Clinical trial NCT01491763: Chemotherapy and Imatinib in Young Adults With Acute Lymphoblastic Leukemia Ph (BCR-ABL) POSITIVE
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE4
Conditions: Acute Lymphoblastic Leukemia Ph Positive
Lead sponsor: PETHEMA Foundation
Sponsor class: OTHER
First posted: 2011-12-14
Enrollment: 70
Sex: ALL
Maximum age (years): 55
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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

Eligibility criteria: 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

Primary outcomes:
measure: Efficacy in terms of number of complete response
timeFrame: 1 year
Secondary outcomes:
Other outcomes:
Locations:
city: Oviedo
country: Spain
facility: Hospital Central de Asturias
state: Asturias
city: Palma de Mallorca
country: Spain
facility: H. Son Llatzer
state: Baleares
city: Badalona
country: Spain
facility: Hospital Germans Trias i Pujol and all Hospital Pethema
state: Barcelona
city: Mataró
country: Spain
facility: Hospital de Mataró
state: Barcelona
city: Tenerife
country: Spain
facility: Hospital Universitario de Canarias
state: Canarias
city: Castello
country: Spain
facility: Hospital general de Castellón
state: Castellón
city: Santiago de Compostela
country: Spain
facility: Complejo Hospitalario Universitario de Santiago
state: La Coruña
city: Pamplona
country: Spain
facility: Clínica Universitaria de Navarra
state: Navarra
city: Pamplona
country: Spain
facility: Hospital de Navarra
state: Navarra
city: Albacete
country: Spain
facility: Hospital General de Albacete
city: Alcorcón
country: Spain
facility: Hospital de Alcorcón
city: Alicante
country: Spain
facility: Hospital General de Alicante.
city: Asturias
country: Spain
facility: Hospital de Cabueñes
city: Badalona
country: Spain
facility: Hospital de Badalona Germans Trias i Pujol
city: Barcelona
country: Spain
facility: Hospital Clinic y Provincial de Barcelona
city: Barcelona
country: Spain
facility: Hospital Clínico y Provincial de Barcelona
city: Barcelona
country: Spain
facility: Hospital de la Santa Creu i Sant Pau.
city: Barcelona
country: Spain
facility: Hospital de la Santa Creu i Sant Pau.
city: Barcelona
country: Spain
facility: Hospital de la Santa Creu i Sant Pau
city: Barcelona
country: Spain
facility: Hospital de la santa Creu i Sant Pau
city: Barcelona
country: Spain
facility: Hospital del Mar
city: Barcelona
country: Spain
facility: Hospital del Mar
city: Barcelona
country: Spain
facility: Hospital del Mar
city: Barcelona
country: Spain
facility: Hospital Duran i Reynals - ICO L'Hospitalet
city: Basurto
country: Spain
facility: Basurtuko Ospitalea
city: Cáceres
country: Spain
facility: Complejo Hospitalario de Cáceres
city: Córdoba
country: Spain
facility: Complejo Hospitalario Reina Sofía
city: Huelva
country: Spain
facility: Area Hospitalaria Juan Ramón Jimenez
city: Huelva
country: Spain
facility: Hospital Juan Ramón Jiménez
city: Jerez de la Frontera
country: Spain
facility: Hospital del SAS de Jerez de la Frontera
city: Jerez de la Frontera
country: Spain
facility: Hospital general de Jerez de la Frontera
city: Lleida
country: Spain
facility: Hospital Arnau de Vilanova
city: Lugo
country: Spain
facility: Complexo Hospitalario Xeral-Calde
city: Madrid
country: Spain
facility: Clínica La Concepción
city: Madrid
country: Spain
facility: Clínica Puerta de Hierro
city: Madrid
country: Spain
facility: Hospital 12 de Octubre. Madrid
city: Madrid
country: Spain
facility: Hospital Clinico San Carlos
city: Madrid
country: Spain
facility: Hospital Clínico San Carlos de Madrid
city: Madrid
country: Spain
facility: Hospital Clínico San Carlos de Madrid
