A Review of Selected Presentations From the 2020 ASCO Meeting
Safety of Acalabrutinib Monotherapy in Hematologic Malignancies: Pooled Analysis From Clinical Trials
Bruton tyrosine kinase (BTK) is critical to all aspects of B-cell development, including proliferation, maturation, differentiation, apoptosis, and cell migration. BTK also plays a role in the progression of B-cell lymphoproliferative disorders, such as mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). Ibrutinib, the first-generation BTK inhibitor, is clinically active in MCL.1 However, a proportion of patients with MCL discontinue ibrutinib after developing adverse events.2 The next-generation BTK inhibitor acalabrutinib is indicated for the treatment of relapsed/refractory MCL and CLL/SLL.3 In vitro studies have shown that acalabrutinib has greater selectivity for BTK compared with ibrutinib.4,5 It has been hypothesized that this greater selectivity may result in an improved safety profile.5-8
Furman and colleagues conducted a pooled analysis to generate an overall summary of the safety profile of acalabrutinib monotherapy.9 The analysis included 1040 patients enrolled in nine phase 1, 2, or 3 clinical trials. The patients had received acalabrutinib for B-cell malignancies, including MCL, CLL/SLL, Richter transformation, activated B-cell like subtype of diffuse large B-cell lymphoma, follicular lymphoma, prolymphocytic leukemia, and Waldenström macroglobulinemia. Most patients were male (68%) and White (89%). Their median age was 67.0 years (range, 32.0-90.0). The median body weight was 79 kg (range, 39-155). Most patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 (42%) or 1 (51%). A total of 35% of patients were treatment-naive, and the remaining 65% had relapsed or refractory disease. The median number of prior systemic regimens was 1 (range, 0-13).
After a median follow-up of 26.4 months (range, 0.0-58.5), the median duration of exposure to acalabrutinib was 24.6 months (range, 0.0-58.5). Treatment with acalabrutinib at the recommended monotherapy dose of 100 mg twice daily was administered to 83% of patients. The median relative dose intensity was 98.7%.
Nearly all patients (96%) experienced an adverse event of any grade; the majority of these events were grade 1 or 2 in severity. The 2 most frequent adverse events were headache, occurring in 37.8%, and diarrhea, occurring in 36.7%. Most of these cases were grade 1 or 2, and most occurred within the first 6 months of treatment. Most headache events occurred early, resolved, and did not recur. One patient (0.1%) discontinued treatment owing to headache. The median duration of headache events was 20 days (range, 1-994).
Other adverse events of note that occurred during or within 30 days after the end of acalabrutinib therapy included neutropenia in 16% of patients (14% with grade ≥3), anemia in 14% (8% with grade ≥3), and thrombocytopenia in 9% (5% with grade ≥3).
Grade 3 or higher adverse events were reported in 54% of patients. The most frequent were neutropenia (11.2%), anemia (7.8%), and pneumonia (5.1%). Serious adverse events of any grade occurred in 39% of patients. The most frequent serious adverse event was pneumonia, reported in 5%. Pneumonia was also the most frequent fatal adverse event, with a mortality rate of 1% (8 patients).
Several events of clinical interest for acalabrutinib were also investigated.9 Infections occurred in 66.7% of patients; grade 3 or higher infections occurred in 17.6%. Upper respiratory tract infections (22%) and sinusitis (11%) accounted for the majority of all-grade infections. The median time to infection onset was 97 days (range, 1-1343). Most patients with infections experienced their first onset within the first 6 months of treatment.
Hemorrhage occurred in 46.3% of patients; cases were grade 3 or higher in 2.7% (Figure 1). Grade 1 or 2 hemorrhage events included contusion in 22%, petechiae in 11%, epistaxis in 7%, ecchymosis in 6%, and an increased tendency to bruise in 5%. There were 3 cases of grade 3 or higher epistaxis, and 4% of patients developed a major hemorrhage event. A hemorrhage event of any grade occurred within the first 6 months of therapy in 38% of patients.
Cardiac events occurred in 15.6% of patients; these events were grade 3 or higher in 4.5%. A total of 4.4% of patients developed any-grade atrial fibrillation, which was a combined term that encompassed atrial fibrillation (4%), as well as atrial flutter (0.4%). Atrial fibrillation occurred at an incidence rate of 2.3 per 100 patient-exposure years (Figure 2). There were no grade 4 or 5 cases of atrial fibrillation. Grade 3 cases occurred in 1.3%. One patient (0.1%) developed ventricular tachyarrhythmia.
Second primary malignancies occurred in 12.2% of patients; severity was grade 3 or higher in 4.1%. The most frequently reported second primary malignancy was nonmelanoma skin cancer, occurring in 7% of patients. Excluding this cancer type, the median time to onset of second primary malignancy was 339 days (range, 7-1499).
At the time of the analysis, 65% of patients were continuing acalabrutinib treatment. Among patients who discontinued treatment, 17% did so owing to progressive disease and 9% owing to an adverse event. In most cases, acalabrutinib discontinuation owing to an adverse event occurred within 6 months of the first treatment dose (Figure 3). Additionally, adverse events led to dose modifications in 4% of patients and dose delays in 38% of patients.
The authors of this pooled analysis concluded that no unexpected safety signals arose throughout these clinical trials, and that the observed toxicity profile supported the long-term safety of acalabrutinib in patients with B-cell malignancies.9
References
1. Rule S, Dreyling M, Goy A, et al. Ibrutinib for the treatment of relapsed/refractory mantle cell lymphoma: extended 3.5-year follow up from a pooled analysis. Haematologica. 2019;104(5):e211-e214.
