Targeted FGFR inhibition results in a durable remission in an FGFR1-driven myeloid neoplasm with eosinophilia

Key Points A novel PCM1-FGFR1 gene rearrangement was identified in a patient with a myeloid neoplasm with eosinophilia. Futibatinib, an oral selective small molecule inhibitor of FGFR1-4, resulted in a durable complete hematologic and cytogenetic remission.

Chronic myeloid leukaemia

Chronic myeloid leukaemia (CML) was recognized in the 1970s by Janet Rowley to be a genetically simple malignancy; resulting as a consequence of a balanced translocation between chromosome 9 and 22. This provided vital insights into the molecular aberration, in the 1990s, which ushered in the current ‘precision medicine’ era, not only for patients of CML, but for cancers in general. As a result, today, a personalized treatment algorithm is available for all newly diagnosed patients with CML. Treatment involves a choice of three first-line orally administered tyrosine kinase inhibitors (TKIs) and two effective next-line TKIs that should be used based on risk stratification, comorbidities, the side effects profile, and the BCR-ABL1 genotype. Regardless of the initial choice of TKI, the vast majority of patients achieve a durable complete cytogenetic remission, with a lifespan approaching that of the general population. In most instances the medication must be continued indefinitely, and a principal challenge now, is to develop strategies to stop TKIs safely and effectively. Challenges remain in how to achieve optimal monitoring of patients with CML on treatment and in achieving a better understanding of the mechanisms and treatment of patients with advanced phase disease. This chapter addresses these questions as well as the concomitant topical issues in CML.

Complete Hematologic and Cytogenetic Remission of Acute Myeloid Leukemia in an Elderly Patient Treated with Decitabine and Venetoclax: A Case Report

We present the case of a 77 year old woman, Caucasian, with medical history of diabetes mellitus, hyperthyroidism, hypertension and hyperlipidemia, that suddenly develops progressive articular pain, dyspnea at rest, easy bruising /ecchymosis in soft tissues, weakness and nose bleeding. At admission no visceromegaly was noted, gums and lymph nodes were normal. Initial lab workup showed severe anemia (Hb 7.7 g/dL), leukocytosis (19.1 x 10^3/uL) with monocytosis (51%) and left shift, severe thrombocytopenia (Plt 33 x 10^3/uL), hyperfibrinogenemia, hyperglycemia and hyperuricemia. Bone marrow morphology was conclusive of Acute Myeloid Leukemia with 45 % of blasts, hypercellular with progressive trilineage hematopoiesis and no ringed sideroblasts. Flow cytometry of peripheral blood detected only 0.8 % of blasts (CD34+) with positive myeloid markers. Flow cytometry of bone marrow detected 17 % of myeloid blasts expressing CD34+, HLA-DR, CD117, cytoplasmic (cy) MPO, CD13, partial CD11b, negative for cyTdT and cy CD79a. Genetically, 5q31/EGR1 deletion (86%) and gain of 20q12 (64%), with no other anomalies or mutations were found. Patient was treated with Decitabine 20mg/m2 IV daily x 10 d, followed by Venetoclax starting gradually from 100 mg escalating up to 300 mg oral as induction therapy. Complications during this phase were pleural effusion, C. difficile-associated diarrhea, urinary infection due to Enterococcus faecium, anemia, thrombocytopenia that required blood and platelet transfusions. After the first cycle of therapy a new bone marrow done showed morphologically < 2 % of blasts with moderate pancytopenia, but presence still of 10 % of CD34+ myeloblasts detected by flow cytometry. After a second course of therapy Decitabine/Venetoclax, peripheral blood leukocytes and platelets normalized, persisting only moderate anemia with no transfusion requirements. Bone marrow FISH report was normal, Del 5q disappeared, no detection of aberrations associated to myelodysplastic syndrome, and no detection of other abnormalities (results below the cut-off) were described, however a new pathogenic alteration in the DNMT3A gene not described before in other cases was detected with the New Generation System analysis. At the moment of presenting this case report there is a leukemia-free survival of 6 months, with impressing improvement in the general status. Conclusion: Therapy with the combination Decitabine/Venetoclax is a good alternative for treating elderly patients with AML, sparing the aggressiveness of regular induction chemotherapies and a tremendous impact in inducing cytogenetic remission. Disclosures No relevant conflicts of interest to declare.

