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ABSTRACT: Primary mediastinal large B cell lymphomas (MLCL) differ from other diffuse large cell lymphomas, leading to a description as a separate entity in the current World Health Organization classification. Dose intensification improves long-term results, but no standard therapy has been established so far. We investigated the use of a high-dose methotrexate-based alternating chemotherapy regimen (B-ALL protocol of the German ALL study group) followed by consolidative mediastinal radiotherapy first as a single-center trial, then later as a prospective multicenter trial in 44 patients with a median age of 33 years. Response rates exceeded 90% with an overall survival rate of 80% in the single-center group (8.6 years median follow-up) and 82% in the multicenter group (2.5 years follow-up).Short-term toxicity was manageable, but required hospitalization: the rates of grade 3 or 4 toxicity were 20% (for mucositis), 42% (for neutropenia), 29% (for thrombocytopenia), and 9% (for neutropenic fever). No relapse occurred more than 2 years after diagnosis and initiation of treatment, but unfortunately, no patient with overt progression or relapse within these 2 years could be salvaged. Future directions in the treatment of MLCL will not focus on further dose intensification, but rather on the incorporation of (radio)immunotherapy as a therapeutic tool and gene expression profiling as well as positron emission tomography-computed tomography as stratifying tools.
Annals of Hematology 11/2008; 88(5):433-9. · 2.62 Impact Factor
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ABSTRACT: We investigated the in vitro toxicity of bendamustine and fludarabine to hematopoietic progenitors and stem cells from healthy donors.
Clonogenic agar colony assays, non-clonogenic long-term liquid cultures (LTC) and apoptosis assays were used to assess the cytotoxicity of both the agents.
Total colony-forming units (CFU) were more sensitive to fludarabine than to bendamustine in agar colony assays (IC(50) 0.7 microM/L and 8.5 microM/L, respectively). Using the Bliss independence model and combining the two agents yielded additive inhibition of progenitors. Non-clonogenic assays, including LTC and an apoptosis assay detecting activated caspases showed that stem cells are characterized by low sensitivity to bendamustine. In contrast, fludarabine strongly inhibited the viability and growth of stem cells in LTC.
Our data show that bendamustine is characterized by lower in vitro toxicity to hematopoietic progenitors and stem cells than fludarabine and might thus be preferable in regimens prior to stem cells apheresis.
Journal of Cancer Research and Clinical Oncology 09/2008; 135(2):227-34. · 2.56 Impact Factor
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ABSTRACT: Reduced-intensity conditioning with fludarabine and treosulfan before allogeneic stem cell transplantation (SCT) was introduced several years ago. Although its feasibility has recently been proven, only limited data are available on myelotoxicity, engraftment kinetics, and the significance of hematopoietic chimerism using this novel conditioning regimen. To clarify these open questions, we analyzed 27 patients with various hematological diseases, who received allogeneic SCT preceded by fludarabine/treosulfan conditioning. Further assessment endpoints included graft-vs-host disease (GvHD), mortality, and overall survival (OS). Allogeneic SCT was followed by neutropenia (absolute neutrophil count < or = 0.5 x 10(9)/l) and thrombocytopenia (platelets < or = 20 x 10(9)/l) in all patients. All patients showed stable neutrophil engraftment, and all except one had stable platelet engraftment. Grades II-IV acute GvHD was found in 48% of patients, whereas 52% developed chronic GvHD. The treatment-related mortality on day +100, 1 year after SCT, and at the last follow-up was 11, 26, and 33%, respectively. We found complete chimerism rates of 46, 57, and 72% on days +28, +56, and at the last follow-up or before death, respectively. The underlying malignancy tended to relapse more frequently in patients with mixed chimerism than in those with complete chimerism on day +28 as well as on day +56 (not significant). Additionally, no significant association was found between hematopoietic chimerism and donor type, GvHD, or OS, respectively. We conclude that reduced-intensity conditioning with fludarabine and treosulfan before allogeneic SCT is myeloablative, provides stable engraftment, and leads to complete chimerism in the majority of patients.
