Advanced renal cell carcinoma (RCC) is a challenging disease with short survival. Conventional cytotoxic chemotherapy and radiotherapy are generally ineffective in RCC. The unspecific immunotherapy with interleukin-2 (IL-2) and interferon-&alpha; (IFN-&alpha;) was regarded as the first effective therapy in patients with RCC. It led to remarkable clinical benefit in attaining durable complete responses.

But these responses were seen in less than 10% of patients treated with high-dose IL-2. The objective response rate (ORR) was also minimal.

Targeted therapies such as inhibitors of vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR) have shown better ORR, progression-free survival (PFS), and overall survival (OS).

The current standard of care for patients with advanced/metastatic RCC includes sunitinib, pazopanib, bevacizumab in combination with IFN, temsirolimus, sorafenib, axitinib, and everolimus. Despite the PFS benefit, the cancer becomes resistant to the targeted therapy, and progressive disease is imminent. Newer agents that can induce complete response and improve PFS and OS in a broad population are warranted. This has led to a quest to better understand T-cell activation and to the discovery of immune checkpoint inhibitors.

Immune checkpoints refer to regulatory pathways in the immunome that inhibit a portion of an active immune response against a specific target.

These are a normal part of the immune system. One such pathway is the programmed cell death (PD-1) and the programmed cell death 1 ligand (PD-L1). It involves the expression of the T-cell inhibitory ligand PD-L1 on the cell surface of tumor cells and infiltrating immune cells and PD-1 receptor on the tumor-infiltrating lymphocytes. The interaction between the PD-L1 and PD-1 receptors leads to inhibition of T-cell activation and effector function.

The inhibition of this interaction with antibodies directed against PD-1 and PD-L1 is being investigated in many tumors, including RCC.

Cytotoxic leukocyte antigen-4 (CTLA-4) is another widely studied immune checkpoint pathway. Immune activation occurs when the T-cell receptor (TCR) on the T cell interacts with the antigen on the antigen-presenting cell (APC) along with costimulation of CD28 on the T cell. This activation is kept under check through inhibitory signals from the interaction of CTLA-4 and its ligands, CD86 or CD80. Antibodies against CTLA-4 impede this inhibition, leading to unregulated T-cell activation (

). This article reviews immune checkpoint inhibitors with a focus on anti-PD-1/PD-L1 antibodies in RCC.

Tumoral PD-L1 expression in RCC is associated with worse prognosis and reduced survival.

In recent studies, it appears that higher expression of PD-L1 might be associated with higher chance of response.

However, the use of PD-L1 expression as a predictive biomarker has not been established because patients with negative PD-L1 also have shown decent responses. Furthermore, there is no standardized assay or definition for PD-L1 positivity.

Phase I Clinical Trials of Checkpoint Inhibitors in RCC

BMS-936558 (nivolumab) is a human immunoglobulin G4 monoclonal anti-PD-1 antibody. Its safety and tolerability were first studied in a dose-escalating phase I clinical trial with 39 patients with advanced solid tumors (NCT00441337). Only 1 of the 39 patients had RCC. The drug was well tolerated with no dose-limiting toxicities. Only 1 patient had a serious adverse effect (AE), inflammatory colitis; 1 patient had a durable complete response and 2 patients had partial responses, one of them the patient with RCC.

Nivolumab was also studied in another phase I trial involving 296 patients with advanced solid tumors; 34 of 296 patients had RCC (NCT0730639). Nivolumab was given in a starting dose of 1 mg/kg and then expanded to 3 mg/kg and 10 mg/kg in cohorts of 3 and 6 patients. Of the 34 patients with RCC, 17 received 1 mg/kg and 16 received 10 mg/kg. Cumulative ORR was 27% (9 of 33 patients). Five of 8 patients with response had a durable response greater than 1 year. Nine (27%) additional patients had stable disease, defined as stability longer than 24 weeks. Of all patients treated, 14% had grade 3 or 4 drug-related AEs, with rash (12%), diarrhea (11%), and pruritus (9%). Endocrine disorders of hypophysitis (2%) and hyperthyroidism (1%) are rare.

A long-term follow-up report of these patients with advanced RCC was reported by McDermott et al. In that study, 10 of 34 (29%) patients achieved objective response, with median response duration of 12.9 months. Median OS in all patients (34 patients) was 22.4 months. Survival rates of 1 year, 2 years, and 3 years were 71%, 48%, and 44%, respectively. Grade 3 to 4 treatment-related AEs occurred in 18% of patients, all of which were reversible.

