scholarly journals Venetoclax Combined with Daunorubicin and Cytarabine (DAV) As Induction Therapy in De Novo Young Adult Acute Myeloid Leukemia

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2334-2334
Author(s):  
Huafeng Wang ◽  
Liping Mao ◽  
Wanzhuo Xie ◽  
Hongyan Tong ◽  
Min Yang ◽  
...  
Keyword(s):  
Young Adult ◽  
Induction Therapy ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Residual Disease ◽  
The Novel ◽  
Poor Risk ◽  
De Novo Aml ◽  
Grade 3

Abstract Background: Anthracycline and cytarabine ("3+7") have been the standard induction therapy for acute myeloid leukemia (AML) for almost 4 decades. Only 60%-70% patients can achieve complete remission (CR) with "3+7" induction treatment in de nove AML. The novel induction regimens with higher CR rate are urgent needed. Venetoclax, a b-cell lymphoma 2 (BCL-2) inhibitor combining with hypomethylation agents (HMA) or low dose cytarabine has showed a high response rate and safe in elder AML patients [Dinardo CD, N Engl J Med. 2020; Dinardo CD, Lancet Oncol 2018; Wei AH, J Clin Oncol 2019]. Recently, venetoclax combined with FLAG-IDA induction achieved 90% CR rate in newly diagnosed adult AML (Dinardo CD, J Clin Oncol. 2021). Whether venetoclax combined with standard 3+7 regimen (daunorubicin + cytarabine) as induction therapy can further improve the CR rate in adult AML patients need to be investigated in a well-designed trial. Objective: To evaluate the efficacy and safety of "3+7" (daunorubicin and cytarabine) combined with venetoclax induction regimen (DAV regimen) in young adult patients with de novo AML. Design, setting and participants: Single-arm, prospective clinical trial conducted in the First Affiliated Hospital, Zhejiang University College of Medicine, China. Eligible patients (18-60 years old) with de novo AML (exclude acute promyelocytic leukemia) were enrolled since December 25, 2020, with final follow-up in July 31,2021. Interventions: Patients were treated with daunorubicin 60mg/m 2 on days 1-3 (d1-3) and cytarabine 100 mg/m 2/d by continuous intravenous infusion daily on d1-7, combined with venetoclax (100mg d4, 200mg d5, 400mg d6-11). Main outcomes and measures: The primary endpoint was the percentage of patients who achieved CR/CR with incomplete count recovery (CRi) after once cycle of DAV regimen. Secondary endpoints included minimal residual disease (MRD), overall survival (OS), event-free survival (EFS) and adverse events. Results: Thirty-two patients were enrolled. Median age was 40 years old (range, 19-59), with poor-risk in 25% (8/32) of patients (European LeukemiaNet 2017 risk). Other characteristics of patients were listed in Table 1. The CR rate were 90.6% (29/32) (Table 1). Seven out eight (87.5%) patients with poor-risk achieved CR. Measurable residual disease-negative composite CR was attained in 65.5% (19 out 29) of total patients achieved CR, and 71.4% (5 out 7) of poor-risk patients achieved CR (Table 1). Common adverse events (>30%) included fatigue, nausea, bleeding, febrile neutropenia, infection, neutropenia, anemia and thrombocytopenia. The main grade ≥ 3 hematologic toxicities during induction were neutropenia (100%), anemia (100%) and thrombocytopenia (100%). The main grade ≥ 3 nonhematologic toxicities during induction were infection (81.3%), bleeding (28.1%) and mucositis (3.1%) (Table 1). No tumor lysis syndrome was observed. After a median follow-up of 118.5 days, no patient relapsed or died, and 24.1% (7/29) received allogeneic hematopoietic stem-cell transplantation in CR1. Conclusions: The novel combination of "3+7" (daunorubicin and cytarabine) with venetoclax (DAV regimen) was effective and well tolerated in young adult patients with de novo AML, with high CR rate and deep remission. Trial registration: The trial was registered in the Chinese Clinical Trial Register, number ChiCTR2000041509. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

scholarly journals Re-Induction Therapy Decisions Based on Day 14 Bone Marrow Biopsy in Acute Myeloid Leukemia,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3590-3590
Author(s):  
Tod A. Morris ◽  
David A. Rizzieri ◽  
Carlos M de Castro ◽  
Louis F. Diehl ◽  
Jon P. Gockerman ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Induction Chemotherapy ◽  
Induction Therapy ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Residual Disease ◽  
Treatment Decisions ◽  
De Novo Aml ◽  
Acute Myeloid

