[Treatment of acute leukemia with allogeneic stem cell transplantation]. / Lijecenje akutnih leukemija transplantacijom alogenicnih maticnih stanica.

Allogeneic hematopoietic stem cell transplantation is a standard therapeutic option in the treatment of patients with malignant hematologic diseases and some acquired or inherited nonmalignant hematologic disorders. It is the most efficacious method for eradication of acute leukemia, its efficacy being described by DFS (Disease Free Survival) and OS (Overall Survival), however, still associated with a high Transplant Related Mortality (TRM) rate. At Department of Hematology, University Department of Medicine, Zagreb University Hospital Center, bone marrow transplantation has been a standard procedure since 1983. Since that time, 281 patients with acute leukemia have undergone allotransplantation at our Department. Results are presented of 72 patients with acute myeloid leukemia transplanted at our Department during the 1993-2007 period.

[Twenty years of severe aplastic anemia treatment at Department of Hematology, University Department of Medicine, Zagreb University Hospital Center, Zagreb, Croatia]. / Dvadeset godina lijecenja teske aplasticne anemije u Zavodu za hematologiju Klinike za unutrasnje bolesti Klinickog bolnickog centra Zagreb.

Aplastic anemia is a bone marrow disease characterized by marrow aplasia and pancytopenia. Because hematopoietic stem cell transplantation (HSCT) cures severe aplastic anemia (SAA), it is the treatment of choice for younger patients. For many years, antithymocyte globulin (ATG) has been standard immunosuppressive therapy for those aplastic anemia patients that have no HLA matched related donor. ATG significantly improves aplastic anemia outcome, especially when combined with cyclosporine (CSP). The response rate varies from 40% to 70% and long-term survival is comparable with patients receiving marrow transplant. From 1983 until 2006, 46 SAA patients received HLA identical sibling marrow graft. In the same period, 50 patients received standard immunosuppressive therapy combined from horse or rabbit ATG, 6 methyl prednisolone and cyclosporine. Out of 46 transplant patients, 27 received a combination of cyclophosphamide and thoraco-abdominal irradiation. The overall probability of survival for SAA patients that underwent marrow grafting is 51%, and for patients receiving immunosuppressive treatment 20%. We analyzed a cohort of patients receiving treatment after 1990 and found the probability of survival to be 64% for bone marrow transplanted patients and 36% for patients receiving immunosuppression. Infection is the main cause of death in both groups. In conclusion, we documented improving results using ATG in patients with SAA.

Gemcitabine in the treatment of relapsed and refractory Hodgkin's disease.

BACKGROUND: Patients with refractory Hodgkin's disease or relapsing after high-dose therapy and autografting have a poor prognosis. Here, we present our experiences with gemcitabine in this setting. PATIENTS AND METHODS: We treated 14 patients with relapsed or refractory Hodgkin's disease with gemcitabine. The treatment was given on a compassionate use basis, off-label and not according to a study protocol. Patients were 17-46 years of age. 1 patient had stage IA disease, 2 patients had stage IIIB disease and 11 patients had stage IVB disease. 9 patients had received radiotherapy. 8 patients had been autografted and 1 patient auto- and allografted. Gemcitabine was administered at a starting dose of 1 g/m(2) on days 1 and 8 every 3 weeks in combination with steroids. RESULTS: The median follow-up period was 10 months. Hematological toxicity grade 3-4 occurred in 12 patients leading to dose reductions. 1 patient died of neutropenic sepsis. No other non-hematological toxicities were observed. The response rate was 64% with 6 patients achieving complete remission (CR) and 3 patients partial remission (PR). The median time to treatment failure was 9 months, and survival was 11 months. Responses were seen in previously transplanted patients and in patients refractory to previous treatment. The so far longest responder has been in CR for over 68 months. CONCLUSION: Gemcitabine is an effective treatment for Hodgkin's disease. Heavily pretreated patients often require dose reductions.

