Nephrotoxicity of high-dose ifosfamide/carboplatin/etoposide in adults undergoing autologous stem cell transplantation.

The objective of this study was to evaluate nephrotoxicity in adult patients treated with high-dose ifosfamide, carboplatin, and etoposide followed by autologous stem cell transplantation. We conducted a retrospective analysis of clinical and laboratory data from 131 patients with various malignancies who received treatment with escalating doses of ifosfamide, carboplatin, and etoposide followed by autologous stem cell transplantation as part of a phase I/II therapeutic trial. Abnormalities in glomerular filtration were evaluated by measuring peak creatinine levels and tubular dysfunction by the lowest recorded serum levels of potassium, magnesium, and bicarbonate, at different time periods after administration of ifosfamide, carboplatin, and etoposide, and after autologous stem cell transplantation. For the entire group of 131 patients, peak creatinine levels were > 1.5 mg/dL but < 3.0 mg/dL in 37% and levels were > 3.0 mg/dL in 11% at some time during their hospital stay. At the time of discharge, creatinine levels were 1.6 mg/dL to 3.0 mg/dL in 25% of patients and were > 3 mg/dL in 5%. Immediately after high-dose therapy, peak creatinine levels were significantly higher in patients receiving higher doses of ifosfamide compared to those receiving lower doses (P < 0.00001) and those receiving intermediate doses (P < 0.005). There was a dramatic decrease in serum bicarbonate, potassium, and magnesium levels immediately after chemotherapy, and they remained significantly decreased throughout the patient's hospital stay, despite massive replacement efforts (P ranging between < 0.008 and < 0.001). This is the largest adult population study documenting the incidence and severity of ifosfamide/carboplatin/etoposide-associated acute nephrotoxicity. Renal dysfunction was dose related and reversible in the majority of patients.

Phase I-II study of high-dose busulfan and cyclophosphamide followed by autologous peripheral blood stem cell transplantation for hematological malignancies: toxicities and hematopoietic recovery.

In a phase I-II study, we evaluated toxicities, tolerability, pace of engraftment, and tumor responses to high-dose bulsulfan and cyclophosphamide followed by autologous peripheral blood stem cell transplantation in patients with hematological malignancies. We treated 51 patients with various hematological malignancies involving the bone marrow with busulfan (16 mg/kg) and cyclophosphamide (120 mg/kg) followed by reinfusion of autologous peripheral blood stem cells. Stem cells were previously collected during hematopoietic recovery after cyclophosphamide (100 mg/kg) and etoposide (600 mg/m2) followed by G-CSF (5 micrograms/kg/day). Neutrophil recovery (>0.5 x 10(9)/I) was rapid in the majority of patients (median 10 days after transplant, range 7-91 days), resulting in a low number of days with severe neutropenia (median 7 days, range 5-85 days) and with fever (median 5 days, range 1-13 days). Platelet recovery, however, was delayed in 60% of patients. There was one acute transplant-related death (2%). Four patients died of late, presumed infections, pulmonary complications (interstitial pneumonia). Tumor responses were documented in a significant proportion of these patients with high-risk hematological malignancies. We conclude that peripheral blood stem cell transplantation results in rapid recovery of neutrophils but variable recovery of platelets after high-dose busulfan and cyclophosphamide, when stem cells are harvested following priming with cyclophosphamide/etoposide and G-CSF. The regimen is well-tolerated with limited non-hematological toxicities and transplant-related mortality. While significant tumor responses were documented in this trial, the ultimate efficacy of the regimen needs to be further defined.

Case report of spontaneous remission of cytogenetic relapse of chronic myelogenous leukemia suggestive of progression to blast crisis after allogeneic bone marrow transplantation.

Detection of the chronic myelogenous leukemia (CML)-related marker, the bcr/abl m-RNA transcript, in blood or bone marrow of patients with CML in hematologic remission after allogeneic bone marrow transplantation (allo-BMT) may be associated with the presence of minimal residual disease but does not uniformly predict hematologic relapse. In contrast, when there is cytogenetic reappearance of the Philadelphia (Ph1) translocation [t(9;22)(q34;q11)] along with additional cytogenetic abnormalities, especially more than 2 years after BMT, progression to hematologic relapse and acceleration of CML usually occur. An exception to this rule may be our patient, who was a 29-year old white woman diagnosed with Ph1-positive CML by cytogenetics. She was initially treated with hydroxyurea. An allo-BMT was performed 4 months after the diagnosis, while the patient was still in the first chronic phase of her disease, her HLA-identical brother serving as bone marrow (BM) donor. The conditioning regimen for BMT consisted of cytosine arabinoside, cyclophosphamide, total body irradiation, splenic irradiation, and intrathecal methotrexate. Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporin A and methotrexate. Her hospital course was unremarkable and without evidence of acute GVHD. Six months after transplantation, the patient had mild chronic GVHD and was treated with azathioprine and prednisone for 6 months. A year later, she recurred with mild chronic GVHD. She was treated with azathioprine alone for 5 months. Subsequently, she received cyclosporin A and prednisone for 8 months, with resolution of her symptoms. Serial BM cytogenetic studies showed normal male donor karyotypes 12 and 24 months after BMT. At 36, 42, and 50 months after BMT, reappearance of the Ph1 was noted along with some cells with additional cytogenetic abnormalities, including t(6;14)(p21;q32). The breakpoint involvement of 14q32, the heavy chain Ig locus, in the new clone may be indicative of B-lymphoid lineage-based evolution. The abnormal clones disappeared 56 months from BMT and remained absent through 69 months after BMT. The patient has remained in hematologic remission during her entire post-BMT course. Clinically, she continues to do well without immunosuppressants at presently 69 months after BMT. The reappearance of the Ph1 chromosome could be associated with the immunosuppressive therapy given for chronic GVHD. This case supports the concept that immunologic mechanisms may be important in the eradication of CML after allo-BMT, and even cytogenetic evidence of blast crisis CML may spontaneously remit after allo-BMT.