De Novo Acute Myeloid Leukemia Involving only Granulocyte-Macrophage Line in Octogenarians with Leucocytes over 15 × 109/L Exhibit a Favorable Response to Standard-Dose Induction Chemotherapy

Research Article

Ann Hematol Oncol. 2018; 5(7): 1216.

De Novo Acute Myeloid Leukemia Involving only Granulocyte-Macrophage Line in Octogenarians with Leucocytes over 15 × 109/L Exhibit a Favorable Response to Standard-Dose Induction Chemotherapy

Lemež P1,2*, Gáliková J1, Michalová K3,4, Fuchs O4, MacWhannell A2, Zemanová Z3, Březinová J4, Cerná M5 and Stejskal J6

1Department of Hematology and Blood Transfusion, Hospital Jihlava, Jihlava, Czech Republic

2Department of Haematology, New Cross Hospital, Wolverhampton, United Kingdom

3Center of Oncocytogenetics, Institute of Clinical Biochemistry and Laboratory Diagnostics, First Faculty of Medicine, Charles University, Prague

4Institute of Hematology and Blood Transfusion, Prague, Czech Republic

5Department of Hematology and Blood Transfusion, Hospital Uherské Hradište, Czech Republic

6Department of Radiotherapy, Hospital Jihlava, Jihlava, Czech Republic

*Corresponding author: Lemež P, Department of Hematology and Blood Transfusion, Hospital Jihlava, 586 33 Jihlava, Czech Republic; Email: plemez@post.cz

Received: September 30, 2018; Accepted: October 11, 2018Published: October 31, 2018

Abstract

Objectives: Octogenarians with Acute Myeloid Leukemia (AML) exhibit poor median survival of 1-3 months after Standard-Dose Induction Chemotherapy (SICT). De novo AML without Erythroblastic And/Or Megakaryocytic Dysplasia (EMD) involving only Granulocyte-Macrophage Line (GM-AML) is associated with a 74-86% Complete Remission (CR) rate after SICT and improved survival in adult patients aged below 65 years. Our aim was to study if octogenarians with GM-AML will achieve CR and improved survival after SICT.

Patients and Methods: Consecutive 12 octogenarians with de novo non-M3 AML with 48-94% (median 80%) bone marrow blasts, classified as AML FAB types: 2×M2, 7×M4, and 3×M5 were offered 3+7 type of SICT. Criteria for EMD were dyserythropoiesis 30% and/or dysmegakaryopoiesis 50% or higher.

Results: Six cases, all with leucocytes over 15×109/L, opted for SICT. Three cases with GM-AML achieved CR and survived 16.5-28 months on maintenance therapy while 3 cases with EMD-AML did not reach CR and had survival 0.4-2.7 months. Genetic findings in GM-AML cases showed 46, XY, del (12) (p13) with deleted ETV6 gene, 46, XX with NPM1 mutation and negative for FLT3-ITD and in the third case normal karyotype, which was found in two resistant EMD-AML cases. Survival 0.2-4.0 months was observed in the 6 remaining patients (two with GM-AML, 4 with EMD-AML) on palliative or supportive treatment.

Conclusion: Octogenarians with GM-AML even with poor performance status (2×PS 3) may achieve CR and survival benefit after SICT, which is further supported by two other elderly GM-AML cases with over 5 years survival.

Keywords: Acute myeloid leukemia; Octogenarians; Classification; Hematopoietic Myelodysplasia; Molecular genetics; Chemotherapy

Abbreviations

CI: Comorbidity Index; DysE: Erythroblastic Dysplasia; DysG: Granulocytic Dysplasia; DysMg: Megakaryocytic Dysplasia; EMD: Erythroblastic and/or Megakaryocytic Dysplasia; EMD: AML-AML With Erythroblastic and/or Megakaryocytic Dysplasia; GM-AML: AML Involving Only Cells of Granulocytic - Macrophage Line; SICTStandard- Dose Induction Chemotherapy

Introduction

Survival of octogenarian patients with Acute Myeloid Leukemia (AML) is dismal [1-6]. The first reported retrospective singleinstitution study on patients with AML aged 80 years and above concluded that currently available chemotherapy is generally not indicated because the treatment, based mostly on high or standard doses of cytarabine (Ara-C) plus 3 doses of anthracyclines, led to median survival of 3-4 weeks in 29 treated patients while 4 untreated patients had median survival 10 weeks [1]. Nine patients (31%) reached Complete Remission (CR) of 3 months median duration and only two survived over one year [1]. In 2006 the same institution reported 82 patients aged 80 years and above treated with similar chemotherapy which induced 37% CR and 54% mortality within 8 weeks and a median survival of 6 weeks [2]. Three studies with highly selected AML octogenarian patients treated with intensive chemotherapy showed 30-37% CR, 33-35% early death rate but significant overall survival benefit in patients who reached CR [3- 6]. Various AML guidelines [7-9] did not recommend Standard Dose Induction Chemotherapy (SICT) in patients with AML over 80 years because of high early treatment-related mortality caused partially by more frequent poor Performance Status (PS), significant comorbidities and the well-known therapeutic resistance of AML to SICT in this age group [10-12]. The resistance of these AML to SICT is related to cytogenetics associated with adverse prognosis [2,7-12], the multidrug resistance phenotype [12,7-9], multilineage dysplasia [13-18], and secondary type of AML after previous Myelodysplastic (MDS) or Myeloproliferative (MPS) syndromes, or to previous chemotherapy/radiotherapy-all found with higher frequency with increasing age [2,7,9-12,19-20]. Furthermore, cytogenetic AML entities associated with favorable prognosis as t(15;17) (q22;q21), t(8;21) (q22;q22), inv(16) (p13.1q22) /t(16;16) (p13.1;q22) are found with very low frequencies in patients over 70 years old [9-12,20]. Therefore one important task in AML octogenarian patients is to identify those who are likely to achieve CR after SICT and benefit from it [2-9].

