Lymphoma – with its main forms Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) – is the most common blood cancer which occurs when cells of the immune-system called lymphocytes, a type of white blood cell, grow and multiply uncontrollably.
In the United States, non-Hodgkin lymphoma (NHL) is the fifth most common cancer and accounts for up to 30% of newly diagnosed cases of the disease which is made up of a group of clinically and biologically diverse diseases ranging from indolent to aggressive clinical courses. [1] According to the American Cancer Society (ACS) about 71,850 people (39,850 males and 32,000 females) are expected to be diagnosed with NHL in 2015. This includes both adults and children. Although death rates have been declining since the late 1990’s, the ACS expects that about 19,790 people will die from this cancer (11,480 males and 8,310 females).
Diffuse large B-cell lymphoma or DLBCL is the most common form of non-Hodgkin lymphoma (NHL). This disease is an aggressive, fast growing, lymphoma that arise in lymph nodes or outside of the lymphatic system, in the gastrointestinal tract, testes, thyroid, skin, breast, bone, or brain.[2]
Treatment challenge
Advances in immunochemotherapy have, in the last decades, led to dramatic improvement in the prognosis of non-Hodgkin’s lymphoma (NHL). This is partly due to the inclusion of rituximab (Rituxan®; Genentech/Biogen IDEC), a chimeric monoclonal antibody targeting CD20, a cell-surface marker present on B-lineage cells and consequently expressed on many B-cell lymphoma subtypes, in the treatment of patients with NHL. But regardless of these advances, relapsed and refractory disease continues to represents a major treatment challenge. Most patients who relapse after rituximab-based treatment, considered the standard of care in front-line treatment regimens, remain resistant to salvage therapy.
While today there is no standard of care for salvage regimens for aggressive and indolent subtypes of NHL and the prognosis after relapse remain relatively poor, a number of regimens, including the combination of ifosfamide, carboplatin, and etoposide (ICE) in DLBCL, have been studied as potential options for salvage therapy. Another commonly used salvage regimen is the combination of rituximab (R) plus etoposide (E), methylprednisolone (SH), cytarabine (A; also known as Ara C) and cisplatinum (P), a combination known as R-ESHAP, which is generally associated with a high response rate in patients who are not refractory to upfront rituximab-based chemotherapy but offers poor survival outcome in patients previously exposed to rituximab, as compared to in those who had not previously been treated with rituximab.[3]
In high-risk patients, first-line R-CHOP immunochemptherapy, a combination of rituximab (R), cyclophosphamide (C), doxorubicin hydrochloride (H), vincristine sulfate (O), and prednisone (P), remains, unfortunately, also unsatisfactory.[4] And intensive treatments, which may include high-dose chemotherapy and autologous stem-cell transplantation, have not shown to be beneficial.[5] Furthermore, these treatments may not be easily tolerated by older patients (>75 years of age) who, on average, make up about one third of all patients with NHL.
However, a number of novel, emerging classes of targeted therapies for relapsed/refractory disease, including antibody– drug conjugates and novel chemotherapeutic agents may offer safe treatment option. [6] Among these novel agents are polatuzumab vedotin (anti-CD79b; DCDS4501A) and pinatuzumab vedotion (anti-CD22; DCDT2980S).[7]
Polatuzumab vedotin
Polatuzumab vedotin, being developed by Genentech Inc. (headquartered in South San Francisco, California; member of the Roche Group), is an antibody-drug conjugate designed to selectively bind to CD79b while minimizing cytotoxic effects on hematologic cells that do not express CD79b. The trial drug is one of 19 antibody-drug conjugates in the company’s development pipeline.
In their 2006 study, Scott Olejniczak, PhD, Assistant Professor of Oncology, Department of Immunology, Roswell Park Cancer Institute and his colleagues evaluated similarities and differences of antigen expression between B-cell neoplasms. Olejniczak et all. showed that each distinct malignant histology has its own quantitative pattern of surface antigen expression and a high expression of specific antigens on a given B-cell malignancy may potentially identify optimal therapeutic targets for monoclonal antibody-based therapies. Interestingly, the majority of B-cell malignancies express CD79b, a B-cell surface protein that is a signaling component of the B-cell receptor, making it a viable target for the treatment of patients with NHL.[8]
And in this investigational drug, the humanized anti-CD79b antibody is conjugated to the synthetic dolastatin 10 analog microtubule-disrupting Monomethyl Auristatin E (MMAE), which has a similar mode of action to that of vincristine, a drug commonly used in the treatment of NHL, through engineered cysteines (THIOMABs) by a protease-cleavable peptide linker (valine–citrulline; Maleimidocaproylvaline-citrulline-p-aminobenzoyloxycarbonyl or MC-VC-PABC). [9] The advantage of the citrulline-valine (VC) linker is that it is highly stable in plasma.