2. Owen C, Berinstein NL, Christofides A, Sehn LH. Review of Bruton tyrosine kinase inhibitors for the treatment of relapsed or refractory mantle cell lymphoma. Curr Oncol. 2019;26(2):e233-e240.
3. Calquence [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2019.
4. Barf T, Covey T, Izumi R, et al. Acalabrutinib (ACP-196): a covalent Bruton tyrosine kinase inhibitor with a differentiated selectivity and in vivo potency profile. J Pharmacol Exp Ther. 2017;363(2):240-252.
5. Byrd JC, Harrington B, O’Brien S, et al. Acalabrutinib (ACP-196) in relapsed chronic lymphocytic leukemia. N Engl J Med. 2016;374(4):323-332.
6. Pal Singh S, Dammeijer F, Hendriks RW. Role of Bruton’s tyrosine kinase in B cells and malignancies. Mol Cancer. 2018;17(1):57.
7. Byrd JC, Furman RR, Coutre SE, et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med. 2013;369(1):32-42.
8. Byrd JC, Brown JR, O’Brien S, et al; RESONATE Investigators. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med. 2014;371(3):213-223.
9. Furman RR, Byrd JC, Owen RG, et al. Safety of acalabrutinib monotherapy in hematologic malignancies: pooled analysis from clinical trials [ASCO abstract 8064]. J Clin Oncol. 2020;38(15 suppl).
Product Characteristics and Pharmacological Profile of KTE-X19 in Patients With Relapsed/Refractory Mantle Cell Lymphoma in the Phase II Registrational ZUMA-2 Trial
The second-generation chimeric antigen receptor (CAR) T-cell therapy KTE-X19 is directed against CD19. ZUMA-2 was a pivotal phase 2 study that investigated KTE-X19 in patients with MCL.1 Enrolled patients had received from 1 to 5 prior therapies, including a BTK inhibitor, and had relapsed during treatment or developed relapsed/refractory disease. After enrollment, patients underwent leukapheresis and an optional bridging therapy consisting of dexamethasone, ibrutinib, or acalabrutinib. The bridging therapy was completed 5 days or fewer before initiation of conditioning chemotherapy (fludarabine plus cyclophosphamide). Subsequently, all patients received their CAR T-cell dose (2 × 106 cells/kg).
The primary efficacy analysis of the ZUMA-2 study occurred in 60 patients, after a median follow-up of 12.3 months. The objective response rate (ORR) was 93%, which included complete responses in 67%.1 At the time of the analysis, 57% of all patients had an ongoing response. Among patients with a complete response, 78% had an ongoing response. Adverse events included grade 3 or higher cytokine release syndrome in 15% of patients, and grade 3 or higher neurologic events in 31% of patients. Most of these cases were reversible.
Wang and colleagues completed an analysis of the ZUMA-2 trial that focused on the pharmacologic profile of KTE-X19 in patients at low-risk vs high-risk.2 The study included 65 patients who had received treatment in the trial. The investigators defined high-risk as an elevated Ki-67 proliferation index (≥50%) and a TP53 gene mutation, both of which are associated with a poor prognosis.3
Overall, the CAR T-cell product characteristics were generally comparable across the 2 prognostic groups.2 For example, the median ratio of CD4-to-CD8 cells was 0.7 (range, 0.04-3.7) in the overall population, 0.8 (range, 0.4-1.7) in patients with a Ki-67 proliferation index of less than 50%, and 0.7 in patients with a Ki-67 proliferation index of 50% or higher. There was a trend toward a more CD4-based phenotype in patients with a TP53 mutation vs without. The median ratio was 1.2 (range, 0.7-3.7) vs 0.7 (range, 0.04-1.9), respectively.
There was also a trend toward more differentiated T-cell phenotypes among patients with a high Ki-67 index (≥50%).2 These patients had a median of 20.1% (range, 0.3-68.8) naive T cells, 12.0% (range, 2.3-51.6) central memory T cells, 29.1% (range, 5.8-70.3) effector memory T cells, and 32.4% (range, 2.8-65.2) effector T cells. In comparison, patients with a low Ki-67 index had a median of 30.4% (range, 11.0-57.0) naive T cells, 10.1% (range, 8.4-45.0) central memory T cells, 19.4% (range, 6.3-56.1) effector memory T cells, and 23.7% (range, 11.5-49.3) effector T cells.
Overall, comparable CAR T-cell expansion was observed regardless of the Ki-67 proliferation index or TP53 mutation status.2 Among the 48 patients with Ki-67 assessments, ORR was 94% in those with a high index vs 100% in those with a low index. TP53 mutation status was available for 36 patients; a response was achieved by all of them, regardless of whether they had the mutation (n=6) or not (n=30).
The pharmacodynamic profile of KTE-X19 remained relatively consistent between the high-risk and low-risk prognostic groups (as defined by the Ki-67 index). There was a consistent trend for increased production of serum cytokine levels and their receptors among patients with a mutated TP53 gene; several differences reached statistical significance. Notably, among the 6 patients with a TP53 mutation, 3 developed grade 3 or higher neurotoxicity and 2 had grade 3 or higher cytokine release syndrome.
In addition, increased peak levels of cytokine expression in the serum were observed in patients with negative minimal residual disease (MRD) status (n=29). Among these patients, interferon gamma (IFN-γ; Figure 4) and interleukin (IL) 6 showed statistically significant increases in expression compared with patients who were MRD-positive at 1 month (n=29). IL-2 showed a trend toward increased expression.
