Acute Leukemias

Recurrent finding of the FIP1L1-PDGFRA fusion gene in eosinophilia-associated acute myeloid leukemia and lymphoblastic T-cell lymphoma

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Abstract

The FIP1L1-PDGFRA fusion gene has been described in patients with eosinophilia-associated myeloproliferative disorders (Eos-MPD). Here, we report on seven FIP1L1-PDGFRA-positive patients who presented with acute myeloid leukemia (AML, n=5) or lymphoblastic T-cell non-Hodgkin-lymphoma (n=2) in conjunction with AML or Eos-MPD. All patients were male, the median age was 58 years (range, 40–66). AML patients were negative for common mutations of FLT3, NRAS, NPM1, KIT, MLL and JAK2; one patient revealed a splice mutation of RUNX1 exon 7. Patients were treated with imatinib (100 mg, n=5; 400 mg, n=2) either as monotherapy (n=2), as maintenance treatment after intensive chemotherapy (n=3) or in overt relapse 43 and 72 months, respectively, after primary diagnosis and treatment of FIP1L1-PDGFRA-positive disease (n=2). All patients are alive, disease-free and in complete hematologic and complete molecular remission after a median time of 20 months (range, 9–36) on imatinib. The median time to achievement of complete molecular remission was 6 months (range, 1–14). We conclude that all eosinophilia-associated hematological malignancies should be screened for the presence of the FIP1L1-PDGFRA fusion gene as they are excellent candidates for treatment with tyrosine kinase inhibitors even if they present with an aggressive phenotype such as AML.

Introduction

Eosinophilia is commonly associated with a large number of disparate non-clonal and clonal disorders. In the majority of cases it is caused by reactive conditions including atopy or allergies, autoimmune disorders or infection. In rare cases, a hematological disorder may be associated with sustained eosinophilia, which can be either non-clonal or clonal. The term idiopathic hypereosinophilic syndrome (HES) is used when the blood eosinophil count is persistently greater than 1.5 × 109/l for at least 6 months, with damage to end organs such as heart, gastrointestinal tract, skin, joints or nervous system and no evidence of clonality.1, 2, 3

Clonal eosinophilia is most frequently associated with chronic myeloproliferative disorders (Eos-MPD), and particularly chronic eosinophilic leukemia (CEL). It is only rarely seen in myelodyplastic syndromes (MDS) or acute leukemias.4 Cytogenetic analysis has identified a number of rare, acquired reciprocal chromosomal translocations in morphologically variable subtypes of Eos-MPDs or MDS. Notably, two clear break point clusters have been identified at chromosome bands 5q31–33 and 8p11 that target the platelet-derived growth factor receptor B (PDGFRB) and the fibroblast growth factor receptor 1 (FGFR1) genes, respectively.1, 5, 6 More recently, a cytogenetically cryptic deletion that targets PDGFRA was identified in patients with Eos-MPD leading to a FIP1L1-PDGFRA fusion gene.7, 8, 9 All these rearrangements generate constitutively active tyrosine kinase fusion proteins which are structurally and functionally analogous to BCR-ABL in chronic myeloid leukemia (CML) and therefore ideal targets for signal transduction therapy. Imatinib is active against platelet-derived growth factor receptors and patients with fusions involving these genes generally achieve complete hematologic and complete cytogenetic remission, with many achieving complete molecular remission.10, 11, 12

Thus far the FIP1L1-PDGFRA fusion has only been described in patients with CEL (usually presenting as idiopathic hypereosinophilic syndrome). We report here that FIP1L1-PDGFRA is also found in patients with acute myeloid leukemia (AML) and lymphoblastic T-cell non-Hodgkin-lymphoma (T-NHL) consistent with the hypothesis that this fusion gene arises in a pluripotent stem cell. Furthermore, we demonstrate the efficacy of imatinib in FIP1L1-PDGFRA-positive hematological malignancies even if they present with an aggressive clinical phenotype.

Materials and methods

Patients

FIP1L1-PDGFRA fusion status was determined by nested reverse transcription-polymerase chain reaction (RT-PCR) in peripheral blood (PB) or bone marrow (BM) samples (n=580) sent from across Germany for investigation of persistent unexplained eosinophilia. Details of individual patients' history and all available laboratory tests plus morphological and histological features of blood or marrow, respectively, were thoroughly screened in all FIP1L1-PDGFRA-positive patients (n=36, 6%).

