Efficacy and safety of CHG regimen (low-dose cytarabine, homoharringtonine with G-CSF priming) as induction chemotherapy for elderly patients with high-risk MDS or AML transformed from MDS

Abstract

Background

To evaluate the efficacy and toxicity of CHG regimen (low-dose cytarabine, homoharringtonine with G-CSF priming) as an induction chemotherapy for elderly patients with high-risk MDS or acute myeloid leukemia transformed from MDS (MDS–AML).

Methods

Thirty-three untreated patients (21 high-risk MDS and 12 MDS–AML) were enrolled in this study. Each patient was administered with the CHG regimen comprised of low-dose cytarabine (25 mg/day, days 1–14) and homoharringtonine (1 mg/day, days 1–14) by intravenous continuous infusion in combination with G-CSF (300 μg/day) by subcutaneous injection from day 0 until neutrophil count recovery to 2.0 × 10⁹/L.

Results

The overall response rate (OR) was 66.7% after one course of the CHG regimen with 19 patients reaching CR (57.6%) and 3 patients reaching partial remission (PR) (9.1%). The median overall survival (OS) was 15.0 months. Patients with normal serum lactate dehydrogenase (LDH) appeared longer median OS when compared to patients with high LDH level (18 months vs. 5 months, P = 0.011). Grade 3/4 thrombocytopenia occurred in 28% of patients, neutropenia in 34%. No treatment-related deaths occurred during the induction therapy.

Conclusions

These data suggest that the CHG priming regimen is effective and safe as a novel induction therapy for elderly patients with high-risk MDS and MDS–AML. The results need to be conformed in further study involving a larger cohort of patients.

Introduction

The myelodysplastic syndrome (MDS) consist of a heterogeneous group of clonal hemopathies characterized by maturation defects that result in ineffective hematopoiesis and a high risk of progression to acute myeloid leukemia (MDS–AML). The majority of MDS patients are elderly, and their prognosis, especially when they have high-risk features or even progressed to AML, is rather poor (Greenberg et al. 1997). Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the most effective curative therapy for MDS and MDS–AML. However, in elderly patients who generally suffer from poor general condition or organ disorders, it is difficult for this particular group of patients to be candidates for allo-HSCT. In addition, because of the obvious pancytopenia as well as bone marrow (BM) hypocellularity when compared to younger patients, elderly MDS/MDS–AML patients usually undergo a high treatment-related mortality (about 15–30%) when they accepted intensive induction chemotherapy (Kantarjian et al. 2006b; Oosterveld et al. 2002).

Low-dose chemotherapy, which has been used in clinical practice for 20 years, reduces the number of myeloblasts, improves pancytopenia, and induces remission not only in MDS patients but also in secondary AML, especially for elderly patients. In 1995, Yamada et al. (1995) first proposed CAG regimen in the AML treatment, which consists of low-dose cytarabine and aclarubicin combined G-CSF priming. The application of this regimen significantly increased AML CR rate, particularly in refractory and relapsed AML (Saito et al. 2000). Aclarubicin was classified into anthracycline, and its main side effect was cardiac toxicity. To a certain extent, cardiac toxicity limited the application of aclarubicin, especially in elderly patients with cardiac disease.

Homoharringtonine (HHT) was first isolated from Cephalotaxus plant alkaloid in China and has been widely used in the treatment of AML for more than 40 years with mild cardiac toxicity, which is different from aclarubicin (Cephalotaxus Research Coordinating Group 1976; Kantarjian et al. 1989; Wang et al. 2009). HTT is a chemotherapeutic that causes leukemic cells to arrest at the G1/G2 phase of the cell cycle (Wang et al. 2009; Mai and Lin 2005). Cytarabine acts at the S phase of the cell cycle to induce apoptosis. The combination of HHT and cytarabine synergistically induces leukemic cell apoptosis, and this drug combination has a definite efficiency in the treatment of AML (Jin et al. 2006).

Based on the above, we applied HHT instead of aclarubicin in CAG regimen to develop a novel regimen comprised of low-dose cytarabine and homoharringtonine with G-CSF priming, abbreviated as CHG. To investigate the efficacy and safety of this regimen in elderly patients with high-risk MDS/MDS–AML, we conducted the current study.

