MRD-negative remission in CLL is achievable with alemtuzumab, leading to an improved overall and treatment-free survival.
T-cell prolymphocytic leukemia (T-PLL) is a chemotherapy-resistant malignancy with a median survival of 7.5 months. Preliminary results indicated a high remission induction rate with the human CD52 antibody, CAMPATH-1H. This study reports results in 39 patients with T-PLL treated with CAMPATH-1H between March 1993 and May 2000. All but 2 patients had received prior therapy with a variety of agents, including 30 with pentostatin; none achieved complete remission (CR). CAMPATH-1H (30 mg) was administered intravenously 3 times weekly until maximal response. The overall response rate was 76% with 60% CR and 16% partial remission (PR). These responses were durable with a median disease-free interval of 7 months (range, 4-45 months). Survival was significantly prolonged in patients achieving CR compared to PR or no response (NR), including one patient who survived 54 months. Nine patients remain alive up to 29 months after completing therapy. Seven patients received high-dose therapy with autologous stem cell support, 3 of whom remain alive in CR 5, 7, and 15 months after autograft. Stem cell harvests in these patients were uncontaminated with T-PLL cells as demonstrated by dual-color flow cytometry and polymerase chain reaction. Four patients had allogeneic stem cell transplants, 3 from siblings and 1 from a matched unrelated donor. Two had nonmyeloablative conditioning. Three are alive in CR up to 24 months after allograft. The conclusion is that CAMPATH-1H is an effective therapy in T-PLL, producing remissions in more than two thirds of patients. The use of stem cell transplantation to consolidate responses merits further study.
SUMMARYSince the retinal vessels have no sympathetic innervation, blood flow in response to raised blood pressure is dependent on autoregulation. To determine the effect of hypertension on retinal haemodynamics and the autoregulatory capacity of the retinal circulation under conditions of normoglycaemia and hyperglycaemia, retinal blood flow was measured before and after raising the systemic blood pressure in ten normal control subjects, ten diabetic subjects with blood glucose < 10 mmol 11 and ten diabetic subjects with blood glucose > 15 mmol 1-'. A controlled nse in systemic blood pressure was achieved using an intravenous infusion of tyramine. Retinal volume flow was determined from red cell velocity using laser Doppler velocimetry and from retinal vessel diameter measurements using digital image analysis of fundus photographs. With a 40 % increase in mean arterial blood pressure (MAP), there was a significant increase in retinal blood flow of 32.9 + 7-1 % in non-diabetic controls. In diabetics at the low blood glucose level, the increase in retinal blood flow was significant at 30% increase in MAP (23.6 + 87 %, P = 0-032) and at 40 % increase (49-9 + 12-03 %, P = 0-004). Diabetics with high blood glucose failed to autoregulate at any of the increased levels of MAP (15 % increase, 27 0 + 11 1 %; 30 % increase, 66.9 + 19.8 %; and 40 % increase, 101 9 + 21 4 %; P < 0.022). The coefficients of autoregulation showed that in non-diabetic controls, retinal vascular autoregulation broke down with increases in MAP of between 30 and 40 %. In diabetic subjects, it broke down between 15 and 30 % in normoglycaemia and at less than 15 % in hyperglycaemia. This study demonstrates an impairment in retinal vascular autoregulation in response to raised systemic blood pressure in diabetic subjects, more so at an elevated blood glucose level, thus providing a mechanism for the detrimental effect of hypertension on diabetic retinopathy.
