Costimulatory Expression Profiling of AML Blasts Identifies Surface Markers with High Correlation to Isolated NPM1 Mutation

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2511-2511
Author(s):  
Felix S Lichtenegger ◽  
Michael Krempasky ◽  
Karsten Spiekermann ◽  
Jan Braess ◽  
Wolfgang Hiddemann ◽  
...  
Keyword(s):  
Stem Cell ◽  
Molecular Markers ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Expression Pattern ◽  
Allogeneic Stem Cell Transplantation ◽  
Risk Group ◽  
Npm1 Mutation ◽  
Mutational Status ◽  
Blast Cells

Abstract Abstract 2511 Acute myeloid leukemia (AML) is a heterogeneous disease. In recent years, numerous cytogenetic and molecular markers providing prognostic information have been established. The success of allogeneic stem cell transplantation and some autologous immunotherapeutic strategies has proven that immunological effects play an important role for treatment of AML, especially for the eradication of minimal residual disease. However, the effect is dampened by immunosuppressive factors provided by AML blasts. One of the possible immunomodulatory mechanisms is the expression pattern of costimulatory and coinhibitory molecules on AML cells, which influences their interaction with specific T cells. In order to elucidate the potential significance of this mechanism in AML, we analyzed the surface expression of a broad panel of costimulatory and coinhibitory molecules (CD80, CD86, CD273, CD274, CD275, CD276, B7-H4, HVEM) on blast cells of 102 AML patients at initial diagnosis by flow cytometry. The mean fluorescence intensity of these markers on the CD33 positive blast cell population was correlated with morphologic, cytogenetic and molecular characteristics of the disease. Statistical significance of differences in expression levels was tested with the Mann-Whitney-U test for independent samples. First, we could show that the AMLs morphologically classified as M4 or M5 according to FAB (n = 35) expressed higher levels of costimulatory markers, especially CD86 (p < 0.001) and CD276 (p = 0.016), compared to the other morphologic subgroups. For CD86, this is in concordance with the literature (e.g. Maeda et al., Br J Haematol 1998). Correlation with CD276 has not been published before, but is well in line with the monocytic lineage of these AML cases, inclining them to good antigen presentation capacities. In contrast to morphologic characteristics, correlations of the AML costimulatory profile with cytogenetic and molecular markers of the disease have never been studied before. AML patients were classified according to ELN prognostic groups, which are based on cytogenetic and molecular markers (Döhner et al., Blood 2010). Interestingly, we found that the AML blast cells of patients allocated to the favorable risk group (n = 23) showed higher expression of CD86 (p = 0.049), CD274 (p = 0.010), CD276 (p = 0.003), and B7-H4 (p = 0.001), compared to patients of the non-favorable risk groups. In particular, the cases of leukemia with normal karyotype and an isolated NPM1 mutation (without accompanying FLT3-ITD mutation), which constituted about half of the favorable risk group (n = 11), were responsible for this pattern. In these cases, the balance of costimulatory and coinhibitory molecules was clearly shifted toward expression of positive costimulatory molecules, reflected by a significantly higher ratio of the positive costimulatory molecule CD86 to various coinhibitory molecules (e.g. p = 0.003 for the ratio CD86/CD274). To further dissect the influence of NPM1 mutation on the costimulatory expression profile, all patients with an NPM1 mutation irrespective of FLT3 mutational status and karyotype were analyzed. In this cohort of 33 patients, a similar trend to higher expression of these molecules was observed, but correlations were less pronounced (p = 0.012 for CD86) or not significant (CD274, CD276, B7-H4). The karyotype and the FLT3 mutational status by itself, however, showed no significant correlation with the costimulatory profile. We hypothesize that the expression pattern of costimulatory molecules contributes to prognosis of blast clearance and especially relapse. If this is the case, we are interested to analyze whether the marker profile constitutes a surrogate for molecular markers or an independent prognostic marker. Potentially, this could be highly relevant for application in immunotherapy, e.g. allogeneic stem cell transplantation. A preliminary analysis of the clinical data will be presented. Disclosures: No relevant conflicts of interest to declare.

