Final results from the prospective phase III WSG-ARA trial: impact of adjuvant darbepoetin alfa on event-free survival in early breast cancer.

BACKGROUND: WSG-ARA plus trial evaluated the effect of adjuvant darbepoetin alfa (DA) on outcome in node positive primary breast cancer (BC). PATIENTS AND METHODS: One thousand two hundred thirty-four patients were randomized to chemotherapy either with DA (DA+; n = 615) or without DA (DA-; n = 619). DA (500 µg q3w) was started at hemoglobin (Hb) levels <13.0 g/dl (<12 g/dl after DA label amendment) and stopped at Hb levels ≥14.0 g/dl (12 g/dl after label amendment). Primary efficacy end point was event-free survival (EFS); secondary end points were toxicity, quality of life (QoL) and overall survival (OS). RESULTS: Venous thrombosis (DA+: 3.0%, DA-: 1.0%; P = 0.013) was significantly higher for DA+, but not pulmonary embolism (0.3% in both arms). Median Hb levels were stable in DA+ (12.6 g/dl) and decreased in DA- (11.7 g/dl). Hb levels >15 g/dl were reported in 0.8% of cycles. QoL parameters did not significantly differ between arms. At 39 months, DA had no significant impact on EFS (DA+: 89.3%, DA-: 87.5%; Plog-rank = 0.55) or OS (DA+: 95.5%, DA-: 95.4%; Plog-rank = 0.77). CONCLUSIONS: DA treatment did not impact EFS or OS in routine adjuvant BC treatment.

Randomized phase-III study of low-dose cytarabine and etoposide + /- all-trans retinoic acid in older unfit patients with NPM1-mutated acute myeloid leukemia.

The aim of this randomized clinical trial was to evaluate the impact of all-trans retinoic acid (ATRA) in combination with non-intensive chemotherapy in older unfit patients (> 60 years) with newly diagnosed NPM1-mutated acute myeloid leukemia. Patients were randomized (1:1) to low-dose chemotherapy with or without open-label ATRA 45 mg/m2, days 8-28; the dose of ATRA was reduced to 45 mg/m2, days 8-10 and 15 mg/m2, days 11-28 after 75 patients due to toxicity. Up to 6 cycles of cytarabine 20 mg/day s.c., bid, days 1-7 and etoposide 100 mg/day, p.o. or i.v., days 1-3 with (ATRA) or without ATRA (CONTROL) were intended. The primary endpoint was overall survival (OS). Between May 2011 and September 2016, 144 patients (median age, 77 years; range, 64-92 years) were randomized (72, CONTROL; 72, ATRA). Baseline characteristics were balanced between the two study arms. The median number of treatment cycles was 2 in ATRA and 2.5 in CONTROL. OS was significantly shorter in the ATRA compared to the CONTROL arm (p = 0.023; median OS: 5 months versus 9.2 months, 2-years OS rate: 7% versus 10%, respectively). Rates of CR/CRi were not different between treatment arms; infections were more common in ATRA beyond treatment cycle one. The addition of ATRA to low-dose cytarabine plus etoposide in an older, unfit patient population was not beneficial, but rather led to an inferior outcome.The clinical trial is registered at clinicaltrialsregister.eu (EudraCT Number: 2010-023409-37, first posted 14/12/2010).

Condensed versus standard schedule of high-dose cytarabine consolidation therapy with pegfilgrastim growth factor support in acute myeloid leukemia.

The aim of this cohort study was to compare a condensed schedule of consolidation therapy with high-dose cytarabine on days 1, 2 and 3 (HDAC-123) with the HDAC schedule given on days 1, 3 and 5 (HDAC-135) as well as to evaluate the prophylactic use of pegfilgrastim after chemotherapy in younger patients with acute myeloid leukemia in first complete remission. One hundred and seventy-six patients were treated with HDAC-135 and 392 patients with HDAC-123 with prophylactic pegfilgrastim at days 10 and 8, respectively, in the AMLSG 07-04 and the German AML Intergroup protocol. Time from start to chemotherapy until hematologic recovery with white blood cells >1.0 G/l and neutrophils >0.5 G/l was in median 4 days shorter in patients receiving HDAC-123 compared with HDAC-135 (P<0.0001, each), and further reduced by 2 days (P<0.0001) by pegfilgrastim. Rates of infections were reduced by HDAC-123 (P<0.0001) and pegfilgrastim (P=0.002). Days in hospital and platelet transfusions were significantly reduced by HDAC-123 compared with HDAC-135. Survival was neither affected by HDAC-123 versus HDAC-135 nor by pegfilgrastim. In conclusion, consolidation therapy with HDAC-123 leads to faster hematologic recovery and less infections, platelet transfusions as well as days in hospital without affecting survival.

