Daniela Nasso

Infections increase the risk of central venous catheter-related thrombosis in adult acute myeloid leukemia

INTRODUCTION Central venous catheters (CVC) related thrombosis (CRT) represents a well known complication in patients with acute myeloid leukemia (AML) receiving intensive chemotherapy but the efficacy of antithrombotic prophylaxis still remains controversial. PATIENTS AND METHODS We analyzed 71 consecutive AML patients whose CVC was inserted before each chemotherapy cycle for an overall number of 106 CVC placements. In 47/106 insertions, a prophylaxis with 100 IU/kg/day low molecular weight heparin (LMWH) was administered for 7 days after CVC insertion and additional 7 after CVC removal. This unconventional dose of LMWH, although higher than usual, appeared adequate for a short-course approach. LMWH was delivered regardless of the platelet (PLT) count once provided that it should have been maintained above 20 x 10(9)/L by transfusions. RESULTS Of 106 insertions, we observed 19 (18%) episodes of CRT, 58 (54%) of sepsis and 50 (47%) infections of CVC-exit site with no difference between LMWH and no-LMWH group. Occurrence of CRT was significantly associated with CVC-exit site infections (14/19, p=0.01) and sepsis (16/19, p=0.005) with no difference between LMWH and no-LMWH group. In multivariate analysis, both CVC-exit site infections and sepsis were confirmed to be independent risk factors for CRT development. CONCLUSION Our retrospective study, although based on a small sample size, suggests that the occurrence of CVC-exit site infections and neutropenic sepsis following chemotherapy significantly increases the risk of CRT in AML, independently from the use of LMWH prophylaxis.

Invasive fungal diseases during first induction chemotherapy affect complete remission achievement and long-term survival of patients with acute myeloid leukemia

We retrospectively evaluated, in a logistic-regression-model, the role of proven/probable invasive fungal diseases (PP-IFD), occurring during first induction chemotherapy, on the achievement of complete remission (CR) and overall survival (OS) in 198 acute myeloid leukemia (AML) patients. A PP-IFD was documented in 34 (17.2%) patients. Younger age, good performance status at AML diagnosis and no development of a PP-IFD (OR 4.09, 95% CI 1.71-9.81, p<0.0001) were independent factors associated to CR achievement. Younger age, good performance status, favorable genetic risk and no development of PP-IFD (HR 1.86, 95% CI 1.20-2.88, p=0.005) were independent factors associated to OS at 3 years.

Phase II Study of Bortezomib as a Single Agent in Patients with Previously Untreated or Relapsed/Refractory Acute Myeloid Leukemia Ineligible for Intensive Therapy.

We explored the safety and efficacy of bortezomib given as single agent in patients with untreated or relapsed/refractory acute myeloid leukemia (AML), unfit for conventional chemotherapy. Fourteen patients were treated with bortezomib 1.5 mg/m2 administered twice weekly for two weeks, every 3 weeks. Median age was 70 years (range 60–81) and the median number of cycles delivered was 2 (range 1–4). Of 13 evaluable patients, in 8 (61%), the administration of bortezomib resulted in an antileukemic effect as demonstrated by peripheral blood and/or bone marrow blast reduction. In 4 (50%) of these 8, a decrease by 37% of transfusion requirement was also observed (P = 0.009). Overall median survival was 4 months (range 0.25–10). Neurotoxicity was the most frequent adverse event with 7 of 13 (54%) patients experiencing grades 3-4 peripheral neuropathy. Neurotoxicity led to treatment discontinuation in 4 (57%) of 7. In conclusion, the observed anti-leukemic activity of bortezomib indicates that there is room for designing additional studies in which combination with other chemotherapeutic agents should be considered. Clinical registration no.: EUDRACT 2006-006923-38.

