A single weekly dose of imatinib is sufficient to induce and maintain remission of chronic eosinophilic leukaemia in FIP1L1-PDGFRA-expressing patients

Hypereosinophilic syndrome (HES) is defined as chronic, unexplained hypereosinophilia with organ involvement. A subset of HES patients presents an interstitial deletion in chromosome 4q12, which leads to the expression of an imatinib-responsive fusion gene, FIP1L1-PDGFRA. These patients are diagnosed as chronic eosinophilic leukaemia (CEL). We treated seven CEL and HES patients, six of which expressed FIP1L1-PDGFRA , with imatinib using initial daily doses ranging from 100 to 400 mg. In a remission maintenance phase, the patients were treated with imatinib once weekly. All imatinib-treated patients achieved a complete haematological remission (CHR), and five of the six patients with FIP1L1-PDGFRA expression exhibited molecular remission. The decreased imatinib doses were as follows: 200 mg/week in three patients, 100 mg/week in two patients and 100 mg/d in the remaining two patients. For remission maintenance, imatinib doses were set at 100 mg/week in five patients and 200 mg/week in two patients. At a median follow-up of 30 months all patients remained in CHR and FIP1L1-PDGFRA expression was undetectable in five of the six FIP1L1-PDGFRA -expressing patients. These data suggest that a single weekly dose of imatinib is sufficient to maintain remission in FIP1L1-PDGFRA - positive CEL patients.     

Safety and efficacy of imatinib in chronic eosinophilic leukaemia and hypereosinophilic syndrome: a phase-II study

This study evaluated the efficacy and safety of imatinib in chronic eosinophilic leukaemia (CEL, n = 23) and hypereosinophilic syndrome (HES, n = 13). In CEL with FIP1L1-PDGFRA (n = 16) or various PDGFRB fusion genes (n = 5), complete haematological remission (CHR) was achieved in 95% (20/21) after 3 months. Complete molecular remission (CMR) was seen in 75% (12/16) of cases with FIP1L1-PDGFRA positive CEL by 6 months, and in 87% (13/15) after 12 months. CMR was achieved in three of five PDGFRB fusion positive patients after 3, 9 and 18 months respectively. All patients are currently on imatinib (100 mg; n = 13, 400 mg; n = 8) and no molecular relapse has yet been observed (median 26.7 months; range, 6.9-39.9). Imatinib was less effective in HES and CEL without known molecular aberration (n = 15); CHR was observed in 40% (6/15) of patients, two patients relapsed after 4.8 and 24.5 months. Three patients died due to imatinib-resistant progressive CEL (n = 2) or myocardial infarction (n = 1) unrelated to study treatment. Overall, imatinib was well tolerated with a low incidence of grade III/IV toxicities. These data confirmed the long-term efficacy of imatinib for PDGFR-rearranged CEL patients, and also showed that a minority of HES cases without known molecular aberrations may benefit from imatinib.     

Complete and long‐lasting cytologic and molecular remission of FIP1L1‐PDGFRA‐positive acute eosinophil myeloid leukaemia,treated with low‐dose imatinib monotherapy

Myeloproliferative neoplasms associated with FIP1L1‐PDGFR rearrangements represent a rare subset of myeloid and lymphoid malignancies, characterised by the presence of eosinophilia and abnormalities of PDGFRA, PDGFRB or FGFR1 genes. The fusion product of such genes is a tyrosine kinase oncoprotein sensitive to imatinib, which to date results to be the standard of care for FIP1L1‐PDGFRA‐positive chronic myeloproliferative disorders with eosinophilia. However, the coexistence of FIP1L1‐PDGFRA rearrangement associated with acute myeloid leukaemia is extremely rare. Here, we report a rare case of FIP1L1‐PDGFRA‐positive acute myeloid leukaemia, with marked peripheral blood and bone marrow eosinophilia, treated with low dose of imatinib monotherapy, achieving a rapid and long‐lasting complete cytologic and molecular remission, without need for intensive chemotherapy.     

Early and tardive skin adverse events in chronic myeloid leukaemia patients treated with imatinib

Imatinib related non-haematological side-effects are reported in <10% of chronic myeloid leukaemia patients and include oedema, weight gain, nausea, vomiting and muscle cramps. Cutaneous reactions are well-recognized events occurring mostly in patients treated at doses of 600 mg/d and higher, either in stable or progressive disease. We report on our experience relating to dermatological toxicities in imatinib treated CML patients showing a spectrum of skin reactions ranging from rashes to cutaneous carcinoma.     

Results of imatinib mesylate therapy in chronic myelogenous leukaemia with variant Philadelphia chromosome

Five to 10 per cent of patients with Philadelphia chromosome (Ph)-positive chronic myelogenous leukaemia (CML) have variant translocations involving chromosomes other than 9 and 22. We investigated the characteristics and outcome of patients with variant translocations treated with imatinib. Among 721 patients, 44 (6%) had variant translocations, involving one (n = 39) or two (n = 4) additional chromosomes. Nineteen patients (44%) were in chronic (12 previously untreated), 24 (55%) in accelerated and one (2%) in blastic phase. A major cytogenetic response was achieved in 14 (74%) patients treated in chronic phase and in 14 (58%) treated in accelerated phase. Six of 13 (46%) evaluable patients had deletion of derivative chromosome 9, and there was a trend for a lower response rate in these patients. We compared the 43 patients in chronic or accelerated phase to 678 patients with classic Ph treated with imatinib. The only significant difference in clinical characteristics was a higher frequency of accelerated phase among those with variant translocations (56%) compared with those with classic translocations (38%). No differences in outcome were evident. In a multivariate analysis, variant Ph translocations had no impact in response rate, overall survival or duration of response. We conclude that patients with variant Ph translocations have a similar prognosis to those with classic Ph translocations when treated with imatinib.     

