Is going for cure in chronic myeloid leukemia possible and justiﬁable?
Francois-Xavier Mahon 1,2
1 Laboratoire d’He´ matologie, Centre Hospitalier Universitaire de Bordeaux, and
2 Laboratoire He´ matopoïe` seLeuce´ mique et Cible The´ rapeutique, Biothe´ rapies des maladies ge´ ne´ tiques et cancers, Inserm U1035,
Universite´ Bordeaux Segalen, Bordeaux, France
After more than a decade of treatment of chronic myeloid leukemia (CML) patients with the BCR-ABL tyrosine kinase
inhibitor imatinib, and despite the impressive clinical results of this targeted therapeutic, many questions remain
unresolved. One major question is how to cure CML, and the next step for the future will be to address this key issue.
CML is a good model of cancer. The fact that the majority of CML patients who respond very well but discontinue
tyrosine kinase inhibitors later show evidence of molecular recurrence focuses attention on the need for further
research on leukemic stem cells. The challenge now is to understand why, after stopping treatment, the leukemia
recurs in some patients but not in others. If we win this battle, this progress will certainly beneﬁt the treatment and
management of other leukemias and solid tumors and will validate this new topic.
"....Having said already that we still do not know if LSCs are really the true enemies because progression to AP may occur predominantly
at the level of a more committed progenitor cell, a large number of publications have focused on targeting the LSCs.46,47 These investigators have clearly been motivated by the important work showing that, at least in vitro, quiescent LSCs are insensitive to TKIs despite
kinase inhibition.48,49 Several strategies have been proposed to target the LSCs. For example, JAK/STAT, JAK2 kinase, the protein
phosphatase 2A (PP2A), arachidonate 5-lipoxygenase gene (ALOX5), histone deacetylases (HDACs), Sirtuin 1 (SIRT1), and ...read more
Minimal Residual Disease and Discontinuation of Therapy in Chronic Myeloid Leukemia: Can We Aim at a Cure? Junia V. Melo1 and David M. Ross2
Minimal Residual Disease and Discontinuation of Therapy in Chronic Myeloid Leukemia: Can We Aim at a Cure?
Junia V. Melo1 and David M. Ross2
Patients with chronic myeloid leukemia (CML) who have achieved a complete molecular response (CMR) defined by no detectable BCR-ABL mRNA on imatinib (IM) treatment often ask whether it is necessary for treatment to continue. We now know that approximately 40% of patients with a stable CMR for at least 2 years are able to stop IM treatment and remain in molecular remission for at least 2 years. This exciting observation has raised hopes that many patients can be cured of CML without the need for transplantation and its attendant risks. One might argue that for many patients maintenance therapy with IM or an alternative kinase inhibitor is so well tolerated that there is no imperative to stop treatment; however, chronic medical therapy may be associated with impaired quality of life and reduced compliance. Inferences about the biology of CML in patients responding to kinase inhibitors can be drawn from clinical experience, molecular monitoring data, and experimental observations. We summarize this information herein, and propose 3 possible pathways to “cure” of CML by kinase inhibitors: stem-cell depletion, stem-cell exhaustion, and immunological control.
CML Stem Cell Burden at Diagnosis Associated With Treatment Outcomes
By Dave Levitan
March 11, 2013
Laboratory studies have suggested that chronic myeloid leukemia (CML) stem cells are resistant to tyrosine kinase inhibitor (TKI) treatment. A new study, though, showed for the first time the effect of stem cell burden on treatment outcome and actually found that TKIs, including imatinib(Drug information on imatinib) and dasatinib(Drug information on dasatinib), can rapidly eradicate most CML stem cells.
Oncology Enters Era of Genomics: Sledge Calls for Overhaul of Clinical Trials System
Anita T. Shaffer
Published Online: Saturday, March 9, 2013
As the genomic era in oncology unfolds, the development of new therapeutics increasingly will involve targeting a range of mutations simultaneously, requiring a “next-generation clinical trials system” to match the advances that technology is delivering, according to George W. Sledge, Jr, MD.
Sledge told attendees at the 30th Annual Miami Breast Cancer Conference Saturday that last year marked a leap forward in understanding breast cancer as the results of many genomic analyses became available. The range of mutations uncovered in individual tumors will necessitate moving beyond battling cancer by identifying a particular molecular process, as has been the case in the targeted therapy era, to multiple driver mutations.
“We’re clearly entering a new age and that age is what I consider to be the genomic era,” said Sledge, who is chief of the Oncology Division at Stanford University School of Medicine in California and a past president of the American Society of Clinical Oncology. “This is an era of great promise. We’re at the point where we’ll be able to tell an individual what’s driving their cancer but it’s going to require a whole lot more of us.”
In developing new therapeutics, researchers will have to focus not only on qualitative mutations but also quantitative aberrations, Sledge said. “We don’t need a magic bullet, we need a magic shotgun,” he said. “We need something that can shoot pellets at a lot of different targets and do so more or less simultaneously.”
