A Distinct Signature of Natural Killer Cell KIR Gene Frequencies In Secondary AML Compared with De Novo AML and Normal Controls

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1697-1697
Author(s):  
Kate Stringaris ◽  
A. John Barrett ◽  
Robert Hills ◽  
David C Linch ◽  
Rosemary Gale ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
De Novo ◽  
Gene Frequencies ◽  
Secondary Aml ◽  
Kir Genes ◽  
De Novo Aml ◽  
Normal Controls ◽  
Kir Gene

Abstract Abstract 1697 There is increasing evidence for the role of KIR genetics in predicting outcome of haematological malignancies. We recently showed that donor (but not recipient) KIR genes 2DS1, 3DS1 and 2DL5a are associated with significantly less relapse in AML patients following matched sibling allogeneic stem cell transplantation. Interestingly, this effect was not seen in patients with AML secondary to MDS but only in de novo AML.1 To explore whether outcome of non-transplant treatment for AML might be affected by KIR genetics we performed KIR genotyping on the DNA sample archive from the Medical Research Council UK AML 10 and 15 trials. All patients underwent four courses of chemotherapy according to MRC protocols. KIR genotyping was performed using Qiagen SSP PCR KIR genotyping kits as previously described.1 We measured KIR gene frequencies in AML samples obtained at diagnosis from 469 de novo AML, and 38 secondary AML and compared the gene distribution with that of a normal control population of 246 individuals. To allow for multiple comparisons, significance was set at p<0.01. The KIR gene frequencies of de novo AML did not differ significantly from those of the normal population but frequency of KIR 2DS2 was significantly lower in secondary AML compared to de novo AML (26% vs. 51% for KIR 2DS2, p=0.004 vs. 44% (111/246) for normal controls). There was some evidence that KIR 2DL2, which shows linkage disequilibrium with KIR 2DS2, was also reduced in secondary AML (32% v 54%, p=0.009). Rates of KIR 2DS2 and KIR 2DL2 were lower in both secondary groups: therapy-related AML (t-AML) and antecedent haematological disorders. Interestingly, patients with t-AML had lower rates of KIR HaploB than those without t-AML (27% v 67%, p=0.005). However, analyses of the AML cohort adjusted for known prognostic factors showed no significant prognostic effect of any single KIR group, or KIR B haplotype. These results suggest that inheritance of KIR 2DS2 may be protective for the development of secondary AML and that individuals lacking haplotype B KIR genes are more prone to develop t-AML. These observations raise the possibility that KIR gene inheritance determines the efficiency of immunosurveillance of AML by NK cells.Figure 1.Distribution of the variably inherited KIR genes in secondary AML compared to de novo AML and normal controlsFigure 1. Distribution of the variably inherited KIR genes in secondary AML compared to de novo AML and normal controls 1. Donor KIR Genes 2DL5A, 2DS1 and 3DS1 Are Associated with a Reduced Rate of Leukemia Relapse After HLA-Identical Sibling Stem Cell Transplantation for Acute Myeloid Leukemia but Not Other Hematologic Malignancies. Stringaris K, Adams S, Uribe M, Eniafe R, Wu CO, Savani BN, Barrett AJ. Biol Blood Marrow Transplant. 2010 Mar 16. [Epub ahead of print] Disclosures: Linch: Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees.

scholarly journals The Prognostic Impact of the Diagnostic CD34+/CD38- Cell Burden and Expression of the Stem Cell Marker GPR56 after Stem Cell Transplantation Depends on the AML Origin

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 323-323
Author(s):  
Madlen Jentzsch ◽  
Marius Bill ◽  
Juliane Grimm ◽  
Dominic Brauer ◽  
Julia Schulz ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Solid Tumors ◽  
Cell Transplantation ◽  
Research Funding ◽  
De Novo ◽  
Prognostic Impact ◽  
Expression Levels ◽  
Rheumatologic Diseases ◽  
De Novo Aml

