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

  

    
Case
    
Units
    
7
    
8
    
9
    
10
    
11
    
12 
  
  

    
Age/Sex
    
Years/
    
82/m
    
82/f
    
87/f
    
83/f
    
89/f
    
86/m 
  
  

    
PS    WHO
    

    
1
    
3
    
3
    
2
    
3
    
3 
  
  

    
Charlson    CI
    

    
2
    
2
    
1
    
0
    
0
    
1 
  
  

    
HCT    CI
    

    
2
    
3
    
2
    
0
    
1
    
2 
  
  

    
Comorbidity
    

    
DM,    TIA
    
CDK4,    ATB
    
Pneumonia    mycob. fortuit, ATB
    
Chr.    Pancreat.,CDK3
    
IHD-AF,CDK3
    
Tb-surgery,ATB 
  
  

    
AML    FAB
    

    
M4
    
M5
    
M4
    
M2
    
M4
    
M5 
  
  

    
WBC
    
10e9/L
    
31.4
    
51.4
    
3
    
19.9
    
2.4
    
9.2 
  
  

    
Blasts
    
%
    
54
    
84
    
50
    
61
    
26
    
46 
  
  

    
Hb
    
g/L
    
109
    
74
    
75
    
69
    
72
    
101 
  
  

    
Platelets
    
10e9/L
    
153
    
58
    
166
    
12
    
127
    
77 
  
  

    
Bone    marr.
    

    

    

    

    

    

    

  
  

    
Blasts
    
%
    
59
    
89
    
80
    
89
    
67
    
76 
  
  

    
Erythroblasts
    
%
    
7.2
    
4.6
    
4
    
2.6
    
10
    
17 
  
  

    
DysE
    
%
    
15
    
20
    
64
    
34
    
72
    
47 
  
  

    
DysMg
    

    
15-Feb
    
12-Mar
    
15/21
    
NE
    
16-Sep
    
12-Oct 
  
  

    
DysG
    
%
    
68
    
NE
    
94
    
75
    
89
    
74 
  
  

    
Line    involved
    

    
GM
    
GM
    
GM,    E, Mg
    
GM,    E
    
GM,    E, Mg
    
GM, E, Mg 
  
  

    
Cell    markers
    

    

    

    

    

    

    
c22,c79a 
  
  

    
CD    positive
    

    
ND
    
7,11b,33,34,117,DR
    
7,13,33,34,117,DR,MPO
    
13,33,MPO
    
13,33,34,117,DR,MPO
    
13,33,117,MPO 
  
  

    
CD    negative
    

    

    
1,2,3,10,19,14
    
c3,c79a;    2,3,4,10,14,15,19
    
14,15,34,117,DR,TdT,    c3,c79a;2,3,4,7,10,19
    
c3,c79a,2,3,4,10,19,TdT
    
c3,2,10,19,34, 14,61,TdT 
  
  

    
Genetics
    

    
ND
    
46,    XX[20], FLT3-ITD, neg: CFB-MYH11, RUNX1-RUNX1T1, MLL gene transloc.
    
43~44,    XX, der(1)t(1;?) (p35;?), del(3)(q?21q?25),del(5)(q22q33),    +6,-4,-8,der(11)t(11;?)(q23;?), -14,-15,+21[cp20], neg: DEK-NUP214,    RUNX1-RUNX1T1, CFB-MYH11, PML-RARA
    
46,XX[8],    neg: PML-RARA
    
46,XX,r(7)(?p?q)[14]/46,XX[14].nucish,    (D7S796,D7S658)x2, (D7S2543,D7S486,D7S2886)x1[98/105]
    
46,XY[20] 
  
  

    
Therapy
    

    
6-MP
    
BSC
    
BSC
    
BSC
    
BSC
    
Hydroxycarb. 
  
  

    
Survival
    
months
    
4
    
0.2
    
1
    
1.8
    
2.5
    
1.3 
  
  

    
CI:    Comorbidity Index; HCT CI: Hematopoietic Cell Transplantation CI;    Blasts-myeloblasts + promyelocytes + promonocytes; DysE: Dysplastic    Erythroblasts; DysMg: number of Dysplastic/total number of examined    Megakaryocytes; DysG: Dysplastic Granulocytes; NE: Not Evaluable; ND: Not    Done 
  

Table 2: Clinical and laboratory data of 6 patients treated with palliative or best supportive therapy.

Induction chemotherapy [17]

a) 3+7: Daunorubicin (DNR) 45 mg/m2 i.v. or Mitozantrone (MTZ) 10 mg/m2 i.v. per day on days 1, 3, 5 and Ara-C 100 mg/m2 per 3-h infusion every 12 h for 7 days (DA or MA cycle),

b) TAD: Ara-C 100 mg/m2 per 3-h infusion and Thioguanine (TG) 100 mg/m2 p.o., both every 12 h for 7 days, and DNR 45 mg/m2 i.v. on days 5, 6, and 7, in cases with IHD.

