1.Successful treatment of lymphoma with fludarabine combined with rituximab after immune thrombocytopenia induced by fludarabine
Yutaka Tsutsumi . Hiroe Kanamori . Hiina Minami . Mio Musashi. Ann Hematol (2005) 84: 269–271
Although partial remission was observed after single courses of CHOP-like (cyclophosphamide, hydroxydaunomycin, vincristine, and etoposide) and CHASE (cyclo-phosphamide, cytosine arabinoside, etoposide, and dexamethasone) regimens and a single course of 50 mg of etoposide (VP-16) orally administered, no further im- provement was observed. After we finished the FND (fludarabine, mitoxantrone, dexamethasone) regimen, the patient’s status improved. The serum soluble interleukin-2 receptor (sIL-2R) level decreased to 904 U/ml. Thrombocytopenia developed, and the platelet count did not recover to previous levels. Bone marrow examination showed adequate megakaryocytes without platelet production. Although platelet-associating immunoglobulin (PAIgG) was not detected in this case, ITP due to fludarabine was considered part of the treatment during bone marrow examination. Standard ITP therapy had little affect on fludarabine-induced thrombocytopenia, and since rituximab is an effective agent for follicular lymphoma, we decided to administer it for the thrombocytopenia in this case. After rituximab was administered for the treatment of ITP, the platelet count recovered. During rituximab treatment, lymph nodes regrew. Since fludarabine is an effective chemotherapeutic agent in this case, and rituximab is also effective for ITP and lymphoma, we combined fludarabine and rituximab for the treatment for NHL. Although fludarabine was administered, the platelet count did not decrease when combined with rituximab.
2.Subcutaneous panniculitis-like T-cell lymphoma: complete remission with fludarabine
R. S. Go • H. Gazelka • J. D. Hogan • S. M. Wester. Ann Hematol (2003) 82:247–250
Because of the patient’s history of ischemic cardiomyopathy, an anthracycline-based regimen was avoided. He received a total of six cycles of fludarabine given at 25 mg/m2 daily for 5 days every 4 weeks. His ulcers started to heal within 2 weeks of the first cycle and were completely healed before the fourth cycle of fludarabine. A repeat CT scan performed after the fourth cycle of fludarabine revealed persistently mild splenomegaly and a single para-aortic lymph node, both of which remained unchanged. He then received an additional two cycles of fludarabine. Follow up CT scan at the time chemotherapy was completed revealed the same findings. It was felt that his mild splenomegaly and isolated paraaortic lymphadenopathy were most likely benign and unrelated to his lymphoma. Three months after the completion of chemotherapy, he developed a fever and a rash on his lower legs consistent with vasculitis. An extensive work-up including a repeat CT scan of the body and bone marrow biopsy did not show recurrence of lymphoma. He was treated with prednisone resulting in resolution of most of his symptoms. Two weeks later, he complained of severe upper abdominal pain and died suddenly of cardiorespiratory arrest. The cause was unknown, but suspected to be either pulmonary embolism or myocardial infarction. The family refused a postmortem examination.
3.Bendamustine, but not Xudarabine, exhibits a low stem cell toxicity in vitro
M. Schmidt-Hieber • A. Busse • B. ReuW • W. Knauf • E. Thiel • I. W. Blau. J Cancer Res Clin Oncol (2009) 135:227–234
Bendamustine structurally combines a purine-like benzamidazol nucleus and a bifunctional alkylating nitrogen mustard group. After intravenous application, bendamustine binds to proteins and is metabolized mainly in the liver. It is hydrolyzed to its mono- and dihydroxy derivates and is eliminated with a plasma half-life of about 30 min. The elimination pathway is renal and biliary (Preiss et al. 1985; Gandhi 2002). Fludarabine, a nucleoside analog, is a prodrug that is converted to free nucleosides and exhibits its cytotoxicity by inhibiting DNA synthesis and DNA repair and causing accumulation of DNA strand breaks. It is rapidly dephosphorylated to 2-Xuoro-vidarabine, which is excreted mainly in urine with a half-life of 9 h (Adkins et al. 1997; Gandhi and Plunkett 2002).
4.Fludarabine-Mediated Circumvention of Cytarabine Resistance Is Associated with Fludarabine Triphosphate Accumulation in Cytarabine-Resistant Leukemic Cells
Shuji Yamamoto,Takahiro Yamauchi,Yasukazu Kawai, Haruyuki Takemura. International Journal of HEMATOLOGY
One strategy that increases the intracellular ara-CTP concentration is pretreatment with the purine nucleoside analogue ﬂudarabine (9-β-D-arabinofuranosyl-2-ﬂuoroadenine 5’-monophosphate). Fludarabine nucleoside (F-ara-A) is taken up by leukemic cells and is phosphorylated into the active form, fludarabine 5’-triphosphate (F-ara-ATP), through the pathway common to ara-C. F-ara-ATP stimulates deoxycytidine kinase in 2 ways, thereby enhancing ara-CTP production. The ﬁrst is a direct effect on deoxycytidine kinase.The second effect is indirect and is mediated through the inhibition of ribonucleotide reductase, an enzyme responsible for the de novo synthesis of deoxyribonucleotides. The inhibition of ribonu- cleotide reductase produces a decline in the intracellular dCTP pool, thereby decreasing dCTP-mediated feedback inhibition of deoxycytidine kinase. In both cases, the intracellular F-ara-ATP concentration is critical to ara-CTP enhancement.On the basis of these in vitro ﬁndings, a com- bination-chemotherapy regimen consisting of ﬂudarabine, ara-C, and granulocyte colony-stimulating factor, designated as FLAG, has been developed for clinical use [20,21]. This regimen and similar regimens further combined with an anthracycline have been safely used to achieve a nearly 50% rate of complete remission in patients with chemoresistant acute myeloid leukemia.