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Received: 02/11/2015

Judged: 02/05/2016

High-intensity chemotherapy versus palliative chemotherapy in patients over 60 years with acute myeloid leukemia

Jesús Medrano-Contreras,^a Juan Osvaldo Talavera-Piña,^b Susana Guerrero-Rivera,^a Guillermo Rodolfo Gutiérrez-Espíndola,^a Cynthia Gómez-Cortés,^a Juan Fernando Pérez-Rocha,^a Eduardo Terreros-Muñoz,^a Luis Antonio Meillón-García^a

^aServicio de Hematología, Hospital de Especialidades

^bCentro de Adiestramiento en Investigación Clínica (CAIC), Coordinación de Investigación en Salud

Centro Médico Nacional Siglo XXI, Instituto Mexictaano del Seguro Social, Ciudad de México, México

Communication with: J. Jesús Medrano Contreras

Email: jjesus1077@yahoo.com.mx

Background: The use of high-intensity chemotherapy (HIC) for acute myeloid leukemia (AML) in the elderly is controversial. In the present study, it was assessed complete remission and overall survival of AML patients over 60 years treated with HIC or palliative chemotherapy.

Methods: Patients with ECOG ≤ 2 and adequate organic function received HIC with a base of cytarabine for five or seven days, and an anthracycline for three days. If patients achieved complete remission of leukemia, they received one or two cycles of consolidation with cytarabine. Palliative treatment consisted of supported measures and/or oral or intravenous low-dose chemotherapy.

Results: Seven patients treated with HIC achieved complete remission versus only one in the palliative group. Only one patient died during HIC treatment. Median survival for HIC-treated patients was 13.25 months, and only 3.35 months for patients treated with palliative therapy (p < 0.05).

Conclusion: AML patients of 60 years or older, with good performance status (ECOG ≤ 2) and adequate organ function, may benefit from HIC treatment, with better survival, compared with palliative therapy.

Keywords: Acute myeloid leukemia; Elderly; Chemotherapy

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Acute myeloblastic leukemia (AML) is a clonal disorder of hematopoietic stem cell (HSC) which is characterized by the inhibition of differentiation, the subsequent proliferation of cells in various stages of maturity and low production of healthy hematopoietic cells. It can occur at any stage of life, but is more common in older than 60 years; about 50 to 65% of AML patients are over 60 years.^1,2

Treatment with intense chemotherapy (QTI) associated with improvements in supportive treatment including better transfusional support with platelets, as well as the availability of broad-spectrum antibiotics, antivirals and antifungals, has increased the survival of younger patients, but this has not been reflected in patients over 60 years.^3-6 it is possible that the few observed developments are due to own characteristics of the disease, as could be the presence of poor prognostic cytogenetic abnormalities or expression of resistance genes multidrug (such as MDR-1 gene), which are more common with advancing age.^7-9 in addition, other factors related to the patient, such as organ damage and the presence of comorbidities itself as well as the deterioration of the state General.¹⁰

There is controversy as to whether to treat patients over 60 years with QTI or palliative chemotherapy. The percentage of complete response (CR) in patients over 60 years with AML treated with QTI based more antracíclico cytarabine is 34 to 56%, with a mortality greater than 25% and survival rarely exceeds one year.^11-19 in contrast, the percentage of RC to palliative treatment or reduced intensity is low or zero, with a survival ranging between 0.8 and 8.8 months without significant difference compared with schemes.^20,21 However QTI other authors have observed increased survival in patients receiving intensive chemotherapy.^22,23 Röllig et al report on a model prognosis in elderly patients with AML in which 909 patients were included; of these 454 achieved CR (50%) plus the five-year overall survival and disease-free survival it was 9.7 and 14%, respectively. Prognostic factors identified were the karyotype, age, mutations in NPM1, leukocyte count and lactate dehydrogenase levels and the expression of CD34.

With the increase in life expectancy is expected to grow in the coming years the number of elderly patients with AML in the general population, including Mexico; for this reason, it is important to evaluate responses to treatments available in this group of patients and finding new ways to improve responses and survival.

The aim of this study was to evaluate the response to treatment and survival with QTI and palliative treatment in patients with AML over 60 years.