Is allogeneic stem cell transplantation for myelofibrosis still indicated at the time of molecular markers and JAK inhibitors era?

2017 ◽  
Vol 99 (1) ◽  
pp. 60-69 ◽  
Author(s):  
Elsa Lestang ◽  
Pierre Peterlin ◽  
Yannick Le Bris ◽  
Viviane Dubruille ◽  
Jacques Delaunay ◽  
...  
Keyword(s):  
Stem Cell ◽  
Molecular Markers ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Allogeneic Stem Cell Transplantation ◽  
Jak Inhibitors

scholarly journals Allogeneic stem cell transplantation for AML patients with RUNX1 mutation in first complete remission: a study on behalf of the acute leukemia working party of the EBMT

2021 ◽  
Author(s):  
Johanna Waidhauser ◽  
Myriam Labopin ◽  
Jordi Esteve ◽  
Nicolaus Kröger ◽  
Jan Cornelissen ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Stem Cell ◽  
Complete Remission ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Allogeneic Stem Cell Transplantation ◽  
Working Party ◽  
Free Survival ◽  
Mutational Status ◽  
First Complete Remission

AbstractAcute myeloid leukemia with runt-related transcription factor 1 gene mutation (RUNX1+ AML) is associated with inferior response rates and outcome after conventional chemotherapy. We performed a retrospective, registry-based analysis to elucidate the prognostic value of RUNX1 mutation after allogeneic stem cell transplantation (alloSCT). All consecutive adults undergoing alloSCT for AML in first complete remission (CR1) between 2013 and 2019 with complete information on conventional cytogenetics and RUNX1 mutational status were included. Endpoints of interest were cumulative relapse incidence, non-relapse mortality, overall and leukemia-free survival (OS/LFS), and GvHD-free/relapse-free survival. A total of 674 patients (183 RUNX1+, 491 RUNX1−) were identified, with >85% presenting as de novo AML. Median follow-up was 16.4 (RUNX1+) and 21.9 (RUNX1−) months. Survival rates showed no difference between RUNX1+ and RUNX1− patients either in univariate or multivariate analysis (2-year OS: 67.7 vs. 66.1%, p = 0.7; 2-year LFS: 61.1 vs. 60.8%, p = 0.62). Multivariate analysis identified age, donor type and poor cytogenetics as risk factors for inferior outcome. Among patients with RUNX+ AML, older age, reduced intensity conditioning and minimal residual disease at alloSCT predicted inferior outcome. Our data provide evidence that the negative influence of RUNX1 mutations in patients with AML can be overcome by transplantation in CR1.

The Significance of Complete Clearance of Peripheral Blasts after 7 Days of Prednisolone in Children with Acute Lymphoblastic Leukemia: Tokyo Children’s Cancer Study Group (TCCSG) Study L99-15.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4524-4524
Author(s):  
Katsuyoshi Koh ◽  
Akira Ohara ◽  
Atsushi Manabe ◽  
Kouichiro Ikuta ◽  
Ryouji Hanada ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Stem Cell Transplantation ◽  
Maintenance Therapy ◽  
Cell Transplantation ◽  
Allogeneic Stem Cell Transplantation ◽  
Risk Group ◽  
Risk Groups ◽  
High Risk Group ◽  
Complete Clearance