Annals of Hematology 09/2007; 86(8):583-9. · 2.62 Impact Factor
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M Schmidt-Hieber,
I W Blau,
R Trenschel,
R Andreesen,
G Stuhler,
H Einsele,
L Kanz,
U Keilholz,
O Marinets,
D W Beelen,
A A Fauser,
L Volin,
T Ruutu,
L Uharek,
T Fietz, W Knauf,
W Hopfenmüller,
E Thiel,
M Freund,
J Casper
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ABSTRACT: In recent years, reduced-intensity conditioning (RIC) regimens before allogeneic stem cell transplantation (SCT) are increasingly used in patients not eligible for conventional conditioning. We did a retrospective, multicenter analysis to assess the feasibility of conditioning with fludarabine and treosulfan before allogeneic SCT in multiple myeloma patients. Thirty-four patients with a median age of 51.5 years were included in the analysis. All patients underwent myeloablation after conditioning followed by stable engraftment, and 29 of 31 evaluable patients (94%) showed early complete hematopoietic chimerism. Non-hematological toxicities were limited and encompassed mainly fever in neutropenia and infections. Grade II-IV acute and chronic graft-versus-host disease was observed in 33 and 39%, respectively. With a median follow-up of 708 days (range 60-1729 days), the median progression-free survival was 180 days. The treatment-related mortality was 10% on day 100 and 25% after 1 year. The median overall survival has not yet been reached. Our data indicate that conditioning with fludarabine and treosulfan before allogeneic SCT is feasible in intensively pretreated multiple myeloma patients and leads to stable engraftment and complete hematopoietic chimerism. Randomized trials are warranted to determine if this approach might be incorporated in an algorithm of multiple myeloma treatment.
Bone Marrow Transplantation 05/2007; 39(7):389-96. · 3.75 Impact Factor
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ABSTRACT: Physical activity has been shown to stimulate haematopoiesis in patients with anaemia due to chronic renal failure or haematological malignancies.
To evaluate the effect of moderate exercise on the production of haematopoietically active factors.
Ten patients (four men and six women, mean (SD) age 51 (10) years) with a haemoglobin concentration under 130 g/l (men) or 120 g/l (women) carried out five three minute exercise bouts at an intensity of 80% of the maximal heart rate, corresponding to a lactate concentration of 3 (0.5) mmol/l. Patients rested for three minutes between bouts. The concentrations of interleukin 6, stem cell factor, granulocyte-monocyte colony stimulating factor, granulocyte colony stimulating factor, erythropoietin, and growth hormone (GH) were evaluated before and in the eight hours after exercise.
GH had risen significantly 15 minutes after exercise (1.1 (1.3) v 2.7 (2.8) ng/ml; p<0.05). No change in the concentration of the other cytokines and growth factors was observed in the eight hours after exercise.
In patients with anaemia, submaximal exercise does not affect the concentration of haematopoietically active cytokines. However, it leads to an increased concentration of GH. This may be responsible for the improved haematopoiesis observed after an exercise programme in patients with chronic diseases.
British journal of sports medicine 12/2004; 38(6):e37. · 2.55 Impact Factor
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ABSTRACT: We report on the response rate and tolerability of Alemtuzumab (Campath-1H) in a series of heavily pretreated patients with B-CLL with a special focus on treatment-related problems. All patients tested positive for CD52 on B-lymphocytes before entering the trial. Thirteen patients with B-chronic lymphocytic leukemia (B-CLL), 1 prolymphocytic leukemia (PLL), 1 mantle cell lymphoma (MCL) and 1 leukemic immunocytoma (IC) transformed into a high-grade NHL were included. Median age was 62 years (range 40-73), and pretreatment consisted of median 3 prior regimens (range 1-11). All patients received 3, 10 and 30 mg of Campath-1H on sequential days, and then were subsequently scheduled for 30 mg 3 times weekly. Nine out of 16 patients responded. One patient attained complete remission (CR), 8 patients achieved partial remission (PR), while 4 patients had stable disease (SD). Three patients had progressive disease (PD). Beginning with initiation of treatment recurrent profound leukopenia became evident in 13 out of 16 patients leading to treatment discontinuation. Severe nonhematological toxicity (WHO grade IV bronchospasm) occurred in the first patient of this series, who initially had no concomitant steroids. Therefore, we developed a steroid co-medication regimen for the first 4 Campath-1H applications with quick tapering thereafter. Following this regimen, no infusion associated side effects WHO grade > II were observed. Infectious complications leading to treatment discontinuation consisted of pulmonary aspergillosis in one and bacterial pneumonia in another case. One patient with refractory B-CLL and Pneumocystis carinii pneumonia plus CMV reactivation died. In summary, Campath-1H appears to be effective against leukemic low-grade B-NHL, also in advanced stage. In our series, application 3 times weekly was not possible due to hematotoxicity. We recommend, therefore, flexible time intervals depending on the leukocyte counts. Whether a cumulative dosage according to 3 x 30 mg Campath-1H for 12 weeks is needed still remains to be clarified.