Methods

Retrospectively analyzed a cohort of AML patients over 60 years, treated between January 2003 and December 2006. The diagnosis of AML was established by morphological analysis smear bone marrow and peripheral blood, stains Wright, periyódico acid-Schiff (PAS) and peroxidase; HLA DR, MPO, CD34, CD13, CD14, CD15, CD33, CD117, CD41 and glycophorin A, and studying karyotype Bone marrow also flow cytometry study it included the following antibodies were made. LMA types were classified according to the criteria of Group-French-American-British (FAB).²⁴ The physical performance of the patients was determined using the scale of ECOG (Eastern Cooperative Oncology Group). Also, to assess organ function tests hepatic, renal and cardiovascular function were made. The QTI or palliative treatment was determined by the treating physician according to the functional and organic state. Those patients who had ECOG values ​​≤ 2 transaminase 2 or more times their normal value, total bilirubin <2 mg/dL, serum creatinine <1.5 or creatinine clearance> 60 mL / min and ejection fraction of the left ventricle (LVEF)> 50% received QTI.

Treatment

Treatment with QTI included one or two cycles with cytarabine 100 mg/m² subcutaneously per day in 24-hour infusion for five or seven days a antracíclico (idarubicin [10 mg] or daunorubicin [45 mg] or mitoxantrone [10 mg/m² subcutaneously [SC] per day]) infusion two or three hours, two or three days. Patients who achieved CR could receive one or two cycles of consolidation with one of the following schemes: cytarabine with mitoxantrone and cytarabine etoposide (cytarabine 1 g/m² SC for one hour every 12 hours for three days, mitoxantrone 8 mg/m² SC every 24 hours in two-hour infusion for three days, etoposide 150 mg/m² SC infusion two or three hours every 24 hours for three days) and then move to maintenance therapy with 50 mg/m² of 6-mercaptopurine via daily subcutaneous 0.5 and 12 mg/m² of methotrexate subcutaneously two days a week. After chemotherapy, patients received 300 mg of filgrastim per day until neutrophil recovery (≥ 1.5 x 10⁹/L) and antifungal prophylaxis with fluconazole 200 mg, orally every day. Patients assigned to palliative treatment received supportive care or oral or intravenous low-dose chemotherapy with the following schemes:

• PAO l (1 mg / kg of prednisone for five days, 45 mg/m² of daunorubicin subcutaneous infusion three hours per dose, and 2 mg of vincristine in a single intravenous dose).
• Cytarabine at low doses (30-50 mg subcutaneously for seven days plus 50 mg of 6-mercaptopurine).
• Per day, 50 mg of 6-mercaptopurine alone, and 0.5 g 1.5 hydroxyurea daily.

Response to chemotherapy

RC was considered when the following criteria are met: 1) less than 5% blasts in the bone marrow study that should be normocellular; 2) absence of blasts in peripheral blood; 3) no Auer bodies; 4) absence of extramedullary leukemia; 5) value of platelets ≥ 100 x 10⁹/L; 6) value of neutrophils ≥ 1 .5 x 10⁹/L.²⁵ Patients who did not respond to two cycles of QTI were considered refractory. Relapse was defined by the appearance of blasts ≥ 5% in patients who had previously been documented RC. The overall survival (OS) was measured from diagnosis of AML to death from any cause or last follow-up, and disease-free survival (DFS) was measured from that achieved CR to relapse of the disease.

adverse effects and alterations observed in laboratory tests were recorded.

For statistical analysis, descriptive statistics were used to assess the demographic and disease characteristics; chi square test was used to determine whether there was an association between categorical variables and the two treatment groups. The exploration of clinical variables and laboratory treatment adjusted as possible indicators of prognosis was performed using test Cox proportional hazards. It was considered significant p ≤ 0.05. The analysis was performed using SPSS version 12 program.

All patients were asked for your written authorization before the retrospective study. The research protocol was approved by the Ethics Committee on Research and Specialty Hospital National XXI Century Mexican Social Security Institute Medical Center.

