COX regressions, and a Kaplan-Meier survival curve analysis. Regarding the cytogenetics, the incidence of IgH/FGFR3 translocation was more frequent in patients with a negative CD56 (p = 0.003). CD56 negativity was an independent adverse factor associated with a poor prognosis (p = 0.019) and indicated a shorter overall survival (OS) (p = 0.021). Patients with dual negative CD56 and CD117 trended toward a poorer OS (CD56-CD117- vs. CD56+CD117-, p = 0.011; CD56-CD117- vs. CD56+CD117+, p = 0.013). In conclusion, CD56 is a prognostic marker that independently affects OS and is associated with adverse cytogenetic abnormalities. Patients with a dual negativity of CD56 and CD117 have a worse clinical outcome.

Therapy-related Myeloid Neoplasms Following PARP Inhibitors: Real-life Experience.

To provide insights into the diagnosis and management of therapy-related myeloid neoplasms (t-MN) following PARP inhibitors (PARPi). In a French cancer center, we identified and described the profiles of 13 t-MN diagnosed among 37 patients with ovarian cancer referred to hematology consultation for cytopenia under PARPi. Next, we described these 13 t-MN post-PARPi among 37 t-MN post ovarian cancer according to PARPi exposure. Finally, we described 69 t-MN post-PARPi in a national cohort. From 2016 to 2021, cumulative incidence of t-MN was 3.5% (13/373) among patients with ovarian cancer treated with PARPi. At time of hematologic consultation, patients with t-MN had a longer PARPi exposure (9 vs. 3 months, P = 0.01), lower platelet count (74 vs. 173 G/L, P = 0.0005), and more cytopenias (2 vs. 1, P = 0.0005). Compared with t-MN not exposed to PARPi, patients with t-MN-PARPi had more BRCA1/2 germline mutation (61.5% vs. 0%, P = 0.03) but similar overall survival (OS). In the national cohort, most t-MN post-PARPi had a complex karyotype (61%) associated with a high rate of TP53 mutation (71%). Median OS was 9.6 months (interquartile range, 4-14.6). In multivariate analysis, a longer time between end of PARPi and t-MN (HR, 1.046; P = 0.02), olaparib compared with other PARPi (HR, 5.82; P = 0.003) and acute myeloid leukemia (HR, 2.485; P = 0.01) were associated with shorter OS. In a large series, we described a high incidence of t-MN post-PARPi associated with unfavorable cytogenetic and molecular abnormalities leading to poor OS. Early detection is crucial, particularly in cases of delayed cytopenia.

Therapy related myeloid neoplasms (t-MNs) following PARP inhibitors (PARPi): Real-life experience.

7057 Background: PARPi have shown promising results in several cancers, especially breast (BC) and ovarian cancer (OC), but may be associated with an increased risk of t-MNs. A careful monitoring of hematologic toxicity to exclude this risk is necessary. Here we described, in a real-life setting, the management of these adverse effect. Methods: First,we described, in a large cancer center, the profile of t-MN patients among OC patients treated with PARPi addressed in hematological consultation for cytopenias. Secondly, we compared t-MN post OC characteristics according to previous exposition to PARPi. Lastly, we described a large national observatory of 69 t-MNs post PARPi to decipher specific characteristics of these t-MNs. Results: From 2016 to 2021, among 373 PARPi treated patients for OC, 37 (10%) were explored for cytopenia’s leading to 13 (3,5%) t-MNs diagnosis. No differences were seen in terms of age, BRCA1/2 status, type of PARPi, hemoglobin level but patients with t-MNs developed delayed cytopenias post-PARPi initiation (11 months vs to 4 months, p = 0.01), had a longer PARPi exposition (9 months vs 3 months, p = 0.01), lower platelets level (74 G/L vs 173 G/L, p = 0.0005), more cytopenias (2 vs 1, p = 0.0005). 77% of t-MNs patients had a TP53 mutated t-MNs, 33% of patients w/o t-MNs had TP53 mutated clonal hematopoiesis. In the last 20 years, 37 patients were addressed for t-MN post OC at our institute, with an increased incidence of 50% during the last 6 years. Compared to t-MN not exposed to PARPi, t-MN-PARPi patients had more BRCA1/2 predisposition (61.5% vs 0% p = 0.03), their OC tended to be non-progressive (CR/PR/SD = 62.5% vs 38.5%, p = 0.3) and tend to have more TP53 mutated t-MNs (77% vs 47%, p = 0.1). Median OS for t-MNs post PARPi was poor at 8.2 months (CI95% [2.03-18.7]) but not significantly different form other t-MNs (p = 0.8). We then studied 69 t-MNs-PARPi including 28 AML and 41 MDS in patient with history of OC (75%), BC (9%) or both (16%). Median age was 64 years, 80% received Olaparib, 72.5% had a BRCA1/2 predisposition. Median time between cancer diagnosis and initiation of PARPi was 44 months and median duration of PARPi treatment was 14 months. History of haematological toxicity secondary to PARPi was reported in 51% of patients. Karyotype was often complex (61%) associated with a high rate of TP53 mutation (70.5%). Median OS was 9.7 months (CI95%, 5.3-13.9). In multivariate analysis, a longer delay between the end of PARPi treatment and t-NM diagnosis (HR 1.046, p = 0.02), as well Olaparib treatment compared to others PARPi (HR 5.82, p = 0.003 and AML diagnosis (HR 2.485, p = 0.01) were associated with shorter OS. Conclusions: We describe in a large series a higher incidence of t-MNs post PARPi than previously reported. Unfavorable cytogenetic and molecular abnormalities associated with these t-MNS explained the poor OS. Early detection is crucial particularly in case of delayed appearance of cytopenias.

