Promising novel approaches in various B-cell malignancies
POLARIX: polatuzumab vedotin in DLBCL
For more than 20 years, the R-CHOP regimen consisting of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone has been the standard of care in the first-line treatment of diffuse large B-cell lymphoma (DLBCL). However, as only 60-70 % of patients achieve cure [1, 2], there is a need to improve on these results. The antibody-drug conjugate polatuzumab vedotin that targets CD79b has already shown activity in combination with rituximab or obinutuzumab plus cyclophosphamide, doxorubicin, and prednisone (CHP) in a phase II study conducted in the first-line setting of DLBCL . Based on these insights, the international, randomized, double-blind, phase III POLARIX trial tested polatuzumab vedotin in combination with rituximab and CHP (Pola-R-CHP) against R-CHOP for 6 cycles. This was followed by 2 additional doses of rituximab.
Patients with previously untreated DLBCL and International Prognostic Index (IPI) scores of 2-5 participated in the trial. Progression-free survival (PFS) was defined as the primary endpoint. The primary analysis presented by Tilly et al. at ASH 2021 after a median follow-up of 28.2 months included approximately 440 individuals in each arm . Seventy percent of them were older than 60 years, more than 85 % had Ann Arbor stages III or IV, and 62 % in each arm had high-intermediate or high risk according to IPI.
Lasting complete remissions with Pola-R-CHP
The primary endpoint of the POLARIX study was met. Pola-R-CHP significantly prolonged PFS compared to R-CHOP, demonstrating a 27 % reduction in the risk of disease progression or death (HR, 0.73; p < 0.02). At 24 months, 76.7 % vs. 70.2 % of patients in the experimental and control arms, respectively, were progression-free. Consistent with the PFS finding, the event-free survival analysis yielded a 25 % risk reduction (HR, 0.75; p = 0.02). In both arms, approximately 95 % of patients responded to treatment. Complete response (CR) rates were similar at 86.6 % and 82.7 %, respectively. However, disease-free survival findings indicated that patients who achieved CR with Pola-R-CHP were more likely to maintain remission than those obtaining CR on R-CHOP treatment (HR, 0.70). Overall survival did not differ yet at the time of the analysis.
The percentages of patients receiving subsequent treatments were lower in the experimental arm for all types of therapies (Figure 1). Regarding safety, the regimes showed comparable profiles; peripheral neuropathy, nausea, neutropenia, and anemia were among the most commonly observed adverse events (AEs) for both strategies. However, the incidence of diarrhea was increased in the Pola-R-CHP arm compared to the R-CHOP arm, as well as the rates of febrile neutropenia episodes without more profound neutropenia or specific infections. In both arms, grade 3/4 events occurred in approximately 58 %, and AEs leading to discontinuation of any study drug emerged in 6.2 % vs. 6.6 %. Fewer dose reductions of any study drug due to AEs were observed in the Pola-R-CHP arm (9.2 % vs. 13.0 %).
As the authors emphasized, these results support the use of Pola-R-CHP in the initial management of patients with DLBCL and intermediate or high risk. Exploratory analyses of the POLARIX trial are ongoing regarding various subgroups and other prognostic classification systems.
Figure 1: Percentages of patients treated with Pola-R-CHP and R-CHOP in the POLARIX trial who received subsequent anti-lymphoma therapies
Bispecific antibody mosunetuzumab: phase II expansion
Mosunetuzumab is a bispecific antibody that redirects T cells to eliminate malignant B cells by binding to CD3 on T cells and CD20 on B cells . In patients with relapsed/refractory follicular lymphoma (FL) and ≥ 2 prior therapies, mosunetuzumab has shown encouraging efficacy and manageable safety in the phase I setting . Findings obtained in the international, single-arm, pivotal phase II expansion study were presented by Budde et al. at ASH 2021 .
This analysis included 90 patients with FL grade 1-3a after ≥ 2 prior regimens including ≥ 1 anti-CD20 antibody and ≥ 1 alkylating agent. They received fixed-duration treatment with 3-weekly mosunetuzumab; those who achieved CR after 8 cycles discontinued their treatment at that time, while those who showed partial response or disease stabilization after 8 cycles went on to receive a total of 17 cycles. Step-up dosing was performed in cycle 1 to mitigate cytokine release syndrome (CRS) and to allow for a higher targeted dose. Hospitalization was not mandatory. CR as best response by independent review facility constituted the primary endpoint and was assessed against the 14 % historical control CR rate . After a median number of 3 prior treatment lines, approximately 50 % of patients were double refractory to any prior anti-CD20/alkylator therapy. Likewise, more than 50 % had experienced disease progression within 24 months (POD24). These are indicators for advanced disease and elevated risk commonly associated with poor prognosis.
