Improved multilineage response of hematopoiesis in patients with myelodysplastic syndromes to a combination therapy with all- trans -retinoic acid, granulocyte colony-stimulating factor, erythropoietin and α-tocopherol

1996 ◽  
Vol 72 (4) ◽  
pp. 237-244 ◽  
Author(s):  
A. Ganser ◽  
A. Maurer ◽  
C. Contzen ◽  
G. Seipelt ◽  
O. G. Ottmann ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Combination Therapy ◽  
Myelodysplastic Syndromes ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Stimulating Factor

scholarly journals Complete Remission of t(11;17) Positive Acute Promyelocytic Leukemia Induced by All-trans Retinoic Acid and Granulocyte Colony-Stimulating Factor

Blood ◽  
1999 ◽  
Vol 94 (1) ◽  
pp. 39-45 ◽  
Author(s):  
J.H. Jansen ◽  
M.C. de Ridder ◽  
W.M.C. Geertsma ◽  
C.A.J. Erpelinck ◽  
K. van Lom ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Acute Promyelocytic Leukemia ◽  
Promyelocytic Leukemia ◽  
Leukemic Cells ◽  
Leukemia Cells ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Stimulating Factor

The combined use of retinoic acid and chemotherapy has led to an important improvement of cure rates in acute promyelocytic leukemia. Retinoic acid forces terminal maturation of the malignant cells and this application represents the first generally accepted differentiation-based therapy in leukemia. Unfortunately, similar approaches have failed in other types of hematological malignancies suggesting that the applicability is limited to this specific subgroup of patients. This has been endorsed by the notorious lack of response in acute promyelocytic leukemia bearing the variant t(11;17) translocation. Based on the reported synergistic effects of retinoic acid and the hematopoietic growth factor granulocyte colony-stimulating factor (G-CSF), we studied maturation of t(11;17) positive leukemia cells using several combinations of retinoic acid and growth factors. In cultures with retinoic acid or G-CSF the leukemic cells did not differentiate into mature granulocytes, but striking granulocytic differentiation occurred with the combination of both agents. At relapse, the patient was treated with retinoic acid and G-CSF before reinduction chemotherapy. With retinoic acid and G-CSF treatment alone, complete granulocytic maturation of the leukemic cells occurred in vivo, followed by a complete cytogenetical and hematological remission. Bone marrow and blood became negative in fluorescense in situ hybridization analysis and semi-quantitative polymerase chain reaction showed a profound reduction of promyelocytic leukemia zinc finger–retinoic acid receptor- fusion transcripts. This shows that t(11;17) positive leukemia cells are not intrinsically resistant to retinoic acid, provided that the proper costimulus is administered. These observations may encourage the investigation of combinations of all-trans retinoic acid and hematopoietic growth factors in other types of leukemia.

scholarly journals Clinical Efficacy Analysis of the Low-Dose Decitabine in Combination with Cytarabine, All-Trans Retinoic Acid and Granulocyte Colony-Stimulating Factor for Patients with MDS-EB

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3685-3685
Author(s):  
Ligen Liu ◽  
Yuanmmei Zhai ◽  
Li Yang ◽  
Limin Zhao ◽  
Li Chang ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Retinoic Acid ◽  
Low Dose ◽  
Gene Mutations ◽  
The Other ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Stimulating Factor

