Federica Gigli

Final Results of a Prospective Evaluation of the Predictive Value of Interim Positron Emission Tomography in Patients With Diffuse Large B-Cell Lymphoma Treated With R-CHOP-14 (SAKK 38/07)

PURPOSE Our main objective was to prospectively determine the prognostic value of [(18)F]fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) after two cycles of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone given every 14 days (R-CHOP-14) under standardized treatment and PET evaluation criteria. PATIENTS AND METHODS Patients with any stage of diffuse large B-cell lymphoma were treated with six cycles of R-CHOP-14 followed by two cycles of rituximab. PET/CT examinations were performed at baseline, after two cycles (and after four cycles if the patient was PET-positive after two cycles), and at the end of treatment. PET/CT examinations were evaluated locally and by central review. The primary end point was event-free survival at 2 years (2-year EFS). RESULTS Median age of the 138 evaluable patients was 58.5 years with a WHO performance status of 0, 1, or 2 in 56%, 36%, or 8% of the patients, respectively. By local assessment, 83 PET/CT scans (60%) were reported as positive and 55 (40%) as negative after two cycles of R-CHOP-14. Two-year EFS was significantly shorter for PET-positive compared with PET-negative patients (48% v 74%; P = .004). Overall survival at 2 years was not significantly different, with 88% for PET-positive versus 91% for PET-negative patients (P = .46). By using central review and the Deauville criteria, 2-year EFS was 41% versus 76% (P < .001) for patients who had interim PET/CT scans after two cycles of R-CHOP-14 and 24% versus 72% (P < .001) for patients who had PET/CT scans at the end of treatment. CONCLUSION Our results confirmed that an interim PET/CT scan has limited prognostic value in patients with diffuse large B-cell lymphoma homogeneously treated with six cycles of R-CHOP-14 in a large prospective trial. At this point, interim PET/CT scanning is not ready for clinical use to guide treatment decisions in individual patients.

Multicenter Experience Using Total Lymphoid Irradiation and Antithymocyte Globulin as Conditioning for Allografting in Hematological Malignancies

A non myeloablative conditioning with total lymphoid irradiation (TLI) and antithymocyte globulin (ATG) was shown to protect against graft-versus-host disease (GVHD). To evaluate the effects of TLI-ATG in a multicenter study, 45 heavily pretreated patients, median age 51, with lymphoid (n = 38) and myeloid (n = 7) malignancies were enrolled at 9 centers. Twenty-eight patients (62%) received at least 3 lines of treatment before allografting, and 13 (29%) had refractory/relapsed disease at the time of transplantation. Peripheral blood hematopoietic cells were from HLA identical sibling (n = 30), HLA-matched (n = 9), or 1 antigen HLA-mismatched (n = 6) unrelated donors. A cumulative TLI dose of 8 Gy was administered from day -11 through -1 with ATG at the dose of 1.5 mg/kg/day (from day -11 through -7). GVHD prophylaxis consisted of cyclosporine and mycophenolate mofetil. Donor engraftment was reached in 95% of patients. Grade II to IV acute GVHD (aGVHD) developed in 6 patients (13.3%), and in 2 of these patients, it developed beyond day 100. Incidence of chronic GVHD (cGVHD) was 35.8%. One-year nonrelapse mortality was 9.1%. After a median follow-up of 28 months (range, 3-57 months) from transplantation, median overall survival was not reached, whereas median event-free survival was 20 months. This multicenter experience confirms that TLI-ATG protects against GVHD and maintains graft-vs-tumor effects.

Early stage gastric diffuse large B-cell lymphomas: results of a randomised trial comparing chemotherapy alone versus chemotherapy + involved field radiotherapy

Here, we present the results of a randomised clinical trial carried out between 1998 and 2004, evaluating the possible role of radiotherapy (RT) as consolidation treatment after induction chemotherapy (CT) in diffuse large B-cell (DLBC) gastric lymphoma. Fifty-four patients were enrolled and all received anthracycline containing regimens as induction CT. Patients were evaluated after four to six cycles and those in complete remission (CR) were randomised to receive gastric involved field (IF) RT or two addition cycles of the same CT. Forty-five patients (83%) were randomised after the induction CT. Clinical results of patients allocated to the RT arm showed a significant reduction in incidence of local relapse versus patients who received CT alone. However, overall survival was not different between the two arms. Our results confirm that CT could be considered as first line therapy for newly diagnosed gastric DLBC lymphoma; IF RT delivered in those patients achieving CR after induction CT is able to prevent local relapse.

