Jiří Vorlíček

Prognostic factors for survival after autologous transplantation: a single centre experience in 133 multiple myeloma patients

Summary:Autologous stem cell transplantation (ASCT) has an established role in the treatment of symptomatic multiple myeloma (MM). Our aim was to analyse the impact of selected prognostic parameters on the survival of patients with MM after ASCT. The new International Staging System (ISS) was also evaluated. A total of 133 MM patients were transplanted in our centre between 1995 and 2002. Following ASCT, 35% of patients were in complete remission (CR) and 60% were in partial remission (PR). The median progression-free (PFS) and overall (OS) survival from transplantation were 29.5 and 68.8 months, respectively. Transplant-related mortality (TRM) was 3%. On multivariate analysis, factors associated with significantly shorter OS were lack of CR after transplant (P=0.002, hazard ratio (HR): 3.1), stage 3 according to ISS (P=0.001, HR: 3.0) and age at transplant over 60 years (P=0.035, HR: 2.0). The status of disease before ASCT did not significantly affect PFS and OS after transplantation. We conclude that ASCT is a safe and effective procedure in MM patients, associated with low TRM. The survival after ASCT was dependent on response after ASCT, stage according to ISS and age.

Inactivation of p53 and deletion of ATM in B-CLL patients in relation to IgVH mutation status and previous treatment.

Inactivation of p53 and deletion of ATM in B-CLL patients in relation to IgVH mutation status and previous treatment

Must we really fear toxicity of conventional amphotericin B in oncological patients

Abstract Fungal infections are an important cause of morbidity and mortality in patients with malignancies. Therefore, the use of amphotericin B (AmB) is essential for these patients. Results from the literature to date show that renal toxicity is the most serious adverse effect of AmB. Renal impairment manifests as a decrease in glomerular filtration and damage to tubular function. Currently, there is no reliable method of preventing nephrotoxicity. We have observed that sodium supplementation alone may not prevent nephrotoxicity. We noted that a large decrease in serum potassium and magnesium was followed by a significant reduction in creatinine clearance and an increase in both serum urea and creatinine. Therefore, we surmised that potassium and magnesium supplements corresponding to the amounts lost by the kidneys, as well as sufficient hydration, are necessary to prevent renal function damage. We decided to test our hypothesis in 32 cancer patients. During AmB therapy, serum electrolyte concentrations and biochemical parameters of renal function and fluid balance were monitored frequently. The daily ion supplementation corresponded to the amount lost through the kidneys. The total duration of administration ranged from 4 to 39 days, with a mean of 13.7 days (median 11.0 days). The mean daily AmB dose was 0.89 mg/kg (median 0.88 mg/kg). The average diuresis was 3863 ml/day, and the median 4000 ml/day. The daily mean i.v.-administered sodium dose was 195.9 mmol, the daily mean dose of i.v. potassium was 103.7 mmol, and the daily mean dose of i.v. magnesium was 9.0 mmol. The frequency of infusion-related side-effects was only 10.0%. These reactions were treated with hydrocortisone. We observed a significant increase in potassium and magnesium lost through the kidneys, and a significant increase in fractional sodium and potassium excretion through the renal tubuli. We did not observe a significant increase in serum creatinine and ion imbalances. Interestingly, the average creatinine clearance did not decrease, but actually increased slightly, though to a statistically insignificant degree, from 1.425 ml/s at the beginning of treatment to 1.589 ml/s on the 20th day of AmB use. Sufficient hydration of patients and ion supplementation corresponding to the amount lost by the kidneys is an effective prophylaxis for prevention of AmB-induced decrease in renal function and for countering imbalances of serum electrolyte concentrations during use of AmB. The frequency of infusion-related side-effects is minimal relative to other reports.

Second autologous transplantation for multiple myeloma patients relapsing after the first autograft -- a pilot study for the evaluation of experimental maintenance therapies. Report of the prospective non-randomized pilot study of the Czech Myeloma Group.