Abstract Abstract 3590 Purpose: Treatment decisions for early re-induction of patients with de novo acute myeloid leukemia (AML) based on sub-optimal cytoreduction as seen on day 14 bone marrow (BM) biopsy is laden with controversy. The aim of our review was to correlate results of the day 14 BM biopsy to overall outcomes of induction therapy. Methods: Between November 1995 and July 2008, medical records for patients treated for de novo AML were retrospectively reviewed for the purpose of evaluating treatment decisions and outcomes based on day 14 BM biopsies. Of all patients treated during that period, 100 patients were categorized as de novo AML, and were treated with standard induction chemotherapy. Seventy-four (n=74) of these patients had paired BM biopsy reports. Response to therapy was based purely on morphology noted by the pathologist on the day 14 BM in this analysis, with indeterminate response (IR) defined as a hypocellular marrow (HM) with moderate increase in blasts above 5% in which the reviewing pathologist could not rule out the possibility of persistent leukemia. Residual disease (RD) was defined by the reviewing pathologist as grossly elevated percentages of abnormal populations of persistent blasts by morphology alone definitively consistent with residual disease (i.e. no flow cytometric or molecular adjuncts). Otherwise, the patients were classified as appropriate response with a HM and less than 5% blasts with no evidence of residual leukemia. Results: Day 14 BM biopsies of the 74 patients (median age = 42 years, range 18 to 77) undergoing standard induction chemotherapy revealed that 45 patients (61%) had a HM with less than 5% blasts. Eleven patient's (15%) BM biopsies were classified as IR. Eighteen patients (24%) had morphologically definitive RD. In all, 29 patients (39%) had a sub-optimal response (SOR) to induction chemotherapy (IR+RD=SOR). The 45 patients with HM and low blast percentage were observed until count recovery as is the usual practice. However, 16 of 29 patients with SOR received re-induction chemotherapy (1 IR and 15 RD) of which 10 patients attained a morphologic CR (9 RD and 1 IR). The 13 remaining patients (3 RD and 10 IR) were observed without any re-induction therapy, and re-evaluated with a follow-up BM biopsy between days 21 and 42 of initial induction. Interestingly, 11 of these 13 patients had a morphologic CR on follow-up biopsy, including 2 of 3 patients initially categorized as RD. Analysis of the paired results from nadir to recovery for the 58 observed patients in this cohort revealed a positive predictive value (PPV) and negative predictive value (NPV) for the day 14 BM biopsy review of 15% and 93% respectively. Conclusions: Our data suggests that those patients with an IR on day 14 may not necessarily require re-induction chemotherapy, and may actually benefit from careful observation by avoiding the risks of reinduction and prolonged cytopenias. Thus, while the day14 BM is an important tool for the evaluation of response in AML patients undergoing induction therapy, it is not always a reliable test for residual leukemic burden, as illustrated by its low PPV. As such, future treatment decisions should be weighted by, but not based solely on this parameter. Our future plans are to evaluate this question prospectively in a larger cohort of de novo AML patients receiving induction therapy with centralized pathologic review, and also to look at the effect of cytogenetic and molecular mutation analysis at day 14 on treatment decision making and outcomes. Disclosures: No relevant conflicts of interest to declare.

Minimal Residual Disease Monitored With Fluorescence In Situ Hybridization (FISH) In CD34+CD38- Population Predicts Clinical Outcome In Core Binding Factor Acute Myeloid Leukemia (CBF-AML)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1356-1356
Author(s):  
Xiaoxia Hu ◽  
Libing Wang ◽  
Lei Gao ◽  
Sheng Xu ◽  
Shenglan Gong ◽  
...  
Keyword(s):  
Minimal Residual Disease ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Residual Disease ◽  
Consolidation Therapy ◽  
Rt Pcr ◽  
Binding Factor ◽  
Minimal Residual

