Despite the amazing successes that have been noted with the treatment of pediatric acute lymphoblastic leukemia (ALL) patients with intensive combination chemotherapies, similar outcomes have not been noted for adults.
Among the reasons cited for the disparity of outcomes between pediatric and adult ALL patients are intolerability of chemotherapy-related toxicities in adult patients, or the biological differences present in pediatric disease states.
To circumvent these shortcomings in treating ALL in adults, the use of various immunotherapy-based regimens has been explored for these patients.
Recently, Andrew Pham, MD, a hematology/oncology expert at Scripps Clinic in San Diego, and Noelle Frey, MD, Assistant Professor of Medicine at the Hospital of the University of Pennsylvania, Philadelphia, published a review that discussed the use of various immunotherapies (Transl Cancer Res 2017;6(1):78–85). “I believe the biggest immunotherapeutic advance in the treatment of ALL is likely CAR T-cell therapy. No other therapy has been able to produce such a significant response, especially in the relapsed and/or refractory setting,” Pham noted.
In this hybrid form of therapy, a monoclonal antibody is typically coupled with a cytotoxic compound, and in doing so, the ability of the monoclonal antibody is utilized to selectively direct the conjugate to cancer cells, where the attached cytotoxic agent then kills the cancer cell.
A humanized CD22-targeting monoclonal antibody (inotuzumab) and the minor groove DNA-binding agent ozogamicin comprise the antibody-drug conjugate inotuzumab ozogamicin. The biomarker CD22 is expressed in most cases of pre B-cell ALL, which makes this a particularly attractive target for monoclonal antibody recognition.
In August 2017, the FDA granted approval for inotuzumab ozogamicin to treat adults with relapsed or refractory B-cell precursor ALL. This approval cited the results of the INO-VATE ALL clinical trial in which patients with Philadelphia chromosome-positive or -negative relapsed or refractory B-cell precursor ALL were randomized in a 1:1 fashion to either inotuzumab ozogamicin or investigator's choice of chemotherapy.
Of patients receiving inotuzumab ozogamicin, 35.8 percent experienced complete remission (CR) for a median 8.0 months, while 89.7 percent attained minimal residual disease (MRD)-negativity. Only 17.4 percent receiving chemotherapy experienced CR for a median 4.9 months and 31.6 percent achieved MRD-negativity.
Moxetumomab pasudotox is an antibody-drug conjugate that consists of a CD22-targeting monoclonal antibody that is coupled to a shortened version of the pseudomonas exotoxin. With the inclusion of the bacterial toxin in this treatment, it was expected that enhanced immunogenicity might be observed in the patients.
A phase I study evaluated moxetumomab pasudotox in adults with previously treated relapsed/refractory ALL to determine dose-limiting toxicities and maximum tolerated dose. Although the therapy was generally well-tolerated, only modest clinical activity was noted, with an objective response rate of 13 percent and a median overall survival of 6.7 months. Despite these results, the researchers feel that the use of the CD22 biomarker to target malignant cells in ALL is a promising strategy (Br J Haematol 2018; doi:10.1111/bjh.14806).
In April 2018, the FDA granted a priority review to the biologics license application for moxetumomab pasudotox in the treatment of adults with hairy cell leukemia who had received two or more prior therapies.
Denintuzumab mafodotin (SGN-19A) consists of an anti-CD19 monoclonal antibody that is tethered to an analog of the antineoplastic agent monomethyl auristatin F. In February 2013, an open-label phase I clinical trial was initiated to evaluate the safety of denintuzumab mafodotin in pediatric and adult patients with relapsed or refractory B-lineage acute lymphoblastic leukemia, Burkitt lymphoma or leukemia, or B-lineage lymphoblastic lymphoma. The trial objectives were the incidence of adverse events and lab abnormalities. It is hoped that a maximum tolerated dose can be determined in this dose-escalation trial.
Rituximab, a chimeric monoclonal antibody, selectively binds to cells expressing the CD20 surface antigen. Some success has been noted for this monoclonal antibody in the treatment of hematologic malignancies, and it has received FDA approval for the treatment of non-Hodgkin lymphoma and chronic lymphocytic leukemia.
In a prior study, GRAALL-2005, adults 18–59 with Philadelphia-negative (Ph-), CD20-positive ALL (i.e., 20% or more of the leukemia cells expressed CD20) were randomized to receive chemotherapy alone or with rituximab. Philadelphia-positive (Ph+) patients were not included, as they are more suited to targeted tyrosine kinase inhibitor (TKI) therapy. The addition of rituximab to standard chemotherapy was found to significantly increase the event-free survival in these patients (N Engl J Med 2016; doi:10.1056/NEJMoa1605085).
