11q23 Rearrangements Research Articles

152 Recurrent Cytogenetic Abnormalities in Intravascular Large B-Cell Lymphoma

Intravascular large B-cell lymphoma (ILBCL) is a rare (<1 per 1,000,000) and aggressive extranodal lymphoma characterized by the proliferation of lymphoma cells almost exclusively within the lumina of small and intermediate vessels. While ILBCL has been associated with complex karyotypes, data characterizing its cytogenetic landscape and the presence of recurrent cytogenetic abnormalities are limited. Here, we present the results of the largest pooled dataset to date. An institutional database was queried for cases of ILBCL with complete cytogenetic analysis and a literature search was performed using PubMed to identify all published cases of definitively diagnosed ILBCL for which a complete karyotype was provided. The identified karyotypes were systematically reviewed for the presence of recurrent abnormalities. Four new cases were identified and pooled, with 25 karyotypes previously published in the literature. Twenty of 29 (69%) patients had abnormalities involving chromosome 1. Ten translocations were present in eight patients, six of which involved either p13 or q21. In three additional patients, three rearrangements involving these breakpoints were also present. Thus, nine of 29 patients had rearrangements involving 1p13 or 1q21. 17/29(58.6%) patients had abnormalities involving chromosome 3. The most common rearrangement was a translocation, which was definitively present in eight patients, of which four (50%) involved 3p21. Seventeen of 29 (58.6%) patients had abnormalities involving chromosome 6. In almost all cases, the long arm of chromosome 6 was implicated, including seven patients with additional material of unknown origin and four 6q deletions. Twelve patients (41.4%) had abnormalities involving chromosome 14, nine (31% of total) of which involved rearrangements of 14q32. Sixteen patients (55.2%) had abnormalities of chromosome 18. Ten of 29 total patients (34.5%) had trisomy 18. ILBCL is associated with multiple recurrent cytogenetic abnormalities, the identification of which may facilitate diagnosis. Further research is warranted to determine the prognostic significance of these aberrations.

3q26/EVI1 rearrangement in myelodysplastic/myeloproliferative neoplasms: An early event associated with a poor prognosis

3q26.2/EVI1 rearrangements resulting in EVI1 overexpression play an important role in leukemogenesis and are associated with treatment resistance and a poorer prognosis in patients with acute myeloid leukemia, myelodysplastic syndrome, chronic myeloid leukemia and BCR-ABL negative myeloproliferative neoplasms. In this study, we aim to explore the clinicopathological features of myelodysplastic/myeloproliferative (MDS/MPN) neoplasms with 3q26.2/EVI1 rearrangements and determine the potential impact of these cytogenetic abnormalities on treatment response and survival. The study group included 12 cases of MDS/MPN with 3q26.2 rearrangements detected by conventional karyotyping. There were 7 men and 5 women with a median age of 67 years (range, 51–79 years) at time of initial MDS/MPN diagnosis. Ten cases were classified as chronic myelomonocytic leukemia (CMML) and 2 were MDS/MPN, unclassifiable. Among CMML cases, 5 (50%) were proliferative type and 5 (50%) were dysplastic type. Based on blast counts, these 10 CMML were: CMML-0 (n = 2), CMML-1 (n = 3), and CMML-2 (n = 5). Eleven (92%) patients had 3q26 rearrangements at the initial diagnosis. Inv(3)(q21q26.2) was most common, identified in 7(58%) patients, followed by t(3;21)(q26.2;q22) in 2 patients and 1 patient each with t(3;3)(q21;q26.2), t(2;3)(p21;q26-27), and t(3;6)(q26.2;q26). Six (50%) patients had 3q26.2 rearrangements as a sole cytogenetic abnormality and 6 (50%) patients had additional cytogenetic abnormalities. Molecular studies revealed DNMT3A mutations in all 3 patients assessed and RAS mutations in 2 of 8 (25%) patients. No mutations in ASXL1 (n = 3), TET2 (n = 3), FLT3 ITD/D835 (n = 10), and CEBPA (n = 7) were detected. Most patients received hypomethylating agent based chemotherapy. The median follow-up was 11.5 months (range, 1.5–24 months) and at time of last follow-up, 11 (92%) died with a median survival of 13.4 months (range, 1.5–24 months). The only patient alive had a relatively short follow-up of 2.4 months and showed disease progression at the last visit. In conclusion, 3q26.2/EVI1 rearrangements are a rare event and usually present at time of initial diagnosis in MDS/MPN. The presence of 3q26.2/EVI1 rearrangements in MDS/MPN is associated with rapid disease progression, poor response to treatment, and a poor prognosis.

Recognition of Recurrent Protein Expression Patterns in Pediatric Acute Myeloid Leukemia Suggests New Therapeutic Targets

