scholarly journals A Cytogenetic Model Predicts Relapse Risk and Survival in Patients with Acute Myeloid Leukemia Undergoing Hematopoietic Stem Cell Transplantation in Morphologic Complete Remission

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2545-2545
Author(s):  
Armin Rashidi ◽  
Amanda F Cashen
Keyword(s):  
Overall Survival ◽  
Risk Group ◽  
Univariate Analysis ◽  
Conditioning Regimen ◽  
Cumulative Risk ◽  
Relapse Free Survival ◽  
Hematopoietic Stem ◽  
Free Survival ◽  
Cytogenetic Abnormalities ◽  
Reduced Intensity

Abstract Objectives: Up to one third of patients with acute myeloid leukemia (AML) and abnormal cytogenetics have persistent cytogenetic abnormalities (pCytAbnl) at morphologic complete remission (mCR). We hypothesized that the prognostic significance of pCytAbnl in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) in mCR varies with the cytogenetic risk group. Previous studies on the subject have been small, inconclusive, or inconsistent. Methods: We analyzed the data from a large cohort of patients (n = 118) with AML and abnormal cytogenetics who underwent allo-HSCT in mCR, and developed a simple risk stratification model based on pCytAbnl and cytogenetic risk group to compare time to relapse (TTR), relapse-free survival (RFS), and overall survival (OS). Results: The mean (standard deviation) age of patients was 51 (14) years, and 58% were male. AML was therapy-related in 21 (31%) patients. The most frequent FAB subtypes were M0/M1/M2 (46%), followed by M4/M5 (26%). Favorable, intermediate and unfavorable cytogenetic risk disease was present in 18%, 28%, and 54% of patients, respectively. The majority (73%) of patients were in CR1. Conditioning was myeloablative in 67% of patients and reduced-intensity in the remainder. The groups with or without pCytAbnl were similar in all baseline and transplant characteristics except age, CR number and cytogenetic risk group. Specifically, patients with pCytAbnl were significantly older (56 ± 12 vs. 48 ± 15 years; P = 0.004), were in first CR more frequently (86% vs. 67%; P = 0.042), and were more likely to have unfavorable risk cytogenetics (P = 0.027) than patients without pCytAbnl. Univariate analysis was performed using the following variables: age, gender, therapy-related AML (present vs. absent), pCytAbnl (present vs. absent), cytogenetic risk group (unfavorable vs. intermediate/favorable), CR number (≥2 vs. 1), conditioning regimen (myeloablative vs. reduced intensity), and donor type (matched unrelated vs. sibling). There was a significant association between outcome (OS, RFS, and TTR) and the following variables: pCytAbnl, cytogenetic risk group, and the conditioning regimen. Additionally, CR number was significantly associated with TTR. In multivariate regression analysis with these four variables (Table 1), only pCytAbnl, cytogenetic risk group, and the conditioning regimen had a significant impact on outcome. A risk scoring system was then built using pCytAbnl and cytogenetic risk group. The model distinguished 3 groups of patients with distinct outcomes (Figure 1). The group with pCytAbnl and unfavorable risk cytogenetics (R2, n = 24) had the shortest median TTR (3 months), RFS (3 months), and OS (7 months). The group with favorable/intermediate risk cytogenetics and without pCytAbnl (R0, n = 47) had the longest median TTR (not reached), RFS (57 months), and OS (57 months). The group with pCytAbnl and favorable/intermediate risk cytogenetics, or without pCytAbnl but with unfavorable risk cytogenetics (R1, n = 47) experienced intermediate TTR (18 months), RFS (9 months), and OS (14 months). Conclusions: A composite cytogenetic risk model identifies patients with AML in mCR with distinct relapse, RFS, and OS rates following allo-HSCT. Table 1:Multivariate analysis for survival outcomes using variables with a significant association in univariate analysis OS RFS TTRHR (95% CI)PHR (95% CI)PHR (95% CI)PpCytAbnl + vs. -0.54 (0.32-0.91)0.0200.53 (0.32-0.86)0.0100.44 (0.24-0.80)0.007Cytogenetic risk U vs. F/I0.60 (0.36-0.99)0.0470.55 (0.34-0.98)0.0140.45 (0.23-0.95)0.023CR number ≥2 vs. 1----1.51 (0.58-3.95)0.404Conditioning MA vs. RI1.71 (1.04-2.81)0.0352.04 (1.27-3.27)0.0032.85 (1.57-5.15)0.001 CI: confidence interval; F/I: Favorable/Intermediate; HR: hazard ratio; MA: myeloablative; RI: reduced intensity; U: unfavorable Figure 1: Cumulative risk of relapse (A), relapse free survival (B) and overall survival (C) based on persistent cytogenetic abnormalities and cytogenetics. R0, R1, and R2 are defined in the text. Figure 1:. Cumulative risk of relapse (A), relapse free survival (B) and overall survival (C) based on persistent cytogenetic abnormalities and cytogenetics. R0, R1, and R2 are defined in the text. Disclosures No relevant conflicts of interest to declare.

