Optimal duration of imatinib treatment/deep molecular response for treatment-free remission after imatinib discontinuation from a Canadian tyrosine kinase inhibitor discontinuation trial
Corresponding Author
Dennis D. H. Kim
Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Canada
Correspondence: Dennis DH Kim, Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Canada.
E-mail: [email protected]
Search for more papers by this authorIgor Novitzky-Basso
Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Canada
Search for more papers by this authorTaehyung S. Kim
Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Canada
Department of Computer Science, Donnelly Centre, University of Toronto, Toronto, Canada
Search for more papers by this authorEshetu G. Atenafu
Department of Biostatistics, Princess Margaret Cancer Centre, University Health Network, Toronto, Canada
Search for more papers by this authorDonna Forrest
Leukemia/BMT Program of British Columbia, Division of Hematology, Vancouver General Hospital, British Columbia Cancer Agency, and University of British Columbia, Vancouver, Canada
Search for more papers by this authorLynn Savoie
University of Calgary, Alberta Health Services, Calgary, Canada
Search for more papers by this authorIsabelle Bence-Bruckler
Medicine, University of Ottawa, Ottawa Hospital Research Institute, Ottawa, Canada
Search for more papers by this authorMary-Margaret Keating
Queen Elizabeth II Health Sciences Centre and Dalhousie University, Halifax, Canada
Search for more papers by this authorLambert Busque
Hematopoiesis and Aging Research Unit, University of Montreal, Hôpital Maisonneuve-Rosemont, Montreal, Canada
Search for more papers by this authorRobert Delage
Centre Universitaire d’Hématologie et d’Oncologie de Québec, CHU de Québec, Hôpital de l’Enfant-Jésus, Québec, Canada
Search for more papers by this authorAnargyros Xenocostas
Department of Medicine, Division of Hematology, London Health Sciences Centre, University of Western Ontario, London, Canada
Search for more papers by this authorElena Liew
Department of Medicine, University of Alberta, Edmonton, Canada
Search for more papers by this authorKristjan Paulson
CancerCare Manitoba, Winnipeg, Manitoba, Canada
Search for more papers by this authorTracy Stockley
Department of Pathology, Toronto General Hospital, University Health Network, University of Toronto, Toronto, Canada
Search for more papers by this authorPierre Laneuville
Division of Hematology, McGill University Health Centre, Montreal, Canada
Search for more papers by this authorJeffrey H. Lipton
Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Canada
Search for more papers by this authorSuzanne Kamel-Reid
Department of Pathology, Toronto General Hospital, University Health Network, University of Toronto, Toronto, Canada
Search for more papers by this authorBrian Leber
Department of Oncology, McMaster University, Hamilton, Canada
Search for more papers by this authorCorresponding Author
Dennis D. H. Kim
Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Canada
Correspondence: Dennis DH Kim, Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Canada.
E-mail: [email protected]
Search for more papers by this authorIgor Novitzky-Basso
Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Canada
Search for more papers by this authorTaehyung S. Kim
Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Canada
Department of Computer Science, Donnelly Centre, University of Toronto, Toronto, Canada
Search for more papers by this authorEshetu G. Atenafu
Department of Biostatistics, Princess Margaret Cancer Centre, University Health Network, Toronto, Canada
Search for more papers by this authorDonna Forrest
Leukemia/BMT Program of British Columbia, Division of Hematology, Vancouver General Hospital, British Columbia Cancer Agency, and University of British Columbia, Vancouver, Canada
Search for more papers by this authorLynn Savoie
University of Calgary, Alberta Health Services, Calgary, Canada
Search for more papers by this authorIsabelle Bence-Bruckler
Medicine, University of Ottawa, Ottawa Hospital Research Institute, Ottawa, Canada
Search for more papers by this authorMary-Margaret Keating
Queen Elizabeth II Health Sciences Centre and Dalhousie University, Halifax, Canada
Search for more papers by this authorLambert Busque
Hematopoiesis and Aging Research Unit, University of Montreal, Hôpital Maisonneuve-Rosemont, Montreal, Canada
Search for more papers by this authorRobert Delage
Centre Universitaire d’Hématologie et d’Oncologie de Québec, CHU de Québec, Hôpital de l’Enfant-Jésus, Québec, Canada
Search for more papers by this authorAnargyros Xenocostas
Department of Medicine, Division of Hematology, London Health Sciences Centre, University of Western Ontario, London, Canada
Search for more papers by this authorElena Liew
Department of Medicine, University of Alberta, Edmonton, Canada
Search for more papers by this authorKristjan Paulson
CancerCare Manitoba, Winnipeg, Manitoba, Canada
Search for more papers by this authorTracy Stockley
Department of Pathology, Toronto General Hospital, University Health Network, University of Toronto, Toronto, Canada
Search for more papers by this authorPierre Laneuville
Division of Hematology, McGill University Health Centre, Montreal, Canada
Search for more papers by this authorJeffrey H. Lipton
Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Canada
Search for more papers by this authorSuzanne Kamel-Reid
Department of Pathology, Toronto General Hospital, University Health Network, University of Toronto, Toronto, Canada
Search for more papers by this authorBrian Leber
Department of Oncology, McMaster University, Hamilton, Canada
Search for more papers by this authorSummary
Although total duration of tyrosine kinase inhibitor (TKI) therapy and of molecular response at 4 log reduction or deeper (MR4) correlates with treatment-free remission (TFR) success after TKI discontinuation, the optimal cut-off values of the duration remain unresolved. Thus, 131 patients were enrolled into the Canadian TKI discontinuation study. The molecular relapse-free survival (mRFS) was defined from imatinib discontinuation till molecular recurrence, that is, major molecular response (MMR) loss and/or MR4 loss. We evaluated mRFS at 12 months after imatinib discontinuation, analyzed it according to the imatinib treatment duration and MR4 duration, and calculated P value, positive (PPV) and negative predictive value (NPV) in the yearly cut-off period of time. The shortest cut-off was sought that met the joint criteria of a P value ≤ 0·05, PPV ≥ 60% and NPV ≥ 60%. We propose six years as the shortest imatinib duration cut-off with a P value 0·01, PPV 68% and NPV 62%: The patients treated with imatinib duration ≥ 6 years showed a superior mRFS rate (61·8%) compared to those with less treatment (36·0%). Also, 4·5 years MR4 duration as the shortest cut-off with a P value 0·003, PPV 63% and NPV 61%: those with MR4 duration ≥ 4·5 years showed a higher mRFS rate (64·2%) than those with a shorter MR4 duration (41·9%).
Conflict of interest
DK has received a research grant from the BMS and Novartis.
Supporting Information
| Filename | Description |
|---|---|
| bjh17447-sup-0001-FigS1-S4.docxWord document, 2 MB |
Fig S1. Kinetics of BCR-ABL transcript level in each individual after IM discontinuation. Fig S2. Molecular relapse-free survival curve according to the toxicity profiles of imatinib therapy (A. GI toxicity, B. musculoskeletal toxicity (i.e. muscle cramps), C. superficial edema, D. fatigue), E. The incidence curve of TKI withdrawal syndrome and F. Simon-Makuch plot of molecular relapse-free survival curve according to the development of TKI withdrawal syndrome taken account it as time-dependent covariate. Fig S3. Distribution of total duration of imatinib treatment (A) and MR4 response duration with imatinib (B) presented with normogram. Fig S4. Cumulative incidence of MMR loss according to the the optimal cut-off of IM treatment duration, 6 years (A) or of MR4 duration, 4.5 years (B). |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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