The Prognostic Significance of c-KIT Mutations in Core Binding Factor Acute Myeloid Leukemia

BackgroundMany recurrent mutations are encountered in core binding factor acute myeloid leukemia (CBF-AML) which may affect the prognosis. Approximately 20 to 45% of CBF-AML patients have KIT mutations which are having poor prognosis and high incidence of relapse. There is still insufficient data to categorize the patients with c-kit mutation into which risk group and there is a debate around whether Tyrosine kinase inhibitors can decrease the relapse risk and improve the prognosis of those patients.Patients and MethodsThis study was conducted throughout a period of 3 years, where 102 CBF-AML were enrolled in our study. We analyzed the incidence of c-KIT exon 8 and 17 D816V mutations in CBF-AML patients and studied the prognosis.ResultsThe prevalence of CBF-AML was 102 of 989 (10.3%), 13.7% and 8.7% in pediatrics and adults’ groups respectively. c-KIT fragment mutation analysis revealed a mutant form in 27 of 102 (26.5%) patients. Exon 8 mutation was found in 4 of 40 pediatric and 2 of 62 adult patients, while exon 17 mutation was found in 9 of 40 pediatric and 12 of 62 adult patients. The c-KIT mutations was more common in t(8;21). There was no significant relationship between c-kit mutation and CR rates, while there was a significant inferior overall, disease free as well as progression free survival in the c-KIT mutant patients as compared to the wild group (P value .045, .036 and .024 respectively) in the pediatric group, however, this significance was not evident in the adults’ group.ConclusionAccording to our study, the results may suggest c-KIT mutation as a poor risk factor in pediatric CBF-AML.     

Outcomes of Patients With Relapsed Core Binding Factor-Positive Acute Myeloid Leukemia

Purpose

To determine the factors associated with outcomes in patients with core binding factor acute myeloid leukemia (CBF-AML) in first relapse.

Outcome of Core Binding Factor Acute Myeloid Leukemia by Receptor Tyrosine Kinase Mutation

BackgroundCore binding factor acute myeloid leukemia (CBF-AML) encodes 2 recurrent cytogenetic abnormalities, t(8;21) and inv(16), which carries an overall good prognosis. However, some patients will develop a relapse. We sought define the unfavorable group of CBF-AML by analysis of (c-KIT and FLT3-ITD) and to correlate them with treatment outcome.Patients and MethodsWe performed a prospective study of 70 patients with CBF-AML diagnosed and managed at the medical oncology department of the (National Cancer Institute), Cairo University, with analysis of c-KIT and FLT3 mutations. All patients had received “3 + 7” induction, followed by 3 to 4 courses of high-dose cytarabine consolidation. The institutional review board approved the present study.ResultsThe median patient age was 31 years (range, 18-60 years), with a male/female ratio of 4:3. Of the 70 patients, 42 (60%) had t(8;21) and 28 had inv(16) (40%). c-KIT mutations (exons 8 and 17) were detected in 10 of 52 tested patients, and FLT3-ITD was detected in 3 of 70 patients. Patients with inv(16) experienced more lymphadenopathy and splenomegaly, had a higher median initial leukocyte count. Hepatitis C antibody positivity (8 of 42) was exclusively present in patients with t(8;21). The median overall survival (OS) was 19.5 months, and the median disease-free survival (DFS) was not reached. Patients with inv(16) had near-significant (P = .07) better DFS than patients with t(8;21). c-KIT mutations had no significant effect on OS or DFS. However, reverse tyrosine kinase mutations had a negative effect on DFS but not OS (P = .04).ConclusionCBF-AML with reverse tyrosine kinase mutation conveys a worse prognosis. Hepatitis C virus antibody positivity might be associated with t(8;21) AML and inv(16) with more extramedullary disease.     

