CD4+CD25highCD127low regulatory T cells in peripheral blood are not an independent factor for chronic graft-versus-host disease after allogeneic stem cell transplantation.

BACKGROUND: The therapeutic efficacy of allogeneic hemopoietic stem cell transplantation (HSCT) largely relies on the graft-versus-leukemia (GVL) effect. Uncontrolled graft-versus-host disease (GVHD) is a feared complication of HSCT. Regulatory T cells (Treg) are a subset of CD4+ T-helper cells believed to maintain tolerance after HSCT. It remains unclear whether low peripheral blood Treg have an impact on the risk for acute (aGVHD) and chronic GVHD (cGVHD). METHODS: In this paper we enumerated the CD4+CD25highCD127low Treg in the peripheral blood of 84 patients after at least 150 days from HSCT and in 20 healthy age-matched controls. RESULTS: Although similar mean lymphocyte counts were found in patients and controls, CD3+CD4+ T-cell counts were significantly lower in patients. Patients also had significantly lower Treg percentages among lymphocytes as compared to controls. Patients with cGVHD had even higher percentages of Treg if compared to patients without cGVHD. In multivariate analysis, Treg percentages were not an independent factor for cGVHD. CONCLUSIONS: This paper did not show a relation between deficient peripheral blood Treg and cGVHD, therefore cGVHD does not seem to occur as a result of peripheral Treg paucity.

Histamine dihydrochloride for the treatment of acute myeloid leukemia, malignant melanoma and renal cell carcinoma.

Histamine dihydrochloride is a vasoactive biogenic amine. It inhibits the reactive oxygen species formation in monocytes via histamine H2 receptors and protects natural killer and T cells from oxidative damage. Histamine has the potential to optimize cytokine-induced activation of T cells and natural killer cells; therefore, the addition of histamine to cytokine treatment may improve treatment efficacy. Clinical trials in solid tumors and in acute myeloid leukemia have demonstrated the potential to improve treatment outcome when histamine dihydrochloride is combined with immunotherapy. In patients with metastatic malignant melanoma, this strategy improved remission rates and increased survival. On the other hand, less promising results were reported for histamine dihydrochloride added to cytokines in patients with other solid tumors, especially in advanced renal cell carcinoma. A recent international Phase III trial performed in 320 patients showed that maintenance therapy with histamine dihydrochloride and IL-2 was able to improve leukemia-free survival in patients with acute myeloid leukemia, without an effect on overall survival. The combination of histamine dihydrochloride with IL-2 potentially offers an efficacious and tolerable maintenance strategy for patients with acute myeloid leukemia; however, its impact on survival remains to be explored.

Evaluation of the serum-free light chain test in untreated patients with AL amyloidosis.

We evaluated the Serum Free Light Chain (FLC) test in a series of 133 untreated patients with systemic AL amyloidosis. The FLC test detected the monoclonal gammopathy in 87% compared with 92% for immunofixation of serum and urine in combination. However, both tests proved complementary. The FLC test was also a valuable tool in patients with advanced renal failure in spite of uninvolved light chain retention. Higher FLC levels were associated with higher bone marrow plasmocytosis, poorer Karnofsky index and heart involvement, and therefore reflected disease severity.

Rapid progression of left ventricular wall thickness predicts mortality in cardiac light-chain amyloidosis.

