Abstract
Purpose
Hypereosinophilic syndrome (HES) and chronic eosinophilic leukemia (CEL) are characterized by sustained overproduction of eosinophils and organ dysfunction. CEL involves the presence of clonal genetic markers, such as a fusion of FIP1-like 1 protein and platelet-derived growth factor receptor α (FIP1L1-PDGFRα, or F/P) or PDGFRα-activating mutations.
Methods
Sixteen patients with HES/CEL were enrolled in the phase 2 nilotinib registration trial (NCT00109707) and treated with nilotinib 400 mg twice daily. The median duration of treatment was 95 days (range 3–1,079).
Results
Twelve patients had HES: 1 achieved a complete hematologic response (CHR), 3 achieved stable disease, 3 had progressive disease, and 5 were not evaluable for response. Four patients had CEL: 2 with the F/P fusion and 2 with PDGFRα-activating mutations. Both patients with an F/P fusion achieved a CHR; 1 also achieved a complete molecular response (CMR). Of the 2 patients with PDGFRα-activating mutations, 1 had stable disease and the other achieved CMR. At 24 months, overall survival in the HES group was 75.0 % (95 % CI 50.5–100.0) and no patients in the CEL group died. Median survival was not yet reached after a median follow-up of 32 months. The most common grade 3/4 hematologic laboratory abnormalities were lymphocytopenia (31.3 %) and neutropenia (25.0 %). The most common drug-related nonhematologic grade 3/4 adverse event was pruritus, which occurred in 2 patients (12.5 %).
Conclusions
Nilotinib 400 mg twice daily was effective in some patients with HES/CEL regardless of F/P mutation status, and the safety profile was consistent with other nilotinib studies.
Keywords: Nilotinib, Hypereosinophilic syndrome, Chronic eosinophilic leukemia
Introduction
Hypereosinophilia is defined as a persistent (>6 months) peripheral blood (PB) eosinophil count greater than 1,500/μL that is associated with tissue damage. After the exclusion of secondary causes of eosinophilia, diagnostic evaluation of eosinophilia relies on a combination of morphologic review of the PB and bone marrow (BM), characterization of organ infiltration, standard cytogenetics and molecular genetics, flow immunocytometry, and T cell clonality assessment to detect histopathologic or clonal evidence for an acute or chronic myeloid or lymphoproliferative disorder (Gotlib 2012).
Chronic eosinophilic leukemia (CEL) is distinguished from hypereosinophilic syndrome (HES) by the evidence of clonal molecular markers or significantly increased numbers of blasts (Gotlib 2012). The estimated age-adjusted incidence rate for HES/CEL is 0.036/100,000 person-years (based on Surveillance Epidemiology and End Results data from 2001 to 2005) (Crane et al. 2010). The median age at HES diagnosis is 52.5 years, with a male-to-female ratio ranging from 1.47 to 9 (Crane et al. 2010; Roufosse et al. 2007).The reported 10-year survival rate for patients with HES is less than 50 % (Verstovsek 2007).
Genetic abnormalities are found in most patients with CEL. The most frequent chromosomal abnormality is a deletion on chromosome 4q12 that creates a fusion of FIP1-like 1 protein with platelet-derived growth factor receptor α (FIP1L1-PDGFRα, or F/P) (Cools et al. 2003a; Loules et al. 2009). F/P is present in approximately 10–20 % of all patients with suspected nonreactive eosinophilia and is associated with increased disease severity due to constitutive tyrosine kinase activity of PDGFRα (Loules et al. 2009; Helbig et al. 2010; Roche-Lestienne et al. 2005). Recently, several activating mutations in PDGFRα, including Y849S, have been identified in F/P-negative patients (Elling et al. 2011). Two patients presented in the report of PDGFRα-activating mutations were enrolled in the present study. This set of activating mutations induces clonogenic growth, growth factor-independent cell proliferation and constitutive phosphorylation of PDGFRα and signal transducer and activator of transcription 5 (STAT5) and is thought to play a role in the pathogenesis of CEL. Other genetic abnormalities associated with eosinophilia include fusions of fibroblast growth factor receptor 1 (FGFR1) or PDGFRβ, each occurring in <1 % of patients. More than 20 gene fusion partners for PDGFRβ and more than 10 for FGFR1 have been identified (Gotlib and Cools 2008; Cross and Reiter 2008).
Patients with HES or CEL, particularly those with the F/P mutation, are sensitive to treatment with the tyrosine kinase inhibitor (TKI) imatinib (Novartis Pharmaceuticals Corporation, January 2012), which is known to inhibit ABL1 and BCR-ABL1, as well as the discoidin domain receptor (DDR)-1 and -2, colony-stimulating factor 1 receptor (CSF1R), KIT, and PDGFRα and β (Buchdunger et al. 2001; Manley et al. 2010). Resistance and intolerance to imatinib develop in some patients, often due to the emergence of clones expressing mutant forms of PDGFRα that are less sensitive to imatinib inhibition (Lierman et al. 2006; Cools et al. 2003a, 2005). For example, the D842V mutation corresponds to the KIT D816V mutation, found in some patients with systemic mastocytosis or gastrointestinal stromal tumors, which confers resistance to imatinib and results in limited clinical activity of nilotinib and sorafenib (Metzgeroth et al. 2012). In addition, the T674I mutation is found in some resistant cases of F/P-positive CEL and is analogous to the T315I gatekeeper mutation in BCR-ABL1 that confers resistance to imatinib and second-generation TKIs (dasatinib, nilotinib and bosutinib) in patients with chronic myeloid leukemia (CML) (Lierman et al. 2006; Cools et al. 2003a, 2005).