Phase II Clinical Trials of Checkpoint Inhibitors in RCC

In a randomized, phase II, dose-ranging clinical trial, 168 patients with metastatic renal cell carcinoma (mRCC) were assigned to nivolumab 0.3 mg/kg, 2 mg/kg, or 10 mg/kg cohorts (NCT01354431); 70% of the patients had received more than one prior therapy. Median PFS was similar in all the cohorts, with 2.7 months, 4.0 months, and 4.2 months, respectively. Median OS ranged from 18.5 months, 25.5 months, and 24.8 months, respectively, with 3-year survival rates of 33%, 40%, and 32%, respectively. The ORR was 20%, 22%, and 20%, respectively. Of these, 75% (9/12), 50% (6/12), and 45% (5/11) were ongoing responders at the time of analysis, respectively. Fourteen of 35 were responding at 24 months from the start of study therapy, 7/35 were ongoing responders who had not yet reached the 24-month mark, and 14 of 35 stopped responding.

In all, 73% of the patients experienced treatment-related AEs, with 11% of them being grade 3 to 4. The incidence of AEs was similar across all cohorts. Fatigue was the most common treatment-related AE. No treatment-related deaths were recorded. Treatment-related discontinuation occurred in 7% of patients. Nivolumab demonstrated OS benefit across all dose cohorts as well as in PD-L1-positive and PD-L1-negative patients in this study with 3 years minimum follow-up. It also demonstrated durable long-term benefit in a handful of patients. This seems to be a favorable result in heavily pretreated patients with mRCC.

Based on these results, a phase III randomized trial (CheckMate 025) was initiated in patients with advanced or metastatic clear-cell RCC who received prior antiangiogenic therapy. The goal of the trial was to compare the clinical benefit of nivolumab versus everolimus, with OS the primary outcome measure (NCT01668784). The study has completed recruitment of patients, and the final data collection for primary outcome measure is expected in February 2016.

Combination Trials of Immune Checkpoint Inhibitors

Nivolumab is being studied in combination with other agents, including VEGF-tyrosine kinase inhibitor (TKI), sunitinib and pazopanib and CTLA-4 antibody ipilimumab. Data of these phase I/II trials were presented at the 2014 American Society of Clinical Oncology (ASCO) meeting.

A phase I trial was conducted with nivolumab plus sunitinib or pazopanib in patients with mRCC who received more than one prior therapy, with the primary aim to assess overall tolerability and safety (NCT01472081). Nivolumab (N) was given in dose escalation, while standard doses of sunitinib and pazaponib were used. In the sunitinib (S) arm (S + N; n = 33), nivolumab was dose escalated from 2 mg/kg (n = 7) to 5 mg/kg (n = 7) and then expanded in another 19 patients who were treatment-na&iuml;ve. In the pazopanib (P) arm (P + N ; n = 20) 10 patients were treated with 2 mg/kg with no further escalation after it was determined as the maximum tolerated dose. The limiting toxicities with this dose included elevated aspartate aminotransferase/alanine aminotransferase (AST/ALT) (n = 3) and fatigue (n = 1). Grade 3 to 4 AEs led to therapy discontinuation in 24% of patients in the sunitinib arm and in 20% of the patients in the pazopanib arm. Immune-mediated renal and hepatic AEs were higher in combination groups than in monotherapy. At the first assessment in 6 weeks, durable responses were noted in 41% in arm S and 56% in arm P. The ORR was 52% in arm S and 45% in arm P. This study showed that combination therapy has a manageable safety profile with reasonable antitumor activity.

Nivolumab (N) in combination with the CTLA-4 antibody, ipilumumab (I), is being studied in a phase I trial (CheckMate 016, NCT01472081).&nbsp;The trial&rsquo;s expanded cohort results were presented at the 2015 ASCO meeting. Patients with mRCC were randomized to N 3 mg/kg plus I 1 mg/kg (N3 + I1), to N 1 mg/kg plus I 3 mg/kg (N1 + I3), or to N 3 mg/kg plus I 3 mg/kg (N3 + I3) IV given every 3 weeks for 4 doses. Following that, all cohorts received N 3 mg/kg IV every 2 weeks until progression or toxicity. Cohorts N1 + I3 and N3 + I1 were expanded to 47 patients per arm while cohort N3 + I3 showed early toxicity and did not proceed to expansion. The primary endpoint was safety. Treatment-related AEs occurred in 88% of patients. Grade 3 to 4 treatment-related AEs occurred in 34% and 64% of patients in N3 + I1 and N1 + I3 arms, respectively, most common of which were gastrointestinal and hepatic. Discontinuation of therapy due to AEs occurred in 16% of patients. Most common AEs were elevated lipase and amylase, transaminitis, diarrhea, and colitis. Efficacy results are summarized in

. These results show promising antitumor activity for this combination therapy, with encouraging OS results. These data also support the development of this combination, leading to initiation of a phase III clinical trial in first-line setting.

