Navigating the Latest Research in Diffuse Large B-Cell Lymphoma

Rituximab (Rituxan), cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP) is the the standard frontline treatment for patients with diffuse large B-Cell lymphoma (DLBCL). However, experts are always looking for ways to improve on the combination to help their patients achieve the best outcomes.¹

During a presentation at the second annual Summit of the Americas on Immunotherapies for Hematologic Malignancies, Matthew J. Matasar, MD, chief of the Medical Oncology Service at Memorial Sloane Kettering Cancer Center Bergen, discussed the updates on treatment approaches in newly diagnosed DLBCL.

“There have been many efforts over these years to try to improve our treatment of patients with a new diagnosis of diffuse large B-cell lymphoma. We now have on record our first positive clinical trial for patients with a new diagnosis of DLBCL in the form of the comparison of polatuzumab vedotin [Polivy] plus R-CHP chemotherapy versus R-CHOP, the so-called, POLARIX trial,” stated Matasar.

Improving DLBCL Treatment With Clinical Trials

POLARIX

The POLARIX study (NCT03274492) examines polatuzumab vedotin with rituximab, cyclophosphamide, doxorubicin and prednisone (Pola-R-CHP) versus R-CHOP therapy in patients with previously untreated DLBCL.²

The randomized, double-blinded study used patients with previously untreated DLBCL aged 18-80 years old. Eligibility in enrollment was open to those with an IPI score of 2-5 and an ECOG performance status of 0-2. Patients were stratified by IPI score (2 vs 3-5), bulky disease and geographical region and randomized 1:1.

Patients in the experimental arm were administered 6 cycles of polatuzumab vedotin at 1.8 mg/kg given intravenously (IV), IV placebo for vincristine, rituximab at 375 mg/m2 IV, cyclophosphamide 750 mg/m2 IV, and doxorubicin 50 mg/m2 IV on day 1 along with prednisone at 100 mg/day orally on days 1-5 of every 21-day cycle for 6 cycles. Rituximab 375 mg/m2 IV was administered as monotherapy in cycles 7 and 8.

In the placebo comparator, patients were given placebo for polatuzumab vedotin, rituximab 375 mg/m2 IV, cyclophosphamide 750 mg/m2 IV, doxorubicin 50 mg/m2 IV, and vincristine 1.4 mg/m2 IV on day 1 with prednisone given at a dose of 100 mg/day on days 1-5 of every 21-day cycle for 6 cycles. Rituximab 375 mg/m2 IV was administered as monotherapy in cycles 7 and 8.

PET-CT and CT scans were obtained at screening, after 4 cycles, and 6–8 weeks after end of study treatment with follow up continuing up to 5 years after treatment.

The primary end point of the trial is investigator-assessed progression-free survival (PFS) with secondary end points consisting of independent review committee-assessed PET-CT complete response (CR) rate at end of treatment, event-free survival (EFS), 2-year PFS rate, and OS.

Findings showed that at the data cut off of June 28, 2021, and the median 28.2 month’s follow up, EFS was HR 0.75 (P=0.02) (95% CI, 0.58-0.96). The best OR in the pola-R-CHP arm was a CR rate of 86.6% and partial response (PR) in 9.3% (n = 440). In the R-CHOP arm, CR was 82.7% with a PR of 11.4% (n = 439).

Pola-R-CHP was shown to significantly prolong PFS compared to R-CHOP (HR 0.73) in this patient population and the safety profiles of the two were comparable.

In regard to adverse events (AEs), any-grade AEs were reported in 97.9% of patients given Pola-R-CHP (n = 435) and in 98.4% of patients administered R-CHOP (n = 438). This consisted of grade 3-4 AEs seen in 57.7% in the Pola-R-CHP group (n =251) and 57.5% in those given R-CHOP (n = 252), as well as grade 5 AEs in 3% of those given Pola-R-CHP (n=13) and 2.3% of patients administered R-CHOP (n= 10).

AEs leading to discontinuation of the study drug was reported in 6.2% (n =27) in the Pola-R-CHP arm and 6.6% (n = 29) in the R-CHOP group while dose reduction of the study drug occurred in 9.2% (n = 40) compared to 13% (n = 57).

