Hainanolide inhibits the progression of colon cancer via inducing the cell cycle arrest, cell apoptosis and activation of the MAPK signaling pathway.

Hainanolide (HN) is a norditerpenoid metabolite extract from Cephalotaxus fortunei Hook. f. C. fortunei Hook. f. is renowned for the active alkaloids, such as harringtonine (HT) and homoharringtonin (HTT), which have been clinically used to treat chronic myeloid leukemia. Nowadays, diterpenoids, another important metabolite, attracted the attention of chemists. Among them, Hainanolide (HN), a cephalotane-type diterpenoid, has been proven to possess potent antitumor activities. However, the underlying therapeutic mechanisms of HN in anti-tumor have not been investigated yet. Our present study demonstrated that HN inhibited HCT-116 and HCT-15 cell proliferation in a dose- and time-dependent manner. Further studies demonstrated that HN can induce G2/M phase arrest and alter the Cdc25C/Cdc2/CyclinB1 proteins. Western blot indicated that HN promoted apoptosis by up-regulating Bax and down-regulated Bcl-2. And the caspase-3 and caspase-9 activities of HCT-116 and HCT-15 cells were increased. Transcriptome analysis is used to reveal the possible mechanism. Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses suggested the genes were mainly enriched in the MAPK signaling pathway. Certainly, HN activates MAPK signaling pathway. In vivo, HN prevented the AOM/DSS-induced tumorigenesis of colon cancer in C57BL/6 mice. Our study indicated that HN inhibits the progression of colon cancer cells by blocking the cell cycle, inducing apoptosis, and activating the MAPK pathway. This study provides a theoretical and experimental scientific basis for future investigations of the antitumor effects of HN against colon cancer.

Efficacy of common salvage chemotherapy regimens in patients with refractory or relapsed acute myeloid leukemia: A retrospective cohort study.

To assess treatment response and overall survival (OS) in refractory or relapsed acute myeloid leukemia (R/R AML) patients treated by different common salvage chemotherapy regimens.Medical records data from 142 R/R AML patients were reviewed in this retrospective study. Patients were treated with regimens based on the following drugs: cytarabine, granulocyte colony-stimulating factor (G-CSF), and fludarabine (FLAG) (n = 46); cytarabine and G-CSF in addition to aclarubicin or daunorubicin (CAG/DAG) (n = 30); cytarabine, G-CSF, and cladribine (CLAG) (n = 27); cytarabine, etoposide, and mitoxantrone (MEA) (n = 17); cytarabine plus idarubicin, daunorubicin, or mitoxantrone (IA/DA/MA) (n = 12); and homoharringtonine, cytarabine, and aclarubicin or daunorubicin (HAA/HAD) (n = 10).A total of 43 (35.2%) patients achieved complete remission (CR), 60 (49.2%) patients achieved overall remission rate (ORR), and 18 (14.8%) patients received allogeneic hematopoietic stem cell transplantation (allo-HSCT) after CR. Median OS was 8.0 (95% CI 6.6-9.4) months with a 1-year OS rate of (29.9 ±â€Š3.9)% and 3-year OS rate of (11.1 ±â€Š3.6)%. No difference of CR (P = .621), ORR (P = .385), and allo-HSCT (P = .537) achievement was observed among different chemotherapy regimens. Interestingly, we observed that the CLAG-based regimen did not affect CR (P = .165), while it achieved a numerically higher ORR (P = .093) and was an independent factor for prolonged OS (P = .016). No other regimens were determined to be correlated with CR, ORR, or OS.FLAG-, CAG/DAG-, CLAG-, MEA-, IA/DA/MA- and HAA/HAD-based regimens were found to achieve similar CR rates, while the CLAG-based regimen achieved numerically higher ORR rates and significant favorable OS. Therefore, CLAG-based regimens should be a prioritized treatment option for R/R AML patients.

Homoharringtonine enhances bortezomib antimyeloma activity in myeloma cells adhesion to bone marrow stromal cells and in SCID mouse xenografts.

