Showing papers by "Guillermo Garcia-Manero published in 2013"
TL;DR: The combination of AZA and sorafenib is effective for patients with relapsed AML and FLT-3-ITD and sixty-four percent of patients achieved adequate FLT3 inhibition during their first cycle of therapy.
356 citations
Harvard University1, University of South Florida2, Center for International Blood and Marrow Transplant Research3, Fred Hutchinson Cancer Research Center4, University of Texas MD Anderson Cancer Center5, University of Pavia6, University of Paris7, Karolinska Institutet8, Imperial College London9, Celgene10, Stanford University11, Memorial Sloan Kettering Cancer Center12, Washington University in St. Louis13, University of Ulm14, University of Minnesota15
TL;DR: For patients with de novo MDS aged 60 to 70 years, favored treatments vary with IPSS risk, and RIC transplantation offers overall and quality-adjusted survival benefit.
Abstract: Purpose Myelodysplastic syndromes (MDS) are clonal hematopoietic disorders that are more common in patients aged ≥ 60 years and are incurable with conventional therapies. Reduced-intensity conditioning (RIC) allogeneic hematopoietic stem-cell transplantation is potentially curative but has additional mortality risk. We evaluated RIC transplantation versus nontransplantation therapies in older patients with MDS stratified by International Prognostic Scoring System (IPSS) risk. Patients and Methods A Markov decision model with quality-of-life utility estimates for different MDS and transplantation states was assessed. Outcomes were life expectancy (LE) and quality-adjusted life expectancy (QALE). A total of 514 patients with de novo MDS aged 60 to 70 years were evaluated. Chronic myelomonocytic leukemia, isolated 5q– syndrome, unclassifiable, and therapy-related MDS were excluded. Transplantation using T-cell depletion or HLA-mismatched or umbilical cord donors was also excluded. RIC transplantation (n = 13...
223 citations
TL;DR: In this paper, a review of existing knowledge of the oncogenic functions of Nrf2 is presented to provide a solid basis for its potential use as a molecular marker and pharmacological target in cancer.
178 citations
TL;DR: Findings indicate that TLR2-centered signaling is deregulated in MDS, and that its targeting may have potential therapeutic benefit in M DS.
Abstract: Recent studies have implicated the innate immunity system in the pathogenesis of myelodysplastic syndromes (MDS). Toll-like receptor (TLR) genes encode key innate immunity signal initiators. We recently identified multiple genes, known to be regulated by TLRs, to be overexpressed in MDS bone marrow (BM) CD34+ cells, and hypothesized that TLR signaling is abnormally activated in MDS. We analyzed a large cohort of MDS cases and identified TLR1, TLR2 and TLR6 to be significantly overexpressed in MDS BM CD34+ cells. Deep sequencing followed by Sanger resequencing of TLR1, TLR2, TLR4 and TLR6 genes uncovered a recurrent genetic variant, TLR2-F217S, in 11% of 149 patients. Functionally, TLR2-F217S results in enhanced activation of downstream signaling including NF-κB activity after TLR2 agonist treatment. In cultured primary BM CD34+ cells of normal donors, TLR2 agonists induced histone demethylase JMJD3 and interleukin-8 gene expression. Inhibition of TLR2 in BM CD34+ cells from patients with lower-risk MDS using short hairpin RNA resulted in increased erythroid colony formation. Finally, RNA expression levels of TLR2 and TLR6, as well as presence of TLR2-F217S, are associated with distinct prognosis and clinical characteristics. These findings indicate that TLR2-centered signaling is deregulated in MDS, and that its targeting may have potential therapeutic benefit in MDS.
135 citations
TL;DR: In this phase II study, low-dose decitabine showed promising results in patients with low- or intermediate-1-risk MDS, and was terminated early on achievement of protocol-defined OIR superiority of schedule A over schedule B.
