The long-term efficacy and safety of nilotinib in pediatric patients with CML: a 5-year update of the DIALOG study

Abstract

The efficacy and safety of nilotinib in pediatric patients with imatinib/dasatinib resistant/intolerant (R/I) or newly diagnosed (ND) Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia in chronic phase (CML-CP) was demonstrated in the phase 2, open-label DIALOG study. In this final analysis, long-term efficacy and safety are presented for patients who completed 66 cycles (of 28 days) of treatment with nilotinib (230 mg/m2 twice daily) or discontinued early. Overall, 59 patients were enrolled and 58 were treated (R/I, n = 33; ND, n = 25; median time on treatment: 60.5 and 51.9 months, respectively). In the R/I cohort, the cumulative major molecular response (MMR; BCR::ABL1 international scale [IS] ≤ 0.1%) rate was 60.6%, and no patients had a confirmed loss of MMR. Among ND patients, the best overall MMR rate was 76.0%; 3 patients had a confirmed loss of MMR. The cumulative molecular response MR4 (BCR::ABL1IS ≤ 0.01%) and MR4.5 (BCR::ABL1IS ≤ 0.0032%) rates by 66 cycles were 27.3% and 12.1% in the R/I cohort, and 56.0% and 44.0% in the ND cohort, respectively. The safety profile of nilotinib was consistent with those of earlier reports. No on-treatment deaths occurred. These long-term (up to ∼5 years) data support the efficacy and safety of nilotinib in pediatric patients with Ph+ CML-CP. This trial was registered at www.clinicaltrials.gov.uk as #NCT01844765.

Graphical abstract

Figure 1.

Study design and patient disposition.^aRepresents that the study design includes a third cohort to recruit patients with CML-AP R/I to imatinib or dasatinib. No patients were enrolled in this cohort. ^bDenotes that nilotinib was administered at a dose of 230 mg/m² twice daily (rounded to the nearest 50 mg, to a maximum dose of 400 mg) based on the recommended dose for adults of 400 mg twice daily, scaled to body surface area. At any time, discontinuation was allowed based on patient/investigator decision or because of unacceptable toxicities, disease progression, protocol deviations resulting in a significant risk to the patient’s safety, use of prohibited treatments, or pregnancy. Patients who discontinued the treatment early were contacted for study evaluation completion and survival status. ^cDenotes that 1 enrolled patient did not receive any study medication. ^dIndicates that administrative problems were 4 cases of “lack of efficacy” (2 in each cohort), 1 case of “lack of study compliance by patient” (R/I imatinib/dasatinib Ph⁺ CML-CP cohort), and 2 cases of “new cancer therapy” (1 in each cohort; the CRF does not have separate reasons for discontinuation for such cases, the information was thus voluntarily stored under the category “administrative problem”). ^eIndicates that protocol deviations were 2 cases of noncompliance. CRF, case report form.

Figure 2.

Cumulative molecular response rates. Cumulative incidence of (A) MMR, (B) MR⁴, and (C) MR^4.5 as per the cohort. In the R/I cohort at baseline, 7 patients were already in MMR, 2 patients were already in MR⁴, and 1 patient was already in MR^4.5; hence, the K-M curves start at 21%, 6%, and 3% from day 0, respectively.

Figure 3.

Height SDS over time by cohort. Height SDS (A) and height velocity SDS (B) with respect to time as per the cohort (FAS). Plot shows boxes (25th to 75th percentiles) with median as horizontal line. The dots in the boxes and joining lines represent mean values. Whiskers extend to 10th and 90th percentiles. Values outside this range are not displayed.