The influence of tumor necrosis factor microsatellite polymorphisms on patient survival following hematopoietic stem cell transplantation

Aim To investigate the influence of tumor necrosis factor (TNF) microsatellite polymorphisms on patient survival following hematopoietic stem cell transplantation. Methods We analyzed TNFa, TNFb, and TNFd microsatellites among 100 patients who underwent allogeneic hematopoietic stem cell transplantation from a human leukocyte antigen (HLA)-identical sibling donor at the Internal Clinic of the University Hospital Center Zagreb in the period 2001-2009. The analysis was performed using polymerase chain reaction amplification and electrophoresis on a polyacrylamide gel in an automated sequencer. Results There was no significant difference in patient survival with respect to the allele length at a given microsatellite. However, a significantly lower survival rate was noticed among patients who were positive for TNFa8 allele (P < 0.001) and a significantly higher survival rate among those who were positive for TNFa10 allele (P = 0.0220). Conclusion These results for the first time suggest an influence of TNFa microsatellite on patient survival following HSCT and indicate a need for further studies of this microsatellite

The influence of tumor necrosis factor microsatellite polymorphisms on patient survival following hematopoietic stem cell transplantation

AIM: To investigate the influence of tumor necrosis factor (TNF) microsatellite polymorphisms on patient survival following hematopoietic stem cell transplantation. ----- METHODS: We analyzed TNFa, TNFb, and TNFd microsatellites among 100 patients who underwent allogeneic hematopoietic stem cell transplantation from a human leukocyte antigen (HLA)-identical sibling donor at the Internal Clinic of the University Hospital Center Zagreb in the period 2001-2009. The analysis was performed using polymerase chain reaction amplification and electrophoresis on a polyacrylamide gel in an automated sequencer. ----- RESULTS: There was no significant difference in patient survival with respect to the allele length at a given microsatellite. However, a significantly lower survival rate was noticed among patients who were positive for TNFa8 allele (P<0.001) and a significantly higher survival rate among those who were positive for TNFa10 allele (P=0.0220). ----- CONCLUSION: These results for the first time suggest an influence of TNFa microsatellite on patient survival following HSCT and indicate a need for further studies of this microsatellite

Treatment of acute myeloid leukemia using reduced intensity conditioning – method reserved for elderly patients only?

Cilj: Svrha članka bila je prezentirati dosadašnje rezultate liječenja ovom metodom u našem transplantacijskom centru, kao i proširiti svijest o potencijalnoj velikoj koristi korištenja kondicioniranja smanjenim intenzitetom u terapiji oboljelih od akutne mijeloične leukemije i mijelodisplastičnog sindroma. Metode: Od ožujka 2008. do prosinca 2010. transplantirano je ukupno 10 bolesnika, medijan dobi bio je 53,5 godina (35,3 – 58,3). Tri bolesnika prethodno su autologno, a jedan alogeno transplantirani. Svi su bolesnici dobili fludarabin-bazirano kondicioniranje, kombinaciju fludarabin, busulfan. Profilaksa GVHD-a provođena je ciklosporinom, s ili bez mikrofenolat-mofetila, te antitimocitnim globulinom u slučaju transplantacije od nesrodnog davatelja. Svi su bolesnici transplantirani perifernim hematopoetskim matičnim stanicama. Rezultati: Kumulativna incidencija akutne bolesti davatelja protiv primatelja (engl. Graft-versus-Host Disease; GVHD) bila je 30 % za gradus I – IV, odnosno 20 % za gradus III – IV; za kronični oblik bolesti 10 %. Ukupno preživljenje iznosi 20 %, a preživljenje bez znakova bolesti iznosi 22 %. Rasprava: U usporedbi s objavljivanim rezultatima, naša skupina bolesnika ima slabije ukupno preživljenje te nešto višu incidenciju GVHD-a. S obzirom na mali broj bolesnika u našoj skupini, direktna usporedba i nije moguća. Iako je ova metoda bila dizajnirana za provođenje u starije populacije bolesnika, u posljednje se vrijeme pokazala adekvatnom i u mlađih bolesnika, no za donošenje konačnog zaključka potrebno je provesti randomizirano istraživanje na većem broju bolesnika. Zaključak: U našem centru transplantirano je 10 bolesnika oboljelih od akutne mijeloične leukemije, odnosno mijelodisplastičnog sindroma, koristeći kondicioniranje smanjenog intenziteta. Iako su postignuti rezultati slabiji u usporedbi s do sada objavljivanima, prava analiza nije moguća na ovako malom broju bolesnika.Aim: The aim of this article was to present the results achieved using this method in our center, as well as to expand the knowledge of potentially great benefit that reduced conditioning is bringing in the treatment of patients with acute myeloid leukemia and myelodisplastic syndrome. Methods: From March 2008 until December 2010, a total of 10 patients were transplanted, median age was 53.5 years (range 35.3 – 58.3). Four patients were previously transplanted, three received autologous and one patient allogeneic bone marrow transplantation. All patients received conditioning consisting of fludarabine and busulphan. For Graft-versus-Host Disease (GVHD) prophylaxis they received cyclosporine, with or without Mycophenolate mofetil, and in case of unrelated donor ATG was given prior to transplantation. All of the patients received grafts consisting of peripheral hematopoietic stem cells. Results: Cumulative incidence of acute GVHD was 30 % for grade I-IV, and 20 % for grade III-IV; for chronic GVHD it was 10 %. Overall survival was 20 %; disease-free survival was 22 %. Discussion: Comparing our results with so far published series, our group has notably lower overall survival rate and somewhat higher incidence of GVHD. Considering the small number of patients in our group, direct comparison was not possible. Even though this method was designed for older group of patients, recently published data shows that this method is suitable for younger patients as well, but randomized studies on larger number of patients are still needed. Conclusion: Ten patients with acute myeloid leukemia or myelodisplastic syndrome were treated in our center using reduced intensity conditioning. Even though achieved results are not as good as those so far reported, a proper analysis is still not possible due to the small number of our patients