Abstract Background: Pediatric acute myeloid leukemia (Pedi-AML) accounts for approximately 15% of childhood acute leukemias and the overall survival is 60-70%. Although cytogenetics provides risk stratification, most recurrent genetic events lack agents that specifically target them. Since genetic events are revealed by the expression and activation status of proteins, we hypothesized that we could define recurrent protein expression signatures that could suggest targets for individualized therapies. Methods:Custom Reverse Phase Protein Arrays (RPPA) with 95 Pedi-AML samples and 10 normal CD34+ bone marrow samples were performed and probed with 194 antibodies to determine protein expression levels and activation status. Proteins were divided in protein functional groups (ProFnGrp) to analyze them in the context of other proteins. Progeny clustering was performed to determine the optimal number of protein clusters and principal component analysis was used to visualize the distribution between protein clusters and normal CD34+ cells. Protein networks were generated using known literature associations combined with computational derived edges from the dataset. Associations between clinical features, outcomes and protein clusters were determined. Hierarchical clustering (Figure 1) was performed on a compilation of all protein clusters into one binary matrix to identify recurrent protein expression signatures (PrSIG) that comprised similar combinations of protein constellations(PrCON). A list of proteins that were over or under expressed was made for each signature. Results: For each ProFnGrp 3 to 6 distinct clusters were recognized. All but 2 ProFnGrp (Cell Cycle, Protein Kinase C) had at least one protein cluster that was similar to normal CD34+ samples and all ProFnGrp had clusters specific to the leukemic state. Protein expression levels were overlaid onto the networks and revealed distinct expression and activation states. Hierarchical clustering showed strong co-correlation between protein clusters from various ProFnGrp and suggested 12 PrCON. Patients that expressed similar recurrent combinations of PrCON compiled 8 PrSIG. Heterogeneity was observed for overall survival (OS) and complete remission duration (RD). High OS rates were seen in PrSIG 5 compared to PrSIG 1 (8/12 vs. 3/11 alive, Median NR vs. 54 wks, P=0.09) and high relapse free survival was observed for PrSIG 3 compared to PrSIG 1 (6/6 vs. 3/8 CCR, (Median RD NR vs 39 wks, P=0.04). Rearrangements of 11q23 were overrepresented in PrSIG 2 (7/16, 43.8%) and 7 (5/19, 26.3%) and underrepresented in PrSIG 4 (1/20, 5%) and 6 (0/5, 0%) (P=0.027). Complex karyotype was highly present in PrSIG 8 (4/6, 67%) compared to the overall population (16/95, 16.7%). Hispanic ethnicity was high in PrSig 7 &amp; 8 (53 &amp; 67%) and low in PrSIG 1, 2 4 &amp; 5 (20%, 25%, 5%, 8%). PrSIG membership was also correlated with FAB classification (P=0.025, M0 with PrSIG 4 and M5 with PrSIG 5) as well as with WBC, blast count, HGB and PLT. As we had both Pedi-AML and acute lymphoblastic leukemia (ALL) samples on this RPPA array (see accompanying ALL abstract), this enabled comparison between protein expression levels in both diseases. Combined re-analysis suggested 12 PrSIG and 12 PrCON; most PrSIG and PrCON were dominant for ALL or AML and only 1 PrSIG and 3 PrCON showed overlap between the two diseases. Identification of significantly altered proteins for each PrSIG can be used to select targeted therapies for combination. For example, for PrSIG1 combined inhibition of RPTOR and RICTOR may be useful as both are overexpressed. Conclusion: As hypothesized we demonstrated the existence of protein expression signatures in Pedi-AML based on strong correlations between different protein clusters. Signatures were correlated with therapeutic outcome, as well as with cytogenetics, Hispanic ethnicity, and laboratory features. Recognition of altered proteins within the signatures suggested combinations of targets that could facilitate personalized therapy. Shared protein constellations between AML and ALL indicate joint protein deregulations that could be targetable in both diseases. Figure 1. Hierarchical clustering shows recurrent patterns of 12 PrCON (y-axis) that form 8 recurrent PrSIG (x-axis). The association with Hispanic ethnicity is shown. Figure 1. Hierarchical clustering shows recurrent patterns of 12 PrCON (y-axis) that form 8 recurrent PrSIG (x-axis). The association with Hispanic ethnicity is shown. Disclosures No relevant conflicts of interest to declare.

Prognostic Significance of 11q23/MLL Fusion Partners in Children with Acute Myeloid Leukemia (AML) - Results from the Children's Oncology Group (COG) Trial AAML0531

Background: Rearrangement of chromosome 11q23 at KMT2A (MLL+) occurs in ~20% of childhood acute myeloid leukemia (AML) cases and is the most common recurrent cytogenetic abnormality in childhood AML. More than 80 fusion partners of MLL have been characterized and the prognostic impact varies by partner and additional cytogenetic aberrations (ACAs). We previously reported superior event-free-survival (EFS), overall survival (OS), relapse risk (RR) and disease free survival (DFS) for patients with MLL+ on AAML0531 treated with gemtuzumab ozogamicin (GO). The impact of fusion partners has not been described for this trial cohort.Objective: To determine the impact of 11q23/MLL+ fusion partners on outcomes for children with AML who were treated uniformly on AAML0531.Methods: AAML0531 (2006 - 2010) was a randomized phase 3 trial of GO with conventional chemotherapy for children, adolescents, and young adults, ages 0 to 29 years, with de novo AML. The trial enrolled 1022 eligible patients without Down syndrome, and cytogenetic data was available for 988 patients. Of those, 215 (21.8%) were classified as 11q23/MLL+ after central cytogenetic review. The majority of patients with 11q23/MLL+ AML (n=200, 93%) were classified as intermediate risk (IR) and a minority (n=15, 7%) were classified as high risk (HR) based upon high FLT3 internal tandem duplication allelic ratio (FLT3-ITD-AR), monosomy 5/5q deletion, monosomy 7, or >15% blasts by morphology following Induction (Ind) I. HSCT was performed for 30 patients (14%).We defined 11q23/MLL+ subgroups for partners identified in ≥5 cases. Partners in <5 cases were grouped as "other"; unidentified fusions were classified as "unknown". Outcomes of minimal residual disease (MRD) at end of Ind I and complete remission (CR) at end of Ind II, 5-yr EFS and OS from study entry, and 5-yr RR from end of Ind II for patients in CR were compared across subgroups. Univariable and multivariable analyses were performed.Results: The median age for the 11q23/MLL+ cohort was 2.5 years and the distribution was equally male and female. The majority of cases (n=175, 81%) were classified into 8 specific partner subgroups, and the remaining cases were classified as other (n=30, 14%) or unknown (n=10, 5%). The most common translocation was t(9;11)(p22;q23) (n= 82, 38%). Central nervous system involvement was rare (<10% overall and in every subgroup). While extramedullary chloromas were rare (7% overall), chloromas were reported in 83% (n=5) of t(10;11)(p11.2;q23), 40% (n=16) of t(10;11)(p12;q23), and 27% (n=4) of t(6;11)(q27;q23). ACAs were observed in 86 of 211 cases (41%) that underwent central review. ACAs were numerical in 54 cases (26%), most commonly trisomy 8 (n=30, 14%) and structural + numerical in 32 cases (15%), most commonly involving chromosome 1 (n=11, 34%). Molecular findings for 3 studied genes were rare: High FLT3-ITD-AR n=4; NPM1 n=1; CEBPA n=0.Clinical outcomes varied significantly by fusion partner and poorer OS was primarily due to relapse (Table 1). CR rate was 86% overall and did not vary by subgroups. MRD was detected in 21% overall and was most common in t(1;11)(q21;q23) and t(6;11)(q27;q23). Complex karyotype (≥3 abnormalities) was seen in 52 cases (25%) and predicted inferior outcome compared to <3 abnormalities (5-yr EFS 29% vs. 41%, p=0.02; 5-yr OS 44% vs. 63%, p=0.001, respectively). Chromosome 1 abnormalities were associated with very poor outcomes, 5-yr EFS 19% and 5-yr OS 29%. The most unfavorable partners for EFS were t(6;11)(q27;q23), t(10;11)(p11.2;q23), t(10;11)(p12;q23), and t(11;19)(q23;p13.3)(Figure 1). In multivariable comparison to patients with t(9;11)(p22;q23), the former 3 groups maintained inferior EFS (HR 2.51, p=0.006; HR 3.10, p<0.001; HR 2.15, p=0.002, respectively) and OS (HR 2.56, p=0.017; HR 4.8, p=0.006; HR 2.14, p=0.016, respectively).Conclusions: Fusion partners critically impact the prognosis of 11q23/MLL+ AML. In this large, uniformly treated cohort, t(6;11)(q27;q23), t(10;11)(p11.2;q23) and t(10;11)(p12;q23) were independently associated with inferior EFS and OS. Children with these unfavorable partners are at high risk for relapse and allogeneic HSCT should be considered in first CR. Complex karyotype, chromosome 1 aberrations, and extramedullary chloromas were additional adverse prognostic factors. Work is ongoing to confirm these results in the subsequent COG trial, AAML1031. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Circulating CD2 Negative T Cells in Pediatric Acute Leukemia

