Svitlana Gumenyuk

Cytomegalovirus reactivation after autologous stem cell transplantation in myeloma and lymphoma patients: A single-center study

AIM To determine the incidence of and the risk factors for cytomegalovirus (CMV) symptomatic infection and end-organ disease after autologous stem cell transplantation (ASCT). METHODS A total of 327 consecutive non CD34(+) selected autografts performed from the Hematology and Stem Cell Transplantation Unit of Regina Elena National Cancer Institute of Rome (Italy) in the period comprised between January 2003 to January 2015, were reviewed. Over the 327 autografts, 201 were performed in patients with multiple myeloma, whereas the remaining 126 in patients affected by non-Hodgkins lymphoma and Hodgkins lymphoma. The patients who underwent an ASCT for an acute leukemia (n = 20) in the same period were excluded from this analysis. CMV DNA load in the blood has been determined by polymerase-chain reaction in the case of a clinical suspicion of reactivation, therefore, no routine monitoring strategy was adopted. In the presence of signs and symptoms of CMV reactivation an antiviral treatment was performed. RESULTS Overall, 36 patients (11%) required a specific antiviral treatment for a symptomatic CMV reactivation (n = 32) or an end-organ disease (n = 4). We observed 20 and 16 cases of CMV reactivation among lymphoma (16%) and myeloma patients (8%), respectively. Among cases of end-organ disease, 3 were diagnosed as interstitial pneumonia and one remaining case as hemorrhagic enteritis. All cases of CMV reactivation were observed in IgG seropositive patients, with no documented cases of primary CMV infection. All patients were treated with a specific antiviral therapy, with a global rate of hospitalization of 55%; four patients received intravenous immunoglobulins. Transplant-related mortality was significantly higher in patients who experienced a CMV reactivation (8.4% ± 4.7% vs 1.7% ± 0.8%; P = 0.047). In univariate analysis, a pre-transplant HBcIgG seropositivity, a diagnosis of T-cell non-Hodgkins lymphoma and higher median age at transplant were significantly associated with the risk of developing a clinically relevant CMV infection requiring specific antiviral therapy (P < 0.001, P = 0.042 and P = 0.004, respectively). In multivariate analysis, only a pre-transplant HBcIgG seropositivity (OR = 8.928, 95%CI: 1.991-33.321; P = 0.023) and a diagnosis of T-cell non-Hodgkins lymphoma (OR = 4.739, 95%CI: 1.511-11.112; P = 0.042) proved to be independent predictors of a post-transplant clinically relevant CMV reactivation. CONCLUSION A symptomatic CMV infection can occur in about 11% of adult patients with lymphoma or myeloma undergoing ASCT. A pre-transplant HBcIgG seropositivity and a diagnosis of T-cell non-Hodgkins lymphoma should be considered as independent predictor factors of CMV reactivation.

Flow cytometry characterization in central nervous system and pleural effusion multiple myeloma infiltration: an Italian national cancer institute experience

Extramedullary relapse of multiple myeloma (MM) can occur in some patients, particularly after a long history of disease. However, central nervous system (CNS) and pleural effusion (PE) malignant myelomatosis, characterized by cerebrospinal fluid (CSF) and PE infiltration by tumour plasma cells (PC) are very rare, accounting for less than 1% of MM patients. The diagnosis of CNS and PE myelomatosis is historically based on PC detection by cytology. Multiparameter flow cytometry (FCM) has recently been shown to be a powerful technique for both diagnosis and minimal residual disease identification in myeloma patients (Paiva et al, 2009; Rawstron et al, 2013). However, to date, there is limited published experience regarding the use of FCM for the diagnosis of CNS and PE myelomatosis (Marini et al, 2014; Keklik et al, 2012). In this report, we describe clinical and biological features of six MM patients with CNS or PE myelomatosis diagnosed by FCM (Table I). Erythrocyte-lysed bone marrow (BM), peripheral blood (PB), CSF and PE samples were processed and stained using a six-colour panel (FITC/PE/PerCP/ PE-Cy7/APC/APC-Cy7) and the ‘Duo-lyse’ program of the Becton Dickinson Bioscience (BDB, Milan, Italy) Lyse-WashAssistant according to the following combinations: (i) CD28/ CD138/CD45/CD38/CD33/CD20; (ii) CD38/CD138/CD45/ CD56/CD117/CD19. The PC surface phenotype aberrancies were used as patient-specific disease markers (PSDM) to document intra-cytoplasm immunoglobulin (cy-Ig) light chains restriction: (iii) cy-Igk/cy-Igj/CD19/CD38/anti-PSDM/CD45 and the Cytofix & Cytoperm technique according to manufacturer’s recommendations. All antibodies were from BDB except CD28, CD33 and CD138 (Beckman Coulter, Milan, Italy). A minimum of 1 9 10 CD138/CD38 bright PC were acquired and analysed in all but one PB sample from Patient 5 (Table II) utilizing a BDB FACSCanto flow cytometer with FACSDiva software. A j/kratio <0 5 or >4 0, evaluated on CD19-positive or CD19negative/PSDM-positive PC, was used to discriminate between normal and neoplastic PC. Table I shows the relevant clinical features of the six patients. Three patients presented a CNS myelomatosis after one or more chemotherapeutic lines including novel agents, autologous and allogeneic haematopoietic stem cell transplantation. These three patients presented neurological signs and symptoms. In particular, one patient presented nausea, vomiting, confusion and headache; the second had cervical discomfort with first and second cervical vertebra body lesions and the third had headache with disturbance of the speech, in association with a neoplastic jaw mass. In two patients PE myelomatosis was documented at disease progression after one or two chemotherapeutic lines with novel agents, presented as progressive dyspnea. Finally, a very aggressive disease relapse with concomitant CNS and PE myelomatosis was documented in one patient after induction