Introduction: Acute myeloid leukemia (AML) developing secondary after other hematologic diseases, or therapy related after cytotoxic treatment for solid tumors or rheumatologic diseases (s/tAML) is clinically, genetically & prognostically distinct from de novo diseases. Data indicate that s/tAML patients (pts) have inferior outcome compared to de novo cases after chemotherapy & therefore often require consolidation therapy using allogeneic stem cell transplantation (HSCT). Leukemic stem cells (LSC) initiate & maintain AML. They are also believed to exist within the CD34+/CD38- &/or high GPR56 expressing bone marrow (BM) population, which have been shown to impact adversely on outcome. The prognostic impact of LSC markers in de novovs s/tAML after HSCT with non-myeloablative conditioning intensity - where the therapeutic approach also relies on immunological graft-versus-leukemia effects - is unknown. Methods: We analyzed 379 AML pts who received an allogeneic peripheral blood HSCT in complete remission (CR, 82%) or CR with incomplete peripheral recovery (CRi, 18%) between 1999 & 2018 after non-myeloablative (3x30 mg/m2 Fludarabine & 2 Gy total body irradiation) conditioning. At diagnosis, cytogenetic & flow cytometric analyses were performed centrally. For pts with pre-treatment BM available the mutation status of CEBPA, NPM1 & presence of FLT3-ITD by fragment analyses as well as expression levels of GPR56 by qPCR were assessed. Using a next-generation targeted amplicon sequencing approach we analyzed a panel comprising 54 recurrently mutated (mut) genes in myeloid malignancies on the MiSeq platform (Illumina). Median follow up after HSCT was 3.7 years. Results: 229 pts (60%) had de novo & 150 pts (40%) had AML secondary to myelodysplastic syndrome (MDS, n=82), myeloproliferative neoplasm (MPN, n=22) or MDS/MPN (n=10), or therapy related after Non-Hodgkin lymphoma (n=9), solid tumors (n=25) or rheumatologic diseases (n=2). At diagnosis, s/tAML pts had lower white blood counts (P=.03), lower blasts in BM (P&lt;.001) or blood (P=.007) & a higher BM CD34+/CD38- cell burden (P=.01) & GPR56 expression (P=.04). They also had worse European LeukemiaNet risk (P=.007), were less likely to have a normal karyotype by trend (P=.06), to have a core binding factor AML (P=.02), to be NPM1mut (P=.003), DNMT3Amut (P=.03) & to harbor a FLT3-ITD (P=.002) but more likely to be JAK2mut (P&lt;.001). Comparing pts with s/tAML vsde novo AML, there was no significant different cumulative incidence of relapse (CIR, P=.85) or overall survival (OS, P=.29). Next, we evaluated the prognostic impact of the LSC-associated populations in pts with de novo or s/tAML separately. In pts with de novo AML, we observed a significantly higher CIR & shorter OS for pts harboring a high CD34+/CD38- cell burden (high vs low, 6% cut, P=.006 [Fig. 1A] & P=.003) & a higher CIR but not significantly different OS for pts with a low GPR56 expression (high vs low, median cut, P=.03 [Fig. 1B] & P=.95). Combining both parameters, we observed a stepwise higher CIR & shorter OS for pts with low expression of both variables vs pts with a low CD34+/CD38- cell burden but high GPR56 expression vs pts with a high CD34+/CD38-cell burden (P=.003 [Fig. 1C] & P=.05). In contrast, in pts with s/tAML, there was no prognostic significance of the CD34+/CD38- cell burden (CIR P=.38 [Fig. 1D] & OS P=.95), the GPR56 expression (CIR P=.64 [Fig. 1E] & OS P=.82) & both markers combined (CIR P=.57 [Fig. 1F] & OS P=.98). Also in multivariate analyses, the combination of both markers significantly impacted CIR (Hazard ratio 2.49, P&lt;.001 after adjustment for donor type) & was the only significant factor for OS (Odds Ratio 0.68, P=.04) in de novo AML but not in s/tAML. Conclusion: While there was no significantly different CIR or OS in s/tAML compared to de novo AML pts undergoing non-myeloablative HSCT we observed a significant impact on outcome for the known LSC-associated prognosticators CD34+/CD38- cell burden & GPR56 expression levels at diagnosis only in de novo AML pts. Different underlying disease biology & possibly different LSC-associated populations may be relevant for disease reoccurrence in s/tAML. Figure Disclosures Jentzsch: Novartis: Honoraria; Jazz Pharmaceuticals: Honoraria. Niederwieser:Daichii: Speakers Bureau; Cellectis: Consultancy. Platzbecker:Abbvie: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Schwind:Daiichi Sankyo: Honoraria; Novartis: Honoraria, Research Funding.

