Treatment-related mortality and graft-versus-leukemia activity after allogeneic stem cell transplantation for chronic lymphocytic leukemia using intensity-reduced conditioning.

Allogeneic stem cell transplantation (SCT) using reduced-intensity conditioning (RIC) has potential to be a promising treatment of aggressive chronic lymphocytic leukemia (CLL). Since available clinical data obtained with this novel approach are very limited, we have performed a survey on this issue. Data of 77 patients were collected from 29 European Group for Blood and Marrow Transplantation centers. Median age was 54 (30-66) years, and the median number of previous chemotherapy regimens was 3 (0-8). HLA-identical sibling donors were used in 81% of the cases. Moderate conditioning regimens (mainly low-dose total body irradiation (TBI) or fludarabine-cyclophosphamide combinations) were administered to 56% of the patients, whereas the remainder received more intense conditioning consisting of fludarabine-busulfan or high-dose melphalan combinations. In 40% of the patients, in vivo T-cell depletion (TCD) with anti-thymocyte globulin or CAMPATH-1H was part of the conditioning regimen. Cumulative treatment-related mortality (TRM) was 18% (95% CI 9; 27) after 12 months. Complete chimerism as well as best response was not achieved immediately post-transplant but took a median of 3 months to develop. The 2-year probability of relapse was 31% (95% CI 18; 44), with no event occurring later than 12 months post transplant in the absence of TCD. With one exception, relapses were not observed after onset of chronic graft-versus-host disease. Event-free and overall survival at 24 months were 56% (95% CI 43; 69) and 72% (95% CI 61; 83), respectively. The median follow-up was 18 (1-44) months. Donor lymphocyte infusions or secondary transplants were performed in 19 patients with insufficient disease control and/or incomplete donor chimerism post-transplant, leading to a response in seven patients (37%). Preliminary multivariate analysis identified less than PR at transplant (hazard ratio (HR) 3.5; P&<0.01) and alternative donor (HR 3.1; P=0.02) as significant risk factors for relapse, whereas number of previous regimens >2 (HR 5.4; P=0.03), TBI (HR 2.5; P=0.05), and alternative donor (HR 2.3; P=0.08) were risk factors for survival. We conclude that RIC might favorably influence the outcome after allogeneic SCT for CLL by reducing TRM while preserving graft-versus leukemia activity.

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.

Interferon-gamma-mediated suppression of erythroid progenitor growth by a HLA-DR- and CD4-positive subset of T lymphocytes in acute myeloid leukemia.

In this study, we examined the effects of peripheral blood T lymphocytes from patients with acute myeloid leukemia (AML) on marrow-derived erythroid progenitors (BFU-DE and CFU-DE) growth in an in vivo culture by using the plasma clot diffusion chamber (DC) technique. The application of double-compartment chambers (each compartment separated by a membrane filter) makes the investigations of humoral effects of T lymphocytes upon marrow erythroid progenitors proliferation possible. T lymphocytes of AML-patients in the absence of a statistically significant number of monocytes suppressed the growth of BFU-DE and CFU-DE from T lymphocyte- and adherent cell-depleted marrows. The inhibition ability was restricted to the CD4-positive enriched fraction obtained from T cells by using the negative selection technique. In contrast, the CD8-positive enriched fraction had no effect on erythroid colony formation. Autologous and allogeneic BFU-DE and CFU-DE were similarly affected by the CD4-positive T cells. Treatment of T cells with monoclonal antibodies against HLA-DR before cocultures, completely abrogated the suppression of BFU-DE and CFU-DE-derived colony formation. Suppressive activity detected in the CD4-positive T cells was also totally abolished by treatment with anti-interferon-gamma antibodies; whereas the inhibition was retained after 30 Gy radiation. Under these experimental conditions, resting T lymphocytes from healthy subjects did not affect the erythroid colony formation. Our data show that in AML-patients, a circulating HLA-DR-positive, less radiosensitive subset within the CD4-positive T cells is capable of inducing an interferon-gamma-mediated suppression of erythropoiesis, at least in DC culture.

Impaired release of colony stimulating activity by monocytes from Hodgkin's disease in response to phorbol myristate acetate activation.

