Characterization of Comparative Clinical Outcomes and Molecular Features of Black Patients with Acute Promyelocytic Leukemia (APL) Reveals Similar Survival and Distinct Genomic Profiles
Alma HabibIsaiah BoatengDeedra NicoletKrzysztof MrózekJames L. FisherAllyson WallerAndrew StiffJill BussAndrea LagansonSienna Martinez CorzineEthan HampYazan Abu-ShihabBayard L. PowellGeoffrey L. UyWendy StockRichard M. StoneJonathan E. KolitzEunice S. WangAndrew J. CarrollJeffrey W. TynerAndrew HantelElectra D. PaskettJohn C. ByrdElaine R. MardisJesse J. PlascakAnn‐Kathrin Eisfeld
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Acute promyelocytic leukemia (APL) is a special subtype of acute myeloid leukemia. Its main clinical features are severe coagulopathy, bleeding tendency and high early mortality. With the continual advances in APL research, APL has become a kind of curable leukemia with the highest cure rate at present. In order to further guide the therapy of APL and improve the quality of life of patients with APL, this article reviews current advances of treatment of APL.
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Leukemia, promyelocytic, acute; Arsenic trioxide; All-trans retinoic acid
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Early mortality in acute promyelocytic leukemia has been reported to occur in less than 10% of patients treated in clinical trials. This study reports the incidence and clinical features of acute promyelocytic leukemia patients treated at Stanford Hospital, CA, USA since March 1997, focusing on early mortality. We show that the risk of early death in acute promyelocytic leukemia patients is higher than previously reported. In a cohort of 70 patients who received induction therapy at Stanford Hospital, 19% and 26% died within seven and 30 days of admission, respectively. High early mortality was not limited to our institution as evaluation of the Surveillance, Epidemiology and End Results Database demonstrated that 30-day mortality for acute promyelocytic leukemia averaged 20% from 1977–2007 and did not improve significantly over this interval. Our findings show that early death is now the greatest contributor to treatment failure in this otherwise highly curable form of leukemia.
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The recent study described a better outcome in acute promyelocytic leukemia patients treated with all-trans retinoic acid and arsenic oxide compared to those treated with all-trans retinoic acid combined with conventional chemotherapy. The pivotal study indicated that favorable-risk acute promyelocytic leukemia patients can be cured without any cytotoxic chemotherapy. Even high-risk patients are treatable with cytotoxic agents. Acute promyelocytic leukemia does not develop only by the dedifferentiation caused by PML-RARA. A determined oncogene other than PML-RARA which promotes cell proliferation would be required. We recently treated a 30-year-old Japanese female who achieved molecular remission with only the administration of all-trans retinoic acid. The patient’s leukemic clones concomitantly had a del(5q) aberrant chromosome with t(15;17) (q22;q12). The patient’s bone marrow cells indicated clonal evolution of the tumor cells expressing CD13dim, CD33+, CD117+, and lacking HLA-DR, CD34 and CD11b. A fluorescence in situ hybridization analysis detected PML-RARA fusion genes in the patient’s bone marrow specimens, leading to the diagnosis of acute promyelocytic leukemia. A del(5q) is one of the characteristic chromosomal abnormalities observed in myelodysplastic syndrome. On the other hand, up to 40 % of acute promyelocytic leukemia cases are known to harbor the addition of a clonal cytogenetic abnormality. However, such a case acute promyelocytic leukemia with del(5q) would be rare, rather than myelodysplastic syndrome, consequently obtaining t(15;17). Which cytogenetic abnormalities, acute promyelocytic leukemia or myelodysplastic syndrome, came first is informative to make a clinical decision for the initial therapy. In this case, we speculated the PML-RARA translocation is an original pathogenesis and thereafter additional cytogenetic abnormalities (del(5q) and -6) common in myelodysplastic syndrome. All-trans retinoic acid lead the patient into molecular remission. We propose that an assessment of additional cytogenetic abnormality in acute promyelocytic leukemia would contribute to the clinical decisions regarding whether to treat disease with all-trans retinoic acid and cytotoxic agents. It would be of interest to know the extent of cytogenetic abnormality in the patients regarding to mixed leukemia. One or more additional cytogenetic abnormalities other than PML-RARA could account for the biological malignant grade and prognostic index.
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Acute promyelocytic leukemia (APL) is a disease described as definite morphological and cytogenetical abnormalities and leads to coagulopathy leaving the patient in a life-threatening condition. A specific chromosomal translocation of 15 and 17 chromosomes leads to retinoic acid receptor-α (RARα) and promyelocytic leukemia (PML) genes fusion that produces an abnormal gene mutation forming an oncogenic protein which is (PML-RARα). Those APL patients, who have been treated with all-trans retinoic acid (ATRA) or arsenic trioxide (ATO) commonly lead a complicated condition called differentiation syndrome which is rarely severe. This case report explains the 37-years old male diagnosed with acute promyelocytic leukemia and later developed a differentiation syndrome after initiation of all-trans retinoic acid and arsenic trioxide induction therapy.