Myeloproliferative Neoplasms with Monocytosis.

Myeloproliferative neoplasms (MPN) are a heterogeneous group of hematopoietic stem cell neoplasms comprising of polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF) that share driver mutations (JAK2/CALR/MPL) resulting in constitutive activation of JAK/STAT and other signaling pathways. Patients with MPN have shortened survival and an inherent risk for leukemic evolution. Prognostically relevant clinical and genetic parameters have been incorporated into mutation-enhanced scoring systems (MIPSS70-plus version 2.0, MIPSS-ET/PV). In the current review, we describe clinical and pathological features along with prognostic significance of MPN with monocytosis. Monocytosis, defined by an absolute monocyte count (AMC) ≥ 1 × 10 9/L, is a typical manifestation of chronic myelomonocytic leukemia (CMML) but is also associated with 21% and 17% of PV and PMF patients, respectively. Recent studies on the subject have reported that MPN patients with monocytosis are older and present with concomitant leukocytosis. In regard to PV, patients with monocytosis harbor unfavorable cytogenetic abnormalities including +8, 7/7q, i(17q), 5/5q-,12p-, inv(3), or 11q23 rearrangement and SRSF2 mutations, whereas PMF patients with monocytosis had significant thrombocytopenia, higher circulating blasts, higher symptom burden, and ASXL1 mutations. Moreover, presence of monocytosis predicted inferior survival in both PV and PMF. Monocytosis in MPN is associated with a distinct clinical and genetic profile and may serve as a marker of aggressive disease biology.

Sustained Long-Lasting Responses after Lenalidomide Discontinuation in Patients with Chronic Lymphocytic Leukemia

Sustained Long-Lasting Responses after Lenalidomide Discontinuation in Patients with Chronic Lymphocytic Leukemia

The Impact of the Administration Schedule and Mutational Profile on Outcomes of Patients with Relapsed and Refractory Acute Myeloid Leukemia Treated with Hypomethylating Agents: A Large, International, Multi-Center Analysis

The Impact of the Administration Schedule and Mutational Profile on Outcomes of Patients with Relapsed and Refractory Acute Myeloid Leukemia Treated with Hypomethylating Agents: A Large, International, Multi-Center Analysis

Genetic Pathway in the Pathogenesis of Therapy-Related Myeloid Neoplasms: A Literature Review.

Therapy-related myeloid neoplasms are a life-threatening and often fatal complication, associated with poor prognosis outcomes and with high-risk unfavorable cytogenetic abnormalities including complex karyotype. They occur after the treatment of primary malignancies using chemotherapy and/or radiation therapy. Such therapy is not specific to cancer cells, and also damages the deoxyribonucleic acid (DNA) of normal cells, resulting in unbalanced and balanced translocations. There are eight genetic pathways, whose details are summarized in this review, depending on the cytogenetic abnormalities induced. This abnormality is the major contributor to the development of therapy-related myeloid neoplasms. The etiology of these neoplasms depends on the complex interaction between the nature and dose of the cytotoxic agent, the environment, and the presence of subsequent inherited mutations. This review aims to elaborate upon recent knowledge regarding the etiology, pathogenesis, and genetic pathways of therapy-related myeloid neoplasms. A deeper understanding of their etiology would aid physicians in more careful monitoring of patients during or after cytotoxic therapy for hematological malignancy. Ultimately, this knowledge could influence initial treatment strategies, with the aim of reducing both the incidence and serious complications of neoplasms. Therefore, early detection of DNA lesions is vital. The authors recommend that primary malignancy be treated with targeted therapy.