Rituximab and subcutaneous cladribine in chronic lymphocytic leukemia for newly diagnosed and relapsed patients.

The aim of this study was to investigate the efficacy of combined treatment with rituximab and subcutaneous cladribine in patients with newly diagnosed and relapsed chronic lymphocytic leukemia (CLL). Forty-three patients with active CLL or small lymphocytic lymphoma received rituximab 375 mg/m2 on day 1 and cladribine 0.1 mg/kg subcutaneously on days 2–6. The treatment was repeated every 4 weeks for a total of four cycles. Sixteen patients were pretreated. The overall response rate was 88% (50% complete remission and 38% partial remission). The median time to treatment failure was 37.9 months. Grade 4 neutropenia developed in 5% of patients. The data indicate that combination therapy with rituximab and cladribine is a valuable and safe treatment for patients with CLL.

Extramedullary Myeloid Sarcoma of the Breast

review. J R Soc Med 80:505-509, 1987 11. Shane E: Clinical review 122: Parathyroid carcinoma. J Clin Endocrinol Metab 86:485-493, 2001 12. Obara T, Fujimoto Y: Diagnosis and treatment of patients with parathyroid carcinoma: An update and review. World J Surg 15:738-744, 1991 13. Eurelings M, Frijns CJ, Jeurissen FJ: Painful ophthalmoplegia from metastatic nonproducing parathyroid carcinoma: Case study and review of the literature. Neuro Oncol 4:44-48, 2002 14. Kebebew E: Parathyroid carcinoma. Curr Treat Options Oncol 2:347-354, 2001 15. Vogl T, Eichler K, Zangos S, et al.: Preliminary experience with transarterial chemoembolization (TACE) in liver metastases of uveal malignant melanoma: Local tumor control and survival. J Cancer Res Clin Oncol 133:177-184, 2007 16. Burger I, Hong K, Schulick R, et al.: Transcatheter arterial chemoembolization in unresectable cholangiocarcinoma: Initial experience in a single institution. J Vasc Interv Radiol 16:353-361, 2005 17. Giroux MF, Baum RA, Soulen MC: Chemoembolization of liver metastasis from breast carcinoma. J Vasc Interv Radiol 15:289-291, 2004 18. Ruszniewski P, O’Toole D: Ablative therapies for liver metastases of gastroenteropancreatic endocrine tumors. Neuroendocrinology 80:74-78, 2004 (suppl)

Filgrastim XM02 (Tevagrastim®) after autologous stem cell transplantation compared to lenograstim: favourable cost-efficacy analysis

Purpose Granulocyte colony-stimulating factors (G-CSFs), filgrastim and lenograstim, are recognised to be useful in accelerating engraftment after autologous stem cell transplantation. Several forms of biosimilar non-glycosylated G-CSF have been approved by the European Medicines Agency, with limited published data supporting the clinical equivalence in peripheral blood stem cell mobilisation and recovery after autologous stem cell transplantation. Method With the aim of comparing cost-effective strategies in the use of G-CSF after autologous stem cell transplantation, we retrospectively evaluated 32 patients consecutively treated with biosimilar filgrastim XM02 (Tevagrastim) and 26 with lenograstim. All patients received G-CSF (biosimilar or lenograstim) at a dosage of 5 mcg/kg/day subcutaneously from day 5 to absolute neutrophil count of 1500/mmc for three days. Results The median time to absolute neutrophil count engraftment was 11 days for the filgrastim XM02 group and 12 days for the lenograstim group. As for platelets recovery, the median time was 12 days in both groups. The median number of G-CSF vials used for patients was 9.5 for Tevagrastim and 10.5 for lenograstim, reflecting a mean estimated cost of about 556.1 euros for Tevagrastim versus 932.2 euros for lenograstim (p< 0.001). The median days of febrile neutropenia were 1.5 and 1 for filgrastim XM02 and lenograstim, respectively. No adverse event related to the use of XM02 filgrastim was recorded. Conclusion In our experience, filgrastim XM02 and lenograstim showed comparable efficacy in shortening the period of neutropenia after cytoreduction and autologous stem cell transplantation, with a favourable cost effect for filgrastim XM02.

