Therapy-related myelodysplastic syndrome with monosomy 5 after successful treatment of acute myeloid leukemia (M2)

We describe a patient who developed myelodysplastic syndrome over 2 years after achieving complete remission of acute myeloid leukemia (AML). The patient was treated in July 1998 with anthracycline, etoposide, and behenoyl cytarabine chemotherapy for AML (French-American-British classification, M2; World Health Organization classification, AML with maturation) and achieved complete remission. At presentation, no chromosomal abnormalities were detected. In December 2000, the patient's peripheral blood revealed pancytopenia, and his bone marrow was hypocellular with trilineage myelodysplasia and no blasts. Chromosomal analysis revealed complex karyotypic abnormalities, including monosomy 5. The patient was diagnosed with high-grade myelodysplastic syndrome (MDS)/refractory anemia with excess blasts (RAEB) subtype. The pancytopenia progressed rapidly, and he died 2 months after the diagnosis of MDS. Therapy-related MDS and AML (t-MDS/t-AML) developing after treatment for acute leukemia is unusual; the primary leukemia associated with most cases of t-MDS/t-AML is acute promyelocytic leukemia (APL). This unusual case suggests that AML excluding APL should be considered a primary hematologic malignancy for t-MDS/t-AML.     

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.     

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.     

Therapy-related acute myeloid leukemia (t-AML) with poor-risk cytogenetics in two patients with persistent molecular complete remission of acute promyelocytic leukemia

Therapy-related acute myeloid leukemia (t-AML) is a clinical syndrome occurring as a complication after cytotoxic and/or radiation therapy. The incidence of t-AML after acute promyelocytic leukemia (APL), all-transretinoic acid (ATRA), and anthracycline-based therapy is rather low. However, because of the high remission rates and long-term overall survival achieved with current APL treatments, late complications related to antileukemic therapy should be taken into account, giving priority to efficacy agents with the lowest potential of leukemogenesis, despite individual genetic susceptibilities that are not well known. Here, we report two cases of t-AML observed in two young women who achieved a rapid, complete molecular remission (CMR) of APL and who were still in CMR when t-AML was diagnosed. These t-AMLs shared some clinical and biological features such as poor-risk cytogenetics and a rapidly progressing, unfavorable outcome. Retrospective RT-PCR WT1 expression from the onset of APL to t-AML diagnosis did not prove to be a good marker for t-AML development.     

Enhancement of fludarabine sensitivity by all-trans-retinoic acid in chronic lymphocytic leukemia cells

Background

A subset of patients with fludarabine-resistant chronic lymphocytic leukemia has previously been shown to express elevated intracellular levels of the concentrative high-affinity fludarabine transporter hCNT3, without any detectable related activity. We have recently shown that all-trans-retinoic acid is capable of inducing hCNT3 trafficking to plasma membrane in the MEC1 cell line. We, therefore, evaluated the effect of all-trans-retinoic acid on hCNT3 in primary chronic lymphocytic leukemia cells as a suitable mechanism to improve fludarabine-based therapy of chronic lymphocytic leukemia.

Design and Methods

Cells from 23 chronic lymphocytic leukemia patients wild-type for P53 were analyzed for ex vivo sensitivity to fludarabine. hCNT3 activity in chronic lymphocytic leukemia cell samples was evaluated by measuring the uptake of [8-³H]-fludarabine. The amounts of transforming growth factor-β1 and hCNT3 messenger RNA were analyzed by real-time polymerase chain reaction. The effect of all-trans-retinoic acid on hCNT3 subcellular localization was analyzed by confocal microscopy and its effect on fludarabine-induced apoptosis was evaluated by flow cytometry analysis using annexin V staining.