Geriatric 8 can predict treatment outcomes of elderly patients with de novo AML who received low-dose chemotherapy

Abstract Background Geriatric assessments (GAs) used to evaluate various aspects in elderly patients have recently been introduced for their usefulness in predicting toxicities of cancer treatments and subsequent patient prognoses. Utilizing GAs to decide on treatment policies has been recommended. However, there are few reports on the relationship between Geriatric 8 (G8), a screening tool for GA, and treatment outcomes of elderly patients with de novo acute myeloid leukemia (AML) who received low-dose chemotherapy (LDC). Patients and Methods We reviewed 47 patients aged≥70 years who were newly diagnosed with de novo AML (except for acute promyelocytic leukemia) and received LDC as an initial treatment at our hospital between April 2012 and June 2018. We divided them into two groups (high: N = 11, low: N = 36) according to G8 scores (cutoff: 14 points) at the time of diagnosis and retrospectively analyzed the differences in clinical features and treatment outcomes. Results Statistically significant differences in age (median, 73 vs. 79 years, p = 0.009) were observed between the two groups. The proportions of sex, median white blood cell and bone marrow blast counts, and percentages of patients with unfavorable cytogenetic abnormalities did not differ significantly between groups. The most frequent initial LDC in both groups was low-dose cytarabine combined with acrarubicine. The complete remission rate and overall survival at two years were significantly higher in the G8 high-score group than those in the low-score group (72.7% vs. 19.4%; p = 0.002 and 55.6% vs. 11.0%; p Conclusion Our data suggest that G8 scores can predict treatment outcomes in elderly patients with de novo AML who received LDC.

PB1742 AGE, KARYOTYPES AND WHETHER RECEIVING INDUCTION CHEMOTHERAPY ARE INDEPENDENT PROGNOSTIC FACTORS IN ELDERLY PATIENTS WITH AML

Background:Acute myeloid leukemia (AML) is an aggressive disease with an unfavorable prognosis. AML is more common in elderly patients, and the treatments for these patients are limited, particularly for those with poor performance status, comorbidities, and unfavorable cytogenetic abnormalities. There are no universally accepted, standard approaches to treat AML in elderly patients.Aims:To analyze the clinical characteristics and prognostic factors of elderly patients with acute myeloid leukemia(AML).Methods:A total of 232 AML patients were enrolled in this retrospective study.The clinical characteristics were collected and analyzed retrospectively. Factors affecting complete remission (CR) were analyzed by using chi square test. Univariateand multivariate analyses of prognostic factors were performed by using Kaplan‐Meier and Cox hazard regression model respectively.Results:195 of 232 patients received induction chemotherapy, among whom 8 patiens died in early phase. 162 patients were able to be evaluated the efficacy, the CR rate after the first circle was 37.0 % (60/162). Overall CR rate was 54.9% (60/162). 37 patiens received palliative treatment, among whom 6 patients died in early phase and none achieved CR. Age between 60‐69 (χ2=4.102, P = 0.043), ECOG score≤2 (χ2=9.917, P = 0.002), NPM1+FLT3‐ITD‐ (χ2=6.423, P = 0.038), favorable karyotypes (χ2=6.033, P = 0.049) were related to a higher CR rate. The median overall survival (OS) was 205 day. Univariate analysis results demonstrated that age≥70 years (χ2=8.7, P = 0.003), white cell count≥100 × 109/L (χ2=4.249, P = 0.039), unfavorable karyotypes (χ2=4.807, P = 0.028), palliative treatment (χ2 = 191.221, P = 0.000) were influence factors on OS. In multivariable analysis, age between 60‐69 (HR = 0.464,95 % CI 0.245∼0.877,P = 0.018), unfavorable karyotypes (HR = 3.618,95 % CI1.491∼6.728,P = 0.003) and receiving induction chemotherapy (HR = 0.076,95 % CI 0.030∼0.194,P = 0.000) were independent prognostic factors for OS in elderly patients with AML.Summary/Conclusion:The prognosis of elderly patients with AML is the result of the combined effect of many factors. Age, karyotypes and whether receiving induction chemotherapy are independent prognostic factors in elderly patients with AML.

