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.

Early complete donor hematopoietic chimerism in peripheral blood indicates the risk of extensive graft-versus-host disease.

Achievement of complete donor hematopoietic chimerism (CC) is the goal of allogeneic stem cell transplantation (allo-SCT). Persistence of recipient hematopoiesis augments the risk of relapse, which is one of the main reasons for mortality after allo-SCT. Another main reason for morbidity and mortality is severe extensive chronic graft-versus-host disease (cGvHD). We examined chimerism in peripheral blood of 54 allogeneic stem cell recipients using multiplex STR-PCR method and compared it with the timing and severity of cGvHD. In total, 25 patients achieved early CC (by day 100 post transplant) at a median time of 60 days. In total, 21 of them developed extensive cGvHD. In those patients CC uniformly preceded emergence of cGvHD by a mean of 85 days. A total of 26 patients obtained late CC at a median time of 270 days post transplant. Of this group, only eight patients developed extensive disease. Development of cGvHD in those patients preceded achievement of CC in 10 of 13 cases by a mean of 100 days. The difference between early and late CC groups as to the frequency of the extensive cGvHD was statistically significant (P<0.001). Also, there was a significant correlation of the time of CC and time between CC and cGvHD. Additionally, patients with early CC developed significantly more severe cGvHD measured by the need of three-drug treatment to control the disease (P<0.005). It can be concluded that achievement of early complete donor hematopoietic chimerism in peripheral blood is strongly predictive of severe extensive GvHD.

The number of particular hematopoietic progenitors cells and the haematopoietic recovery following Allo PBSCT.

AlloPBSC-T is rapidly replacing bone marrow transplantation. The minimum number of progenitor cells required for rapid engraftment following PBSCT is unknown. 12 patients underwent alloPBSC-T during treatment for haematological malignancy. PBSC's were mobilised with Filgrastim (10microg/kg/day sc). The mobilisation was monitored daily by the number of mononuclear cells (MNC) and CD34+ cells in peripheral blood. Collections were normally performed on days 4 and 5, by means of apheresis (Fenwall CS 3000+). No further manipulation of PBSC was performed. A median of 10.15x10(8)/kg MNC (range 5.87-12.24), 9.075x10(6)/kg CD34+ (range 0.78-18.98), 53.85x10(4)/kg CFU-G (range 17.2-138.4), 28.05x10(4)/kg CFU-M (range 4.1-102.2), 115.65x10(4)/kg BFU-E (range 9.1-255.2), 3.65x10(4)/kg CFU-GEMM (range 0.3-10.4) were infused into recipients following BuCyl20 conditioning. Haematopoietic reconstitution was observed in 11 patients. The median number of days to achieve a neutrophil count of 0.5x10(9)/l was 16 (range 12-20), the platelet count of 20x10(9)/l was 12 (range 8-20) and RBC transfusion independence was 11 (range 8-20). 9 recipients developed acute GVHD (3 grade I0, 2 grade II0, 1 grade III0, 3 grade IV0). We found that the number of MNC in PBSC had no influence on the number of progenitors. All the patients who received G-CFU>20x10(4)/kg, BFU-E>60x10(4)/kg and CFU-GEMM>1x10(4)/kg experienced a rapid haematopoietic recovery. No relation was found between the number of reinfused progenitors and the appearance of GVHD.

The effect of short G-CSF administration on the numbers and clonogenic efficiency of hematopoietic progenitor cells in bone marrow and peripheral blood of normal donors.