Pre-transplant persistence of minimal residual disease does not contraindicate allogeneic stem cell transplantation for adult patients with acute myeloid leukemia

Despite progress in treatment and supportive therapies, outcome of high-risk adult AML remains dismal with ~ 20% of patients becoming long-term survivors. Since the pretreatment genetics/cytogenetics of AML do not always anticipate the individual outcome, there is a strong rationale to implement laboratory techniques capable of exploring the quality of CR and allowing post-remission therapy to be optimally directed. In this view, minimal residual disease (MRD) assessment promises to be a robust approach. It captures the diversities of the underlying genetic/cytogenetic features of AML and recapitulates other patient heterogeneities regarding drug bioavailability, metabolism and resistance. Multiparametric flow cytometry (MFC) is one of the leading techniques successfully exploited to quantify MRD in AML expressing leukemia-associated immunophenotypes (LAIP). This assay applies to the vast majority of patients after chemotherapy-induced morphologic CR and has been shown to predict the clinical outcome when measured at several time points, potentially prompting prospective treatment adjustments. Recent studies have demonstrated that pretransplant MRD levels negatively affect post-transplant outcome. Years ago, we showed that MRD persistence at the end of consolidation was associated with an unfavorable outcome and that autologous stem cell transplantation (AuSCT) was not able to alter such an unfavorable course. More recently, other authors have extended this observation to either pediatric or adult patients receiving allogeneic stem cell transplantation (ASCT), showing that pretransplant MRD is a major determinant of prognosis, regardless of the occurrence of graft-versus-leukemia (GVL). Nevertheless, whether MRD positivity is an indication or a contraindication to deliver ASCT is still a matter of debate. On the basis of these premises, we analyzed a retrospective series of MRD-positive adults with AML who were submitted to ASCT. Our aim was to evaluate the impact of pretransplant MRD status on overall survival (OS) and DFS. We analyzed 230 consecutive patients achieving CR after the induction cycle of intensive EORTC/GIMEMA protocols and who harbored in their leukemic cells a LAIP suitable for MRD monitoring. The present series represents an extension of a cohort of patients already analyzed for different purposes and reported previously. Following our previous experience, MRD positivity was defined if ⩾ 3.5 × 10 4 (0.035%) residual leukemic cells (RLCs) were detected in the BM upon full hematological recovery after consolidation cycle. According to this definition, 176/230 patients (76.5%) were classified as MRD positive (MRD) and 54/230 (23.5%) as MRD negative (MRD). In the overall series, 84/230 patients (36.5%) received no transplant because of age, poor performance status or insufficient stem cell harvest, 28/230 (12.2%) relapsed before transplant delivery whereas 118/230 (51.3%) underwent ASCT (N= 50) or AuSCT (N= 68) in first CR. For the purpose of the present analysis, we focused on the 81 patients who tested MRD and who were submitted to ASCT (N= 45) or AuSCT (N= 36), respectively. The same analysis was not feasible for MRD patients due to the low numbers in the ASCT group (N= 5), preventing any statistical significance from being demonstrated. The clinico-biological characteristics of the patients are detailed in Table 1. The two groups were balanced regarding white blood cell count (WBCc), ELN risk category, FLT3 and NPM1 mutational status. Karyotypic analysis was available in 77 (95%) out of 81 patients. Intermediate risk category accounted for 78%

Minimal residual disease as biomarker for optimal biologic dosing of ARA-C in patients with acute myeloid leukemia

We assessed by flow cytometry minimal residual disease (MRD) in patients with acute myeloid leukemia (AML) given standard‐dose (SDAC) and high‐dose ARA‐C (HDAC) regimens. Of 163 patients enrolled, 130 (median age, 45 years; range, 18–59 years) qualified for analysis, all achieving complete remission after treatment with SDAC (n = 78) or HDAC (n = 52) plus etoposide and daunorubicin. Consolidation consisted of intermediate‐dose ARA‐C and daunorubicin. MRD negativity was significantly more frequent in the SDAC vs. HDAC arm after both induction (37% vs. 15%, P = 0.007) and consolidation (44% vs. 18%, P = 0.002). Respective median residual leukemic cell counts with SDAC and HDAC use were 1.5 × 10−3 and 4 × 10−3 (P = 0.033) after induction and 5.7 × 10−4 and 2.9 × 10−3 (P = 0.008) after consolidation. Based on ARA‐C schedule and post‐consolidation MRD status, the four patient groups (SDAC‐MRD−, HDAC‐MRD−, SDAC‐MRD+, and HDAC‐MRD+) displayed 5‐year overall survival rates of 60%, 33%, 24%, and 42% (P = 0.007), respectively, with 24%, 35%, 74%, and 48% (P < 0.0001) respective cumulative incidence of relapse estimates. MRD may serve as a biomarker for optimal biologic dosing of ARA‐C, and SDAC regimen appears to yield more frequent MRD negativity. Am. J. Hematol. 90:125–131, 2015.

