Hairy cell leukemia (HCL) is a fairly rare hematologic malignancy which is characterized by an overproduction of B cells (lymphocytes) in the patient's bone marrow. This disease is typically chronic but slowly progressing, and is more frequently found in men, often appearing in middle-aged or older adults. Those with the disease will often present with a number of physical symptoms such as easy bruising, frequent infections, weakness, discomfort below the left rib cage, and weight loss.
Currently, HCL is typically managed with purine nucleoside analogs such as cladribine or pentostatin, which often produce extended periods of complete response (CR) in those patients. However, roughly half of those patients will eventually undergo a noticeable relapse within about 15 years and require additional therapy. In HCL patients experiencing a relapse, subsequent purine nucleoside analog therapy is often characterized by lower CR rates, shorter durations of response, and a greater risk for treatment-related toxicities and infections (a result of neutropenia).
The excessive B cells in HCL have an overexpression of the protein CD22 on their surfaces. This provides a means of therapeutically targeting these cells. One recently developed therapy which is being evaluated in HCL patients is the CD22-targeting moxetumomab pasudotox, formerly referred to as CAT-8015 or HA22. Recently, results from a pivotal, multicenter, single-arm phase III open-label international trial (NCT01829711) were reported for this therapy (Leukemia 2018;32:1768-1777). This study was conducted in patients with relapsed/refractory HCL at 32 treatment centers in 14 different countries.
One leading investigator for this study was Robert J. Kreitman, MD, Head, Clinical Immunotherapy Section at the NCI. Regarding the trial results, he stated, “The complete response rate (CRR) of 41 percent, which was assessed by blinded, independent central review, represented a substantial improvement over historical controls, while the durable complete response rate (DCR) of 30 percent met the primary endpoint.”
Citing the results obtained within this study, on Sept. 13, 2018, the FDA granted approval to moxetumomab pasudotox for the treatment of adult patients with relapsed or refractory HCL who have received at least two prior systemic therapies, either two lines of a purine nucleoside analog or one line of a nucleoside analog and one course of a BRAF inhibitor or rituximab.
The potent immunotoxin moxetumomab pasudotox consists of the Fv portion of the anti-CD22 monoclonal antibody which is coupled to a large fragment (~38 kDa) of the PE38 Pseudomonas exotoxin A (Clin Cancer Res 2011;17:6398-6405). Mechanistically, this therapy is directed to cells overexpressing sialic acid-binding transmembrane protein CD22. Once the immunotoxin binds to the CD22 receptor, the complex is then internalized via endocytosis. After internalization, the toxin is released from the complex, ultimately leading to initiation of the apoptotic cascade.
When asked about the selection of CD22 as a target for this form of therapy, Kreitman explained, “CD22, which is a lineage-restricted differentiation B-cell antigen, is an excellent target because it is absent on normal tissues like liver and skin, and although it is present on normal B cells, its lack of expression on B-cell precursors allows normal CD22-positive B cells to be rapidly regenerated after immunotoxin therapy ceases.”
Study inclusion was limited to adults having histologically confirmed HCL with an indication for treatment (i.e., displayed at least one of the following criteria: neutrophils less than 1.0×109/L, platelets less than 100×109/L, hemoglobin less than 10 g/dL, or symptomatic splenomegaly. Study participation was also limited to those having an Eastern Cooperative Oncology Group performance status of 0, 1, or 2 and adequate liver and kidney functioning.
Patients were required to have received at least two previous systemic therapies, including either two courses of a purine nucleoside analog or one course of rituximab or a BRAF inhibitor subsequent to a single course of purine nucleoside analog.
Moxetumomab pasudotox was dosed at 40 μg/kg intravenously over 30 minutes on days 1, 3, and 5 of each 28-day cycle for a maximum of 6 cycles or until investigator-assessed documentation of minimal residual disease-negative (MRD-negative) CR, disease progression, initiation of a different therapy, or unacceptable toxicity. Prophylaxis was administered to patients to prevent renal insufficiency (fluids and low-dose aspirin) and hypersensitivity reactions (hydroxyzine, acetaminophen, and ranitidine).
The primary endpoint was DCR, which was defined as blinded, independently and centrally reviewed CR with maintenance of hematologic remission for more than 180 days. The definition of CR was based on pathology (i.e., absence of hairy cells in bone marrow using routine hematoxylin and eosin staining techniques), imaging (resolution of enlarged spleen, enlarged liver, and lymphadenopathy documented by CT or MRI), and normalization of hematologic parameters (i.e., neutrophil level of 1.5×109/L or greater, platelet level of 100×109/L or greater, and hemoglobin of 11.0 g/dL or greater without growth factors or transfusions in 4 weeks). “Relapse was defined as loss of any criteria needed for best response, including the asymptomatic reappearance of hairy cells in the bone marrow by hemoxylin and eosin staining,” Kreitman explained.
Among the key secondary efficacy endpoints were objective response rate (ORR), duration of complete and objective response, progression-free survival, safety/tolerability, immunogenicity, and pharmacokinetics (PK).
Immunohistochemistry (IHC) was utilized in independent MRD assessment, however, during treatment, MRD was locally assessed (i.e., at study sites) using flow cytometry of peripheral blood and/or bone marrow aspirate, according to each site's protocols.
Safety assessments included adverse events (AEs), serious AEs, and changes in clinical laboratory evaluations and vital signs through 30 days after the last dose of investigational drug. Investigator-assessed AEs or serious AEs were graded using NCI Common Terminology Criteria for Adverse Events V4.03 and coded using Medical Dictionary for Regulatory Activities V20.0.