Abstract BACKGROUND: A rapid clearance of leukemic blasts in the peripheral blood (PB) is well known to be correlated with a good prognosis in children with ALL. Most groups use a cut-off of Day 8 PB blasts as 1000/μ L. It is possible that patients with no blasts may have an even better outcome. In L99-15 study, we tested the utility of a cut-off of 0 (zero) blasts to stratify children with ALL. OBJECTIVE: To evaluate the significance of complete clearance of peripheral blasts after 7 days of PSL in children with ALL. PATIENTS AND METHODS: Children newly diagnosed as ALL between 1999 and 2003 were consecutively enrolled on the TCCSG L99-15 study. All patients initially received 7 days prednisolone 60mg/m2 monotherapy (without intrathecal therapy) and day 8 PB blasts were classified into 3 categories, 0, 1-999, 1000 or more/μL. Risk stratification was based on the age, initial white blood cell (WBC) count, immunophenotype, cytogenetics and the response to prednisolone. Induction treatment consisted of a standard 4-drug regimen in standard-risk group (SR) groups whereas cyclophosphamide was added in high-risk group (HR) and very high-risk group (HEX). After induction, SR and HR patients received BFM-type early intensification, consolidation, reinduction, and maintenance therapy. HEX patients received early intensification and intensive rotational consolidation therapy including AML-type consolidation, and no maintenance therapy. Total duration of therapy was 3 years for SR, 2 years for HR, and 1year for HEX patients. Allogeneic stem cell transplantation was indicated approximately in 50% of the HEX patients. RESULTS: Totally, 267 (35%) out of 770 children were categorized into SR, 317 (41%) into HR and 186 (24%) into HEX. Remission was obtained in 259 (97%) patients in SR, 311 (98%) in HR and 171 (92%) in HEX. Event-free survival (EFS) (SE) at 4 years was 80.5% (1.7%) in B precursor ALL (n = 669), and 66.0% (5.1%) in T ALL (n = 92). In B precursor ALL, patients with day 8 PB blasts as 0 were 129 (44%) out of 295 initial SR group, 85 (29%) out of 289 initial HR group, 6 (10%) out of 59 initial HEX group, and 4y-DFS was 91.1% (2.6%), 89.4% (3.6%), 83.3% (15.2%), respectively. In T ALL, patients with day 8 PB blasts as 0 were 22 (26%) out of 84, and 4y-DFS was 100% (0%). CONCLUSION: Patients with Day8 PB blasts as 0 (zero) constituted about 30% of all the cases with childhood ALL. Excellent outcome (4-year EFS of 90%) was obtained for those with 0 blasts. Initial Risk Groups WBC/age 1–6y 7–9y 10y– K = 1,000 μL −20K SR HR HR 20–50K HR HR HR 50–100K HR HR HEX 100k– HEX HEX HEX Final Risk Groups day 8 blast 0 1–999 1000– HEX/SCT: HEX and allogeneic stem cell transplantation Initial Risk Groups non-T/SR SR SR HR non-T/HR HR HR HEX non-T/HEX HR HEX HEX/SCT T-ALL HR HEX HEX/SCT

Allogeneic Stem-Cell Transplantation May Overcome the Adverse Prognosis of Unmutated VH Gene in Patients With Chronic Lymphocytic Leukemia

2005 ◽  
Vol 23 (15) ◽  
pp. 3433-3438 ◽  
Author(s):  
Carol Moreno ◽  
Neus Villamor ◽  
Dolors Colomer ◽  
Jordi Esteve ◽  
Rodrigo Martino ◽  
...  
Keyword(s):  
Stem Cell ◽  
Chronic Lymphocytic Leukemia ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Allogeneic Stem Cell Transplantation ◽  
Negative Impact ◽  
Lymphocytic Leukemia ◽  
Mutational Status ◽  
Vh Genes ◽  
Risk Of Relapse

Purpose To investigate whether allogeneic stem-cell transplantation (allo-SCT) may overcome the negative impact of unmutated VH genes in the outcome of patients with chronic lymphocytic leukemia (CLL). Patients and Methods We analyzed the outcome of patients who underwent SCT according to their VH mutational status. Results Thirty-four patients (14 allo-SCT and 20 autologous SCT [auto-SCT]) presented unmutated VH genes and 16 patients presented mutated VH genes (nine allo-SCT and seven auto-SCT). Tumoral burden pre-SCT was significantly higher in the allo-SCT patients independent of the VH mutational status. The risk of relapse was significantly higher after auto-SCT (5-year risk, 61%; 95% CI, 44% to 84%) than after allo-SCT (5-year risk 12%, 95% CI, 3% to 44%; P < .05). In the unmutated group, 13 of 20 auto-SCT and two of 14 allo-SCT patients experienced disease progression, with a risk of relapse at 5 years of 66% (95% CI, 48% to 93%) v 17% (95% CI, 5% to 60%), respectively (P = .01). Conclusion These results show that allo-SCT may overcome the unfavorable effect of unmutated VH genes in patients with CLL.