Prognostic Implications of Chromosome 17 Abnormalities in the Context of Monosomal Karyotype in Patients With Acute Myeloid Leukemia and Complex Cytogenetics

BackgroundChromosome 17 abnormalities are associated with poor outcome in leukemias including AML. Recently, MK was introduced as an independent predictor of dismal outcome in AML. The additional prognostic effect of C17 abns in patients with MK in a CK background is not clear.Patients and MethodsWe conducted a retrospective analysis of 1086 patients with newly diagnosed AML treated between January 1998 and December 2007. Patients received treatment with one of the institution's first-line protocols.ResultsFour hundred eighty-three patients had CK. Among them, 370 patients (77%) had CK-MK, and 195 patients (53%) had CK-MK-C17 abns. Patients with CK-MK had significantly shorter OS rates compared with patients with CK without MK (4.4 vs. 8 months, respectively; P = .002). The median OS for patients with CK-C17 abns was shorter than for patients without C17 abns (4 vs. 6.1 months, respectively; P = .004). In a multivariate analysis, the presence of MK among patients with CK was identified as an independent prognostic marker for OS. In addition, presence of C17 abns had a significant negative effect on OS among patients with CK-MK (P = .04).ConclusionAmong patients with CK-AML, MK was associated with poor outcomes. Additional presence of C17 abns further worsens the outcome in these particularly poor-risk patients with AML.     

Therapy of Core Binding Factor Acute Myeloid Leukemia: Incremental Improvements Toward Better Long-Term Results

BackgroundDespite being considered as good prognostic acute myelogenous leukemia (AML), the long-term survival rate in core binding factor (CBF) AML leaves room for substantial improvement.Materials and MethodsWe reviewed relevant English language literature related to treatment of CBF AML available in PubMed. Review also included meeting abstracts.ResultsMulticycle high dose cytarabine in consolidation improves remission duration but larger groups report overall survival in the range of 40% to 50% at 5 years or longer.ConclusionsConcerted effort is needed toward improving outcomes in CBF AML through clinical trials and risk-adapted approach.     

Clinical Outcomes of Patients With Chronic Myeloid Leukemia With Concurrent Core Binding Factor Rearrangement and Philadelphia Chromosome

BackgroundAcquisition of additional cytogenetic abnormalities (ACAs) in addition to Philadelphia chromosome is frequently observed in patients with chronic myeloid leukemia (CML) in advanced phase. The presence of core binding factor (CBF) translocations determines the diagnosis of acute myeloid leukemia regardless of blast percentage, and CBF rearrangements are rarely identified as ACAs.Patients and MethodsA retrospective chart review of patients with CML who had CBF rearrangement, t(8;21) or inv(16), in Philadelphia chromosome-positive clones was conducted. Additional cases of CML with CBF rearrangements were identified through literature review.ResultsBetween August 1997 and December 2014, we identified 11 patients who had Philadelphia chromosome and CBF rearrangement in the same clones: 1 (9%) with t(8;21) and 10 (91%) with inv(16). Nine (82%) patients were in blast phase, and 2 (18%) in second chronic phase. Four (36%) patients received tyrosine kinase inhibitor monotherapy, 2 (18%) received tyrosine kinase inhibitor and chemotherapy, and 5 (45%) received chemotherapy only. Three (27%) patients achieved complete remission with incomplete count recovery, and 4 (36%) had no response after the initial therapy. Three (27%) patients underwent allogeneic stem cell transplantation. The median event-free survival and overall survival for the 11 patients were 2 months and 6 months, respectively. Literature review identified 14 patients with CML with CBF rearrangement with a median overall survival of 14 months.ConclusionAcquisition of CBF rearrangement in addition to Philadelphia chromosome is a rare phenomenon associated with poor prognosis. CBF rearrangements as ACAs in patients with CML can be considered high-risk features.     

Acute Myeloid Leukemia Possibly Producing Thrombopoietic Factor(s)

A 75-year-old man developed a cluster of differentiation (CD)4-positivebut human T-cell lymphotropic virus type I (HTLV-I)-negativeT lymphoid neoplasm with overwhelming cutaneous involvementand mild thrombocytosis. Twelve courses tetrahydropyranyl adriamycin,cyclophosphamide, vincristine and predonisone (THP-COP) combinationchemotherapy led him to complete remission. After four monthsof complete remission, however, atypical immature cells (blasts)appeared in peripheral blood and bone marrow. Surface markeranalysis revealed the blasts to be CD2–, CD3–, CD4–,CD5–, CD7+, CD8–, CD10, CD13±, CD19–,CD20–, CD25–, CD33+ and human leukocyte antigen-DR(HLA-DR+). Staining for myeloperoxidase, esterases, PAS andplatelet peroxidase were all negative. The patient was diagnosedas having both CD7 and CD33 positive acute myeloid leukemia(AML). The relation between the T cell lymphoid neoplasm andAML was not clear. Thrombocytosis became more marked after acuteleukemia occurred and the platelet count varied in parallelwith the blast cell count in peripheral blood. When the leukemiccell count was high, thrombopoietic activity could be detectedin the serum. In addition, conditioned medium obtained fromprimarily-cultured blasts had detectable thrombopoietic activity,which implied the blasts directly to produce a thrombopoieticfactor(s). Analysis of the serum concentration for cytokineswith associated thrombopoietic activity indicated that the blastspossibly produced a thrombopoietic factor(s) distinct from interleukin(IL)6, IL3, leukemia inhibitory factor (LIF), erythropoietinand granulocyte macrophagecolony stimulating factor. To ourknowledge, this is the first reported case of an acute myeloidleukemia with marked thrombopoiesis (more than 2000x10³/µlof maximum platelet count in peripheral blood).     