Induction with Combined Modality Therapy Followed by Immunomodulated Post Remission Therapy for Newly Diagnosed Acute Myeloid Leukemia (AML).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2802-2802
Author(s):  
Seema Gupta ◽  
Mark A. Weiss ◽  
Joseph G. Jurcic ◽  
Suzanne Chanel ◽  
Bri-Anne Wilson ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
De Novo ◽  
Combined Modality Therapy ◽  
Initial Therapy ◽  
Gm Csf ◽  
Combined Modality ◽  
De Novo Aml

Abstract Targeted modalities are playing a an increasing role in modern oncology. We have previously demonstrated that the unconjugated humanized anti-CD33 monoclonal antibody, HuM195 has activity in the setting of relapsed AML. Given these results, we designed a clinical trial investigating whether antibody therapy can be combined with other therapeutic approaches including dose intensive chemotherapy and drug/growth factor immunomodulation as the initial therapy for adults with AML and whether such patients can safely proceed to stem cell transplantation. Patients in this study were treated with MEC (mitoxantrone 8 mg/m2, etoposide 80 mg/m2, and cytarabine 1 gm/m2 daily for 6 days). HuM195 was administered for 4 days at a dose of 12 mg/m2 on days 6–9 and days 19–22. GM-CSF (250 ug/m2/day) was begun on day 8 and continued until neutrophil recovery. Patients who achieved CR and had a suitable related donor proceeded directly to allogeneic stem cell transplantation (SCT). Others received two additional cycles of high-dose cytarabine followed by autologous SCT augmented by combination cyclosporin and GM-CSF in an effort to induce an autologous graft versus leukemia (GvL) effect. Thirty patients have been treated to date (15 patients with de novo AML; 15 patients with secondary AML). The median age was 51 years (range 24–71). Nineteen of the 28 evaluable patients (68%) achieved CR with 14 of the 15 (93%) de novo AML patients achieving a CR. Three deaths from uncontrolled infection occurred during induction. In patients achieving CR, the median time to recover an ANC &gt; 500/mm3 was 23 days (range 20–36) and a platelet count &gt; 20,000/mm3 was 17 days (range 12–42). Four patients proceeded directly to allogeneic stem cell transplantation without any consolidation therapy and three remain free of disease with a median follow-up of 24 months. One patient is too early for evaluation. Five patients went on to autologous stem cell transplant (AuSCT) and two remain in remission after 13 and 24 months. Three patients relapsed after AuSCT. Two expired from refractory leukemia, and one was salvaged with allogeneic SCT. Among the AuSCT patients, the median time to recovery of the ANC &gt; 500/mm3 and platelet count &gt; 20k/mm3 was 7 days (range 1–9) and 7.5 days (range 5–22), respectively, comparable to patients who received standard induction regimens. There was no clinical evidence of graft verses host disease in the AuSCT patients. No evidence of veno-occlusive disease was observed after either autologous or allogeneic transplantation. Preliminary results suggest combined modality therapy is feasible and well-tolerated as initial therapy for AML. Patients are able to receive dose intensive consolidation therapy including transplantation safely after the use of an intensive induction with combined modality therapy incorporating HuM195. All patients who underwent an allograft after induction remain in remission with two year follow up. Further follow-up is needed to determine the effect on long term outcomes.

scholarly journals Impact of Somatic Mutations on Clinical Outcomes Following Flamsa-Bu Conditioning and Allogenic Stem Cell Transplantation in Patients with Poor-Risk Myeloid Malignancies

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2277-2277
Author(s):  
Karl Haslam ◽  
Niamh Appleby ◽  
Christopher Armstrong ◽  
Catherine M. Flynn ◽  
Stephen Langabeer ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Myeloid Leukemia ◽  
Somatic Mutations ◽  
De Novo ◽  
Driver Mutations ◽  
Prognostic Impact ◽  
Poor Risk ◽  
De Novo Aml

