Imatinib +/- Brentuximab Vedotin Induces Sustained Complete Remission in Chemotherapy-Resistant Anaplastic Large Cell Lymphoma Expressing PDGFR

Background. Anaplastic lymphoma kinase positive systemic anaplastic large cell lymphoma (ALK+ ALCL) represents an aggressive T-cell malignancy that primarily affects children and younger adults. Upon treatment with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) or CHOP-like regimens its prognosis is relatively favourable compared to other aggressive T-cell lymphomas, however, the rare event of disease reoccurrence remains particularly challenging. ALCL is CD30 positive, and mono treatment with brentuximab vedotin (BrV) can achieve long term remissions in only few relapsed patients not receiving consolidating stem cell transplantation (Pro B. et al. Blood 2017). A subset of ALCL patients express platelet derived growth factor receptor (PDGFR) alpha or beta in their tumour cells which is induced by ALK via AP-1 transcription factor activation. We previously demonstrated that PDGFR blockade by the Abl/c-Kit/PDGFR kinase inhibitor imatinib is an effective treatment concept for ALK+ ALCL in experimental mouse models (Laimer D. et al. Nature Med. 2012). Here we aimed to assess the prognostic value of PDGFR expression and to probe the clinical value of its targeting by imatinib in ALK+ ALCL patients. Methods. The impact of PDGFR expression to predict clinical outcome was analyzed in samples of 98 ALK+ ALCL patients included in the studies NHL-BFM 90, 95 and ALCL99 between 1992 and 2006. Six patients (age 18-45) with chemo-refractory ALK+ ALCL were prospectively treated with imatinib plus (4) or minus (2) BrV. 33% (2/6) had previously received salvage treatment with stem cell transplantation (SCT). Three of the patients had been enrolled in a prospective single-arm study combining imatinib and BrV, a trial that was terminated due to poor patient recruitment (AGMT ALCL1 trial, EudraCT No.: 2013-003505-26, supported by Takeda®). PDGFR alpha and beta expression analyses were performed on tumour samples of treated patients. Results. ALK+ ALCL patients with high PDGFR expression on tumor cells (n=11) had a significantly lower event-free survival rate (EFS) at 5 years compared to patients with no or low expression (n=87) (27±13% versus 70±5%, respectively, p<0.001, figure 1a). Four of the six patients with relapsed/ refractory ALK+ ALCL responded to imatinib +/- BrV with a rapid metabolic complete remission (CR). At a median clinical follow-up of 52 months (range 20 to108) all responding patients demonstrated an ongoing CR without SCT even after imatinib was discontinued with an average time on imatinib of 49 weeks (range 32 to 130; figure 1b). Half (2/4) of responding patients received no or only 1 infusion of BrV; both non-responding patients had received BrV. Importantly, despite the few patients that could be prospectively treated, PDGFR expression status had a significant impact on clinical course. All patients (4/4) who expressed either PDGFR alpha or beta in tumour cells and in the lymph node microenvironment responded with an ongoing metabolic CR, whereas the two patients whose lymphoma cells had negative PDGFR expression failed to respond (EFS: 4 versus 210 weeks, p = 0.018; figure 1c). Conclusions. 1) PDGFR expression is a poor risk factor in ALK+ ALCL. 2) Imatinib alone or in combination with BrV overcomes chemo-resistance conferred by PDGFR expression. 3) Imatinib treatment can be discontinued with ongoing CR. 4) These observations suggest that PDGFR expressing ALK+ ALCL patients might benefit from early treatment with imatinib. Disclosures Staber: Takeda-Millenium: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; MSD: Honoraria, Speakers Bureau; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Klapper:Roche, Takeda, Amgen, Regeneron: Honoraria, Research Funding. Mayerhoefer:Siemens: Research Funding, Speakers Bureau; BMS: Speakers Bureau. Greil:Gilead: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Ratiopharm: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Eisai: Honoraria; Genentech: Honoraria, Research Funding; Janssen-Cilag: Honoraria; GSK: Research Funding; Sandoz: Honoraria; Roche: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria; MSD: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Sanofi Aventis: Honoraria; Boehringer Ingelheim: Honoraria; Mundipharma: Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Jaeger:Novartis, Roche, Sandoz: Consultancy; AbbVie, Celgene, Gilead, Novartis, Roche, Takeda Millennium: Research Funding; Amgen, AbbVie, Celgene, Eisai, Gilead, Janssen, Novartis, Roche, Takeda Millennium, MSD, BMS, Sanofi: Honoraria; Celgene, Roche, Janssen, Gilead, Novartis, MSD, AbbVie, Sanofi: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Imatinib - bcr-abl Inhibitor