Prognostic Factors in Pediatric Acute Myeloid Leukemia

Acute myeloid leukemia (AML), a heterogeneous group of diseases with variable responses to the same therapy, comprises nearly a quarter of childhood acute leukemias. Although historically very few prognostic markers have been incorporated into therapeutic decision making in AML, recent advances in technology have enabled identification of numerous factors associated with disease outcome. This review provides a detailed analysis of most clinically relevant factors associated with disease outcome in childhood AML.     

Peripheral Blasts on Day 21 of Induction Chemotherapy in a Patient With Core Binding Factor Acute Myeloid Leukemia: More Than Meets the Eye

The combination of fludarabine, high-dose cytarabine, gemtuzumab ozogamicin, and granulocyte colony-stimulating factor (G-CSF), the FLAG-GO protocol, has resulted in excellent response rates and superior relapse-free survival as first-line therapy for patients with core binding factor acute myeloid leukemia (AML). A side effect of administration of G-CSF is an increase in peripheral white blood cell count and blast cell percentage during the recovery phase of the bone marrow after induction chemotherapy. A 60-year-old man with inversion 16 AML was admitted for induction chemotherapy with the FLAG-GO protocol at our institution. On day 21 of his induction regimen, he was noted to have blasts in both the peripheral smear and in the bone marrow that resolved on their own without any intervention by day 28. Our case report underscores the importance of recognizing this phenomenon associated with the administration of G-CSF, and waiting for 5-7 days before administering re-induction therapy or classifying the disease as primary refractory AML.     

Predictive and Prognostic Markers in Adults With Acute Myeloid Leukemia: A Single-Institution Experience

Background

Acute myeloid leukemia (AML) is a heterogeneous malignancy with diverse genetic abnormalities, clinical presentations, and outcomes. Known predictive and prognostic factors in AML include age, performance status, comorbidities, cytogenetics, and molecular mutations. Identifying prognostic and predictive factors can inform the choice of induction therapy and outcomes prediction.

MDR1 RNA Expression as a Prognostic Factor in Acute Myeloid Leukemia: An Update

In order to confirm our initial report on the negative impact of MDR1 gene expression on the outcome of de novo acute myeloid leukemia (AML), we present an update of our prospective study with a larger number of patients and a longer duration of follow-up. At diagnosis, MDR1 RNA expression of the leukemic cells was negative in 37% and positive in 63% of the patients (N = 79). The complete remission rate of induction chemotherapy was 76% for MDR1 RNA negative and 54% for MDR1 RNA positive patients (p = 0.05). At a median observation duration of 33 months, the duration of overall survival was 19 months for the MDR1 RNA negative patients but only 8 months for the patients with MDR1 gene expression (p = 0.02). Thus the long-term data also indicate that MDR1 gene expression is an unfavourable prognostic factor in AML.     

Prognostic Effect of Complex Karyotype,Monosomal Karyotype,and Chromosome 17 Abnormalities in B-Cell Acute Lymphoblastic Leukemia

BackgroundThe effect of monosomal karyotype (MK), complex karyotype (CK), and chromosome 17 abnormalities (abnl 17) on prognosis in B-cell acute lymphoid leukemia (B-ALL) has not yet been established.Patients and MethodsWe conducted a retrospective analysis of prognostic factors on 237 adult patients with B-ALL treated at our institution.ResultsOlder age (older than 60 years), higher white blood cell count (> 30), and abnl 17 were associated with shorter overall survival in univariate analysis, but multivariable analysis only identified older age as an independent poor prognostic actor. There was a significant correlation between abnl 17 and older age.ConclusionIn contrast to the patients with acute myeloid leukemia, our results show that MK and CK do not play a predictive role in patients with B-ALL, but further study is required to determine whether specific changes on chromosome 17 might have prognostic value when investigated separately.     

