micronavigation ELN path item Leukemias path item CML path item Registry path item Imatinib Failure  · 
Workpackage 4

European Registry of CML patients in failure after Imatinib therapy

Created by: Hellenbrecht (ELIC Project 2) , generated 2008/07/24 , last changed: 2008/07/28


Author: Professor François Guilhot, Université de Poitiers for Project 4 CML

Although imatinib is now the first line therapy for chronic myelogenous leukemia patients, experimental and clinical studies suggest that imatinib as a single drug might not be sufficient to eradicate Ph-positive stem cells.
Moreover, a concern with any single agent administered chronically is that resistant clones may emerge. Molecular studies of resistant leukemia cells isolated from patients have implicated BCR-ABL kinase domain point mutation as the most common mechanism of resistance. However, other mechanisms of resistance such as drug efflux, drug metabolism, BCR-ABL amplification have also been described. Current knowledge of the efficacy of imatinib is based on the results of the large IRIS trial. In this trial the risk of progression after 5 years of therapy is near zero for patients who achieved a complete and sustained cytogenetic response. However the true rate of failure patients treated with imatinib as a single agent is currently unknown. Knowledge on this subject is essential since no information is available concerning the true rate of failure outside clinical trials or unpublished studies.

Introduction

Following initial preclinical studies showing that Imatinib was effective at inhibiting the autophosphorylation of Abl, clinical phase I trials demonstrated significant therapeutics benefits at a dose of 300mg and above (1).
Phase II trials rapidly confirmed the initials results. In chronic phase patients who had failed IFN-α therapy, 95% of patients achieved a complete hematologic response (CHR) and 60% a major cytogenetic response (Mcyr) (2). However with a median follow-up of 29 months, 13% of these patients have relapsed.
In a recent large phase III randomized trial imatinib mesylate produced significantly better results at one year as compared to the combination of IFN-α and Ara-C( 3). Patients randomised to imatinib had significantly better results than patients treated with IFN-α plus Ara-C in all parameters measured, including rates of hematologic response (97% v 56%), major and complete cytogenetic response (Ccyr) (85% and 74% v 22% and 8%), discontinuation of assigned therapy due to intolerance (3% v 31%) and progression to accelerated phase or blast crisis (3% v 8%). Thus, imatinib mesylate has been recommended as first line therapy for chronic phase disease. An update of the trial has confirmed these results (4). Using a Kaplan Meier approach, the estimated rate of complete hematologic response with Imabinib first line therapy was 98 % at 42 months. The estimated rates of major and complete cytogenetic responses at 42 months were 91 and 84 % respectively. The estimated rates of complete cytogenetic response with Imatinib first line therapy by Sokal group at 42 months demonstrated significant differences within each of the 3 risk groups with a lowest rate of 69 % for high risk patients whereas 91 % of the low risk patients achieved complete cytogenetic response. Currently, progression free survival (including hematological relapse, loss of cytogenetic response and progression to blastic phase), which was a primary endpoint of the trial, is 84 % whereas survival without accelerated or blastic phases is 94 %. Yearly hazards of events such as overall progression or accelerated and blastic phases only seems to be low with an estimated risk of progression to accelerated or blastic phase of 1.5% to 2.8%. For first line Imatinib patients, the estimated overall survival at 42 months is 97 % when CML-related deaths are considered and patients censored at transplant whereas it was 93 % when all deaths are considered and patients censored at transplant and 91 % when patients are not censored at transplant.

Thus based on this phase III trial, the percentage of imatinib-failure patients seems to be low.

However, experimental and clinical studies suggest that imatinib mesylate as a single drug might not be sufficient to eradicate Ph positive stem cells (5). Moreover, a concern with any single agent administered chronically is that resistant clones may emerge. Molecular studies of resistant leukaemia cells isolated from patients have implicated BCR-ABL kinase domain point mutation as the most common mechanism of resistance. However other mechanisms of resistance such as drug efflux, drug metabolism, Bcr-Abl amplification have also been described (6, 7, 8). Thus new therapeutic strategies exploring higher doses of Imatinib or combination therapies are currently investigated (9).
However the true rate of failure patients is currently unknown. Essentially because no information is available concerning the true rate of failure outside clinical trials or unpublished studies.
Based on the considerations listed above, reasons for stopping imatinib could be multiple and the therapeutic decisions following imatinib failure are not well described.
Failure patients could represent several possibilities such as primary resistance, relapse, progression to blastic phase, treatment discontinuation for numerous reasons.

Members of the Leukemia Net agreed to support a number of projects and targets which have scientific and clinical value and are likely to be accomplished in a defined period of time. There are already some positive experiences with this model. Relevant examples are the European collaborative study which led to the formulation of a new prognostic classification, the European collaborative study of complete cytogenetic responders to alpha-as well as the meta-analysis of IFN vs conventional chemotherapy (10, 11, 12).

