A Case of Myeloproliferative Neoplasm with BCR-FGFR1 Rearrangement: Favorable Outcome after Haploidentical Allogeneic Transplantation

Hematopoietic myeloproliferative neoplasms with FGFR1 rearrangement result in the 8p11 myeloproliferative syndrome that in the current Word Health Organization classification is designated as “myeloid and lymphoid neoplasm with FGFR1 abnormalities.” We report the case of a 66-year-old man who had clinical features that resembled chronic myeloid leukaemia (CML), but bone marrow cytogenetic and fluorescent in situ hybridization (FISH) studies showed t(8;22)(p11;q11) and BCR-FGFR1 fusion gene. He was initially managed with hydroxyurea, and given the aggressive nature of this disease, four months later, the patient underwent an allogeneic hematopoietic stem-cell transplantation (HSCT) from an HLA-haploidentical relative. Currently, HSCT may be the only therapeutic option for long-term survival at least until more efficacious tyrosine kinase inhibitors (TKIs) become available.


Introduction
Hematopoietic myeloproliferative neoplasms (MPN) with rearrangements of fibroblast growth factor receptor 1 (FGFR1) gene (located on chromosome 8p11) are uncommon and extremely aggressive entities. Translocations associated with this syndrome result in the fusion of the FGFR1 gene with various partners [1], resulting in ligandindependent FGFR activity. Patients with t(8;22)(p11;q11) and BCR-FGFR1 fusion gene have clinical features that resemble chronic myeloid leukaemia (CML) [2,3].
It has been reported that MPN with a t(8;22) translocation and a chimeric BCR-FGFR1 fusion gene either present or rapidly transform into an acute leukaemia [3,4], usually refractory to currently available chemotherapeutic regimens including tyrosine kinase inhibitors (TKIs) [2,5]. No consensus on management is available for this condition. Allogeneic hematopoietic stem-cell transplantation (HSCT) is currently the only therapeutic option in BCR-FGFR1 MPN patients [6][7][8]. Patients who lack an HLA-matched sibling might benefit from alternative donors such as HLAhaploidentical relatives.

Case Presentation
We report the case of a 66-year-old man who was referred to us in January 2017 because of leukocytosis in a routine blood count.
e patient was asymptomatic. On examination, there was no palpable lymphadenopathy, splenomegaly, or hepatomegaly.
BCR-FGFR1 reverse-transcriptase polymerase chain reaction was not possible to carry out. Four months later, the patient underwent an allogeneic HSCT from an HLA-haploidentical relative (haplo-HSCT). A nonmyeloablative conditioning regimen was used (cyclophosphamide, busulfan, and fludarabine). Five × 10 6 /kg CD34 cells were infused. Initial transplant course was unremarkable. Time to neutrophils >0.5 × 10 9 /L was 17 days, and time to platelets >20 × 10 9 /L was 20 days. No signs or symptoms of graft-versus-host disease (GVHD) were noted.
BM exams were performed regularly after HSCT. Cytogenetic remission as well as peripheral blood full-donor chimerism was documented from day 30. At the time of this writing (more than 8 months from HSCT), the patient remained clinically well without evidence of GVHD and in cytogenetic complete remission.

Discussion
Hematopoietic neoplasms with FGFR1 rearrangements are uncommon entities. Most recent WHO classification [16], has included them among "myeloid and lymphoid neoplasms associated with FGFR1 abnormalities (MLNAF)," which are characterized by reciprocal chromosome translocations involving FGFR1 gene located at chromosome 8p11 with a variety of fusion partner genes. One of the most frequently observed cytogenetic abnormalities is t(8;22) (p11.2;q11.2). e t(8;22) results in an in-frame fusion of FGFR1 on 8p11 and BCR on 22q11. e resultant fusion proteins activate tyrosine kinases which may result in the development of hematologic malignancies.
Patients with BCR-FGFR1 rearrangements may present with clinical and PB pictures which resemble chronic myeloid leukaemia [2,4,15,17,18]. e underlying BCR-FGFR1 rearrangement may thus be missed, so BM cytogenetic analysis remains the mainstay of diagnosis. In our case, cytogenetic analysis confirmed the presence of t(8;22) as the sole aberration, and no other additional chromosomal abnormalities were observed at diagnosis or during followup.
Patients carrying the t(8;22)(p11;q11) and the subsequent BCR-FGFR1 fusion gene follow an aggressive course. ere are a few reported patients who have been treated unsuccessfully with hydroxyurea [6], chemotherapy or TKIs [2,5]. More potent TKIs, such as ponatinib which exhibits pan-FGFR inhibitory activity, may be of clinical benefit [10,11]. Cardiovascular risk factors precluded the use of ponatinib in our case.
Myeloproliferative neoplasms with BCR-FGFRq rearrangement are usually refractory to chemotherapy, resulting in poor prognosis. We performed a literature search and found an additional 11 cases with BCR-FGFR1 rearrangement treated with allogeneic HSCT (Table 1), and to our knowledge, this case is the first report of a patient with a BCR-FGFR1 MPN treated with haploidentical HSCT. Haploidentical donors allow patients who lack a HLA- Case Reports in Hematology matched one to receive a HCST with outcomes which are much like those obtained with matched donors [21]. HSCT may be the only therapeutic option for long-term survival at least until more efficacious TKIs become available.

Conflicts of Interest
e authors declare that they have no conflicts of interest.