Neutropenic enterocolitis after high-dose chemotherapy and autologous stem cell transplantation: incidence, risk factors, and outcome.

BACKGROUND: Neutropenic enterocolitis (NE) is a life-threatening complication occurring after intensive chemotherapy; however, no data are available on NE development after hematopoietic stem cell transplantation (SCT). The aim of this study was to determine the incidence, risk factors, and outcome of NE after high-dose chemotherapy and autologous SCT (autoSCT). METHODS: A total of 297 adult patients who qualified for autoSCT with non-Hodgkin's lymphoma (NHL), Hodgkin's disease, multiple myeloma, and acute myeloid leukemia were analyzed. Patients were conditioned with carmustine, etoposide, cytarabine, melphalan (BEAM); melphalan alone; or busulfan and cyclophosphamide (BuCy2), and transplanted with peripheral blood or bone marrow CD34(+) cells. Diagnosis of NE was established in case of neutropenic fever, abdominal pain or diarrhea, and bowel wall thickening >4 mm on abdominal sonography. RESULTS: Neutropenic infections occurred in 262 patients (88%). NE was diagnosed in 32 patients (12%), a median +3 (1-5) days after SCT. Bloodstream infections were present in 18 patients, with gram-negative bacteria in 11 patients. All patients were treated conservatively with carbapenems and total parenteral nutrition with bowel rest. The course of disease was complicated by ileus or septic shock in 9 patients, and was fatal for 3 (9.6%) patients. In univariate analysis, the initial diagnosis of NHL (P = 0.017) and conditioning with BEAM (P = 0.043) had prognostic value. In multivariate analysis, only initial diagnosis of NHL (P = 0.017) had prognostic significance. CONCLUSIONS: NE is a rare but severe complication in patients undergoing autoSCT. Gram-negative bacteria remain the main causative pathogen. Abdominal sonography allows early diagnosis and treatment, effective in most of patients without surgery. In our analysis, NE was seen more often in NHL patients treated with a BEAM regimen.

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.

Two autologous transplants in the treatment of patients with Hodgkin's lymphoma: analysis of prognostic factors and comparison with a single procedure.

We summarized registry data of the long term observation of 35 patients treated with two autologous transplants. Prognostic factors for overall survival (OS) and DFS were analyzed. The OS was compared with 105 patients from a single transplant group. Two factors were significant in univariate analysis of DFS after the second transplant: response to the first transplant (complete remission (CR) versus progressive disease (PD) p = 0.041) and the disease status at the time of the second autologous stem cell transplantation (ASCT) (CR versus partial remission (PR) p = 0.004; CR versus PD p = 0.0002). In the multivariate analysis only the last of the parameters remain significant (RR 2.30, p = 0.004, 95% CI; 1.30 - 4.04). In the analysis of OS, two factors were significant in univariate analysis: status of the disease at the first transplant (PR versus PD p = 0.008) and response to the first transplant (CR versus PD p = 0.025). None of those factors remained significant in a multivariate analysis. A probability of 5-year survival after the first transplant in patients treated with two transplants was 83% (95% CI; 70 - 97%). A tendency towards better survival was seen in patients treated with two transplants (p = 0.01). The trend toward better survival from the time of diagnosis is kept for those who entered CR or PR after standard chemotherapy (p = 0.097) but not for the whole group (p = 0.13).

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.

The effect of 2-h infusion of 2-chlorodeoxyadenosine (cladribine) with prednisone in previously untreated B-cell chronic lymphocytic leukaemia.

2-Chlorodeoxyadenosine (2-CdA) is a new antimetabolite chemotherapeutic agent active in indolent lymphoid malignancies. In this retrospective study, 69 previously untreated patients with B-cell chronic lymphocytic leukaemia (B-CLL) were treated with 2-CdA administered at a dose of 0.12 mg/kg daily in 2-h intravenous infusion for 5 consecutive days. 45 patients also received prednisone 30 mg/m2 orally each day for 5 days starting with 2-CdA courses. Patients were given 2-6 courses (mean 4.6) of 2-CdA repeated usually at monthly intervals. If a complete response was achieved, no further 2-CdA courses were administered. Guidelines for response were those developed by the NCI Sponsored Working Group. Complete response (CR) was achieved in 26 (38%) and partial response (PR) in 27 (39%) cases, giving an overall response rate of 77%. 16 patients (23%) did not respond to 2-CdA. In the subgroup of 45 patients receiving 2-CdA with prednisone, CR was obtained in 15 (33%) and PR in 20 (44%) patients giving an overall response rate of 78%. CR was achieved in 11 (46%) out of 24 patients treated only with 2-CdA and in 7 cases (29%) PR was observed, giving an objective response rate of 75%. The differences between both subgroups were not statistically significant. However, we observed a relationship between the response and the number of courses of 2-CdA given in patients receiving and those not receiving prednisone. In the subgroup receiving 2-CdA with prednisone, an earlier response to 2-CdA was observed. In this group a response was achieved in 9 (20%) patients after two courses of 2-CdA and in 18 (40%) after four courses. In the subgroup receiving only 2-CdA, 17 (71%) responses were obtained after six cycles.