Background: High-dose chemotherapy followed by autologous stem cell transplantation (AT) is accepted as first-line therapy for patients with multiple myeloma (MM), with very good tolerance and low mortality (2–3%). Study Design: We tested repeated transplantation with different experimental maintenance therapies in patients with MM relapsing/progressing after first AT. Results were compared using intra-individual analyses, therefore inter-individual differences are excluded (T2 model). Patients and Methods: Between January 1997 and January 2003, 32 patients with relapsing/progressing MM after first AT were included in the pilot study, median follow-up was 75.2 months. They received the following experimental therapies: IL-2-activated PBSC (10 pts), pamidronate (4 pts), thalidomide (15 pts), consolidation chemotherapy CED (3 pts). Results: Sensitivity to C-VAD reinduction chemotherapy (4 cycles) was 50%, response to the second AT compared to the first was better in 7, the same in 16 and worse in 9 patients. Toxicity of the first and second transplantation was similar and usually did not exceed grade II (SWOG). Transplant-related mortality was 3% (1/32). Event-free survival after second AT (EFS II) is known in 22 patients; 7 have achieved prolongation of EFS II versus EFS I. In the whole group median EFS I was 15.7 months, median EFS II was 12.9 months, median overall survival (OS) was 79.1 months; 20/32 patients were alive at the time of analysis. Conclusions: Repeated AT is a feasible and successful strategy in treatment of relapsing MM; response to second AT and toxicity were acceptable and similar to the first AT in our assessment.

Clinical outcomes and direct hospital costs of reduced-intensity allogeneic transplantation in chronic myeloid leukemia

A reduced-intensity conditioning allogeneic stem cell transplantation was given to 19 patients (aged 15–59 years) in the first chronic phase and one patient in the accelerated phase with chronic myeloid leukemia (CML) after a regimen consisting of fludarabine (Flu), busulfan (Bu) and ATG Fresenius. The median follow-up was 27 months. Until day +100, no transplant-related mortality was recorded. The incidence of acute and chronic graft-versus-host disease (GvHD) was 55 and 75%, respectively. Two patients (10%) died from GvHD. Fourteen (70%) patients achieved molecular remission. Additional post-transplant intervention (donor lymphocyte infusion, imatinib) was necessary, however, in 10 patients (50% of the patients; non-achievement of stable molecular remission or later relapses). The total direct cost of the transplantation treatment for all of the patients came to 1 572 880 euro. If the patients had been treated with imatinib and followed-up with the same time period as they were following a transplantation, the direct cost of the imatinib treatment would have been 2 005 117 euro. The transplantation treatment appears to be less expensive after approximately 2 years of follow-up. Flu+Bu+ATG is a low-toxicity regimen for patients with CML. However, a close follow-up is necessary and about 50% of the patients require further therapeutic intervention.

Trends in stage-specific population-based survival of cancer patients in the Czech Republic in the period 2000-2008

BACKGROUND The objective of this study was to assess trends in overall and in stage-specific 5-year relative survival rates of the Czech cancer patients between periods 2000-2004 and 2005-2008. METHODS All Czech cancer patients diagnosed between 1995 and 2008 were included in the analysis. Period analysis was employed to calculate 5-year relative survival for 21 cancers. RESULTS Significant improvements in crude 5-year relative survival for 14 of 21 assessed types of cancer, including the most frequent diagnoses, such as, colorectal, prostate, breast, lung, kidney, pancreatic, and bladder cancer and melanoma, were identified. Moreover, in case of colorectal, lung, and prostate cancer, improvement in stage-specific 5-year relative survival was confirmed as statistically significant for all clinical stages. No diagnosis showed significant decrease in the 5-year relative survival. However, the 5-year relative survival remained poor in patients with metastatic cancers at diagnosis, particularly in case of liver, pancreatic, lung, and oesophageal cancer. CONCLUSIONS The cancer-specific outcomes in the Czech Republic are improving. Nevertheless, despite the overall significant improvement in 5-year relative survival of most of the cancer diagnoses, the high proportion of patients primarily diagnosed with metastatic cancer still represents a substantial challenge for prevention and early detection.