Deep responses in heavily pretreated FL patients
After a median follow-up of 18.3 months, 60 % of patients had completed treatment. Eight and 17 cycles had been administered in 58.9 % and 12.2 %, respectively. The study met its primary endpoint, with the 60 % CR rate being significantly greater than the historical control rate (p < 0.0001). Overall, 80 % of patients responded to treatment. Subgroup analyses demonstrated that high-risk groups including those with double-refractory disease and POD24, as compared to other groups, obtained similar response rates. Median duration of response was 22.8 months both in all responders and complete responders. At 18 months, 70 % of complete responders were event-free. Median PFS amounted to 17.9 months.
Mosunetuzumab showed a favorable tolerability profile. Treatment-related grade 3/4 AEs and AEs necessitating discontinuation occurred in 51.1 % and 2.2 %, respectively. No patient died due to mosunetuzumab-related AEs. CRS was the predominant AE, with an any-grade incidence rate of 44.4 %. Most events were low-grade and were confined to cycle 1. CRS management required the administration of corticosteroids and tocilizumab in 11.1 % and 7.8 %, respectively. All events eventually resolved. Immune effector cell-associated neurotoxicity syndrome events were infrequent (4.4 %) and confined to grade 1 and 2. No cases of aphasia, seizures, encephalopathy, or cerebral edema occurred. As the authors noted in their conclusion, mosunetuzumab is the first T-cell–engaging bispecific antibody to demonstrate clinically meaningful outcomes for patients with relapsed/refractory FL in the pivotal phase II setting.
Naratuximab emtansine plus rituximab
A medical need for new treatment options is evident in patients with relapsed/refractory non-Hodgkin lymphoma (NHL), particularly relapsed/refractory DLBCL, who are no candidates for stem cell transplant or CAR-T cell therapy. The CD37-targeting antibody-drug conjugate naratuximab emtansine was tested in combination with rituximab in an open-label, multicenter, adaptive phase II study conducted in patients with DLBCL and other NHL B-cell lymphomas after 1-6 treatment lines . The study consisted of two parts. Patients included in Part 1 had a confirmed diagnosis of relapsed/refractory NHL including DLBCL, FL, mantle cell lymphoma (MCL), and marginal zone lymphoma (MZL). These were treated 3-weekly (Q3W). Part 2 was limited to patients with relapsed/refractory DLBCL ineligible for stem cell transplantation; here, two dosing strategies were evaluated. Cohort A was dosed Q3W, while Cohort B received weekly treatment (QW). Overall, 50 and 30 DLBCL patients received Q3W and QW treatment with naratuximab emtansine, respectively. Another 20 had other types of NHL and were treated Q3W (Table 1).
This study enrolled patients who are often excluded from DLBCL trials due to double- or triple-hit morphologies, bulky disease, transformed lymphoma, and primary refractory disease or disease refractory to the last treatment. Thus, the population mirrored the difficult-to-treat patients seen in everyday practice. The overall response rate was defined as the primary endpoint.
Efficacy across lines and treatment schemas
Substantial proportions of patients in the three groups managed to complete ≥ 6 cycles (Table 1). In the efficacy-evaluable DLBCL population (n = 76), 44.7 % of patients responded, and 31.6 % achieved complete responses. CR rates were 43.3 % and 33.3 % for Cohorts A (Q3W) and Cohort B (QW). The objective response rate (ORR) was 50 % for both cohorts. Similar rates resulted in patients treated in the third and later lines who were non-primary refractory (ORR, 46.4 %; CR, 32.1 %). Patients with relapsed/refractory FL obtained an ORR of 57.1 %. Median duration of response had not been reached for either DLBCL or FL. Sixty-six percent of patients with DLBCL showed a duration of response > 12 months.
The most frequently observed grade 3/4 treatment-emergent AEs (TEAEs) were hematological in nature and manageable. G-CSF prophylaxis was offered to 22 % of patients. Three liver TEAEs grade ≥ 3 occurred, as well as 2 cases of non-serious neuropathy grade ≥ 3. Most of the patients discontinued treatment because of disease progression rather than AEs (Table 1). Ten patients died due to TEAEs; 2 of these were considered related to the treatment. According to the assessment of health-related quality of life, the administration of naratuximab emtansine was associated with a significant increase in well-being in 38 % of responders. The vast majority of patients reported that they were not or hardly bothered by the side effects of treatment. In their summary, the authors noted that naratuximab emtansine plus rituximab might represent a new option for patients with relapsed/refractory NHL, especially DLBCL, including heavily pretreated patients.