Objectives

The registry of Imatinib failure patients (IFP) will be organized as a sub-registry under the CML European Registry (WP4). The New European Registry of Imatinib failure patients (IFP) may have several different targets and may serve as many different aims.

  1. The first target of this sub-registry will be to collect data of Imatinib failure CML patients (IFP). At present, the incidence of such cases is unknown.
  2. Secondly each sub categories of the IFP registry will be documented
  3. Third, the IFP registry will collect information on the risk profile of these patients.
  4. Fourth, the IFP registry will collect information on the treatment which has been proposed to the patients. Outcome of the patients with the new treatment will be recorded.

Thus the research questions are as followed:

  • How many patients stopped imatinib therapy whatever the reason?
  • What are the subcategories of failure patients? (Primary resistance, relapse, progression to blasic phase, treatment discontinuation because of side effecs, lack of compliance, desire of pregnancy).
  • What are the clinical and biological profiles of failure patients?
  • What was the duration of treatment by imatinib until discontinuation because of failure and what was the daily dose of imatinib at time of discontinuation?
  • What was the medical decision after discontinuation of imatinib therapy?
  • When resistance, were the biological mechanisms explored?

Mechanisms of resistance will not be detailed, and the different categories of mutations will not be recorded in this registry. A specific sub-registry concerning this topic is currently organized. A link between this sub-registry and the IFP will be established.

Methods

Inclusion criteria

Previously treated and untreated chronic phase bcr-abl positive patients who failed imatinib therapy and who matched one or more the following sub-categories of failure.

Definition of imatinib-failure patients

  • No complete hematological response after 3 months of therapy
  • Hematological relapse at any time
  • Progression to accelerated phase or blast crisis at any time
  • Cytogenetic relapse at any time. A cytogenetic relapse is define as follow: an increased of at least 30% in the percentage of Ph+ cells as compared to a previous cytogenetic analysis.
  • Treatment discontinuation because of side effect, lack of compliance, patient choice such as desire of pregnancy, physician choice, or other treatment planned such as stem cell transplantation.
  • No major cytogenetic response after 6 months of therapy
  • No complete cytogenetic response after 18 months of therapy

Data collection

As described in Annex, data collection includes :

  • Identification
  • Demographic patterns
  • Disease characteristics at diagnosis (clinical data, hematology, bone marrow aspirate, cytogenetic exam and molecular biology)
  • Treatments and outcome of the disease
  • Discontinuation of Imatinib therapy data, mainly
  •       
  • Date of discontinuation of imatinib therapy
  •       
  • Daily dose of imatinib at discontinuation
  •       
  • Reasons for discontinuation
  •       
  • Therapeutic decision
  •       
  • Clinical outcome after imatinib discontinuation
  • Survival status

Follow up reports should be supplied every 3 months after discontinuation of imatinib therapy Data may be supplied either on paper forms which will be provided.
The registry will be divided in two phases (simultaneous):

Registration – Phase A:

During this phase we will collect already existing cases of failure patients that have been defined as “IFP” according to the definitions. The characteristics of the IFP patients at diagnosis will be registered, together with cytogenetic and molecular data.

Full data collection Phase B:

All the IFP will be enrolled in the IFP registry at the time of the detection of the first occurrence of failure and complete forms will be collected

Forms for Registration

application/pdf Form A (127KB)
Form_A_Europe.pdf
application/pdf Form B (225KB)
Form_B_Europe.pdf

Data management and Quality Control

Data will be entered in an ACCES database in the University Hospital of Poitiers.
Rules will be in accordance with the Principles and Guidelines of the European Community and the French Law “Informatique, fichiers et liberté”. Regulations are currently in process.
Once the data have been received, it will be closely cheeked for completeness and accuracy and once it has been computerized, it will be check for consistancy.

Statistical analysis

Data will be analysed using SAS software (SAS institute, CARY, NC, USA)

At regular intervals the data will be descriptively analysed and presented.
All collected parameters will be presented first with the whole cohort of patients and then by categories, according to reasons for discontinuation.
When relevant, these categories will be compared.

Final analyses will be provided within 3 years from start of the registry.

Logistics

Board of scientist

A. Hochhaus
G. Martinelli
G. Rosti
J.L. Steegmann
D. Marin
R. Clark
J. Mayer
H. Klamova
T. Sacha
K. Foryciarz
M. Gardembas
F.X. Mahon
F. Maloisel
F. Nicolini
C. Preudhomme
PH. Rousselot
F. Guilhot
J. Guilhot

Data Management

F.Tartarin

Other European Members

 
AT J. THALER
CH A. GRATWOHL, D. HEIM
DE J. HASFORD, R. HEHLMANN, A. HOCHHAUS, P. LE COUTRE, M. PFIRMANN, S. SAUSSELE
DK J. STENTOFT
FI K. PORKKA
IT E. ABBRUZE, M. BACCARANI, C. GAMBACORTI, G. ROSTI
IL A. NAGLER
NL G. OSSENKOPPELE
RU AG TURKINA
SE M. HOGLUND, B. SIMONSSON
SP F. CERVANTES

All analysis will be presented and discussed with the board.
All those physicians who submit data will be informed of the analysis by members of the board.

