chemo sensitization before hematopoietic stem cell transplantation in patients with acute leukemia in complete remission

Conditions: Acute Myeloid Leukemia; Acute Lymphoid Leukemia

Summary: the purpose of this study is to evaluate the disease free survival and the overall survival in patients with acute leukemia in first or second complete remission after administrating a cxcr4 antagonist, as a chemo sensitization strategy, plus chemotherapy as the conditioning regimen for autologous or allogeneic hematopoietic stem cell transplantation (hsct).

in the last decade, hsct has become an efficient strategy for the treatment of many malignant and non-malignant hematological diseases, being the most common, according to the european bone marrow transplantation (ebmt), acute leukemias. both myeloid and lymphoid acute leukemias are considered malignant clonal diseases of the hematopoietic stem cells, and represent a therapeutic challenge due to the high relapse rate and mortality using conventional chemotherapy regimens. hsc reside mainly within the bone marrow, protected by a microenvironment or niche, which is perivascular, created partly by mesenchymal stromal cells and endothelial cells. interactions between these cells and many adhesion molecules are considered a key factor for growing, transformation, and migration of neoplastic cells. the main pathway involved in the cellular transit regulation is chemokine receptor 4 (cxcr4) and its chemokine ligand 12 (cxcl12), responsible of mediating interactions between the hsc and stromal cells, and whose blocking through other cytokines and antagonists of the cxcr4 receptor (plerixafor) favors chemotaxis and hsc output to peripheral blood. such strategy has become an effective technique to increase mobilization and harvesting in patients undergoing stem cell transplantations. on the other hand, some preclinical studies have shown that the activation of cxcl12 pathway favors tumor growth, promoting survival and invasion of the malignant cells, recruiting stromal cells that facilitate their proliferation and promote angiogenesis directly. in such way, this pathway has been considered a therapeutic target to block their activity and inhibit tumor progression. patients with acute leukemia in first or second complete remission undergoing autologous or allogeneic hematopoietic stem cell transplantation (hsct), commonly present low response rates and low survival due to persistent minimal residual disease, despite conventional high dose chemotherapy regimens. it is necessary to create strategies to increase the destruction rate of neoplastic cells in patients with acute leukemia candidates to hsct. our hypothesis is that the administration of a cxcr4 antagonist as part of the conditioning regimen in patients with acute leukemia candidates to hsct will allow the mobilization and sensitization of leukemia blast cells, eradicating efficiently the minimal residual disease, responsible of posterior relapse, and will achieve a higher response rate and survival of patients undergoing this procedure.

Eligibility criteria:
inclusion criteria: * diagnosis of acute myeloid leukemia (aml) or acute lymphoblastic leukemia (all), candidates to hsct * allogeneic hsct: high risk aml in first complete remission (cr), aml in second cr, and all in first or second cr with a matched or half-matched (haploidentical) related or unrelated donor * autologous hsct: intermediate risk aml in first cr, all in first or second cr without a donor * normal liver function enzyme tests * preserved renal function * eastern cooperative oncology group score ≤2 or karnofsky ≥80% * left ventricle ejection fraction (lvef) \>40% * hemoglobin (hb) ≥ 10 g/dl, absolute neutrophil count ≥ 1 x 103/mm3, and platelets ≥ 100,000 /µl * signed informed consent exclusion criteria: * patients not willing to participate or to sign the informed consent * patients who do not meet the inclusion criteria

Keywords: bone marrow transplantation conditioning regimen