Neuroblastoma with localization in the neck. Own experience Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology

Introduction.Neuroblastoma (NB) is the most common extracranial solid tumor in children. As a rule, NB is localized in the adrenal gland, retroperitoneal space and posterior mediastinum. The head and neck area belongs to the rare localization of NB, which accounts for 2.6 % of cases, and is most common in children aged 0–3 years. Localization of NB in the neck in most cases has a favorable prognosis.Materials and methods.For the period from September 2013 to September 2017 (48 months) in the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology received treatment for 8 patients with NB in the neck. Examination, assessment of the prevalence of the process and stratification into risk groups in all patients were carried out according to the recommendations of the protocol of the German group for the treatment of NB NB-2004. For the purpose of histological verification of the diagnosis and detection of unfavorable molecular genetic markers, patients underwent surgical intervention, performed risk-adapted therapy according to the NB-2004 protocol.Results.The median age of diagnosis was 8.7 (1.2–34.1) months. In our cohort of patients in 87.5 % of cases, the diagnosis was made in the first year of life. In most cases, there was not only the identification of tumor masses, but also other symptoms of the disease. In 3 (37.5 %) patients the 2nd stage was established, in 1 (12.5 %) patient – the 3rd stage, in 3 (37.5 %) patients – the 4th stage and in 1 (12.5 %) patient – 4S stage of the disease. When stratifying patients into risk groups, in the observation group and the high-risk group was stratified by 3 (37.5 %) children and 2 (25 %) patients were classified as high-risk group. 3 (37.5 %) patients showed unfavorable cytogenetic abnormalities. When evaluating the response to therapy in most patients, a complete and very good partial response was stated. Overall (OS) and event-free (EFS) survival rates were 75 ± 15 % and 50 ± 17 %, respectively. The median of observation is 43 (26–61) months.Discussion.NB with the localization of the primary tumor in the head and neck area is a favorable form in terms of the stage of the disease and the risk group, however, it should be noted that in our patient cohort half of the subjects showed the development of certain adverse events, which was also reflected in the OS and EFS. Moreover, this localization dictates its risks from the point of view of the surgical stage of treatment. The main danger is complications after surgical treatment associated with the anatomical proximity of the central arteriovenous trunks, cranial nerves, and their involvement in the tumor process. In the case of the development of life threatening conditions (LTC), it is possible to use low-intensity chemotherapy courses.Conclusion.Experience Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology shows the need for timely diagnosis and the start of treatment of NB with localization in the neck. The choice of management tactics in favor of carrying out only surgical treatment is possible in patients of the observation group without the development of LTC. Not always the localization of NB in the neck region correlates with a favorable prognosis.Conflict of interest. The authors declare no conflict of interest.Funding. The study was performed without external funding.

Prognostic Value of Cpss Cytogenetic Risk Classification in Patients with CMML after Allogeneic Hematopoietic Stem Cell Transplantation: A Retrospective Multicenter Study of the Chronic Malignancies Working Party of the EBMT

