A Case of Acute Myeloid Leukemia Harboring a Rare Three-Way Translocation t(5;7;7) Involving the PDGFRB Gene and Successfully Treated with Imatinib

Introduction

Platelet-derived growth factor (PDGF) is a dimeric protein composed of two receptor tyrosine kinases, α and β, encoded by the PDGFRA (4q12) and PDGFRB (5q32) genes.¹ PDGFRB gene rearrangements create chimeric proteins that can cause constitutive tyrosine kinase activity, which leads to upregulation of transcription factors affecting cell growth and survival.^2,3 The first described, and most common PDGFRB rearrangement, is the (5;12)(q33;p13) translocation with ETV6; however, approximately 30 other different fusion partners of PDGFRB have been identified to date.^4–8

Myeloid and lymphoid neoplasms with eosinophilia associated with PDGFR or fibroblast growth factor receptor 1 (FGFR-1) rearrangements are grouped into their own clinical entity according to the World Health Organization (WHO) classification, although eosinophilia may be absent in a subset of cases with these rearrangements.⁹ The PDGFRB fusion genes have been reported in all major groups of myeloid neoplasms including myelodysplastic syndrome (MDS)/myeloproliferative neoplasms (MPN), acute myeloid leukemia (AML), and in lymphoid neoplasms, such as B-cell and T-cell acute lymphoblastic leukemias (ALL).^5,6,10–12 Among patients with MPNs, PDGFRB rearrangement is seen in approximately 2% of patients and is associated with leukocytosis, eosinophilia and anemia.¹³ The presence of PDGFRB rearrangement is associated with excellent response to imatinib, including in patients that have failed standard chemotherapy.^4,14–18

We report a case of a 29-year-old man who initially presented with AML and achieved a complete response (CR) after induction chemotherapy. However, when he was admitted for consolidation chemotherapy, he was found to have an elevated white cell count of 35,000/mm³, for which a repeat bone marrow biopsy with cytogenetic analysis was performed. He was subsequently found to have an MPN harboring a unique three-way translocation t(5;7;7)(q33.2;q32;q11.2) involving the PDGRB gene. The patient achieved a good response with the addition of imatinib to his consolidation chemotherapy and subsequently underwent an allogeneic stem cell transplant (alloSCT).

Case Presentation

Our patient was a 29-year-old male who presented with loss of vision in the right eye. He also reported fatigue, dyspnea, night sweats and left upper quadrant fullness for approximately one month before presentation. His initial complete blood count revealed a total leukocyte count of 380,000/mm³ with 66% blasts, 5% segmented neutrophils, 8% monocytes, 3% eosinophils, and other immature myeloid cells (Table 1). He was anemic and thrombocytopenic with a hemoglobin of 7.8 gm/dL and a platelet count of 35,000/mm³. A bone marrow biopsy was a diagnostic of AML with monocytic differentiation. There were no FLT3 nor NPM1c terminal mutations. Cytogenetic analysis showed a 3-way translocation involving chromosome 5 and both chromosomes 7 with breakpoints at 5q33.2, 7q32 and 7q11.2 [(46, XY,t(5;7;7)(q33.2;q32;q11.2)] as the only abnormality (Figure 1). Interphase fluorescence in situ hybridization (FISH) was positive for PDGFRB rearrangement. Metaphase FISH with PDGFRB and with whole chromosome painting probes to chromosomes 5 and 7 confirmed the 3-way translocation and showed that sequences 5ʹ to PDGFRB were translocated to the derivative chromosome 7 with the 7q32 breakpoint (Figure 2). For other PDGFRB fusions, the critical oncogenic fusion is on the derivative chromosome 5, which retains the 3ʹ portion of PDGFRB (Figure 3). Thus, the partner gene for this unidentified PDGFRB rearrangement appeared to lie at the 7q11.2 breakpoint (Figure 4). BCR-ABL1 fusion was not observed. The patient was started on induction chemotherapy with cytarabine and daunorubicin (7+3). Bone marrow biopsies on days 14 and 28 were negative for AML consistent with a successful induction.

Table 1 Peripheral Blood and Bone Marrow Trends Throughout Treatment Course

Figure 1 Karyotype. 46,XY,t(5;7;7) (q33.2; q32; q11.2). Arrows indicate the direction of the transfer of chromosomal material between the derivative chromosomes 5, 7 and 7.

Figure 2 Metaphase FISH using break apart probes for 3ʹPDGFRB (red signal) and 5ʹPDGFRB (green signal). Arrow A shows the normal chromosome 5 with an intact PDGFRB fusion signal (yellow). Arrow B shows the derivative chromosome 5 containing only the 3ʹ portion of PDGFRB (red signal). Arrow C shows the derivative chromosome 7 with the translocated 5ʹ portion of PDGFRB (green signal).

Figure 3 Whole chromosome 5 paint with green fluorescent probes. Arrow A shows the normal chromosome 5 with fluorescence label seen throughout the chromosome indicating intact chromosomal material. Arrow B shows the derivative chromosome 5; the unlabeled end of the long arm indicates the translocated chromosomal material from the derivative chromosome 7. Arrow C shows the derivative chromosome 7 containing translocated material from the der(5).

Figure 4 Whole chromosome 7 paint with red fluorescent probes. Arrow A shows the derivative chromosome 7. Arrow B shows the derivative chromosome 7 with the unlabeled part at the end indicating the translocated chromosomal material from the derivative chromosome 5. Arrow C shows the der(5) with translocated chromosomal material from der(7).

