Mycophenolate mofetil therapy for severe immune thrombocytopenia.

Severe immune thrombocytopenia purpura (ITP) presents a clinical challenge. Second-line treatment options are variable without a precise protocol. We present 46 severe ITP patients treated with mycophenolate mofetil (MMF), retrospectively identified from three London teaching hospitals. Data was collected on patient demographics, co-morbidities and previous treatment strategies. Our key interest was whether there was a sustained response in platelet count to MMF. Patients included 27 males and 19 females whose ages ranged from 19 to 93 years old (median 52·5 years). Twenty-nine had primary ITP and 17 had secondary ITP, a third of whom had viral-associated disease. The standard dose of MMF was 1 g/day. Twenty-four patients (52%) responded with 15 (33%) achieving a complete response. No active viral-associated ITP patients demonstrated a response to MMF, although numbers were small (n = 4). We were not able to demonstrate a difference between responders and non-responders based on gender, age, previous therapies or time since diagnosis of ITP. Three of four previously splenectomized patients responded, two achieving complete response. We conclude that MMF is a useful steroid-sparing immunosuppressant to be considered in the second-line or later treatment of ITP.

Is B-cell depletion still a good strategy for treating immune thrombocytopenia?

B cells play an important role in the pathophysiology of immune thrombocytopenia (ITP). Thus, a rational approach to ITP treatment involves B-cell depletion such as with rituximab. More than 10 years after the first reports of data suggesting that anti-CD20 MoAbs could be effective treatment for ITP, we have now a clear view of its efficacy, with an overall response in about 60% of patients. The report of fatal opportunistic infections was initially a matter of concern, but to date, reassuring data have been reported and rituximab appears well tolerated with an acceptable risk of infection. In view of these data, rituximab may always be a valid option for ITP. However, relapses are frequent, and the long-term response appears modest. Therefore, strategies to ameliorate the long-term efficacy of the treatment must be developed. Several options may be tested including giving rituximab upfront or early on after ITP diagnosis, maintenance treatment with repeated infusions, and combining rituximab with other treatments able to modulate T-cell compartment to achieve a synergistic effect. New generations of B-cell targeted treatment, including new-generations anti-CD20 MoAbs, may be also tested.

A curious case of haemolysis, seizure and acute renal failure associated with pregnancy.

Differential diagnosis between thrombotic microangiopathies in pregnancy is challenging due to overlapping clinical and pathological findings and the rapid progression of disease. We present here an unusual case of Haemolysis, Elevated Liver enzymes and Low Platelets (HELLP) syndrome, which represents this diagnostic dilemma. The patient was treated with steroids and plasma exchange, leading to a favourable outcome. Subsequent genetic testing for complement dysregulation revealed a previously unknown variant in intron 3 of the gene coding for the alternative complement pathway factor H: (c.350+9T>C). We discuss here the diagnostic dilemma presented, the treatment pathway in the current literature, and the potential involvement of complement deregulation in severe HELLP. This case underlines the complexity in the diagnosis and management of pregnancy-related thrombotic microangiopathies.

Sequential combination of gemtuzumab ozogamicin and standard chemotherapy in older patients with newly diagnosed acute myeloid leukemia: results of a randomized phase III trial by the EORTC and GIMEMA consortium (AML-17).

PURPOSE: This randomized trial evaluated the efficacy and toxicity of sequential gemtuzumab ozogamicin (GO) and standard chemotherapy in older patients with newly diagnosed acute myeloid leukemia (AML). PATIENTS AND METHODS: Patients (n = 472) age 61 to 75 years were randomly assigned to induction chemotherapy with mitoxantrone, cytarabine, and etoposide preceded, or not, by a course of GO (6 mg/m(2) on days 1 and 15). In remission, patients received two consolidation courses with or without GO (3 mg/m(2) on day 0). The primary end point was overall survival (OS). RESULTS: The overall response rate was comparable between the two arms (GO, 45%; no GO, 49%), but induction and 60-day mortality rates were higher in the GO arm (17% v 12% and 22% v 18%, respectively). With median follow-up of 5.2 years, median OS was 7.1 months in the GO arm and 10 months in the no-GO arm (hazard ratio, 1.20; 95% CI, 0.99 to 1.45; P = .07). Other survival end points were similar in both arms. Grade 3 to 4 hematologic and liver toxicities were greater in the GO arm. Treatment with GO provided no benefit in any prognostic subgroup, with the possible exception of patients age < 70 years with secondary AML, but outcomes were significantly worse in the oldest age subgroup because of a higher risk of early mortality. CONCLUSION: As used in this trial, the sequential combination of GO and standard chemotherapy provides no benefit for older patients with AML and is too toxic for those age ≥ 70 years.