Reported AEs included peripheral neuropathy, nausea, diarrhea, neutropenia, armenia, constipation, fatigue, alopecia, decreased appetite, pyrexia, vomiting, febrile neutropenia, cough, headache, decreased weight, asthenia, and dysgeusia.

Ongoing, exploratory analyses are currently looking at subgroups and other prognostic classification systems to understand the management of patients with DLBCL even more. However, the results of this trial support the use of Pola-R-CHP as initial care for this patient population.

PHOENIX

The phase 3 PHOENIX study (NCT01855750) examined ibrutinib (Imbruvica) in combination with R-CHOP in newly diagnosed patients with non-germinal center B-cell subtype (GCB) of DLBCL.³ Patients were selected by immunohistochemistry or were newly diagnosed patients with activated B cell-like subtype of DLBCL identified by gene expression profiling or both populations.

A total of 838 participants enrolled in the, double-blind, placebo-controlled study and were randomized in a 1:1 ratio to receive either placebo plus R-CHOP for 6-8 cycles (treatment arm A) or ibrutinib at 560 mg plus R-CHOP (treatment arm B).

Eligibility for enrollment was open to patients with untreated, histologically-confirmed non-GCB DLBCL. Additional requirements included stage 2-4 disease by Ann Arbor Classification, at least 1 measurable site of disease, and an ECOG score of 0-2.

All participants received placebo plus R-CHOP as background therapy for 6 or 8 cycles (21 days per cycle).Patients with progressive disease or relapsed disease after CR were discontinued from treatment. Additionally, those who discontinued R-CHOP without disease progression continued use of either the placebo or ibrutinib until the completion of 6 or 8 cycles, disease progression, or unacceptable toxicity.

The primary end point of the study was EFS in both the intent-to-treat and activated B-cell populations. Secondary end points included PFS, percentage of patients who achieved CR, OS, and safety.

Findings revealed the overall response rate (ORR) to be 89.3% in the ibrutinib plus R-CHOP arm versus 93.1% in the placebo plus R-CHOP arm along with CR rates of 67.3% and 68.0%. CNS progression was observed in 10 patients (2.4%) compared to 16 (3.8%) in the ibrutinib plus R-CHOP and placebo plus R-CHOP arms.

CAVALLI

The CAVALLI trial (NCT02055820) evaluated safety, efficacy, and pharmacokinetics of venetoclax (Venclexta) in combination with R-CHOP in a total of 211 patients with DLBCL. Patients were aged 18 and older with an IPI of 2−5, an ECOG status of 0-2, and at least 1 measurable lesion less than 1.5cm.⁴

Patients were administered venetoclax at 800mg orally on days 4-10 of cycle 1 and days 1-10 of cycles 2-8 and rituximab was given at 375 mg/m2 IV on day 1 of every 21-day cycle along with CHOP for 6 cycles.

The primary end point was PET-CR rate at the end of treatment with secondary end points consisting of OR rate, CR rate, DOR, PFS, OS, PK, and safety.

In regard to safety, AEs were shown in 99% of patients (n= 206) with a total of 86% being grade 3 or 4 (n = 179) and 24% leading to withdrawal from treatment (n = 50). Grade 5 AEs with fatal outcomes occurred in 2% of patients. In the 4 patients who reported a fatal outcome, 3 occurred during follow-up and 1 due to sepsis with multiple medical issues. Those AEs included neutropenia, sudden cardiac death, sepsis and MDS.

Other Trials

Matasar also discussed various trials which have impacted the field. The First-MIND trial aimed to evaluate safety and efficacy of tafasitamab in addition to R-CHOP or tafasitamab and lenalidomide in addition to R-CHOP in adult patients with newly diagnosed, previously untreated DLBCL.⁵ A Total of 66 treatment-naive patients with DLBCL were administered either 6 21-day cycles of tafasitamab at 12 mg/kg IV on days 1, 8 and 15 in addition to R-CHOP (arm A), or 6 21 day cycles of tafasitamab at the same dosage along with R-CHOP on days 1-10 and lenalidomide administered orally at 25 mg on those days (arm B).

Incidence and severity of treatment-emergent adverse events (TEAEs) is the primary end point of the trial with the secondary end point consisting of ORR, CR, safety, PFS, EFS, OS and more.