The influence of tumor necrosis factor microsatellite polymorphisms on patient survival following hematopoietic stem cell transplantation

Aim To investigate the influence of tumor necrosis factor (TNF) microsatellite polymorphisms on patient survival following hematopoietic stem cell transplantation. Methods We analyzed TNFa, TNFb, and TNFd microsatellites among 100 patients who underwent allogeneic hematopoietic stem cell transplantation from a human leukocyte antigen (HLA)-identical sibling donor at the Internal Clinic of the University Hospital Center Zagreb in the period 2001-2009. The analysis was performed using polymerase chain reaction amplification and electrophoresis on a polyacrylamide gel in an automated sequencer. Results There was no significant difference in patient survival with respect to the allele length at a given microsatellite. However, a significantly lower survival rate was noticed among patients who were positive for TNFa8 allele (P < 0.001) and a significantly higher survival rate among those who were positive for TNFa10 allele (P = 0.0220). Conclusion These results for the first time suggest an influence of TNFa microsatellite on patient survival following HSCT and indicate a need for further studies of this microsatellite

Treatment of patients with advanced Hodgkin’s lymphoma with escalated BEACOPP

Cilj: Svrha rada je pokazati rezultate, kao i nuspojave, u bolesnika s Hodgkinovim limfomom stadija III ili IV, koji su liječeni s 4 ciklusa eBEACOPP-a i 4 ciklusa sBEACOPP-a. Metode: U razdoblju od listopada 2003. do ožujka 2011. godine liječeno je 15 bolesnika. Medijan dobi bio je 28 godina (19 – 47), s medijanom praćenja od 14 mjeseci (1 – 90). Svi su bolesnici liječeni s 4 ciklusa eBEACOPP-a, 11 bolesnika liječenje je nastavilo s 4 ciklusa sBEACOPP-a, kod 3 bolesnika, zbog značajnih nuspojava, primijenjen je program ABVD, dok je jedan bolesnik (plućna toksičnost) liječen programom COPP. Rezultati: U 10 bolesnika liječenjem je postignuta kompletna remisija bolesti, a u 5 bolesnika parcijalna remisija bolesti; ukupan odgovor na terapiju bio je 100 %. U 5 bolesnika koji su postigli parcijalnu remisiju bolesti provedena je radioterapija. Nakon praćenja od 14 mjeseci, preživljenje bez znakova bolesti, kao i ukupno preživljenje, iznosi 100 %. Kod većine bolesnika primijećena je ozbiljna hematotoksičnost, a 5 bolesnika (33 %) je zbog febrilne neutropenije liječeno bolnički. Rasprava i zaključak: Ova preliminarna studija potvrđuje da je program liječenja eBEACOPP-om izrazito učinkovit, a rezultati su u skladu s rezultatima dosad provedenih studija. Radi se o malom uzorku bolesnika s kratkim razdobljem praćenja. Treba naglasiti da za sada nisu zamijećeni rani relapsi bolesti. Toksičnost je značajna, naročito hematotoksičnost uz neutropenijske vrućice.Aim: We present the outcome and toxicity of intensive chemotherapy protocol escalated BEACOPP (eBEACOPP 4 cycles) followed by standard BEACOPP (sBEACOPP 4 cycles). Methods: From October 2003 untill March 2011, 15 patients were treated with eBEACOPP. The median age was 28 years with a range of 19 to 47 years; median follow-up was 14 months (range 1 to 90 months). All patients received 4 cycles of eBEACOPP; 11 patients continued their therapy with 4 cycles of sBEACOPP; in 3 patients ABVD was given because of severe toxicity, while in one patient with lung toxicity COPP was the therapy of choice after eBEACOPP. Results: Complete remission and partial remission has been achieved in 10 and 5 patients, respectively. The response to treatment was 100 %. In 5 patients with PR, radiotherapy was given after chemotherapy. After the median of 14 months follow-up the probability of progression-free survival and overall survival is 100 %. The majority of patients experienced serious hematological toxicity and 5 patients (33 %) had to be admitted to hospital because of febrile neutropenia. Discussion and conclusion: This study confirms the efficacy of eBEACOPP protocol, and the results are similar with the reported data. However, the number of patients and relatively short follow-up is the weakness of this study. It has to be stressed out that relapse of Hodgkin lymphoma was not reported. Toxicity is a serious problem, especially hematological toxicity with febrile neutropenia

