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J Szer

Publications and source records attributed to J Szer.

At least 73 records · Page 4Linked to original sources
PubMed1997

A randomized, double-blind, placebo-controlled, phase III study of filgrastim in remission induction and consolidation therapy for adults with de novo acute myeloid leukemia. The International Acute Myeloid Leukemia Study Group.

The safety and efficacy of filgrastim as an adjunct to acute myeloid leukemia (AML) induction and consolidation therapy was assessed in this prospective double-blind, randomized, placebo-controlled, multicenter trial. A total of 521 consecutive de novo AML patients aged 16 or more years were randomized to receive filgrastim (5 microg/kg/d subcutaneously) or placebo after standard induction as well as consolidation chemotherapy. Blinded study drug was given from 24 hours after chemotherapy until the absolute neutrophil count was >/=1.0 x 10(9)/L for 3 consecutive days. The overall complete remission rate was 68%. After a median follow-up of 24 months (range 5 to 40) the median disease-free survival was 10 months (95% confidence interval [CI], 8.7 to 10.8) and the median overall survival was 13 months (95%CI, 12.2 to 14.6). These did not differ between treatment groups. Patients receiving filgrastim experienced neutrophil recovery 5 days earlier after induction 1 than those receiving placebo (P < .0001). This was accompanied by reductions in the duration of fever (7 v 8.5 days; P = .009), parenteral antibiotic use (15 v 18.5 days; P = .0001), and hospitalization (20 v 25 days; P = .0001). Similar reductions were seen after induction 2 and the consolidation courses. There was a significant reduction in the number of patients requiring systemic antifungal therapy in the filgrastim group during induction treatment (34% v 43%; P = .04). In conclusion, filgrastim is safe in that it had no negative impact on the prognosis of the AML patients. In addition, it effectively reduced the duration of neutropenia, leading to significant clinical benefits by reducing the duration of fever; requirement for parenteral anti-infectives, specifically amphotericin B; and the duration of hospitalization.

Adolescent↗
PubMed1997

Perturbation in the ability of bone marrow stroma from patients with acute myeloid leukemia but not chronic myeloid leukemia to support normal early hematopoietic progenitor cells.

The ability of bone marrow (BM) stroma derived from patients with acute myeloid leukemia (AML) or chronic myeloid leukemia (CML) to support normal hematopoiesis was investigated using a two-stage long-term bone marrow culture (LTBMC) procedure. Of particular interest was whether leukemia-derived stroma were capable of supporting the very immature, uncommitted hematopoietic progenitor cells (HPC) which are considered to have a higher dependence and association with the BM stroma than the more mature committed HPC. Confluent stromal layers were recharged with selected populations of normal HPC enriched for the CD34+CD38- cells (immature, uncommitted HPC) or the CD34+CD38+ cells (mature, committed HPC). The weekly output of clonable granulocyte-macrophage progenitor cells (CFU-GM) was used as an indicator of the hematopoietic-supporting ability of the cultures. Stromal layers derived from 5/7 patients newly diagnosed with AML, showed significantly depressed ability to support the CD34+CD38- cells compared to stroma derived from normal donors. The supporting function of the AML-derived stroma for the more mature CD34+CD38+ cells was similar to that of the normal stroma (3/3 cases). Stromal layers derived from patients with chronic-phase CML showed normal or enhanced supporting function for the CD34+CD38- cells (5/6 cases), and likewise for the CD34+CD38+ cells (3/3 cases). This study revealed a selective defect in the ability of BM stroma from patients with AML to support the maturation of normal early uncommitted HPC, represented by the CD34+CD38- cells, whilst the ability to support the committed CD34+CD38+ cells was not affected. This suggests that the BM microenvironment may be implicated in the disease mechanism of AML. It does not, however, appear to be as clearly implicated in chronic-phase CML.

Acute Disease↗
PubMed1997

Alloresponses to HLA-DP detected in the primary MLR: correlation with a single amino acid difference.