Abstract: Purpose This open-label, randomized phase II trial assessed efficacy and tolerability of two low-dose regimens of subcutaneous (SC) decitabine in patients with low- or intermediate-1–risk myelodysplastic syndrome (MDS). Patients and Methods Patients received decitabine 20 mg/m2 SC per day for 3 consecutive days on days 1, 2, and 3 every 28 days (schedule A) or 20 mg/m2 SC per day once every 7 days on days 1, 8, and 15 every 28 days (schedule B) for up to 1 year. Primary efficacy end point was overall improvement rate (OIR: complete remission [CR], partial remission [PR], marrow CR [mCR], or hematologic improvement [HI]). Secondary end points were HI, transfusion independence, cytogenetic response, overall survival (OS), and time to acute myeloid leukemia or death. Results Efficacy and safety populations were identical: schedule A, n = 43; schedule B, n = 22. Median time from MDS diagnosis to treatment was 3.6 months; 89% had de novo MDS. The trial was terminated early on achievement of protocol-defined OI...
97 citations
TL;DR: FMS‐like tyrosine kinase III (FLT3) mutations occur in myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML) at a lower frequency than AML and does not predict poor outcome.
Abstract: FMS-like tyrosine kinase III (FLT3) mutations occur in one-third of acute myeloid leukemia (AML) patients and predict poor outcome. The incidence and impact of FLT3 in myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML) is unknown. We conducted a retrospective review to identify WHO MDS and CMML patients with FLT3 mutations at diagnosis. A total of 2,119 patients with MDS and 466 patients with CMML were evaluated at MD Anderson between 1997 and 2010. Of these, FLT3 mutation analysis was performed on 1,232 (58%) MDS and 302 (65%) CMML patients. FLT3 mutations were identified in 12 (0.95%) MDS patients: 9 (75%) had FLT3-ITD mutation and 3 had FLT3-tyrosine kinase domain (TKD) mutation. MDS patients with FLT3 mutations were younger (P = 0.02) and presented as RAEB (P = 0.03) more frequently. Median overall survival (OS) for FLT3-mutated MDS patients was 19.0 months versus 16.4 months for FLT3-nonmutated MDS patients (P = 0.08). FLT3 mutations were identified in 13 (4.3%) CMML patients: 8 had FLT3-ITD mutation and 5 had FLT3-TKD mutation. There were no significant differences in demographic and disease characteristics among CMML patients with and without FLT3 mutations. Median OS for FLT3-mutated CMML patients was 10.8 months versus 21.3 months for FLT3-nonmutated CMML patients (P = 0.12). FLT3 occurs in MDS and CMML at a lower frequency than AML and does not predict poor outcome.
83 citations
TL;DR: Data indicate the deregulation of H3K4me3 and associated abnormal activation of innate immunity signals have a role in the pathogenesis of MDS and that targeting these signals may have potential therapeutic value in MDS.
Abstract: The molecular bases of myelodysplastic syndromes (MDS) are not fully understood. Trimethylated histone 3 lysine 4 (H3K4me3) is present in promoters of actively transcribed genes and has been shown to be involved in hematopoietic differentiation. We performed a genome-wide H3K4me3 CHIP-Seq (chromatin immunoprecipitation coupled with whole genome sequencing) analysis of primary MDS bone marrow (BM) CD34+ cells. This resulted in the identification of 36 genes marked by distinct higher levels of promoter H3K4me3 in MDS. A majority of these genes are involved in nuclear factor (NF)-κB activation and innate immunity signaling. We then analyzed expression of histone demethylases and observed significant overexpression of the JmjC-domain histone demethylase JMJD3 (KDM6b) in MDS CD34+ cells. Furthermore, we demonstrate that JMJD3 has a positive effect on transcription of multiple CHIP-Seq identified genes involved in NF-κB activation. Inhibition of JMJD3 using shRNA in primary BM MDS CD34+ cells resulted in an increased number of erythroid colonies in samples isolated from patients with lower-risk MDS. Taken together, these data indicate the deregulation of H3K4me3 and associated abnormal activation of innate immunity signals have a role in the pathogenesis of MDS and that targeting these signals may have potential therapeutic value in MDS.
