Impact of stem cell source on allogeneic stem cell transplantation outcome in hematological malignancies

Background/Aim. Peripheral blood (PB) is used more frequently as a source of stem cells (SCs) for allogeneic transplantation. However, the influence of cell source on the clinical outcome of SC transplantation is not yet well established. The aim of this study was to compare the results of PBSC transplantation (PBSCT) with bone marrow transplantation (BMT) on the basis of engraftment, frequency and severity of immediate (mucositis, acute Graft versus Host Disease - aGvHD) and delayed (chronic GvHD - cGvHD) complications, as well as transplant-related mortality (TRM), transfusion needs, relapses and overall survival (OS). Methods. We analyzed 158 patients, women/men ratio 64/94 median age 29 (range 9-57), who underwent allogeneic SC transplantation between 1989 and 2009. All included patients had diseases as follows: acute myeloid leukemia (AML) - 39, acute lymphoblastic leukemia (ALL) - 47, chronic myeloid leukemia (CML) - 32, myelodysplastic syndrome (MDS) - 10, Hodgkin’s lymphoma (HL) - 2, multiple myeloma (MM) - 3, granulocytic sarcoma (GrSa) - 3, severe aplastic anemia (sAA) - 22. The patients underwent transplantations were divided into two groups: BMT group (74 patients) and PBSCT group (84 patients). Each recipient had HLA identical sibling donor. SCs from bone marrow were collected by multiple aspirations of iliac bone and from PB by one “Large Volume Leukapheresis” (after recombinant human granulocyte colony stimulating factor, rHuG-CSF) application (5-12 μg/kgbm, 5 days). Conditioning regimens were applied according to primary disease, GvHD prophylaxis consisted of combination of a cyclosporine A and methotrexate. Results. Engraftment, according to the count of polymorphonuclear and platelets, were significantly (p < 0.001) faster in the PBSCT vs BMT group. The needs for transfusion support were significantly (p < 0.01) higher in the BMT group. Those patients had more frequently oropharingeal mucositis grade 3/4 (33.3% vs 10.0%, p < 0.05). There were no significant differences in the incidence of aGvHD and cGvHD between the two groups. The patients who underwent PBSCT had more frequently extensive cGvHD in comparison with the BMT group (29.1% vs 11.29%, p < 0.05). SC source (SCS) had no significant influence on the TRM (21.62% vs 23.8%, p = 0.64) and the incidence of relapses (21.6% vs 29.7%, p = 0.32). Finally, the patients treated by BMT had a significantly better OS (logrank 2.33, p < 0.05). Conclusion. SCs harvesting from PB resulted in improved cell yield, faster engraftment, as well as in a decrease of immediate transplantation related complications with a reduced treatment cost. Allogeneic PBSCT were associated with more frequent extensive cGvHD, while the influence of SCS in TRM and relapses was not observed. Finally, the longterm OS was better in the patients treated by BMT. To verify impact of SC source on transplantation (PBSCT vs BMT) overall efficacy, more larger randomized clinical studies are needed

Hypermethylation of p15 Gene in Diffuse - Large B-Cell Lymphoma: Association with Less Aggressiveness of the Disease

In this study, methylation-specific polymerase chain reaction was used to investigate the potential prognostic significance of the methylation status of p15, p16, MGMT, and DAPK genes in 51 specimens of diffuse large B-cell lymphoma (DLBCL). Hypermethylation of p15 gene was significantly more prevalent in patients without relapse (p = 0.001) and there was a trend toward more frequent presence of p15 methylation in patients without death outcome within 5-year follow-up period (p = 0.086) Also, there was a trend toward accumulation of p15 methylation with favorable clinicopathological parameters including: age 60 years (p = 0.091), normal levels of lactate dehydrogenase (p = 0.090), Eastern Cooperative Oncology Group performance status LT 2 (p = 0.095), and low/intermediate low International Prognostic Index (p = 0.076). In the female group and group of the patients without bulky tumor mass, treated with chemotherapeutic regimens including rituximab, methylation of p15 was significantly related to longer overall survival (p = 0.036 and 0.027, respectively). Our results suggest that promoter methylation of p15 gene could have prognostic value in DLBCL patients treated with rituximab when used in combination with gender and tumor size

