[Show abstract][Hide abstract] ABSTRACT: In the two consecutive German studies III and IIIA on chronic myeloid leukemia, between 1995 and 2004, 781 patients were randomized to receive either allogeneic hematopoietic stem cell transplantation with a related donor or continued drug treatment. Despite comparable transplantation protocols and most centers participating in both studies, the post-transplant survival probabilities for patients transplanted in first chronic phase were significantly higher in study IIIA (144 patients) than in study III (113 patients). Prior to the decision on a combined analysis of both studies, reasons for this discrepancy had to be investigated.
The Cox proportional hazard cure model was used to identify prognostic factors for post-transplant survival.
Donor-recipient matching for human leukocyte antigen, patient age, time between diagnosis and transplantation, and calendar time showed a significant influence on survival and/or the incidence of cure. Added as a further factor, affiliation to study IIIA had no significant impact any longer.
Discrepancies in influential prognostic factors explained the different post-transplant survival probabilities between the studies. The significance of calendar time suggests a lack of consistency of transplantation practice over time. Accordingly, the prerequisite for a common assessment of overall survival in the two randomized transplantation arms was not met. Moreover, our analyses provide an independent validation of established prognostic factors and their cutoffs. The statistical approach in investigating and modeling potential prognostic factors for survival sets an example for the examination of studies with unexpected outcome differences in concurrent treatment arms.
Journal of Cancer Research and Clinical Oncology 04/2014; 140(8). DOI:10.1007/s00432-014-1662-y · 3.08 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Deep molecular response (MR(4.5)) defines a subgroup of patients with chronic myeloid leukemia (CML) who may stay in unmaintained remission after treatment discontinuation. It is unclear how many patients achieve MR(4.5) under different treatment modalities and whether MR(4.5) predicts survival.
Patients from the randomized CML-Study IV were analyzed for confirmed MR(4.5) which was defined as ≥ 4.5 log reduction of BCR-ABL on the international scale (IS) and determined by reverse transcriptase polymerase chain reaction in two consecutive analyses. Landmark analyses were performed to assess the impact of MR(4.5) on survival.
Of 1,551 randomly assigned patients, 1,524 were assessable. After a median observation time of 67.5 months, 5-year overall survival (OS) was 90%, 5-year progression-free-survival was 87.5%, and 8-year OS was 86%. The cumulative incidence of MR(4.5) after 9 years was 70% (median, 4.9 years); confirmed MR(4.5) was 54%. MR(4.5) was reached more quickly with optimized high-dose imatinib than with imatinib 400 mg/day (P = .016). Independent of treatment approach, confirmed MR(4.5) at 4 years predicted significantly higher survival probabilities than 0.1% to 1% IS, which corresponds to complete cytogenetic remission (8-year OS, 92% v 83%; P = .047). High-dose imatinib and early major molecular remission predicted MR(4.5). No patient with confirmed MR(4.5) has experienced progression.
MR(4.5) is a new molecular predictor of long-term outcome, is reached by a majority of patients treated with imatinib, and is achieved more quickly with optimized high-dose imatinib, which may provide an improved therapeutic basis for treatment discontinuation in CML.
[Show abstract][Hide abstract] ABSTRACT: Since the advent of tyrosine kinase inhibitors, the impact of age on outcome of chronic myeloid leukemia (CML) patients has changed. We therefore analyzed patients from the randomized CML study IV to investigate disease manifestations and outcome in different age groups. One thousand five hundred twenty-four patients with BCR-ABL-positive chronic phase CML were divided into four age groups: (1) 16–29 years, n = 120; (2) 30–44 years, n = 383; (3) 45–59 years, n = 495; and (4) ≥60 years, n = 526. Group 1 (adolescents and young adults (AYAs)) presented with more aggressive disease features (larger spleen size, more frequent symptoms of organomegaly, higher white blood count, higher percentage of peripheral blasts and lower hemoglobin levels) than the other age groups. In addition, a higher rate of patients with BCR-ABL transcript levels >10 % on the international scale (IS) at 3 months was observed. After a median observation time of 67.5 months, no inferior survival and no differences in cytogenetic and molecular remissions or progression rates were observed. We conclude that AYAs show more aggressive features and poor prognostic indicators possibly indicating differences in disease biology. This, however, does not affect outcome.
Electronic supplementary material
The online version of this article (doi:10.1007/s00277-013-1937-4) contains supplementary material, which is available to authorized users.