Risk assessment in primary myelodysplastic syndromes: validation of the Düsseldorf score.

We have recently proposed a scoring system for risk assessment in primary myelodysplastic syndromes (MDS). In this score, one point is allocated to each of the following four parameters: bone marrow blasts > or = 5%, LDH > 200 U/l, hemoglobulin concentration < or = 9 g/dl, and platelet count < or = 100 x 10(9)/l. In a published series of 235 untreated patients with primary MDS, three prognostic groups (group A, score 0; group B, score 1 or 2; group C, score 3 or 4) were identified which differed significantly in both survival and rates of leukemic transformation. The present study was undertaken to reexamine the usefulness of our scoring system by applying it to an independent population of 263 newly diagnosed MDS patients. Morphological subtypes were RA in 53 (20%), RARS in 32 (12%), pure sideroblastic anemia (PSA) in 41 (16%), RAEB in 60 (23%), RAEB/T in 34 (13%), and CMML in 43 cases (16%). The predictive value of the Düsseldorf score could be assessed in 244 of 263 patients (initial LDH levels or platelet counts lacking in 19 cases). Forty-two patients were assigned to group A (low risk), 132 to group B (intermediate risk), and 70 to group C (high risk). Two-year cumulative survival was 86% in group A, 57% in group B and 14% in group C. Five-year cumulative survival was 53, 26 and 0%, respectively (p < 0.00005). Cumulative risk of AML 2 years after diagnosis was 3% in group A, 12% in group B, and 41% in group C (p < 0.05). Additional validation of the score was provided by extended follow-up of the initial patient population on which the scoring system was based. Survival curves in this patient population developed as predicted by the score. An important advantage of the Düsseldorf score is its ability to identify high-risk patients among the RA and RARS subgroups, even though by definition medullary blasts are less than 5%. The inclusion of LDH levels as a prognostic parameter also qualifies the Düsseldorf score for a correct assessment of CMML patients. In the new study population, LDH was confirmed as an important prognostic factor. After 2 years, actuarial survival for patients with LDH levels < or = 200 U/l was 61%, compared with 34% for patients with LDH > 200 U/l. Five-year cumulative survival was 32 and 14%, respectively (p < 0.00005).(ABSTRACT TRUNCATED AT 400 WORDS)

Acute leukemia coexpressing myeloid, B- and T-lineage associated markers: multiparameter analysis of criteria defining lineage commitment and maturational stage in a case of undifferentiated leukemia.

Coexpression of myeloid, B-, and T-lineage associated markers was found in a patient with morphologically and cytochemically undifferentiated acute leukemia. Surface marker analysis using two-color immunofluorescence staining characterized blast cells to express CD34, CD38, CD117, and class II antigens, coexpressing TdT, CD4, CD7, CD13, CD19, and CD33. Cytoplasmic expression of myeloperoxidase, CD3, and CD22 could not be demonstrated. Monosomy for chromosome 7 was found by cytogenetic analysis. The absence of clonal rearrangements of immunoglobulin or T-cell receptor genes was shown by Southern blot analysis. Using a 3H-thymidine incorporation assay, DNA synthesis of leukemic blasts could be stimulated by IL-3, IL-6 and G-CSF in vitro. The present case did not offer specific criteria of lineage commitment. Corresponding to an equivalent counterpart in normal hematopoiesis, the involved cell population may reflect an early, most immature developmental stage within a multipotent progenitor cell compartment.