Twenty-nine patients were diagnosed as CEL. The FIP1L1-PDGFRA fusion gene was also found in five patients with previously diagnosed AML, one patient with contemporaneously diagnosed AML and lymphoblastic T-NHL and one patient with contemporaneously diagnosed Eos-MPD and lymphoblastic T-NHL. All patients were male, the median age at diagnosis was 58 years (range, 40–66). AML patients presented with various subtypes of AML according to the FAB classification (M0, n=2; M2, n=2; M4, n=1; T-NHL and acute eosinophilic leukemia, n=1) and all cases were negative for the CBFB-SMMHC fusion gene, commonly associated with eosinophilia in AML. Diagnosis of AML M0 was confirmed by immunophenotyping revealing myeloid (CD13, CD33) but no lymphoid markers (CD7, TdT, CD19, CD79a and CD10). Detailed clinical data are summarized in Table 1. In addition, we studied 22 cases with peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS). The study was approved by Ethics Committee of participating institutions and informed consent was provided according to the Declaration of Helsinki.

Table 1 Patients' characteristics

Cytogenetic analysis

BM cells were cultured for 24 or 48 h. Metaphases were analyzed after G-banding or R-banding and karyotypes were described according to the International System for Human Cytogenetic Nomenclature (2005).

Characterization of FIP1L1-PDGFRA fusion sequences by RT-PCR and genomic PCR

RNA and DNA were extracted from PB or BM samples by standard procedures after isolation of total leukocytes following red cell lysis using standard techniques (Qiagen, Hilden, Germany). Nested RT-PCR for the detection of the FIP1L1-PDGFRA fusion gene was performed on BM and blood samples as described.7, 13 Primers derived from sequences flanking the putative genomic break points within FIP1L1 and PDGFRA were used in various combinations to amplify the forward genomic junction sequences from DNA by long-template PCR (LT-PCR) following the manufacturers7 instructions (Roche Diagnostics, Mannheim, Germany). Amplified products were sequenced either directly or after cloning using the TOPO cloning kit (Invitrogen, Leek, The Netherlands). The sequences of the primers are available on request.

Fluorescence in situ hybridization and immunostaining

A two-color fluorescence in situ hybridization (FISH) approach for the detection of the CHIC2 deletion as a surrogate marker for the FIP1L1-PDGFRA fusion gene at 4q12 was used on conventional paraffin-embedded lymph node biopsies from the two patients with T-NHL according to standard procedures.9, 14 In addition, immunostaining with CD3 antibodies was used in combination with FISH to confirm the presence of the FIP1L1-PDGFRA fusion gene in T cells. Bacterial artificial chromosome (BAC) clones 120K16 (centromeric of FIP1L1), 3H20 (between FIP1L1 and PDGFRA) and 24010 (telomeric of PDGFRA) from were used as probes. The FISH signals were evaluated as follows: a fusion was seen as the appearance of an orange signal as the result of overlapped green and red signals (3H20-green signal, BAC 120K16-red signal and BAC 24010-red signal), a deletion was detected using a combination of BAC 120K16-red signal and 3H20-green signal. The 3H20 signal is lost in cases with the FIP1L1-PDGFRA fusion (Figure 1). A deletion of one of the CHIC2 alleles results in one green and two red signals.

Figure 1
figure1

Two-color interphase FISH in a CD3+ T-lymphocyte. Deletion of one of the CHIC2 alleles results in loss of the green signal (RP11-3H20), which is usually located next to the red signal (RP11-24O10 and RP11-120K16 in red) in the nuclei of a CD3+ T-lymphocyte obtained from a lymph node biopsy of a patient with lymphoblastic T-NHL.

Mutation analysis

RNA extraction and cDNA synthesis was performed using standard procedures. Since acquired, activating mutations of FLT3, NRAS, NPM1, KIT and MLL are frequently found in AML, respective samples were screened for known mutations of those genes as described previously:15, 16, 17, 18, 19 length mutations within the juxtamembrane domain of FLT3, point mutations within the tyrosine kinase domain of FLT3 and KIT, point mutations of NRAS at codons 12, 13 and 61, point mutations of NPM1 and partial tandem duplications (PTD) of MLL. AML M0 cases were screened for mutations within RUNX1 using cDNA coding for the whole coding region of variant AML1b.20 In addition, all cases were screened for the presence of the JAK2 V617F mutation.

