Mathias Freund

Preservation from left ventricular remodeling by front-integrated revascularization and stem cell liberation in evolving acute myocardial infarction by use of granulocyte-colony-stimulating factor (FIRSTLINE-AMI)

Background— Considering experimental evidence that stem cells enhance myocardial regeneration and granulocyte colony–stimulating factor (G-CSF) mediates mobilization of CD34+ mononuclear blood stem cells (MNCCD34+), we tested the impact of G-CSF integrated into primary percutaneous coronary intervention (PCI) management of acute myocardial infarction in man. Methods and Results— Fifty consecutive patients with ST-segment elevation myocardial infarction were subjected to primary PCI stenting with abciximab and followed up for 6 months; 89±35 minutes after successful PCI, 25 patients were randomly assigned in this pilot study (PROBE design) to receive subcutaneous G-CSF at 10 &mgr;g/kg body weight for 6 days in addition to standard care, including aspirin, clopidogrel, an ACE inhibitor, &bgr;-blocking agents, and statins. By use of CellQuest software on peripheral blood samples incubated with CD45 and CD34, mobilized MNCCD34+ were quantified on a daily basis. With homogeneous demographics and clinical and infarct-related characteristics, G-CSF stimulation led to mobilization of MNCCD34+ to between 3.17±2.93 MNCCD34+/&mgr;L at baseline and 64.55±37.11 MNCCD34+/&mgr;L on day 6 (P<0.001 versus control); there was no indication of leukocytoclastic effects, significant pain, impaired rheology, inflammatory reactions, or accelerated restenosis at 6 months. Within 35 days, G-CSF and MNCCD34+ liberation led to enhanced resting wall thickening in the infarct zone of between 0.29±0.22 and 0.99±0.32 mm versus 0.49±0.29 mm in control subjects (P<0.001); under inotropic challenge with dobutamine (10 &mgr;g · kg−1 · min−1), wall motion score index showed improvement from 1.66±0.23 to 1.41±0.21 (P<0.004 versus control) and to 1.35±0.24 after 4 months (P<0.001 versus control), respectively, coupled with sustained recovery of wall thickening to 1.24±0.31 mm (P<0.001 versus control) at 4 months. Accordingly, resting wall motion score index improved with G-CSF to 1.41±0.25 (P<0.001 versus control), left ventricular end-diastolic diameter to 55±5 mm (P<0.002 versus control), and ejection fraction to 54±8% (P<0.001 versus control) after 4 months. Morphological and functional improvement with G-CSF was corroborated by enhanced metabolic activity and 18F-deoxyglucose uptake in the infarct zone (P<0.001 versus control). Conclusions— G-CSF and mobilization of MNCCD34+ after reperfusion of infarcted myocardium may offer a pragmatic strategy for preservation of myocardium and prevention of remodeling without evidence of aggravated restenosis.

Chemotherapy compared with bone marrow transplantation for adults with acute lymphoblastic leukemia in first remission.

OBJECTIVEnTo compare efficacy of intensive postremission chemotherapy with allogeneic bone marrow transplantation in adults with acute lymphoblastic leukemia (ALL) in first remission.nnnDESIGNnRetrospective comparison of two cohorts of patients.nnnSETTINGnChemotherapy recipients were treated in 44 hospitals in West Germany in two cooperative group trials; transplants were done in 98 hospitals worldwide.nnnPATIENTSnPatients (484) receiving intensive postremission chemotherapy and 251 recipients of HLA-identical sibling bone marrow transplants for ALL in first remission. Patients ranged from 15 to 45 years of age and were treated between 1980 and 1987.nnnMAIN RESULTSnSimilar prognostic factors predicted treatment failure (non-T-cell phenotype, high leukocyte count at diagnosis, and 8 or more weeks to achieve first remission) of both therapies. After statistical adjustments were made for differences in disease characteristics and time-to-treatment, survival was similar in the chemotherapy and transplant cohorts: Five-year leukemia-free survival probability was 38% (95% CI, 33% to 43%) with chemotherapy and 44% (CI, 37% to 52%) with transplant. No specific prognostic group had a significantly better outcome with one treatment compared with the other (6% for the difference; CI, -3% to 15%). Causes of treatment failure differed: With chemotherapy, 268 (96%) failures were from relapse and 11 (4%) were treatment-related; with transplants, 43 (32%) failures were from relapse and 92 (68%) were treatment-related.nnnCONCLUSIONSnThese results suggest that bone marrow transplants currently offer no special advantage over chemotherapy for adults with acute lymphoblastic leukemia in first remission.