Among 6 patients who developed grade 4 neurologic events, 3 patients had concurrent grade 4 cytokine release syndrome. Compared with patients without these events, these 3 patients had higher peak serum levels of IFN-γ (Figure 5), tumor necrosis factor alpha (TNF-α), monocyte chemoattractant protein 1 (MCP-1), IL-2, and IL-6. The one patient who developed grade 4 cerebral edema also experienced an increase of cytokine expression levels that was several-fold higher than the median increase observed in the clinical trial.1,2
The investigators concluded that the pharmacokinetic and pharmacodynamic profiles of KTE-X19 were comparable overall in this group of patients, regardless of the Ki-67 proliferation index or TP53 mutational status.2 The pharmacodynamic profile of KTE-X19 was associated with efficacy outcomes, particularly MRD-negative status, as well as safety endpoints, such as cytokine expression levels.
References
1. Wang M, Munoz J, Goy A, et al. KTE-X19 CAR T-cell therapy in relapsed or refractory mantle-cell lymphoma. N Engl J Med. 2020;382(14):1331-1342.
2. Wang M, Rossi JM, Munoz J, et al. Product characteristics and pharmacological profile of KTE-X19 in patients with relapsed/refractory mantle cell lymphoma in the phase II registrational ZUMA-2 trial [ASCO abstract 3023]. J Clin Oncol. 2020;38(15 suppl).
3. Cheah CY, Seymour JF, Wang ML. Mantle cell lymphoma. J Clin Oncol. 2016;34(11):1256-1269.
Clinical Activity of Cirmtuzumab, an Anti-ROR1 Antibody, in Combination With Ibrutinib: Interim Results of a Phase Ib/II Study in Mantle Cell Lymphoma or Chronic Lymphocytic Leukemia
The monoclonal antibody cirm-tuzumab is directed against ROR1, an onco-embryonic tyrosine kinase receptor whose expression is increased in hematologic malignancies and solid tumors. In tumor cells, ROR1 signaling is associated with enhanced tumor growth and survival, a stem cell-like phenotype (cancer cell stemness), and epithelial-mesenchymal transition. In preclinical studies, cirmtuzumab showed activity as a single agent and in combination with other treatments, including BTK inhibitors.1,2
A phase 1b/2 clinical trial by Lee and colleagues evaluated the combination of cirmtuzumab with ibrutinib.3 The trial enrolled adult patients with MCL (limited to relapsed/refractory disease) or CLL (relapsed/refractory or treatment-naive disease). The patients had radiographically measurable disease, and they had no or limited prior exposure to a BTK inhibitor. Other eligibility criteria included an ECOG performance status of 0, 1, or 2 and a requirement for therapy.
The study consisted of 3 parts. Part 1 was the phase 1 dose escalation of cirmtuzumab. Sequential patients were enrolled and received increasing dose levels of cirmtuzumab together with standard doses of ibrutinib (specific to the indication) that were initiated on day 28 of cirmtuzumab treatment. Enrollment into part 1 has been completed, and included 12 patients with MCL and 18 patients with CLL/SLL. Part 2 was designed as an expansion cohort, in which patients were treated with the recommended cirmtuzumab dose of 600 mg together with standard doses of ibrutinib (560 mg for patients with MCL and 420 mg for patients with CLL/SLL). Enrollment into part 2 has been completed for patients with CLL/SLL (n=16), and continues for patients with MCL. Part 3 is the phase 2 portion of the study, in which patients with CLL/SLL are randomly assigned to treatment with cirmtuzumab plus ibrutinib vs ibrutinib alone. This part of the study is actively enrolling patients.
Among the 12 patients with MCL enrolled in part 1, the median age was 63.5 years (range, 49.0-70.0).3 The median time from diagnosis was 2.5 years (range, <1 to 9). Patients had received a median of 2.5 prior therapies (range, 1-5).
There were no dose-limiting toxicities or grade 3 adverse events deemed related to cirmtuzumab alone. Among the 15 patients with MCL who had safety data (including 3 patients from part 2), the most common treatment-emergent adverse events were diarrhea (46.7%), fatigue (46.7%), confusion (26.7%), and rash (20.0%). The 3 patients in part 1 who discontinued treatment did so owing to progressive disease.
Among the 12 patients with MCL in part 1, the best ORR was 83.3%, which included complete remissions in 58.3% and partial remissions in 25%. An additional 16.7% of patients (n=2) achieved stable disease, equating to a clinical benefit rate of 100%. The maximum change in tumor regression from the baseline sum of the perpendicular diameters (SPD) is shown in Figure 6. Most patients exhibited a rapid and sustained regression in their tumor burden over time (Figure 7). One patient showed transient tumor growth at day 28, but then developed rapid regression that led to a complete remission. After a median of 8.3 months of follow-up for the MCL patients in part 1, the median progression-free survival (PFS) was 17.5 months. However, the authors noted that at the time of this analysis, only 2 patients had been on-study for longer than 15 months.3
References
1. Yu J, Chen L, Cui B, et al. Cirmtuzumab inhibits Wnt5a-induced Rac1 activation in chronic lymphocytic leukemia treated with ibrutinib. Leukemia. 2017;31(6):1333-1339.
2. Yu J, Chen Y, Chen L, et al. Cirmtuzumab inhibits ibrutinib-resistant, Wnt5a-induced Rac1 activation and proliferation in mantle cell lymphoma. Oncotarget. 2018;9(37):24731-24736.