Results

Acute myeloid leukemia

Screening for the FIP1L1-PDGFRA fusion gene was initiated by clinicians because of significant eosinophilia (>1500/μl) before and/or at diagnosis of AML (UPN 1–4, 6) and because of persisting eosinophilia after achievement of otherwise complete hematologic remission after intensive chemotherapy (UPN 2, 3 and 5). The presence of FIP1L1-PDGFRA was confirmed in all cases by amplification and sequencing of the RNA fusion sequences by RT-PCR and of the genomic DNA fusion sequences by LT-PCR and bubble-PCR.21

Details of the positive patients are summarized in Table 1. The median time of known eosinophilia (n=5) before diagnosis of AML was 6 months (range, 2–186). One patient relapsed 72 months after intensive chemotherapy of an eosinophilia-associated AML (Eos-AML) M0 with typical features of FIP1L1-PDGFRA-positive CEL in accelerated phase with 25% blasts and promyelocytes in the marrow (UPN 4). The presence of the FIP1L1-PDGFRA fusion gene could be confirmed in samples derived from initial diagnosis of AML and overt relapse of AML 72 months later. UPN 5 revealed about 70–80% blasts in the marrow and interphase-FISH analysis demonstrated FIP1L1-PDGFRA-positive cells in more than 90% of all marrow cells clearly indicating that blast cells were indeed FIP1L1-PDGFRA-positive. None of the common mutations of FLT3, NRAS, NPM1, KIT, MLL or JAK2 could be identified in any of the AML samples. In a single patient with AML M0 (UPN 2) a deletion of RUNX1 exon 7 (according to exon 7b of AML1b) was detected, most likely due to a splice site mutation within intron 6.

Lymphoblastic T-NHL

The FIP1L1-PDGFRA fusion gene was also found in two patients with a lymphoblastic T-NHL. In both patients, inguinal lymph node biopsies revealed diffuse infiltration by blast cells with interspersion of small areas with neutrophilic and eosinophilic granulocytes. Both T-NHLs (UPN 6 and 7) were of T-lymphoblastic subtype (CD1+, CD3+, CD4+, CD10+, TdT+, CD34+, Ki67 proliferation index of 70 and 90%, respectively) with involvement of multiple lymph nodes and diffuse infiltration of the marrow. Expression of B-cell markers (CD20, FMC-7 and CD79a) was very weak or not detectable. Screening for the presence of the FIP1L1-PDGFRA fusion gene in lymph node biopsies was initiated because of a contemporaneously diagnosed FIP1L1-PDGFRA-positive AML (UPN 6) or because of a 3-year-history of significant hypereosinophilia before diagnosis of T-NHL and persisting eosinophilia for 3 years, whereas in complete clinical and hematologic remission after several cycles of intensive chemotherapy (UPN 7). A CHIC2 deletion was present in more than 50% of lymph node cells in both cases (UPN 6 and 7). The presence of the CHIC2 deletion in cells of lymphoid origin was confirmed by combination of FISH analysis and immunostaining with antibodies against CD3 (UPN 7, Figure 1).

Peripheral T-cell lymphoma, not otherwise specified

Although PTCL-NOS is not usually associated with eosinophilia, global gene expression analysis has revealed overexpression of PDGFRA.22 Given the finding of FIP1L1-PDGFRA in T-NHL above, we hypothesized that this overexpression might be a consequence of a cryptic PDGFRA fusion gene. As all break points involving this gene are tightly clustered within exon 12, we tested BM or lesion DNA from 20 cases of PTCL-NOS for PDGFRA rearrangements by bubble-PCR. This strategy has been used successfully to identify a variant PDGFRA fusion in CEL.21 For all cases of PTCL-NOS, however, only normal PDGFRA was amplified.

FIP1L1-PDGFRA fusion sequences

The details of FIP1L1-PDGFRA fusion sequences are presented in Table 1. In chronic-phase disease a truncated PDGFRA exon 12 is most frequently fused to regularly spliced FIP1L1 exons 10, 11, 12 or 13. With exception of FIP1L1 exon 13, which is fused to a truncated PDGFRA exon 12 in about 20% of all cases (European LeukemiaNet, unpublished), the same FIP1L1 exons (10, 11 and 12) were involved in our series. Therefore, we could not identify any obvious sequence features, for example, location of breakpoints and presence or length of inserts, which could explain the more aggressive phenotype.