Abstract Acute myeloid leukemia (AML) is generally regarded as a stem cell disease, known as leukemic initiating cells (LIC), which initiate the disease and contribute to relapses. Although the phenotype of these cells remains unclear in most patients, they are enriched within CD34+CD38- compartment. In core binding factor (CBF) AML, the cytogenetic abnormablities are also existed in LIC. The aim of this study was to determine the prognostic power of minimal residual disease measured by fluorescence in situ hybridization (FISH) in flow sorted CD34+CD38- cells (FISH+CD34+CD38- population) at different period during the therapy. Thirty-six patients under 65 years of age with de novo CBF AML and treated with CHAML 2010 protocol were retrospectively included in this study. FISH efficiently identified the LICs (FISH+CD34+CD38-) in the CD34+CD38- population. The last follow-up was March 31, 2013, and the median follow-up was 336 days (range: 74-814 days). 33 patients with complete remission (CR) were eligible for the study, and 23 patients (23/33, 69.7%) with t (8;21) or AML1/ETO, and the remaining (10/33, 30.3%) with inv(16)/t(16;16) or CBFβ/MYH11. Flow-cytometry based FISH (F-FISH) procedure was performed at diagnosis, before every cycle of consolidation therapy, and every 3 months during follow-up. The FISH+ percentage at diagnosis constituting an average of 2.1% (range: 0.01%-27.5%) of the blast cells and 64.6% (range: 14%-87.8%) of the CD34+CD38- cells. Before the consolidation, FISH+CD34+CD38- population was detected in 13/33 (39.4%) patients. At this checkpoint, we have found the existence of FISH+CD34+CD38- population had prognostic value for the end points relapse free survival (RFS, 12% versus 68%, P=.008), and retained prognostic significance for RFS in multivariate analysis. Furthermore, the detection of FISH+CD34+CD38- before consolidation was found to be significantly associated with decreased OS. (11% versus 75%, P=.0005) Minimal residual disease (MRD) detected with F-FISH had a prognostic value at an earlier checkpoint when compared with flow cytometry and RT-PCR. Meanwhile, the concordance of flow cytomety, RT-PCR and F-FISH was investigated in the same patient cohort. 14 (70%) of 20 samples with detectable fusion transcripts by PCR did not have detectable leukemic cells by F-FISH. Therefore, the concordance for PCR and F-FISH was 63.7%. The concordance of FC and F-FISH was 64.3%: in 40 samples MRD was detected by both methods and in 61 samples MRD was ruled out by a negative result with the tests. With further analysis, the discrepancies among MRD detected with different MRD monitoring approaches before consolidation and after the first consolidation therapy contribute to 84% of the disconcordance. In summary, the detection of FISH+CD34+CD38- cells before consolidation therapy was significantly correlated with long-term survival in de novo CBF AML patients. F-FISH might be easily adopted as MRD monitor approach in clinical practice to identify patients at risk of treatment failure from the early stage during therapy. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Comparison of Subcutaneous Injection Versus Intravenous Infusion of Cytarabine for Induction Therapy in Young Adult Acute Myeloid Leukemia: Results of a Prospective, Multicenter, Noninferiority, Randomized Trial

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 4-4
Author(s):  
Huafeng Wang ◽  
LU LIU ◽  
Jianfeng Zhou ◽  
Jianyong Li ◽  
Ying Lu ◽  
...  
Keyword(s):  
Young Adult ◽  
Blood Cell ◽  
Intravenous Injection ◽  
Induction Therapy ◽  
Intravenous Infusion ◽  
Subcutaneous Injection ◽  
De Novo ◽  
Continuous Intravenous Infusion ◽  
Injection Group ◽  
De Novo Aml

