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Old 01-24-2012, 01:23 PM
gdpawel gdpawel is offline
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Default Rituxan (rituximab) Maintenance Therapy in CLL

Rituximab Maintenance In Patients with Chronic Lymphocytic Leukemia (CLL) After Upfront Treatment with Rituximab Plus Fludarabine, Cyclophosphamide, and Mitoxantrone (R-FCM): Final Results of a Multicenter Phase II Trial On Behalf of the Spanish CLL Study Group (GELLC)

Francesc Bosch, MD, PhD, Pau Abrisqueta, Neus Villamor, MD. PhD, María José Terol, MD, PhD, Eva González-Barca, MD, Marcos González, MD, Christelle Ferrà, Eugenia Abella, Julio Delgado, Jose A. Garcia-Marco, MD, PhD, Yolanda Gonzalez, Felix Carbonell, MD, Secundino Ferrer, Encarna Monzo, MD, Isidro Jarque, Ana Muntanola, Mireia Constants, Lourdes Escoda, and Emili Montserrat, MD. PhD

Abstract 293

The effectiveness of rituximab, fludarabine, cyclophosphamide, and mitoxantrone (R-FCM) followed by rituximab maintenance in the treatment of CLL has been investigated in a phase II clinical trial that includes two treatment parts. First, patients were given induction therapy with R-FCM up to 6 cycles, achieving an overall response (OR) rate of 93% and a CR rate of 82% (46% MRD-negative CR) (Bosch et al. J Clin Oncol 27:4578–4584, 2009). Patients achieving CR or PR with the initial part of the treatment received rituximab maintenance. Here we present the final results of the treatment maintenance part, initiated three months after concluding R-FCM, and consisting of rituximab 375 mg/m2 every three months for two years (up to 8 cycles). Sixty-four patients (median age 60 years, 70% male) receiving > 4 cycles of maintenance therapy were evaluated for response, including bone marrow (BM) examination and MRD assessment by four-color flow cytometry of peripheral blood and BM. Patients in whom rituximab maintenance was prematurely interrupted ( 4 cycles) due to toxicity were considered as failures. Median number of cycles of maintenance administered was 8 (range, 1 to 8) and 76% of patients completed the entire planned treatment. Treatment was delayed due to insufficient hematological recovery in 9 cycles (2%) and to non-hematological toxicity in 4 cycles (0.8%). Neutropenia was observed in 31.3% of cycles (grade 3&4 in 8.5%), thrombocytopenia in 4.6%, and anemia in 1.2%. At the end of the maintenance therapy, 45% of patients had low IgA serum levels, 37% low IgG, and 66% low IgM. Sixteen patients experienced grade 3&4 infectious episodes, including 9 pneumonia, 2 febrile neutropenia, 1 appendicitis, 1 myositis, 1 herpes zoster, and 1 cerebral abscess. Two patients died, one due to multifocal leukoencephalopathy and the other due to hemophagocytic syndrome. Infectious episodes grade 3&4 were observed in 19.5% of cycles with neutropenia 3&4, but in only 3% of cycles with neutropenia inferior to grade 3 (p<0.001). In contrast, no relationship was observed between infectious events and the presence of low levels of immunoglobulins or diminished CD4+ T lymphocyte counts. After rituximab maintenance, 40.6% of patients were in MRD-negative CR, 40.6% in CR, 7.9% in PR, and 10.9% failed to treatment. Failures were due to disease progression (two patients), severe neutropenia (three patients), infectious toxicity (one patient) and death (one patient). Among 35 patients in MRD-negative CR after R-FCM induction, 22 maintained the MRD-negative status at the end of maintenance treatment, 9 (25.7%) switched from MRD-negative to MRD-positive, and 4 failed to treatment (Table 1). Median time to conversion from negative to positive MRD was 45.4 months, significantly longer than that observed in patients treated with FCM only (45.4 vs. 16.4 months; p=0.011) (Bosch et al. Clin Can Res 14:155–161,2008) (Figure 1). Moreover, among 21 patients that achieved MRD-positive CR with the initial R-FCM treatment, 2 (9.5%) became MRD-negative upon rituximab maintenance, 17(81%) continued in MRD-positive CR, 2 achieved PR, and 2 failed to maintenance therapy. Among the 8 patients in PR, 4 patients achieved CR (2 MRD-negative and 2 MRD-positive), 3 patients continued in PR, and one patient progressed (Table I). Three-year progression-free survival was 94% (95% CI 88–100%). Compared to the FCM series, maintenance with rituximab significantly prolonged the time to next treatment in patients that after the initial treatment with R-FCM were in MRD-positive CR (44.1 vs. 54.5 months, p=0.049) or PR (6.5 vs. 54.4 months, p=0.001). In conclusion, treatment maintenance with rituximab after R-FCM in patients with CLL is feasible and might improve patients' outcome, particularly those who do not attain a MRD-negative CR after the initial, upfront therapy. However, its toxicity is not negligible. Further, ongoing studies should help to clarify the role of maintenance therapy with rituximab in the management of patients with CLL.