BACKGROUND: Cardiac amyloidosis (CA) is the most problematic cause of heart failure because medical treatment strategies are not well tolerated. Due to its high mortality, identification of patients at high risk is crucial for treatment strategies such as heart transplantation prior to chemotherapy for amyloid disease. METHODS: Left ventricular wall thickness (LVT) progression was retrospectively compared with electrocardiographic and echocardiographic parameters for risk prediction in 39 patients with histologically proven cardiac amyloidosis. RESULTS: Seventeen deaths occurred, equivalent to 1- and 3-year survival rates of 62.1% and 55.0%, respectively. LVT progression in deceased patients was 2.02 +/- 0.85 mm/month compared with 0.19 +/- 0.03 mm/month in survivors (p < 0.001). Autologous stem-cell transplantation (n = 22, or 54%) reduced LVT progression as compared with not receiving stem cells (0.21 +/- 0.04 mm/month vs 1.45 +/- 0.57 mm/month, p < 0.005). LVT progression correlated with maximal LVT and absolute LVT increase. Progression of LVT was more rapid in patients with impaired LV ejection fraction (LVEF) than preserved LVEF (2.16 +/- 1.04 mm/month vs 0.30 +/- 0.13 mm/month, p < 0.001). LVT closely correlated with survival, whereas initial, maximum or absolute increase in LVT did not. Further predictors of survival were LVEF, autologous stem-cell transplantation and low voltage, but not diastolic dysfunction. Multivariate analysis identified LVT progression as the strongest independent parameter for survival. CONCLUSIONS: LVT progression is a powerful risk predictor in light-chain CA, superior to parameters such as LVEF, LVT or a low-voltage pattern. Improved survival by high-dose chemotherapy and stem-cell transplantation is paralleled by a reduction in LVT progression. Repetitive echocardiographic assessment appears indicated in CA patients to identify candidates for heart transplantation in amyloidosis.

Impact of HLA class I and class II DNA high-resolution HLA typing on clinical outcome in adult unrelated stem cell transplantation after in vivo T-cell depletion with alemtuzumab.

Survival after volunteer unrelated donor (VUD) stem cell transplantation (SCT) is influenced by matching for human leucocyte antigens (HLA). We analysed the effects of serological and molecular typing at HLA-A, -B, -C and -DRB1 in 100 patient/VUD pairs from a single transplant centre. Patients received SCT for good risk [chronic myeloid leukaemia in first chronic phase (CML-CP1), n=55] or poor risk (n=45) diseases after myeloablative conditioning and T-cell depletion with alemtuzumab. By serological typing, 70 pairs were fully matched, whereas molecular typing revealed 10 pairs with additional mismatches. The day 100 transplant related mortality was 15%. Acute graft versus host disease (GvHD) grades III-IV occurred in 11%, whilst extensive chronic GvHD in 13% of evaluable patients. There was no statistical difference in GvHD rates between patients who received grafts from fully matched or from mismatched donors. In univariate analysis the disease risk group and CMV seronegativity of recipient and donor were the only significant predictors for survival, with 3-year survival probabilities of 71.2% for CML-CP1 and 28% for poor risk diseases. In the poor risk group, HLA mismatches had a negative impact on survival (p=0.003) and progression free survival (p=0.009) contrary to CML-CP1 patients, in whom HLA mismatches at molecular or serological level did not have any impact.

Posttransplantation imatinib as a strategy to postpone the requirement for immunotherapy in patients undergoing reduced-intensity allografts for chronic myeloid leukemia.

Disease relapse is a major cause of treatment failure after reduced-intensity allografts and while donor lymphocyte infusions (DLIs) can be effective salvage therapy they are associated with severe graft-versus-host disease (GVHD) when administered early after transplantation. We have therefore examined whether imatinib mesylate can delay relapse and postpone the requirement for DLI in 22 patients with chronic myeloid leukemia (CML) allografted using a reduced-intensity regimen. Imatinib was commenced on day + 35 and continued until 1 year after transplantation. Posttransplantation imatinib was well tolerated and abolished the risk of relapse during this period. Twenty-one patients completed 11 months of imatinib therapy, 15 of whom subsequently relapsed and received DLI. Ten patients to date have achieved molecular remission after DLI. Adjunctive targeted therapy allows the kinetics of disease relapse after a reduced-intensity allograft to be manipulated and represents a novel strategy by which outcome may be improved in patients who undergo transplantation for CML and other leukemias.

Incidence of hyperthyroidism after unrelated donor allogeneic stem cell transplantation.

We report on three patients who developed overt thyrotoxicosis after volunteer unrelated donor bone marrow transplantation for Philadelphia chromosome positive chronic myeloid leukemia shortly after the onset of chronic graft versus host disease. In all three cases, the etiology of hyperthyroidism is likely to be a combination of toxic factors and an immune process. Systematic evaluation of thyroid function tests in 97 unrelated allograft recipients from our center who survived at least 100 days from stem cell or bone marrow transplantation for hematological diseases gave a rate of overt thyrotoxicosis at 3.1% in this cohort.