When he presented for consolidation chemotherapy, the patient was found to have a total white blood cell count of 35,000/mm³ with 50% segmented neutrophils, 21% monocytes, and no blasts. Due to concern for disease relapse, a repeat bone marrow biopsy was performed which demonstrated 95% hypercellular marrow with granulocytic hyperplasia, monocytosis, eosinophilia, and megakaryocytic hypoplasia. Morphologically, the bone marrow was consistent with chronic myelomonocytic leukemia (CMML) with eosinophilia of 7%. Eosinophilia was not present in the peripheral blood. The patient had persistence of the same clonal rearrangement. The patient proceeded with high-dose ARA-C (HiDAC) for consolidation. Due to the PDGFRB translocation, imatinib 400 mg daily was added to his consolidation regimen.

A repeat bone marrow one month after initiation of imatinib therapy demonstrated continued morphological remission but persistent PDGFRB rearrangement. He subsequently underwent a matched unrelated donor alloSCT 3 months after initiation of imatinib with myeloablative conditioning. He has remained in a clinical and pathological CR 8 years later.

Discussion

We report a patient with a rare translocation involving the PDGFRB gene, who was initially treated with induction 7+3 chemotherapy for AML and was subsequently found to have an underlying MPN. Metaphase chromosome analysis demonstrated a three-way translocation (5;7;7)(q33.2;q32;q11.2); FISH confirmed the involvement of the PDGFRB gene. To the best of our knowledge, this is the first such reported case of a PDGFRB translocation with a fusion product that would be equivalent to that generated by a more straight-forward two-way translocation, t(5;7;7)(q33.2;q11.2). The patient was treated with HiDAC consolidation chemotherapy for the AML along with targeted therapy with imatinib. He maintained his counts for 3 months until alloSCT and remains in remission to this date. As in our case, the PDGFRB translocation in acute leukemia is often not found until the patient experiences relapse.¹⁹ Additionally, the diagnosis may be more difficult if peripheral eosinophilia is not present. In one study, approximately 4 of 19 patients (21%) with hematological malignancies with PDGFRB rearrangements did not have eosinophilia and only 11/19 (58%) of cases had eosinophils ≥ 1.5 × 10⁹/L.⁷

The mechanism by which PDGFR fusion proteins lead to malignant neoplasms is thought to occur through constitutive activation of the PDGFRs. Normally, the PDGF proteins assemble causing dimerization of the PDGFRs, which activate the cell’s tyrosine kinase activity. This sequence of events leads to downstream signaling cascades important in cell migration, proliferation and survival through many overlapping signaling pathways.^2,20 One such pathway activated by the PDGFR is the PI3K/AKT/mTOR pathway, which is frequently dysregulated in many cancers.²¹

Identifying the PDGFRB rearrangement in hematological malignancies early in disease has important treatment implications as they have been shown to respond favorably to tyrosine kinase inhibitors (TKIs). In a cohort of 26 patients with hematological malignancies with PDGFRB translocations treated with imatinib therapy, Cheah et al demonstrated a 10-year overall survival (OS) of 90% after a median duration of imatinib of 6.6 years, and the 6-year progression-free survival (PFS) of 88%. No patients developed treatment resistance; furthermore, all patients that achieved hematological response did so within 2 months.⁴ Jawhar et al also evaluated 22 patients with PDGFRB translocations with myeloid and lymphoid malignancies (17 patients in chronic phase, and 5 patients in blastic phase) and found all the chronic phase patients achieved a CR with imatinib alone. The 5 patients in blastic phase (2 myeloid, and 3 lymphoid) were treated with a combination of intensive chemotherapy and imatinib, consolidated with alloSCT for 3 of the patients. The 5-year OS was 50% in those who presented in blastic phase versus 92% in chronic phase.⁷

It is important to note that only a few cases have been reported with AML involving the PDGFRB gene, and the response to TKIs is not as clearly established. In a review of case reports, Naymagon et al documented 4 cases of AML associated with PDGFRB translocations.¹⁹ Three cases resulted from de novo AML, while one had an underlying MPN. All four cases achieved a CR with induction chemotherapy and imatinib, but only 2 of 4 maintained a CR after 12 months or more of follow-up.¹⁹ Tokita et al reported a patient with chronic idiopathic myelofibrosis with TEL-PDGFRB fusion that transformed into AML. The patient was similarly treated with induction chemotherapy and imatinib. The patient responded well for three months until his AML relapsed, and he died shortly thereafter.²² Shimomura et al reported the first case of AML with PDGFRB rearrangement to be treated with single-agent imatinib for induction therapy and achieved hematological remission; however, his AML shortly relapsed. They hypothesized treatment resistance was due to a point mutation in the PDGFRB gene.¹⁶ Several PDGFRB rearrangements have also been associated with resistance to imatinib and other TKIs.^23–25 No studies have reported the role of later generation TKIs in the setting of AML with PDGFRB rearrangements after resistance to imatinib.

Conclusion

The PDGFRB rearrangement can present as a wide array of hematological malignancies. Our patient’s AML responded to induction chemotherapy; however, his MPN surfaced once he achieved remission for AML. He subsequently achieved a hematological response after initiation of imatinib, which he maintained until transplantation; as such, it is unclear how he would have responded with long-term tyrosine kinase inhibition. This case further argues for early cytogenetic analysis of PDGFR rearrangements in patients with a diverse presentation of hematological malignancies.