Targeting non-hodgkin Lymphoma with Blinatumomab

Transcription

1 Expert Opinion on Biological Therapy ISSN: (Print) (Online) Journal homepage: Targeting non-hodgkin Lymphoma with Blinatumomab Sheilagh Sanders & Douglas A. Stewart To cite this article: Sheilagh Sanders & Douglas A. Stewart (2017): Targeting non- Hodgkin Lymphoma with Blinatumomab, Expert Opinion on Biological Therapy, DOI: / To link to this article: Accepted author version posted online: 22 May Submit your article to this journal View related articles View Crossmark data Full Terms & Conditions of access and use can be found at Download by: [The UC San Diego Library] Date: 25 May 2017, At: 08:17

2 Publisher: Taylor & Francis Journal: Expert Opinion on Biological Therapy DOI: / Targeting non-hodgkin Lymphoma with Blinatumomab. Sheilagh Sanders, Douglas A. Stewart Sheilagh Sanders, MD FRCPC Division of Hematology, Queen s University Room 2015 Etherington Hall 94 Stuart Street Kingston, Ontario, Canada K7L 2V sanderss@kgh.kari.net Douglas A. Stewart, MD FRCPC Tom Baker Cancer Center th Street NW Calgary, AB, Canada T2N 4N2 douglas.stewart@ahs.ca (Corresponding Author) Abstract Introduction: Management of patients with relapsed or refractory non-hodgkin lymphoma (NHL) remains challenging, and novel effective agents are eagerly awaited. Blinatumomab is a bispecific T-cell engager, targeting CD19. While blinatumomab s primary clinical use has been in B-cell acute lymphoblastic leukemia (B-ALL), there are increasing data for its use in B-lineage lymphomas. Areas covered: The aim of this review is to highlight the clinical data for blinatumomab use in NHL. Herein, the authors provide an overview of

3 blinatumomab, its mechanism of action, its proven efficacy against B-ALL, and its phase I-II data assessing its use in NHL Expert opinion: Blinatumomab has modest activity in phase I-II trials in NHL, and may represent a means of bridging patients with relapsed disease to hematopoietic stem cell transplant. More widespread use is currently hampered by lack of phase III data, multiple competing agents, an onerous administration schedule and significant side effect profile. Further studies are eagerly awaited assessing its use in combination with other immunotherapy strategies. Keywords: Monoclonal Antibody, BiTE, blinatumomab, CD19, non-hodgkin lymphoma 1. Introduction Chemoimmunotherapy using the anti-cd20 monoclonal antibody Rituximab has significantly improved survival rates for patients with B-lineage non-hodgkin lymphoma (NHL). Unfortunately, patients who experience lymphoma recurrence are not commonly cured with subsequent therapies, and their management continues to be extremely challenging [1]. The incidence of NHL is rising, with 32 new cases of NHL per persons per year in the USA [2]. Despite good response rates with standard therapy, one third of diffuse large B cell lymphoma (DLBCL) patients develop relapsed or refractory disease [3]. Approximately half of relapsed/refractory DLBCL patients are

4 sufficiently young and fit to be considered candidates for autologous stem cell transplantation (ASCT), however only half respond to salvage chemotherapy, and only half of those (approximately 10-15% of all relapsed/refractory DLBCL) are subsequently cured by ASCT[4]. For patients with indolent lymphomas, 20% relapse within 2 years and 40-50% relapse within 6 years of initial therapy [5]. More effective salvage therapies are definitely required for patients with relapsed/refractory NHL, especially those who are deemed ineligible for ASCT. Novel agents are increasingly being developed in the quest to improve outcomes for patients with relapsed, chemo-resistant lymphoma. Blinatumomab, a bispecific T- cell engager (BiTE), is one such novel therapy, designed to harness the ability of cytotoxic T-cells to kill B-cells. While its primary clinical use has been in B-cell acute lymphoblastic leukemia, its use is expanding to other B-cell malignancies. 2. Mechanism of Action Blinatumomab is a unique, flexible, bispecific antibody that has two linked, singlechain variable fragments, one targeting CD3 on T-cells and the other directed against CD19 on malignant B-cells. The single-chain variable fragments are bound together by a non-immunogenic linker. Blinatumomab potently triggers the signaling cascade of the T cell receptor complex only when both of its binding sites