Second malignancies and Richter's syndrome in patients with chronic lymphocytic leukaemia treated with cladribine.

The increased frequency of second malignancies in chronic lymphocytic leukaemia (CLL) is well known. Moreover, antineoplastic therapy additionally increases the risk of secondary cancers. In this study, we analysed whether treatment with cladribine (2-chlorodeoxyadenosine, 2-CdA) during the course of CLL had an impact on the subsequent occurrence of either secondary solid tumours or Richter's syndrome. There were 1487 eligible patients, 251 treated with 2-CdA alone, 913 treated with alkylating agents (AA)-based regimens alone and 323 treated with both 2-CdA and AA. Median time from the start of CLL treatment to the diagnosis of secondary malignancy was 1.9 years (0.5-5.1 years) for the 2-CdA group, 1.8 years (0.3-7.9 years) for the AA group and 3.9 years (0.3-8.4 years) for the 2-CdA+AA group. A total of 68 malignancies were reported in 65 patients. Ten events were non-melanotic skin cancers and were excluded from the analysis, leaving 58 events in 58 patients. In the group of patients treated with 2-CdA alone, there were 15 (6.0%) cases, in the group of patients treated with AA alone there were 26 (2.8%) cases, and in the group treated with 2-CdA+AA there were 17 (5.3%) cases of secondary malignancies. The differences between the frequency of secondary malignancies in the 2-CdA and 2-CdA+AA versus AA alone groups were not significant (P=0.05 and P=0.06, respectively). Only lung cancers occurred significantly more frequently in the 2-CdA (2.8%) and 2-CdA+AA (2.2%) treated groups compared with the AA patients (0.3%) (P<0.001 and P<0.01, respectively). In conclusion, 2-CdA in CLL patients does not seem to increase the risk of secondary malignancies except for lung cancers. However, further studies are necessary to establish the real risk of lung cancer in CLL patients treated with 2-CdA.

Platelet aggregation and prostaglandin metabolism in uremic patients.

The pathogenesis of depressed platelet activity in uremia is still unknown. The influence of some uremic toxins on platelet aggregation (PLA) and prostaglandin metabolism in 50 uremic patients treated by hemodialysis (HD) or continuous ambulatory peritoneal dialysis (CAPD) was studied. Fifty-seven healthy volunteers (HVs) served for reference values. Adenosine diphosphate (ADP) and thrombin (Thr) were used as agonists of PLA. PLA was determined using the Born method. Malonyldialdehyde (MDA) levels in platelets as an indicator of prostaglandin metabolism, after stimulation with arachidonic acid, were measured according to Stuart. The relationship of PLA and prostaglandin metabolism with plasma concentrations of methylguanidine (MG), guanidinosuccinic acid (GSA), and creatinine (Cr) was assessed. PLA-ADP values in regular HD patients (42 +/- 5 mm) were significantly lower than in CAPD patients (65 +/- 8 mm) and HVs (73 +/- 3 mm). PLA-Thr values in HD patients (25 +/- 4 mm) were significantly lower than in CAPD patients (34.9 mm) and HVs (36 +/- 3 mm). MDA levels in HD patients (7 +/- 1 nmol/L/10(9)) were significantly lower than in CAPD patients (12 +/- 2 nmol/L/10(9)) and HVs (15 +/- 1 nmol/L/10(9)). In HD patients, inverse correlations of PLA-ADP with MG levels (r = -0.92), PLA-Thr with Cr levels (r = -89), and MDA levels with GSA levels (r = -0.86) were found. In CAPD patients, no relationship of PLA and MDA with uremic toxins was observed. Depressed activity of platelets and prostaglandin metabolism was strongly expressed in HD patients.

Efficacy and safety of fludarabine and cyclophosphamide combined therapy in patients with refractory/recurrent B-cell chronic lymphocytic leukaemia (B-CLL)-Polish multicentre study.

