Identification of Highly Radiosensitive Patients May Lead to Side Effect-free Personalized Radiotherapy

An international group of scientists has taken the first step on the road to targeting radiotherapy dosage to individual patients by means of their genetic characteristics, a radiation oncologist told Europe’s largest cancer congress, ECCO 15 – ESMO 34, the 15th congress of the European CanCer Organization and the 34th congress of the European Society for Medical Oncology, in Berlin today.

Professor Dirk de Ruysscher, from Maastricht University Medical Centre, Maastricht, The Netherlands, said that his team’s work might provide the basis for personalized radiotherapy in which, with a simple blood test, doctors may be able to select the optimal radiation dose for a particular patient.

The team of scientists from The Netherlands, Belgium, Germany, and Canada studied a group of patients with hypersensitivity to radiation therapy, drawn from the largest world-wide database available – the European Union-funded Genetic pathways for the prediction of the effect of irradiation (GENEPI) study, which integrates biological material with patient data and treatment specifications. The database included information from more than 8000 European patients.

“Part of this project is the establishment of a sub-database in which very rare patient characteristics are brought together with the hypothesis that their genetic traits will enable the characterization of molecular pathways related to radio-sensitivity,” explained Professor de Ruysscher. “A major problem for radiation oncologists at present is that we are bound by the need to avoid damage to normal tissues. This means that the dose of radiation generally used is governed by the response of the most radiosensitive patients, and this may lead to many patients receiving lower than optimal doses, hence affecting the ability to deliver a higher dose that may result in better local tumor control.”

A tissue bank including skin fibroblasts (the structural framework of skin cells), whole blood, lymphocytes (white blood cells involved in the immune system), plasma, and lymphoblastic (immature lymphocyte) cell lines from patients who were known to be hypersensitive to radiation was established from patients in Europe and Canada.

When compared with a control group, also drawn from the GENEPI study, the hypersensitive patients showed either severe side effects occurring at very low radiation levels, or severe side effects lasting for more than four weeks after the end of radiotherapy and/or requiring surgery, or severe late side effects occurring or persisting more than 90 days after the end of radiotherapy.

The scientists identified 33 such patients, 10 males and 23 females, of whom 11 (two males and nine females) ultimately proved to be really hypersensitive to radiation, underlining the rarity of this condition. Their mean age was 61.6 ± 8.5 years (range 49 – 74). One patient had non-small cell lung cancer, six breast cancer, two head and neck cancer and one lymphoma. The radiation doses, the overall treatment times, and the follow-up times all fell within the usual parameters.

The mean radiation dose to the tumor was 45.3 ± 18.3 Gy (range 8 – 66), delivered in a mean of 21.5 ± 10.5 fractions (range 1 – 33), in a mean overall treatment time of 31.4 ± 17.6 days (range 1 – 57). The mean follow-up time after radiotherapy was 1658 ± 1048 days (range 84 – 3752).

“The severe side effects included acute skin reactions, extreme skin thickening or fibrosis, lung tissue inflammation and blindness due to optical nerve damage,” said Professor de Ruysscher. “Although radiotherapy is a highly effective way of treating cancer, it is important that we are able to identify the patients who will react badly to it and adjust their dosage accordingly.”

Radiotherapy works by causing DNA damage in cells in a particular area so that they destroy themselves. Because cancer cells reproduce more and are undifferentiated (lacking the ability to become a more specialized cell type), they are less able to repair the damage caused by radiotherapy than are differentiated, normal cells which can usually repair themselves. However, some of the normal cells surrounding the treatment site may also be damaged during radiotherapy, and it is this damage that leads to side effects.

Scientists already know that different types of tumors respond differently to radiotherapy; highly radiosensitive cancer cells such as leukemia can be killed by quite low radiation doses, whereas melanomas need such a high dose that it would be unsafe to use radiation therapy in this case. The finding that individuals, as well as tumors, react differently will enable doctors in the future to target doses even more carefully, taking into account not just the radiosensitivity of the tumor type but also the potential reaction of the particular patient to treatment.