Nilotinib is a TKI that inhibits ABL1, BCR-ABL1, DDR, CSF1R and KIT, as well as PDGFRα and β in vitro (Verstovsek et al. 2006; Stover et al. 2005; Manley et al. 2010). Follow-up data from a multicenter, phase 2, open-label registration trial demonstrated that nilotinib 400 mg twice daily continued to be safe and effective in patients with CML in chronic phase (Giles et al. 2013), accelerated phase (le Coutre et al. 2012) and blast phase (Giles et al. 2012) who were resistant to or intolerant of previous therapies and had a different adverse-effect profile to that of imatinib (Cortes et al. 2011). Nilotinib showed comparable effectiveness to imatinib in a xenograft model of CEL in which mice were injected with F/P-positive human CEL cells (Wicklein et al. 2012), and nilotinib has demonstrated activity in individual patients with HES/CEL who were intolerant or resistant to imatinib (Tabouret et al. 2011; Ikezoe et al. 2010). The present analysis evaluated the efficacy and safety of nilotinib 400 mg twice daily in patients with HES/CEL enrolled in the phase 2 nilotinib registration trial (CAMN107A2101, registered at ClinicalTrials.gov as NCT00109707).
Materials and methods
Patient population
Eligibility criteria for patients enrolled in the phase 2, multicenter A2101 trial have been previously described (Kantarjian et al. 2007). Briefly, for the phase 2 portion of the study, adult patients with hematologic malignancies were recruited into 6 parallel treatment arms. Patients who met the standard disease criteria for HES/CEL (Vandenberghe et al. 2004) and had clinical indications for treatment were recruited into the HES/CEL arm of the study and were assessed for efficacy according to a Simon 2-stage mini-max design. Patients were initially classified as either HES or CEL based on investigator assessment. Subsequently, patients with either an activating mutation in PDGFRα or presence of the F/P fusion protein were classified as CEL, and all other patients were classified as HES. Standard disease criteria for all patients in the study included eosinophilia >1,500/mm3 for at least 6 months; signs and symptoms of organ involvement; and exclusion of other causes of eosinophilia (e.g., clonal or abnormal T cell populations, reactive eosinophilia).
Previous imatinib use was permitted, but not required. A washout period of 5 days was required before starting this study. Key inclusion criteria consisted of World Health Organization (WHO) performance status of ≤2 and levels of potassium, total calcium and magnesium no lower than the lower limit of normal. Exclusion criteria included disease infiltration into the central nervous system and impaired cardiac function (including a left ventricular ejection fraction <45 %, congenital long QT syndrome or corrected QT interval using Fridericia’s correction (QTcF >450 ms).
Dosing
Nilotinib 400 mg twice daily was selected as the study dose based on safety and pharmacokinetic data and preliminary efficacy data from the phase 1 portion of this study (Kantarjian et al. 2006). One treatment cycle included 28 days of continuous dosing with nilotinib 400 mg twice daily. Patients remained on nilotinib treatment until disease progression or unacceptable toxicity. Patients responding to therapy were allowed to enter an extension study after 24 months of treatment and continued to receive drug. The extension study was ongoing at the time of data cutoff on November 18, 2008.
Dose modifications, including dose reductions and dose interruptions, were allowed for patients who developed intolerance to nilotinib. Patients with treatment interruptions >21 days were discontinued from the study, except in the case of hematologic toxicity, whereby treatment interruptions >42 days required discontinuation from the trial. Patients discontinuing due to adverse events (AEs) were followed up until resolution or stabilization of the AE. All patients were followed up for 28 days after the final dose of nilotinib for possible development of AEs.
Study objectives
The primary efficacy endpoint was the rate of complete hematologic response (CHR), as assessed by the investigator. CHR involved normalization of PB counts, including eosinophil counts, and complete disappearance of all signs and symptoms of disease (i.e., normal white blood cell and platelet counts, absence of blasts and promyelocytes in the PB, absence of extramedullary involvement, and <5 % eosinophils and <5 % blasts in the BM). Organ dysfunction was not considered as a response parameter. Partial hematologic response (PHR) was defined as ≥50 % reduction in total white blood cell count and absolute eosinophil count compared with study entry (without normalization of these parameters), and ≥50 % reduction in PB and BM blasts (if >5 % BM and/or PB blasts at study entry) compared with the start of the study. Stable disease included no change in the range of peripheral eosinophil counts or any response not meeting CHR, PHR or progressive disease criteria. Progressive disease was defined as ≥50 % increase over baseline in BM or PB blasts and/or eosinophils, or interval development of extramedullary disease, or in patients who responded to treatment, a return to pretreatment eosinophil counts.
The secondary efficacy endpoint was overall survival, which was estimated using the Kaplan–Meier method. The analysis of overall survival included all deaths occurring during treatment or after discontinuation of study drug.
There is no standardized method to detect F/P transcripts. Biomarker assessment of F/P transcript status was performed using real-time quantitative reverse-transcription polymerase chain reaction (RQ-PCR) and direct sequencing methods (Metzgeroth et al. 2008, 2012; Elling et al. 2011). PB or BM samples were collected prior to nilotinib dosing. The rate of hematologic response and overall survival stratified by F/P mutation status at baseline or after baseline was assessed.
Complete molecular response (CMR) was determined in patients with CEL and defined as the loss of clonal markers (F/P or PDGFRα-activating mutations, as determined by RQ-PCR or direct sequencing of PB or BM samples) during the course of the treatment. CMR was summarized by mutation status in patients with CEL.
Toxicity was assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 (National Cancer Institute 2006). Patients were carefully monitored for cardiac changes occurring during the study. AEs and hematologic and nonhematologic laboratory abnormalities were assessed.
Study ethics
Written informed consent was obtained from all patients according to institutional guidelines. The study was conducted in accordance with the Declaration of Helsinki, and the protocol was reviewed and approved by the ethics board or institutional review board at each participating trial center.
Results
Baseline patient characteristics
A total of 16 patients were enrolled in the HES/CEL arm of the A2101 study: 12 with HES and 4 with CEL. Baseline demographic and disease characteristics are presented in Table 1. The median patient age was 62 years (range 25–84). Patients in the HES arm were generally older (65 years; range 42–84) than in the CEL arm (38 years; range 25–67]). WHO performance status was 0 or 1 in most patients (93.8 %); 1 patient with HES had a WHO performance status of 2. The median time since diagnosis of HES/CEL was 10.7 months (range 0.2–192.7), with disease duration shorter in the HES arm (7.2 months; range 0.2–128) than in the CEL arm (19.6 months; range 2.1–192.7). Five patients (31.3 %; 3 with HES and 2 with CEL) had received no previous treatment for HES/CEL.
