Approval of Nilotinib Gives Patients With Newly Diagnosed Ph+ Chronic Myeloid Leukemia New Medical Option

The European Commission has approved nilotinib (Tasigna®, Novartis) as a treatment for adult patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) in chronic phase.

Nilotinib is indicated for the treatment of adult patients with newly diagnosed Philadelphia chromosome-positive chronic myelogenous leukemia (CML) in the chronic phase. The new agent has also been approved in over 90 countries for the treatment of chronic phase and accelerated phase Ph+ CML in adult patients resistant or intolerant to at least one prior therapy, including imatinib (Glivec®; known as Gleevec® in the USA, Canada and Israel)[8]. The effectiveness of nilotinib for this indication is based on confirmed hematologic and unconfirmed cytogenetic response rates. There are no controlled trials demonstrating a clinical benefit, such as improvement in disease-related symptoms or increased survival.

The approval from the European Commission followed a positive opinion from the Committee for Medicinal Products for Human Use (CHMP). It is based on findings from a pivotal Phase III trial demonstrating superiority to the standard of care imatinib in achieving molecular and cytogenetic response and delaying cancer progression. These data were first published in the June 17 issue of The New England Journal of Medicine [1] and were confirmed by 18-month median follow-up data presented at the 46th American Society of Clinical Oncology (ASCO) annual meeting held in June 2010 [2].

The US Food and Drug Administration (FDA), Swissmedic and Japan's Ministry of Health, Labour and Welfare have also approved nilotinib in this first-line indication. Regulatory submissions are under review in other countries worldwide.

"We are pleased that Tasigna is now approved for newly diagnosed Ph+ CML patients in chronic phase in the member states of the European Union," said Hervé Hoppenot, President, Novartis Oncology. "With this expanded indication, newly diagnosed patients can benefit from a Bcr-Abl tyrosine kinase inhibitor that, according to pivotal data, surpassed the standard of care Glivec, in key measures of efficacy, including delaying disease progression at 12 months."

In laboratory studies, nilotinib has been shown to be a potent and selective inhibitor of the Bcr-Abl protein that causes production of cancer cells in Ph+ CML,[3]. It has also been shown to be active against a broad spectrum of Bcr-Abl mutations associated with resistance to imatinib [4].

In its pivotal head-to-head trial, nilotinib surpassed imatinib in key measures of treatment efficacy, as has been reported. nilotinib eliminated Bcr-Abl faster and more deeply than imatinib and resulted in lower rates of cancer progression after 12 months of therapy[1]. Major molecular response (MMR), a measure of deep reduction in Bcr-Abl, is considered to be a critical therapeutic milestone associated with good long-term outcomes for patients with Ph+ CML in chronic phase[5]-[7]. Treatment with nilotinib led to higher rates of both MMR and complete cytogenetic response (CCyR) (undetectable levels of the Philadelphia chromosome that is the hallmark of this cancer) compared with imatinib [1].

After a median of 18 months of follow-up treatment, two patients on the nilotinib 300 mg twice daily arm progressed to either accelerated phase or blast crisis while 17 patients on the imatinib arm progressed to either accelerated phase or blast crisis. In the study, nilotinib and imatinib were generally well tolerated. Fewer patients discontinued due to adverse events from the nilotinib 300 mg twice daily arm of the study compared to the imatinib 400 mg once daily arm.

The randomized, open-label, multicenter trial, called ENESTnd (Evaluating Nilotinib Efficacy and Safety in Clinical Trials of Newly Diagnosed Ph+ CML Patients), compared the efficacy and safety of nilotinib versus imatinib in adult patients with newly diagnosed Ph+ CML in chronic phase[1]. It is the largest global randomized comparison of two oral therapies ever conducted in newly diagnosed Ph+ CML patients in chronic phase.

This year, Novartis also began collaboration with molecular diagnostics company Cepheid to develop a new FDA cleared/approved Bcr-Abl test, which adheres to the International Scale. The goal of the collaboration is to help doctors more reliably monitor Ph+ CML patients. Cepheid and Novartis also will develop a next generation test, which is expected to enable even more sensitive testing, indicating the depth of a patient's response to tyrosine kinase inhibitors, including nilotinib and imatinib. Currently, there are no FDA cleared/approved tests to monitor for Bcr-Abl.

Earlier this month nilotinib was also approved by Japan's Ministry of Health, Labour and Welfare to offer as a treatment for adult patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) in chronic phase.