Our previous study showed that adult patients (18-64 years) with de novo non-M3 AML M0-M5 without Erythroblastic And/Or Megakaryocytic Dysplasia (EMD) treated with Standard Dose 3+7 Type of Chemotherapy (SICT) reached CR in 78.6% in comparison to 28.6% CR in cases with AML plus EMD (EMD-AML, AML involving multiple myeloid lines) [17]. The patients without EMD exhibited a significant survival benefit after consolidations with cycles of highdoses of Ara-C and daunorubicin (DNR) [17]. Similar results were found in patients with AML and normal karyotype [21]. Patients with de novo AML without EMD exhibited either normal karyotype or karyotypes associated with intermediate prognosis and represented a special biological AML category involving only one (granulocytemacrophage) myeloid line with favorable prognosis (GM-AML) [17,21]. Our findings of the high CR rate after SICT in patients with de novo GM-AML were supported by results of other studies of adult patients under 60/65 years of age with de novo AML [13-16] with CR rates 74-86 % or in patients with AML not otherwise specified without myelodysplasia-related changes [22].

The aim of our study was to investigate if octogenarian patients with de novo GM-AML may achieve CR and a survival benefit after SICT similar to adults aged less than 65 years. This report describes our experience with 12 consecutive octogenarian patients with de novo AML and the observation that all three of them with GM-AML treated with SICT reached CR and had an improved survival in spite of a poor performance status and significant comorbidities. Our two other elderly GM-AML cases and a review of literature support our findings of the good sensitivity of leukemic cells of GM-AML to SICT and its use in octogenarian patients with de novo GM-AML.

Patients and Methods

Ethical aspects

Informed consent for clinical and laboratory examinations and the type of therapy chosen by each patient was obtained according to the principles of the Declaration of Helsinki. The study was approved by the Institutional Scientific Review Board of Hospital Jihlava.

Study group

The 12 consecutive Caucasian patients with de novo AML aged 80 years and above were diagnosed between October 1992 and March 2011. Patients with secondary AML were not eligible for this study because of the known poor response to SICT.

The French-American-British (FAB) classification [23] with standard cytochemical and immunophenotyping methods was used for establishing the diagnosis of AML [23,17]. Cytogenetic and I-FISH analyses were made from 24-hour unstimulated cultures of patients’ bone marrow cells at diagnosis [17,24]. Molecular-genetic analyses were performed on cDNA obtained by reverse transcription of RNA (or for CEBPA from genomic DNA by sequencing the multiplied entire coding region of CEBPA) from bone marrow mononuclear cells at diagnosis as reported [24]. Morphological dysplastic features of erythroblasts, megakaryocytes, and granulocytes, in diagnostic Bone Marrow (BM) smears from patients were evaluated according to the FAB criteria [25] independently by two experienced hematologists (PL,JG) [17]. EMD was diagnosed when more than 30% of 50-200 evaluable erythroblasts had to show dyserythropoietic features (DysE, (Table 1,2)) and/or when 50% or more of at least 5 megakaryocytes (DysMg) were dysplastic. Dysgranulopoiesis (DysG) was diagnosed when 50% or more of 50-200 neutrophilic segments, stabs, and metamyelocytes were dysplastic. If less than the required number of cells evaluable for dysplasia was found in any line, the dysplasia in the line was not evaluable (NE - (Table 1,2)) [17,21]. Performance status (PS WHO/ECOG), comorbidities (IHD - ischemic heart disease; CKD - chronic kidney disease, etc.), Comorbidity Index (CI) according to Charlson et al. [26] and Hematopoietic Cell Transplantation (HCT) CI [27] were evaluated at diagnosis (Table 1,2).

Citation: Lemež P, Gáliková J, Michalová K, Fuchs O, MacWhannell A, Zemanová Z, et al. De Novo Acute Myeloid Leukemia Involving only Granulocyte-Macrophage Line in Octogenarians with Leucocytes over 15 × 109/L Exhibit a Favorable Response to Standard-Dose Induction Chemotherapy. Ann Hematol Oncol. 2018; 5(7): 1216.