“The evaluation of that gene chip that you order will be incredibly complicated and will require a significant amount of playing out over the next decade in terms of how we use it,” he said. Sledge said genomics research has revealed that cancers can be described broadly as either “stupid” or “smart.” ...read more
Deﬁnitions, methodological and statistical issues for phase 3 clinical trials in chronic myeloid leukemia: a proposal by the European LeukemiaNet
Deﬁnitions, methodological and statistical issues for phase 3 clinical trials in
chronic myeloid leukemia: a proposal by the European LeukemiaNet
Joelle Guilhot,1 Michele Baccarani,2 Richard E. Clark,3 Francisco Cervantes,4 Francois Guilhot,1 Andreas Hochhaus,5 Sergei Kulikov,6 Jiri Mayer,7
Andreas L. Petzer,8 Gianantonio Rosti,2 Philippe Rousselot,9 Giuseppe Saglio,10 Susanne Saussele,11 Bengt Simonsson,12,13 Juan-Luis Steegmann,14 Andrey Zaritskey,15 and Rudiger Hehlmann,11
The treatment policy of chronic myeloid leukemia (CML), particularly with tyrosine kinase inhibitors, has been inﬂuenced by
several recent studies that were well designed and rapidly performed, but their interpretation is of some concern because different end points and methodologies were used. To understand and compare the results of the previous and future studies and to translate their conclusion into clinical practice, there is a need for common deﬁnitions and methods for analyses of CML studies. A panel of experts was appointed by the European LeukemiaNet with the aim of developing a set of deﬁnitions and recommendations to be used in design, analyses, and reporting of phase 3 clinical trials in this disease.
This paper summarizes the consensus of the panel on events and major end points of interest in CML. It also focuses on speciﬁc issues concerning the intention to-treat principle and longitudinal data analyses in the context of long-term follow-up. The panel proposes that future clinical trials follow these recommendations. (Blood. 2012;119(25):5963-5971)
Suboptimal Responses in Chronic Myeloid Leukemia
Elias Jabbour, MD,1 Giuseppe Saglio, MD, PhD,2 Timothy P Hughes, MD,3 and Hagop Kantarjian, MD1
The high response rates and increased survival associated with imatinib therapy prompted a paradigm shift in the management of chronic myeloid leukemia. However, 25% to 30% of imatinib-treated patients develop drug resistance or intolerance, increasing the risk of disease progression and poor prognosis. In 2006, the European LeukemiaNet proposed criteria to identify patients with a suboptimal response to, or failure associated with, imatinib; these recommendations were updated in 2009. Suboptimal responders represent a unique treatment challenge. Although they may respond to continued imatinib therapy, their long-term outcomes may not be as favorable as those for optimally responding patients. Validation studies demonstrated that suboptimal responders are a heterogeneous group, and that the prognostic implications of suboptimal response vary by time point. There are few data derived from clinical trials to guide therapeutic decisions for these patients. Clinical trials are currently underway to assess the efficacy of newer tyrosine kinase inhibitors in this setting. Identification of suboptimal responders or patients failing treatment using hematologic, cytogenetic, and molecular techniques allows physicians to alter therapy earlier in the treatment course to improve long-term outcomes. Cancer 2012;. © 2011 American Cancer Society.
Susan Branford 1,2
1 Department of Genetics and Molecular Pathology, Centre for Cancer Biology, SA Pathology, Adelaide,
Australia; and 2 University of Adelaide, Adelaide, Australia
Monitoring response to therapy for patients with chronic myeloid leukemia using an effective strategy is fundamental
for achieving optimal patient outcomes. It will allow the initiation of timely therapeutic intervention for patients with a
suboptimal response or kinase inhibitor therapy failure. Evidence is mounting that reaching molecular targets early in
therapy is as important as the initial hematologic and cytogenetic response for the identiﬁcation of patients who may
have a poorer outcome. When the molecular target of a major molecular response is achieved at 18 months, patients
reach a safe haven where loss of response is rare. However, this beneﬁt is dependent on continuous drug adherence in
most patients. As some patients reach their second decade of successful imatinib therapy, how long will frequent
response monitoring be necessary? Assuming that very late relapse will be extremely rare for responding patients
remaining on kinase inhibitor therapy, there are reasons for maintaining a regular molecular monitoring frequency,
including monitoring adherence assessment and conﬁrming sustained undetectable BCR-ABL1 for those considering
a discontinuation trial and for late molecular recurrence in patients who maintain response after treatment
Monitoring disease response in chronic-phase chronic myeloid leukemia: the age of molecular assays? David T. Yeung 1-3 and Susan Branford 1,3
David T. Yeung 1-3 and Susan Branford 1,3
1Department of Molecular Pathology and Centre for Cancer Biology, and 2 Department of Haematology,SA Pathology, Adelaide, Australia; and
3Department of Medicine, University of Adelaide, Adelaide, Australia
An 80-year-old man has newly diagnosed chronic myeloid leukemia. His BM and blood examination at diagnosis
conﬁrms chronic-phase disease, with the Philadelphia chromosome as the sole cytogenetic abnormality. He has
intermediate Sokal and Hasford risk,1
and is started on imatinib 600 mg once daily. He lives 5 hours away from the
nearest specialist hematology service and prefers followup with his local physician, who cannot perform BM
examinations. In patients such as this, is it acceptable to monitor his therapeutic response solely with molecular
studies of his peripheral blood?
Hammersmith Hospital, Imperial College London, London, United Kingdom.
Imatinib has been the preferred initial therapy for newly diagnosed chronic myeloid leukemia patients for the past
10 years. Recently, other, possibly better, tyrosine kinase inhibitors have been licensed for ﬁrst-line use based on the
early results of 2 large, randomized clinical trials. The pros and cons of the various alternatives to imatinib are analyzed
herein, and I try to answer the question of are we ready to abandon imatinib and, if yes, then what treatment should a
patient diagnosed today receive.
"...Three months ago, my PCR result was .07% (or 0.0245% on the IS). It doesn’t take a genius (I wish it literally did take a genius) to see that the results aren’t as good as they were three months ago. However, it’s important to remember that these results are really subjective. They all depend on the sample that they’re testing. In September, we looked at a different sample than we did in December, which was drawn from a different location in the hip. There was going to be a slight dissimilarity anyway. Therefore, a 0.02% (or 0.0055% on IS) differential isn’t particularly alarming. Cognitively, this is all that matters....."more