city: Madrid
country: Spain
facility: Hospital de Fuenlabrada
city: Madrid
country: Spain
facility: Hospital de la Princesa
city: Madrid
country: Spain
facility: Hospital de Madrid, S.A.- Norte Hospital General
city: Madrid
country: Spain
facility: Hospital Gregorio Marañón
city: Madrid
country: Spain
facility: Hospital Ramón y Cajal
city: Madrid
country: Spain
facility: Hospital Universitario de la Princesa
city: Madrid
country: Spain
facility: Hospital Universitario Princcipe de Asturias
city: Manresa
country: Spain
facility: Althaia, Xarxa Asistencial de Manresa
city: Murcia
country: Spain
facility: Hospital General Univeristario Morales Messeguer
city: Murcia
country: Spain
facility: Hospital Sta. Maria del Rosell
city: Málaga
country: Spain
facility: . Hospital Clínico Universitario Virgen de la Victoria
city: Málaga
country: Spain
facility: . Hospital Clínico Universitario Virgen de la Victoria
city: Málaga
country: Spain
facility: Hospital Carlos Haya
city: Málaga
country: Spain
facility: Hospital Carlos Haya
city: Málaga
country: Spain
facility: Hospital Carlos Haya
city: Mérida
country: Spain
facility: Hospital de Mérida
city: Palencia
country: Spain
facility: Hospital del Río Carrión
city: Palma De Gran Canaria
country: Spain
facility: Hospital de Gran Canaria Doctor Negrín
city: Pamplona
country: Spain
facility: Clínica Universitaria de Navarra
city: Pontevedra
country: Spain
facility: Hospital de Montecelo
city: Sabadell
country: Spain
facility: Corporació Sanitaria Parc Taulí
city: Salamanca
country: Spain
facility: Hospital Clínico de Salamanca
city: Salamanca
country: Spain
facility: Hospital Clínico Universitario de Salamanca
city: Salamanca
country: Spain
facility: Hospital Clínico Universitario
city: San Sebastián
country: Spain
facility: Hospital de Donostia
city: Santander
country: Spain
facility: Hoaspital Marqués de Valdecilla
city: Segovia
country: Spain
facility: Hospital General de Segovia
city: Sevilla
country: Spain
facility: Complejo Hospitalario Regional Virgen del Rocío
city: Tarragona
country: Spain
facility: Hospital Joan XIII de
city: Tarragona
country: Spain
facility: Hospital Joan XXIII
city: Valencia
country: Spain
facility: Hospital Clínico de Valencia.
city: Valencia
country: Spain
facility: Hospital Clínico Universitario de Valencia
city: Valencia
country: Spain
facility: Hospital Clínico Universitario
city: Valencia
country: Spain
facility: Hospital Clínic
city: Valencia
country: Spain
facility: Hospital Dr Pesset
city: Valencia
country: Spain
facility: Hospital La Fe
city: Valencia
country: Spain
facility: Hospital Universitario Dr. Peset
city: Valladolid
country: Spain
facility: Hospital Clínico de Valladolid
city: Vigo
country: Spain
facility: Complejo Hospitalario Xeral-Cies
city: Vigo
country: Spain
facility: Hospital do Meixoeiro
city: Vitoria
country: Spain
facility: Hospital Txagorritxu
city: Zaragoza
country: Spain
facility: Hospital Clínico Lozano Blesa
Study officials:
References:
citation: Ribera JM, Garcia O, Moreno MJ, Barba P, Garcia-Cadenas I, Mercadal S, Montesinos P, Barrios M, Gonzalez-Campos J, Martinez-Carballeira D, Gil C, Ribera J, Vives S, Novo A, Cervera M, Serrano J, Lavilla E, Abella E, Tormo M, Amigo ML, Artola MT, Genesca E, Bravo P, Garcia-Belmonte D, Garcia-Guinon A, Hernandez-Rivas JM, Feliu E; PETHEMA Group of the Spanish Society of Hematology. Incidence and outcome after first molecular versus overt recurrence in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia included in the ALL Ph08 trial from the Spanish PETHEMA Group. Cancer. 2019 Aug 15;125(16):2810-2817. doi: 10.1002/cncr.32156. Epub 2019 Apr 23.