Long-term safety and tolerability of romiplostim in patients with primary immune thrombocytopenia: a pooled analysis of 13 clinical trials.

BACKGROUND AND OBJECTIVES: Thrombopoietin receptor agonists (TPOra) are the only treatments for immune thrombocytopenia (ITP) for which evidence of efficacy and safety from randomized, placebo-controlled trials is available. We sought to determine the long-term tolerability of the TPOra romiplostim, with a particular focus on thrombosis, bleeding, bone marrow (BM) reticulin, neoplasms/haematological malignancies and fatal events. METHODS: Data from 13 romiplostim clinical trials in which 653 patients with ITP received romiplostim for up to 5 yr (921.5 patient-years) were pooled; subject incidence rates and exposure-adjusted event rates (per 100 patient-years) were calculated. RESULTS: The rate of thrombotic events (6% of patients, 7.5 events per 100 patient-years) did not appear to increase over time; 9 events were associated with platelet counts >400 × 10(9) /L and 10 with romiplostim doses exceeding current recommendations. Serious and grade ≥3 bleeding each occurred in approximately 8% of patients (~11 events per 100 patient-years). Adverse events of BM reticulin were recorded for 12 patients (1.8%, 1.3 events per 100 patient-years, confirmed by bone biopsy in ten patients) and BM collagen for one patient (0.2%, 0.1 event per 100 patient-years, confirmed by trichrome staining). Neoplasms and haematological malignancies occurred in 2.1% and 0.8% of patients, respectively (2.2 and 0.7 events per 100 patient-years). Fatal events occurred in 3.7% of patients (2.6 events per 100 patient-years, four events treatment-related). CONCLUSIONS: Romiplostim is the TPOra for which the longest duration of safety data is available. Our data demonstrate that long-term romiplostim treatment is well tolerated, with no new safety signals, even in patients treated for up to 5 yr.

Rozrolimupab, a first-in-class recombinant monoclonal antibody product for primary immune thrombocytopaenia.

INTRODUCTION: Over the last decade the field of medicine has dramatically changed with the introduction of biological therapies, among which monoclonal antibodies play a pivotal role in the management of many diseases. Rozrolimupab is the first of a new class of recombinant human monoclonal antibody mixtures, consisting of 25 genetically unique IgG1 antibodies, targeted against the RhD erythrocyte antigen. It is currently being investigated for its use in the treatment of primary immune thrombocytopenia. AREAS COVERED: This article outlines the impetus for the development of rozrolimupab in the treatment of ITP. In addition, the literature regarding the development of rozrolimupab and the recent clinical trials involving this agent are also reviewed. EXPERT OPINION: Although rozrolimupab is only in the very early phases of clinical development we believe that this agent represents a very interesting agent not only for its potential benefits in the management of ITP but potentially for the prevention of haemolytic disease of the foetus and newborn.

Standardization of bleeding assessment in immune thrombocytopenia: report from the International Working Group.