Leukemia and Lymphoma 02/2004; 45(2):345-9. · 2.58 Impact Factor
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J Casper, W Knauf,
I Blau,
T Ruutu,
L Volin,
H Wandt,
K Schafer-Eckart,
J Holowiecki,
S Giebel,
J Aschan,
A Zander,
N Kroger,
G Doelken,
M Freund
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ABSTRACT: Recently, the water-soluble bifunctional alkylating agent treosulfan demonstrated broad stem cell toxicity, immunosuppressive as well as antileukemic activity. Due to its well known low non-hematologic toxicity profile, treosulfan was considered an alternative agent for conditioning prior to allogeneic transplantation. A first clinical study, combining 3 x 10 g/m2 of treosulfan with 5 x 30 mg/m2 of fludarabine, demonstrated the feasibility of this conditioning. A fast, reliable and complete development of the donor hematopoiesis was evident as well as a low non-hematologic toxicity, transplantation-related mortality and relapse rate. In a second study treosulfan was escalated from 3 x 10 to 3 x 12 and 3 x 14 g/m2. In this protocol, 55 pts (patients) not amenable to standard conditioning suffering from various hematological malignancies were included. Complete donor chimerism was reached by day 28 in 80% of the pts. So far, 8 pts (11%) died without disease progression and 11 pts (20%) relapsed. Treosulfan was very well tolerated. Especially no hepatic VOD, severe cardiac or pulmonary toxicity was noted. Acute GvHD (degrees 11-IV) occurred in 44% and chronic GvHD in 45% of pts. Considering the poor prognosis of these study populations, treosulfan-based conditioning is considered to be safe and efficient. New phase 11 clinical protocols in AML and MDS will be initiated.
Annals of Hematology 02/2004; 83 Suppl 1:S70-1. · 2.62 Impact Factor
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R Arnold,
G Massenkeil,
M Bornhäuser,
G Ehninger,
D W Beelen,
A A Fauser,
U Hegenbart,
B Hertenstein,
A D Ho, W Knauf,
H J Kolb,
K Kolbe,
H G Sayer,
R Schwerdtfeger,
H Wandt,
D Hoelzer
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ABSTRACT: The feasibility of nonmyeloablative stem cell transplantation (NST) was evaluated in 22 adults with high-risk ALL. 16/22 patients had advanced disease and 11/22 had Ph+ ALL. Eleven patients received NST as first stem cell transplantation (SCT). Eleven patients had relapses after allogeneic or autologous SCT and underwent a salvage NST. 18/22 patients (82%) engrafted after NST. 13/16 patients (81%) with active disease reached complete remission (CR). 11 of 13 patients developed GVHD. After first NST 10/11 patients (91%) engrafted. Six of seven patients with active disease reached CR. Three of five relapsing patients reached subsequent CR after donor lymphocyte infusions, termination of immunosuppression or imatinib. Three of 11 patients (27%) are alive in CR 5 to 30 months after NST. Eight of 11 patients have died, 3/8 from leukemia and 5/8 from transplant-related causes. After salvage NST, 8/11 patients (73%) engrafted. Seven of nine patients with active disease reached CR. Only one of 11 patients transplanted, who was in CR before undergoing salvage NST is alive 19 months after NST. Five of 11 have died from leukemia, one of 11 after graft failure and four of 11 from transplant-related causes. Four of 22 patients (18%) are alive in CR 5, 14, 19 and 30 months after NST. NST is feasible in adults with high risk ALL. However, transplant-related mortality remains high and only patients transplanted in CR seem to have long-term disease-free survival.