Introduction: Leukemia cells are able to escape from immunosurveillance using immune tolerance mechanisms as the majority of leukemia antigens are either shared or aberrantly expressed self-proteins. T cells reactive to these antigens are purged during thymic selection. CD2, a pan-T-cell antigen, is expressed early during T cell developments in thymus and is found on all subsets of mature T cells. Recent studies show that there are low levels of extrathymic CD2 negative (CD2-) T cells, which show immature T cell features and can be induced to differentiate into mature helper and cytotoxic T cells in vitro. Since circulating CD2- T cells could represent pre-selection immature T cells, they may play an important role in tumor immunity.Methods: 81 pediatric B-cell acute lymphoblastic leukemia (B-ALL) patients, 22 pediatric acute myeloid leukemia (AML) patients and 22 normal controls were included in this study. B-ALL group included 45 NCI-standard risk (SR) patients and 36 NCI-high risk patients. All the leukemia patients were diagnosed at Children's Mercy Hospital in the past ten years with a diagnostic peripheral blood (PB) specimen. The PB specimens were studied by four-color multiparameter flow cytometry with antibodies for T cell markers (CD2, CD3, CD4, CD5, CD7 and CD8) and CD45, and analyzed by BD FACSDiva 8.0.1. CD2- and CD3+ T cells were recorded as % of total T cells. Student's t-test was used to compare results.Results: The percentages of CD2- T cells in AML (mean ± STD: 1.31% ± 1.41%) and B-ALL (0.84% ± 0.67%) were significantly higher than that seen in control group (0.51% ± 0.52%, p<0.05). No significant difference was found between AML and B-ALL. There was no significant difference between HR B-ALL (0.96% ± 0.81%) and SR B-ALL (0.74% ± 0.52%). Interestingly, CD2- T cells in 4/5 B-ALLs with 11q23 (KMT2A) rearrangement were undetectable. All 3 therapy-related AML patients studied had KMT2A gene rearrangement, and had no detectable CD2- T cells with poor clinical outcome (overall survival less than 1 year). The 3 AMLs associated with Down syndrome, a prognostically favorable AML group, showed relative high levels (≥ 1.49%) of CD2- T cells.Conclusions: Circulating CD2- T cells are increased in peripheral blood in pediatric AML and B-ALL patients. KMT2A gene rearrangement, an unfavorable cytogenetic abnormality, is associated with a decrease in CD2- T cells. The relationship of KMT2A gene rearrangement and decrease in circulating CD2- T-cells as well as the relationship of CD2- T cells to clinical outcome should be evaluated in future studies. The role of CD2- T cells in tumor specific immunomodulation should be explored, and may impact future studies of cell-based cancer immunotherapeutics. DisclosuresNo relevant conflicts of interest to declare.

Comparison of Efficacy and Safety of Two Types of E.coli Asparaginase (Native or Pegylated) for Treatment of Adult Patients with High-Risk (HR), Philadelphia (Ph) Chromosome-Negative ALL Included in the Prospective MRD-Oriented Protocol ALL-HR-11 from the Spanish Pethema Group

Background and objective. Asparaginase (ASP) is an essential drug for ALL treatment. Two types of E.coli ASP (native and pegylated) are used in clinical trials for treatment of children and adults with ALL, but to our knowledge direct comparison between these two types of ASP in the same protocol has not been performed. This study aimed to compare the efficacy and safety of native vs. PEG-ASP in adult patients with HR, Ph-negative ALL.Patients and methods. HR ALL included one or more of the following parameters at baseline: age 30-60 yr., WBC count >30x109/L for B-cell precursor ALL or >100x109/L for thymic T-ALL, pro-B, early or mature T-ALL, 11q23 or MLL rearrangements or complex karyotype. Induction therapy consisted of vincristine, prednisone, daunorubicin and ASP (native 10,000 IU/m2, i.v., days 16-20 and 23-27 or PEG 2,000 IU/m2, iv, day 15 depending on center decision) for 4 weeks (Induction-1). FLAG-Ida was administered as intensified induction (Induction-2) in patients not achieving CR or in those in CR with MRD≥0.1% at the end of induction, and those patients proceeded to allogeneic HSCT if CR was attained. Patients in CR and MRD<0.1% proceeded to early consolidation therapy including 3 cycles with rotating cytotoxic drugs with high-dose methotrexate, high-dose ARA-C and ASP (native 20,000 IU/m2 on day 3 of each cycle or PEG 2,000 IU/m2 on day 3 of each cycle). Patients continued with delayed consolidation (identical to that of early consolidation) followed by maintenance therapy up to 2 yr. in continuous CR if MRD levels after consolidation were <0.01%, otherwise they were assigned to allogeneic HSCT. The cumulated doses of native ASP and PEG-ASP for patients who completed the induction and early+delayed consolidation were 220,000 IU/m2 and 14,000 IU/m2, respectively. No ASP levels were assessed.Results. Ninety-onepatients received native ASP and 35 PEG-ASP in Induction-1. The two groups of patients were comparable for the main clinical and hematologic ALL parameters. No differences were observed in the CR rate (86% vs. 86%), in the frequency of MRD level <0.1% after Induction-1 (63% vs. 70%), and that of MRD level <0.01% after early consolidation (74% vs. 92%, p=0.19), as well as in the proportion of patients submitted to allogeneic HSCT (20% vs. 14%). No differences were found in overall survival or disease-free survival probabilities at 3-years according to the type of ASP (OS: 60% [95%CI: 47% ; 73%] vs. 57%[95%CI: 36% ; 78%], p=0.872 and DFS: 40% [95%CI: 25% ; 55%] vs. 58% [95%CI: 36% ; 80%], p=0.302). Abnormalities in the coagulation parameters were significantly more frequent in patients receiving PEG-ASP in Induction-1 (18% vs. 35%, p=0.045). These abnormalities, together with hepatic toxicity were significantly more frequent in patients receiving PEG-ASP in early consolidation (1% vs. 13%, p=0.003, and 5% vs. 34, p<0.001, respectively). A trend for more allergic reactions was seen in patients receiving native ASP (18% vs. 5%, p=0.1) No differences in the frequency of ASP discontinuation rate were observed (6 % vs. 3%).Conclusions. In HR, Ph-negative adult ALL patients included in the PETHEMA ALL-HR 11 protocol the type of E.coli ASP (native vs. PEG) did not have impact on response and outcome. Allergic reactions were more frequently seen with native ASP and coagulation abnormalities and hepatic toxicity were most frequent with PEG-ASP. Most of the differences in toxicity can be explained by the schedule of ASP given in consolidation (single dose of native ASP vs. single dose of PEG-ASP in each cycle).Supported in part by grants RD12/0036/0029 (RTICC, FEDER), PI14/01971 FIS, Instituto Carlos III, and SGR225 (GRE), Spain DisclosuresNo relevant conflicts of interest to declare.