Background: Acute myeloid leukemia (AML),which is the most common type of acute leukemia, is a clonal malignant hematological disease originated from hematopoietic stem cells, characterized with blocked differentiation, excessive proliferation, organs infiltration. "3+7" regimen [anthracyclines + cytarabine (Ara-c)] is the first choice of induction chemotherapy in young adult de novo AML, and cytarabine is always given by continuous intravenous infusion. It has been reported the concentration of Ara-CTP (active metabolite with anti-leukemia effect) was higher after subcutaneous injection than during continuous intravenous infusion for about 5 hours [Liliemark JO, Semin Oncol], and the subcutaneous injection is much more convenient and inexpensive for patients comparing to continuous intravenous infusion. However, no prospective, multicenter clinical evidenceto evaluate the efficacy and safety of subcutaneous injection administration compared with intravenous infusion of cytarabine. Objective: To evaluated whether subcutaneous injection of cytarabine is noninferior to intravenous infusion of cytarabine in "3+7" induction regimen for young adult patients with de novo AML. Design, setting and participants: Open-label, prospective, multicenter, noninferior, randomized clinical trial conducted in 10 hematological centers in China. Eligible patients (n=240) with de novo AML (exclude acute promyelocytic leukemia) has been enrolled. Patients were recruited between March 2015 and August 2017, with final follow-up in June 2020. Interventions: Patients were randomized to receive idarubicin 10 mg/m2 for 3 days and cytarabine 100 mg/m2/d by continuous intravenous infusion daily for 7 days (n=120) or idarubicin 10 mg/m2 for 3 days and cytarabine 100mg/m2/d subcutaneous injection every 12 hours for 7 days (n=120). Main outcomes and measures: The primary end point was the percentage of patients who achieved complete remission (CR). The noninferiority margin for the difference in CR was -15%. Secondary end points included overall survival (OS), event-free survival (EFS) and adverse events. Results: Among 240 randomized patients, the baseline characteristics including sex, age, ECOG, white blood cell, blasts percentage, FAB subtype, karyotype and NPM1, FLTS-ITD, c-kit, CEBPA, DNMT3A, IDH1 and IDH2 mutations were similar between two groups. CR was achieved by 86 of 120 (71.7%) patients in subcutaneous injection group vs 85/120(70.8%) in intravenous injection (difference, 0.9%[1-sided 95% CI, -8.8% to ∞]); p value for noninferiority=0.003) after first cycle of induction therapy. CR was achieved by 93 of 120 (77.5%) patients in subcutaneous injection group vs 91/120(75.8%) in intravenous injection group (difference, 1.7% [1-sided 95% CI, -7.3% to ∞]); p value for noninferiority=0.001) after first two cycles of induction therapy. 3-year OS were 60% [95% CI:50%-69%]in subcutaneous injection group vs 58% [95% CI:49%-67%] in intravenous injection group (Figure 1A). After adjustment for sex, age, region, white blood cell, ECOG, platelet, FAB subtype, integrated risk and transplantation, the adjusted hazard ratio (AHR) of OS for subcutaneous vs intravenous was 0.95 [95% CI:0.62-1.47]. 3-year EFS were 49% [95% CI:39%-58%]in subcutaneous injection group vs 44% [95% CI:35%-53%] in intravenous injection group (Figure 1B). After adjustment for sex, age, region, white blood cell, ECOG, platelet, FAB subtype, integrated risk and transplantation, the HAR of EFS for subcutaneous vs intravenous was 0.84[95% CI:0.58-1.22]. No differences of hematologic toxicity, non-hematologic toxicity and early death rate were observed between two groups. Conclusions: The efficacy of subcutaneous injection of cytarabine was non inferior to continuous intravenous infusion of cytarabine for the standard induction therapy in young adult de novo AML. The toxicity is equivalent between two groups. Subcutaneous injection of cytarabine offers a convenient and inexpensive alternative therapy to young adult de novo AML. Trial registration: The trial was registered in the Chinese Clinical Trial Register, number ChiCTR-IPR-17012643. Figure 1 Disclosures No relevant conflicts of interest to declare.

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.

scholarly journals FLAG-IDA As First Line Induction Treatment for Children De Novo AML

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4900-4900
Author(s):  
Xiaoqin Feng ◽  
Chunfu Li ◽  
Lan He
Keyword(s):  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Induction Therapy ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Primary Study ◽  
Induction Treatment ◽  
First Line ◽  
Acute Myeloid

Abstract Objective: The complete remission after induction therapy is very important for the prognosis of AML. Fludarabine, cytarabine, granulocyte colony-stimulating factor (G-CSF), and idarubicin (FLAG-IDA) regimen has been proven to be an effective chemotherapy for relapsed or refractory acute myeloid leukemia. The aim of this study was to evaluate complete remission rate and toxicity in children with de novo acute myeloid leukemia (none APL) who received the FLAG-IDA regimen as induction therapy. Method: Between March 2014 and July 20015, 14 children with de novo acute myeloid leukemia (none APL) were received FLAG-IDA regimen as first line induction treatment in our center. The regimen including: Fludarabine 30 mg/(m2.d), PI 0.5hr, qd, d2-6; Ara-C 2g/(m2.d), PI 3hr, d2-6; Ida (Idarubicin) mg/(m2.d), PI 1hr, qd, d4-6; G-CSF 5μg/(Kg.d), s.c./i.v. qd,d1-7. Of the 14 children, age 1-13 years old (median age 7 years old), including 2 (14.3%) children with favorable gene, 4 (28.6%) children with high risk gene. 3(21.4%) children received 1 cycle, 11 (78.6%) received 2 cycles of FLAG-IDA regimen. The CR rate and toxicity in total 25 cycles were evaluated. Result: After 25 cycles of FLAG-IDA regimen, only 1 child (7.1%) did not get CR, 13/14 (92.9%) got CR after 1 or 2 cycles of FLAG-IDA induction treatment. In 25 FLAG-IDA cycles, the neutropenic time was from 13-43 days (mean 24.8 days). In the induction period, 2(14.3%) children suffered sepsis, 3 children (21.4%) had proven invasive fungal infection. Of 14 children, 2 children(14.3%) combined with cutaneous anaphylaxis, 2 children combined with transient fever after venous transfusion of chemicals. None obvious cardiac toxicity (arrhythmia or heart failure) was proved. One child died of ARDS in the neutropenic period after 2nd FLAG-IDA cycle. Of 14 children, 12 children (85.7%) got continues CR with the follow up 1-19 months (median 8 months). Discussion: Our primary study showed quite high CR rate combined with quite toxicity but can be tolerated using the FLAG-IDA regimen as first line induction treatment. Comprehensive supportive care should be given during the induction therapy. The LFS and OS need to be feedback after long time follow up. Disclosures No relevant conflicts of interest to declare.

