Marta Medeot

Rituximab therapy in adult patients with relapsed or refractory immune thrombocytopenic purpura: long-term follow-up results

Objective:  To evaluate the long‐term activity and toxicity profile of rituximab in adult patients with idiopathic immune thrombocytopenic purpura (ITP).

Low‐dose rituximab in adult patients with primary immune thrombocytopenia

Backgrounds: Rituximab 375 mg/m2 weekly for 4 wks has significant activity in adults with primary immune thrombocytopenia (ITP). In this setting, several evidences support the possible use of lower doses of rituximab. Objectives: To investigate the activity of low‐dose rituximab as salvage therapy in previously treated symptomatic ITP. Methods: Forty‐eight adult patients were treated prospectively with rituximab 100 mg weekly for 4 wks. Results: Overall and complete responses (CR) (platelet level ≥ 50 and 100 × 109/L) were 60.5% and 39.5%, respectively. In responders, the median time to response was 35 d (range: 7–112 d). The median time of observation was 18 months (range 3–49 months). Sixteen of 29 responding patients (55%) relapsed and 14 needed further treatments. The 12‐ and 24‐month cumulative relapse‐free survival was 61% and 45%, respectively. In univariate analysis, CR rate was in inverse relation with weight OR = 0.95, CI95% [0.91; 0.99] (P = 0.019) and age OR=0.96, CI95% [0.93; 0.99] (P = 0.047). Cox regression model showed that relapse probability increases as weight (HR = 1.06, CI95% [1.0031; 1.111]) and period between diagnosis and rituximab therapy (HR = 1.01, CI95% [1.002; 1.017]) increase. One patient developed an interstitial pneumonia 1 month after the end of rituximab treatment. No other infectious, hematologic or extra‐hematologic complications were documented during follow‐up. Conclusions: Low‐dose rituximab is active in ITP but has moderate long‐term effect. A comparative study with standard dose is warranted.

Prognostic factors and outcome of Epstein–Barr virus DNAemia in high-risk recipients of allogeneic stem cell transplantation treated with preemptive rituximab

This study assessed incidence, predictive factors, and outcome of Epstein–Barr virus (EBV) DNAemia in 100 recipients of allogeneic hematopoietic stem cell transplant. A total of 68 patients received anti‐thymocyte globulin before unrelated grafts.

Clinical Presentation, Outcome and Risk Factors of Late-Onset Non- Infectious Pulmonary Complications After Allogeneic Stem Cell Transplantation

The term late-onset non-infectious pulmonary complications (LONIPCs) has been used to refer to events occurring later than 3 months after allogeneic hematopoietic stem transplant (HSCT), such as bronchiolitis obliterans, bronchiolitis obliterans with organizing pneumonia, and lymphocytic or idiopathic interstitial pneumonia. The incidence of LONIPCs varies widely, ranging between 10% and 26%. Median time for LONIPC development is about 8-12 months after HSCT. Clinical symptoms may be insidious and non specific at the beginning and can be present in different types of infections. The diagnosis is made on the basis of thoracic high-resolution computed tomography and pulmonary function tests (PFT). It usually requires that standard cultures for infective agents on bronchoalveolar lavage are negative and is confirmed by transbronchial or lung biopsy, whenever possible. Total body irradiation and high doses of drugs used in the conditioning regimens, HLA disparity between donor and recipient, and chronic graft-versus-host disease (GVHD) are the main risk factors for LONIPCs. Since patients with LONIPCs have an increased risk of mortality because of infections or respiratory failure, pre- and post-transplant PFTs are strongly recommended in order to timely identify affected patients. The administration of antithymocyte globulin before unrelated donor transplants and slow taper of cyclosporine after transplant have been shown to prevent chronic GVHD and, therefore, the occurrence of LONIPCs.

Experts' considerations on HLA-haploidentical stem cell transplantation.