Multiple joint effusions associated with high-dose imatinib therapy in a patient with chronic myelogenous leukaemia

Imatinib mesylate is a small molecule tyrosine kinase inhibitor that has significant efficacy in the treatment of chronic myelogenous leukaemia (CML). However, it is likely that patients with CML will require prolonged and perhaps life-long therapy. In general, the side-effects of imatinib therapy have been mild to moderate, with the large majority of patients tolerating prolonged periods of therapy. However, a minority of patients are completely intolerant of therapy, while others are able to remain on therapy despite significant side-effects. Here, we describe a novel form of fluid retention presenting as multiple joint effusions in a patient with advanced phase CML on high-dose imatinib, as well as successful measures that were undertaken to control this adverse event. Although fluid retention, including periorbital oedema, pleural and pericardial effusions, as well as life-threatening cerebral oedema have been previously described and attributed to imatinib, this is the first case of imatinib-associated polyarticular effusions that we are aware of. Further work will be required to confirm a casual relationship between imatinib therapy and this novel side-effect, as well as to determine the underlying pathophysiologic mechanisms.     

Effects of imatinib and interferon on primitive chronic myeloid leukaemia progenitors

Imatinib has impressive activity against chronic myeloid leukaemia (CML), but does not appear to completely eradicate the disease. Although responses to interferon-alpha (IFN) are slower and less dramatic than those to imatinib, they can be durable even after discontinuation of the drug. Unlike imatinib, the specific mechanisms responsible for IFN's clinical activity in CML are unknown. We found that IFN induced a G1 cell cycle arrest, as well as terminal differentiation, of the CML cell line KT-1 and CML CD34+ cells from clinical specimens. Myeloid growth factors augmented the antileukaemic activity of IFN, and neutralising antibodies directed against myeloid growth factors inhibited IFN's antileukaemic activity. We next directly compared the effects of imatinib and IFN against differentiated and primitive CML progenitors from newly-diagnosed patients. Although less active against CML granulocyte-macrophage colony forming units than imatinib, IFN was significantly more toxic to primitive CML progenitors responsible for the maintenance of long-term cultures. Imatinib and IFN appear to have divergent effects on CML progenitors at different stages of maturation, with imatinib more active against differentiated CML progenitors and IFN more active against primitive CML progenitors. The different target cells for these agents may explain the disparities in the kinetics and durability of their clinical responses. At least part of the clinical effect of IFN in CML appears to result from its ability to differentiate primitive CML progenitors.     

The hypereosinophilic syndromes: current concepts and treatments

The hypereosinophilic syndromes (HES) encompass a spectrum of diseases that have increased blood eosinophils and tissue damage in common. The clinical manifestations are protean and may involve any organ system, but especially the skin. Our understanding of these diseases has drastically changed over the past 15 years, along with new classifications that characterize patients with marked eosinophilia. One HES variant, myeloproliferative, is actually chronic eosinophilic leukaemia with a unique genetic marker, FIP1L1-PDGFRA . Such patients are well-controlled by administration of the kinase inhibitor, imatinib, and remissions appear durable with continued imatinib therapy. FIP1L1-PDGFRA is expressed in several cell lineages, thus explaining increases in neutrophils and mast cells in HES. The lymphocytic HES variant is associated with T-cell clones producing interleukin-5 (IL-5) and can evolve into lymphoma. While myeloproliferative and lymphocytic HES are well established and permit elimination of the term, idiopathic, to these varieties, most HES patients do not fall into these categories and are classified as complex (using the 2006 Workshop Report). A recent study showed that a monoclonal antibody to IL-5, mepolizumab, reduced glucocorticoid therapy in HES patients who did not possess the FIP1L1-PDGFRA mutation while controlling eosinophilia and preventing recurrence or progression of tissue damage. These advances augur well for continued progress in the understanding and treatment of HES.     

Chronic eosinophilic leukaemia (CEL): a distinct myeloproliferative disease

Chronic eosinophilic leukaemia has not yet been clearly defined, mainly due to the fact that it has not been conclusively shown as a monoclonal disease which should be separated from chronic myelogenous leukaemia, acute myelogenous leukaemia with eosinophilia (AML, FAB M4Eo), and the idiopathic hypereosinophilic syndrome.
We report a patient with a white blood cell count of 17.6 × 10⁹/l with 74% eosinophils, normal platelet count and haemoglobin. No blasts were seen in the peripheral blood and the percentage of blasts in the bone marrow was <3%. A diagnosis of chronic eosinophilic leukaemia was made. Chromosome analysis of a bone marrow aspirate disclosed a trisomy 15 together with loss of the Y chromosome. Moreover, FISH analysis on May-Grünwald-Giemsa-stained peripheral blood smears demonstrated trisomy 15 in the eosinophils. 3 months after initial diagnosis the patient went into blast crisis and died. The blast cells exhibited trisomy 15 and loss of the Y chromosome in a complex, aberrant karyotype.
In conclusion, the case shows that chronic eosinophilic leukaemia is a monoclonal, myeloproliferative disease with eosinophils as part of the malignant clone. Clinically, chronic eosinophilic leukaemia can be separated into a chronic phase and a blast crisis.