Disclosures: Bosch: Hoffman La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Off Label Use: Rituximab is currently not approved as maintenance therapy for patients with chronic lymphocytic leukemia.

Blood (ASH Annual Meeting Abstracts) 2011 118: Abstract 293 2011 American Society of Hematology
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Old 02-01-2013, 02:30 AM
gdpawel gdpawel is offline
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Default Roche’s GA101 Met Goals in Stage One of Trial to Replace Rituxan

A next-generation blood cancer drug met its target in the first stage of a trial that could help the treatment replace Rituxan (rituximab) in patients with chronic lymphocytic leukemia (CLL), in a bid to defend from biosimilar competitors after its patent expires.

GA101 combined with chemotherapy helped CLL patients live longer without their disease progressing than chemotherapy alone, according to the drugmaker Roche. The medicine is a partnership with U.S. biotechnology company Biogen Idec Inc.

Still to come is data comparing GA101 directly with Rituxan. An analysis after the first stage of the CLL trial showed there is a possibility that GA101 will be better than Rituxan, Roche said.

Like Rituxan, GA101 targets CD20, a type of immune cell that plays a role in non-Hodgkin’s lymphoma and chronic lymphocytic leukemia. People with non-Hodgkin’s lymphoma are the larger group of potential patients for GA101, and Roche is also testing the drug in that patient group.

Full results from the trial in CLL patients will be presented at a medical conference, the company said.

Bloomberg.com
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Old 02-20-2013, 10:25 PM
gdpawel gdpawel is offline
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Default Possible Development of PML from Rituxan Treatment

FDA and Genentech informed healthcare professionals of important emerging safety information about Rituxan. Two patients died after being treated with Rituxan for systemic lupus erythematosus (SLE). Rituxan is approved for the above indication and is prescribed off-label for other serious diseases and conditions such as SLE. The cause of death was a viral infection of the brain called progressive multifocal leukoencephalopathy (PML) that is caused by reactivated JC virus which is present in about 80 percent of adults. Physicians should maintain a high index of suspicion for the development of PML in patients under treatment with Rituxan.

This is from the FDA website which has a pdf version of the health advisory for patients and physicians.

[url]http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm187791.htm

Leukoencephalopathy syndrome is a disorder that results from structural alterations of cerebral white matter, is characterized by cerebral edema, and can occur in patients of any age. Cranial irradiation and certain chemotherapy agents, especially those used in high-dose protocols, are causal agents. The prevalence of toxic leukoencephalopathy is unknown; however, this syndrome has been reported increasingly in the literature in patients who develop neurobehavioral changes following exposure to various toxins. Diagnosis must confirm exposure to a toxin and the presence of neurobehavioral deficits and neuroradiologic abnormalities. In most reported cases, clinical symptoms are reversible after the offending toxin is withdrawn.