Patients and methods

Eligibility

Eligibility criteria were as follows (1) age 60 years and older; (2) diagnosis of high-risk MDS (with ≥5% blast in bone marrow) or AML arising from MDS; (3) a performance status of 0–3 according to the Eastern Cooperative Oncology Group (ECOG); (4) no evidence of severe concurrent cardiac, pulmonary, neurologic, or metabolic diseases; (5) adequate hepatic (serum bilirubin level <2 × upper normal limit) and renal (serum creatinine < 2 × upper normal limit) function tests; and (6) exclusion criteria included other progressive malignant diseases.

Patients

Between March 2006 and December 2009, patients (age 60 years or older) with a confirmed diagnosis of high-risk MDS (with ≥5% blast in bone marrow) or MDS transformed AML(MDS–AML) were enrolled in the study after informed consent in accordance with the Declaration of Helsinki. All the tested patients received the examinations including blood count, BM smear analysis, BM section analysis, chromosome analysis, and serum lactate dehydrogenase (LDH) detection when they entered this study, and none of them had undergone either cytokine therapy or chemotherapy when the study was initiated. The criteria used to describe the bone marrow cell karyotype followed the recommendations of the International System for Human Cytogenetic Nomenclature (ISCN 1991). For each patient, only when at least 20 metaphases were analyzed by two observers could the karyotype be determined. Pretreatment cytogenetic analysis was performed to define risk groups as follows: good = normal, -Y alone, del (5q) alone, del (20q) alone; poor = complex (≥3 abnormalities), chromosome 7 anomalies; and intermediate = other abnormalities (according to the International Prognostic Scoring System (IPSS)) (Greenberg et al. 1997). This study was approved by the Ethics Committee of the Sixth hospital affiliated to Shanghai Jiaotong University.

CHG regimen

CHG chemotherapy consisted of an intravenous continuous infusion of low-dose cytarabine (25 mg/day) (Pharmacia, Italy) and homoharringtonine (1 mg/day) (Minsheng pharma, Hangzhou, China) in combination with G-CSF (300 μg/day) (Kirinkunpeng, Japan) by subcutaneous injection from day 0 until peripheral neutrophil count recovery to 2.0 × 10⁹/L. G-CSF was given intermittently when the peripheral white blood cell (WBC) count increased above 20 × 10⁹/L. Bone marrow aspirates were performed to assess the treatment response 2–3 weeks after the CHG regimen was completed.

Evaluation of efficacy

Each patient underwent baseline and efficacy evaluation. The baseline evaluation included a routine blood cell count, urine and biochemical analysis, and bone marrow aspiration, which were performed 3 days prior to the start of the CHG regimen. Efficacy evaluation, which was performed after the completion of each treatment, consisted of bone marrow smear analysis and a blood cell count.

The treatment response was determined according to the standardized response criteria for myelodysplastic syndromes and the revised recommendations of the International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia and MDS (Cheson et al. 2003, 2006).

Subsequent treatment and follow-up

If the response reached CR after one course of CHG, further conventional chemotherapies were applied to keep the disease from relapse. The postremission therapy was given every 1–2 months according to patients’ general situation. The protocols included HA (homoharringtonine 2 mg/m²/day for 5–7 days, and Ara-C 100 mg/m²/day for 5–7 days); DA (daunorubicin 30 mg/m²/day for 2–3 days, and Ara-C 100 mg/m²/day for 5–7 days); or IDA (Idarubicin 10 mg/day for 2–3 days, and Ara-C 100 mg/m²/day for 5–7 days). Conventional chemotherapy or other clinical trails were applied if the patients did not achieve CR after one course of CHG protocol. The terminal point of the follow-up was December 2010. The duration of overall survival (OS) was calculated from the beginning of induction chemotherapy to the date of the last follow-up or death, irrespective of the cause of death.

Evaluation of toxicity

Drug-induced toxicity was evaluated in each patient enrolled in this study. This evaluation consisted of a complete physical examination, a blood cell count (every 3 days), an evaluation of biochemical parameters (every week), and a urine analysis (every week). Other appropriate laboratory examinations were performed as needed. With respect to the hematologic toxicity evaluation, most of the patients had experienced leukocytopenia or thrombocytopenia before treatment. It was documented if a patient experienced leukocytopenia or thrombocytopenia higher than National Cancer Institute (NCI) grade II during treatment. All other adverse drug effects were recorded.

Statistical analysis

All included patients were considered in the statistical analysis. Data were analyzed using SPSS 10.0 software (SPSS Inc.; Chicago, IL, USA). The duration of OS was calculated from the beginning of induction chemotherapy to the date of last follow-up or death, whatever the cause of death was. Patients were censored at the last known date they were alive. Fisher’s exact test was performed to compare different groups of nonparametric data, and Kaplan–Meier survival analysis was performed to estimate the OS parameter (Kaplan and Meier 1958). Prognostic factors for response were analyzed with logistic regression. Factors impacting OS were analyzed by multiple linear regression method. The limit of significance for all analyses was defined as P < 0.05.