Age up to 75 Years Does Not Influence the Outcomes of Allogeneic Hematopoietic Stem Cell Transplantation in Acute Myeloid Leukemia and Myelodysplastic Syndrome

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3501-3501
Author(s):  
Dipenkumar Modi ◽  
Abhinav Deol ◽  
Seongho Kim ◽  
Kendra Mellert ◽  
Marie Ventimiglia ◽  
...  
Keyword(s):  
Overall Survival ◽  
Relapse Rate ◽  
Cumulative Incidence ◽  
Relapse Free Survival ◽  
Hematopoietic Stem ◽  
Free Survival ◽  
Allogeneic Hsct ◽  
Gvhd Prophylaxis ◽  
Reduced Intensity

Abstract Introduction: Patients with AML and MDS who are age 60 or above represent a discrete group of patients with a different disease biology compared to younger patients. These patients are often not offered allogeneic hematopoietic stem cell transplant (HSCT) as a curative intent because of concern of increased nonrelapse mortality (NRM) and poor overall survival (OS). Hence, the information on transplant outcomes among this population is very limited. Recently with the use of better supportive care measures and reduced intensity preparative regimens, patients greater than 60 are often recommended to proceed to transplant. This study evaluates our single center experience of allogeneic transplantation in patients with MDS and AML aged 60 and older. Patients and Methods: We retrospectively evaluated 60 years or older consecutive patients with AML and MDS who underwent allogeneic HSCT between January 2005 and December 2014. The primary objectives of our study were to determine NRM, relapse, relapse free survival (RFS) and OS at 1 year following transplant. The secondary objectives were to estimate cumulative incidence of acute (aGVHD) and chronic GVHD (cGVHD) at 1 year, length of stay and readmission rate in the first 100 days following transplant. Results: Between January 2005 and December 2014, 159 patients underwent allogeneic HSCT with the median age of 64 (range, 60-75) years and median follow-up duration for OS of 3.34 (95% CI, 2.51-3.87) years. Increasing number of patients were transplanted in recent years, i.e., 67% patients between 2010-2014 compared to 33% between 2005-2009. One hundred three patients (65%) had AML and 56 patients (35%) had MDS. Forty-nine patients (31%) received full intensity regimen and 110 patients (69%) received reduced intensity regimen. Fifty-two patients (33%) underwent allogeneic related transplant and 107 patients (67%) had allogeneic unrelated transplant. Thymoglobulin based GVHD prophylaxis was given in 77 patients (48%) whereas non-thymoglobulin based GVHD prophylaxis was given in 82 patients (52%). The median day to neutrophil and platelet engraftment was 11 (range, 7-22) days and 16 (range, 0-675) days, respectively. Graft failure occurred in 3 patients. At 1-year follow-up, the cumulative incidence of grade II-IV aGVHD was 39.7% (95% CI, 32.0-47.2%), grade III-IV aGVHD was 20.8% (95% CI, 14.9-27.5%) and cGVHD was 54.1% (95% CI, 46.0-61.5%). The cumulative incidence of chronic extensive GVHD was 39.8% (95% CI, 32.1-47.4%). Blood stream infection, cytomegalovirus reactivation, Epstein-Barr virus reactivation, C. difficile diarrhea occurred in 44%, 35%, 22% and 26% of patients, respectively. At 1-year follow-up, NRM was 25.3% (95% CI, 18.8-32.3%), RFS was 53.3% (95% CI, 46.1-61.7%), relapse rate was 21.4% (95% CI, 15.4-28.1%) and OS was 56.4% (95% CI, 49.2-54.7%). The median day of hospitalization following transplant was 26 (range, 19-112) days and almost half (52%) of patients were readmitted in the first 100 days following transplant. Leukemia recurrence was the most common cause of death. Multivariable analysis demonstrated high disease risk index to be the independent predictor of poor RFS, OS and higher relapse rate (p<0.03), whereas non-thymoglobulin based GVHD prophylaxis, higher comorbidity index (≥3) and MDS were found to be associated with higher NRM (p<0.03). Most importantly, age did not shown to have any effect on relapse rate, OS, RFS, or NRM. Conclusion: Our results indicate that allogeneic HSCT is well tolerated and had acceptable NRM, and OS among this group. Hence, older age alone should not be considered a contraindication to HSCT. Figure 1 Overall survival (OS) and relapse-free survival (RFS) estimates. The median OS is 1.60 years (95% CI, 0.94 to 5.00 years) and the median RFS is 1.15 years (95% CI, 0.63 to 3.07 years). The median follow-up time of OS and RFS are 3.34 years (95% CI, 2.51 to 3.87 years) and 3.25 years (95% CI, 2.51 to 3.87 years), respectively. Figure 1. Overall survival (OS) and relapse-free survival (RFS) estimates. The median OS is 1.60 years (95% CI, 0.94 to 5.00 years) and the median RFS is 1.15 years (95% CI, 0.63 to 3.07 years). The median follow-up time of OS and RFS are 3.34 years (95% CI, 2.51 to 3.87 years) and 3.25 years (95% CI, 2.51 to 3.87 years), respectively. Figure 2 Cumulative incidences of aGVHD, cGVHD, relapse and non-relapse mortality after transplantation. Figure 2. Cumulative incidences of aGVHD, cGVHD, relapse and non-relapse mortality after transplantation. Disclosures Deol: Jazz Pharmaceuticals: Consultancy.

