An effective salvage treatment using ifosfamide, etoposide, cytarabine, dexamethasone, and rituximab (R-IVAD) for patients with relapsed or refractory aggressive B-cell lymphoma.

We evaluated the efficacy and toxicity of a new salvage regimen, consisting of rituximab (375 mg/m(2), day 1), ifosfamide (1500 mg/m(2) on days 3-7), etoposide (150 mg/m(2), days 3-5), cytarabine (100 mg/m(2), days 3-5) and dexamethasone (40 mg/body, days 3-5) (R-IVAD) for relapsed or refractory aggressive B-cell lymphoma. In this study, a total of 32 patients with a median age of 64 years (range 38-79) who received an average of 2.6 cycles of R-IVAD from 2001 to 2009 in our institution were retrospectively analyzed. R-IVAD was given every 3 weeks up to a total of three courses with support by granulocyte colony stimulating factor. The overall response rate was 72%, with 56% complete response. On a median follow-up of 16 months (range 2-99), estimated 2-year overall survival (OS) and event-free survival were 55% and 36%, respectively. Of these patients, 10 successfully proceeded to consolidating high-dose chemotherapy followed by autologous stem cell transplantation, accounting for 90% of the 2-year OS. No treatment-related mortality was observed during the investigation. We, therefore, conclude that R-IVAD regimen is a safe and efficacious alternative for patients with relapsed or refractory aggressive B-cell lymphoma.

A case of treatment-related myelodysplastic syndrome spontaneously resolved by drug discontinuance.

Although great advancements have been witnessed in treatment results for hematopoietic tumors in recent years, development of secondary malignant tumors induced by anti-cancer drugs still remains a serious issue. We experienced a case of secondary myelodysplastic syndrome (MDS), possibly induced by cyclophosphamide (CY), which was spontaneously resolved by discontinuance of CY. A 24-year-old woman was diagnosed with follicular lymphoma in January 1998: she had developed bulky intra-abdominal lymphadenopathy, with repeated relapse and remission by several chemotherapy treatments. Remission was induced by rituximab, administered at the time of relapse in 2001, followed by administration of 50 mg/day of CY since December 2001 for the prevention of relapse. Anemia and thrombocytopenia developed around January 2003. Bone marrow aspiration revealed abnormality in two lineages and a complicated chromosomal anomaly, and the patient was diagnosed with MDS. Discontinuance of CY and administration of an anabolic steroid improved anemia and thrombocytopenia within 2 years. Bone marrow aspiration in 2006 showed improvement in morphological abnormality and disappearance of chromosomal abnormality.

Effect of L-asparaginase combined with vincristine and prednisolone on acute myeloblastic leukemia (M0) associated with non-Hodgkin lymphoma.

A 66-year-old Japanese woman was referred to us because of severe anemia and fever and presented at our hospital. She was eventually diagnosed as having acute myeloblastic leukemia (AML; M0) with non-Hodgkin lymphoma (NHL). We investigated the therapeutic efficacy of L-asparaginase (L-Asp), vincristine and prednisolone for both her AML and NHL. Asparagine synthetase (AS) activity in her AML blast cells was undetectable. A lymph node biopsy specimen revealed NHL of the marginal zone B cell type. Complete remission (CR) of AML and NHL was achieved. CR of the AML lasted for 18 months without further consolidation therapy. We conclude that L-Asp can be an effective drug for the treatment of AML in which blasts are negative for AS.

The value of oral cytarabine ocfosfate and etoposide in the treatment of refractory and elderly AML patients.

Twenty-one acute myeloid leukemia (AML) patients were enrolled and received oral induction therapy with cytarabine ocfosfate (SPAC) and etoposide (EP). The median age was 69 years (range: 33-86). There were 11 patients with de novo AML and 10 AML cases that had evolved from myelodysplastic syndromes. Seventeen patients had abnormal karyotypes including eight complex abnormalities, various complications, and 7 of 21 had a poor performance status (PS) with Eastern Cooperative Oncology Group (ECOG) scores of 3-4. All patients completed induction therapy without severe adverse events. Seven achieved complete remission (CR), and two achieved partial remission (PR). Uni- and multivariate analyses demonstrated a positive and significant correlation between the results of therapy (CR +/- PR) and overall survival. The plasma concentrations of cytosine arabinoside (ara-C) in some cases were higher than those previously reported, indicating the accumulation of ara-C with increasing numbers of days of SPAC administration. We conclude that this therapy is well tolerated and useful for refractory and elderly AML patients.