Leukemia 01/2003; 16(12):2423-8. · 9.56 Impact Factor
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ABSTRACT: Recombinant human granulocyte colony-stimulating factor (rhG-CSF) mobilized peripheral blood progenitor cells (PBPCs) from healthy individuals are a rapidly emerging alternative source to bone marrow for allogeneic transplantation. Although widely applied in the meantime, only limited information on feasibility and safety of mobilization and collection of PBPCs is currently available from prospective multicenter studies specifically designed to investigate this donation modality. This ongoing multicenter study on the performance as well as the short- and long-term safety profile of rhG-CSF-induced mobilization and collection of PBPCs was initiated in October 1999. The study is designed to recruit a total of 300 healthy family donors who will be followed regularly for a period of 5 years after donation. The first interim report presented here summarizes results obtained after enrollment of 150 donors from nine German institutions. The study protocol allowed the individual choice between two dose regimens of rh-CSF (10 micro g/kg per day vs 2x8 micro g/kg per day of donor body weight). The primary endpoint was defined as a yield of > or =5x10(6) CD34(+) cells/kg of recipient body weight in a single leukapheresis product. This endpoint was attained by 50% of donors receiving the lower rhG-CSF dose regimen and by 75% of donors with the higher dose regimen ( p<0.0009). A total of 478 acute adverse events attributable to the mobilization procedure were recorded and manifested predominantly as transient bone pain and headaches (80%). No persistent hematologic or nonhematologic adverse events have occurred in this study so far. Thus, the current experience in a prospective multicenter study supports previous single-center and retrospective registry reports in that the collection of PBPCs after rhG-CSF mobilization is feasible and associated with frequent, but generally mild and acceptable side effects.
Annals of Hematology 12/2002; 81(12):701-9. · 2.62 Impact Factor
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M Hallek,
M Bergmann,
G Brittinger,
H Döhner,
P Dreger,
M Herold,
G Hopfinger,
U Jäger, W Knauf,
C Nerl,
M Rummel,
B Schmitt,
C M Wendtner,
B Emmerich
Der Internist 11/2002; 43(10):1245-54. · 0.30 Impact Factor
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ABSTRACT: High-dose chemotherapy with subsequent autologous stem cell transplantation is believed to be of therapeutic benefit in patients with acute myeloid leukemia (AML), especially when no allogeneic bone marrow donor is available. One of the main risks is contamination of the stem cell preparations with leukemic blasts, which may account for a higher relapse rate compared to allogeneic bone marrow transplantation. Since overexpression of WT1 is common in leukemic blasts, we investigated, whether PBSCs from AML patients express WT1 at a higher level as compared to patients with solid cancers. PBSCs of seven patients with AML and of five patients with solid cancers were investigated for WT1 expression. Total WT1 copy count was determined in a standardized quantitative real time RT-PCR. WT1 expression was found in all AML PBSCs with an average copy number of 49.99 +/- 61.09. In solid cancers WT1 expression was statistically significantly lower with a copy number of 3.51 +/- 1.92. In AML patients with sustained complete remission we found a nearly significantly lower WT1 expression than in patients who relapsed within the first year after stem cell transplantation. Our data show a higher WT1 expression in PBSCs of AML patients compared to patients with solid cancers. This finding might indicate a contamination with leukemic blasts. Quantification of WT1 in PBSCs might therefore be useful to estimate the risk of relapse after autologous stem cell transplantation in AML patients.