Recurrence of a t(8;21)-Positive Acute Myeloid Leukemia in the Form of a Granulocytic Sarcoma Involving Cranial Bones: A Diagnostic and Therapeutic Challenge

Granulocytic sarcoma (GS) is a rare extramedullary solid tumor defined as an accumulation of myeloblasts or immature myeloid cells. It can cooccur with or precede the acute myeloid leukemia (AML) as well as following treated AML. The incidence of GS in AML patients is 3–8% but it significantly rises in M2 FAB subtype AML. This variety of AML harbors t(8;21) in up to 20–25% of cases (especially in children and black ones of African origin) and, at a molecular level, it is characterized by the generation of a fusion gene known as RUNX1-RUNX1T1. Approximately 10% of M2 AML patients will develop GS, as a consequence, the t(8;21) and the relative transcript represent the most common cytogenetic and molecular abnormalities in GS. FLT3-ITD mutation was rarely described in AML patients presenting with GS. FLT3 ITD is generally strongly associated with poor prognosis in AML, and is rarely reported in patients with t(8;21). GS presentation is extremely variable depending on organs involved; in general, cranial bones and sinus are very rarely affected sites. We report a rare case of GS occurring as a recurrence of a previously treated t(8;21), FLT3-ITD positive AML, involving mastoid bones and paravertebral tissues.

A case of oral mycosis fungoides successfully treated by combination of alemtuzumab and chemotherapy

Dear Editor, Mycosis fungoides (MF) represents the most common cutaneous T cell lymphoma [1]. Oral cavity involvement occurs in less than 1 % of MF patients [2] and is generally associated with a poor prognosis when treated with standard therapies (PUVA, etc.). Here, we report a 60-year-old man affected with MF that showed a mucosal involvement and that was successfully treated with systemic chemotherapy combined with alemtuzumab. In 2010, the patient referred the appearance of both an ulcerate tumor on his leg and a painless plaque on his upper left gingival buccal mucosa (Fig. 1) derived from an initial tender nodule appeared 2 years before. There was no palpable lymphadenopathy and no other cutaneous or extra-cutaneous involvement. A computed tomography scan (CT) showed an enlargement of both masseter muscle and parotid gland. The presence of a 1-cm submandibular lymph node was also found. In 2011, a needle biopsy of the oral lesion revealed fragments of muscle tissues with massive infiltration of atypical lymphocytes. A first diagnosis of peripheral T cell lymphoma unspecified was achieved. After a few months, a further biopsy better characterized the T cells phenotype which was: CD3++, CD2+, CD4+, CD8−, and CD7−, with a low proliferative fraction and the monoclonal expression of TCR (Figs. 1 and 2). The final diagnosis was MF. After an informed consent was obtained, the patient underwent six monthly cycles of CHOEP [3] . Chemotherapy was combined with alemtuzumab, 15 mg subcutaneously once a week on day +1,+8,+15, and +22. The treatment was well tolerated. One month after the end of therapy, the total-body positron emission (PET) CT showed absence of disease and the patient received photophoresis and interferon-alpha 18 MU/month, three doses per week for 6 months. After 6 months, the patients suffered a relapse and was again successfully treated with six cycles of chemotherapy, based on gemcitabine 1200 mg/mq on day +1 and day +8 [4] and alemtuzumab 15 mg on day 1. To date, the patient presents a skin stable disease and receives a regular maintenance treatment with photophoresis. During alemtuzumab treatment, we performed a preemptive therapy against CMV reactivation by weekly quantitative and qualitative PCR assay. No specific prophylaxis was performed, and there was no CMV reactivation. Prophylactic

Recurrent Sweet's syndrome in a patient with multiple myeloma

We report on a case of Sweets syndrome associated with multiple myeloma, as harbinger for disease relapse.