“We hope that the EU will fund a successor project to elucidate genetic pathways in combination with other patient data so that we can make predictive models that can be implemented in standard clinical practice,” said Professor de Ruysscher. “We believe that, if we can understand what it is going on at a molecular level, we may be able to develop a blood test that will allow us to know precisely how an individual patient will react to radiotherapy, and to target the dose accordingly. Such personalized treatment will be a major advance, allowing us to minimize both radiotherapy doses and unpleasant side effects, while treating the tumor in the most effective way possible. Perhaps even more importantly, it will enable us to give higher doses to many patients and hence improve control of their tumors.”

For more information

• Abstract no: 2007, Radiotherapy and Radiobiology session, Thursday 10.45 hrs CEST (Hall 15.3)
• Genetic Pathways for the Prediction of the Effects of Ionising Radiation: Low Dose Radiosensitivity and Risk to Normal Tissue after Radiotherapy
• GENEtic pathways for the Prediction of the effect of Irradiation-European normal an tumour tissue bank and data base

Advisory Committee Recommends Randomized Trial to Support Proposed Indication for Clofarabine in Adult AML

The FDA’s Oncologic Drugs Advisory Committee voted 9 to 3 that a randomized, controlled trial is needed to support the currently proposed label expansion for clofarabine (Clolar® , Genzyme) in adult myeloid leukemia (AML). Clofarabine is currently approved as the standard of care for pediatric acute lymphoblastic leukemia (ALL) patients who have relapsed or have refractory disease after at least two prior regimens. The drug has an Orphan Drug designation.

The committee found that the single-arm clinical study results submitted to support the label expansion showed clofarabine was an active agent in acute AML patients, but concluded that a randomized clinical trial should be necessary to better interpret clofarabine’s efficacy and safety in the proposed patient population.

“I am happy that the three panel members who have significant experience in treating older adults with AML recognized the value of clofarabine in these patients and did not see the need for a randomized trial,” said Harry P. Erba, M.D., Ph.D., University of Michigan, one of the co-principal investigators of the CLASSIC II study.

“The panel indicated that it wasn’t an easy decision to vote for a randomized trial as Clolar was clearly active in these patients,” said Mark Enyedy, president of Genzyme Oncology and Multiple Sclerosis. “The requirement for a randomized control trial as a standard of evidence was a major focus of the discussion. We remain committed to the clinical development of Clolar in this patient population with high unmet medical need.”

Genzyme is conducting a randomized Phase 3 trial comparing clofarabine in combination with cytarabine to cytarabine alone in relapsed and refractory adult AML patients 55 years old or older. The trial continues to exceed patient accrual expectations, and results are expected in 2011. Clofarabine is also being investigated in clinical trials by most of the leading AML experts and major cooperative leukemia investigation groups in the United States and Europe.

The CLASSIC II study, discussed at the Oncologic Drugs Advisory Committee (ODAC), analyzed 112 adult AML patients aged 60 years and older with one or more unfavorable prognostic factors, including age 70 years or older, an antecedent hematologic disorder (AHD), poor performance status, or intermediate or unfavorable cytogenetics. As reported in peer-reviewed literature, and discussed by a separate panel of AML experts who recommended the trial, these risk factors predict poor outcomes in older patients with conventional induction therapy.

Patients in the trial had a 45.5 percent overall remission rate, including a 37.5 percent complete remission (CR) rate, and remission rates were consistent regardless of the type or number of unfavorable risk factors. The study also found that clofarabine remissions were durable. Durable CR is accepted as an established surrogate for clinical benefit in patients with acute leukemias. The median duration of remission in overall responders (CR+CR with incomplete platelet recovery) was estimated as 52 weeks (12 months). Most patients who responded to treatment achieved remission after one cycle.