Bone Marrow Transplantation 04/2002; 29(5):379-81. · 3.75 Impact Factor
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ABSTRACT: Clinical efficacy of As2O3 has been shown in patients with relapsed acute promyelocytic leukaemia (APL). There is evidence that the effects of As2O3 are not restricted to events specific for APL. As2O3 might target mechanisms involved in the pathogenesis of other malignancies. We assessed susceptibility to induction of apoptosis by As2O3 and cytostatics in 22 myeloid and non-myeloid malignant cell lines. As2O3 was used in concentrations of 0.01-10 micromol/l. Cell lines displayed different kinetics of response and different sensitivity to As2O3. The minimum concentration of As2O3 for induction of apoptosis was 0.1 micromol/l. High concentrations of As2O3 (5 micromol/l) induced apoptosis in a large proportion of cells in all cell lines tested. Low (1 micromol/l As2O3) concentrations induced apoptosis in NB-4, HL-60, U-937, CEM, HL-60, KG-1a, PBL-985, ML-2 and MV-4-11, but not in HEL, K-562, KG-1 and Jurkat up to 35 d of incubation. However, the non-apoptotic population of 1 micromol/l As2O3-treated HEL, K-562, K-562 (0.02), K-562(0.1) and Jurkat showed reduced proliferation. CEM as well as its' multidrug-resistant derivatives were sensitive to 1 micromol/l As2O3. In summary, these data demonstrate that As2O3-induced apoptosis is not restricted to cell lines with t(15;17). Apoptosis was induced in vitro by As2O3 concentrations that are achievable in vivo after infusion of well-tolerated As2O3 doses. Thus, As2O3 might be a suitable therapeutic agent for malignancies other than APL provided the adequate dose and duration of As2O3 treatment are used.
British Journal of Haematology 04/2002; 116(3):555-63. · 4.94 Impact Factor
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M. Hallek,
M. Bergmann,
G. Brittinger,
H. Döhner,
P. Dreger,
M. Herold,
G. Hopfinger,
U. Jäger, W. Knauf,
C. Nerl,
M. Rummel,
B. Schmitt,
C.M. Wendtner,
B. Emmerich,
für die Deutsche CLL-Studiengruppe
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ABSTRACT: Die chronische lymphatische Leukämie (CLL) ist die häufigste Leukämie der westlichen Welt. In den letzten 10 Jahren haben
sich die Konzepte zur Therapie der CLL erheblich geändert. Neue Therapieverfahren wie Purinanaloga, Hochdosistherapie und
monoklonale Antikörper trugen wesentlich zu diesem Fortschritt bei. Die Behandlung der CLL ist heute wesentlich differenzierter
als vor wenigen Jahren und erfordert eine alters- und risikoangepasste Vorgehensweise. Dabei ist zu betonen, dass noch viele
wesentliche Fragen zur Therapie der CLL offen sind. Nur durch Einbringen der Patienten in multizentrische Protokolle, wie
sie die Deutsche CLL-Studiengruppe im deutschsprachigen Raum durchführt, werden diese Fragen in den nächsten Jahren zu beantworten
sein.
Der Internist 01/2002; 43(10):1245-1254. · 0.30 Impact Factor
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ABSTRACT: As there are few reports on early evaluation of chimerism, we assessed fluorescence short tandem repeats (STR) by polymerase chain reaction (PCR) assays to analyse donor and recipient characteristics at early time points after peripheral stem cell transplantation (PBSCT). Peripheral blood of 13 patients was analysed in 1- to 2-day intervals starting from the day of PBSCT. Donor and recipient allelic patterns were determined by a commercially available multiplex STR assay that simultaneously evaluates four or five gene loci. Mixed chimerism appeared in all patients during days 1-9 after transplantation and preceded haematologic engraftment for 3-12 days. Even patients without myeloablative conditioning therapy (n=4) revealed donor allelic patterns within 1-5 days. Nine patients changed during the following days to a complete donor allelic pattern and had an uncomplicated post-transplant disease course. Four patients did not consistently retain complete donor chimerism; two of them relapsed within the next 3 months, one died from septicemia within 7 days, and the fourth, transplanted for aplastic anaemia, is still in complete remission. Overall, STR analysis using a simple and comparatively cheap multiplex system permits the detection of chimerism very early after transplantation and may provide relevant information that correlates with the clinical follow-up.
