Chemotherapy and Imatinib in Young Adults With Acute Lymphoblastic Leukemia Ph (BCR-ABL) POSITIVE
Chemotherapy and Imatinib in Young Adults With Acute Lymphoblastic Leukemia Ph (BCR-ABL) POSITIVE
20-25% of patients over 15 years with acute lymphoblastic leukemia (ALL) have the
 Philadelphia chromosome or BCR-ABL rearrangement. Traditionally, intensive chemotherapy
 followed by hematopoietic stem cell transplantation (HSCT) have formed the basis allogeneic
 treatment of this disease, but the results have been poor (60-75% complete remissions-RC-and
 probability of long-term survival less than 20%). The effectiveness of imatinib for
 hematologic responses in patients with Ph + (observed in phase I and II) led to its use in
 phase III trials in combination with chemotherapy. They saw a chance of obtaining the RC
 above 90%, with acceptable toxicity, a molecular response rate (MR) of 40-50%, and prolonged
 follow-up studies, a probability of disease-free survival (DFS ) of 30-50%, significantly
 higher than historical controls with the same chemotherapy without imatinib. This led to the
 approval of imatinib by the rating agencies in the U.S., Europe and Japan as a treatment for
 Ph + in combination with chemotherapy.

 Of the studies that led to the approval of this indication for imatinib, and other incurred
 after, the following conclusions can be drawn:

 There is no specific pattern of combination of imatinib (at doses of 600 mg / day, po) and
 chemotherapy. However, when compared with concomitant alternating with the first achieved a
 higher rate of RM at the end of induction, although this did not influence DFS.

 In studies in elderly patients has achieved a high CR rate (almost 100% in all series), only
 imatinib and glucocorticoids, suggesting that an attenuated induction may be sufficient to
 achieve CR in young patients with minimal toxicity, which further compromises the
 administration of treatment and allow for an allogeneic HSCT with minimal toxic load
 possible.

 Although there is no consensus on the indication of allogeneic HSCT in first CR when given
 imatinib associated with intensive chemotherapy is an option that is done in most studies.

 The allogeneic HSCT is most effective when carried out in complete molecular response to or
 greater than when there is more residual disease. However, the impact of MRI to obtain early
 (after induction) on survival is not clear. So far-reaching goal is to make the TPH in
 complete molecular response situation or greater.

 The relapse of the disease at the molecular level is still short-term (less than 3 months) of
 hematological relapse. This implies the need for frequent monitoring of residual disease (ER)
 The frequency of relapse post HSCT is high (around 30%), raising the need for any post HSCT
 treatment, including imatinib included. Are currently ongoing clinical trials comparing the
 systematic administration of imatinib after administration TPH face is detected only when ER.

 The applicability of the administration of imatinib after HSCT is limited by toxicity related
 to the procedure of TPH, is making frequent dose reduction or discontinuation.

 Therefore, a reasonable approximation treatment of Ph + outside the context of a clinical
 trial is to get as many molecular responses before allogeneic HSCT in a position to make the
 same MRI complete or greater. After TPH, must be very close monitoring of the ER, and
 imatinib is administered as soon as you notice the loss of molecular response.

 In patients who can not make an allogeneic HSCT for lack of histocompatible donor or
 contraindications for its realization it is recommended imatinib and chemotherapy, although
 there are studies that have undergone an autologous HSCT, followed or not treatment
 "maintenance" with imatinib. The low toxicity of autologous HSCT and no effect of graft
 versus leukemia are strongly recommended the administration of maintenance therapy with
 imatinib combined with chemotherapy or not.
Induction Chemotherapy

 -  Vincristine (VCR): 1.5 mg/m2 (maximum dose 2 mg) iv days 1, 8, 15 and 22

 -  daunorubicin (DNR) 45 mg/m2 i.v. days 1, 8, 15 and 22

 -  Prednisone (PDN): 60 mg/m2 per day, i.v. or p.o., days 1-27

 -  Imatinib 600 mg p.o. from day 1 until the beginning of the consolidation. Important
 Note: The administration of imatinib be initiated as soon as the outcome of cytogenetic
 and molecular study, which will be known under normal conditions during prophase
 consolidation

 Patients should be in RC and shall be a minimum of 2 weeks of finding it. Patients did not
 discontinue treatment with imatinib during this period. Minimum counts to start the
 consolidation are: neutrophils> 1x109 / L and platelets> 100x109 / L.

 -  Mercaptopurine (MP) 50 mg/m2, p.o. days 1 to 7, 28 to 35 and 56 to 63

 -  MTX: 1.5 g/m2, i.v. continuous infusion for 24 hours on days 1, 28 and 56.

 -  VP-16: 100 mg/m2 every 12 hours, i.v. (1 hour infusion) on days 14 and 42

 -  ARA-C: 1000 mg/m2 every 12 hours, i.v. (3-hour infusion) days 14-15 and 42-43

 -  triple intrathecal treatment days 1, 28 and 56

 -  Imatinib 600 mg / d po, from day 1 to 15 days before the TPH.

 During consolidation therapy is recommended in primary prophylaxis with G-CSF or found
 neutropenia (<0.5 x109 / L). This factor was administered daily until the neutrophil count is
 > 1x109 / L in two consecutive measurements. Alternatively, PEG-filgrastim can be used (eg 16
 and 44), at the discretion of each center

 Allogenic THP or Autologous TPH
Inclusion Criteria:

 -  Patients with Ph (BCR/ABL) positive de novo < 55 years old (it is advisable to include
 patients over 55 years LAL07OPH protocol).

 -  Performance status 0-2 (Appendix B) may include patients with performance status > 2
 attributable to LAL.

 -  Patients without functional impairment of organs: liver function: total bilirubin,
 AST, ALT, alfa-GT and alkaline phosphatase less than 3 times the upper limit of normal
 laboratory renal function: serum creatinine < 2 mg/dL or clearance creatinine > 30
 ml/min (except renal function attributable to LAL) cardiac function (Appendix B)
 normal: ventricular EF > 50%, absence of severe chronic respiratory disease. In the
 event that alterations are secondary to the disease is at the discretion of the
 investigator to determine if the patient can be included in the trial.

 Exclusion Criteria:

 -  Any other variety of LAL

 -  Patients with a history of coronary artery disease, valvular or hypertensive heart
 disease

 -  Patients with chronic liver disease

 -  Patients with chronic respiratory failure

 -  Renal failure not due to LAL

 -  Patients with positive HIV status

 -  No serious neurological abnormalities due to LAL

 -  Impact on overall severe (grade 3 or 4 of the WHO scale) not attributable to the LAL

 -  Pregnant or breastfeeding

 -  initial blast crisis CML