References:
[1] Saglio G, Kim D-W, Surapol Issaragrisil S, et al. Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N Engl J Med. 2010 Jun 17;362(24):2251-9.
[2] Larson R, Philipp le Coutre, Reiffers J, Hughes T. et al. Nilotinib is Superior to Imatinib in Patients (pts) with Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase (CML-CP): ENESTnd Beyond One Year. Abstract # CRA6501. American Society of Clinical Oncology 2010 Annual Meeting
[3] le Coutre P, Ottmann OG, Giles F, et al. Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is active in patients with imatinib-resistant or-intolerant accelerated-phase chronic myelogenous leukemia. Blood. 2008 Feb 15;111(4):1834-9.
[4] Swords R, Mahalingam D, Padmanabhan S, et al. Nilotinib: optimal therapy for patients with chronic myeloid leukemia and resistance or intolerance to imatinib. Drug Des Devel Ther. 2009 Sep 21;3:89-101
[5] Hochhaus A, O'Brien SG, Guilhot F,et al. IRIS Investigators. Six-year follow-up of patients receiving imatinib for the first-line treatment of chronic myeloid leukemia. Leukemia. 2009 Jun;23(6):1054-61.
[6] Müller MC, Hanfstein B, Erben P, et al. Molecular response to first line imatinib therapy is predictive for long term event free survival in patients with chronic phase chronic myelogenous leukemia - an interim analysis of the randomized German CML Study IV. Blood (ASH Annual Meeting Abstracts) 2008, 112: Abstract 333.
[7] Baccarani M, Cortes J, Pane F, et al. Chronic myeloid leukemia: an update of concepts and management recommendations of European LeukemiaNet. J Clin Oncol. 2009 Dec 10;27(35):6041-51.
[8] Glivec® (imatinib) prescribing information. Basel, Switzerland: Novartis International AG; March 2009

For more information:
[9] Summary of Product Characteristics (Nilotinib, Tasigna®)
[10] EPAR Summary for the Public.

Society to Fund Research Focused on Long-Term and Late Effects of Cancer Treatment

Over the past decades, cure rates for many cancers have improved dramatically. The harsh reality is, however, that too many cancer survivors suffer serious side-effects of their curative treatments. Toxic side-effects can occur months or years after the treatments are finished, sometimes as chronic conditions, sometimes life-threatening, but always unacceptably reducing a patient's quality of life.

While research continues to seek new safe and effective drugs, what patients need now is for current therapies to be made less harmful without sacrificing their effectiveness.

In a new initiative, The Leukemia & Lymphoma Society (LLS), the world's largest voluntary health agency dedicated to blood cancer founded in 1949 and headquartered in White Plains, NY, will invest in research designed to discover the biological mechanisms that cause late effects, and to develop and test measures to prevent or at least significantly reduce toxicities. LLS is seeking requests for proposals from scientists studying these issues.

The pediatric cancer story has shown us that the goal is achievable. Years of research and clinical trials enabled survival rates to reach nearly 90% for children with acute lymphocytic leukemia. But then the medical and research community recognized that the serious late effects were severely impacting quality of life. High-dose radiation treatments, once thought critical to cures, have been eliminated for most children, significantly reducing cognitive deficits and other once common side-effects.

Now The Leukemia & Lymphoma Society has set a goal of doing for all cancer patients, regardless of age, what has been achieved for many children -- survival with good quality of life.

The initiative is being led by Anna T. Meadows, M.D., medical director of the Cancer Survivorship and Living Well After Cancer Program at the Children's Hospital of Philadelphia. Dr. Meadows is an internationally recognized pioneer in late effects research; she helped quantify the serious consequences of high-dose radiation and eliminate it from curative treatments for most children with leukemia and lymphoma.

"We must find the answers and test them as soon as possible," says Dr. Meadows. "We must be determined and courageous - funders, researchers, and patients alike - because survival is just the first part of the struggle to cure cancer; the quality of that survival matters."

Retuximab receives positive opinion in Europe for first-line treatment of chronic lymphocytic leukemia (CLL)

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.

Impact
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.

Label extension

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.’

For more information:

• 50th ASH Annual Meeting and Exposition, Online Abstracts: Chronic Lymphocytic Leukemia - Therapy, Excluding Transplantation (abstract 325 - 330).
• The official MabThera website (Roche).
• International Standard Randomised Controlled Trial Number (ISR CTN) Register: ISRCTN02757147
• National Cancer Institute rituximab
• The Nobel Prize in Physiology or Medicine 1984 laureates
• The Nobel Prize: Presentation Speech (1984)
• Click here for an overview of FDA approved antibodies for the parenteral use in the detection and treatment of cancer.
• Understanding Cancer Series (National Cancer Institute) Slide 36.
• Oldham RK, Dillman RO, Monoclonal Antibodies in Cancer Therapy: 25 Years of Progress. Journal of Clinical Oncology, Vol 26, No 11 (April 10), 2008: pp. 1774-1777 (Full Text Aricle).

