Treatment of Relapsed Promyelocytic Leukemia With Arsenic Trioxide (ATO)
- Conditions
- Acute Promyelocytic Leukemia
- Registration Number
- NCT00504764
- Lead Sponsor
- PETHEMA Foundation
- Brief Summary
Summary Acute promyelocytic leukemia is defined by a characteristic morphology (AML FAB M3/M3v), by the specific translocation t(15;17) and its molecular correlates (PML/RARa and RARa/PML). Thereby it can be separated from all other forms of acute leukemia.
By all-trans retinoic acid in combination with chemotherapy cure rates of 70 to 80% can be reached. On average, about 10% of patients still die in the early phase of the treatment and about 20 to 30% relapse. Molecular monitoring of the minimal residual disease (MRD) by qualitative nested RT-PCR and quantitative REAL-time PCR of PML/RARa allows to follow the individual kinetics of MRD and to identify patients with an imminent hematological relapse.
A standardized treatment for patients with relapsed APL has not yet been established. With arsenic trioxide (ATO) monotherapy remission rates over 80% were achieved and long-lasting molecular remissions are described. The drug was mostly well tolerated. ATO exerts a dose dependent dual effect on APL blasts, apoptosis in higher and partial differentiation in lower concentrations. ATO was also successfully administered before allogeneic and autologous transplantation. ATO is approved for the treatment of relapsed and refractory APL in Europe and in the USA.
After remission induction, there are several options for postremission therapy Previous studies shows that risk of relapse is higher in patients treated with ATO postremission in monotherapy , than in other that receive ATO plus chemotherapy or transplantation (TPH). Also, compared with chemotherapy, ATO induction and consolidation has a favorable impact in posterior response to transplantation. It is due to a low toxicity or a best quality of remission to TPH. It seems better, for these reasons, the intensification with TPH (autologous or allogenic) in patients with relapsed APL treated with ATO. For another hand, patients no candidates to TPH can be treated with ATO combined with other active agents in APL, as ATRA, anthracyclines o Mylotarg
- Detailed Description
Induction ATO 0.15 mg/kg/día IV in continuous perfusion 1-2 hours/day until complete response (CR) or maximum of 60 days.
Oral hydroxyurea treatment (initial dose 2 g/day)is recommended in patients with leucocyte counts at relapse \>10x109/L or in the two first weeks of induction.
Isolated molecular relapsed patients will be treated with ATO (same dose) 5 days at week, during 6 weeks.
Consolidation ATO 0.15 mg/kg/día IV 5 days at week, during 5 weeks, combined with oral ATRA 45 mg/m²/day during the same 5 weeks.
Post-consolidation therapy TPH (autologous or allogenic) in candidate patients. In case of molecular remission, is recommended autologous-TPH.
Patients no candidates to auto-TPH or alo-TPH, should will follow treatment with ATO cycles + ATRA +/- Mylotarg.
1. Option Alo-TPH If PCR post-consolidation is negative is recommended auto-TPH. However, if alo-TPH is decided, it will be done immediately without preceding chemotherapy.
If PCR post-consolidation is positive, should done alo-TPH.
2. Option Auto-TPH If PCR post-consolidation is negative it will be administered one cycle of MTZ + Ara-C follow by auto-TPH.
In cas of failure: a) if patient has autologous stem cells preserved (PCR negative) are suitable for auto-TPH; b) patients with HLA-compatible donor who are suitable for allogenic stem cell transplantation should be transplanted; c) Patients who are not eligible for allogenic or autologous transplantation, receive various cycles with ATO + ATRA combined or not with Mylotarg.
If PCR post-consolidation is positive and patient is eligible for allogenic TPH, should be done a allogenic TPH.
If patient is no eligible for allogenic TPH or dont has compatible donor, will be administrate one cycle of MTZ + Ara-C and collect stem cells. Autologous transplantation will be done if after this cycle, a molecular remission is obtained. No molecular remission or no enough stem cells collection, patient follows treatment with subsequent cycles of ATO + ATRA combined or no with Mylotarg.
3. ATO + ATRA combined or no with Mylotarg Patients no eligible to autologous TPH or allogenic TPH follows treatment with subsequent cycles of ATO + ATRA combined or no with Mylotarg.
If Mylotarg is no possible, treatment will be with subsequent cycles of ATO + ATRA.