Despite the great progress in the treatment, multiple myeloma (MM) still remains incurable. Bortezomib (BTZ), a reversible inhibitor of the 26S proteasome, is very effective against MM but unable to eradicate the MM cells in bone marrow niche eventually causing the disease relapse. Homoharringtonine (HHT) is a known anti-leukemia drug that inhibits MM both in vitro and in vivo. This study aimed to investigate whether HHT could potentiate the anti-tumor activity of BTZ in MM cells cocultured with bone marrow stromal cells and in vivo xenograft models. We found that coculture of myeloma cells with a human stroma cell line significantly decreased the sensitivity of myeloma cells to BTZ treatment. HHT inhibited the proliferation of MM cells and potentiated the anti-myeloma effects of BTZ by inhibition of both canonical and noncanonical NF-κB pathways. HHT also enhanced the anti-myeloma effect of BTZ in vivo xenograft models. Taken together, our data suggest that HHT can enhance the anti-myeloma activity of BTZ both in vitro and in vivo, which may represent a new clinical treatment in MM.

[Research Progress of Homoharringtonine Effect on IM-resistant Chronic Myelogenous Leukemia -Review].

Homoharringtonine(HHT) is an alkaloid with anti-tumor activity, having a good therapeutic effect on chronic myeloid leukemia(CML), and its toxicity is much lower than other anti-cancer drugs. However, the remarkable therapeutic efficacy of imatinib on CML treatment made HHT to be forgotten gradually. Today, the omacetaxine mepesuccinate, a semisynthetic form of HHT, display a good clinical response to TKI-resistant CML patients. Therefore, the HHT again attracts more attention from the medical field. Here, the clinical effects of HHT on IM-resistant CML patients and its mechanism are briefly reviewed.

Homoharringtonine (omacetaxine mepesuccinate) as an adjunct for FLT3-ITD acute myeloid leukemia.

An in vitro drug-screening platform on patient samples was developed and validated to design personalized treatment for relapsed/refractory acute myeloid leukemia (AML). Unbiased clustering and correlation showed that homoharringtonine (HHT), also known as omacetaxine mepesuccinate, exhibited preferential antileukemia effect against AML carrying internal tandem duplication of fms-like tyrosine kinase 3 (FLT3-ITD). It worked synergistically with FLT3 inhibitors to suppress leukemia growth in vitro and in xenograft mouse models. Mechanistically, the effect was mediated by protein synthesis inhibition and reduction of short-lived proteins, including total and phosphorylated forms of FLT3 and its downstream signaling proteins. A phase 2 clinical trial of sorafenib and HHT combination treatment in FLT3-ITD AML patients resulted in complete remission (true or with insufficient hematological recovery) in 20 of 24 patients (83.3%), reduction of ITD allelic burden, and median leukemia-free and overall survivals of 12 and 33 weeks. The regimen has successfully bridged five patients to allogeneic hematopoietic stem cell transplantation and was well tolerated in patients unfit for conventional chemotherapy, including elderly and heavily pretreated patients. This study validated the principle and clinical relevance of in vitro drug testing and identified an improved treatment for FLT3-ITD AML. The results provided the foundation for phase 2/3 clinical trials to ascertain the clinical efficacy of FLT3 inhibitors and HHT in combination.

HAG (Homoharringtonine, Cytarabine, G-CSF) Regimen for the Treatment of Acute Myeloid Leukemia and Myelodysplastic Syndrome: A Meta-Analysis with 2,314 Participants.

BACKGROUND: In China, the combination of homoharringtonine, cytarabine, and G-CSF (HAG) has been extensively applied for treatment of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). METHODS: We performed a meta-analysis of 2,314 patients (AML, n = 1754; MDS, n = 560) to determine the overall safety and efficacy of this regimen. RESULTS: The complete response (CR) rate of AML patients (53%) was significantly higher than that of MDS/transformed-AML patients (45%; P = 0.007). The CR rate of patients with newly diagnosed AML (62%) was significantly higher than in patients with relapsed/refractory AML (50%; P = 0.001). There were no significant difference in CR rates between elderly AML patients (54%) and all AML patients (P = 0.721). When compared with non-HAG regimens for AML/MDS induction therapy, the CR rate of patients treated with HAG was significantly higher than in treated with intensive chemotherapy (P = 0.000). No significant differences in CR rates were observed between patients treated with HAG and those treated with CAG (cytarabine, aclarubicin, G-CSF) regimens (P = 0.073). HAG regimen was well tolerated, with early death (ED) in 2%, grade IV myelosurrpression in 52% and infection in 50%. Reports of ED and rates of myelosuppression were reduced as compared with intensive chemotherapy (P = 0.000 and P = 0.000, respectively). CONCLUSION: The HAG regimen is an effective and safe regimen for the treatment of AML and MDS, and appears to be more effective and better tolerated than intensive chemotherapy. Future randomized controlled trials and further meta-analyses are strongly needed to confirm its efficacy and safety, especially in comparison with intensive chemotherapy.

