17 december 2013: referentielijst toegevoegd van studies met dasatinib en Nilotinib. En ook toegevoegd een tussenevaluatie een een review studie waarbij Nilotinib en Dasatinib worden vergeleken met Gleevec - Imatinib en ook alleen gegeven voor betere resultaten zorgt in vergelijking met Gleevec bij patiënten met nieuw gediagnosteerde CML.

Ook onderaan het abstract van het studierapport: Dasatinib, nilotinib and standard-dose imatinib for the first-line treatment of chronic myeloid leukaemia: systematic reviews and economic analyses.

En onderaan ook abstract van het volledige studierapport uit The Lancet: Nilotinib versus imatinib for the treatment of patients with newly diagnosed chronic phase, Philadelphia chromosome-positive, chronic myeloid leukaemia: 24-month minimum follow-up of the phase 3 randomised ENESTnd trial.

Wederom dus goede resultaten van een op receptoren gerichte aanpak, een vorm van personalised medicin.

22 juni 2006: Bron: N Engl J Med. 2006;354:2542-2551, 2531-2541, 2594-2596.

Dasatinib en Nilotinib, twee zogeheten tyrase kinase remmers (BCR-ABL remmers) en is een klasse van medicijnen gericht op receptoren / bepaalde eiwitten op of in de tumor, blijken bij patiënten met CML en ALL, twee vormen van leukemie, die resistent waren geworden voor Gleevec - Imatinib, alsnog voor langdurige remissies te zorgen. Als u hier klikt kunt u het volledige studierapport: Nilotinib in Imatinib-Resistant CML and Philadelphia Chromosome–Positive ALL gratis inzien, inclusief statistieken enz.

Hier een gedeelte uit dit studierapport, daaronder het abstract van de studie:

Response

All patients in our study had disease that was resistant to imatinib. Overall, of 33 patients with the blastic phase, 13 had a hematologic response to nilotinib (39 percent) (Table 3Table 3Hematologic and Cytogenetic Responses.) and 9 patients (27 percent) had a cytogenetic response, 6 of whom had a major cytogenetic response (Ph-positive cells in metaphase, ≤35 percent). Of 46 patients with accelerated-phase CML (excluding those with clonal evolution only), 33 had a hematologic response; 22 had a cytogenetic response, and 9 of those responses were major. Among the 10 patients who had clonal evolution as the only feature of the accelerated phase of CML, 5 had active disease and 5 were in complete hematologic remission. All 5 patients with clonal evolution and hematologic disease had a complete hematologic response; 6 of 10 had a major cytogenetic response (Table 3).

Table 4Table 4Dose Escalation and Hematologic Response in Patients with Accelerated and Blastic Phases of Disease. shows the results in patients who had accelerated or blastic phases of disease who had a dose escalation owing to inadequate response at the initial dose level. Overall, 13 of 23 patients who were initially treated at daily doses of 50 to 400 mg had hematologic responses when they received 600 mg daily or 400 mg twice daily. At once-daily doses of 600 mg or more, less than 10 percent of patients required a dose escalation. Response rates at the twice-daily doses of 400 and 600 mg were similar.

Among 17 patients with the chronic phase of disease, the median duration of therapy was 4.9 months (range, 1.4 to 9.3), and all of the patients have continued therapy. At the present time, 11 of 12 patients with active disease have had a complete hematologic remission. There were cytogenetic responses in 9 of 17 patients who could be evaluated, including 6 responses that were complete (Table 3). Complete cytogenetic responses were noted in 3 of 12 patients who had hematologic disease at baseline and in 3 of 5 patients who were in complete hematologic remission at the start of therapy (Table 5Table 5Response to Nilotinib among Patients with Chronic-Phase CML, According to the Starting-Dose Cohort.).

One of 10 patients with Ph-positive ALL (hematologic relapse) had a partial hematologic response, and 1 of 3 patients with Ph-positive ALL and persistent molecular signs of ALL had a complete molecular remission.