Allogeneic stem cell transplantation from matched unrelated donor

Cilj: Transplantacija od nesrodnog podudarnog davatelja napretkom metodologije određivanja HLA sustava (engl. Hystocompatibility Leukocie Antigen) posljednjih se godina primjenjuje jednako kao i transplantacija od srodnog davatelja. Cilj ovog rada je prikazati iskustva liječenja alogeničnom transplantacijom od HLA podudarnog nesrodnog darivatelja u Zavodu za hematologiju KBC-a Zagreb. Metode: U razdoblju od 1991. do 2010. u Zavodu za hematologiju KBC-a Zagreb alogenom transplantacijom od HLA podudarnog nesrodnog darivatelja liječen je 71 bolesnik prosječne dobi od 28 godina (raspon: 1 mjesec – 61 godinu). Razlozi liječenja bili su akutna leukemija (34 bolesnika), kronična mijeloična leukemija (16 bolesnika), kronična limfocitna leukemija (4 bolesnika), limfomi i mijelom (7 bolesnika), teška aplastična anemija ili druge bolesti (8 bolesnika). Nesrodni darivatelji bili su HLA podudarnosti 6/6 (niska razina razlučivanja), HLA podudarnost 8/8, 8/10, 9/10 ili 10/10 (visoka razina razlučivanja). U pripremi za transplantaciju primijenjeni su ili standardni mijeloablativni program (ozračenje cijelog tijela i ciklofosfamid ili busulfan i ciklofosfamid) ili programi smanjenog intenziteta s fludarabinom. Rezultati: Vjerojatnost ukupnog preživljenja je 24 %. Plato krivulje preživljenja postiže se nakon 18 mjeseci. Trend boljeg terapijskog odgovora s preživljenjem od 37 % postignut je u bolesnika HLA podudarnosti 10/10. Neposredni uzroci smrtnosti u ranoj fazi nakon transplantacije su infekcije, GvHD, ponovna pojava bolesti i multiorgansko zatajenje. Rasprava i zaključak: Transplantacija od nesrodnog darivatelja primjenom optimalnog podobnog davatelja u ranoj fazi bolesti standardni je terapijski postupak mnogih zloćudnih tumora krvotvornog sustava i teške aplastične anemije.Aim: Stem cell transplantation from HLA-matched unrelated donor (MUD) is a standard therapy similar to allografting from related donor. Here we present the treatment outcome of MUD transplantation in the University Hospital Center Zagreb. Methods: From 1991 to 2010 at the Department of Hematology, University Hospital Center Zagreb 71 patients (average of 28 years, range 1 month to 61 year) underwent MUD transplantation; the reason for transplantation was acute leukemia (34 patients), chronic myeloid leukemia (16 patients), chronic lymphocytic leukemia (4 patients) lymphoma and myeloma (8 patients) and severe aplastic anemia or other disorders (8 patients). According to HLA, the donors were compatible in 6 out of 6 antigens (with low resolution) or in 8 out of 8 antigens, and 8 out of 10, 9 out of 10 and 10 out ten 10 antigens (with high resolution). For conditioning, patients received either standard myeloablative regimen (total body irradiation with cyclophosphamide or busulfan and cyclophosphamide) or fludarabine based reduced intensity regimen. Results: The probability of overall survival was 24 %. The plateau was reached after follow-up of 18 month. Trend for better treatment outcome and survival of 37 % was documented for patients months received stem cells from donors compatible in 10 out of 10 antigens. The principal causes of death after allografting were infections, GvHD, relaps and multiorgan failure. Discussion and conclusion: MUD-transplantation especially with the donor compatible in 10 out of 10 antigens performed in early phase of disease is currently the standard treatment for many malignant hematopoietic tumors and severe aplastic anemia

