Evidence for deletion of 9q as a two-step process in chronic myeloid leukemia.

Evidence for deletion of 9q as a two-step process in chronic myeloid leukemia. Chronic myeloid leukemia (CML) is characterized by the Philadelphia translocation t(9;22)(q34;q11) resulting in the BCR/ABL fusion gene. Submicroscopic deletion of the derivative chromosome 9 occurs in a subset of these patients and is associated with poor prognosis. In the current study, we present two unusual cases of CML selected from a series of 54 consecutive cases. A detailed study using classical cytogenetics and fluorescence in situ hybridization (FISH) analysis was done using dual color extra signal FISH and whole chromosome paint in order to elucidate the mechanism of 9q deletion. One case had two clones on interphase FISH, one with and one without chromosome 9q deletion. The other case had two clones on both cytogenetic and FISH analyses, one with and one without a marker chromosome carrying chromosome 9q sequences. In this latter case, the clone with deletion of the derivative chromosome 9 comprised 21.1% at diagnosis, increasing to 36.8% after 11 months, suggesting a growth advantage. We report here evidence that deletions on 9q in CML may occur through breakage and rearrangement of chromosomes resulting in derivative chromosomes and either a marker chromosome or fragment/episome, followed by loss of chromosome material from the cell.

A randomized trial of amifostine as a cytoprotectant for patients receiving myeloablative therapy for allogeneic hematopoietic stem cell transplantation.

We initiated a randomized study of amifostine (the organic thiophosphate formerly known as WR-2721) given to patients during myeloablative conditioning therapy for allogeneic bone marrow transplantation. Amifostine was given at a dose of 1000 mg/day of conditioning and was well tolerated if attention was given to serum calcium levels, blood pressure and antiemetics. Since August 1998, 60 patients (30 on each arm) have completed the study. There was no significant difference in the days to neutrophil or platelet engraftment in either arm of the study. Significantly, the duration of grade I-IV mucositis was decreased in the group that received amifostine (P=0.02). Also grade III or IV infections (P=0.008), duration of antibiotic therapy (P=0.03) and duration of fever (P=0.04) were significantly reduced with amifostine. However, there were no differences in the incidence of grade III or IV mucositis, liver toxicity or renal toxicity. There were also no differences in early mortality, relapse and long-term survival. We conclude that amifostine, while reducing the duration of mucositis and infections (possibly through some preservation of gut mucosal integrity), has a modest effect in allogeneic bone marrow transplants given the multiplicity of factors influencing organ toxicity and survival in this setting.

Therapeutic plasmapheresis for the treatment of the thrombotic thrombocytopenic purpura-haemolytic uraemic syndromes.

INTRODUCTION: The thrombotic thrombocytopenic purpura-haemolytic uraemic syndromes (TTP-HUS) are uncommon disorders that are fatal if untreated. Therapeutic plasma exchange has resulted in excellent remission and survival rates in this patient population. METHODS: We reviewed our experience of therapeutic plasmapheresis for TTP-HUS syndromes for 11 patients who presented in the last five years. Parameters captured included haemoglobin and platelet counts at presentation as well as the number of plasmapheresis sessions and adjunctive treatment given. RESULTS: We found a response rate of 82 percent to plasma exchange, of whom 55 percent attained complete remission. Responses were excellent in the five patients who presented with primary or idiopathic TTP (100 percent response) among whom 80 percent had sustained long term responses. Responses were poor and often unsustained (only one out of six survived) in patients who presented with thrombotic microangiopathies secondary to underlying disorders such as bone marrow transplantation and metastatic carcinoma. CONCLUSION: Plasmapheresis is mandatory and extremely effective for primary TTP. However, it is at most an adjunct for patients who developed it secondary to an underlying disorder until and if the primary disorder can be successfully treated.

Long term follow-up of Asian patients with chronic myeloid leukemia (CML) receiving allogeneic hematopoietic stem cell transplantation (HSCT) from HLA-identical sibling-evaluation of risks and benefits.