Table 1.
Baseline characteristics
| Baseline characteristics | HES (n = 12) | CEL (n = 4) | Total (N = 16) |
|---|---|---|---|
| Median age, years (range) | 65 (42–84) | 38 (25–67) | 62 (25–84) |
| Male, n (%) | 9 (75.0) | 4 (100) | 13 (81.3) |
| WHO performance status, n (%) | |||
| Grade 0 | 6 (50.0) | 3 (75.0) | 9 (56.3) |
| Grade 1 | 5 (41.7) | 1 (25.0) | 6 (37.5) |
| Grade 2 | 1 (8.3) | 0 | 1 (6.3) |
| Median time since diagnosis of HES/CEL, months (range) | 7.2 (0.2–128.0) | 19.6 (2.1–192.7) | 10.7 (0.2–192.7) |
| <6 months, n (%) | 4 (33.3) | 1 (25.0) | 5 (31.3) |
| 6 months to <1 year, n (%) | 3 (25.0) | 0 | 3 (18.8) |
| 1 year to <2 years, n (%) | 1 (8.3) | 2 (50.0) | 3 (18.8) |
| 2 years to <5 years, n (%) | 3 (25.0) | 0 | 3 (18.8) |
| ≥5 years, n (%) | 1 (8.3) | 1 (25.0) | 2 (12.5) |
| No previous treatment, n (%) | 3 (25.0) | 2 (50.0) | 5 (31.3) |
| FIP1L1-PDGFRα fusion, n (%) | |||
| Yes | 0 | 2 (50.0)a | 2 (12.5) |
| No | 10 (83.3) | 2 (50.0) | 12 (75.0) |
| Missing | 2 (16.7)b | 0 | 2 (12.5) |
| PDGFRα-activating mutations, n (%) | 0 | 2 (50.0) | 2 (12.5) |
CEL chronic eosinophilic leukemia, FIP1L1-PDGFRα fusion of FIP1-like 1 and platelet-derived growth factor receptor α, HES hypereosinophilic syndrome, WHO World Health Organization
aOne of these 2 patients was FIP1L-PDGFRα positive 1.5 months after starting treatment (the only mutational assessment available). Based on the definition of CEL used in this study (i.e., the presence of clonal markers), this patient was considered FIP1L-PDGFRα positive at baseline
bThe 2 patients with missing baseline mutation data subsequently tested negative for the FIP1L-PDGFRα fusion
Extensive molecular analysis was performed using PB or BM at baseline and throughout the study. At baseline, 2 patients were F/P positive, 12 were F/P negative, and 2 had missing data. This included 1 patient with 1 mutational assessment 1 month after starting treatment; this patient was classified as F/P positive at baseline as per the definition of CEL (i.e., the presence of clonal markers). With subsequent analysis, the 2 patients with missing baseline data were determined to be F/P negative. Activating mutations in PDGFRα were identified in 2 F/P-negative patients: 1 patient had a Y849S mutation and 1 patient had both Y849S and L507P mutations (Elling et al. 2011). The CEL population included the 2 patients who were F/P positive and the 2 patients who had PDGFRα-activating mutations; all other patients did not have clonal genetic markers and were allocated to the HES population.
Patient disposition and exposure to drug
At the time of data cutoff, 3 patients (2 with CEL and 1 with HES) had entered the extension study and 13 patients had discontinued treatment (Table 2). Patients received a median of 778 mg of nilotinib per day (range 193–800) for a median of 95 days (range 3–1,079). This includes 5 patients (31.3 %) who were exposed to nilotinib for less than 1 month. The median dose received was close to the planned total daily dose of 800 mg. One-half of patients (50.0 %) were treated with nilotinib for a minimum of 3 months, and 31.3 % of patients received nilotinib for at least 6 months. Eleven patients (68.8 %) had a nilotinib dose reduction and nearly one-third (31.3 %) had a dose interruption. Dose interruptions lasted a median of 18 days (range 2–21). Interruptions constituted a median of 12.7 % of total dosing days (range 1.8–60.0).
Table 2.
Patient’s disposition
| Disposition | HES (n = 12) | CEL (n = 4) | Total (N = 16) |
|---|---|---|---|
| Total patients treated | 12 (100.0) | 4 (100.0) | 16 (100.0) |
| Entered extension studya | 1 (8.3) | 2 (50.0) | 3 (18.8) |
| Discontinued core treatment | 11 (91.7) | 2 (50.0) | 13 (81.3) |
| Adverse event(s) | 4 (33.3) | 1 (25.0) | 5 (31.3) |
| Disease progression | 4 (33.3) | 1 (25.0) | 5 (31.3) |
| Administrative reasonsb | 2 (16.7) | 0 | 2 (12.5) |
| Withdrew consent | 1 (8.3) | 0 | 1 (6.3) |
CEL chronic eosinophilic leukemia, HES hypereosinophilic syndrome
aEnrolled in the ongoing extension portion of the study at the time of data cutoff
bTwo patients were discontinued under the category “administrative reasons” and were reported as having an unsatisfactory therapy effect (no response)
Efficacy
Three patients (18.8 %) had a CHR to nilotinib 400 mg twice daily, 2 with CEL and 1 with HES (Table 3). None of these 3 had previous treatment with a TKI. No patient had a PHR in this study. Stable disease was observed in 4 patients (25.0 %; 3 with HES and 1 with CEL). Three patients (18.8 %), all with HES, had disease progression. Six patients (37.5 %; 5 with HES and 1 with CEL) were not evaluable for hematologic response.
Table 3.