We have analysed the cellularity, the number of clonogenic cells and their clonogenic efficiency (the number of clonogenic cells/2 x 10(5) MNC) in peripheral blood (PB) and bone marrow (BM) during and after filgrastim (rhG-CSF) mobilization of CD34+ cells in 12 healthy donors for allogeneic stem cell donation. G-CSF was administrated subcutaneously for 5 consecutive days at a dose of 10 micrograms/kg/day. WBC, MNC, CD34+ cell counts, CFU-GM and BFU-E assays in PB were performed at baseline and then daily 12 hours after each G-CSF dose. BM was assayed before start (day 1) and after the last dose (day 6) of G-CSF. Results are given as medians, with ranges in parentheses. In PB the total WBC and MNC increased 7.4-fold (6.0-12.3) and 3.3-fold (1.5-9.4), respectively, reaching a peak of 49.4 x 10(9)/l (32.5-66.6) on day 6 for WBC and 6.28 x 10(9)/l (4.7-13.3) for MNC on day 5. CD34+ cell number reached a peak value of 48.0 x 10(6)/l (45.6-285) on day 6 whereas CFU-GM and BFU-E reached their peaks on day 5, 0.95 x 10(4)/ml (0.05-6.08) and 1.04 x 10(4)/ml, respectively. CFU-MIX, not detectable at baseline, reached a peak of 0.95 x 10(4)/ml (0.006-0.51) on day 5 as well. This was accompanied by an increase in CFU-GM, BFU-E and CFU-MIX clonogenic efficiency: 23-fold (3-150), 9.75-fold (2.2-27.8) and 20-fold (2.5-210), respectively. In BM the total WBC number increased 2.5-fold (1.3-4.9) from the baseline value of 52.6 x 10(9)/l (7.9-137.0) whereas the MNC count increased 2.0-fold (0.81-3.7) from a baseline of 13.6 x 10(9)/l (3.5-54.8). This was, however, not significant. The number of CD34+ cells increased significantly 2.9-fold (0.8-8.3). In 8 donors CFU-MIX were detectable before but not after G-CSF treatment. A similar decrease in CFU-GM and BFU-E clonogenic efficiency occurred but was not significant. CFU-GM and BFU-E numbers did not change. We conclude that the total body numbers of lineage committed progenitors increased during G-CSF administration, which indicate their proliferation in addition to mobilization. The effect of G-CSF on the number of more primitive progenitors in BM is less clear and needs further investigation.

[Essential thrombocythemia as a cause of headache in young woman]. / Nadplytkowosc samoistna przyczyna bólów glowy u mlodej kobiety.

A case of severe headache in a young woman is described. The headache was not associated with additional neurological findings. In peripheral blood extremely high count of platelets was found. Additional examinations supported the diagnosis of essential thrombocythemia (ET). As a first line treatment thrombocytapheresis was performed. The introduced hydroxyurea treatment was complicated with dysmenorrhea and neutropenia. It was the reason to the use anagrelide--a new antiplatelet drug--in the therapy of ET. The treatment with anagrelide was free of previously mentioned complications. After one year of observation the platelet count was still effectively reduced.

[Allogenic blood stem cell transplants: characteristics of transplantation material and clinical transplantation course]. / Allogeniczne transplantacje komórek macierzystych z krwi obwodowej:charakterystyka materialu do przeszczepu i przebieg kliniczny transplantacji.

