Prospective Study of a Pirarubicin, Intermediate-Dose Cytarabine, and Etoposide Regimen in Children With Down Syndrome and Acute Myeloid Leukemia: The Japanese Childhood AML Cooperative Study Group

Abstract

A B S T R A C T PurposeTo evaluate a less intensive chemotherapeutic regimen specifically designed for patients with Down syndrome (DS) and acute myeloid leukemia (AML), and to determine the prognostic factors for event-free survival. Patients and MethodsSeventy-two patients with AML-DS were treated with remission induction chemotherapy consisting of pirarubicin (25 mg/m 2 /d for 2 days), cytarabine (100 mg/m 2 /d for 7 days), and etoposide (150 mg/m 2 /d for 3 days). Patients received four courses of intensification therapy of the same regimen. Prophylaxis for CNS leukemia was not included. ResultsAll but two patients were younger than 4 years, and 67 of the 72 patients (93%) were diagnosed as acute megakaryoblastic leukemia (AMKL). Seventy of the 72 patients (97.2%) achieved a complete remission (CR), and the estimated 4-year event-free survival (EFS) rate was 83% Ϯ 9%. Nine patients relapsed, and one died as a result of pneumonia during CR. Multivariate analysis revealed that the presence of monosomy 7 was a greater risk factor of adverse outcome (odds ratio ϭ 5.67; P ϭ .027). ConclusionA less intensive chemotherapeutic regimen produces excellent outcomes in standard-risk AML-DS patient. Risk-oriented therapy should be considered for future trials in AML-DS.We would like to emphasize that the TRM in the current study was only 1.4% (one of 72 patients) which is much lower than those of previous reports. 7-9,16 On the other hand, relapse and induction failure were found in 11 of 72 patients (14%), which is more frequent than in other reports with intensive regimens. 6,8,13 On the basis of the results of the present study, we have designed a risk-oriented therapy protocol for our next trial with AML-DS. The patients with M1 marrow after induction therapy should be classified into a standard-risk group and receive the same dose of pirarubicin and cytarabine regimen. In POG 8498, daunorubicin was used only in induction, with a total dose of 135 mg/m 2 , and high-dose cytarabine in consolidation. Although this study included only small cohort of 14 DS patients, all were alive as last updated in 2005. 31 We will include high-dose cytarabine for patients with M2 or M3 marrow after induction therapy, classified into a high-risk group, who might have adverse prognostic factors such as age older than 3 and the presence of monosomy 7. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTERESTThe author(s) indicated no potential conflicts of interest.

Pirarubicin inhibits multidrug-resistant osteosarcoma cell proliferation through induction of G2/M phase cell cycle arrest

“…These results suggest that THP partially overcomes the resistance caused by overexpression of P-gp and that THP may play an important role in treatment of patients with refractory or recurrent high-grade osteosarcoma. In fact, THP has also shown favorable activity in various types of cancer cells, including P-gp overexpressing breast cancer [27] , ADM-resistant lymphoblastoma [28] , MG-63 cells [29] and bladder cancers [30] in vitro, and has substantial clinical activity against various tumors without severe side effects [4][5][6][7]15,16] . Despite the ability of THP to overcome MDR in clinical studies [6,16,17] , very little is known about THP-induced cytotoxicity and the underlying mechanisms of pirarubicin on MDR osteosarcoma cells.…”

“…Recently, pirarubicin (THP), a novel anthracycline derivative of ADM, has been used clinically to treat tumors such as osteosarcoma, breast cancer, lymphoma and acute myeloid leukemia [4][5][6][7] . Moreover, THP has shown a greater antitumor activity [8][9][10] and lower cardiotoxicity [11] than ADM.…”

Hematological manifestation in Down Syndrome

“…Although TAM resolves in the majority of DS infants, 20-30 % may developed ML-DS Volume 3 Issue 6, July 2017 ML-DS is classified as subtype of AML in WHO classification its present in the first 2y and rare after 4 y of age and usually proceed neonatal TAM (12-13) that may be because of inappropriate diagnostic test for TAM in early life GATA1 mutations are found neonates with ML-DS even in the absence of an antecedent history of TAM ( 14)ML-DS presented with progressive pancytopenia with low percentage of circulating blasts for many months before the development of ML-DS (12-15-16) . bone marrow aspiration is essential of the diagnosis as the circulating blast is low and the aspiration often associated with dry tap secondary to marked bone marrow fibrosis and bone marrow biopsy is necessary to confirm ML-DS(10) the blast cell similar to those in TAM with a typical megakaryoblatic morphology and co-operation of stem cell marker (CD34,CD117), MYLOID (CD33), megakaryocytic (CD42b and CD41) and erythroid markers (CD36 and glycophorinA) as well as CD7 (17)(18)) the cytogenattic differences between DS and non-DS AML including absence of taranslocation t (1:22) ,and instead ,the presence of trisomies involving chromosomes 8 and 1, as well as monosomy 7 . (19-20) the conventional treatment oF ML-DS has been associated with excessive treatment mortality ,cardiac toxicity due to anthracyclines and serious infections( 21) Several collaborative study groups have adapted their standard AML protocol for ML-DS by reducing the dose of drugs (Table 1)( 21) AML99 DS protocol consisted of pirarubicin (25 mg/m2/d, on days 1 and 2), which was estimated to be equivalent as 25mg/m2/d of daunomycin (DNR), cytarabine (100 mg/m2/d on day 1 through 7), and etoposide (150 mg/m2/d on day 3 through 5).…”

The key role of stem cell factor/KIT signaling in the proliferation of blast cells from Down syndrome-related leukemia

“…DS children suffer high rates of treatment toxicity, with an increased risk of treatment-related death. 2,3 Combining cytarabine and KIT-targeting tyrosine kinase inhibitor treatments might exterminate the TL clone without serious drug-related toxicity and provide a beneficial therapeutic effect in cases of severe TL.…”

“…1 In comparison with non-DS children with acute myeloid leukemia (AML), ML-DS patients have a better clinical outcome. 2,3 However, approximately 20% of the patients with severe TL are still subject to life threatening or fatal complications. 4,5 Improved treatments for TL are necessary for a better long-term prognosis of DS patients.…”