Favorable Therapeutic Responses in Newly Diagnosed CML-CP Patients Induced by Dasatinib Are Reflected At the CD34+CD38+ Progenitor Cell but Not At the CD34+CD38− Stem Cell Level: Results From Randomized NordCML006 Study

In vitro studies have suggested that CML stem cells are resistant to tyrosine kinase inhibitors (TKIs), but in vivo effects in patients have not been prospectively assessed. Furthermore, the inter-individual variation of the leukemic stem cell pool at diagnosis and its possible prognostic value is unknown.

46 newly diagnosed CML-CP patients were randomized 1:1 to receive either dasatinib 100 mg or imatinib 400 mg QD. The primary endpoint was a comparison of the proportion of Ph+ cells in CD34+CD38− and CD34+CD38+ compartment at 6 months between the study arms. Key secondary endpoints were the fraction of Ph+ cells in the stem cell compartments at 1 and 3 months, and molecular and cytogenetic responses at 3, 6, 12 and 18 months. Experimental endpoints included the percentage of Ph+ cells in the stem cell compartment at diagnosis and its correlation with therapeutic response.

One patient in the imatinib arm and none in the dasatinib arm progressed to blast crisis within first 12 months. 4/22 of dasatinib patients have discontinued the treatment due to side-effects (mainly pleural effusion) and 1 patient due to insufficient response. 3/24 imatinib patients have discontinued the therapy (1 blast crisis, 1 side-effects, 1 other malignancy).

Early cytogenetic responses were superior in the dasatinib arm: the median percentage of Ph+ cells in the bone marrow was 81% (imatinib) vs. 70% (dasatinib) at 1 month (p=0.15) and 5% vs. 0% at 3 months (p=0.0085). At 12 months all dasatinib (n=20) and 19/20 imatinib patients were in CCyR (results based on patients on treatment at 12 months).

MMR rate was significantly higher in the dasatinib arm already at 6 months (70% vs. 20%, p=0.002) and similarly at 9 (75 vs. 26%, p=0.004) and 12 months (88% vs. 40%, p=0.009). Undetectable BCR-ABL1 transcripts (at least CMR4) were observed in 20% of the dasatinib patients at 6 months compared to none in the imatinib arm (p=0.11) and 44% in the dasatinib arm at 12 months compared to 7% in the imatinib arm (p=0.037).

The median percentage of Ph+ cells, as measured by FISH (1000 cells analyzed), in the CD34+CD38− fraction at diagnosis was 79% (range 1–100%) compared to 96% (range 50–100%) in CD34+CD38+ fraction. The proportion of Ph+ cells in CD34+CD38− fraction correlated with WBC count (r=0.50, p<0.001), splenomegaly (r=0.43, p=0.0055), anemia (r=-0.44, p=0.004) and blood blast percentage (r=0.57, p=0.0001) at diagnosis. There was also a significant correlation between Ph+ cells in CD34+CD38− fraction at diagnosis and cytogenetic response at 1 (r=0.63, p<0.0001), 3 (r=0.48, p=0.0025) and 6 months (r=0.36, p=0.0271). Furthermore, leukemic stem cell burden at diagnosis correlated significantly with BCR-ABL1 transcript levels at 3 (r=0.54, p=0.0005), 6 (r=0.42, p=0.0088) and 9 months (r=0.40, p=0.0123). All patients who were not in MMR at 18 months, had >79% of Ph+ cells in CD34+CD38− fraction at diagnosis.

During TKI therapy, the proportion of Ph⁺ cells decreased rapidly in the stem cell fractions. At 1 month, the median proportion of Ph⁺ cells was 14% and 56% in CD34+CD38− and CD34+CD38+ fractions compared to 69% in whole BM (p<0.0001, n=38). At 3 months, the respective numbers were 0.40%, 0.20% and 0.80% (p=0.087, n=33) and at 6 months 0%, 0% and 0.1% (p=0.23, n=41).

Dasatinib-treated patients had significantly lower proportion of Ph+ cells in CD34+CD38+ fraction at 3 months than imatinib patients (0.05% vs. 0.68%, p=0.0318). A similar trend was also observed at 1 month (24% vs. 69%, p=0.05), but no difference existed at 6 months. In CD34+CD38− fraction the proportions of Ph+ cells did not differ significantly at 1 (11 vs. 17%, p=0.91), 3 (0.2 vs. 0.3%, p=0.44) or 6 months (0 vs. 0%, p=0.75).

In comparison to imatinib, dasatinib induced superior therapeutic responses with remarkably high MMR and CMR rates. This was associated with a faster reduction of Ph+ cells at the progenitor CD34+CD38+ cell level. Surprisingly, both drugs rapidly depleted Ph+ cells from the more primitive CD34+CD38− compartment.

The proportion of Ph⁺ stem cells at diagnosis varied significantly among individual patients and bore prognostic value. Patients with a low proportion of Ph+ leukemic stem cells at diagnosis achieved faster and better cytogenetic and molecular responses. The leukemic stem cell burden at diagnosis may be a biomarker predicting treatment outcome and reflecting key biological factors in CML.

Mustjoki:Novartis: Honoraria; Bristol-Myers Squibb: Honoraria. Richter:Novartis: Honoraria; Bristol-Myers Squibb: Honoraria. Dybedal:Novartis: Travel support. Fioretos:Cantargia AB: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Qlucore AB: Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Weiss Bjerrum:Novartis: Consultancy; Bristol-Myers Squibb: Consultancy. Simonsson:Novartis, BMS, Merck, Pfizer: Consultancy, Honoraria. Porkka:Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding. Hjorth-Hansen:Novartis: Honoraria; Bristol-Myers Squibb: Honoraria.