Fludarabine plus cyclophosphamide is an efficient treatment for advanced chronic lymphocytic leukaemia (CLL): results of a phase II study of the German CLL Study Group.

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 59u2003years) received a regimen that consisted of fludarabine 30u2003mg/m2 in a 30‐min IV infusion, du20031–3, and cyclophosphamide 250u2003mg/m2 in a 30‐min IV infusion on du20031–3. Cycles were repeated every 28u2003d. 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.

Recombinant human interferon (IFN) alpha-2b in chronic myelogenous leukaemia: dose dependency of response and frequency of neutralizing anti-interferon antibodies

Summary. Twenty‐seven patients with Philadelphia chromosome positive chronic myelogenous leukaemia in the chronic phase were treated with low doses of recombinant interferon (IFN) alpha‐2b. Ten patients entered a complete and six a partial haematologic remission with a median duration of 5·8 and 9·1 months respectively. Five minor cytogenetic responses were observed. These results are inferior compared to other studies with higher interferon‐doses. Fever was an acute side effect after injection of IFN, limb pains and fatigue occurred protractedly. Haematologic side effects, nonspecific EEG changes, weight loss, and development of pulmonary infiltrates were observed in later periods of the treatment. Eight patients developed neutralizing anti‐IFN antibodies after 4·2–20·4 months (median 12·8 months). Anti‐IFN antibodies were associated with relapse or refractoriness to IFN treatment: five out of nine patients with rising WBC after initial fall had antibodies, while four did not. Two out of four patients with primary non‐response had IFN‐antibodies. These results may indicate a serious problem in the long‐term treatment of CML with recombinant interferon.

Correlation of cytogenetic, molecular cytogenetic, and clinical findings in 59 patients with ANLL or MDS and abnormalities of the short arm of chromosome 12

Abnormalities of the short arm of chromosome 12 (12p) are found in about 5% of acute nonlymphocytic leukaemias (ANLL) and myelodysplastic syndromes (MDS). They are described to be characteristic of secondary leukaemias, especially after prior mutagenic exposure, and to be associated with a poor prognosis. In our series of 59 patients with 12p abnormalities and ANLL or MDS, exposure to genotoxic agents was proven only in five patients, but in 13/44 patients ANLL evolved from an MDS. Patients with a small deletion del(12)(p11.2p13) having a mild clinical course were distinguished from those with a large del(12)(p11.2), additional chromosomal anomalies, and a poor clinical course. Among the 31 patients with translocations or dicentric chromosomes involving 12p, a group of eight with t/dic(12;13) was the most frequent and was associated with a poor prognosis. The clinical outcome was adverse in the majority of patients with complex karyotype abnormalities, but in some patients a milder clinical course seems likely. A new, hitherto undescribed, abnormality in an MDS case with a duplication dup(12)(p11.2p13) was the amplification of the signal of the yeast artificial chromosome (YAC) clone 964c10 (D12S736). In 38 cases with deletions or unbalanced translocations/dicentrics one YAC signal was lost. Five patients with balanced translocations demonstrated breakpoints within the YAC, containing the ETV6 (TEL) gene. The breakpoints were telomeric to the YAC 964c10 in seven cases and centromeric in one patient.

Altered surface marker expression and function of G-CSF-induced neutrophils from test subjects and patients under chemotherapy

We have previously reported an altered surface marker expression and chemotaxis of G‐CSF‐induced neutrophils from patients with severe congenital neutropenia. However, effects of G‐CSF and influence of the underlying disease on neutrophils could not be discerned. In this study we have evaluated the effects of G‐CSF on neutrophil phenotype and function in patients under chemotherapy and in healthy test subjects. We found a significantly enhanced expression of FcγRI, CD14 and CD54 and a decrease in the level of FcγRIII during G‐CSF treatment. In addition, motility of G‐CSF‐induced neutrophils was significantly decreased. The effects were seen in patients under cytotoxic chemotherapy and in healthy test subjects. Surface marker alterations and neutrophil motility were affected by G‐CSF administration in a dose‐dependent manner. Kinetic studies on neutrophils from healthy test subjects demonstrated that all effects could be seen after a single administration of 300 μg G‐CSF and began to appear within 4 h. Release of partially immature neutrophils from the bone marrow and indirect activation of these cells by G‐CSF are discussed as possible reasons for the findings presented. They demonstrate that G‐CSF has profound effects on neutrophil phenotype and function in vivo which might have clinical implications.