Signaling Molecules

Phosphorylation of AKT, CRKL, STAT1, and STAT5 in all cells was compared at baseline and on day 15 in patients in blastic and accelerated phases of disease whose leukemic cells had phosphorylation of these proteins at baseline and who received 400 or 600 mg of nilotinib twice daily. In all four signaling molecules, there was significantly decreased phosphorylation on day 15 of nilotinib treatment, as compared with that at baseline after adjustment for multiple testing (overall significance level for all comparisons, 0.05). (See the section entitled “Assessment of Biomarker Inhibition” in the Supplementary Appendix.)

ABL Mutations and Response to Nilotinib

In about 50 percent of samples, a duplicate baseline sample was available for confirmatory analysis of ABL mutations by an academic laboratory; the concordance was 100 percent between the central and academic laboratories. A total of 51 ABL mutations were observed in 37 of 91 patients who had a baseline assessment for mutational status. Nilotinib was active in patients with and in those without mutations, but there were no significant differences in the response rates between the two groups. (See the section entitled “Assessment of BCR-ABL Mutational Status” in the Supplementary Appendix.) Two patients with a T315I mutation (one with chronic-phase CML and one with blastic-phase CML) had no response to nilotinib.

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Nilotinib has a relatively favorable safety profile and is active in imatinib-resistant CML.

Source: N Engl J Med. 2006 Jun 15;354(24):2542-51.

Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL.

Kantarjian H, Giles F, Wunderle L, Bhalla K, O'Brien S, Wassmann B, Tanaka C, Manley P, Rae P, Mietlowski W, Bochinski K, Hochhaus A, Griffin JD, Hoelzer D, Albitar M, Dugan M, Cortes J, Alland L, Ottmann OG.

Author information

Abstract

BACKGROUND:

Resistance to imatinib mesylate can occur in chronic myelogenous leukemia (CML). Preclinical in vitro studies have shown that nilotinib (AMN107), a new BCR-ABL tyrosine kinase inhibitor, is more potent than imatinib against CML cells by a factor of 20 to 50.

METHODS:

In a phase 1 dose-escalation study, we assigned 119 patients with imatinib-resistant CML or acute lymphoblastic leukemia (ALL) to receive nilotinib orally at doses of 50 mg, 100 mg, 200 mg, 400 mg, 600 mg, 800 mg, and 1200 mg once daily and at 400 mg and 600 mg twice daily.

RESULTS:

Common adverse events were myelosuppression, transient indirect hyperbilirubinemia, and rashes. Of 33 patients with the blastic phase of disease, 13 had a hematologic response and 9 had a cytogenetic response; of 46 patients with the accelerated phase, 33 had a hematologic response and 22 had a cytogenetic response; 11 of 12 patients with the chronic phase had a complete hematologic remission.

CONCLUSIONS:

Nilotinib has a relatively favorable safety profile and is active in imatinib-resistant CML. (ClinicalTrials.gov number, NCT00109707 [ClinicalTrials.gov].).

Comment in

Circumventing resistance to kinase-inhibitor therapy. [N Engl J Med. 2006]

PMID:: 16775235; [PubMed - indexed for MEDLINE]

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Nilotinib continues to show better efficacy than imatinib for the treatment of patients with newly diagnosed CML in chronic phase. These results support nilotinib as a first-line treatment option for patients with newly diagnosed disease

Lancet Oncol. 2011 Sep;12(9):841-51. doi: 10.1016/S1470-2045(11)70201-7. Epub 2011 Aug 17.

Nilotinib versus imatinib for the treatment of patients with newly diagnosed chronic phase, Philadelphia chromosome-positive, chronic myeloid leukaemia: 24-month minimum follow-up of the phase 3 randomised ENESTnd trial.

Kantarjian HM, Hochhaus A, Saglio G, De Souza C, Flinn IW, Stenke L, Goh YT, Rosti G, Nakamae H, Gallagher NJ, Hoenekopp A, Blakesley RE, Larson RA, Hughes TP.

