scholarly journals Prognostic Impact of the Latency Time from the Administration of Cytotoxic Therapy to the Development of Therapy-Related Myeloid Neoplasms

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 34-35
Author(s):  
Claudia Nunez-Torron ◽  
Adolfo Saez ◽  
Berta Mercedes Michael Fernández ◽  
Irene Garcia-Garcia ◽  
Juan Marquet Palomanes ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Research Funding ◽  
Topoisomerase Ii ◽  
Univariate Analysis ◽  
Molecular Characteristics ◽  
Prognostic Impact ◽  
Latency Time ◽  
Cytotoxic Therapy ◽  
Topoisomerase Ii Inhibitors ◽  
Myeloid Neoplasms

Introduction: Among Therapy-Related Myeloid Neoplasms (t-MNs), there are two large groups depending on the cytotoxic trigger. A first group arises after exposure to alkylating agents and / or radiation in the previous 5-10 years and it is associated with unbalanced chromosomal abnormalities, frequently with alterations in Cr 5, 7, complex karyotype and mutated TP53. The second arises after exposure to topoisomerase II inhibitors in the previous 1-5 years, and it is characterized by frequent balanced translocations and KMT2A rearrangement. In those cases with a latency time from cytotoxic exposure to T-MNs diagnosis greater than 10 years, there is doubt about whether they should be considered T-MNs or de novo leukemias. Material and methods: We performed a retrospective analysis of 34 patients with diagnosis of T-MNs treated in our center between 2013 and 2019. We have reviewed the cytogenetic alterations at diagnosis and alterations in TP53 and / or 17p and rearrangements in KMT2A. We divided the cohort into two groups based on the latency time of ≤10 years or> 10 years. The comparison between both groups was carried out using the chi2 test for qualitative variables and the t-student for quantitative variables. The Kaplan Meier method has been used for the calculation of Overall Survival (OS) and Event Free Survival (EFS) and the Cox regression model for the univariate and multivariate analysis. Results: The median follow-up of the global cohort was 8.5 months (0-74). The median OS of the global cohort was 10 months and the EFS was 8 months. In patients with a latency time ≤10 years the median OS was 12 months vs 9 months in those with latency >10 years, with a Hazard Ratio (HR) of 0.6 [95% CI (0.2-1.7), p = 0.3] and the EFS was 7 months vs 9 months respectively [HR 0.3, 95% CI (0.3-1.8), p = 0.7]. The baseline characteristics of the population are reflected in Table 1. A similar percentage of patients with complex or monosomal karyotype at diagnosis is observed in both groups, as well as alterations in TP53 and/or 17p. In the >10-year latency subgroup, there were no patients with prior exposure to Topoisomerase II Inhibitors. Within the <10-year latency group, we divided the cohort into two groups: 1 to 5 years and 5 to 10 years of latency. No differences were found for OS [HR 1.5 95% CI (0.4-5), p = 0.4] or for EFS [HR 2.1 95% CI (0.7-6.2), p = 0.1]. A univariate analysis was performed including the characteristics reflected in Table 2. The variables with a significant HR for OS and EFS were to present a monosomic karyotype at diagnosis and alterations in TP53 and/or 17p. In the multivariate analysis, only the alterations in TP53 and/or 17p maintained a significant HR. Conclusions: Patients with a latency time from exposure to cytotoxic therapy to the diagnosis of T-MNs > 10 years, presented cytogenetic and molecular characteristics similar to those with an exposure time ≤10 years, as well as a similar OS and EFS. Regarding the cytogenetic characteristics at diagnosis of the general cohort, patients with monosomic karyotype and especially those with TP53 and/or 17p alterations had a worse prognosis. Disclosures Garcia-Gutiérrez: Incyte:Consultancy, Other: Travel, Accommodation, Expenses, Research Funding;Novartis:Consultancy, Other: Travel, Accommodation, Expenses, Research Funding;Bristol-Myers Squibb:Consultancy, Other: Travel, Accommodation, Expenses, Research Funding;Pfizer:Consultancy, Other: Travel, Accommodation, Expenses, Research Funding.

scholarly journals Therapy-Related Myeloid Neoplasm Has a Distinct Pro-Inflammatory Bone Marrow Microenvironment and Delayed DNA Damage Repair

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 37-38
Author(s):  
Monika M Kutyna ◽  
Li Yan A Wee ◽  
Sharon Paton ◽  
Dimitrios Cakouros ◽  
Agnieszka Arthur ◽  
...  
Keyword(s):  
Dna Damage ◽  
Board Of Directors ◽  
Research Funding ◽  
High Dose ◽  
Cytotoxic Therapy ◽  
Advisory Committees ◽  
Myeloid Neoplasm ◽  
Myeloid Neoplasms ◽  
Damage Repair