Annals of Hematology 10/2013; 93(1). DOI:10.1007/s00277-013-1937-4 · 2.63 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Eight cycles of BEACOPP(escalated) (escalated dose of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) followed by radiotherapy (RT) to initial bulk or residual tumor mass is the German Hodgkin Study Group standard of care for advanced-stage Hodgkin's lymphoma (HL). However, treatment-related toxicity is a concern, and the role of RT in this setting is unclear. The HD12 study thus aimed to reduce toxicity while maintaining efficacy.
In this prospectively randomized multicenter trial, eight cycles of BEACOPP(escalated) was compared with four cycles of BEACOPP(escalated) followed by four cycles of the baseline dose of BEACOPP (BEACOPP(baseline); 4 + 4), and RT with no RT in the case of initial bulk or residual disease. The study was designed to exclude a difference in 5-year freedom from treatment failure (FFTF) rate of 6%.
Between January 1999 and January 2003, 1,670 patients age 16 to 65 years were enrolled onto the HD12 study. At 5 years, FFTF was 86.4% in the BEACOPP(escalated) arm and 84.8% in the 4 + 4 arm (difference, -1.6%; 95% CI, -5.2% to 1.9%), and overall survival was 92% versus 90.3% (difference, -1.7%; 95% CI, -4.6% to 1.1%). Deaths related to acute toxicity of chemotherapy were observed in 2.9% of patients (BEACOPP(escalated), n = 19; 4 + 4, n = 27). FFTF was inferior without RT (90.4% v 87%; difference, -3.4%; 95% CI, -6.6% to -0.1%), particularly in patients who had residual disease after chemotherapy (difference, -5.8%; 95% CI, -10.7% to -1.0%), but not in patients with bulk in complete response after chemotherapy (difference, -1.1%; 95% CI, -6.2% to 4%).
The reduction of BEACOPP to the 4 + 4 regimen did not substantially reduce severe toxicity but might decrease efficacy. Our results do not support the omission of consolidation RT for patients with residual disease. Alternative strategies for improving the risk-to-benefit ratio for patients with advanced HL are needed.
[Show abstract][Hide abstract] ABSTRACT: Treatment of chronic-phase (CP) chronic myeloid leukemia (CML) with imatinib 400 mg/d can be unsatisfactory. Optimization of treatment is warranted.
In all, 1,014 newly diagnosed CP-CML patients were randomly assigned to imatinib 800 mg/d (n = 338), imatinib 400 mg/d (n = 325), or imatinib 400 mg/d plus interferon alfa (IFN-α; n = 351). Dose adaptation to avoid higher-grade toxicity was recommended. First primary end point was major molecular remission (MMR) at 12 months.
A higher rate of MMR at 12 months occurred with tolerability-adapted imatinib 800 mg/d than with imatinib 400 mg/d (59% [95% CI, 53% to 65%] v 44% [95% CI, 37% to 50%]; P < .001) or imatinib 400 mg/d plus IFN-α (59% v 46% [95% CI, 40% to 52%]; P = .002). Median dose in the 800-mg/d arm was 628 mg/d with a maximum dose of 737 mg/d during months 4 to 6 and a maintenance dose of 600 mg/d. All three treatment approaches were well tolerated with similar grade 3 and 4 adverse events. Independent of treatment approach, MMR at 12 months showed better progression-free survival (99% v 94%; P = .0023) and overall survival (99% v 93%; P = .0011) at 3 years when compared with > 1% on the international scale or no MMR but showed no difference in 0.1% to < 1% on the international scale, which closely correlates with complete cytogenetic remission.
Treatment of early-phase CML with imatinib can be optimized. Early high-dose therapy followed by rapid adaptation to good tolerability increases the rate of MMR at 12 months. Achievement of MMR by month 12 is directly associated with improved survival.
[Show abstract][Hide abstract] ABSTRACT: Peripheral T-cell lymphomas (PTCLs) are rare malignancies with poor outcome after conventional chemotherapy. The role of myeloablative therapy and autologous stem-cell transplantation (autoSCT) is still unclear. Therefore, we initiated the first prospective multicenter study on upfront autoSCT in PTCL and recently reported good feasibility and efficacy of this approach. Here, we present the final analysis of the study.