In a previous publication on new terminology, definitions, and outcome criteria for immune thrombocytopenia (ITP), the International Working Group (IWG) on ITP acknowledged that response to treatment should consist of clinically meaningful end points such as bleeding manifestations and that platelet count may not be the ideal parameter for capturing the benefits of therapy. The IWG now proposes a consensus-based ITP-specific bleeding assessment tool (ITP-BAT) with definitions and terminology consistent with those adopted for other bleeding disorders. Bleeding manifestations were grouped into three major domains: skin (S), visible mucosae (M), and organs (O), with gradation of severity (SMOG). Each bleeding manifestation is assessed at the time of examination. Severity is graded from 0 to 3 or 4, with grade 5 for any fatal bleeding. Bleeding reported by the patient without medical documentation is graded 1. Within each domain, the same grade is assigned to bleeding manifestations of similar clinical impact. The "worst bleeding manifestation since the last visit" (observation period) is graded (a suitable database collection form is provided), and the highest grade within each domain is recorded. The SMOG system provides a consistent description of the bleeding phenotype in ITP, and the IWG unanimously supports its adoption and validation in future clinical studies.

Splenectomy as a curative treatment for immune thrombocytopenia: a retrospective analysis of 233 patients with a minimum follow up of 10 years.

The treatment of choice in steroid-resistant immune thrombocytopenia is still controversial due to the recent advent of new drugs (anti-CD20 antibodies and thrombopoietin mimetics) that have encouraged a generalized tendency to delay splenectomy. Consequently, it is extremely importance to define the efficacy and safety of splenectomy in the long term. We retrospectively analyzed the data of 233 patients affected by immune thrombocytopenia who underwent splenectomy between 1959 and 2001 in 6 European hematologic institutions and who have now a minimum follow up of ten years from surgery. Of the 233 patients, 180 (77%) achieved a complete response and 26 (11%) a response. Sixty-eight of 206 (33%) responsive patients relapsed, mostly (75%) within four years from first response. In 92 patients (39.5%), further treatment was required after splenectomy that was effective in 76 cases (83%). In 138 patients (59%), response was maintained free of any treatment at last contact. No significant association between baseline characteristics and likelihood of stable response was found. Overall, 73 (31%) and 58 (25%) patients experienced at least one infectious or hemorrhagic complication, which was fatal in 2 and 3 patients, respectively. A stable response to splenectomy was associated with a lower rate of infections (P=0.004) and hemorrhages (P<0.0001). Thrombosis developed in 18 patients (8%) and was fatal in 4. Splenectomy achieved a long-term stable response in approximately 60% of cases. Complications mainly affected non-responding patients and were fatal in a minority.

How I treat thrombocytopenia in pregnancy.

A mild thrombocytopenia is relatively frequent during pregnancy and has generally no consequences for either the mother or the fetus. Although representing no threat in the majority of patients, thrombocytopenia may result from a range of pathologic conditions requiring closer monitoring and possible therapy. Two clinical scenarios are particularly relevant for their prevalence and the issues relating to their management. The first is the presence of isolated thrombocytopenia and the differential diagnosis between primary immune thrombocytopenia and gestational thrombocytopenia. The second is thrombocytopenia associated with preeclampsia and its look-alikes and their distinction from thrombotic thrombocytopenic purpura and the hemolytic uremic syndrome. In this review, we describe a systematic approach to the diagnosis and treatment of these disease entities using a case presentation format. Our discussion includes the antenatal and perinatal management of both the mother and fetus.

How to approach thrombocytopenia.

Thrombocytopenia is a common hematologic finding with variable clinical expression. A low platelet count may be the initial manifestation of infections such as HIV and hepatitis C virus or it may reflect the activity of life-threatening disorders such as the thrombotic microangiopathies. A correct identification of the causes of thrombocytopenia is crucial for the appropriate management of these patients. In this review, we present a systematic evaluation of adults with thrombocytopenia. The approach is clearly different between outpatients, who are frequently asymptomatic and in whom we can sometimes indulge in sophisticated and relatively lengthy investigations, and the dramatic presentation of acute thrombocytopenia in the emergency department or in the intensive care unit, which requires immediate intervention and for which only a few diagnostic tests are available. A brief discussion of the most common etiologies seen in both settings is provided.

Effectiveness, safety, and local progression after percutaneous laser ablation for hepatocellular carcinoma nodules up to 4 cm are not affected by tumor location.