Maintenance therapy consisted of repeated 4 cycles. The first with DNR 45 mg/m2 or MTZ 10 mg/m2 i.v. on day 1 and Ara-C 100 mg/m2 per 3-h inf. every 12 h for 5 days was given to patients in CR. The 2nd, 3rd, 4th maintenance cycles were identically composed of Ara-C 60 mg/ m2 s.c. and TG 70 mg/m2 p.o., both every 12 h for 5 days. Maintenance cycles were administered every 4-12 weeks according to the patient’s clinical status and tolerance until relapse. Cardioprotective agent dexrazoxane was administered in maintenance cycles in 30 minute infusion of 250 ml Ringer’s lactate solution before DNR or MTZ given in 30-minute infusion of 200ml saline. The dose ratio of dexrazoxane to DNR was 10:1 and to MTZ 50:1 [28].

Standard criteria were used to define CR [29]. CR duration was calculated from the date of achieving CR to the date of relapse or death. Overall Survival (OS) was calculated from the date of diagnosis until the date of death.

Results

The 12 consecutive Caucasian patients (5 men, 7 women) diagnosed with de novo AML were 80-90 (median 83) years old. Their clinical and laboratory data, type of therapy administered, outcome of patients with CR duration and OS are summarized in (Tables 1,2). All patients had hypercellular BM films with 48-94% (median 80%) leukemic blasts, classified as AML FAB types: 2×M2, 7×M4, and 3×M5. Eleven patients had hypertension well controlled by medication. Further comorbidities are described in individual cases and (Tables 1,2) with usual abbreviations and summarized as Charlson-CI and HCT-CI. Five patients were febrile and on antibiotics at diagnosis (ATB, (Table 1,2)).

Six patients opted for SICT (Table 1), although four had poor performance status PS 3. Four also had significant comorbidities (HCT-CI 2-3). All 6 cases had higher WBC 17.5-97.8 (median 58.0)×10⁹/L. Three patients (80-85 years old), all with GM-AML, reached CR after SICT on day 33-36 from the start of treatment and two continued on maintenance therapy. Case 1 with IHD and Left Ventricular Ejection Fraction (LVEF) 25% at diagnosis developed cardiac arrhythmia and congestive heart failure after 14 cycles of maintenance chemotherapy but refused pacemaker insertion and died in CR of heart failure and bronchopneumonia shortly after. Case 2 relapsed after the 11th cycle of maintenance therapy (CR duration 19.6 months) and was later treated with hydroxycarbamide and died from progression of AML with CNS hemorrhage and infection 28 months after diagnosis. Case 3 experienced severe mycotic bronchopneumonia during induction treatment and thus was treated later with consolidation DA 2+5 only. She was 10.1 months in CR. At relapse she was treated with two cycles of low-dose Ara-C according to her preference and died of progression of AML. Her OS was 16.5 months.

Three patients with EMD-AML (3×DysMg, 1×DysE) did not achieve CR after SICT. Case 4 died from zygomycotic pneumonia after a month in pancytopenia with persisting leukemic BM infiltration. Case 5 with IHD experienced acute myocardial infarction and Geotrichum capitatum fungaemia during pancytopenia, he recovered from these complications with appropriate treatments but leukemia persisted and his OS was 2.7 months. Case 6 was septic with acute renal failure requiring 7 episodes of haemodialysis and died in septic shock from generalized Candida glabrata infection in pancytopenia on day 10 of therapy. Cases 2-5 had severe mycotic generalized infection or pneumonia in spite of itraconazole prophylaxis with 200- 400 mg p.o. daily in pancytopenia.

Six patients were not treated with SICT (Table 2) and died of complications of AML progression. Case 7 with GM-AML and PS 1 preferred 6-Mercaptopurine (6-MP) ambulatory treatment and survived 4 months. Case 8 with GM-AML died of sepsis on day 6 after admission. Cases 9-12 with EMD-AML opted for palliative or Best Supportive Care (BSC) and survived 1.0-2.5 months.

Five patients had GM-AML and did not exhibit any karyotype associated with adverse prognosis. Case 2 had 46, XY, del(12) (p13) and three cases normal karyotype. Blasts of Case 3 exhibited NPM1 mutation and FLT3-ITD negativity and in Case 8 were FLT3-ITD positive. CEBPA mutations were not found in two tested cases. Four patients had bone marrow blasts 89-94 % and all had rapidly rising WBC > 15.0×10⁹/L.

Seven patients had EMD-AML and four had normal karyotype and three karyotype associated with adverse prognosis including Case 6 treated with SICT. None of the three cases treated with SICT reached CR and their survival was 0.4-2.7 months similar to survival of 1.0-2.5 months in 4 patients with EMD treated with palliative or Best Supportive Care (BSC). Interestingly we found in EMD-AML that leukemic blasts of two tested cases (No. 5 and 6) expressed surface CD5 antigen and blasts of Case 12 expressed cytoplasmic CD22 and CD79a.