scholarly journals Complete Hematologic and Molecular Response in Adult Patients With Relapsed/Refractory Philadelphia Chromosome–Positive B-Precursor Acute Lymphoblastic Leukemia Following Treatment With Blinatumomab: Results From a Phase II, Single-Arm, Multicenter Study

2017 ◽  
Vol 35 (16) ◽  
pp. 1795-1802 ◽  
Author(s):  
Giovanni Martinelli ◽  
Nicolas Boissel ◽  
Patrice Chevallier ◽  
Oliver Ottmann ◽  
Nicola Gökbuget ◽  
...  
Keyword(s):  
Overall Survival ◽  
Stem Cell ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Relapse Free Survival ◽  
Hematopoietic Stem ◽  
Free Survival ◽  
Disease Response ◽  
Minimal Residual

Purpose Few therapeutic options are available for patients with Philadelphia chromosome–positive (Ph+) B-precursor acute lymphoblastic leukemia (ALL) who progress after failure of tyrosine kinase inhibitor (TKI) −based therapy. Here, we evaluated the efficacy and tolerability of blinatumomab in patients with relapsed or refractory Ph+ ALL. Patients and Methods This open-label phase II study enrolled adults with Ph+ ALL who had relapsed after or were refractory to at least one second-generation or later TKI or were intolerant to second-generation or later TKIs and intolerant or refractory to imatinib. Blinatumomab was administered in 28-day cycles by continuous intravenous infusion. The primary end point was complete remission (CR) or CR with partial hematologic recovery (CRh) during the first two cycles. Major secondary end points included minimal residual disease response, rate of allogeneic hematopoietic stem-cell transplantation, relapse-free survival, overall survival, and adverse events (AEs). Results Of 45 patients, 16 (36%; 95% CI, 22% to 51%) achieved CR/CRh during the first two cycles, including four of 10 patients with the T315I mutation; 88% of CR/CRh responders achieved a complete minimal residual disease response. Seven responders (44%) proceeded to allogeneic hematopoietic stem-cell transplantation, including 55% (six of 11) of transplantation-naïve responders. Median relapse-free survival and overall survival were 6.7 and 7.1 months, respectively. The most frequent AEs were pyrexia (58%), febrile neutropenia (40%), and headache (31%). Three patients had cytokine release syndrome (all grade 1 or 2), and three patients had grade 3 neurologic events, one of which (aphasia) required temporary treatment interruption. There were no grade 4 or 5 neurologic events. Conclusion Single-agent blinatumomab showed antileukemia activity in high-risk patients with Ph+ ALL who had relapsed or were refractory to TKIs. AEs were consistent with previous experience in Ph– ALL.