Author information

The University of Texas, MD Anderson Cancer Center, Leukemia Department, Houston, TX 77030, USA. hkantarj@mdanderson.org

Erratum in

Lancet Oncol. 2011 Oct;12(11):989.

Abstract

BACKGROUND:

Nilotinib has shown greater efficacy than imatinib in patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukaemia (CML) in chronic phase after a minimum follow-up of 12 months. We present data from the Evaluating Nilotinib Efficacy and Safety in clinical Trials-newly diagnosed patients (ENESTnd) study after a minimum follow-up of 24 months.

METHODS:

ENESTnd was a phase 3, multicentre, open-label, randomised study. Adult patients were eligible if they had been diagnosed with chronic phase, Philadelphia chromosome-positive CML within the previous 6 months. Patients were randomly assigned (1:1:1) to receive nilotinib 300 mg twice a day, nilotinib 400 mg twice a day, or imatinib 400 mg once a day, all administered orally, by use of a computer-generated randomisation schedule, using permuted blocks, and stratified according to Sokal score. Efficacy results are reported for the intention-to-treat population. The primary endpoint was major molecular response at 12 months, defined as BCR-ABL transcript levels on the International Scale (BCR-ABL(IS)) of 0·1% or less by real-time quantitative PCR in peripheral blood. This study is registered with ClinicalTrials.gov, number NCT00471497.

FINDINGS:

282 patients were randomly assigned to receive nilotinib 300 mg twice daily, 281 to receive nilotinib 400 mg twice daily, and 283 to receive imatinib. By 24 months, significantly more patients had a major molecular response with nilotinib than with imatinib (201 [71%] with nilotinib 300 mg twice daily, 187 [67%] with nilotinib 400 mg twice daily, and 124 [44%] with imatinib; p<0·0001 for both comparisons). Significantly more patients in the nilotinib groups achieved a complete molecular response (defined as a reduction of BCR-ABL(IS) levels to ≤0·0032%) at any time than did those in the imatinib group (74 [26%] with nilotinib 300 mg twice daily, 59 [21%] with nilotinib 400 mg twice daily, and 29 [10%] with imatinib; p<0·0001 for nilotinib 300 mg twice daily vs imatinib, p=0·0004 for nilotinib 400 mg twice daily vs imatinib). There were fewer progressions to accelerated or blast phase on treatment, including clonal evolution, in the nilotinib groups than in the imatinib group (two with nilotinib 300 mg twice daily, five with nilotinib 400 mg twice daily, and 17 with imatinib; p=0·0003 for nilotinib 300 mg twice daily vs imatinib, p=0·0089 for nilotinib 400 mg twice daily vs imatinib). At 24 months, survival was comparable in all treatment groups, but fewer CML-related deaths had occurred in both the nilotinib groups than in the imatinib group (five with nilotinib 300 mg twice daily, three with nilotinib 400 mg twice daily, and ten with imatinib). Overall, the only grade 3 or 4 non-haematological adverse events that occurred in at least 2·5% of patients were headache (eight [3%] with nilotinib 300 mg twice daily, four [1%] with nilotinib 400 mg twice daily, and two [<1%] with imatinib) and rash (two [<1%], seven [3%], and five [2%], respectively). Grade 3 or 4 neutropenia was more common with imatinib than with either dose of nilotinib (33 [12%] with nilotinib 300 mg twice daily, 30 [11%] with nilotinib 400 mg twice daily, and 59 [21%] with imatinib). Serious adverse events were reported in eight additional patients in the second year of the study (four with nilotinib 300 mg twice daily, three with nilotinib 400 mg twice daily, and one with imatinib).

INTERPRETATION:

Nilotinib continues to show better efficacy than imatinib for the treatment of patients with newly diagnosed CML in chronic phase. These results support nilotinib as a first-line treatment option for patients with newly diagnosed disease.