Repetitive DNA polymorphisms in following chimerism after allogeneic bone marrow transplantation.

Information about the chimeric status of patients is of great importance in comparison of different conditioning and prophylactic regimens as well as for the post-bone marrow transplantation (BMT) therapies. In some cases, mixed chimerism (MC) can also be predictive of relapse. Analysis of the short tandem repeats (STR) loci by polymerase chain reaction (PCR) is a choice method for this purpose. In this study, we monitored 15 patients after BMT. Twelve of them underwent classical-conditioning regimen while the remaining three patients were subjected to non-myeloablative conditioning (minitransplantation). Evaluation of chimerism was performed using five STR and one variable number of tandem repeats (VNTR) locus. Four additional loci were PCR-amplified in cases of minitransplantation. Samples were analyzed by electrophoresis in an ALFexpress sequencer. MC was detected in seven cases of which it was predictive of relapse for two patients, who suffered from acute lymphocytic leukemia (ALL). The PCR-STR method proved to be a fast and relatively simple method, while the tested STR loci showed a high level of informativeness.

[Risk factors for invasive fungal infections during intensive chemotherapy of acute leukemia--retrospective study]. / Cimbenici rizika invazivnih gljivicnih infekcija tijekom intenzivne terapije akutnih leukemija--retrospektivna studija.

AIM: The incidence, outcome and risk factors for developing invasive fungal infection were retrospectively analyzed in 150 patients with acute leukemia during intensive cytostatic therapy. PATIENTS AND METHODS: Patients with and without the diagnosis of fungal infection were compared according to age, sex, diagnosis, stage of disease, type of therapy, antimicrobial prophylaxis, duration of febrile episodes, duration of antimicrobial therapy, duration of antifungal therapy, chest x-ray findings, results of surveillance cultures for fungal species isolation, clinical diagnosis at discharge from hospital, and autopsy findings. Clinical findings in patients with confirmed fungal infection on autopsy were analyzed separately. RESULTS: The incidence of fungal infection according to clinical diagnosis was 38.5%. The incidence among patients who died during therapy at autopsy was 78.5%. The incidence of Candida and Aspergillus infections at autopsy was 40% and 60%, respectively. Specific incidence could not be determined during life. The mortality was 59% in the group of patients with fungal infection, and 43% in the group of patients without fungal infection. During the study, an increase in the rate of fungal infection as well as a trend to prolonged survival of these patients were observed. On multivariate analysis, independent risk factors associated with a greater incidence of fungal infection were duration of hospitalization (p=0.04), duration of granulocytopenia with granulocyte count less than 0.5x10(9)/L (p=0.05), number of febrile episodes (p=0.01), duration of febrile episode (p=0.001), intestinal decontamination (p=0.02), duration of antibiotic therapy (p=0.01), positive chest x-ray finding (p=0.001), and year of therapy (p=0.02). On univariate analysis, a greater incidence of fungal infections was also associated with younger age, acute lymphatic leukemia, newly diagnosed disease and second relapse of the disease. The occurrence of fungal infections showed no correlation with the type of therapy, number of chemotherapy cycles, type of fungal species isolated from particular locations and frequency of colonization at particular locations. However, the number of colonized locations and number of fungal species was two to three times greater in patients with than in those without fungal infection. CONCLUSIONS: Fungal infections are becoming an increasing problem during intensive therapy of acute leukemia and contribute to poor therapy outcome. The diagnosis of fungal infection during life is extremely difficult and frequently late. There is the need of a more precise diagnostic test that would provide earlier diagnosis. The knowledge of risk factors is helpful in the diagnosis and therapy of fungal infections. The suspicion of fungal infection in patients at risk justifies the introduction of antifungal therapy and contributes to better therapeutic outcome.

[Treatment of chronic myeloid leukemia with imatinib in the accelerated stage of the disease]. / Lijecenje kronicne mijeloicne leukemije u uznapredovaloj fazi bolesti imatinibom.

Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML), in advanced stage of disease, is resistant to standard chemotherapy. Imatinib was found to be effective in these patients. This paper shows our preliminary results. Imatinib mesylate was given to 15 patients during a 9-month period. Nine of them were in accelerated phase and 6 in blastic crisis of Ph+ CML. Patients were evaluated for hematologic and cytogenetic responses. Imatinib mesylate induced complete haematologic response in 12 patients (80% and cytogenetic response in 8 patients (53%). Six patients (40%) had a major cytogenetic response. After a 9-month follow up Ph+ CML progressed in 9 patients (60%) and 4 of them died. The most frequent adverse effects were edema, nausea, neutropenia and thrombocytopenia. Imatinib mesylate has a substantial, but short term activity in the accelerated phase and blastic crisis of the Ph+ CML.

Management of Gaucher disease in a post-communist transitional health care system: Croatian experience.

AIM: To evaluate the feasibility of financing the treatment of Gaucher disease with recombinant human imiglucerase in the Croatian health care system. METHODS: Treatment with enzyme replacement therapy of 5 patients with Gaucher disease was started on January 2001. In 4 patients the typical signs of Gaucher disease (organomegaly, bone changes, anemia, and thrombocytopenia) were documented at the time of diagnosis. One patient received bone marrow stem cell transplant as treatment for acute myeloid leukemia from a HLA-matching sibling with Gaucher disease. All patients underwent therapy with imiglucerase (Cerezyme) infusion every 14 days. The outcome and actual cost of the treatment were followed during 12 months. RESULTS: After 3 months of therapy, hemoglobin rose above low normal range in 2 patients. After 6 months, 3 patients had platelet count above 100x10(9)/L, and bone pain crises completely disappeared in patients with severe bone involvement. After 12 months, normal blood counts were restored in all patients. At the same time point, bone destruction remained unchanged in 3 patients and showed marked improvement in one. In agreement with the Ministry of Health, the Croatian Institute for Health Insurance restructured its funds and established a special "Fund for expensive drugs." This fund covers the treatment costs for patients with Gaucher disease (approximately 150,000 per patient per year) as well as the cost of treatment for patients with Fabry disease, AIDS, adenosine deaminase deficiency, multiple sclerosis, chronic myeloid leukemia, juvenile arthritis, and ovarian cancer. CONCLUSION: Collaboration of the institutions in a post-communist transition health care system can provide an effective model for financing expensive treatment for patients with rare diseases in a resource-poor health system.

Combination of ifosfamide, methotrexate, and etoposide (IMVP) as a salvage therapy for relapsed and refractory aggressive non-Hodgkin lymphoma: retrospective study.

AIM: There are contradictory reports on the outcomes of IMVP (ifosfamide, methotrexate, and etoposide) treatment in patients with aggressive non-Hodgkin s lymphomas. Our aim was to evaluate retrospectively the results of this treatment in our institution. METHODS: Twenty eight patients with refractory or relapsed aggressive non-Hodgkin s lymphomas received IMVP between April 1997 and June 2001. Median follow-up of the survivors was 24 months. There were 15 women and 13 men, aged 15-68 years. Twelve patients were refractory to primary treatment. The number of previous treatment lines varied between one and five. The overall response rate to IMVP treatment was 39%, with 6 patients achieving complete and 5 partial response/remission. Eleven patients received a subsequent hematopoietic stem cell transplant after IMVP therapy. RESULTS: Median duration of the survival for all patients was 6 months, and the response duration for responders 6 months. Nine patients had grade 3 hematologic toxicity or higher, 5 developed significant infectious complications, and one developed the tumor lysis syndrome. There was one treatment-related death due to infection. The patients with a low or low-intermediate international prognostic index at the start of IMVP had a significantly better survival and progression-free survival rates than those with high or high-intermediate score. Seven patients with hematopoietic stem cell transplant were alive in December 2001. CONCLUSION: IMVP is an active regimen with acceptable level of toxicity in patients with relapsed or refractory aggressive non-Hodgkin s lymphoma. However, outcomes of this treatment are unsatisfactory and better treatment is still needed.