OBJECTIVE: A high-risk location--defined as the tumor margin being less than 5 mm from large vessels or vital structures--represents a well-known limitation and contraindication for radiofrequency ablation of hepatocellular carcinoma (HCC) nodules. The aim of this study was to verify whether HCC nodule location negatively affected the outcome of percutaneous laser ablation in terms of its primary effectiveness, safety, and ability to prevent local tumor progression. MATERIALS AND METHODS: The medical records and radiologic examinations of 164 cirrhotic patients (90 men, 74 women; mean age ± SD, 68.6 ± 8.3 years) with 182 HCC nodules 4 cm or smaller (mean diameter ± SD, 2.7 ± 0.78 cm) that had been treated by laser ablation between 1996 and 2008 were retrospectively analyzed. One hundred six patients had 116 nodules in high-risk sites (high-risk group), whereas 58 patients had 66 tumors located elsewhere (standard-risk group). RESULTS: The overall median follow-up was 81 months (range, 6-144 months). The initial complete ablation rate per nodule did not significantly differ between the high-risk group and the standard-risk group (92.2% vs 95.5%, respectively; p = 0.2711). Rates of major complications (high-risk group vs standard-risk group, 1.9% [including one death] vs 0%) and minor complications (5.6% vs 1.0%) were not statistically different between the two groups. Only side effects were recorded significantly more often in high-risk patients than in standard-risk patients (31.5% vs 19.8%; p = 0.049). There was no significant difference in either cumulative incidence of local tumor progression (p = 0.499) or local tumor progression-free survival (p = 0.499, log rank test) between the high-risk group and the standard-risk group. CONCLUSION: When laser ablation is used to treat small HCC nodules, tumor location does not have a significant negative impact on the technique's primary effectiveness or safety or on its ability to achieve local control of disease.

Immune thrombocytopenia: pathophysiologic and clinical update.

Immune thrombocytopenia (ITP) is an autoimmune disorder characterized by both reduced platelet survival and suppression of megakaryocyte and platelet development. It can either be primary or secondary to other autoimmune disorders, infections, vaccines, lymphoproliferative disorders, and drugs. Antibodies reacting against platelet glycoproteins are typical of ITP; these antibodies can mediate destruction of platelets by the monocyte-macrophage system as well as suppress megakaryocyte proliferation and maturation. Abnormalities of cell-mediated immunity are known to contribute to the pathologic process. Like many other autoimmune diseases, ITP has a T helper cell type 1 bias and a reduced activity of T-regulatory cells. Cytotoxic T cells may directly lyse platelets and possibly suppress megakaryopoiesis. Recent studies suggest that mesenchymal stem cells are dysfunctional in ITP and may contribute to an aberrant amplification of the autoimmune response. Significant advances in the treatment of chronic ITP have been witnessed in the past decade, first with the introduction of rituximab and more recently with the thrombopoietin-receptor agonists. While splenectomy is still considered the gold standard in this setting, effective medical therapy is now available for patients in whom surgery is not an option.

Platelet-associated antibodies, cellular immunity and FCGR3a genotype influence the response to rituximab in immune thrombocytopenia.

Rituximab is widely used in autoimmune diseases including immune thrombocytopenia (ITP), although the mechanism of effect remains unclear. This study describes the effects of rituximab on platelet-associated antibodies (PA-APAs), B and T cell counts and clonality ( IGHV and TRG@ gene rearrangements), FCGR3A (FcγRIIIa) and FCGR2A (FcγRIIa) polymorphisms and correlation to anti-CD40 ligand (CD40L) response. PA-APA levels fell more frequently in responders (6/8) than in non-responders (2/10: P = 0·08-0·15). Two responders had no PA-APAs. Two non-responders with a fall in PA-APAs had very high CD8 levels. One non-responder had a B cell clone, one responder and one non-responder had a T cell clone. 15/16 patients had the same responses to rituximab and antiCD40L. Patients with FCGR3A V/V polymorphisms were more likely to respond to rituximab (P = 0·03). In summary, the fall in PA-APAs in responders confirms the humoural effect of rituximab. Failure to respond in patients with very high CD8 levels, despite PA-APA fall indicates a role for T cell-mediated platelet/megakaryocyte destruction. Concordance of response to anti-CD40L suggests autoantibody-producing cells are under T cell control. Finally, the effect of FCGR polymorphisms on response confirms the importance of FCGR-mediated depletion of B cells in autoimmunity. This has implications on the pathology of ITP as well as the immunological effect of B cell depletion.

