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Novel Immunotherapies and Their Role in the Treatment of Acute Lymphoblastic Leukemia

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Novel Immunotherapies and Their Role in the Treatment of Acute Lymphoblastic Leukemia 85 Review Article Novel immunotherapies and their role in the treatment of acute lymphoblastic leukemia Andrew Pham1, Noelle Frey2 1Department of Internal Medicine, Scripps Mercy Hospital, San Diego, CA, USA; 2Department of Hematology-Oncology, University of Pennsylvania, Philadelphia, PA, USA Contributions: (I) Conception and design: A Pham; (II) Administrative support: None; (III) Provision of study materials or patients: All authors; (IV) Collection and assembly of data: All authors; (V) Data analysis and interpretation: All authors; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors. Correspondence to: Noelle Frey. Department of Hematology-Oncology, University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA 19104, USA. Email: [email protected]. Abstract: Acute lymphoblastic leukemia (ALL) remains incurable for many adult patients. The success observed in the pediatric population with intensive combination chemotherapy regimens is not matched in older populations due to inability to tolerate treatment and biological differences in the disease. The development of immune therapies has ushered in a new much needed approach to treat ALL in the adult population as well as in the pediatric population with relapsed or refractory disease. While not heavily studied in the upfront setting, immune therapies have demonstrated astounding results in patients with minimal residual disease (MRD) and those with relapsed and refractory disease. The wide array of immunotherapy available consists of simple unconjugated monoclonal antibodies, immunotoxins or drug conjugated monoclonal antibodies, bispecific T cell engagers, and chimeric antigen receptor (CAR) T cells. In this article, we review the clinical data, efficacy, toxicity, and future direction of these therapies. Keywords: Chimeric antigen receptor T cells (CAR T cells); acute lymphoblastic leukemia (ALL); immunotherapy; blinatumomab Submitted Dec 13, 2016. Accepted for publication Dec 21, 2016. doi: 10.21037/tcr.2017.01.12 View this article at: http://dx.doi.org/10.21037/tcr.2017.01.12 Introduction be more effective given the more ubiquitous expression in precursor and mature B cells (9). There are many different Acute lymphoblastic leukemia (ALL) represents 20% of methods of modulating the immune system and directing acute leukemias in adults, and there are about 6,000 new immune mediated activity against the cells carrying these cases diagnosed annually in the United States (1). ALL antigens. Traditional unconjugated monoclonal antibodies, in the pediatric patient population treated with intensive antibody-drug conjugates, bispecific T cell engagers and chemotherapy induction regimens has an overall survival (OS) chimeric antigen receptor (CAR) T cells are the different approaching 90% (2-4). Unfortunately, this is not the case modalities of immunotherapy that have been utilized thus far. for the majority of adult patients with ALL, and long-term survival is only achieved in roughly 30% of patients (5,6). Immunotherapy in the form of targeting selective Unconjugated monoclonal antibodies surface antigens on leukemic cells has been a promising Rituximab adjunct to traditional therapy and is continuously evolving. Therapies against CD20 and CD52 have been previously Rituximab is a murine derived monoclonal antibody that evaluated and used for quite some time (7,8). However, targets CD20. Studies investigating the use of rituximab in immunotherapy directed against CD19 and CD22 may conjunction with standard induction chemotherapy have © Translational Cancer Research. All rights reserved. tcr.amegroups.com Transl Cancer Res 2017;6(1):78-85 Translational Cancer Research, Vol 6, No 1 February 2017 79 been performed by several groups (7,10,11). In one study diagnosed ALL (NCT02419469). by Thomas et al., 2 doses of rituximab were added to each of the four cycles of conventional hyper-CVAD to treat Epratuzumab patients with Philadelphia chromosome negative (Ph−), CD20+ patients with ALL. Patients who were treated with Epratuzumab is an unconjugated humanized monoclonal rituximab in additional to standard induction chemotherapy antibody that binds to CD22. Upon binding to CD22, were found to have an improved 3-year complete remission the receptor antibody complex becomes internalized. (CR) rate when compared with historical controls. This was The proposed mechanism of activity includes antibody especially evident in younger patients less than 60 years old, mediated cell cytotoxicity, CD22 phosphorylation and where 3-year OS was at 75% in the modified hyper-CVAD downstream signaling resulting in B cell modulation and plus rituximab group