The influence of palifermin (Kepivance) on oral mucositis and acute graft versus host disease in patients with hematological diseases undergoing hematopoietic stem cell transplant.

In this multicenter study, we assessed the use of palifermin (recombinant human-keratinocyte growth factor 1) in the prevention of oral mucositis (OM) and acute GvHD (aGvHD) induced by a hematopoietic stem cell transplant (HSCT). Fifty-three patients with hematological diseases received three doses of palifermin (60 mug/kg once daily i.v.) pre- and post-conditioning regimens (total six doses). A retrospective control group of 53 transplant patients received no palifermin. There was a significant reduction in the incidence of OM of WHO (World Health Organization) grades 1-4 (58 vs 94%, P<0.001), 3-4 (13 vs 43%, P<0.001) and the median duration of OM (4 vs 9 days, P<0.001) in the palifermin group compared to the control group. The incidence of analgesics (32 vs 75.5%, P<0.001), opioid analgesics (24 vs 64%, P<0.001) and total parenteral nutrition (11 vs 45%, P<0.001) was also significantly reduced. The analysis of distribution of affected organs revealed that aGvHD was less prevalent in the palifermin group (P=0.036). There was no significant difference in the onset of any OM after HSCT, time to engraftment and length of hospitalization between groups. The drug was generally well tolerated and safe. Our results suggest that the use of palifermin reduces OM and probably aGvHD after HSCT, but a randomized trial is needed.

Addition of cladribine to daunorubicin and cytarabine increases complete remission rate after a single course of induction treatment in acute myeloid leukemia. Multicenter, phase III study.

To assess the efficacy of an original DAC-7 regimen: daunorubicine (DNR) 60 mg/m2/day, days 1-3; cytarabine (AraC) 200 mg/m2/day, days 1-7; cladribine (2-CdA) 5 mg/m2/day, days 1-5, 400 untreated adult acute myeloid leukemia patients (including 63 with preceding myelodysplastic syndrome), aged 45 (16-60) years were randomized to either DAC-7 (n=200) or DA-7 (without 2-CdA, n=200). The overall CR rate equaled 72% for DAC-7 and 69% for DA-7 arm (P=NS). After a single course of DAC-7 induction, the CR rate equaled 64% and was significantly higher compared to 47% in the DA-7 arm (P=0.0009). Median hospitalization time during the induction was 7 days shorter for DAC-7 compared to the DA-7 group (33 vs 40 days, P=0.002). Toxicity was comparable in both groups. The probability of 3-year leukemia-free survival (LFS) for DAC-7 and DA-7 group equaled 43 and 34%, respectively (P=NS). There was a trend toward higher LFS rate for patients aged >40 years receiving DAC-7 compared with DA-7 regimen (44 vs 28%, P=0.05). This study proves that addition of 2-CdA increases antileukemic potency of DNR+AraC regimen, thus resulting in a higher CR rate after one induction cycle when compared to DA-7, without additional toxicity. It shortens hospitalization time and may improve long-term survival in patients aged >40 years.

Addition of cladribine to induction/consolidation regimen does not impair peripheral blood stem cell mobilization and bone marrow harvest for autotransplantation in acute myeloid leukemia patients.

BACKGROUND: The previous study by the Polish Adult Leukemia Group has demonstrated that addition of cladribine to standard DNR+AraC induction potentiates the antileukemic activity. The goal of this study was to compare the efficacy of bone marrow or peripheral blood hematopoietic cell collection in patients who obtained remission after daunorubicine plus cytarabine induction with cladribine (DAC-7) or without addition of cladribine (DA-7) in preparation for autotransplantation. PATIENTS AND METHODS: Sixty-six patients aged 41 years (range, 17-58 years) were included in this study: 33 cases in the DAC-7 and 33 in the DA-7 arm. Hematopoietic cells were collected from the bone marrow (ABMT, n = 29) or from the peripheral blood (ABCT, n = 37) using cytopheresis after administration of AraC (2 x 2 g/m2) on days 1, 3, 5 and subsequent G-CSF (10 microg/kg) from day 7 as mobilization therapy. RESULTS: The numbers of harvested CD34+ cells were similar in the DAC-7 and DA-7 pretreated patients both after harvesting from peripheral blood (2.55 x 10(6)/kg vs 2.5 x 10(6)/kg) and from bone marrow (1.62 x 10(6)/kg vs 1.55 x 10(6)/kg), respectively. The proportion of patients with sufficient material for autologous bone marrow transplantation was higher in the DAC-7 compared with the DA-7 arm. All patients engrafted; hematopoietic recovery was similar in both subgroups. CONCLUSION: Addition of cladribine to a standard DA induction does not impair the harvesting of hematopoietic cells and their engraftment after autotransplantation.