76 citations
TL;DR: Adding romiplostim to decitabine treatment is well tolerated and may be beneficial, as indicated by trends toward higher platelet counts at the beginning of each treatment cycle and lower platelet transfusion rates and percentages of patients with bleeding events.
Abstract: Patients with myelodysplastic syndrome (MDS) receiving hypomethylating agents commonly develop thrombocytopenia. This double-blind study evaluated the efficacy and safety of romiplostim, a peptibody protein that increases platelets, in patients with MDS receiving decitabine. Patients received romiplostim 750 μg (n = 15) or placebo (n = 14) and decitabine. Median platelet counts at the beginning of each decitabine cycle trended lower in placebo-treated than in romiplostim-treated patients. Bleeding events occurred in 43% of placebo-treated and 27% of romiplostim-treated patients, and platelet transfusions were administered to 57% of placebo-treated and 47% of romiplostim-treated patients. Overall clinical therapeutic response was achieved by 21% of placebo-treated and 33% of romiplostim-treated patients. Treatment was generally well tolerated. Progression to acute myeloid leukemia (AML) occurred in one patient per group. Adding romiplostim to decitabine treatment is well tolerated and may be beneficial, as indicated by trends toward higher platelet counts at the beginning of each treatment cycle and lower platelet transfusion rates and percentages of patients with bleeding events.
67 citations
TL;DR: It is concluded that HUM-195/rGel can be safely administered in a multi-dose cycle to patients with advanced myeloid malignancies and warrants further investigation.
Abstract: We conducted a phase 1 study of an anti-CD33 immunotoxin, humanized monoclonal antibody M195 conjugated to recombinant gelonin (HUM-195/rGEL), in patients with relapsed, refractory myeloid leukemias. Twenty-eight patients received the construct intravenously at four dose levels (12, 18, 28 and 40 mg/m2 per course) in a “3+3” study design. The dose-limiting toxicity was infusion-related allergic reaction including hypoxia and hypotension. The 28 mg/m2 total dose was considered the maximally tolerated dose. Four patients developed a reduction in peripheral blood blasts of at least 50%. Three patients treated with the 10, 12 and 28 mg/m2 doses showed a 38-50% reduction in bone marrow blasts. There was normalization of platelets in one patient treated with 40 mg/m2. Pharmacokinetic analysis demonstrated that the highest blood levels achieved were 200-300 ng/mL which cleared with a half-life of ∼20 hours. Antigenicity was low with one patient at the 12 mg/m2 dose and one patient at the 18 mg/m2 dose (2/23, <10%) developing antibodies to the recombinant gelonin component after 28 days. We concluded that HUM-195/rGel can be safely administered in a multi-dose cycle to patients with advanced myeloid malignancies and warrants further investigation.
66 citations
TL;DR: The results indicate that MYD88 plays a role in the pathobiology of MDS and may have prognostic and therapeutic value in the management of patients with this disease.
Abstract: MYD88 is a key mediator of Toll-like receptor innate immunity signaling. Oncogenically active MYD88 mutations have recently been reported in lymphoid malignancies, but has not been described in MDS. To characterize MYD88 in MDS, we sequenced the coding region of the MYD88 gene in 40 MDS patients. No MYD88 mutation was detected. We next characterized MYD88 expression in bone marrow CD34+ cells (N=64). Increased MYD88 RNA was detected in 40% of patients. Patients with higher MYD88 expression in CD34+ cells had a tendency for shorter survival compared to the ones with lower MYD88, which was significant when controlled for IPSS and age. We then evaluated effect of MYD88 blockade in the CD34+ cells of patients with lower-risk MDS. Colony formation assays indicated that MYD88 blockade using a MYD88 inhibitor resulted in increased erythroid colony formation. MYD88 blockade also negatively regulated the secretion of interleukin-8. Treatment of MDS CD34+ cells with an IL-8 antibody also increased formation of erythroid colonies. These results indicate that MYD88 plays a role in the pathobiology of MDS and may have prognostic and therapeutic value in the management of patients with this disease.
62 citations
TL;DR: At the 18‐ and 24‐month landmark analysis, patients achieving UND have no advantage in TFS and OS compared to those achieving a lesser degree of MR, and achieving susMR4·5 does not appear to further reduce the risk of transformation or death.