Recently, novel strategies to control graft‐versus‐host disease and facilitate engraftment have allowed an increasing number of human leukocyte antigen (HLA)‐haploidentical hematopoietic stem cell transplantation (haploHSCT) to be performed. A meeting was convened to review the biological rationale and the clinical results of various T‐cell‐depleted (TCD) and T‐cell‐replete (TCR) HLA‐haploidentical ‘transplant platforms’. The objective of the meeting was to promote discussion and consent among leading researchers in the field on three main crucial issues for haploHSCT: (i) eligibility criteria, (ii) choice of the most suitable donor, and (iii) choice of the most appropriate transplant platform. The experts in attendance agreed that a patient who is eligible for an allogeneic transplant and lacks an HLA‐identical sibling or an HLA‐matched unrelated donor should be considered for an alternative donor transplant. Together with the experience of the individual center, the most important decision criteria in choosing an alternative donor source should be the rapidity of transplantation so as to avoid disease relapse/progression. The choice of the mismatched donor should be driven by younger age, ABO blood group compatibility, and Cytomegalovirus status. If a TCD transplant is planned, NK‐alloreactive donors and/or the mother should be preferred. Prospective comparative studies are needed to establish the relative efficacy of different transplant platforms. However, expertise in stem cell manipulation and in adoptive immunotherapy is essential if a TCD transplant platform is chosen.

Brain natriuretic peptide level as marker of cardiac function in imatinib—Treated chronic myeloid leukemia patients: No evidence of cardiotoxicity of imatinib therapy

To the Editor: In the last year, the issue of cardiotoxicity of imatinib mesylate (IM) was on focus. After the original work from Kerkelä et al. [1], various papers reported a low incidence of severe cardiac adverse events in large groups of patients treated with imatinib for chronic myeloid leukemia (CML) [2–5] and gastrointestinal stromal tumor (GIST) [6]. Safety issues are particularly important, as imatinib is the frontline treatment of CML [7], and patients are expected to receive treatment for indefinite time. B-type natriuretic peptide (BNP) is released by the heart in response to myocardial tension [8] and is considered an accurate test for the diagnosis of heart failure. The measurement of BNP in the serum is a rapid and easy tool for evaluation of left ventricular ejective function (LFEV), also in asymptomatic patients [9]. We have measured BNP level in 49 consecutive patients with chronic phase CML during imatinib therapy and in five newly diagnosed CML patients that were tested before IM start and after 1, 2, and 3 months of therapy. BNP level was measured using a direct chemiluminescent sandwich immunoassay: the analytical range extends from 0 to 5,000 pg/ml, with a sensitivity <2 pg/ml. Normal range is as follows: <100 pg/dl. Characteristics of the 49 patients studied while in treatment with IM are provided in Table I. All patients were asymptomatic and without signs of cardiac impairment at time of BNP evaluation. The mean level of BNP was 22.4 pg/ml (SD ± 26.6); only two patients had values >100 pg/ml. As expected [10], there was a linear correlation between age and BNP levels (t-value 1⁄4 3.850). Fifteen out of 24 (62.5%) patients aged 60 had BNP >22 pg/ml (mean 37.2 ± 31.4), compared to only 1/25 (4%) in the cohort <60-years-old (mean 8.2 ± 5.7) (P < 0.0001). BNP level was not affected by IM daily dose or by therapy duration. Patients with hypertension had higher levels of BNP (33.4 ± 35.6 vs 16.5 ± 18.3, P 1⁄4 0.03), despite an equivalent IM dose and treatment duration. This data could be explained by a higher incidence of hypertension in the older patients. No patient experienced major cardiac adverse event during IM therapy. An echocardiogram was performed in the two patients with higher BNP values: both of them were older than 60 and suffered from hypertension, but echocardiogram revealed a normal cardiac function (LVEF >65%). In the five consecutive patients (Table II) tested for BNP before start of IM and monthly during treatment there was no significant change in BNP levels during imatinib therapy (Fig. 1). Mean BNP value before start of IM was 20.9 ± 10.6, after three months of therapy was 14.8 ± 13.8. With the limits of a relatively small study population, our data indicates that imatinib therapy does not cause an increase in BNP, a rapid and reliable marker for the assessment of ventricular function. The role of BNP in monitoring heart function of CML patients treated with this drug deserves confirmation in larger groups of patients.