Conditioning with 8 Gy Total Body Irradiation and Fludarabine for Allogeneic Hematopoietic Stem Cell Transplantation in Acute Myeloid Leukemia: Projected 4-Year Update.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3016-3016
Author(s):  
Matthias Stelljes ◽  
Martin Bornhaeuser ◽  
Matthias Kroger ◽  
Joerg Beyer ◽  
Maria C. Sauerland ◽  
...  
Keyword(s):  
Overall Survival ◽  
Stem Cell ◽  
Myeloid Leukemia ◽  
Dna Typing ◽  
Relapse Free Survival ◽  
Hematopoietic Stem ◽  
Free Survival ◽  
Unrelated Donors ◽  
Total Body ◽  
Acute Myeloid

Abstract Seventy-one patients with acute myeloid leukemia (AML), most of them (63/71) considered ineligible for conventional allogeneic hematopoietic stem cell transplantation (HSCT), were enrolled into a phase II study on reduced intensity myeloablative conditioning with fractionated 8 Gy total body irradiation (TBI) and fludarabine (120 mg/m2) (Blood. 2005 Nov 1;106(9):3314–21). Patients received mobilized peripheral blood stem cells (n=68) or bone marrow (n=3) from siblings (n=39) or unrelated donors (n=32). HLA-typing was performed for HLA-A, -B, -Cw (serological matching or intermediate resolution DNA typing), DRB1 and DQB1 (high resolution DNA typing). Three patients had unrelated donors with an allele mismatch in HLA DRB1 (2 with an additional mismatch in HLA Cw) and 7 patients were transplanted from unrelated donors with an antigen mismatch in HLA Cw. Thirty-six patients were transplanted in complete remission (CR) and 35 with untreated or refractory disease (non-CR). Median patient age was 51 years (range, 20–66). Sustained engraftment was attained in all evaluable patients. With a median follow-up of now 41.3 months (range, 20.4–70.4) in surviving patients, probabilities of overall survival for patients transplanted in CR and non-CR were 80% (95% CI, 66 to 94%) and 17% (95% CI, 5 – 29%) at 4 years, respectively. Relapse-free survival rates were 57% (95% CI, 39 – 75%) and 14% (95% CI, 2 – 26%). Of the 35 evaluable patients transplanted in CR, 10 patients suffered a relapse between days 68 and 868 after transplantation (cumulative incidence 29%). Five patients with late relapse (>1 year after transplantation) achieved a subsequent CR after conventional chemotherapy, blood stem cell boost and treatment with granulocyte-macrophage colony-stimulating factor, lasting 2000+, 1841+, 909+, 847+ and 480 days, respectively. Depending on donor type, relapse-free survival was similar in patients transplanted from unrelated or sibling donors. Overall survival in patients transplanted in complete remission from unrelated vs. sibling donors was 84% (95% CI, 73 – 95%) vs. 77% (95% CI, 68 – 86%). The cumulative incidence of non-relapse mortality (NRM) in CR patients was 11% at 4 years and beyond (3 patients deceased before day 100 and 1 patient 25 months after transplantation), but amounted to 37% at 4 years in non-CR patients. Nine of the 33 surviving patients (27%) have actually active chronic GvHD (5 limited and 4 extensive disease). This update confirms that allogeneic HSCT from related or unrelated donors with 8 Gy TBI/fludarabine conditioning is feasible with low NRM and preserved long-term antileukemic activity in AML patients in first or later CR.