Imatinib Combined with Chemotherapy and Allogeneic Stem Cell Transplantation Results In Long Time Survival In Patients with De Novo Ph+ AML

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4368-4368
Author(s):  
Jie Sun ◽  
Zhen Wang ◽  
Yi Luo ◽  
Yamin Tan ◽  
Jimin Shi ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Allogeneic Stem Cell Transplantation ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Molecular Response ◽  
Str Analysis ◽  
Hla Dr ◽  
Blast Cells

Abstract Abstract 4368 De novo Philadelphia chromosome-positive acute myeloid leukemia is a rare condition with a poor prognosis. Allogeneic stem cell transplantation (allo-SCT) is always recommended to treat this disease although its results are not always satisfactory even in young patients. Imatinib is a protein tyrosine kinase inhibitor that has now been shown to be active in Ph+ chronic myeloid leukemia and Ph+ acute lymphoblastic leukemia, however its role in Ph+ AML has not been extensively investigated. We present two patients with de novo Ph+ AML who received Imatinib combined with chemotherapy and allogeneic stem cell transplantation (allo-SCT), followed by Imatinib maintainance treatment after allo-SCT. These patients achieved long-term disease-free survival for 34 and 44 months respectively. Patient 1: A 19-year-old woman was admitted in October 2007 with fever and fatigue for one week. Physical examination showed pallor and severe sternal tenderness. Blood routine showed WBC 93.7×109/L, Hb 80.7g/L, platelets 42×109/L, 60% blast cells. Flow cytometry analysis of marrow mononuclear cells showed 84.41% blast cells positive for CD34, 80.49% for HLA-DR, 34.63% for CD13, and 5.71% for MPO. Karyotype at diagnosis was 46, XX, t (9; 22) (q34; 11) in 10 analyzed metaphases. Major BCR/ABL rearrangement (M-BCR-ABL, P210) was positive tested by real-time quantitative polymerase chain reaction(RQ-PCR). She was diagnosed with Ph+ AML (FAB M0). The patient was treated with 2 courses of DA chemotherapy then achieved bone marrow remission after the first course and achieved Complete Hemotology Response (CHR) after the second course. Then another 2 courses of high dose cytarabine were given. The status of minimal residual disease (MRD) was monitored by RQ-PCR for BCR-ABL/ABL ratio. After that BCR-ABL/ABL ratio was 68%, and then oral treatment with Imatinib 300mg/d×14d was started 4 months after diagnosis. Then 2 more cycles of Imatinib (300 mg/day for 14 days) following IA consolidation chemotherapy were taken and the patient maintained CHR and achieved statuses Complete Molecular Response (CMR) by her BCR-ABL/ABL ratio reducing to 0.4% 8 months after diagnosis. Then she took another course of Imatinib 400mg×4w therapy before allo-SCT. The patient underwent allo-SCT from a HLA-identical unrelated donor 9 months after diagnosis. STR analysis showed completely donor phenotype 1, 3 and 6 months after SCT. Imatinib (300 mg/day) was continued 74 days after SCT and the patient remains continuous CHR with Complete Cytogenetic Response (CCyR) and CMR till now. Patient 2: A 46-year-old man was admitted in Dec. 2004 with fever, cough and fatigue. Physical examination showed pallor and a small submaxillary lymphnode on the right. Blood Routine showed Hb 59g/L, platelets 115×109/L, WBC 3.1×109/L, and 24% blast cells. Bone barrow immunophenotype was CD34+, CD13+, CD117+, HLA-DR+ and MPO-. Karyotype analysis showed 46, XY, t (9; 22) (q34; 11) in 10 analyzed metaphases. Major BCR-ABL rearrangement was positive. He was diagnosed as Ph+ AML (FAB M0). The patient received induction chemotherapy as MA/VP plus Imatinib (400 mg/day×4w) and achieved CHR. Imatinib combined chemotherapy continued for another 7 more cycles. Imatinib was taken as 400 mg/day×2 w during the intermission period of chemotherapy. He had a bone marrow relapse with 18% blasts 48 days after the last chemotherapy, although CCyR and CMR were still maintained. Imatinib was added in a dose of 600mg/day and CHR achieved again 1 month later. The patient then took continuous Imatinib (400mg/day) until he received allo-SCT 26months after diagnosis. STR analysis showed completely donor phenotype 1, 3 and 6 months after SCT. Imatinib (400 mg/day) administration was continued and the patient maintained CHR and CMR in the following clinical course. However, he developed interstitial pneumonia 11 months after SCT and died from severe respiratory failure 30 months after SCT with CHR and CMR still maintained at that time. Our cases indicate that Imatinib combined with daunorubicin based chemotherapy followed by allo-SCT and Imatinib maintenance treatment appears to be the best way to treat Ph+ de novo AML, especially when Imatinib is used in an early phase of AML and when a complete molecular response is achieved before allo-SCT. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Clinical Features and Prognosis of Unselected Patients with AML and RAEB-2: Japan Adult Leukemia Study Group CS-07 Study