versus 47% in historical controls inhibition of cell proliferation. It has been studied in the treated with standard hyper-CVAD (10). context of pediatric patients with CD22 positive relapsed or The German multicenter study group evaluated the addition refractory ALL. In the study conducted by the Children’s of rituximab to induction chemotherapy in 263 patients with Clinical Oncology Group, epratuzumab was studied in CD20+ ALL. This study demonstrated an improved CR rate the relapsed disease setting. It was given initially as single and 5-year OS when compared with historical controls (11). agent therapy twice weekly for 2 weeks, then concurrently CRR at 16 weeks of treatment was 90% vs. 59% in standard with re-induction chemotherapy as 4 weekly doses. There risk disease and 64% vs. 40% in high risk disease. The 5-year were improved rates of MRD negativity, but there was no OS rate was 71% vs. 57% in standard risk disease and 55% difference in remission rates when compared with historical vs. 36% in the high risk disease group. It is important to controls (15). note that both of the above studies are prospective but The Southwestern Oncology Group tested epratuzumab without randomized controls. in combination with clofarabine and cytarabine in 31 adult A phase III randomized controlled trial labeled, patients with relapsed or refractory ALL (SWOG S0910). GRAALL-2005, evaluated standard chemotherapy against While there was an increased response rate of 52% compared standard chemotherapy plus rituximab in 209 patients with to 17% in historical controls (SWOG 0530), the median OS newly diagnosed ALL. Both groups had a similar CR rate and remained similar at approximately 5 months (16). There is level of minimal residual disease (MRD). The rituximab group an international European randomized phase III clinical had lower incidence of relapse at 2 years (18% vs. 30.5%), trial currently ongoing that is comparing epratuzumab hence the 2-year event free survival was also improved in the plus standard chemotherapy (BFM protocol) with standard rituximab cohort at 65% vs. 52% in the control group (7). chemotherapy alone in first relapse pediatric patients with standard risk ALL (NCT01802814). Ofatumumab Alemtuzumab Ofatumumab is a second generation human derived monoclonal antibody against CD20. It binds to a small Alemtuzumab is a humanized monoclonal antibody against loop epitope of CD20 and is generally considered more CD52 and causes cell death through antibody dependent potent than rituximab in terms of greater binding affinity cell mediated cytotoxicity. The CALGB 100102 study and ability to produce antibody dependent cell mediated was a phase I trial that studied alemtuzumab in the setting cytotoxicity (12,13). A phase 2 study performed by Jabbour of post-remission therapy, in between consolidation and et al. investigated the addition of ofatumumab to hyper- maintenance chemotherapy. It was administered 3 times CVAD induction in 25 patients with ALL. This study weekly up to a maximum dose of 30 mg. Median OS was showed a CRR of 96%. The 1-year progression free survival 55 months and there was a median 1 log reduction in (PFS) was 94% and the OS rate was 92% (14). Additional MRD. However, there were significant adverse effects ongoing studies are examining combination therapy with noted, such as viral infections and myelosuppression (17). augmented Berlin-Frankfurt-Munster (BFM) therapy A single institution phase II trial studied the use of single (daunorubicin, vincristine, prednisone, dexamethasone, agent alemtuzumab in 13 pediatric patients with relapse or PEG asparaginase, and methotrexate) and ofatumumab in refractory ALL, and a CR was only seen in one patient (18). adolescent and young adult patients aged 12–30 with newly A phase I/II study combined alemtuzumab with intensified © Translational Cancer Research. All rights reserved. tcr.amegroups.com Transl Cancer Res 2017;6(1):78-85 80 Pham and Frey. Immunotherapy and its evolving role in the treatment of ALL combination chemotherapy in upfront treatment for ALL of inotuzumab and bosutinib in CD22+, Ph+, relapsed or in 302 adult patients and achieved a CRR of around 80% refractory ALL (NCT02311998). (NCT00061945). Alemtuzumab was also investigated as Most recently, a phase 3 randomized control clinical part of a myeloablative conditioning regimen for stem cell trial has been completed comparing the use of single transplantation in 15 patients with high risk ALL, but did agent inotuzumab against conventional chemotherapy in not yield promising results (19). While alemtuzumab was relapsed or refractory ALL in adult patients. Conventional safely added to the conditioning regimen, it was proposed chemotherapy consisted of one of three regimens: fludarabine that the antileukemic activity of alemtuzumab was nullified and cytarabine, cytarabine and mitoxantrone,
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