3. Lee HJ, Choi MY, Siddiqi T, et al. Clinical activity of cirmtuzumab, an anti-ROR1 antibody, in combination with ibrutinib: interim results of a phase Ib/II study in mantle cell lymphoma or chronic lymphocytic leukemia [ASCO abstract 8036]. J Clin Oncol. 2020;38( 15 suppl).
Mantle Cell Lymphoma: Initial Report From the North American Mantle Cell Lymphoma Consortium
The North American Mantle Cell Lymphoma Consortium presented findings regarding the use of a modified MCL International Prognostic Index (MIPI) scoring system to predict patient prognosis.1 Since the North American Mantle Cell Lymphoma Project was initiated in 2013, a total of 589 patients with MCL have been recruited from across 23 institutions in North America. For each of these patients, the initial diagnosis of MCL was confirmed by a panel of expert hematopathologists at the University of Nebraska Medical Center.
Among these patients, the median age was 63 years (range, 24-104).1 The male-to-female ratio was 3.6 to 1. Most patients (89.1%) presented with advanced Ann Arbor stage III or IV disease at diagnosis. Additionally, 28% presented with B symptoms, and 72% showed extranodal involvement. The median follow-up was 5.2 years (range, <1 year to 18.4 years). The 5-year rate of PFS was 24.1%, and the 5-year overall survival rate was 60.2%.
Initially, the investigators conducted a multiple univariate analysis for the entire patient cohort, with the goal of identifying risk factors that significantly correlated with overall survival. The analysis identified several characteristics that significantly correlated with overall survival, although some factors showed distinct predictive values in younger patients (≤60 years) vs older patients (>60 years). For example, 3 factors were significant for overall survival in younger patients but not older patients: disease limited to 1 site vs more than 1 site, classical/small vs blastoid/pleomorphic cytomorphology, and a Ki-67 level of 30% or higher. In contrast, a nodular, diffuse growth pattern was statistically significant for overall survival among older, but not younger, patients. The researchers suggested that these differences may have arisen because some of the factors were evaluated within small sample sizes, and future studies are therefore needed for confirmation.
Traditionally, the MIPI2 and the combined MIPI (MIPI-C, a combination of MIPI and the Ki-67 index)3 systems have been effective tools to stratify risk groups in younger patients, but are less accurate for older patients. Thus, a new, simplified scoring system was developed to incorporate more pathologic parameters to predict overall survival. This scoring system is referred to as MIPI-Pathology (MIPI-P). The MIPI-P score includes high Ann Arbor stage (stage III or IV), elevated lactate dehydrogenase (above the normal upper limit), cytology (blastoid/pleomorphic), and Ki-67 proliferation index (≥30%). One point is assigned to each of these parameters. The MIPI-P was then used to stratify patients from this study into 3 risk groups: low (0), intermediate (1 to 2), and high (3 to 4).
Using the MIPI-P system, patients were successfully stratified into 3 risk groups (Figure 8). The scoring system was particularly accurate among patients ages 60 years or younger (P=.00093). MIPI-P was able to stratify older patients into the same risk groups, but the P value was only marginally significant (P=.07). This was attributed, at least in part, to the lower number of patients in the low-risk group.
The investigators summarized that in this preliminary report, univariate analysis identified multiple risk factors that correlate with overall survival in patients with MCL. Some of these factors may have distinct predictive value in younger vs older patient cohorts. Further, this work identified a novel, simplified scoring system, referred to as MIPI-P, that incorporates more pathology parameters and may provide a useful prognostic tool.
References
1. Fu K, Yu G, Bi C, et al. Mantle cell lymphoma: initial report from the North American Mantle Cell Lymphoma Consortium [ASCO abstract 8035]. J Clin Oncol. 2020;38(15 suppl).
2. Hoster E, Dreyling M, Klapper W, et al; German Low Grade Lymphoma Study Group (GLSG); European Mantle Cell Lymphoma Network. A new prognostic index (MIPI) for patients with advanced-stage mantle cell lymphoma. Blood. 2008;111(2):558-565.
3. Hoster E, Rosenwald A, Berger F, et al. Prognostic value of Ki-67 index, cytology, and growth pattern in mantle-cell lymphoma: results from randomized trials of the European Mantle Cell Lymphoma Network. J Clin Oncol. 2016;34(12):1386-1394.
Results of a Completed Phase I Study of LAM-002 (Apilimod Dimesylate), a First-in-Class Phosphatidylinositol-3-Phosphate 5 Kinase (PIKfyve) Inhibitor, Administered as Monotherapy or With Rituximab or Atezolizumab to Patients With Previously Treated Follicular Lymphoma or Other B-Cell Cancers
The novel agent LAM-002 is a selective inhibitor of the phosphatidylinositol-3-phosphate 5 kinase (PIKfyve) protein, a lipid kinase that controls membrane trafficking via the endosome.1,2 LAM-002 (also known as apilimod dimesylate), is an orally available small-molecule inhibitor that is highly selective for PIKfyve. Importantly, LAM-002 does not inhibit the different isoforms of phosphoinositide 3-kinase (PI3K), thereby providing a unique mechanism of action distinct from idelalisib, copanlisib, duvelisib, and umbralisib. LAM-002 induces tumor cell death via disruption of lysosomal homeostasis.3 In preclinical animal models, LAM-002 showed antitumor activity both as a single agent and in combination with either anti-CD20 or anti–PD-L1 antibodies.4
Diefenbach and colleagues presented results from a phase 1 clinical trial that evaluated LAM-002 administered as monotherapy or in combination with either the anti-CD20 antibody rituximab or the anti–PD-L1 antibody atezolizumab.4 Stage 1 of this study was a dose-ranging portion that aimed to define the maximum tolerated dose and characterize the safety of this agent as monotherapy and in combination. Stage 2 was a dose-expansion portion that continued to evaluate the safety and efficacy of LAM-002 at the selected recommended dosing regimen of 125 mg once daily, either as monotherapy or in combination with rituximab or atezolizumab.