Intensive Chemotherapy for Acute Myeloid Leukemia in Elderly Patients

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4341-4341
Author(s):  
Kathryn A Jackson ◽  
Glen A Kennedy ◽  
Peter Mollee ◽  
Kirk Morris
Keyword(s):  
Elderly Patients ◽  
Induction Chemotherapy ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Allogeneic Transplantation ◽  
Refractory Disease ◽  
Intensive Chemotherapy ◽  
De Novo Aml ◽  
Disease Free

Abstract Abstract 4341 Aim Acute myeloid leukemia (AML) incidence increases with age, yet treatment of elderly patients has reduced efficacy compared with younger patients and is often poorly tolerated. We aimed to determine the outcome of elderly patients with de novo AML treated with intensive chemotherapy with or without allogeneic stem cell transplantation. Methods All patients with de novo AML (excluding APML) aged ≥ 60 years treated with induction chemotherapy at our institutions between February 1999 and July 2011 were retrospectively identified from institutional databases. Information on cytogenetic risk, chemotherapy protocols, response to therapy, disease-free survival (DFS), and overall survival (OS) were then determined retrospectively by review of individual medical records. Survival analyses were calculated by the Kaplan-Meier method and compared using the log-rank test. Results Intensive induction chemotherapy was received by 128 patients (57.7% of elderly patients diagnosed with de novo AML), including 105 patients (82.0%) treated with standard-dose cytarabine (SDAC) (100mg/m2 days 1–7) and 14 patients (10.9%) treated with high-dose cytarabine (HiDAC) (≥ 2000mg/m2/day for at least 4 days). The median age of this cohort was 67 years (range 60–83 years). Based on cytogenetic profile, 3.1% of patients had favourable, 54.7% had intermediate, and 27.3% had adverse-risk disease. Responses to 1–2 cycles of induction chemotherapy were complete remission (CR1) in 73.4% of patients, refractory disease in 14.8%, and induction death in 11.7%. 83.0% of patients who achieved CR1 received consolidation chemotherapy, incorporating SDAC in 74.4% and HiDAC in 23.1%. At a median follow-up of 22 months for survivors, intensive induction chemotherapy resulted in a median DFS of 11 months, and median OS of 13 months (Figure 1); 3 year OS for the entire cohort was 27.9%, with favourable, intermediate, and adverse risk groups having 50.0%, 31.6%, and 12.6% 3 year OS, respectively. Thirteen patients (10.2%) proceeded to allogeneic transplantation in CR1; median age was 63 years (range 60–66 years). These patients did not reach median DFS or OS; 11 (84.6%) remain alive and disease-free at a median follow-up of 27 months post-transplant (Figure 2). The elderly patients were compared to the cohort of younger patients (15–59 years) with de novo AML treated over the same time period. This analysis found that the older patients had a higher rate of adverse-risk cytogenetics (27.3% vs 16.1%, respectively; P = 0.02), refractory disease (14.8% vs 3.3%, respectively; P = 0.0002) and induction death (11.7% vs 4.7%, respectively; P = 0.03), and lower CR1 rate (73.4% vs 91.9%, respectively; P < 0.0001), DFS (median DFS 11 months vs 25 months, respectively; P = 0.0009) and OS (median OS 13 months vs 78 months, respectively; P < 0.0001). Conclusions Despite intensive chemotherapy, the majority of patients ≥ 60 years with AML have poor outcomes, with high rates of induction death, refractory disease, and relapsed AML. However, a proportion of these patients experience long-term survival. While patients selected for allogeneic transplantation in CR1 have high DFS and OS, only a minority of patients receive this therapy. Disclosures: No relevant conflicts of interest to declare.