5 are occupied [6]. Cytotoxic T cells then release toxic secretory proteins and induce apoptosis of tumor cells [7] (see Figure 1). CD19 is expressed on all developmental stages of B cells, except for plasma cells. In addition, it is expressed on all B-lineage leukemias and the majority of B-cell lineage lymphomas, making it an excellent target antigen. CD19 is not expressed on pluripotent stem cells in the bone marrow, allowing for non-lymphomatous B-cell reconstitution following therapy [8]. 4. Pharmacokinetics and Pharmacodynamics Due to its small molecular size of 50kDa, blinatumomab is rapidly cleared from the circulation with a biological half-life of only 2-3 hours. In order to maintain steadystate serum levels, it is administered as a continuous intravenous infusion via an ambulatory pump over a 4-8 week period per cycle. Steady state serum concentration is reached within one day. Because of its potent ability to activate T cells, only relatively small doses are needed. The mechanism of metabolism is unclear, but is thought to be enzymatic, with degradation into smaller peptides via catabolic pathways. There are no manufacturer-recommended dose adjustments for patients with renal or hepatic dysfunction, as pharmacokinetic trials have not been conducted in these populations [9]. Immediately following blinatumomab administration, T cells are redistributed and activated. T cells transiently decline in numbers within 1 to 2 days, as they adhere to

6 blood vessel endothelium [10]. T cells then return to baseline numbers, as cytokine release stimulates T cell proliferation over the subsequent 1-2 weeks. The B cell population is depleted within 2 days of administration, and does not recover until approximately 2 weeks following administration cessation. [11]. 3. Clinical Use and Efficacy Blinatumomab s primary clinical use has been in B-precursor acute lymphoblastic leukemia (B-ALL). A phase II study assessing its use in 189 patients with relapsed/refractory B-ALL reported a complete remission (CR) rate of 43%, and bridging a subset of patients to allogeneic stem cell transplant [12]. In a separate study of 116 B-ALL patients who had persistent minimal residual disease (MRD) following induction and consolidation chemotherapy, blinatumomab induced a CR rate of 78% [13]. A recently published phase III trial reported significantly longer overall survival (OS) following blinatumomab than conventional chemotherapy (median OS 7.7 vs 4.0 months, respectively, p=0.01) in 405 adults with heavily pretreated B-cell precursor ALL [14]. Additional outcomes that significantly favored blinatumomab over chemotherapy in this trial included: complete remission with full hematologic recovery (34% vs. 16%), event-free survival (6-month estimates, 31% vs. 12%), and longer median durations of remission (7.3 vs. 4.6 months). Thus far, only a few clinical studies have evaluated blinatumomab for patients with NHL. The initial reports involved 21 relapsed NHL patients and one chronic lymphocytic leukemia patient treated in three phase I studies [15]. Doses from 0.75

7 to 13 μg/m 2 were administered over 2-4 hours once, twice or thrice weekly. All three of these phase I trials were halted prematurely due to presence of side effects (neurologic events, cytokine release syndrome, and infections) without clinical response. The discrepancy between in vitro activity and clinical activity was attributed to the dosing schedule, and lack of sustained serum levels of drug. A subsequent phase I study included 76 patients with relapsed NHL (follicular n=28, mantle cell n=24, other indolent n=10, diffuse large B-cell lymphoma (DLBCL) n=14), administering blinatumomab as a continuous infusion [16]. The median number of previous treatment regimens was three. Patients received doses of 0.5, 1.5, 5, 15, 30, 60 or 90 μg/m 2 /day at a constant flow rate for 4-8 weeks until dose limiting toxicity or relevant disease progression occurred. Clinical responses were noted at 15 μg/m 2 /day and above, while the maximum tolerated dose was determined to be 60 μg/m 2 /day. Among the 35 patients treated at the 60 μg/m 2 /day dose, the objective response rate (ORR) across all subtypes was 69%, with a CR rate of 37%. The highest response rates were seen in follicular lymphoma (CR = 40%, ORR 80%). The median duration of response (mdor) for all patients who received the target dose was 404 days, while the mdor after CR was 508 days. A multi-center, open-label, single-agent phase II trial of relapsed/refractory DLBCL was conducted in 25 patients to assess efficacy and safety of blinatumomab using either weekly dose escalation or initiation of treatment at target dose [17]. The chosen target dose was 112 μg/day by continuous IV infusion for up to 8 weeks. A