Both stages of the study were conducted in patients with relapsed/refractory non-Hodgkin lymphoma (NHL) who had an ECOG performance status of 0, 1, or 2 and measurable disease. A total of 40.3% of patients had diffuse large B-cell lymphoma and 30.7% had follicular lymphoma, accounting for the majority of NHL subtypes. Five patients (8.1%) had MCL. The trial evaluated 62 patients through stages 1 and 2. Their median age was 69 years (range, 46-89), and 51.2% were male. The majority of patients had an ECOG performance status of 0 (29.0%) or 1 (62.9%).
The chief toxicities reported during the study were gastrointestinal events and fatigue (Table 1). The gastrointestinal events were dose-dependent, and most often occurred in patients who received doses of LAM-002 that exceeded the recommended regimen during the stage 1 portion. Single-agent LAM-002, at the recommended dosing regimen of 125 mg once daily (n=20), led to fatigue in 45.0% of patients, nausea in 40.0%, decreased appetite in 35.0%, diarrhea in 25.0%, and vomiting in 20.0%. The combination of LAM-002 plus rituximab or atezolizumab (n=39) led to fatigue in 38.5% of patients, nausea in 35.9%, diarrhea in 25.6%, vomiting in 25.6%, and decreased appetite in 23.1%. The investigators noted that LAM-002 was not associated with myelosuppression, a common toxicity with other treatments for hematologic malignancies, such as lenalidomide or PI3K inhibitors.4
At the time of the analysis, efficacy data in patients with MCL were not reported.4 Antitumor activity was observed among patients with previously treated follicular lymphoma. The ORR was 53% (9 out of 17 patients), and the median duration of response (in 8 patients) was 6.6 months. The ORR in patients who were treated with LAM-002 as monotherapy (n=7) was 29%. LAM-002 in combination with rituximab (n=8) or atezolizumab (n=2) was associated with ORRs of 63% and 100%, respectively. The median PFS (n=17) was 7.0 months. In addition, 1 patient with relapsed/refractory mantle zone lymphoma achieved a partial remission, with a duration of response of 9.2 months. All responses occurred rapidly, by the time of the first (8 weeks) or second (16 weeks) postbaseline scan.
References
1. Alinari L. Toward autophagy-targeted therapy in lymphoma. Blood. 2017;129(13):1740-1742.
2. Gayle S, Landrette S, Beeharry N, et al. B-cell non-Hodgkin lymphoma: selective vulnerability to PIKFYVE inhibition. Autophagy. 2017;13(6):1082-1083.
3. Gayle S, Landrette S, Beeharry N, et al. Identification of apilimod as a first-in-class PIKfyve kinase inhibitor for treatment of B-cell non-Hodgkin lymphoma Blood. 2017;129(13):1768-1778.
4. Diefenbach CS, Cohen JB, Harb WA, et al. Results of a completed phase I study of LAM-002 (apilimod dimesylate), a first-in-class phosphatidylinositol-3-phosphate 5 kinase (PIKfyve) inhibitor, administered as monotherapy or with rituximab or atezolizumab to patients with previously treated follicular lymphoma or other B-cell cancers [ASCO abstract 8017]. J Clin Oncol. 2020;38(15 suppl).
Multi-Omics Analysis of Mantle Cell Lymphoma Reveals an Immune-Cold Tumor Microenvironment Associated With Ibrutinib Resistance
Although MCL is an incurable B-cell lymphoma, clinical outcomes have greatly improved throughout the last decade with the introduction of new therapies, including BTK inhibitors such as ibrutinib. Although the majority of MCL patients initially respond to ibrutinib, disease progression is common; the rate of 1-year overall survival is only 22%.
The mechanisms that underlie ibrutinib resistance in MCL cells have become an increasing focus of study in the past few years. Several potential mechanisms of resistance have been elucidated, including B-cell receptor signaling, increased signaling through the PI3K pathway, and activation of OXPHOS. Thus far, most resistance mechanisms that have been identified are considered intrinsic to the tumor. Nomie and colleagues presented findings from an investigation of how extrinsic mechanisms within the tumor microenvironment may contribute to ibrutinib resistance.1
The researchers performed whole- exome sequencing (n=41) and RNA sequencing (n=93) on MCL clinical specimens such as peripheral blood, apheresis samples, and clinical biopsies with an intact tumor microenvironment (harboring components such as macrophages, T cells, NK cells, and monocytes). Additionally, the investigators analyzed 2 previously published cohorts.2,3
The investigators first established 26 knowledge-based gene expression signatures that were related to different activities in the tumor and its microenvironment. The signatures included angiogenesis and fiberglass activities, protumor immune infiltration, antitumor immunity, and malignant cell properties, such as proliferation. Using these 26 gene expression signatures, unsupervised clustering of the previously published datasets revealed 4 distinct subtypes of the MCL tumor microenvironment: immune-enriched fibrotic, immune-enriched nonfibrotic, mesenchymal, and depleted. The immune-enriched fibrotic subtype was defined as showing immune infiltration combined with increased stromal signatures. The immune-enriched nonfibrotic subtype was defined by high expression of immune and checkpoint molecules, combined with low expression of stromal signatures. The mesenchymal subtype was nonimmune, with an increased stromal signature as well as expression of tumor-promoting cytokines. The depleted subtype lacked immune infiltration and stromal expression, and showed the highest content of malignant B cells of the subtypes.