Collection and composition of autologous peripheral blood stem cells graft in patients with acute myeloid leukemia: influence on hematopoietic recovery and outcome [Skupljanje i sastav transplantata autolognih krvotvornih matičnih stanica periferne krvi u bolesnika s akutnom mijeloičnom leukemijom: utjecaj na hematološki oporavak i ishod]

Hematopoietic stem cell (HSC) transplantation is a standard approach in the treatment of hematological malignant diseases. For the last 15 years the main source of cells for trasplantation have been peripheral blood stem cells (PBSC). With the availability of hematopoietic growth factors and understanding the advantages of treatment with PBSC, the application of bone marrow (BM) was supplanted. The aim of this survey was to explore the success of PBSC collection, the factors which influence the success of PBSC collection, the composition and the quality of graft and their infuence on hematopoietic recovery and outcome after transplantation in patients with acute myeloid leukemia (AML). PBSC were collected by the method of leukapheresis after applying a combination of chemotherapy and growth factors or only growth factors. The quality of graft was determined with the clonogenic progenitor cell assay and with the flow citometry analysis. Of the total 134 patients with AML, who were submitted to HSC mobilization, the collection was successful in 78 (58.2%) patients. The collection was more successful after the first than after the second attempt of HSC mobilization (49% vs. 11%). The criteria for effective mobilization were the number of leukocytes >3´109/L and the concentration of CD34+ cells >20´103/mL in the peripheral blood on the first day of leukapheresis. The number of CD34+ cells infused had the strongest impact on hematopoietic recovery. We noted significantly faster hematological recovery of neutrophils and platelets, fewer number of transfused units of red blood cells and platelets, shorter duration of the tranfusion support, shorter treatment with intravenous antibiotic therapy and shorter hospitalization after PBSC compared to BM transplantation. These advantages could provide their standard application in the treatment of patients with AML