Results

Patient characteristics

A total of 33 patients (21 men and 12 women) with a median age of 71 (range, 60–88 years of age) were enrolled in this study between March 2006 and December 2009. Twenty-one patients had high-risk MDS and 12 patients had MDS–AML. According to the FAB classification (Delacretaz et al. 1987), 19 of the 21 high-risk MDS cases had refractory anemia with excess blasts (RAEB) (11 with 5–10% marrow blasts and 8 with 11–20% marrow blasts). Two patients were diagnosed with chronic myelomonocytic leukemia (CMML). Based on the IPSS, 6 patients (29%) were intermediate-1, 12 patients (57%) were intermediate-2, and 3 patients (14%) were in the high-risk category. The 12 MDS–AML patients included 4 with M2, 7 with M4, and 1 with M5. The patient characteristics are summarized in Table 1.

Table 1.

Characteristics of patients received CHG regimen

Variable	Number (%)
Median age, years (range)	71 (60–88)
Sex
Male	21 (64%)
Female	12 (36%)
FAB classification
RAEB-1	11 (33%)
RAEB-2	8 (24%)
CMML	2 (6%)
M2	4 (12%)
M4	7 (21%)
M5	1 (3%)
IPSS (for 21 MDS patients)
Intermediate-1	6 (29%)
Intermediate-2	12 (57%)
High	3 (14%)
Cytogenetic risk group
Good	18 (60%)
Intermediate	7 (23%)
Poor	5 (17%)
Serum LDH level
Normal	17 (65%)
High	9 (35%)

FAB French–American–British, RAEB refractory anemia with excess blasts, CMML chronic myelomonocytic leukemia, IPSS International Prognostic Scoring System, LDH lactate dehydrogenase

Response to CHG treatment

After one round of CHG, 19 of the 33 patients (57.6%) achieved CR and 3 (9.1%) achieved PR, with an overall response rate of 66.7%. Eleven (33.3%) patients had no response (NR). For patients who had fewer than 10% of blasts in the BM, the overall response was 67.7% (8/12 cases) (50.0% CR and 17.7% PR). Patients with 10–20% blasts in the bone marrow had a CR rate of 62.5% (5/8) (no PR). The overall response was 69.2% (9/13) (61.5% CR and 7.7% PR) in patients with more than 20% blasts in BM. The response rates among these groups were not significantly different (P > 0.05). There was also no significant difference between patients with high-risk MDS and MDS–AML (P > 0.05). Karyotype detection was performed in 30 patients: 18 patients had a good karyotype, 5 had a poor karyotype, and 7 had an intermediate karyotype, according to IPSS. Of the 18 patients with a good karyotype, 11 (61.1%) responded to treatment (55.6% CR and 5.5% PR). Of the five patients with a poor karyotype, the CR rate was 60.0% (3 CR and no PR). For the other 7 patients with an intermediate karyotype, the response rate was 71.4% (4 CR and 1 PR). Treatment response was not statistically different among different cytogenetic groups. The serum LDH level was available for 26 patients: 17 patients had a normal LDH level, whereas 9 had a higher than normal level. An overall response rate of 76.5% (13/17) was observed in patients with normal LDH (70.6% CR and 5.9% PR), whereas patients with a high LDH level had an overall response rate of 55.6% (5/9) (4 CR and 1 PR) (P > 0.05) (Table 2). None of factors including gender, age, blasts in BM, cytogenetics, white blood cell count, and LDH were associated with response of CHG regimen when analyzed by logistic regression (Table 3).

Table 2.

Factors affect treatment response to CHG

Disease status	No. of patients	CR (%)	P value	CR + PR (%)	P value
Blast(%) in BM			0.820		0.951
<10%	12	6 (50.0)		8 (67.7)
10–20%	8	5 (62.5)		5 (62.5)
>20%	13	8 (61.5)		9 (69.2)
Karyotype			0.984		0.878
Good	18	10 (55.6)		11 (61.1)
Intermediate	7	4 (57.1)		5 (71.4)
Poor	5	3 (60.0)		3 (60.0)
Serum LDH			0.234		0.382
Normal	17	12 (70.6)		13 (76.5)
High	9	4 (44.4)		5 (55.6)

Good = normal, -Y alone, del (5q) alone, or del (20q) alone; Poor = complex (≥3 abnormalities), chromosome 7 anomalies; Intermediate = other abnormalities

BM bone marrow, CR complete remission, PR partial remission, LDH lactate dehydrogenase

Table 3.