Abstract: Most patients with chronic myeloid leukemia (CML) in chronic phase (CP) treated with tyrosine kinase inhibitors (TKI) achieve complete cytogenetic response (CCyR). An increasing number of patients also achieve deep molecular responses (MR). We determined the frequency and significance of deep MR after TKI therapy for CML in CP. MR included: major molecular response (MMR), MR4, MR4.5, and undetectable transcripts (UND), i.e., BCR-ABL/ABL of ≤0.1, ≤0.01, ≤0.0032%, and undetectable transcripts, respectively. Four hundred eighty-three patients received imatinib 400 mg/day (IM400, 71, July 2000 to April 2001), imatinib 800 mg/day (IM800, 204, June 2001 to July 2005), nilotinib (106, July 2005 to date), or dasatinib (102, November 2005 to date). UND rates at 36 months were 18.1, 30.6, 29.2, and 28.6%, respectively. Patients achieving UND have superior transformation-free survival (TFS) and overall survival (OS) versus those obtaining ≤MMR, but not other MR levels. At the 18- and 24-month landmark analysis, patients achieving UND have no advantage in TFS and OS compared to those achieving a lesser degree of MR. Among patients achieving MR4.5, those who maintain it for ≥2 years (susMR4·5) have no additional benefit in TFS or OS. Most patients with early CP CML receiving TKI achieve MMR. BCR-ABL transcripts become undetectable in a significant fraction of them. Deeper MR at 18 or 24 months are not associated with a benefit in TFS or OS. Furthermore, achieving susMR4·5 does not appear to further reduce the risk of transformation or death. Am. J. Hematol. 88:1024–1029, 2013. © 2013 Wiley Periodicals, Inc.
TL;DR: NRAS mutations with low allele burden have independent prognostic significance for patients with lower risk myelodysplastic syndromes.
Abstract: NRAS mutations with low allele burden have independent prognostic significance for patients with lower risk myelodysplastic syndromes
TL;DR: Questions remain regarding the role of the microenvironment, which may or may not facilitate the survival and proliferation of EML, and the implications of these interactions with regard to minimal residual disease, tumor cell quiescence and relapse, and prospective studies of detection and characterization of E ML in patients with AML are warranted.
Abstract: Extramedullary manifestations of acute myeloid leukemia (AML) were described as early as the 19th century. However, the incidence, clinical significance and pathobiology of extramedullary AML remain ill defined. We reviewed case reports, retrospective case series, pilot studies and imaging studies of extramedullary leukemia (EML) to determine its frequency, characteristics, clinical presentation and significance. EML precedes or accompanies development of AML and occurs during or following treatment, even during remission. Although imaging studies are rarely conducted and the true incidence of EML has yet to be verified, authors have reported several estimates based on retrospective and autopsy studies. The incidence of EML in patients with AML of all ages is estimated to be about 9% and EML in children with AML was detected in 40% of patients at diagnosis. The combination of positron emission tomography and computed tomography were the most sensitive and reliable techniques of detecting and monitoring EML. Based on our literature review, the frequency of EML is likely underreported. The well-documented nature of EML in patients with AML suggests that AML can manifest as a solid tumor. The extent to which EML accompanies AML and whether EML is derived from bone marrow are unknown. Furthermore, questions remain regarding the role of the microenvironment, which may or may not facilitate the survival and proliferation of EML, and the implications of these interactions with regard to minimal residual disease, tumor cell quiescence and relapse. Therefore, prospective studies of detection and characterization of EML in patients with AML are warranted.
TL;DR: It is suggested that compared with de novo CMML, t-CMML is associated with more high-risk cytogenetics that manifest as poor outcomes and should be recognized as one of the therapy-related myeloid neoplasms.
TL;DR: CIA is an effective and safe therapy for patients ≤60 years with newly diagnosed AML and retained its favorable impact on OS compared to IA, in multivariate analysis.