Serum 2-Hydroxyglutarate Production in IDH1- and IDH2-Mutated De Novo Acute Myeloid Leukemia: A Study by the Acute Leukemia French Association Group

2014 ◽  
Vol 32 (4) ◽  
pp. 297-305 ◽  
Author(s):  
Maxime Janin ◽  
Elena Mylonas ◽  
Véronique Saada ◽  
Jean-Baptiste Micol ◽  
Aline Renneville ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Induction Therapy ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Residual Disease ◽  
Characteristic Curve ◽  
Disease Free Survival ◽  
Serum Levels ◽  
Strong Positive Correlation ◽  
Acute Myeloid

Purpose Mutated isocitrate dehydrogenases (IDHs) 1 and 2 produce high levels of 2-hydroxyglutarate (2-HG). We investigated whether, in acute myeloid leukemia (AML), serum 2-HG would predict the presence of IDH1/2 mutations at diagnosis and provide a marker of minimal residual disease (MRD). Patients and Methods Serum samples from 82 patients at diagnosis of de novo AML (IDH1/2 mutated, n = 53) and 68 patients without AML were analyzed for total 2-HG and its ratio of D to L stereoisomers by mass spectrometry. We measured 2-HG levels and molecular markers of MRD (WT1 and NPM1) in serial samples of 36 patients with IDH1/2 mutations after induction therapy. Results In patients with AML with IDH1/2 mutations, 2-HG serum levels were significantly higher than in patients with IDH1/2 wild type (P < .001). Area under the receiver operating characteristic curve was 99%. The optimum diagnostic cutoff between IDH1/2 mutated and normal was 2 μmol/L (sensitivity, 100%; specificity, 79%). Quantification of the D/L stereoisomers increased specificity (100%; 95% CI, 83% to 100%) compared with total 2-HG (P = .031). In patients with IDH2 R172 mutations, 2-HG levels were higher relative to those with other IDH1/2 mutations (P < .05). During follow-up, serum 2-HG levels showed strong positive correlation with WT1 and NPM1 (P < .001). After induction therapy, total 2-HG serum levels < 2 μmol/L were associated with better overall (P = .008) and disease-free survival (P = .005). Conclusion Serum 2-HG is a predictor of the presence of IDH1/2 mutations and outcome in these patients. Discrimination between D/L stereoisomers improved specificity.

scholarly journals Retrospective Evaluation of Correlations Between Genetic Backgrounds and Stem Cell Transplantation for De Novo Pediatric Acute Myeloid Leukemia: A Study from the Japan Pediatric Leukemia/Lymphoma Study Group (JPLSG) AML-05 Clinical Trial

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2904-2904
Author(s):  
Taeko Ueno ◽  
Genki Yamato ◽  
Norio Shiba ◽  
Yusuke Hara ◽  
Kentaro Ohki ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
De Novo ◽  
The Other ◽  
Study Group ◽  
Pediatric Leukemia ◽  
Pediatric Acute Myeloid Leukemia ◽  
De Novo Aml ◽  
Lymphoma Study Group ◽  
Acute Myeloid