We have analysed the clinical course of the 14 consecutive allogeneic peripheral blood stem cell transplantations (PBSCT) and cellular composition of the grafts. Donors were HLA-identical siblings except for the one donor who was only HLA-phenotypically identical brother. Nine of them were sex-mismatched to their recipient. Donors received filgrastim (G-CSF) at a dose of 10 microkilograms/kg for 5 days (4-6). Leukaphereses were started at 5 day to obtain the target dose 4 x 10(6) CD34+ cells/kg recipient weight. Median 24 l of blood (24-36) was processed collecting: 10.3 x 10(8)/kg (6.69-18.8) WBC, 9.9 x 10(8)/kg (5.87-16.02) MNC, 9.72 x 10(6)/kg (0.74-18.98) CD34+ cells, 242.5 x 10(6)/kg (77.9-422) T lymphocytes (CD4+ to CD8+ ratio was 1.5), 76 x 10(6)/kg (24-113) B lymphocytes, 33 x 10(6)/kg (14-88) NK cells and 168.8 x 104/kg (23.1-271.4) CFU-GM with 131.7 x 10(4)/kg (8.4-297.6) BFU-E. Engraftment times to a neutrophil count (ANC) > 0.5 x 10(9)/l was achieved at a median of 15 days (range 10-23) in all patients whereas the platelet count > 20 x 10(9)/l at a median of 14 days (9-19) in all but one patient who received the smallest dose of CD34+ cells. Acute graft versus host disease (GvHD) developed in 8 patients who survived more than 30 days. Most of them (75%) were patients with chronic myeloid leukaemia (CML). In 4 of them GvHD was steroid resistant. Chronic GvHD developed in 3 of 6 evaluable patients. We confirm that allogeneic PBSCT result in rapid and longterm trilineage engraftment. However, the observation of the increasing incidence and severity of acute GvHD in patients with CML will require verification in the larger setting of patients after completion of ongoing clinical trials.

Relationships between thrombohemorrhagic complications and platelet function in patients with essential thrombocythaemia.

Three subgroups have been distinguished in essential thrombocythaemia (ET) patients, on the basis of clinical and laboratory findings. ET patients with bleeding incidents had smaller platelet volume, lower concentrations of beta-thromboglobulin and platelet factor 4 in their plasma, 10%, 26%, and 26% lower compared to patients without complications, respectively. ATP secretion from platelets of bleeders, clotters, and "no-complications" ET patients was found to be 75%, 36%, and 45%, respectively, lower than in healthy people. Spontaneous platelet aggregation appeared to be normal in about 90% of ET patients with no complications and in all bleeders but only in 35% patients with clotting incidents. All bleeders had abnormal agonist-evoked aggregation assays. Among remaining ET patients 30%-60% displayed normal values of different evoked aggregation tests. Thus, clinically distinguished group of bleeding ET patients may be differentiated from other subgroups on the basis of laboratory findings.

2-Chlorodeoxyadenosine treatment of Waldenström's macroglobulinemia--the analysis of own experience and the review of literature.

INTRODUCTION: The aim of the study was to evaluate the results of treatment of Waldenström's Macroglobulinemia with 2-chlorodeoxyadenosine. The evaluation was based on our own experience as well as on the data published previously in the literature. MATERIAL AND METHODS: 25 patients with Waldenström's Macroglobulinemia (MW) were treated with 2-chlorodeoxyadenosine (2-CdA) at the dose of 0.14 mg/kg b.w./day for five consecutive days as 2-hour intravenous infusions. Chemotherapy was repeated every 28 to 35 days. RESULTS: In one case (4%) a complete remission and in 15 patients (60%) a partial remission was achieved. In 6 patients (24%) stabilization of the disease was observed while in 3 patients (12%) progression was noted during the treatment. As a result of the therapy, the mean monoclonal protein concentration decreased from 28.7 g/l (range 5.5-62.5 g/l) to 16.7 g/l (range 0-62.9 g/l) and the mean hemoglobin concentration increased from 10.6 g/dl (range 6.9-13.4) to 12.4 g/dl (range 8.2-14.8 g/dl). CONCLUSION: Our own experience, as well as conclusions of other authors, confirm the effectiveness of 2-CdA in MW treatment. Both the results of treatment and intensity of side effects observed in our treatment group were comparable to those described in previous reports.

[Treatment of essential thrombocythemia--personal experience]. / Leczenie nadplytkowosci samoistnej--doswiadczenia wlasne.

