Chemotherapy and Imatinib in Young Adults With Acute Lymphoblastic Leukemia Ph (BCR-ABL) POSITIVE
- Conditions
- Acute Lymphoblastic Leukemia Ph Positive
- Registration Number
- NCT01491763
- Lead Sponsor
- PETHEMA Foundation
- Brief Summary
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.
- Detailed Description
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
Recruitment & Eligibility
- Status
- UNKNOWN
- Sex
- All
- Target Recruitment
- 70
- 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.
- 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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Primary Outcome Measures
Name Time Method Efficacy in terms of number of complete response 1 year
- Secondary Outcome Measures
Name Time Method
Trial Locations
- Locations (72)
Hospital general de Castellón
🇪🇸Castello, Castellón, Spain
Hospital Germans Trias i Pujol and all Hospital Pethema
🇪🇸Badalona, Barcelona, Spain
Hospital Central de Asturias
🇪🇸Oviedo, Asturias, Spain
H. Son Llatzer
🇪🇸Palma de Mallorca, Baleares, Spain
Clínica La Concepción
🇪🇸Madrid, Spain
Basurtuko Ospitalea
🇪🇸Basurto, Spain
Hospital Clinico San Carlos
🇪🇸Madrid, Spain
Althaia, Xarxa Asistencial de Manresa
🇪🇸Manresa, Spain
Hospital Universitario Princcipe de Asturias
🇪🇸Madrid, Spain
Hospital Arnau de Vilanova
🇪🇸Lleida, Spain
Hospital Clínico San Carlos de Madrid
🇪🇸Madrid, Spain
Hospital Universitario de la Princesa
🇪🇸Madrid, Spain
Hospital Sta. Maria del Rosell
🇪🇸Murcia, Spain
Hospital Carlos Haya
🇪🇸Málaga, Spain
Hospital General de Segovia
🇪🇸Segovia, Spain
Corporació Sanitaria Parc Taulí
🇪🇸Sabadell, Spain
Hospital General Univeristario Morales Messeguer
🇪🇸Murcia, Spain
Hospital de Donostia
🇪🇸San Sebastián, Spain
Hospital Dr Pesset
🇪🇸Valencia, Spain
Hospital do Meixoeiro
🇪🇸Vigo, Spain
Hospital Clínico de Valladolid
🇪🇸Valladolid, Spain
Hospital General de Alicante.
🇪🇸Alicante, Spain
Hospital de Mataró
🇪🇸Mataró, Barcelona, Spain
Hospital de Cabueñes
🇪🇸Asturias, Spain
Hospital Juan Ramón Jiménez
🇪🇸Huelva, Spain
Hospital Clinic y Provincial de Barcelona
🇪🇸Barcelona, Spain
Hospital de la Princesa
🇪🇸Madrid, Spain
Hospital Gregorio Marañón
🇪🇸Madrid, Spain
Hospital del SAS de Jerez de la Frontera
🇪🇸Jerez de la Frontera, Spain
Hospital Ramón y Cajal
🇪🇸Madrid, Spain
Hospital general de Jerez de la Frontera
🇪🇸Jerez de la Frontera, Spain
Hospital de Mérida
🇪🇸Mérida, Spain
Hospital del Río Carrión
🇪🇸Palencia, Spain
Hospital de Gran Canaria Doctor Negrín
🇪🇸Palma De Gran Canaria, Spain
Hospital Joan XIII de
🇪🇸Tarragona, Spain
Hospital Joan XXIII
🇪🇸Tarragona, Spain
Hoaspital Marqués de Valdecilla
🇪🇸Santander, Spain
Complejo Hospitalario Regional Virgen del Rocío
🇪🇸Sevilla, Spain
Complejo Hospitalario Universitario de Santiago
🇪🇸Santiago de Compostela, La Coruña, Spain
Clínica Universitaria de Navarra
🇪🇸Pamplona, Spain
Hospital General de Albacete
🇪🇸Albacete, Spain
Hospital de Badalona Germans Trias i Pujol
🇪🇸Badalona, Spain
Hospital de Alcorcón
🇪🇸Alcorcón, Spain
Hospital Clínico y Provincial de Barcelona
🇪🇸Barcelona, Spain
Hospital de la Santa Creu i Sant Pau.
🇪🇸Barcelona, Spain
Hospital de la santa Creu i Sant Pau
🇪🇸Barcelona, Spain
Hospital de la Santa Creu i Sant Pau
🇪🇸Barcelona, Spain
Hospital del Mar
🇪🇸Barcelona, Spain
Hospital Duran i Reynals - ICO L'Hospitalet
🇪🇸Barcelona, Spain
Complejo Hospitalario Reina Sofía
🇪🇸Córdoba, Spain
Area Hospitalaria Juan Ramón Jimenez
🇪🇸Huelva, Spain
Complejo Hospitalario de Cáceres
🇪🇸Cáceres, Spain
Complexo Hospitalario Xeral-Calde
🇪🇸Lugo, Spain
Clínica Puerta de Hierro
🇪🇸Madrid, Spain
Hospital 12 de Octubre. Madrid
🇪🇸Madrid, Spain
Hospital de Fuenlabrada
🇪🇸Madrid, Spain
Hospital de Madrid, S.A.- Norte Hospital General
🇪🇸Madrid, Spain
Hospital Clínico Universitario
🇪🇸Valencia, Spain
Hospital Clínico de Salamanca
🇪🇸Salamanca, Spain
. Hospital Clínico Universitario Virgen de la Victoria
🇪🇸Málaga, Spain
Hospital Clínic
🇪🇸Valencia, Spain
Hospital Clínico Universitario de Salamanca
🇪🇸Salamanca, Spain
Hospital Clínico de Valencia.
🇪🇸Valencia, Spain
Complejo Hospitalario Xeral-Cies
🇪🇸Vigo, Spain
Hospital Txagorritxu
🇪🇸Vitoria, Spain
Hospital La Fe
🇪🇸Valencia, Spain
Hospital Clínico Universitario de Valencia
🇪🇸Valencia, Spain
Hospital de Montecelo
🇪🇸Pontevedra, Spain
Hospital Universitario Dr. Peset
🇪🇸Valencia, Spain
Hospital Clínico Lozano Blesa
🇪🇸Zaragoza, Spain
Hospital Universitario de Canarias
🇪🇸Tenerife, Canarias, Spain
Hospital de Navarra
🇪🇸Pamplona, Navarra, Spain