This is a single-arm, phase II study to evaluate safety and efficacy of tyrosine kinase
inhibitor (TKI) cessation for chronic myeloid leukemia (CML) patients with stable molecular
response in a real world population.
Transitioning from busulfan, hydroxyurea, IFN-α to tyrosine kinase inhibitors (TKIs) has
dramatically altered the natural history of CML. Patients with CML appropriately managed with
TKIs are able to benefit from near normal life expectancy. Given the age-adjusted incidence
of 1.6 per 100,000 people combined with a reduced annual mortality of less than 2% to 3% per
year, it is expected the prevalence in the US to increase from approximately 70,000 in 2010
to a projected 144,000 in 2030. Thus, advancing our knowledge regarding clinical management
is critical in order to care for this expanding population.
However the morbidity associated with prolonged TKI exposure remains a substantial burden on
this patient population. In addition to a relatively benign side effect profile (edema,
muscle cramps, diarrhea, nausea, musculoskeletal pain, rash and other skin problems,
abdominal pain, fatigue, joint pain, and headaches), patients continued to experience grade 3
and 4 adverse events (neutropenia, thrombocytopenia, anemia, elevated liver enzymes,
congestive heart failure, and other drug-related adverse events) more than 2 years after
initiating therapy. For patients with high-risk CML that may benefit from faster and/or
deeper molecular responses, or who develop intolerance or resistance to imatinib, second
generation TKIs (dasatinib, nilotinib, and bosutinib) are available. Indeed, there is a
structural and dose-dependent relationship between TKIs and ischemic heart disease, ischemic
cerebrovascular events and/or peripheral artery disease accompanied with a linear increase in
the cumulative frequency of these cardiovascular events over time. Additionally, experts
believe the cost of CML medicines "are too high, are unsustainable, may compromise access of
needy patients to highly effective therapy, and are harmful to the sustainability of our
national health care systems." Given the implications on quality of life, adverse events and
financial burden on patients, TKI therapy should be discontinued when medically appropriate.
Thankfully, discontinuation of TKIs in CML-CP patients with RT-PCR negative for BCR-ABL1
transcripts (Undetectable Minimal Residual Disease, UMRD) or MR has established that 38% to
45% of patients are able to achieve TFR with persistence of UMRD and MR at 5 and 8 years,
respectively. Subsequent studies (EURO-SKI, ENESTfreedom, ENESTop, and DADI) have
independently validated these results, and patients who experience MR will mostly do so
within three to six months after discontinuation.
Furthermore, in patients with complete cytogenetic response, those who have a deeper
molecular response (>3 log reduction in transcripts) compared to those without have an
improved estimated 7-year event-free survival. ddPCR is a powerful tool that allows for the
absolute quantitation of nucleic acids and provides a more precise and sensitive assay than
real-time PCR (RT-PCR) in detecting BCR-ABL1 transcripts. There is neither a precise
molecular mechanism to characterize MR, nor a clinically actionable assay to determine which
patients will benefit from TKI cessation and achieve TFR. Thus, leveraging ddPCR can impact
patient outcomes in CML-CP patients undergoing TKI treatment by potentially determining who
is expected to achieve of TFR.
Cancer causing mutations can affect oncogenes that normally stimulate growth, suppressor
genes that normally inhibit growth, and repair genes that normally limit mutations. Of the
20,000 protein coding genes in the human genome, approximately ~140 genes can promote
tumorigenesis while the remaining passenger mutations confer no selective growth advantage.
In CML, genomic analysis has identified variants in patients with poor outcomes. Therefore,
mutational analysis of clinically relevant genes and genes of emerging clinical relevance
could provide insight into which patients are at risk for relapse.
Prior to these findings, a truly curable clinical status after CML diagnosis was previously
attainable only with allogeneic stem cell transplantation. It is known that successful
remission in relapsing CML patients who have undergone stem cell transplantation was
primarily driven by an alloreactive T-cell dependent graft-versus-leukemia effect. The
cytotoxic role of a WT-1 peptide specific TCR Vβ21 T-cell clone against K562 cells has been
demonstrated in vitro. Taken together, these data suggest a role of immune cells and the
subsequent maturation, generation, and homing of CML-antigen-specific T-lymphocytes - the
hallmark of elimination during cancer immune surveillance. Massively paralleled sequencing of
the complementarity determining region 3 by TCR-sequencing (TCR-seq) allows for a detailed
understanding of the T-cell repertoire and is representative of clonal distribution,
antigenic response diversity, and the degree of T-cell immunomodulation. A diverse T-cell
repertoire capable of recognizing CML-specific antigens with concomitant clonal expansion may
be associated with successful TFR and potentially provide additional biomarkers towards
identifying patients with CML-CP who should be optimal candidates for TKI cessation.
Inclusion Criteria:
1. Patients who are 18 years or older
2. Patients have a diagnosis of Philadelphia chromosome- or BCR-ABL1-positive CML (as
determined by cytogenetics, FISH, or PCR).
3. Prior evidence of a quantifiable BCR-ABL1 transcript by RT-PCR
4. Patients who have been taking TKI for > 36 months; patient cannot have had a known
continuous interruption of TKI therapy of greater than 14 days or for a total of 6
weeks in the six months prior to registration.
5. Patients must have a history of stable molecular response, defined as MR4.5 for ≥24
months, as documented by ≥3 separate tests performed at least three months apart.
6. Patient must have a current status of complete molecular remission (CMR), defined as
MR4.5 (per section 5.1), to be done after signed consent.
7. ECOG performance status < 2
8. Patients must have normal marrow function within 30 days of registration, as defined:
- Absolute Neutrophil Count (ANC) ≥ 1.5 x 10E9/L
- Hemoglobin ≥ 9.0 g/dL
- Platelets ≥ 100 x 10E9/L
9. Patients must not have any signs of extramedullary leukemia
10. Patients must have a life expectancy of more than 12 months in the absence of any
intervention
11. All participants must be informed of the investigational nature of this study and must
sign and give written informed consent
12. Contraception requirements will be as per routine clinical practice.
Exclusion Criteria:
1. Patients who are unable or unwilling to give their consent to participate to the
study.
2. Previous or planned allogeneic stem cell transplantation
3. Patients who have pathologies or treatments that are able to enhance the potential
relapse risk after stopping Imatinib.
4. Patient has received an investigational agent within last 2 years
5. Atypical BCR-ABL transcript not quantifiable by standard RQ-PCR.
6. Another primary malignant disease, except those that do not currently require
treatment (adequately treated conditions, such as excised skin cancer or cervical
intra-epithelial neoplasia would not be considered exclusion criteria. If in doubt,
please refer to the Principal Investigator).
7. Any medical condition that, in the opinion of the investigator, would exclude the
patient from participating in this study.
8. Active liver disease (e.g., chronic active hepatitis, cirrhosis).
9. Known diagnosis of human immunodeficiency virus (HIV) infection.