The one-way mixed lymphocyte reaction (MLR-1) response was measured in both directions in 50 HLA-A, B, DR and DQ identical pairs and the role of DP studied in MLR stimulation. DR, DQ and DP typing was performed at the allele level by the polymerase chain reaction-sequence specific oligotyping (PCR-SSO) technique. The group consisted of 19 potential bone marrow transplant recipients and 34 matched unrelated donors. When more than one matched donor was available for a patient, donor/donor MLR-1 was also studied. DP identity was observed in 3 out of 50 pairs (6%), however due to homozygosity no incompatibility was present in the stimulating cells in 21 out of 100 cases (21%). There was a significant difference in the range of relative responses (RR) between zero DPB1 mismatches and one (p = 0.002) and two (p = 0.02) DPB1 mismatches: 52.4% of cases in the zero DPB1 mismatch group had RR < 1.0% compared with 31.6% and 27.3% in the one and two DPB1 mismatches. Stimulation by DPB1*0201 and 0301 gave the highest RR (12.9 +/- 22.5 and 17.5 +/- 17.0, respectively) while stimulation with DPB1*0401 and 0402 resulted in low levels of T cell response (1.3 +/- 8.2 and 0.6 +/- 11.5, respectively). When the responses were restricted to DPB1*0401 homozygotes to standardise for responder type similar results were obtained (DPB1*0201 v DPB1*0402 p = 0.008). The protein products of the DPB1*0201 and 0402 alleles differ by a single amino acid at position 69 (DPB1*0402--Lysine, DPB1*0201--glutamic acid). A further analysis was performed therefore scoring responders and stimulators as glutamic acid positive (E+) or negative (E-). There was a highly significant increase in the response to E+ stimulators compared with E- stimulators (p = 0.004). There was also a significant difference in the distribution of relative responses between the E+ stimulator group and the subgroups of E- responders/E- stimulators (p = 0.012) and E+ responders/E- stimulators (p = 0.009). However the amino acid difference at position 69 does not explain all responses due to DP in the MLR-1 as evidenced by the strong responses observed in cases where DPB1*0301 (lysine pos.) was the only difference on the stimulator cells. The results indicate that not all DP incompatibilities elicit a measurable T cell MLR response, but where a response does occur residue 69 in the first domain of DP appears to be pivotal. These results may have implications with respect to GVHD in bone marrow transplantation.

Alleles↗
PubMed1997

Early cyclosporine taper in high-risk sibling allogeneic bone marrow transplants.

Graft-versus-tumour reactions as a form of adoptive immunotherapy may help prevent the recurrence of haematological malignancy following allogeneic BMT. We hypothesised that such reactions may be maximised by shortening the duration of post-transplant immunosuppression by a rapid taper of cyclosporine (CYA). CYA dose was tapered between days 30 and 60 in patients at high risk of relapse, provided there was no evidence of prior significant acute GVHD. Twenty-six of 58 high-risk patients eligible at the time of transplant were subsequently tapered. Seven (27%) developed grade III/IV acute GVHD after completion of the taper, which was fatal in one patient. Chronic GVHD was observed in most patients, although with minimal overall impact on performance status. The overall probability of survival at 2 years was 43%. This non-randomised experience indicates that a rapid taper of CYA is tolerable and may provide an alternative to immunotherapy with donor leukocyte infusion in the high-risk allograft setting.

Adolescent↗
PubMed1997

Mobilization of predominantly Philadelphia chromosome-negative blood progenitors using cyclophosphamide and rHUG-CSF in early chronic-phase chronic myeloid leukaemia: correlation with Sokal prognostic index and haematological control.