8 subsequent 4 week treatment-free interval could then be followed by a 4-week consolidation cycle for patients with CR, partial response (PR) or stable disease following the first cycle. The median number of previous treatment regimens was 3. Only two patients were enrolled in a flat dosing arm with initiation at 112 μg/day, since both experienced serious grade 3 neurologic adverse events. The other patients received a step-wise dosing schedule (9 μg/d week 1, 28 μg/d week 2, then 112 μg/d thereafter) and dexamethasone premedication at treatment initiation and for each dose increase using 20mg orally 6-12 and 1 hour pre-infusion and then 8mg 3 times daily for 2 days. Despite step-wise dosing and dexamethasone, 5 (22%) patients stopped treatment due to adverse events; mainly neurological. Of the 21 evaluable patients who reached target dosing, 9 (43%) responded, 4 (19%) achieved CR, and their median progression free survival (PFS) was 3.7 months. 4. Safety and Toxicity Adverse events with blinatumomab are common, and typically occur during the initial few days of therapy and then become less frequent and severe over time. In the above reported studies by Goebeler et al [16], and Viardot et al [17], the most common toxicities from blinatumomab each occurring in approximately 25-50% of patients were tremor, pyrexia, fatigue, headache, and edema. This was similar to prior reports [18]. The most commonly reported grade 3 adverse events were thrombocytopenia, leukopenia, and neutropenia ANC (10-20% each). Even with the better tolerated step-wise dosing schedule, neurologic toxicity occurred in

9 approximately 2/3 of patients. The most common severe grade 3 neurologic adverse events were aphasia and encephalopathy (~5-10% each), but tremor, speech disorder, dizziness, disorientation and seizures were also reported (~3-4% each). These side effects were usually reversible with treatment discontinuation. Infection was also noted, with reports of both pneumonia and device-related infections from the administering pump. It is estimated that approximately 25% of patients receiving blinatumomab will have serious infections, although the incidence was lower in the NHL trials. Although cytokine release syndrome is a boxed warning for blinatumomab treatment of B-ALL, this syndrome was not reported in either NHL study. 5. Conclusion Blinatumomab has reasonable efficacy against non-hodgkin lymphoma in phase I/II trials. Use in relapsed/refractory diffuse large B cell lymphoma demonstrates an ORR of 41%. Given that treatment options in this patient population are limited, blinatumomab may provide a mechanism to bridge patients to stem cell transplant. Adverse effects are a significant burden, with 22% of patients stopping treatment early due to intolerable side effects. Blinatumomab use in indolent non-hodgkin lymphomas also shows promising early results. However, side effects, availability of other less cumbersome alternative

10 therapies, and cost remain barriers to more widespread use of blinatumomab in this population. 6. Expert Opinion Initial phase I and II trials have demonstrated modest activity of Blinatumomab against relapsed/refractory NHL. However, its use is currently limited by a lack of phase III data as well as a complicated 4-8 week continuous infusion schedule of administration, high cost ($ USD per cycle) [19], and significant toxicity [20]. Nevertheless, relapsed/refractory DLBCL patients have poor outcomes. Blinatumomab may help address this unmet need and possibly bridge these DLBCL patients to curative ASCT. Additionally, studies incorporating novel agents such as blinatumomab into upfront therapy for high-risk DLBCL are much anticipated. Blinatumomab also has activity against multiply relapsed/refractory indolent lymphomas, although it faces a great deal of competition from other agents including inhibitors of PI3kinase (Idelalisib), BTK (Ibrutinib) or BCL2 (Venetoclax), as well as antibody-drug conjugates (Polatuzumab Vedotin-CD79b, Denintuzumab Mafodotin-CD19A), immune checkpoint inhibitors of PD1 (Nivolumab, Pembrolizumab), and Chimeric Antigen Receptor (CAR) T-cell therapy. Many of these other novel therapies seem to be at least equally effective, less toxic and easier to administer than blinatumomab [21, 22, 23]. The possible exception might be CAR T-cell therapy, which requires cell collection and manipulation, but induces a somewhat similar immune response as Blinatumomab.

