Sustained complete molecular remissions after treatment with imatinib-mesylate in patients with failure after allogeneic stem cell transplantation for chronic myelogenous leukemia: results of a prospective phase II open-label multicenter study.
OBJECTIVE
In the era of molecular therapy of chronic myelogenous leukemia (CML) applying BCR-ABL tyrosine kinase inhibitors, the usefulness of molecular end points, in particular, quantitative polymerase chain reaction (PCR) for BCR-ABL in monitoring responses has been broadly accepted. Therefore, we have designed a prospective phase II trial in CML, which, for the first time, evaluated the feasibility and safety of molecular end points as surrogate markers to guide through a stratified treatment algorithm within a multicenter trial.


METHODS
As a clinical model, we adopted minimal residual disease (MRD) found in relapse after allogeneic stem cell transplantation (SCT) in CML. Forty-four patients were enrolled and received the BCR-ABL tyrosine kinase inhibitor imatinib (IM) at a starting dose of 400 mg/d. The quality of molecular responses achieved then decided on discontinuation of IM or dose escalation up to 800 mg/d, and finally, on application of donor lymphocyte infusions. Results Seventy percent of patients achieved a complete molecular response (CMR), defined as nested PCR-negativity for BCR-ABL in three consecutive samples. Interestingly, in four out of 10 patients who discontinued IM, CMR was durable even after cessation of IM with a median follow-up of 494 days. This suggests the possibility of long-term tumor control in a subset of patients.


CONCLUSIONS
The treatment strategy showed that IM treatment was well-tolerated and highly efficacious in MRD after allogeneic SCT. Moreover, this study demonstrated that evaluation of a molecular end point within a multicenter trial can be a safe and effective tool for clinical decision making.
Hess
Georg
G
III. Med. Klinik, Johannes Gutenberg-University, Mainz; University of Ulm, II. Med. Klinik, Charité, Germany.
Bunjes
Donald
D
Siegert
Wolfgang
W
Schwerdtfeger
Rainer
R
Ledderose
Georg
G
Wassmann
Barbara
B
Kobbe
Guido
G
Bornhäuser
Martin
M
Hochhaus
Andreas
A
Ullmann
Andrew J
AJ
Kindler
Thomas
T
Haus
Ulrike
U
Gschaidmeier
Harald
H
Huber
Christoph
C
Fischer
Thomas
T
D000328:Adult; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001549:Benzamides; D005240:Feasibility Studies; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000378:metabolism; D006086:Graft vs Host Disease / Q000517:prevention & control; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy*; D020714:Maximum Tolerated Dose; D010879:Piperazines / Q000627:therapeutic use*; D016133:Polymerase Chain Reaction; D011446:Prospective Studies; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011743:Pyrimidines / Q000627:therapeutic use*; D012074:Remission Induction; D033581:Stem Cell Transplantation / Q000009:adverse effects*; D013997:Time Factors; D014184:Transplantation, Homologous; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl