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Novel Treatments Show Improvements In Survival And Response Rates For Leukemia And Lymphoma

Date:
December 6, 2008
Source:
American Society of Hematology
Summary:
The use of dexamethasone early in the treatment of children with acute lymphoblastic leukemia, the most common type of childhood cancer, may help reduce the risk of relapse according to study results being presented in a press conference on Saturday, Dec. 6, at 2 p.m., during the 50th Annual Meeting of the American Society of Hematology in San Francisco, Calif.

The use of dexamethasone early in the treatment of children with acute lymphoblastic leukemia, the most common type of childhood cancer, may help reduce the risk of relapse according to study results being presented on Saturday, December 6 during the 50th Annual Meeting of the American Society of Hematology in San Francisco, CA.

New research describes 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 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.

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.

Fostamatinib Disodium (FosD), an Oral Inhibitor of SYK, Is Well-Tolerated and Has Significant Clinical Activity in Diffuse Large B-Cell Lymphoma and Chronic Lymphocytic Leukemia

Results of the first clinical study examining the use of fostamatinib disodium, an investigational treatment that targets a protein called SYK (spleen tyrosine kinase), showed that the new agent represents a safe and novel therapeutic approach that should be further developed for the treatment of B-cell non-Hodgkin lymphoma. In the study, presented by Jonathan W. Friedberg, MD and James P. Wilmot of the Cancer Center in Rochester, NY, fostamatinib disodium, 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 fostamatinib disodium was chosen for further evaluation in a phase II study conducted with 68 patients with relapsed or refractory B-cell non-Hodgkin lymphoma. The 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 (nine patients), MALT lymphoma (three patients), and lymphoplasmacytic non-Hodgkin lymphoma (one 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.

Dexamethasone in Induction Can Eliminate One-Third of All Relapses in Childhood Acute Lymphoblastic Leukemia

The results of a study presented by Martin Schrappe, MD, University Medical Center and Schleswig-Holstein, Campus Kiel, Kiel, Germany found that the use of dexamethasone in the induction phase of combination chemotherapy led to a one-third reduction in the risk of relapse as compared with the standard corticosteroid, prednisone, translating into a significant benefit in terms of event-free survival in children with acute lymphoblastic leukemia. Dexamethasone was associated with a greater risk of severe side effects, mainly invasive infections; hence, more intensive clinical monitoring and, in particular, early antimicrobial therapy in patients should be implemented to preserve the advantage of using dexamethasone, rather than prednisone, as part of induction therapy.

Following a pre-phase treatment regimen of prednisone and intrathecal methotrexate, a total of 3,655 children (ages 1 to 17) with acute lymphoblastic leukemia were randomized to receive induction therapy consisting of either prednisone (60 mg/m2/d) or dexamethasone (10 mg/m2/d) in addition to vincristine, daunorubicine, and L-asparaginase combination therapy. Post-induction therapy was also given to patients.

Six-year event-free survival reached 84.1 percent in patients who received dexamethasone as compared with 79.1 percent of those who received prednisone in the induction phase. The six-year cumulative incidence of relapse was 11 percent and 18 percent for patients randomized to dexamethasone and prednisone, respectively. The difference between the two groups was observed for bone marrow relapses (8 percent versus 12 percent), central nervous system relapses (2 percent versus 4 percent), and other relapses (2 percent versus 3 percent) in dexamethasone as compared with prednisone.

Higher toxicity was seen in those treated with dexamethasone. The cumulative incidence for death in the induction phase was 2 percent for dexamethasone compared with 0.9 percent for prednisone; however, the cumulative incidence of death during remission was similar between the two treatment groups (2 percent for dexamethasone and 1.6 for prednisone).

