Elena Trabacchi

Role of Anti-Hepatitis C Virus (HCV) Treatment in HCV-Related, Low-Grade, B-Cell, Non-Hodgkin's Lymphoma: A Multicenter Italian Experience

PURPOSE Hepatitis C virus (HCV) is endemic in some areas of Northwestern Europe and the United States. HCV has been shown to play a role in the development of both hepatocellular carcinoma and B-cell non-Hodgkins lymphoma (B-NHL). The biologic mechanisms underlying the lymphomagenic activity of the virus so far are under investigation. In this study, the role of antiviral (anti-HCV) treatment in B-NHL associated with HCV infection is evaluated. PATIENTS AND METHODS Thirteen patients with histologically proven low-grade B-NHL characterized by an indolent course (ie, doubling time no less than 1 year, no bulky disease) and carrying HCV infection were enrolled on the study. All patients underwent antiviral treatment alone with pegilated interferon and ribavirin. Response assessment took place at 6 and 12 months. RESULTS Of the twelve assessable patients, seven (58%) achieved complete response and two (16%) partial hematologic response at 14.1 +/- 9.7 months (range, 2 to 24 months, median follow-up, 14 months), while two had stable disease with only one patient experiencing progression of disease. Hematologic responses (complete and partial, 75%) were highly significantly associated to clearance or decrease in serum HCV viral load following treatment (P = .005). Virologic response was more likely to be seen in HCV genotype 2 (P = .035), while hematologic response did not correlate with the viral genotype. Treatment-related toxicity did not cause discontinuation of therapy in all but two patients, one of whom, however, achieved complete response. CONCLUSION This experience strongly provides a role for antiviral treatment in patients affected by HCV-related, low-grade, B-cell NHL.

Testing Sokal's and the new prognostic score for chronic myeloid leukaemia treated with α‐interferon

As it has been shown that α‐interferon (αIFN) treatment modifies the survival of chronic myeloid leukaemia (CML) patients in comparison with conventional chemotherapy, a new prognostic score was devised with the aim of providing a treatment‐adapted risk evaluation. We have tested the new prognostic score (the Euro score) in an independent series of 272 patients less than 56 years old with previously untreated, chronic phase, Philadelphia (Ph)‐positive CML who had been assigned prospectively to αIFN treatment between 1989 and 1991. The Sokal score system was used as a reference. The new Euro score predicted the response to αIFN as the Sokal score. The median survival of low‐risk, intermediate‐risk and high‐risk patients was similar using the Euro score (105, 65 and 45 months) and Sokal score (105, 76 and 45 months) but, by multivariate analysis, the Euro was more potent than Sokal for predicting survival time. The new Euro score identified more low‐risk cases (59% vs. 48%) and fewer high‐risk cases (9% vs. 23%) than the Sokal score. The main differences between the Euro and Sokal scores concerned age (it is more important in the Euro than in Sokal), spleen size and the percentage of myeloblasts in peripheral blood (more important in Sokal than in Euro). We conclude that the new Euro score marks an improvement in the prognostic evaluation of CML treated with αIFN. By comparison with the Sokal score, the Euro was more potent and identified more low‐risk patients but left only a small number of cases in the high‐risk group.

Long-term outcome of a phase 2 trial with nilotinib 400 mg twice daily in first-line treatment of chronic myeloid leukemia

Nilotinib is a second-generation tyrosine kinase inhibitor that has been approved for the first-line treatment of chronic-phase chronic myeloid leukemia, based on the results of a prospective randomized study of nilotinib versus imatinib (ENESTnd). Apart from this registration study, very few data are currently available on first-line nilotinib treatment. We report here the long-term, 6-year results of the first investigator-sponsored, GIMEMA multicenter phase 2, single-arm trial with nilotinib 400 mg twice daily as first-line treatment in 73 patients with chronic-phase chronic myeloid leukemia. Six-year overall survival and progression-free survival rates were 96%, with one death after progression to blast phase. At 6 years, 75% of the patients were still on nilotinib. The cumulative incidence of major molecular response was 98%; only one patient had a confirmed loss of major molecular response. The cumulative incidence of deep molecular response (MR 4.0) was 76%. Deep molecular response was stable (≥2 years) in 34% of these patients. Cardiovascular adverse events, mainly due to arterial thrombosis, occurred in 11/73 patients (15%), after 24 to 76 months of therapy. They were more frequent in elderly patients, and in those with baseline cardiovascular risk factors. None was fatal, although there was a relevant morbidity. This is the study with the longest follow-up of a high dose of nilotinib (400 mg twice daily): it highlights the high efficacy and the cardiovascular toxicity of the drug (CTG.NCT.00481052).