Abstract Introduction Pediatric acute myeloid leukemia (AML) comprises less than 20% of pediatric leukemia, representing one of the major therapeutic challenges in pediatric oncology. Approximately 40% of patients still have a relapse after first-line therapies, and the expected long-term survival rate decreases following relapse. Stem cell transplantation (SCT) was a conclusive strategy for de novo AML patients with a high risk and relapsed or refractory patients with standard and intermediate risk in a recent clinical trial. AML is a molecularly and clinically heterogeneous disease caused by various genetic alterations. Thus, it is difficult to accurately evaluate risk stratification even if known representative molecular markers, including KIT, FLT3-ITD, t(8;21)/RUNX1-RUNX1T1, and KMT2A (also known as MLL)-rearrangements, are used. Methods We investigated differences in the genetic background between SCT and non-SCT groups in participants of the Japan Pediatric Leukemia/Lymphoma Study Group (JPLSG) AML-05 trial. Among 369 patients with de novo AML, 175 patients received SCT. A standardized form was used to record clinical variables, including patient demographic information. The clinical data of patients in each risk group were followed for 3 years after the date of final registration. JPLSG performed a central review of morphologic classification and karyotyping based on the World Health Organization Classification, French-American-British classification, and cytogenetic analysis using conventional G-banding. Molecular characterization included mutational analyses of KIT (exons 8 and 17), N- and K-RAS (exons 1 and 2), NPM1 (exon 12), CEBPA (exon 12), FLT3-ITD, NUP98-NSD1,and CBFA2T3-GLIS2 gene rearrangement, as well as KMT2A- partial tandem duplication (MLPA methods). We also evaluated the gene expression of MECOM (also known as EVI1) and PRDM16 (also known as MEL1) because their high expressions are known poor prognostic markers. Overall survival (OS) was defined as the time from AML diagnosis to death or censorship at the last follow-up. Event-free survival (EFS) was defined as the time from AML diagnosis to treatment failure, relapse, death, or last follow-up. Results The 3-year OS among SCT patients (n = 175) was approximately 50%. It was significantly worse than that of non-SCT patients (n = 194, 90%; P < 0.001). Among 137 CBF-AML patients, 44 patients (32%) received SCT and their 3-year OS was 80%. On the other hand, among 232 non-CBF-AML patients, 131 patients (57%) received SCT, and their 3-year OS was only 35%. This result indicated that SCT is beneficial for relapsed CBF-AML, whereas most non-CBF patients who received SCT did not obtain the clinical benefit. In terms of the molecular characteristics, among 58 patients with high EVI1 expression, 39 patients (67%) received SCT, and their 3-year OS was approximately 35%. EVI1 expression was especially useful when using with MLL rearrangement because prognosis of patients with both MLL rearrangement andhigh EVI1 expression were extremely poor. On the other hand, among 84 patients with high PRDM16 expression, 63 patients (75%) received SCT, and their 3-year OS was approximately 20%. Although all AML patients with FLT3-ITD were assigned to receive SCT in the AML-05 trial, FLT3-ITD(+) patients withlow PRDM16 expression had a better outcome than FLT3-ITD(+) patients with high PRDM16 expression (3-year OS: 70% vs. 21%; P < 0.001). This result indicated that FLT3-ITD itself might not necessarily be associated with poor prognosis. PRDM16 gene expression is a useful marker to select patients needing SCT, particularly for patients with FLT3-ITD. Conclusion SCT was beneficial for patients with CBF-AML, whereas SCT was insufficient to rescue patients with non-CBF AML who relapsed, particularly patients with both FLT3-ITD(+) and high PRDM16 expression. New strategies, such as gemtuzumab ozogamicin or haploidentical SCT, are urged to rescue high risk/refractory patients. Disclosures No relevant conflicts of interest to declare.

scholarly journals Effectiveness and antimicrobial susceptibility profiles during primary antimicrobial prophylaxis for pediatric acute myeloid leukemia

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ting-Chi Yeh ◽  
Jen-Yin Hou ◽  
Ting-Huan Huang ◽  
Chien-Hung Lu ◽  
Fang-Ju Sun ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Antimicrobial Prophylaxis ◽  
Pediatric Acute Myeloid Leukemia ◽  
Life Threatening ◽  
De Novo Aml ◽  
Susceptibility Profiles ◽  
Acute Myeloid

AbstractLimited data are available on antimicrobials exposure and microbiology evolution in pediatric acute myeloid leukemia (AML) patients underwent antimicrobials prophylaxis. To assess the effectiveness of antimicrobials prophylaxis, antibiotic susceptibilities of bacteria, and exposure of antimicrobials during intensive chemotherapy for AML patients, 90 consecutive de novo AML patients aged 0–18 years between January 1, 1997 and March 31, 2018 were enrolled. Vancomycin, ciprofloxacin and voriconazole prophylaxis was administered from January 1, 2010. During the preprophylaxis period, January 1997 to December 2009, 62 patients experienced a total of 87 episodes of bloodstream infection (BSI) and 17 episodes of invasive fungal infection (IFI) among 502 courses of chemotherapy. In contrast, 16 episodes of BSI occurred and no IFIs were reported to occur in 28 patients who received 247 courses of chemotherapy in the prophylaxis period. Patients who received antimicrobial prophylaxis had a significant reduction of BSI, IFI, and febrile neutropenia in comparison with patients without prophylaxis. Exposure to amikacin, carbapenem, amphotericin B was reduced in the prophylaxis period. Imipenem susceptibility of Enterobacter cloacae as well as vancomycin susceptibility of Enterococcus species were reduced in the prophylaxis period. At the time of the last follow up, patients with prophylaxis had a better subsequent 5-year overall survival rate than those without prophylaxis. Prophylactic antimicrobials administration in children with AML who undergo chemotherapy can significantly reduce the rates of life-threatening infection, exposure to antimicrobials, and might result in a better outcome.