Best responses and overall survival after a median follow-up of 32 months (ITT population)
| HES (n = 12) | CEL (n = 4) | Total (N = 16) | |
|---|---|---|---|
| Best hematologic response | |||
| Overall response, n (%; 95 % CI) | 1 (8.3; 0.2–38.5) | 2 (50.0; 6.8–93.2) | 3 (18.8; 4.0–45.6) |
| CR | 1 (8.3) | 2 (50.0) | 3 (18.8) |
| PR | 0 | 0 | 0 |
| Absence of response, n (%) | 11 (91.7) | 2 (50.0) | 13 (81.3) |
| SD | 3 (25.0) | 1 (25.0) | 4 (25.0) |
| PD | 3 (25.0) | 0 | 3 (18.8) |
| NE | 5 (41.7) | 1 (25.0) | 6 (37.5) |
| Overall survival, % (95 % CI) | |||
| 6 months | 83.3 (62.3–100) | 100 (100–100) | 87.5 (71.3–100) |
| 12 months | 75.0 (50.5–99.5) | 100 (100–100) | 81.3 (62.1–100) |
| 18 months | 75.0 (55.5–99.5) | 100 (100–100) | 81.3 (62.1–100) |
| 24 months | 75.0 (50.5–99.5) | 100 (100–100) | 81.3 (62.1–100) |
CEL chronic eosinophilic leukemia, CHR complete hematologic response, HES hypereosinophilic syndrome, ITT intention to treat, NE not evaluable, PD progressive disease, PHR partial hematologic response, SD stable disease
No patients with CEL died during the study, whereas the deaths of 3 patients with HES were reported. Overall survival at 24 months was 75.0 % (95 % CI 50.5–100.0) in patients with HES, with the median overall survival not yet reached after a median follow-up of 32 months (Fig. 1).
Fig. 1.
Overall survival (intention-to-treat population). CEL chronic eosinophilic leukemia, HES hypereosinophilic syndrome
Response according to mutation status
Response was assessed according to the underlying genetic event in patients with CEL (Table 4). Of the 2 patients with an F/P fusion, both achieved a CHR. One of these 2 patients tested positive for F/P at screening (BM and PB) and after 1 and 2 months of treatment (PB only); this patient then had 2 negative results after 2.5 and 5.5 months of treatment (BM samples), suggesting a CMR. In the other F/P-positive patient, no molecular follow-up data are available. Of the 2 patients with PDGFRα-activating mutations, 1 achieved stable disease and 1 was not evaluable for hematologic response. The patient with stable disease was not evaluable for molecular response. The patient not evaluable for hematologic response achieved a CMR by losing the PDGFRα-activating mutation during the study; the Y849S mutation was found at screening and was absent 1.5 months after starting treatment (both samples from PB).
Table 4.
Hematologic and molecular response by clonal marker present at baseline in patients with CEL
| CEL patient no. | Clonal marker at baseline | Best hematologic response | Molecular response |
|---|---|---|---|
| 1 | FIP1L1-PDGFRα | CR | NE (no subsequent mutation analysis) |
| 2 | FIP1L1-PDGFRα | CR | CMR (F/P not detected after 2.5 and 5.5 months of treatment) |
| 3 | PDGFRα activating (L507P, Y849S) | SD | NE (no subsequent mutation analysis) |
| 4 | PDGFRα activating (Y849S) | NE | CMR (mutation not detected after 1.5 months of treatment) |
CEL chronic eosinophilic leukemia, CMR complete molecular response, CR complete response, FIP1L1-PDGFRα fusion of FIP1-like 1 and platelet-derived growth factor receptor α, NE not evaluable, PDGFRα platelet-derived growth factor receptor α, SD stable disease
Safety
All patients reported at least 1 AE. Drug-related AEs of any grade were experienced by 15 patients (93.8 %), with grade 3/4 drug-related AEs occurring in 9 patients (56.3 %). The most frequent drug-related nonhematologic AEs of any grade included pruritus (37.5 %), rash (31.3 %), fatigue (25.0 %) and headache (25.0 %) (Table 5).The most common grade 3/4 AE was pruritus (12.5 %). Gastrointestinal and skin toxicities were consistent with the overall safety profile for nilotinib in other diseases.
Table 5.
Most common study drug-related nonhematologic AEs (occurring in ≥2 patients) and newly occurring or worsening grade 3/4 laboratory abnormalities
| HES (n = 12) | CEL (n = 4) | Total (N = 16) | ||||
|---|---|---|---|---|---|---|
| Any grade | Grade 3/4 | Any grade | Grade 3/4 | Any grade | Grade 3/4 | |
| Nonhematologic AEs occurring in >10 % of patients, n (%) | ||||||
| Pruritus | 5 (41.7) | 2 (16.7) | 1 (25.0) | 0 | 6 (37.5) | 2 (12.5) |
| Rash | 4 (33.3) | 1 (8.3) | 1 (25.0) | 0 | 5 (31.3) | 1 (6.3) |
| Fatigue | 4 (33.3) | 0 | 0 | 0 | 4 (25.0) | 0 |
| Headache | 3 (25.0) | 0 | 1 (25.0) | 0 | 4 (25.0) | 0 |
| Diarrhea | 3 (25.0) | 0 | 0 | 0 | 3 (18.8) | 0 |
| Nausea | 2 (16.7) | 0 | 1 (25.0) | 0 | 3 (18.8) | 0 |
| Peripheral edema | 2 (16.7) | 0 | 1 (25.0) | 0 | 3 (18.8) | 0 |
| Arthralgia | 2 (16.7) | 1 (8.3) | 0 | 0 | 2 (12.5) | 1 (6.3) |
| Dyspepsia | 2 (16.7) | 0 | 0 | 0 | 2 (12.5) | 0 |
| Papule | 2 (16.7) | 0 | 0 | 0 | 2 (12.5) | 0 |
| Abdominal pain | 1 (8.3) | 0 | 1 (25.0) | 1 (25.0) | 2 (12.5) | 1 (6.3) |
| Angina pectoris | 1 (8.3) | 0 | 1 (25.0) | 0 | 2 (12.5) | 0 |
| Bone pain | 1 (8.3) | 0 | 1 (25.0) | 0 | 2 (12.5) | 0 |
| Myalgia | 1 (8.3) | 1 (8.3) | 1 (25.0) | 0 | 2 (12.5) | 1 (6.3) |
| HES | CEL | Total | ||||
|---|---|---|---|---|---|---|
| Laboratory abnormality, n/N (%)a | ||||||
| Hematologic | ||||||
| Lymphocytopenia | 3/12 (25.0) | 2/4 (50.0) | 5/16 (31.3) | |||
| Neutropenia | 2/12 (16.7) | 2/4 (50.0) | 4/16 (25.0) | |||