Factors affecting response (analyzed by logistic regression) and survival (using multiple linear regression analysis)

Factor	Response		Survival
	Coefficient	P value	Coefficient	P value
Gender	−0.117	0.897	0.094	0.592
Age	0.116	0.137	−0.119	0.546
BM blasts	−0.006	0.805	0.011	0.952
Cytogenetics	−0.119	0.843	−0.397	0.054
WBC	0.02	0.797	0.262	0.155
Serum LDH	−0.01	0.053	−0.409	0.027

BM bone marrow, WBC white blood cell, LDH lactate dehydrogenase

Overall survival

Of the 18 patients, 14 (77.8%) relapsed including 3 patients relapsing early (in 6 months). The median CR duration of 18 patients (one patient lost) was 13 months. The median overall survival (OS) of the 29 patients evaluated (4 patients did not undergo follow-up evaluation) was 15.0 months (1–48 months) (Fig. 1). Median OS of male and female patients did not differ from each other (P > 0.05) (Fig. 2a). The median OS of patients with <10, 10–20, and >20% blasts in the bone marrow was 6, 13.5, and 16 months, respectively (P > 0.05) (Fig. 2b). Patients with a good, intermediate, and poor karyotype had a median OS of 15, 12, and 16 months, respectively (P > 0.05) (Fig. 2c). Patients with a normal serum LDH level had a longer median OS in comparison with patients who had a high LDH level (18 months vs. 5 months, P = 0.011) (Fig. 2d). LDH level of patients was the only factor (among six factors) associated with OS when analyzed by multiple linear regression method (P = 0.027) (see Table 3).

Fig. 1.

Overall survival of all patients. Median survival time was 15.0 months

Fig. 2.

Overall survival (OS) of patients grouped by gender, blast percentage in bone marrow, karyotype, or serum LDH level, respectively. a, b, and c showed no difference with respect to different gender, blast, or karyotype (P > 0.05). Higher LDH level was an unfavorable factor for OS (P = 0.011) in d

Toxicities

No induction-related deaths occurred during the CHG protocol. Grade 3/4 (according to National Cancer Institute Common Toxicity Criteria [version 3.0]) thrombocytopenia occurred in 28% of patients, neutropenia in 34% during the induction therapy. The median time for the recovery of ANC (>0.5 × 10⁹/L) was 10 days (2–22 days), and the platelet recovery (>50 × 10⁹/L) was 18.5 days (5–35 days). Four patients (12.2%) experienced neutropenic fever without the presence of micro-organisms or sites of infection. No patient suffered from severe hemorrhage due to decreased platelet counts. Nonhematological toxicities were comparatively light. Grades 1–2 nausea/vomiting occurred in three patients (9.1%), and toxicity in the heart, liver, kidney and central nervous system was not observed.

Discussion

Management for elderly patients with high-risk MDS or MDS–AML still remains a challenge for clinicians. Chemotherapy trials for elderly high-risk MDS or MDS–AML using standard or high-dose antileukemic drugs in different combinations indicate relatively lower CR rate but at the cost of a high incidence of deaths from toxicity (15–30%) (Kantarjian et al. 2006b; Oosterveld et al. 2002). Low-dose chemotherapy, which reduces the number of myeloblasts, improves pancytopenia and induces remission while brings mild myelosuppression, may be more suitable for elderly MDS/AML patients. The CAG regimen showed 45% CR rate in patients older than 65 years, and the toxicity was mild. Whereas aclarubicin in CAG regimen was limited when be used in MDS/AML patients for its cardiac toxicity, especially in elderly patients with cardiac disease. To further reduce the toxicity to patients and based on the advantages of the combination of homoharringtonine and cytarabine with the priming effect of G-CSF as mentioned in “Introduction”, a new regimen abbreviated as CHG was developed in the current study. A CR rate of 57.6% of CHG treatment in our study was superior or at least comparable to the effects of the CAG regimen (45% CR reported by Saito et al., 30.8% reported by Li et al., and 49% by Suzushima et al.) (Saito et al. 2000; Li et al. 2005; Suzushima et al. 2010) and is comparable to the effects of intensive chemotherapy (The overall CR rate was 45% by Kantarjian et al.) (Kantarjian et al. 2006b). The two hypomethylating agents, 5-azacytidine (azacitidine) and 5-aza-2-deoxycytidine (decitabine), have led to the expansion of the therapeutic arsenal for high-risk MDS. But about 50% of high-risk MDS patients fail to achieve a meaningful response. The current trials of decitabine and 5-azacytidine have shown modest clinical efficacy (OR, 17–34% and CR, 9–17%) in elderly patients with higher-risk MDS (Silverman et al. 2002; Kantarjian et al. 2006a; Fenaux et al. 2009; Steensma et al. 2009; Lübbert et al. 2011). Further studies maybe required to compare the efficacy of the CHG regimen with decitabine or azacitidine in elderly high-risk MDS or MDS–AML patients head-to-head.

