SummaryA new automated method to reliably quantify reticulated platelets, expressed as the immature platelet fraction (IPF), has been developed utilizing the XE-2100 blood cell counter with upgraded software (Sysmex, Kobe, Japan). The IPF is identified by flow cytometry techniques and the use of a nucleic acid specific dye in the reticulocyte/optical platelet channel. The clinical utility of this parameter was established in the laboratory diagnosis of thrombocytopenia due to increased peripheral platelet destruction, particularly autoimmune thrombocytopenic purpura (AITP) and thrombotic thrombocytopenic purpura (TTP). Reproducibility and stability results over 48 h were good. An IPF reference range in healthy individuals was established as 1AE1-6AE1%, with a mean of 3AE4%. Patients in whom platelet destruction might be abnormal, were studied and two of these patients followed serially during the course of treatment. The IPF was raised in several disease states. The most significant increases in IPF values were found in patients with AITP (mean 22AE3%, range 9AE2-33AE1%) and acute TTP (mean 17AE2%, range 11AE2-30AE9%). Following patients during treatment demonstrated that as the platelet count recovered the IPF% fell. These results show that a rapid, inexpensive automated method for measuring the IPF% is feasible and should become a standard parameter in evaluating the thrombocytopenic patient.
Summary. In this study, we retrospectively analysed the clinical features, risk factors and outcome of 22 patients with thrombotic thrombocytopenic purpura (TTP) occurring after allogeneic stem cell transplantation. All but two of these patients received stem cells from unrelated donors (UDs), two-thirds were female, three-quarters were adults and leukaemia was the major reason for transplant. The incidence of TTP was 20 out of 332 patients (6%) with UD transplants and two out of 104 recipients (2%) of matched sibling allografts (P 0´16). In order to ascertain basic demographic risk factors for the development of TTP, we compared the 22 patients with 434 patients who did not develop TTP. Compared with patients who did not develop TTP, patients with TTP were nearly three times older (P , 0´001) and were more than twice as likely to be female (P 0´001). Because . 90% of patients were recipients of UD marrow, we then compared the 20 UDbone marrow transplantation (BMT) patients with 60 randomly selected UD-BMT patients who did not develop TTP. On univariate analysis, age and female gender were again significant risk factors, as was grade II±IV acute graft-versus-host disease (GvHD) (P 0´002), and there was a trend towards an association with chronic GvHD (P 0´083). However, after logistic regression analysis, only age and sex remained significant (P , 0´001 and 0´009 respectively). We report an 86% mortality with only three survivors out of 22 patients, and one of these remains thrombocytopenic and red cell transfusion dependent, possibly in part because of graft hypoplasia. Six out of 17 patients responded to plasmapheresis, but the majority of them ultimately succumbed because of TTP, often in association with GvHD or fungal infection.
A new automated method to reliably quantitate reticulated platelets, expressed as the immature platelet fraction (IPF), has been developed on an automated cell counter (XE-2100, Sysmex). The IPF is identified by flow cytometery using a polymethine dye, staining platelet RNA, in the reticulocyte channel; the results are available at the same time as the CBC. The IPF normal range is 1.1–6.1%, mean 3.4%, 2 SD 2.3%. Reproducibility and stability results over 48 hours were acceptable. The IPF is raised when there is increased peripheral consumption/destruction. In untreated idopathic thrombocytopenic purpura, n = 12, mean 22.3%, range 9.2–33.1% and active thrombotic thrombocytopenic purpura, n = 5, mean 17.2%, range 11.2–30.9%. Patients who may require prophylactic platelet transfusion, usually at threshold counts less than 10 x 109/L, to support periods of marrow aplasia were monitored daily for platelet count and IPF%. The recovery phase of thrombocytopenia in most chemotherapy (n=13) and stem cell/bone marrow transplant patients (n=15) was preceded by a rise in IPF% several days prior to platelet recovery, mean IPF 13.7%, range 7–27.3%. In particular, patients undergoing autologous transplantation (n=8) using peripherally collected stem cells have a very characteristic IPF% motif, with a rise 1 day prior to engraftment for all patients except one where it was 2 days prior. For bone marrow derived transplant patients the increase in IPF was more variable, the rise preceded the rise in platelet count by 2–7days. These patients suffer more septic episodes where there is a rise in the IPF with no immediate increase in the platelet count, and require more regular platelet transfusions. Following a platelet transfusion there is a 24-hour transitory fall in the IPF response, which may impede platelet recovery. A parameter that could predict the timing of platelet recovery could be used clinically to reduce the use of prophylactic platelet transfusion in these patients, thus minimising donor exposure, infection risk and allowing substantial financial savings. The IPF is a useful parameter in the evaluation of the thrombocytopenic patient and has the potential to allow more optimal transfusion of platelet concentrates.
FDG PET scanning is increasingly being used to establish poor response and early relapse in patients with lymphoid malignancies in order to direct early intensification of treatment. We have performed a prospective study to assess the role of PET scans in directing immune manipulation (withdrawal of immune suppression and donor lymphocyte infusions (DLI)) following reduced intensity transplants (RIT) in patients with lymphoid malignancies. 34 patients (8 Hodgkin’s lymphoma, 3 Mantle cell lymphoma, 23 Non-Hodgkin’s Lymphoma), median age 44 years (range 20 to 64 years) have been entered since May 2002 and have > 3months follow up. PET and CT scans were performed pre-RIT and at 3, 6, 9, 15 and 24 months post RIT. Patients were conditioned with fludarabine (30mg/m2x5) and melphalan (140mg/m2x1) and in vivo alemtuzumab. Cyclosporin (CSA) was given day −1 to 3 months after RIT. Progression was defined as persistent and/or increasing PET positivity. Relapse was defined as either new PET positive imaging (PET+), progression on CT scan (CT+) or clinical progression. DLI was subsequently given to patients who progressed or relapsed at escalating doses of 1 x 106/kg T cells up to 1 x 108/kg. Patients with active GVHD were excluded from DLI. Results: 17 patients had positive PETs pre-treatment. 9 of these became PET negative, showing an anti-lymphoma effect of the conditioning regime. There were 7 TRMs, leaving 27 of 34 patients evaluable to assess the role of PET in post-transplant management. Of these 27 patients, 6 have had positive CT scans (CT+) with negative PET scans (PET-), with no evidence of clinical relapse. 10/27 patients have subsequently progressed on PET scan (PET+): 2 with PET+ and CT+ disease were not eligible for DLI (GVHD). Both progressed and died at 9 months. One patient is too early to evaluate. The remaining 7 patients received immunotherapy: 4/7 had CT negative (−) disease at PET+ relapse. One patient responded to CSA withdrawal, 6 responded to escalating DLI +/− rituximab (n=3): 3/7 having never developed CT+ disease. 2 patients have subsequently relapsed at 18 and 30 months and are being re-treated. In summary, negative PET scans prevented 6 patients from either undergoing invasive investigations or receiving potentially harmful DLI because of persistently abnormal CT scans. PET scans became positive before CT scans in 4 of 7 patients who relapsed, allowing earlier treatment with immunotherapy, resulting in PET remissions all 7 patients, 3 without CT or clinical relapse. There were no cases of CT relapse before PET relapse. The use of regular PET scanning therefore altered therapy (either delayed or initiated immunotherapy) in 10/27 (37%) evaluable patients in this study. The use of PET scans in identifying early relapse in patients undergoing RIT for lymphoid malignancies, where early DLI can be beneficial is very promising and needs further evaluation, with larger event numbers and longer follow-up.
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