Chromosome 17 Abnormalities Are Associated with Worse Overall and Relapse Free Survival in Patients with Acute Myelogenous Leukemia and Poor-Risk Cytogenetics.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1501-1501
Author(s):  
Gautam Borthakur ◽  
Constantine Tam ◽  
Hagop Kantarjian ◽  
E. Lin ◽  
Jorge Cortes ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myelogenous Leukemia ◽  
Myelogenous Leukemia ◽  
Chromosome 17 ◽  
Relapse Free Survival ◽  
Free Survival ◽  
Cytogenetic Abnormalities ◽  
Kaplan Meier ◽  
Variate Analysis ◽  
Acute Myelogenous

Abstract Purpose: Chromosome 17 abnormalities define a group of patients with acute myelogenous leukemia (AML) (Nahi, H. et al. Leukemia and Lymphoma2008;49:508) with poor outcomes. We analyzed the additional impact of chromosome 17 abnormalities (−17, −17p, −17q, der17) among patients with AML and cytogenetic abnormalities traditionally considered to be of adverse prognosis. Patients and Methods: 1086 patients with AML [excluding inv 16, t (8;21), t (15;17), Diploid/-y abnormality] were included in this analysis. Based on cytogenetic abnormalities patients were grouped into: −5,−7,−5and −7, complex. The following parameters were included in uni and multi-variate analysis: age, performance status, WBC, hemoglobin, platelets, marrow blast percentage, bilirubin, creatinine, albumin, LDH, chromosome 17 abnormality (yes/no). Results: Four hundred and fourteen (45%) patients achieved complete remission (CR) or CR with incomplete platelet recovery (CRp) and 267 (64.5%) patients relapsed. Two hundred seventy (24.9%) patients had abnormalities of chromosome 17. Abnormalities of chromosome 17 were associated with lower CR or CRp rate (p=0.02) and higher possibility of having cytogenetic abnormality of −5 or −7 (p&lt;0.0001). Multivariate analysis showed that patients with abnormalities of chromosome 17 had worse overall survival (OS) compared to patients without (p= 0.003)(Fig.1). Multi-variate analysis within cytogenetic subgroups showed that chromosome 17 abnormalities were associated with worse OS in patients with chromosome 5 abnormality(p=.02) (data not shown) and in those with complex cytogenetics (p=.04)(Fig.2) and not in patients with chromosome 7 (p=.17)or combined 5 and 7 abnormalities (p=.33). Similar analysis restricted to patients achieving CR/CRp after induction therapy showed that impact of chromosome 17 abnormalities on relapse free survival (RFS) mirrored their impact on OS. Conclusion: chromosome 17 abnormalities are associated with worse OS and RFS in patients with AML and adverse cytogenetics and have additional negative impact on the outcomes in certain well-known adverse cytogenetic subgroups. Figure 1: Kaplan-Meier estimates of overall survival by status of chromosome 17 Figure 1:. Kaplan-Meier estimates of overall survival by status of chromosome 17 Figure 2: Kaplan-Meier estimates of overall survival by status of chromosome 17 in subgroup of patient, complex Figure 2:. Kaplan-Meier estimates of overall survival by status of chromosome 17 in subgroup of patient, complex

Flamsa Reduced-Intensity Conditioning Regimen in AML Patients – Role of Re-Induction and Disease State Prior to Transplant

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3904-3904
Author(s):  
Udo Holtick ◽  
Alexander Shimabukuro-Vornhagen ◽  
Geothy Chakupurakal ◽  
Sebastian Theurich ◽  
Silke Leitzke ◽  
...  
Keyword(s):  
Stem Cell ◽  
Induction Therapy ◽  
Conditioning Regimen ◽  
Induction Treatment ◽  
Refractory Disease ◽  
Relapse Free Survival ◽  
Reduced Intensity Conditioning ◽  
Free Survival ◽  
Reduced Intensity

