On 2017 Apr 18, Andrea Messori commented:

First-line treatment of chronic myeloid leukemia with imatinib or nilotinib: modelling the achievement of major molecular response

Andrea Messori

In the study by Hochhaus et al.(1), the data reported in Figure 2 describe the cumulative molecular response rates observed in three patients cohorts treated with nilotinib 300mg bid (n=282), nilotinib 400 mg twice daily (n=281), and imatinib 400 mg once daily (n=283). These data represent the results at 5 years of the ENESTnd trial. Over a follow-up from 0 to 60 months after the start of TKI treatment, Panel A of Figure 2 shows, at yearly intervals, the percent rates of major molecular response (MMR) for the three agents. These percentages are the following:

a) nilotinib 300mg bid: 55% at 12 mos, 71% at 24 mos, 73% at 36 mos, 76% at 48 mos, and 77% at 60 mos;

b) nilotinib 400 mg twice daily: 51% at 12 mos, 67% at 24 mos, 70% at 36 mos, 73% at 48 mos, and 77% at 60 mos;

c) imatinib 400 mg once daily: 27% at 12 mos, 44% at 24 mos, 53% at 36 mos, 56% at 48 mos, and 60% at 60 mos.

These findings show that nilotinib achieves a greater cumulative response rate than imatinib and also that the rates with nilotinib grow faster than that of imatinib. Current therapeutic strategies for handling TKIs are aimed at testing whether drug discontinuation can safely lead to a durable condition of treatment-free remission. Studying this issue is complex, and simulation models based on Markov methodology are often needed for this purpose (2). To facilitate this type of modelling, we have fitted the data reported above at items (a), (b), and (c) to the following exponential equation:

rate = 100 x (1 – e–Kt)

where: 100 represents the maximum percentage that can be achieved under this experimental condition; K is a first order rate constant, the units of which are reciprocal months; t is the time of the follow-up, the values of which are 0, 12, 24, 36, 48, and 60 in Figure 2 of the referenced article. To fit the rate-vs-t data pairs, a standard least-squares fitting procedure can be employed. In the present analysis, we used the procedure available under Microsoft Excel; the original observations were firstly converted into values of 100-rate and were then subjected to a logarithmic transformation; in this way, the function of these latter values becomes linear and the (negative) slope of the line represents the value of K. We obtained the following results:

a) nilotinib 300mg bid: K = 0.0307 reciprocal mos (half-time of the process = 22.6 mos);

b) nilotinib 400 mg twice daily: K = 0.029 reciprocal mos (half-time of the process = 23.9 mos);

c) imatinib 400 mg once daily: K = 0.0176 reicprocal mos (half-time of the process = 39.4 mos).

Figure 1 (available at http://www.osservatorioinnovazione.net/papers/mmrbestfit.gif ) shows the graph of the three functions estimated for nilotinib 300 mg, nilotinib 400 mg, and imatinib, respectively.

References

1) Hochhaus A, Saglio G, Hughes TP, Larson RA, Kim DW, Issaragrisil S, le Coutre PD, Etienne G, Dorlhiac-Llacer PE, Clark RE, Flinn IW, Nakamae H, Donohue B, Deng W, Dalal D, Menssen HD, Kantarjian HM. Long-term benefits and risks of frontline nilotinib vs imatinib for chronic myeloid leukemia in chronic phase: 5-year update of the randomized ENESTnd trial. Leukemia. 2016 May;30(5):1044-54.

2) Marsh K, Xu P, Orfanos P, Gordon J, Griebsch I. Model-based cost-effectiveness analyses for the treatment of chronic lymphocytic leukaemia: a review of methods to model disease outcomes and estimate utility. Pharmacoeconomics. 2014 Oct;32(10):981-93.

On 2017 Apr 18, Andrea Messori commented:

First-line treatment of chronic myeloid leukemia with imatinib or nilotinib: modelling the achievement of major molecular response

Andrea Messori

In the study by Hochhaus et al.(1), the data reported in Figure 2 describe the cumulative molecular response rates observed in three patients cohorts treated with nilotinib 300mg bid (n=282), nilotinib 400 mg twice daily (n=281), and imatinib 400 mg once daily (n=283). These data represent the results at 5 years of the ENESTnd trial. Over a follow-up from 0 to 60 months after the start of TKI treatment, Panel A of Figure 2 shows, at yearly intervals, the percent rates of major molecular response (MMR) for the three agents. These percentages are the following:

a) nilotinib 300mg bid: 55% at 12 mos, 71% at 24 mos, 73% at 36 mos, 76% at 48 mos, and 77% at 60 mos;

b) nilotinib 400 mg twice daily: 51% at 12 mos, 67% at 24 mos, 70% at 36 mos, 73% at 48 mos, and 77% at 60 mos;

c) imatinib 400 mg once daily: 27% at 12 mos, 44% at 24 mos, 53% at 36 mos, 56% at 48 mos, and 60% at 60 mos.

These findings show that nilotinib achieves a greater cumulative response rate than imatinib and also that the rates with nilotinib grow faster than that of imatinib. Current therapeutic strategies for handling TKIs are aimed at testing whether drug discontinuation can safely lead to a durable condition of treatment-free remission. Studying this issue is complex, and simulation models based on Markov methodology are often needed for this purpose (2). To facilitate this type of modelling, we have fitted the data reported above at items (a), (b), and (c) to the following exponential equation:

rate = 100 x (1 – e–Kt)

where: 100 represents the maximum percentage that can be achieved under this experimental condition; K is a first order rate constant, the units of which are reciprocal months; t is the time of the follow-up, the values of which are 0, 12, 24, 36, 48, and 60 in Figure 2 of the referenced article. To fit the rate-vs-t data pairs, a standard least-squares fitting procedure can be employed. In the present analysis, we used the procedure available under Microsoft Excel; the original observations were firstly converted into values of 100-rate and were then subjected to a logarithmic transformation; in this way, the function of these latter values becomes linear and the (negative) slope of the line represents the value of K. We obtained the following results:

a) nilotinib 300mg bid: K = 0.0307 reciprocal mos (half-time of the process = 22.6 mos);

b) nilotinib 400 mg twice daily: K = 0.029 reciprocal mos (half-time of the process = 23.9 mos);

c) imatinib 400 mg once daily: K = 0.0176 reicprocal mos (half-time of the process = 39.4 mos).

Figure 1 (available at http://www.osservatorioinnovazione.net/papers/mmrbestfit.gif ) shows the graph of the three functions estimated for nilotinib 300 mg, nilotinib 400 mg, and imatinib, respectively.

References

1) Hochhaus A, Saglio G, Hughes TP, Larson RA, Kim DW, Issaragrisil S, le Coutre PD, Etienne G, Dorlhiac-Llacer PE, Clark RE, Flinn IW, Nakamae H, Donohue B, Deng W, Dalal D, Menssen HD, Kantarjian HM. Long-term benefits and risks of frontline nilotinib vs imatinib for chronic myeloid leukemia in chronic phase: 5-year update of the randomized ENESTnd trial. Leukemia. 2016 May;30(5):1044-54.

2) Marsh K, Xu P, Orfanos P, Gordon J, Griebsch I. Model-based cost-effectiveness analyses for the treatment of chronic lymphocytic leukaemia: a review of methods to model disease outcomes and estimate utility. Pharmacoeconomics. 2014 Oct;32(10):981-93.