PROPEL: A Multicenter Phase II Open-Label Study of Pralatrexate (PDX) With Vitamin B12 and Folic Acid Supplementation in Patients With Relapsed or Refractory Peripheral T-Cell Lymphoma

This study, presented by Owen A. O'Connor, MD, PhD, of Columbia University Medical Center, New York, NY, the largest prospective clinical trial in patients with relapsed or refractory peripheral T-cell lymphoma, found that the investigational chemotherapy agent pralatrexate produces complete responses (disappearance of all signs of cancer) in patients who had previously failed an average of three treatment regimens, including an autologous stem cell transplant for some patients. Designed to be selectively transported into tumor cells, the novel antifolate pralatrexate accumulates to high concentrations in the tumor cell, inhibiting DNA synthesis.

A total of 115 patients were enrolled into this phase II, single-arm, non-randomized, open-label study and received weekly intraveneous infusions of pralatrexate (30 mg/m2) for seven weeks. All patients also received vitamin B12 and folic acid throughout the study in order to prevent potential side effects of the pralatrexate. The primary endpoint of the study was the objective response rate, including all patients who had some response of their disease to therapy. Secondary endpoints included duration of response, progression-free survival, and overall survival.

Interim data of the first 65 evaluable patients showed that 29 percent of patients responded to treatment, with 11 percent experiencing a complete response and 18 percent experiencing a partial response. The most common severe (grade 3 and 4) side effects associated with pralatrexate were thrombocytopenia (31 percent), mucositis (14 percent), anemia (12 percent), and neutropenia (11 percent).

Immunochemotherapy With Fludarabine, Cyclophosphamide, and Rituximab Versus Fludarabine and Cyclophosphamide Improves Response Rates and Progression-Free Survival of Previously Untreated Patients With Advanced Chronic Lymphocytic Leukemia

Results from this multinational phase III clinical trial presented by Michael Hallek, MD, University of Cologne, Cologne, Germany, and German CLL Study Group, suggest that fludarabine, cyclophosphamide, and rituximab (FCR) chemoimmunotherapy may become the new standard first-line therapy for the treatment of advanced chronic lymphocytic leukemia.

In this study, a total of 817 patients with previously untreated chronic lymphocytic leukemia were randomized to receive six 28-day cycles of fludarabine (25 mg/m2 intravenously on days 1 to 3) and cyclophosphamide (FC) (250 mg/m2 intravenously on days 1 to 3) alone or FCR (375 mg/m2 intravenously at start of first cycle and 500 mg/m2 on day 1 for all subsequent cycles). The primary objective of the study was to determine response rates and progression-free survival.

After an average follow-up of 25.5 months, a total of 761 patients were evaluable for response and 787 were evaluable for progression-free survival and overall survival. The overall response rate was significantly higher in the FCR arm (95 percent) as compared with the FC arm (88 percent). The complete response rate was also significantly higher in the FCR arm (52 percent) as compared with the FC arm (27 percent).

At two years, the progression-free survival rate was 76.6 percent in the FCR arm as compared with 62.3 percent in the FC arm. While FCR was found to cause more neutropenia (33.6 percent versus 20.9 percent) and leukopenia (24 percent versus 12.1 percent), it did not increase the incidence of severe infections (18.8 percent versus 14.8 percent) as compared with FC. Taken together, fludarabine, cyclophosphamide, and rituximab chemoimmunotherapy is a safe first-line treatment for chronic lymphocytic leukemia that improves response rates and progression-free survival.


Story Source:

The above story is based on materials provided by American Society of Hematology. Note: Materials may be edited for content and length.


Cite This Page:

American Society of Hematology. "Novel Treatments Show Improvements In Survival And Response Rates For Leukemia And Lymphoma." ScienceDaily. ScienceDaily, 6 December 2008. <www.sciencedaily.com/releases/2008/12/081206224604.htm>.
American Society of Hematology. (2008, December 6). Novel Treatments Show Improvements In Survival And Response Rates For Leukemia And Lymphoma. ScienceDaily. Retrieved April 20, 2014 from www.sciencedaily.com/releases/2008/12/081206224604.htm
American Society of Hematology. "Novel Treatments Show Improvements In Survival And Response Rates For Leukemia And Lymphoma." ScienceDaily. www.sciencedaily.com/releases/2008/12/081206224604.htm (accessed April 20, 2014).

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