| Prothrombin time (INR) | 1/10 (10.0) | 0/3 | 1/13 (7.7) | |||
| Thrombocytopenia | 1/12 (8.3) | 0/4 | 1/16 (6.3) | |||
| Anemia | 1/12 (8.3) | 0/4 | 1/16 (6.3) | |||
| Nonhematologic, n/N a (%) | ||||||
| Increased serum lipase | 1/11 (9.1) | 2/4 (50.0) | 3/15 (20.0) | |||
| Decreased serum phosphate | 1/11 (9.1) | 2/4 (50.0) | 2/15 (13.3) | |||
| Increased serum bilirubin (total) | 2/12 (16.7) | 0/4 | 2/16 (12.5) | |||
| Decreased sodium | 1/11 (9.1) | 0/4 | 1/15 (6.7) | |||
| Increased potassium | 0/11 | 1/4 (25.0) | 1/15 (6.7) | |||
AEs adverse events, CEL chronic eosinophilic leukemia, HES hypereosinophilic syndrome; INR international normalized ratio
a n/N, where n is the number of patients experiencing the event and N is the number of patients who had <grade 4 at baseline and were evaluable post-baseline
Newly occurring or worsening grade 3/4 hematologic laboratory abnormalities included lymphocytopenia (31.3 %), neutropenia (25.0 %), increased prothrombin time (international normalized ratio, 7.7 %), thrombocytopenia (6.3 %) and anemia (6.3 %) (Table 5). Newly occurring or worsening grade 3/4 biochemical laboratory abnormalities included increased levels of lipase (20.0 %), bilirubin (12.5 %) and potassium (6.7 %), and decreased levels of serum phosphate (13.3 %) and sodium (6.7 %).
Patients were monitored for cardiac changes occurring during the study. A QTcF increase >60 ms from baseline occurred in 1 patient; QTcF in this patient remained normal (413 ms), but this patient subsequently discontinued treatment due to noncardiac myopathy. The investigator did not consider the myopathy or the QT prolongation to be study drug-related. No patient had a QTcF > 480 ms.
Five patients (31.3 %) discontinued from the study because of ≥1 AE. The most frequent AEs leading to discontinuation were endocarditis fibroplastica, sepsis, acute pancreatitis, general physical health deterioration, myopathy, asthma, pruritus and rash, each occurring in 1 patient. One patient died within 28 days of treatment discontinuation. This patient died due to endocarditis fibroplastica and sepsis, which occurred within the 28-day follow-up period; the investigator did not attribute these AEs to the study drug.
Discussion
Patients with HES/CEL can be treated with a variety of modalities, including glucocorticoids, hydroxyurea, interferon-α, allogeneic stem cell transplantation and TKIs; however, with the exception of TKIs, responses to many of these agents are typically short lived (Butterfield and Weiler 2012; Valent et al. 2012). While imatinib has shown high rates of response in patients with CEL with the F/P mutation, the response is less robust in patients with HES without this abnormality (Butterfield 2009; Vandenberghe et al. 2004; Pardanani and Tefferi 2004; Metzgeroth et al. 2008). Because of the rare responses observed in F/P-negative patients, it is possible that F/P is not the only molecular target of imatinib in patients with HES (Pardanani and Tefferi 2004). The approval for use of imatinib in patients with HES/CEL was based on an open-label, multicenter phase 2 study (n = 14) as well as 35 published case reports and case series (n = 162) (Novartis Pharmaceuticals Corporation, January 2012). CHR was achieved in 61 of 61 (100 %) patients positive for F/P, 12 of 56 (21 %) F/P-negative patients and 34 of 59 (58 %) patients with unknown F/P status. PHR was achieved in 9 of 56 (16 %) F/P-negative patients and 7 of 59 (12 %) patients with unknown F/P status. Response duration ranged from 6 weeks to 44 months. Similarly, in a phase 2 study, 13/15 (87 %) F/P-positive patients achieved CMR within 12 months of imatinib treatment, whereas CHR was only achieved in 6/15 (40 %) of patients without a known mutation (Metzgeroth et al. 2008). In another prospective study of patients with HES, 5 of 36 patients without the F/P mutation (14 %) achieved CHR, but response was lost in all cases after 1–15 months of treatment (Baccarani et al. 2007). In the same study, 27 of 27 patients with the F/P mutation (100 %) achieved both CHR and CMR; both types of response were maintained until last contact (range 15–60 months).
The recommended starting dose of imatinib for patients with HES is 100 mg daily. Higher doses of imatinib (up to 400 mg daily) are generally required to elicit a response in the absence of the F/P mutation (Cools et al. 2003a; Metzgeroth et al. 2008; Butterfield 2009; Roufosse 2009). While the incidence of imatinib resistance is infrequent in patients with HES/CEL, some events have been reported (Gotlib and Cools 2008). Resistance and intolerance to imatinib develop in some patients, often due to the emergence of clones expressing mutant forms of PDGFRα, which are less sensitive to inhibition with imatinib (Gotlib and Cools 2008). PDGFRα T674I is analogous to the T315I mutation in BCR-ABL that confers imatinib resistance in patients with CML (Cools et al. 2003a, 2005; Lierman et al. 2006; Metzgeroth et al. 2012). PDGFRα D842V is analogous to the D816V mutation in KIT that confers resistance to several TKIs and is often found in patients with systemic mastocytosis (Metzgeroth et al. 2012).