CheckMate 214 (NCT02231749) is a phase III trial comparing nivolumab (N) 3 mg/kg IV plus ipilimumab (I) 1 mg/kg IV given every 3 weeks for 4 doses, followed by N monotherapy 3 mg/kg every 2 weeks and sunitinib monotherapy (50 mg orally once a day for 4 weeks followed by 2 weeks off). The trial expects to randomize about 1070 treatment-na&iuml;ve patients stratified by International mRCC Database Consortium prognostic score and by region. Primary endpoints are PFS and OS. Secondary endpoints include ORR and safety. Treatment will be continued beyond progression if it is well-tolerated and if investigator-assessed clinical benefit is achieved. Treatment will be discontinued for unacceptable toxicity or withdrawal of consent.

Pembrolizumab (MK3475) is another PD-1 antibody that is being studied extensively. In patients with treatment-na&iuml;ve mRCC, it is being studied in combination with the TKI axitinib in a phase Ib dose-finding study to evaluate the safety, pharmacokinetics, and pharmacodynamics of this combination (NCT02133742). The study plans to initiate axitinib at a starting dose of 5 mg twice a day, and MK3475 with 2 mg/kg and 1 mg/kg every IV 3 weeks, to find the maximum tolerated dose and continue treatment in a dose-expansion phase. The study, which is recruiting participants, will enroll an estimated 60 patients and is expected to be completed in March 2017.

BMS-936559 is a fully humanized PD-L1-specific antibody. It was evaluated in a phase I trial (NCT00729664) with 207 patients with advanced solid tumors, of which 17 had RCC. Patients were administered 10 mg/kg of PD-L1 antibody IV on days 1, 15, and 29 in a 6-week cycle, up to 16 cycles or until complete response or confirmed progression of disease. Two of 17 patients had objective response with duration of 4 and 17 months; 7 of 17 patients had stable disease at 24 weeks. The most common drug-related AEs were fatigue, rash, arthralgia, nausea, and headache. Treatment-related grade 3 to 4 AEs occurred in 19 of the 207 patients (9%).

Ipilimumab and tremelimumab are the two humanized CTLA-4 antibodies studied in various malignancies. Ipilimumab has been approved in advanced melanoma based on OS benefit in phase III trials, while tremelimumab failed to demonstrate any survival benefit in these patients. Both drugs were also studied in RCC in phase I and II trials. In a phase II trial with ipilimumab, the association between autoimmune toxicity and objective tumor response was found to be significant.

Tremelimumab was studied in combination with sunitinib in a phase I dose-escalating trial to evaluate drug safety. The continuance of this trial was not recommended because the combination caused significant dose-limiting toxicities.

summarizes the salient features of these trials.

PD-1/PD-L1 is regarded as the lead axis for immune checkpoint inhibition. Numerous antibodies targeting this pathway are being investigated at various stages in many tumors, especially in mRCC, where immunotherapy has proven to be beneficial (

). Preliminary results from these trials demonstrated acceptable and manageable toxicity along with promising efficacy. But we await the results of the ongoing phase III trials to see if there is any significant improvement in durable responses and in OS. The antitumor responses of these drugs are heterogeneous and are distinct from cytotoxic chemotherapy. Responses beyond disease progression, which are commonly seen with these drugs, are not captured by the response criteria for solid tumors. Hence, Wolchok et al evaluated a novel immune-related response criteria to assess these responses.

Nevertheless, prospective studies of these criteria and their association to OS are necessary. With better and broader patient selection in clinical trials, identification of predictive biomarkers, better response evaluation criteria, and superior combination therapies, we can envisage a significant shift in the treatment of RCC with immune checkpoint inhibitors.

Fyfe GA, Fisher RI, Rosenberg SA, Sznol M, Parkinson DR, Louie AC. Long-term response data for 255 patients with metastatic renal cell carcinoma treated with high-dose recombinant interleukin-2 therapy.