Results

Chronic lymphocytic leukemia cases showing higher ex vivo basal sensitivity to fludarabine also had a greater basal hCNT3-associated fludarabine uptake capacity compared to the subset of patients showing ex vivo resistance to the drug. hCNT3 transporter activity in chronic lymphocytic leukemia cells from the latter patients was either negligible or absent. Treatment of the fludarabine-resistant subset of chronic lymphocytic leukemia cells with all-trans-retinoic acid induced increased fludarabine transport via hCNT3 which was associated with a significant increase in fludarabine sensitivity.

Conclusions

Improvement of ex vivo fludarabine sensitivity in chronic lymphocytic leukemia cells is associated with increased hCNT3 activity after all-trans-retinoic acid treatment.     

Low-dose cytosine-arabinoside in the treatment of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS)

Summary Ten AML- and two MDS-patients in whom conventional chemotherapy was contraindicated or ineffective were treated with low dose ARA-C, 10 mg/m² per 12^hs.c. for 2–4 weeks. Seven patients obtained a complete and two a partial remission. Our findings suggest that low dose ARA-C may act both by induction of differentiation and/or inhibition of proliferation.Supported by the Hamburger Krebsgesellschaft     

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.     

Coexistence of myelodysplastic syndrome and untreated chronic lymphocytic leukemia with development of acute myeloid leukemia immediately after treatment of chronic lymphocytic leukemia

A 72-year-old man originally seen for anemia and thrombocytopenia was determined to have chronic lymphocytic leukemia (CLL). Bone marrow examination at the time of CLL diagnosis revealed a small but significant population of atypical blasts. Cytogenetic analysis of the bone marrow aspirate disclosed chromosomal abnormalities (-7, +8) suggestive of a myelodysplastic syndrome. Shortly after treatment of the CLL, there was proliferation of the previously noted blast population, which cytochemical studies demonstrated to be of the myeloid series thus indicating acute myeloid leukemia superimposed on CLL. This report presents microscopic, cytogenetic, immunophenotypic, and cytochemical evidence to document the evolution of acute myeloid leukemia in the bone marrow of a patient with CLL after one course of chemotherapy.     

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.     

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     

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.     

Fludarabine plus cyclophosphamide for the treatment of advanced chronic lymphocytic leukemia

OBJECTIVES: Therapeutic results in advanced chronic lymphocytic leukemia (CLL) are still unsatisfactory in terms of complete remission achievement and duration, in spite of the extensive use of purine analogs. The objective of this study was to describe the clinical characteristics and treatment results from a series of 32 patients managed with a therapeutic program based on the combination of fludarabine and cyclophosphamide (CTX). METHODS: Thirty-two patients (median age 63 yr, range 42-75 yr) with newly diagnosed (47%) or refractory-relapsed (53%) CLL were programmed to receive six courses of a 3-d combination of fludarabine at 30 mg/m2/d plus CTX at 300 mg/m2/d. Refractory-relapsed patients had previously received different chemotherapy lines from 1 to 5. RESULTS: Fourteen of 32 (44%) patients achieved a complete remission, 16 (50%) obtained partial remission and two (6%) failed to respond. The CR rate was higher in untreated patients; in particular, CR was achieved in nine of 15 (60%) newly diagnosed cases as opposed to five of 17 (29%) among pretreated patients. Toxicity was caused by myelosuppression and/or infections in most cases. After a median follow-up of 24 months (range 8-48 months), 20 of 32 patients (62%) are alive, and 14 of 32 (44%) are free from progression. Median overall survival and median time to progression were 35 and 25 months, respectively. CONCLUSION: The combination of fludarabine with CTX is effective in advanced CLL with acceptable toxicity, either as first-line therapy or in refractory-relapsed patients. In particular, a considerable rate of complete remission can be achieved in untreated patients. Myelosuppression represents the major side-effect.     

Myelodysplasia occurring after fludarabine treatment for chronic lymphocytic leukaemia

The purine analogue, fludarabine, is of proven efficacy in the treatment of lymphoid malignancies. The drug appears to be well tolerated with minimal side-effects, and few toxicities have been observed. A case of myelodysplasia occurring after therapy with fludarabine is presented and its implications are discussed.     

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.