ACTR-56. PHASE II TRIAL OF NILOTINIB IN PDGFR-ALPHA ENRICHED RECURRENT GLIOBLASTOMA

BACKGROUND This phase II study was designed to determine the efficacy of nilotinib in a biomarker-selected population of recurrent glioblastoma (GBM), enriched for platelet-derived growth factor receptor-alpha (PDGFR-alpha) activation. Nilotinib is a multi-kinase inhibitor approved as treatment for Philadelphia-chromosome/Bcr-Abl chronic myelogenous leukemia. In addition to targeting Bcr-Abl tyrosine kinase, it also inhibits PDGFR-alpha signaling. METHODS Patients with recurrent GBM, with either PDGFR-alpha amplification or PDGFR-alpha overexpression by immunohistochemistry (IHC) were enrolled in a single-arm, single institution phase II study. Nilotinib was administered at 400 mg twice a day. The primary end point was progression-free survival at 6 months (PFS6). Secondary end points were safety, overall survival (OS) and Objective Response Rate (ORR). RESULTS 34 patients were treated (22 IDH-wild type GBM, 2 IDH-mutant GBM, 10 GBM NOS). 26 were male and 8 were female. Median age was 55.5 (range 22–78 years). Four patients had PDGFR-alpha amplification, and 30 had overexpression by IHC. Median lines of prior therapy were 1 (range 1–7). 6/34 patients (18%) experienced related adverse events grade ≥ 3. There were no grade 5 events. The PFS6 was 9% (3/34), and PFS12 was 6% (2/34). Median PFS was 1.3 months and the median OS was 6.6 months. Best response was stable disease (SD) for 8 patients and complete response (CR) for one patient. ORR was 1/34 patients (3%). The patient with a CR was IDH-wild type, unmethylated, had PDGFR-alpha overexpression by IHC, and had a durable response > 5 years. CONCLUSION Nilotinib had limited activity in recurrent GBM enriched for PDGFR-alpha, although there were a small number of durable responders. Further molecular characterization is warranted to determine additional biomarkers of response that could be used to select patients that may benefit from nilotinib.

Extramedullary Myeloid Sarcoma With Eosinophilia and FIP1L1-Pdgfra Rearrangement: Complete Cytogenetic Response To Imatinib Therapy

Background Myeloid sarcomas are rare extramedullary manifestations of acute myeloid leukemia (AML) representing less then 1% of all cases. Since they invariably progress into systemic disease, early AML-like chemotherapy is mandated. Myeloproliferations with eosinophilia and involvement of the PDGFRA, PDGFRB or FGFR1 genes are distinct entities in the 2008 WHO classification with peculiar sensitivity to tyrosine kinase inhibitors. Extramedullary myeloid sarcomas with eosinophilia and FIP1L1-PDGFRA fusion gene expression are extremely rare with only two cases described. Here we report a case of extramedullary leukemia, eosinophilia and FIP1L1-PDGFRA rearrangement responding favourably to imatinib. Case history A 32-year old man presented with a 3-month history of subcutaneous nodules growing gradually in the occipital, chest, abdominal and perianal regions, the largest being 50 x 60 x 18 mm in size and exulcerated. There was no weight loss or fever. Complete blood count showed WBC of 6,8 x 109/L, Hb level of 104 g/dl and platelet count of 377 x 109/L. The differential revealed 42% neutrophils, 25% lymphocytes, 5% monocytes and 28% eosinophils with an absolute eosinophil count of 1,92 x 109/L. Apart from mildly elevated LDH (539 U/L, normal range: 153 - 463 U/L), other laboratory results were unremarkable. CT scan found no lymphadenopathy or hepatosplenomegaly. Histology of the nodules showed infiltration with immature monoblasts, negative for CD34, CD117 and weakly positive for MPO and CD68. Mutations of the FLT3 and nucleophosmin genes were not present and TCR gene rearrangement analysis did not reveal clonality. Bone marrow biopsy showed an increase of eosinophilic precursors without apparent blast excess. FISH analysis of the nodules performed with the LSI FIP1L1/PDGFR alpha probe detected deletion of the CHIC2 gene in most interphase nuclei. Bone marrow karyotype was normal, and FISH probes proved negative for AML/ETO and inv(16). In 15% of interphases, the FIP1L1/PDGFR alpha fusion signal could be detected. RT PCR showed FIP1L1-PDGFR alpha gene fusion in the marrow. A diagnosis of extramedullary myeloid sarcoma with concomittant eosinophilia and FIP1L1/PDGFRA fusion gene expression was established. To our knowledge, this is the third such case reported so far. Induction regimen consisted of 7 days of Ara-C (200 mg/m2) and 3 days of daunorubicin (60 mg/m2). This resulted in regression but not complete disappearance of the subcutaneous nodules. After the therapy-induced aplasia, restitution of platelets preceded neutrophils and mild thrombocytosis developed. The bone marrow showed increased eosinophils without blast excess. FISH analysis detected the presence of the FIP1L1-PDGFRA fusion signal in 11% of nuclei. Imatinib mesylate, 100 mg/day was started. In 14 days, the platelet count returned to normal and the residual nodules disappeared completely. After 5 weeks of imatinib therapy, the patient is doing well without any complaints and the bone marrow shows complete cytogenetic response. Conclusion this case of extramedullary AML, eosinophilia and FIP1L1/PDGFRA rearrangement persisting after intensive chemotherapy but responding well to low-dose imatinib emphasizes the importance to screen for mutations of the PDGFR gene in AML with major eosinophilic component due to the major therapeutic implications. Disclosures: No relevant conflicts of interest to declare.