H. J. Ng

A randomized trial of amifostine as a cytoprotectant for patients receiving myeloablative therapy for allogeneic hematopoietic stem cell transplantation

Summary:We initiated a randomized study of amifostine (the organic thiophosphate formerly known as WR-2721) given to patients during myeloablative conditioning therapy for allogeneic bone marrow transplantation. Amifostine was given at a dose of 1000 mg/day of conditioning and was well tolerated if attention was given to serum calcium levels, blood pressure and antiemetics. Since August 1998, 60 patients (30 on each arm) have completed the study. There was no significant difference in the days to neutrophil or platelet engraftment in either arm of the study. Significantly, the duration of grade I–IV mucositis was decreased in the group that received amifostine (P=0.02). Also grade III or IV infections (P=0.008), duration of antibiotic therapy (P=0.03) and duration of fever (P=0.04) were significantly reduced with amifostine. However, there were no differences in the incidence of grade III or IV mucositis, liver toxicity or renal toxicity. There were also no differences in early mortality, relapse and long-term survival. We conclude that amifostine, while reducing the duration of mucositis and infections (possibly through some preservation of gut mucosal integrity), has a modest effect in allogeneic bone marrow transplants given the multiplicity of factors influencing organ toxicity and survival in this setting.

Imatinib mesylate (STI-571) given concurrently with nonmyeloablative stem cell transplantation did not compromise engraftment and resulted in cytogenetic remission in a patient with chronic myeloid leukemia in blast crisis

Summary:The main obstacles to successful hematopoietic stem cell transplantation for patients with chronic myeloid leukemia (CML) in blast crisis (BC) are increased post-transplant relapse and high treatment-related mortality. We report a patient with CML in BC who was treated initially with imatinib mesylate and was then concurrently treated with a nonmyeloablative stem cell transplant. Successful engraftment of donor cells followed by complete cytogenetic remission was achieved in the absence of severe therapy-related toxicities. This case demonstrates that imatinib mesylate given through nonmyeloablative transplant is a minimally toxic therapeutic approach, which does not compromise engraftment and may result in a favorable outcome in patients with CML in BC.

Successful Treatment of Idiopathic Hypereosinophilic Syndrome with Imatinib Mesylate : A Case Report

Patients with idiopathic hypereosinophilic syndrome (HES) show persistent hypereosinophilia of unknown etiology that is associated with end-organ damage. Different treatments, including the use of corticosteroids and cytotoxics, have been investigated for HES with modest success. We describe a patient with HES who had significant end-organ damage from hypereosinophilia and remained refractory to conventional therapy. Therapy with imatinib mesylate, a selective tyrosine kinase inhibitor that is highly effective in treating patients with BCR-ABL-positive chronic myeloid leukemia, was tried with the patient. The result was impressive, with hematologic remission achieved after 12 days of administration. Our finding concurs with recent reports that imatinib mesylate may be a promising agent in the treatment of some cases of HES.

Attainment of at least a very good partial response after induction treatment is an important surrogate of longer survival for multiple myeloma

The importance of achieving a very good partial response or better (⩾VGPR) after induction treatment of myeloma has traditionally only been discussed in the context of high-dose therapy with auto-SCT (HDT/auto-SCT). Of late, the advent of novel agents for induction treatment has resulted in improved CR and VGPR rates, which are comparable with those observed with HDT/auto-SCT. We show that in an unselected group of 179 myeloma patients with diverse baseline characteristics, and treated with different modern induction regimens within a single institution, the attainment of ⩾VGPR with or without HDT/auto-ASCT represents a major surrogate marker of better clinical outcomes. On the basis of a 1-year landmark survival analysis, patients achieving ⩾VGPR enjoy a significantly longer PFS, which translated to a longer OS. Superseding the adverse effects of advanced age, high International Staging System (ISS) stage, adverse cytogenetics and independent of the transplant status, the attainment of ⩾VGPR emerged as the single most significant predictor of long-term survival on multivariate analysis.

Stem cell transplantation programme at Singapore General Hospital

The adult transplant programme at Singapore General Hospital (SGH) was established in 1985 and more than 820 transplants have been performed to date. An average of about 60 adult transplants (autologous and allogeneic) are performed each year. Transplants offered at SGH run the range from autologous to mismatched cord and unrelated transplants. Special interests of the transplant programme include non-myeloablative transplants in aplastic anaemia, cell therapy protocols including cytokine-induced killer cells, patterns of GVHD, cord blood transplantation for autoimmune diseases and graft engineering. A cGMP (good manufacturing practice) cell therapy laboratory was recently established to facilitate bench-to-bedside translational cell therapy trials. A BMT consortium has been formed among the various paediatric and adult transplant centres for harmonization of protocols and research activities.