McDermott DF, Cheng SC, Signoretti S, et al. The high-dose aldesleukin &ldquo;select&rdquo; trial: a trial to prospectively validate predictive models of response to treatment in patients with metastatic renal cell carcinoma.

Articles

Clinical Articles

Unspecific immunotherapy with interleukin-2 (IL-2) and interferon-alpha was regarded as the first effective therapy in patients with RCC, leading to remarkable clinical benefit in attaining durable complete responses.

Immune Checkpoint Inhibitors in Renal Cell Carcinoma

Acute lymphoblastic leukemia (ALL) is a heterogeneous hematologic malignancy characterized by the proliferation of immature lymphoid cells in the bone marrow. ALL is a relatively rare malignancy in adults, with an estimated 6250 new cases and 1450 deaths expected in the United States in 2015.

Although most patients (>80%) achieve complete remission (CR) with conventional combination chemotherapy regimens, at least two-thirds of high-risk patients relapse.

While overall survival (OS) for children has significantly improved in the last 30 years, newly diagnosed adults continue to have a poor 5-year OS rate, approximating 35%, depending on age and risk factors.

Outcomes for relapsed/refractory patients remain worse: Only ~30%-45% of patients achieve a second CR, with a 5-year OS of 7%-10%.

Salvage regimens consist mainly of high-dose combination chemotherapy, including augmented hyper-fractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone, and PEG-asparaginase (hyper-CVAD), alternating with methotrexate and cytarabine, and clofarabine-, cytarabine-, or alkylator-combination regimens, and liposomal vincristine.

Hematopoietic stem cell transplantation (HSCT) remains the only curative option for adult patients with ALL.

Blinatumomab (Blincyto, MT103, Amgen Inc, Thousand Oaks, CA) is the first-in-class bispecific T-cell engager (BiTE) antibody approved by the US Food and Drug Administration (FDA). Blinatumomab&rsquo;s mechanism allows it to physically link T cells to malignant B cells by simultaneously binding CD3 on cytotoxic T cells and CD19 on B cells. It received breakthrough therapy designation in December 2014 for the treatment of Philadelphia chromosome-negative (Ph-) relapsed or refractory precursor B-cell ALL (B-ALL).

The National Comprehensive Cancer Network (NCCN) lists blinatumomab as a category 2A recommendation for Ph- relapsed/refractory B-ALL.

. The purpose of this article is to review the mechanism of action, pharmacokinetics/pharmacodynamics, clinical efficacy, adverse effects (AEs), dosage, administration, and future directions for blinatumomab.

was conducted in April and May 2015. Other information was obtained from the product labeling, ClinicalTrials.gov, and the FDA approval letters, reviews, accepted abstracts, and related documents.

antibody engineered to incorporate a linker sequence that allows it to be reduced to two variable binding domains on a single polypeptide chain, essentially combining two single-chain antibodies with different binding specificity in tandem. This functionally allows for cell lysis independent of the major histocompatibility complex (MHC)-1-peptide-T cell receptor (TCR) complex.

Cytotoxic T cells are the most potent and effective killer cells. They lack Fc&gamma; receptors and are therefore unable to participate in the regular antibody-dependent cellular cytotoxicity (ADCC) that relies on the binding of Fc&gamma; receptors on cytolytic immune cells to the Fc region on antibodies. Blinatumomab is the first type of antibody therapy that is able to overcome this obstacle in activating the immune T-cell response.

T cells are effective killer cells because of their mechanism of cell lysis; they contain vesicles that harbor pore-forming perforins and proteases (granzymes) that are subsequently delivered onto the target cell. This is only possible once the cytotoxic T cell is bound to its target through the MHC-1-TCR complex. Blinatumomab engages T cells by forming a cytolytic synapse between the CD3-bound T cell and the CD19-bound B cell. The CD3 binding on blinatumomab to cytotoxic T cells activates the T cells, circumventing the MHC-1-TCR binding, which is its typical mechanism of activation. Blinatumomab does not remain attached to the target cell during its lysis and therefore is able to be recycled and subsequently activate other T cells. The CD3 binding region on blinatumomab allows monovalent binding to all T cells with low affinity, triggering T-cell signaling only when presented with multivalent binding to target cells, therefore redirecting tumor cell lysis only when concomitantly bound to a CD19+ B cell.