The responsible clinician will be:

Pr François Guilhot
Oncology Hematology and Cell Therapy
CHU La Milétrie
86021 POITIERS FRANCE
Phone 33 5 49 44 42 01
Fax 33 5 49 44 38 63
E mail f.guilhot@chu-poitiers.fr

The responsible biostatistician will be:
Joelle Guilhot
Clinical Research Center
CHU La Milétrie
86021 POITIERS FRANCE
E mail j.guilhot@chu-poitiers.fr

Publications

There is agreement that all relevant results will be published. Co-authors are ranked considering the number of contributed evaluable patients and input for the manuscript. However members of the board will be first and last authors.

References

  1. Druker BJ, Talpaz M, Resta DJ, Bin Peng RN, Buchdunger E, Ford JM, Lydon NB, Kantarjian H, Capdeville R, Ohno-Jones S, Sawyers C. Efficacy and safety of a specific inhibitor of the BCR- ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med 2001 ; 344 : 1031-7.
  2.  
  3. H. Kantarjian, C. Sawyers, A. Hochhaus, F. Guilhot, Hematologic And Cytogenetic Responses To Imatinib Mesylate In Chronic Myelogenous Leukemia New Engl. J Med. , 2002 ; 346 : 645-652.
  4. S. O’brien, F. Guilhot, R.A. Larson, Gathmann I, Baccarani M, Cervantes F, Cornelissen Jj, Fischer T, Hochhaus A, Hughes T, Lechner K, Nielsen Jl, Rousselot P, Reiffers J, Saglio G, Shepherd J, Simonsson B, Gratwohl A, Goldman Jm, Kantarjian H, Taylor K, Verhoef G, Bolton Ae, Capdeville R, Druker Bj. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2003, 348:994-1004.
  5. F.Guilhot. Sustained durability or responses and long term benefit in newly diagnosed chronic phase CML patients treated with Imatinib: 42-months update from the IRIS study Blood 2004, :
  6. Graham S.M., Jorgensen H.G., Allan E., et al. Primitive, quiescent, Philadelphia-positive stem cells from patients with chronic myeloid leukemia are insensitive to STI571 in vitro. Blood 2002, 99: 319-325.
  7. Shah N.P and Sawyers CL. Mechanisms of resistance to STI571 in Philadelphia chromosome-associated leukemias. Oncogene 2003, 22: 7389-95
  8. Mahon,F.X., Belloc,F., Lagarde V., Chollet C., Moreau-Gaudry F., Reiffers J., Goldman J., Melo J. MDR1 gene overexpression confers resistance to imatinib mesylate in leukemia cell line models.Blood 2003 ; 101: 2368-2373.
  9. Hocchaus A, Kreil S, Corbin AS, et al. Molecular and chromosomal mechanisms of resistance to Imatinib (STI571) therapy. Leukemia 2002, 16/ 2190-96
  10. F. Guilhot, M. Gardembas M, Ph. Rousselot, M. Tulliez, M. Vigier, A. Buzyn, F. Rigal-Huguet, L. Legros, M. Michallet, C. Berthou, A. Najman, F. Maloisel, F.X. Mahon, T. Facon, P. Berthaud, J. Guilhot. Imatinib in combination with cytarabine for the treatment of Philadelphia-positive chronic myelogenous leukaemia chronic phase patients: rational and design of phase I/II trials. Seminar Hematol. 2003 ; 40:92-97
  11. Bonifazi F, de Vivo A, Rosti G, Guilhot F, Guilhot J, Trabacchi E, Hehlmann R, Hochhaus A, Shepherd PC, Steegmann JL, Kluin-Nelemans HC, Thaler J, Simonsson B, Louwagie A, Reiffers J, Mahon FX, Montefusco E, Alimena G, Hasford J, Richards S, Saglio G, Testoni N, Martinelli G, Tura S, Baccarani M. Chronic myeloid leukemia and interferon-alpha: a study of complete cytogenetic responders. Blood. 2001;98:3074-3081
  12. Hasford J, Pfirrmann M, Hehlmann R, Allan NC, Baccarani M, Kluin-Nelemans JC, Alimena G, Steegmann JL, Ansari H. A new prognostic score for survival of patients with chronic myeloid leukemia treated with interferon alfa. Writing Committee for the Collaborative CML Prognostic Factors Project Group. J Natl Cancer Inst. 1998;90:850-858
  13. Group CMLTC. Chronic Myeloid Leukemia Trialists Collaborative Group. J Natl Cancer Inst. 1997;89::1616-1620

 

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