Targeting the Creatine Kinase Pathway in EVI1-Positive Acute Myeloid Leukemia

Abnormal expression of the transcription factor EVI1 through chromosome 3q26 rearrangements has been implicated in the development of one of the most therapeutically challenging high-risk subtypes of acute myeloid leukemia (AML). Here we integrated genomic and metabolic screening of hematopoietic stem cells to reveal that EVI1 overexpression altered cellular metabolism. A pooled shRNA screen targeting metabolic enzymes identified the ATP-buffering, mitochondrial creatine kinase CKMT1 as a druggable dependency in EVI1-positive AML.Of 18 screened AML cell lines harboring various genetic alterations, only the four EVI1-expressing lines exhibited markedly elevated CKMT1 protein expression and activity. Treatment of this cell line panel with either CKMT1-targeting shRNAs or cyclocreatine, an analog of the CKMT1 substrate creatine and inhibitor of the creatine biosynthesis pathway, showed that elevated CKMT1 protein expression correlated with sensitivity to CKMT1 pathway inhibition. Consistent with these data, flow cytometry analysis of a panel of 68 unselected primary AML patient specimens revealed that the four leukemias with the highest levels of EVI1 expression also had elevated CKMT1 protein levels and enhanced sensitivity to cyclocreatine treatment.We next established that enforced EVI1 expression increased CKMT1 protein and mRNA levels and that three independent shRNA molecules targeting EVI1 drastically reduced CKMT1 expression in two EVI1-positive AML cell lines. A luciferase-based reporter system established that RUNX1 represses CKMT1 expression through direct binding to its promoter. ChIP-qPCR approaches were then applied to dissect the sequential events involved in EVI1-induced CKMT1 upregulation and the possible role of RUNX1 as an intermediate. In both primary AML samples and cell lines, we determined that EVI1 represses RUNX1 expression by directly binding to its promoter. This, in turn, eliminates repressive RUNX1 binding at the CKMT1 promoter and thereby promotes CKMT1 expression. Based on these data, we explored the relationship between EVI1 and RUNX1 expression with CKMT1 mRNA levels in two AML transcriptional datasets (GSE14468 and GSE10358). We divided these cohorts into four subgroups with high versus low expression of EVI1 and RUNX1. Consistent with our mechanistic analysis, primary AML samples within the EVI1high/RUNX1low subgroup were significantly more likely to express high levels of CKMT1 than AML samples in the other three subgroups.CKMT1 promotes the metabolism of arginine to creatinine. To determine the effect of CKMT1 suppression on this pathway, we measured the metabolic flux of stable-isotope labeled L-arginine 13C6 through creatine synthesis using mass spectrometry. CKMT1-directed shRNAs or cyclocreatine selectively decreased intracellular phospho-creatine and blocked production of ATP by mitochondria. Salvage of the creatine pathway by exogenous phospho-creatine restored normal mitochondrial function, prevented the loss of viability of human EVI1-positive AML cells induced by cyclocreatine or CKMT1-directed shRNAs, and maintained the serial replating activity of Evi1-transformed bone marrow cells.Primary human EVI1-positive AML is frequently associated with somatic NRAS mutations. Thus, to investigate whether EVI1 over-expression sensitizes primary AMLs to CKMT1 inhibition in vivo, we transplanted primary NrasG12D mutant AMLs with and without elevated Evi1 expression into congenic recipient mice. In this system, Ckmt1 knockdown did not significantly alter the outgrowth of control Nras mutant AML cells compared to a shControl (63% versus 71%). By contrast, NrasG12D AML cells characterized by elevated Evi1 expression were profoundly depleted by Ckmt1 suppression to 2% versus 58% in shControl recipients. Consistent with these results, pharmacologic or genetic inhibition of the CKMT1-dependent pathway blocked disease progression and prolonged the survival of mice injected with human EVI1-positive cells but not with EVI1-negative cells, without noticeable cytotoxic effect on normal murine cells.In conclusion, we have integrated "omic" approaches to identify CKMT1 as a druggable liability in EVI-positive AML. This study supports a potential therapeutic avenue for targeting the creatine kinase pathway in EVI1-positive AML, which remains one of the worst outcome subtypes of AML. DisclosuresDeAngelo:Incyte: Consultancy; Novartis: Consultancy; Celgene: Consultancy; Amgen: Consultancy; Baxter: Consultancy; Pfizer: Consultancy; Ariad: Consultancy. Stone:Pfizer: Consultancy; Agios: Consultancy; Jansen: Consultancy; Celator: Consultancy; Merck: Consultancy; Amgen: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy; Novartis: Consultancy; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Xenetic Biosciences: Consultancy; Sunesis Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy; Roche: Consultancy; Juno Therapeutics: Consultancy; ONO: Consultancy.

Primary myelofibrosis: 2017 update on diagnosis, risk-stratification, and management.

Diagnosis is based on bone marrow morphology. The presence of JAK2, CALR or MPL mutation is supportive but not essential for diagnosis; approximately 90% of patients carry one of these mutations and 10% are "triple-negative." None of these mutations are specific to PMF and are also seen in essential thrombocythemia (ET). According to the revised 2016 World Health Organization (WHO) classification and diagnostic criteria, "prefibrotic" PMF (pre-PMF) is distinguished from "overtly fibrotic" PMF; the former might mimic ET in its presentation and it is prognostically relevant to distinguish the two. Risk stratification: The Dynamic International Prognostic Scoring System-plus (DIPSS-plus) uses eight predictors of inferior survival: age >65 years, hemoglobin <10 g/dL, leukocytes >25 × 109 /L, circulating blasts ≥1%, constitutional symptoms, red cell transfusion dependency, platelet count <100 × 109 /L and unfavorable karyotype (i.e., complex karyotype or sole or two abnormalities that include +8, -7/7q-, i(17q), inv(3), 5/5q-, 12p-, or 11q23 rearrangement). The presence of 0, 1, "2 or 3" and ≥4 adverse factors defines low, intermediate-1, intermediate-2 and high-risk disease with median survivals of approximately 15.4, 6.5, 2.9 and 1.3 years, respectively. Most recently, DIPSS-plus-independent adverse prognostic relevance has been demonstrated for certain mutations including ASXL1 and SRSF2 whereas patients with type 1/like CALR mutations, compared to their counterparts with other driver mutations, displayed significantly better survival. Risk-adapted therapy: Observation alone is a reasonable treatment strategy for asymptomatic low or intermediate-1 DIPSS-plus risk disease, especially in the absence of high-risk mutations. All other patients with high or intermediate-2 risk disease, or those harboring high-risk mutations such as ASXL1 or SRSF2, should be considered for stem cell transplant, which is currently the only treatment modality with the potential to favorably modify the natural history of the disease. Non-transplant candidates should be encouraged to participate in clinical trials, since the value of conventional drug therapy, including the use of JAK2 inhibitors, is limited to symptoms palliation and reduction in spleen size. Specifically, JAK2 inhibitors have not been shown to induce complete clinical or cytogenetic remissions or significantly affect JAK2/CALR/MPL mutant allele burden. Splenectomy is considered for drug-refractory splenomegaly. Involved field radiotherapy is most useful for post-splenectomy hepatomegaly, non-hepatosplenic EMH, PMF-associated pulmonary hypertension and extremity bone pain. Am. J. Hematol. 91:1262-1271, 2016. © 2016 Wiley Periodicals, Inc.

