Eosinophilia during fludarabine treatment of chronic lymphocytic leukemia

 Although eosinophilia has been reported as a side effect of purine analogues, there is no report on fludarabine-induced eosinophilia in chronic lymphocytic leukemia (CLL). During chemotherapy with fludarabine and cyclophosphamide, we observed two cases of significant eosinophilia. A 67-year-old patient with CLL developed bone marrow and peripheral blood eosinophilia up to 7.9×10⁹/l, the highest eosinophil count ever reported during treatment with a purine analogue. The eosinophilia persisted for 33 days. Another patient developed bone marrow eosinophilia without eosinophilia in the peripheral blood. These are the first documented cases of fludarabine-induced eosinophilia in CLL, and this side effect may conceivably be more common than previously recognized. Received: January 12, 1999 / Accepted: April 28, 1999     

Listeriosis after fludarabine treatment for chronic lymphocytic leukemia

The authors report a case of Listeria monocytogenes septicemia in a patient with advanced CLL after a single course of fludarabine, without any other immunosuppressive therapy e.g. corticosteroids. The immunosuppressive action of fludarabine in patients who are already severely immunosuppressed must be considered from a diagnostic and therapeutic point of view. Listeriosis and other opportunistic infections, like pneumocystis carinii pneumonia, have been reported during and after treatment with purine analogues. Prophylaxis with cotrimoxazole must therefore be discussed in patients with CLL treated with fludarabine.     

Role of fludarabine as monotherapy in the treatment of chronic lymphocytic leukemia

Fludarabine is a synthetic adenine nucleoside analog that is indicated for first- and second-line treatment of chronic lymphocytic leukemia (CLL). The recommended intravenous (i.v.) dosage regimen is 25 mg/m2 daily for 5 consecutive days, with treatment cycles repeated every 28 days. In treatment-na?ve patients with Binet stage B and C CLL, i.v. fludarabine produces superior responses to established first-line chemotherapies. Fludarabine produces a higher overall remission rate (60-70%) and longer progression-free survival (median approximately 20-30 months) than standard therapy with chlorambucil+/-prednisone and CAP (cyclophosphamide/doxorubicin/prednisone), and a comparable overall remission rate to CHOP (cyclophosphamide/vincristine/prednisone/doxorubicin). Fludarabine demonstrates high efficacy in both intermediate-risk (Rai stage I or II) and high-risk (Rai stage III or IV) patients. Furthermore, fludarabine is equally effective in younger (< or =65 years) and older (>65 years) patients. Fludarabine has significant activity as monotherapy in previously treated CLL, producing objective response rates of up to 94% in typically small-scale, noncomparative studies, with the majority of studies yielding rates of 30-60%. In a phase III multicenter study, the overall remission rate was significantly higher with fludarabine than with CAP (48 versus 27%) among the subset of treatment-refractory patients (n=96). For those patients who are refractory to or have relapsed following conventional chemotherapy (chlorambucil, CAP and CHOP), fludarabine can be considered the treatment of choice for second-line therapy. Moreover, patients with relapsed CLL may benefit from retreatment with fludarabine if they have previously demonstrated sensitivity to the drug. Standard-dose i.v. fludarabine has an established safety profile and comparable tolerability to anthracycline-based regimens (CAP and CHOP) in terms of its myelosuppressive and immunosuppressive effects, and offers the advantage of a markedly lower incidence of gastrointestinal effects (nausea/vomiting) and alopecia.     

氟达拉滨治疗慢性淋巴细胞白血病的临床观察

目的:观察氟达拉滨(Fludarabine)治疗慢性淋巴细胞白血病的疗效和不良反应。方法:收集氟达拉滨治疗慢性淋巴细胞白血病15例患者的临床资料,其中10例为首次疗程即使用氟达拉滨单药,5例为COP或CHOP方案1～2疗程或服用苯丁酸氮芥(瘤可宁)半年无效改用氟达拉滨,部分疗程为氟达拉滨和环磷酰胺联合用药;评估CR率和PR率,同时观察不良反应。结果:9例(60%)完全缓解,2例部分缓解,4例无效(1例耐药),总有效率73.3%。不良反应粒细胞减少7例,血小板减少3例,其中1例示ITP,1例发生溶血。结论:氟达拉滨治疗慢性淋巴细胞白血病有较高的疗效;不良反应以骨髓抑制常见,感染、ITP、AIHA最为严重,如在化疗前检查Coombs’test,可能避免发生自身免疫性溶血。     