Cerdulatinib alone and combined with rituxmab
The dual SYK/JAK kinase inhibitor cerdulatinib is being evaluated as monotherapy and in combination with rituximab in an open-label, phase IIa study conducted in adult patients with relapsed/refractory B-cell and T-cell malignancies. Hamlin et al. presented the results for patients with FL at ASH 2021 . Forty-two and 26 of these had been treated with cerdulatinib monotherapy and cerdulatinib plus rituximab, respectively. The median number of prior regimens was 2 and 3, respectively. In FL, the proposed mechanisms of action of cerdulatinib include disruption of survival signals imparted by BCR and JAK/STAT signaling pathways, as well as disruption of the supportive tumor microenvironment and forced mobilization of tumor-infiltrating leukocytes [11-15].
Cerdulatinib monotherapy gave rise to an ORR of 52.9 %. Both patients after ≤ 3 and ≥ 4 prior regimens responded to treatment (Table 2). In the combination group, the ORR was 76.9 %; here, patients treated in early lines showed higher responses. Median PFS was 12.7 and 18.3 months for single-agent cerdulatinib and the combination, respectively. Cerdulatinib was generally well tolerated. No differences emerged between the safety profiles of cerdulatinib monotherapy and cerdulatinib plus rituximab. The most frequent grade ≥ 3 AEs included increases of lipase levels, neutropenia, and pneumonia.
Overall, these data demonstrated that targeting the JAK/STAT pathway with oral cerdulatinib can provide clinical benefit in relapsed/refractory FL, thus supporting registrational studies. The novel mechanism of action of cerdulatinib did not appear to be subject to cross-resistance with other agents, which makes combination therapy attractive.
Zanubrutinib in BTK inhibitor-intolerant patients
Although BTK inhibitors are an effective option in the setting of several B-cell malignancies, duration of treatment is limited due to AEs leading to discontinuation [16-18]. The multicenter, US-based, single-arm, open-label, phase II BGB-3111-215 study assessed the safety and efficacy of zanubrutinib in patients intolerant to ibrutinib and/or acalabrutinib with previously treated B-cell malignancies including CLL/SLL, Waldenström’s macroglobulinemia (WM), MCL, and MZL. Cohort 1 was intolerant to ibrutinib, and Cohort 2 was intolerant to acalabrutinib ± ibrutinib. Results for the safety of zanubrutinib were compared with the patients’ ibrutinib and/or acalabrutinib intolerance as assessed by the recurrence and the change in severity of AEs. The analysis reported at ASH 2021 related to 57 and 10 patients in Cohorts 1 and 2, respectively .
Within a median follow-up of 12.0 months, most ibrutinib and acalabrutinib intolerance events (i.e., 70.4 % and 83.3 %, respectively) did not recur on zanubrutinib. If they recurred, their severity was equal or reduced. Of the 34 recurrent ibrutinib intolerance events, 76.5 % recurred at lower severity, and 23.5 % recurred at the same severity. Among the 3 recurrent acalabrutinib intolerance events, 1 and 2 recurred at lower and the same severity, respectively. Almost 60 % and 70 % of patients who took ibrutinib and acalabrutinib, respectively, did not have recurrence of any intolerance event. In the category of grade 3 intolerance events, 65.8 % and 75 %, respectively, did not recur while on zanubrutinib. No grade 4 events recurred. The most common grade ≥ 3 AEs on zanubrutinib treatment were neutropenia/neutrophil count decrease (12.0 %). At the time of data cutoff, 83.6 % of patients remained on zanubrutinib, and 7.5 % had discontinued due to AEs.
Regarding efficacy, zanubrutinib was shown to at least maintain response. In 93.8 %, disease control was achieved, and the ORR amounted to 64.1 %. An exploratory biomarker analysis indicated that relapse on zanubrutinib was associated with BTK inhibitor resistance mutations. In their entirety, these data suggested that zanubrutinib might provide a therapeutic option in patients intolerant to other BTK inhibitors across hematologic malignancies.
Early results for novel BCL2 inhibitor BGB-11417
BCL2 inhibitors have been shown to be safe and effective, although treatment with the currently approved BCL2 inhibitor venetoclax can be limited by gastrointestinal toxicities, neutropenia, and the emergence of specific BCL2 mutations around the BH3-binding groove causing resistance [20, 21]. BGB-11417 has been developed as a potent and highly selective BCL2 inhibitor with a favorable pharmacokinetic profile providing excellent bioavailability and selectivity for BCL2 at concentrations < 1 nM . At ASH 2021, Tam et al. reported preliminary results of the open-label, multicenter, phase I, dose-escalation and dose-expansion BGB-11417-101 trial that is assessing BGB-11417 alone (Parts 1 and 2) and in combination with zanubrutinib (Parts 3 and 4) in patients with relapsed/refractory B-cell malignancies . At the time of the analysis, 36 patients had been treated, with 25 and 11 having received the monotherapy and the combination, respectively. In the monotherapy group, 19 and 6 had NHL and CLL/SLL, respectively. The combination group contained 10 and 1 patients with CLL/SLL and mantle cell lymphoma, respectively.