Abstract Reduced intensity conditioning (RIC) regimens as compared to myeloablative protocols have demonstrated lower toxicity profiles at similar efficacy in the context of allogeneic haematopoietic stem cell transplantation (allo-SCT) for patients with acute myelogenous leukaemia (AML) in first or second remission. In addition, the FLAMSA RIC regimen, combining a cytoreductive part and a transplant-conditioning part, has been described to be efficacious in patients with refractory disease. Re-induction treatment after AML relapse or refractory disease is often accompanied by severe, in particular, infectious complications such as fungal pneumonia caused by long neutropenic phases, precluding a significant proportion of patients from completing allo-SCT. To have a closer look on the role of re-induction therapy prior to transplant, we retrospectively analysed clinical data of 118 consecutive patients with AML after allogeneic stem cell tranplantation following FLAMSA conditioning at our center. No prophylactic donor lymphocyte infusions were administered. Median age of the cohort was 53 years (19-73 years). Donors were matched related, matched unrelated or mismatched unrelatred in 33, 49 and 18% of the transplants. Complete remission prior to transplant was detected in 29% and 21% of the patients after induction or re-induction, respectively. Twenty-five percent of the patients were transplanted with blast persistence, both in the group of patients after first induction and re-induction treatment. Median follow-up was 27 months. The 4-yr overall survival of the whole cohort is 44% with a 4-yr relapse-free survival of 42%. Cumulative incidence of relapse was 26, 30 and 40% at one, two and four years, respectively. Cumulative incidence of non-relapse mortality (NRM) was 15, 18 and 18% at one, two and four years, respectively. There were no significant differences regarding overall and relapse-free survival for patients transplanted in CR1, CR2 or blast persistence after induction treatment. Patients who failed remission after re-induction therapy showed significantly worse overall and relapse-free survival (p=0,049 and 0,003, repectively, log-rank test). NRM was similar in all cohorts. FLAMSA is a highly effective conditioning regimen for AML patients even not in CR. Thus, the decision for re-induction therapy prior to allogeneic SCT has to be weighted against the potential toxicity of this approach. Disclosures No relevant conflicts of interest to declare.

scholarly journals Expression of FAM83H and ZNF16 are associated with shorter survival of patients with gallbladder carcinoma

2020 ◽  
Author(s):  
Sung Woo Ahn ◽  
Ae-Ri Ahn ◽  
Sang Hoon Ha ◽  
Usama Khamis Hussein ◽  
Jae Do Yang ◽  
...  
Keyword(s):  
Overall Survival ◽  
Cancer Progression ◽  
Gallbladder Carcinoma ◽  
Expression Patterns ◽  
Univariate Analysis ◽  
Prognostic Indicators ◽  
Relapse Free Survival ◽  
Human Gallbladder ◽  
Free Survival ◽  
The Public

Abstract BackgroundRecently, FAM83H was reported to have roles in cancer progression in conjunction with oncogenic molecules such as MYC and b-catenin. Moreover, the data from the public database indicates a molecular relationship between FAM83H and zinc finger proteins, especially between FAM83H and ZNF16. However, studies on FAM83H and ZNF16 in gallbladder cancer have been limited. MethodsThis study investigated the expression of FAM83H and ZNF16 in 105 gallbladder carcinomas. ResultsIn human gallbladder carcinomas, immunohistochemical expression of FAM83H was significantly associated with ZNF16 expression. In univariate analysis, nuclear and cytoplasmic expression of FAM83H or ZNF16 were significantly associated with shorter survival of gallbladder carcinoma patients. Multivariate analysis revealed the nuclear expression of FAM83H as an independent indicator of poor prognosis of overall survival (p = 0.005) and relapse-free survival (p = 0.005) of gallbladder carcinoma patients. Moreover, co-expression patterns of nuclear FAM83H and ZNF16 were also independent indicators of shorter survival of gallbladder carcinoma patients (overall survival; p < 0.001, relapse-free survival; p < 0.001). ConclusionsThis study suggests FAM83H and ZNF16 are associated with the progression of gallbladder carcinoma, and the expressions of FAM83H and ZNF16 might be novel prognostic indicators of gallbladder carcinoma patients.