Chemotherapy combination treatment regimens with fludarabine in chronic lymphocytic leukemia

Fludarabine monotherapy is an established treatment for chronic lymphocytic leukemia (CLL), achieving superior remission rates compared with other treatment regimens containing alkylating agents or corticosteroids. However, CLL remains incurable and research continues into finding new treatments for this, the most common leukemia in the Western world. Recent research has focused on the use of fludarabine in combination with other chemotherapeutic agents. Studies published to date indicate that regimens containing fludarabine plus cyclophosphamide, with or without mitoxantrone, achieve overall response (OR) rates of 64-100% and complete response (CR) rates of up to 50%. Administration of cyclophosphamide at a lower dosage (< or =300 mg) appears to reduce the risk of myelosuppression without compromising efficacy. Combinations of fludarabine with prednisone or chlorambucil have been shown to be no more effective than fludarabine monotherapy (OR 27-79% with these combinations), while the combination of fludarabine plus cytarabine proved to be less effective than fludarabine monotherapy. Further studies are needed to evaluate the combinations of fludarabine plus doxorubicin and fludarabine plus epirubicin, as results to date have been inconclusive. More trials are also needed to examine a fludarabine, cytarabine, mitoxantrone and dexamethasone combination that has achieved a promising CR rate of 60% in the one trial reported thus far. Taken together, the results obtained so far with fludarabine plus cyclophosphamide suggest that this combination is more potent than fludarabine monotherapy and is able to increase the CR rate, the OR rate, event-free survival and progression-free survival in patients with CLL.     

Bendamustine monotherapy in advanced and refractory chronic lymphocytic leukemia

Bendamustine, an alkylating agent without cross-resistance to cyclophosphamide is active in a variety of lymphoproliferative and other malignancies. In an open phase-II study we treated 23 patients with a median age of 62 years at study entry (43-86 years) with advanced, refractory or relapsed (Rai stage III n = 9, Rai stage IV n = 14) chronic lymphocytic leukemia (CLL) with bendamustine. At study entry, only 13 patients were chemotherapy-naive. The treatment schedule with bendamustine was as follows: for patients up to 70 years 60 mg/m2 for 5 days, for patients over 70 years 50 mg/m2 for 5 days, repetition at day 29. Remission criteria were used according to Cheson et al. (1996). All patients were evaluable for toxicity and 20 for response. An objective remission was achieved in 15/20 patients (75%), including six patients with complete remission (CR). Three of the complete responders had no chemotherapy prior to bendamustine. No change (NC) occurred in 5/20 patients (25%). Median overall survival after bendamustine treatment is 13.6 months (1-46 months) and 16.6 months (1-46 months) in patients responding to bendamustine. In total, 74 courses of bendamustine were applied. Therapy-related anemia and thrombocytopenia were rare. However, WHO grade III/IV leukocytopenia occurred in 38/74 cycles (51%), resulting in treatment-related mortality in 3/23 patients (13%). These patients were severely immunocompromised due to pretreatment or the underlying disease. As a corollary of the study, a general prophylactic antibiotic treatment (trimethoprim/ sulfamerazine) was instituted. A general feature was the decline of the CD4/CD8 ratio: mean before therapy: 1.36; after two courses: 0.98; after four courses: 0.6, as documented in all patients who received at least two courses of bendamustine (n = 12). All evaluable patients showed a decline in the CD4/8 ratio. However, this decline was not clearly related to an increased risk of infectious episodes. We observed mainly cutaneous allergic reactions (three WHO grade I; one WHO grade II) leading to a cessation of bendamustine treatment in 4/23 patients (18%). Bendamustine is highly effective in advanced or refractory CLL. In multiple pretreated or otherwise severely immunocompromised patients bendamustine might lead to additional immunosuppression with subsequent infectious complications.     

