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Frontiers of Medicine

ISSN 2095-0217

ISSN 2095-0225(Online)

CN 11-5983/R

Postal Subscription Code 80-967

2018 Impact Factor: 1.847

Front. Med.    2019, Vol. 13 Issue (3) : 378-387    https://doi.org/10.1007/s11684-018-0658-4
RESEARCH ARTICLE
Homoharringtonine is a safe and effective substitute for anthracyclines in children younger than 2 years old with acute myeloid leukemia
Xiaoxiao Chen, Yanjing Tang, Jing Chen, Ru Chen, Longjun Gu, Huiliang Xue, Ci Pan, Jingyan Tang(), Shuhong Shen()
Key Laboratory of Pediatric Hematology and Oncology Ministry of Health, Department of Hematology and Oncology, Pediatric Translational Medicine Institute, Shanghai Children’s Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
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Abstract

Homoharringtonine (HHT), a plant alkaloid from Cephalotaxus harringtonia, exhibits a unique anticancer mechanism and has been widely used in China to treat patients with acute myeloid leukemia (AML) since the 1970s. Trial SCMC-AML-2009 presented herein was a randomized clinical study designed based on our previous findings that pediatric AML patients younger than two years old may benefit from HHT-containing chemotherapy regimens. Patients randomized to arm A were treated with a standard chemotherapy regimen comprising mainly of anthracyclines and cytarabine (Ara-C), whereas patients in arm B were treated with HHT-containing regimens in which anthracyclines in all but the initial induction therapy were replaced by HHT. From February 2009 to November 2015, 59 patients less than 2 years old with de novo AML (other than acute promyelocytic leukemia) were recruited. A total of 42 patients achieved a morphologic complete remission (CR) after the first course, with similar rates in both arms (70.6% vs.72.0%). At the end of the follow-up period, 40 patients remained in CR and 5 patients underwent hematopoietic stem cell transplantation in CR, which could not be considered as events but censors. The 5-year event-free survival (EFS) was 60.2%±9.6% for arm A and 88.0%±6.5% for arm B (P=0.024). Patients in arm B experienced shorter durations of leukopenia, neutropenia, and thrombocytopenia and had a lower risk of infection during consolidation chemotherapy with high-dosage Ara-C. Consequently, the homoharringtonine-based regimen achieved excellent EFS and alleviated hematologic toxicity for children aged younger than 2 years with de novo AML compared with the anthracycline-based regimen.