Treatment

All 7 FIP1L1-PDGFRA-positive patients were treated with 100 mg (n=5) or 400 mg (n=2) imatinib per day (Figure 2). The median time from diagnosis of AML or T-NHL to start of imatinib was 6 months (range, 1–72). Treatment was well tolerated and all patients are still on imatinib (median 20 months, range, 9–36) at the date of analysis. Four patients received imatinib as monotherapy because of (i) morbidity (UPN 1, 100 mg), (ii) overt relapse as accelerated phase Eos-MPD diagnosed 72 months after conventional intensive chemotherapy of FIP1L1-PDGFRA-positive Eos-AML M0 (UPN 4, 400 mg), (iii) patients' decision (UPN 6, 400 mg) or (iv) persisting eosinophilia and diagnosis of FIP1L1-PDGFRA-positive MPD in chronic-phase 43 months after diagnosis and treatment of FIP1L1-PDGFRA-positive T-NHL (UPN 7, 100 mg), which was otherwise in complete clinical and hematologic remission. Three patients (UPN 2, 3 and 5) received imatinib (100 mg) as maintenance treatment after intensive chemotherapy of AML (one course, n=1; two courses, n=2). All patients are currently alive, disease-free and in complete hematologic and complete molecular remission. The median time to achievement of complete molecular remission was 6 months (range, 1–14) after start of treatment as determined by nested RT-PCR.

Figure 2
figure2

Response to imatinib. All patients achieved a rapid complete hematologic remission, defined as a complete clearance of blasts and normalization of eosinophil counts, and a complete molecular remission as determined by nested RT-PCR.

Discussion

The occurrence of significant eosinophilia in blood and marrow of patients with AML (Eos-AML) is rare and usually found in association with a CBFB-SMMHC fusion gene in AML M4Eo with inv(16)/t(16;16) or in a minority of patients with an AML1-ETO fusion gene in AML M1 or M2 with a t(8;21). Acute eosinophilic leukemia is diagnosed in less than 1% of all AML cases and a substantial proportion of patients present with a normal karyotype. However, recent reports have highlighted the association of Eos-AML with recurrent breakpoint clusters at chromosome bands 5q31–33, 8p11 and 9p24. Molecular analysis demonstrated that these clusters are linked to the tyrosine kinase genes PDGFRB, FGFR1 and JAK2, respectively. In consequence, fusion genes are created encoding novel chimeric kinase proteins, which are constitutively active in the absence of the natural ligands resulting in deregulation of hemopoiesis in a manner that is similar to BCR-ABL in CML.23, 24

Here, we report on a larger series of patients with AML and associated FIP1L1-PDGFRA fusion gene, which has otherwise been described almost exclusively in Eos-MPD. Thus far, only two patients have been reported with FIP1L1-PDGFRA-positive AML.7, 25 Of interest, both patients developed AML during treatment with imatinib and progression was associated with a T674I mutation. This mutation is homologous to the imatinib-resistant T315I BCR-ABL mutation in CML. All but one of the FIP1L1-PDGFRA-positive AML patients of our series presented with a history of marked eosinophilia indicating the evolvement of a ‘CML-like’ chronic-phase disease to blast crisis or secondary AML.26 The additional finding of a PTD within the MLL gene led to the suggestion that FIP1L1-PDGFRA and mutated MLL may cooperate to cause the progression of CEL to AML. As other acquired mutations of FLT3, NRAS, NPM1, KIT and MLL are also thought to play a substantial role in the pathogenesis of AML,15, 16, 17, 18, 19, 27 we have checked all cases for the presence or absence of these common mutations. In contrast to the EOL-1 cell line, we could not identify any of these mutations in the presented FIP1L1-PDGFRA-positive AMLs indicating that they are not involved in the transformation process of FIP1L1-PDGFRA-positive MPD.28 Only one patient with an AML M0 carried a deletion/splice site mutation of RUNX1 exon 7. The detailed analysis of FIP1L1-PDGFRA fusion sequences did not allow to draw any conclusions regarding the predicted location of break points and the clinical phenotype in comparison to own (European LeukemiaNet, unpublished) and other series.7, 26

These data clearly demonstrate distinct clinical and morphological differences between CBF-associated Eos-AML and TK-associated Eos-AML. Whereas CBFB-SMMHC and AML1-ETO fusion genes are predominantly found in de novo AML, the majority of patients with TK-associated Eos-AML, for example, ZNF198-FGFR1 and PCM1-JAK2, present similar to FIP1L1-PDGFRA-positive AML with a history of variable intervals of a ‘CML-like’ chronic-phase myeloproliferative disorder with eosinophilia.29 Marrow fibrosis and increased numbers of mast cells are indicative for a TK-associated Eos-AML (Table 1). In contrast to CBF fusion genes, some of the TK fusion genes are also found in de novo B-ALL, for example, PCM1-JAK2, or secondary ‘blast-crisis-like’ B-ALL, for example, PCM1-JAK2 or BCR-PDGFRA. This is similar to the variable phenotypes of de novo or secondary acute leukemias of myeloid or lymphoid origin in association with the BCR-ABL fusion gene.