EVI1 expression, clinical and cytogenetical characteristics in 447 patients with acute myeloid leukemia

目的分析447例急性髓系白血病（AML）患者EVI1基因的表达及其临床和细胞遗传学特征。方法检测2007年1月至2015年4月收治的447例初诊AML患者的EVI1基因表达水平，分析其临床和细胞遗传学资料以及部分患者的分子学突变资料，总结EVI1基因高表达患者的特征。结果EVI1基因高表达者占17.9%，低表达者占82.1%。两组患者的年龄、性别、外周血血红蛋白水平、白细胞计数、血小板计数差异均无统计学意义；EVI1基因高表达组M0、M5和M6患者比例较低表达组显著增高（P值分别为0.027、0.004和0.011）。在细胞遗传学特征方面，EVI1基因高表达组11p15重排、11q23/MLL重排、3q26重排、−7/7q−以及t (9;11）患者比例较低表达组显著增高（P值分别为<0.001、< 0.001、<0.001、<0.001、0.014）；而正常核型、inv (16）、t (8;21）在EVI1基因低表达组占优势（P值分别为0.001、0.009、0.002）。EVI1基因高表达更多见于细胞遗传学高危组。NPM1突变更倾向分布于EVI1基因低表达组（P<0.001）。EVI1基因高表达组缓解率明显低于低表达组（P<0.001）。异基因造血干细胞移植（allo-HSCT）显著改善EVI1基因高表达者的无白血病生存。结论EVI1基因高表达多见于M5；核型分布中11p15重排、11q23/MLL重排、3q26重排、−7/7q−以及t (9;11）占优势；缓解率低，allo-HSCT能够改善预后。

Acute Myeloid Leukemia with the 11q23 Rearrangement in a Patient with Klinefelter Syndrome

Acute Myeloid Leukemia with the 11q23 Rearrangement in a Patient with Klinefelter Syndrome

Definition of MYC genetic heteroclonality in diffuse large B-cell lymphoma with 8q24 rearrangement and its impact on protein expression

AbstractMYC rearrangement can be detected in a subgroup of diffuse large B-cell lymphoma characterized by unfavorable prognosis. In contrast to Burkitt lymphoma, the correlation between MYC rearrangement and MYC protein expression in diffuse large B-cell lymphoma is less clear, as approximately one-third of rearranged cases show negative or low expression by immunohistochemistry. To better understand whether specific characteristics of the MYC rearrangement may influence its protein expression, we investigated 43 de novo diffuse large B-cell lymphoma positive for 8q24 rearrangement by FISH, using 14 Burkitt lymphoma for comparison. Different cell populations (clones), breakpoints (classical vs non-classical FISH patterns), partner genes (IGH vs non-IGH) and immunostaining were detected and analyzed using computerized image systems. In a subgroup of diffuse large B-cell lymphoma, we observed different clones within the same tumor distinguishing the founder clone with MYC rearrangement alone from other subclones, carrying MYC rearrangement coupled with loss/extra copies of derivatives/normal alleles. This picture, which we defined MYC genetic heteroclonality, was found in 42% of cases and correlated to negative MYC expression (P=0.026). Non-classical FISH breakpoints were detected in 16% of diffuse large B-cell lymphoma without affecting expression (P=0.040). Non-IGH gene was the preferential partner of rearrangement in those diffuse large B-cell lymphoma showing MYC heteroclonality (P=0.016) and/or non-classical FISH breakpoints (P=0.058). MYC heteroclonality was not observed in Burkitt lymphoma and all cases had positive MYC expression. Non-classical FISH MYC breakpoint and non-IGH partner were found in 29 and 20% of Burkitt lymphoma, respectively. In conclusion, MYC genetic heteroclonality is a frequent event in diffuse large B-cell lymphoma and may have a relevant role in modulating MYC expression.

48 - A Variant of inv(3)(q21q26.2) or t(3;3)(q21;q26.2) (MECOM) Rearrangement in AML

Acute myeloid leukemia with inv(3)(q21q26.2) or t(3;3)(q21;q26.2) is a distinct entity recognized by the WHO Classification of Tumors of Haematopoietic Tissue as an aggressive disease with short survival. EVI1 overexpression in AML with 3q rearrangements is frequently driven by its new proximity to an enhancer of the GATA2 gene. We report the cytogenetic analysis of a bone marrow aspirate from a 77 year old man with AML. Karyotype analysis of bone marrow cell G banded metaphases revealed a subtle abnormality in 3q26.2. Analysis with a FISH probe encompassing the entire MECOM (MDS1 and EVI1 complex) locus on chromosome 3q26.2 revealed that this rearrangement was actually an insertion of MECOM into the other chromosome 3 homologue at 3p24 to produce ins(3;3)(p24;q26.2q26.2). The rearrangement was not apparent in a previous karyotype analysis when his disease was described as CMML; its appearance marked the change to a very aggressive form of AML to which he unfortunately succumbed within a few months. The “formerly known as EVI1 locus” actually harbours two transcription start sites and thus has now been renamed MECOM for “MDS1 and EVI1 complex locus” gene. MECOM harbours both a hematopoietic stem cell factor that blocks both myeloid cell differentiation and apoptosis, and a chromatin remodelling activity that promotes cell quiescence and likely contributes to chemotherapy resistance. Both functions present potential targets for therapy. Discussion is underway whether the presence of inv(3)(q21q26.2) or t(3;3)(q21;q26.2) should be used to diagnose AML regardless of blast count and whether other 3q abnormalities such as t(3;12)(q26;p13) EV1/ETV6 fusion or t(3;21)(q26;q22) RUNX1/EVI1 fusion should be classed together in this category. There are likely more chromosome variants of MECOM to be recognized as the function of this locus is better understood.