Non-invasive predictors of survival in cardiac amyloidosis.

BACKGROUND: Patients with cardiac amyloidosis (CA) have increased mortality. AIMS: Clinical, electrocardiographic, and echocardiographic parameters were assessed for risk-stratification of CA. METHODS AND RESULTS: CA was confirmed by endomyocardial biopsy in 59 patients (54.8+/-1.2 years) with light-chain (n = 43) or transthyretin amyloidosis (n = 16). Six patients without CA served as controls (NCA). Clinical symptoms, electrocardiographic, and echocardiographic parameters were analyzed for prognostic significance. Of the patients with light-chain amyloidosis, 14 died and 2 underwent heart transplantation. 1-/3-year survival was 68%/63%. Survival depended on left ventricular function (LV-EF), LV mass, radius/wall thickness, septum thickness, low voltage pattern (LVP), conduction delay, NYHA class, and stem cell transplantation. A multivariate model only contained LV-EF and LVP; the beneficial effect of stem cell transplantation was cancelled out as this treatment was withheld in patients with highest cardiac risk. Survival was most limited if both risk factors occurred. Cardiac involvement in transthyretin amyloidosis showed better survival (2 deaths, 1-/3-year survival 91%/83%). Analysis of prognostic risk factor utility in all amyloid patients (light-chain and transthyretin) again revealed LVP and LV-EF, and aetiology of amyloidosis as independent survival parameters. CONCLUSION: Prognosis of CA is poor, but aetiology of amyloid, LVP, and LV-EF allows identification of patients at highest risk of death, who may require individual treatment approaches (heart transplantation prior to causative therapy).

Imatinib preceding allogeneic stem cell transplantation in chronic myeloid leukemia.

In 37 adults with chronic myeloid leukemia undergoing allogeneic stem cell transplantation imatinib prior to transplant had no discernible negative impact on 100-day mortality (13%) and severe acute (22%) or extensive chronic graft-versus- host disease (31%). After a median of 203 days (range: 18-1419) overall and progression-free survival rates are 62% and 54%, respectively.

Alternating versus concurrent schedules of imatinib and chemotherapy as front-line therapy for Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL).

The best strategy for incorporating imatinib in front-line treatment of Ph+ acute lymphoblastic leukemia (ALL) has not been established. We enrolled 92 patients with newly diagnosed Ph+ ALL in a prospective, multicenter study to investigate sequentially 2 treatment schedules with imatinib administered concurrent to or alternating with a uniform induction and consolidation regimen. Coadministration of imatinib and induction cycle 2 (INDII) resulted in a complete remission (CR) rate of 95% and polymerase chain reaction (PCR) negativity for BCR-ABL in 52% of patients, compared with 19% in patients in the alternating treatment cohort (P = .01). Remarkably, patients with and without a CR after induction cycle 1 (INDI) had similar hematologic and molecular responses after concurrent imatinib and INDII. In the concurrent cohort, grades III and IV cytopenias and transient hepatotoxicity necessitated interruption of induction in 87% and 53% of patients, respectively; however, duration of induction was not prolonged when compared with patients receiving chemotherapy alone. No imatinib-related severe hematologic or nonhematologic toxicities were noted with the alternating schedule. In each cohort, 77% of patients underwent allogeneic stem cell transplantation (SCT) in first CR (CR1). Both schedules of imatinib have acceptable toxicity and facilitate SCT in CR1 in the majority of patients, but concurrent administration of imatinib and chemotherapy has greater antileukemic efficacy.

Risk stratification in cardiac amyloidosis: novel approaches.