Introduction: The only curative treatment approach for patients with Chronic Myelomonocytic Leukemia (CMML) is allogeneic hematopoietic stem cell transplantation (HSCT), but disease relapse after transplantation is a major concern. Predictors for disease outcome after HSCT are limited. However, unfavorable cytogenetic abnormalities have been shown to serve as predictors for relapse after transplantation. The aim of this large multicentric, international study was to retrospectively determine the impact of cytogenetic information according to the CMML-specific prognostic scoring system (CPSS) on outcome after allogeneic HSCT.Patients and Methods: Patients were selected from the EBMT database who had received a first allogeneic HSCT for the treatment of CMML between 2000 and 2015. 268 centers participated into this study. In total, 1503 patients were included. Impact of CPSS-cytogenetic classification was analyzed regarding overall survival (OS) and cumulative incidence of relapse and non-relapse mortality after HSCT (gray test).Results: 488 female (32.5%) and 1013 male (67.5%) patients were included to the study. Median age at HSCT was 57.6 years (range 0.3-75.4). At time of HSCT, only 422 (28.1%) patients were in complete remission, whereas 1004 (66.8%) had active disease (77 missing). Matched related donor HSCT was performed in 35.7% of the patients, matched unrelated donor HSCT in 57.6%, mismatched related in 3.3% and mismatched unrelated in 3.4%. Bone marrow (12.6%), peripheral blood (84.3%), or both (0.3%) served as the stem cell graft. Cord blood was used as a graft in 2.8%. Myeloablative preparative regimens wereused in 223 patients (15.0%), and less intensive regimens were given to 1268 patients (85.0%). Median survival of patients included into this study was 52.2 months. 637 patients had sufficient cytogenetic information according to CPSS (866 missing), complete relapse information was available in 1385 patients. 143 patients could be categorized into CPSS-high, 85 in intermediate and 375 in low risk cytogenetics, respectively. In univariate analysis high risk CPSS cytogenetic information was found to be strongly associated with OS (low 38% (32-44%), intermediate 41% (30-53%), high 26% (18-34%)), and higher cumulative incidence of relapse (low 40% (35-46%), intermediate 42% (30-54%), high 48% (39-56%)), but not with non relapse mortality (low 28% (23-33%), intermediate 25% (16-35%), high 30% (22-38%)) at 60 months (Figure 1).Conclusion: In this international, multicentric analysis we show that CMML patients with high-risk cytogenetics had significantly worse OS after HSCT than patients with intermediate or low risk cytogenetics according to CPSS. New therapeutic strategies to prevent relapse after HSCT in CMML patients with high-risk cytogenetics are needed. [Display omitted] DisclosuresKoenecke:Amgen: Consultancy; abbvie: Consultancy; BMS: Consultancy; Roche: Consultancy. Beelen:Medac: Consultancy, Other: Travel Support. Finke:Novartis: Consultancy, Honoraria, Other: travel grants, Research Funding; Riemser: Consultancy, Honoraria, Research Funding; Medac: Consultancy, Honoraria, Other: travel grants, Research Funding; Neovii: Consultancy, Honoraria, Other: travel grants, Research Funding. Niederwieser:Novartis: Research Funding; Miltenyi: Speakers Bureau. Chalandon:Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel costs. Ganser:Novartis: Membership on an entity's Board of Directors or advisory committees. Kobbe:Amgen: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Celgene: Honoraria, Other: Travel Support, Research Funding.

Efficacy and Safety of Autologous Stem Cell Transplantation in Elderly Patients with Multiple Myeloma in the Era of Novel Agents