These early findings suggested that BGB-11417 is tolerable in patients at the dose levels tested. One dose-limiting toxicity of grade 3 febrile neutropenia was observed across 4 dose levels assessed in NHL, and 1 DLT of grade 4 neutropenia was seen in a CLL cohort. Among TEAEs regardless of causality, nausea emerged most commonly in both monotherapy and combination groups. With respect to BCL2 inhibitor events of interest, it was noted that one patient receiving monotherapy with high baseline tumor lysis syndrome (TLS) risk had a marked tumor flare on BTK inhibitor withdrawal and developed laboratory TLS in late ramp-up. This patient experienced no sequelae, and BGB-11417 did not need to be held. Neutropenia was the most frequent grade ≥ 3 AE as it occurred in 5 of 6 patients receiving monotherapy.
Efficacy data were limited as dose escalation was not complete for any cohort and not all patients had reached their first response assessment. Nevertheless, responses were observed, with decreases in sum of the products of perpendicular diameters at all dose levels. Substantial decreases in absolute lymphocyte counts occurred during ramp-up for CLL patients (Figure 2). Evaluation of patients with MCL, treatment-naïve CLL and WM is planned for future cohorts.
Figure 2: Reduction in absolute leukocyte counts on BGB-11417 plus zanubrutinib during ramp-up in CLL patients
Real-world burden of NHL
Survival spanning several years with multiple interspersed treatment periods due to frequent relapses is typical of the NHL subtypes CLL, MCL, MZL, and WM. Chanan-Khan et al. retrospectively assessed real-world treatment patterns, costs, and resource utilization of hospital-based care among patients with these lymphomas . The data source was the PINC AITM Healthcare Database, a hospital administrative database currently containing data from more than 1 billion inpatient and outpatient encounters in the USA. Overall, 31,805 patients received treatment from January 2014 to October 2019. Those with CLL constituted the largest group (n = 23,952). In all lymphoma types, the majority were older than 65 years. Medicare was the most frequent insurance in all cohorts, followed by commercial insurance.
CLL and MCL patients received chemo-immunotherapy as the most frequently used treatment aside from steroids alone. In MZL and WM patients, rituximab was the most frequent therapy other than steroids alone. High proportions were treated with steroids alone to control their symptoms; for CLL, this was 74.7 %, for MCL, 40.3 %, for MZL, 51.3 %, and for WM, 59.7 %.
Once patients were hospitalized, they incurred considerable costs, with significantly higher impact to minority populations. Patients aged ≤ 65 years, males and those who were non-white had higher hospital costs in all 4 lymphoma types. Hispanic patients incurred higher costs compared to non-Hispanics in CLL, MCL, and MZL, but not in the WM group. Disparities across primary payor were seen in WM patients, with Medicaid patients associated with increased total hospital cost compared to Medicare patients. Total hospital costs increased significantly during the follow-up period when patients received supportive care (i.e., blood transfusion, G-CSF) and regimens including any chemotherapy, immunotherapy, and targeted therapy.
The authors noted in their conclusion that given the increased availability of effective oral therapeutics, optimal and timely disease control in the outpatient setting can potentially prevent or decrease hospitalizations and reduce economic burden on healthcare systems and payors. Future studies should explore the reasons for admission, clinical outcomes, and potential preventive interventions. As the analyzed period ended in 2019, the overall cost structure is likely to have changed in recent years due to the increased use of novel drugs.
Productivity loss among patients and caregivers
NHL patients are often heavily reliant upon caregiver support. At the same time, many of both patients and caregivers are of working age. A retrospective cohort study evaluated the productivity loss and indirect costs for patients with CLL, MCL, MZL and WM, and their caregivers . De-identified US claims data from the IBM MarketScan® Commercial and Health Productivity and Management Databases were obtained from January 2009 to December 2019. Mean age of the NHL patients ranged from 52.1 to 54.0 years, and mean age of the caregivers ranged from 51.2 to 52.9 years.
For all NHL types, average illness-related absentee hours were higher in patients than in caregivers; a similar pattern was observed for short-term disability days. Average per-patient-per-month indirect costs were higher for patients with long-term disability than with short-term disability or absentee claims, except for patients with MCL. Costs of absenteeism, short-term disability and long-term disability were substantial for all NHL types and ranged from 365 $ to 2,056 $ per patient per month (Figure 3).
Similar trends emerged among caregivers, although indirect costs due to absenteeism and short-term disability were comparatively higher in patients. The authors concluded that effective treatments offering cure or better remission rates, longer duration and/or less toxicities might not only enhance patients’ and caregivers’ quality of life, but also reduce work loss. Future studies are required to understand the impact of therapies that result in higher remission and more manageable toxicities, such as oral targeted agents, on work loss and indirect costs of NHL.
Figure 3: Costs of absenteeism, short-term disability, and long-term disability among patients with CLL, MCL, MZL, and WM in the USA
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