Comparison between biosimilar filgrastim vs other granulocyte‐colony stimulating factor formulations (originator filgrastim, peg‐filgrastim and lenograstim) after autologous stem cell transplantation: a retrospective survey from the Rome Transplant Network

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Cryotherapy reduces oral mucositis and febrile episodes in myeloma patients treated with high-dose melphalan and autologous stem cell transplant: a prospective, randomized study

Cryotherapy reduces oral mucositis and febrile episodes in myeloma patients treated with high-dose melphalan and autologous stem cell transplant: a prospective, randomized study

Biosimilar filgrastim (Zarzio(®)) vs. lenograstim (Myelostim(®)) for peripheral blood stem cell mobilization in adult patients with lymphoma and myeloma: a single center experience.

1 Hematology and Stem Cell Transplantation Unit, Regina Elena National Cancer Institute, 2 Immuno-Transfusional Medicine, Leukapheresis and Cellular Therapy Unit, S. Camillo-Forlanini Hospital, 3 Immuno-Transfusional Medicine Unit, Regina Elena National Cancer Institute, 4 Scientifi c Direction, Regina Elena National Cancer Institute, and 5 Intensive Care and Pain Therapy Unit, Regina Elena National Cancer Institute, Rome, Italy

Ponatinib Induces a Persistent Molecular Response and Graft-versus-Host Disease/Graft-versus-Leukemia Effect in a Patient with Philadelphia-Positive Acute Lymphoblastic Leukemia with a T315I Mutation following Early Relapse after Allogeneic Transplant

We describe the case of a patient with a Philadelphia-positive (Ph+) acute lymphoblastic leukemia (ALL) treated with dasatinib plus steroids as the first-line therapy who achieved a molecular complete remission and then underwent a matched, unrelated donor allogeneic transplant. Five months after the transplant, he experienced a disease relapse with an T315I mutation, which was resistant to salvage chemotherapy. Once the details of the T315I mutation were acquired, we initiated ponatinib treatment at a standard dosage and observed a rapid decrease of minimal residual disease (MRD) at molecular assessment. The bone marrow evaluation after 2, 3, 6, 10 and 13 months was negative for MRD. After starting ponatinib, the patient experienced a skin graft-versus-host disease (GVHD), whereas no occurrence of GVHD was observed after transplant, suggesting that the efficacy of ponatinib could be related not only to the direct antileukemic effect, but also to its ability to promote an indirect graft-versus-leukemia effect. Ponatinib was well tolerated but a thyroid dysfunction mimicking a cardiovascular toxicity was observed and solved with hormonal substitutive treatment.

The predictive value of Aspergillus PCR testing on bronchoalveolar lavage fluid for early diagnosis of invasive pulmonary aspergillosis in hematologic patients

Francesco Marchesi, Antonio Spadea, Fulvia Pimpinelli, Grazia Prignano, Maria Grazia Paglia, Daniele Forcella, Svitlana Gumenyuk, Daniela Renzi, Francesca Palombi, Antonella Vulcano, Francesco Pisani, Atelda Romano, Elena Papa, Francesco Facciolo, Fabrizio Ensoli, Corrado Girmenia and Andrea Mengarelli Hematology and Stem Cell Transplant Unit, Regina Elena National Cancer Institute, Rome, Italy; Molecular Virology, Pathology and Microbiology Laboratory, San Gallicano Dermatological Institute, Italy; Microbiology and Infectious Diseases Biorepository Laboratory, National Institute of Infectious Diseases “L. Spallanzani”, Italy; Thoracic Surgery Unit, Regina Elena National Cancer Institute, Rome, Italy; Hematology, “Sapienza” University, Rome, Italy

Lenograstim 5 µg/kg is not superior to biosimilar filgrastim 10 µg/kg in lymphoma patients undergoing peripheral blood stem cell mobilization after chemotherapy: preliminary results from a prospective randomized study: LENO VS BIOSIMILAR FIL FOR MOBILIZATION

Randomized trials comparing chemomobilization efficiency between lenograstim and biosimilar filgrastim are lacking. Our previous retrospective study suggested that lenograstim could be more effective than biosimilar filgrastim when used at the same conventional dosage (5 µg/kg) only in lymphoma patients undergoing peripheral blood stem cell mobilization. We planned a prospective randomized study comparing lenograstim 5 µg/kg with biosimilar filgrastim 10 µg/kg to verify the hypothesis of lenograstim superiority even at half the dosage (stress test). Herein we report data after enrolling 60% of planned patients.