Introduction : In the past decade, the combination of high-dose melphalan (MEL) and auto-hematopoietic stem cell transplantation (auto-HCT) with novel agents substantially improved the outcomes in younger patients with multiple myeloma. However, the safety and efficacy of auto-HCT in patients aged ≥65 years remain uncertain. Large clinical trials evaluating the role of auto-HCT in multiple myeloma mostly included patients aged Methods: We examined 2,056 patients aged ≥16 years who underwent auto-HCT for multiple myeloma from 2007 to 2014; they were selected based on the following criteria: (1) first auto-HCT with peripheral blood stem cells; (2) use of MEL alone (100, 140, and 200 mg/m2) as a conditioning regimen; and (3) without planned tandem transplantation. A total of 2,056 patients met these criteria, and 287 of them were aged ≥65 years. The era of novel agents was defined as the date of transplantation after December 2006 because bortezomib was approved for public administration in Japan in December 2006. The primary end-point was 100-day treatment-related mortality (TRM), i.e., not myeloma-related or accidental deaths within 100 days after the first auto-HCT, and the secondary end-point was overall survival (OS). To adjust for a selection bias, the 100-day TRM was compared between two age groups ( Results: The median age at transplantation was 66 (range, 65-76) and 57 (range, 18-64) years in the elderly and younger groups, respectively. The number of patients who used 100, 140, and 200 mg/m2 MEL were 17 (1.0%), 71 (4.0%), and 1,681 (95.0%), respectively, in the younger group and 19 (6.6%), 51 (17.8%), and 217 (75.6%), respectively, in the elderly group, with a significant difference (p Conclusion: The 100-day TRM and OS were not significantly different between the younger and elderly patients who underwent auto-HCT for multiple myeloma in 2007-2014. We showed that auto-HCT is safe and effective for treating multiple myeloma in elderly patients, particularly in the era of novel agents. A comparable benefit was observed in elderly patients who underwent auto-HCT for multiple myeloma, highlighting the fact that chronologic age alone should not be used to determine transplantation eligibility. Disclosures Hanamura:CHUGAI PHARMACEUTICAL CO., LTD.: Research Funding; Kyowa Hakko Kirin Company, Limited: Research Funding; Bristol-Myers Squibb: Other: Lecture fee, Research Funding; Celgene: Other: Lecture fee; Takeda Pharmaceutical Company Limited.: Other: Lecture fee; Fujimoto Pharmaceutical Corporation: Research Funding. Sunami:Sanofi: Research Funding; AbbVie: Research Funding; Daiichi-Sankyo: Research Funding; MSD: Research Funding; Takeda: Research Funding; Bristol-Myers Squibb K.K.: Honoraria, Research Funding; GlaxoSmithKline: Research Funding; Ono: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Novartis: Research Funding; Janssen: Research Funding. Mori:Janssen: Honoraria; Eisai: Honoraria; Japan Blood Products Organization: Honoraria; Shire Japan: Honoraria; Kyowa Hakko Kirin: Honoraria; Ono: Honoraria; Celgene: Honoraria; MSD: Honoraria; Taisho Toyama Pharmaceutical Co: Honoraria; Pfizer: Honoraria; Novartis Pharma: Research Funding; Asahi Kasei: Research Funding; Astella Pharma: Honoraria; CHUGAI: Honoraria; SHIONOGI: Honoraria; Novartis Pharma: Honoraria; MSD: Research Funding. Iida:MSD: Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Ono: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Kyowa-Hakko Kirin: Research Funding; Gilead: Research Funding; Sanofi: Consultancy; Teijin Pharma: Research Funding; Toyama Chemical: Research Funding; Astellas: Research Funding; Chugai: Research Funding. Kako:Takeda Pharmaceutical Company Limited.: Honoraria; Takeda Pharmaceutical Company Limited.: Honoraria; Celgene K.K.: Honoraria; Bristol-Myers Squibb: Honoraria; Sumitomo Dainippon Pharma Co., Ltd.: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria; Otsuka Pharmaceutical Co., Ltd.: Honoraria; Ono Pharmaceutical Co., Ltd.: Honoraria; Janssen Pharmaceutical K.K.: Honoraria. Sawa:Celgene Corporation: Honoraria; Takeda Pharmaceutical Company Limited: Honoraria; Bristol-Myers Squibb: Honoraria; Novartis International AG: Honoraria; CHUGAI PHARMACEUTICAL CO., LTD.: Honoraria; Mundipharma K.K.: Honoraria. Kanda:Dainippon-Sumitomo: Consultancy, Honoraria, Research Funding; Eisai: Consultancy, Honoraria, Research Funding; Chugai: Consultancy, Honoraria, Research Funding; Otsuka: Research Funding; Nippon-Shinyaku: Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Kyowa-Hakko Kirin: Consultancy, Honoraria, Research Funding; Taiho: Research Funding; Pfizer: Research Funding; MSD: Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Asahi-Kasei: Research Funding; Ono: Consultancy, Honoraria, Research Funding; Sanofi: Research Funding; Novartis: Research Funding; Shionogi: Consultancy, Honoraria, Research Funding; Taisho-Toyama: Research Funding; CSL Behring: Research Funding; Tanabe-Mitsubishi: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Mochida: Consultancy, Honoraria; Alexion: Consultancy, Honoraria; Takara-bio: Consultancy, Honoraria. Ichinohe:Celgene: Honoraria; JCR Pharmaceuticals: Honoraria; Bristol-Myers Squibb: Honoraria; Alexion Pharmaceuticals: Honoraria; Zenyaku Kogyo Co.: Research Funding; Janssen Pharmaceutical K.K.: Honoraria; Mundipharma: Honoraria; Takeda Pharmaceutical Co.: Research Funding; Taiho Pharmaceutical Co.: Research Funding; Sumitomo Dainippon Pharma Co.: Research Funding; Repertoire Genesis Inc.: Research Funding; Otsuka Pharmaceutical Co.: Research Funding; MSD: Research Funding; Nippon Shinyaku Co.: Research Funding; Pfizer: Research Funding; Ono Pharmaceutical Co.: Research Funding; Kyowa Hakko Kirin Co.: Research Funding; Eisai Co.: Research Funding; CSL Behring: Research Funding; Chugai Pharmaceutical Co.: Research Funding; Astellas Pharma: Research Funding; Novartis.: Honoraria. Takamatsu:Bristol-Myers Squibb: Research Funding; Ono: Research Funding; Janssen: Honoraria; Celgene: Honoraria, Research Funding. Takami:Chugai: Research Funding; Bristol-Myers Squibb: Research Funding; Kyowa Hakko Kirin: Research Funding.