Also read PubMed abstracts:

• Foon KA, Boyiadzis M, Land SR, et al. Chemoimmunotherapy With Low-Dose Fludarabine and Cyclophosphamide and High Dose Rituximab in Previously Untreated Patients With Chronic Lymphocytic Leukemia. J Clin Oncol. 2008 Dec 15. [Epub ahead of print].
• Nissim A, Chernajovski Y. Historical development of monoclonal antibody therapeutics. Handb Exp Pharmacol. 2008;(181):3-18.
• Hallek M; German CLL Study Group. Prognostic factors in chronic lymphocytic leukemia. Ann Oncol. 2008 Jun;19 Suppl 4:iv51-3.
• Eichhorst B, Hallek M, Dreyling M; ESMO Guidelines Working Group. Chronic lymphocytic leukemia: ESMO clinical recommendations for diagnosis, treatment and follow-up. Ann Oncol. 2008 May;19 Suppl 2:ii60-2. Click here for Full Text Article.
• Keating MJ, O’Brien S, Albitar M, et al, Early results of a chemoimmunotherapy regimen of fludarabine, cyclophosphamide, and rituximab as initial therapy for chronic lymphocytic leukemia. J Clin Oncol. 2005 Jun 20;23(18):4079-88. Epub 2005 Mar 14.
• Cartron G, Blasco H, Paintaud G, et al. Pharmacokinetics of rituximab and its clinical use: thought for the best use? Crit Rev Oncol Hematol. 2007 Apr;62(1):43-52. Epub 2007 Feb 6.
• Kim H, Csaky KG, Chan CC, et al. The pharmacokinetics of rituximab following an intravitreal injection. Exp Eye Res. 2006 May;82(5):760-6. Epub 2005 Nov 11.
• Sharkey RM, Goldenberg DM. Targeted therapy of cancer: new prospects for antibodies and immunoconjugates. CA Cancer J Clin. 2006 Jul-Aug;56(4):226-43. Click here for Full Text Article. http://caonline.amcancersoc.org/cgi/content/full/56/4/226
• Olszewski AJ, Grossbard ML. Empowering targeted therapy: lessons from rituximab.
  Sci STKE. 2004 Jul 6;2004(241):pe30. Review.
• Grillo-López AJ, White CA, Varns C, et al. Overview of the clinical development of rituximab: first monoclonal antibody approved for the treatment of lymphoma. Semin Oncol 1999; 26: 66-73.
• Piro LD, White CA, Grillo-López AJ, et al. Extended Rituximab (anti-CD20 monoclonal antibody) therapy for relapsed or refractory low-grade or follicular non-Hodgkin's lymphoma. Ann Oncol. 1999 Jun;10(6):655-61.
• Ritz J. Pesando JM, Sallan SE, et al. Serotherapy of acute lymphoblastic leukemia with monoclonal antibody. Blood. 1981 Jul;58(1):141-52.
• De StGroth SF, Scheidegger D. Production of monoclonal antibodies: strategy and tactics. J Immunol Methods. 1980;35(1-2):1-21
• Köhler G, Milstein C. Continuous cultures of fused cells secreting antibody of predefined specificity. Nature. 1975 Aug 7;256(5517):495-7.
• Currie GA, Eighty years of immunotherapy: a review of immunological methods used for the treatment of human cancer. Br J Cancer. 1972 Jun;26(3):141-53.

Download:

• European Summary of Product Characteristics (only for healthcare professionals outside the Unites States of America). The ESPC provides comprehensive clinical, pharmacological and prescribing information about MabThera. Detailed information about the safety experience with MabThera can be found in the ESPC.

Additional references:

• Hericourt J, Richet CH. ‘Physologie pathologique’ - de la serotherapie dans la traitement du cancer. Comptes Rendus Hebd Seanc Acad Sci (Paris) 1895; 120: 567–569
• Himmelweit F. The Collected Papers of Paul Ehrlich. Vol. 3. London: Pergamon; 1960: 59.

