Treatment of Newly Diagnosed Patients With Acute Promyelocytic Leukemia (PETHEMA LPA 2005)

Acute Promyelocytic Leukemia Clinical Trial

Official title:

Treatment of Newly Diagnosed Patients With Acute Promyelocytic Leukemia (PETHEMA LPA 2005): Remission Induction With ATRA + Idarubicin. Risk-adapted Consolidation With ATRA and Anthracycline-based Chemotherapy (Idarubicin/Mitoxantrone) With Addition of Ara-C for High-risk Patients. Maintenance Therapy With ATRA + Low Dose Chemotherapy (Methotrexate + Mercaptopurine).

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00408278
• Other study ID #: LPA 2005
• Status: Completed
• Phase: Phase 4
• First received: December 5, 2006
• Last updated: October 27, 2014
• Start date: July 2005
• Est. completion date: December 2013

Study information

• Verified date: October 2014
• Source: PETHEMA Foundation
• Contact: n/a
• Is FDA regulated: No
• Health authority: Spain: Ministry of Health
• Study type: Interventional

Clinical Trial Summary

Primary objectives

• To evaluate the efficacy and toxicity of a risk-adapted protocol that use idarubicin for induction and consolidation therapy in patients with APL.

• To evaluate the impact of mitoxantrone reduction on the event-free, disease-free, and overall survival, as well as on the duration of remission and cumulative incidence of relapse in low- and intermediate-risk patients with APL.

• To evaluate the impact of the addition of ara-C to idarubicin courses of consolidation for high-risk patients (administered as in the original GIMEMA protocols) on the event-free, disease-free, and overall survival, as well as on the duration of remission and cumulative incidence of relapse.

• To evaluate the toxicity of the induction, consolidation, and maintenance chemotherapy in the whole series and in each treatment group in patients with APL.

Secondary objectives

• To compare all outcomes with those achieved with the PETHEMA LPA99 protocol.

Description:

Treatment of induction with the simultaneous administration of ATRA (45 mg/m2 day until the RC) and idarubicine (12 mg/m2 days 2, 4, 6 and 8), 3 monthly cycles of consolidation with ATRA (45 mg/m2 days 1-15) and idarubicine (5 mg/m2 days 1-4) in the cycle #1, mitoxantrone (10 mg/m2 days 1-3) in the cycle #2 and idarubicine (12 mg/m2 day 1) in the cycle #3. The consolidation was reinforced for the group of patients with intermediate risk by means of an increase of the idarubicine to 7 mg in the cycle #1 and to 2 days in the cycle #3. In the patients of high risk, the consolidation was reinforced with the addition of altar-c in the cycles #1 and #3. For the maintenance treatment, one will administer to intermittent ATRA (15 days every 3 months) and chemotherapy low doses with methotrexate and 6-mercaptopurina during two years

Recruitment information / eligibility

• Status: Completed
• Enrollment: 300
• Est. completion date: December 2013
• Est. primary completion date: April 2012
• Accepts healthy volunteers: No
• Gender: Both
• Age group: N/A to 75 Years

Eligibility

Inclusion Criteria:

• Age = 75 years.

• ECOG = 3.

• Morphologic Diagnosis of LPA (FAB M3 or variant M3). Those cases without typical morphology but with PML-RARa reordering also must be including.

• Genetic Diagnosis: t (15; 17) demonstrated by cariotipo conventional, FISH, PML-RARa reordering detected by RT-PCR or a pattern microspeckled demonstrated with antibody anti-PML (positive PGM3). Obvious, it will be had the result of these tests once initiated the treatment on the basis of a suspicion diagnoses morphologic

Exclusion Criteria:

• Age >75 years (the treatment with this protocol can be considered individually)

• Absence of PML-Rare reordering.

• To have received previously some type of treatment for LPA, including chemotherapy or retinoides. The previous treatment with corticoids, hidroxiurea or leucoaféresis is not reason for exclusion.

• To have received chemotherapy or x-ray for the treatment of a disease vitiates previous.

• Associate Neoplasia.

• Serious psychiatric Disease.

• Seropositividad for VIH.

• Contraindication to receive intensive chemotherapy, specially antraciclinas.

• Sérica Creatinina = 2,5 mg/dL (= 250 µmol/l).

• Bilirrubina, fosfatasa alkaline, or GOT > 3 times the normal limit

• Test of positive pregnancy.

Study Design

Allocation: Non-Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Acute Promyelocytic Leukemia
• Leukemia
• Leukemia, Promyelocytic, Acute

Intervention

Drug:
• ATRA
45 mg/m2 day until CR Consolidation: 3 cycles (45 mg/m2 days 1-15) Maintenance:15 days every 3 months
• Idarubicina
Induction: 12 mg/m2 days 2, 4, 6 and 8 Consolidation: 5 mg/m2 days 1-4 in cycle 1 and 12 mg/m2 day 1 in cycle 3.
• Mitoxantrone
Consolidation: Mitoxantrone 10 mg/m2 days 1-3 in cycle 2
• ARA-C
In high risk patients, consolidation with ara-C in cycles 1 and 3.

