Bernard De Prijck

Darbepoetin-alfa and intravenous iron administration after autologous hematopoietic stem cell transplantation : A prospective multicenter randomized trial

We conducted a randomized study analyzing the impact of darbepoetin alfa (DA) administration with or without intravenous (i.v.) iron on erythroid recovery after autologous hematopoietic cell transplantation (HCT). Patients were randomized between no DA (Arm 1), DA 300 μg every 2 weeks starting on Day 28 after HCT (Arm 2), or DA plus i.v. iron 200 mg on Days 28, 42, and 56 (Arm 3). The proportion achieving complete hemoglobin (Hb) response within 18 weeks (primary end point) was 21% in Arm 1 (n = 24), 79% in Arm 2 (n = 25), and 100% in Arm 3 (n = 23; P < 0.0001). Erythropoietic response was shown to be significantly higher in Arm 3 (n = 46) than in Arm 2 (n = 50; P = 0.008), resulting in lower DA use, reduced drug costs, and improved quality of life scores, but the effect on transfusions was not significant. In multivariate analysis, DA administration (P < 0.0001), i.v. iron administration (P = 0.0010), high baseline Hb (P < 0.0001), and low baseline creatinine (P = 0.0458) were independently associated with faster achievement of complete Hb response. In conclusion, DA is highly effective to ensure full erythroid reconstitution after autologous HCT when started on Day 28 post‐transplant. I.v. iron sucrose further improves erythroid recovery. Am. J. Hematol. 88:990–996, 2013.

Enteroviral meningoencephalitis as complication of Rituximab therapy in a patient treated for diffuse large B-cell lymphoma

Haematology, 147, 43–70. Scheinberg, P., Fischer, S., Nunez, L., Wu, C.E., Cohen, J., Young, N. & Barrett, A. (2007) Distinct EBV and CMV reactivation patterns following antibody-based immunosuppressive regimens in patients with severe aplastic anemia. Blood, 109, 3219–3224. The Board of the German Medical Association on the recommendation of the Scientific Advisory Board. (2009) Cross-sectional guidelines for therapy in blood components and plasma derivatives, 11. Adverse reactions. Transfusion Medicine and Hemotherapy, 36, 465– 478. The Trial to reduce Alloimmunisation to Platelets study group. (1997) Leukocyte reduction and ultraviolet B irradiation of platelets to prevent alloimmunisation and refractoriness to platelet transfusions. New England Journal of Medicine, 337, 1861–1869. Williamson, L.M., Stainsby, D., Jones, H., Love, E., Chapman, C.E., Navarrete, C., Lucas, G., Beatty, C., Casbard, A. & Cohen, H. (2007) The impact of universal leukodepletion of the blood supply on hemovigilance reports of post transfusion purpura and transfusionassociated graft-versus-host disease. Transfusion, 47, 1455–1467.

Clinical characteristics and outcome of isolated extracerebral relapses of primary central nervous system lymphoma: a case series

There is very limited data on isolated systemic relapses of primary central nervous system lymphomas (PCNSL). We retrospectively reviewed the clinical characteristics and outcome of 10 patients with isolated systemic disease among 209 patients with PCNSL mainly treated with methotrexate‐based chemotherapy (CT) with or without radiation therapy (RT). Isolated systemic relapse remained rare (4.8%, 10/209 patients). Median time from initial diagnosis to relapse was 33 months (range, 3–94). Sites of relapse were mostly extranodal. Three patients presented with early extra‐cerebral (EC) relapse 3, 5 and 8 months from the beginning of initial treatment, respectively, and 7 patients had later relapses (range, 17–94 months). Treatment at relapse included surgery alone, RT alone, CT with or without radiotherapy, or CT with autologous stem cell transplantation (ASCT). Median overall survival (OS) after relapse was 15.5 months (range, 5.8–24.5) compared to 4.6 months (range, 3.6–6.5) for patients with central nervous system (CNS) relapse (p = 0.35). In conclusion, isolated systemic relapses exist but are infrequent. Early EC relapse suggests the presence of systemic disease undetectable by conventional evaluation at initial diagnosis. Patient follow‐up must be prolonged because systemic relapse can occur as late as 10 years after initial diagnosis. Whether EC relapses of PCNSL have a better prognosis than CNS relapses needs to be assessed in a larger cohort. Copyright

