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Immunotherapy in ALL
How I Interpret Clinical Trial Results to Choose Salvage Immunotherapies for Adult Patients With B-Precursor ALL

Released: September 01, 2016

Expiration: August 31, 2017

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Case Study
A 32‑year‑old woman presented with fever and weakness. She was found to have a white blood cell count of 70,000/mm3 and anemia and thrombocytopenia. The marrow was 50% infiltrated by blasts (premature B-cells) that express TdT, CD10, CD20, CD19, CD22, and CD34 but are negative for MPO and all T-cell markers. She also was Philadelphia chromosome (Ph) negative by FISH. She was diagnosed with precursor B ALL and treated on a pediatric protocol. She entered a CR within 4 weeks that was minimal residual disease (MRD) negative and remained in this status throughout consolidation and for 6 months of maintenance, at which time she relapsed. Her blast percentage has now risen to 80%, with the same immunophenotype. She has an HLA‑identical sibling donor.

How should we approach this patient?

Treatment After Relapse
Chemotherapy has been the main approach for relapsed ALL, with the goal of a second CR followed by allogeneic transplantation. In this setting, the duration of remission tends to be very short—a patient can relapse before the transplant is ready for transplantation. Patients who have a short remission, like the case patient, or who relapse after transplantation have a CR rate with chemotherapy of just 20% to 30%, and a median OS of 3-6 months. Therefore, new treatments are greatly needed for these patients.

Targeting CD19: Blinatumomab and CAR T-Cells
CD19 is a highly specific B-cell marker expressed throughout B-cell development and in > 90% of B-cell lineage cancers. Two immunotherapies that target CD19 are the bispecific antibody blinatumomab, FDA approved for relapsed/refractory ALL, and CAR T-cells, which are in clinical trials.

In a large phase II study in relapsed/refractory precursor B-ALL, the CR rate with blinatumomab was 33% (CR+CRh: 43%). Of note, CR rates in patients treated with blinatumomab are slightly lower with each successive relapse, but these are overall impressive results for a single agent. Also, 82% of patients receiving blinatumomab with a CR achieved MRD negativity, indicating a deep response with significant decrease in the tumor burden; 40% proceeded to allogeneic transplantation. Median OS was 11.5 months if MRD negative after blinatumomab vs 6.7 months if MRD positive. A subgroup analysis found that blinatumomab is more effective in patients with a low tumor burden. Side effects included fever, a 2% incidence of cytokine release syndrome (CRS), and central nervous system disorders (eg, seizures, encephalopathy) in up to 5% of patients. More recently, the randomized phase III TOWER trial (N = 405) comparing blinatumomab with standard chemotherapy in adult patients with relapsed/refractory ALL was presented at the 2016 EHA meeting. Results showed CR rates of 39% vs 19% and a median OS of 7.8 months vs 4.0 months (P =.011), for blinatumomab and chemotherapy, respectively.

Blinatumomab is given as a continuous IV infusion (CIV) and patients should be hospitalized for the first week of treatment to monitor for side effects, at a starting blinatumomab dose of 9 μg/day CIV. The dose is then increased to 28 μg/day on an outpatient basis in 6-week cycles, 4 weeks on, 2 weeks off; patients in remission after 2 cycles can continue treatment until relapse.

Chimeric antigen receptor (CAR) T-cell therapy is an investigational approach that also targets CD19. After leukapheresis, a patient’s T-cells are isolated and genetically engineered to express a CD19-targeted CAR and activate their T cell function. The cells are infused back into the patient where they proliferate and kill the leukemia cells. Production of the cells in the lab can take a few weeks, and patients may need additional therapies to maintain the remission while awaiting the infusion. The advantage of CAR T-cell therapy is HLA‑independent antigen recognition; as the cells are autologous instead of allogeneic, CAR T-cells can multiply and then persist for several months in adults (years in some children) and do not cause graft vs host disease.