Development of hypogammaglobulinemia in patients treated with imatinib for chronic myeloid leukemia or gastrointestinal stromal tumor

These data demonstrate that imatinib treatment induces hypogammaglobulinemia which can be severe in 10% of cases, both in patients with chronic myeloid leukemia and in those with gastrointestinal stromal tumor. Imatinib mesylate is a tyrosine kinase inhibitor used as first line treatment in chronic myeloid leukemia and gastrointestinal stromal tumorpatients. Although several in vitro and animal studies demonstrated that imatinib affects immune response, few immune alterations are described in humans. We retrospectively studied hematologic and immunological parameters in 72 chronic myeloid leukemia and 15 gastrointestinal stromal tumor patients treated with imatinib at standard dosage and in 20 chronic myeloid leukemia patients treated before the introduction of imatinib in clinical practice. Both chronic myeloid leukemia and gastrointestinal stromal tumor patients developed a significant reduction of gammaglobulin and immunoglobulin serum levels. No significant hypogammaglobulinemia was observed in chronic myeloid leukemia patients in the pre-imatinib era. These data demonstrate that imatinib treatment induces hypogammaglobulinemia that can reach a severe entity in 10% of cases, both in chronic myeloid leukemia and in gastrointestinal stromal tumor patients. Prospective studies are needed to evaluate immune humoral alterations and to define the real incidence of infectious events, including viral reactivations.

Nilotinib 300 mg twice daily: an academic single-arm study of newly diagnosed chronic phase chronic myeloid leukemia patients.

The introduction and the extended clinical use of nilotinib in the first-line treatment of chronic myeloid leukemia have been based on company-sponsored trials. Independent confirmations are extremely important. We report an investigator-sponsored study of nilotinib 300 mg twice daily in 130 chronic myeloid leukemia patients in early chronic phase. A deep molecular response was achieved in 46% (MR4.0) and 17% (MR4.5) of patients at 2 years; 58% of the enrolled patients achieved a MR4.0 at least once, with a sustained MR4.0 in 52% of them. With a median observation of 29 months (range 24–37 months), 77% of patients were still on treatment with nilotinib. The reasons for permanent discontinuation were: 3% progression, 5% failure or suboptimal response, 8% adverse events, 1% treatment-free remission, and 5% other reasons. Thirteen thrombotic arterial events were reported in 12 patients. A prospective evaluation of metabolic effects showed an increase of fasting glucose without significant variations of glycated hemoglobin, an increase of total cholesterol (both low density lipoprotein and high density lipoprotein fractions) and a decrease of triglycerides. This study confirms a high and rapid efficacy of nilotinib 300 mg twice daily and provides detailed information on the type and incidence of non-hematologic and metabolic adverse events (clinicaltrials.gov identifier: 01535391).

A phase II study of α -interferon and oral arabinosyl cytosine (YNK01) in chronic myeloid leukemia

YNK01 (Starasid) is a prodrug that is adsorbed in the gut and is transformed in the liver in arabinosyl cytosine (AC). Low-dose AC (LDAC) is useful for the treatment of Philadelphia positive (Ph+) chronic myeloid leukemia (CML), especially in combination with α-interferon (αIFN). The use of YNK01 can avoid the daily s.c. injection of conventional AC. To assess the safety and the efficacy of αIFN and YNK01, we enrolled 86 consecutive previously untreated chronic phase Ph+ CML patients in a phase II study of αIFN (Intron-A) 5 MIU/m2 daily and YNK01 600 mg daily 14 days a month. The 6-month complete hematologic response and the 12-month major cytogenetic response rates were 78 and 28%, respectively. In a prior study of αIFN and conventional LDAC, they were 62 and 22%, respectively. However, the compliance to the treatment was poor, with 25% of cases discontinuing the treatment within the first year. This was not because of the severity of the side effects but because of the frequency, duration and repetition of the side effects, for an overall frequency of 13.17 adverse events, mostly grade 1 and 2, per patient per year. Therefore, the study of this effective combination is being pursued, testing lower doses of αIFN and YNK01.

Translisin recognition site sequences flank translocation breakpoints in a Philadelphia chromosome positive chronic myeloid leukemia patient expressing a novel type of chimeric BCR-ABL transcript (E8-INT-A2)

Translisin recognition site sequences flank translocation breakpoints in a Philadelphia chromosome positive chronic myeloid leukemia patient expressing a novel type of chimeric BCR-ABL transcript (E8-INT-A2)

Safety and efficacy of granulocyte colony-stimulating factor biosimilars in engraftment after autologous stem cell transplantation for haematological malignancies: a 4-year, single institute experience with different conditioning regimens.