[Epstein-Barr virus infection in patients after bone marrow and heart transplantation]. / Zakazenie wirusem Epsteina-Barr u pacjentów po przeszczepie szpiku kostnego i serca.

UNLABELLED: Epstein-Barr virus (EBV) infections in immunosuppressed patients cause the severe clinical problems. Posttransplant lymphoproliferative disease (PTLD) might occur as a result of the latent EBV activation. OBJECTIVE: Occurrence of active EBV infection in heart and bone marrow transplant patients. METHODS: 68 serum samples obtained from 13 allogenic bone marrow and 20 heart transplant patients were tested by IF and ELISA methods. Antibodies against VCA, EA and EBNA antigens were measured. RESULTS: All patients showed the presence of anti-VCA IgG antibodies, thus all were seropositive. Three patients (9%) showed primary EBV infection while in 12 (36%) patients virus reactivation or reinfection was confirmed. CONCLUSIONS: 1. EBV infection in immunosuppressed patients is mainly caused by latent virus reactivation. 2. Type of EBV infection can be confirmed serologically only by the detection of specific anti-VCA, EA and EBNA antibodies. 3. The risk of PTLD in transplant patients creates the need for frequent monitoring.

[Fungal infection in patients with granulocytopenia. Pathogenetic, diagnostic and therapeutic aspects]. / Infekcje grzybicze u chorych z granulocytopenia. Aspekty patogenetyczne, diagnostyczne i terapeutyczne.

The invasive diagnostic procedures, use of the broad-spectrum antibiotics, adrenal corticoids, immunosuppressive and cytostatic drugs have lead to the increase in the number of fungal infections in granulocytopenic patients. For the most part fungal infections in those patients consist of the opportunistic, systemic infections in granulocytopenic patients is exceptionally frustrating because more often than not, diagnosis is very difficult to establish. The article presents some problems regarding their pathogenesis, classification, diagnosis and management.

[The role of autologous hematopoietic cell transplantation in adult acute myelogenous leukemia]. / Rola autologicznego przeszczepiania komórek hemopoetycznych w leczeniu ostrej bialaczki szpikowej u doroslych.

High dose chemotherapy with autologous hemopoietic cell transplantation (AHCT) is a common method of treatment of acute myelogenous leukemia (AML). AHCT is a treatment of choice for patients who have no matched family donor. AHCT is particularly recommended for older patients, excluded from allogeneic transplantation procedures. Prospective randomised trials have shown better efficacy of AHCT comparing with conventional chemotherapy in postremission treatment of AML. Both in vitro and in vivo bone marrow purging allow to achieve better transplantation results. Since two years peripheral blood instead of bone marrow is increasingly used as a source of transplant material. It allows more rapid hemopoiesis regrowth. Various methods of immunotherapy such as interleukin-2, Linomid and mixed hemopoietic cell transplantation (delayed donor lymphocytes transfusion) are used to evoke an autologous graft versus leukemia (GvL) phenomenon and to reduce AML relapse rate. Analysis of prognostic factors allows to identify a group of AML patients for whom AHCT is strongly recommended.

[Autologous transplantation in acute lymphoblastic leukemia in adults]. / Transplantacja autologiczna w ostrej bialaczce limfoblastycznej doroslych.

Over the past ten years considerable experience has been gained in autologous bone marrow transplantation (ABMT) for acute myelogenous leukemia and it is becoming possible to identify patients who may benefit from this approach. In acute lymphoblastic leukemia (ALL)the precise role of autologous transplantation particularly in first remission is much less clear than in AML. Formerly, most adult ALL patients who underwent ABMT did so in relapse or in second or subsequent remission. The fact that some of these patients could become long term survivors has encouraged the use of ABMT in first remission. In most studies 40-50% of first remission patients attained long term disease free survival (DFS). Relapse rates are considerably higher in patients receiving ABMT when compared to those receiving an allogeneic transplant, but the latter group of patients experience significant morbidity and mortality (15-30%) due to graft-versus-host disease and opportunistic infections. ABMT clearly has the potential to effect cures in ALL patients and its role and timing are now the subject of major clinical studies. As the mortality of ABMT for ALL rapidly decreases to approximately 5%, more widespread use of such a procedure may replace the protracted maintenance chemotherapy usually given in this disease.

