Despite advances in treating chronic lymphocytic leukemia (CLL), the 5% to 10% of patients who develop Richter transformation continue to have poor outcomes. For these patients, median progression-free survival is approximately 6 months, and median overall survival is about 8 months. Phase II studies presented at the 2016 American Society of Hematology (ASH) Annual Meeting & Exposition evaluated new treatment approaches for these poor-prognosis patients.
The hypothesis of our study was that checkpoint inhibition could result in a correction of this immune dysregulation and exert an antileukemia effect.— Nitin Jain, MD
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Nitin Jain, MD, and colleagues from MD Anderson Cancer Center, Houston, combined the checkpoint inhibitor nivolumab (Opdivo) with ibrutinib (Imbruvica).1 The combination demonstrated encouraging activity in the Richter cohort but modest activity in the patients with CLL.
“Immune dysfunction is common in CLL,” Dr. Jain noted. The immune dysregulation in this malignancy is the result of overexpression of checkpoint receptors, ie, programmed cell death protein 1 (PD-1) by T cells and respective ligands (PD-L1/2) on CLL cells.
“We hypothesized that blocking this interaction should enable T-cell recognition and reactivity against CLL cells,” he said. “Ibrutinib is known to modulate immune responses and has been shown to be synergistic with checkpoint blockade in preclinical models. Therefore, we designed a clinical trial that combined the monoclonal antibody nivolumab with ibrutinib for patients with relapsed or refractory CLL or Richter transformation. The hypothesis of our study was that checkpoint inhibition could result in a correction of this immune dysregulation and exert an antileukemia effect.”
Key Findings
The phase II study enrolled two cohorts: cohort 1 (n = 10) included patients who had relapsed/refractory disease or Richter transformation, and cohort 2 (n = 3) were patients with CLL who achieved partial remission after at least 9 months with ibrutinib and remained on treatment. Almost half the patients (46%) had del(17p) or TP53 mutations. IGHV was mutated in 58%.
In cohort 1, patients received a lead-in window of nivolumab monotherapy (3 mg/kg intravenously every 2 weeks) for the first course, with the addition of ibrutinib (420 mg once daily) starting with the second course. In cohort 2, patients were already receiving ibrutinib, and nivolumab was added with the first course as a consolidation strategy.
Outcomes
Reporting on the five patients in cohort 1 with relapsed/refractory CLL, Dr. Jain noted that by fluorescence in situ hybridization (FISH), three patients had del(13q), one had del(17p), and one was FISH-negative. All but one patient had mutated IGHV; in this group, one patient achieved a complete response, three achieved a partial response, and one had no response.
In cohort 2—patients with CLL responding to ibrutinib (response duration of 13–32 months)—two patients had del(17p) and one had del(13q); two had unmutated IGVH (one was undetermined). Their best response was stable disease, which all three demonstrated.
Novel Therapies for Richter Transformation
- Phase II studies evaluated two strategies for Richter transformation: combining a checkpoint inhibitor with ibrutinib and use of a more selective BTK inhibitor, acalabrutinib.
- In a study from MD Anderson Cancer Center, three of five patients with Richter transformation responded to the combination of nivolumab and ibrutinib; activity was modest, however, in patients with CLL without transformation.
- In a multinational study, acalabrutinib produced responses in 38% of patients with Richter transformation.
“In cohort 2, activity was modest. We did not notice any incremental improvement in their tumor burden with the addition of nivolumab. One patient continues on treatment at 9 months, and the other two were taken off study,” Dr. Jain reported. “All were getting ibrutinib at the same time as nivolumab, so it’s difficult to tease out the activity of the anti–PD-1 drug.”
Outcomes were more encouraging among the five patients in cohort 1 with Richter transformation, of whom three responded to the doublet. Two patients achieved complete responses for the Richter’s component and partial responses for the CLL component. A third patient had a partial response.
Among these three patients was a 62-year-old patient with del(17p), unmutated IGHV, and a complex karyotype who developed Richter transformation with a large oropharyngeal mass. Within 3 months of treatment, the mass completely resolved, Dr. Jain revealed.
The only immune-related adverse events were a grade 2 pneumonitis and grade 2 thyroiditis in one patient. One patient in the CLL cohort had a tumor flare within 1 week of treatment, which resolved on steroids; his response continues 9 months later.
The investigators are amending the study to further boost checkpoint inhibition by adding ipilimumab (Yervoy) to ibrutinib and nivolumab.
BTK Inhibitor Acalabrutinib
The initial data in this particularly bad-prognosis group of patients are leading us to look at the role of acalabrutinib in combination with chemoimmunotherapy and possibly other targeted treatments.— Peter Hillmen, MD
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B-cell–receptor signaling through Bruton’s tyrosine kinase (BTK), one of the essential proliferation pathways for CLL, has been shown to be involved in the pathogenesis of Richter transformation. “This makes BTK an obvious target for treatment of Richter transformation,” said Peter Hillmen, MD, of St. James University Hospital in Leeds, United Kingdom.
Dr. Hillmen presented findings for the Richter transformation cohort of the ongoing, multinational phase I/II ACE-CL-001 clinical trial of the BTK inhibitor acalabrutinib.2 “In this heavily pretreated, poor-prognosis group of patients with Richter transformation, acalabrutinib produced responses in 38%,” Dr. Hillmen reported.
Acalabrutinib is a highly selective, potent BTK inhibitor being developed to minimize off-target activity. Compared with ibrutinib, acalabrutinib has less activity against TEC, BMX, TXK, EGFR, and a host of other kinases. This allows for increased dosing, more specific targeting of BTK, and increased inhibition, Dr. Hillmen explained.
Study Results
Data were presented for 29 patients with Richter transformation or other transformations for safety and for 21 patients for efficacy. All patients received acalabrutinib at 200 mg twice daily. Almost half the patients had received prior treatment with ibrutinib, 42% had del(17p) or del(11q), and 81% had unmutated IGHV.
Of the 21 patients, 2 (9.5%) achieved a metabolic complete response and 6 (28.6%) had a partial response, yielding an overall response rate of 38.1%. Of the eight responders, three remain on study.
Responses were achieved in 5 of 12 ibrutinib-naive patients (42%) and in 3 of 9 patients with prior exposure (33%). Two responders subsequently underwent hematopoietic cell transplantation; one relapsed, and the other remains in remission on treatment.
The median time to response was 1.8 months. The median duration of response was 5.2 months, and the median progression-free survival was 2.1 months. “Obviously, most patients are progressing,” he noted.
Adverse events grade ≥ 3 occurred in 62% of patients, primarily anemia (14%), neutropenia (14%), hypercalcemia (10%), and back pain (10%). Serious adverse events occurred in 55%, primarily hypercalcemia (10%), fatigue (7%), and acute kidney injury (7%). Two patients had grade 5 adverse events deemed unrelated to treatment.
“The initial data in this particularly bad-prognosis group of patients are leading us to look at the role of acalabrutinib in combination with chemoimmunotherapy and possibly other targeted treatments,” Dr. Hillmen concluded. ■
Disclosure: Dr. Jain has served as a consultant for and received honoraria from Novartis, Servier, ADC Therapeutics, Pfizer, Pharmacyclics, and Novimmune; and received research funding from Seattle Genetics, Bristol-Myers Squibb, AbbVie, ADC Therapeutics, Genentech, Incyte, Celgene, Pfizer, Infinity, and Pharmacyclics. Dr. Hillmen has received research funding from Pharmacyclics, Janssen, Roche, Gilead, and AbbVie; and received honoraria from Janssen, Roche, and Gilead.
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