Abstract Allogeneic stem cell transplantation (allo-SCT) offers a potentially curative option for eligible patients with poor-risk myeloid malignancies. The prognostic impact of specific mutations such as TP53 is unclear in this context1,2. We report the prognostic impact of mutations in a panel of 19 genes (covering entire coding regions of DNMT3A, CEBPA, GATA2, TET2, TP53 and mutation hot spots of ASXL1, BRAF, CBL, FLT3, IDH1, IDH2, JAK2, KIT, KRAS, NPM1, NRAS, PTPN11, RUNX1 and WT1) identified by targeted sequencing in patients undergoing allo-SCT with FLAMSA-Bu conditioning. Twenty-one patients (10 male, 11 female; median age 55 years; range 36-64 years) were included and identified as having poor risk disease on the basis of acute myeloid leukemia (AML) with primary induction failure (n=5), myelodysplasia (MDS) with high or very high risk R-IPSS scores (n=8, 4 of whom had therapy related MDS), therapy related acute myeloid leukemia with MLL rearrangement (n=1), intermediate-2 or high risk prognostic score for chronic myelomonocytic leukemia (CMML) (n=4), blast crisis of chronic myeloid leukemia (n=1), primary myelofibrosis with blasts > 10% on bone marrow trephine (n=1), mixed phenotype acute leukemia (T/myeloid) with complex karyotype (n=1). Overall, complex karyotypes were detected in 8/21 (38.1%) patients. The median Hematopoietic Cell Transplantation-Comorbidity Index score was 4 (range 0-10). All 21 patients underwent allo-SCT with fludarabine, cytarabine, amsacrine, busulphan, and anti-thymocyte globulin (FLAMSA-Bu) conditioning. Twelve (57.1%) received stem cells from fully HLA matched unrelated donors. Neutrophil engraftment occurred at a median of 24 days (range 11-124 days) and platelet engraftment at a median of 26 days (range 10-221 days) post-transplant. Seven (33.3%) patients developed acute graft versus host disease (GVHD). Ten (47.6%) patients received planned donor lymphocyte infusions. Genomic DNA was available from 16/21 patient samples and was sequenced using the Ion-Torrent platform. Somatic driver mutations were identified in 13/16 (81.2%) patients, 10 of whom had two or more driver mutations. TET2 mutations were the most common lesion, detected in 6/16 (37.5%) cases, followed by RUNX1, ASXL1 and DNMT3A in 3/16 (18.8%) patients each. Ten (47.6%) patients remain alive and disease-free after a median of 19.3 months follow-up. Two treatment-related deaths occurred; one from sepsis in the context of steroid-refractory GVHD and a second patient died of toxoplasmosis infection. Nine (42.9%) patients have relapsed post allo-SCT, three of whom remain alive following salvage therapy. The median progression free survival (PFS) is 841 days and the median overall survival (OS) has not yet been reached. Patients with therapy-related myeloid neoplasms trended towards shorter PFS and OS compared with all other diagnosis (396 vs 841 days, p=0.54; 373 days vs undefined, p=0.11, respectively). All four CMML patients have relapsed at a median of 694 days post FLAMSA-Bu allo-SCT. The median PFS for de novo AML and MDS has not been reached. Monosomal karyotype was associated with a non-significant trend towards shortened PFS (148 days vs 751 days, p=0.11). Cases with TET2 mutations trended towards a shorter PFS compared with wild-type TET2 (751 days vs undefined, p=0.6407) but this did not reach statistical significance. No difference was observed in PFS between TP53 mutated vs wild-type TP53 cases (517 days vs 751 days, p=0.99). FLAMSA-Bu allo-SCT remains a viable treatment option for selected patients with de novo AML and MDS, even patients in whom multiple or adverse somatic mutations are detected. Conversely, durable remissions are uncommon for patients with therapy-related myeloid neoplasms or CMML. These patients may benefit from consideration for alternative treatment strategies. References: 1. Christopeit, M., Badbaran, A., Alawi, M., et al. (2016), Correlation of somatic mutations with outcome after FLAMSA-busulfan sequential conditioning and allogeneic stem cell transplantation in patients with myelodysplastic syndromes. Eur J Haematol. doi:10.1111/ejh.12724 2. Bejar, R., Stevenson, K.E., Caughey, B., et al (2014), Somatic Mutations Predict Poor Outcome in Patients With Myelodysplastic Syndrome After Hematopoietic Stem-Cell Transplantation. JCO 32(25) 2691-2698. Table Patient population and transplant characteristics Table. Patient population and transplant characteristics Disclosures No relevant conflicts of interest to declare.