Genotypically nonidentical related donors for transplantation of patients with myelodysplastic syndromes: comparison with unrelated donor transplantation and autologous stem cell transplantation.

Transplantation with histocompatible identical siblings is a curative treatment for patients with myelodysplastic syndromes (MDS). Alternative treatments, such as transplantation with other family donors, are an option for patients without HLA-identical siblings. This study evaluated transplantation with genotypically nonidentical family donors and compared the results to those obtained with unrelated donors and autologous stem cell transplantation. Overall 3-year survival was 35% for the 79 patients transplanted using genotypically nonidentical donors, DFS was 31%, relapse risk 16%, and the treatment-related mortality (TRM) 62%. Patients transplanted using phenotypically identical family donors had a significantly superior survival and a lower TRM than patients transplanted with mismatched family donors. Age had no influence on the outcome of transplantation. The DFS of patients transplanted in early stage of the disease was 42% compared to 28% in patients transplanted with more advanced disease (P = 0.03). The results of transplantation with mismatched family donors were comparable to those obtained with unrelated donor transplantation. This suggests that nonidentical family donors may be considered if a fully matched unrelated donor is not available. The TRM of patients transplanted with nonidentical family donors is significantly higher than the TRM of patients transplanted with autologous stem cells. The disease-free survival of ASCT is not inferior to allogeneic transplantation using nonidentical family donors, and the intensity of the treatment is much lower. The choice of ASCT or alternative donor transplantation must be influenced by the age of the patient and the risk of relapse. For patients under the age of 20 years the treatment of choice may indeed be an alternative donor transplantation.

Serum erythropoietin concentrations in patients with myelodysplastic syndromes.

Medullary dyserythropoiesis with reduced production of erythrocytes is an early and consistent feature of myelodysplastic syndromes (MDS). The mechanism underlying the disturbed red cell proliferation and maturation is presently unknown. In order to study the role of erythropoietic growth factors, we determined by radioimmunoassay the serum concentrations of immunoreactive erythropoietin (Epo) in 42 non-transfused patients with primary and secondary MDS. Their median hemoglobin concentration at the time of Epo measurement was 9.1 g/dl (range, 5.7-14.6). Compared with the control group, 83% of the MDS patients had increased serum Epo levels, ranging from 26-4530 mU/ml. Although in the entire patient population an inverse relationship between serum Epo and hemoglobin concentrations was noted (r = -0.35; p = 0.02), Epo titers differed markedly between patients at comparable degrees of anemia. In 7 patients presenting with a hemoglobin concentration between 5.9 and 11.9 g/dl, excessive elevations of Epo levels (greater than 500 mU/ml) were found. In contrast to previous observations, serum Epo concentrations were not shown to correlate with the percentage of erythroblasts in the bone marrow. There was, however, a significant relationship between the Epo activity and the degree of medullary dyserythropoiesis, as assessed by morphological criteria (p less than 0.01). From these data we conclude that the anemia in MDS is not due to an endogenous Epo deficiency. The marked variability of Epo production in these disorders is not fully explained by the degree of anemia, but may also reflect inherent abnormalities of the myelodysplastic erythropoiesis.

Expression of cd34 and p-glycoprotein - prognostic-significance in primary myelodysplastic syndromes.

Expression of stem cell phenotype (CD34) and multidrug resistance (MDR) on blast cells of 49 untreated patients with primary myelodysplastic syndromes (MDS) was studied by means of the alkaline phosphatase antialkaline phosphatase technique (APAAP). In 29 patients (59%) CD34 and in 19 patients (39%) MDR positivity was found. Both immunocytological markers showed a strong positive correlation (p<0.0005) and MDR expression was only detectable in CD34 positive cases. When comparing CD34 and MDR expression with well established prognostic parameters, medullary bone marrow (BM) blast percentage was found to be the sole variable which correlated with expression of both cell surface markers. CD34 and MDR negative patients had a better prognosis although only the difference between CD34 positive and CD34 negative cases reached statistical significance. Regarding the prognostic value of immunocytological results and other clinical and hematological parameters medullary blast cell infiltration remained the strongest predictive variable for survival and AML transformation. In 6 patients sequential immunocytological analysis during progression of disease were performed. In contrast to stable CD34 expression a marked increase in MDR expression after AML development could be noted in 2 cases.