A safety evaluation of omacetaxine mepesuccinate for the treatment of chronic myeloid leukemia.

INTRODUCTION: Therapy of chronic myeloid leukemia (CML) has been completely transformed by the development of tyrosine kinase inhibitors (TKIs). However, a subset of patients will fail TKI therapy due to resistance or intolerance. Omacetaxine mepesuccinate (OM), a protein translation inhibitor, is currently the only approved therapy that does not directly target the kinase domain. It has activity for CML patients irrespective of the phase or underlying kinase domain mutation status. AREAS COVERED: We searched the MEDLINE database for articles published in English on homoharringtonine or omacetaxine from 1970 to present. This article reviews the pharmacokinetics of OM and its clinical evolution for the treatment of CML pre- and post TKI development. Toxicity profile, drug administration and future directions are also discussed. EXPERT OPINION: OM represents a unique addition to the CML therapeutic armamentarium with its distinct mechanism of action and activity. The adverse event profile is manageable and with subcutaneous administration at the approved dose, cardiac toxicity is no longer a concern. The recent approval of home administration will facilitate access to this therapy and increase patient compliance. We conclude with specific scenarios where OM use should be considered in CP and AP-CML patients in the era of TKI therapy.

[Homoharringtonine in newly diagnosed acute promyelocytic leukemia treatment: a prospective, randomized controlled trial].

OBJECTIVE: To compare the efficacy and toxicities of combining homoharringtonine (HHT)±daunorubicin (DNR) with all-trans-retinoic acid (ATRA) based therapy and DNR plus ATRA based therapy in newly diagnosed low/intermediate risk acute promyelocytic leukemia (APL). METHODS: A total of 96 newly diagnosed patients with APL were randomized to HHT group, DNR group and HHT+ DNR group prospectively. The complete remission (CR) rate, the overall survival (OS) and event-free survival (EFS) of three groups were analyzed. RESULTS: There were 31 patients in HHT group, 33 patients in DNR group and 32 patients in HHT+ DNR group. The baseline characteristics of three groups were similar. No patient died during induction therapy. The morphologic CR rate was 100.0%. The median time to peak WBC counts in HHT+DNR group (4 days, range: 1-23 days) was significantly shorter than that in HHT group (9 days, range: 1-27 days) (P=0.008) and DNR group (7 days, range: 1-27 days) (P=0.240). There was no difference among three groups about the incidence of differentiation syndrome, the median interval to achieve CR, peak WBC counts and transfusions (P >0.05). All patients achieved complete molecular remission (CMR) during consolidation therapy. The interval to achieve CMR was no significantly difference among three groups (P >0.05). The 3-year OS rates for HHT group, DNR group and HHT+DNR group were 95.0%, 100.0% and 91.0%, respectively (P=0.595). The 3-year EFS rates for three groups were 93.0%, 90.0% and 85.0% (P=0.382). No difference was found in the incidence of adverse events among three groups (P >0.05). CONCLUSIONS: Similar to DNR plus ATRA based therapy, HHT plus ATRA based induction and consolidation therapy should be one of highly-efficient treatment options for newly diagnosed APL. Clinical trial registration Chinese Clinical Trial Registry, ChiCTR-TRC-12002628.

[Long-term outcomes of homoharringtonine, cytarabine, daunorubicin or idarubicin (HAD/HAI) as induction chemotherapy in de novo acute myeloid leukemia].