大剂量粒系集落刺激因子使老年急性髓系白血病患者受益

目的 探讨老年急性髓系白血病（AML）化疗期间预防性大剂量（>5 μg/kg）和标准剂量（5 μg/kg）使用G-CSF对感染、输血情况的影响。方法 回顾性对比分析82例老年AML 273个化疗周期中两组G-CSF进行支持治疗中抗生素和抗真菌药物使用情况、发热天数、发热程度、粒缺时间、输血情况等。结果 273个化疗周期中合并感染223次（81.7%）,因感染中断治疗11例（13.4%）;标准剂量组中2例（2.3%）患者在诱导治疗期间死亡。亚组分析发现,大剂量组可明显缩短巩固治疗期间粒缺时间、发热天数及减少抗真菌药物的使用。结论 大剂量G-CSF可提高老年AML患者化疗期间的安全性、耐受性。     

Elderly Patients (Age 70 Years or Older) With Secondary Acute Myeloid Leukemia or Acute Myeloid Leukemia Developed Concurrently to Another Malignant Disease

Introduction

Secondary acute myeloid leukemia (sAML) remains a therapeutic challenge. In elderly patients with AML, it is unclear whether sAML displays an inferior outcome compared with de novo AML.

Decitabine in the Treatment of Acute Myeloid Leukemia and Myelodysplastic Syndromes,Which Combined with Complex Karyotype Respectively

Background: We conducted a study exploring the clinical safety and efficacy of decitabine in patients withacute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), combined with a complex karyotype.Materials and Methods: From April 2009 to September 2013, a total of 35 patients with AML/MDS combinedwith a complex karyotype diagnosed in the First Affiliated Hospital of Soochow University were included forretrospective analysis. All patients were treated with decitabine alone (20mg/m2 daily for 5 days) or combinationAAG chemotherapy (Acla 20mg qod*4d, Ara-C 10mg/m2 q12h*7d, G-CSF 300μg qd, the dose of G-CSF adjustedto the amount in blood routinely). Results: In 35 patients, 15 exhibited a complete response (CR), and 6 a partialresponse (PR), the overall response rate (CR+PR) being 60% (21 of 35). Median disease-free survival was 18months and overall survival was 14 months. In the 15 MDS patients with a complex karyotype, the CR rate was53.3% (8 of 15); in 20 AML patients with complex karyotype, the overall response rate was 65% (13 of 20). Theresponse rate of decitabine alone (22 cases) was 56.5% (13 of 22), while in the combination chemotherapy group(13 cases), the effective rate was 61.5% (8 of 13)(P>0.05). There are 15 patients with chromosome 7 aberration,after treatment with decitabine, 7 CR, 3 PR, overall response rate was 66.7% (10 of 15). Of 18 patients with 3 to5 kinds of chromosomal abnormalities, 66.7% demonstrated a response; of 17 with more than 5 chromosomalabnormalities, 52.9% had a response. In the total of 35 patients, with one course (23 patients) and ≥two courses(12 patients), the overall response rate was 40.9% and 92.3% (P<0.05). Grade Ⅲ to IV hematological toxicitywas observed in 27 cases (75%). Grade Ⅲ to IV infections were clinically documented in 7 (20%). Grades Ⅰ toⅡ non-hematological toxicity were infections (18 patients), haematuria (2 patients), and bleeding (3 patients).With follow-up until September 2013, 7 patients were surviving, 18 had died and 10 were lost to follow-up. Inthe 6 cases who underwent allogeneic hematopoietic stem cell transplantation (HSCT) all were still relapse-freesurvivors. Conclusions: Decitabine alone or combination with AAG can improve outcome of AML/MDS witha complex karyotype, there being no significant difference decitabine in inducing remission rates in patientswith different karyotype. Increasing the number of courses can improve efficiency. This approach with fewertreatment side effects in patients with a better tolerance should be employed in order to create an improvedsubsequent chance for HSCT.