The subtype known as immune-enriched nonfibrotic was composed only of ibrutinib-sensitive samples. In contrast, the majority of the ibrutinib-resistant samples were divided into the immune-enriched fibrotic subtype and the depleted subtype.
The investigators then evaluated the genetic mutations associated with ibrutinib resistance and the different tumor microenvironment subtypes. Frequent inactivating mutations in the epigenetic modifier KMT2D were identified within the immune-suppressed mesenchymal microenvironment. Additionally, NOTCH1 gain-of-function mutations were identified exclusively in ibrutinib-resistant samples. Expression of the programmed death ligand 1 (PD-L1) was decreased in ibrutinib-resistant samples, as well as in the immunosuppressive mesenchymal and depleted tumor microenvironment subtypes (Figure 9). The authors suggested that this finding could mean that targeting the PD-1/PD-L1 checkpoint may not help overcome ibrutinib resistance.1 PD-L1 expression levels associated with therapeutic resistance according to the microenvironment cluster are shown in Figure 10.
The investigators concluded that classifying the tumor microenvironment using a transcriptomic-based platform provided insight into therapeutic resistance in mantle cell lymphoma.1 The analysis revealed extrinsic mechanisms regulating the growth and progression of the disease, as well as response to ibrutinib. The identification of an immune-enriched microenvironment, consisting solely of ibrutinib-sensitive samples, suggests that this subset of MCL may be sensitive to immune checkpoint blockade. According to these portraits of the tumor microenvironment, sensitivity and resistance to ibrutinib are separate. The study suggests that the tumor microenvironment has a prominent role in regulating the activity of ibrutinib and response to treatment.
References
1. Nomie K, Jain P, Kotlov N, et al. Multi-omics analysis of mantle cell lymphoma reveals an immune-cold tumor microenvironment associated with ibrutinib resistance [ASCO abstract 8055]. J Clin Oncol. 2020;38(15 suppl).
2. Zhang L, Yao Y, Zhang S, et al. Metabolic reprogramming toward oxidative phosphorylation identifies a therapeutic target for mantle cell lymphoma. Sci Transl Med. 2019;11(491):eaau1167.
3. Scott DW, Abrisqueta P, Wright GW, et al; Lymphoma/Leukemia Molecular Profiling Project. New molecular assay for the proliferation signature in mantle cell lymphoma applicable to formalin-fixed paraffin-embedded biopsies. J Clin Oncol. 2017;35(15):1668-1677.
Highlights in Mantle Cell Lymphoma From the 2020 American Society of Clinical Oncology Annual Meeting: Commentary
Brad S. Kahl, MD
Professor of Medicine
Director, Lymphoma Program
Washington University School of Medicine
St Louis, Missouri
The American Society of Clinical Oncology (ASCO) annual meeting was presented in a virtual format in 2020. Several important presentations provided data for patients with mantle cell lymphoma.
Dr Richard Furman and colleagues evaluated pooled data from studies of acalabrutinib in hematologic malignancies to generate a more robust safety dataset.1 The studies evaluated acalabrutinib as a single agent. Acalabrutinib is a newer-generation Bruton tyrosine kinase (BTK) inhibitor that is somewhat more selective than the first-generation BTK inhibitor, ibrutinib.2 In theory, the increased kinase selectivity of acalabrutinib might lead to fewer adverse events. Whether acalabrutinib is better tolerated than ibrutinib is an area of interest.
The study by Dr Furman pooled safety data from 9 different trials of acalabrutinib in patients with mantle cell lymphoma, chronic lymphocytic leukemia, Waldenström macroglobulinemia, follicular lymphoma, diffuse large B-cell lymphoma, and a few other less common subtypes.1 Together, the studies included more than 1000 patients. Approximately one-third were treatment-naive, and two-thirds had relapsed/refractory disease. The median follow-up was 26 months.
Approximately 96% of patients reported an adverse event. The most commonly reported adverse events were the typical ones associated with acalabrutinib, and included headache, diarrhea, upper respiratory tract infection, bruising, nausea, and fatigue. Importantly, serious adverse events were relatively infrequent, occurring in 39% of patients. Of note, headache—a frequent adverse event with acalabrutinib3—tends to improve with time and is fairly easy to manage with caffeine and/or acetaminophen. Throughout the entire dataset, headache led only 1 patient to discontinue acalabrutinib, which shows that this side effect is manageable.
The most frequently reported serious adverse event was pneumonia. There is a background risk for infection and pneumonia in patients with mantle cell lymphoma, so it can be difficult to discern whether cases are attributable to the drug vs the underlying disease.
The most important information conveyed by this analysis concerns the treatment discontinuation rate, which indicates the percentage of patients who were unable to continue treatment, even with dose reductions, because of side effects. In this pooled dataset, the discontinuation rate was 9%. This rate is somewhat less than that seen with ibrutinib,4 and suggests that acalabrutinib is fairly well-tolerated.
Other adverse events of special interest include atrial fibrillation and hypertension, both of which can be problematic developments in patients receiving BTK inhibitors. In the pooled data analysis, the rate of atrial fibrillation was 4.4%, which is lower than the rate seen with pooled ibrutinib, which ranges from approximately 6% to 16%.5 The rate of hypertension was 7.6%, which is lower than that for ibrutinib.6
Bleeding is common to all of the BTK inhibitors.7 In the pooled analysis of acalabrutinib data, only 3% of patients developed grade 3 hemorrhage or worse. Therefore, there was not a high rate of serious bleeding in this study.