Fostamatinib Disodium Shows Promise in the Treatment of Diffuse Large B-Cell Lymphoma and Chronic Lymphocytic Leukemia

Results of the first multicenter clinical study examining the use of fostamatinib disodium or FosD (R788), an investigational treatment that targets a protein called spleen tyrosine kinase or SYK, presented by Jonathan Friedberg, MD from the James P. Wilmot Cancer Center, Rochester, NY, and lead investigator for the clinical trial, showed that this new agent represents a safe and novel therapeutic approach and is well tolerated in patients with diffuse large B cell lymphoma (DLBCL) and chronic lymphocytic leukemia (CLL). Friedberg presented these results during the 50th Annual Meeting of the American Society of Hematology (ASH) in San Francisco, CA (December 6 – 9).

Lymphoma affects an estimated 500,000 people in the United States, with 332,000 of them suffering from non-Hodgkin's lymphoma. Diffuse large B-cell lymphoma is the most common type of NHL and is generally categorized as aggressive, marked by rapidly growing tumors in the lymph nodes, spleen, liver, bone marrow and other organs. A variety of treatment options for NHL exist, including chemotherapy and radiation, but the five-year survival rate for NHL patients is estimated to be around 50%. Even for those who respond to treatment, recurrence of the disease is common.

B cell chronic lymphocytic leukemia (CLL) is the most prevalent B cell malignancy in adults. The disease is characterized by expansion of monoclonal mature B lymphocytes. Despite advances in treatment, the disease remains incurable warranting further efforts to identify novel molecular targets in CLL. B cell receptor (BCR) signaling contributes to apoptosis resistance in CLL limiting the efficacy of therapeutic approaches.

SYK Inhibition
Fostamatinib disodium (FosD), an orally available inhibitor of protein kinase SYK which is currently being developed by Rigel Inc. (1180 Veterans Blvd, South San Francisco, CA 94080) for the treatment of rheumatoid arthritis, has demonstrated significant in vitro activity against B-cell receptor (BCR)-dependent NHLs. FosD disrupts B-cell receptor mediated signaling by inhibiting SYK. Furthermore, FosD blocks IgG receptor (Fc receptor) signaling in macrophages and B-cells, and addresses multiple inflammatory mechanisms including TNF-α, IL-1, and IL-6.

Because SYK is overexpressed in CLL and found to be constitutively phosphorylated in several common B-cell lymphoma subtypes, researchers believe that it plays a role in antigen-independent SYK activation in the pathogenesis of chronic lymphocytic leukaemia, and therefore represents a potential therapeutic target.

In the study by Friedberg et al, FosD, administered as a tablet, produced significant responses in patients who had failed previous treatments for diffuse large B-cell lymphoma, chronic lymphocytic leukemia, and small lymphocytic lymphoma, as well as prolonged stable disease in patients with follicular lymphoma.

Following a phase I dose-limiting study of 13 patients, the regimen of a 200 mg twice-daily dose of FosD was chosen for further evaluation in a phase II study conducted with 68 patients with relapsed or refractory B-cell non-Hodgkin lymphoma. These patients were divided into three groups: those with diffuse large B-cell lymphoma (23 patients), those with follicular lymphoma (21 patients), and those with other B-cell non-Hodgkin lymphomas (24 patients), including chronic lymphocytic leukemia/small lymphocytic lymphoma (11 patients), mantle cell lymphoma (9 patients), MALT lymphoma (3 patients), and lymphoplasmacytic non-Hodgkin lymphoma (1 patient). Patients previously received an average of five therapies, and many had previously received an autologous stem cell transplant or radioimmunotherapy.

The study found that fostamatinib disodium produced complete or partial responses in 21 percent of patients with diffuse large B-cell lymphoma, 54 percent of patients with chronic lymphocytic leukemia/small lymphocytic lymphoma, 11 percent of mantle cell lymphoma patients, and 10 percent of those with follicular lymphoma. Stable disease was also seen in an additional 23 patients, including 12 with follicular lymphoma, four with diffuse large B-cell lymphoma, four with mantle cell lymphoma, two with chronic lymphocytic leukemia/small lymphocytic lymphoma, and one with MALT lymphoma. A proportion of these responses was prolonged, with some patients remaining on therapy for more than one year.

Given the refractory nature of these patients’ lymphoma, the toxicity profile was quite favorable. There were four cases of febrile neutropenia with eight patients requiring a dose-modification due to neutropenia, hypertension, liver function test abnormalities, fever, and mucositis.