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To evaluate factors predictive for relapse in a cohort of adult patients with acute promyelocytic leukemia monitored by molecular methods during consolidation and during at least one month of maintenance therapy. The charts and laboratory data of 65 adult patients with acute promyelocytic leukemia treated according to the International Consortium on Acute Promyelocytic Leukemia 2006 protocol were reviewed. The identification of the promyelocytic leukemia-retinoic acid receptor-alpha gene rearrangement at diagnosis, post-induction, post-consolidation and during maintenance treatment was performed by qualitative and quantitative reverse transcription polymerase chain reaction. Eighty-nine patients were diagnosed with acute promyelocytic leukemia over a seven-year period and of these 65 were eligible for treatment with the protocol. Among the 45 patients who received consolidation and maintenance treatment, six (13%) relapsed, three of whom presented hematologic and three presented molecular relapse. The first relapses occurred at a median of 39 months. Relapsed patients were from all risk groups (low, intermediate and high) and both morphological types (M3 and M3variant) were found. Three of these patients are alive and in molecular remission after salvage treatment. There were no statistically significant differences regarding gender, age, risk group, morphology, promyelocytic leukemia breakpoint cluster region, use of all-trans retinoic acid, development of differentiation syndrome and number of days to complete remission between the patients who relapsed and those who did not. Our results reinforce the importance of prolonged monitoring of acute promyelocytic leukemia patients using molecular methods to detect relapse early.
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Abstract Two main causes of early mortality of acute promyelocytic leukemia (APL) are rewieved, unique type ofcoagulopathy typical for APL and differentiation syndrome sometimes complicating treatment of APL with all-trans retinoic acid (ATRA) or arsenic trioxide (ATO). The information covers analysis of the patophysiologies of both conditions and also recommendations considering treatments and preventive measures.
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Objective:To observe the arsenic trioxide (As2O3) combined with alltransretinoic acid (ATRA) treatment of acute promyelocytic leukemia (APL) of the efficacy and toxicity.Methods: 21 patients with acute promyelocytic leukemia (APL) patients with doubleAs2O3 combined ATRA induction therapy,patients with high white blood cell with a single chemotherapy drug third year plus tipshirt ester base (H) or daunorubicin (DNR).Results:In 21 patients,19 cases of complete remission,complete remission (CR) rate of 90.47%;1 patient died of intracranial hemorrhage.Conclusion:arsenic trioxide combined with alltrans retinoic acid treatment of acute promyelocytic leukemia precise and well tolerated in patients.
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The mechanism of effect of arsenic trioxide on promyelocytic leukemia is different from that of all-trans retinoic acid. Arsenic trioxide exerts its action by accelerating cell apoptosis, while all-trans retinoic acid by inducing cell differentiation. However, both drugs can inhibit the transcription of tissue factor (TF) mRNA in acute promyelocytic leukemia, and decrease TF level and coagulative activity to normalize coagulopathy. The objective of the study was to observe whether combination of the two drugs could improve efficacy or in contrary accentuate adverse reactions.Two groups of patients with acute promyelocytic leukemia were included. Twenty-two patients (17 untreated cases and 5 relapsed cases) from January 2000 to October 2001 in group I were treated only with oral retinoic acid [25 mg/(m(2)x d) in two divided doses] for less than 50 days. Nineteen cases (15 untreated cases and 4 relapsed cases) from November 2001 to June 2003) in Group II were treated with combination of arsenic trioxide and all-trans retinoic acid. 0.1% AS2O3 10 ml in 500 ml 5% glucose solution was given intravenously for 4 to 6 hours per day for 28 days. The dosage of retinoic acid in group II was the same as that in group I.Nineteen of 22 cases in retinoic acid-treated group (group I)(16 untreated cases and 3 relapsed cases) achieved complete remission (CR). The CR rate was 86.4%. Seventeen of 19 cases in combination therapy group (group II)(15 untreated cases and 2 relapsed cases) achieved CR. The CR rate was 89.5%. The death rates were 13.6% (3/22, 1 untreated case, 2 relapsed cases) in group I and 10.5% (2/19, 2 relapsed cases) in group II, respectively. The median time to CR was 23 days in group I and 26 days in group II, and the median time to normalization of coagulopathy was 7 days in group I and 4 days in group II. Significant differences were found between the two groups. No significant adverse reaction was observed in both groups.The CR rate and death rate were not different between the two groups. The combination therapy with AS2O3 and all-trans retinoic acid can shorten the time to CR and normalization of coagulopathy.
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