Clinical & Laboratory Haematology 01/2002; 23(6):401-6. · 1.11 Impact Factor
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D Huhn,
C von Schilling,
M Wilhelm,
A D Ho,
M Hallek,
R Kuse, W Knauf,
U Riedel,
A Hinke,
S Srock,
S Serke,
C Peschel,
B Emmerich
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ABSTRACT: Rituximab (IDEC-C2B8) is a chimeric antibody that binds to the B-cell surface antigen CD20. Rituximab has significant activity in follicular non-Hodgkin lymphomas. Much less is known about the effects in chronic lymphocytic leukemia (CLL). We have initiated a phase II trial to evaluate the efficacy and safety of rituximab in patients with CD20+ pretreated CLL. To avoid the rituximab-associated toxicity, we restricted the tumor cell load, as measured by the number of circulating lymphocytes and the spleen size, in the first 2 cohorts of patients included in the study. Patients received 4 intravenous infusions of 375 mg/m2 once a week over a period of 1 month. Of the 28 patients evaluable for response, 7 patients showed a partial remission (National Cancer Institute criteria) lasting for a median of 20 weeks, with 1 patient still in remission after 71 weeks. Based on lymphocyte counts only, we found at least a 50% reduction of lymphocyte counts lasting for at least 4 weeks in 13 (45%) of 29 patients. Fifteen patients from 3 institutions were monitored for the immunophenotype profile of lymphocyte subsets. The number of CD5+CD20+ cells decreased significantly and remained low until day 28 after therapy. T-cell counts were not affected. With the exception of one rituximab-related death, adverse events in the remaining patients were mild. The results suggest that rituximab has clinical activity in pretreated patients with B-CLL. Toxicity is tolerable. Response duration after withdrawal of rituximab is rather short. Therefore, other modes of application and the combination with other agents need to be tested.
Blood 10/2001; 98(5):1326-31. · 9.90 Impact Factor
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M Hallek,
B Schmitt,
M Wilhelm,
R Busch,
A Kröber,
H P Fostitsch,
O Sezer,
M Herold, W Knauf,
C M Wendtner,
R Kuse,
M Freund,
A Franke,
F Schriever,
C Nerl,
H Döhner,
E Thiel,
W Hiddemann,
G Brittinger,
B Emmerich
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ABSTRACT: The efficacy and toxicity of a combination of fludarabine and cyclophosphamide (FC) was evaluated in patients with B-cell chronic lymphocytic leukaemia (CLL). Between April 1997 and July 1998, 36 patients with CLL (median age 59 years) received a regimen that consisted of fludarabine 30 mg/m(2) in a 30-min IV infusion, d 1-3, and cyclophosphamide 250 mg/m(2) in a 30-min IV infusion on d 1-3. Cycles were repeated every 28 d. Twenty-one patients had received between one and three different treatment regimens prior to the study, while 15 patients had received no prior therapy. The median Eastern Cooperative Oncology Group performance score was 1. One patient was at Binet stage A, 18 were stage B and 17 patients were stage C. Objective responses, assessed according to the revised guidelines of the National Cancer Institute-sponsored Working Group, were recorded in 29 out of 32 assessable patients (90.6%). Twenty-four partial remissions and five complete remissions were observed. Two patients showed no change and one patient showed disease progression. At February 2000, three of the responders had relapsed. Severe neutropenia, anaemia and thrombocytopenia (Common Toxicity Criteria grade 3 and 4) were observed in 25, six and six patients (69.4%, 16.7% and 16.7%) respectively. Other side-effects were uncommon. No treatment-related deaths and no grade 3 or 4 infections occurred. We conclude that the combination of fludarabine and cyclophosphamide showed significant activity in patients with CLL. Myelosuppression was the major side-effect. These results warrant further study on the FC combination in randomized trials.
British Journal of Haematology 09/2001; 114(2):342-8. · 4.94 Impact Factor
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ABSTRACT: Patients with advanced multiple myeloma (stage III or progressive myeloma) received the CAD protocol every three weeks: cyclophosphamide 200 mg/m2 i.v./orally days 1-4, adriamycin 30 mg/m2 i.v. on day 1 and dexamethasone 40 mg p.o. days 1-4.
Forty-six patients with a median age of sixty years (range 34-84 years) were enrolled. According to Durie-Salmon 44 patients were in stage III, 2 in stage II; 6 patients had renal insufficiency (stage B). Twenty-three patients were pre-treated at least with melphalane/prednisone.