Outcomes of Clostridioides difficile infection in adult cancer and non-cancer patients hospitalised in a tertiary hospital: a prospective cohort study

Background Clostridioides difficile infection (CDI) is one of the most common healthcare-associated (HA) infections. Cancer patients, particularly haemato-oncological patients, have an increased risk for CDI due to more risk factors compared with non-cancer patients. The aim of this study was to investigate differences in outcomes associated with HA CDI in patients with solid and haematological malignancies compared with patients with no underlying malignant disease in a tertiary healthcare centre in Serbia. Methods A prospective cohort study was conducted including adult patients diagnosed with an initial episode of HA CDI. Their demographic and clinical characteristics associated with risk factors for CDI were documented. Outcomes such as all-cause 30-day mortality, cure of infection, diarrhoea relaps and recurrence of disease were followed. Patients were assigned to cancer and non-cancer groups. Within the cancer group, patients were divided into the solid tumour subgroup and haematological malignancy subgroup. Results During a 7-year period, HA CDI was observed in 28 (5.1%) patients with haematological malignancy, 101 (18.3%) patients with solid tumours and 424 (76.7%) non-cancer patients. Older age (OR 1.04, 95% CI 1.02 to 1.07, p<0.001), admission to the intensive care unit (ICU) (OR 2.61, 95% CI 1.37 to 4.95, p=0.003), mechanical ventilation (OR 5.19, 95% CI 2.78 to 9.71, p<0.001) and use of antibiotics prior to CDI (OR 1.04, 95% CI 1.02 to 1.06, p=0.02) were associated with increased mortality. Compared with patients with solid tumours, patients with haematological malignancy were younger (65 vs 57 years, p=0.015), did not require ICU admission (25.0% vs 0%) or mechanical ventilation (8.9% vs 0%) and were treated longer with antibiotics prior to CDI (14 vs 24 days, p=0.002). Conclusions Patients with haematological malignancy were exposed to different risk factors for CDI associated with mortality compared with patients with solid tumours and non-cancer patients. Older age, ICU stay and mechanical ventilation, but not presence or type of cancer, predicted the all-cause 30-day mortality

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Acquired factor V inhibitors in a polytraumatized patient

Background. Factor V (FV) inhibitors are a rare disorder reported for the first time about fifty years ago, mostly with the unknown cause. The appearance of FV inhibitors is usually preceded by surgery, infections, administration of antibiotics or transfusions. Clinical manifestations of the presence of FV inhibitors vary from mild to severe and in some instances fatal hemorrhage. Case report. A healthy 51-year-old man with severe multiple injuries (traffic accident), and hemorrhage, which occurred during the orthopedic treatment, was admitted with hemoptysis, epistaxis and hematoma of the right upper leg, and with prolonged prothrombin time (PT), and activated partial thromboplastin time (aPTT). Treatment with vitamin K, fresh-frozen plasma and cryoprecipitate stopped the hemorrhage, but the results of coagulation tests were not normalized. The correction of aPTT and PT with normal plasma showed the decreased activity of FV (1%) due to the presence of inhibitors (titer 17.5 IU). The abnormal results of coagulation tests remained for three weeks, but without clinically manifested hemorrhagic syndrome. At the fourth week after the appearance of FV inhibitors PT, aPTT and the activity of FV became normal and antibodies disappeared spontaneously. Conclusion. Our patient with polytrauma developed a mild hemorrhagic syndrome due to the presence of FV inhibitors five weeks after the accident. Hemorrhage was treated with substitution therapy. The cause of the development of FV inhibitors was unclear (“fibrin glue” was not used during the orthopedic treatment). Factor V inhibitors disappeared spontaneously within four weeks. The fast spontaneous disappearance of FV inhibitors in our patient, confirmed the observations of some authors that they disappeared faster in those patients who were surgically treated prior to their appearance