Introduction: Therapy-related myeloid neoplasms (t-MN) are associated with extremely poor clinical outcomes in otherwise long-term cancer survivors. t-MN accounts for ~20% of cases of myeloid neoplasms and is expected to rise due to the increased use of chemotherapy/radiotherapy (CT/RT) and improved cancer survivorship. Historically, t-MN was considered a direct consequence of DNA damage induced in normal hematopoietic stem cells (HSC) by DNA damaging cytotoxics. However, these studies have largely ignored the bone marrow (BM) microenvironment and the effects of age and concurrent/previous cancers. Aim: We performed an exhaustive functional study of mesenchymal stromal cells (MSC) obtained from a comparatively large cohort of t-MN patients and carefully selected control populations to evaluate the long-term damage induced by cytotoxic therapy to BM microenvironment and its impact on malignant and normal haematopoiesis. Methods: Four different cohorts were used: (1) t-MN, in which myeloid malignancy occurred after CT/RT for a previous cancer (n=18); (2) patients with multiple cancer and in which a myeloid neoplasm developed following an independent cancer which was not treated with CT/RT (MC-MN; n=10); (3) primary MN (p-MN; n=7) untreated and without any prior cancer or CT/RT; (4) age-matched controls (HC; n=17). Morphology, proliferation, cellular senescence, differentiation potential and γH2AX DNA damage response was performed. Stem/progenitor supportive capacity was assessed by co-culturing haematopoietic stem cells on MSC feeder-layer in long-term culture initiating assay (LTC-IC). Cytokine measurements were performed using 38-plex magnetic bead panel (Millipore) and RNA sequencing libraries were prepared with Illumina TruSeq Total RNA protocol for 150bp paired-end sequencing on a NextSeq500 instrument. Functional enrichment analysis was performed using EnrichR software. Results: MSC cultured from t-MN patients were significantly different from HC, p-MN and MC-MN MSC according to multiple parameters. They exhibited aberrant morphology consisting of large, rounded and less adhesive cells compared to typical spindle-shaped morphology observed with controls. MSC from myeloid neoplasm also showed impaired proliferation, senescence, osteo- and adipogenic differentiation with t-MN MSC showing the greatest differences. DNA repair was dramatically impaired compared to p-MN and HC (Fig.1A). Importantly, these aberrant t-MN MSC were not able to support normal or autologous in vitro long-term haematopoiesis (Fig.1B). The biological characteristic and poor haematopoietic supportive capacity of MSC could be "cell-intrinsic" or driven by an altered paracrine inflammatory microenvironment. Interestingly, several inflammatory cytokines were higher in t-MN compared with marrow interstitial fluid obtained from p-MN patients (Fig.1Ci) and many of these including Fractalkine, IFNα2, IL-7 and G-CSF were also significantly higher in t-MN MSC conditional media (Fig.1Cii). Together, this data suggest that t-MN microenvironment is distinct from p-MN with paracrine production of pro-inflammatory milieu that may contribute to poor HSC supportive capacity. Preliminary whole transcriptome analysis revealed differential gene expression between t-MN and HC (Fig.1Di) and p-MN MSC. Importantly, the deregulated genes play critical role in cell cycle, DNA damage repair, and cellular senescence pathways explaining phenotypical characteristic of t-MN MSC (Fig.1Dii). Moreover CXCL12 expression, a key regulator of haematopoiesis, was significantly lower in t-MN compared to HC (p=0.002) and p-MN MSC (p=0.009), thus explaining poor HSC supportive capacity. The key difference between the p-MN, MC-MN and t-MN is prior exposure to CT/RT. To study this we obtained MSC from two t-MN patients for whom we had samples at the time of their primary cancer, post high-dose chemotherapy and at the time of t-MN. MSC displayed aberrant proliferation and differentiation capacity after high-dose cytotoxic therapy (2 to 4 years prior to developing t-MN) and remained aberrant at t-MN diagnosis (Fig.1E). Conclusions: BM-MSC from t-MN patients are significantly abnormal compared with age-matched controls and typical myeloid neoplasm. Importantly, prior CT/RT leads to long-term irreversible damage to the BM microenvironment which potentially contributes to t-MN pathogenesis. Disclosures Hughes: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Hiwase:Novartis Australia: Research Funding.

Incidence and Characteristics of Therapy-Related Myeloid Neoplasms in Patients with Non-Hodgkins Lymphoma Treated with Radioimmunotherapy

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4924-4924
Author(s):  
Salman Waheed ◽  
Iva Ferreira ◽  
Deborah A. Katz ◽  
Reem Karmali ◽  
Stephanie A. Gregory ◽  
...  
Keyword(s):  
Median Time ◽  
Topoisomerase Ii ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Myelogenous Leukemia ◽  
Cytotoxic Agents ◽  
Ibritumomab Tiuxetan ◽  
Topoisomerase Ii Inhibitors ◽  
Myeloid Neoplasms ◽  
131I Tositumomab

Abstract Abstract 4924 Purpose: Radioimmunotherapy (RIT) delivers targeted radiation to tumor cells using cancer-specific monoclonal antibodies. Two agents, 90Y-ibritumomab tiuxetan (Zevalin®) and 131I-tositumomab (Bexxar) have been approved for the treatment of relapsed or refractory CD20 positive low-grade, follicular, or transformed NHL. With increasing use of RIT, it is important to elucidate short and long-term toxicities of treatment, particularly the development of therapy-related myelodysplastic syndrome and/or acute myelogenous leukemia (t-MDS/AML). We are reporting on the incidence and characteristics of t-MDS/AML in 149 patients with NHL treated at a single institution. Methods: We conducted a retrospective chart review of 149 patients with NHL treated with radioimmunotherapy at our institution. Incidences of t-MDS/AML, along with patient and disease characteristics were investigated. Results: 149 patients with NHL were included in this analysis: All patients had received at least one cytotoxic chemotherapy regimen prior to RIT. Regimens most commonly included purine analogues, anthracyclines, alkylating agents, and topoisomerase II inhibitors. Seven out of 149 patients developed t-MDS/AML with an estimated incidence of 4. 69%, (t-MDS: 5, t-AML: 2). Five patients had follicular lymphoma, 1 with mantle cell lymphoma, and 1 with diffuse large B-cell lymphoma. Three patients received 131I-tositumomab and 4 patients received 90Y-ibritumomab tiuxetan. The median age at RIT, and at diagnosis of t-MDS/AML, was 71. 3 and 73. 1 years respectively. The median time from RIT to diagnosis of t-MDS/AML was 1266 days (3. 47 years). The median time from initial NHL treatment to t-MDS/AML was 1680 days (4. 60 years). Two patients developed t-AML without a preceding t-MDS; one of whom had received topoisomerase II inhibitors. Six patients had cytogenetic abnormalities, with complex karyotype present in 4 patients. The majority of the karyotypic abnormalities involved chromosomes 5, 7, 11, and 20. The median time from diagnosis of t-MDS/AML to death was 278 days (0. 76 years). Conclusion: Therapy –related myeloid neoplasms develop after exposure to cytotoxic agents and carry a worse prognosis than de novo disease as is shown in our series. Incidence varies according to underlying disease, specific agents received, timing of exposure, and dose. The incidence rate of 4. 69% observed in this study is within the range previously described for NHL patients treated with conventional-dose chemotherapy (Armitage J. O. et al., 2003). Most patients received fludarabine, an agent linked to a high incidence of t-MDS/AML (Carney D. A. et al., 2010). Roboz et al., 2007, noted that the median time to t-MDS/AML after standard initial therapy is approximately 6 years, which is slightly longer than our study (4. 60 years). This difference may be attributed to differences in chemotherapeutic agents utilized in that analysis for NHL therapy. T-AML without antecedent t-MDS was likely related to etoposide as has been observed in previous studies (Ratain M. J. et al., 1987, 1992). Chromosome 5 and 7 abnormalities were seen with the greatest frequency, a finding typical of t-MDS/AML (Armitage J. O. et al., 2003). This study provides an estimate of 4. 69% for the development of t-MDS/AML after NHL therapy which included chemotherapy/RIT, and suggests that RIT may not contribute to an increased risk of developing t-MDS/AML beyond what is expected with chemotherapy alone. Longer follow-up of NHL patients treated with RIT alone is necessary to determine the precise role of RIT in the development of t-MDS/AML. Disclosures: No relevant conflicts of interest to declare.