Refusal of blood transfusion by Jehovah's Witness women: a survey of current management in obstetric and gynaecological practice in the U.K.

BACKGROUND: Refusal of blood transfusion by Jehovah's Witness (JW) women poses potential problems for obstetrics worldwide as haemorrhage remains a major cause of maternal morbidity and mortality. There is a general consensus that morbidity and mortality rates in association with childbirth and gynaecological interventions are higher in these women than in the general population. We conducted a postal questionnaire survey of current practice among U.K. consultant obstetricians and gynaecologists to establish the practices that could contribute to poor outcomes in these women. MATERIALS AND METHODS: The main variables of interest were: use of a multi-disciplinary approach; the acceptable minimum haemoglobin (Hb) concentration before vaginal delivery and abdominal hysterectomy as low to medium risk scenarios and open myomectomy as a high risk scenario for haemorrhage; Hb concentration thresholds for iron supplementation; and the use of oral iron, intravenous iron, erythropoietin and cell salvage as potential management tools. RESULTS: The response rate was 28%. Sixty percent of gynaecologists and 85% of obstetricians reported having a protocol for the management of JW women. Forty-six percent of consultants adopt a multi-disciplinary approach which include anaesthetists and haematologists. A Hb concentration of >11-12 g/dL is considered the minimum acceptable level by a majority (47%) prior to normal delivery and by 42% of gynaecologists prior to abdominal hysterectomy. For open myomectomy 28% of gynaecologists prefer a minimum level of 11-12 g/dL but a further 31% of gynaecologists prefer a minimum level of 12-13 g/dL. DISCUSSION: A small but substantial proportion of consultants do not have protocols, operate on JW women with low Hb concentrations, do not use a lower Hb concentration threshold for supplementation, and do not adopt a multi-disciplinary approach, all of which could contribute to the reported poor outcomes in these women.

Outcomes 5 years after response to rituximab therapy in children and adults with immune thrombocytopenia.

Treatments for immune thrombocytopenic purpura (ITP) providing durable platelet responses without continued dosing are limited. Whereas complete responses (CRs) to B-cell depletion in ITP usually last for 1 year in adults, partial responses (PRs) are less durable. Comparable data do not exist for children and 5-year outcomes are unavailable. Patients with ITP treated with rituximab who achieved CRs and PRs (platelets > 150 × 10(9)/L or 50-150 × 10(9)/L, respectively) were selected to be assessed for duration of their response; 72 adults whose response lasted at least 1 year and 66 children with response of any duration were included. Patients had baseline platelet counts < 30 × 10(9)/L; 95% had ITP of > 6 months in duration. Adults and children each had initial overall response rates of 57% and similar 5-year estimates of persisting response (21% and 26%, respectively). Children did not relapse after 2 years from initial treatment whereas adults did. Initial CR and prolonged B-cell depletion predicted sustained responses whereas prior splenectomy, age, sex, and duration of ITP did not. No novel or substantial long-term clinical toxicity was observed. In summary, 21% to 26% of adults and children with chronic ITP treated with standard-dose rituximab maintained a treatment-free response for at least 5 years without major toxicity. These results can inform clinical decision-making.

Evaluation of bleeding-related episodes in patients with immune thrombocytopenia (ITP) receiving romiplostim or medical standard of care.