Abstract: Clofarabine is a second generation nucleoside analogue with activity in adults with acute myeloid leukemia (AML). A phase I trial of clofarabine, idarubicin, and cytarabine (CIA) in relapsed and refractory AML had shown an overall response rate (ORR) of 48%. To explore this combination further, we conducted a phase II study of (CIA) in patients with newly diagnosed AML ≤60 years. Patients ≥18–60 years with AML and adequate organ function were enrolled. Induction therapy consisted of clofarabine (C) 20 mg m−2 IV daily (days 1–5), idarubicin (I) 10 mg m−2 IV daily (days 1–3), and cytarabine (A) 1 g m−2 IV daily (days 1–5). Patients in remission received up to six consolidation cycles (C 15 mg m−2 × 3, I 8 mg m−2 × 2, and A 0.75 g m−2 × 3). Fifty-seven patients were evaluable. ORR was 79%. With a median follow up of 10.9 months, the median overall survival (OS) was not reached, the median event-free survival (EFS) was 13.5 months. Most toxicities were ≤grade 2. Four week mortality was 2%. In subgroup analysis, patients ≤40 years had better OS (P = 0.04) and EFS (P = 0.04) compared to patients >40 years. Compared to historical patients treated with idarubicin and cyarabine (IA), the OS and EFS were significantly longer for CIA treated patients. In multivariate analysis, CIA retained its favorable impact on OS compared to IA. Thus, CIA is an effective and safe therapy for patients ≤60 years with newly diagnosed AML. Am. J. Heamtol. 88:961–966, 2013. © 2013 Wiley Periodicals, Inc.
TL;DR: Data suggest that epigenetic modifications are implicated in silencing of tumor suppressor of Notch/Hes pathway in B-ALL.
Abstract: The Notch pathway can have both oncogenic and tumor suppressor roles, depending on cell context. For example, Notch signaling promotes T cell differentiation and is leukemogenic in T cells, whereas it inhibits early B cell differentiation and acts as a tumor suppressor in B cell leukemia where it induces growth arrest and apoptosis. The regulatory mechanisms that contribute to these opposing roles are not understood. Aberrant promoter DNA methylation and histone modifications are associated with silencing of tumor suppressor genes and have been implicated in leukemogenesis. Using methylated CpG island amplification (MCA)/DNA promoter microarray, we identified Notch3 and Hes5 as hypermethylated in human B cell acute lymphoblastic leukemia (ALL). We investigated the methylation status of other Notch pathway genes by bisulfite pyrosequencing. Notch3, JAG1, Hes2, Hes4 and Hes5 were frequently hypermethylated in B leukemia cell lines and primary B-ALL, in contrast to T-ALL cell lines and patient samples. Aberrant methylation of Notch3 and Hes5 in B-ALL was associated with gene silencing and was accompanied by decrease of H3K4 trimethylation and H3K9 acetylation and gain of H3K9 trimethylation and H3K27 trimethylation. 5-aza-2′-deoxycytidine treatment restored Hes5 expression and decreased promoter hypermethylation in most leukemia cell lines and primary B-ALL samples. Restoration of Hes5 expression by lentiviral transduction resulted in growth arrest and apoptosis in Hes5 negative B-ALL cells but not in Hes5 expressing T-ALL cells. These data suggest that epigenetic modifications are implicated in silencing of tumor suppressor of Notch/Hes pathway in B-ALL.
TL;DR: It is hypothesized that the dynamic acquisition of cytogenetic abnormalities during the follow up of myelodysplastic syndromes (MDS) could be associated with poor prognosis, and it is shown that ACA occurs in close to one third of patients with IPSS defined lower risk MDS, more common among patients with t‐MDS, but has a significant prognostic impact on de novo MDS.