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.

scholarly journals The Impact of HLA Mismatch Direction on the Outcome of Allogeneic Hematopoietic Stem Cell Transplantation in AML Patients

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4608-4608
Author(s):  
Wen-Chun Chen ◽  
Jyh-Pyng Gau ◽  
Liang-Tsai Hsiao ◽  
Chia-Jen Liu ◽  
Yao-Chung LIU ◽  
...  
Keyword(s):  
Overall Survival ◽  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Relapse Free Survival ◽  
Hematopoietic Stem ◽  
Free Survival ◽  
Matched Group ◽  
The Impact

Background: For patients with acute myeloid leukemia (AML) who were classified as high risks, failed to achieve complete remission, or relapsed disease after remissions, allogeneic hematopoietic stem cell transplantation (allo-HSCT) offers the chance of durable remission and the potential to cure. In the absence of 8/8 matched donors, an HLA 1-allele mismatched (7/8 1-MM) unrelated donor is an alternative source of hematopoietic stem cell. However, the impact of HLA homozygosity at 1-MM on the outcome and the consensus at desirable donor screening in 7/8 HLA mismatched is not yet clear. A 1-MM in the host-versus-graft (HVG) direction is a 7/8 unidirectional mismatch for a homozygous recipient receiving a graft from a heterozygous donor. A 1-MM in the graft-versus-host (GVH) is for a heterozygous recipient receiving a graft from a homozygous donor. 7/8 bidirectional mismatch is a heterozygous recipient receiving a graft from heterozygous donor. From the biological perceptions, the impact of different histocompatibility transplantations may differ on the prognosis. This study evaluated the outcome of unidirectional and bidirectional 7/8 mismatches in recipients receiving either bone marrow or peripheral blood hematopoietic stem cell for AML patients. Methods: Patients who were at least 12 years of age with AML receiving first hematopoietic stem cell transplantation from a serologically HLA-A, -B, -C, and -DR allele data were included in our study between 2009 and 2014. Data were obtained from Taiwan Society of Blood and Marrow Transplantation (TBMT) Research Database. We excluded those who received HLA-matched sibling grafts, HLA-haploidentical grafts, or unrelated donors who had more than 1-allele mismatch. Those who lacked the clinical information on survival status or survival date were also eliminated. Patients were divided into four histocompatibility groups based on typing at HLA-A, -B, -C, and -DR as unidirectional 7/8 HVG, unidirectional 7/8 GVH, bidirectional 7/8, and 8/8 matched group. Descriptive statistics were used to describe the patients' characteristics, disease status on the time receiving HSCT, intensity of conditioning regimen and treatment features. Associations between four groups and outcomes of overall survival, relapse-free survival, acute GVHD, chronic GVHD, treatment-related mortality (TRM), relapse rate, neutrophil engraftment, engraftment syndrome, and engraftment failures were reviewed. Results: A total of 222 recipients of all-HSCT were included in the analysis. The four comparison groups included nine patients designated as 1-MM HVG, nine as 1-MM GVH, 71 as 1-MM bidirectional, and 133 as 8/8 matched group. Table 1 shows patient and transplant characteristics. Superior overall survival was significantly associated with the higher intensity of induction regimen (myeloablative conditioning, MAC and reduced intensity conditioning, RIC, p<0.05) and the disease status on the time receiving allo-HSCT (p=0.1). Relapse-free survival was significantly decreased with RIC regimen (p < 0.05, figure 1). The cumulative 5-year overall survival rate was 75% in the 1-MM HVG group, 50% in the 1-MM GVH group, 50% in the 1-MM bidirectional group, and 44% in the 8/8 matched group. Median survival of 1-MM HVG and 8/8 matched group didn't reach under analysis, and which is 62.2 months in 1-MM GVH, 30.9 months in 1-MM bidirectional group. The outcome of overall survival was more favorable in the 1-MM HVG group (Figure 2 and Figure 3), especially comparing with 1-MM bidirectional group (p=0.07), where there was no significant difference between 8/8-matched group and 1-MM GVH group or the 1-MM bidirectional group. Superior overall survival and relapse free survival was observed in 1-MM HVG group, although the differences were not statistically significant. Hyper-acute GVHD was slightly higher in 7/8 bidirectional group, while no significant difference was observed in acute and chronic GVHD among four groups. The primary causes of death were reviewed. 8/8 matched group had higher deaths attributed to disease relapse (26.3%), while 1-MM GVH group had more deaths attributed to GVHD (22.2%). Conclusion: Myeloabltive conditioning regimen is associated with more favorable outcomes of overall survival and relapse free survival. 1-MM HVG also tends to have superior overall survival and relapse free survival, although there is no statistical significance due to limited cases. Disclosures No relevant conflicts of interest to declare.

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