Based on the results of this study, researchers believe that FosD should be further developed for the treatment of B-cell non-Hodgkin lymphoma (NHL). ‘Despite the fact that the patients enrolled in this trial had advanced disease and had failed treatment with marketed therapies, a significant number of them were particularly responsive to SYK inhibition with FosD,’ Friedberg explained. ‘I am encouraged by this data and look forward to conducting additional trials of FosD, particularly in patients with DLBCL and CLL/SLL types of non-Hodgkin's lymphomas,’ he added.

More research, better results
A growing field of research on the cellular signaling associated with these lymphomas indicates that inhibiting SYK in aberrant cells may control spread of the disease. Two additional research studies on the topic were also being presented at the ASH meeting. They include: Abstract 377, entitled ‘BCR, Signaling Diversity in Human Lymphoma B Cells Correlates with Follicular Lymphoma Patient Clinical Outcomes’ and Abstract 802, entitled ‘BCL-6 Regulates Tonic BCR Signaling in Diffuse Large B-Cell Lymphomas.’ Furthermore, an independent group of European researchers at the University Hospital Freiburg, Freiburg, Germany in collaboration with the Department of Hematology, Pitie-Salpetriere Hospital, Paris, France and the Institute of Cancer, Barts and The London School of Medicine, London, United Kingdom, noted that in contrast to conventional chemotherapy, stimulation with CD40L significantly sensitized CLL cells towards SYK inhibition. In their study, they conclude that SYK inhibition as a rational and promising therapeutic principle in CLL.

For more information, read:
Friedberg JW, Sharman J, Schaefer-Cutillo J, Johnston PB, De Vos S, et al. Fostamatinib Disodium (FosD), An Oral Inhibitor of Syk, Is Well-Tolerated and Has Significant Clinical Activity in Diffuse Large B Cell Lymphoma (DLBCL) and Chronic Lymphocytic Leukemia (SLL/CLL). (Plenary Session). Blood (ASH Annual Meeting Abstracts) 2008 112: Abstract #3

Other abstracts:

• Maike Buchner M, Fuchs S, Prinz G, Pfeifer D, et al. Spleen Tyrosine Kinase (SYK) Is Overexpressed and Represents a Potential Therapeutic Target in Chronic Lymphocytic Leukemia (Plenary Session). Blood (ASH Annual Meeting Abstracts) 2008 112: Abstract #543
• Irish JM, Houot R, Myklebust JH, Czerwinski DK, et al. Signaling Diversity in Human Lymphoma B Cells and in Tumor Infiltrating T Cells Correlates with Follicular Lymphoma Patient Clinical Outcomes (Oral Session). Blood (ASH Annual Meeting Abstracts) 2008 112: Abstract #377
• JuszczynsKi P, Chen L, Polo JM, Ranuncolo SM, et al. BCL6 Regulates Tonic BCR Signaling in Diffuse Large B-Cell Lymphomas by Repressing the SYK Phosphatase, PTPROt.(Oral Session), Blood (ASH Annual Meeting Abstracts) 2008 112: Abstract #802

Also read PubMed abstracts:

• Gobessi S, Laurenti L, Longo PG, Carsetti L, et al. Inhibition of constitutive and BCR-induced Syk activation downregulates Mcl-1 and induces apoptosis in chronic lymphocytic leukemia B cells. Leukemia 2008 Dec 18. [Epub ahead of print]
• Chen L, Monti S, Juszcynski P, Daley J, et al. SYK-dependent tonic B-cell receptor signaling is a rational treatment target in diffuse large B-cell lymphoma.Blood 2008 Feb 15;111(4):2230-7. Epub 2007 Nov 15.
• Takano T, Sada K, Yamamura H, et al. Role of protein-tyrosine kinase syk in oxidative stress signaling in B cells. Antioxid Redox Signal 2002 Jun;4(3):533-41
• Weinblatt ME, Kavanaugh A, Bargos-Vargos R, Dikranian AH et al. Treatment of rheumatoid arthritis with syk kinase inhibitor: A twelve-week randomized, placebo-controlled trial. Arthritis Rheumatism. 2008 Nov;58(11):3309-18.
• Irish, J. M., Czerwinski, D. K., Nolan, G. P. & Levy, R. Altered B-cell receptor signaling kinetics distinguish human follicular lymphoma B cells from tumor-infiltrating nonmalignant B cells. Blood 2006 Nov 1;108(9):3135-42. Epub 2006 Jul 11. PDF Full article
  

Clinical trials:

• Efficacy and Safety Study of R935788 Tablets to Treat T-Cell Lymphoma (Phase II trial) ClinicalTrials.gov Identifier: NCT00798096, Verified by Rigel Pharmaceuticals, November 2008.