Autologous stem cell transplantation in the treatment of Hodgkin's disease

Background/Aim. High-dose chemotherapy with autologous stem cell transplantacion (ASCT) has shown to produce long-term disease-free survival in patients with chemotherapysensitive Hodgkin disease. The aim of the study was to evaluate efficacy of ASCT in the treatment of Hodgkin's disease. Methods. Between May 1997 and September 2008, 34 patients with Hodgkin's disease in median age of 25 (range 16-60) years, underwent ASCT. Autologous SCT were performed as consolidation therapy in one poor-risk patients with complete response (CR) and in 10 patients in partial remission (PR) after induction chemotherapy (32.5%), for chemosensitive relapse (CSR 1 and CSR 2) in 47% patients and in 20.5% patients with chemoresistant disease (CRD). All except one patient were in stage III/IV, extranodal site of disease had 24 patients and bulky disease had l0 patients. All the patients received a uniform preparatory regimen (BEAM). Results. An overall response was achieved in 30 of 32 evaluated patients, with 62.5% in CR and 31.25% in PR. After applying radiotherapy, two patients with PR after ASCT reached CR. Median follow-up was 15.5 months (range 3-133 months). The probability of overall survival (OS) and progression-free survival (PFS) at a 3-year period for all patients was 51.9 % and 48.9%, respectively. For 22 patients in CR after ASCT, a 3-year DFS was 66.5%. Estimates of 2.5-year survival were 14.3%, 61.9% and 100% for CRD, CSR and for patients with CR/PR, respectively (p &lt; 0.01). However, when patients undergoing consolidation were analyzed separately from those in CSR, no significant difference in OS and PFS was observed according to the disease status at ASCT. In univariate analysis for OS, PFS i DFS, extranodal site of disease and disease bulk had no predictive value. Twelve patients died. The main cause of death was Hodgkin's disease. Transplant-related mortality was 3.1%. One patient with CRD developed secondary acute myeloid leukemia and died 28 months after the transplantation. Conclusion. Autologous SCT is efficient as consolidation therapy in high-risk patients and in chemosensitive relapse, but it has no benefit in patients with chemoresistant disease

Autologous stem cell transplantation in the treatment of multiple myeloma single center experience

Background/Aim. In comparison to standard therapy autologous stem cell transplant (ASCT) with high doses melphalane has improved treatment of multiple myeloma (MM) patients. The aim of this study was to evaluate the results of treatment of MM patients in our center with ASCT conditioning with melphalane or combining busulphane, cyclophosphamide and melphalane. Methods. We performed 62 ASCT procedures in 47 patients from 1998 till 2008. Single ASCT were performed in 32 patients (68%), after 3-6 cycles of vincristine, adriamycin, dexamethasone (VAD) protocol and double in 9 patients (19%). Secondary ASCT was performed in 6 (13%) patients during progression of the disease after single ASCT. Mobilization of stem cells (SC) was either with a combination of etoposide and cyclophosphamide with granulocyte colony-stimulating factor (G-CSF) in 39 (83%) patients or cyclophosphamide plus G-CSF in 8 (17%) patients. All the patients received G-CSF five days after the ASCT and maintenance therapy afterwards in the patients with a complete remission (CR) or a partial remission (PR) was interferon alpha in 14 (30%) patients, thalidomide in 13 (28%) and others in 12 (26%) patients. Results. Median engraftment was on 12th day. In a 50-month follow-up period 64% patients were alive. The overall response rate (ORR), which was reached in 38 (80%) patients, was better in the group of patients treated in the early phase of MM. Totally 25 (53%) patients were without progression in a 25-month follow-up period. Twenty patients met criteria for CR + VGPR (very good partial remission), that was 5 patients more than in the period before ASCT. Fourteen (30%) patients died and median time till death was 17 months. Conclusion. The ASCT perfomed in early phase of MM after VAD induction had a significant influence on the treatment of MM patients. Reaching CR + VGPR before and after the ASCT is predictive factor for overall survival (OS) or prolongation of period till recidive appears, progression, therapy withdrowal or death

Allogeneic stem cell transplant for chronic myeloid leukemia as a still promising option in the era of the new target therapy