Risk Factors and Outcomes of Infections by Multidrug-Resistant Gram-Negative Bacteria in Patients Undergoing Hematopoietic Stem Cell Transplantation

The objective of this study was to determine risk factors and outcomes of infections by multidrug-resistant gram-negative (MDR GN) bacteria in 241 recipients of hematopoietic stem cell transplantation (HSCT). The cumulative incidence of infections was 10.5% (95% CI, 12.0% to 25.8%), with 57% of infections occurring during the period of severe neutropenia (neutrophil count < .1 × 106/L). In multivariate analysis, allogeneic transplant and colonization with MDR GN bacteria at admission to the transplant unit were significantly associated with an increased risk of infection. Although we observed neither transplant-related mortality (TRM) nor deaths due to infections by MDR GN bacteria after autologous transplant, in the allogeneic setting a significant difference was reported in terms of overall survival (OS) and TRM between patients who developed infections and those who did not (1-year OS, 39% versus 68%; 1-year TRM, 42% versus 19%). In multivariate analysis, refractory disease and development of grades III to IV graft-versus-host disease (GVHD) were factors that affected both TRM and OS, whereas occurrence of infections by MDR GN pathogens significantly reduced OS. We conclude that eligibility to allogeneic HSCT in MDR GN bacteria carriers should be carefully evaluated together with all other factors that independently influence outcome (disease status, donor, and GVHD risk).

How could patient reported outcomes improve patient management in chronic myeloid leukemia

ABSTRACT Introduction: Patients reported outcome (PRO) are still under-used in patients with chronic myeloid leukemia (CML) treated with tyrosine kinase inhibitors (TKIs), though data on the correlation between quality of life (QoL) and therapeutic efficacy are increasingly known. Chronic low-grade toxicities can reduce patient’s QoL and negatively impact on adherence. Areas covered: This review will focus on the role of QoL questionnaires in patients with CML, receiving imatinib or newer TKIs (dasatinib, nilotinib, bosutinib, ponatinib). Physicians tend to underestimate the impact of TKI-related symptoms, in particular fatigue, that negatively affect QoL and can be a reason of poor adherence to therapy, with detrimental effect on long-term response. Few studies pointed out the role of PRO in CML, and there is paucity of questionnaires specifically designed for CML patients. Expert commentary: We recommend a wider use of PRO to join the pursuit of a rapid and deep responses with an optimization of QoL.

Combination of EUTOS score and 3-month BCR-ABL transcript level identifies a group of good-risk chronic myeloid leukemia patients with favorable response to frontline imatinib therapy.

as one of the potential putative driver mutations. ZEB2 has been implicated to have crucial role in hematopoietic stem cell differentiation, mobilization, and homing [3]. Conditional overexpression of ZEB2 in mice has been reported to induce T-cell leukemia and deleterious mutations of ZEB2 have been identified in other leukemias [4,5], further suggesting the possible association between altered ZEB2 function and leukemogenesis. These are consistent with ZEB2 being a likely driver mutation in this case. The PCR capillary electrophoresis (PCR-CE) assay detected an NPM1 p.W288fs and several different sizes of FLT3-ITD in both samples (Supporting Information table). We next inferred a model of clonal evolution by tracing cancer cell fraction (CCF) of the detected variants (Fig. 1). Both primary and relapse AML shared the same founder clone with IDH1, ZEB2, and most likely the NPM1 mutation. Although the method of variant allelic fraction (VAF) calculation is different between WES and PCR-CE, VAF of NPM1 mutation on PCR-CE was stable around 0.5. Further, a previous study has shown that NPM1 mutation is almost always an early founding event in AML, consistent with the NPM1 mutation as early clonal event in this case. We did not incorporate FLT3-ITD into our model because association between respective ITD sizes and clonality has not been well understood. However, as a whole, FLT3-ITD was clearly detected at two time points, suggesting that this mutation persisted in the dominant clone. Our model suggests that the founder clone persisted after initial therapy and relapsed 19 years later with additional mutations acquired. Overall, it is consistent with one of the models that were proposed by Ding et al., who performed whole genome sequencing on eight relapsed AML cases, all of which relapsed within 3 years of remission [6]. Our report differs in that our case had a larger fraction of relapse-specific mutations and fewer shared mutations between primary and relapse AML. This would be consistent with the much longer period before relapse and accumulation of additional mutations over this time period. We also observed the emergence of a minor population with an SF3B1 mutation at relapse. CCF of the SF3B1 mutation did not follow that of the founder clone after salvage therapy (Fig. 1). SF3B1 mutation is frequently associated with MDS but rare in AML. The studied patient was suspected to have MDS 3 years before she experienced relapse (Supporting Information Appendix). Taken together, it is likely that the clone with SF3B1 mutation represents the co-occurrence of MDS in the context of a relapsing AML. In summary, longitudinal genomic characterization of an individual with a late relapse of AML revealed that the founder clone of the primary AML persisted after treatment and constituted the basis of relapsed disease 19 years later, hence confirming “true” relapse. More cases of late relapse in AML need to be examined to better characterize the mechanisms of relapse and disease latency.