Locations

Country	Name	City	State
Poland	PALG	Lodz
Spain	Hospital General	Albacete
Spain	Hospital general	Alicante
Spain	Hospital germans Trias i Pujol	Badalona
Spain	Hospital Clinic	Barcelona
Spain	Hospital de Sant Pau	Barcelona
Spain	Institut Català d'Oncologái	Barcelona
Spain	Basurtuko Ospitalea	Bilbao
Spain	Hospital general	Castellon
Spain	Hospital de Fuenlabrada	Fuenlabrada
Spain	Hospital "Dr. Trueta"	Gerona
Spain	Hospital de Jerez de la Frontera	Jerez de la Frontera
Spain	Hospital Juan Canalejo	La Coruña
Spain	Hospital Insular de las Palmas	Las Palmas de Gran Canaria
Spain	Complejo Hospitalario León	Leon
Spain	Complexo Hospitalario Xeral-Calde	Lugo
Spain	Hospital 12 de Octubre	Madrid
Spain	Hospital Clínico San Carlos	Madrid
Spain	Hospital Puerta de Hierro	Madrid
Spain	Hospital Reina Sofia	Madrid
Spain	Hospital San Pedro de Alcántara	Madrid
Spain	Hospital Severo Ochoa	Madrid
Spain	H. Carlos Haya	Málaga
Spain	H. Universitario Virgen de la Victoria	Málaga
Spain	Hospital Sta. Maria del Rosell	Murcia
Spain	Hospital Central de Asturias	Oviedo
Spain	Hospital Dr Negrín	Palma de Gran Canaria
Spain	Hospital de Navarra	Pamplona
Spain	Hospital de Montecelo	Pontevedra
Spain	Hospital Clínico Universitario	Salamanca
Spain	Hospital de Cruces	Santander
Spain	Hospital de Santiago de Compostela	Santiago de Compostela
Spain	H.U. Virgen del Rocio	Sevilla
Spain	Hospital Joan XXIII	Tarragona
Spain	Hospital Dr. Peset	Valencia
Spain	Hospital general	Valencia
Spain	Hospital La Fe	Valencia
Spain	Hospital Clínico de Valladolid	Valladolid
Spain	Hospital Txagorritxu	Vitoria
Spain	Hospital Virgen de la Concha	Zamora
Spain	Hospital Clínico Universitario Lozano Blesa	Zaragoza
Uruguay	Hospital Maciel	Montevideo

Sponsors (1)

Lead Sponsor	Collaborator
PETHEMA Foundation

Countries where clinical trial is conducted

Poland,  Spain,  Uruguay, 

References & Publications (13)

Asou N, Adachi K, Tamura J, Kanamaru A, Kageyama S, Hiraoka A, Omoto E, Akiyama H, Tsubaki K, Saito K, Kuriyama K, Oh H, Kitano K, Miyawaki S, Takeyama K, Yamada O, Nishikawa K, Takahashi M, Matsuda S, Ohtake S, Suzushima H, Emi N, Ohno R. Analysis of prognostic factors in newly diagnosed acute promyelocytic leukemia treated with all-trans retinoic acid and chemotherapy. Japan Adult Leukemia Study Group. J Clin Oncol. 1998 Jan;16(1):78-85. — View Citation

Burnett AK, Grimwade D, Solomon E, Wheatley K, Goldstone AH. Presenting white blood cell count and kinetics of molecular remission predict prognosis in acute promyelocytic leukemia treated with all-trans retinoic acid: result of the Randomized MRC Trial. Blood. 1999 Jun 15;93(12):4131-43. — View Citation

Falini B, Flenghi L, Fagioli M, Lo Coco F, Cordone I, Diverio D, Pasqualucci L, Biondi A, Riganelli D, Orleth A, Liso A, Martelli MF, Pelicci PG, Pileri S. Immunocytochemical diagnosis of acute promyelocytic leukemia (M3) with the monoclonal antibody PG-M3 (anti-PML). Blood. 1997 Nov 15;90(10):4046-53. — View Citation

Fenaux P, Chastang C, Chevret S, Sanz M, Dombret H, Archimbaud E, Fey M, Rayon C, Huguet F, Sotto JJ, Gardin C, Makhoul PC, Travade P, Solary E, Fegueux N, Bordessoule D, Miguel JS, Link H, Desablens B, Stamatoullas A, Deconinck E, Maloisel F, Castaigne S, Preudhomme C, Degos L. A randomized comparison of all transretinoic acid (ATRA) followed by chemotherapy and ATRA plus chemotherapy and the role of maintenance therapy in newly diagnosed acute promyelocytic leukemia. The European APL Group. Blood. 1999 Aug 15;94(4):1192-200. — View Citation