[Supportive therapy in patients with autologous hemopoietic stem cell transplantation]. / Terapia wspomagajaca u chorych poddawanych autologicznej transplantacji szpiku kostnego.

Infectious complications remain one of the most serious diagnostic and therapeutic problems in modern hematology and are the major cause of morbidity and mortality following stem cell transplantation. Myeloablative therapy supported by haemopoietic stem cell transplantation remains standard policy in the treatment of certain haematological malignancies and solid tumors. Proper preventive strategies for patients in deep immunosuppression including prompt diagnosis and treatment of infections correlate with favourable prognosis and survival. Prophylaxis and therapy of bacterial, fungal and viral infections in neutropenic patients following myeloablative chemotherapy have been submitted in this article. Our guidelines are based on European Group for Bone and Marrow Transplantation recommendations and some European transplantological centres protocols. These standards were adapted to Polish conditions and now are used at Bone Marrow Transplantation Ward at Haematology Department at the Jagiellonian University.

[Hemorrhagic cystitis related to the high-dose conditioning therapy in a bone marrow recipient]. / Krwotoczne zapalenie pecherza moczowego wywolane wysokodozowana chemioterapia kondycjonujaca przed przeszczepieniem szpiku kostnego.

Hemorrhagic cystitis (HC) is the syndrome of hematuria combined with symptoms of lower urinary tract irritation in the absence of bacterial infection or generalized hemorrhagic diathesis. HC often occurs as a difficult complication after autologous as well as allogeneic hematopoietic cell transplantation (HCT). It may be secondary to pretransplant preparative regimen (chemotherapy and/or radiation therapy) or viral infection by adenovirus, JC and BK viruses. The most effective treatment for HC has not been established yet. We report a case of a 17-year-old male with common acute lymphoblastic leukemia (cALL) in second CR, who was treated with high-dose chemotherapy (BuCy conditioning regimen) followed by autologous bone marrow transplantation (ABMT), complicated by hemorrhagic cystitis on day 0 (several hours after infusion of transplant material). The immediate use of increased dose of 2-mercaptoethane sulfonate sodium (mesna), bladder irrigation and intensive hydration with forced diuresis resulted in resolution of macroscopic hematuria on day +3 after the transplant and urinary tract recovery with normalization of urine analysis parameters on day +7.

[Hematologic remission and disappearance of hemolytic anemia in chronic lymphocytic leukemia after therapy with 2-chlorodeoxyadenosine (2-CDA)]. / Remisja hematologiczna oraz ustapienie niedokrwistosci hemolitycznej u chorego z bialaczka limfocytowa przewlekla w nastepstwie terapii 2-chlorodeoksyadenozyna (2-CDA).

A 62 yr old patient with CLL (Binet C) with severe hemolytic anemia, resistant to conventional immunosuppressive treatment (cyclophosphamide, azathioprine, steroids) had been treated with two cycles of 2-CDA. The therapy resulted in the decrease of leukocyte count (even below 1000/microliters), with subsequent recovery of fairly normal granulopoiesis, eradication of lymphocyte infiltration of the bone marrow, and inhibition of the autoimmune phenomena.

[The diagnostic significance of blast immunophenotype assay in patients with acute leukemia]. / Znaczenie diagnostyczne okreslania immunofenotypu blastów u chorych na ostre bialaczki.

A detailed analysis of immunophenotypes of 120 adult newly diagnosed patients with acute leukaemias was performed. Using the immunopheno-typing, it was possible to defined 96,7% of leukemia cases. The proportion of leukemia subtypes was: AML in 62,5%, ALL in 32,5%, acute biphenotypic leukaemia 1,7% and acute undifferentiated leukaemia (AUL) in 3,3%. The diagnosis initially made according FAB criterias in 12,5% cases after the immunophenotyping was verified. Above analyses showed the existence of the atypical blasts phenotypes in 31%: co-expression of CD 19, CD2 and CD7 markers in AML, co-expression of CD 33 marker in ALL, co-expression of CD 19 marker in T cell ALL and biphenotypic (mixed-lineage) leukaemia.

Status of minimal residual disease determines outcome of autologous hematopoietic SCT in adult ALL.