We assessed the humoral effect of resting and phorbol esters preincubated monocytes from Hodgkin's disease patients (HDMo) and healthy subjects (nMo), on granulocyte progenitors (CFU-dG) growth using a double diffusion chamber technique. The release of colony stimulating activity and indomethacin-dependent inhibitors by resting HDMo and nMo was found to be cell-concentration dependent. However, phorbol myristate acetate preincubated HDMo (PMA-HDMo) in contrast to nMo at low concentrations (2.5 x 10(4] were unable to increase the CFU-dG growth stimulation. On the other hand, at a higher cell number (5 x 10(4], phorbol treated HDMo stimulated the myeloid colony formation, whereas nMo suppressed the CFU-dG proliferation. Further enhancement of HDMo and nMo concentrations induced a pronounced inhibition of CFU-dG-derived colony formation, caused by an increased PGE2 production. After incubation with the cyclooxygenase inhibitor-indomethacin, PMA-HDMo showed considerably more granulocyte colony formation than nMo. Our results suggest that the observed abnormalities in the function of HDMo could be associated with an excessive production of PGE2 and a general dysfunction of these cells in Hodgkin's disease.

Treatment for primary refractory Hodgkin's disease: a comparison of high-dose chemotherapy followed by ASCT with conventional therapy.

Our previously published study showed promising results of autologous stem cell transplantation (ASCT) in patients with primary resistant Hodgkin's disease (HD). Probabilities of overall survival (OS) and progression-free survival (PFS) at 3 years were 55 and 36%, respectively. The present study was undertaken to compare these results with conventionally treated patients and thus evaluate therapeutic options. Retrospective data on 76 adult patients who underwent ASCT were matched with 76 conventionally treated patients from 17 centers. Comparison of clinical characteristics in both groups showed that ASCT patients were younger (24 vs 31.5 years, P=0.001), more frequently presented with 'B' symptoms (P=0.03) and that more patients treated with chemotherapy (CT) had elevated LDH (P=0.03). In univariate analyses, bulky disease (P=0.0043) and complete resistance to standard CT (P=0.051) were found to be risk factors for OS. In a multivariate survival analysis only bulky disease was found to an independent prognostic factor (P=0.005). There was no difference in survival between the treatment groups with 5 years OS 33.7 (CI: 23-46) in the ASCT group and 35.6% (CI: 25-50) for the CT group (P=0.92). We conclude that ASCT is not superior to standard CT for treatment of patients with primary refractory HD.

High-dose chemotherapy with autologous stem cell transplantation is an effective treatment of primary refractory Hodgkin's disease. Retrospective study of the Polish Lymphoma Research Group.

We analysed the treatment outcome of primary refractory HD patients managed with high-dose chemotherapy and haematopoietic cell transplantation. Data of 65 adult patients who underwent HDC/ASCT in nine Polish centres for primary resistant Hodgkin's disease between June 1991 and July 2000 were collected retrospectively. Response rate to HDC/ASC: CR, 54%; PR, 20%; less than PR, 15%; early deaths, 11%. Actuarial 3-year OS and PFS were 55% and 36%, respectively. In multivariate analysis, lack of bulky lymph nodes and use of immunotherapy were favourable factors for both OS and PFS. IPF <3 at the time of transplantation was predictive for PFS. However, the prognostic impact of immunotherapy should be interpreted with caution since this group included more patients who achieved CR after HDC/ASCT. The results of HDC/ASCT are encouraging and confirm earlier findings. The role of immunotherapy should be further investigated in prospective trials.

Hematopoietic stem cell transplantation for multiple sclerosis. A retrospective multicenter study.