Gomis F, Sanz J, Sempere A, Plumé G, Senent ML, Pérez ML, Cervera J, Moscardó F, Bolufer P, Barragán E, Martín G, Sanz MA. Immunofluorescent analysis with the anti-PML monoclonal antibody PG-M3 for rapid and accurate genetic diagnosis of acute promyelocytic leukemia. Ann Hematol. 2004 Nov;83(11):687-90. Epub 2004 Jul 24. — View Citation

Grimwade D, Gorman P, Duprez E, Howe K, Langabeer S, Oliver F, Walker H, Culligan D, Waters J, Pomfret M, Goldstone A, Burnett A, Freemont P, Sheer D, Solomon E. Characterization of cryptic rearrangements and variant translocations in acute promyelocytic leukemia. Blood. 1997 Dec 15;90(12):4876-85. — View Citation

Lengfelder E, Reichert A, Schoch C, Haase D, Haferlach T, Löffler H, Staib P, Heyll A, Seifarth W, Saussele S, Fonatsch C, Gassmann W, Ludwig WD, Hochhaus A, Beelen D, Aul C, Sauerland MC, Heinecke A, Hehlmann R, Wörmann B, Hiddemann W, Büchner T. Double induction strategy including high dose cytarabine in combination with all-trans retinoic acid: effects in patients with newly diagnosed acute promyelocytic leukemia. German AML Cooperative Group. Leukemia. 2000 Aug;14(8):1362-70. — View Citation

Ohno R, Asou N, Ohnishi K. Treatment of acute promyelocytic leukemia: strategy toward further increase of cure rate. Leukemia. 2003 Aug;17(8):1454-63. Review. — View Citation

Sanz MA, Lo Coco F, Martín G, Avvisati G, Rayón C, Barbui T, Díaz-Mediavilla J, Fioritoni G, González JD, Liso V, Esteve J, Ferrara F, Bolufer P, Bernasconi C, Gonzalez M, Rodeghiero F, Colomer D, Petti MC, Ribera JM, Mandelli F. Definition of relapse risk and role of nonanthracycline drugs for consolidation in patients with acute promyelocytic leukemia: a joint study of the PETHEMA and GIMEMA cooperative groups. Blood. 2000 Aug 15;96(4):1247-53. — View Citation

Sanz MA, Martín G, González M, León A, Rayón C, Rivas C, Colomer D, Amutio E, Capote FJ, Milone GA, De La Serna J, Román J, Barragán E, Bergua J, Escoda L, Parody R, Negri S, Calasanz MJ, Bolufer P; Programa de Estudio y Traitmiento de las Hemopatías Malignas. Risk-adapted treatment of acute promyelocytic leukemia with all-trans-retinoic acid and anthracycline monochemotherapy: a multicenter study by the PETHEMA group. Blood. 2004 Feb 15;103(4):1237-43. Epub 2003 Oct 23. — View Citation

Sanz MA, Martín G, Lo Coco F. Choice of chemotherapy in induction, consolidation and maintenance in acute promyelocytic leukaemia. Best Pract Res Clin Haematol. 2003 Sep;16(3):433-51. Review. — View Citation

Tallman MS, Nabhan C, Feusner JH, Rowe JM. Acute promyelocytic leukemia: evolving therapeutic strategies. Blood. 2002 Feb 1;99(3):759-67. Review. — View Citation

van Dongen JJ, Macintyre EA, Gabert JA, Delabesse E, Rossi V, Saglio G, Gottardi E, Rambaldi A, Dotti G, Griesinger F, Parreira A, Gameiro P, Diáz MG, Malec M, Langerak AW, San Miguel JF, Biondi A. Standardized RT-PCR analysis of fusion gene transcripts from chromosome aberrations in acute leukemia for detection of minimal residual disease. Report of the BIOMED-1 Concerted Action: investigation of minimal residual disease in acute leukemia. Leukemia. 1999 Dec;13(12):1901-28. Review. — View Citation

* Note: There are 13 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	To evaluate the efficacy and toxicity of a risk-adapted protocol that use idarubicin for induction and consolidation therapy in patients with APL.		1 year	Yes
Primary	To evaluate the impact of mitoxantrone reduction on the event-free, disease-free, and overall survival.		1 year	No
Primary	To evaluate the impact of the addition of ara-C to idarubicin courses of consolidation for high-risk patients on the event-free, disease-free, and overall survival		1 year	No
Primary	To evaluate the toxicity of the induction, consolidation, and maintenance chemotherapy in the whole series and in each treatment group in patients with APL.		1 year	Yes
Secondary	To compare all outcomes with those achieved with the PETHEMA LPA99 protocol.		2 years	No

External Links

•   Hovon Data Center
•   Pethema Foundation web
•   Spanish association of Haematology