ABCA3 Expression Predicts Response to Gemtuzumab Ozogamicin in AML

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3946-3946 ◽  
Author(s):  
Antony Ceraulo ◽  
Aminetou Mint-Mohamed ◽  
Delphine Maucort-Boulch ◽  
Etienne Paubelle ◽  
Xavier Thomas ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Prognostic Factors ◽  
Relapse Rate ◽  
Small Sample Size ◽  
Univariate Analysis ◽  
Gemtuzumab Ozogamicin ◽  
Small Sample ◽  
Control Group ◽  
Prognostic Impact ◽  
Significant Difference

Abstract Background. The ATP binding cassette transporter 3 (ABCA3) has been recently found to induce a significant reduction in cytotoxicity following exposure to anthracyclines, mitoxantrone, etoposide, Ara-C, vincristine, and rituximab. ABCA3 acts through the modulation of multivesicular bodies (MVB) and contributes to drug sequestration in late endosomal organelles, i.e. MVB and lysosomes. Studies having investigated the prognostic impact of ABCA3 expression in AML have yielded conflicting results as ABCA3 expression has both been reported to exert unfavorable or neutral effects on patient outcomes. In addition, the small sample size of these studies precluded the use of multivariate analyses. Methods. Our goal was to investigate the prognostic impact of ABCA3 expression in adult patients with AML treated with IC with or without gemtuzumab ozogamicin (GO). To this end we investigated the relationship between ABCA3 expression and EFS in a representative series of 221 AML homogeneously treated in the ALFA-0701 trial. qRTPCR amplification of conserved ABCA3 mRNA sequences, as identified with FasterDB database, was performed with GUS and ABL as reference genes. Primer sets were complementary to conserved ABCA3 exons 6-7 and exon 19-20 junctions. Patients were given a 3+7 induction course without (control group, n=110) or with fractionated intravenous GO (n=111) (Castaigne S, Lancet 2012; 379:1508-1516). Results. Among the 278 randomized patients, 221 had available bone-marrow diagnostic samples with high-quality RNA. The same benefits associated with GO were observed in the 221 patients from the present study as in the entire trial population. Overall, median age, CR rate, relapse rate, median follow-up, 3-years EFS were 62.1 years, 76.5%, 66%, 47.45 months, 28±3%, respectively. There was no significant difference in the level of ABCA3 expression between responders and non-responders. In the 169 responders, ABCA3 expression at diagnosis was more than 3-fold higher in the 111 remitters who subsequently relapsed than in the 58 patients who remained in persistent CR (p=0.033). The level of ABCA3 expression was significantly lower in ELN favorable group than in intermediate and adverse risk AML (p= 0.004) and negatively correlated with CD33 expression (R=-0.272, p<10-4). Through univariate analysis, higher ABCA3 expression was associated with shorter EFS (3-years: 22±3 vs 45±7 % p=0.002). Multivariate analysis identified age, treatment arm, and ELN risk group as independent prognostic factors for EFS. In the control group, there was no significant association between ABCA3 expression and CR rate, relapse rate, and EFS. In the 111 patients within the GO arm, there was no significant difference in the level of ABCA3 expression between responders and non-responder whereas in the 89 responders, ABCA3 expression at diagnosis was more than 7-fold higher in the 53 remitters who subsequently relapsed than in the 36 patients who remained in persistent CR (p=0.006). Through univariate analysis, higher ABCA3 expression was associated with shorter EFS (3-years: 22±5 vs 64±9 % p=0.0002). Multivariate analysis identified ABCA3 expression, cytogenetics, CD33 expression, and ECOG as independent prognostic factors for EFS (Figure 1). Conclusion. WhileABCB1 has been previously found to attenuate GO-induced cytotoxicity in AML cells (Walter RB, Blood 2003; 102:1466-1473), present results indicate that higher ABCA3 expression independently predicts poor outcome in AML patients treated with fractionated GO and intensive chemotherapy (IC). GO is an anti-CD33 antibody carrying a toxic calicheamicin derivative that, after hydrolytic release within lysosomal vesicles, induces DNA strand breaks, apoptosis, and cell death. Whether the clinical effect of ABCA3 expression relies on the modulation of CD33 internalization, calicheamicin release or combination thereof is under investigation. Finally our results encourage inhibiting ABCA3, such as with indomethacin, in order to overcome drug resistance in AML treated with GO-IC. Figure 1 Figure 1. Disclosures Thomas: Pfizer: Consultancy.