Targeted FGFR Inhibition Results in Hematologic and Cytogenetic Remission in a Myeloid Neoplasm Driven By a Novel PCM1-FGFR1 Fusion: Data from an Expanded Access Program

Introduction In 2008, the World Health Organization defined a new classification of myeloid and lymphoid neoplasms with eosinophilia that result from gene rearrangements of PDGFRA, PDGFRB, and FGFR1. While rearrangements involving PDGFRA and PDGFRB generally respond well to imatinib, those associated with FGFR1 are typically aggressive and require treatment with allogeneic hematopoietic stem cell transplantation (SCT). Here we present the case of a patient with a previously unreported fusion of PCM1-FGFR1. The patient was treated with an Oral, potent, selective, and irreversible small-molecule inhibitor of FGFR 1- 4 (futibatinib (TAS-120)) under an expanded access program, resulting in the first reported instance of complete hematologic and cytogenetic remission using futibatinib in an FGFR-driven myeloid neoplasm. Results A 55-year-old male presented with dyspnea and fatigue and was found to have peripheral eosinophilia (3,660/microliter) and thrombocytopenia (46,000/microliter). Diagnostic bone marrow biopsy was notable for a hypercellular (cellularity >95%), erythroid dominant marrow with increased eosinophilic forms and increased pronormoblasts. Break-apart fluorescence in situ hybridization (FISH) studies revealed an FGFR1 gene rearrangement in 11.3% of nuclei (normal < 5.7%). The nature of the rearrangement was shown to be a paracentric inversion of chromosome 8p based on the distinct gap between the 5'FGFR1 and 3'FGFR1 probes in metaphase FISH (Figure 1). A validated, targeted next generation sequencing assay for fusion transcript detection (heme fusion assay) revealed a previously unreported PCM1-FGFR1 fusion transcript (40 unique fusion reads), with an in-frame fusion of PCM1 (exons 1-36) to FGFR1 (exons 11-18). No additional clonal markers were identified. The patient was not considered an SCT candidate due to medical comorbidities and was enrolled on a single-patient protocol expanded access program for futibatinib. He was initially treated with prednisone for control of his eosinophilia, and then started on oral therapy with futibatinib (20 mg daily). Within 1 month of initiation of futibatinib, prednisone was tapered without recurrence of eosinophilia and with improvement in platelet count (169,000/microliter). After 6 months, repeat bone marrow biopsy showed a moderately hypocellular marrow with maturing trilineage hematopoiesis. Additionally, the paracentric inversion of chromosome 8p was no longer observed in metaphase FISH, consistent with cytogenetic remission. Furthermore, the PCM1-FGFR1 fusion transcript was no longer detectable by heme fusion assay. The patient has experienced grade 2 skin rash requiring brief dose interruption (7 days) followed by dose reduction to 16 mg daily, on which he remains. He has also experienced grade 2 hyperphosphatemia, a known side effect of futibatinib, which is adequately controlled with sevelamer. The patient continues on futibatinib, with ongoing evidence of hematologic and cytogenetic remission after 11 months of therapy. Conclusions To our knowledge, this case represents the first report of a PCM1-FGFR1 fusion driving a myeloid neoplasm with eosinophilia. Treatment with futibatinib has resulted in hematologic and cytogenetic remission, with treatment successfully ongoing after 11 months. Our findings support further exploration of FGFR inhibitors as a therapeutic strategy for myeloid/lymphoid neoplasms driven by FGFR1 rearrangement, particularly in individuals who are not candidates for SCT. A phase 2 study of futibatinib in patients with FGFR1 driven myeloid/lymphoid neoplasms is planned. Disclosures Brunner: Astra Zeneca: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Forty Seven Inc: Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding. Chen:Magenta: Consultancy; Takeda: Consultancy; Kiadis: Consultancy; Incyte: Consultancy; Abbvie: Consultancy. Fathi:Amphivena, Kite, Jazz, NewLink Genetics,: Honoraria; Agios, Astellas, Celgene, Daiichi Sankyo, Novartis, Takeda, Amphivena, Kite, Forty Seven,Trovagene, NewLink genetics, Jazz, Abbvie, and PTC Therapeutics: Consultancy. Narayan:Genentech: Other: Equity ownership (spouse); Merck: Other: Equity ownership (spouse); Takeda: Other: Employment (spouse). Benhadji:Taiho Oncology: Employment. Hobbs:Incyte: Consultancy, Research Funding; Merck: Research Funding; Jazz pharmaceuticals: Consultancy; Celgene: Consultancy; Bayer: Research Funding; Agios: Consultancy.