Several agents have demonstrated activity against F/P, with or without the T674I mutation. The TKIs ponatinib, sorafenib and dasatinib have demonstrated inhibition of F/P; ponatinib and sorafenib had activity against the T674I mutant; and dasatinib showed activity against F/P without the T674I mutation (Lierman et al. 2006, 2012; Baumgartner et al. 2008). Nilotinib is not effective against the PDGFRα D842V mutation (Stover et al. 2005) and is not likely to be effective against the T674I mutation because it is also ineffective against the BCR-ABL T315I mutation (Soverini et al. 2007). In a murine model, the multikinase inhibitor midostaurin (PKC412) showed activity against PDGFRα T674I (Cools et al. 2003b). Midostaurin has also shown activity against KIT D816V in patients with mastocytosis (Gotlib et al. 2010, 2012) and thus may be a rational alternative therapy in HES/CEL patients with the imatinib-resistant D842V mutation. Clinical studies have shown that monoclonal antibodies directed toward interleukin-5 (e.g., mepolizumab and reslizumab) and toward CD52 (e.g., alemtuzumab) can be used to treat patients with HES/CEL (Rothenberg et al. 2008; Klion et al. 2004; Verstovsek et al. 2009). Although an initial response (as measured by hematologic improvements or tapering of glucocorticoid doses) was achieved, relapse in eosinophil counts to prebaseline levels occurred after stopping treatment with reslizumab and alemtuzumab.
Nearly one-third of patients (31.3 %) were exposed to nilotinib for less than 1 month, which could have contributed to the low response rate observed in this study. Although the rate of response was low, overall survival was more than 80 % at 24 months and the median overall survival was not reached after a median follow-up of 32 months. In the CEL group, 4 of 4 patients survived throughout the follow-up period and the 2 patients with the F/P fusion achieved a CHR, with 1 of these patients achieving CMR. While this suggests that nilotinib increases survival in patients with CEL, the small number of patients precludes any definitive conclusions. The reported survival rate for patients with HES is 80 % at 5 years (Gotlib et al. 2004) and less than 50 % at 10 years (Verstovsek 2007). In a recent study, patients with CEL had a median survival of 22.2 months (range 2.2–186.2) from diagnosis to death (Helbig et al. 2012). Based on the present study, it is unclear whether nilotinib may prolong survival in patients with HES/CEL. One patient died of endocarditis fibroplastica within 28 days of study treatment, which could be a symptom of progressive disease rather than an adverse event attributable to treatment. Additional long-term studies are warranted to confirm any association of treatment with nilotinib and clinical benefit in this population.
The AE profile of nilotinib in patients with HES/CEL was similar to the known safety profile of nilotinib in other hematologic malignancies (Kantarjian et al. 2007; Novartis Pharmaceuticals Corporation, May 2012). The relatively high rate of grade 3/4 AEs was consistent with a study population that has substantial underlying disease. Given the limitations of the data, it is difficult to draw firm conclusions about the activity of nilotinib in this population relative to the presence or absence of F/P mutations, but it is clear that a CHR or CMR can be achieved in some patients, even in the absence of F/P. Additional studies are needed to determine the potential utility of nilotinib in patients with HES/CEL.
Acknowledgment
Financial support for medical editorial assistance was provided by Novartis Pharmaceuticals Corporation. The authors thank Erinn Goldman, PhD, and Pamela Tuttle, PhD, for medical editorial assistance with this manuscript.
Conflict of interest
AH received research funding from Novartis Pharmaceuticals Corporation. PDlC received research funding from Novartis and honoraria as a speaker from Novartis, Bristol-Myers Squibb (BMS), Pfizer, and ARIAD Pharmaceuticals. HMK received research funding from Novartis Pharmaceuticals Corporation, Pfizer, ARIAD Pharmaceuticals, and BMS. MB acted as a consultant, received honoraria and attended a speakers’ bureau for Novartis Pharmaceuticals Corporation, BMS, and Pfizer. PE has no financial conflicts to disclose. AR acted as a consultant and received honoraria from Novartis Pharmaceuticals Corporation. TM and XF are employees of Novartis Pharmaceuticals Corporation. SN is an employee and stockholder of Novartis Pharmaceuticals Corporation. FJG acted as a consultant and received research funding from Novartis Pharmaceuticals Corporation.