EXTRACORPOREAL PHOTOPHERESIS IN TREATMENT OF CHRONIC GRAFT VERSUS HOST DISEASE

Ekstrakorporalna fotofereza (EF) jest imunomodulatorna terapija koja se rabi u liječenju kronične reakcije transplantata protiv primatelja (engl. chronic graft versus host disease, cGVHD). Tijekom EF-a leukaferezom se iz krvi izdvajaju mononuklearne stanice, ex vivo im se dodaje 8-metoksipsoralen, stanice se ozrače UVA-zrakama i potom reinfundiraju bolesniku. Cilj istraživanja bio je procijeniti klinički i imunomodulatorni učinak postupka EF-a u bolesnika s cGVHD-om. Analiziran je 341 postupak EF-a u 7 bolesnika s cGVHD-om s medijanom EF-a po bolesniku 37 (raspon 13–131). U svih bolesnika cGVHD se manifestirao kožnim promjenama u kombinaciji sa simptomima drugih organskih sustava. EF su provođene dva dana za redom: prvih mjesec dana svaki tjedan, sljedeća 2 mjeseca svaki drugi tjedan, a potom jednom na mjesec. Medijan trajanja liječenja postupkom EF-a iznosio je 10 mjeseci (raspon 2 do 58). EF je većinom povoljno utjecao na simptome cGVHD-a pa je u 6 bolesnika došlo do poboljšanja i/ili stabilizacije promjena kože te bolje pokretljivosti zglobova, a u 2 bolesnika s ulceracijama sluznice usne šupljine promjene su se u cijelosti povukle. Do kliničkog poboljšanja došlo je 2 do 3 mjeseca nakon početka EF-a, što je omogućilo značajno smanjenje ili prestanak primjene glukokortikoida. Neželjene reakcije javile su se tijekom 4,9% postupaka. U bolesnika u kojih je došlo do poboljšanja kliničkog stanja normalizirale su se vrijednosti omjera CD4+/CD8+ stanica, kao i broj NK-stanica. Rezultati našeg istraživanja pokazuju da primjena EF-a povoljno utječe na simptome cGVHD-a i omogućuje sniženje doze kortikosteroida uz poboljšanje kvalitete života bolesnika pa se stoga može preporučiti za bolesnike koji ne odgovaraju na standardno liječenje.Extracorporeal photopheresis (ECP) is an immunomodulatory therapy which has been used in the treatment of chronic GVHD (cGVHD). ECP involves separation of the mononuclear cells with leukapheresis, followed by ex vivo administration of 8-methoxypsoralen and UV-A radiation and reinfusion to the patient. Aim of the study was to evaluate clinical and immunomodulatory effect of ECP procedures in patients with cGVHD. We analyzed 341 ECP procedures performed in 7 patients with cGVHD; median ECP per patient was 37 (range 13–131). All patients suffered from skin changes in combination with impaired joint mobility and symptoms of oral disease. ECP procedures were performed for two consecutive days: in initial phase weekly, followed by every two weeks and than monthly according to clinical response. Median of ECP treatment duration was 10 months (range 2–58). The effect of ECP in patients with cGVHD with skin and joint involvement was mostly beneficial: 6 patients experienced either improvement or stabilization in skin changes and joint mobility. In 2 patients who suffered from oral disease, the total recovery was observed. Clinical response was typically delayed until 2 to 3 months, and reduction in glucocorticoid dose was observed. Adverse reactions were observed in 4.9% procedures. In patients who responded to ECP treatment, CD4+/CD8+ ratio and number of NK cells were normalized. ECP proved to be an efficient and safe procedure that may be recommended for patients with cGVHD who do not respond to conventional therap

Which questionnaires should we use to evaluate quality of life in patients with chronic graft-vs-host disease?

Aim To investigate the ability of two standard quality of life (QOL) questionnaires – The Short Form (36-item) Health Survey (SF-36) and The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire- Core 30 (EORTC QLQ C30) to evaluate QOL in patients with chronic graft-vs-host disease (cGVHD) graded according to National Institutes of Health (NIH) consensus criteria. Methods In this cross-sectional study, QOL was assessed in patients who underwent allogeneic stem cell transplantation (allo-SCT) at the University Hospital Centre Zagreb and were alive and in complete remission for more than one year after allo-SCT. Results The study included 58 patients, 38 patients with cGVHD and 20 controls, patients without cGVHD. Patients with cGVHD scored according to the NIH criteria had significantly lower scores of global health status and lower QOL on all SF-36 subscales and most of QLQ C30 functional subscales (P < 0.050 for all comparisons). Furthermore, patients with active cGVHD had significantly lower QOL scores than patients with inactive cGVHD, and this difference was most evident in physical functioning subscale of SF-36 (P = 0.0007) and social functioning subscale of QLQ C30 (P = 0.009). Conclusion cGVHD scored according to the NIH criteria is correlated with patient-reported QOL, particularly in the physical domains as detected by SF-36. QLQ C30 questionnaire adds more information on social functioning and should be used as a valuable tool in the evaluation of social domains in cGVHD patients