Efficacy and Safety of Nilotinib in First Line Therapy in a Real Life Cohort of Chronic Myeloid Leukemia Patients
Authors: Luciano Luigia , Annunziata Mario , Esposito Maria Rosaria , Francesco Palmieri , Iovine Maria , Danise Paolo , Pagliuca Simona , Giagnuolo Giovanna , Sica Antonello , Vallone Roberto , Spiezia Marilena , Pane Fabrizio 
Published: October 2019

Abstract
Introduction
Consistent data show that the real goal in CML therapy is to obtain a very rapid and deep response because the cinetic of molecular response (MR) is important for quickly reducing the tumor burden by reducing the BCR/ABL level.
The second generation TKIs Nilotinib was designed to have enhanced selectivity and potency toward BCR-ABL compared with imatinib and was able to obtain very rapid and deeper response as shown by many clinical trials. Nilotinib has been approved in multiple countries for use in first line therapy in CML-CP Pts. In order to verify the efficacy and safety of Nilotinib used in first line treatment, we collected the results of a real life cohort of Pts treated in some italian hematological Institutions.
Patients and Methods
68 Pts affected by CML-CP were treated in 9 hematologic units with Nilotinib as first line therapy from 2010 to 2014. The median age was 47.7y with equal distribution by sex. Cytogenetic analysis at diagnosis showed in 66/68 Pts the presence of the typical Ph1 chromosome, 1 pt showed a Ph1 in a complex translocation and 1 pt showed the typical Ph1 chromosome plus der(17). The molecular analysis confirmed the presence of a BCR/ABL hybrid gene (55/68: b3a2 transcript; 12/68 b2a2 transcript; 1/68 both transcripts). The Sokal risk was: Low 24 Pts (35.3%), Intermediate 33 Pts (48.5%), High 11 Pts (16.2%); the Hasford risk was: Low 35 Pts (51.5%), Intermediate 27 Pts (39.7%), High 6 Pts (8.8%); the EUTOS risk was: Low 61 Pts (89.7%) and High 7 Pts (10.3%). All Pts have an ECOG 0/1 out of 1 with an ECOG 2. 45/68 pts received a cytoreduction by HU. All Pts received the Nilotinib standard dose of 600 mg/die except 1 pt who received 300 mg/die. At diagnosis some Pts showed comorbidities (21/68: hypertension; 6/68: diabetes; 5/68: dyslipidemia; 2/68: previous myocardial infarction; 1/68 was in treatment for HIV infection)
Results
66/68 Pts received at least 3 months of treatment and were considered for analysis. At 3 months, all Pts obtained hematological response; cytogenetic response was complete for 65/68 and partial in 3/68.
At 6, 12 and 18 months cytogenetic response was complete in all Pts except for 1 that showed a partial response (pt not compliant); at 24 mo the cytogenetic response was complete for all 25 evaluable Pts.
The molecular results at the different time points are summarized in table 1.
6/68 Pts showed G1/G2 cutaneous side effects (pruritus, erithema, alopecia) , 6/68 a G1 increase of amylase and/or lipase, but only 1 developed clinical pancreatitis (at diagnosis: hypertension, hypercolesterolemia and cardiac disfunction). One pt underwent to leg amputation for PAOD (at diagnosis: hypertension and hypertriglyceridemia). He discontinued treatment in optimal response at 12mo. One pt had ischemic cerebral event (at diagnosis had hypertension and a previous heart attack). One pt discontinued treatment for pancitopenia in failure of response at 3mo and one pt died at 12mo in failure of response for IMF diagnosed during treatment.
No pts developed mutations of BCR/ABL during treatment. In 24 months of observation no Pts lost the response.
Conclusion
The response to Nilotinib treatment at 3 months according to ELN revealed that all evaluable Pts were in optimal response; at 6 mo 51/55 (92,7 %) Pts were in optimal response, while at 12 mo 38/45 (86,7%) Pts were in optimal response. At 18 mo 94,1% reached at least MMR with a very deep response (MR>= 4) in 55,9% of Pts. This kind of response was mantained at 24 mo (92% of Pts had at least an MR3 and 15/25 had an MR 4).
Notabily starting from 12 months, at least 40 % of pts showed a very deep response (MR >= 4) and the number increased at the subsequent time points.
The side effects were few and of low grade. Only 3 Pts discontinued the treatment because side effects. Only a severe side effect (PAOD) was reported in a pt who already had a vascular risk because affected from hypertension and hypertriglyceridemia. It is recommended to check at diagnosis and carefully follow during the treatment for all comorbidities to prevent toxicity.
These data collected in a real life treatment with Nilotinib in first line in CML -CP patients, confirmed the results of the clinical trials. The rapid and deep response with a tolerable toxicity profile allow to consider Nilotinib as a good choice for first line treatment also in consideration of a stop therapy in a future.
Table 1
Time Pts MR1 MR2 MR3 MR4 MR4.5 MR5
(mo) (N)
3 60 10 31 13 4 2 -
6 55 4 16 20 4 11 -
12 45 1 6 20 4 13 1
18 34 0 2 13 6 12 1
24 25 0 2 8 6 8 1

Disclosures
No relevant conflicts of interest to declare.