The median overall survival (OS) of the patients evaluated in our study was 15.0 months, which is longer than untreated elderly patients with high-risk MDS/MDS–AML (Greenberg et al. 1997), and is comparable to patients treated with CAG (9 months reported by Suzushima et al., 8 months for AML and 17 months for RAEB-t as reported by Saito K) (Saito et al. 2000; Suzushima et al. 2010) and intensive chemotherapy (12–14 months) (Kantarjian et al. 2006b; Morita et al. 2010). Until recently, best supportive care (BSC) was considered the only accepted standard treatment for older high-risk MDS patients. The hypomethylating agents offer only a modest survival benefit. The only randomized clinical trial to prove the survival benefits by hypomethylating agent in higher-risk MDS was AZA-001 trial (median OS 24.5 months for azacitidine) (Fenaux et al. 2009). Decitabine treatment in GMDSSG/EORTC 06011 trial failed to prove survival benefits in elderly patients with higher-risk MDS versus BSC (median OS, 10.1 months vs. 8.5 months, respectively) (Lübbert et al. 2011). A comparative randomized phase III trial of CHG regimen compared to BSC or low-dose decitabine or 5-azacytidine should be required to further evaluate the effect and safety of the regimen.

None of the 33 patients that received the CHG regimen died during the induction period, whereas the induction mortality after treatment with intensive chemotherapy was reported to be as high as 10–30% (Kantarjian et al. 2006a, b; Oosterveld et al. 2002; Morita et al. 2010), and the CAG regimen had a mortality rate of 1–7.6% during the induction period (Saito et al. 2000; Li et al. 2005; Suzushima et al. 2010). No cardiac problem occurred during induction therapy using CHG regimen. Therefore, our data strongly suggest that the CHG regimen is a safe treatment for elderly patients with high-risk MDS/MDS–AML. Reduced adverse effects may be due to the prevention of infection by continuous treatment with G-CSF (Löwenberg et al. 2003) and mild marrow suppression by reduced dosage of antileukemic drugs. Furthermore, the toxicity of homoharringtonine (total amount was 14 mg) was significantly lower than the cardiotoxic agent-aclacimomycin (80 mg) in CAG regimen, which may contribute to the safety profile of the CHG regimen.

Of note, the responses to CHG regimen were also satisfactory in patients with a high marrow blast percentage, including RAEB patients with >10% BM blast and MDS–AML as well as patients with unfavorable karyotypes (Table 2). In addition, the median OS of patients with a high blast percentage, as well as those with unfavorable karyotypes, was not statistically different from that of other patients. These results imply that poor prognosis factors included in IPSS such as high blast percentage and unfavorable karyotypes may not be contraindications for these patients to receive CHG regimen. Although higher serum LDH level was not related to the response of CHG regimen, it was proved to be a poor prognostic factor for OS. This result is consistent with a previous report that the serum LDH level can be used as predictor of prognosis in MDS patients (Germing et al. 2005).

Although the CR rate of 57.6% was achieved after one round of CHG and postremission chemotherapy was administered, 77.8% CR patients relapsed, including 16.7% in 18 CR patients relapsing early (in 6 months). The fact that CHG did not induce severe marrow suppression may account for the early relapse. It is still a challenge for CR patients induced by CHG regimen to maintain continues CR and therefore achieve long-term survival. Although the impact of continuation and consolidation therapy on patient survival was not included in this study, the application of consolidation chemotherapy regimens is considered to be also crucial to OS of patients according to our experiences. Altered regimens with second-line and different chemotherapeutic agents, which may eliminate minor residual disease and prevent drug resistance, are necessary to remain continuous CR and prolong survival period. New strategies such as molecular targeting agents or allo-HSCT with reduced-intensity conditioning regimens may be also necessary to prolong the survival period of high-risk MDS and MDS–AML patients.