Allogeneic hematopoietic stem cell transplantation (HSCT) is the only known curative therapy for patients with chronic myeloid leukemia (CML), but is associated with significant morbidity and mortality. The recent introduction of imatinib mesylate (STI-571) and reduced intensity transplant regimens has made the choice of primary treatment for patients with CML increasingly difficult. We have evaluated the outcome of 53 patients who have received allogeneic HSCT from human leukocyte antigen (HLA)-identical sibling donors between October 1985 and March 2002, determined the variables affecting the outcome, and tried to define indications for this aggressive approach. Successful engraftment occurred in 49 (98%) of evaluable patients. Acute graft-versus-host disease (GVHD) of grade II to IV severity was observed in 63% of the evaluable patients whereas the incidence of chronic GVHD was 57.5%. The Kaplan-Meier estimate of survival at 10 years was 54% [95% confidence interval (CI): 38-70%] and 31% (95% CI: 6-56%) for patients with first chronic phase and more advanced diseases, respectively. Multivariate analysis showed that younger age, absence of grade III-IV GVHD, the use of busulphan and cyclophosphamide (BuCy) as preparative regimen, and transplantation performed after January 1992 were factors associated with improved survival. Patients who were 30 years of age or younger who had transplantation done within 1 year after diagnosis during their first chronic phase of disease had a particularly good prognosis, with a probability of surviving 10 years of 72% (95% CI: 52-92%). We conclude that allogeneic HSCT remains a feasible option for Asian patients with CML. The most favorable outcome is observed in younger patients with early phase of the disease.

MARS therapy in critically ill patients with advanced malignancy: a clinical and technical report.

BACKGROUND/METHODS: Molecular Adsorbent Recirculating System (MARS) was used in three consecutive critically ill patients at the Singapore General Hospital with advanced malignancy and acute liver failure (ALF). Case 1 was a male patient with hepatocellular carcinoma (HCC) for which initial right hepatectomy was followed by left hepatectomy 5 months later for recurrent HCC. The postoperative course following second surgery was complicated by severe methicillin-resistant Staphylococcus aureus (MRSA) sepsis, mild azotaemia and subacute cholestatic liver failure. MARS was used thrice in this patient. Case 2 was a female patient with advanced acute lymphoblastic leukaemia (ALL) with post bone marrow transplantation (BMT) acute haemolytic-uraemic syndrome (HUS) secondary to cyclosporin A (Cy A), cytomegalovirus (CMV) infection, severe nosocomial pneumonia, acute renal failure (ARF) treated with continuous haemofiltration and acute veno-occlusive disease resulting in Budd-Chiari syndrome. The latter precipitated ALF. MARS was instituted twice. Case 3 was a male patient with advanced, refractory Hodgkin's disease previously treated with multiple courses of chemotherapy. ALF developed secondary to acute viral hepatitis B flare. He was given a trial of MARS once in the ICU. All the three patients eventually died. RESULTS: Mean MARS intradialytic systemic pressures were as follows: systolic pressure range was 95 +/- 17 to 128 +/- 17 mmHg and diastolic pressure range was 51 +/- 5 to 67 +/- 7 mmHg. Pressure at albumin dialysate exit point from dialyser 1 (Ae) ranged from 253 +/- 11 to 339 +/- 15 mmHg and that at albumin dialysate entry point into dialyser 1 (Aa) ranged from 142 +/- 11 to 210 +/- 6 mmHg. Ultrafiltration (UF) was 633 +/- 622 mL over mean treatment duration of 6.3 +/- 0.9 h with a total heparin dose of 1583 +/- 817 IU. Coagulation status pre- and 6-h post-MARS was similar: aPTT (P=0.116) and platelet count (P=0.753). There were no bleeding complications or circuit thromboses. MARS had a significant de-uraemization effect (pre- and post-MARS serum creatinine and urea: P=0.046 and 0.028, respectively) but did not significantly attenuate blood lactate, ammonia or total bilirubin levels. Albumin dialysate (Ae - Aa) urea and creatinine concentrations appeared to be sharply attenuated after 6 h of MARS. In contrast, the removal of total bilirubin by albumin dialysate from the blood compartment appeared to plateau after 4 h of continuous MARS operation. CONCLUSIONS: MARS was well-tolerated in critically ill patients with advanced and complicated cancer. Low-dose heparin was safe and did not compromise MARS circuit integrity. Although MARS had a significant de-uraemization effect, this appeared to be limited by the duration of MARS operation. Our data suggested that such a limit was reached earlier for total bilirubin. More data are needed to confirm the present findings and further delineate the saturation limit of MARS for different toxins that accumulate in ALF. This would affect the optimal duration of MARS therapy.