The role of autologous hematopoietic SCT (autoHSCT) in the treatment of high-risk (HR) adult ALL is controversial. In this study, we retrospectively analyzed the results of autoHSCT according to the status of minimal residual disease (MRD) at transplantation, as a joint analysis of the European Study Group for Adult ALL (EWALL). Data on 123 recipients of autoHSCT, aged 31 (16-59) years, with B-lineage (n=77) or T-lineage (n=46) ALL were included. In a cohort of Ph-negative ALL, the probability of leukemia-free survival at 5 years was higher for patients with MRD <0.1% compared with those with MRD > or = 0.1% (57 vs 17%, P=0.0002). The difference was significant for T-lineage ALL (62 vs 8%, P=0.001), and a tendency was observed for B-lineage ALL (54 vs 26%, P=0.17). In a multivariate analysis, adjusted for other potential prognostic factors, high MRD level remained the only independent factor associated with increased risk of failure (risk ratio, 2.8; P=0.0005). We conclude that MRD determines the outcome of autoHSCT in HR adult ALL. Our results suggest the need to reevaluate the role of this treatment option in prospective trials.

Outcome of treatment in adults with Philadelphia chromosome-positive and/or BCR-ABL--positive acute lymphoblastic leukemia-retrospective analysis of Polish Adult Leukemia Group (PALG).

Patients with Philadelphia chromosome-positive (Ph+) and/or BCR-ABL+ acute lymphoblastic leukemia (ALL) have extremely poor prognoses. Most of these patients have additional, heterogenous karyotype abnormalities, the majority of which have uncertain clinical significance. In this study we analyzed the clinical characteristics, karyotype abnormalities, and outcome of 77 patients with Ph+ and/or BCR-ABL+ ALL registered in Poland in 1997-2004. In 31/55 patients with known karyotype, the sole t(9;22)(q34;q11) abnormality had been diagnosed; in one patient, variant translocation t(4;9;22)(q21q31.1;q34;q11), and additional abnormalities in 23 (42%) patients, had been diagnosed. The characteristics of the patients with Ph chromosome and additional abnormalities were not significantly different when compared with the entire analyzed group. Out of 77 patients, 54 (70%) achieved first complete remission (CR1) after one or more induction cycles. The overall survival (OS) probability of 2 years was 63, 43, and 17% for patients treated with allogeneic stem cell transplantation (alloSCT), autologous SCT, and chemotherapy, respectively (log rank p=0.002). Median OS from the time of alloSCT was significantly longer for patients transplanted in CR1 compared with alloSCT in CR >1 (p=0.032). There were no significant differences in CR rate, disease-free survival (DFS), and OS for patients with t(9;22) and additional abnormalities compared with the whole group. Only WBC >20 G/l at diagnosis adversely influenced OS probability (log rank p=0.0017). In conclusion, our data confirm poor outcome of Ph+ and/or BCR-ABL+ ALL. Only patients who received alloSCT in CR1 had longer DFS and OS. We have shown that additional karyotype abnormalities did not influence the clinical characteristics of the patients; however, their influence on treatment results needs to be further assessed.

Acute lymphoblastic leukemia in elderly: the Polish Adult Leukemia Group (PALG) experience.

This is a retrospective, multicenter study to evaluate biological features and outcome of elderly patients diagnosed with acute lymphoblastic leukemia (ALL) during the last 10 years in ten hematological centers in Poland. Eighty-seven patients aged 60 years or older were studied. To our knowledge, this is one of the largest group of elderly patients with ALL evaluated. We have not observed differences in immunological subtypes and Ph chromosome incidence as compared with younger adult ALL presented in the literature. Induction chemotherapy was administered in 75 patients. We observed complete remission (CR) in 34 (45%, 95% CI: 33-56%) patients. Induction death occurred in 11 (15%) patients. Thirty patients (40%) showed primary resistance to chemotherapy. Median overall survival (OS) of all patients was 150 days. Median disease-free survival (DFS) of responding patients was 180 days. We observed four long-term survivors (DFS longer than 3 years) in our group of patients. Factors influencing OS were CR achievement, female gender, and WBC below 30 x 10(9)/l. Male gender was the only prognostic factor negatively affecting probability to achieve CR. We have not observed any differences in either biology or outcome between patients aged 60-69 years and those aged more than 70 years. ALL of the elderly is a rare disease with poor prognosis. Further clinical trials evaluating the disease features, outcome, and new therapeutic approaches are warranted.