Efficacy of polymerase chain reaction for detection of deep mycotic infections: confirmation by autopsy

Summary. A method based on polymerase chain reaction (PCR) amplification of fungal 18S rDNA sequences was tested for the detection of fungi in blood samples. In order to increase sensitivity and specificity, PCR products were hybridized to the radioactively labelled fragment of 18S rDNA gene. Blood from 28 patients with haematological malignancies was taken immediately after death and the results of PCR analysis were compared with results of autopsy examination. To the best of our knowledge, no study of such a design has been published previously. PCR analysis turned out to be very sensitive (92%) and specific (92%) as well as capable of detecting various kinds of fungal infections (localized as well as generalized).

Treatment of chronic myeloid leukemia with autologous transplantation using peripheral blood stem cells or bone marrow cultured in IL-2 followed by IL-2, GM-CSF, and IFN-alpha administration.

Interleukin-2 (IL-2) is able to generate nonspecific cytotoxic effectors from hematopoietic precursors. We evaluated the feasibility and efficacy of chronic myeloid leukemia (CML) treatment with autologous hematopoietic stem cell transplantation (HSCT) using grafts cultured in IL-2 followed by immunotherapy with IL-2, granulocyte-macrophage colony-stimulating factor (GM-CSF), and interferon (IFN)-α. Eight patients with CML were enrolled: five in an accelerated phase and three in a chronic phase. They received peripheral blood stem cells (PBSC) or bone marrow (BM) cultured in a medium containing IL-2 for 24 h. A median of 1.29 × 106 CD34+ cells/kg were infused after conditioning with busulfan (12–16 mg/kg) in PBSC recipients. BM was infused without prior myeloablative therapy. The engraftment occurred with a median of 15 d. Engraftment failure developed in one patient. The transplantation was followed by a 1-mo regimen of IL-2 (0.5 × 106 IU/m2 daily) and GM-CSF, and 6 mo of IFN-α. One complete and one transient minor cytogenetic remission were observed. At 24 mo after transplantation, two patients had died of progressive disease and one of infection. Five patients had stable disease in the chronic phase. Autologous transplantation using IL-2-activated graft is feasible and the subsequent IL-2, GM-CSF, and IFN-α administration has acceptable toxicity. However, no benefits in comparison with conventional autologous transplantation for CML were identified in our study.

Pulmonary Infiltrate Etiology in Leukemic Patients with Fever

Pulmonary involvement in patients with leukemia can be caused either by the progression of the underlying disease by opportunistic or other infection, by a reaction of the lung tissue to administered drugs, by other various pulmonary diseases, or by a combination of these causes. In the majority of leukemic patients these pulmonary infiltrates are associated with fever, nonproductive cough, and dyspnea. Clinical examination, laboratory investigations, X-ray, and physical examinations seldom reveal the exact nature of these pulmonary infiltrates. Noninvasive examinations such as study of the sputum, serology, and blood cultures are affected by a number of factors that make the overall yield quite disappointing. Fiberoptic bronchoscopy is used increasingly frequently to determine the etiology of pulmonary infiltrates in leukemic patients with fever. We chose bronchoalveolar lavage (BAL) to establish the etiology of primary infiltrates in leukemic patients because BAL is less invasive and is more frequently feasible than open lung or transbronchial biospsies. BAL was performed after premedication, under local anesthesia, through a fiberoptic bronchoscope in the most abnormal area of the bronchial tree as shown by chest X-ray. We used buffered saline warmed to 37° C (150–300 ml, in 20- or 50-ml aliquots). Bronchoelveolar fluid (BAF) was subjected to bacteriological and virological examinations and was screened for the presence of fungi; we also used immunofluorescence by monoclonal antibodies to confirm antigens of cytomegalovirus, herpes simplex virus, and Pneumocystis carinii, and we also used cytological examination after staining the samples according to May-Grunwald-Giemsa and Groccot (methenamine silver).