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5164-5164
Author(s):  
Yasushi Miyazaki ◽  
Sumihisa Honda ◽  
Toru Sakura ◽  
Kiyotoshi Imai ◽  
Masamitsu Yanada ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Allogeneic Stem Cell Transplantation ◽  
Research Funding ◽  
Risk Group ◽  
Study Group ◽  
Age Group ◽  
First Remission ◽  
Adult Leukemia

Abstract [Background] In practice, the clinical features of acute myeloid leukemia (AML) and refractory anemia with excess blasts-2 (RAEB-2) are much more heterogeneous than cases selected in clinical trials. It is also not easy in prospective trials to evaluate the efficacy of allogeneic stem cell transplantation during the first remission for AML, since the selection of treatment is not random but is mostly dependent on the donor availability. In Japan Adult Leukemia Study Group CS-07 study, we tried to see the real world of AML and RAEB-2 in Japan, aiming to see the prognosis and the applicability of known prognostic factors for cases in practice, and to address the efficacy of allogeneic stem cell transplantation for AML during the first remission. [Methods] All AML and RAEB-2 cases that were diagnosed at participating institutions were prospectively registered between Mar 2003 and December 2011. Data of 3054 patients from 117 institutes were updated as of June 2016. [Results] Male patients were predominant (n=1,944); female (n=1,100). Mean age at the diagnosis was 61.3 years (range, 15 to 96 years), and the disease type was diagnosed as de novo, secondary, and therapy-related in 2,255, 593, and 206 patients, respectively. Among 2937 patients with available cytogenetic data, 517, 1626, and 794 patients were classified in the favorable-, intermediate-, and adverse-risk group, respectively. Transplantation was performed in 23.3% of cases, and 39.8% were done during the first remission. For AML, the 3- and 5-year overall survival rate (OS) was 36.3% (SE 1.0%) and 32.5% (SE 1.0%), and those for RAEB-2 were 19.4% (SE 2.2%) and 13.3% (SE 4.2%), respectively. OS in favorable-, intermediate-, and adverse-risk group were 89.6% and 80.6%, 75.4% and 48.2%, and 39.7% and 17.3%, respectively, for younger patients (P<.001), and were 69.0% and 56.5%, 49.1% and 37.3%, and 18.9% and 3.7%, respectively, for elderly patients (P<.001). Age group was significantly related with the clinical results. To address the efficacy of allogeneic transplantation during the first remission, the propensity score analysis was performed making nested pairs in these registered cases, in which transplantation did not demonstrate the significant improvement of OS. [Conclusion] The result of this study would mirror the overall features of AML and RAEB-2 patients in our country, and confirmed the prognostic values of age group, and cytogenetic risk not only in younger but also in elderly patients. The usefulness of allogeneic stem cell transplantation for AML during the first remission needs to be addressed further in "real world" situation. Disclosures Aoyama: Alexion: Honoraria. Kiyoi:Chugai Pharmaceutical Co., Ltd.: Research Funding; Kyowa Hakko Kirin Co., Ltd.: Research Funding; Zenyaku Kogyo Co., Ltd.: Research Funding; Nippon Shinyaku Co., Ltd.: Research Funding; Astellas Pharma Inc.: Consultancy, Research Funding; Eisai Co., Ltd.: Research Funding; Alexion Pharmaceuticals: Research Funding; Nippon Boehringer Ingelheim Co., Ltd.: Research Funding; FUJIFILM Corporation: Patents & Royalties, Research Funding; JCR Pharmaceutlcals Co.,Ltd.: Research Funding; AlexionpharmaLLC.: Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; Toyama Chemikal Co.,Ltd.: Research Funding; Mochida Pharmaceutical Co., Ltd.: Research Funding; Novartis Pharma K.K.: Research Funding; MSD K.K.: Research Funding; Takeda Pharmaceutical Co., Ltd.: Research Funding; Phizer Japan Inc.: Research Funding; Yakult Honsha Co.,Ltd.: Research Funding; Celgene Corporation: Consultancy. Kobayashi:SymBio Pharmaceuticals: Research Funding; Celgene: Research Funding; Pfizer: Research Funding; Ohtsuka Pharmaceutical: Research Funding; Ariad: Research Funding. Naoe:Kyowa-Hakko Kirin Co.,Ltd.: Honoraria, Patents & Royalties, Research Funding; Pfizer Inc.: Research Funding; Fujifilm Corporation: Honoraria, Patents & Royalties, Research Funding; Sumitomo Dainippon Pharma Co.,Ltd.: Honoraria, Research Funding; Chugai Pharmaceutical Co.,LTD.: Honoraria, Patents & Royalties; Celgene K.K.: Honoraria, Research Funding; CMIC Co., Ltd.: Research Funding; TOYAMA CHEMICAL CO.,LTD.: Research Funding; Otsuka Pharmaceutical Co.,Ltd.: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria; Nippon Boehringer Ingelheim Co., Ltd.: Honoraria, Research Funding; Astellas Pharma Inc.: Research Funding; Amgen Astellas BioPharma K.K.: Honoraria.