Mobilization of Philadelphia chromosome (Ph) negative blood progenitors was attempted in 23 newly diagnosed chronic myeloid leukaemia (CML) patients using a regimen of cyclophosphamide (CY) 5 g/m2 and rHUG-CSF 150 microg/m2 daily. This regimen was well tolerated with no major adverse events reported. More than 2 x 10(6)/kg CD34+ cells were collected in 21 patients (91%). Predominantly Ph-negative mobilization (0-25% Ph-positive) was seen in 30% of cases overall and was confined to patients with a Sokal prognostic score < 1 (7/11 with Sokal score <1; 0/12 with Sokal score > or = 1). Within the low Sokal index group, a low WBC count pre-mobilization and a low WBC nadir both correlated strongly with Ph-negative mobilization (P = 0.006 and 0.02 respectively). Five of 19 patients receiving at least 6 months of Roferon A therapy post mobilization achieved a major cytogenetic response; all five patients were Ph-negative mobilizers. Therefore CML patients can be divided into a good-prognosis group in whom predominantly Ph-negative progenitors can be mobilized using a regimen of moderate intensity if haematological control is achieved pre-mobilization, and a poor-prognosis group for whom predominantly Ph-positive cells are mobilized with this regimen regardless of haematological control.

Adult↗
PubMed1997

Factors influencing the outcome of donor marrow transplantation in adults from less than ideal donors: experience from two Australian centres.

BACKGROUND: This paper reports the results of 78 marrow transplants in two Australian hospitals between 1991 and 1996, using unrelated (n = 54) or mismatched related (n = 24) donors. Twenty-six patients received granulocyte-macrophage colony stimulating factor (GM-CSF) post-transplant as part of a phase II study. Fifty-four patients (74%) had advanced disease. AIMS: To identify factors associated with a superior outcome post-transplant, to evaluate the effect of GM-CSF on engraftment and other transplant parameters, and to compare the overall results with those of published series. METHODS: Review of patient records, a Medline search of the relevant literature and appropriate statistical analysis. RESULTS: The probability of overall survival and event-free survival (EFS) at three years was 35 +/- 6% and 22 +/- 6% respectively. Pre-transplant factors significantly associated with an inferior EFS were advanced disease, poorer performance status and age > 30 years. The EFS in patients with standard risk disease was 51 +/- 13% versus 10 +/- 5% in patients with advanced disease, p < 0.0001. Severe acute graft-versus-host disease was also associated with a poorer outcome. Neutrophil engraftment was faster in patients who received GM-CSF but there was no difference in any other transplant parameters. CONCLUSIONS: These results are consistent with reported series elsewhere and suggest that an extended family or unrelated donor transplant should generally be limited to patients with a good performance status and early phase but otherwise incurable haematological disease.

Acute Disease↗
PubMed1997

Multiple cycles of aggressive chemotherapy prior to autologous peripheral stem cell transplantation for lymphoma.

BACKGROUND: Based on in vitro evidence of synergy between certain chemotherapeutic agents and of improved efficacy of cytotoxics administered as continuous infusions we devised a novel chemotherapy regimen for use in patients with lymphoma. AIMS: To assess the efficacy and tolerability of this regimen alone and in combination with autologous stem cell transplantation (ASCT) in patients with relapsed or refractory lymphoma. METHODS: The regimen consisted of cytosine arabinoside and etoposide given as five day continuous infusions, bolus doses of methotrexate and cyclophosphamide and four days of oral dexamethasone (MADEC), together with prophylactic G-CSF. Fifty-one patients aged 17 to 65 years (median 43) were treated; 34 had intermediate or high grade non-Hodgkin's lymphoma and 17 had Hodgkin's disease. Patients with responsive disease received a second cycle. RESULTS: Eleven patients (22%) achieved a complete response and 19 patients (38%) achieved a partial response, eight of whom were gallium negative. Previous chemosensitivity was highly predictive for response; minimal response was seen in patients with primary refractory disease. The probability of survival and event-free survival at 40 months for the entire group is 46% (+/- 8% SEM) and 26 +/- 8% respectively. Thirty-one patients proceeded to ASCT; the probability of survival of the transplanted group is 65 +/- 11% at 40 months. The regimen caused significant myelosuppression. The majority of cycles were complicated by febrile neutropenia and the requirement for platelet and red cell transfusions. Non-haematological toxicity was predominantly mucositis and was generally mild. CONCLUSIONS: MADEC is a highly active regimen in patients with relapsed lymphoma. Patients responding to MADEC who proceed to ASCT have a good chance of achieving a durable remission.