Abstract: We hypothesized that the dynamic acquisition of cytogenetic abnormalities (ACA) during the follow up of myelodysplastic syndromes (MDS) could be associated with poor prognosis. We conducted a retrospective analysis of 365 patients with IPSS low or intermediate-1 risk MDS who had at least two consecutive cytogenetic analyses during the follow up. Acquisition of cytogenetic abnormalities was detected in 107 patients (29%). The most frequent alteration involved chromosome 7 in 21% of ACA cases. Median transformation-free and overall survival for patients with and without ACA were 13 vs. 52 months (P = 0.01) and 17 vs. 62 months (P = 0.01), respectively. By fitting ACA as a time-dependent covariate, multivariate Cox regression analysis showed that patients with ACA had increased risk of transformation (HR = 1.40; P = 0.03) or death (HR = 1.45; P = 0.02). Notably, female patients with therapy-related MDS (t-MDS) had an increased risk of developing ACA (OR = 5.26; P < 0.0001), although subgroup analysis showed that prognostic impact of ACA was not evident in t-MDS. In conclusion, ACA occurs in close to one third of patients with IPSS defined lower risk MDS, more common among patients with t-MDS, but has a significant prognostic impact on de novo MDS.
TL;DR: BARD1 expression and function in human acute myeloid leukemias and its modulation by epigenetic mechanism(s) and microRNAs are investigated and it is shown that the HDACi (histone deacetylase inhibitor) Vorinostat reduces BARD1 mRNA levels by increasing miR-19a and miR -19b expression levels.
Abstract: Over the past years BARD1 (BRCA1-associated RING domain 1) has been considered as both a BRCA1 (BReast Cancer susceptibility gene 1, early onset) interactor and tumor suppressor gene mutated in breast and ovarian cancers. Despite its role as a stable heterodimer with BRCA1, increasing evidence indicates that BARD1 also has BRCA1-independent oncogenic functions. Here, we investigate BARD1 expression and function in human acute myeloid leukemias and its modulation by epigenetic mechanism(s) and microRNAs. We show that the HDACi (histone deacetylase inhibitor) Vorinostat reduces BARD1 mRNA levels by increasing miR-19a and miR-19b expression levels. Moreover, we identify a specific BARD1 isoform, which might act as tumor diagnostic and prognostic markers.
TL;DR: The development of t-MN in patients with multiple myeloma is associated with poor outcomes, and these patients, in general, have complex cytogenetic abnormalities and short complete remission and OS times.
Abstract: Background Patients with multiple myeloma (MM) have had significant improvements in outcomes. An increased risk of therapy-related myeloid neoplasms (t-MNs) has also developed. Little is known about the characteristics and outcomes of these patients. Patients and Methods Patients with MM treated at our institution from 1993 to 2011 were reviewed. Forty-seven patients were diagnosed with t-MN. Our primary objective was to evaluate the interval to t-MN, response to treatment, and overall survival (OS). Results The median patient age at the MM diagnosis was 65 years. Of the 47 patients, 32 (68.0%) initially received conventional chemotherapeutic agents, 7 (14.9%), novel agents (eg, lenalidomide, thalidomide, bortezomib), and 8 (17.0%), a combination. Twenty patients (42.6%) underwent high-dose chemotherapy and autologous hematopoietic stem cell transplantation. The median interval from the MM diagnosis to t-MN was 7 years (95% CI, 5.0-28.0). Of the 47 patients, 33 (70.2%) developed therapy-related myelodysplastic syndrome (t-MDS), 11 (23.4%) acute myeloid leukemia (t-AML), and 3 (6.4%) chronic myelomonocytic leukemia (t-CMML). The median age at the t-MN diagnosis was 65 years. Of the 47 patients, 26 (78.8%) with t-MDS, 9 (81.8%) with t-AML, and 1 (33.3%) with t-CMML had complex/high-risk cytogenetics. The median OS for all 47 patients after the t-MN diagnosis was 6.3 months (95% CI, 4.0-8.7). Conclusion The development of t-MN in patients with MM is associated with poor outcomes. These patients, in general, have complex cytogenetic abnormalities and short complete remission and OS times. A better understanding of the disease biology and novel therapeutic approaches are warranted.
TL;DR: TCN-PM therapy was well tolerated in patients with advanced hematological malignancies, and reduced levels of phosphorylation of Akt and its substrate Bad were shown, consistent with inhibition of this survival pathway and induction of cell death.
