[Show abstract][Hide abstract] ABSTRACT: Abstract: E1345
Background: The Eosinophilias (Eos) encompass a broad range of nonhematologic (secondary or reactive) and hematologic (primary, clonal) disorders. Hypereosinophilia has been defined as a peripheral blood eosinophils (Eo) count greater than 1,500/mm3 The HES is characterized by marked unexplained blood and tissue Eos and defined (1975) by Chusid’s criteria: (1) blood Eo ≥1500/mm3 for longer than 6 months, (2) lack of evidence for parasitic, allergic, or other known causes of Eos, and (3) presumptive signs or sympthoms of organ involvement.
Disease prognosis relies on identifying the origin of Eos. The 2008 WHO establishes a semimolecular classification of eosinophilic disorders (ED) based on the presence of recurrent molecular alterations (PDGFRA, PDGFRB, or FGFR1), or of other clonal markers, and where HES is a diagnosis of exclusion. The incidence and prevalence of ED and HES is not well characterized, and also the frequency of PDGFRA rearrangement is really unknown, with a high median rate of 23% from 8 clinical studies, that probably depends from the selection bias of patients.
Aims: The aim of this study was to investigate the prevalence of ED in the Greater Romagna Area (AVR), an homogeneous large geographic area served by the Italian National Health System (INHS).
Methods: The Hub Laboratory (HL) of AVR serves more than one million (1.124.866 in 2012) inhabitants living in an area of about 5000 square km in North of Italy, that provides Laboratory Medicine service for all general practitioners and for all the hospitals of the INHS. It includes hematology laboratory, and genetic sections. The results of all the tests carried out by the HL since 2009, including the differential cell counts (DIFF), are stored in the LIS database. We downloaded from the LIS the DIFF results obtained in 2012 and selected the cases with ≥ 1.5 x109/L Eo among the 574.380 unique individuals with at least one DIFF. In order to verify if the first Chusid criteria for HES was satisfied we searched for other DIFF requests in the semesters before and after the selected cases and for Eo ≥ 1.5 x109/L in these DIFFs. For this total cohort of possible HES patients, we performed further data extraction from LIS with the intent to exclude the more frequent causes of secondary Eos (e.g. total IgE, fecal parasites, CRP, vitamin B12, bone marrow smears and cytogenetic). Moreover we matched the clinical records (InfoClin, LOG80, ONAMB) of the uncertain cases for final diagnosis.
Results: Of 574.380 unique individuals with one DIFF in 2012, 452 satisfied the first Chusid’s criteria, and on these cohort we will performed our investigations. Here we report the preliminary results on 44 patients (10% of the total cohort). We excluded 27 patients with secondary Eos (61,3%), and 15 asymptomatic patients no further investigated despite a persistent mild Eos (< 2.5 x 109/L), and finally we identified 2 patients with sign and sympthoms of HES, with a prevalence in the AVR of 0.034%. Of note, the 2 patients were male, and died in 3 and 15 months without evaluation of the presence of molecular rearrangements.
Summary: The low prevalence of HES (< 0.05%) is confirmed by these preliminary data. With the completion of this analysis we will achieve a better characterization of ED and, since we are investigating half of the resident population of AVR, also the real prevalence of these rare diseases will be known, including PDGFRA positive clonal disease, primary HES, but probably with the exclusion of the ED with specific tissue Eos without peripheral Eos.
[Show abstract][Hide abstract] ABSTRACT: Mast cell leukemia (MCL) is a very rare form of systemic mastocytosis (SM) with a short median survival of 6 months. We describe a case of a 65-year-old woman with aleukaemic variant of MCL with a very high serum total tryptase level of 2255 μg/L at diagnosis, which occurred following an episode of hypotensive shock. She fulfilled the diagnostic criteria of SM, with a bone marrow smear infiltration of 50-60% of atypical mast cells (MCs). She tested negative for the KIT D816V mutation, without any sign of organ damage (no B- or C-findings) and only few mediator-related symptoms. She was treated with antihistamine alone and then with imatinib for the appearance of anemia. She maintained stable tryptase level and a very indolent clinical course for twenty-two months; then, she suddenly progressed to acute MCL with a serum tryptase level up to 12960 μg/L. The patient died due to haemorrhagic diathesis twenty-four months after diagnosis. This clinical case maybe represents an example of the chronic form of mast cell leukemia, described as unpredictable disease, in which the serum total tryptase level has confirmed itself as a reliable marker of mast cells burden regardless of the presence of other signs or symptoms.
[Show abstract][Hide abstract] ABSTRACT: A 63-year-old woman with chronic myeloid leukemia (CML) received treatment with interferon (IFN)-α for 6 years. After achieving a complete cytogenetic response that was repetitively documented, IFN-α treatment was stopped. Despite maintenance of a complete cytogenetic response, a progressive rise of the BCR-ABL1 transcript was detected and loss of major molecular response occurred about 2 years after stopping IFN-α therapy. Disease remained at molecular level.