Immunogenicity was assessed at multiple time points during the study. Samples testing positive for anti-drug antibodies were evaluated for the following properties: neutralization, specificity (i.e., PE38 vs. CD22 binding domain), and titer. Pharmacodynamic assessment was performed at multiple time points via peripheral blood B-cell counts (i.e., CD19-positive B cells which include hairy cells).
All 80 patients enrolled in this study were included in the intent-to-treat population (i.e., all patients who enrolled and received moxetumomab pasudotox) for efficacy evaluations and the safety population (patients receiving at least one dose of the investigational drug).
The data cut-off date was May 24, 2017. A total of 80 patients were enrolled and treated, and of these, 50 patients (62.5%) completed 6 treatment cycles, while 12 (15.0%) discontinued early after achieving MRD-negative CR. Patients in this study had a median of three previous lines of prior therapy. For the patients in this study, 70 (87.5%) had received at least two lines of purine nucleotide analogs, 60 (75.0%) previously received rituximab, and 14 (17.5%) had prior BRAF-inhibitor therapy.
Hematologic remission was attained by 64 patients (80%) in about 1 month (median–1.1 months, [95% CI: 1.0-1.2 months]). At a median follow-up of 16.7 months (range–2.1-48.8 months), the DCR rate was 30 percent (24/80 patients; [95% CI: 20.3-41.3%]), while the ORR was 75 percent (60/80 patients, [95% CI: 64.1-84.0%]) based on blinded independent central review. The CRR was 41 percent (33/80 patients; [95% CI: 30.4-52.8]). CR was observed in 33 patients, including elimination of leukemic cells in bone marrow (morphologic assessment); partial response, defined as significant (>90%) reductions in bone marrow involvement, was also observed in eight patients (29.6%).
The most frequently encountered treatment-related AEs were nausea (27.5%), peripheral edema (26.3%), headache (21.3%), and pyrexia (20.0%). The most common treatment-related grade 3/4 AEs included decreased lymphocyte count (7.5%) and hemolytic uremic syndrome (5.0%). Additionally, grade 3 or 4 infections occurred in 13 patients, with two of the patients' infections being deemed treatment-related. Some treatment-related AEs resulted in permanent discontinuation of the investigational drug. The most common of these were hemolytic uremic syndrome (n=4), capillary leak syndrome (n=2), and hemolytic uremic syndrome-associated increased blood creatinine levels (n=2). “It should be noted that all hemolytic uremic syndrome and capillary leak syndrome events were reversible,” Kreitman stated. The three deaths that occurred in this study, due to pneumonia, septic shock, and sepsis syndrome and underlying HCL, were not considered treatment-related.
The PK profile for moxetumomab pasudotox showed rapid plasma concentration decline following IV dosing. Drug exposure was higher after subsequent doses relative to the initial dose, presumably a result of treatment-mediated CD22 sink reduction.
Antibodies were detected in 45 of the 76 evaluable patients at baseline. The frequency of neutralizing antibodies, as well as the anti-drug antibody titer, increased with the number of treatment cycles. Reduced drug exposure was observed in patients with high titer anti-drug antibodies. The median peripheral blood CD19 B-cell counts (i.e., hairy cells and normal B cells), which were reduced by 90 percent on day 8, remained low until treatment cessation, and, for patients with partial or CR, returned to approximately normal levels at 6 months post-treatment.
When asked about some of the challenges when treating relapsed/refractory HCL patients, Kreitman replied, “These patients tend to have bone marrow damage as a result of their prior treatment with purine-based nucleoside analogs. Treatment of these patients with the same agents is often less-effective, as their disease may now be resistant and often greater toxicities will be observed.
“This is especially problematic in older patients. In order to achieve the best outcomes in cases of HCL, it is crucial to eliminate MRD from the patient, which can be quite difficult to do.”
When discussing other forms of therapy for HCL, Kreitman stated, “In some cases, HCL patients are treated with vemurafenib, as that compound inhibits the V600E-mutant form of BRAF that is present in the majority of HCL patients. However, that particular type of therapy is static, which means that if treatment is ceased, the disease returns; thus, for this therapy, chronic dosing may be required.”
“One immunotherapy which is often applied in cases of HCL,” he noted, “is the CD20-targeting monoclonal antibody rituximab. However, the combination of rituximab plus purine nucleoside analogs was shown to be more effective than the antibody monotherapy at eliminating MRD in the patient.”
Concerning the efficacy observed in the study, Kreitman observed, “The blinded independent central review-assessed CRR of 41 percent represents a substantial improvement over historical controls, and the DCR rate of 30 percent met the study's primary endpoint.”
A total of 28 of the 33 CRs were achieved at the end of treatment disease assessment, with the remaining five patients achieving CR at disease assessment 6 months post-treatment, hence not qualifying as DCR technically due to timing. Only two of the 33 CRs didn't qualify for DCR due to normal blood counts worsening during the 6 months after CR, while another two didn't qualify for DCR due to the patients deciding not to follow the assessment plan. Among the complete responders, 27 patients (85%) achieved IHC-confirmed MRD-negative status. For the MRD+ patients, the median DCR was 5.9 months, however, for MRD-negative patients, most stayed in CR and the median value was not reached.
“In HCL,” Kreitman explained, “IHC staining of a high-quality bone marrow biopsy may provide more consistent MRD evaluation than flow cytometry of bone marrow aspirates, which cannot be accessed by a central lab.
“Published data suggest that the extent of MRD remaining after therapy in HCL is important in predicting long-term outcome (Blood 2018;131:2331).
“To date,” he noted, “this pivotal study is the largest prospective study in third-line or beyond relapsed/refractory HCL; it is also the first study using DCR as the primary endpoint. Patients were heavily pretreated; 50 percent received three or more prior courses of purine nucleoside analogs and 75 percent received prior rituximab.”
Richard Simoneaux is a contributing writer.