Therapy-related acute myeloid leukemia after single-agent treatment with fludarabine for chronic lymphocytic leukemia

A 70-year-old man with B-cell chronic lymphocytic leukemia (CLL) received single-agent treatment with the purine analogue fludarabine, which led to complete remission. After 8 years, he presented with pancytopenia. Marrow examination showed acute myeloid leukemia (AML) with trilineage myelodysplasia (MDS). Cytogenetic analysis showed an unbalanced der(1;7)(p10;q10) that resulted effectively in deletion 7q; confirming the diagnosis of therapy-related AML (t-AML). No residual CLL was present. Together with previous reports of secondary cancers after fludarabine treatment and the association of monosomy 7/7q- with another purine analogue azathioprine, results suggest that t-AML might develop after fludarabine therapy.     

Progressive multifocal leukoencephalopathy following oral fludarabine treatment of chronic lymphocytic leukemia

Progressive multifocal leukoencephalopathy (PML) is a subacute demyelinating disorder of the central nervous system usually affecting immunocompromised individuals and is due to infection of the oligodendrocytes by the JC virus. A case of PML in a chronic lymphocytic leukemia (CLL) patient treated with fludarabine is reported, representing the second such instance in which the diagnosis of the neurological disorder was established by brain biopsy. A 61-year-old man with a 14-year history of B-cell type CLL, for which he had received chlorambucil therapy 10 years earlier, developed progressive paresis of both left extremities at 7 months of receiving low doses of oral fludarabine, when his CD4 count has decreased to 0.08 ×10⁹/l. Cranial magnetic resonance imaging revealed a subcortical focal lesion at the right precentral gyrus and a focal lesion at the right thalamus, and a stereotactic brain biopsy showed pathological findings consistent with PML, namely severe myelin breakdown, reactive astrocytosis, and abnormal, huge glial cells with large bizarre nuclei showing granular basophilic inclusions, whereas the presence of the JC virus was demonstrated by in situ hybridization. The present case, in addition to a few previously reported, calls attention to the possibility that severe neurological side effects can be associated with the immunosuppression provoked by the use of fludarabine in CLL patients. Received: 10 May 1999 / Accepted: 16 November 1999     

Long-term follow-up after fludarabine treatment in pretreated patients with chronic lymphocytic leukemia

BACKGROUND AND OBJECTIVES: A study update to assess long-term survival following fludarabine salvage treatment in previously treated patients with chronic lymphocytic lymphoma (CLL). DESIGN AND METHODS: From September 1992 to December 1995, 74 patients with advanced, relapsing B-cell CLL were enrolled in the study. Fludarabine was given for 5 consecutive days at the dose of 25 mg/m2/day in a 30 min infusion. Treatment was repeated every 28 days for a maximum of 6 courses.E RESULTS. Nineteen (26%) patients achieved a complete response (CR) and 20 (27%) patients had a partial response (PR), giving an overall response rate of 53%. The median overall survival was 68 months, and there was a strong negative correlation with the number of previous treatments. The median time to progression was 18 months for patients who achieved a CR and 12 months for those with a PR. INTERPRETATION AND CONCLUSIONS: The results obtained with fludarabine alone in this subset of CLL patients indicate the existence of a conspicuous disease-free survival period. This time window could be used to consolidate the initial response with either biological approaches or high-dose therapeutic strategies such as autologous bone marrow transplantation, with the aim of eventual eradication of the disease.     

Treatment of advanced chronic lymphocytic leukemia by fludarabine

Summary In a clinical phase-II study fludarabine phosphate was given to 20 patients with advanced chronic lymphocytic leukemia who had failed on prior conventional therapy. Fludarabine was administered at a dose of 25 mg/m²/d for 5 days. Treatment cycles were repeated every 4 weeks until maximal response, followed by two cycles for consolidation. Four of the 20 patients achieved complete remission and seven patients partial remission, resulting in an overall response rate of 55% (11/20). Fludarabine therapy was well tolerated, with mild myelosuppression and secondary infections comprising the predominant side effects. These data warrant further confirmation and a randomized comparison of fludarabine with established regimens, which is currently underway.Dedicated to Prof. Dr. G. Schellong on the occasion of his 65th birthday     