Results

Between January 2003 and December 2006 admitted 40 patients with AML over 60 years, 25 men and 15 women. The mean age was 72 years (range 60-83 years). Diagnosis 21 patients (52 .5%) had one or more non-communicable chronic diseases such as hypertension in 13 cases, type 2 diabetes mellitus in six patients, ischemic heart disease in five patients, three hepatic failure, chronic renal failure three and chronic obstructive pulmonary disease in two patients. The index of functional activity evaluated by ECOG income averaged 3 (range 1-4), and 21 (52.5%) was ≥ 3.

The mean time of evolution at diagnosis was 68 days (range 3-365). The most frequent clinical manifestations diagnosis were anemic syndrome in 85% weight loss 55%, hemorrhagic syndrome in 50%, 47% fever and infections in patients 45%. Only 10 patients had hemoglobin> 10 g/dL to diagnosis and four one platelet count> 100 x 10⁹/L; the initial leukocyte count was <4.5 x 10⁹/L in seven cases and eight was> 100 x10⁹/L. Lactic dehydrogenase (LDH) was normal in 10 cases (250-450) and serum creatinine was greater than 1.5 mg/dL in 12 patients.

LMA types are described below: seven cases as AML M1, M2 as AML 15, 11 cases as M4, M5 and four as three subtype was not defined. The karyotype was normal in seven patients and altered in six (hyperdiploidy, t [8, 21], dupp [14] more hipodiploidías [complex], the [7], 11q23 more hipodiploidías and another with monosomy of chromosome 7 [-7 ]). In the remaining patients it was not possible to obtain the karyotype.

Of the 40 patients, six died within the first six days. Of the remaining 34, 13 (38%) were treated with QTI and 21 (62%) with palliative chemotherapy. The average age QTI group was 66 years, compared with 75 years for the palliative group; no differences in hemoglobin levels, platelet count and leukocyte counts were observed; QTI in the group included patients with better functional and organic status (Table I). Group QTI patients, 11 received scheme 5:2 (cytarabine plus idarubicin or daunorribicina) and two patients scheme 7:3 (cytarabine plus idarubicin); four patients achieved CR, two received scheme 7:3. Of the nine who failed to RC, six patients received a second course of QTI (three with cytarabine plus mitoxantrone and three cytarabine plus etoposide); of these, three patients achieved CR. In total, seven of 13 patients (55%) achieved CR; of these, three had normal karyotype and another hyperdiploidy. After induction chemotherapy remission, five of the seven patients received one or two cycles of consolidation chemotherapy six continued maintenance.

Of the 21 patients in palliative treatment, eight received low-dose cytarabine (30-50 mg bolus or subcutaneous injection) plus 50 mg of 6-mercaptopurine, five received only 50 mg per day of 6-mercaptopurine, four received monthly cycles chemotherapy that included: prednisone (1 mg/kg) for five days, antracíclico (daunorubicin 45 mg/m² SC, IV infusion dose 3 hours), and a single intravenous dose of 2 mg every month vincristine; one patient received hydroxyurea and the remaining three patients only received blood transfusions. Of these, only one managed to RC (treated with cytarabine and 6-mercaptopurine); this patient had normal karyotype.

The median survival of the entire group was 5 months; however, patients treated with RC QTI that obtained showed a median of 13 (3-23) months while patients who failed to QTI RC had a survival of only 4 (2-11) and 3 months (0.5-19) months for patients with palliative treatment (p <0.036). In the seven patients who achieved CR, the median disease-free survival was 10.5 months (range 1 3-17) (Figure 1).

Leukocytosis (whose value is> 10,000 leukocytes) appeared to have an impact with HRR 1.009 (95% CI = 1 000-1.017, p = 0.053).

100% of patients who received QTI presented myelosuppression grade 3 and 4; in 22 of 29 cycles of QTI febrile neutropenia (76%) was observed, six had pneumonia three neutropenic colitis and two Aspergillus infection.

two episodes of cerebral hemorrhage and one of digestive tract were recorded. Only one patient died from septicemia during a cycle of consolidation.