scholarly journals Favorable impact of allogeneic stem cell transplantation in patients with therapy-related myelodysplasia regardless of TP53 mutational status

Haematologica ◽  
2017 ◽  
Vol 102 (12) ◽  
pp. 2030-2038 ◽  
Author(s):  
Ibrahim Aldoss ◽  
Anh Pham ◽  
Sierra Min Li ◽  
Ketevan Gendzekhadze ◽  
Michelle Afkhami ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Allogeneic Stem Cell Transplantation ◽  
Mutational Status ◽  
Tp53 Mutational Status

NPM1 Mutations Are Valid Minimal Residual Disease Parameters Following Allogeneic Stem Cell Transplantation: A Study on 116 AML Patients.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1655-1655
Author(s):  
Ulrike Bacher ◽  
Anita Badbaran ◽  
Axel R. Zander ◽  
Boris Fehse ◽  
Nicolaus Kroger
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Minimal Residual Disease ◽  
Cell Transplantation ◽  
Quantitative Pcr ◽  
Allogeneic Stem Cell Transplantation ◽  
Residual Disease ◽  
Npm1 Mutation ◽  
Minimal Residual ◽  
Mutation Type

Abstract Mutations of the Nucleophosmin gene (NPM1) account for the most frequent molecular markers in acute myeloid leukemia (AML). A very limited number of studies analyzed the prognostic impact of NPM1 mutations in minimal residual disease (MRD) diagnostics, but so far no study analyzed the predictive value following allogeneic stem cell transplantation (SCT). We here performed a retrospective study by quantitative PCR in 116 patients with AML who received allogeneic stem cell transplantation (SCT) between January 2002 and May 2007 in the University Medical Center Hamburg-Eppendorf. We retrospectively performed mutational screening by PCR for NPM1 mutations in 116 pts with AML from bone and peripheral blood marrow samples which had been taken before and after SCT. Cases that were positive for the NPM1 mutation type A before SCT were analyzed by quantitative Taqman based real-time PCR as assessed by a standard curve based on the dilution of the OCI/AML3 cell line in the buffy coat of healthy donors. Cases with the mutation type B were analyzed by semiquantitative methods. In total 139 quantitative PCR analyses were performed during a median follow-up of 216 days after SCT (mean 370; range 35–1825 days) at a median of 7 time points (mean 9; r. 2–25) per patient. Results were correlated with cytomorphology, chimerism, and the clinical course. NPM1 mutations of the subtype A were detected in 13/116 pts (11.2%) before SCT, and a mutation of the subtype B was detected in 1/15 pts (0.7%). There were 6 male pts and 8 females (median age: 47 years; range 21–66 years), who received standard conditioning in 8 and reduced intensity conditioning in 7 transplantations (one patient had two allogeneic transplantations due to relapse of AML after the first SCT). Cytogenetics showed a normal karyotype in 12/13 available cases and a del(20q) in one case. 11/14 had de novo AML, 2/14 pts had secondary AML following myelodysplastic syndrome (MDS), and one had CMML-2. At the time of SCT, 3 pts were at first manifestation, 9 at the first and 3 at the second relapse of the disease. The 4 pts with &lt;5% of bone marrow blasts