Romiplostim increases platelet counts and reduces the risk of bleeding in patients with immune thrombocytopenia (ITP). This post hoc analysis compared the effect of romiplostim versus medical standard of care (SOC) on clinically relevant bleeding-related episodes (BREs) in a 52-week open-label study of patients with ITP. BREs were defined as actual bleeding events and/or use of rescue medication. Nonsplenectomized adult patients with ITP were randomized to receive weekly subcutaneous injections of romiplostim (n = 157) or SOC (n = 77). The rate of all BREs (per 100 patient-weeks) was lower in patients treated with romiplostim (3.1) than in those treated with SOC (9.4); the relative rate (romiplostim/SOC) was 0.33 (95 % CI 0.27-0.40). The rate of BREs associated with immunoglobulin (Ig) rescue medication was also lower for romiplostim (0.2) than SOC (4.8); the relative rate (romiplostim/SOC) was 0.05 (95 % CI 0.03-0.08). BRE rates were lower in patients with platelet counts ≥50 × 10(9)/L, and patients treated with romiplostim spent more time with platelet counts ≥50 × 10(9)/L than did patients treated with SOC. Bleeding-related hospitalizations were rare in both groups. Thus, romiplostim treatment provided greater reductions in all BREs, as well as BREs involving Ig rescue medications, than did SOC.

Influence of ablative margin on local tumor progression and survival in patients with HCC ≤4 cm after laser ablation.

BACKGROUND: Ablation of the normal hepatic parenchyma surrounding the tumor (ablative margin [AM]) is necessary to prevent local tumor progression. PURPOSE: To assess the prognostic value of the ablative margin in patients with HCC ≤4 cm treated with US-guided laser ablation. MATERIAL AND METHODS: A cohort of 116 patients (53 women and 63 men, age range 42-82 years) with 132 HCC nodules ≤4 cm completely ablated by US-guided laser ablation was retrospectively analyzed. Rates of local tumor progression were compared using different ablative margin cut-offs (≥2.5, 5.0, 7.5, and 10.0 mm). Survival probability curves were obtained with the Kaplan-Meier method. RESULTS: The mean period of follow-up was 42 months (range 3-114 months). Local tumor progression was identified in 24 out of 132 lesions (18%), with an average time to progression of 24 months (range 6-36 months). A significant difference in local tumor progression was observed only if the ablative margin was ≥7.5 mm (7% vs. 23%, P = 0.020). Survival curves of patients with or without an ablative margin ≥7.5 mm were not different (P = 0.665; mean survival time 43.8 ± 3.1 and 46.8 ± 6.1 for an AM < or ≥7.5 mm, respectively). CONCLUSION: An ablative margin ≥7.5 mm turned out to be useful in preventing local tumor progression but did not affect long-term survival in patients with HCC ≤4 cm treated with laser ablation.

Temsirolimus, an mTOR inhibitor, in combination with lower-dose clofarabine as salvage therapy for older patients with acute myeloid leukaemia: results of a phase II GIMEMA study (AML-1107).

The mammalian target of rapamycin (mTOR) signalling pathway has emerged as an important therapeutic target for acute myeloid leukaemia (AML). This study assessed the combination of temsirolimus, an mTOR inhibitor, and lower-dose clofarabine as salvage therapy in older patients with AML. Induction consisted of clofarabine 20mg/m(2) on days 1-5 and temsirolimus 25mg (flat dose) on days 1, 8 and 15. Patients achieving complete remission with (CR) or without (CRi) full haematological recovery could receive monthly temsirolimus maintenance. In 53 evaluable patients, the overall remission rate (ORR) was 21% (8% CR, 13% CRi). Median disease-free survival was 3·5months, and median overall survival was 4months (9·1months for responders). The most common non-haematological severe adverse events included infection (48%), febrile neutropenia (34%) and transaminitis (11%). The 30-d all-cause induction mortality was 13%. Laboratory data from 25 patients demonstrated that a >50%in vivo inhibition of S6 ribosomal protein phosphorylation was highly correlated with response rate (75% with inhibition versus 0% without inhibition; P=0·0001), suggesting that targeting the mTOR pathway is clinically relevant. The acceptable safety profile and the predictive value of target inhibition encourage further investigation of this novel regimen.