Once engaged, blinatumomab activates T cells and then releases cytokines (ie, interleukin 2 [IL-2], IL-6, IL-10, interferon gamma [INF-&gamma;]), induces B-cell apoptosis, and produces a polyclonal expansion of memory T cells.

An advantage of targeting CD19 is its expression on most B-lineage malignancies, while lacking expression on hematopoietic stem cells and plasma cells. Its expression by early pre-B cells through mature B- cell development has shown to involve the PI3 kinase pathway, therefore magnifying B-cell activation and survival signaling.

In the adult dose-finding studies, there was no clinically meaningful effect of size or weight on blinatumomab clearance (age 18-80 years; body weight 44 kg to 134 kg; body surface area [BSA] 1.39-2.57 m

). Hence, flat dosing for blinatumomab can be used. The dose of 9 &micro;g/day was based on the initial 5 &micro;g/m

/day dose and the 28 &micro;g/day dose was based on 15 &micro;g/m

/day in an average-sized adult (BSA 1.8 m

Initially, phase I studies used short-term infusion dosing in patients with non-Hodgkin lymphoma (NHL) and blinatumomab was given once, twice, or three times a week as a 2-hour or 4-hour IV infusion. The phase I studies that used short-term infusions were terminated early because of lack of efficacy likely related to the lack of sustained reduction of peripheral CD19+ cells, the short serum half-life of blinatumomab, and its mechanism of action that focuses on continued B-cell depletion and prolonged T-cell activation.

Blinatumomab demonstrated linear pharmacokinetics in terms of dose proportionality and time-dependent clearance. The mean half-life was ~2 hours, which requires continuous infusion dosing to obtain adequate serum concentrations. The mean volume of distribution in adult patients was estimated at ~5 L.

Only 0.2% of unchanged blinatumomab was shown to be eliminated in the urine. Additionally, clearance among patients with mild to moderate renal dysfunction was similar to that in patients with normal renal function (1.6 L/hr to 3.3 L/hr); therefore, patients with mild to moderate renal dysfunctin do not require a dose adjustment. In clinical trials, patients with mild to moderate renal dysfunction experienced a higher incidence of grade 3 and 4 toxicities, although this was confounded by age, given that elderly patients could have an increased risk of AEs and renal dysfunction. It is worth noting that patients with severe renal impairment (

[CrCL] <30 mL/min) were excluded from the trials, so that no dosing recommendations can be made for this population.

There was no association between baseline transaminase levels and the clearance of blinatumomab. While the metabolic pathway has not been elucidated, it is expected to follow normal protein catabolic pathways.

In terms of blinatumomab&rsquo;s pharmacodynamic properties, complete B-cell depletion was dose dependent and achieved within 48 hours at doses &ge;5 &micro;g/m

Cytokines (IL-6, IL-10, INF-&gamma;) were elevated in more than 50% of patients with relapsed/refractory ALL on days 1-2 of cycle 1, and less in later cycles.

For the purpose of this review, we will highlight the studies that gained blinatumomab approval for Ph- precursor B-ALL, including the dose-finding phase II study that supports the approved dosing.

Phase II in Ph- relapsed/Refractory B-ALL

A small phase II study by Topp et al evaluated three sequential blinatumomab dosing cohorts in 36 patients with relapsed/refractory B-ALL.

Patients had &ge;5% leukemic bone marrow blasts, an Eastern Cooperative Oncology Group (ECOG) performance status of &le;2, and had Ph- disease or Philadelphia chromosome-positive (Ph+) disease unable to be treated with tyrosine kinase inhibitors (TKIs). Blinatumomab was given as an intravenous continuous infusion (IVCI) for 4 weeks every 6 weeks. During the first cohort of the dosing-finding run-in phase, patients (n = 7) received blinatumomab 15 &micro;cg/m

/day IVCI on days 1-28 (cohort 1). After one patient experienced grade 4 cytokine-release syndrome (CRS), a dose-step approach was implemented and a dexamethasone prephase (up to 24 mg/m

per day for &le;5 days and/or cyclophosphamide 200 mg/m

for &le;4 days) was permitted. Patients in cohort 2a (n = 5) received a starting dose of 5 &micro;g/m

/day IVCI on days 1-7, then increased to 15 &micro;g/m

/day IVCI for days 8-28. Finally, patients in cohort 2b (n = 6) received 5 &micro;g/m