The treatment regimen consisted of four to six cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone followed by mobilizing therapy with either the dexamethasone, carmustine, melphalan, etoposide, and cytarabine protocol or the etoposide, methylprednisolone, cytarabine, and cisplatin protocol and stem-cell collection. Patients in complete remission (CR) or partial remission (PR) underwent myeloablative chemoradiotherapy (fractionated total-body irradiation and high-dose cyclophosphamide) and autoSCT.
From June 2000 to April 2006, 83 patients were enrolled onto the study. Main subgroups were PTCL not specified (n = 32) and angioimmunoblastic T-cell lymphoma (n = 27). Fifty-five (66%) of the 83 patients received transplantation. The main reason for not receiving autoSCT was progressive disease. In an intent-to-treat analysis, the overall response rate after myeloablative therapy was 66% (56% CR and 8% PR). With a median follow-up time of 33 months, 43 patients are alive; the estimated 3-year overall and disease-free survival rates for patients in CR (calculated from CR to the date of relapse) and 3-year progression-free survival rate were 48%, 53%, and 36%, respectively.
The results of this prospective study suggest a substantial impact on outcome for upfront autoSCT in PTCL and should be further evaluated in randomized trials. Pretransplantation treatment needs to be improved to increase the transplantation rate.
[Show abstract][Hide abstract] ABSTRACT: Early allogeneic hematopoietic stem cell transplantation (HSCT) has been proposed as primary treatment modality for patients with chronic myeloid leukemia (CML). This concept has been challenged by transplantation mortality and improved drug therapy. In a randomized study, primary HSCT and best available drug treatment (IFN based) were compared in newly diagnosed chronic phase CML patients. Assignment to treatment strategy was by genetic randomization according to availability of a matched related donor. Evaluation followed the intention-to-treat principle. Six hundred and twenty one patients with chronic phase CML were stratified for eligibility for HSCT. Three hundred and fifty four patients (62% male; median age, 40 years; range, 11-59 years) were eligible and randomized. One hundred and thirty five patients (38%) had a matched related donor, of whom 123 (91%) received a transplant within a median of 10 months (range, 2-106 months) from diagnosis. Two hundred and nineteen patients (62%) had no related donor and received best available drug treatment. With an observation time up to 11.2 years (median, 8.9 years), survival was superior for patients with drug treatment (P = .049), superiority being most pronounced in low-risk patients (P = .032). The general recommendation of HSCT as first-line treatment option in chronic phase CML can no longer be maintained. It should be replaced by a trial with modern drug treatment first.
[Show abstract][Hide abstract] ABSTRACT: Leukemia is one of the leading journals in hematology and oncology. It is published monthly and covers all aspects of the research and treatment of leukemia and allied diseases. Studies of normal hemopoiesis are covered because of their comparative relevance.
[Show abstract][Hide abstract] ABSTRACT: The objective of our study was to evaluate high-dose cytarabine in consolidation therapy in patients with newly diagnosed acute promyelocytic leukemia (APL). Patients (age 16-60 years) received induction therapy according to the AIDA protocol (all-trans retinoic acid, idarubicin) followed by one cycle of ICE (idarubicin, cytarabine, etoposide) and two cycles of HAM (cytarabine 3 g/m(2) q12h, days 1-3; mitoxantrone 10 mg/m(2), days 2 and 3). From 1995 to 2003, 82 patients were enrolled. In total, 72 patients (88%) achieved a complete remission, and 10 patients (12%) died from early/hypoplastic death (ED/HD). A total of 71 patients received at least one cycle of HAM. Relapse-free survival (RFS) and overall survival (OS) after 46 months were 83 and 82%, respectively. White blood cell count above 10.0 x 10(9)/l at diagnosis and additional chromosomal aberrations were unfavorable prognostic markers for OS, whereas no prognostic markers for RFS were identified including FLT3 mutations. In conclusion, high-dose cytarabine in consolidation therapy for patients with newly diagnosed APL is an effective treatment approach.