Перестройки хромосомного района 11q23 при острых миелоидных лейкозах у детей

Aim. To study characteristics of 11q23 involvement, agespecific differences in the incidence of these chromosomal markers in acute myeloid leukemias (AML) in children, and to determine their prognostic significance in patients treated according to the protocols applied in leading Russian pediatric hematological clinics. Methods. The chromosomal analysis of bone marrow and peripheral blood cells has been performed prior to initiation of treatment in 395 children with primary AML aged from 0 to 16 years. The patients were treated in pediatric hematological clinics of Moscow and Moscow Region and in Yekaterinburg District Children's Hospital No. 1. Clinical outcomes of 300 followed-up pediatric patients treated with similar modern therapy protocols were analyzed to evaluate the prognostic impact of 11q23/MLL abnormalities. To determine the incidence of 11q23/MLL rearrangements in AML of different age groups, we examined not only children, but also adult patients (n = 212). Results. In AML, the frequency of changes in the 11q23 region exceeded 40 % in children aged from 0 to 2 years. The frequency decrease with age and in patients over 40 years it was only 2 %. Significant heterogeneity of changes in karyotypes with 11q23/MLL rearrangements was observed: both various translocations with different regions of other chromosomes, and 11q23 deletions were detected. In addition, a great variability of numerical and structural additional chromosomal abnormalities was observed. The 10-year relapse-free survival rates (30.4 ± 6.7 %) and overall survival rates (35.1 ± 7.0 %) in AML with changes in the 11q23 region (n = 61) were significantly lower than those in patients from the intermediate risk group (n = 103): 48.9 ± 5.8 % and 43.8 ± 7.5 %, respectively (p = 0.035). The data are close to those in the high-risk group (n = 44): 35.9 ± 8.1 % and 38.3 ± 7.6 %, respectively. The study failed to confirm the published data that t(9; 11) is a more favorable prognostic factor, and that t(6; 11) and t(10; 11) are less favorable ones than all other 11q23 translocations. Our results did not confirm a negative prognostic effect of additional chromosome abnormalities associated with 11q23 rearrangements. Conclusion. Pediatric AML patients with 11q23 abnormalities should be included in a high-risk group if therapy is performed according protocols applied in leading hematological centers of Russia.

Genetic aberrations in multiple myeloma characterized by cIg-FISH: a Brazilian context.

Genetic abnormalities are critical prognostic factors for patients diagnosed with multiple myeloma (MM). This retrospective, multicenter study aimed to contribute with the genetic and clinical characterization of MM patients in a country with continental dimensions such as Brazil. Genetic abnormalities were assessed by cIg-fluorescent in situ hybridization (cIg-FISH) in a series of 152 MM patients (median age 55 years, 58.5% men). Overall, genetic abnormalities were detected in 52.7% (80/152) of patients. A 14q32 rearrangement was detected in 33.5% (n=51), including t(11;14), t(4;14) and t(14;16) in 18.4, 14.1, and 1% of cases, respectively. del(13q) was identified in 42.7% (n=65) of patients, of whom 49.2% (32/65) presented a concomitant 14q32 rearrangement. del(17p) had a frequency of 5.2% (n=8). del(13q) was associated with high plasma cell burden (≥50%, P=0.02), and del(17p) with advanced ISS stages (P=0.05) and extramedullary disease (P=0.03). t(4;14) was associated with advanced Durie-Salmon stages (P=0.008), renal insufficiency (P=0.01) and was more common in patients over 60 years old. This study reports similar frequencies of genetic abnormalities to most series worldwide, whereas the t(14;16) and del(17p), two high risk factors for newly diagnosed patients, exhibited lower frequencies. Our results expand the knowledge on the molecular features of MM in Brazil, a country where innovative therapies that could overcome a poor prognosis for some genetic abnormalities are not always available.

Impact of Cytogenetics on Outcome of AML after Allogeneic Hematopoietic Stem Cell Transplantation

Background. Chromosomal abnormalities (CA) are the most prognostic factor in acute myeloid leukemia (AML). However, it is still not clear whether the cytogenetic risk groups established for patients (pts), treated by standard chemotherapy, are so optimal for pts undergoing allogeneic hematopoietic stem cell transplantation (alloHSCT). Recent studies have confirmed negative effects of both monosomal and complex karyotypes (MK, CK) on outcomes after alloHSCT [1,2]. Meantime, some investigators consider that immune effects of alloHSCT can reduce negative impact of these CA [3].Aim. To evaluate impact of the CA in AML pts with adverse cytogenetic risk group on outcome after alloHSCT.Material and Methods. In this study, outcomes of alloHSCT, which were performed in a single institution between 2009 and 2014 years for 97 AML pts have been analyzed. Patients and transplantation characteristics are presented in Table I. The probabilities of overall survival (OS), leukemia free survival (LFS), cumulative incidence of relapse (CIR) were evaluated for different cytogenetic groups.Results. According to univariateanalysis, the probabilities of 4-year OS in pts with 5q-, KMT2A translocations and monosomy 7 were 66%, 59% and 56%, respectively. At the same time, OS in pts with CK, 7q- and 3q26 rearrangements were lower i.e. 33%, 25% and 25%, respectively (p=0.01). Multivariate analysis showed, that clinical stage at HSCT, age and HSC source are independent predictors of OS in AML pts (Table 2). Four-year LFS were various in pts with different CA. The higher LFS was noted in pts with 5q- and KMT2A translocations (66% and 52%, respectively), whereas lower LFS were in pts with 3q26 rearrangements, CK, monosomy 7 and 7q- (0, 18%, 23% and 37%, respectively) (Fig. 1). Besides, LFS distinguished between groups with CK+ and CK- (18% vs 41%, p=0.008), as well as with MK+ and MK- (17% vs 30%, p=0.04). Multivariate analysis evidenced clinical stage at HSCT, cytogenetic groups, MK and number of transplanted CD34+ cells to be independent predictor of LFS in AML pts (Table 2).Cumulative incidence of relapses in pts transplanted in remission (n=42) was higher in those with CK+ (55% vs 14%, p=0.03) and MK+ (75% vs 31%, p=0.013).Discussion. The study showed that 4-year OS in AML pts with 5q-, KMT2A translocations and monosomy 7 significantly distinguished from those with CK, 7q- and 3q26 rearrangements. Furthermore, OS depended on clinical stage at HSCT, patient's age and HSC source. On the other hand, EFS differed from all above-mentioned cytogenetic groups, including MK. Finally EFS depended on clinical stage at HSCT and number of transplanted CD34+ cells.Conclusion. On the basis of this data, a conclusion may be drawn that alloHSCT in AML pts with adverse CA should be performed at complete remission, with bone marrow as HSC source and enough number of transplanted CD34+ cells.Reference.1. Hemmatti et al. Eur J Haematol. 2013; 92:102-10.2. Fang et al. Blood 2011; 118:1490-4.3. Guo et al. Biol Blood Marrow Transplant 2014; 20: 690-5.Table 1Patients and Transplant characteristicsPatients, n (%)97 (100)Gender, n (%)MaleFemale53 (54.6)44 (45.4)Age at HSCT, median, (range) years25 (1.5-60)Cytogenetics, n (%) 3q26 rearrangementsDeletion 5q (sole)Monosomy 7 (sole)Deletion 7q (sole)KMT2A translocationComplex karyotype ³3 CA Monosomal karyotype4 (4)10 (10.3)12 (12.4)4 (4)11 (11.3)56 (58)18 (18.5)Time from diagnosis to HSCT, median (range) days477 (47 - 3482)Clinical stage at HSCT, n (%)CR1³CR2Active disease29 (30)13 (13)55 (57)HSC source, n (%)Bone marrowPeripheral bloodBM+PB54 (56)34 (35)9 (9)Conditioning regimen, n (%)MANon-MA35 (36)62 (64)Donor type, n (%)HLA-id siblingMatched unrelatedHaploidentical17 (17.5)53 (54.6)27 (27.8)Number of transplanted CD34+ cellsmedian (range), x106/kg6.1 (1.5-17.9)Table 2Multivariate analysesHR95% CIPOverall survivalClinical stage at HSCT2.651.72-4.090.00001Median age<18 years)2.051.05-3.990.034HSC source1.661.12-2.450.011Cytogeneticgroups1.720.81-3.660.15Median number of transplanted CD34+ cells>6x106/kg1.770.91-3.420.08Leukemia-free survivalClinical stage at HSCT2.591.8-3.70.0001Cytogeneticgroups1.311.03-1.690.031Monosomal karyotype1.880.97-3.660.044Median number of transplanted CD34+ cells>6x106/kg2.781.51-5.110.0003 [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Differential Regulation of c-Myc/Lin28 Discriminates Subclasses of Rearranged MLL Leukemia

