Outcome of Pregnancy in the Era of PEGylated Interferon-α2a in Females with Chronic Myeloid Leukemia: An Experience from Qatar

Chronic myelogenous leukemia (CML), also known as chronic myeloid leukemia, is a myeloproliferative neoplasm characterized by increased proliferation of the granulocytic cell line without loss of its capacity to differentiate. It accounts for 20% of all adults affected by leukemia. Tyrosine kinase inhibitors revolutionized the treatment for CML and improved quality of life. Fertility is an important issue for both males and females. Here, we report our experience with a pregnant female with CML, and shed light on safety and efficacy of PEGylated interferon-αa in pregnant women with CML and its outcome.

Oral idasanutlin in patients with polycythemia vera

A limited number of drugs are available to treat patients with polycythemia vera (PV) and essential thrombocythemia (ET). We attempted to identify alternative agents that may target abnormalities within malignant hematopoietic stem (HSCs) and progenitor cells (HPCs). Previously, MDM2 protein levels were shown to be upregulated in PV/ET CD34+ cells, and exposure to a nutlin, an MDM2 antagonist, induced activation of the TP53 pathway and selective depletion of PV HPCs/HSCs. This anticlonal activity was mediated by upregulation of p53 and potentiated by the addition of interferon-α2a (IFN-α2a). Therefore, we performed an investigator-initiated phase 1 trial of the oral MDM2 antagonist idasanutlin (RG7388; Roche) in patients with high-risk PV/ET for whom at least 1 prior therapy had failed. Patients not attaining at least a partial response by European LeukemiaNet criteria after 6 cycles were then allowed to receive combination therapy with low-dose pegylated IFN-α2a. Thirteen patients with JAK2 V617F+ PV/ET were enrolled, and 12 (PV, n = 11; ET, n = 1) were treated with idasanutlin at 100 and 150 mg daily, respectively, for 5 consecutive days of a 28-day cycle. Idasanutlin was well tolerated; no dose-limiting toxicity was observed, but low-grade gastrointestinal toxicity was common. Overall response rate after 6 cycles was 58% (7 of 12) with idasanutlin monotherapy and 50% (2 of 4) with combination therapy. Median duration of response was 16.8 months (range, 3.5-26.7). Hematologic, symptomatic, pathologic, and molecular responses were observed. These data indicate that idasanutlin is a promising novel agent for PV; it is currently being evaluated in a global phase 2 trial. This trial was registered at www.clinicaltrials.gov as #NCT02407080.

Chemoimmunotherapy in Advanced Renal Cell Carcinoma: A Case Report of a Long-Term Survivor Adjunctly Treated with Viscum album Extracts

Introduction: Metastatic renal cell carcinoma has a poor prognosis. Treatment approaches with immunotherapy show promising results in subpopulations. Viscum album extracts – used as an adjunct to cancer treatment – have cytotoxic, apoptogenic, and immune-stimulating properties and show synergistic effects with chemotherapy agents. Case Report: A 51-year-old man was diagnosed with metastatic renal cell carcinoma of clear cell histology which was classified as pT3a, N1, M1, G3. Nephrectomy was performed, and the patient received chemoimmunotherapy (interferon-α2a, interleukin-2, fluorouracil, isotretinoin). Additionally, he received V. album extracts as intravenous infusions and subcutaneous injections. One year after surgery, the patient was in complete remission, which is ongoing 18 years after the initial diagnosis. Discussion: This case shows an extraordinarily long survival of a metastasized renal cell carcinoma patient under chemoimmunotherapy and fever-inducing V. album extracts. This combined treatment might have synergistically contributed to tumor remission and control. With regard to clinical relevance, further investigations are needed.

Effectiveness and safety of interferon α2a as an add-on treatment for refractory Behçet’s uveitis

Objective: The objective of this study was to investigate the effectiveness and safety of interferon (IFN) α2a as an add-on treatment for refractory Behçet’s uveitis (BU). Methods: In this retrospective cohort study, 30 refractory BU patients who received IFNα2a treatment in Peking Union Medical College Hospital between February 2015 and June 2018 were consecutively included. IFNα2a was used mainly as an add-on treatment for BU patients who underwent relapse under corticosteroids and conventional immunosuppressive agents. The primary outcome was treatment success rate before and after initiation of IFNα2a. Changes in ocular relapse rates, disease activity, corticosteroid- and immunosuppressant-sparing effects, as well as side effects were secondary outcomes. Results: A total of 30 patients (27 males and 3 females) with a mean age of 30.5 ± 8.7 years were included. Twenty-one patients (70%) were treated with at least 2 immunosuppressive agents before the initiation of IFNα2a. Treatment success was achieved in 26 patients (86.7%), and the median uveitis relapse rate decreased from 7.3 (range 2–12) to 0 (range 0–6) per patient-year ( p = 0.000002) during a mean follow-up of 21.7 ± 7.5 months, corticosteroids were lowered in 25 cases (83.3%) and completely withdrawn in four (13.3%). In addition, immunosuppressive agents were reduced in number and dosage in 22 (73.3%) and 29 patients (96.7%), respectively, and were completely withdrawn in 12 cases (40%). No severe adverse events were observed and serum autoantibodies remained negative during the treatment of IFNα2a. Conclusion: IFNα2a is effective and relatively safe in refractory BU, with significant steroid- and immunosuppressant-sparing effects.