Epratuzumab, the CD22 surface antigen, which tends to be overexpressed on malignant B cells, is specifically targeted by this humanized monoclonal antibody. In a pediatric ALL study performed by the Children's Oncology Group, epratuzumab was evaluated in the relapsed setting. The two arms were reinduction chemoimmunotherapy with epratuzumab once weekly and reinduction chemoimmunotherapy with epratuzumab twice weekly. There was a slightly higher rate of MRD for the reinduction chemoimmunotherapy with epratuzumab twice weekly (0.295 vs. 0.195).
Another study for this antibody is the CHEPRALL clinical trial, which evaluated epratuzumab plus chemotherapy with a different chemotherapy combination in adults with relapsed/refractory CD22+ ALL. In this study, stratification was done by age, with those who were 60 years or older receiving vincristine/aracytine/dexamethasone combination and those younger than 60 receiving the hyper-CVAD (cyclophosphamide/vincristine/doxorubicin/dexamethasone) plus epratuzumab. Noteworthy was the fact that nearly half of the responders attained negative MRD status (Haematologica 2017; doi:10.3324/haematol.2016.159905).
Based on those findings, particularly in a patient sub-population with typically poor prognosis, the investigators feel that epratuzumab should be evaluated as a first-line therapy, as it may also assist in decreasing the MRD, particularly prior to allogeneic stem cell transplantation.
Bi-Specific T-Cell Engagers
Blinatumomab is an antibody that consists of two separate binding sites; one receptor binds to the CD19 antigen overexpressed on the surface of malignant B cells, while the other binds to CD3, which is present on the patient's T cells. Inclusion of the CD3 receptor on this monoclonal antibody thus allows the patient's T cells to be both activated against and directed to the malignant B cells.
In December 2014, the FDA approved blinatumomab for the treatment of Philadelphia chromosome-negative (Ph-) relapsed or refractory B-cell precursor ALL. In July 2017, it received approval from the FDA for the treatment of adult or pediatric patients with relapsed or refractory B-cell precursor ALL based on the TOWER clinical trial.
At that time, the scope of the approval for blinatumomab was broadened to include patients with relapsed or refractory Philadelphia chromosome-positive (Ph+) B-cell precursor ALL. This was based on results obtained in the ALCANTARA study for patients either intolerant to second-generation TKIs and had imatinib-resistant disease, or had second-generation TKI-resistant disease. The median duration of remission was 6.7 months, while 36 percent of the patients attained complete remission with complete or partial hematological recovery.
In March 2018, accelerated approval was granted by the FDA to blinatumomab for the treatment of adult and pediatric patients with B-cell precursor ALL in first or second complete remission with MRD of 0.1 percent or greater. In giving this approval, the FDA cited the results obtained in the open label, multicenter, single-arm BLAST trial, which included adult patients (18 years or older) who were in complete hematologic remission and had received at least 3 courses of standard ALL chemotherapy. For the majority of patients transplanted in the study, those in CR1 and CR2 had median estimated hematological relapse-free survival values of 35.2 and 12.3 months, respectively.
CAR T-Cell Therapy
In tisagenlecleucel treatment, T cells harvested from the patient are genetically modified ex vivo to target cells that overexpress the CD19 surface antigen, such as tumor cells derived from B cells. The modification made to the T cells include the addition of the CAR, and then the engineered cells are returned to the patient via infusion.
In August 2017, the FDA granted approval for tisagenlecleucel in the treatment of relapsed or refractory B-cell precursor ALL in patients 25 years or younger. The FDA noted results from the B2202 clinical trial that included 63 pediatric and young adult patients, where the overall remission rate was 83 percent. Concurrent to the approval of tisagenlecleucel was the expansion of the approval for tocilizumab to allow treatment of CAR-T therapy-induced severe or life-threatening cytokine release syndrome (CRS) in patients 2 years or older.
Richard Simoneaux is a contributing writer.
- To address chemotherapy-related toxicities in adult ALL patients, various immunotherapy-based approaches are being explored.
- A number of antibody drug conjugates have shown promise among this patient population.
- Rituximab is being studied with chemotherapy.
- CAR T-cell therapy has been shown to have remission rates of up to 80 percent.
For more discussion on the role of immunotherapy in ALL, visit bit.ly/HemOncTimes.