Analysis of Transfusion Dependency Development and Disease Evolution in Patients with MDS with 5q- and without Transfusion Needs at Diagnosis

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3180-3180
Author(s):  
Felix Lopez-Cadenas ◽  
Blanca Xicoy ◽  
Silvia Rojas P ◽  
Kaivers Jennifer ◽  
Ulrich Germing ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Board Of Directors ◽  
Research Funding ◽  
Statistical Significance ◽  
Univariate Analysis ◽  
Rank Test ◽  
Advisory Committees ◽  
Disease Evolution ◽  
Free Survival

Abstract Introduction: Myelodysplastic syndrome with del5q (MDSdel5q) is the only cytogenetically defined MDS category recognized by WHO in 2001, 2008 and 2016 and is defined as a MDS with deletion on the long arm of chromosome 5 and less than 5% of blast cells in bone marrow. It is known that for patients with MDSdel5q and transfusion dependence (TD), Len (LEN) is the first choice of treatment. However, data regarding factors that may impact on the development of TD or disease evolution in patients diagnosed without TD are scanty. In our study a retrospective multicenter analysis on patients with low-int 1 MDSdel5q without TD at diagnosis has been performed in order to answer these questions. Patients and methods: We performed a multicenter collaborative research from the Spanish (RESMD) and German MDS registries. Data from 153 low risk MDSdel5q without TD at diagnosis were retrospectively analyzed. Statistical analysis: Data were summarized using median, range, and percentage. The event of TD was defined as the development of TD according to the IWG criteria (2006) and/or the beginning of a treatment which could modify disease course (LEN or ESA). Transfusion or treatment free survival (TFS), overall survival (OS) and leukemia free survival (LFS) were measured from diagnosis to TD or treatment, the first occurred (or to last follow up if none), last follow up or death from any cause and evolution to AML, respectively. TFS, OS and LFS were analyzed using the Kaplan Ð Meier method. The Log-rank test was used to compare variables and their impact on survival for univariate analysis.Multivariate analysis was performed using Cox's proportional hazards regression model. For comparison of Kaplan Meier curves the long rank test was used, with statistical significance with p<0.05. Statistical analysis was performed using SPSS 20.0. Results: Main clinical and biological characteristics were summarizing in table 1. From the total of 153 patients, finally 121 were evaluable. During the study 56 patients (46.2%) became in TD and 47 (38.8%) did not develop TD but received a modified disease course treatment. In this sense, most of the patients developed relevant anemia regarding those data (103 out of 121 patients, 85%). Median time to TD or treatment (TFS) was 20 months (1-132) from diagnosis. Secondary MDS (p=0.02), thrombocytosis (>350 109/L) (p=0.007), and neutropenia (<1.5 x 109/L) (p=0.02) were associated with poorer TFS. Thrombocytosis and neutropenia retained statistical significance in the multivariate analysis (Table 2). Among the TD patients (N=56), 42 (75%) received treatment: 28 LEN, 7 ESA and 7 other treatments. Among patients that did not develop TD (N=65), 47 (72.3%) received treatment before TD development: 16 LEN, 28 ESA and 3 other treatments. In order to know the evolution of these patients, survival analysis was performed. Median follow up was 58.9 months among alive patients and 57% of them were alive at the time of the last follow up. Estimated OS at 2 and 5 years was 94% and 64%. Regarding Univariate analysis, platelet <100 x 109/L (p=0.03), patients older than 71 years (p=0.001), and progression into AML (p=0.02) were associated with poorer OS. On the contrary, patients who had received treatment showed better OS (p<0.0001). This benefit is more evident among patients receiving LEN, median OS for patients receiving LEN, ESA/other treatments and not treated group was 137 months (CI 95%: 59,4 -215,5), 99,3 months (CI 95%: 46,6 -152) and 57,9 months (CI 95%: 38,2 -77,6), respectively, p<0.0001 (Figure 1). In the multivariate analysis, patients older than 71 years and LEN treatment retained the statistical significant impact on OS (Table 2). Twenty-eight patients (23%) progressed into AML, median time to AML was 35 months (5-122). When univariate analysis was performed, variables with adverse impact on LFS were platelets <100 x 109/L(p=0.019), neutropenia < 0.8 x 109/L (p=0.026), an additional cytogenetic abnormality (p=0.013) while treatment with LEN had a favorable impact (p=0.035). In the multivariate analysis only the presence of additional cytogenetic abnormalities retained statistical significance (Table 2). CONCLUSIONS: Most of the patients with low risk del(5q) MDS and no TD at diagnosis developed symptomatic anemia very early after diagnosis (20 months). Carefully monitoring should be stablished in order to detect this time point. Outcome of this subset of patients could improve after target therapy. Figure 1 Figure 1. Disclosures Del Cañizo: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; janssen: Research Funding; Astex: Membership on an entity's Board of Directors or advisory committees. Díez Campelo:celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Research Funding; Astex: Membership on an entity's Board of Directors or advisory committees.

scholarly journals The immunohistochemical expression of SSTR2A is an independent prognostic factor in meningioma

2021 ◽  
Author(s):  
Christina Fodi ◽  
Marco Skardelly ◽  
Johann-Martin Hempel ◽  
Elgin Hoffmann ◽  
Salvador Castaneda ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Intensity Distribution ◽  
Tumor Recurrence ◽  
Univariate Analysis ◽  
Somatostatin Receptors ◽  
Tumor Grade ◽  
Neurofibromatosis Type ◽  
Prognostic Impact ◽  
Immunohistochemical Expression ◽  
Who Grade

AbstractThe expression of somatostatin receptors in meningioma is well established. First, suggestions of a prognostic impact of SSTRs in meningioma have been made. However, the knowledge is based on few investigations in small cohorts. We recently analyzed the expression of all five known SSTRs in a large cohort of over 700 meningiomas and demonstrated significant correlations with WHO tumor grade and other clinical characteristics. We therefore expanded our dataset and additionally collected information about radiographic tumor recurrence and progression as well as clinically relevant factors (gender, age, extent of resection, WHO grade, tumor location, adjuvant radiotherapy, neurofibromatosis type 2, primary/recurrent tumor) for a comprehensive prognostic multivariate analysis (n = 666). The immunohistochemical expression scores of SSTR1, 2A, 3, 4, and 5 were scored using an intensity distribution score ranging from 0 to 12. For recurrence-free progression analysis, a cutoff at an intensity distribution score of 6 was used. Univariate analysis demonstrated a higher rate of tumor recurrence for increased expression scores for SSTR2A, SSTR3, and SSTR4 (p = 0.0312, p = 0.0351, and p = 0.0390, respectively), while high expression levels of SSTR1 showed less frequent tumor recurrences (p = 0.0012). In the Kaplan–Meier analysis, a higher intensity distribution score showed a favorable prognosis for SSTR1 (p = 0.0158) and an unfavorable prognosis for SSTR2A (0.0143). The negative prognostic impact of higher SSTR2A expression remained a significant factor in the multivariate analysis (RR 1.69, p = 0.0060). We conclude that the expression of SSTR2A has an independent prognostic value regarding meningioma recurrence.