scholarly journals Treatment Patterns and Outcomes of Unselected Elderly Acute Myeloid Leukemia (AML) Patients Referred to a Combined Acute Leukemia and Hematopoietic Stem Cell Transplant (HSCT) Program

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2675-2675
Author(s):  
Scott R Solomon ◽  
Katelin C Jackson ◽  
Xu Zhang ◽  
Melhem Solh ◽  
Asad Bashey ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Induction Therapy ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Risk Category ◽  
Hematopoietic Stem ◽  
Factors Associated ◽  
Poor Risk ◽  
Elderly Aml ◽  
Acute Myeloid

Abstract The median age of acute myeloid leukemia (AML) diagnosis is 69 years with 60% of newly diagnosed patients > 60 years. Due to a perceived intolerance to therapy, many elderly AML patients do not receive therapy. Of those that do, few are eligible for curative intent therapy with hematopoietic stem cell transplantation (HSCT) due to perceived lack of fitness, excessive comorbidity or absence of a donor. To better understand the outcomes of elderly AML patients, we evaluated a cohort of 323 consecutive elderly AML patients (≥60 years) referred to the Leukemia Program at Northside Hospital from January 2009 to December 2017 for evaluation and management. Our treatment algorithm is to offer intensive chemotherapy (IC) to all potentially eligible patients and HSCT to all transplant-eligible non-favorable risk patients that achieve complete remission, with or without complete platelet recovery (CR1(p)). Median patient age was 70 years (range 60-88). AML occurred de novo in 218 (67%), therapy-related in 33 (10%) and secondary in 72 (22%) patients. NCCN risk category was favorable (fav) in 48 (15%), intermediate (int) in 112 (35%) and poor in 161 (50%). Leukemia induction therapy, either IC (n=204) or hypomethylating agents (HMA, n=58), was given to all but 61 (19%) patients (IC - 78%, HMA - 22%). Of patients receiving IC, the major regimens were FLAG+/-Ida (n=117), 7+3 (n=58) and CPX-351 (n=18). Of the IC/HMA-treated patients (n=262), 130 (50%) achieved CR1(p) with the first induction, while 158 (60%) ultimately achieved CR1(p). In patients with fav, int and poor risk AML, CR1(p) was achieved in 73%, 52% and 41% respectively. HSCT was performed on 63 patients (59 - int/poor risk, 4- fav risk): autologous [5], matched sibling donor [21], matched unrelated donor [24], haploidentical donor [13]. Of the non-fav risk AML CR1(p) patients, where the treatment goal is HSCT if feasible, 57 (46%) of 124 received HSCT. After a median f/u of 34 months, 2-year overall survival (OS) for the whole cohort was 31%; corresponding rates for fav, int and poor risk AML was 58%, 35% and 20% respectively. Survival was similar in patients aged 60-66 and 67-72 years (2-yr OS 35% and 38%), but superior to those in the 73-88 yr tertile (2-yr OS 19%, p<0.001). The 2-yr OS was similar for IC- or HMA-treated patients (40% and 33% respectively) vs. 0% for patients not receiving induction therapy. For patients achieving CR1(p), 2-yr OS was 50% vs. 16% for those never reaching CR1(p). Of the patients receiving HSCT, 2-yr OS was 64%. In the subset of non-fav risk AML CR1(p) patients, OS was improved with HSCT (p<0.001, 2-yr OS 66% vs. 27%). In multivariate analysis, we analyzed factors associated with mortality including age, gender, race, year of diagnosis, WBC, de novo vs. secondary, NCCN risk category, and induction chemo type (receipt of HSCT was not analyzed given inherent bias in such as analysis). Factors associated with superior OS included WBC <2.5 at diagnosis (2.5-25.7, HR 1.92, p<0.001; ≥25.8, HR 1.93, p<0.001), NCNN fav risk (int, HR 2.02, p=0.002; poor, HR 2.71, p<0.001) and receipt of either IC or HMA induction (no induction vs. IC, HR 7.65, p<0.001; HMA vs. IC, HR 1.20, p=0.315). With the caveat that any such analysis is subject to referral bias, these results suggest that survival may be improved in elderly AML patients through a coordinated approach of remission induction therapy followed by HSCT when feasible. Disclosures Solh: Celgene: Speakers Bureau; Amgen: Speakers Bureau; ADC Therapeutics: Research Funding.

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