herapy for remission induction and consolidation was able to achieve morphologic remission in 95 100% and molecular remission in �?0% of adults with Philadelphia Dacinostat NVP-LAQ824 positive ALL. Outcomes were significantly improved as compared with historical controls who received similar chemotherapy regimens but no imatinib. Presently, imatinib combined with chemotherapy is standard for Ph positive ALL proceeding to a possible transplantation. Since most adult patients would relapse after chemotherapeutic treatment alone, allogeneic HSCT is still being recommended for adult patients with Philadelphia positive ALL in first CR. Also in the posttransplant period, imatinib has been integrated for prophylactic reasons.
Other options for Ph positive ALL include the use of second generation TKIs, which have higher BCR ABL1 affinity and are effective in many patients with resistance to firstgeneration TKIs, for example, due to de novo variant BCRABL1 isoforms YM155 781661-94-7 or imatinib resistance conferring mutations at the BCR ABL1 kinase domain. Ottmann et al. evaluated the success of dasatinib in 36 patients with Ph positive ALL who were refractory or intolerant to imatinib. Major hematologic responses were achieved in 42% of patients with a median interval to MHR of 1.8 months. Among patients who achieved MHR, response duration ranged up to 8.7 months. Ten of the 15 patients who achieved an MHR remained free of progression at the 8 month follow up. Complete cytogenetic responses were attained by 58% of patients. Only 6% of patients discontinued therapy as a result of study drug toxicity.
Unfortunately, the multi TKI resistant T315I mutation develops more frequently and relatively faster in patients with Philadelphia positive ALL than in patients with chronic phase of CML who receive TKI treatment. In a recently concluded phase I clinical trial, the multikinase and pan BCR ABL1 inhibitor, ponatinib induced a complete cytogenetic and major molecular response rates of 89% and 78%, respectively, in CML patients with T315I, and most responses were maintained after 12 months of follow up. However, it remains to be seen if these responses will be confirmed. Additionally, DCC 2036, a new TKI in a novel class of so called switch pocket inhibitors, is undergoing trials for patients who carry T315I or who have failed TKI treatment.
DCC 2036 targets a pocket that governs transition to the active state of ABL1, thus locks the kinase into its inactive state through a selective, non ATPcompetitive mechanism. GNF 2, another new agent, inhibits the T315I kinase by binding to the autoregulatory allosteric myristate cleft at the N terminus of ABL1, also effectively freezing the kinase in its inactive state. These new compounds represent interesting new options for patients with BCR ABL1 positive leukemias. 3.2. Monoclonal Antibodies with Anti CD20 Activity. Rituximab is a chimeric monoclonal antibody directed at the CD20 receptor. Its activity is associated with induction of antibody dependent cytotoxicity, or direct apoptosis. As the CD20 antigen is frequently expressed in B lineage ALL, rituximab has been successfully combined with intensive chemotherapy regimens in B lymphatic neoplasms of low and of high grade malignancy. Thomas et al. suggested the inclusion of rituximab into a modified hyper CVAD regimen for adolescents and adults with de novo precursor B lineage ALL. In patients with C