RATIONALE: Phase I/II studies of autologous hematopoietic stem cell transplantation (HSCT) for multiple sclerosis ( MS) were initiated, based on results of experimental transplantation in animal models of multiple sclerosis and clinical observations in patients treated concomitantly for malignant disease. PATIENTS: Eighty-five patients with progressive MS were treated with autologous HSCT in 20 centers and reported to the autoimmune disease working party of the European Group for Blood and Marrow Transplantation (EBMT). 52 (61 %) were female, median age was 39 [20-58] years. The median interval from diagnosis to transplant was 7 [1-26] years. Patients suffered from severe disease with a median EDSS score of 6.5 [4.5-8.5]. Active disease prior to transplant was documented in 79 of 82 evaluable cases. RESULTS: The stem cell source was bone marrow in 6 and peripheral blood in 79, and stem cells were mobilized into peripheral blood using either cyclophosphamide combined with growth factors or growth factors alone. Three patients experienced transient neurological complications during the mobilization phase. The high dose regimen included combination chemotherapy, with or without anti-lymphocyte antibodies or, with or without, total body irradiation. The stem cell transplants were purged of lymphocytes in 52 patients. Median follow-up was 16 [3-59] months. There were 7 deaths, 5 due to toxicity and infectious complications, 2 with neurological deterioration. The risk of death of any cause at 3 years was 10 (+/-7)% (95 % confidence interval). Neurological deterioration during transplant was observed in 22 patients; this was transient in most but was associated with MS progression in 6 patients. Neurological improvement by > or = 1 point in the EDSS score was seen in 18 (21 %) patients. Confirmed progression-free survival was 74 (+/-12)% at 3 years being 66 (+/-23)% in patients with primary progressive MS but higher in patients with secondary progressive or relapsing-remitting MS, 78 (+/-13)%; p = 0.59. The probability of confirmed disease progression was 20 (+/-11)%. MRI data were available in 78 patients before transplant showing disease activity (gadolinium enhancing, new or enlarging lesions) in 33 %. Posttransplant MRI showed activity at any time in 5/61 (8 %) evaluable cases. CONCLUSION: Autologous HSCT suggest positive early results in the management of progressive MS and is feasible. These multicentre data suggest an association with significant mortality risks especially in some patient groups and are being utilised in the planning of future trials to reduce transplant related mortality.

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.

[Use of cytokines in allogeneic bone marrow transplantation]. / Zastosowanie cytokin w allogenicznym przeszczepianiu szpiku kostnego.

Presently the following cytokines are applied in allogeneic bone marrow transplantation: GM-CSF (granulocyte/macrophage colony stimulating factor), G-CSF (granulocyte colony stimulating factor), interleukin 3 (IL-3) and interferon-alfa (IFN-alfa). GM-CSF and G-CSF applied after bone marrow transplantation accelerate the granulopoietic reconstitution, whereas IL-3 in addition exerts an effect on platelet recovery. These growth factors show also high efficiency in the therapy of graft failure. INF-alfa is used early after allogeneic bone marrow transplantation in patients with hig risk for relapse. This cytokin is also very effective as single therapy or together with marrow donor leukocyte infusions for the treatment of patients with chronic myeloid leukemia in relapse after allogeneic bone marrow transplantation.

[Lysine metabolism in acute leukemia]. / Metabolizm lizyny w ostrych bialaczkach.

The metabolism of 14C-lysine by leukaemic cells in acute myeloblastic, myelomonocytic, lymphoblastic and chronic myeloid leukaemia with blast crisis was studied. The investigations included lysine metabolism to CO2, lipids, organic acids and nucleotides and its incorporation into cellular proteins. The obtained results were compared with determinations carried out in granulocytes and lymphocytes of healthy subjects. Cells in acute leukaemias metabolized 14C-lysine in a similar range. In relation to normal cells the range of lysine metabolism to lipids in the leukaemic cells was significantly higher (p less than 0.01), while that of organic acids was significantly lower (p less than 0.05). The activity of 14C-lysine metabolism depended on the number of blast cells in the sample and the type of acute leukaemia. Neoplastic cells in blast crisis and in acute myeloblastic leukaemia incorporated more actively 14C-lysine into proteins than cells in acute myelomonocytic and acute lymphoblastic leukaemia (p less than 0.05). Similar differences in lysine metabolism were observed between myelomonocytes and blast cells from acute lymphoblastic leukaemia (p less than 0.05).

[Bone marrow transplantation in chronic myeloid leukemia]. / Przeszczepianie szpiku kostnego w przewleklej bialaczce szpikowej.

Bone marrow transplantation (BMT) is at present the only curative therapy for chronic myelogenous leukemia (CML). The outcome of this therapy is much better if marrow transplantation from HLA-matched siblings is performed within 1 year of diagnosis, in young patients and in the chronic phase of the disease. BMT from HLA-matched unrelated donors expands the application of this therapy among CML patients with no available identical siblings. Autologous bone marrow transplantation is presently considered in patients unresponsive to interferon therapy or with high risk of blastic transformation.