Treatment of high-risk peripheral T-cell lymphomas other than anaplastic large-cell lymphoma with a dose-intensified CHOP regimen followed by high-dose chemotherapy. A single institution study.

We investigated the efficacy of a dose-intensified double-CHOP regimen followed by high-dose chemotherapy with or without peripheral blood stem cell transplantation (PBSCT) in 11 patients with four types of peripheral T-cell lymphoma (PTCL). Three of the 4 patients with unspecified PTCL (PTCLu) achieved complete response (CR); 1 patient relapsed and 1 died of secondary leukemia after consolidation therapy. All angioimmunoblastic T-cell lymphoma (AILT) and subcutaneous panniculitis-like T-cell lymphoma (SPTCL) patients achieved CR; 5 of 6 have remained disease free for more than 3 years. The patient with hepatosplenic lymphoma did not achieve CR even after PBSCT and underwent allogenic bone marrow transplantation (allo-BMT). Thus, our regimen appears to be effective for high-risk AILT and SPTCL. However, allo-BMT should be considered for high-risk of PTCLu and hepatosplenic T-cell lymphoma.

Analysis of changes in CD20, CD55, and CD59 expression on established rituximab-resistant B-lymphoma cell lines.

Rituximab has markedly improved treatment results for B-cell lymphoma, but there are resistance problems similar to those of other chemotherapy drugs. With regard to the acquisition of rituximab resistance, there have been several reports describing the relation between rituximab and complement regulatory factors or CD20, but many points remain unclear. To further investigate acquisition of resistance to rituximab-related complement-dependent cytotoxicity (CDC), we established rituximab-resistant B-lymphoma cell lines (RAMOS) in vitro and then analyzed expression of CD20, CD55, and CD59 on these resistant cells by flow cytometry. With repeated exposure to a low concentration of rituximab and complement, RAMOS cells gradually acquired rituximab resistance, and selection and increase of CD55(bright) and CD59(bright) cell populations due to rituximab-related CDC were observed. With repeated exposure to a high concentration of rituximab and complement, RAMOS cells promptly acquired rituximab resistance, and CD20 expression of RAMOS cells was decreased. Not only selection of CD20(dim) cells but also down-modulation of CD20 caused by rituximab-related CDC appeared to cause the decrease in CD20 expression. We believe our findings will prove to be useful for prevention of or release from rituximab resistance in cases of B-cell lymphoma.

[Pure red cell aplasia occurring during the course of chronic myelogenous leukemia].

The patient was a 47-year-old man who was diagnosed in 1989 as having chronic myelogenous leukemia (CML). He had been treated with interferon-alpha (IFN-alpha) and hydroxyurea. In August 1999, he was admitted to our hospital for examination of severe anemia and increased platelet count. On admission, his hemoglobin level was 6.3 g/dl, reticulocyte count was 0.7%, WBC count was 5,100/microliter, and platelet count was 57.3 x 10(4)/microliter. Bone marrow aspiration showed myeloid hyperplasia and near absence of erythroblasts. Bone marrow karyotype analysis showed a Ph chromosome with additional abnormalities. Pure red cell aplasia (PRCA) with accelerated-phase CML was considered. The IFN-alpha therapy was discontinued. Hydroxyurea at an increased dosage was effective in controlling the CML. In contrast, administration of cyclosporin A was not effective for the PRCA. The patient's condition was later complicated by acute hepatitis C virus infection. The IFN-alpha was restarted to control the CML and hepatitis. The patient remained erythroblastopenic and transfusion-dependent for more than 2 years. Association of CML and PRCA is rare. We discuss the mechanisms underlying PRCA occurring during the course of CML.

[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.