Detection of TT virus DNA in specimens other than blood.

BACKGROUND: Recently, a new infective agent of humans, TT virus (TTV), was identified. Very high prevalence rates of TTV in different population groups, including apparently healthy individuals, were reported for several countries. OBJECTIVES, STUDY DESIGN: In order to investigate whether or not non-parenteral transmission routes can contribute to TTV spread, we have tested saliva, urine, and stool samples from eight TT viraemic individuals for the presence of TTV DNA by polymerase chain reaction. RESULTS: TTT DNA was detected in saliva of five subjects and stools of four patients. None of the urine samples contained TTV DNA. Viral titres in saliva were close to those found in serum. In feces, TTV DNA could only be detected in low concentrations. CONCLUSIONS: Our findings on the presence of TTV DNA in saliva and stool suggest that TTV might be transmitted non-parenterally.

Influence of intestinal decontamination using metronidazole on the detection of methanogenic Archaea in bone marrow transplant recipients.

Methane-forming microbes of the phylogenetic domain Archaea are part of the strictly anaerobic microflora of the human intestine. In bone marrow transplant (BMT) recipients, the regimen of intestinal decontamination with metronidazole is targeted to anaerobic bacteria. The effect on the anaerobic methanoarchaea, however, is unknown. Therefore, the faeces of patients undergoing BMT were investigated for methane production. The anoxic Hungate technique and an archaeal growth medium were used to culture faecal specimens. Methane production was measured in the head space of the culture bottles by gas chromatography using a thermal conductivity detector. In a testing serial specimen of 100 patients, 13 patients were found to bear methanogens, and 11 of these patients received metronidazole. The methane-producing faecal specimens occurred before metronidazole use in three patients, during the first week in five patients, and after cessation in three patients. No specimen of the 11 patients that was obtained during the 2nd-5th week of gut decontamination showed methane production. It is concluded that use of metronidazole directed against faecal anaerobic bacteria also suppresses or eliminates faecal methanogenic Archaea.

Faster engraftment of peripheral blood progenitor cells compared to bone marrow from unrelated donors.

Twenty-six patients received peripheral blood progenitor cells (PBPC) from unrelated donors at five European Centres. Twenty-five donors were HLA-A, -B and -DR identical and one had a one antigen mismatch. PBPC were mobilised by treatment with G-CSF for 4-5 days. Eleven patients receiving PBPC were compared to 11 patients receiving unrelated bone marrow with comparable prognostic factors. The median mononuclear cell count, the CD3+ cells and the CD56+ cells were seven to 10 times higher in PBPC, compared to bone marrow (P < 0.001). The median CD34+ cell content was 6.1 x 10(6)/kg recipient weight with PBPC, compared to 4.3 with bone marrow (NS). Time from transplantation to neutrophils >0.5 x 10(9)/l was a median of 11 (range 6-21) days using PBPC vs 15 (10-22) days after transplantation of bone marrow (P = 0.03). Transfusions and time to discharge did not differ between the two groups. All 26 patients receiving PBPC engrafted. Acute GVHD grades II-IV was seen in 8/26 (31%) and chronic GVHD in 8/18 (44%). Overall, 13/26 (50%) of the patients are alive and well with a median follow-up of 9 (2-35) months.

Adenoviral infection after allogeneic stem cell transplantation (SCT): report on 130 patients from a single SCT unit involved in a prospective multi center surveillance study.