Sustained long-lasting responses after lenalidomide discontinuation in patients with chronic lymphocytic leukemia.

Sustained long-lasting responses after lenalidomide discontinuation in patients with chronic lymphocytic leukemia.

Combination of t(4;14), del(17p13), del(1p32) and 1q21 gain FISH probes identifies clonal heterogeneity and enhances the detection of adverse cytogenetic profiles in 233 newly diagnosed multiple myeloma

BackgroundOur aim was to set the FISH combination of del(17p13), t(4;14), 1q21 gain and del(1p32), four adverse cytogenetic factors rarely evaluated together, and compare our technical thresholds with those defined in the literature.MethodsTwo hundred thirty-three patients with MM at diagnosis were studied using FISH to target 4 unfavorable cytogenetic abnormalities: 17p13 deletion, t(4;14) translocation, 1p32 deletion and 1q21 gain. Technical thresholds were determined for each probe using isolated CD138-expressing PC from patients without MM.ResultsThe FISH analysis identified abnormalities in 79.0% of patients. Del(17p13) was detected in 15.0% of cases, t(4;14) in 11.5%, 1q21 gain in 37.8% and del(1p32) in 8.7%. Adding 1p32/1q21 FISH probes has enabled us to identify adverse cytogenetic profiles in 39.0% of patients without del(17p13) or t(4;14). Clonal heterogeneity was observed in 51.1% of patients as well as an increase in the number of adverse abnormalities when related clones were greater than or equal to 2 (85.1% against 45.6%).ConclusionFISH allowed detecting accumulation of adverse abnormalities and clonal heterogeneity in MM with a combination of 4 probes. The impacts of these two parameters need to be evaluated, and could be included in future cytogenetic classifications.

Identification and expression of MMSA-8, and its clinical significance in multiple myeloma.

In our previous studies, we identified 12 multiple myeloma (MM)-associated antigens by serological analysis of tumor-associated antigens with a recombinant cDNA expression library (SEREX) on MM. MM-associated antigen-8 (MMSA-8) was one of the new antigens identified. We determined the 3′- and 5′-ends of MMSA-8 using SMART-rapid amplification of cDNA ends (RACE) and then cloned its full-length cDNA in the U266 cell line. The full cDNA sequence revealed that MMSA-8 is RPS27A-related transcript variant 1 that is specifically associated with MM. We examined its prognostic significance for the first time, by investigating the correlations between MMSA-8 expression and definite clinicopathological features. We quantitatively assessed MMSA-8 expression using qRT-PCR and western blot analysis in healthy donors and MM patients. The expression levels of MMSA-8 were upregulated with statistical significance in MM patients in contrast to those in healthy donors. The expression of MMSA-8 was also upregulated in relapsed patients compared with that in the complete remission (CR) group. Contrasting MMSA-8 expression levels in different patients with definite clinicopathological features suggested an association between MMSA-8 with unfavorable clinicopathological characteristics, such as international staging system (ISS) stage III, higher lactate dehydrogenase (LDH) levels and higher C-reactive protein (CRP) levels. The expression of MMSA-8 was also increased in patients with unfavorable cytogenetic and genetic abnormalities, including the presence of t(11;14), t(4;14), t(14;16), del(17p), del(13q) and p53 deletion, which was statistically significant. The expression of MMSA-8 exhibited significant variance in the treatment responses of the CR, PR, progression and relapse groups. Univariate and multivariate analyses revealed that high MMSA-8 values were associated with poorer progression-free survival (PFS) and overall survival (OS) in MM patients independently. In conclusion, our data indicated that MMSA-8 is an independent and unfavorable prognostic risk factor in MM; MMSA-8 is also a promising diagnostic and therapeutic target in MM patients, but further validation is needed.