before SCT all had residual levels of the NPM1 mutation (NPM1mut) ≤0.1%. All 3 pts with ≥11% NPM1mut positive cells at the time of SCT relapsed. After SCT, 10/14 pts became NPM1mut negative, whereas 4 remained NPM1mut positive. All 4/14 pts (29%) who achieved stable remissions became PCR-negative after SCT, whereas all 4 pts who remained PCR-positive after SCT developed relapse. The relapse rate after SCT was 10/15 cases (67%) (the patient with two transplantations had another relapse after the 2. SCT). In 9/10 cases (90%) relapse was associated with an increase in NPMmut positivity. In 6/7 cases (86%) for which the exact time point of relapse was established, an increase in NPM1mut levels preceded the morphological manifestation of relapse with a mean interval of 24 days (range 12–38 days). The increase of NPM1mut was detected by PCR earlier than the decrease of chimerism in 6/9 cases (67%) with a mean interval of 15 days (range 1–36 days). Conclusions: The quantitative assessment of NPM1 mutations provides a reliable MRD marker in pts with AML for the allogeneic transplantation setting and predicts relapse earlier than morphology or chimerism. This might be helpful for earlier therapeutical interventions such as withdrawal of immunsuppression or adoptive immunotherapy by donor lymphocyte infusions (DLI).

Contribution of IPSS-R Cytogenetics to Predict Outcome after Allogeneic Stem Cell Transplantation for Myelodysplastic Syndromes: A Study from the French Society of Bone Marrow Transplantation and Cell Therapy (SFGM-TC)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5609-5609
Author(s):  
Jordan Gauthier ◽  
Damaj Gandhi ◽  
Carole Langlois ◽  
Marie Robin ◽  
Patrice Chevallier ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Allogeneic Stem Cell Transplantation ◽  
Myelodysplastic Syndromes ◽  
Conflicts Of Interest ◽  
Risk Group ◽  
Poor Risk ◽  
The Poor ◽  
The Impact

Abstract The prognosis of myelodysplastic syndromes (MDS) after allogeneic stem cell transplantation (allo-SCT) is critically determined by cytogenetic abnormalities. In this study, we assessed the impact of the IPSS-R cytogenetic score (C-IPSS-R) on the outcome of 367 patients with MDS transplanted from HLA-identical siblings or HLA allele-matched unrelated donors. According to the C-IPSS-R 178 patients (48%) fell in the good risk, 102 (28%) in the intermediate risk, 77 (21%) in the poor risk and 10 (3%) in the very poor risk group. In multivariate analysis, the poor and very poor-risk categories correlated with shorter overall survival (HR = 1.59, P = 0.009 and HR = 3.18, P = 0.002, respectively) and higher relapse rates (HR = 1.82, P = 0.004 and HR = 2.44, P = 0.060, respectively), after a median follow-up of 4 years. Overall, the C-IPSS-R changed the IPSS cytogenetic risk only in 8% of cases but identified a new risk group with dismal prognosis. These findings urge the investigation of new post-transplant therapeutic approaches for patients with very poor C-IPSS-R karyotypes, including maintenance therapy. Disclosures No relevant conflicts of interest to declare.

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