Allogeneic Stem Cell Transplantation with Reduced Intensity Conditionning Regimen (RIC) for Adult Patients with AML: Same Results in Secondary and De Novo AML.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3015-3015
Author(s):  
Noel-Jean Milpied ◽  
Reza Tabrizi ◽  
Thierry Guillaume ◽  
Patrice Chevallier ◽  
Arnaud Pigneux ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Allogeneic Stem Cell Transplantation ◽  
De Novo ◽  
Negative Impact ◽  
Chronic Gvhd ◽  
Disease Status ◽  
Secondary Aml ◽  
Autologous Transplant

Abstract We have evaluated the outcome of RIC in 114 adult pts with AML either de novo (74) or secondary to cancer or MDS (40). There were 43 men, median age was 55 yo (22–65). Cytogenetic was available in 104 and was abnormal in 55 (favorable: 13; intermediate: 21; poor: 21). Pts had received a median of 1 line of Tx before RIC (0–3). Twenty had a previous autologous transplant. At time of RIC, 28 patients were refractory or in relapse while 71 were in CR (1st: 48; 2d: 20). The donor was an id sib for 80 and a MUD in 34 (with1allelic mismatch in 6). The cond regimen was of Slavin type in 56, only 11 pts received the Seattle program. Overall 74 had ATG as part of cond reg. GVHD prophylaxis consisted of CSA or CSA-MTX in 95 pts, 14 had CSA-MMF. With a median FU of surviving pts of 21 m (3–73) the 3y survival (OS) and EFS are 40% and 38% respectively. Sixty pts died with the main cause of death being relapse. The probability of TRM at 100 d and 1 y are 7% and 14% respectively. The 2y probability of relapse is 50%. These figures are strictly superimposable for pts with de-novo or secondary AML. The factors affecting significantly (p<0.05) the 3y OS and EFS were: disease status at time of RIC (50% vs 0 to 24% in pts in CR vs not), the N° of previous lines of Tx (55% vs 0 to 24% after one line vs more), an id sib as donor ( 45% vs 32% for OS and 44% vs 19% for EFS), having an aGVHD grade 1 or 2 ( OS: 75% vs 25% if aGVHD grade 3–4 vs 38% if no aGVHD), and a CGVHD limited or extensive (OS: 50% or 78% respectively vs 29% if no CGVHD; EFS: 50% or 56% respectively vs 29% if no CGVHD). The single factors that affected the risk of relapse was the occurence of an acute and or chronic GVHD. The TRM was significantly increased in pts with previous autologous transplant, a MUD, an aGVHD and a female donor. Conclusion: RIC allo is well tolerated ( max TRM :14% at 1 y) and allows the same result in de-novo and secondary AML. The best results are achieved in patients in CR1 ( 3y OS and EFS: 63% and 62% respectively) whatever was the type of donor. As most of the pts beyond CR1 were transplanted with a MUD, it is not possible to separate the negative impact of advanced disease or MUD. An active search of a donor at the time of diagnosis, particularly in patients with secondary AML, could allow early RIC with MUD in pts with an indication of allogeneic stem cell transplantation.

The Distribution of KIR Gene in Chinese Population and the Effect of Donor KIR and Patient HLA Genotypes on Outcome Following Allogeneic Hematopoietic Stem Cell Transplantation.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2236-2236
Author(s):  
He Huang ◽  
Gongqiang Wu ◽  
Xiaoyu Lai ◽  
Yamin Tan ◽  
Yi Luo ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Nk Cells ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Chinese Population ◽  
Hematopoietic Stem ◽  
Kir Genes ◽  
Kir Gene