Diagnosis and follow-up of monoclonal gammopathies of undetermined significance; information for referring physicians

Abstract The prevalence of monoclonal gammopathy of undetermined significance (MGUS) is generally estimated at 3.4% in the general population over 50 years, and its incidence increases with age. MGUS represents a preneoplastic entity that can transform into multiple myeloma or other lymphoproliferative disorders. The risk of malignant transformation is estimated at 1% per year and persists over time. Predictors of malignant transformation have been identified such as the heavy chain isotype, The level of monoclonal proteins, increasing levels of the monoclonal component during the first years off follow-up, the percentage of bone marrow plasmocytosis, the dosage of serum free light chains, the presence of immunophenotypically abnormal plasma cells, aneuploidy, and the presence of circulating plasma cells. Prognostic scores that combine certain of these factors have been proposed and allow the identification of high-risk patients. Their use could assist in tailoring the care for each patient, based on his/her risk profile.

Long-term safety follow-up of a randomized trial of darbepoetin alpha and intravenous iron following autologous hematopoietic cell transplantation.

To the Editor: Anemia is quite frequent in cancer patients, due to the cancer itself, its treatment, or both. Erythropoiesis-stimulating agents (ESA) have proven effective in increasing hemoglobin levels and improving quality of life. After autologous hematopoietic cell transplantation (auto-HCT), many patients experience prolonged anemia. However, ESA use in this context remains sparse. We recently reported the efficacy of darbepoetin alpha (DA) (AranespVR ) and intravenous (IV) iron (VenoferVR ) on erythroid reconstitution following auto-HCT [1]. Although there was no short-term safety issue, longer follow-up was required as some metaanalyses suggest increased mortality on study and worsened overall survival in cancer patients receiving ESA [2,3], particularly when no concomitant chemotherapy is administered. On the other hand, some in vitro and animal studies raised a possible effect of iron on tumor growth [4], but there are no available data in cancer patients receiving IV iron. In addition, the impact of ESA and/or IV iron on long-term safety, relapse, and survival has never been examined after transplantation. Therefore, we analyzed long-term outcome to verify the safety of DA and IV iron therapy after auto-HCT. We randomized 127 patients with lymphoid malignancies [1] between no erythropoietic therapy (n 5 25), DA from day 28 post-auto-HCT (n 5 52) or DA 1 3 IV iron injections (n 5 50). Median follow-up was 1.4 year (range 89 days–9.5 years). Survival analyses were performed according to the Kaplan–Meier method. More details about patients and methods can be found in the Supporting Information. The incidence of infections between end of study (day 126) and last follow-up remained comparable: three patients in control group (12%), eight in DA group (15%), and six in DA1iron group (12%) experienced at least one infection. Numbers of infections per patient were 0.2 6 0.7, 0.2 6 0.4, and 0.1 6 0.3 in control, DA, and DA1iron groups, respectively (NS). During follow-up, 4/25 (16%) patients in control group, 13/52 (25%) in DA group, and 6/50 (12%) in DA1iron group experienced at least one other complication (NS). While three patients (two in control and one in DA1iron groups) presented a thrombosis on study, no other thrombo-embolic event (TEE) occurred during follow-up. Two patients (one in control and one in DA groups) developed a benign tumor, whereas four (three in DA and one in DA1iron groups) presented a secondary malignancy (NS). Other complications were: hypertension (one in control and one in DA groups), ischemic cardiomyopathy (three in DA group) including one myocardial infarction, four arrhythmias (one in control and three in DA groups), peripheral arteriopathy (one in DA group), diabetes (two in DA and one in DA1iron groups), radiopneumonitis (one in control group), vasculitis (one in DA group), nephritis (one in DA and one in DA1iron groups), thyroiditis (one in DA group), spondylarthritis (one in DA1iron group), osteonecrosis (one in DA and two in DA1iron groups), peripheral neuropathy (one in DA and one in DA1iron groups), sudden transient deafness (one in DA group), and sarcoidosis (one in DA1iron group). One-year overall survival were 100%, 88%, and 100% and 5-year overall survival were 86%, 78%, and 91% in control, DA, and DA1iron groups, respectively (P 5 0.43) (Fig. 1A). One-year and 5-year progression-free survival were 85% and 71% in control group, compared to 86% and 57% in DA group, and 94% and 78% in DA1iron group (P 5 0.30) (Fig. 1B). One year after auto-HCT, 15%, 12%, and 10% of patients in control, DA, and DA1iron groups, respectively, had progressed or relapsed; at five years postHCT, 29%, 42%, and 22% had progressed (P 5 0.35) (Fig. 1C). Disease progression was the major cause of death (three in control group, eight in DA group, and three in DA1iron group). The impact of ESA on survival in untreated cancer patients has been studied in several meta-analyses [2,3,5], but results differed depending on included studies and data and methods used. Glaspy [5] did not find any difference in survival or disease progression, whereas Bohlius [2] and Bennett [3] showed increased mortality in patients receiving ESA. However, there are no data about the effect of ESA on overall or progressionfree survival after transplantation, or about the impact of IV iron in cancer patients, let alone after transplantation. Although our study was not designed to establish an impact on mortality, survival was obviously not different among the groups. The mechanisms responsible for increased mortality with ESA in oncology remain unclear. Whereas some suggested that it was partly explained by TEE [2,3], in our study TEE were no more frequent in the ESA groups on study, and no TEE was observed during long-term follow-up. However, three major non-fatal cardiovascular events occurred in DA group versus none in DA1iron and control groups (NS). Another cause of worsened survival could be an effect of ESA on disease progression [6] as ESA could promote cell growth directly in tumor cells expressing erythropoietin (Epo) receptors and indirectly by stimulating angiogenesis through endothelial cells expressing Epo receptors. We did not observe impaired survival reported in untreated cancer patients receiving ESA, possibly because few patients had active disease. On the other hand, iron could also impact disease progression. In animal models, tumor growth can be favored by iron overload [4] but in these models, iron-replete animals received much larger doses of iron. In our study, iron therapy did not affect disease progression. Whereas patients with pre-transplant iron overload may develop more infections after transplantation, the rates of infection were similar in our three groups, indicating that 900 mg of IV iron post-transplant has no such deleterious effect. The other serious complications were uncommon and hardly attributable to ESA or iron treatment. In conclusion, DA and IV iron therapy following auto-HCT did not affect long-term safety, disease outcome, or survival.