ATO + ATRA + Mylotarg: Mylotarg 6 mg/m2 day 1, ATO 0.15 mg/kg days 1 to 5 and 8 to 12, and ATRA 45 mg/m2/d days 1 to 15. Doses of mylotarg should be reduced to 3 mg/m2 in patients aged over 60 years. Administration of 3 cycles with a month interval, follow of 3 to 6 cycles of ATO + ATRA without Mylotarg. After, ATRA 45 mg/m2/d 15 days every 3 months until complete two years of maintenance.
ATO + ATRA: ATO 0.15 mg/kg days 1 to 5 and 8 to 12, and ATRA 45 mg/m2/d days 1 to 15, every 29 days. Administration of 9 cycles, and followed by ATRA 45 mg/m2/d during 15 days every 3 months until complete two years of maintenance.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 60
- ECOG ≤ 3.
- Patients in first or subsequent hematological or molecular relapse of APL
- Persistence of a positive PCR (positive PCR after 3 consolidation cycles of first line therapy).
- Diagnostic measures Confirmation of relapse by RT-PCR of PML/RARa, cytogenetics, FISH or positive PGM3.
- Age over 18 years (No upper age limit)
- Informed consent of the patient
- ECOG 4.
- Heart failure NYHA grade III and IV.
- Renal or hepatic failure WHO grade ³III
- Positive HIV.
- Psychological dysfunction
- Associated active neoplasia
- Pregnancy.
- Arsenic Hypersensibility.
- QTc-interval prolonged over 460 msec before therapy (normal electrolytes, no other drugs prolonging the QT-interval )
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Primary Outcome Measures
Name Time Method Evaluate the hematological and molecular remission rate after induction and consolidation with ATO 1 year Evaluate the induction mortality with ATO in monotherapy 1 year Evaluate the hematological and molecular relapse rate in patients treated with autologous transplantation, allogenic transplantation or ATO + ATRA +/- Mylotarg 1 year
- Secondary Outcome Measures
Name Time Method Overall survival 2 years Evaluate kinetics of the MDR of PML/RARa during and after ATO 2 years Side effects of ATO and the different treatments post-consolidation 2 years Evaluate the mortality related with postremission treatment 1 year
Trial Locations
- Locations (85)
Hospital Central de Asturias
🇪🇸Oviedo, Asturias, Spain
Hospital de Mataró
🇪🇸Mataró, Barcelona, Spain
Hospital Germans Trias i Pujol
🇪🇸Badalona, Barcelona, Spain
Fundación Hospital Alcorcón
🇪🇸Alcorcón, Spain
Complejo Hospitalario Universitario de Santiago
🇪🇸Santiago de Compostela, La Coruña, Spain
Clínica Universitaria de Navarra
🇪🇸Pamplona, Navarra, Spain
Complejo Hospitalario Universitario de Albacete
🇪🇸Albacete, Spain
Hospital general de Castellón
🇪🇸Castello, Castellón, Spain
Hospital General de Alicante
🇪🇸Alicante, Spain
Hospital de Alcorcón
🇪🇸Alcorcón, Madrid, Spain
Hospital Verge de la Cinta
🇪🇸Tortosa, Tarragona, Spain
Hospital de la Ribera
🇪🇸Alzira, Spain
Hospital Ntra. Sra. Sonsoles
🇪🇸Avila, Spain
Hospital Clinic
🇪🇸Barcelona, Spain
Hospital de la Santa Creu i Sant Pau
🇪🇸Barcelona, Spain
Hospital del Mar
🇪🇸Barcelona, Spain
Hospital Valle Hebrón
🇪🇸Barcelona, Spain
Basurtuko Ospitalea
🇪🇸Basurto, Spain
Hospital de Cruces
🇪🇸Bilbao, Spain