The aim of this study was to investigate the efficacy of a combination of fludarabine (F) and cyclophosphamide (C) in the treatment of patients with refractory/recurrent B-cell chronic lymphocytic leukaemia (B-CLL). Between November 1999 and December 2001, 63 patients with B-CLL (median age 60 years) received a regimen that consisted of F 25 mg/m2 and C 250 mg/m2, days 1-3, intravenously, every 4 weeks, for a maximum of 6 courses, Response and toxicity were assessed according to current criteria (NCI-WG and WHO). Complete and partial remissions were achieved in 17.5% and 55.6% of patients, respectively; 19% of patients had stable disease and 7.9% of patients showed disease progression. The median follow-up was 16.5 (range 1.5-32) months. The median duration of progression-free survival (PFS) has not been reached among patients treated with FC regimen as second-line therapy. The median PFS was 13 (range 8-26) months in the 19 responding patients treated with FC regimen as third-line therapy. The most frequent side-effects were neutropenia (45%), thrombocytopenia (42%) and infections (57%). We conclude that the combination of fludarabine and cyclophosphamide demonstrated significant efficacy in pretreated, advanced B-CLL patients, with tolerable toxicity.

2-chlorodeoxyadenosine (2-CdA) in 2-hour versus 24-hour intravenous infusion in the treatment of patients with hairy cell leukemia.

Forty one patients with hairy cell leukemia (HCL) were treated with 2-chloro-deoxyadenosine (2-CdA) administered in various schedules. Complete remission (CR) was achieved in 31 (76%) patients and partial remission (PR) in 9 (22%). The mean duration of remission (CR + PR) was 25.2 months (range 9-45 months). One patient did not respond to therapy. Twelve out of 16 patients (75%) achieved CR after 5-day intravenous infusions of 2-CdA and 19 out of 25 patients (76%) after 7-day courses. In 19 out of 23 patients (82.6%) CR was achieved after intermittent 2-hour infusions and in 12 out of 18 (66.7%) after continuous 24-hour infusion. The differences were not statistically significant. Side effects of 2-CdA were similar in both groups except for infections, which were less frequently observed in the group treated for 5 days. The results of our study suggest that 2-CdA can be effectively administered to patients with HCL using 5-day courses and a 2-hour daily infusion.

Intermittent 2-hour intravenous infusions of 2-chlorodeoxyadenosine in the treatment of 110 patients with refractory or previously untreated B-cell chronic lymphocytic leukemia.

The purpose of our study was to determine the effectiveness of 2-CdA in 2-hour intravenous infusions in the treatment of B-CLL. One hundred and ten patients with B-CLL received 1 to 10 courses of 2-CdA (median 2.5) at a dosage of 0.12 mg/kg daily for 5 consecutive days. Eighteen of them were untreated and 92 relapsed or became refractory to previous therapeutic modalities. Complete remission (CR) was achieved in 8 (7.3%) and partial remission (PR) in 35 patients (31.8%) giving an overall response rate of 39.1%. In 3 patients, cross-resistance to fludarabine was noticed. Toxic effects of 2-CdA were more frequently observed in previously treated patients. Hemorrhagic complications due to drug-induced thrombocytopenia were noticed in 25 (22.7%) and severe infections including sepsis in 14 (12.7%) patients.

Treatment of hairy cell leukemia patients with 2-chloro-2'-deoxyadenosine (2-CdA).

A preliminary study of six hairy cell leukemia patients treated with one course of 2-chloro-2'-deoxyadenosine (2-CdA) is presented. 2-CdA was administered 0.1 mg/kg/daily by intravenous infusion over 7 days. Two patients achieved CR and four PR.

Rituximab (Mabthera, Rituxan) in patients with recurrent indolent lymphoma: evaluation of safety and efficacy in a multicenter study.

The objective of this multiinstitutional study was to evaluate the safety and efficacy of rituximab at standard four weekly doses in patients with recurrent indolent lymphoma. Thirty-eight patients entered into this study, 63% had follicular lymphoma and 61% had an IPI score of 2 or more. Median disease duration was 3 yr, median number of prior treatments was three, and 66% of patients responded to the immediate past treatment with a median remission duration of 3 mo. A total of 158 antibody doses were given, including two patients who received two courses of four infusions each. One patient developed acute respiratory failure after the second dose and required assisted ventilation. There was no immediate relationship to the antibody infusion and no evidence of infection. This complication resolved and the patient successfully completed the full course of the antibody treatment. Another patient discontinued therapy after the second dose owing to intolerable fever and painful erythema. Sixty percent of the first, and 20% of subsequent rituximab infusions were associated with infusion-related reactions including mild fever, chills, and occasional skin eruptions. Complete and partial responses were achieved in 24% and 35% of 34 evaluable patients, respectively, for an overall response rate of 59%. The median time to progression/relapse in responding patients was 16 mo (95% CI, 6.4, 25.6) compared with a median of 3 mo duration of response to the immediate previous therapy in these patients. Longer response duration post rituximab monotherapy than with previous treatment in this series of heavily pretreated patients suggests a major role for the antibody in the therapy of patients with indolent lymphoma.

Mechanisms of platelet aggregation disturbances and their relation to treatment in patients with chronic uremia.