BACKGROUND Filgrastim biosimilars have recently been introduced into clinical practice. To date biosimilars have demonstrated comparable efficacy and safety as the originator in chemotherapy-induced neutropenia. Published experience in engraftment after autologous stem cell transplantation (ASCT) is limited and concerns relatively few patients. MATERIALS AND METHODS With the aim of assessing the efficacy and the safety of filgrastim biosimilars in post-ASCT bone marrow recovery, we conducted a single institution, retrospective study in 56 lymphoma and myeloma patients who received filgrastim biosimilars (Tevagrastim(®) and Zarzio(®)) at standard doses from day 5. We compared our results with recently published data on the originator. A cost analysis of each biosimilar was performed. RESULTS Neutrophil counts recovered in 55 patients. The median number of filgrastim biosimilar vials injected was seven per patient. The median time to neutrophil and platelet recovery was 10 and 12 days, respectively. Twenty-six patients had febrile neutropenia, in half of whom the agent involved was identified. In the cost analysis, the use of Tevagrastim(®) and Zarzio(®) was associated with cost reductions of 56% and of 86%, respectively. DISCUSSION Despite differences in CD34+ cell counts and time of starting filgrastim, our results in terms of time to engraftment and median number of vials injected are similar to published data. Comparing our results by single conditioning regimen to recent literature data, the time to engraftment and duration of hospitalisation were equivalent. Significant differences were observed in the incidence of febrile neutropenia, perhaps due to different preventive and prophylactic protocols for infections. Although prospective studies should be performed to confirm our results, filgrastim biosimilars were found to be effective and safe in engraftment after ASCT.

A population‐based study of chronic myeloid leukemia patients treated with imatinib in first line

Chronic myeloid leukemia (CML) treatment is based on company‐sponsored and academic trials testing different tyrosine kinase inhibitors (TKIs) as first‐line therapy. These studies included patients selected according to many inclusion–exclusion criteria, particularly age and comorbidities, with specific treatment obligations. In daily clinical practice (real‐life), inclusion–exclusion criteria do not exist, and the treatment outcome does not only depend on the choice of first‐line TKI but also on second‐ and third‐line TKIs. To investigate in a real‐life setting the response and the outcome on first‐line imatinib, with switch to second generation TKIs in case of unsatisfying response or intolerance, we analyzed all newly diagnosed patients (N = 236), living in two Italian regions, registered in a prospective study according to population‐based criteria and treated front‐line with imatinib. A switch from imatinib to second‐generation TKIs was reported in 14% of patients for side effects and in 24% for failure or suboptimal response, with an improvement of molecular response in 57% of them. The 5‐year overall survival (OS) and leukemia‐related survival (LRS) were 85% and 93%, respectively; the 4‐year rates of MR3.0 and MR4.0 were 75% and 48%, respectively. Cardiovascular complications were reported in 4% of patients treated with imatinib alone and in 6% of patients receiving nilotinib as second‐line. Older age (≥70 years) affected OS, but not LRS. These data provide an unbiased reference on the CML management and on the results of TKI treatment in real‐life, according to ELN recommendations, using imatinib as first‐line treatment and second‐generation TKIs as second‐line therapy. Am. J. Hematol. 92:82–87, 2017.

Long term outcome of Ph+ CML patients achieving complete cytogenetic remission with interferon based therapy moving from interferon to imatinib era

Interferon α (IFNα) prolongs survival of CML patients achieving CCyR and potentially synergizes with TKIs. We report on the molecular status and long term outcome of 121 patients who were treated in Italy between 1986 and 2000 with IFNα based therapy and who obtained CCyR. After a median follow up of 16.5 years, 74 (61%) patients were switched to standard imatinib: 48 (65%) lost the CCyR on IFNα, and 36 (75%) are alive and in CCyR; 26 (35%) were switched to imatinib when they were still in CCyR on IFNα, and all 26 are alive and in CCyR. Forty‐seven patients (39%) were never switched to imatinib: 24 (51%) continued and 23 (49%) discontinued IFNα, respectively, and 39/47 (83%) are alive and in CCyR. At last follow‐up, the BCR‐ABL transcripts level was available in 96/101 living patients (95%) The BCR‐ABL:ABL ratio was between 0.1 and 0.01% (MR3.0) in 17%, and less than 0.01% (MR4.0) in 81% of patients. No patient was completely molecular negative (MR4.5 or MR5.0). The OS at 10 and 20 years is 92 and 84%, respectively. This study confirms that CCyR achieved with IFNα and maintained with or without imatinib or any other therapy significantly correlates with long term survival in CML patients who mostly have MR4.0. Complete molecular response (MR4.5 or MR5.0) seems to be unnecessary for such a long survival. This study further supports development of studies testing the clinical effect of the combinations of TKIs with IFNα. Am. J. Hematol. 89:119–124, 2014.