scholarly journals Prognostic Impact of Gastrointestinal Involvement in Newly Diagnosed Diffuse Large B-Cell Lymphoma

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5400-5400
Author(s):  
David Kasouha ◽  
Nicola Lehners ◽  
Katharina Kriegsmann ◽  
Gerlinde Egerer ◽  
Anthony D Ho ◽  
...  
Keyword(s):  
Research Funding ◽  
Cell Lymphoma ◽  
Univariate Analysis ◽  
Elevated Serum ◽  
B Cell Lymphoma ◽  
Treatment Modalities ◽  
Prognostic Impact ◽  
Newly Diagnosed ◽  
Curative Intent ◽  
Large B Cell Lymphoma

Abstract Introduction: Involvement of >1 extranodal site is regarded as a poor prognostic factor for patients with diffuse large B-cell lymphoma (DLBCL). It is necessary to clarify the prognostic impact of specific extranodal sites. Gastrointestinal (GI) involvement is one of the most frequently involved extranodal sites. Methods: Patients with newly diagnosed DLBCL treated at the University of Heidelberg between 06/2001 and 07/2015 were identified and included in this retrospective analysis. Data on clinical characteristics and treatment modalities were obtained by review of medical charts. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. The impact of variables on PFS and OS was evaluated by univariate log-rank tests and by multivariate analysis using the Cox proportional hazards model. Results: A total of 1001 patients were identified of whom 119 (11.9%) presented with GI involvement. Median age of patients with GI involvement was 63.3 years [range 19.1-86.7], 71 (59.7%) were male. 92 patients had an available international prognostic index (IPI) score, 36 (39.1%) IPI 0-1, 33 (35.9%) IPI 2-3, and 23 (25%) IPI 4-5. The most frequently involved organs of GI were stomach (51.3%), small intestine (39.5%), colon (20.2%), and esophagus (2.5%). 107 (89.9%) patients were treated in curative intent and were further analyzed regarding the prognostic impact of several factors on outcome. 80.4% of them received CHOP-like therapies, 17.8% received chemotherapy more aggressive than CHOP, typically addition of etoposide or treatment with high-dose methotrexate in case of CNS involvement, 87.9% received additional rituximab, and 22.4% additional radiotherapy In DLBCL patients with GI involvement, we identified factors associated with worse OS (P<.05) by univariate analysis: B symptoms, elevated serum LDH, and involvement of more than two extranodal sites. On the contrary, age (>60 years), sex, Ann Arbor Stage (AAS) III/IV, and Performance Status of Eastern Cooperative Oncology Group (ECOG) more than one, and elevated serum sCD25 did not have any significant impact on OS. B symptoms were as well associated with decreased PFS (P<.05) by univariate analysis. Multivariate Cox Regression analysis revealed that patients with elevated serum LDH at diagnosis had significantly worse OS (P<.05), and patients with B symptoms had significantly worse PFS (P<.05). Regarding first-line treatment modalities, escalation of chemotherapy to more aggressive regimes than CHOP was associated with a prolonged OS and PFS in univariate analysis, not in multivariate analysis. Radiotherapy did not have any significant impact on OS or PFS. Regarding all DLBCL patients treated with curative intent, GI involvement did not have any significant prognostic impact on OS or PFS. Conclusions: In this retrospective registry analysis of patients with newly diagnosed DLBCL with GI involvement, B symptoms, elevated serum LDH, and involvement of more than two extranodal sites were identified as risk factors for inferior OS. Escalation of chemotherapy to more aggressive regimes than CHOP was associated with a prolonged OS and PFS. Further analyses are required as toward which treatment modalities might be best suited to improve prognosis of GI involvement. Disclosures Kriegsmann: Celgene: Research Funding; BMS: Research Funding.

scholarly journals Risk Factors for Severe Form of COVID-19 after Allogeneic Hematopoietic Stem Cell Transplantation: A SFGM-TC Multicentre Cohort Study

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 34-34
Author(s):  
Alienor Xhaard ◽  
Constance Xhaard ◽  
Maud D'Aveni ◽  
Hélène Salvator ◽  
Marie-Laure Chabi-Charvillat ◽  
...  
Keyword(s):  
Risk Factors ◽  
Multivariate Analysis ◽  
Intensive Care ◽  
Platelet Count ◽  
Board Of Directors ◽  
Research Funding ◽  
Univariate Analysis ◽  
Immunosuppressive Treatment ◽  
Severe Form ◽  
Advisory Committees