The most frequently occurring hematologic TEAEs of any grade were neutropenia (72.7%), anemia (57.6%), thrombocytopenia (28.8%), leukopenia (18.2%), febrile neutropenia (18.2%), and lymphopenia (16.7%). The average relative dose intensity of R-CHOP in each cycle was maintained in both arms. The ORR at EoT was observed in 25 of the 33 patients (75.8%; 95%CI: 57.7–88.9) in R-CHOP-Tafa and 27 of the 33 (81.8%; 95%CI: 64.5–93.0) in R2-CHOP-Tafa.

The phase 3 ESCALADE trial (NCT04529772) looks to assess the efficacy and safety of acalabrutinib (Calquence)plus R-CHOP versus placebo plus R-CHOP in subjects aged 18 to 70 years with previously untreated non-GCB DLBCL.⁶

The randomized, double-blind, placebo-controlled, study enrolled patients into either the experimental arm where they were given acalabrutinib plus R-CHOP or the placebo comparator where patients were administered placebo plus R-CHOP.

Enrollment was open to individuals with pathologically confirmed DLBCL who had prior treatment. Other requirements include an ECOG performance status of 2 or greater, an IPI score of 1 to 5, disease stage 2-5, and adequate organ and marrow function. The primary end point is PFS with secondary end points consisting of EFS, OS, and patients who achieved CR.

Additionally, the ZUMA-12 examined axicabtagene ciloleucel (axi-cel; Yescarta) consolidation in patients with high-risk large B-cell lymphoma (LBCL) in the first-line setting. Some of the key findings of the primary analysis revealed patients with centrally confirmed disease to have experienced a high ORR of 89% and a CR rate of 78%.

Ongoing Research

Various trials are current and planned including obinutuzumab plus CHOP/CHP-Pola in fit DLBCL, mosunetuzumab and miniCHOP in elderly DLBCL, mosunetuzumab and polatuzumab in frail elderly DLBCL, mosunetuzumab consolidation in 1L DLBCL, glofitamab plus RCHOP in fit DLBCL, and epcoritamab plus R-CHOP in fit DLBCL.

“As much progress as we've made in diffuse large B-cell lymphoma over these last years, there is a tremendous amount of work ongoing both in some of the studies already mentioned in newly diagnosed patients trying to incorporate novel therapies to cure more patients the first time, as well as how best to deploy some of these powerful immunotherapies for patients with relapsed/refractory disease,” added Matasar.

References:

1. Updates on Treatment Approaches in Newly Diagnosed Diffuse Large B-Cell Lymphoma (DLBCL). Presented at: 3rd Summit of the Americas on Immunotherapies for Hematologic Malignancies; April 8-9, 2022; Miami, FL.

2. Study Comparing the Efficacy and Safety of Polatuzumab Vedotin With Rituximab-Cyclophosphamide, Doxorubicin, and Prednisone (R-CHP) Versus Rituximab-Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone (R-CHOP) in Participants With Diffuse Large B-Cell Lymphoma (POLARIX). Clinicaltrials.gov. Accessed April 8, 2022. https://clinicaltrials.gov/ct2/show/NCT03274492

3. A Study of the Bruton's Tyrosine Kinase Inhibitor, PCI-32765 (Ibrutinib), in Combination With Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone in Patients With Newly Diagnosed Non-Germinal Center B-Cell Subtype of Diffuse Large B-Cell Lymphoma. Clinicaltrials.gov. Accessed April 8, 2022.https://www.clinicaltrials.gov/ct2/show/NCT01855750

4. A Study Evaluating the Safety, Efficacy and Pharmacokinetics of Venetoclax Combined With Chemotherapy in Participants With B-Cell Non-Hodgkin's Lymphoma (NHL) and DLBCL. Clinicaltrials.gov. Accessed April 8, 2022. https://www.clinicaltrials.gov/ct2/show/NCT02055820

5. Phase Ib Study to Assess Safety and Preliminary Efficacy of Tafasitamab or Tafasitamab Plus Lenalidomide in Addition to R-CHOP in Patients With Newly Diagnosed DLBCL. Clinicaltrials.gov. Accessed April 8, 2022. https://clinicaltrials.gov/ct2/show/NCT04134936

6. A Combination of Acalabrutinib With R-CHOP in Subjects With Previously Untreated Non-GCB DLBCL (ACE-LY-312) (ESCALADE). Clinicaltrials.gov. Accessed April 8, 2022.https://clinicaltrials.gov/ct2/show/NCT04529772