We have examined platelet aggregation in patients with chronic uremia using ADP, thrombin and calcium ionophore A23187 as inducers. The study was performed on patients treated conservatively, by hemodialysis and peritoneal dialysis. Platelet aggregation was most significantly depressed in patients treated conservatively and by hemodialysis. Different mechanisms are responsible for platelet dysfunction.

[Platelets and the fibrinolytic system]. / Plytki a uklad fibrynolityczny.

The authors present interactions between fibrinolysis and platelets. Platelets may exert both stimulatory and inhibitory effect on fibrinolysis. Also the problem of fibrinolysis activation on platelets function is considered.

[Bone marrow fibrosis in neoplastic diseases of the hematopoietic system]. / Wlóknienie szpiku w chorobach rozrostowych ukladu krwiotwórczego.

Bone marrow fibrosis appears with diverse extension in most neoplastic diseases of blood. It may cause difficulties in establishing a firm diagnosis. In some cases bone marrow fibrosis has a prognostic value.

[Myopathy as a first symptom in Hodgkin's disease]. / Miopatia jako pierwszy objaw w chorobie Hodgkina.

We present a case of Hodgkin's disease first symptom of which was paraneoplastic syndrome in a form of myopathy. It caused a delay in putting forward an appropriate diagnosis.

Standard heparin and low molecular weight heparin effect on spontaneous platelet aggregation measured in whole blood and in platelet-rich plasma.

The evaluation of both standard heparin (SH) and low molecular weight heparin (LMWH) (Fraxiparine) impact on spontaneous platelet aggregation assessed in the whole blood and in platelet-rich plasma (PRP). The results obtained reveal that SH enhance spontaneous aggregation in a similar degree both in the whole blood (34.5 +/- 3.0, control 21.3 +/- 4.1) and in PRP (33.5 +/- 2.7, control 13.8 +/- 3.2). LMWH significantly intensifies spontaneous aggregation in the whole blood (46.9 +/- 3.2, control 21.3 +/- 4.1) but not in PRP (19.4 +/- 4.3, control 13.8 +/- 3.2).

[Platelet function in acute myeloid leukemia. II. Aggregation of isolated platelets]. / Czynnosc plytek krwi w ostrej bialaczce szpikowej. II. Agregacja izolowanych plytek.

In 22 patients with acute myeloid leukaemia (17 cases of myeloblastic leukaemia, 4 cases of myelomonocytic leukaemia and 1 case of undifferentiated-cell leukaemia) platelets were isolated from the plasma by the method of Nicholls and Hampton as modified by Levy-Toledano by centrifugation in albumin gradient. The aim of platelet isolation was their "concentration" in cases of thrombocytopenia to values making possible aggregation tests, and platelet separation from the influence of plasma factors. Then aggregation of isolated platelets caused by ADP was studied. In 16 out of 22 patients a fall of aggregation was observed, with the mean values of aggregation rate and intensity were significantly lower. Parallelly done determinations of aggregating activity released from the platelets by thrombin showed lower values as compared with platelets from healthy subjects. In might be thought, in this connection, that the demonstrated reduction of isolated platelets is associated with a diminution of the nucleotide pool or disturbances of the platelet release reaction. The disturbances of the platelet release reaction. The disturbances of aggregation of isolated platelets and reduction of the aggregating activity were most pronounced in acute myelomonocytic leukaemia.

[Effect of thrombin stimulated blood platelets on plasma fibrinolytic activity]. / Wplyw krwinek plytkowych stymulowanych trombina na aktywnosc fibrynolityczna osocza.

The influence of thrombin stimulated-blood platelets on plasma fibrinolytic activity was evaluated. Thrombin-activated blood platelets have been shown to significantly inhibit plasma fibrinolytic activity before and after venous stasis. This was expressed by a reduction of the digestion area of fibrin dish from 10.3 +/- 3.3 cm2 to 3.7 +/- 1.5 cm2 and from 15.6 +/- 6.8 cm2 to 3.7 +/- 1.7 cm2, respectively.

[Significance of histologic bone marrow evaluation in diagnosis of chronic granulocytic leukemia. I. Reticulin fibrosis]. / Znaczenie oceny histologicznej szpiku w diagnostyce przewleklej bialaczki szpikowej. I. Wlóknienie retikulinowe.

The aim of the study was the evaluation of bone marrow reticulin fibrosis in non-treated patients suffering from chronic granulocytic leukaemia (cgl). We have examined 40 patients (19 female and 21 male, average age 41.2 years) with chronic phase, Ph'-positive cgl. Reticulin fibrosis grade I and II (according to Dekmezian and co.) was detected in 47.5% of patients and grade III and IV in 42.5%. Statistically significant correlation was found between reticulin fibrosis intensity and spleen size, platelets count and Sokal index. We believe that reticulin fibrosis assessment is of prognostic value.