Abstract Killer cell immunoglobulin-like receptors (KIR) are a family of inhibitory and activatory receptors and are expressed by most NK cells. The interaction between KIR and human leukocyte antigen (HLA) molecules expressed on target cells is known to modulate the cytolytic activity of NK cells. At present, seventeen KIR genes have been identified, and the number of KIR gene loci has been reported to vary among individuals, resulting in a heterogeneous array of KIR genes in different populations. KIR haplotypes are divided into two distinctive groups based on their gene contents. Ruggeri, et al, first reported that KIR-ligand mismatch can alleviate aGVHD, reduce relapse and improve disease-free survival in mismatched hematopoietic stem cell transplants, while some studies show that this kind of mismatch is deleterious. Now the effect of NK cells alloreactivity on outcome of hematopoietic stem cell transplantation remains controversial. Our study is to analyze the KIR gene contents and investigate the impact of KIR-ligand mismatch on outcome following hematopoietic stem cell transplantation in Chinese population. METHODS: 203 cases of allogeneic hematopoietic stem cell transplantation between Jan. 2001 to May. 2008 were involved in the study. KIR genes were typed by using PCR-SSP, and HLA-A, -B and -C loci genes were used by PCR-SSP or PCR-SSO technology. KIR-ligand incompatibility were assessed based on HLA-Cw (divided into C1 and C2 group) and three major inhibiting KIR genotypes (KIR2DL1, KIR2DL2 and KIR2DL3) of 203 donor/recipient pairs. These patients received myeloablative (n=180) or nonmyeloablative (n=23, with ATG) conditioning followed by hematopoietic stem cell transplantation from HLA matched (n=164) or mismatched (n=39) donors. All patients received mycophenolate mofetil (MMF) combined with CsA and short course MTX regimen as prophylaxis for aGVHD. RESULTS: All seventeen KIR genes were observed in the Chinese population. Framework genes KIR3DL3, KIR3DP1, KIR2DL4 and KIR3DL2 were present in all individuals. The most frequent non-framework KIR genes were: KIR2DL1 (99.5%), KIR3DL1 (97.0%), KIR 2DS4 (97.5%), KIR2DL3 (99.5%) and KIR2DP1 (99.5%). The other gene frequencies were KIR2DS2 (25.1%), KIR2DL2 (25.6%), KIR2DL5A (32.5%), KIR2DL5B (30.0%), KIR2DS5 (23.6%), KIR2DS1 (43.8%), KIR2DS3 (21.2%) and KIR3DS1 (34.0%). The most prevalent haplotype group found in the population was A haplotype. Group A haplotypes outnumbered group B haplotypes in frequency by approximately 3:1, with individuals having two group A haplotypes accounting for 48.8% (99/203). HLA genotyping showed that 156 out of 203 (76.8%) donor-recipient pairs could be characterized by lack of recipient HLA-Cw ligand for donor KIR2DL1, KIR2DL2/2DL3. KIR-ligand mismatch was not associated with any deleterious or beneficial influence on relapse or overall survival (OS) in Chinese population with hematopoietic stem cell transplantation. But KIR-ligand mismatch could lead to a decreased incidence of aGVHD (36.1% vs 56.3%, P=0.018). When donor NK cells had KIR2DS2 gene, the recipient acquired a decreased incidence of aGVHD (13.2% vs 49.3%, P&lt;0.001), and had better OS (20.8% vs 34.7%, P=0.041). We also found that the presence of donor KIR2DS5 have a positive effect on aGVHD (25.0% vs 44.5%, P=0.011), however, it didn’t improve OS (27.1% vs 32.9%, P=0.197). There was almost no effect on relapse rate even if donor expressed KIR2DS2 or KIR2DS5. CONCLUSION: Our data demonstrated that Chinese population was distinct in KIR gene frequencies and putative KIR haplotypes in comparison to some other populations. KIR-HLA mismatch was not any better effect on relapse, OS, but it had a better effect on aGVHD. Donors with gene KIR2DS2 or KIR2DS5 were associated with lower incidence of aGVHD in allogeneic hematopoietic stem cell transplantation.