Prevention of Bortezomib-Related Peripheral Neuropathy With Docosahexaenoic Acid and α-Lipoic Acid in Patients With Multiple Myeloma: Preliminary Data

Background and Aims: Peripheral neuropathy is a common complication of chemotherapy that can induce marked disability that negatively affects the quality of life in patients with multiple myeloma (MM). The aim of this study was to prevent the onset or the worsening of peripheral neuropathy in MM patients treated with bortezomib (BTZ), using a new nutritional neuroprotective compound. We report preliminary results of 18 out of 33 patients who completed the study. Methods: We administered a tablet of Neuronorm to patients, containing docosahexaenoic acid 400 mg, α-lipoic acid 600 mg, vitamin C 60 mg, and vitamin E 10 mg bid for the whole follow-up period. Neurological visit assessment, electroneurography, and evaluation scales were performed at baseline and after 6 months. Results: At 6 months, 8 patients had no chemotherapy-induced peripheral neuropathy, while 10 patients experienced chemotherapy-induced peripheral neuropathy of grade 1 according to the Common Terminology Criteria for Adverse Events, one of them with pain. Seventeen patients did not report painful symptoms; no limitation of functional autonomy and stability in quality of life domains explored was observed. Conclusions: Our results seem to indicate that early introduction of a neuroprotective agent in our patients with MM treated with BTZ could prevent the onset or the worsening of neuropathic pain, avoiding the interruption of the therapy with BTZ, and maintaining a good functional autonomy to allow normal daily activities. Despite the limitations due to the fact that this is a preliminary study, in a small population, with short follow-up, our data seem to indicate that the nutraceutical may have some potential to be considered for a future trial.

Epstein-Barr virus-positive lymphoma after alemtuzumab therapy for B-cell chronic lymphocytic leukemia.

B-cell chronic lymphocytic leukemia (B-CLL) is an indolent lymphoproliferative disorder with a progressive accumulation of small, morphologically mature B lymphocytes in the bone marrow, blood and lymphoid tissues. Alemtuzumab (MabCampath) is a IgG1 monoclonal antibody (mAb) that target the CD52 antigen, a glycosylated peptide highly expressed on B-CLL cells. This mAb is active in patients with B-CLL refractory to alkylating agents and purine nucleoside analogues. The primary adverse event so far reported is the induction of a profound and prolonged depletion of CD4 and CD8 subpopulations leading to an immunodeficient status and the development of opportunistic infections [1,2]. Recently, Epstein-Barr virus (EBV) related lymphoma have been reported in patients with T and B cell lymphoproliferative disorder after treatment with alemtuzumab [2–5]. Here, we report a case of an EBV related lymphoproliferative disorder secondary to alemtuzumab therapy for B-CLL. A 53 years old man diagnosed in January 1999 as having stage Rai II classical B-CLL, was admitted to our department in June 2007 as a consequence of disease progression. Analysis of IgVH mutational status was not performed. However, peripheral blood flow cytometry analysis revealed that tumor cells expressed ZAP-70, but were negative for CD38 expression. He was previously treated with two cycles of fludarabine 25 mg/m with no response. In March 2001, he received six doses of rituximab 375 mg/m obtaining a partial remission. In December 2005, because of disease progression associated with Coombs positive autoimmune hemolytic anemia (AHA) he was treated with rituximabþfludarabineþ cyclophosphamide (FCR) for six cycles obtaining a partial remission with resolution of the (AHA). From June 2007 to July 2007, he received 12 doses of alemtuzumab 30 mg/m, obtaining the clearance of bone marrow neoplastic cells with persistence of lymph nodes involvement. CD4 and CD8 levels prior alemtuzumab therapy were 517/mL and 1380/mL, respectively. After 4 weeks of anti CD52 therapy, treatment was interrupted because of CMV reactivation which was successfully treated with ganciclovir. In October 2007, the patient presented with fever AHA recrudescence and hepatomegaly. Laboratory analysis showed high LDH level (1299 UI/L), hypoalbuminemia (2.5 g/dL), elevated liver enzyme (ALT: 92 UI/L; AST: 87 UI/L) and anemia (Hb 8.4 g/dL). Lymphocyte count on peripheral blood was less than 40/mL. A CT scan revealed the presence of multiple enlarged lymph nodes at both sides of the diaphragm and liver enlargement. An abdominal ecography revealed multiple hypoechogenic liver lesions which were biopsied and showed large B cells CD20þ. In situ hybridisation for EBV-RNA was strongly positive and serum EBV DNA viral load showed more than 6500 copies/mL. Bone marrow evaluation didn’t show any infiltration by neoplastic cells. The diagnosis of stage IV CD20þ