/day IVCI on days 1-7, then 15 &micro;g/m

/day IVCI on days 8-14, followed by 30 &micro;g/m

/day IVCI on days 15-28. Cohort 1 had the highest rates of AEs overall while cohort 2a, had the lowest rates of AEs and, therefore, was the treatment approach used to treat 18 patients in the extension stage. Among all patients, 69% achieved a CR or CR with partial hematologic recovery (CRh) of peripheral blood counts (n = 15 CR, n = 10 CRh), with the lowest proportion of CR/CRh in those who had relapsed after HSCT. One of the two patients with Ph+ B-ALL achieved CR/CRh. Among the 25 responders, 88% (n = 22) achieved a minimal residual disease (MRD) response, defined as a decrease of MRD to <10

blasts by polymerase chain reaction (PCR). Median relapse-free survival (RFS) was 7.6 months and median OS (mOS) was 9.8 months (mOS if CR = 13.2 months; CRh = 8.3 months), and of the 25 responders, 52% (n = 13) proceeded to HSCT.

The phase II confirmatory study that led to blinatumomab&rsquo;s accelerated approval was a multicenter, single-arm, open-label study by Topp et al that enrolled 189 patients with Ph-, relapsed/refractory precursor B-ALL.

Patients were either primary refractory after induction, relapsed within 12 months of first remission or after having received allogeneic (allo-) HSCT, or failed or relapsed after at least first salvage therapy. Patients with central nervous system or testicular involvement, Ph+ B-ALL, ECOG performance status >2, acute or grade 2-4 chronic graft-versus-host-disease (GVHD), autoimmune disease, auto-HSCT within 6 weeks or allo-HSCT within 3 months of starting blinatumomab, and hepatic or renal insufficiency were excluded. Chemotherapy, radiation, and systemic treatment of GVHD were not allowed within 2 weeks of starting blinatumomab.

Blinatumomab was given as an IVCI at a target dose of 28 &micro;g/day (9 &micro;g/day on days 1-7, followed by 28 &micro;g/day on days 8-28 in cycle 1; 28 &micro;g/day on days 1-28 in cycles 2-5). This was given every 6 weeks for up to 5 cycles. Patients were premedicated with dexamethasone 20 mg within 1 hour of starting treatment in each cycle and before the dose step in cycle one. Patients with bone marrow blasts >50%, peripheral blood blasts &ge;15,000 cells/mcL, or elevated lactate dehydrogenase (LDH) levels were treated with a dexamethasone prephase of 10-24 mg/m

per day for up to 5 days because of the high risk for CRS. The primary endpoint was CR + CRh within the first 2 cycles.

Of the 189 patients, 39% had failed &ge;2 prior salvage regimens, 34% relapsed after allo-HSCT, and 69% had bone marrow blasts >50%. Patients received blinatumomab for a median of 42.2 days, and 51% of patients received the dexamethasone prephase treatment. Forty-three percent of patients achieved CR/CRh (n = 81/189; 33% CR, 10% CRh) within the first 2 cycles, with most (79%) of CR/CRh achieved in cycle 1. Patients with a lower percentage of bone marrow blasts (<50%) at presentation were more likely to achieve CR/CRh compared with those with &ge;50% bone marrow blast (73% vs 29%); however, response was seen across all subgroups in respect to age and prior lines of therapy, including HSCT. Median RFS was 5.9 months for the 82 patients in CR/CRh and median OS was 6.1 months for all 189 patients. Of the patients who achieved CR/CRh, 40% proceeded to allo-HSCT after receiving at least 2 cycles of blinatumomab and had a 100-day mortality rate of 11%. Of the 73 patients evaluable for MRD, 82% (n = 60) achieved MRD negativity. Although RFS and OS were relatively short, median RFS was longer for patients with MRD-negativity in CR/CRh compared with patients without MRD response (6.9 vs 2.3 months), as was OS (11.5 vs 6.7 months). It is worth noting that response rates were achieved despite the patient population having several negative prognostic factors, including high tumor burden and failure of multiple lines of salvage therapy, which typically correlate with low response rates to therapy.

99% of patients experienced at least one AE of any grade, most commonly pyrexia (60%), headaches (34%), febrile neutropenia (28%), peripheral edema (26%), nausea (26%), hypokalemia (24%), constipation (21%), and anemia (20%). The most common grade 3 or 4 AEs were hematologic in nature: febrile neutropenia (25%), neutropenia (16%), and anemia (14%). Twelve percent of patients (n = 23) had fatal AEs, predominately infection-related (74%), which is not uncommon in this patient population. Three patients experienced grade 3 CRS, and 52% (n =9 8) of patients had neurologic events (11% grade 3-4).