Abstract Abstract Purpose: Treatment of patients with myelodysplastic syndromes with excess blasts (MDS-EB) remains a great challenge. In this study, we evaluated the tolerance and efficacy of the combination of low-dose decitabine, cytarabine, all-trans retinoic acid and granulocyte colony-stimulating factor (DLAAG) for MDS-EB patients. Methods: A total of 18 patients with MDS-EB were enrolled in this study and 1 patient who did not follow-up the bone marrow evaluation was excluded from analysis. This study is registered at ClinicalTrials.gov, NCT03356080.The DLAAG regimen consisted of subcutaneous injection of decitabine (0.1-0.2mg/kg, d1-3/w, lasted for 1-3 weeks), cytarabine (6-15mg/m 2,q12h,d1-10), oral all-trans retinoic acid (45mg/m 2/d, d4-6; 15mg/m 2/d, d7-20) and G-CSF (300ug, from d0 until neutrophil count recovery to 20×10 9 cells/L). Results: Patient characteristics A total of 18 patients (11 males, 7 females) with a median age of 61 years (range 45 to 88 years) were enrolled in our study. The clinical characteristics of the patients were shown in Table 1. Response and survival The clinical outcome and overall survival (OS) of patients were summarized in Table2 including 1 could not evaluable after the first protocol. As shown in Table3, after one course of DLAAG, the CR and OR rate was 55.56% and 77.78% respectively. In addition, 3 patients suffered the disease progression (PD) (n=3,16.67%). We found that those who achieved the bone marrow remission after DLAAG had significantly pro-longed OS than others (p=0.0001, Fig.1). The Kaplan-Meier analysis revealed the median overall survival for all patients enrolled was 15 months (Fig.2A), and the relapse-free survival (RFS) for patients achieving CR or CRm was 11 months (Fig.2B). Genetic mutations and response to DLAAG Paired samples (pre- and post-treatment) of the objects were tested for gene mutations which were recurrently mutated in myeloid malignancies, except 1 patient who was failure to perform bone marrow review. 2 patients (11.1%) had no genetic or cytogenetic abnormalities either at baseline or during therapy (they were tested at baseline and d28). Most patients (15 out of 18) had at least one somatic mutation. In this latter group, only 1 patient acquired specific mutation of IDH2 during the therapy (it was tested on d28, data was not shown), while all the other genes were mutated in patients at baseline. Collectively, the most frequently mutated genes at diagnosis were RUNX1 (n=5, 29.4%), ASXL1 (n=4, 23.5%), as well as the overexpression of WT1 (n=4, 23.5%), and the others with an incidence of more than 10% were TET2(n=3,17.6%),TP53 (n=2, 11.8%), EZH2 (n=2, 11.8%), STAG2 (n=2, 11.8%), SF3B1 (n=2, 11.8%) and U2AF1 (n=2, 11.8%).Genes less frequently mutated such as CEBPA,CUX1 et al. were not shown. Remarkably, the proportion of patients with the above gene mutations showing no significant increasing during therapy as compared to baseline, the clones of WT1/TET2/TP53/EZH2/STAG2 can decrease or even disappear(Fig.3A).Moreover, we noted the complete response in patients with ASXL1, TP53 mutations or WT1 overexpression despite the concomitant presence of complex cytogenetic at diagnosis, whereas patients with the EZH2 mutation were less likely to respond (Fig.3B). Subgroup analysis A subgroup analysis based on the 2016 WHO classification revealed an association of EB-I patients with longer OS(P=0.002) (Fig. 4A). On the other hand, based on the IPSS score our study revealed that the lower-risk group patients have better OS (p= 0.0054) (Fig. 4B).In addition to this, we also compared the OS in different groups of age and karyotype, but there were no statistical difference (Fig. 4C-D). Safety and Tolerability All patients who received the therapy were eligible for toxicity evaluation. Given the patient-population enrolled and treatment regimen, myelosuppression occurred in all patients (Table 4). The grade 3 to 4 hematological toxicities including neutropenia and thrombocytopenia were common after treatment. Febrile neutropenia occurred in 77.8% of the patients. Conclusion: This study suggested the novel combination of LD-DAC, Ara-C, ATRA and G-CSF might be an optimal introduction therapy for patients with MDS-EB, and this combination warrants further investigation in larger trials. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Maintenance of retinoic acid receptor alpha pools by granulocyte colony-stimulating factor and lithium chloride in all-trans retinoic acid–treated WEHI-3B leukemia cells: relevance to the synergistic induction of terminal differentiation

Blood ◽  
2000 ◽  
Vol 96 (6) ◽  
pp. 2262-2268 ◽  
Author(s):  
Rick A. Finch ◽  
Jianming Li ◽  
T-C. Chou ◽  
Alan C. Sartorelli
Keyword(s):  
Retinoic Acid ◽  
Retinoic Acid Receptor ◽  
Terminal Differentiation ◽  
Fold Increase ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
D Cells ◽  
Stimulating Factor

Abstract Previous studies have demonstrated that combinations of all-trans retinoic acid (ATRA) with either granulocyte-colony stimulating factor (G-CSF) or lithium chloride (LiCl) produced synergistic terminal differentiation of WEHI-3B myelomonocytic leukemia (D+) cells. It was found that steady-state retinoic acid receptor alpha (RARα) protein levels were markedly reduced in these cells after exposure to ATRA. Because the presence of receptors for a hormone ligand is required for its action, differentiation therapy with ATRA may be self-limiting. The combination of G-CSF with ATRA significantly attenuated the loss of RARα protein, and synergistic terminal differentiation occurred. LiCl was more effective than G-CSF in preserving RARα pools and synergized with ATRA more strongly than G-CSF. These findings suggested that the prevention of RARα protein loss by G-CSF or LiCl in ATRA-treated cells functioned to extend the differentiation response to the retinoid and was responsible, at least in part, for the observed synergism. D+ cells transfected with an expression plasmid containing RARα cDNA had a 6- to 8-fold increase in steady-state RARα mRNA compared with vector-transfected cells and showed a 2- to 3-fold increase in RARα protein. ATRA caused a reduction, but not a complete loss, of RARα protein in these transfectants, which were considerably more responsive than parental D+ cells to ATRA as a single agent, supporting the concept that the protection of RARα pools results in a heightened differentiation response to ATRA.

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