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New Therapies for R/R ALL
New Options for Patients With Relapsed/Refractory ALL

Released: February 20, 2015

Expiration: February 19, 2016

Elias Jabbour
Elias Jabbour, MD
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In the salvage setting in adult patients with acute lymphoblastic leukemia (ALL), complete remission (CR) rates are typically < 50% and long-term disease-free survival is rare. So the question is: How do you treat patients after multiple relapses? To answer this question, we will examine 3 novel agents that have shown good responses in both pediatric and adult patients with relapsed/refractory ALL.

Blinatumomab
Recently approved for the treatment of adult patients with Philadelphia chromosome–negative relapsed/refractory B-precursor ALL, blinatumomab is a bispecific T-cell engaging antibody that directs cytotoxic T cells to the CD19 marker on tumor cells, leading to T-cell activation and serial lysis of tumor cells.

Approval was based on results from 2 single-arm phase II trials of patients that evaluated blinatumomab in relapsed/refractory ALL. In the earlier trial, 25 of 36 patients (69%) achieved CR or CR with incomplete platelet recovery, with 52% going on to allogeneic stem cell transplantation (SCT). In the larger follow-up trial, 81 of 189 patients (43%) achieved CR or CR with incomplete hematologic recovery, with 40% going on to SCT.

The blinatumomab label contains a black box warning instructing prescribers to interrupt or discontinue therapy if patients develop grade ≥ 3 cytokine release syndrome (CRS), neurologic toxicity, or other clinically relevant adverse events. A single cycle of blinatumomab treatment is 6 weeks in duration, which includes 4 weeks of blinatumomab continuous infusion followed by a 2 week treatment-free interval. To mitigate for potential CRS and central nervous system events associated with introduction to blinatumomab, in the first induction cycle, the initial dose of blinatumomab is 9 μg/day for the first 7 days of treatment which then is escalated (dose step) to 28 μg/day starting on day 8 (week 2) through day 28 (week 4). For all subsequent cycles, 28 μg/day is the dose for all 4 weeks of continuous treatment.

Blinatumomab has also shown activity earlier in the disease continuum. In the phase II BLAST study, patients with a CR to their previous therapy, but with persistent minimum residual disease (MRD), were treated with blinatumomab (Capsule Summary). Most of the patients (78%) with a positive MRD status were converted to negative MRD status after 1 cycle of therapy. There is a need for a long-term study to examine the impact of MRD-negative status with blinatumomab on clinical outcomes.

Blinatumomab is a good option and there are other options that we hope will further expand a patient’s choice. One choice every eligible patient should consider is participating in a clinical trial, because we have some really impressive novel approaches to develop in ALL.

Inotuzumab Ozogamicin
Inotuzumab ozogamicin is an antibody–drug conjugate combining the anti-CD22 antibody inotuzumab with a calicheamicin cytotoxin. Inotuzumab binds to CD22 on the tumor cell, releasing the cytotoxin, inducing double-stranded DNA breaks and tumor cell apoptosis.

Kantarjian and colleagues studied 90 patients with relapsed/refractory ALL treated with single-agent inotuzumab; 58% achieved a CR, CR with incomplete platelet recovery, or CR with incomplete bone marrow recovery. Veno-occlusive disease was observed in 17% of patients undergoing allogeneic SCT after treatment.

Results of a phase I trial by my colleagues and me with inotuzumab ozogamicin combined with low-intensity chemotherapy (mini-hyperCVAD) in 35 patients with relapsed/refractory ALL showed a combined CR rate of 71%, and a median overall survival of 14 months for responders vs 1 month in patients with refractory disease. These results are better than any other agent available for these patients and allow for the possibility of transplantation. Twelve (34%) patients proceeded to receive SCT.

Chimeric Antigen Receptor–Modified T Cells
Chimeric antigen receptor (CAR)–modified T cells, or CAR-T cells, take a different approach, redirecting the patient’s immune system with reprogrammed T cells to target the CD19 marker on B cells. One therapy that uses this approach is called CTL019, which has demonstrated promise in patients with relapsed/refractory ALL, receiving an FDA Breakthrough Therapy designation in 2014. In a phase I/II study by Grupp and colleagues of 39 heavily pretreated pediatric patients with relapsed/refractory ALL treated with CTL019, 92% of patients experienced a CR, with some going on to allogeneic SCT (Capsule Summary). Although these were all pediatric patients, we are starting to see encouraging results in other trials with adult patients as well. Interestingly, high levels of proliferating CTL019 cells were detected in some patients up to 12 months after infusion, with a 76% probability of maintaining response at 6 months. These are very good results, although longer follow-up is needed. Serious toxicities including CRS were seen in approximately 25% of these patients. Elevations were managed with a single tocilizumab treatment or corticosteroids. B-cell aplasia is another serious but treatable adverse event. There are multiple groups exploring CAR-T cell immunotherapy in hematological malignancies, and we expect to hear a lot more about this approach during the next few years.

Improvements for Adult Patients With ALL
Improvements in therapy options for adult patients with ALL are highly encouraging. Targeted therapies have been shown to improve survival when combined with conventional chemotherapy. Blinatumomab is now approved for use and inotuzumab ozogamicin and CAR-T cell therapies have demonstrated marked activity even in patients who are refractory to multiple therapies, bridging at least some to potential curative allogeneic SCT. Furthermore, blinatumomab has shown great efficacy overcoming the negative impact of persistent or recurrent MRD. Moving forward, such approaches may replace allogeneic SCT, a current standard approach for patients with positive MRD.

The role of monoclonal antibodies, CAR-T cell therapies, and other novel targeted approaches in adult ALL continue to be defined. Most of these agents are currently being evaluated in the salvage setting, although the most active agents will likely need to be incorporated into the frontline treatment plan to optimize efficacy and decrease toxicities. Strategies such as these will continue to be developed and refined with the goal of achieving cure rates in adults that approach those observed in pediatric patients.

Your Thoughts?
What do you think about these approaches to improve outcomes in relapsed/refractory ALL? Please share your perspective in the comments box below and answer the question to the right.

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What treatment strategy do you use most often in adult patients with relapsed/refractory ALL in your current practice?
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