Extensive toxic epidermal necrolysis following brentuximab vedotin administration.

Dear Editor, In June 2013, we observed a 22-year-old man with a diagnosis of CD30 positive, anaplastic large cell lymphoma (ALCL). Lymphoma was at stage IIIA and positive for anaplastic lymphoma kinase (ALK) molecule [1]. A total body positron emission tomography and computerized tomography (TB PET/CT) scan showed latero-cervical and mediastinal lymph nodes and abdominal bulky disease. From June to December 2013, the patient was treated with three consecutive lines of chemotherapy with no evidence of response. In January 2014, he reported symptoms of sub-ileus associated with renal failure and anuria, requiring dialysis sessions. A first dose of brentuximab vedotin (BV; 1.8 mg/kg) was administered intravenously, being uneventful. Concomitant drugs were piperacillin-tazobactam, omeprazole, morphine, granisetron, pregabalin, and amisulpride. Seven days after BV infusion, we observed a diffuse erythema of the trunk, extremities, and face, which rapidly evolved in overt blistering lesions (Fig. 1a) extending to >90 % of the body surface area. The histologic examination of a skin patch documented necrosis of epidermis, vacuolization, and sub-epidermal blistering of the basal membrane zone with rare eosinophils in the papillary dermis (Fig. 1b). The picture was consistent with a diagnosis of toxic epidermal necrolysis (TEN). The patient received topical treatments, intravenous antibiotics, steroids, and immunoglobulins. After 20 days of treatment, the signs and symptoms of TEN resolved, but eventually, the patient died due to disease progression. Although our patient was on therapy with intravenous piperacillin-tazobactam, which has been recognized as potentially responsible for TEN [2], we cannot exclude the causative role of BVin the reported clinical events. Time span between BVinfusion and onset of TENwas short [3], and at the time when TEN developed a number of concomitant drugs (including piperacillin-tazobactam) have already been given for several days and most of them were administered again. Indeed, no other episodes of TEN were seen after BV discontinuation. The mechanism by which BV might have damaged the patient’s epidermis is unclear. During development, epidermal cells of fetal skin can express CD30 antigen on membrane [4]. In the present case, immunohistochemistry analysis of skin biopsies failed to demonstrate any epidermal CD30 expression. Nevertheless, cytokines released during inflammatory processes may prompt transient expression of CD30 on epidermal cells. Actually, our patient suffered from several episodes of Staphylococcus aureus infection, which might have boosted CD30 expression in the epidermidis. Alternatively, TEN might have been triggered by a delayed-type (type IV) hypersensitivity reaction [5] taking place through the activation of antigen-specific T helper lymphocytes. Actually, type IV cutaneous hypersensitivity reactions have been associated with other monoclonal antibody-based immunotherapy including ibritumomab and rituximab [3, 5]. Finally, as described for other drugs, TEN could be related to patient genetic susceptibility to the toxic effects of BV through specific HLA class I alleles and/or polymorphisms of some metabolic enzymes [6]. To the best of our knowledge, this is the first report of an extensive BVM. I. Del Principe (*) : F. Buccisano :M. Cefalo :A. Di Veroli : G. De Santis :D. Nasso : L.Maurillo :M. Postorino :G. Del Poeta : S. Amadori :A. Venditti Istituto di Ematologia, Dipartimento di Biomedicina e Prevenzione, Universita Tor Vergata, Viale Oxford 81, 00133 Rome, Italy e-mail: del.principe@med.uniroma2.it