TL;DR: SGI-110 differentiated pharmacokinetic profile resulted in potent hypomethylation and clinical responses in previously treated MDS and AML patients in the phase 1 trial and safety findings based on adverse events as graded by the CTCAE v4 criteria and pharmacodynamic data on Long Interspersed Nucleotide Element (LINE-1) DNA methylation (an index of globalDNA methylation) activity were also assessed and reported.
TL;DR: A single cycle of SL-401 demonstrated single agent activity in relapsed or refractory AML paties, and the maximum tolerated dose (MTD) and antitumor activity were evaluated.
Abstract: 7029^ Background: SL-401 is a novel biologic targeted therapy directed to the interleukin-3 receptor (IL-3R). IL-3R is overexpressed on cancer stem cells (CSCs) and tumor bulk relative to normal he...
TL;DR: RAS mutations are infrequent in patients with MDS and do not appear to negatively impact their outcome, and no differences were observed between both groups regarding the risk of AML transformation and overall survival.
Abstract: RAS is an oncogene frequently mutated in human cancer. RAS mutations have been reported in 10–15% of cases of acute myeloid leukemia (AML) but they appear to be less frequent among patients with myelodysplastic syndrome (MDS). The impact of RAS mutations in patients with MDS is unclear. We conducted a retrospective study in 1,067 patients with newly diagnosed MDS for whom RAS mutational analysis was available. Overall, 4% of patients carried mutant RAS alleles. Notably, FLT3 mutations, which were found in 2% of patients, were mutually exclusive with RAS mutations. Patients with RAS mutations had a higher white blood cell count as well as bone marrow blasts compared with patients carrying wild-type RAS. However, no differences were observed between both groups regarding the risk of AML transformation (9% vs. 7%) and overall survival (395 days vs. 500 days, P = 0.057). In summary, RAS mutations are infrequent in patients with MDS and do not appear to negatively impact their outcome. Am. J. Hematol. 88:365–369, 2013. © 2013 Wiley Periodicals, Inc.
TL;DR: Elderly AML patients with NPM1-MUT/FLT3-WT genotype have significantly improved outcomes compared with patients with other NPM2/NPM1/ FLT3 genotypes when treated with cytotoxic chemotherapy.
Abstract: Background The effect of prognostically important gene mutations (MUTs), nucleophosmin (nucleolar phosphoprotein B23, numatrin) (NPM1) and fms-related tyrosine kinase 3 (FLT3), in elderly patients with acute myeloid leukemia (AML) is not well defined. Patients and Methods We analyzed 557 patients, 65 years of age or older with newly diagnosed AML, treated at our institution between 2000 and 2010 with cytotoxic chemotherapy. NPM1 and FLT3 analysis were available in 146 patients (26%) and 388 patients (70%), respectively. Results NPM1 and FLT3 MUTs occurred in 16% and 12% of patients, respectively. No difference in median overall survival was observed between FLT3-MUT and NPM1-MUT patients who received cytotoxic chemotherapy. Outcome was significantly better among patients with NPM1-MUT/FLT3-wild type (WT) genotype (n = 14) compared with patients carrying FLT3/NPM1 genotypes other than NPM1-MUT/FLT3-WT (n = 125). The complete remission rates were 71% and 49%, respectively ( P = .11). The median survival was 21.5 months vs. 9.0 months and estimated 2-year survival rates were 51% vs. 38%, respectively ( P = .003). NPM1 and FLT3 MUTs appear to occur less frequently in elderly AML patients. The prognostic effect of isolated NPM1- or isolated FLT3-MUT is minimal. Conclusion Elderly AML patients with NPM1-MUT/FLT3-WT genotype have significantly improved outcomes compared with patients with other NPM1/FLT3 genotypes when treated with cytotoxic chemotherapy.
TL;DR: Ofatumumab (HuMax-CD20) targets a membrane proximal small-loop epitope on the CD20 molecule and was found to be more potent than rituximab in promoting complement-dependent cytotoxicity in vitro and may be associated with better response rates, higher 3-year complete remission duration (CRD) and overall survival rates.