11 Table 1 lists multiple upcoming trials that will further investigate the use of blinatumomab in NHL including a phase II trial in relapsed/refractory indolent lymphoma (NCT ) and a phase Ib trial evaluating pharmacokinetics of subcutaneous blinatumomab in relapsed/refractory indolent lymphoma (NCT ). Of interest, an ongoing phase I trial in relapsed NHL is evaluating the combination of blinatumomab with lenalidomide (NCT ). Additional blinatumomab studies are planned in aggressive B-cell lymphomas including a phase II multicenter trial assessing blinatumomab immediately following frontline Rituximab-chemotherapy in high risk DLBCL, and will include those with MYC/BCL2 double hit or double protein expression (NCT ). Finally, a phase II/III trial is planned in relapsed/refractory aggressive B-cell NHL patients who do not achieve a complete response to 2 cycles of standard platinum-based chemotherapy (NCT ). Further work needs to be done to decrease toxicity and increase efficacy of blinatumomab. For example, pentosan polysulfate blocks P-selectin related adhesion of T-cells to blood vessel endothelium, decreasing trafficking of T-cells into the brain, and may prove effective prophylaxis against neurotoxicity [24]. As an alternate strategy, patients could possibly be stratified into different dosing regimens based upon predictors of neurotoxicity such as low blood B:T cell ratio [25]. Strategies to improve efficacy could include combination or sequencing with other agents. Theoretically, the immunomodulatory effects of Lenalidomide may

12 increase T-cell activation and proliferation associated with blinatumomab. Also of interest are studies that reported increased expression of PD-L1 on ALL cells refractory to blinatumomab [26]. Clinical trials combining blinatumomab with Lenalidomide or PD1-inhibitors are eagerly awaited. Finally, blinatumomab may find a role with donor lymphocyte infusions after relapse following allogeneic stem cell transplantation (allosct) [27]; however allosct is not a common treatment for NHL. Blinatumomab is a unique player in the field of anti-lymphoma agents. While initial studies show activity of blinatumomab in NHL, further studies are needed to delineate its niche in the hierarchy of available therapies. Funding: This manuscript has not been funded. Declaration of Interest The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. Figure 1 Single-Chain Antibody Blinatumomab Redirects CD3+ T-Cells To Kill CD19+ B-Cells. Reproduced from [8] with permission of Taylor & Francis.

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15 [14] Kantarjian H, Stein A, Gökbuget N, et al. Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia. N Engl J Med. 2017;376(9): **Landmark study assessing blinatumomab use for B-ALL [15] Nagorsen D, Kufer P, Baeuerle PA, et al. Blinatumomab: a historical perspective. Pharmacol Ther. 2012;13693): *A good review of development and use of blinatumomab [16] Goebeler ME, Knop S, Viardot A, et al. Bispecific T-Cell Engager (BiTE) antibody construct blinatumomab for the treatment of patients with relapsed/refractory non- Hodgkin lymphoma: Final results from a Phase I study. J Clin Oncol 2016;34(10): **Early clinical data assessing blinatumomab use in various types of non-hodgkin lymphoma [17] Viardot A, Goebeler ME, Hess G, et al. Phase 2 study of the bispecific T-cell engager (BiTE) antibody blinatumomab in relapsed/refractory diffuse large B-cell lymphoma. Blood. 2016;127(11): ** The largest clinical trial to date assessing blinatumomab use specifically in diffuse large B cell lymphoma [18] Amgen. (2014). BLINCYTO (blinatumomab): Full Prescribing Information. Retrieved from