Intralesional Administration of the CD47 Antagonist TTI-621 (SIRPαFc) Induces Responses in Both Injected and Non-Injected Lesions in Patients with Relapsed/Refractory Mycosis Fungoides and Sézary Syndrome: Interim Results of a Multicenter Phase I Trial

Background CD47 is an immune checkpoint that binds signal regulatory protein alpha (SIRPα) and delivers a "do not eat" signal to suppress macrophage phagocytosis. Tumor cells, including T-cell lymphomas, frequently overexpress CD47 to escape immune surveillance. TTI-621 (SIRPαFc) is a fusion protein consisting of the CD47 binding domain of human SIRPα linked to the Fc region of human IgG1, designed to enhance phagocytosis and antitumor activity by blocking the CD47-SIRPα interaction between malignant cells and macrophages, and engaging activating Fcγ receptors. It is hypothesized that direct intralesional (IL) administration of TTI-621 may enhance both local and systemic antitumor activity. Methods A multicenter, open-label Phase 1 study is ongoing to characterize the safety, tolerability, pharmacokinetics, pharmacodynamics and antitumor activity of IL injections of TTI-621 (NCT02890368) in adult patients with relapsed/refractory (R/R) percutaneously accessible solid tumors and mycosis fungoides (MF) who have progressed on standard anticancer therapy or for whom no other approved therapy exists. The current report analyzed a cohort of R/R MF/Sézary syndrome (SS) patients enrolled by the data cut-off date. Patients received induction therapy consisting of a single IL injection (1, 3 or 10 mg), three 10 mg injections over one week, or six 10 mg injections over two weeks distributed across one to three lesions. The protocol was recently amended to enable weekly post-induction IL maintenance dosing and to explore IL TTI-621 administration in combination with subcutaneous pegylated interferon-α2a. Responses were evaluated using the Composite Assessment of Index Lesion Severity (CAILS) score a week after induction therapy and at later time points in some patients. Serial biopsies were collected to assess the impact of TTI-621 on the tumor microenvironment. Results Twenty-two patients (16 M/6F, median age 65.5 years, range 32-85) were enrolled as of June 15, 2018. Primary diagnosis included MF (n=18), MF with transformation (n=3) and SS (n=1). Clinical stages included stage IA (n=2), IB (n=3), IIA (n=1), IIB (n=13), IVA (n=2) and IVB (n=1). Patients received a median of 3 prior systemic therapy regimens. Twenty-one patients were treated with TTI-621 monotherapy and one patient with TTI-621 in combination with pegylated interferon-α2a. Single and multiple IL injections of up to 10 mg TTI-621 have been well tolerated. The most frequently reported treatment-related adverse events (AEs) were chills (n=8), injection site pain (n=7) and fatigue (n=6). All treatment-related AEs were Grade 1 or 2 in severity. No treatment-related serious AEs or dose-limiting toxicity have been observed. CAILS scores for injected lesions obtained after the last injection were available for 17 patients: 15 (88%) had measurable improvement; 7 (41%) exhibited ≥50% decrease from baseline (Figure 1). Responses were rapid and in some patients occurred after a single injection of varying doses of TTI-621. CAILS scores continued to decrease in 5/5 (100%) monotherapy patients for which post-induction therapy assessments were conducted. Seven patients with reduced CAILS of varying degree (-14% to -67%) in the injected lesions had paired assessments available in adjacent, non-injected lesions. In 6/7 patients, a reduction in CAILS was observed in the non-injected lesions (-12% to -67%), indicating that TTI-621 could induce local-regional responses that were not confined to the site of injection. Additionally, one patient with transformed MF exhibited clear evidence of abscopal effects with rapid resolution of lesions on the abdomen, left flank/back and arms less than two weeks after receiving IL TTI-621 injections in lesions on the foot and leg. The only SS patient on study achieved a reduction in circulating Sézary cells after a single 3 mg local injection of TTI-621. Conclusions Preliminary data from this ongoing study indicate that IL TTI-621 administration is well-tolerated and has single agent activity in heavily pre-treated MF/SS patients across various disease stages. The rapid responses observed occurred in both injected and non-injected lesions indicating a local-regional effect with initial evidence of distant abscopal or systemic effects. Enrollment in this study is continuing to evaluate the impact of weekly maintenance dosing and further characterize the systemic effect and durability of responses. Disclosures Querfeld: Kyowa: Membership on an entity's Board of Directors or advisory committees; Acelion: Membership on an entity's Board of Directors or advisory committees; Bioniz: Membership on an entity's Board of Directors or advisory committees; Medivir: Membership on an entity's Board of Directors or advisory committees; Trillium Therapeutics: Membership on an entity's Board of Directors or advisory committees. Thompson:Trillium Therapeutics: Research Funding. Taylor:Trillium Therapeutics: Research Funding. Johnson:Trillium Therapeutics: Employment. Catalano:Trillium Therapeutics: Employment. Petrova:Trillium Therapeutics: Employment. Thompson:Trillium Therapeutics: Employment. Uger:Trillium Therapeutics: Employment. Shou:Trillium Therapeutics: Employment. Akilov:Kyowa Kirin: Consultancy; Pfizer: Research Funding; Seattle Genetics: Consultancy; Trillium Therapeutics: Research Funding; Actelion Pharmaceuticals: Consultancy.