A First Report on [18F]FPRGD2 PET/CT Imaging in Multiple Myeloma

An observational study was set up to assess the feasibility of [18F]FPRGD2 PET/CT for imaging patients with multiple myeloma (MM) and to compare its detection rate with low dose CT alone and combined [18F]NaF/[18F]FDG PET/CT images. Four patients (2 newly diagnosed patients and 2 with relapsed MM) were included and underwent whole-body PET/CT after injection of [18F]FPRGD2. The obtained images were compared with results of low dose CT and already available results of a combined [18F]NaF/[18F]FDG PET/CT. In total, 81 focal lesions (FLs) were detected with PET/CT and an underlying bone destruction or fracture was seen in 72 (89%) or 8 (10%) FLs, respectively. Fewer FLs (54%) were detected by [18F]FPRGD2 PET/CT compared to low dose CT (98%) or [18F]NaF/[18F]FDG PET/CT (70%) and all FLs detected with [18F]FPRGD2 PET were associated with an underlying bone lesion. In one newly diagnosed patient, more [18F]FPRGD2 positive lesions were seen than [18F]NaF/[18F]FDG positive lesions. This study suggests that [18F]FPRGD2 PET/CT might be less useful for the detection of myeloma lesions in patients with advanced disease as all FLs with [18F]FPRGD2 uptake were already detected with CT alone.