This pooled analysis of more than 1000 patients provides a valuable dataset. The data provide important insights into the risks of adverse events associated with acalabrutinib. Overall, it appears that acalabrutinib has a fairly favorable safety profile.
Dr Michael Wang and colleagues presented an analysis of the product characterization and pharmacologic profile of KTE-X19, a next-generation chimeric antigen receptor (CAR) T-cell therapy.8 The phase 2 ZUMA-2 study evaluated KTE-X19 in patients with relapsed/refractory mantle cell lymphoma.9 The data were encouraging, although follow-up was short. Among approximately 60 patients, the overall response rate was 93%, with a complete remission rate of 67%. After a median follow-up of 1 year, approximately 60% of patients maintained an ongoing remission. It is hoped that these patients will remain in remission for a prolonged period; the results of longer follow-up will be key to understanding the benefits of KTE-X19 in this setting. There is a reasonable chance that the US Food and Drug Administration (FDA) will approve KTE-X19 based on this dataset. Physicians who treat relapsed/refractory mantle cell lymphoma would be interested in having this agent in the armamentarium.
The abstract presented at the ASCO meeting evaluated biomarkers that might predict for response and toxicity.8 The investigators measured several serum cytokines. They identified a correlation between increased peak levels of select cytokines, such as interferon gamma, interleukin (IL) 6, and IL-2, and a higher likelihood of negative minimal residual disease (MRD) status. This finding raises the possibility that the T-cell expansion that occurs in these patients after T-cell infusion might be important in generating an optimal response. However, patients who had higher levels of these cytokines were more likely to develop complications of CAR T-cell therapy, including cytokine release syndrome and serious neurologic events. The challenge moving forward will be to develop strategies to fine-tune CAR T-cell proliferation after infusion in order to strike the appropriate balance between efficacy and toxicity.
Dr Hun Ju Lee and colleagues presented a study evaluating the clinical activity of cirmtuzumab, a novel monoclonal antibody.10 Cirmtuzumab is an antibody that targets a receptor tyrosine kinase known as ROR1. The physiologic function of ROR1 appears to be important in embryonic development.11 It appears to signal through the Wnt pathway, and supports the growth and survival of cells. ROR1 is highly expressed by fetuses, but then expression seems to diminish over time. In some cancers, expression of ROR1 is elevated, making it a therapeutic target for drug therapy.
The investigators identified high ROR1 expression in several hematologic malignancies, particularly chronic lymphocytic leukemia and mantle cell lymphoma.10 Studies of single-agent cirmtuzumab showed modest single-agent activity in these diseases, providing proof of concept of both preclinical and clinical activity.12-14 The investigators were interested in studying this novel monoclonal antibody in combination with ibrutinib in mantle cell lymphoma and chronic lymphocytic leukemia.
The poster presented at the 2020 ASCO meeting provided data for an ongoing phase 1 clinical trial in patients with relapsed chronic lymphocytic leukemia (n=34) or relapsed mantle cell lymphoma (n=12).10 Of note, there were no reports of grade 3 toxicity. There did not appear to be any significant increased additive toxicity for combining cirmtuzumab with ibrutinib. In the mantle cell lymphoma cohort, the overall response rate was 83%, with a complete response rate of 58%. These responses, particularly the rate of complete response, are somewhat higher than would be expected with ibrutinib alone in mantle cell lymphoma.15 There may be some additive or synergistic effects with combination treatment. However, a larger dataset would be needed before any definitive statements about clinical activity could be made. Among the CLL cohort, the overall response rate was 88%, consisting almost entirely of partial remissions. This outcome is similar to that expected with ibrutinib alone,16 so it is unclear whether the addition of cirmtuzumab improved outcome in the CLL population.
These preliminary results are interesting. It is not yet known whether cirmtuzumab will represent a significant advance in the field, but continued study is warranted. The investigators plan to undertake additional dose expansions in both study populations. The study will then pivot into a randomized phase 2 trial, in which patients will be randomly assigned to treatment with single-agent cirmtuzumab vs cirmtuzumab plus ibrutinib. In CLL/SLL, the investigators have initiated a phase 2 study, which will be the true test of whether the antibody provides additional benefit to ibrutinib in these patient populations.
An initial report provided data on mantle cell lymphoma from the North American Mantle Cell Lymphoma Consortium.17 The consortium consists of 23 centers, and is led by investigators at the University of Nebraska. This pooled dataset includes 589 patients with mantle cell lymphoma who have been treated and observed over the past 15 to 20 years. The median age of the cohort was 63 years. The population was typical of patients with mantle cell lymphoma. Most patients were male, and the vast majority had stage 3 or 4 disease.
The median follow-up was 5.2 years. An interesting finding is that the median 5-year progression-free survival was only 24%, and the 5-year overall survival was approximately 60%. These outcomes are somewhat inferior to what is usually seen in mantle cell lymphoma.18 However, most of the survival data in mantle cell lymphoma is derived from clinical trials, and there is always an inherent selection bias in patients who enroll in studies. This population database may provide a more accurate representation of survival among patients with mantle cell lymphoma in the community.