Autologous or allogeneic stem cell transplantation versus chemotherapy in acute myeloid leukemia and subgroups: A multicenter trial by the German AML Cooperative Group

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 6556-6556
Author(s):  
T. Buchner ◽  
W. E. Berdel ◽  
J. Kienast ◽  
H. Kolb ◽  
P. Staib ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Allogeneic Stem Cell Transplantation ◽  
De Novo ◽  
Multicenter Trial ◽  
Matched Pair ◽  
Secondary Aml ◽  
Matched Pair Analysis ◽  
Present Trial

6556 Background: From the data available the role of autologous and allogeneic stem cell transplantation (auto/allo SCT) versus post-remission chemotherapy appears uncertain and is readdressed in the present trial. Methods: Pts were stratified for cytogenetic groups, de-novo/secondary AML, LDH, WBC, and were up-front randomized in one step to induction by HAM-HAM vs TAD-HAM, and to G-CSF priming vs. no G-CSF. These two randomizations did not result in different outcome. Pts were also upfront randomized to auto SCT vs monthly maintenance chemotherapy. Within the two randomized arms pts with histocompatible family donors underwent priority allo SCT. Results: Since 1999 840 pts 16–60 y of age entered the trial. 14%, 62%, 21%, and 3% of pts had favorable, intermediate, unfavorable and unknown karyotype, and 19% had secondary AML. 70% of pts went into complete remission (CR). The probability of overall survival (OS) at 3 years in the auto SCT and the maintenance arm is 43% vs 41% (p=0.52), the relapse-free survival (RFS) is 40% vs 40% (p=0.78), and the ongoing remission duration (RD) is 48% vs 46% (p=0.65). Among pts alive and in CR 73% did receive auto SCT or maintenance or allo SCT, similar to previous trials (NEJM 332:217,1995, Blood 90:2978,1997, Lancet 351:700,1998, NEJM 339:1649,1998). The outcome according to therapy given in the auto SCT arm and the maintenance arm shows ongoing RD of 44% vs 50% (p=0.31), RFS of 44% vs 48% (p=0.35), and OS of 53% vs 69% (p=0.005). 128 pts underwent allo SCT. In a matched pair analysis with concordance of pairs in karyotype, de-novo/secondary AML, induction chemotherapy, and RFS at the time of SCT, RD shows a superiority of allo SCT (p<0.001), while OS is similar between the two arms (p=0.65). No prognostic subgroup with a special benefit from auto or allo SCT can be identified so far. Conclusions: Among current alternative strategies only novel approaches in allo SCT reducing the high transplant related death rate may further improve the cure of pts with AML and subgroups. No significant financial relationships to disclose.

scholarly journals ELN risk stratification and outcomes in secondary and therapy-related AML patients consolidated with allogeneic stem cell transplantation

2020 ◽  
Author(s):  
Madlen Jentzsch ◽  
Juliane Grimm ◽  
Marius Bill ◽  
Dominic Brauer ◽  
Donata Backhaus ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Risk Stratification ◽  
Cell Transplantation ◽  
Allogeneic Stem Cell Transplantation ◽  
De Novo ◽  
Residual Disease ◽  
Disease Status ◽  
Dismal Prognosis ◽  
De Novo Aml

AbstractSecondary or therapy-related acute myeloid leukemia (s/tAML) differs biologically from de novo disease. In general s/tAML patients have inferior outcomes after chemotherapy, compared to de novo cases and often receive allogeneic stem cell transplantation (HSCT) for consolidation. The European LeukemiaNet (ELN) risk stratification system is commonly applied in AML but the clinical significance is unknown in s/tAML. We analyzed 644 s/tAML or de novo AML patients receiving HSCT. s/tAML associated with older age and adverse risk, including higher ELN risk. Overall, s/tAML patients had similar cumulative incidence of relapse (CIR), but higher non-relapse mortality (NRM) and shorter overall survival (OS). In multivariate analyses, after adjustment for ELN risk and pre-HSCT measurable residual disease status, disease origin did not impact outcomes. Within the ELN favorable risk group, CIR was higher in s/tAML compared to de novo AML patients likely due to a different distribution of genetic aberrations, which did not translate into shorter OS. Within the ELN intermediate and adverse group outcomes were similar in de novo and s/tAML patients. Thus, not all s/tAML have a dismal prognosis and outcomes of s/tAML after allogeneic HSCT in remission are comparable to de novo patients when considering ELN risk.

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