Complejo Hospitalario Reina Sofía
🇪🇸Córdoba, Spain
Complejo Hospitalario de Cáceres
🇪🇸Cáceres, Spain
Hospital Donostia
🇪🇸Donostia, Spain
Hospital Puerta del Mar
🇪🇸Cádiz, Spain
Hospital General de Elda
🇪🇸Elda, Spain
Hospital de Fuenlabrada
🇪🇸Fuenlabrada, Spain
Hospital General de Guadalajara
🇪🇸Guadalajara, Spain
Hospital Virgen de las Nieves
🇪🇸Granada, Spain
Area Hospitalaria Juan Ramón Jimenez
🇪🇸Huelva, Spain
Hospital de San Jorge
🇪🇸Huesca, Spain
Hospital Médico Quirúrgico Ciudad de Jaén
🇪🇸Jaen, Spain
Hospital General de Lanzarote
🇪🇸Lanzarote, Spain
Hospital Juan Canalejo
🇪🇸La Coruña, Spain
Hospital de Jerez de la Frontera
🇪🇸Jerez de la Frontera, Spain
Complejo Hospitalario León
🇪🇸Leon, Spain
Complexo Hospitalario Xeral-Calde
🇪🇸Lugo, Spain
Clínica La Concepción
🇪🇸Madrid, Spain
Hospital Arnau de Vilanova
🇪🇸Lleida, Spain
Clínica Moncloa
🇪🇸Madrid, Spain
Clínica Puerta de Hierro
🇪🇸Madrid, Spain
Clínica Rúber
🇪🇸Madrid, Spain
Fundación Jiménez Díaz
🇪🇸Madrid, Spain
Hospital Central de la Defensa
🇪🇸Madrid, Spain
Hospital 12 de Octubre
🇪🇸Madrid, Spain
Hospital Clínico San Carlos de Madrid
🇪🇸Madrid, Spain
Hospital de la Princesa
🇪🇸Madrid, Spain
Hospital Doce de Octubre
🇪🇸Madrid, Spain
Hospital General Universitario Gregorio Marañón, Madrid
🇪🇸Madrid, Spain
Hospital la Paz
🇪🇸Madrid, Spain
Fundación Hospital Sant Joan de Déu de Martorell
🇪🇸Martorell, Spain
Althaia, Xarxa Asistencial de Manresa
🇪🇸Manresa, Spain
Hospital General Morales Meseguer
🇪🇸Murcia, Spain
. Hospital Clínico Universitario Virgen de la Victoria
🇪🇸Málaga, Spain
Hospital de Mérida
🇪🇸Mérida, Spain
Hospital Son Dureta
🇪🇸Palma de Mallorca, Spain
Hospital de Móstoles
🇪🇸Móstoles, Spain
Hospital de Gran Canaria Doctor Negrín
🇪🇸Palma de Gran Canaria, Spain
Hospital del Río Carrión
🇪🇸Palencia, Spain
Hospital Son Llàtzer
🇪🇸Palma de Mallorca, Spain
Complejo Hospitalario de Pontevedra_Hospital Montecelo
🇪🇸Pontevedra, Spain
Hospital Verge del Toro
🇪🇸Palma de Mallorca, Spain
Complejo Hospitalario de Pontevedra_Hospital Provincial
🇪🇸Pontevedra, Spain
Corporació Sanitaria Parc Taulí
🇪🇸Sabadell, Spain
Hospital de Sagunto
🇪🇸Sagunto, Spain
Hospital Clínico de Salamanca
🇪🇸Salamanca, Spain
Hospital Universitario Marqués de Valdecilla
🇪🇸Santander, Spain
Hospital General de Segovia
🇪🇸Segovia, Spain
Clínica Sant Camil
🇪🇸Sant Pere de Ribes, Spain
H.U. Virgen del Rocio
🇪🇸Sevilla, Spain
Hospital Universitario de Canarias
🇪🇸Tenerife, Spain
Hospital Joan XXIII
🇪🇸Tarragona, Spain
Hospital Clínic
🇪🇸Valencia, Spain
Hospital Nuestra Señora del Prado
🇪🇸Toledo, Spain
Fundación Instituto Valenciano de Oncología
🇪🇸Valencia, Spain
Hospital Dr. Peset
🇪🇸Valencia, Spain
Hospital Francesc de Borja
🇪🇸Valencia, Spain
Hospital General Universitario
🇪🇸Valencia, Spain
Hospital La Fe
🇪🇸Valencia, Spain
Hospital Clínico de Valladolid
🇪🇸Valladolid, Spain
Complejo Hospitalario Xeral-Cies
🇪🇸Vigo, Spain
Hospital Comarcal Pius de Valls
🇪🇸Valls, Spain
Comarcal de Vinaros
🇪🇸Vinaros, Spain
Hospital Txagorritxu
🇪🇸Vitoria, Spain
Hospital Clínico Lozano Blesa
🇪🇸Zaragoza, Spain
Hospital Miguel Servet
🇪🇸Zaragoza, Spain
Hospital de Galdakao
🇪🇸Vizcaya, Spain