The analysis presented at the 2020 ASCO meeting focused on prognostic factors in mantle cell lymphoma.17 There are several prognostic tools already in use, such as the Mantle Cell Lymphoma International Prognostic Index (MIPI) and the combined MIPI (MIPI-C).19,20 The MIPI-C takes the 4 clinical factors of the MIPI (age, performance status, lactate dehydrogenase [LDH], and leukocyte count) and then incorporates the proliferation index measured by Ki-67 staining. The consortium investigators mined the data to develop an alternative prognostic system known as MIPI-P, with the “P” standing for pathology. This scoring system assigns 1 point each based on the following factors: disease stage, LDH level, cytology under the microscope, and the Ki-67 score. The investigators identified 3 risk groups with different outcomes. They noted that the prognostic index worked well in both older and younger patients.
This study provided an interesting initial interrogation of this dataset, which will likely provide valuable information. I anticipate seeing more studies of these data in the future. It is not clear whether the new prognostic tool substantially improves upon the existing tools. There are many prognostic indices among the different lymphomas, and they all have value. Further study will be needed to confirm the value of this new scoring system.
Dr Catherine Diefenbach and colleagues reported results from a phase 1 study of the novel agent LAM-002, which is a first-in-class, small-molecule PIKfyve inhibitor.21 Several phosphoinositide 3 (PI3) kinase inhibitors are approved in follicular lymphoma and CLL. LAM-002 has a different mechanism of action from the PI 3-kinase inhibitors already in use. PIKfyve is a lipid kinase that regulates endosomal membrane trafficking. LAM-002 disrupts the normal lysosomal homeostasis, which can result in cell death.
Dr Diefenbach reported ongoing experience with a completed phase 1 clinical trial of 62 patients with previously treated B-cell malignancies, including 5 patients with mantle cell lymphoma.21 Lower doses of LAM-002 were well-tolerated, but excessive toxicity—in the form of nausea, vomiting, and diarrhea—was seen with doses of 150 mg twice a day. The dose was decreased to 125 mg twice daily for expansion cohorts that evaluated LAM-002 as a single agent, in combination with rituximab, and in combination with the PD-L1 inhibitor atezolizumab.
The abstract presented at the 2020 ASCO meeting focused on patients with follicular lymphoma.21 LAM-002 was fairly well-tolerated at 125 mg administered twice daily. Objective responses were seen in 2 of 7 patients receiving LAM-002 monotherapy, in 5 of 8 patients treated with LAM-002 plus rituximab, and in 2 of 2 patients treated with LAM-002 plus atezolizumab. (In addition, a patient with marginal zone lymphoma had a partial response.) With these small numbers, it is difficult to assess the activity of this agent. The single-agent activity is modest; data for the combination regimens are somewhat better. Of note, there were no reports of significant myelosuppression or any of the typical toxicities associated with PI 3-kinase inhibitors. LAM-002 may be relatively easy to use in combination regimens, and it appears that the investigators will continue this line of study to better characterize the activity of this agent in patients with relapsed follicular lymphoma. The phase 1 study is completed, and provides proof of concept of activity and tolerability. I look forward to seeing results of phase 2 studies.
An electronic abstract from Dr Reem Karmali and coworkers provided retrospective outcome data for older patients with mantle cell lymphoma from a pooled analysis from several academic medical centers.22 The analysis evaluated treatment patterns, practice patterns, and outcomes. The analysis was limited to patients with mantle cell lymphoma receiving frontline therapy who were older than 65 years and had received treatment between 2000 and 2015. The study identified 465 patients, with a median age of 70 years. These patients are therefore a representative older population.
The most commonly used frontline treatment regimen, bendamustine/rituximab, was used in 36% of patients.22 Other treatments included a cytarabine combination in 16% and lenalidomide-based therapy in 2%. Nineteen percent of the patients were treated in a clinical trial. Of note, after patients completed induction therapy, 24% were referred to autologous stem cell transplant, and 44% were referred to maintenance rituximab. The use of autologous stem cell transplant was not associated with better progression-free survival or overall survival, which is interesting and perhaps unexpected. In contrast, maintenance rituximab improved progression-free survival and overall survival. These valuable data might provide more evidence that intensive strategies in the older patient population may not be the optimal approach. There is some evidence that maintenance rituximab is a beneficial intervention in older patients with mantle cell lymphoma.
In another electronic abstract, Dr Nilanjan Ghosh and colleagues presented results from a health care resource utilization analysis of patients with relapsed/refractory mantle cell lymphoma.23 They evaluated a database to compare health care costs and utilization with ibrutinib vs chemoimmunotherapy.
The researchers identified 146 patients treated with ibrutinib and 158 treated with chemoimmunotherapy. They looked at healthcare expenditures over a 6-month period and a 12-month period. After factoring in all of the health care costs—such as those for the doctor visits, scans, laboratory tests, monitoring, and hospitalization— chemoimmunotherapy was associated with higher costs for both the 6-month and 12-month intervals. Ibrutinib is generally fairly easy to administer as an outpatient, is not associated with many complications, and rarely results in hospitalizations.
It will be important to evaluate healthcare costs over longer periods than just 6 and 12 months. For example, if a patient receives chemoimmunotherapy, usually the treatment is completed near the 6-month mark. One would expect that once treatment ends, the healthcare utilization and costs would start to diminish substantially. Among patients treated with ibrutinib or any other continuous oral therapy, expenses will accumulate over time. Therefore, the putative savings for ibrutinib that are realized in the first 6 months may actually diminish substantially in year 2 and year 3, as compared with other approaches. I hope these investigators perform a subsequent analysis to calculate healthcare resource utilization in years 2 and 3.
Disclosure
Dr Kahl has received consulting fees from AbbVie, AstraZeneca, ADC Therapeutics, BeiGene, Celgene, Gilead, Genentech, and Janssen.
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