[Production of activity stimulating an increase of clonal granulocytic precursors by normal B lymphocytes under the influence of various mitogens]. / Wytwarzanie aktywnosci pobudzajacej wzrost klonalny prekursorów granulocytarnych przez limfocyty B, poddane dzialaniu róznych mitogenów.

The effect of mitogen-stimulated (concanavalin A, Con A; phytohemagglutinin, PHA; pokeweed mitogen, PWM; Staphylococcus aureus Cowan I, SAC I) normal B lymphocytes on the clonal proliferation of granulocytic progenitors from marrow of healthy subjects (CFU-dG) was studied in diffusion chamber culture. PWM-, SAC- and Con A-stimulated B lymphocytes produced an humoral activity that increased the CFU-dG-derived colony formation. The highest growth-stimulating effect was induced by SAC I-preincubated B lymphocytes and to a lesser degree by PWM- or Con A-stimulated B cells. In contrast, PHA-preincubated and unstimulated B lymphocytes revealed no effect on the CFU-dG proliferation.

[Clonal proliferation of less mature granulocytic precursors (CFU-dG) under the influence of neoplastic B lymphocytes in low grade non-hodgkin's lymphomas]. / Proliferacja klonalna mniej dojrzalych prekursorów ukladu granulocytarnego (k.u.-dG) pod wplywem nowotworowych limfocytów B chloniaków nie-ziarniczych o niskim stopniu zlosliwosci.

The effect of peripheral blood lymphoma B cells from low grade malignancy non-Hodgkin's lymphoma patients (Kiel classification: lymphocytic, centrocytic, centroblastic-centrocytic lymphomas) on clonal growth of normal marrow granulocytic precursors (CFU-dG) was studied. Using in vivo diffusion chamber culture method it was shown that all the tested lymphoma cells enhanced the CFU-dG growth by releasing humoral factor(s). The effect of stimulation was cell-concentration and cell-source dependent. The colony stimulating activity produced by centrocytic lymphoma cells had higher potency than that released by centroblastic-centrocytic lymphoma cells, whereas lymphocytic lymphoma cells showed the lowest ability to generate the CFU-dG growth-promoting activity (p < 0.01). It was shown that the CFU-dG growth enhancing effect was independent of marrow-derived macrophages and T lymphocytes (p > 0.05). Normal peripheral blood B lymphocytes used as a control did not show any substantial effect on the granulocytic precursors proliferation.

[Comparative evaluation of treatment results in advanced multiple myeloma with the help of polychemotherapy with vincristine, doxorubicin, dexamethasone (VAD) or only with dexamethasone]. / Ocena porównawcza wyników leczenia zaawansowanych postaci szpiczaka mnogiego za pomoca polichemioterapii winkrystyna, doksorubicyna i deksametazonem (VAD) oraz wylacznie deksametazonem.

A prospective clinical trial was undertaken to determine the therapeutical effectiveness of multidrug chemotherapy consisting of vincristine, doxorubicin and dexamethasone (VAD) or only high dose of dexamethasone (D) in 56 patients with multiple myeloma (MM). The group of patients included 41 with intermediate (II) and 15 with high (III) tumor mass. The final evaluation was performed in 19 patients treated with D and in 19 receiving VAD regimen. Improvement was defined by at least 50% reduction of serum myeloma protein concentration or disappearance of light chain proteinuria. The VAD regimen was more effective giving improvement in 90% of patients with no prior therapy and in 44% of patients with reflectory myeloma. In this respect, cytoreduction of the same magnitude was noted both in stages II and III. Higher therapeutical effect of VAD regimen was observed independently of the immunological type of MM. The treatment with D has given the improvement in 56% of patients with no previous therapy. Our results support the usefulness of VAD regimen in MM-patients with no prior therapy and with refractory myeloma. High frequency of therapy-related complications, however, indicates that VAD treatment should rather be reserved for the patients with resistant MM.

[Clinical usefulness of determination of the sensitivity of myeloblastic leukemia cells to antiproliferative drugs in cell culture in vivo]. / Przydatnosc kliniczna oznaczen wrazliwosci na leki antyproliferacyjne komórek ostrych bialaczek szpikowych w hodowli pllnnej in vivo.