Acquired factor V deficiency in a patient with myeloma and amyloidosis

INTRODUCTION We describe our experience with managing an unusual case of acquired Factor V deficiency (aFVd) in a myeloma patient with demonstrated amyloidosis. METHODS Following diagnosis, records of previous investigations were sought. Specific clotting factors and inhibitors were tested. The clinical progress and treatment response measured by serial factor V levels and coagulation parameters was then prospectively tracked. RESULTS A 57 year-old woman presented with spontaneous right knee haemarthrosis in association with bilateral symmetrical polyneuropathy and proteinuria. Coagulation screen showed prolongation of both PT (18.6 s, normal range [9.9-11.4 s]) and aPTT (41.4 s, normal range [25.7-32.9 s]), which were both fully correctable following a mixing study. Liver function, fibrinogen, clotting factor II/VIII/X assays and disseminated intravascular coagulopathy screen was normal. FV level was reduced (19%, normal range [70-170%]). Inhibitor titer was undetectable. Congenital FVd was excluded as her previous coagulation screen was normal. Bone marrow investigation performed for suspected underlying plasma cell dyscrasia showed 60% neoplastic plasma cells. Congo red staining was positive for amyloid within vascular walls of the marrow trephine. She was diagnosed with light chain myeloma and aFVd. She received Bortezomib/Cyclophosphamide/Dexamethasone (VCD) chemotherapy. After one cycle of VCD, serum kappa free light chain (SFLC) was reduced from 6951 mg/L to 3354 mg/L with serial measurements of FV levels showing increment to 76% and normalization of PT/aPTT. CONCLUSION Plasma cell dyscrasia with amyloidosis should be sought as a cause for aFVD, in particular one where bleeding manifestation is profound even with the absence of demonstrable inhibitors.

Agreement of point-of-care INR test with standard venous sampling assay at higher extreme ranges.

Dear Editor, The use of point-of-care (POC) coagulometers in clinical and home settings for monitoring of patients on oral anticoagulation therapy had been increasingly prevalent since its introduction. The safety and reliability of these devices had been repeatedly demonstrated [1–3]. In 2007, we reported the agreement of the international normalised ratio (INR) results between the CoaguChek® XS (Roche Diagnostics, Basel, Switzerland) and a venous sampling standard for readings less than 3.5 (r=0.945) [4]. Agreement was poor for INR readings above 3.5, though the corresponding number of samples gathered in that study was small. Since then, our working protocol for the CoaguChek XS in the hospital required mandatory venous sampling for INR results above 3.5. In a follow-up to that study, we investigated the correlation between CoaguChek XS readings against standard venous assay in a more representative sample size of warfarinised patients with INR readings above 3.5. POC INR samples were collected by CoaguChek® XS as in the previous study. Its disposable test strips use recombinant human thromboplastin and a peptide substrate, electrochyme TH, to produce an electrochemical signal with an internal quality control system. The time elapse from sample application to signal generation is then used to calculate the INR value. For every POC INR that is more than 3.5, a corresponding venous sample was drawn from the same patient. The venous samples were collected in 3.5-ml sodium citrate tubes, and standard assay was performed on a Sysmex CS-2100i analyser with a Dade Innovin reagent. In total, 74 pairs of readings were obtained and analysed using Stata version 13.1. The samples were stratified according to their POC INR results, of which 56 pairs fell between an INR of 3.5 to 5 (stratum A) and 18 pairs above 5 (stratum B). Paired sample t test was performed, and Pearson correlation coefficient was computed in both strata. Figure 1 shows a Bland–Altman Plot of the difference between INR by CoaguChek® XS and routine laboratory testing against increasing INR. The magnitude of residual variation was observed to be smaller in stratum A than stratum B. In stratum A, 66 % and 84 % of the POC INR readings fell within ±0.5 and ±0.8 of the standard assay results, respectively. The correlation between POC and venous sampling method was found to be moderate (r=0.487), with a mean difference of 0.33±0.49 (p<0.05, 95 % confidence interval (CI) 0.20–0.46), showing POC tests consistently overestimated the actual INR measured using a standard assay. In stratum B, 39 % and 44 % of the POC INR readings fell within ±0.5 and ±0.8 of the standard assay results, respectively. The correlation between POC and standard assay was found to be poor (r=0.205), with a mean difference of 0.61±1.22 (p= 0.48, 95 % CI 0.006–1.22), showing POC tests consistently * Y. F. Lai laiyifeng@gmail.com

Safety and efficacy of warfarin in patients with moderate thrombocytopenia

INTRODUCTION Patients with moderate thrombocytopenia and comorbidities requiring anticoagulation are currently sub-optimally treated because of bleeding concerns. Guidance on anticoagulating such patients is currently lacking because of limited data on safety and efficacy of anticoagulation in such patients. METHODS This retrospective study compared the incidence of bleeding and thrombosis in a cohort of warfarinized patients with sustained platelet counts below 100×109/L against a cohort with normal platelet counts (>140×109/L). Primary outcomes of safety and efficacy were determined by incidence rate ratios (IRR) of bleeding and thrombotic events. International normalized ratio (INR) and platelet counts during adverse events in thrombocytopenic arm were secondary outcomes. RESULTS 137 thrombocytopenic patients (104,985 patient-exposure days) were compared against 939 normal patients (715,193 patient-exposure days). IRR of minor, major bleeding and thrombosis among thrombocytopenic patients were 3.03 (95% CI: 1.57-5.60), 1.48 (95% CI: 0.44-3.98), and 0.807 (95% CI: 0.09-3.43) respectively. Median INR and platelet count readings during minor and major bleeds were 3.60 (IQR: 2.70-4.12) and 3.12 (IQR: 2.82-4.22), and 99×109/L (IQR: 77.0-147.0×109/L) and 115×109/L (IQR: 107.5-169.5×109/L) respectively. CONCLUSION Warfarinized thrombocytopenic patients are at higher risk of minor bleeding complications with a higher tendency for major bleeding but derive similar benefits against thrombotic events compared to normal patients. Bleeding events are associated with higher INRs. A narrow INR target with an upper limit below 2.5 together with closer anticoagulation monitoring may improve safety of patients.