Study design
Initial study results of a clinical trial (NCT01290549) with polatuzumab vedotin in relapsed or refractory B-cell NHL and chronic lymphocystic leukemia (CLL), published in the April 27, 2015 online edition of the Lancet Oncology, showed that this novel drug has an acceptable safety and tolerability profile in patients with NHL. [10] Hence, the results of this Phase I, international multicenter [a], open label study, which followed a “3 + 3” dose-escalation design and enrolled a total of 95 patients (35 in the dose-escalation cohort, 18 in the CLL dose-escalation cohort, 34 NHL patients in the expansion cohort at the recommended Phase II dose of the trial drug and 9 in the rituximab combination cohort) confirmed the therapeutic potential of polatuzumab vedotin. [10]
The researchers noted that combination of polatuzumab vedotin with rituximab, which has important implications in the ability to combine the trial drug with standard rituximab-containing treatment regimes in both relapsed or refractory and newly diagnosed B-cell lymphoma, showed encouraging clinical activity with single agent polatuzumab vedotin. This response was especially interesting because the majority of these patients had advanced disease and were heavily pretreated. [10]
In addition to assessing the safety and tolerability of polatuzumab vedotin, the primary objective of the researchers included determining the dose-limiting toxic effects and the recommended Phase II dose of the trial drug. Secondary objectives included the characterization of pharmacokinetics and (preliminary) evaluate the antitumor activity as assessed by objective response (OR) and progression-free survival (PFS).
Adverse events
In this Phase I trial, Maria Corinna A. Palanca-Wessels, MD, PhD, a clinical assistent professor and researcher at Fred Hutchinson Cancer Research Center in Seattle, Washington (USA), and a team of international researchers, showed polatuzumab vedotin to be generally well tolerated.
At the recommended Phase II dose (2.4. mg/kg) one of the most important adverse events related to the treatment with polatuzumab vedotin was a cumulative, dose-related peripheral neuropathy.[10][11]
The researchers noted that the development of peripheral neuropathy was consistent with the mechanism of action – the microtubule assembly inhibition – of Monomethyl Auristatin E, the cytotoxic component of the trial drug. The researchers also observed that the frequency and severity of peripheral neuropathy – which was generally manageable – was similar to the frequency and severity of patients with relapsed refractory Hodgkin’s lymphoma who were being treated with brentuximab vedotin (Adcetris®; Seattle Genetics).[11] And while grade 3-4 toxicity was relatively uncommon in patients treated with polatuzumab vedotin, neutropenia occurred in about 40% of patients with NHL but without significant clinical complications.
Each antibody-drug conjugate conveys a distinct toxicity profile which is largely based on the mechanism of action (MOA) of the cytotoxic agent. The preliminary trial results of this trial further showed that the toxicity profiles between the combination of polatuzumab vedotin and single agent treatment were similar. Pharmacokinetics were unaffected by co-administration with rituximab. [11] This makes the trial drug a potential drug candidate for the treatment of NHL in the first-line setting. Furthermore, in relapsed and refractory disease, which continues to represents a major treatment challenge, it may be possible to include the drug into second-line regimes. This may, the researchers expect, improve salvage therapy. [12]
Improving outcomes
Although the researchers, based on the preliminary data, concluded that the riks-benefit profile of the trial drug needs further optimization and investigation, they also noted that it compared favorably with both vincristine (Oncovin ®, Vincasar Pfs ®, Vincrex®) and liposomal vincristine (Marqibo®; Spectrum Pharmaceuticals). Hence, one clinical trial is investigating the option to replace vincristine or liposomal vincristine with polatuzumab vedotin in patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) receiving R-CHOP. [13]
Other studies
In an article published in the February 24, 2015 edition of Leukemia, Matthias Pfeifer, PhD, at the Imperial College in London (UK), and a team of researchers analyzed the activity of polatuzumab vedotin in different molecular subtypes of diffuse large B-cell lymphoma (DLBCL) both in vitro and in early clinical trials. These researchers observed that polatuzumab vedotin was highly active and induced cell death in the vast majority of activated B-cell-like (ABC) and germinal center B-cell-like (GCB) DLBCL cell lines. The researchers also noted that polatuzumab vedotin induced cytotoxicity in models with and without mutations in the signaling molecule CD79B. In line with their observations, the researchers noted that relapsed and refractory DLBCL patients of both subtypes responded favourably to the trial drug, suggesting that the trial drug is an active agents for the treatment of patients with different subtypes of DLBCL. [14]
The expectation is that antibody-drug conjugates, including polatuzumab vedotin, will greatly ad to the arsenal of treatment options for patients with non-Hodgkin lymphoma. Ongoing trials are investigating polatuzumab vedotin in combination with other anti lymphoma agents and new ongoing clinical trials are being designed.