References
- Baccarani M, Cilloni D, Rondoni M, Ottaviani E, Messa F, Merante S et al (2007) The efficacy of imatinib mesylate in patients with FIP1L1-PDGFRalpha-positive hypereosinophilic syndrome. Results of a multicenter prospective study. Haematologica 92(9):1173–1179 [DOI] [PubMed] [Google Scholar]
- Baumgartner C, Gleixner KV, Peter B, Ferenc V, Gruze A, Remsing Rix LL et al (2008) Dasatinib inhibits the growth and survival of neoplastic human eosinophils (EOL-1) through targeting of FIP1L1-PDGFRalpha. Exp Hematol 36(10):1244–1253 [DOI] [PubMed] [Google Scholar]
- Buchdunger E, Matter A, Druker BJ (2001) Bcr-abl inhibition as a modality of CML therapeutics. Biochim Biophys Acta 1551(1):M11–M18 [DOI] [PubMed] [Google Scholar]
- Butterfield JH (2009) Success of short-term, higher-dose imatinib mesylate to induce clinical response in FIP1L1-PDGFRalpha-negative hypereosinophilic syndrome. Leuk Res 33(8):1127–1129 [DOI] [PubMed] [Google Scholar]
- Butterfield JH, Weiler CR (2012) Treatment of hypereosinophilic syndromes—the first 100 years. Semin Hematol 49(2):182–191 [DOI] [PubMed] [Google Scholar]
- Cools J, DeAngelo DJ, Gotlib J, Stover EH, Legare RD, Cortes J et al (2003a) A tyrosine kinase created by fusion of the PDGFRA and FIP1L1 genes as a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome. N Engl J Med 348(13):1201–1214 [DOI] [PubMed] [Google Scholar]
- Cools J, Stover EH, Boulton CL, Gotlib J, Legare RD, Amaral SM et al (2003b) PKC412 overcomes resistance to imatinib in a murine model of FIP1L1-PDGFRalpha-induced myeloproliferative disease. Cancer Cell 3(5):459–469 [DOI] [PubMed] [Google Scholar]
- Cools J, Maertens C, Marynen P (2005) Resistance to tyrosine kinase inhibitors: calling on extra forces. Drug Resist Updat 8(3):119–129 [DOI] [PubMed] [Google Scholar]
- Cortes JE, Hochhaus A, le Coutre PD, Rosti G, Pinilla-Ibarz J, Jabbour E et al (2011) Minimal cross-intolerance with nilotinib in patients with chronic myeloid leukemia in chronic or accelerated phase who are intolerant to imatinib. Blood 117(21):5600–5606 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Crane MM, Chang CM, Kobayashi MG, Weller PF (2010) Incidence of myeloproliferative hypereosinophilic syndrome in the United States and an estimate of all hypereosinophilic syndrome incidence. J Allergy Clin Immunol 126(1):179–181 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Cross NC, Reiter A (2008) Fibroblast growth factor receptor and platelet-derived growth factor receptor abnormalities in eosinophilic myeloproliferative disorders. Acta Haematol 119(4):199–206 [DOI] [PubMed] [Google Scholar]
- Elling C, Erben P, Walz C, Frickenhaus M, Schemionek M, Stehling M et al (2011) Novel imatinib-sensitive PDGFRA-activating point mutations in hypereosinophilic syndrome induce growth factor independence and leukemia-like disease. Blood 117(10):2935–2943 [DOI] [PubMed] [Google Scholar]
- Giles FJ, Kantarjian HM, le Coutre PD, Baccarani M, Mahon FX, Blakesley RE et al (2012) Nilotinib is effective in imatinib-resistant or -intolerant patients with chronic myeloid leukemia in blastic phase. Leukemia 26(5):959–962 [DOI] [PubMed] [Google Scholar]
- Giles FJ, le Coutre PD, Pinilla-Ibarz J, Larson RA, Gattermann N, Ottmann OG et al (2013) Nilotinib in imatinib-resistant or imatinib-intolerant patients with chronic myeloid leukemia in chronic phase: 48-month follow-up results of a phase II study. Leukemia 27(1):107–112 [DOI] [PubMed] [Google Scholar]
- Gotlib J (2012) World health organization-defined eosinophilic disorders: 2012 update on diagnosis, risk stratification, and management. Am J Hematol 87(9):903–914 [DOI] [PubMed] [Google Scholar]
- Gotlib J, Cools J (2008) Five years since the discovery of FIP1L1-PDGFRA: what we have learned about the fusion and other molecularly defined eosinophilias. Leukemia 22(11):1999–2010 [DOI] [PubMed] [Google Scholar]
- Gotlib J, Cools J, Malone JM III, Schrier SL, Gilliland DG, Coutre SE (2004) The FIP1L1-PDGFRalpha fusion tyrosine kinase in hypereosinophilic syndrome and chronic eosinophilic leukemia: implications for diagnosis, classification, and management. Blood 103(8):2879–2891 [DOI] [PubMed] [Google Scholar]
- Gotlib J, DeAngelo DJ, George TI, Corless CL, Linder A, Langford C et al (2010) KIT inhibitor midostaurin exhibits a high rate of clinically meaningful and durable responses in advanced systemic mastocytosis: report of a fully accrued phase II trial. Blood 116(21): abstract 316 [Google Scholar]
- Gotlib J, Kluin-Nelemans HC, George TI, Akin C, Sotlar K, Hermine O et al (2012) KIT inhibitor midostaurin in patients with advanced systemic mastocytosis: Results of a planned interim analysis of the global CPKC412D2201 trial. Blood 120(Suppl): abstract 799 [Google Scholar]
- Helbig G, Moskwa A, Hus M, Piszcz J, Swiderska A, Urbanowicz A et al (2010) Clinical characteristics of patients with chronic eosinophilic leukaemia (CEL) harbouring FIP1L1-PDGFRA fusion transcript–results of Polish multicentre study. Hematol Oncol 28(2):93–97 [DOI] [PubMed] [Google Scholar]
- Helbig G, Soja A, Bartkowska-Chrobok A, Kyrcz-Krzemien S (2012) Chronic eosinophilic leukemia-not otherwise specified has a poor prognosis with unresponsiveness to conventional treatment and high risk of acute transformation. Am J Hematol 87(6):643–645 [DOI] [PubMed] [Google Scholar]
- Ikezoe T, Togitani K, Tasaka T, Nishioka C, Yokoyama A (2010) Successful treatment of imatinib-resistant hypereosinophilic syndrome with nilotinib. Leuk Res 34(8):e200–e201 [DOI] [PubMed] [Google Scholar]
- Kantarjian H, Giles F, Wunderle L, Bhalla K, O’Brien S, Wassmann B et al (2006) Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL. N Engl J Med 354(24):2542–2551 [DOI] [PubMed] [Google Scholar]
