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Expert Guidance on Optimizing Treatment Strategies for Acute Lymphoblastic Leukemia
  • CME
  • CE

Amir Fathi, MD
Released: April 16, 2020

BiTE Therapy for ALL

Patient Case 2

Let’s review another patient case. A 55‑year‑old male patient is diagnosed with B‑cell precursor ALL. The bone marrow biopsy reveals a 60% B‑lymphoid leukemic blast population. The cytogenetic karyotype is normal with no BCR‑ABL fusion. The patient goes on to receive 1 cycle of induction chemotherapy per the CALGB 8811 protocol. Following induction course and count recovery, a bone marrow biopsy reveals morphologic remission, but flow cytometry reveals MRD with 0.2% residual lymphoid blasts. The patient goes on to receive 2 more cycles of induction chemotherapy, which he tolerates well. However, flow cytometry still reveals MRD with 0.18% B-lymphoid blasts.

Patient Case 2: Treatment Recommendation

As demonstrated by data arising from the phase II BLAST trial that will be discussed below, blinatumomab given following completion of induction therapy in the setting of hematologic CR with MRD leads to MRD clearance and improved outcomes in adult patients with B-cell ALL. In March 2018, blinatumomab was approved by the FDA for treating patients with B-cell ALL who are in first or second CR but have evidence of MRD of more than 0.1%. Therefore, my treatment recommendation for this patient would be blinatumomab. [Note: In the new Interactive Decision Support Tool for B-cell ALL, all 5 experts recommended blinatumomab followed by alloSCT if feasible. To view this tool, please visit https://www.clinicaloptions.com/oncology/tools or download the CCO Decision Support App.]

Phase III TOWER Trial of Blinatumomab vs Chemotherapy in Relapsed/Refractory B-Cell ALL: Study Design

The randomized phase III TOWER study evaluated the safety and efficacy of blinatumomab in 405 patients with pretreated B‑cell ALL.[36] Patients were randomized 2:1 to receive blinatumomab or investigator choice of standard-of-care chemotherapy, including FLAG, high-dose cytarabine‑based regimens, high‑dose methotrexate‑based regimens, or clofarabine‑based conventional therapy. Blinatumomab was given as a continuous infusion for 4 weeks followed by 2 weeks off, at 9 μg/day for 7 days, then 28 μg/day in Weeks 2 to 4 during the initial induction phase. The primary endpoint was OS.

TOWER: Hematologic Response in Induction

After the induction phase, blinatumomab led to a higher ORR (44% vs 25%; P < .001) as well as CR rate (34% vs 16%; P < .001) compared with standard-of-care chemotherapy.[36]

TOWER: OS in ITT Population

Blinatumomab also significantly improved OS vs chemotherapy (median: 7.7 vs 4.0 months; HR: 0.71; 95% CI: 0.55-0.93; P = .012).[36] After 75% of planned deaths had occurred, the independent data monitoring committee recommended stopping the study early for benefit related to blinatumomab. At this time, EFS was also markedly improved with blinatumomab vs chemotherapy (HR 0.55; 95% CI: 0.43-0.71; P < .001).

TOWER: Adverse Events

Blinatumomab is associated with certain unique toxicities. These include cytokine-release syndrome (CRS), a condition that can manifest as fevers, weight gain, hemodynamic compromise, and potentially lethal complications requiring transfer for intensive care unit (ICU) management. Blinatumomab can also cause various neurologic adverse events that range from mild confusion to aphasia and seizures, along with less well-defined neurologic toxicities that generally emerge following a week of treatment. In the TOWER study, grade ≥ 3 CRS occurred in 4.9% of patients receiving blinatumomab.[36] Grade ≥ 3 neurologic events occurred in 9.4% of patients receiving blinatumomab.

Phase II BLAST Trial of Blinatumomab in B-ALL With CR and MRD: Study Design

The phase II BLAST study was an open‑label, international, single‑arm trial that evaluated blinatumomab in 116 adults with B‑cell ALL who were in hematologic CR but continued to have MRD following upfront therapy.[37] Patients received blinatumomab at a dose of 15 mg/m2 continuous infusion daily, 4 weeks on, 2 weeks off, for up to 4 cycles. The primary endpoint was MRD response at 10-4 after 1 cycle of blinatumomab.

BLAST: Complete MRD Response After Cycle 1

Overall, 80% of patients achieved a complete MRD response after cycle 1.[37] These impressive responses were seen in patients across various subgroups, regardless of their MRD level at baseline, relapse history, sex, or age.

BLAST: Adverse Events

Common AEs seen with blinatumomab included fever, headaches, cytopenias, as well as various neurologic events, such as tremor, aphasia, dizziness, and occasionally, encephalopathy and seizures.[37] Overall, grade 3 AEs occurred in 33% of patients, and grade 4 AEs in 27%. CRS occurred in 4 (3%) patients, all in cycle 1.