16 [19] Pierson R. Amgen s new leukemia drug to carry $ price tag. Reuters [Internet] Dec 17 [cited 2016 Feb 6]; HealthNews [page 1] Available from: [20] MacDonald D, Prica A, Assouline S, et al. Emerging therapies for the treatment of relapsed or refractory follicular lymphoma. Curr Oncol. 2016;23(6): [21] Phillips T, Brunvand M, Chen A, et al. Polatuzumab vedotin combined with obinutuzumab for patients with relapsed or refractory non-hodgkin lymphoma: preliminary safety and clinical activity of a phase Ib/II Study. Blood 2016; 128(22):622 [22] Chong EA, Svoboda J, Nasta SD, et al. Chimeric antigen receptor modified T cells directed against CD19 (CTL019) in patients with poor prognosis, relapsed or refractory CD19+ follicular lymphoma: Prolonged remissions relative to antecedent therapy. Oral abstract presented at: American Society of Hematology Annual Meeting; 2016 Dec 3-6; San Diego, CA. [23] Köhnke T, Krupka C, Tischer J, et al. Increase of PD-L1 expressing B-precursor ALL cells in a patient resistant to the CD19/CD3-bispecific T cell engager antibody blinatumomab. J Hematol Oncol. 2015;8:111 [24] Klinger M, Zugmaier G, Naegele V, et al. Pathogenesis-based development of potential mitigation strategies for blinatumomab-associated neurologic events. Poster absract 1589 presented at: American Socieyt of Hematology Annual Meeting; 2016 Dec 3-6; San Diego, CA.

17 [25] Goebeler M, Viardot A, Noppeney R, et al. CD3/CD19 bispecific BiTE antibody blinatumomab treatment of non-hodgkin lymphoma (NHL) patients: 60 μg/m2/d by continuous infusion is tolerable and results in durable responses [abstract 0559]. Haematologica. 2010;95(Suppl.2):230 [26] Feucht J, Kayser S, Gorodezki D, et al. T-cell responses against CD19+ pediatric acute lymphoblastic leukemia mediated by bispecific T-cell engager (BiTE) are regulated contrarily by PD-L1 and CD80/CD86 on leukemic blasts. Oncotarget. 2016;7(47): [27] Ueda M, de Lima M, Caimi P, et al. Concurrent blinatumomab and donor lymphocyte infusions for treatment of relapsed pre-b-cell ALL after allogeneic hematopoietic cell transplant. Bone Marrow Transplant. 2016;51(9): Drug Summary Box Drug name Blinatumomab Phase III Indication Non-Hodgkin Lymphoma Pharmacology description Bispecific T-cell engager (BiTE) antibody construct, targeting CD19 and CD3 Route of administration Subcutaneous, continuous infusion Pivotal trial(s) [16][17] Pharmaprojects - copyright to Citeline Drug Intelligence (an Informa business). Readers are referred to Informa-Pipeline ( and Citeline (

18 Table 1. Clinical Trials Evaluating Blinatumomab for NHL Author Phase Patient population Goebeler, I NHL 2016 [16] Follicular n = 28 MCL = 24 DLBCL = 14 Other = 10 Viardot, 2016 [17] Number of patients Administration ORR CR PFS/OS 76 Continuous infusion, At MTD: At MTD: Median escalating doses Follicular Follicular = response = 80% 40% duration MTD of 60 Mantle cell MCL = 43% 404 days ug/m2/day given in = 71% DLBCL = n=35 DLBCL = 36% 55% Other = 0% Other = 50% II R/r DLBCL 25 Continuous infusion with weekly dose escalation, to target 112ug/day NCT I Relapsed NHL NCT Ib R/r indolent NHL lymphoma NCT II R/r indolent NHL lymphoma NCT II High risk DLBCL Recruiting Not yet open Not yet open Not yet open Continuous infusion plus lenalidomide Subcutaneous Continuous infusion Continuious infusion following upfront R- chemo Evaluable (n=21) =43% All patients = 36% Evaluable= 19% All patients, 16% Evaluable PFS = 3.7 months All patients, OS = 5.0 months NCT II/III R/r aggressive B- cell NHL Not yet open Continuous infusion

19 Figure 1. Single-Chain Antibody Blinatumomab Redirects CD3+ T-Cells To Kill CD19+ B-Cells

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