- Kantarjian HM, Giles F, Gattermann N, Bhalla K, Alimena G, Palandri F et al (2007) Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is effective in patients with Philadelphia chromosome-positive chronic myelogenous leukemia in chronic phase following imatinib resistance and intolerance. Blood 110(10):3540–3546 [DOI] [PubMed] [Google Scholar]
- Klion AD, Law MA, Noel P, Kim YJ, Haverty TP, Nutman TB (2004) Safety and efficacy of the monoclonal anti-interleukin-5 antibody SCH55700 in the treatment of patients with hypereosinophilic syndrome. Blood 103(8):2939–2941 [DOI] [PubMed] [Google Scholar]
- le Coutre PD, Giles FJ, Hochhaus A, Apperley JF, Ossenkoppele GJ, Blakesley R et al (2012) Nilotinib in patients with Ph + chronic myeloid leukemia in accelerated phase following imatinib resistance or intolerance: 24-month follow-up results. Leukemia 26(6):1189–1194 [DOI] [PubMed] [Google Scholar]
- Lierman E, Folens C, Stover EH, Mentens N, Van Miegroet H, Scheers W et al (2006) Sorafenib is a potent inhibitor of FIP1L1-PDGFRalpha and the imatinib-resistant FIP1L1-PDGFRalpha T674I mutant. Blood 108(4):1374–1376 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lierman E, Smits S, Cools J, Dewaele B, Debiec-Rychter M, Vandenberghe P (2012) Ponatinib is active against imatinib-resistant mutants of FIP1L1-PDGFRA and KIT, and against FGFR1-derived fusion kinases. Leukemia 26(7):1693–1695 [DOI] [PubMed] [Google Scholar]
- Loules G, Kalala F, Giannakoulas N, Papadakis E, Matsouka P, Speletas M (2009) FIP1L1-PDGFRA molecular analysis in the differential diagnosis of eosinophilia. BMC Blood Disord 9:1 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Manley PW, Stiefl N, Cowan-Jacob SW, Kaufman S, Mestan J, Wartmann M et al (2010) Structural resemblances and comparisons of the relative pharmacological properties of imatinib and nilotinib. Bioorg Med Chem 18(19):6977–6986 [DOI] [PubMed] [Google Scholar]
- Metzgeroth G, Walz C, Erben P, Popp H, Schmitt-Graeff A, Haferlach C et al (2008) Safety and efficacy of imatinib in chronic eosinophilic leukaemia and hypereosinophilic syndrome: a phase-II study. Br J Haematol 143(5):707–715 [DOI] [PubMed] [Google Scholar]
- Metzgeroth G, Erben P, Martin H, Mousset S, Teichmann M, Walz C et al (2012) Limited clinical activity of nilotinib and sorafenib in FIP1L1-PDGFRA positive chronic eosinophilic leukemia with imatinib-resistant T674I mutation. Leukemia 26(1):162–164 [DOI] [PubMed] [Google Scholar]
- National Cancer Institute (2006) Common terminology criteria for adverse events (CTCAE), version 3.0
- Novartis Pharmaceuticals Corporation (January 2012) Gleevec [package insert]
- Novartis Pharmaceuticals Corporation (May 2012) Tasigna [package insert]
- Pardanani A, Tefferi A (2004) Imatinib therapy for hypereosinophilic syndrome and eosinophilia-associated myeloproliferative disorders. Leuk Res 28(Suppl 1):S47–S52 [DOI] [PubMed] [Google Scholar]
- Roche-Lestienne C, Lepers S, Soenen-Cornu V, Kahn JE, Lai JL, Hachulla E et al (2005) Molecular characterization of the idiopathic hypereosinophilic syndrome (HES) in 35 French patients with normal conventional cytogenetics. Leukemia 19(5):792–798 [DOI] [PubMed] [Google Scholar]
- Rothenberg ME, Klion AD, Roufosse FE, Kahn JE, Weller PF, Simon HU et al (2008) Treatment of patients with the hypereosinophilic syndrome with mepolizumab. N Engl J Med 358(12):1215–1228 [DOI] [PubMed] [Google Scholar]
- Roufosse F (2009) Hypereosinophilic syndrome variants: diagnostic and therapeutic considerations. Haematologica 94(9):1188–1193 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Roufosse FE, Goldman M, Cogan E (2007) Hypereosinophilic syndromes. Orphanet J Rare Dis 2:37 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Soverini S, Iacobucci I, Baccarani M, Martinelli G (2007) Targeted therapy and the T315I mutation in Philadelphia-positive leukemias. Haematologica 92(4):437–439 [DOI] [PubMed] [Google Scholar]
- Stover EH, Chen J, Lee BH, Cools J, McDowell E, Adelsperger J et al (2005) The small molecule tyrosine kinase inhibitor AMN107 inhibits TEL-PDGFRβ and FIP1L1-PDGFRα in vitro and in vivo. Blood 106(9):3206–3213 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Tabouret E, Charbonnier A, Mozziconacci MJ, Ivanov V (2011) Low-dose nilotinib can maintain complete molecular remissions in FIP1L1/PDGFRA-positive hypereosinophilic syndrome. Leuk Res 35(1):136 [DOI] [PubMed] [Google Scholar]
- Valent P, Klion AD, Rosenwasser LJ, Arock M, Bochner BS, Butterfield JH et al (2012) ICON: eosinophil disorders. World Allergy Organ J 5(12):174–181 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Vandenberghe P, Wlodarska I, Michaux L, Zachee P, Boogaerts M, Vanstraelen D et al (2004) Clinical and molecular features of FIP1L1-PDFGRA (+) chronic eosinophilic leukemias. Leukemia 18(4):734–742 [DOI] [PubMed] [Google Scholar]
- Verstovsek S (2007) New hematological indications for imatinib. Eur Oncol Dis 1(2):26–28 [Google Scholar]
- Verstovsek S, Giles FJ, Quintas-Cardama A, Manshouri T, Huynh L, Manley P et al (2006) Activity of AMN107, a novel aminopyrimidine tyrosine kinase inhibitor, against human FIP1L1-PDGFR-alpha-expressing cells. Leuk Res 30(12):1499–1505 [DOI] [PubMed] [Google Scholar]
- Verstovsek S, Tefferi A, Kantarjian H, Manshouri T, Luthra R, Pardanani A et al (2009) Alemtuzumab therapy for hypereosinophilic syndrome and chronic eosinophilic leukemia. Clin Cancer Res 15(1):368–373 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Wicklein D, Ramos Leal N, Salamon J, Thamer M, Herrmann H, Valent P et al (2012) Nilotinib and imatinib are comparably effective in reducing growth of human eosinophil leukemia cells in a newly established xenograft model. PLoS One 7(2):e30567 [DOI] [PMC free article] [PubMed] [Google Scholar]