The incidence of adenovirus (AV) infections following SCT was determined in a prospective multicenter trial. Over 1 year, 130 consecutive patients undergoing allogeneic SCT at Essen University Hospital were included and followed for 6 months. Source of stem cells was blood in 68 cases. Fifty-eight patients had HLA-identical sibling donors. Throat swabs, urine and stool samples were screened weekly for AV antigen and DNA by ELISA and nested PCR, respectively. In 35 cases adenovirus infection was detected. There was no seasonal variation. Throat swabs were positive in 24, urine in 12, and stool in 11 cases, resulting in a cumulative risk of infection of 29%. The incidences of AV infection of the respiratory, gastrointestinal and urinary tract were 19%, 10%, and 9%, respectively, and infections were diagnosed after a median (range) interval of 44 (-2-179), 37 (-2-168), and 53 (17-153) days after transplantation. On multivariate analysis, presence of AV antibody in the donor and acute graft-versus-host disease grade IV were found to be independent risk factors for AV infection. Eleven patients had AV isolated from more than one site and five patients had probable AV disease. We were not able to identify patients in whom AV infection was the leading cause of death. The majority of patients infected with AV suffered from severe acute graft-versus-host disease often accompanied by other opportunistic infections, such as aspergillosis or CMV reactivation. Nineteen out of 36 patients who died during the observation period had AV infection. In summary, AV infection after allogeneic SCT was observed in a substantial number of patients. In addition to well-known risk factors for viral infection after SCT we were able to demonstrate that a positive AV antibody test in the donor is an important risk factor for AV infection. Further studies are needed, however, before final conclusions on the clinical sequelae of AV infection can be made and the role of preventive and therapeutic strategies toward AV infection after allogeneic SCT can be defined.

Fungal colonization and invasive fungal infections following allogeneic BMT using metronidazole, ciprofloxacin and fluconazole or ciprofloxacin and fluconazole as intestinal decontamination.

Invasive fungal infections (IFI) are increasingly diagnosed in patients undergoing allogeneic BMT. We have previously shown that the addition of metronidazole to ciprofloxacin for gastrointestinal bacterial decontamination significantly reduces the incidence of grades II-IV aGVHD by reduction of the anaerobic intestinal bacterial flora. Here, we found that the combined use of ciprofloxacin, metronidazole and fluconazole as antifungal prophylaxis increased intestinal yeast colonization when compared to ciprofloxacin and fluconazole alone (P < 0.01). Based on the EORTC criteria, a total of 18 out of 134 study patients developed IFI: seven of 68 (10%) patients who received metronidazole compared to 11 of the 66 (17%) patients decontaminated without metronidazole developed IFI (log-rank P = 0.36). Lethal IFI occurred in two of seven patients receiving metronidazole and in four of 11 patients without anaerobic decontamination. In conclusion, bacterial intestinal decontamination using metronidazole as an antibiotic with activity against most anaerobic intestinal bacteria significantly increases the intestinal yeast burden without influencing the incidence of IFI in patients undergoing allogeneic BMT.

Reduced risk of persisting cytomegalovirus pp65 antigenemia and cytomegalovirus interstitial pneumonia following allogeneic PBSCT.

In order to evaluate the risk of cytomegalovirus (CMV) associated disease after allogeneic stem cell transplantation (SCT), 158 consecutive patients at risk for infection were analyzed. BMT was performed in 101 patients and peripheral blood stem cell transplantation (PBSCT) in 57 patients. CMV antigenemia was found in 57 cases (56%) after BMT and 27 cases (47%) after PBSCT, respectively. CMV antigenemia resistant to a 14-day course of GCV was found in 26 patients (26%) after BMT but in only four patients (7%) after PBSCT (P < 0.01). Eighteen patients (11%) developed CMV disease, 14 post BMT and four post PBSCT. Lethal CMV-related interstitial pneumonia (CMV-IP) occurred in 13 cases of whom 12 patients were bone marrow recipients (P = 0.04). The subgroup of seronegative patients with a CMV seropositive donor had a significantly lower risk of developing CMV antigenemia, GCV-resistant CMV antigenemia (P < 0.01) and CMV-related disease (P = 0.01). In conclusion, the incidence of persistent CMV antigenemia and CMV-IP was significantly reduced when allogeneic transplantation was performed with peripheral blood stem cells instead of bone marrow. These findings suggest that our previous in vitro data on improved immune reconstitution after allogeneic PBSCT as compared to allogeneic BMT have clinical relevance.

Unrelated bone marrow transplantation in patients with myelodysplastic syndromes and secondary acute myeloid leukemia: an EBMT survey. European Blood and Marrow Transplantation Group.