The present paper summarizes 13-years our center's experience in the treatment of essential thrombocythemia (ET). We analyzed a group of 36 patients treated with busulphan (Bu), 16 with hydroxyurea (HU) and 4 with interferon alpha (INF alpha). The results of therapy were assessed using proposed self-defined criteria of ET remission. The remission of ET was achieved in 75% of the patients treated with Bu and 57% treated with HU followed for at least 2 years. In the INF alpha treated group cytoreduction was achieved only in patients in whom initial dose of INF alpha was 6 mln I.U. per day. HU seems to be the drug of choice in younger patients because of possible mutagenic effect of Bu as well as in those, in whom Bu was administered in high total dose. During the cytoreductive or maintenance therapy with HU the blood morphology should be often controlled because of relatively high frequency (40%) of leukopenia. In each case of ET cytogenetic examination is necessary. Ph-positive ET determine the choice of the treatment.

[Essential thrombocythemia--clinical course from personal material]. / Nadplytkowosc samoistna--analiza przebiegu klinicznego w materiale wlasnym.

The article presents clinical course analysis of essential thrombocythemia in 17 patients aged 29-82. The diagnostic criteria were the same as described by Polycythemia Vera Study Group. Mean platelet level of diagnosis was 1680 x 10(9)/l. Haemorrhagic complications were observed in 42% of the patients, while thrombotic ones or embolisms in 35%. In two cases both types of complications occurred. Asymptomatic course of the disease was observed in 5 patients. The statistical analysis proved that the patients with platelet count between 900-1900 x 10(9)/l are in danger of developing thrombotic episodes and thus antiaggregation treatment should be considered. If platelet level exceeds 1900 x 10(9)/l the risk of haemorrhage increases, so antiaggregation treatment is contraindicated and thrombocytapheresis is advised instead. The patients was started on treatment when platelet count was above 1000 x 10(9)/l in asymptomatic cases or with lower platelet level in symptomatic ones. The treatment consisted of busulphan, hydroxyurea or interferon alpha (in one of the patients) until lowering platelet level below 600 x 10(9)/l.

Effect of a 2-hour infusion of 2-chlorodeoxyadenosine in the treatment of refractory or previously untreated Waldenström's macroglobulinemia.

2-Chlorodeoxyadenosine (2-CdA) is a new purine analogue active in indolent lymphoid malignancies. In this retrospective study 22 patients with Waldenström's macroglobulinemia (MW) were treated with 2-CdA given in 2-h intravenous infusions. Nine of them were untreated and 13 relapsed or were refractory to previous therapeutic modalities with chlorambucil/prednisone (11 patients) or COP (2 patients). The patients were given 1-11 (median 4) courses of 2-CdA at the dose of 0.14 mg/kg daily in 2-h intravenous infusion for 5 consecutive days. The courses were repeated every 28-35 d. If severe myelosuppression or infection developed, 2-CdA therapy was stopped until the haematological parameters increased. The effectiveness of the treatment was evaluated after the 3 cycles and after completion of therapy. None of the patients has achieved complete response (CR) after 3 courses of treatment and only one (4.5%) has obtained CR after 5 courses. Partial response (PR) was achieved in 8 (36.4%) patients, giving an overall response rate of 40.9%. Ten further patients (45.4%) responded to the treatment with less than 50% decrease in monoclonal protein (defined as stabilisation). There was no significant difference between the response rate in previously pretreated (38.5%) and untreated (44.4%) patients (p>0.05). Mean observed decrease in monoclonal protein was 41%. In the group of 9 patients responding to 2-CdA treatment mean duration of response was 12 months (range 3-34). Myelosuppression was the most prominent side-effect. Neutropenia was present in 17 (77.3%) and thrombocytopenia in 7 (31.8%) patients. In 6 patients myelosuppression was the reason for treatment discontinuation after 1 or 2 courses without significant therapeutic effect. Seven patients died, including 4 from the responding group and all three non-responding patients. Treatment-related thrombocytopenia and fatal haemorrhage was the course of death in 1 patient. In conclusion, the results of our study show that 2-CdA given in 2-h infusions is an effective agent in WM and may be given on an outpatient basis. However, myelosuppression is frequent and the drug must be administered with caution.