[Show abstract][Hide abstract] ABSTRACT: Peripheral T-cell lymphomas (PTCL) show a poor outcome following conventional chemotherapy. However, the role of high-dose therapy is still unclear. We initiated a prospective multicenter phase II study to evaluate the feasibility and the efficacy of myeloablative radiochemotherapy followed by autologous peripheral blood stem cell transplantation (APBSCT) as first-line treatment in PTCL. After 4-6 courses CHOP (cyclophosphamide, doxorubicine, vincristine, and prednisone) chemotherapy, an induction therapy with either the DexaBEAM (dexamethasone, carmustine, melphalan, etoposide, and cytarabine) or the ESHAP (etoposide, methylprednisolone, cytarabine, and cisplatin) protocol was administered. If a complete (CR) or a partial remission (PR) was achieved, myeloablative radiochemotherapy (hyperfractionated total body irradiation and high-dose cyclophosphamide) with APBSCT was performed. From June 2000 to November 2002, 30 patients (pts) were enrolled into the study. The two main PTCL subgroups included were PTCL not specified and angioimmunoblastic T-cell lymphoma (each n=12). In all, 21 of the 30 pts (70%) were transplanted. The main toxicities were myelosuppression and infections. The overall response rate after myeloablative therapy was 100% (20 CR, one PR). In total, 16 of 21 transplanted pts (76%) remained in CR at a median follow-up of 15 months (range, 6-32 months) from treatment start. Nine pts received no APBSCT mainly due to progressive disease. In conclusion, this first prospective PTCL-restricted study of frontline myeloablative radiochemotherapy with APBSCT shows feasibility and high efficacy. Our data suggest a substantial impact on outcome, however, longer follow-up is necessary to confirm survival benefit.
The Hematology Journal 02/2004; 5(4):304-11. DOI:10.1038/sj.thj.6200359 · 1.86 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We sought to determine dynamics of BCR-ABL mRNA expression levels in 139 patients with chronic myelogenous leukemia (CML) in early chronic phase, randomized to receive imatinib (n=69) or interferon (IFN)/Ara-C (n=70). The response was sequentially monitored by cytogenetics from bone marrow metaphases (n=803) and qualitative and quantitative RT-PCR from peripheral blood samples (n=1117). Complete cytogenetic response (CCR) was achieved in 60 (imatinib, 87%) vs 10 patients (IFN/Ara-C, 14%) after a median observation time of 24 months. Within the first year after CCR, best median ratio BCR-ABL/ABL was 0.087%, (imatinib, n=48) vs 0.27% (IFN/Ara-C, n=9, P=0.025). BCR-ABL was undetectable in 25 cases by real-time PCR, but in only four patients by nested PCR. Median best response in patients with relapse after CCR was 0.24% (n=3) as compared to 0.029% in patients with continuous remission (n=52, P=0.029). We conclude that (i) treatment with imatinib in newly diagnosed CML patients is associated with a rapid decrease of BCR-ABL transcript levels; (ii) nested PCR may reveal residual BCR-ABL transcripts in samples that are negative by real-time PCR; (iii) BCR-ABL transcript levels parallel cytogenetic response, and (iv) imatinib is superior to IFN/Ara-C in terms of the speed and degree of molecular responses, but residual disease is rarely eliminated.
[Show abstract][Hide abstract] ABSTRACT: The vitamin D3 derived hormone 1,25 (OH)2 vitamin D3 (1,25 D3) is able to induce growth arrest and differentiation in myelomonocytic leukaemia cells. In order to allow for specific delivery to leukaemic cells the lipophilic compound was incorporated into the lipid membranes of liposomes. Liposomal 1,25 D3 reduced proliferation as measured by 3H-thymidine incorporation in HL60 leukaemia cells by up to 60%. When liposomes were prepared at different concentrations of 1,25 D3 65% inhibition was achieved at 48 nM. The MC 1288 stereoisomer of 1,25 D3 was more potent and had the same activity at 48 nM.The effect of the liposomal compounds was specific to myeloid cells as they reduced proliferation in myelomonocytic HL60, monoblastic U937 and monocytic Mono Mac 6 cells but not in the T-cell lines Jurkat and Molt 4.The antiproliferative effect of liposomal 1,25 D3 was associated with an induction of differentiation since treated HL60 cells showed a monocytic morphology, increased expression of CD14 and decreased expression of CD33.When peripheral blood leukaemic cells from M4 and M5 acute myeloid leukaemia (AML) patients were admixed with liposomal compounds an antiproliferative effect was seen in all five cases, including the two cases where free compounds led to enhanced growth. Liposomal delivery of 1,25 (OH)2 vitamin D3 may offer a novel approach to treatment of myelomonocytic leukaemia.
