Treatment of Relapsed Promyelocytic Leukemia With Arsenic Trioxide (ATO)

Sponsor

PETHEMA Foundation (Other)

Overall Status

Completed

CT.gov ID

NCT00504764

Collaborator

(none)

Enrollment

Locations

Duration (Months)

0.7

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

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

Condition or Disease	Intervention/Treatment	Phase
Acute Promyelocytic Leukemia	Drug: Arsenic Trioxide Procedure: Autologous Transplantation Procedure: Allogenic Transplantation Drug: ATRA	Phase 4

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.

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.

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.

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

60 participants

Allocation:

Non-Randomized

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

APL-R2007: Treatment of Relapsed Promyelocytic Leukemia With Arsenic Trioxide (ATO)

Study Start Date :

Jul 1, 2007

Actual Primary Completion Date :

Oct 1, 2014

Actual Study Completion Date :

Oct 1, 2014

Outcome Measures

Primary Outcome Measures

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

Evaluate kinetics of the MDR of PML/RARa during and after ATO [2 years]
Evaluate the mortality related with postremission treatment [1 year]
Side effects of ATO and the different treatments post-consolidation [2 years]
Overall survival [2 years]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

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

Exclusion Criteria:

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 )

Contacts and Locations

Locations

	Site	City	State	Country
1	Hospital Central de Asturias	Oviedo	Asturias	Spain
2	Hospital Germans Trias i Pujol	Badalona	Barcelona	Spain
3	Hospital de Mataró	Mataró	Barcelona	Spain
4	Hospital general de Castellón	Castello	Castellón	Spain
5	Complejo Hospitalario Universitario de Santiago	Santiago de Compostela	La Coruña	Spain
6	Hospital de Alcorcón	Alcorcón	Madrid	Spain
7	Clínica Universitaria de Navarra	Pamplona	Navarra	Spain
8	Hospital Verge de la Cinta	Tortosa	Tarragona	Spain
9	Complejo Hospitalario Universitario de Albacete	Albacete		Spain
10	Fundación Hospital Alcorcón	Alcorcón		Spain
11	Hospital General de Alicante	Alicante		Spain
12	Hospital de la Ribera	Alzira		Spain
13	Hospital Ntra. Sra. Sonsoles	Avila		Spain
14	Hospital Clinic	Barcelona		Spain
15	Hospital de la Santa Creu i Sant Pau	Barcelona		Spain
16	Hospital del Mar	Barcelona		Spain
17	Hospital Valle Hebrón	Barcelona		Spain
18	Basurtuko Ospitalea	Basurto		Spain
19	Hospital de Cruces	Bilbao		Spain
20	Complejo Hospitalario de Cáceres	Cáceres		Spain
21	Hospital Puerta del Mar	Cádiz		Spain
22	Complejo Hospitalario Reina Sofía	Córdoba		Spain
23	Hospital Donostia	Donostia		Spain
24	Hospital General de Elda	Elda		Spain
25	Hospital de Fuenlabrada	Fuenlabrada		Spain
26	Hospital Virgen de las Nieves	Granada		Spain
27	Hospital General de Guadalajara	Guadalajara		Spain
28	Area Hospitalaria Juan Ramón Jimenez	Huelva		Spain
29	Hospital de San Jorge	Huesca		Spain
30	Hospital Médico Quirúrgico Ciudad de Jaén	Jaen		Spain
31	Hospital de Jerez de la Frontera	Jerez de la Frontera		Spain
32	Hospital Juan Canalejo	La Coruña		Spain
33	Hospital General de Lanzarote	Lanzarote		Spain
34	Complejo Hospitalario León	Leon		Spain
35	Hospital Arnau de Vilanova	Lleida		Spain
36	Complexo Hospitalario Xeral-Calde	Lugo		Spain
37	Clínica La Concepción	Madrid		Spain
38	Clínica Moncloa	Madrid		Spain
39	Clínica Puerta de Hierro	Madrid		Spain
40	Clínica Rúber	Madrid		Spain
41	Fundación Jiménez Díaz	Madrid		Spain
42	Hospital 12 de Octubre	Madrid		Spain
43	Hospital Central de la Defensa	Madrid		Spain
44	Hospital Clínico San Carlos de Madrid	Madrid		Spain
45	Hospital de la Princesa	Madrid		Spain
46	Hospital Doce de Octubre	Madrid		Spain
47	Hospital General Universitario Gregorio Marañón, Madrid	Madrid		Spain
48	Hospital la Paz	Madrid		Spain
49	Althaia, Xarxa Asistencial de Manresa	Manresa		Spain
50	Fundación Hospital Sant Joan de Déu de Martorell	Martorell		Spain
51	Hospital General Morales Meseguer	Murcia		Spain
52	. Hospital Clínico Universitario Virgen de la Victoria	Málaga		Spain
53	Hospital de Mérida	Mérida		Spain
54	Hospital de Móstoles	Móstoles		Spain
55	Hospital del Río Carrión	Palencia		Spain
56	Hospital de Gran Canaria Doctor Negrín	Palma de Gran Canaria		Spain
57	Hospital Son Dureta	Palma de Mallorca		Spain
58	Hospital Son Llàtzer	Palma de Mallorca		Spain
59	Hospital Verge del Toro	Palma de Mallorca		Spain
60	Complejo Hospitalario de Pontevedra_Hospital Montecelo	Pontevedra		Spain
61	Complejo Hospitalario de Pontevedra_Hospital Provincial	Pontevedra		Spain
62	Corporació Sanitaria Parc Taulí	Sabadell		Spain
63	Hospital de Sagunto	Sagunto		Spain
64	Hospital Clínico de Salamanca	Salamanca		Spain
65	Clínica Sant Camil	Sant Pere de Ribes		Spain
66	Hospital Universitario Marqués de Valdecilla	Santander		Spain
67	Hospital General de Segovia	Segovia		Spain
68	H.U. Virgen del Rocio	Sevilla		Spain
69	Hospital Joan XXIII	Tarragona		Spain
70	Hospital Universitario de Canarias	Tenerife		Spain
71	Hospital Nuestra Señora del Prado	Toledo		Spain
72	Fundación Instituto Valenciano de Oncología	Valencia		Spain
73	Hospital Clínic	Valencia		Spain
74	Hospital Dr. Peset	Valencia		Spain
75	Hospital Francesc de Borja	Valencia		Spain
76	Hospital General Universitario	Valencia		Spain
77	Hospital La Fe	Valencia		Spain
78	Hospital Clínico de Valladolid	Valladolid		Spain
79	Hospital Comarcal Pius de Valls	Valls		Spain
80	Complejo Hospitalario Xeral-Cies	Vigo		Spain
81	Comarcal de Vinaros	Vinaros		Spain
82	Hospital Txagorritxu	Vitoria		Spain
83	Hospital de Galdakao	Vizcaya		Spain
84	Hospital Clínico Lozano Blesa	Zaragoza		Spain
85	Hospital Miguel Servet	Zaragoza		Spain