Increased numbers of mast cells identified by conventional morphology and immunostaining with tryptase were found in three of three patients with available biopsies. However, positivity of CD2 and CD25 was only found in one patient. The association of the FIP1L1-PDGFRA gene with various eosinophilia-associated hematological malignancies including MPD, AML and T-NHL and the recently shown presence of the FIP1L1-PDGFRA fusion gene in multiple cell lineages, including myeloid, lymphoid and mast cells,14 indicate that the FIP1L1-PDGFRA-positive MPD is rather a distinct stem cell disorder with a variable phenotype including marrow fibrosis and increased numbers of mast cells rather than a pure mast cell disease with associated eosinophilia.

These data also demonstrate the association of the FIP1L1-PDGFRA fusion gene with lymphoblastic T-NHL. Eosinophilia is a common finding in T-NHLs and thought to be reactive in the vast majority of cases caused by overproduction of eosinophilopoietic cytokines such as IL3, IL5 and GM-CSF.30 Clonal eosinophilia in association with a T-NHL is generally very rare but regularly found in the 8p11 myeloproliferative syndrome or stem cell leukemia-lymphoma syndrome, which is associated with rearrangements of the FGFR1 gene on chromosome band 8p11.5, 31 The unique clinical phenotype of Eos-MPD in conjunction with T-cell lymphoma and progression to AML has now been reported in association with two distinct receptor-tyrosine kinases, FGFR1 and PDGFRA. Furthermore, the demonstration of FIP1L1-PDGFRA in both myeloid and T cells clearly indicates that this disease, like CML, is a stem cell disorder.

It has recently been shown that FIP1L1-PDGFRA-positive MPDs respond very well to low (50–100 mg per day) or intermittent (once daily to once weekly) doses of imatinib based on the 250-fold lower IC50 as compared to BCR-ABL.12 The vast majority of patients achieve rapid complete hematologic and complete molecular remission within weeks. Strikingly, we have demonstrated here also an excellent response in patients who presented with a more aggressive phenotype such as AML or T-NHL with all patients being in complete molecular remission for a median time of 20 months after start of imatinib. This is in stark contrast to blast crisis of BCR-ABL positive CML, in which any responses to imatinib are very short lived. However, regular monitoring of residual disease in FIP1L1-PDGFRA cases is important as the emergence of an imatinib-resistant T674I mutation in the ATP-binding site has been described in two patients during treatment.7, 25 This mutation is homologous to the T315I BCR-ABL mutation in CML, which is also resistant to nilotinib and dasatinib. However, it was recently shown that the T674I FIP1L1-PDGFRA mutation responds to PKC412 and sorafenib.32, 33

In conclusion, we have demonstrated that FIP1L1-PDGFRA is seen in diverse eosinophilia-associated hematological disorders and that these patients show an excellent response to imatinib. We suggest that all patients who present with eosinophilia-associated hematological malignancies should be screened for the cytogenetically invisible FIP1L1-PDGFRA fusion gene by RT-PCR and/or FISH analysis, as they are excellent candidates for treatment with tyrosine kinase inhibitors even if they present with an aggressive phenotype.

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Acknowledgements

This work was supported by the ‘Deutsche José Carreras Leukämie-Stiftung e.V.’ (CW, AR, Grant no. DJCLS R06/02), Germany, the Leukaemia Research Fund, United Kingdom, the Competence Network ‘Acute and chronic leukemias’, sponsored by the German Bundesministerium für Bildung und Forschung (Projektträger Gesundheitsforschung; DLR e.V. – 01GI9980/6) and the ‘European LeukemiaNet’ within the 6th European Community Framework Programme for Research and Technological Development.

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Correspondence to A Reiter.

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Keywords

  • FIP1L1-PDGFRA
  • acute myeloid leukemia
  • lymphoblastic T-NHL

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