British Journal of Haematology 10/2003; 98(1):186 - 194. DOI:10.1046/j.1365-2141.1997.1682984.x · 4.71 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The optimum treatment conditions of interferon (IFN) alpha therapy in chronic myeloid leukemia (CML) are still controversial. To evaluate the role of hydroxyurea (HU) for the outcome of IFN therapy, we conducted a randomized trial to compare the combination of IFN and HU vs HU monotherapy (CML-study II). From February 1991 to December 1994, 376 patients with newly diagnosed CML in chronic phase were randomized. In all, 340 patients were Ph/BCR-ABL positive and evaluable. Randomization was unbalanced 1:2 in favor of the combination therapy, since study conditions were identical to the previous CML-study I and it had been planned in advance to add the HU patients of study I (n=194) to the HU control group. Therefore, a total of 534 patients were evaluable (226 patients with IFN/HU and 308 patients with HU). Analyses were according to intention-to-treat. Median observation time of nontransplanted living patients was 7.6 years (7.9 years for IFN/HU and 7.3 years for HU). The risk profile (new CML score) was available for 532 patients: 200 patients (38%) were low, 239 patients (45%) intermediate, and 93 patients (17%) high risk. Complete hematologic response rates were higher in IFN/HU-treated patients (59 vs 32%). Of 169 evaluable IFN/HU-treated patients (75%), 104 patients (62%) achieved a cytogenetic response that was complete in 12% (n=21), major in 14% (n=24), and at least minimal in 35% (n=59). Of the 534 patients, 105 (20%) underwent allogeneic stem cell transplantation in first chronic phase. In the low-risk group, 65 of 200 patients were transplanted (33%), 30 (13%) in the intermediate-risk group, and nine (10%) in the high-risk group. Duration of chronic phase was 55 months for IFN/HU and 41 months for HU (P<0.0001). Median survival was 64 months for IFN/HU and 53 months for HU-treated patients (P=0.0063). We conclude that IFN in combination with HU achieves a significant long-term survival advantage over HU monotherapy. In view of the data of CML-study I, these results suggest that IFN/HU is also superior to IFN alone. HU should be combined with IFN in IFN-based therapies and for comparisons with new therapies.
[Show abstract][Hide abstract] ABSTRACT: The tumour load of peripheral blood stem cell (PBSC) harvests and the outcome of ex vivo immunomagnetic B-cell purging was investigated in 19 patients with low-grade lymphoma. To quantify the tumour load, we combined fluorescence-activated cell sorting measurement of CD19+ B-cells and determination of the B-cell light chain ratio (LCR) with consensus complementarity-determining region III-polymerase chain reaction (CDRIII-PCR) and gene scan analysis. The number of tumour cells was calculated using B-cell extracts from the PBSCs. Two different patterns were distinguished. In eight patients (42%) with CD19+ B cells >1% in the apheresis product, a high tumour load was found, characterized by a monoclonal LCR, positive PCR in seven out of eight cases, >5 x 10(7) extracted lymphoma cells in six out of seven PCR-assessable cases, and the presence of residual lymphoma after purging in six of seven cases. In 11 patients (58%) with <1% CD19+ B-cells in the product, a low tumour load was indicated by a polyclonal LCR, positive PCR in only 4 out of 11 cases, >5 x 10(7) extracted lymphoma cells in zero out of four PCR-assessable cases, and the presence of residual lymphoma after purging in zero out of four of these cases. The level of residual lymphoma following purging largely depended on the level of tumour contamination. CD19+ B-cells >50/microl in the peripheral blood at mobilization predicted a high tumour load in the apheresis product.
British Journal of Haematology 03/2002; 116(3):695-701. DOI:10.1046/j.0007-1048.2001.03313.x · 4.71 Impact Factor
[Show abstract][Hide abstract] 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
Der Internist 01/2002; 43(10):1245-1254. DOI:10.1007/s00108-002-0707-5 · 0.31 Impact Factor
[Show abstract][Hide abstract] 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. DOI:10.1046/j.1365-2141.2001.02959.x · 4.71 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The response to interferon-alpha (IFNalpha) treatment in leukemias of the B-cell lineage shows a marked heterogeneity. A distinct subset of patients with B-CLL responds to treatment with IFNalpha, while the drug has no therapeutic effect in the majority of patients. The mechanism of this phenomenon is poorly understood. The cellular events induced by this cytokine mediated by a number of specific signaling events. Therefore, we studied the effect of recombinant IFNalpha on tyrosine phosphorylation and proliferation of cytosolic proteins in human cell lines and in freshly isolated B-CLL cells in order to test the potential value of these events as a pretreatment test for IFNalpha in CLL. In human lymphoid cell lines, IFNalpha induced tyrosine phosphorylation of multiple cytosolic proteins in a time- and concentration-dependent manner. This effect correlated with its growth-inhibitory effect in almost all cell lines. In marked contrast, in freshly isolated B-CLL cells IFNalpha seemed to have both stimulatory and inhibitory effects on proliferation, but it consistently stimulated tyrosine phosphorylation. Moreover, the clinical response of B-CLL to IFNalpha did not correlate with the activation of tyrosine kinases nor with the inhibition of cell growth in vitro. Therefore, the assessment of IFNalpha-induced tyrosine phosphorylation of cytosolic phospho-proteins does not allow to predict the treatment response to IFNalpha in CLL patients.