In a recent study, 45 patients with relapsed/refractory ALL received lymphodepleting chemotherapy followed by CD19-targeted CAR T-cells. The CR rate with morphologic disease was 75%, 90% with molecular disease, and 83% if MRD negative. It takes approximately 3-4 weeks to achieve a CR, and the low white blood cell count during this time can contribute to adverse events. Median OS was not yet reached in MRD‑negative patients vs 6 months in MRD-positive patients, with 6-month OS of 80% vs 43%, respectively. Despite these strong results, CAR T-cells are not considered to be curative, as they likely dissipate over months. Eligible patients should still receive transplantation.

The most important adverse event of CAR T-cell therapy is CRS, which usually occurs in the first 2 weeks, and it is more common and more severe than with blinatumomab: 24% of patients in this study had severe CRS, several requiring intensive unit care for hemodynamic and respiratory support and treatment and often received IL-6R inhibitor (tocilizumab) and/or steroids. All had morphologic disease; no CRS was seen with minimal disease. Another serious adverse event is grade 3/4 neurotoxicity, which occurred in 28% of patients. Neurotoxicity can require treatment with steroids, which may inhibit the CAR T-cells.

Targeting CD22: Inotuzumab Ozogamicin
Inotuzumab ozogamicin is an antibody–drug conjugate that binds CD22 on leukemic cells and then delivers a toxin called calicheamicin. The drug is given weekly on days 1, 8, and 15 in a 28 day cycle and can be administered in an outpatient setting. A recent phase III trial compared inotuzumab with chemotherapy as first or second salvage (N = 218). Unlike the blinatumomab trials where the population was Ph negative, approximately 15% of patients in this study who had progressed on tyrosine kinase inhibitors were Ph positive. The CR rate was 36% for inotuzumab vs 19% for chemotherapy (CR + CRi: 81% vs 29%). MRD negativity among responders was 78% for inotuzumab vs 28% for chemotherapy. Of importance, 41% of the inotuzumab arm proceeded to transplantation vs 11% in the chemotherapy arm. Again, this drug is not curative, so the goal is to get patients to CR and then proceed to transplantation.

Unlike blinatumomab, the response rate to inotuzumab was not affected by baseline blast levels. Median PFS was significantly longer with inotuzumab vs chemotherapy (5.0 vs 1.8 months, respectively), and median OS was 7.7 months with the inotuzumab group, which is similar to blinatumomab, vs 6.7 months with chemotherapy (P = .04).

The most common toxicity with inotuzumab is myelosuppression. Rates of neutropenia were similar, but thrombocytopenia was more common with chemotherapy. The most important toxicity associated with this agent is sinusoidal obstruction syndrome (SOS), also known as veno-occlusive disease, a potentially life-threatening complication mostly associated with allogeneic transplantation that occurred in 11% of patients receiving inotuzumab vs 1% of patients receiving chemotherapy.

Case Study, Continued
I believe immunotherapy will provide our patients a better chance of transplantation and better survival over salvage chemotherapy. CAR T-cells can be considered, but the process can take a few weeks to prepare, is only available in clinical trial, and requires patients with a low tumor burden, good performance status, no heart disease, and no neurologic history. Inotuzumab is another possibility, but for the most part unavailable since the clinical trial has been completed and the agent has not yet been approved. Inotuzumab cannot be given to a patient who is CD22 negative, whereas blinatumomab and CAR T-cells cannot be used if a patient is CD19 negative, and it is also possible for a patient to lose CD19 expression. Blinatumomab is more effective in patients with a low tumor burden, whereas inotuzumab is not affected by tumor burden. The risk of SOS is greater with inotuzumab than blinatumomab, particularly if transplantation occurs soon after treatment. The risk of CRS is highest with CAR T-cells and is less of a concern with blinatumomab if the drug is administered properly. There is no CRS risk with inotuzumab. Taking all this into consideration, for this case study patient, I would start with blinatumomab, the only approved option.

There are still challenges, but given that outcomes of chemotherapy seem to be inferior to immunotherapies in randomized trials, immunotherapies are likely to become the preferred option for relapsed ALL in first relapse, and chemotherapy will more likely be used for subsequent salvages. In addition, the efficacy of all 3 immunotherapies vs chemotherapy make them promising treatments for study as frontline therapy in ALL.

Which of these agents shows the most promise for your clinical practice? Share your thoughts below!

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Which of these therapies would you consider for the case patient with relapsed/refractory ALL?
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