1Haematology, SA Pathology, and School of Medicine, University of Adelaide, Adelaide
2Haematology and Genetic Pathology, Flinders University, Adelaide
3Haematology, Peter MacCallum Cancer Centre and University of Melbourne, Melbourne
4Dept. of Haematology, Austin Hospital, Melbourne, Australia
Correspondence: David M. Ross, Dept. of Haematology, SA Pathology, and School of Medicine, University of Adelaide, Adelaide, Australia. E-mail: email@example.com
Received May 25, 2011; Revised July 13, 2011; Accepted August 2, 2011.
Keywords: complete molecular response, CML, dasatinib, imatinib
Patient 2 is a 37-year old male who had been diagnosed with chronic phase CML in January 2001. He initially declined therapy, but then in December 2001 commenced treatment with imatinib at a dose of 400 mg daily. He achieved a CCR but not an MMR, despite serial imatinib dose escalation to 800 mg daily. Thirty-two months after commencing treatment he had a significant rise in BCR-ABL1 mRNA and was found to have a cytogenetic relapse with the kinase domain mutations F359I and G250E. In October 2005, he commenced dasatinib at a dose of 70 mg twice daily. After four months a CMR was achieved. On one occasion whilst in CMR on dasatinib he had a slight lymphocytosis with normal T-cell subsets. TCR gene analysis showed a dominant band in a polyclonal background suggestive, but not diagnostic, of a small clonal expansion. After 35 months of stable CMR, the patient stopped dasatinib against medical advice, in the absence of any significant toxicity. He remains in a stable CMR after 18 months with no detectable BCR-ABL mRNA in any of 6 samples (Figure 1B). Follow-up TCR gene analysis (whilst off treatment) was polyclonal. Quantitative BCR-ABL1 DNA PCR was performed on one sample collected 17 months after withdrawal of dasatinib. BCR-ABL1 DNA was detected at around 5.5 log below the level at diagnosis.
Patient 3 is a 53-year old male who had been diagnosed with chronic phase CML in August 1997. He commenced treatment with interferon, and in May 2003 developed cytogenetic clonal evolution with a tetraploid karyotype and duplication of the Philadelphia chromosome. He commenced second-line treatment with imatinib at a dose of 400 mg daily. He achieved a major molecular response, but after three years on imatinib lost response with a kinase domain mutation, E292V. In May 2007, dasatinib treatment was commenced at a dose of 70 mg twice daily. After four months on dasatinib a CMR was achieved. The patient developed a T-cell lymphocytosis with an excess of CD8+ cells. In June 2010, the patient developed an interstitial pneumonitis for which no other cause could be found. A relationship to dasatinib was suspected and treatment was ceased in August 2010 after 33 months of stable CMR. Molecular relapse occurred after four months with the BCR-ABL1 mRNA level rising to 0.89%. Dasatinib treatment was resumed, without significant toxicity to date, and the patient regained CMR after three months (Figure 1C).
Dasatinib is a dual Src/ABL1 inhibitor which inhibits ABL1 with a potency in vitro of approximately 300 times that of imatinib.7 It is associated with the emergence, in a significant proportion of patients, of lymphocytosis with evidence of T-cell clonality by PCR.8 The emergence of these aberrant lymphoid or NK cell populations has been reported to be associated with an improvement in molecular response, and possibly also with immune-mediated side effects, such as pleural effusion.8 These features led us to speculate that patients in CMR on dasatinib who manifest these immunological responses might be more likely to remain in CMR when the kinase inhibitor was withdrawn. We found a clonal T-cell population in one of the 2 patients in stable CMR. The one patient who had a dasatinib-induced lymphocytosis relapsed when treatment was stopped. The impact of dasatinib-related immunological phenomena on the stability of CMR after dasatinib treatment remains to be determined in a larger number of patients.
All 3 dasatinib-treated patients had evidence of MRD whilst in CMR (defined by conventional RQ-PCR): in 2 cases this was demonstrated by patient-specific DNA PCR, whereas in the third patient the presence of MRD was proven by molecular relapse. Despite the higher potency of dasatinib the level of MRD measured by sensitive DNA PCR was similar to that seen in patients in the ALLG CML8 study on patients in CMR.2 The presence of BCR-ABL1-positive cells in the blood of a patient in a stable drug-free CMR appears to indicate that eradication of the leukemic clone is not a pre-requisite for the achievement of an operational cure of CML.
These results in 3 dasatinib-treated patients show close parallels to what has previously been reported in patients undergoing a trial of imatinib cessation. As in the imatinib data, if relapse occurred, it did so within several months of therapy withdrawal, and was responsive to re-institution of the TKI.3 The number of patients in this series is too small for us to determine whether the risk of relapse after dasatinib cessation differs from that after imatinib cessation. The patients that we describe all started dasatinib after imatinib failure in accelerated phase and/or with kinase domain mutations and, therefore, constitute a group of higher risk patients than those in the STIM3 or ALLG CML82 studies of imatinib cessation in CMR. These preliminary results suggest that the nature of the molecular remission on dasatinib is not qualitatively different from imatinib-induced CMR, at least in these patients with advanced disease features, despite the observation of immunological responses that appear to be relatively specific to dasatinib treatment. A prospective clinical trial of dasatinib withdrawal will be required to estimate accurately the probability of drug-free CMR and to identify factors that influence the risk of molecular relapse. The cases described here establish that durable disease control is possible following dasatinib cessation in CMR, despite prior imatinib failure and adverse disease features, including BCR-ABL1 kinase domain mutations.