OBJECTIVE: To estimate the long-term outcomes and the prognostic factors of homoharringtonine, cytarabine, daunorubicin or idarubicin (HAD/HAI) as induction chemotherapy in de novo acute myeloid leukemia (AML). METHODS: The CR rate, overall survival (OS) rate, relapse free survival (RFS) rate were retrospectively assayed in 143 de novo AML patients who received the HAD/HAI induction chemotherapy. The outcomes were compared among prognostic groups according to world health organization (WHO) classification, genetic prognosis and initial white blood cell (WBC) count. The role of consolidation chemotherapy consisting of middle-dosage Ara-C (MD-Ara-C) on long term survival was evaluated. RESULTS: Of 143 patients, 112 (78.3%) achieved CR after the first course of HAD/HAI induction treatment, and early death occurred in only one case. Notably, the CR rate of patients with an initial WBC count ≥100×10(9)/L was not significantly different from those with an initial WBC count<100× 10(9)/L (70.4% vs 80.2%, P=0.266). The CR rate for the patients with favorable, intermediate and unfavorable integrated genetics risk factors was 93.7%, 71.4% and 61.3%, respectively, the difference between groups was statistically significant (P=0.001). Patients with FLT3-ITD mutation obtained similar CR rate (70.6%) to that of patients with FLT3 wild type (79.3%, P=0.528).The estimated 5-year OS rate and 5-year RFS rate for all patients was 40.0% and 37.0%, respectively, with a median follow-up of 24 (range 1-104) months. The median survival time was 30 [95%CI (12, 48)] months. 5-year OS and 5-year RFS of the 96 patients who achieved CR after first course chemotherapy without undergoing allo-HSCT in complete remission was 47.0% and 38.0%, respectively. 5-year OS was significantly higher in MD-Ara-C consolidation group than in no MD-Ara-C consolidation group among CR patients without allo-HSCT (58.0%, 19.0%, respectively, P=0.004). In patients who obtained CR after first course and received MD-Ara-C consolidation without allo-HSCT, the 5-year OS of patients with hyperleukocytosis was not significantly lower than that of patients without hyperleukocytosis (55.5%, 58.8%, respectively,P=0.419). FLT3-ITD mutation patients showed similar 5-year OS to that of wild type FLT3 patients (51.4%, 60.2%, respectively, P=0.482). And furthermore, 5-year OS of favorable, intermediate and unfavorable integrated genetics groups were 59.1%, 62.5%, 51.9%, respectively (P=0.332) in this subgroup. CONCLUSION: HAD/HAI induction chemotherapy with sequential consolidation of MD-Ara-C could obtain satisfactory CR rate and long-term survival rate in de novo AML, especially for patients with hyperleukocytosis or FLT3-ITD mutation. It yet remains to be verified by large sample, prospective studies.

[Efficacy of HAA regimen in the treatment of 64 patients with refractory/relapsed acute myeloid leukemia].

OBJECTIVE: To evaluate the efficacy and safety of the HAA regimen (homoharringtonine,cytarabine and aclarubicin)as salvage chemotherapy in the treatment of refractory/relapsed acute myeloid leukemia (AML). METHODS: We retrospectively analyzed 64 patients with refractory/relapsed AML who received the HAA regimen as salvage chemotherapy. The complete remission (CR)rate was analyzed. Kaplan-Meier method was used to estimate overall survival (OS) and relapse free survival (RFS), and the differences were compared by Log-rank test. RESULTS: The overall CR rate was 70.1%, and 67.1% of the patients attained CR after the first induction course. The early death rate was 0. The median follow-up time was 61 (range:6-120) months. The estimated 3-year OS rate was 46.8% and the estimated 3-year RFS rate was 42.8%. The CR rates of patients with favorable/intermediate and unfavorable cytogenetics were 76.4% and 33.3%, respectively. The 3-year OS of favorable/intermediate and unfavorable group were 53.7% and 10.0%, respectively. The median survival time of unfavorable group was only 8 months. The side effects associated with the HAA regimen were tolerable, in which the most common toxicities were myelosuppression and infection. CONCLUSION: HAA regimen is associated with a higher rate of CR and longer-term survival and its toxicity can be tolerated. The regimen is suitable for refractory/relapsed AML patients with favorable or intermediate risk .

Omacetaxine Mepesuccinate for Chronic Myeloid Leukemia.

Omacetaxine mepesuccinate is approved by the Food and Drug Administration in the United States for the treatment of chronic myeloid leukemia in chronic or accelerated phase resistant to two or more tyrosine kinase inhibitors. This review summarizes the mode of action, pharmacokinetics, efficacy and safety of omacetaxine mepesuccinate. Omacetaxine mepesuccinate has activity in chronic myeloid leukemia, especially in the chronic phase, regardless of the presence of ABL1 kinase domain mutations. Omacetaxine mepesuccinate has distinct but manageable adverse events profile. Omacetaxine mepesuccinate is a treatment option for a subset of patients with refractory chronic myeloid leukemia.

Incidence and management of myelosuppression in patients with chronic- and accelerated-phase chronic myeloid leukemia treated with omacetaxine mepesuccinate.