Discussion

AML is more common in subjects aged 60 years; It is associated with poor prognosis and survival <20% at five years. AML patients over 60 years are considered as a separate entity because biological characteristics of the disease that make them different. Treatment options in this patient group are scarce due to the presence of organ damage and the association of comorbidities that further impoverish prognosis. The best treatment option with the highest percentage of RC is the QTI;^15-17 however, not all patients are candidates for this therapy. Palliative treatment with the lowest percentage of RC is another option in patients with impaired organ function.^20,21

In this paper the answers and complications observed in a retrospective cohort of patients with AML aged 60 years treated with QTI and palliative treatment are reported.

It was noted that half of the patients had comorbidities and similarly 52% of patients had a ECOG ≥ 3; these two factors seriously limit the use of QTI in these patients, so that only 38% were candidates for QTI; of this group 55% achieved CR, similar to that reported in other studies of patients in this age group^12-19 and unobtrusively less similar to the results observed in studies of patients under 60 years.^3,4

The frequency of infectious and bleeding complications during the period of myelosuppression was similar to that reported in other studies; however, in this cohort only one patient died from this cause, unlike that observed in other studies in which the mortality rate is> 25%.

The median overall survival in patients randomized to treatment QTI who achieved CR was higher compared to the survival of patients who were assigned to palliative treatments. The survival of patients receiving intensive chemotherapy but failed to complete remission was similar to that of patients receiving palliative treatments.

To our knowledge, this is the first study of patients with AML over 60 years in the Mexican population. a search for national publications was performed and found only two studies in the Mexican population, of which both include patients younger than 60 years. Buitrón et al.²⁶ reported a cohort of 53 patients with AML under 60 years treated with QTI at the National Institute of Nutrition. The median age was 44 years (range 15-79), only four patients were over 60 years and two of them achieved CR. Lobato et al.²⁷ elaborated a study of adult patients under 60 years with AML (median age 28 years, range 15-60) treated with two chemotherapy protocols, one QTI (cytarabine / daunorubicin 7 + 3) and one with a scheme to Nonmyeloablative dose; in this study there was no difference in the percentage of RC and three-year survival were found, nor in the fatal myelotoxicity.

It has been noted that some patients older than 60 years can not tolerate treatment with QTI, and even can be precipitated his death with this chemotherapy.²⁵ The risk of dying during treatment with QTI is related to age and organic functional status; in patients with good performance status (ECOG ≤ 2), the possibility of dying in the course of the administration of the QTI is 10 to 13%; however, if the general condition is bad (ECOG> 3) mortality is 40%.¹⁰ Other studies have identified as prognostic factors of response: 1) secondary AML 2) the presence of unfavorable cytogenetic abnormalities and 3) protein expression of MDR1 drug resistance as.^6-9 the results show complete response rates in 81% of cases in the absence of these factors, compared with 11% when present all.²⁶ Although the study objective did not identify prognostic factors, leukocytosis was observed that the higher value of 100 000 seems to adversely influence to achieve CR.

Although not all patients had karyotype was observed that there is a tendency to have better results with favorable prognostic cytogenetic abnormalities. For example, patients with normal karyotype and hyperdiploidy receiving QTI achieved CR, and patients with impaired unfavorable prognosis as monosomy 7 karyotype complex and nonresponders. A patient with normal karyotype in the group of palliative chemotherapy achieved CR.²⁷

While the quality of life of patients was not assessed, it is a very important aspect when treatment for these patients is decided. Mohamedali et al.²⁸ reported a quality of life and a similar physical function in patients older than 60 years who received QTI, compared to younger patients; the authors concluded that the toxicity and impaired quality of life should not be a limiting factor for QTI in this group of patients. The chances of achieving a higher percentage of RC and increased survival with improved quality of life justifies the careful selection of patients over 60 candidates QTI and other therapies that seek to increase survival with less toxicity.^28-32

Conclusion

Half of AML patients over 60 treated in hospital have some type of comorbidity and functional status that limits the use of the QTI. A third of patients over 60 years with AML can benefit from QTI, achieving higher percentage of RC and overall survival. Careful selection of patients can optimize QTI treatment with acceptable response rate and low mortality. They are prospective, controlled studies are needed to evaluate the role of QTI in this group of patients.

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