COVID-19 greatly affected Europe between March and May 2020. Initial reports suggest cancer and haematological malignancies as risk factors for severity and mortality, but the role of allogeneic stem cell transplantation (alloHSCT) remains unclear. The Société Francophone de Greffe de Moelle et Thérapie Cellulaire conducted a multicentre retrospective study of alloHSCT recipients diagnosed with COVID-19. We described the COVID-19 disease characteristics in this population and examined risk factors for severity and mortality. Data were collected retrospectively from the patients' charts and the ProMISe database. Diagnosis was retained only if a reverse transcription polymerase chain reaction assay test from a nose swab was positive for SARS-CoV-2. Patients were classified as severe if they were transferred to an intensive care unit (ICU) due to COVID-19 or died of COVID-19, and non-severe in other cases. Comparisons of characteristics were performed using student's t-tests and Mann-Whitney U tests for normally and abnormally distributed data, respectively, for continuous variables and χ2 or Fisher's exact tests, when appropriate for categorical variables. Risk factors associated with a severe form of COVID-19 were assessed using both univariate and multivariate logistic regressions. All analyses were performed using SAS version 9.4.6 (SAS Institute Inc., Cary, NC, USA. A two-tailed significance level p&lt;0.05 was used. Fifty-four patients were diagnosed, including 21 with severe forms (intensive care transfer and/or death). Haematological characteristics did not vary between patients with severe or non-severe forms of COVID-19. Patients with a severe form of COVID-19 were more likely to be diagnosed earlier after alloHSCT (0.78 vs. 2.1 years, p=0.01), to have comorbidities (80.9% vs. 54.5%, p=0.05) and to receive immunosuppressive treatment (81% vs. 51.5%, p=0.03). Severe COVID-19 patients were more likely to have symptoms at COVID-19 diagnosis (100% vs. 81.8%, p=0.04), especially pneumonia and symptoms other than respiratory or digestive (asthenia, neurological symptoms, myalgia, dysgeusia, skin lesions and arthralgia), and to experience co-infection during the course of the disease (52.4% vs. 21.2%, p= 0.001). At COVID-19 diagnosis, patients with a non-severe form were more likely to have a higher platelet count (226 G/L vs. 98 G/L, p= 0.01), while other biological characteristics did not vary between the two cohorts. In univariate analysis, shorter time from transplant to COVID-19 (before 211 days, p=0.01), pneumonia (OR 12.21 [95% CI 2.43 - 61.46], p=0.002), symptoms other than pulmonary or digestive (OR 1.21 [95% CI 1.02 - 11.16], p=0.04), immunosuppressive treatment (OR 5.97 [95% CI 0.75 - 47.42], p=0.03) , co-infection (OR 5.84 [95% CI 1.65-20.63], p=0.006) and comorbidity (OR 3.54 [95% CI 0.98-12.83], p=0.05) were associated with severe COVID-19. The only biological parameter associated with severity was a lower platelet count &lt;71G/L (OR 28.00 [95% CI 2.07-379.25]), p=0.008. In multivariate analysis, pneumonia and other symptoms retained a significant association with severe COVID-19. Thirteen patients died of COVID-19: in univariate analysis, risk factors for death from COVID-19 were similar to the risk factors for severe COVID-19 (i.e. shorter time from alloHSCT, p=0.03; pneumonia, p=0.01; co-infection during the course of COVID-19, p&lt;0.01, and lower platelet count, p&lt;0.01). In multivariate analysis, none of the above mentioned factors remained significantly associated with death from COVID-19. As SARS-CoV-2 continues to spread internationally, given the lack of vaccine or treatment, alloHSCT recipients should maintain a high level of awareness to avoid contamination. Figure Disclosures Dalle: Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria; Bellicum: Consultancy, Honoraria; AbbVie Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Orchard: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; bluebird bio: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi-Genzyme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Medac: Consultancy, Honoraria; Jazz Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Rubio:MSD: Honoraria; Novartis: Honoraria; Neovii: Research Funding; Medac: Consultancy; Gilead: Honoraria.

scholarly journals Prognostic Impact of MYC Oncoprotein Expression on Survival Outcome in Secondary AML Patients

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2756-2756
Author(s):  
Seongseok Yun ◽  
Rohit Sharma ◽  
David A Sallman ◽  
Nicole D. Vincelette ◽  
Kendra L. Sweet ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Research Funding ◽  
Tp53 Mutation ◽  
Somatic Mutations ◽  
De Novo ◽  
Chromosomal Abnormalities ◽  
Survival Outcomes ◽  
Prognostic Impact ◽  
Poor Prognostic Factor ◽  
De Novo Aml

Abstract INTRODUCTION: Treatment outcomes of secondary Acute Myeloid Leukemia (sAML) including AML with myelodysplasia related changes (AML-MRC) and therapy related AML (tAML) are dismal compared to de novo AML patients, where long term disease free survival (DFS) remains less than 40%. Studies in pediatric AML identified frequent MYC somatic mutation and gene amplification, and although MYC somatic mutations are rare in adult AML, a recent study showed de novo AML patients expressing high levels of the MYC oncoprotein have inferior survival outcomes versus low levels of MYC. Compared to other AML subtypes, AML-MRC patients were shown to have dynamic range of MYC protein expression, yet the clinical significance of MYC levels in these patients group is unknown. Here we report the prognostic impact of MYC protein levels on survival outcomes in AML-MRC patients. METHODS: Using Total Cancer Care (TCC) Moffitt Cancer Center (MCC) databases, we retrospectively identified histologically confirmed AML-MRC patients from 2011 to 2018. MYC protein expression was assessed by immunohistochemistry (IHC) staining. TP53 mutation was tested by 54 myeloid targeted gene sequencing. We used 5% as cut-off (calculated as MYC positive cells out of total counted blasts in the selected area with sheets of blasts) as previously reported (Ohanian et al. 2018). Clinical variables and disease-related prognostic factors including age, gender, cytogenetics and somatic mutations were characterized at the time of AML-MRC diagnosis and were annotated using descriptive statistics. The overall survival (OS) were estimated with the Kaplan-Meier method and compared using the log-rank test. All statistical analyses were performed using SPSS v24.0 and GraphPad Prism 7. RESULTS: A total of 132 AML-MRC patients were included in this study. The median age at AML-MRC diagnosis was 67 (22-86) years and 64% of patients were male (n=84). A total of 49% (n=65) patients had chromosome 17p deletion [del(17p)] based on cytogenetic analyses or/and fluorescence in situ hybridization (FISH) assays. A total of 42% (n=55) patients had TP53 mutation and 29% (n=38) patients had both del(17p) and TP53 mutation. Additional chromosomal abnormalities including deletion 5q, trisomy 8, deletion 7q, deletion 20q, and complex karyotypes were observed in 28% (n=37), 17% (n=23), 20% (n=27), 7% (n=9), and 31% (n=41) of patients, respectively. A total of 55% (n=73) of patients were treated with intensive chemotherapy, 18% (n=24) were treated with hypomethylating agents and 20% (n=27) patients underwent allogeneic stem cell transplant. A total of 39% (n=51) patients had high MYC expression and 61% (n=81) patients had low MYC expression. Notably, the median OS was significantly longer in low MYC patients compared to high MYC patients (median OS 33.1 vs. 15.2 months, p=0.0222). Further, when considering only TP53 wild type patients without del(17p), low MYC patients had even longer median OS (median OS 58.6 vs. 17.7 months, p=0.0224). In AML-MRC patients with either TP53 mutation and/or del(17p), the median OS was not statistically different between low and high MYC groups (median OS 21.0 vs. 15.1 months, p=0.3101). Finally, multivariate analysis including TP53 mutation status, del(17p), transplantation status, gender, and age, revealed that high MYC expression is a poor prognostic factor (HR 2.08, 95%CI=1.136-3.807, p=0.018). CONCLUSIONS: AML-MRC patients with high MYC expression have inferior OS outcome compared to low MYC patients. Further, multivariate analysis established that high MYC level is a poor prognostic factor in AML-MRC patients. These findings warrant further study of the prognostic impact of MYC expression in addition to MYC gene amplification or/and somatic mutations in AML patients, with larger numbers of patients having other somatic mutations or chromosomal abnormalities that have adverse outcomes. Figure. Figure. Disclosures Sallman: Celgene: Research Funding, Speakers Bureau. Sweet:BMS: Honoraria; Jazz: Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Agios: Consultancy; Astellas: Consultancy; Agios: Consultancy; Phizer: Consultancy; Astellas: Consultancy; Celgene: Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Jazz: Speakers Bureau; BMS: Honoraria; Phizer: Consultancy. Komrokji:Novartis: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Speakers Bureau. List:Celgene: Research Funding.