Allogeneic bone marrow transplantation for Langerhans' cell histiocytosis

A group of proliferative diseases of the epidermal Langerhans cells are commonly referred to as Langerhans cell histiocytosis (LCH). A small number of the patients with this disease face an unfavorable disease course despite chemotherapy and radiation therapy. in LCH patients with a poor prognosis, allogeneic bone marrow transplantation (BMT) could be the appropriate treatment with proven antiproliferative effects and may be able to repopulate the recipient with stem cell‐derived Langerhans cells from the donor or correct the presumed underlying immunodeficiency. An LCH was diagnosed in a 15‐year‐old boy with multiple osteolytic lesions, anemia, and diabetes insipidus centralis. Repeated flare‐ups of the disease had necessitated several courses of conventional chemotherapy including cyclophosphamide (CY), prednisolone (P), 6‐mercaptopurine (6‐MP), vincristine (VCR), and additional local irradiation without stable remission. Three years after first being diagnosed with LCH the patient underwent high‐dose chemotherapy‐radiation therapy followed by allogeneic BMT from his human lymphocyte antigen (HLA)‐identical brother. Currently, he is alive and well and has been disease‐free for more than 41 months after BMT.

Treatment of anti-recombinant interferon-alpha 2 antibody positive CML patients with natural interferon-alpha

Summary Of 38 patients with a Philadelphia‐chromosome positive chronic myeloid leukaemia treated with recombinant interferon alpha (rIFN‐α) 2a or 2b and monitored for emergence of IFN‐antibodies in their sera 11 patients developed rIFN‐α2 binding and 10 rIFN‐α2 neutralizing antibodies. rIFN‐α neutralizing antibody positive patients experienced significantly (P<0·025) more clinical relapses (6/10) than IFN‐antibody negative patients (6/28) during continuous IFN‐therapy. Furthermore, IFN‐antibody‐positive patients with titre above 400 INU/ml were more likely to relapse under rIFN‐α‐therapy than IFN‐antibody‐negative patients with titre below 400 INU/ml (P<0·05).

Myeloablative intensified conditioning regimen with in vivo T-cell depletion (ATG) followed by allografting in patients with advanced multiple myeloma. A phase I/II study of the German Study-group Multiple Myeloma (DSMM)

Summary:We investigated toxicity and efficacy of in vivo T-cell depletion with anti-thymocyte globulin (ATG) as part of an intensified myeloablative conditioning regimen followed by allogeneic stem cell transplantation in patients with advanced multiple myeloma. The conditioning regimen consisted of modified total body irradiation, busulfan and cyclophosphamide (n=15) or in the case of prior dose-limiting radiotherapy of busulfan and cyclophosphamide (n=3). The median age was 44 years (range, 29–53) and the median time from diagnosis to transplant was 12 months (range, 6–144). Grade II–IV acute graft-versus-host disease (GvHD) occurred in six patients (35%). Severe grade III/IV GvHD developed in one patient (6%). Three patients died of therapy-related causes (17%). A complete remission (CR) with negative immunofixation after allogeneic transplantation was seen in eight of the evaluable patients (53%). After a median follow-up of 41 months (range, 8–84), the estimated overall survival at 6 years for all patients is 77% (CI 95%: 58–96%). The estimated progression-free survival at 6 years for all patients is 31% (CI 95%: 2–59%) and 46% (CI 95%: 9–83%) for patients with CR. In vivo T-cell depletion with ATG resulted in a low rate of severe GvHD with low treatment-related mortality, and a substantial number of long-term survivors.

Progressive interstitial fibrosis of the lung in sclerodermoid chronic graft-versus-host disease

Sclerodermoid chronic graft-versus-host disease (sGVHD) is a well-known complication in patients with a long history of chronic GVHD. Pulmonary involvement in chronic GVHD presents typically as bronchiolitis obliterans (BO). Pulmonary fibrosis after allogeneic hematopoietic stem cell transplantation (HSCT) is presumed to be caused by the long-term toxicity of the conditioning regimen or the result of lung injury elicited predominantly by viral infections or GVHD. We present two patients with late onset pulmonary fibrosis associated with moderate sGVHD of the skin after HSCT. At the initial diagnosis of chronic GVHD both patients presented with symptoms of interstitial pneumonia. Years later both patients developed moderate to severe interstitial pulmonary fibrosis in association with sGVHD. One patient showed additional clinical and histological signs of BO. While one patient responded to increased immunosuppression including total nodal irradiation (1u2009Gy), the other patient died due to complications related to pulmonary fibrosis.Bone Marrow Transplantation (2002) 29, 357–360. doi:10.1038/sj.bmt.1703386