Annals of Hematology 04/2000; 79(3):119-26. DOI:10.1007/s002770050566 · 2.63 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The influence of interferon-alpha (IFN) pretreatment on the outcome after allogeneic bone marrow transplantation (BMT) in chronic myelogenous leukemia (CML) is controversial. One goal of the German randomized CML Studies I and II, which compare IFN +/- chemotherapy versus chemotherapy alone, was the analysis of whether treatment with IFN as compared to chemotherapy had an influence on the outcome after BMT. One hundred ninety-seven (23%) of 856 Ph/bcr-abl-positive CML patients were transplanted. One hundred fifty-two patients transplanted in first chronic phase were analyzed: 86 had received IFN, 46 hydroxyurea, and 20 busulfan. Forty-eight patients (32%) had received transplants from unrelated donors. Median observation time after BMT was 4.7 (0.7 to 13.5) years. IFN and chemotherapy cohorts were compared with regard to transplantation risks, duration of treatments, interval from discontinuation of pretransplant treatment to BMT, conditioning therapy, graft-versus-host disease prophylaxis and risk profiles at diagnosis and transplantation, and IFN cohorts also with regard to performance and resistance to IFN. Outcome of patients receiving related or unrelated transplants pretreated with IFN, hydroxyurea, or busulfan was not significantly different. Five-year survival after transplantation was 58% for all patients (57% for IFN, 60% for hydroxyurea and busulfan patients). The outcome within the IFN group was not different by duration of prior IFN therapy more or less than 5 months, 1 year, or 2 years. In contrast, a different impact was observed in IFN-pretreated patients depending on the time of discontinuation of IFN before transplantation. Five-year survival was 46% for the 50 patients who received IFN within the last 90 days before BMT and 71% for the 36 patients who did not (P =.0057). Total IFN dosage had no impact on survival after BMT. We conclude that outcome after BMT is not compromised by pretreatment with IFN if it is discontinued at least 3 months before transplantation. Clear candidates for early transplantation should not be pretreated with IFN.
[Show abstract][Hide abstract] ABSTRACT: Chronic lymphocytic leukemia (CLL) shows a remarkably heterogeneous clinical outcome; survival ranges from several months in advanced stages to more than 10 years in early stages. The Binet and Rai staging systems distinguish three major prognostic subgroups, but do not accurately predict the individual risk of disease progression in early CLL (Binet stage A or Rai stage 0 to II). Because most newly diagnosed CLL patients present with early disease, it seems desirable to search for additional prognostic factors to identify early CLL patients at high risk of rapid progression. It has been shown that elevated serum thymidine kinase (s-TK) levels predict disease progression in CLL. Therefore, this study aimed to assess the prognostic value of s-TK in 122 previously untreated patients with Binet stage A CLL (mean age +/- SD, 58.7 +/- 8.5 years). In univariate analyses, 18 of the 22 parameters investigated predicted progression-free survival (PFS). In a stepwise multiple regression analysis, only three parameters provided independent prognostic information on PFS: s-TK greater than 7.1 U/L; presence of lymphadenopathy; and white blood cell (WBC) count greater than 75, 000/microL. When added to the classification of smoldering versus nonsmoldering CLL, s-TK levels separated two groups within the group of nonsmoldering stage A patients: patients with s-TK values greater than 7.1 U/L had a median PFS of 8 months, whereas patients with s-TK values </= 7.1 U/L expected a much longer PFS (49 months; P <. 001), similar to smoldering CLL (42 months). The results demonstrate that s-TK is a prognostic parameter that adds independent prognostic information to the definitions of smoldering and nonsmoldering CLL in Binet stage A.