Toxic leukoencephalopathy is a disorder that is characterized by edema of cerebral white matter (Filley & Kleinschmidt-DeMasters, 2001). Because this syndrome alters neurobehavioral function, patients may present in a confused state, which can progress quickly to irreversible dementia, coma, or death, depending on its severity (Cossaart, SantaCruz, Preston, Johnson, & Skikne, 2003; Filley, 1999; Filley & Kleinschmidt-DeMasters). Caused by toxins, such as chemotherapy agents, the prevalence of this disorder is unknown; however, it has been reported increasingly in the literature.
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Old 06-06-2013, 01:51 PM
gdpawel gdpawel is offline
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Default Tysabri Screening Test May Be Unreliable

In this study, a relatively high percentage of patients with multiple sclerosis treated with natalizumab had JC viremia and were seronegative at a rate greater than the false-negative rate identified previously.

The study therefore indicates that a single measurement of viral activity, such as a test for antibodies to JC virus, may be useful but not sufficient to assess risk for PML in patients receiving potent immunomodulatory therapies.

About one-third of multiple sclerosis patients testing negative for antibodies against the JC virus -- suggesting that natalizumab (Tysabri) would be relatively safe -- were found to have active viremia, researchers said.

The report, published in the June 6 issue of the New England Journal of Medicine, raises the specter that patients with negative JC serology results could be given natalizumab when they may actually be at high risk for progressive multifocal leukoencephalopathy (PML), an often fatal type of brain inflammation.

PML is caused by JC virus becoming active in the brain. Natalizumab appears to contribute to reactivation of latent JC virus infections. MS patients with such infections face a PML risk while on natalizumab ranging from about 0.01% to 0.1% depending on the presence of other risk factors

Eugene O. Major, PhD, of the National Institute of Neurological Disorders and Stroke in Bethesda, Md., and colleagues reported having tested blood samples from 49 patients for anti-JC virus antibodies and for JC virus DNA.

In 26 of the patients, the samples were obtained immediately before starting on natalizumab. Samples from the other 23 were obtained after at least 2 years of periodic natalizumab infusions.

Ten patients in the first group were found to have JC viral DNA in their blood, with four lacking a positive result in anti-JC virus antibody testing. (Seronegativity was defined as antibody titers of less than 2,560 units.)

In the group of 23 patients tested after 2 years of natalizumab treatment, seven were found to be viremic and two were seronegative, the researchers reported.

Overall, they indicated, six of 17 patients (35%) showing JC viremia were seronegative with the antibody test.

Fisher's exact test indicated that the rate of viremia in the 49 patients was significantly greater than in 18 healthy volunteers also undergoing viral DNA testing (P=0.003), in whom none showed evidence of the virus in blood.

"The relatively high percentage of patients who had viremia and were seronegative appears to be greater than the false negative rate identified previously," Major and colleagues wrote.

Currently, the FDA and natalizumab's label recommend JC virus antibody testing before the drug is started in MS patients. The risk of PML is believed to be virtually nil for patients without JC virus infection, but false-negative serological test results would lead to incorrect PML risk prediction.

"To establish risk-stratification algorithms for PML in patients who receive potent immunomodulatory therapies, a single measurement of viral activity, such as a test for antibodies to JC virus, may be useful but not sufficient to assess risk," the researchers wrote. They recommended "a more comprehensive risk-mitigation strategy" that involves periodic testing during natalizumab treatment.

Natalizumab's label now calls for repeat serology testing every 6 months, citing the risk of new JC virus infections that may occur during treatment. Infections are relatively common in the general population. In the current study, 12 of the 18 healthy volunteers were seropositive.

On the other hand, a positive test result is not an absolute contraindication to natalizumab. "The risks and benefits of continuing treatment with Tysabri should be carefully considered in patients who are found to be anti-JCV antibody positive and have one or more additional risk factors," it says. Such risk factors include duration of natalizumab therapy and prior history of immunosuppressant treatment.

Reference: Major E, et al "JC Viremia in natalizumab-treated patients with multiple sclerosis" New Engl J Med 2013; 368: 2240-2241.

Citation: Tysabri Screening Test May Be Unreliable. John Gever MedPage Today: June 05, 2013.
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