Rearrangements of the 11q23 locus account for ~70% of infant ALL and ~50% of infant AML1 and about 10% of leukemia overall. The prognosis for 11q23 patients is generally poor, however, outcomes vary depending on the fusion partner2. Rearrangements fuse the N-terminus of MLL with one of >70 different partner genes that includes both nuclear and cytoplasmic proteins. Despite the different intracellular localization of these partner proteins, to date, all studied MLL fusion proteins (MLL-FPs) localize to chromatin in the nucleus and drive aberrant transcriptional activation. Recent seminal work by a number of groups has revealed that several of the most common nuclear translocation partner genes (including AF9, ENL, AFF1 (AF4), AFF4 (AF5q31), AF10, AF17 and ELL) assemble into a transcriptional activation complex that includes p-TEFb and/or the histone H3K79 methyltransferase DOT1l. Translocation of MLL with members of this complex results in deregulated transcriptional activation of target genes. Conversely, oligomerization motifs are necessary for transformation following 11q23 translocation with a cytoplasmic partner. However, these mechanisms fail to explain different survival outcomes observed in patients. Further, the transcriptional programs induced in these diverse 11q23 leukemias are currently not well understood. In this study, we examined the genome wide expression profiles in leukemic cells transformed by several MLL-FPs representative of nuclear translocations [t(9;11) (MLL-AF9), t(10;11) (MLL-AF10) and t(11;19) (MLL-ENL)] or cytoplasmic translocations [t(1;11) (MLL-AF1p), t(6;11) (MLL-AF6) and t(11;17) (MLL-Gas7)]. Leukemia cell lines established from mouse bone marrow cells expressing these MLL-FPs proliferated at different rates and mice transplanted with the transformed cells develop leukemia with different latencies remarkably consistent with differences observed in patients harboring different MLL translocations. To elucidate differences in the gene programs induced by different MLL-FPs we performed genome wide expression profiling by RNA-sequencing. These data demonstrated that while the MLL-AF9 and MLL-ENL fusion proteins induce very similar gene programs, the cytoplasmic fusion proteins (MLL-AF6, MLL-AF1p and MLL-GAS7) all possess unique gene signatures. We then performed a pathway analysis comparing nuclear fusion proteins and cytoplasmic fusion proteins and discovered the Myc transcription factor program as one of the top distinguishing features. Myc overexpression significantly increased the growth rate of slow-growing cells that also had low intrinsic Myc, while the growth rate change of more highly proliferative cells was minimal. While all leukemic cell lines were sensitive to the BET inhibitor JQ1 which regulates c-Myc expression, greater sensitivity was observed in those with low c-Myc expression demonstrating the universal importance of this gene program. The Myc target and micro RNA binding protein Lin28B is also differentially expressed between nuclear and cytoplasmic fusions. Negative regulation of miR-150 by Lin28B was observed in all MLL-FP cell lines, which is necessarily downregulated in 11q23 leukemias. We then investigated another Lin28B microRNA target let-7. Interestingly, let-7g expression was significantly increased in MLL-FP transformed cells associated with the longest disease latency. These data demonstrate that differential activation of the c-Myc/Lin28 program accounts for changes in let-7g expression and is associated with MLL-FP disease latency. These data also suggest that patients harboring different 11q23 rearrangements will respond differentially to therapeutic targeting of c-Myc expression dependent on fusion partner.

Tumor Vs Normal Gene Expression Profiles Identify Deregulated Pathways in ETV6/RUNX1 Positive Acute Lymphoblastic Leukemia: A Microarray-Based Meta-Analysis

Acute lymphoblastic leukemia (ALL), a clinically and biologically heterogeneous disease, is the most common type of childhood cancer. Approximately 25% of B-cell precursor ALL (BCP-ALL) carry the cryptic chromosomal translocation t(12;21)(p13;q22), the most frequent genetic aberration in pediatric ALL. This translocation combines two transcription factors and essential regulators of normal hematopoiesis, ETV6 and RUNX1, generating the fusion oncogene ETV6/RUNX1 (synonym TEL/AML1). Recent studies in various animal models have strengthened the view that ETV6/RUNX1 positive cells give rise to preleukemic clones with a differentiation block in the pro/pre-B stage of B cell development that, after acquisition of additional mutations, may transform into full malignancy. However, the effects triggered by the expression of ETV6/RUNX1 and the associated additional mutated genes are not well understood.We compared global gene expression data from ETV6/RUNX1 positive ALL and normal hematopoietic progenitor cells to identify expression signatures underlying the malignant phenotype. Our meta-analysis comprised Affymetrix HG-U133A und HG-U133 Plus 2.0 data from a total of 321 patients with ETV6/RUNX1 positive ALL, different ETV6/RUNX1 positive cell models, leukemias with 11q23 rearrangements and hyperdiploid ALL, as well as 251 samples from various normal controls including normal bone marrow, hematopoietic stem cells (HSCs) and normal B-(progenitor) cells (multipotent progenitor, pro-, pre-, immature-, naive-, centrocyte-, centroblast-, memory-, plasmablast-B cells). To eliminate potential lab batch effects, we performed RMA normalization of all microarray CEL files and next applied the batch effect removal algorithm ComBat. For determination of differentially expressed genes and pathway analyses, the R/Bioconductor packages limma and SPIA were used, respectively.We generated a gene expression landscape of the normal B-cell development and were able to show that pre-B cells are the closest normal counterpart of ETV6/RUNX1 positive ALL. Furthermore, in comparisons with normal HSCs the p53-, mTOR-, PI3K-AKT-, Apoptosis-, and JAK-STAT signaling pathways were found to be deregulated in those ALL. The combination of multiple global gene expression data sets from ETV6/RUNX1 positive ALL offers the possibility of an integrated large-scale meta-analysis and reveals novel insights into deregulated gene networks in this type of leukemia. DisclosuresNo relevant conflicts of interest to declare.

