The European Union’s Committee on Human Medicinal Products (CHMP), on January 22, 2009, issued a positive recommendation for the use of rituximab, (MabThera®, F. Hoffmann-La Roche, Grenzacherstrasse 124, CH-4070 Basel, Switzerland / Rituxan®, co-marked in the United Sates by Genentech, 1 DNA Way South San Francisco, CA 94080-4990 and Biogen Idec , 14 Cambridge Center, Cambridge, MA 02142), with any chemotherapy combination as a first-line treatment for chronic lymphocytic leukemia (CLL), the most common form of adult leukemia. This recommendation is considered an important step towards license extension for rituximab in combination with chemotherapy as initial treatment.
Rituximab is a chimeric monoclonal antibody (mAb) against the protein CD20+ B-cell antigen used to treat previously untreated patients with stage III-IV follicular lymphoma in combination with chemotherapy, as maintenance therapy for patients with relapsed/refractory follicular lymphoma responding to induction therapy with chemotherapy with or without rituximab, for the treatment of patients with CD20 positive diffuse large B cell non-Hodgkin’s lymphoma in combination with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) chemotherapy and as monotherapy for treatment of patients with stage III-IV follicular lymphoma who are chemoresistant or are in their second or subsequent relapse after chemotherapy.
Early predictions, great potential
The FDA approved rituximab in 1997 as the first antibody approved for the treatment of patients with non-Hodgkin's lymphoma (approval in Europe followed in 1998). The launch of rituximab as a therapeutic agent fulfilled predictions dating back to the early 1900s regarding the therapeutic effect of antibodies and their potential in medicine.
In 1895 Charles Robert Richet (1850 – 1935) and Jules Héricourt described the first attempts of a novel anti-cancer treatment. Their approach was a radical departure from the standard cancer treatments available at that time. Instead of surgery, Richet and Héricourt immunized dogs with a human sarcoma and then transferred the serum to patients with advanced cancer. The idea was to raise an antiserum for treating the patient.
These bold scientists believed that a mechanism to target diseases selectively, know today as ‘passive serotherapy’, which was realized only a few years earlier when scientists discovered that resistance to infectious disease (diphtheria) could be transferred from one animal to another through their serum, would also work in treating cancer. Their pioneering work was the forerunner of the ‘magic bullet’ concept, later developed by the German scientist Paul Ehrlich (1854-1915), believed that ‘toxins’ could be targeted to cancer and other diseases.
The results of these initial attempts seemed very promising. And while several patients with different types of advanced cancer were treated and showed significant improvements in their symptoms, none of them were actually cured. These trials were repeated during the early 1900s, but, again, did not yield the results hoped for. Problems were readily acknowledged. Inconsistent and contradictory results, lack of specificity and reproducibility, lack of purity and xenogeneic immune responses ultimately led to disappointing conclusion that ‘nothing may be hoped for at present in respect to a successful therapy from this direction’.
The science of the times was not yet ready for a proper understanding of idea of a ‘magic bullet’ proposed by Ehrlich in 1908. More than a half-century passed before antibodies were identified as the substance in serum responsible for the effects initially observed by Richet, et al. Ultimately, Ehrlich’s concept of a ‘magic bullet’ was fully realized with the development of monoclonal antibodies (mAbs) in the 1970s.
The great leap forward
In 1975 Georges Jean Franz Köhler (1946 -1995) César Milstein (1927 – 2002) and Niels Kaj Jerne ( 1911 – 1994), started major developments in the field of monoclonal antibodies (mAbs) for which they were awarded the 1984 Nobel Prize in Physiology for Medicine.
Köhler’s and Milstein’s development of the hybridoma technique, the first practical method for mass-producing monoclonal antibodies, is considered one of the most important advances in medicine during the 1970s. This technique has, in less than a decade, revolutionized the use of antibodies in health care and research.
During the following two decades, potential monoclonal antibodies as laboratory tools were rapidly exploited for biotechnology and biomedical applications. Today, mAbs represent over 30% of all biological proteins undergoing clinical trials and are the second largest class of biodrugs after vaccines. With the help of antibody engineering, mAbs have been reduced in size, rebuilt into multivalent molecules, and conjugated with drugs, toxins, or radioisotopes for the treatment of cancer, autoimmune disorders, graft rejection, and infectious diseases. Additionally, in the past few years, important advances have been made in the design, selection, and production of new types of engineered antibodies.
Since the introduction of rituximab, hundreds of thousands of patients have been treated with the drug. In 2002, rituximab became the number one anticancer drug worldwide. During its first decade of use (1993-2003), rituximab has had an important impact on treatment strategies for lymphoma and other hematologic malignancies. During the 5 years following approval, its applications expanded beyond non-Hodgkin's lymphoma to a variety of malignant and non-malignant B-cell disorders. Also, as a result of its early clinical trials, initiatives came about that eventually led to the development of the new international response criteria for non-Hodgkin's lymphoma. Rituximab has been characterized as the most important therapeutic development of the decade.