Abnormal Karyotype and Prognosis in Polycythemia Vera: A Single Center Experience in 239 Informative Cases

BackgroundIn polycythemia vera (PV), abnormal karyotype at diagnosis has been reported in 10% to 20% of patients and some studies have suggested an association with inferior survival (Leukemia 2013;27:1874) . In the current study, we examined the prognostic contribution of abnormal karyotype, in general, and specific abnormalities, in particular, in newly diagnosed PV.MethodsStudy patients were selected from our institutional database of myeloproliferative neoplasms (MPN) and fulfilled the 2008 World Health Organization (WHO) criteria for diagnosis of PV (Blood. 2009;114:937). Cytogenetic analysis and reporting was done according to the International System for Human Cytogenetic Nomenclature (Cytogenetic and Genome Research 2013;141:1-6). Assignment as "unfavorable karyotype" was according to criteria established for PMF: favorable = normal + favorable abnormalities; unfavorable = unfavorable abnormalities (Leukemia. 2011;25:82). Screening for the two most frequent mutations in PV, other than JAK2 (i.e. TET2 and ASXL1), were performed according to conventional methods (Leukemia. 2014;28:2206). Statistical analyses considered clinical and laboratory parameters obtained at time of diagnosis.ResultsPatient characteristics:Median (range) values for the 239 study patients (53% females) included: age 62 (17-94), leukocyte count 11.7 x 10(9)/L (4.3-59.3) and platelet count 479 x 10(9)/L (37-2747). Palpable splenomegaly was present in 26% of the patients, pruritus in 27%, erythromelalgia in in 8%, hypertension in 47%, diabetes in 10% and hyperlipidemia in 28%. Thrombosis history at diagnosis was documented in 33% of the patients and 20% experienced the same after diagnosis. 73% of the patients were "high risk" by conventional risk stratification. Mutation screening for TET2 and ASXL1 was performed in 80 patients and mutational frequencies were 19% and 11% respectively. All study patients provided cytogenetic information, which was abnormal in 46 (19%) patients. The most frequent abnormalities were isolated +9 (n=11; 24% of abnormal karyotype and considered favorable), isolated del(20q) (n=8; 17% of abnormal karyotype and considered favorable), isolated loss of Y chromosome (n=7; 15% of abnormal karyotype and considered favorable) and isolated +8 (n=5; 11% of abnormal karyotype and considered unfavorable). A total of 9 (20% of abnormal karyotype) patients displayed unfavorable karyotype that included +8 in 7 patients, del(11q) in one patient and +20 in one patient. After a median follow-up of 83 months, 70 (29%) deaths, 48 (20%) thrombotic events, 20 (8%) fibrotic progressions and 7 (3%) leukemic transformations were documented.Comparison of patients with and without cytogenetic abnormalitiesPatients with abnormal cytogenetics were older (p=0.048), displayed lower platelet count (p=0.005) and were more likely to be high risk (p=0.02); there was no significant correlation with TET2 or ASXL1 mutation. In univariate analysis, patients with abnormal cytogenetics displayed inferior leukemia-free (p=0.007; HR 10.6, 95% CI 1.9-58.7), myelofibrosis-free (p<0.0001; HR 7.7, 95% CI 3.1-19.3) and overall (p=0.13; HR 1.6, 95% CI 0.9-2.8) survival. Furthermore, the difference in overall survival became significant when cytogenetic abnormalities were classified into unfavorable (p=0.006) and favorable (p=0.6) categories. On the other hand, inferior leukemia-free and myelofibrosis-free survival was noted in both patients with favorable and unfavorable cytogenetic abnormalities, when compared to normal karyotype. During multivariable analysis that included age and leukocytosis (≥15 x 10 (9)/L) as covariates, the adverse effect of abnormal cytogenetics on leukemia-free (p=0.009) or myelofibrosis-free (p<0.0001) survival and that of unfavorable karyotype on overall (p=0.05) survival were shown to be independent. Finally, patients with abnormal cytogenetics were less likely to experience thrombosis after diagnosis (p=0.04; HR 0.3, 95% CI 0.09-0.97), an effect that was independent of both age and thrombosis history.ConclusionsCytogenetic abnormalities in PV confer an independent adverse prognostic effect on overall, leukemia-free and myelofibrosis-free survival, but not thrombosis-free survival; the adverse effect on leukemia-free and myelofibrosis-free survival was seen with both favorable and unfavorable cytogenetic abnormalities. DisclosuresNo relevant conflicts of interest to declare.