The Combination of Conventional Chemotherapy with New Targeted Therapy in Hematologic Malignancies: The Safety and Efficiency of Low- Dose Cytarabine Supports its Combination with New Therapeutic Agents in Early Clinical Trials

Abstract

Cytarabine (cytosine arabinoside) is commonly used in the treatment of hematologic malignancies, including both myeloid and lymphoid disorders. The cytotoxic effect of the drug depends on conversion to its triphosphate form in the targeted cells, and the intracellular levels of this active form depend on the balance between phosphorylating and dephosphorylating enzymes. The sensitivity to cytarabine-triphosphate induced cytotoxicity is in addition dependent on the balance between pro-and antiapoptotic signalling in the malignant cells, especially the balance between various members of the bcl-2 family. Even though differentiation induction has been claimed to be important in low-dose cytarabine, most clinical studies suggest that the cytotoxic affect is most important even in this therapeutic strategy. The clinical experience with the low-dose therapy is based on studies in hematological malignancies, mainly acute myeloid leukemia and myelodysplastic syndromes. These studies clearly document the clinical efficiency of low-dose therapy. However, even this low-dose strategy has a risk of severe hematological toxicity and eventually serious or fatal infections especially in elderly patients. Our understanding of the molecular mechanisms behind chemoresistance and chemosensitivity to cytarabine thereby forms the scientific basis for the design of future clinical studies where cytarabine can be combined with new targeted therapy. Low-dose cytarabine may then represent an efficient alternative with an acceptable toxicity even when combined with new anticancer agents in early clinical studies. However, the possibility of pharmacological interactions with the intracellular metabolism of cytarabine by these new agents has to be considered when combination regimens are designed.

The combination of valproic acid, all-trans retinoic acid and low-dose cytarabine as disease-stabilizing treatment in acute myeloid leukemia

“…[41] used cytarabine 20 mg/m 2 once daily for 10 days at four-week intervals and had a remission rate of 7.9%; whereas (iii) we used an even lower dose of 10 mg/m 2 for 10 days at 12- week intervals, but despite this our remission rate of 6% is comparable to Kantarjian et a l. even though we included patients with AML relapse. Our present observations are also consistent with earlier AML studies of low-dose cytarabine [38]. …”

“…These authors also included patients with MDS; they used higher cytarabine doses that were administered more frequently and ATRA was not included. Previous studies of low-dose cytarabine have demonstrated that even this treatment can have a treatment-related mortality [38]. However, our study of an unselected patient population has demonstrated that this low-toxicity regimen can give disease stabilization for a subset of AML patients.…”

Gelsolin Induces Promonocytic Leukemia Differentiation Accompanied by Upregulation of p21CIP1

“…The maturation arrest of acute promyelocytic leukaemia (APL), for instance, can be reversed with all-trans retinoic acid (Germain, 2006). More recent trials involving differentiation induction demonstrate that this can be applied even in combination with intensive chemotherapy to increase the susceptibility of AML blasts to druginduced apoptosis (Fredly et al, 2009). Besides the standard therapy for AML, the use of site-specific ligands, receptors and cytokines, disruption of dominant fusion leukaemogenic proteins, chromatin remodeling and the combination of the above with cytotoxic chemotherapy have been shown to be synergistic in inducing myeloid differentiation and apoptosis in several AML cell lines and in patients with APL (Koeffler, 2010).…”

Histone deacetylase inhibition in the treatment of acute myeloid leukemia: the effects of valproic acid on leukemic cells, and the clinical and experimental evidence for combining valproic acid with other antileukemic agents

“…In these four trials, the CR rates were 14 to 52% and the cytarabine dose varied between 15 to 20 mg/m 2 /d for 10 to 14 days. Although low-dose cytarabine is frequently used, the mechanism of action is not known in detail and may include differentiation induction, as well as direct cytotoxic effects [85]. …”

“…The biological effects and clinical results of low-dose cytarabine have been recently reviewed [85]. The following conclusions can be made based on the currently available clinical studies in human AML: 1) the treatment has an antileukemic effect and can improve survival; 2) the treatment is most effective for patients with low- and intermediate-risk disease, and the improved survival is mainly due to a beneficial effect in a minority of patients achieving complete hematological remission; 3) survival is not improved for patients with high-risk cytogenetic abnormalities; 4) the cytarabine dose used in these studies varies between 10 and 40 mg/m 2 given once or twice daily, and the duration of treatment is usually 10 days but up to 21 days has been used; 5) treatment-related mortality is seen at least when using the higher doses, but this mortality shows a wide variation between studies; and 6) combination with other cytotoxic drugs is possible, but this has been investigated mainly in very small clinical studies and some of these studies suggest that the treatment-related mortality will then be increased.…”