Peripheral blood quantitative real-time PCR every 3 months and periodical bone marrow aspirate were performed to monitor disease.
Chronic-phase, Philadelphia-positive CML that was still detectable after complete cytogenic response 2 years after cessation of IFN-α therapy.
The patient was treated with a target immune approach receiving a therapeutic vaccine that consisted of an immunogenic 25-mer b2a2 breakpoint-derived peptide (CMLb2a2-25) with binding properties for several HLA-DR molecules. After nine boosts of vaccine the patient developed an adequate b2a2-25 peptide-specific CD4(+) T-cell response and BCR-ABL1 transcript started to decline in peripheral blood. No hematological or extrahematological effects were documented during therapy. At the last evaluation, 39 months since vaccinations commenced, the patient is in complete molecular response with an undetectable level of BCR-ABL1 transcript both in peripheral blood and in bone marrow and she continues to receive boosts of vaccine every 3 months as the only treatment.
[Show abstract][Hide abstract] ABSTRACT: The aim of the study is to evaluate clinical features, treatments and outcome of patients with systemic mast cell disease (MCD) who arrived to the attention of hematologists. A retrospective study was conducted over 1995-2006 in patients admitted in 18 Italian hematological divisions. Twenty-four cases of advanced MCD were collected: 12 aggressive SM (50%), 8 mast cell leukemia (33%), 4 SM with associated clonal non-mast cell-lineage hematologic disease (17%). Spleen and liver were the principal extramedullary organ involved. The c-kit point mutation D816V was found in 13/18 patients in which molecular biology studies were performed (72%). Treatments were very heterogeneous: on the whole Imatinib was administered in 17 patients, alpha-Interferon in 8, 2-CdA in 3; 2 patients underwent allogeneic hematopoietic stem cell transplantation. The overall response rate to Imatinib, the most frequently employed drugs, was of 29%, registering one complete remission and four partial remission; all responsive patients did not present D816V c-kit mutation. Overall three patients (12%) died for progression of disease. We conclude that MCD is characterized by severe mediator-related symptoms but with a moderate mortality rate. D816V c-kit mutation is frequent and associated with resistance against Imatinib. Because of the rarity of these forms, an effective standard of care is lacking. More data are needed to find new and successful therapeutic strategies.
International journal of hematology 12/2008; 88(5):483-8. DOI:10.1007/s12185-008-0166-4 · 1.68 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The fusion protein between the platelet-derived growth factor receptor alpha (PDGFRalpha, P) gene and the Fip1-like1 (FIP1L1, F) may be identified in 14 to 60% of HES and it indicates a clonal hypereosinophilic syndrome called F/P-positive CEL. We herein report a case of F/P-positive CEL with retro-orbital localization, who was successfully treated with imatinib.
A 53-year-old male presented an absolute eosinophil count of 25,000/mm(3), anemia (Hb 10.2 g/dl) and a moderate increase in the platelet count (571,000/mm(3)). A clinical examination revealed left exophthalm, associated with diffuse hypoesthesia and diplopia. A CT scan of orbits showed a lesion located in the lachrymal fossa of the left orbit with intra- and extra-conical extension. Molecular analysis excluded the presence of bcr/abl transcript while a F/P fusion tyrosine kinase signal was documented. Imatinib mesylate (IM) was started and, after 7 days of treatment eosinophil count significantly declined along with a dramatic reduction of the left exophthalm. IM dosage was increased up to 300 mg/day. The drug was well tolerated with an initial modest haematological toxicity. The left exophthalm, as well as hypoesthesia and diplopia, disappeared after IM therapy. MRI showed a clear reduction of the intra- and extra-conical growth process. BM molecular signal of the F/P fusion gene resulted undetectable after 4 weeks of treatment.
In our case, the diagnosis of FIPIL1-PDGFRA-positive CEL and IM therapy has allowed the patient to experience an excellent clinical therapeutic result, avoiding surgical treatment of the retro-orbital mass.
Cancer Chemotherapy and Pharmacology 05/2008; 61(4):713-6. DOI:10.1007/s00280-007-0507-7 · 2.57 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We evaluated safety and efficacy of imatinib (600 mg) in 36 c-KIT+ acute myeloid leukemia patients not amenable to receive conventional chemotherapy. No patient achieved complete remission. One patient obtained a hematologic improvement (platelet increase with transfusion independence). Median overall survival was 3 months (0.5-44+). Non-hematologic toxicity was overall mild.