The safety profile of clofarabine in the Phase 2 study was generally predictable and manageable. The all-cause induction 30-day mortality was 9.8 percent and was consistent regardless of the presence or number of unfavorable prognostic factors. The safety findings were consistent with those for the approved clofarabine pediatric ALL indication. The most commonly occurring adverse reactions included nausea, vomiting, diarrhea, febrile neutropenia, rash, headache, fever, fatigue, hypokalemia, pneumonia, anorexia, pruritus, increased liver transaminases, neutropenia, thrombocytopenia, mucosal inflammation.

The American Cancer Society estimates that approximately 12,810 people will be diagnosed with AML in the United States in 2009. About 70 percent of these patients will die from the disease, and almost all will be adults. The median age of a patient with AML is about 67 years. As an acute disease, AML progresses rapidly and is typically fatal within weeks or months if left untreated.

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.

Novel Treatments Demonstrate Improvements in Overall Survival (OS) and Response Rates (RR) in Difficult to Treat forms of Leukaemia and Lymphoma

The use of dexamethasone early in the treatment of children with acute lymphoblastic leukemia (ALL), the most common type of childhood cancer, may help reduce the risk of relapse. This is the conclusion from study results presented during the 50th Annual Meeting of the American Society of Hematology (ASH) in San Francisco, CA (December 6 – 9)

Additional research featured during the annual meeting included: the potential role of a combination therapy regimen that includes rituximab as the new standard first-line therapy for the treatment of advanced chronic lymphocytic leukemia, the examination of pralatrexate or 10-propargyl-10-deazaaminopterin (PDX), for the treatment of peripheral T-cell lymphoma in the largest prospective study of this subset of patients, and the results of the first study examining a promising new molecular target for the treatment of B-cell non-Hodgkin lymphoma.

'By conducting ongoing research with new, investigational treatments as well as with different combinations of existing treatment options that have been used for years, we are working to improve the survival of our patients with leukemia and lymphoma,' explained Dr. Linda Burns, MD, Professor of Medicine, Division of Hematology, Oncology, and Transplantation, University of Minnesota, Minneapolis, MN. 'The research presented today showcases the great advances we are continuously making in treating various blood cancers.'

Leukemia and lymphoma are two of the most common blood cancers. Leukemias are categorized based on the speed at which the cancer grows – acute leukemias grow quickly while chronic leukemias develop at a slower rate. Leukemias also are categorized as lymphocytic or myelogenous depending on whether they affect lymphocytes (a type of white blood cell) or stem cells found in the bone marrow. According to the National Cancer Institute, each year there are approximately 44,000 new cases and 22,000 deaths associated with leukemia in the United States.

Lymphoma is cancer of the lymphatic system that begins with a change in the lymphocytes, impairing the ability of the body’s immune system to fight infection. Lymphomas are divided into two categories: Hodgkin lymphoma and non-Hodgkin lymphoma. Most non-Hodgkin lymphomas are B-cell lymphomas, which are further classified into 14 different sub-types based on the stage of cell development during which the B cell has been affected. The rest are T-cell lymphomas, which affect another type of white blood cell. There are approximately 66,000 new cases of lymphoma and nearly 20,000 deaths each year in the United States according to the National Cancer Institute.

Also read blog entry:

• Fostamatinib Disodium shows promise in the treatment of Diffuse Large B-Cell Lymphoma and Chronic Lymphocytic Leukemia
• Dexamethasone can Eliminate One-Third of All Relapses in Childhood Acute Lymphoblastic Leukemia
• New Drug Shows Promise in the Treatment of Patients With Relapsed or Refractory Peripheral T-Cell Lymphoma
• Immunochemotherapy with Fludarabine, Cyclophosphamide, and Rituximab Improves Response Rates and Progression-Free Survival of Previously Untreated Patients with Advanced Chronic Lymphocytic Leukemia.