Amyloidosis is a term for diseases with extracellular deposition of insoluble beta-fibrillar proteins in different organs. The heart is primarily involved in more than half of patients with immunoglobulin light-chain amyloidosis or hereditary amyloidosis and associated with poor prognosis. Different traditional diagnostic tools that have been described for risk stratification lack of sufficient sensitivity and specificity for patient survival. Until November 2004 in 50 consecutive patients with light chain amyloidosis and 15 patients with hereditary amyloidosis electrocardiography, echocardiography, Holter monitoring, cardiopulmonary exercise test, lung function testing, tilt-test, and laboratory investigations have been performed at our department. Cardiac amyloidosis was found in 32 patients. Interventricular septum (14.3+/-0.5 mm vs. 12.3+/-0.7 mm, P<0.05), plasma NT-proBNP (7154+/-2122 ng/l vs. 380+/-113 ng/l; P<0.01), cardiac Troponin T (0.105+/-0.030 vs. 0.019+/-0.010 microg/l; P<0.05) were increased in patients with cardiac amyloidosis as compared to patients light chain amyloidosis but no cardiac involvement. Maximal inspiratory (Pimax) and expiratory (Pemax) mouth pressure were decreased with CA compared to controls. Correlation of NT-proBNP and interventricular septum thickness (r=0.53, P=0.029) as well as and Pimax (r=0.72, P<0.01) or Pemax (r=0.69; P<0.01) was noticed. A correlation of grade of arrhythmias in Holter monitoring and syncopes was not observed. Cardiac involvement of amyloid disease carries a poor prognosis and is not well characterized by classic heart failure determinants. Heart transplantation based on novel risk markers including NT-proBNP might be a suitable therapeutic approach for patients with manifest cardiac amyloidosis, but will require alternative patient selection and listing criteria.

Indications for high-dose chemotherapy with autologous stem cell support in patients with systemic amyloid light chain amyloidosis.

Systemic amyloid light chain amyloidosis is a protein conformation disorder caused by a clonal plasma cell dyscrasia. Symptoms result from fibrillar extracellular deposits in kidney, heart, liver, gut, peripheral nervous system and other tissues. The deposits disrupt organ function and ultimately lead to death. The prognosis of systemic amyloid light chain (AL) amyloidosis is poor; less than 5% of all patients survive 10 years or longer. Using conventional chemotherapy, the median survival could be prolonged by 4 months. Treatment with high-dose melphalm (HDM) and autologous stem cell transplantation (ASCT) of selected patients has been shown to arrest and even to reverse the disease course. This procedure however remains controversial because treatment related mortality (TRM) in AL amyloidosis is substantially higher (15-40%) than in multiple myeloma (<5%). Here we review recent results of ASCT, eligibility criteria for HDM and report our own treatment results in 41 patients.

Early molecular response to posttransplantation imatinib determines outcome in MRD+ Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL).

In adult Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL), minimal residual disease (MRD) after stem cell transplantation (SCT) is associated with a relapse probability exceeding 90%. Starting imatinib in the setting of MRD may decrease this high relapse rate. In this prospective multicenter study, 27 Ph+ ALL patients received imatinib upon detection of MRD after SCT. Bcr-abl transcripts became undetectable in 14 (52%) of 27 patients, after a median of 1.5 months (0.9-3.7 months) ((early)CR(mol)). All patients who achieved an (early)CR(mol) remained in remission for the duration of imatinib treatment; 3 patients relapsed after imatinib was discontinued. Failure to achieve polymerase chain reaction (PCR) negativity shortly after starting imatinib predicted relapse, which occurred in 12 (92%) of 13 patients after a median of 3 months. Disease-free survival (DFS) in (early)CR(mol) patients is 91% +/- 9% and 54% +/- 21% after 12 and 24 months, respectively, compared with 8% +/- 7% after 12 months in patients remaining MRD+ (P < .001). In conclusion, approximately half of patients with Ph+ ALL receiving imatinib for MRD positivity after SCT experience prolonged DFS, which can be anticipated by the rapid achievement of a molecular complete remission (CR). Continued detection of bcr-abl transcripts after 2 to 3 months on imatinib identifies patients who will ultimately experience relapse and in whom additional or alternative antileukemic treatment should be initiated.

High-dose melphalan with autologous stem cell transplantation after VAD induction chemotherapy for treatment of amyloid light chain amyloidosis: a single centre prospective phase II study.