Surgical resection in the treatment of primary gastrointestinal non-Hodgkin's lymphoma: retrospective study.

AIM: To evaluate the role of surgical resection in the treatment of patients with primary gastrointestinal non-Hodgkin s lymphoma in our institution. METHOD: The retrospective study included 79 patients with a histologically confirmed primary gastrointestinal lymphoma, who were diagnosed and treated for the disease in the 1978-1997 period. According to the treatment modality, the patients were divided into surgically treated and surgically non-treated group. Data were analyzed with Fisher s exact test, long-rank test, and Kaplan-Meier method. RESULTS: The stomach was the primary site of non-Hodgkin s lymphoma in 45 (57%) patients, small intestine in 19 (24%), and colon in 9 (11%) patients. Six patients (8%) had multifocal disease. There were 56 (71%) patients with stages IE and IIE, and 23 (29%) with stages III and IV. Aggressive histology was found in 51 cases (65%), and low grade mucosa-associated lymphoid tissue (MALT) lymphoma in 28 (35%). Helicobacter pylori infection was registered in 20 out of 45 patients with gastric lymphoma. Twenty-six (33%) patients underwent surgical resection followed by chemotherapy, 47 (59%) were treated with chemotherapy alone, and 6 (8%) received antibiotics plus chemotherapy. Fifteen patients needed urgent surgical intervention. The overall response rate was 77%. Complete remission was achieved in 54 (68%) patients and partial remission in 7 (9%). Eighteen patients (23%) experienced progressive disease. A 10-year overall survival (OS) was 63% and event-free survival (EFS) was 52% for all patients. Patients with gastric lymphoma had better OS and EFS than patients with primary lymphoma at other sites (65% vs 42%, and 62 vs 28%, respectively) (p=0.005). A 10-year EFS rates were 58% and 52% for surgically treated and non-treated group, respectively. There was no significant difference between patients with resected and non-resected tumors (p=0.855). Patients with early-stage disease had significantly better OS and PFS than patients with advanced-stage disease (p=0.048). CONCLUSION: Primary gastrointestinal lymphoma can be successfully treated with chemotherapy alone but surgery remains an important therapeutic option for emergency problems. The main prognostic factors were primary tumor site and extent of the disease.

Allogeneic stem cell transplantation in treatment of aggressive lymphomas: case series.

AIM: To assess the outcome of allogeneic stem cell transplantation in patients with aggressive lymphoma. METHODS: Between 1991 and 2002, 22 patients with aggressive lymphoma in advanced phase of the disease underwent allogeneic stem cell transplantation at the Division of Hematology, Zagreb University Hospital Center. Seventeen patients received stem cells from the bone marrow. Eighteen patients underwent total body irradiation and received cyclophosphamide for conditioning, whereas the rest of the patients received busulfan and cyclophosphamide (n=2) or chemotherapeutic protocol combining carmustine, melphalan, etoposide, and cytarabine (BEAM regimen) (n=2). All patients received cyclosporin and short methotrexate for the prophylaxis of graft-versus-host disease (GVHD). RESULTS: Three months after allotransplantation, 17 patients had complete remission, 3 patients had active disease, and the outcome in 2 patients was early death. Nine patients were alive and in complete remission for 4 to 124 months, whereas 13 patients died (8 because of disease progression and 3 because of GVHD and infection). The probability of overall survival at 4 years was 47%. CONCLUSION: Allogeneic transplantation is an effective therapy for advanced aggressive lymphoma. Because of high treatment-related toxicity and mortality, prospective trials are needed to asses the best time when to apply this treatment.