Successful treatment with fludarabine of chronic lymphocytic leukemia associated with nephrotic syndrome

We successfully treated a patient with chronic lymphocytic leukemia (CLL) associated with a nephrotic syndrome. An 82-year-old man had been diagnosed as having CLL and been under observation for a year without treatment. In January, 2001, he developed hypoprotenemia, proteinurea, and edema in the extremities and face. With the exacerbation of the symptoms, he was admitted to our hospital in March of the same year. Under the diagnosis of nephrotic syndrome with CLL, the patient underwent induction therapy for CLL with fludarabine (13 mg/m2/day for 4 days), which brought about a complete remission of CLL and the disappearance of the edema. To our knowledge, this was the first case in Japan where fludarabine was dramatically effective in treating both CLL and the nephrotic syndrome. This result indicated that fludarabine is beneficial for not only CLL but also complications like nephrotic syndrome.     

Fatal intravascular autoimmune hemolytic anemia after fludarabine treatment for chronic lymphocytic leukemia

We report the case of a patient with chronic lymphocytic leukemia (CLL) who developed fatal intravascular autoimmune hemolytic anemia (AIHA) after fludarabine treatment. He had previously received several treatments including two courses of fludarabine. The direct antiglobulin test (DAT) was negative at diagnosis but was found to be positive with anti-IgG after the first fludarabine treatment. When the patient was treated again with fludarabine nine months later, the DAT became positive with anti-IgG and anti-C3d antiglobulins after the second course of treatment. Abrupt, fatal intravascular hemolysis occurred after the third course. The occurrence of severe AIHA in CLL patients treated with fludarabine has been reported by several authors. Physicians should be aware of the risk of severe AIHA in CLL patients with a history of AIHA or positivation of the DAT during previous fludarabine administration, or in case of secondary fixation of complement to the red cell membrane occurring during fludarabine treatment.     

Fatal intravascular autoimmune hemolytic anemia after fludarabine treatment for chronic lymphocytic leukemia

We report the case of a patient with chronic lymphocytic leukemia (CLL) who developed fatal intravascular autoimmune hemolytic anemia (AIHA) after fludarabine treatment. He had previously received several treatments including two courses of fludarabine. The direct antiglobulin test (DAT) was negative at diagnosis but was found to be positive with anti-IgG after the first fludarabine treatment. When the patient was treated again with fludarabine nine months later, the DAT became positive with anti-IgG and anti-C3d antiglobulins after the second course of treatment. Abrupt, fatal intravascular hemolysis occurred after the third course. The occurrence of severe AIHA in CLL patients treated with fludarabine has been reported by several authors. Physicians should be aware of the risk of severe AIHA in CLL patients with a history of AIHA or positivation of the DAT during previous fludarabine administration, or in case of secondary fixation of complement to the red cell membrane occurring during fludarabine treatment.     

Whipple's disease as a complication of chronic lymphocytic leukemia treated with fludarabine

The case of 53-year-old man who suffered from chronic lymphocytic leukemia since 1993 was presented. In the 6th year of treatment fludarabine was administered. Few days after administration of drug the patient developed watery diarrhoea not responding to treatment. We excluded both infectious etiological factors and infiltration of intestine in course of chronic lymphocytic leukemia. Histopathological examination with monoclonal antibodies and periodic acid-Schiff stain (PAS) revealed Whipple's disease as the reason of enteropathy. During 6 months diarrhoea caused extreme dyselectrolitemia, renal insufficiency and finally death of the patient.     

Severe respiratory syncytial virus pneumonia complicating fludarabine and cyclophosphamide treatment of chronic lymphocytic leukemia

The potential for life-threatening pneumonia due to respiratory syncytial virus (RSV) infection is recognised among patients with acute leukaemia and recipients of allogeneic or autologous bone marrow transplantation. RSV pneumonia has a high mortality rate in these settings. Less intensively treated patients are not usually considered to be at risk for serious RSV pneumonia. We describe the case of a 62-yr-old patient with chronic lymphocytic leukaemia (CLL) treated with fludarabine and cyclophosphamide who developed severe RSV pneumonia and recovered following treatment including intravenous ribavirin.