Phase III COG AALL1331 Trial of Blinatumomab Plus Dexamethasone in Relapsed B-Cell ALL: Study Design

More recently, the open-label phase III COG AALL1331 trial compared blinatumomab plus dexamethasone with conventional chemotherapy in younger patients (aged 1-30 years) with B‑cell ALL.[38] In total, 208 patients at first relapse and deemed high or intermediate risk were randomized 1:1 to receive either blinatumomab 15 μg/m²/day for 28 days followed by 7 days off plus dexamethasone or conventional chemotherapy. The primary endpoint was DFS. Secondary endpoints included OS, MRD response, and proceeding to SCT.

COG AALL1331: Survival

After a median follow-up of 1.4 years, the 2-year DFS rate was 59.3% ± 5.4% with blinatumomab vs 41.0 ± 6.2% with chemotherapy (P = .050).[38] The 2-year OS rate was significantly improved as well with blinatumomab vs chemotherapy (79.4% ± 4.5% vs 59.2 ± 6.0%, respectively; P = .005).

This collection of studies highlight the utility and efficacy of blinatumomab in various settings of B-cell ALL, including the relapsed/refractory setting in adult patients compared with reinduction regimens, in combination with steroids in younger patients at first relapse, and in CR patients with MRD to clear residual disease.

BiTE Therapy for ALL: Advantages and Limitations

BiTE constructs such as blinatumomab offer both clinical advantages and notable limitations in the setting of B-cell ALL.[39,40] One advantage is that a BiTE agent is an off‑the‑shelf therapy, meaning that as opposed to CAR T‑cell therapy, which is logistically challenging and requires time to manufacture, blinatumomab is available and can be administered to patients as needed. Second, blinatumomab is associated with less nonspecific cytotoxicity as seen with traditional chemotherapies. Third, its activity is independent of MHC and T‑cell antigen specificity that is associated with other immune‑based therapies. There are immunomodulatory effects with BiTE agents: They can reactivate T‑cells within the tumor microenvironment and redirect T‑regulatory cells into tumor‑directed cytotoxicity. In addition, a short half‑life associated with blinatumomab means that toxicity can resolve relatively quickly.

There are some limitations to BiTE therapy, including challenges regarding safety. Patients can develop neurologic toxicity, CRS, and generalized AEs from T-cell activation. Continuous infusion can be logistically challenging for some patients. There are also resistance mechanisms that can emerge. Blinatumomab targets CD19 and, in some cases, CD19 can be lost as a result of targeting that antigen, thus limiting future CD19-targeted therapeutic approaches.

Blinatumomab: Approval by the FDA and Indications in ALL

Blinatumomab is currently approved by the FDA with 2 separate indications in B-cell ALL.[41] The initial indication was for treating adult or pediatric patients with relapsed/refractory B‑cell ALL. More recently, it was approved for patients with B-cell ALL who are in first or second CR but have evidence of MRD of > 0.1%. As noted, blinatumomab is associated with CRS and various neurologic toxicities, and there are boxed warnings for toxicities.

Blinatumomab: Managing CRS

Premedication with dexamethasone should be initiated before treatment with blinatumomab for CRS prevention, and with any step-up in dose, or any restart following > 4 hours of discontinuation. Inpatient initiation is recommended for patients with a higher risk of CRS.

For patients with grade 3 CRS, holding the infusion and initiating steroid therapy is generally recommended. When the CRS has resolved, treatment can be restarted at the lower dose of 9 μg/day for 7 days and then escalated to 28 μg/day continuous infusion.

Grade 4 CRS is more concerning. In this scenario, the infusion should be permanently discontinued and dexamethasone should be administered for 3 days, with tapering over 4 days. In severe cases, treatment with tocilizumab should be considered.[42]

Blinatumomab: Managing Neurotoxicity

Neurotoxicity management for patients starting blinatumomab also involves premedication with dexamethasone before initiation, step-up, and restart after > 4 hours of discontinuation and inpatient initiation for high‑risk patients. Patients who are older, non‑white, those who have had previous neurologic events, or are in later salvage have been observed to be at higher risk of neurologic toxicity with blinatumomab.[43]

Individuals who have seizures should have their infusion held, and anticonvulsant therapy and dexamethasone should be considered. If the seizure has resolved, blinatumomab can be restarted at a lower dose and then escalated after 7 days. If seizure recurs, then the treatment should be stopped permanently.

With grade 3 neurologic toxicity, recommendations are similar: the infusion should be held, steroids should be considered and, when resolved, blinatumomab can be restarted at a lower dose for 7 days and then escalated, if the patient continues to do well.

With grade 4 toxicity, the infusion should be held and steroids should be considered. Blinatumomab should be permanently discontinued.

Provided by Clinical Care Options, LLC

Clinical Care Options, LLC
12001 Sunrise Valley Drive
Suite 300
Reston, VA

Sophia Kelley

Supported by educational grants from
Jazz Pharmaceuticals, Inc.
Pfizer Inc.

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