scholarly journals Clinical Significance of Clonal Cytogenetic Heterogeneity (CCH) at Diagnosis in Adult Patients with Acute Lymphoblastic Leukemia (ALL)

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2820-2820
Author(s):  
Hiroaki Shimizu ◽  
Nahoko Hatsumi ◽  
Satoru Takada ◽  
Takuma Ishizaki ◽  
Akihiko Yokohama ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Prognostic Factors ◽  
Research Funding ◽  
Clonal Evolution ◽  
Statistical Significance ◽  
Prognostic Impact ◽  
Common Ancestry ◽  
Complex Karyotype ◽  
Abnormal Karyotype ◽  
Cytogenetic Abnormalities

Abstract Background:Although cytogenetic abnormalities at diagnosis are recognized as one of the most potent prognostic factors in acute leukemia patients, CCH acquisition at diagnosis, which are considered as a result of clonal evolution of leukemia cells, is not taken into account in prognostic classifications. Recent studies reported that CCH acquisition was observed in 24 - 32% of adult AML patients with abnormal karyotype, was more likely to occur in patients with older age and complex karyotype, and showed adverse prognostic impact. However, the clinical significance of CCH acquisition has not been investigated in adult ALL patients to date. Patients and methods: Of the 238 adult ALL patients diagnosed between 1990 and 2016, 120 patients with abnormal karyotype at diagnosis, who underwent intensive chemotherapy, were included in this study. CCH was defined as presence of two or more cytogenetically abnormal clones. A defined ancestral clonal evolution included either mother-daughter and/or branched patterns. In the mother-daughter pattern, a daughter clone showed all cytogenetic abnormalities of a mother clone plus additional abnormality(s), which define a distinct subclone. In a branch pattern, all subclones possessed common cytogenetic abnormalities suggesting presence of a common ancestry, but each subclone acquires unique additional abnormality(s), which define them as distinctive subclones. Both patterns of cytogenetic clonal evolution were sometimes seen in a patient. Composite karyotypes were applied to patients where a common ancestry could not be clearly determined because of too complicated cytogenetic findings. Fisher's exact test was used to compare binary variables. The logistic regression model was used for multivariate analysis of predisposing factors. Overall survival (OS) was estimated with the Kaplan-Meier method and compared using the log-rank test. The Cox proportional hazard model was used for multivariate analysis of prognostic factors. Values of p < 0.05 were considered to indicate statistical significance. Results:Of the 120 patients included in this study, 64 patients were male, and 56 were female. The median age was 50 years (range, 16-79 years). Karyotypes at diagnosis were Philadelphia chromosome (Ph) in 56 patients, complex in 15, and t(8;14) in seven. According to the definition described above, 47 patients (39%) showed CCH at diagnosis, and two (4%) among them were categorized as composite karyotype. Of the 45 patients harboring a defined ancestral clonal evolution, numbers of subclones were two, three, and four in 32 patients (68%), 11 (24%), and 2 (4%), respectively. Mother-daughter pattern, branched pattern, and both were seen in 34 patients (76%), 5 (11%), and 6 (13%). In univariate analysis for predisposing factors of CCH acquisition, only younger age was significantly associated with CCH acquisition (48% in age <= 50 vs. 29% in age > 50; p = 0.04), but not karyotype. This statistical significance was confirmed with multivariate analysis (odds ratio = 0.44; p = 0.03). When investigating the prognostic impact of CCH acquisition, patients were divided into Ph-negative or Ph-positive ALL groups. In the 64 Ph-negative ALL patients, the CR rates were not significantly different between patients with or without CCH (78% vs. 78%, respectively; p = 1.00). The OS rates were similar between two groups (26% vs. 39% at five years, respectively; p = 0.56). Multivariate analysis for OS revealed that complex karyotype and t(8;14) were independent prognostic factors, but not CCH acquisition. Likewise, in the 56 Ph-positive ALL patients, CCH acquisition was not significantly associated with the CR rates (92% vs. 78%, respectively; p = 0.27), and the OS rates did not significantly differ between the two groups (34% vs. 40% at five years, respectively; p = 0.90). In multivariate analysis for OS, no independent prognostic factor was identified. Conclusion: Adult ALL patients with abnormal karyotype acquired CCH at diagnosis with a frequency comparable to that of AML patients. However, unlike AML patients, CCH acquisition was more frequently observed in younger population and did not show any prognostic impact in ALL patients. These findings suggested that biological backgrounds of CCH acquisition at diagnosis were possibly different between in patients with ALL and AML. So, to confirm these important findings, clinical studies with larger study subjects are warranted. Disclosures Handa: Celgene: Honoraria, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau.

