Interim Results of the Canadian Tyrosine Kinase Inhibitor Discontinuation Trial for 2^nd Attempt of Treatment Free Remission: Treatment Free Remission Accomplished By Dasatinib (TRAD)

Introduction:

Multiple studies have demonstrated that 40-50% of patients can maintain a treatment free remission (TFR) after having achieved a deep and sustained response to tyrosine kinase inhibitors (TKI) for the treatment of CML. However, the remaining 60% of patients require reinitiation of TKI therapy to control the leukemia.

Among the TKIs, dasatinib has an additional activity that may be relevant for successful treatment discontinuation: approximately 30% of patients have increased large granular lymphocytes (LGL) and/or natural killer cells. Preliminary analysis indicates the patients with LGL lymphocytosis have a higher likelihood of attaining a deep molecular response than others. Our study is designed to determine if re-treatment with dasatinib (DA) after an initial failure to maintain TFR after imatininb (IM) discontinuation will lead to a second successful TKI discontinuation with sustained TFR.

Methods and materials:

This prospective clinical trial (BMS CA180543, NCT#02268370) includes all major CML treatment centers across Canada (n=12). The study has 3 phases: 1) IM discontinuation, 2) DA rechallenge, and 3) DA discontinuation. The planned enrollment is 117 pts. Key inclusion criteria include: 1) CML in chronic phase, 2) total duration of IM therapy of minimum 3 yrs, 3) total duration of MR4.5 or deeper response over 2 yrs with 2 consecutive confirmed MR4.5 or deeper response with a 3 month interval. Key exclusion criteria include prior allogeneic stem cell transplant or prior accelerated or blastic phase CML. Molecular relapse was defined as an increase in BCR-ABL transcript level above MR4.0 on at least two consecutive occasions, or a single increase in BCR-ABL transcript level above MR3.0. DA is started at a dose of 100mg daily once molecular relapse is confirmed. The primary objective is to determine the proportion of patients who remain in molecular remission (defined as maintaining ≥MR4.0) after DA discontinuation after achieving ≥MR4.5 although the primary endpoint has not been evaluated yet.

Results:

The study was started in March 2015. As of July 21 2017, 147 pts were screened of whom 23 pts did not qualify due to 1) screening failure (n=15) or 2) consent withdrawal (n=8). Ultimately 118 pts were enrolled into IM discontinuation phase, and 108 pts are ongoing with 7 additional patients on screening awaiting enrollment.

Of 107 pts evaluated for molecular relapse, 41 pts (38.3%) lost molecular response defined as loss of major molecular response only (MMR; n=7), loss of MR4 on 2 consecutive tests only (n=9) or both (n=25). The 12 month relapse free survival (RFS) rate was estimated as 56.8% (46.1-66.1%), while TFR rate using loss of MMR as an event was 66.6% (56.2-75.1%) at 12 months. Of 41 pts who lost molecular response, currently 40 pts are in DA rechallenge phase with 37 of these patients who have already been on DA for at least 1 month. Thirty-five patients achieved MMR. The median time to MMR, MR4.0 and MR4.5 was 55 days, 56 days and 66 days, respectively.

Cox's proportional hazard regression model suggested a strong correlation of RFS with total duration of IM therapy prior to IM discontinuation (p<0.001, HR 0.835), MR4 duration (p=0.002, HR 0.853) or MR4.5 duration (p=0.032, 0.896), time to MR4.5 (p=0.021, HR 0.851), but not with time to achieve MR4 (p=0.143). By recursive partitioning we have defined the best cutoff for those variables: the group treated with IM for over 8.7 years (n=56) had RFS rate 79.5% vs 27.9% in others (n=47; p<0.001, HR 0.198). The group with MR4 duration of more than 7.8 years (n=41) had RFS rate 80.0% vs 39.7% in others (n=61; p=0.001, HR 0.264).

Out of 40 pts treated with DA at molecular relapse, 7 pts have attained MR4.5 or deeper response over 12 months and have discontinued DA therapy. Two pts have lost MMR at day 61 and 125 respectively after DA discontinuation. The other five pts are currently being monitored monthly for BCR-ABL transcript level at day 6, 41, 67, 75 and 122 after DA discontinuation without losing molecular response.

Conclusion:

The preliminary results of this Canadian TKI discontinuation trial show a RFS rate of 56.8% after IM discontinuation, consistent with the results observed in other TKI discontinuation studies. DA can be safely administered in CML patients who lose molecular response after IM discontinuation with 100% of MMR rate at 3 months. Prolonged duration of IM duration, or MR4/MR4.5 duration with IM increases TFR success by 11-17% per year.