Adolescent↗
PubMed1997

Variability in determination of body weight used for dosing busulphan and cyclophosphamide in adult patients: results of an international survey.

Fifty-two BMT institutions were sent a questionnaire asking for details of dosing for busulphan, cyclophosphamide (bu-cy), cyclosporin and methotrexate (CSA-MTX). The following data were requested: (a) the method used to determine the body weight for dosage calculations (b) the actual dose per weight and (c) the schedule of administration. Thirty-six (69%) institutions responded and 33 were evaluable. There was substantial variation in the method used to determine weight for bu-cy. No single method was used in more than 30% of units, although most units made some allowance for discrepancies between actual and ideal body weight. There was more uniformity in the method of weight determination for CSA-MTX, with the majority of units using actual body weight. Conversely, there was much more variation in the dose per weight formulae and schedules used for CSA-MTX than for bu-cy. These substantial differences highlight the importance of specifying these criteria when the toxicity and efficacy of chemotherapy regimens is reported and the need for further studies to determine the optimal weight formulae for dosage calculations.

Adult↗
PubMed1997

High dose cytosine arabinoside is a major risk factor for the development of hepatosplenic candidiasis in patients with leukemia.

A retrospective study of hepatosplenic candidiasis in patients with acute leukemia from a single centre was performed. The significance of age, sex, type of leukemia, dose of cytosine arabinoside (Ara-C), duration of neutropenia, steroid use and period of therapeutic antibiotics in the development of hepatosplenic candidiasis was analyzed, using logistic regression analysis. Nine of 51 patients had hepatosplenic candidiasis. Ara-C use was highly associated with the development of hepatosplenic candidiasis (p = 0.001); with a high association with a higher dose (p < 0.0001). On the basis of these results consideration should be given to further trial of antifungal prophylaxis for patients receiving high dose Ara-C.

Adult↗
PubMed1996

Relationship between minimal residual disease and outcome in adult acute lymphoblastic leukemia.

In children with acute lymphoblastic leukemia (ALL), the level of minimal residual disease (MRD) at the end of induction strongly predicts outcome, presumably because it measures both drug sensitivity and the number of leukemic cells requiring elimination. Children with high levels (> 10(-3) leukemic cells per marrow cell) nearly always relapse, whereas those with low levels (<2 x 10(-5)) seldom do. However, the importance of MRD in adult ALL is unclear. We studied 27 patients aged 14 to 74 who were treated with a standard protocol and who attained morphological remission. MRD in the marrow at first remission was quantified by using the polymerase chain reaction (PCR), with the rearranged immunoglobulin heavy chain gene as a molecular marker. Levels of MRD varied from 3 x 10(-1) to <7 x 10(-7). The probability of long-term relapse-free survival was significantly related to the level of MRD and only one of nine patients with MRD >10(-3) did not relapse. For patients who did relapse, there was an inverse relationship between MRD level and the length of remission. Overall, MRD in adults in whom a translocation had not been identified was significantly higher than in comparably-treated children, suggesting that ALL in adults is more drug-resistant than in children.

Adolescent↗
PubMed1996

A randomized study of high-dose cytarabine in induction in acute myeloid leukemia.