The Chronic Leukemia Working Party of the EBMT has collected data on 118 patients of median age 24 years (range 0.3 to 53 years) who underwent an allogeneic bone marrow transplantation from unrelated donors for treatment of MDS or secondary AML (RA/RARS, n = 24; RAEB, n = 26; RAEB-t, n = 34; CMML, n = 12; sAML, n = 22) between 1986 and 1996. The data were reported by 49 EBMT centers. Thirty-four of 118 patients are alive, relapse was the cause of death in 19 of 84 patients and the remaining patients died of transplant-related mortality. For the whole group the actuarial probability of survival at 2 years is 28%, disease-free survival 28%, relapse risk 35% and transplant-related mortality is 58%. The transplant-related mortality is significantly influenced by the age of the recipient (<18 years 40%, 18-35 years 61%, >35 years 81%). The relapse rate after BMT is influenced by FAB classification of the disease at BMT. Patients with a low blast count (RA, RAEB) have a lower probability of relapse (13%, 15%) compared to patients with RAEB-t or sAML (29%, 45%). Furthermore, we found evidence of a graft-versus-leukemia effect in MDS/sAML. Patients with acute GVHD, grade II-IV, had a probability of relapse of 26% vs 42% in patients with no acute GVHD or grade I only. Allogeneic transplantation with an HLA-matched, unrelated donor may be offered to younger patients (age <35 years) with poor risk myelodysplasia or secondary AML.

Faster engraftment of neutrophils and platelets with peripheral blood stem cells from unrelated donors: a comparison with marrow transplantation.

Engraftment was achieved in 43/45 (95%) recipients of peripheral blood stem cells (PBSC) from HLA-compatible unrelated donors (n = 45), compared to all 45 patients in matched controls receiving bone marrow and 14/18 (78%) recipients of CD34-selected PBSC (P < 0.01). The time to reach ANC >0.5 x 10(9)/l was a median of 16 days in the PBSC and CD34 groups, compared to 20 days in the bone marrow controls (P < 0.001 vs PBSC). The time to reach platelets >50 x 10(9)/l was a median of 23 days in the PBSC group and 24 days in the CD34 group, which was significantly faster than 29 days in the bone marrow controls (P < 0.01). Acute GVHD grades II-IV developed in 30% in the PBSC group, 20% in the recipients of bone marrow and 18% in the CD34 group. The corresponding figures for chronic GVHD were 59%, 85% and 0% (P < 0.01) in the three groups, respectively. The probability of non-relapse death was 27% in the recipients of PBSC, 21% in the bone marrow controls and 60% in the CD34 group (NS). The 2-year leukaemia-free survival was 46% in the PBSC group, 41% in the bone marrow group and 25% in the CD34 group (NS).

Reduced-intensity conditioning with busulfan and fludarabine with or without antithymocyte globulin in HLA-identical sibling transplantation--a retrospective analysis.

It is unknown whether the addition of antithymocyte globulin (ATG) to reduced-intensity conditioning with busulfan (BU) and fludarabine (FLU) is beneficial in HLA-identical sibling transplantation. Therefore, we analyzed retrospectively data on 83 patients, who received peripheral blood stem cells from HLA-identical siblings after conditioning with either 8 mg/kg BU and 150 mg/m2 FLU (n=45) or 8 mg/kg BU, 180 mg/m2 FLU and 40 mg/kg ATG (n=38). Graft-versus-host disease (GVHD) prophylaxis consisted of CSA alone (n=32) or a combination with either MTX or MMF (n=51). The median age was 52 years. Graft failure occurred in two patients after BU/FLU and in three after BU/FLU/ATG (P=0.66). After conditioning with BU/FLU, platelet recovery was significantly faster (P=0.017), and less platelet (P<0.001) and red blood cell (P=0.002) support was needed. Incidences of acute GVHD grades II and IV were 46 and 49%, respectively. Limited chronic GVHD occurred more often after BU/FLU compared to BU/FLU/ATG (54 vs 23%, P=0.02). The overall survival, non-relapse and relapse mortality did not differ significantly. We conclude that in peripheral blood stem cell transplantation from HLA-identical siblings after reduced-intensity conditioning with BU and FLU, ATG has no major impact on the rate of graft rejection and acute GVHD, but it reduces the incidence of limited chronic GVHD.