The most serious AEs associated with blinatumomab are CRS and neurologic toxicity, both associated with black box warnings and have prompted a Risk Evaluation and Mitigation Strategy (REMS) program to inform health care providers (HCP) about these risks. Manifestations of severe CRS mimic that of sepsis and disseminated intravascular coagulopathy; patients can experience severe pyrexia, hypotension, coagulopathy, and multiorgan failure. Patients with CRS are known to have elevations of proinflammatory cytokines, specifically IL-6, IL-10, and INF-&gamma;, during the height of T-cell activation.

While both nonsteroidal anti-inflammatory drugs and steroids can inhibit increases in cytokine levels, dexamethasone did not appear to effect blinatumomab-mediated cytotoxicity, since there was no notable effect of dexamethasone prephase on blinatumomab response in the large Topp trial.

While CRS events were observed at higher rates in earlier blinatumomab studies, implementation of a dose-step approach during the first cycle, dexamethasone premedication, and a required steroid prephase for patients with high tumor burden have reduced the rates of severe CRS. However, given the risk for serious CRS, close monitoring of patients when initiating treatment and with any dose escalation is critical.

highlights important recommendations for dose modifications.

Other strategies used to manage CRS include targeting the cytokines directly, specifically targeting IL-6 given the high amounts released with blinatumomab administration.

Tocilizumab, a recombinant humanized monoclonal antibody against the IL-6 receptor, approved for rheumatoid and juvenile idiopathic arthritis, has recently been used for the management of CRS. Patients treated with blinatumomab who develop grade 3 or greater CRS refractory to steroids and are treated with tocilizumab typically see resolution of symptoms within hours,

making it a treatment that should be considered for patients with steroid-refractory blinatumomab-induced CRS. However, tocilizumab has not been prospectively evaluated in a clinical trial and future studies are warranted to provide a better understanding about its role in CRS management, given that it could potentially blunt T-cell proliferation by interfering with cytokine feedback loops, possibly compromising the efficacy of blinatumomab.

Neurotoxicity related to blinatumomab use is seen significantly more than CRS. In the Topp study,

52% of patients (n = 98/189) experienced neurologic toxicities, which included tremor, dizziness, confusion, encephalopathy, somnolence, ataxia, and aphasia. This risk increased in patients &ge;65 years of age. Neurologic events were predominately grade 1-2, typically occurred in cycle 1, and were treated with dexamethasone without interruption of blinatumomab. However, of the 98 patients who experienced neurologic toxicities, 29 required treatment interruptions. In the smaller phase II study,

patients with epilepsy or convulsions were successfully resumed on blinatumomab with the addition of an anticonvulsant. Because of this warning, the manufacturer recommends that patients avoid operating machinery or motor vehicles while being treated with blinatumomab. While the mechanism behind the neurotoxicity remains largely unknown, it has been hypothesized to be IL-6 directed,

which would not be ameliorated with tocilizumab given its lack of penetration across the blood-brain barrier. Strict monitoring and prompt initiation of steroids are critical in preventing and treating neurotoxicity while continuing blinatumomab. However, dose interruption may also be warranted.

Blinatumamab also carries a warning about hepatotoxicity. Grade &ge;3 increases in aspartate transaminase (AST), alanine transaminase (ALT) and/or bilirubin were seen in >10% of patients early in treatment and may have been associated with cytokine release. Nearly all increases in liver enzymes resolved with treatment continuation or interruption, and patients who had therapy interrupted were successfully rechallenged.

Acute lymphoblastic leukemia (ALL) is a relatively rare malignancy in adults, with an estimated 6250 new cases and 1450 deaths expected in the United States in 2015. Although most patients achieve complete remission with conventional combination chemotherapy regimens, at least two-thirds of high-risk patients relapse.2 While overall survival for children has significantly improved in the last 30 years, newly diagnosed adults continue to have a poor 5-year OS rate, approximating 35%, depending on age and risk factors.

October 2015 | The Journal of Targeted Therapies in Cancer

Immune Checkpoint Inhibitors in Renal Cell Carcinoma

New Targeted Therapy in Acute Lymphocytic Leukemia: A Review of Blinatumomab in Relapsed/Refractory Acute Lymphocytic Leukemia