Amyloid light chain (AL) amyloidosis is the result of a clonal plasma cell expansion, in which monoclonal light chains transform to amyloid deposit in various tissues and can lead to organ dysfunction and organ failure. The median survival of patients with AL amyloidosis without therapy is 10-14 months. With high-dose melphalan (HDM) and autologous stem cell transplantation (ASCT), haematological and clinical remission rates of up to 50% of treated patients have been reported from phase II studies. HDM followed by ASCT appears to prolong survival in patients, if haematological remission can be reached. In this phase II study, we evaluated vincristine, adriamycin and dexamethasone (VAD) as induction chemotherapy prior to stem cell mobilization and HDM with ASCT. The regimen was, in general, feasible in patients with AL amyloidosis, but VAD chemotherapy had a considerable World Health Organization (WHO) grade III-IV toxicity (25%) and mortality (7%) rate. VAD pretreatment did not interfere with stem cell mobilization and HDM with ASCT was possible in 86% of patients. The overall treatment efficacy was comparable with reported results of HDM and ASCT without preceding chemotherapy. We could not show an additional benefit of VAD induction in terms of increasing haematological response rate; however the 13% mortality rate after HDM and ASCT in our series was lower than the previous report.

Early prediction of response in patients with relapsed or refractory Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) treated with imatinib.

Imatinib has pronounced but brief antileukemic activity in advanced Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph(+)ALL). We assessed the prognostic impact of pretreatment disease features and the early bone marrow (BM) response in 68 consecutive patients with Ph(+)ALL receiving imatinib salvage therapy. A complete hematologic or marrow response was achieved by 92% of patients with BM blasts below 5% on day 14, whereas 62.5% of patients with more than 5% BM blasts on day 14 were nonresponders. Similarly, time to progression (TTP) was superior in patients with a good day 14 response (5.2 versus 0.9 months; P <.0001). Prior complete remission of less than 6 months, white blood cell count of more than 10 x 10(9)/L, circulating peripheral blood blasts at diagnosis, additional Philadelphia chromosomes, or at least 2 Bcr-Abl fusion signals were associated with significantly inferior remission rate and response duration. In patients without poor prognostic features, single-agent imatinib may be appropriate before transplant salvage therapy. Conversely, patients with clinically or cytogenetically defined poor-risk features are candidates for trials of upfront imatinib in combination with other agents.

No regression of renal AL amyloid in monoclonal gammopathy after successful autologous blood stem cell transplantation and significant clinical improvement.

BACKGROUND: High-dose chemotherapy followed by autologous blood stem cell transplantation induces remission of plasma cell dyscrasia in patients with AL amyloidosis. The impact of this treatment on the glomerular amyloid mass is still unknown. METHODS: In the present study, the quantity of the renal amyloid mass before and more than 3 years after high-dose melphalan treatment and autologous blood stem cell transplantation was assessed in two patients. At the time of the second renal biopsy, both patients were in complete remission without detectable serum and urinary monoclonal IgA-lambda and a normal percentage of plasma cells in the bone marrow. RESULTS: In both patients with biopsy-proven AL amyloidosis, urinary protein excretion decreased from 7 g/24 h to <2 g/24 h more than 3 years after autologous blood stem cell transplantation. In contrast, glomerular amyloid deposits persisted, as shown in the second biopsy. CONCLUSION: Despite complete remission of the plasma cell dyscrasia and improvement of glomerular permeability, the amount of glomerular amyloid mass did not regress.

Level of CD 20-expression and efficacy of rituximab treatment in patients with resistant or relapsing B-cell prolymphocytic leukemia and B-cell chronic lymphocytic leukemia.

Rituximab (IDEC C2B8) is a chimeric human-mouse monoclonal anti-CD20 antibody that has been proven to be effective for the treatment of patients with CD20 positive leukemia and lymphoma. The level of CD20-expression in patients with B-cell chronic lymphocytic leukemia (B-CLL) is low in comparison to other B-cell lymphomas and normal B-cells. Previous experience with rituximab treatment in small series of patients with B-CLL suggest that it is less effective in B-CLL than in follicular lymphomas. We analyzed the correlation between CD20-expression level and efficacy of rituximab treatment in eight patients with refractory or relapsed B-CLL and two patients with B-cell prolymphocytic leukemia (B-PLL). We could not identify any correlation between CD20-expression and efficacy of rituximab treatment.