Nineteen patients with high‐risk myelodysplastic syndrome (MDS)/acute myeloid leukaemia (AML) received fludarabine, cytarabine, granulocyte‐colony stimulating factor (G‐CSF), and idarubicin chemotherapy (de novo MDS/MDS‐AML, nine; relapsed/refractory MDS/AML, seven; therapy‐related MDS, three). Median age was 44 years and median disease duration 10 months. 16/19 (84%) patients had abnormal cytogenetics with seven (37%) harbouring abnormalities of chromosome 7. 18/19 (94.7%) patients responded to FLAG‐idarubicin with 12 (63%) achieving complete remission (CR) (<5% blasts and normal cytogenetics). 7/9 (78%) patients with de novo MDS/MDS‐AML achieved CR compared to 5/10 (50%) with alternative diagnoses. Response was associated with age < 50 years, disease duration < 3 months, and cytogenetics other than abnormalities of chromosome 7. Haemopoietic regeneration was rapid in most patients and there were no toxic deaths. Nine patients received a second course of chemotherapy, three have proceeded to allogeneic bone marrow transplant and three to autologous blood stem cell/bone marrow transplantation. Follow‐up is short (median 10 months). 12/19 (63%) patients remain alive and 5/12 (42%) have relapsed at a median 5 months following CR achievement. FLAG‐idarubicin was well tolerated. High rates of morphological and cytogenetic remission, especially in de novo MDS, offer a window of opportunity for assessment of autologous BMT in this group of diseases where no treatment except alloBMT has led to prolongation of survival.
Summary. Acute leukaemias in relapse after allogeneic stem cell transplantation (SCT) respond poorly to donor leucocyte infusions (DLI) compared with chronic myeloid leukaemia (CML), at least in part because of faster disease kinetics. Fludarabine-containing`non-myeloablative' chemotherapy followed by further allo SCT may offer more rapid and effective disease control. We report 14 patients with relapse after allo SCT for acute leukaemia [seven acute myeloid leukaemia (AML), five acute lymphoblastic leukaemia (ALL)] or refractory anaemia with excess blasts in transformation (RAEB-t, n 2) treated with fludarabine, high-dose cytosine arabinoside (ara-C) and granulocyte colony-simulating factor (G-CSF) with (n 10) or without (n 2) idarubicin (FLAG^Ida) or DaunoXome (FLAG-X) (n 2) and second allo SCT from the original donor. Donors were fully human leucocyte antigen (HLA) -matched in 13 cases with a single class A mismatch in one. Actuarial overall survival was 60% and disease-free survival was 26% at 58 months. Remissions after the second SCT were longer than those after the first bone marrow transplantation (BMT) in eight of the 13 assessable patients to date. Haematopoietic recovery was rapid. Transplants were well tolerated with no treatment-related deaths. The major complication was graft-versus-host disease (GvHD, acute > grade II22 cases, chronic ± eight cases, two limited, six extensive) although there have been no deaths attributable to this. FLAG^Ida and second allo SCT is a safe and useful approach and may be more effective than DLI in the treatment of acute leukaemias relapsing after conventional allo SCT.
The effect of the carbonic anhydrase inhibitor, acetazolamide, on the retinal circulation was studied in 10 healthy volunteers. Acetazolamide was administered intravenously at a dose of 500 mg. Retinal blood flow was determined from red cell velocity using laser Doppler velocimetry and vessel diameter measurement using computerised digital image analysis of monochromatic fundus photographs. There was a significant increase in retinal blood flow at 30 minutes and 60 minutes after acetazolamide injection (p = 0.002). Retinal vessels showed vasodilatation reaching significant levels 60 minutes after the injection (p < 0.03). An increase in red cell velocity was observed at 30 and 60 minutes (p < 0.002). A significant reduction in intraocular pressure occurred at 30 and 60 minutes after the injection (p < 0.001). The mechanisms responsible for the increase in retinal blood flow acted via significant increases in perfusion pressure (p < 0.05), red cell velocity (p < 0.002) and retinal vessel dilatation (p < 0.03). An increase in tissue PCO2 and a reduction in pH are thought to be responsible for the vascular dilatation. The increase in retinal blood flow with acetazolamide may serve to limit optic disc and retinal ischaemia in acute glaucoma and central retinal artery occlusion respectively.
A method of semi-automated image analysis for the measurement of retinal vessel diameters is described. This was compared with an observer-driven method for reproducibility and accuracy. The coefficient of variation for the data from the semi-automated method was 1.5-7.5% (depending on the vessel diameter) compared to 6-34% with the observer-driven method. The mean vessel diameters using the observer-driven method tended to be higher; however, this did not reach significance. The speed and low inter- and intra-observer variability for the semi-automated method make it a useful technique for measuring retinal blood vessel diameters. A larger variability was found between photographs taken at different times. This may be due to changes in retinal vessel diameter with changes in retinal perfusion pressure during the cardiac cycle.
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