Factors affecting outcome of allogeneic stem cell transplantation as salvage in patients with acute myeloid leukemia primary refractory to intensive induction therapy

To the Editor: In an attempt to provide a short term, practical, and effective regimen for perioperative anemia therapy as an alternative to autologous blood transfusion, Rutherford et al., evaluated three different regimens of recombinant human erythropoietin and concluded that irrespective of dose, “normal” iron stores for basal erythropoiesis may not always be sufficient to supply optimal amounts of iron for the accelerated erythropoiesis associated with acute recombinant erythropoietin administration, even with oral iron supplementation [1]. The comorbidity burden of surgical complications of perioperative anemia, present in one-third to one-half of all surgical patients remains clinically and economically formidable. Perioperative allogeneic blood transfusion is associated with an increased postoperative infection rate, longer hospital stays, poorer outcomes, and increased cost. Much of the data on the use of erythropoietic therapy in the perioperative setting is observational. Garcia Erce et al., randomized patients undergoing elective knee arthroplasty who had preoperative hemoglobin levels of <13.0 g/dl to one dose of 40,000 units of erythropoietin plus two 200 mg doses of intravenous iron sucrose plus or minus red cell salvage. Both arms were compared to intrainstitutional historic controls. The observed transfusion reduction was nearly 90% with no significant difference in the two treatment arms [2]. In a prospective, randomized controlled study Serrano et al. studied 200 patients with hip fractures and hemoglobin levels <12 g/dl randomized to the standard no treatment of 600 mg of intravenous iron sucrose without erythropoiesis stimulating agents, preoperatively [3]. Perioperative transfusions overall were reduced from 41 to 33% and with subcapital fractures, more likely to be transfused, from 46 to 14% with intravenous iron. No quantitatively significant toxicity was observed with intravenous iron in either study. Despite such a formidable benefit, regulatory bodies do not recommend the routine use of intravenous iron in anemic subjects undergoing elective surgery. Shander et al. described a multidisciplinary, multimodal, individualized strategy collectively termed Patient Blood Management with the aim to reduce allogeneic blood transfusion [4]. Perioperative anemia is detected and treated along with a higher transfusion threshold if or when transfusion is indicated. In an amalgam of published evidence (see Fig. 1, presented by Shander at the 2014 Annual Meeting of the European Society of Anaesthesiology) the use of allogeneic red blood cell transfusion provides the lowest benefit, highest risk, and sadly, has the highest use The Spanish consensus statement recommends routine, proactive diagnostic, and interventional anemia management [5]. In line with these conclusions, the clinical practice guidelines published by the American Association of Blood Banks [6] recommend adhering to a restrictive transfusion strategy (7–8 g/dl) in hospitalized stable patients as well as those with preexisting cardiovascular disease and limit transfusion to those with symptoms. In a pooled analysis of 2,547 perioperative patients who underwent either hip fracture repair or lower limb arthroplasty, Munoz et al. reported a decrement in transfusion rate from 48.8 to 32.4% in those who received perioperative intravenous iron versus those who did not [7]. Postoperative infections were reduced from 26.9 to 10.7%, length of stay from 13.4 to 11.9 days and remarkably thirty day mortality from 9.4 to 4.8% in the IV iron group. Nonetheless, perioperative anemia management is not a priority for most surgeons. A simple therapeutic paradigm directing the administration of intravenous iron 2–4 weeks preoperatively would now be nearly seamless with the availability of four new intravenous iron whose carbohydrate cores bind the elemental iron much more tightly, allowing full replacement dosing in a single 15–60 min visit. The cost/benefit would be substantial. In my community, the actual Committee for Medicare and Medicaid Services payment for two units of blood, administered in the ambulatory setting is greater than