Targeted Therapy for DLBCL Patients Who Cannot Undergo Bone Marrow Transplant

When Standard Therapy Is Insufficient

Some patients with DLBCL do not respond to standard chemoimmunotherapy or their disease relapses after completing treatment. They then undergo salvage chemotherapy and, if their condition allows, autologous stem cell transplant (ASCT). This approach can cure 30–40% of patients with refractory or relapsed DLBCL. Patients who cannot undergo ASCT due to age, comorbidities, or inadequate response to salvage chemotherapy have a poor prognosis with a survival of approximately 6 months. Currently, there is no standard procedure for further care of these patients.

Therefore, polatuzumab vedotin, a conjugate of a monoclonal antibody and a cytostatic, was tested in this patient population, combining the benefits of targeting B cells and chemotherapy. The results of a single-arm phase Ib study examining the safety of the polatuzumab vedotin + bendamustine + obinutuzumab (pola-BG) combination, a single-arm extension of this study, and a randomized controlled phase II study in which patients were treated either with polatuzumab vedotin + bendamustine + rituximab (pola-BR) or only with bendamustine and rituximab (BR) were analyzed.

Side Effects of the Treatment

The initial phases of clinical evaluation generally focus on proving an acceptable safety profile, which was confirmed for both pola-BG and pola-BR combinations. Compared with patients treated with BR alone, those on pola-BR more frequently experienced hematotoxicity, such as neutropenia (grade 3–4 affected 46.2% of patients treated with pola-BR versus 33.3% with BR), anemia (28.2% versus 17.9%), or thrombocytopenia (41.0% versus 23.1%). However, the higher rate of neutropenia did not translate into an increased risk of severe infections (grade 3–4), with similar rates in both the pola-BR and BR groups (23.1% versus 20.5%). Peripheral neuropathy typical for polatuzumab vedotin occurred in 43.6% of treated patients, although it was mostly mild (grade 1–2) and reversible.

Efficacy of Polatuzumab Vedotin

Patients treated with pola-BG (a total of 27 patients) achieved a median overall survival (OS) of 10.8 months, and 29.6% attained a complete response (CR) to treatment.

In the randomized study with 80 participants, it was shown that adding polatuzumab vedotin to BR significantly improved clinical outcomes compared to BR alone – a higher rate of CR, longer progression-free survival (PFS), and longer OS:

• CR: 40.0% versus 17.5% (p = 0.026).
• PFS: median 9.5 months versus 3.7 months (hazard ratio [HR] 0.36; 95% confidence interval [CI] 0.21–0.63; p < 0.001).
• OS: median 12.4 months versus 4.7 months (HR 0.42; 95% CI 0.24–0.75; p = 0.002).

Conclusion and Discussion

Combined treatment with polatuzumab vedotin + bendamustine + rituximab reduced the risk of death by 58% in patients with relapsed or refractory DLBCL who cannot undergo autologous stem cell transplant and allowed many patients to achieve complete remission. This treatment combination also has acceptable toxicity.

Although the results were obtained from a relatively small patient sample, their statistical and clinical significance is undeniable. Further studies have already been initiated to test polatuzumab vedotin in combination with other drugs used in DLBCL therapy, investigating its efficacy in later treatment phases and in the first line of treatment.

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Source: Sehn L. H., Herrera A. F., Flowers C. R. et al. Polatuzumab vedotin in relapsed or refractory diffuse large B-cell lymphoma. J Clin Oncol 2020; 38 (2): 155–165, doi: 10.1200/JCO.19.00172.