Keywords homoharringtonine      acute myeloid leukemia      pediatrics     
Corresponding Authors: Jingyan Tang,Shuhong Shen   
Just Accepted Date: 29 November 2018   Online First Date: 14 January 2019    Issue Date: 05 June 2019
 Cite this article:   
Xiaoxiao Chen,Yanjing Tang,Jing Chen, et al. Homoharringtonine is a safe and effective substitute for anthracyclines in children younger than 2 years old with acute myeloid leukemia[J]. Front. Med., 2019, 13(3): 378-387.
 URL:  
http://academic.hep.com.cn/fmd/EN/10.1007/s11684-018-0658-4
http://academic.hep.com.cn/fmd/EN/Y2019/V13/I3/378
Fig.1  Schema of the SCMC-AML-2009 trial design. The regimen comprised induction (weeks 1–4), consolidation (weeks 4–8), intensification (weeks 8–24), and continuation (weeks 24–40). DAE: daunorubicin (DNR) 40 mg/m2, days 1–3; cytarabine (Ara-C) 100 mg/m2 every 12 h for a total of 14 doses, days 1–7; and etoposide (VP16) 100 mg/m2, days 5–7. MAE: mitoxantrone (MTZ) 10 mg/m2, days 1–3, and Ara-C and VP16 administered as in DAE. hAD/hAE/hAM: Ara-C 3000 mg/m2 every 12 h for a total of 6 doses from day 1, DNR 40 mg/m2 or VP16 100 mg/m2 or MTZ 10 mg/m2, days 1–2; AT, Ara-C 75 mg/m2 every 12 h for a total of 14 doses from day 1, 6-mercaptopurine (6MP) 75 mg/m2 for 9 days starting from day 1. HAE: homoharringtonine (HHT) 3 mg/m2, days 1–9, and Ara-C and VP16 as in DAE. hAH: Ara-C 3,000 mg/m2 every 12 h for a total of 6 doses from day 1, HHT 3 mg/m2, days 1–5. HA: HHT 3 mg/m2, days 1–9, Ara-C 75 mg/m2 every 12 h for a total of 14 doses from day 1. The arrows indicate intrathecal injections.
Arm A
(n=34)
Arm B
(n=25)
P
Age (year) 1.14±0.45 0.99±0.38 0.175
Gender (n) 0.022
Male 25 11
Female 9 14
FAB subtype (n) 0.089
M1 1 0
M2 1 1
M4 4 5
M5 16 17
M7 12 2
Features at diagnosis
WBC median, range (×109/L) 13.85 (2.20–355.4) 15.00 (2.10–160) 0.230
PLT median, range (×109/L) 36 (8–224) 49 (8–244) 0.632
LDH median, range (U/L) 2123 (503–9000) 2460 (689–11 250) 0.821
Fusion genes (n)
RUNX1-RUNXT1 0 1 0.876
CBFb-MYH11 1 2 0.784
MLLr 5 4 1.0
Tab.1  Clinical and biologic characteristics of the patients
Fig.2  The patients’ estimated 5-year EFS rates. (A) The 5-year EFS rates were 60.2%±9.6% in arm A and 88.0%±6.5% in arm B (P =0.024). (B) The 5-year EFS rates of patients without M7 (87.0%±7.0% vs. 71.1%±11.3%, P =0.222).
Fig.3  Myelosuppression during the courses in the two study arms. Orange bars represent data from arm A, whereas green bars represent data from arm B (with HHT). In panels A–D, the horizontal line indicates the average, whereas the perpendicular line indicates the standard deviation. (A) During induction, the two study arms did not differ in the durations of leukopenia and neutropenia, whereas arm A showed a longer duration of thrombocytopenia (PLT<50×109/L: 14.0±4.70 days vs. 8.48±4.18 days, P<0.001). (B) During intensification, patients in arm A showed longer durations of leukopenia and neutropenia (WBC<1.0×109/L: 9.94±5.17 days vs. 6.64±5.43 days, P =0.022; ANC<0.5×109/L: 17.94±4.92 days vs. 11.88±4.10 days, P<0.001). (C) During consolidation, patients in arm A showed longer durations of leukopenia, neutropenia, and thrombocytopenia (WBC<1.0×109/L: 9.23±2.15 days vs. 7.38±1.82 days, P =0.001; ANC<0.5×109/L: 9.75±3.62 days vs. 7.47±1.94 days, P =0.006; PLT<50×109/L: 7.41±3.71 days vs. 5.08±1.88 days, P =0.006). (D) During continuation, arm A exhibited shorter durations of leukopenia, neutropenia, and thrombocytopenia (WBC<1.0×109/L: 2.56±2.53 days vs. 7.52±3.04 days, P<0.001; ANC<0.5×109/L: 5.91±3.10 days vs. 7.97±2.69 days, P =0.023; PLT<50×109/L: 3.67±1.82 days vs. 5.63±2.20 days, P =0.003). (E) Incidences of infection in each study arm. Children treated with HHT experienced fewer infectious episodes, especially during intensification (55.2% vs. 83.6%, P<0.001). (F) Incidences of severe infection in each study arm: 14.71%, 11.76%, 0.91%, and 1.30% during each period in arm A, compared with 16.0%, 4.0%, 1.04%, and 1.12% in arm B, respectively. * P<0.05.
Fig.4  Categorization of infectious episodes. A fever of unknown origin (FUO) accounted for 56.3%. Microbiologically documented bloodstream infections (BSI), pneumonia, and soft tissue infections accounted for 17.2%, 11.4%, and 0.9% of infections, respectively. Patients with gastrointestinal manifestation (13.0%) were those who had a fever with diarrhea, abdominal pain, or hematochezia. Other infections included mumps, herpes zoster, and varicella.
Pathogeny A B
Gram positive 17 11
Staphylococci
S. aureus 3 0
S. hemolyticus 1 0
S. simulans 0 1
S. hominis 1 0
S. epidemidis 1 4
S. lentus 3 1
Streptococci
S. oralis 1 0
S. mitis 4 3
S. pneumonia 0 1
Granulicatella adiacens 1 0
Micrococcus luteus 1 0
E. enterococcus 1 0
Others* 0 1
Gram negative 14 14
E. coli 2 2
E. cloacae 1 0
Klebsiella spp. 10 5
Morganella 0 1
Sphingomonas paucimobilis 1 0
Burkholderia cepacia 0 2
P. aeruginosa 0 3
Others* 0 1
Candida parapsilosis 0 1
Tab.2  Distribution of Gram-negative and Gram-positive in arms
Fig.5  The specific patients’ estimated 5-year EFS rates. (A)The EFS rates of patients without HSCT who achieve CR after induction therapy were 61.1%±11.1% in arm A and 94.4%±5.4% in arm B (P=0.017). (B)The EFS rates of patients without HSCT who achieve CR or CRi after induction therapy were 64.7%±10.3% and 91.3%±5.9%, respectively (P=0.035). (C)The EFS of patients without HSCT (59.2%±9.6% vs. 88%±6.5%, P=0.020).
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