Core needle biopsy as a front line diagnostic approach for lymphoma patients

The modern concept of personalized medicine acknowledges the ancient teaching ‘first do no harm’ by delivering the minimum efficacious rather than the maximum tolerable treatment. Along this line, a diagnostic procedure should be well-tolerated and associated with very low morbidity, besides sensitive, accurate, reproducible and cost-effective. As a consequence, core needle biopsy (CNB) is increasingly used for the diagnosis as well as the evaluation of predictive and prognostic characteristics of primary and metastatic solid tumours. Diagnosing lymphomas is a challenging task accomplished only by carefully integrating clinical, morphological, phenotypical and molecular data [1]. None of these tools may be considered the ‘magic bullet’, but the traditional histopathological evaluation still maintains its pivotal role in the diagnostic algorithm, contributing to the narrow spectrum of the most likely diseases, and therefore appropriately driving the subsequent phenotypical and molecular analyses. On the other hand, the introduction of commercial fluorescent in situ hybridization kits for detecting the hallmark translocations of the commonest types of lymphomas has further improved the efficacy of the ‘molecular’ diagnostic armoury, already including a continuously broadening panel of antibodies for immunophenotyping and polymerase chain reaction for clonality detection. In this rapidly evolving scenario, the diagnostic guidelines for lymphomas still establish that a surgically excised lymph node should always be available for ensuring the histopathological evaluation of lymph node architecture, tumour growth pattern and cell composition, and providing enough tissue for molecular analyses and research purposes [1]. Although theoretically faultless and certainly reassuring for pathologists and researchers, a surgical procedure devoted merely to diagnostic purposes has a number of practical and psychological downsides for patients and their physicians, because it requires hospitalization and potentially harmful interventions under local or general anaesthesia. CNB is associated with fewer complications and lower costs than excision biopsy, especially when deeply seated lymph nodes are involved, and is already used in lymphomas arising in extranodal sites, either because there are no alternative options, as in the case of bone or central nervous system lymphomas, or because surgery itself has been demonstrated to jeopardize patients’ prognosis, as in the case of gastric marginal zone lymphomas.

Successful mobilisation of peripheral blood stem cells in children using plerixafor: a case report and review of the literature.

High-dose chemotherapy followed by autologous peripheral blood stem cell (PBSC) support is a salvage therapy for patients with relapsed or refractory malignant disease. Previous chemotherapy treatments, such as alkylating agents, purine analogues and radiotherapy, are known to affect subsequent mobilisation of PBSC1. On the basis of a history of a previously failed mobilisation attempt or the presence of one or more factors predicting an unsuccessful harvest (advanced disease, prior extensive radiotherapy, prolonged treatment with stem cell poisons, advanced age, or extensive bone marrow involvement) these patients have been identified as “predicted poor mobilisers”2. In fact, in about 10 to 30% of patients it is not possible to collect an adequate number of PBSC to support haematopoietic stem-cell transplantation when growth factor alone or in combination with chemotherapy is used for the mobilisation3. Plerixafor is a new agent that inhibits stromal cell-derived factor-1a/CXCR4 binding, resulting in rapid mobilisation of CD34+ cells into peripheral blood and is well recognised as a solution to save adults in whom conventional mobilisation regimens have failed4,5. In this context, in combination with growth factor, plerixafor leads to successful mobilisation in 70% of adult patients with non-Hodgkin’s lymphoma, Hodgkin’s lymphoma and multiple myeloma6. Give the low rate of poor mobilisation in children, few experiences have been reported regarding the use of plerixafor in this context7–11. Since Plerixafor is not yet authorised as a standard mobilising regimen in paediatric patients its administration should be considered as off-label therapy, thus requiring parental informed consent. A European Bone Marrow Transplantation (EBMT) study is currently investigating the off-label use of plerixafor (“Non-interventional study on the off-label transplant use of plerixafor”). Here we describe our experience using plerixafor on demand to mobilise PBSC in a young patient with Hodgkin’s lymphoma.