TL;DR: It is concluded that downregulation of MYBL2 activity below levels predicted by classical haploinsufficiency underlies the clonal expansion of hematopoietic progenitors in a large fraction of human myeloid malignancies.
Abstract: A common deleted region (CDR) in both myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN) affects the long arm of chromosome 20 and has been predicted to harbor a tumor suppressor gene. Here we show that MYBL2, a gene within the 20q CDR, is expressed at sharply reduced levels in CD34+ cells from most MDS cases (65%; n = 26), whether or not they harbor 20q abnormalities. In a murine competitive reconstitution model, Mybl2 knockdown by RNAi to 20-30% of normal levels in multipotent hematopoietic progenitors resulted in clonal dominance of these 'sub-haploinsufficient' cells, which was reflected in all blood cell lineages. By 6 months post-transplantation, the reconstituted mice had developed a clonal myeloproliferative/myelodysplastic disorder originating from the cells with aberrantly reduced Mybl2 expression. We conclude that downregulation of MYBL2 activity below levels predicted by classical haploinsufficiency underlies the clonal expansion of hematopoietic progenitors in a large fraction of human myeloid malignancies. DOI:http://dx.doi.org/10.7554/eLife.00825.001.
TL;DR: It is concluded that treatment failure after first-line therapy with 2G-TKIs is mostly associated with toxicity or patient preference, and these patients respond well to alternative TKIs.
Abstract: Introduction
The outcome of patients with CML who discontinue 2G-TKI initial therapy is unknown. We analyzed the characteristics of patients in whom treatment with first-line 2G-TKIs had failed.
TL;DR: The combination of IO with low-intensity mini-hyper-CVD chemotherapy is safe and shows very encouraging results (93% CR/CRp) in the frontline setting in older patients with ALL, which appear to be better than those achieved with a chemotherapy only approach and may become the new standard of care for frontline treatment of older pts with ALL.
TL;DR: With a median follow-up of 11.5 months, patients with moderate/severe BM fibrosis showed a similar risk of acute myeloid leukemia transformation and a comparable overall survival in univariate and multivariate analyses.
Abstract: The presence of moderate to severe bone marrow (BM) fibrosis has been shown to be an adverse feature in patients with primary myelodysplastic syndromes (MDS) However, the clinical importance of BM fibrosis is not clear in therapy-related MDS We retrieved all therapy-related MDS (t-MDS) cases (n = 266) diagnosed at our hospital over a 10-year period (2003–2012) Reticulin and trichrome stains were performed in cases in which BM fibrosis was suspected on initial evaluation of hematoxylin and eosin-stained slide BM fibrosis was graded according to European consensus guidelines, and a score of MF2/MF3 was defined as moderate/severe fibrosis Moderate/severe BM fibrosis was found in 47 (17 %) patients Compared to 219 patients with no/mild BM fibrosis, the patients with moderate/severe fibrosis presented with severer thrombocytopenia (p = 0039) and higher numbers of circulating blasts (p = 0051) but with similar degrees of anemia and neutropenia, transfusion requirements, and similar incidences of hepatosplenomegaly and constitutional symptoms Histological examination revealed a comparable BM cellularity and BM blast percentage, but markedly increased megakaryocytes (p < 0001) in the fibrotic group Although the risk distribution of cytogenetic data was similar according to the New Comprehensive Cytogenetic Scoring criteria, −5 and −17 were more frequently observed in t-MDS with moderate/severe BM fibrosis (p = 0031 and p = 0043, respectively) With a median follow-up of 115 months, patients with moderate/severe BM fibrosis showed a similar risk of acute myeloid leukemia transformation and a comparable overall survival in univariate and multivariate analyses Moderate/severe BM fibrosis in patients with t-MDS is associated with certain clinicopathological and genetic features However, unlike the situation in patients with primary MDS, moderate/severe BM fibrosis does not add additional risk to patients with therapy-related MDS
TL;DR: The data suggest that patients with AML and unfavorable cytogenetics at diagnosis and a persistent abnormal clone at allo-HSCT are at high risk for relapse after allo -HSCT.