Imatinib mesylate (STI-571) given concurrently with nonmyeloablative stem cell transplantation did not compromise engraftment and resulted in cytogenetic remission in a patient with chronic myeloid leukemia in blast crisis.

The main obstacles to successful hematopoietic stem cell transplantation for patients with chronic myeloid leukemia (CML) in blast crisis (BC) are increased post-transplant relapse and high treatment-related mortality. We report a patient with CML in BC who was treated initially with imatinib mesylate and was then concurrently treated with a nonmyeloablative stem cell transplant. Successful engraftment of donor cells followed by complete cytogenetic remission was achieved in the absence of severe therapy-related toxicities. This case demonstrates that imatinib mesylate given through nonmyeloablative transplant is a minimally toxic therapeutic approach, which does not compromise engraftment and may result in a favorable outcome in patients with CML in BC.

Randomized trial of fluconazole versus low-dose amphotericin B in prophylaxis against fungal infections in patients undergoing hematopoietic stem cell transplantation.

Over the past decade, invasive fungal infections have become an increasingly important problem in patients undergoing hematopoietic stem cell transplantation (HSCT). The optimal approach for prophylactic antifungal therapy has yet to be determined. To resolve this issue, we performed a prospective randomized study to compare the efficacy of fluconazole (FL) versus low-dose amphotericin B (AmB) in preventing fungal infections during the first 100 days after HSCT. Patients undergoing allogenic or autologous HSCT were randomized to receive fluconazole 200 mg/day PO or amphotericin B 0.2 mg/kg/day IV beginning 1 day prior to commencement of conditioning regimen and continuing until engraftment, drug-associated toxicity was suspected, or systemic fungal infection was suspected or proven. High-dose amphotericin B (0.5-1.0 mg/kg/day) was started for patients with suspected or proven fungal infections. From January 1993 to December 1998, a total of 186 patients were enrolled into the trial, with 100 receiving FL and 86 receiving AmB. Eighty (43%) patients were removed from prophylaxis for persistent fever despite broad-spectrum antibacterial therapy or suspected fungal infections (FL 46 vs. AmB 34, P > 0.05). The incidence of proven fungal infections (FL 12% vs. AmB 12.8%), suspected fungal infections (FL 4% vs. AmB 2.3%), superficial fungal infections (FL 1% vs. AmB 4.6%) did not show any significant difference. The survival at 100 days post transplant was similar between the 2 groups (FL 78% vs. AmB 70%, P = 0.254). Death attributable to fungal infections was similar in both groups (6% vs. 7%, P > 0.05). We conclude that fluconazole is as effective as low-dose amphotericin B in prophylaxis against fungal infections in patients undergoing hematopoietic cell transplantation.

High-dose therapy followed by autologous haematopoietic stem cell transplantation in multiple myeloma.

INTRODUCTION AND OBJECTIVES: The median survival of patients with multiple myeloma (MM) after conventional chemotherapy is 3 years or less. Previous studies have shown that high-dose therapy, supported by haematopoietic stem cell rescue, improves survival of patients with MM. We analysed the outcome of 29 myeloma patients who had autologous haematopoietic stem cell transplantation (AHSCT) in our institution over an 8-year period. MATERIALS AND METHODS: Between May 1993 and August 2001, 29 patients with MM underwent high-dose therapy followed by unpurged AHSCT. There were 16 male and 13 female patients. The median age of the patients was 52 years (range, 31 to 67 years). All patients had at least a partial remission after initial chemotherapy. The preparative regimen for the AHSCT was melphalan 200 mg/m2 in 25 patients, melphalan-total body irradiation in 1 patient, and busulphan-cyclophosphamide (BuCy) in 3 patients. Twenty-three patients received peripheral blood stem cells (PBSCs) autograft, 3 patients received bone marrow autograft and 3 patients received both. RESULTS: Treatment-related death occurred in only 2 patients (7%). The median time to neutrophil engraftment was 11 days (range, 8 to 22 days). With a median follow-up period of 18.5 months, the 5-year overall survival (OS) and event-free survival (EFS) rates were 71% and 21%, respectively. The OS was found to be superior to a group of historical controls who were treated with conventional chemotherapy without transplantation (71% vs 19%; P = 0.014). CONCLUSION: In conclusion, high-dose therapy followed by AHSCT is safe and beneficial for patients with MM.