[Show abstract][Hide abstract] ABSTRACT: The treatment of hematologic malignancies has been based for many years on chemotherapy and possibly, for the more aggressive forms, stem cell transplantation. In 2001, the signal transduction inhibitor 571 (STI571, imatinib mesylate) was reported to have striking effects in chronic myeloid leukaemia patients. Since then, imatinib became the first molecular-targeted agent approved for the treatment of human cancer and was later on demonstrated to be effective in other malignancies, such as Philadelphia positive acute lymphoid leukemia, hypereosinophilic syndromes, gastrointestinal stromal tumours and more recently, systemic mastocytosis and other myeloprolipherative disease-carrying platelet-derived growth factor receptor abnormalities. In this article, the authors review the evidence which led to imatinib approval in the treatment of several of the above mentioned diseases.
[Show abstract][Hide abstract] ABSTRACT: The hypereosinophilic syndrome (HES) may be associated with the fusion of the platelet derived growth factor receptor a (PDGFRalpha) gene with the FIP1L1 gene in chromosome 4 coding for a constitutively activated PDGFRalpha tyrosine kinase. These cases with FIP1L1-PDGFRalpha rearrangement have been reported to be very sensitive to the tyrosine kinase inhibitor imatinib mesylate.
A prospective multicenter study of idiopathic or primary HES was established in 2001 (Study Protocol Registration no. NCT 0027 6929). One hundred and ninety-six patients were screened, of whom 72 where identified as having idiopathic or primary HES and 63 were treated with imatinib 100 to 400 mg daily.
Twenty-seven male patients carried the FIP1L1-PDGFRalpha rearrangement. All 27 achieved a complete hematologic remission (CHR) and became negative for the fusion transcripts according to reverse transcriptase polymerase chain reaction (RT-PCR) analysis. With a median follow-up of 25 months (15-60 months) all 27 patients remain in CHR and RT-PCR negative, and continue treatment at a dose of 100 to 400 mg daily. In three patients imatinib treatment was discontinued for few months, the fusion transcript became rapidly detectable, and then again undetectable upon treatment reassumption. Thirty-six patients did not carry the rearrangement; of these, five (14%) achieved a CHR, which was lost in all cases after 1 to 15 months.
All patients meeting the criteria for idiopathic or primary HES should be screened for the FIP1L1-PDGFRalpha rearrangement. For all patients with this rearrangement, chronic imatinib treatment at doses as low as 100 mg daily ensures complete and durable responses.
[Show abstract][Hide abstract] ABSTRACT: Idiopathic hypereosinophilic syndromes (HES) comprise a spectrum of indolent to aggressive diseases characterized by persistent hypereosinophilia. Hypereosinophilia can result from the presence of a defect in the hematopoietic stem cell giving rise to eosinophilia, it can be present in many myeloproliferative disorders or alternatively it may be a reactive form, secondary to many clinical conditions. The hybrid gene FIP1L1-PDGRFalpha was identified in a subset of patients presenting with HES or chronic eosinophilic leukemia (CEL). In spite of this, the majority of HES patients do not present detectable molecular lesions and for many of them the diagnosis is based on exclusion criteria and sometimes it remains doubt. In this study we explored the possibility to distinguish between HES/CEL and reactive hypereosinophilia based on WT1 transcript amount. For this purpose, 312 patients with hypereosinophilia were characterized at the molecular and cytogenetic level and analyzed for WT1 expression at diagnosis and during follow-up. This study clearly demonstrates that WT1 quantitative assessment allows to discriminate between HES/CEL and reactive eosinophilia and represents a useful tool for disease monitoring especially in the patients lacking a marker of clonality.
[Show abstract][Hide abstract] ABSTRACT: The FIP1L1-PDGFRA fusion gene is a recurrent molecular lesion in eosinophilia-associated myeloproliferative disorders, predicting a favorable response to imatinib mesylate. To investigate its prevalence, 376 patients with persistent unexplained hypereosinophilia were screened by the United Kingdom reference laboratory, revealing 40 positive cases (11%). To determine response kinetics following imatinib, real-time quantitative-polymerase chain reaction (RQ-PCR) assays were developed and evaluated in samples accrued from across the European LeukemiaNet. The FIP1L1-PDGFRA fusion transcript was detected at a sensitivity of 1 in 10(5) in serial dilution of the EOL-1 cell line. Normalized FIP1L1-PDGFRA transcript levels in patient samples prior to imatinib varied by almost 3 logs. Serial monitoring was undertaken in patients with a high level of FIP1L1-PDGFRA expression prior to initiation of imatinib (100 mg/d-400 mg/d). Overall, 11 of 11 evaluable patients achieved at least a 3-log reduction in FIP1L1-PDGFRA fusion transcripts relative to the pretreatment level within 12 months, with achievement of molecular remission in 9 of 11 (assay sensitivities 1 in 10(3)-10(5)). In 2 patients, withdrawal of imatinib was followed by a rapid rise in FIP1L1-PDGFRA transcript levels. Overall, these data are consistent with the exquisite sensitivity of the FIP1L1-PDGFRalpha fusion to imatinib, as compared with BCR-ABL, and underline the importance of RQ-PCR monitoring to guide management using molecularly targeted therapies.