Discussion

Our study showed good response to SICT in three octogenarian cases with de novo GM-AML with improved survival in spite of poor PS3 and significant comorbidities in two that usually prevent SICT administration. Sensitivity of GM-AML to SICT seems to be the most important factor for reaching CR in AML similar to results found in adult GM-AML cases aged below 60/65 years in previous studies [17,21], including 156 cases without any dysplasia [15] or in cases without Multi-Lineage Dysplasia (MLD), containing mostly GMAML cases in comparison to usual poor sensitivity to SICT in AML with MLD (EMD-AML) [13-18,22].

Two further cases of patients over 65 years old enlarge our knowledge of a good sensitivity of GM-AML to SICT. A 67-year old man with de novo Near-Tetraploid (NT) GM-AML M0 with WBC 52.9×10⁹/L reached CR and survived 51 months in CR after three 3+7 cycles [24] while most European cases with de novo NT-AML were EMD-AML with 33 % CR rate and maximal survival 31.5 months after SICT [30]. In 2017-8 we treated an 86-year old man diagnosed with GM-AML, normal karyotype with NPM1 mutation and FLT3- ITD, WBC 33.7×10⁹/L in 2011, who reached CR after two cycles of Low-Dose Ara-C 20 mg s.c. twice daily for 10 days (LDAC) in 4 week intervals. His CR has been maintained on repeated LDAC cycles for 6 years [Dignum H, Lemež P, et al., manuscript in preparation].

These two cases of patients over 65 years with GM-AML and all of our 6 octogenarian cases treated with SICT had WBC over 15×10⁹/L, the threshold over which treatment with Hypomethylating Agents (HMA) azacytidine or decitabine has not been recommended [31,32]. A median survival of selected AML cases over 65 years old (PS 0-2, WBC < 15×10⁹/L, expected survival 12 weeks) treated with HMA varied between 7.7-10.4 months [31,32] but our three GM-AML octogenarian cases with worse PS exhibited much longer survival 16.5-28.0 months after SICT. Treatment with SICT in GM-AML cases represents a patient-oriented AML-biology targeted therapy.

A retrospective subanalysis of 8 large cooperative AML trials dealing with intensive treatment based mostly on standard or high doses of Ara-C with anthracyclines or mitozantrone in 4584 patients aged over 60/65 years recruited 138 (3%, range 0.5-5.0% per study) octogenarian patients with AML between 1984 and 2010 [4]. Only patients deemed fit for chemotherapy and with good LVEF were selected for this study. Swedish AML population based studies showed that octogenarian AML patients constitute 30-40% of patients aged over 60/65 years [5,6] and thus by our estimate only 5-10% of all octogenarian patients with AML were deemed fit for intensive induction chemotherapy by their hematologists in these 8 studies. Forty-eight octogenarians (34.8%) died within 30 days and 41 (29.7%) reached CR and showed improved relapse-free survival 37% (15 patients) at 1 year (by our estimate approx. 0.5-1.0% of all octogenarians diagnosed with AML) [4]. Only 8 octogenarian patients (one case per trial), all with de novo AML, survived more than 3 years. Six of them survived 3 years in continuous CR including three patients of nine who were diagnosed with NPM1 mutation but dysplastic features had not been reported [4]. The authors concluded that intensive induction treatment is effective in selected fit octogenarian AML patients with normal karyotype and NPM1 mutation [4] which was found in Case 3.

We conclude that leukemic blasts of de novo GM-AML in octogenarians may be sensitive to SICT and this therapy may lead to survival benefit. Patients with de novo GM-AML may constitute by our estimate about 20% of all AML among octogenarians, because nearly 50% of AML may represent secondary AML and among de novo AML patients with EMD-AML seem more frequent than GMAML patients [19,5-10]. The quantitative evaluation of dysplastic features according to the FAB criteria [25] requires at least two hematologists experienced in BM cell morphology and two or more well prepared BM smears immediately after BM aspiration. The advantage is that GM-AML or EMD-AML categorization results can be usually obtained within 2 hours. Correlations of GM-AML diagnosis with immunophenotype, karyotype, and molecular genetic findings are needed for better characterization of GM-AML subtypes. Further discoveries of novel molecular targeted therapies for patients with AML [9], including octogenarians, may be useful to further improve their survival in the future after this first step of separation GM-AML and EMD-AML biological categories differing in response to SICT.

Acknowledgement

This publication is dedicated to our teacher and friend prof. MUDr. Jan Neuwirt, DrSc., (November 26, 1927 - December 31, 1993), experimental hematologist and director of the Institute of Hematology and Blood Transfusion in Prague.

PL diagnosed and treated the patients, performed design of the study and wrote the first draft. JG performed morphological evaluation of dysplastic changes and checked FAB diagnosis. KM, OF, ZZ, JB performed cytogenetic and genetic examinations. AM, MC, JS contributed to diagnosis and treatment of the patients. All authors reviewed, corrected the manuscript and approved the final version.

The study was supported in part by research grants No. 00023736 (OF, JB); RVO-VFN64165 (KM, ZZ) from the Czech Health Research Council of the Czech Republic, and P302/12/G157 (KM, ZZ) from the Grant Agency of the Czech Republic:

Conflict of Interest

The authors declare no potential conflict of interest.

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