Omacetaxine mepesuccinate (Synribo) is an inhibitor of protein synthesis indicated for the treatment of patients with chronic- or accelerated-phase chronic myeloid leukemia (CML) with resistance and/or intolerance to two or more tyrosine kinase inhibitors. Myelosuppression is the most common and clinically significant toxicity experienced by patients treated with omacetaxine. Here, we further examine the patterns of hematologic toxicity observed in clinical trials and describe the approach to management as well as resolution of events. Omacetaxine-related myelosuppression typically occurs more frequently during induction cycles. In general, the myelosuppression observed with omacetaxine treatment is manageable and reversible, and long-term administration is feasible. Careful monitoring, dose delays and reduction in administration days, and appropriate supportive care are critical for successful management of hematologic toxicity. Concerns regarding myelosuppression, observed with many cancer treatments, should not prevent eligible patients from receiving omacetaxine, particularly CML patients with unsatisfactory responses to multiple lines of prior treatment.

Off-Target Effects of BCR-ABL and JAK2 Inhibitors.

The advent of targeted oncolytic agents has created a revolution in the treatment of malignancies. Perhaps best exemplified in myeloproliferative neoplasms (MPN), the tyrosine kinase inhibitors, including inhibitors of BCR-ABL tyrosine kinase and JAK2, have dramatically changed outcomes in persons with MPN. However, clinically relevant dosing of these adenosine triphosphate-mimetic agents in humans leads to inhibition of numerous tyrosine kinases beyond those touted by drug manufacturers and studied in landmark clinical trials. These so-called off-target effects have been linked to both clinical efficacy and toxicity. Rational drug development and serendipitous discovery of drug molecules allows the clinician to select targeted oncolytic agents to treat a specific clinical diagnosis and/or avoid exacerbation of concomitant disease states due to effects upon signaling pathways. Understanding the off-target binding and effects upon signaling pathway of the agents approved for the treatment of MPN will empower the clinician to adroitly select pharmacotherapy, predict toxicities, and utilize these agents in clinical practice for indications beyond MPN.

Recent Advances in the Development of Antineoplastic Agents Derived from Natural Products.

Through years of evolutionary selection pressures, organisms have developed potent toxins that coincidentally have marked antineoplastic activity. These natural products have been vital for the development of multiagent treatment regimens currently employed in cancer chemotherapy, and are used in the treatment of a variety of malignancies. Therefore, this review catalogs recent advances in natural product-based drug discovery via the examination of mechanisms of action and available clinical data to highlight the utility of these novel compounds in the burgeoning age of precision medicine. The review also highlights the recent development of antibody-drug conjugates and other immunotoxins, which are capable of delivering highly cytotoxic agents previously deemed too toxic to elicit therapeutic benefit preferentially to neoplastic cells. Finally, the review examines natural products not currently used in the clinic that have novel mechanisms of action, and may serve to supplement current chemotherapeutic protocols.

Effects of changes in serum endostatin and fibroblast growth factor 19 on the chemotherapeutic sensitivity in acute myeloid leukemia patients.

The present study aimed to explore the changes in serum endostatin and fibroblast growth factor 19 (FGF-19) in acute myeloid leukemia patients, and to determine their effects on chemotherapeutic sensitivity. Sixty acute myeloid leukemia patients and 30 healthy controls were included in the study. Patient serum endostatin and FGF-19 levels were measured on admission, and then, standard chemotherapy was administered. The patients were divided into 2 groups according to chemotherapeutic effects: 21 patients in the chemotherapeutic sensitivity group (complete remission + partial remission) and 39 in the chemotherapeutic resistance group (no remission + degradation). A receiver operating characteristic (ROC) curve was used to analyze the relationship of serum endostatin and FGF-19 levels with chemotherapeutic sensitivity in acute myeloid leukemia patients. The levels of serum endostatin and FGF-19 in acute myeloid leukemia patients before chemotherapy were significantly higher than those in the control group. Moreover, these levels significantly decreased after chemotherapy (P < 0.01). The levels of serum endostatin and FGF-19 in the chemotherapeutic sensitivity group were lower than those in the chemotherapeutic resistance group, both before and after chemotherapy (P < 0.05 and P < 0.01, respectively). ROC curve analysis showed that the predictive values of endostatin and FGF-19 were good, and there was no significant difference between these results. In conclusion, serum endostatin and FGF-19 can be used as predictors of chemotherapeutic sensitivity for acute myeloid leukemia patients, and may be important for determining prognosis.