scholarly journals Prognostic Impact of Kinase Mutations and Minimal Residual Disease in Core-Binding Factor Leukemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3828-3828
Author(s):  
David Sanford ◽  
Jorge E. Cortes ◽  
Farhad Ravandi ◽  
Wei Qiao ◽  
Keyur P. Patel ◽  
...  
Keyword(s):  
Overall Survival ◽  
Research Funding ◽  
Residual Disease ◽  
Univariate Analysis ◽  
Prognostic Impact ◽  
Rt Pcr ◽  
Relapse Free Survival ◽  
Free Survival ◽  
Log Reduction ◽  
Binding Factor

Abstract Background Core-binding factor (CBF) acute myeloid leukemia (AML) is characterized by recurrent cytogenetic abnormalities t(8;21)(q22;q22) or inv(16)(p13q22)/t(16;16)(p13;q22), amenable for minimal residual disease (MRD) monitoring by quantitative reverse transcription polymerase chain reaction (RT-PCR). Kinase mutations (KIT, RAS, FLT3) have been reported to carry adverse prognostic implication. Promising results using FLAG-based treatment (fludarabine/Ara-C/G-CSF) in CBF leukemia in phase 2 [Borthakur G, Am J Hematol, 10, 89 (2014)] and phase 3 [Burnett AK, JCO, 27, 31 (2013)] clinical trials prompted us to review the prognostic impact of MRD evaluation and mutations. Methods The primary aim was to assess the prognostic impact of kinase-activating mutations (KIT, FLT3-TKD, FLT3-ITD, KRAS and NRAS) and MRD in CBF leukemia treated with FLAG-based regimens. Newly diagnosed patients were treated in 2 consecutive phase 2 clinical trials (clinicaltrials.gov identifier: NCT00801489) and received FLAG during induction (1 cycle) and consolidation (up to 6 cycles) in combination with either gemtuzumab (for 3 cycles) or idarubicin (for 2 cycles). Mutation analysis was performed at baseline on bone-marrow aspirates and MRD was measured on serial bone marrow aspirates using RT-PCR to detect RUNX1-RUNX1T1 and CBFB-MYH11 fusion transcripts, normalized to ABL1 transcript. The Kaplan-Meier method was used to estimate unadjusted overall survival (OS) and relapse-free survival (RFS). The Cox-proportional hazards model was used to estimate the association of covariates with OS and RFS. Landmark survival analysis was used to determine the association between OS/RFS and MRD, to account for time-dependent nature of this covariate. Results: One hundred and seven patients were included [t(8;21)=54, inv(16)=53]. Forty-eight were treated with FLAG + gemtuzumab and 59 were treated with FLAG + idarubicin. The 3 year OS and RFS for the cohort was 79% (95% CI, 71-89%) and 82% (95% CI, 74 - 91%) respectively with comparable outcomes with both regimens. The incidence of mutations in KIT, FLT3-ITD, FLT3-TKD and NRAS/KRAS was 13%, 7%, 10% and 38.5% respectively. In univariate analysis, the presence of mutations in KIT, FLT3 and NRAS/KRAS individually or together were not associated with OS or RFS. A 3-log or greater reduction in RT-PCR level at 1 month and 3-4 months was associated with improved RFS. A 3-log or greater reduction in RTPCR level at 6-9 months was also significantly associated with improved OS (HR 0.19, 95% CI 0.03 -1.0, p=0.05) and there was a trend towards improved OS with 3-log reduction at 1 month (HR 0.39, 95% CI 0.14 - 1.06, p=0.06). Conclusion: In contrast to some reports, mutations in KIT, FLT3 and RAS were not prognostic for RFS or OS in our study. Favorable outcomes using FLAG-based therapy in CBF leukemia may abrogate adverse impact of kinase mutations and this hypothesis needs to be clinically tested. The incidence of KIT mutations was slightly lower in our cohort in comparison to most previous reports, which may relate to differences in sensitivity of detection. Significantly, quantitative detection of MRD by PCR early on appears to be a broadly applicable predictor of relapse and may be the most relevant prognostic factor for clinical management of CBF leukemia patients. Table 1. Univariate analysis showing hazard of relapse for all patients HR 95% CI p-value Age 1.00 0.97 - 1.04 0.89 Performance status (ECOG 1,2 vs. 0) 3.59 1.3 - 9.95 0.01 Therapy related (Y vs. N) 0.38 0.05 - 2.93 0.36 CBF Type - [inv(16) vs. t(8;21)] 0.95 0.34 - 2.62 0.92 Treatment (FLAG-ida vs. FLAG-GO) 1.59 0.56 - 4.51 0.38 Mutated KIT (Y vs. N) 1.55 0.35 -6.91 0.56 FLT3-ITD (Y vs. N) 0.7 0.09 - 5.39 0.73 FLT3-TKD (Y vs. N) 2.07 0.46 - 9.32 0.34 RAS - NRAS/KRAS (Y vs. N) 0.79 0.24 - 2.63 0.7 Any mutation -KIT/FLT3/ RAS (Y vs. N) 1.17 0.42 - 3.22 0.76 MRD - 3 log reduction at 1 month (Y vs. N) 0.23 0.06 - 0.81 0.02 MRD - 3 log reduction at 3-4 months (Y vs. N) 0.18 0.05 - 0.61 <0.01 MRD - 3 log reduction at 6-9 months (Y vs. N) 0.29 0.06 - 1.41 0.12 MRD - negative at 6-9 months (Y vs. N) 0.3 0.06 - 1.47 0.13 Figure 1. Outcomes by mutation status (KIT or FLT3 or RAS). (a) Overall survival; (b) Relapse free survival. Figure 1. Outcomes by mutation status (KIT or FLT3 or RAS). (a) Overall survival; (b) Relapse free survival. Disclosures Cortes: Teva: Research Funding; Novartis: Consultancy, Research Funding; BerGenBio AS: Research Funding; Pfizer: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Ambit: Consultancy, Research Funding; Arog: Research Funding; Celator: Research Funding; Jenssen: Consultancy.

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