In 15 patients with acute myeloblastic leukaemia and 4 with acute myelomonocytic leukaemia the sensitivity of blast cells was determined to cytosine arabinoside and and rubidomycin in cultures in diffusion chambers implanted into irradiated mice. The degree of sensitivity of leukaemic cells to antiproliferative drugs was determined after incubating the samples with cytosar and cerubidine on the basis of blood cell count changes on the 1st, 3rd and 6th days of the culture as compared with control determinations. The results of culture tests were confronted with the clinical condition of the patients. It was found that in cultures with the cells of the patients, in whom remission was achieved the number of myeloblasts decreased after incubation with cytosar and cerubidine from the 1st or 3rd day on. In patients refractory to treatment in most determinations the number of leukaemic cells incubated in cultures with the drugs remained at the level of the values obtained in control samples or after an initial slight fall this number increased again.

[Empiric antibiotic therapy for treatment of infection in patients with severe neutropenia]. / Empiryczna antybiotykoterapia w leczeniu infekcji u chorych w okresie glebokiej neutropenii.

Infection is the most frequent cause of death in patients with severe neutropenia. Fever and other signs of infection with neutrophil count below 0.5 G/L require an early and rapid treatment--the empiric antibiotic therapy. This treatment comprises various combinations of bactericidal broad-spectrum antibiotics such as ureidopenicillins, cephalosporins, quinolones and aminoglycosides. If defervescence is not attained within 3 days, modification of the treatment scheme should be done. The addition of vancomycin or teicoplanin, antibiotics active against Gram + cocci, and changing of the beta-lactams should be considered. In the case of persistent microbiologically not recognized infection after 7 days of therapy, empiric antimycotic treatment with amphotericin B is indicated. Duration of the empiric antibiotic therapy is dependent on the granulocyte recovery and the resolution of infection.

[Contemporary possibilities of prognosis in myelodysplastic syndromes]. / Wspólczesne mozliwosci rokowania w zespolach mielodysplastycznych.

Myelodysplastic syndromes (MDS) comprise a heterogenous group of closely related, acquired stem cell disorders. Various patterns of clinical evolution have been observed in patients with different subtypes according to the FAB (French-American-British) criteria. The marked differences in clinical outcome among MDS patients have encouraged us to search the alternative variables for predicting leukemic transformation and survival. During the past 10 years different prognostic scoring systems based on age combined with blood and bone marrow parameters have been described. This has enabled the identification of patients with better and worse prognosis among different MDS types. Additionally, studies of cytogenic patterns in MDS patients and widespread availability of bone marrow histological specimens extended the possibility of prognosis in this disease. Similarly, the in vitro culture results of hematopoietic cells using growth and differentiation factors have given very promising results. The high prevalence of RAS mutation in patients with MDS has been defined, but its clinical usefulness is under discussion.

[Current approaches of treatment for myelodysplastic syndrome (MDS)]. / Obecne mozliwosci terapii zespolów mielodysplastycznych (MDS).

The number of treatment modalities for patients with myelodysplastic syndromes (MDS) has increased, but curative options are still limited. For the majority of patients with low risk there is no standard therapy other than appropriate supportive care. In selected patients anabolic steroids, differentiation inducers such as cis-retinoic acid (RA), interferon alpha or gamma have been claimed to be active. Application of growth factors such as granulocyte-macrophage colony stimulating factor (GM-CSF), granulocyte colony stimulating factor (G-CSF), and interleukin 3 (IL-3) improves neutrophil count and diminishes frequency of infectious complications, but responses are incomplete and of short duration. Preliminary results of erythropoietin (Epo) applied in therapeutical doses are disappointing, giving an improvement in 15-20% patients. Epo in large doses produces greater and sustained responses, but this treatment is too expensive. Low-dose cytosine arabinoside (Ara-C) induces a response rate in 25-30% patients, however, no survival advantage has been obtained. Addition of RA or GM-CSF produces response rates comparable to Ara-C alone, but also with no prolongation in survival. Bone marrow transplantation (BMT) offers a good chance of long-term disease-free survival if is performed in an early stage of the disease or in complete remission, however, it is limited to patients below 55 years with an HLA-identical donor. Relatively young, high risk patients not eligible for allogeneic BMT should be considered for treatment with intensive polychemotherapy.