Discontinuation of imatinib mesylate could improve renal impairment in chronic myeloid leukemia

We aim to report a CML case that had fluid retention and serum creatinine increase under long-term imatinib mesylate (IM) treatment. A 68-year-old woman was diagnosed with chronic myeloid leukemia, and IM was started in 2002 with a dose of 400 mg/day. She had achieved complete hematological, molecular and cytogenetic remission under IM treatment. In September 2015, her creatinine level was 1.7 mg/dl. In May 2016, she was admitted to our hospital with dyspnea. Hypervolemia secondary to fluid retention was detected in our patient. Her laboratory tests results showed hemoglobin 9.7 gr/dl, white blood cell 7.6x103/μl, platelet 157x103/μl, creatinine 3.2 mg/dl, blood urea nitrogen (BUN) 88 mg/dl. In her X-ray chest film, bilateral pleural effusion was detected. The effusion was detected as transuda. The other reasons of pleural effusion were excluded and the development of pleural effusion was considered secondary to IM. IM was also considered responsible for the acute rise of serum creatinine levels of our patient. Therefore for these two reasons IM was stopped. After the discontinuation of IM, her creatinine levels decreased to 1.6 mg/dl and her pleural effusions disappeared. IM treatment was considered as the reason of serum creatinine elevation since serum creatinine levels decreased after the discontinuation of IM. All of the side-effects disappeared after discontinuation of IM.

Moleculary Confirmed, Cytogenetic Remission in a Case with Myelodysplastic Syndrome Treated with Azacitidne

Myelodysplastic syndrome (MDS) is a diverse group of clonal hematologic neoplasms. The only curative treatment for MDS is allogeneic stem cell transplantation (SCT). Epigenetic changes play an important role in the pathogenesis of MDS and treatment with DNA methyl transferase inhibitors, Azacitidine, significantly prolong the survival of high-risk MDS patients. Here we report a case of a 58-year-old male presented with pancytopenia, macrocytosis, and hyperplastic bone marrow with 3-lineage dysplasia with ~14% of myeloid blasts. Cytogenetic studies with G banding showed normal karyotype. Multiplex ligation-dependent probe amplification (MLPA) screening for most predictive cytogenetic abnormalities of MDS showed loss of the Y chromosome. Those findings later were confirmed with Quantitative Fluorescent (QF)-PCR and specific MLPA for Y chromosome, showing loss of the Y chromosome in >80% of cells. He was diagnosed with MDS-RAEB2 according to 2008 WHO classification and stratified into high risk group (IPSS score 5). Unrelated allogeneic SCT was planed and bridging treatment with Azacitidine at a dose of 75mg/m2/daily subcutaneously for 7 days every 28 days was initiated. Hematologic improvements, according to the International Working Group 2006 criteria, were observed after 4 cycles of Azacitidine treatment. After 6 cycles, complete hematological remission was achieved. Interestingly, molecular analysis performed after the 8th cycle showed normal presence of Y chromosome indicating a cytogenetic remission, molecularly confirmed. Maintenance treatment with Azacitidine was assigned, and the scheduled SCT was postponed. Experience from our case showed that the loss of the Y chromosome was related to the disease onset, and indicated that Azacitidine might be consider as effective treatment for MDS cases associated with good cytogenetic

Extramedullary Relapse in a CML Patient after Allogeneic Stem Cell Transplantation

Myeloid or granulocytic sarcoma (GS) is a tumoral lesion consisting of immature granulocytic cells. It is a rare entity during the course of CML patients especially after allogeneic stem cell transplantation (SCT). Relapse without bone marrow involvement is much rarer. We report a case of CML patient who relapsed with isolated granulocytic sarcoma after allogeneic SCT during cytogenetic and molecular remission. 28-year-old male was diagnosed as CML and allogeneic SCT was performed because of refractory disease to tyrosine kinase inhibitors. Complete cytogenetic and molecular response was achieved after allogeneic SCT followed by dasatinib treatment. Approximately 5 years after the transplantation, very rapidly progressive lesion was documented and diagnosed as GS although he was at molecular and cytogenetic remission. The patient died during chemotherapy due to sepsis. GS relapse after allogeneic SCT is a very rare type of relapse in CML patients with molecular and cytogenetic remission. Since it is a very aggressive disease with a poor prognosis, combined chemoradiotherapies with other possible options like DLI or second allogeneic SCT should be considered as soon as the diagnosis is confirmed.