Post-Remission Treatment with Chemotherapy or Allogeneic Hematopoietic Stem Cell Transplantation (alloHSCT) of High-Risk (HR) Philadelphia Chromosome-Negative (Ph-neg) Adult Acute Lymphoblastic Leukemia (ALL) According to Minimal Residual Disease (MRD). Preliminary Results of the Pethema ALL-HR-11 Trial

▪Introduction: Recent studies have shown that young to middle-aged adults who receive a pediatric-inspired chemotherapy regimen for treatment of Ph-neg ALL do not appear to require an alloHSCT if they achieve good response on MRD testing after induction therapy. Patients (pts) who are not good MRD responders achieve better outcomes with alloHSCT than their counterparts who do not receive alloHSCT. However, it is not clear if this approach can be translated to adult ALL pts with HR features at baseline. The aim of the prospective ALL-HR-11 trial from the Spanish PETHEMA Group was to evaluate the response to a differentiated post-induction therapy (chemotherapy or alloHSCT) according to MRD levels (assessed by 8-color, centrally-performed flow cytometry at the end of induction-week 5- and consolidation therapy-week 17-) in HR Ph-neg adult ALL patients. Patients and methods: HR ALL included one or more of the following parameters at baseline: age 30-60 yr, WBC count >30x109/L for B-cell precursor ALL or >100x109/L for thymic T-ALL, pro-B, early or mature T-ALL, 11q23 or MLL rearrangements or complex karyotype. Induction therapy included vincristine, prednisone, daunorubicin and asparaginase (E coli native or PEG according to center availability) for 4 weeks (Induction-1). FLAG-Ida was administered as intensified induction (Induction-2) in pts not achieving CR or those in CR with MRD≥0.1% at the end of induction. For pts in CR and MRD<0.1% early consolidation therapy included 3 cycles with rotating cytotoxic drugs with high-dose methotrexate, high-dose ARA-C and high-dose asparaginase (E coli native or PEG). These pts continued with delayed consolidation (identical to that of early consolidation) followed by maintenance therapy up to 2 yr. in CR if MRD levels after consolidation were <0.01%, otherwise they were assigned to alloHSCT. Pts in CR after Induction-2 received one consolidation cycle and were assigned to alloHSCT. Results: On June 2015, 115 HR ALL pts were evaluable [mean (SD) age 38(13) yr, 67 males, 80/114 precursor B-ALL, 34/114 T-ALL, WBC count 56(96) x109/L]. Results of Induction-1: therapy-related death: 4(4%), resistance: 11 (10%), CR: 95(86%). MRD<0.1% at the end of induction was observed in 75% of CR patients. Induction-2 was administered to 33 patients (no CR: 11, CR and MRD≥0.1%: 22). No differences in the CR rate or in the rate of MRD clearance after induction were observed according to the type of asparaginase administered, although significantly increased hepatic toxicity in consolidation was observed in patients treated with PEG-asparaginase. The 2-yr DFS and OS probabilities for whole series were 51%±18% and 62%±13%. By intention-to treat after Induction-1 36 pts were assigned to alloHSCT and 68 to delayed consolidation and maintenance. The 2-yr DFS and OS probabilities were 54%±25% and 49%±20%, respectively, for pts assigned to alloHSCT, and 50%±22% and 73%±17%, respectively, for those assigned to chemotherapy (P =0.002 for OS comparison). Patients with MRD<0.1% at the end of induction and <0.01% at the end of consolidation (n=51) showed a 2-yr DFS and OS of 55%±25% and 81%±18%, respectively. Conclusions: The preliminary results of this trial, in which the post-induction therapy decision is only based on MRD results, suggest that in HR, Ph-neg adult ALL pts with adequate MRD response after induction and after consolidation the results of therapy are not hampered by avoiding alloHSCT. Supported by grants RD12/0036/0029 (RTICC, FEDER), PI14/01971 FIS, Instituto Carlos III, and SGR225 (GRE), Spain DisclosuresNo relevant conflicts of interest to declare.

T(3;8)(q26;q24) With MYC Rearrangement in Acute Myeloid Leukemia: A Case Report

Rearrangements of 3q26 have been described in 5% of de novo or therapy-related acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and blast phase of chronic myeloid leukemia. The most common translocations involving 3q26 are t(3;12)(q26;p13), t(3;21)(q26;q22), t(3;3)(q21;q26), t(2;3)(p15∼23;q26∼27), and rarely, t(3;7)(q26;q21). However, t(3;8)(q26;q24) with or without monosomy 7 is …

Influence of CD117 Expression on Response of Multiple Myeloma Patients to Chemotherapy

To investigate the influence of CD117 expression on response of multiple myeloma patients to chemo-therapy. A total of 65 cases of newly diagnosed multiple myeloma in our hospital from 2011 to 2013 were enrolled in this study. Cytogenetic abnormalities and immunophenotype were detected by using fluorescence in situ hybridization and flow cytometry before chemotherapy. The therapeutic efficacy of patients was evaluated after 4 cycles of PAD or TAD regimen. The positive rates of 1q21 amplification, RB1: 13q14 deletion, D13S319: 13q14.3 deletion, IgH: 14q32 rearrangement and p53: 17p13 deletion were 32.2%, 40%, 40%, 20% and 3.1% respectively; the positive rates of CD38, CD138, CD56, CD117, CD20 were respectively 100%, 100%, 60%, 20%, 10.8%; the positive rates of CD19 and CD10 were 4.6% and 4.6% respectively; the positive CD22, CD7, CD5, CD103 did not found in any patients. The therapeutic efficacy of CD117⁻ patients was better than that of CD117⁺ patients (P < 0.05), there was no correlation of the remaining indicators with efficacy; the proportion of CD117⁺ patients with β2-microglobulin ≥ 5.5 mg/L was significantly higher than that of CD117⁻ patients (P < 0.05); the rest of baseline data had no significant difference (P > 0.05). CD117 can be used as an indicator for evaluating efficacy of patients with newly diagnosed multiple myeloma.