High-dose cytarabine (ara-c) may overcome cytarabine resistance in leukemic blasts. It has been used as a successful salvage and in postremission therapy but not as initial induction treatment. Patients aged 15 to 60 years, presenting with newly diagnosed acute myeloid leukemia (AML) were randomized to receive either high-dose cytarabine, 3 g/m2 12 hourly on days 1, 3, 5, and 7 for 8 doses, daunorubicin 50 mg/m2 days 1 to 3, etoposide 75 mg/m2 days 1 to 7, (HIDAC-3-7) or standard dose cytarabine 100 mg/m2 continuous intravenous infusion for 7 days with daunorubicin and etoposide at the same dose and schedule as above (7-3-7). Patients could receive a second or third induction course if complete remission (CR) was not achieved. All patients received the same postinduction consolidation therapy (5-2-5) for 2 courses. Eligible patients had no prior chemotherapy or myelodysplastic disease. Patients have been followed for a median of 4.5 years. Of 301 patients treated, complete response (CR) was achieved in 71% with HIDAC-3-7 and 74% with 7-3-7. For patients in CR, the estimated median remission duration was 45 months with HIDAC-3-7 and 12 months with 7-3-7 (P = .0005 univariate analysis, P = .0004 multivariate analysis). The estimated percentage of patients relapse free 5 years after achieving a CR was 49% on HIDAC-3-7 and 24% on 7-3-7. Patients in CR tended to survive longer with HIDAC-3-7 but there were no overall survival differences between the two arms. HIDAC-3-7 was associated with significantly more toxicity in induction with more leukopenia, thrombocytopenia, nausea, and vomiting and eye toxicity (all P < .001) but a similar incidence of severe central nervous system and cerebellar toxicity compared to 7-3-7. The consolidation treatment was the same in both arms but caused significantly more leukopenia and thrombocytopenia in patients previously treated with HIDAC-3-7 induction (P < .0001). We conclude that a dose-effect exists for cytarabine in AML and that HIDAC-3-7 prolongs remission duration and disease-free survival and is tolerable when used as initial induction therapy in patients with de novo AML.

Acute Disease↗
PubMed1996

G-CSF stimulated donor granulocyte collections for prophylaxis and therapy of neutropenic sepsis.

BACKGROUND: The administration of granulocyte colony-stimulating factor (G-CSF) increases the granulocyte count in normal donors and enables the collection of large numbers of mature myeloid cells by leukapheresis. This has potential value in the treatment of sepsis unresponsive to antibiotics in patients with severe neutropenia. AIM: To evaluate the tolerability of granulocyte collections in normal donors receiving G-CSF, the optimal method of collection and the clinical factors influencing the efficacy of granulocyte infusions. METHODS: Analysis of the outcome of 55 granulocyte collections from 26 donors for progressive bacterial or fungal sepsis in neutropenic patients (n = 8) or as prophylaxis in patients with recent fungal infections undergoing allogeneic bone marrow transplantation (BMT) (n = 3). RESULTS: G-CSF was well tolerated in most donors. Fatigue occurred commonly after the second collection. The median WCC per 200-220 mL bag was 351 x 10(9)/L. Collections were optimised with the use of a sedimenting agent (dextran) and a deepened interface setting on the cell separator. There was only a weak correlation between the number of granulocytes infused and the increment in the patient, but levels were usually maintained > or = 0.5 x 10(9)/L for the next 24 hours. The infusions were successful in three septic patients without multi-organ dysfunction and prophylactically, in two patients with localised fungal infections undergoing MBT. The infusions were not beneficial in patients with septicaemia and established organ dysfunction or with extensive pulmonary aspergillosis. CONCLUSIONS: G-CSF mobilised granulocyte collections are feasible and the preliminary evidence suggests that the infusion of these cells may be useful early in the prophylaxis or treatment of severe neutropenic sepsis.

Adult↗
PubMed1996

Multi-organ dysfunction associated with high-dose carboplatin therapy prior to autologous transplantation.

The specific contribution of high-dose carboplatin to regimen-related toxicity after autologous transplantation has been difficult to determine, particularly in patients receiving cyclophosphamide or ifosfamide. We report five cases of severe multi-system failure in patients receiving high-dose carboplatin in addition to other cytotoxics prior to autologous transplantation. Two of these patients did not receive ifosfamide or cyclophosphamide as part of their chemotherapy. The clinical picture consisted of early onset acute renal failure, arrhythmias and/or myocardial hypokinesia, mental obtundation and other neurological deficits and, in two patients, an acute myopathy. In the two patients in whom serum platinum was measured, levels were very high at the time of marrow infusion. All patients had received prior cisplatin therapy but showed either normal or only modestly impaired creatinine clearance before the transplant. These observations are consistent with a specific clinical syndrome associated with carboplatin toxicity and suggest that creatinine clearance may be inadequate as an indicator of potential renal failure when high-dose carboplatin is used.

Adult↗