Homoharringtonine induces apoptosis and inhibits STAT3 via IL-6/JAK1/STAT3 signal pathway in Gefitinib-resistant lung cancer cells.

Tyrosine kinase inhibitors (TKIs) are mostly used in non-small cell lung cancer (NSCLC) treatment. Unfortunately, treatment with Gefitinib for a period of time will result in drug resistance and cause treatment failure in clinic. Therefore, exploring novel compounds to overcome this resistance is urgently required. Here we investigated the antitumor effect of homoharringtonine (HHT), a natural compound extracted from Cephalotaxus harringtonia, on Gefitinib-resistant NSCLC cell lines in vitro and in vivo. NCI-H1975 cells with EGFR T790M mutation are more sensitive to HHT treatment compared with that of A549 cells with wild type EGFR. HHT inhibited cells growth, cell viability and colony formation, as well as induced cell apoptosis through mitochondria pathway. Furthermore, we explored the mechanism of HHT inhibition on NSCLC cells. Higher level of interleukin-6 (IL-6) existed in lung cancer patients and mutant EGFR and TGFß signal requires the upregulation of IL-6 through the gp130/JAK pathway to overactive STAT3, an oncogenic protein which has been considered as a potential target for cancer therapy. HHT reversiblely inhibited IL-6-induced STAT3 Tyrosine 705 phosphorylation and reduced anti-apoptotic proteins expression. Gefitinib-resistant NSCLC xenograft tests also confirmed the antitumor effect of HHT in vivo. Consequently, HHT has the potential in Gefitinib-resistant NSCLC treatment.

Immunological status of chronic myelogenous leukemia patients with complete cytogenetic response after treatment.

BACKGROUND: The aim of this study was to compare the T lymphocyte subsets of chronic myelogenous leukemia (CML) patients who had a complete cytogenetic response (CCyR) after treatment with imatinib (IM) or homoharringtonine (HHT). METHODS: T and Th lymphocyte subsets in CCyR patients treated with HHT (n = 15) or IM (n = 16) were assayed with flow cytometry. RESULTS: It was found that there were no differences in T lymphocyte subset proportions at the time of achieving CCyR0 and also no difference in the CD8+T cell proportions at the 12th month after CCyR (CCyR12), between the 2 groups. The values of CD3+T, CD4+T, CD8+T, CD4+T/CD8+T, Th1 and Th2 cells were 54.21% ± 6.12% vs. 44.32% ± 4.85%, 29.83% ± 5.53% vs. 22.27% ± 3.22%, 24.66 ± 4.91 vs. 25.41% ± 5.72% , 1.11 ± 0.23 vs. 0.92 ± 0.19, 10.23% ± 4.24% vs. 8.34% ± 3.45% and 11.12% ± 3.91% vs. 13.67% ± 4.78%, respectively in the HHT group and IM group at CCyR12, which meant that the proportions of CD3+T, CD4+T and Th1 cells and the ratio of CD4+T to CD8+T cells were higher and the CD8+T and Th2 cell proportions were lower in the HHT group than in the IM group. CONCLUSIONS: HHT has a weaker immunodepression effect on T lymphocyte subsets compared with IM.

Long-term follow-up of homoharringtonine plus all-trans retinoic acid-based induction and consolidation therapy in newly diagnosed acute promyelocytic leukemia.

We conducted a retrospective study to evaluate the efficacy of combining homoharringtonine (HHT) with all-trans-retinoic acid (ATRA)-based induction therapy, followed by three courses of consolidation chemotherapy and 2-year sequential maintenance therapy in acute promyelocytic leukemia (APL). Fifty-three patients were enrolled in the study. The complete remission (CR) rate was 100 %. No patient died during induction therapy. The 9-year event-free survival (EFS) and 9-year overall survival (OS) for all patients were 79.0 and 83.0 %, respectively. Outcome estimates according to the body mass index (BMI) were carried out. Twenty-three (43.4 %) were underweight/normal (BMI < 23.0 kg/m(2)), whereas 30 patients (56.6 %) were overweight/obese (BMI ≥ 23.0 kg/m(2)). Underweight/normal-weight patients had a 9-year OS of 100 %, compared with 73.0 % for overweight/obese patients (P = 0.044). These results indicate that HHT plus ATRA-based induction and consolidation therapy may be a highly efficacious treatment option for newly diagnosed APL. Increased BMI had an adverse prognostic impact in APL.