Remission rates were as follows: complete remission 4%, partial remission 70%, minimal change 11%, no change 11%, progressive disease 4%. After an observation time of 14 months the median progression free interval for 33 patients not treated with subsequent high-dose chemotherapy with stem-cell support was more than 14 months. Overall, treatment was well tolerated. After 209 cycles given febrile neutropenia occurred in 11% of cycles including one fatal outcome. Neutropenia or thrombocytopenia grade 3-4 WHO was recorded in 18% and 6% of the cycles, respectively.
This study shows that CAD is an effective regimen with an overall remission rate of 74%. The CAD protocol should be further evaluated in prospective trials.
Annals of Oncology 02/2001; 12(1):105-8. · 6.43 Impact Factor
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ABSTRACT: To circumvent aGVHD in the early phase after allogeneic stem cell transplantation but to provide GVL activity later on, we performed alloPBSCT with CD34+ selected grafts followed by delayed add-back of CD3+ T cells. Ten consecutive patients having an HLA-identical sibling donor were enrolled on to this trial. Four patients were in first CR of high-risk ALL, another four in first CR of AML, one was in second myeloid blast crisis of CML, and one was in PR of relapsed NHL. Conditioning consisted of 2 x 60 mg/kg CY plus 12 Gy TBI. G-CSF (Filgrastim) mobilized peripheral cells were CD34+ selected using the Isolex 300i system in nine patients and the CliniMacs system in one. Median CD34+ purity was 86%. A median of 2.8 x 10(6)/kg CD34+ cells were transplanted. The number of CD3+ cells in the allografts was 5.7 x 10(4)/kg (median) after Isolex 300i, and 0.2 x 10(4)/kg after CliniMacs. All patients received G-CSF (Filgrastim) and engrafted rapidly. Standard-dose CsA was administered, and until day +60 no aGVHD occurred. At that time point, seven patients received 2 x 10(6)/kg CD3+ cells while CsA had been tapered to 50% of the starting dose. One of these patients died after a second T cell boost given on day +90 without concomitant immunosuppression due to grade IV intestinal aGVHD. Three others developed cutaneous cGVHD. Taken together, T cell depletion by CD34+ selection does not impair rapid engraftment in the HLA-identical sibling donor setting. Using standard-dose CsA the risk for acute GVHD seems to be minimized. Add-back of 2 x 10(6)/kg CD3+ cells on day +60 with CsA protection is feasible. However, whether this is the optimal time point and number of T cells remain to be further elucidated.
Bone Marrow Transplantation 06/2000; 25 Suppl 2:S2-5. · 3.75 Impact Factor
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ABSTRACT: CD82 (KAI1) is a member of the tetraspan transmembrane protein family which has been cloned from lymphoblastoid variant cell lines. However, a role for CD82 in early normal and malignant haemopoiesis has not yet been characterized. We studied the CD82 expression in 33 normal donor samples and 98 leukaemias by fluorescence activated cell sorting (FACS) and reverse transcriptase polymerase chain reaction (RT-PCR). We demonstrated that CD82 was moderately expressed in the vast majority of normal granulocytes and monocytes. In contrast, only about one third of the peripheral blood lymphocytes were weakly CD82 positive (CD82+). Interestingly, judgement of the CD82 transcription and expression in various leukaemias revealed that CD82 was overexpressed in chronic myeloid leukaemia (CML) patients in accelerated or blastic phase (CML-AP/BP) as well as in acute myeloid leukaemia (AML) and chronic lymphocytic leukaemia (CLL) patients. Analysis of AML patients with CD34+/CD82+ blasts prompted us to expand our studies on haemopoietic CD34+ progenitor cells. Intriguingly, 84-95% of the CD34+ cells isolated from healthy bone marrow, cord blood or peripheral blood were highly CD82+. CD82 was abundantly expressed on primitive as well as on committed haemopoietic progenitor cells. After in vitro induction of myeloid differentiation in CD34+ peripheral blood progenitor cells (PBPC), the expression of CD82 decreased to levels similar to those found on peripheral blood granulocytes. These observations suggest for the first time a role for CD82 in normal and malignant haemopoiesis.
British Journal of Haematology 01/2000; 107(3):494-504. · 4.94 Impact Factor
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Leukemia and Lymphoma 11/1999; 35(5-6):641-2. · 2.58 Impact Factor