Background/Aim. Introducing tyrosine kinase inhibitors (TKIs) has essentially changed curative approach, to be precise, clearly improved treatment efficacy for chronic myeloid leukemia (CML). Thus, the place and usage of allogeneic stem cell transplant (SCT) in CML treatment - as a former "nearly monopolistic" therapeutic manner - is nowadays controversial. The objective of this retrospective study was to evaluate the results obtained in the treatment of CML patients, with a particular attempt to define parameters critical for clinical benefit and superior overall outcome following allogeneic SCT. Methods. A total of 32 CML patients (27 in chronic phase and 5 with advanced disease), with female/male ratio 11/21, aged from 9 to 54 (32 in average) years, underwent allogeneic SCTs (1993 to 2009). The initial treatment for 25 patients was interferon alpha (IFN-α) with or without ARA-C, and additional 7 patients with no response to imatinib mesylat (IM). The time from diagnosis to SCT was approximately 12 (range 3- 37) months. The patient were categorized according to the risk for the disease, transplant-related mortality (TRM) scoring system, and stem cell (SC) source. The basic conditioning regimen was a combination of busulphan and cyclophosphamide (BuCy-2). Graft-versus-host disease (GvHD) was typically prevented with cyclosporine-A (CsA) and methotrexate (MTX). Results. Engraftment was observed in 26 (84.4%) patients, with polymorphonuclear (PMNs) and platelet (Plt) recovery on the 15th (range 10-22) and 19th (range 11-29) posttranspalnt days, respectively. Acute GvHD (aGvHD) had 13/26 (50%), and chronic GvHD (cGvHD) 10/21 (47.1%) patients. The incidence of overall TRM was 46.8% (15/32), while early death was noticed in 4 (12.5%) patients. A cause of death in 9 (28.1%) patients was cGvHD, in 2 (6.25%) patients infection, and in 3 (9.35%) cases disease-relapse was occurred. Fourteen (43.7%) of the patients are still alive, 9 from the low-risk group for TRM, with long-term survival from 1 to 16 years. Patients who received SCs from peripheral blood (PB) vs bone marrow (BM) had significantly faster engraftment (p &lt; 0.05), lower oropharingeal mucositis rate (25% vs 70%; p &lt; 0.05), but more frequent cGvHD (83.3% vs 30.3%; p &lt; 0.05). A significantly improved (log-rank = 2.39; p &lt; 0.01) overall survival (OS) was obtained in BM-setting. Conclusion. The results obtained in this study are in accordance with data from analogous clinical trials. Exactly, in the era of the new target therapy (TKI application), allogeneic SCT can be still a convenient therapeutic approach for well-selected CMLpatients, especially for those with initial high-risk disease and lower probability of TRM

Successful treatment with cladribine of Erdheim-Chester disease with orbital and central nervous system involvement developing after treatment of langerhans cell histiocytosis

Introduction. Erdheim-Chester disease (ECD) is a rare, systemic form of non-Langerhans cell histiocytosis of the juvenile xantho-granuloma family with characteristic bilateral symmetrical long bone osteosclerosis, associated with xanthogranulomatous extras-keletal organ involvement. In ECD, central nervous system (CNS) and orbital lesions are frequent, and more than half of ECD patients carry the V600E mutation of the proto-oncogene BRAF. The synchronous or metachronous development of ECD and Langerhans cell histiocytosis (LCH) in the same patients is rare, and the possible connection between them is still obscure. Cladribine is a purine substrate analogue that is toxic to lymphocytes and monocytes with good hematoencephalic penetration. Case report. We presented a 23-year-old man successfully treated with cladribine due to BRAF V600E-mutation-negative ECD with bilateral orbital and CNS involvement. ECD developed metachronously, 6 years after chemotherapy for multisystem LCH with complete disease remission and remaining central diabetes insipidus. During ECD treatment, the patient received 5 single-agent chemotherapy courses of cladribine (5 mg/m2 for 5 consecutive days every 4 weeks), with a reduction in dose to 4 mg/m2 in a fifth course, delayed due to severe neutropenia and thoracic dermatomal herpes zoster infection following the fourth course. Radiologic signs of systemic and CNS disease started to resolve 3 months after the end of chemotherapy, and CNS lesions completely resolved within 2 years after the treatment. After 12-year follow-up, there was no recurrence or appearance of new systemic or CNS xanthogranu-lomatous lesions or second malignancies. Conclusion. In accordance with our findings and recommendations provided by other authors, cladribine can be considered an effective alternative treatment for ECD, especially with CNS involvement and BRAF V600E-mutation-negative status, when interferon-α as the first-line therapy fails