Mechanism of Action
Rituximab effectively eradicates CD20+ cells in lymphoma patients by several unique and distinct mechanisms, including complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC) and apoptosis. It binds to CD20 on the surface of normal and malignant B-cells and then recruits the body's natural defenses to attack and kill the marked B-cells. B-cell progenitors in bone marrow lack the CD20 antigen, allowing healthy B-cells to regenerate after treatment and return to normal levels within several months.
The label extension which will be possible as a result of CHMPs positive recommendation for the use of rituximab, is based on the impressive, highly significant results of the international CLL-8 study which showed that the median time until patients progressed with their disease, experienced a relapse or died was 40 months if patients were given rituximab plus chemotherapy compared to just 32 months for those that received chemotherapy alone.
Pending the final approval by the EU authorities, physicians will soon be able to prescribe rituximab to CLL patients in combination with their preferred chemotherapy regimen.
‘Treatment with MabThera achieved significantly better outcomes for the patients than chemotherapy alone. This provides hope for the future treatment of a disease that remains life-threatening and incurable,’ said William M. Burns, CEO of the Pharmaceuticals Division of Roche.
Incidence of CLL
Chronic lymphocytic leukemia (CLL) is the most common type of leukemia in adults, accounting for approximately 25-30% of all forms of leukemia. Overall incidence of CLL is around three per 100,000 and is twice as common in men compared to women. It mainly affects the elderly with up to 95% of patients diagnosed after the age of 55 and the median age for diagnosis believed to be approximately between 65 and 70 years of age. Despite the fact that the incidence has been reported to increase in younger patients, with about one-third of CLL patients younger than 55 years, the overall incidence of CLL has decreased during the past 15 years.
While CLL is generally considered a disease that is slow to progress, a significant proportion of patients have rapidly progressing forms of the disease.
Two pivotal trials
Significant new data from two pivotal phase III studies, presented at the 50th Annual Meeting of the American Society of Hematology in San Francisco (December 6 – 9, 2008), showed that patients with chronic lymphocytic leukemia (CLL) treated with rituximab in combination with chemotherapy live considerably longer without their disease progressing, compared to patients treated with chemotherapy alone.
The first trial, the CLL-8 study, an international study conducted by the German CLL Study Group and Professor Michael Hallek (Klinik I für Innere Medizin, Universitaet zu Koeln, Joseph-Stelzmann-Str. 9, Cologne, D-50924, Germany) in collaboration with F. Hofmann La Roche, included 817 patients with CLL receiving first-line treatment. The study was conducted at 191 study sites across 11 countries. In this randomized study, patients received either rituximab in combination with chemotherapy (fludarabine and cyclophosphamide) or chemotherapy alone. The primary endpoint of the study was progression-free survival. No new or unexpected safety signals were observed.
Results from the CLL-8 study showed that at two years, more than three quarters (76.6%) of patients receiving rituximab plus chemotherapy lived without their disease progressing compared to 63.3 % of those treated with chemotherapy alone.
The second trial, the REACH study, a randomized international study that included 552 patients with relapsed or refractory CLL, was conducted at 88 study sites across 17 countries. The study was set up to investigate whether treatment of patients with relapsed or refractory CLL with rituximab in combination with chemotherapy (fludarabine and cyclophosphamide) was more beneficial than treatment with chemotherapy alone. The primary endpoint of the study was to show an increase in terms of median progression-free survival.
After analyzing the data, the REACH study demonstrated that with rituximab, patients who had relapsed lived an average 10 months longer without their disease progressing compared to those receiving chemotherapy alone (30.6 months vs 20.6 months).
‘The positive results from both of these trials is very encouraging news for patients suffering from a disease that remains life-threatening and incurable ,’ noted Roche's Burns. ‘The outcome of these trials clearly demonstrates the important role MabThera will have in the treatment of this devastating disease.’
‘Rituximab has already revolutionized the treatment of people living with non-Hodgkin's lymphoma’, explained Professor Tadeusz Robak, Medical University of Lodz, Poland, and principle investigator for the REACH trial. ‘These results add to a growing body of evidence that underscores the important role MabThera has to play in the management of CLL, which currently remains a life-threatening and incurable disease.’
A new Standard of Care
Based on the results of both trials, the researchers involved feel that rituximab is set to change the face of chronic lymphocytic leukemia management. Commenting on the results of the CLL-8 trial, professor Hallek, who led the German CLL Study Group (GCLLSG) in conducting the study, said, ‘With new therapies emerging, the management of CLL is set to change markedly, with physicians having more options and greater treatment expectations for their patients. These data, which come from the largest randomized clinical trials ever reported in CLL, suggest that rituximab used in combination with chemotherapy has the potential to become the new standard of care for CLL patients.’