Secondary haematological malignancies after radioimmunotherapy

Dear Editor, Concerning the letter to the editor by Piccin et al. [1], we would like to report the experience of the Haematoncology Division of European Institute of Oncology. We recently observed two patients treated with radioimmunotherapy (RIT; 90Y-DOTATOC/Lu177-DOTATOC) because of the presence of neuroendrocrine tumours. The first patient was a male of 75 years old; he had a bowel neuroendocrine tumour with secondary liver localizations. He developed an AML with trilineage dysplasia at 2 years following RIT, with this karyotype: 59,XYY,+4,+6, +10,+11,+11,+15,+16, -9,+20,+5mar[3]/46,XY[47]. The blood count at diagnosis was WBC 2,270/mmc, platelets 44,000/mmc and Hb 8.6 g/dl. The second patient was a male, 41 years old. He had a prostatic neuroendocrine tumour with secondary lymph nodes, bone and lung localizations. He developed a secondary AML at 4 years following RIT, with this karyotype: 43∼50,XY,+1[8],del(1)(q21)[6],del(5)(q22q33) [14],+del(5)(q22q33)[9],-7[13],+8[12],+9[13],+11[12],del (12)(p12)[9],-14[14],-16[2],-17[12],-18[6],-18[3],+21[7], +22[12][cp15]/46,XY[5]. The blood count at diagnosis was WBC 18,560/mmc, blasts 76%, platelets 141,000/mmc, Hb 8.5 g/dl. The first patient received from 2005 to 2006 a cumulative dose of Y90 DOTATOC 200 mCi, then received LU 177 DOTATOC from 2006 to 2009 (with a cumulative dose of more than 300 mCi). The second patient received Y90 DOTATOC from 2006 to 2007 with a cumulative dose of 200 mCi. Both patients receiving standard induction chemotherapy for acute leukaemia (ARA-C and daunorubicin) did not achieve any remission for leukaemia showing a resistant/ refractory disease; the first patient died after 113 days following diagnosis, the second one was lost to follow-up after 58 days following diagnosis. It is well known as RIT could induce renal toxicity but is not well established the possible incidence of secondary tumours, as well as haematological malignancies, as late complications of this treatment. The presence of these complications in our patients as well as the other one presented by Piccin et al. [1] raises the issue of how to investigate the real incidence of such late complications. We suggest data collection from all patients with neuroendocrine tumours treated with RIT in a specific registry to evaluate the real incidence of haematological malignancies and solid tumours that may affect clinical results achieved in such indolent disease, using radio-labelled compounds.

Efficacy of photopheresis extracorporeal procedure as single treatment for severe chronic GVHD: A case report

Allogeneic hematopoietic stem cell transplantation is the only potentially curative therapeutic option for many malignant and nonmalignant hematologic disorders. Despite this, several factors unfavorably affect the outcome of this procedure and in particular chronic graft-versus-host disease (cGVHD) remains the principal cause of morbidity after allogeneic transplantation. Here we present our experience regarding a patient affected by extensive chronic GVHD (cGVHD) treated only with extracorporeal photopheresis procedure (ECP) as first line treatment. The patient, presenting an high risk myelodysplastic syndrome (MDS), underwent an allogeneic peripheral stem cells transplantation. About 2 months after transplantation she experienced a hematological and clinical relapse of MDS. After reinduction therapy with azacitidine she obtained a second complete remission. Because of the risk of relapse related to a strong immunosuppressant therapy and the previous infectious complication, we decided to start a treatment with ECP alone for cGVHD. After six procedure the patient obtained a complete resolution of all signs and symptoms of the cGVHD. This experience may support the possibility to use only an immunomodulant treatment like ECP for the cGVHD, reducing the risk of complications of prolonged immunosuppressant treatment.