Reduced intensity conditioning for allogeneic hematopoietic stem cell transplantation in patients with acute myeloid leukemia: disease status by marrow blasts is the strongest prognostic factor.

We analyzed predictive factors for the outcome of 113 acute myeloid leukemia patients receiving reduced-intensity conditioning prior to allogeneic hematopoietic stem cell transplantation (HSCT). Patients were ineligible for conventional-intensity HSCT. Conditioning consisted of fludarabine and 50% of the conventional dose of busulfan (n=93) or total body irradiation (n=20). The source of stem cells was blood in 102 patients, marrow in 10, and both in one. In total, 50 (44.2%) donors were HLA-matched siblings, 50 (44.2%) unrelated fully matched and 13 (11.5%) partially mismatched family (n=1) or unrelated (n=12) donors. In all, 107 (94.6%) patients showed neutrophil and platelet engraftment after a median time of 13.5 and 13 days. The probabilities of event-free survival (EFS) (median follow-up: 12 months) were 49% for patients with less than 5% blasts in the marrow, 24% for patients with 5-20% blasts (P=0.002) and 14% with >20% blasts (P

Bone marrow transplantation from HLA-identical siblings as first-line treatment in patients with myelodysplastic syndromes: early transplantation is associated with improved outcome. Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation.

Allogeneic bone marrow transplantation (BMT) offers a potential cure for younger patients with myelodysplastic syndromes (MDS) or secondary acute myeloid leukemia (sAML). More than 600 patients from 50 European centers have now been reported to the European Group for Blood and Marrow Transplantation (EBMT). We retrospectively analyzed 131 patients reported to the Chronic Leukemia Working Party of the EBMT who underwent BMT from HLA-identical siblings without prior remission induction chemotherapy. At the time of BMT 46 patients had refractory anemia (RA) or RA with ringed sideroblasts, 67 patients had more advanced MDS subtypes and 18 patients had progressed to sAML. The 5-year disease-free (DFS) and overall survival (OS) for the entire group of patients was 34 and 41%, respectively. Fifty patients died from transplant-related complications, most commonly graft-versus-host disease and/or infections. Relapse occurred in 28 patients between 1 and 33 months after BMT, resulting in an actuarial probability of relapse of 39% at 5 years. DFS and OS were dependent on pretransplant bone marrow blast counts. Patients with RA/RARS, RAEB, RAEB/T and sAML had a 5-year DFS of 52, 34, 19 and 26%, respectively. The 5-year OS for the respective patient groups was 57, 42, 24 and 28%. In a multivariate analysis, younger age, shorter disease duration, and absence of excess of blasts were associated with improved outcome. From these data we conclude that patients with myelodysplasia who have appropriate marrow donors, especially those aged less than 40 years and those with low medullary blast cell count should be treated with BMT as the primary treatment early in the course of their disease. Transplantation early after establishing the diagnosis of MDS may improve prognosis due to a lower treatment-related mortality and a lower relapse risk.

Frequency of clonal B lymphocytes in chronic myelogenous leukemia evaluated by fluorescence in situ hybridization.

The demonstration of the Philadelphia (Ph) chromosome in B lymphocytes from patients with chronic myelogenous leukemia (CML) has provided evidence that the disorder originates in a pluripotent progenitor cell. Divergent results, however, exist as to the degree of contribution of clonally derived cells to the B-cell compartment. To address this issue, B lymphocytes were selected from the blood of seven patients in the chronic phase of Ph-positive CML and were examined with dual-color fluoresence in situ hybridization for the presence of the Ph translocation. The purity of the B-cell preparations ranged from 88% to 97% (mean 93%). The Ph translocation was detected in 22-34% (mean, 27%) of the sorted B cells. There was no evidence that the duration of the disease affects the ratio of Ph-positive and -negative B cells. In summary, clonally derived circulating B lymphocytes were present in all patients studied but made only minor contribution to this compartment.