Piero Galieni

Nongastrointestinal Low-Grade Mucosa-Associated Lymphoid Tissue Lymphoma: Analysis of 75 Patients

PURPOSE Nongastrointestinal locations represent about 30% to 40% of all low-grade mucosa-associated lymphoid tissue (MALT) lymphomas. We report a retrospective analysis of 75 patients with nongastrointestinal low-grade MALT lymphoma, presenting their clinical, therapeutic, and follow-up data with respect to the initial location of the lymphoma. PATIENTS AND METHODS From January 1988 to October 1997, 75 patients with untreated nongastrointestinal low-grade MALT lymphoma were subjected to treatments ranging from local radiotherapy and local interferon alfa administration to chemotherapy. The lymphomas were located in the lung (19 patients), orbital soft tissue (16 patients), skin (seven patients), thyroid (seven patients), lachrymal gland (six patients), conjunctiva (six patients), salivary gland (six patients), breast (three patients), eyelid (two patients), larynx (one patient), bone marrow (one patient), and trachea (one patient). RESULTS Complete and partial remissions were achieved in 59 (79%) and 16 (21%) of the 75 patients, respectively, with an overall response rate of 100%. All but two of the patients are still alive, with a median follow-up of 47 months; these two patients died from other causes. The estimated time to treatment failure rate is 30% at 5 years. In the thyroid and lachrymal gland sites, no relapses were reported. CONCLUSION Our data regarding the largest reported series of nongastrointestinal MALT lymphomas confirm the good prognosis of this particular clinicopathologic entity and the significant efficacy of different therapeutic approaches to specific sites.

BeEAM (bendamustine, etoposide, cytarabine, melphalan) before autologous stem cell transplantation is safe and effective for resistant/relapsed lymphoma patients

We designed a phase 1-2 study to evaluate the safety and the efficacy of increasing doses of bendamustine (160 mg/m², 180 mg/m², and 200 mg/m² given on days -7 and -6) coupled with fixed doses of etoposide, cytarabine, and melphalan (BeEAM regimen) as the conditioning regimen to autologous stem cell transplantation for resistant/relapsed lymphoma patients. Forty-three patients (median age, 47 years) with non-Hodgkin (n = 28) or Hodgkin (n = 15) lymphoma were consecutively treated. Nine patients entered the phase 1 study; no patients experienced a dose-limiting toxicity. Thirty-four additional patients were then treated in the phase 2. A median number of 6 × 10⁶ CD34(+) cells/kg (range, 2.4-15.5) were reinfused. All patients engrafted, with a median time to absolute neutrophil count > 0.5 × 10⁹/L of 10 days. The 100-day transplantation-related mortality was 0%. After a median follow-up of 18 months, 35 of 43 patients (81%) are in complete remission, whereas 6 of 43 relapsed and 2 of 43 did not respond. Disease type (non-Hodgkin lymphomas vs Hodgkin disease) and disease status at transplantation (chemosensitive vs chemoresistant) significantly influenced DFS (P = .01; P = .007). Remarkably, 4 of 43 (9%) patients achieved the first complete remission after receiving the high-dose therapy with autologous stem cell transplantation. In conclusion, the new BeEAM regimen is safe and effective for heavily pretreated lymphoma patients. The study was registered at European Medicines Agency (EudraCT number 2008-002736-15).

Clinical and radiological presentation of 95 orbital lymphoid tumors.

Abstract• Background: Although most orbital lymphoid tumors are characterized by a slow, painless onset and a mass that molds to orbital structures, different presentations may occur. Intensity on T2-weighted MRI is a possible means for differentiating lymphoid tumors (hyperintense) from pseudotumors (hypointense). In addition, it is generally assumed that 75% of orbital lymphomas are at stage I on presentation.• Methods: The clinical, CT, and MRI presentation of 95 primary and secondary orbital lymphoid tumors (63 non-Hodgkin lymphomas and 32 lymphoid hyperplasias) and their histological grade and staging were reviewed. Immunohistochemistry and PCR were used to determine clonality.• Results: No significant differences were found between non-Hodgkin lymphomas and lymphoid hyperplasias, except for the mean age of the patients (6.3 years older in non-Hodgkin lymphomas). In both groups the most common presentation was a mass with an indolent course; visual impairment was seen in 13%, conjunctival redness in 25%, pain in 12%, and acute orbital inflammation in 15% of the patients. In most cases, the CT showed one or more lobulated or rounded masses, molding to adjacent structures, or a wedge-shaped enlargement of the lacrimal gland. Intramuscular lymphomas were rare and always associated with extramuscular masses. On T2-weighted MRI, only 35% of lymphoid tumors were hyperintense. Only 49% of lymphomas were at stage I on presentation.• Conclusion: An inflammatory presentation is not uncommon in orbital lymphoid tumors. Shape, molding and multiple masses can help radiological diagnosis, whereas MRI T2 intensity is unreliable. Accurate staging can disclose systemic disease in more than 50% of cases of non-Hodgkin lymphoma.

Results of high-dose imatinib mesylate in intermediate Sokal risk chronic myeloid leukemia patients in early chronic phase: a phase 2 trial of the GIMEMA CML Working Party

Imatinib mesylate has become the treatment of choice for chronic myeloid leukemia (CML): the standard dose for chronic- phase (CP) CML is 400 mg daily. Response rates are different according to Sokal score, being significantly lower in intermediate and high Sokal risk patients. Phase 1 and 2 trials have shown a dose-response effect and high-dose imatinib trials in early CP CML showed better results compared with standard dose. Our study is the first prospective trial planned to evaluate the efficacy and tolerability of high-dose imatinib in previously untreated intermediate Sokal risk CML patients. Seventy-eight patients were treated with 400 mg imatinib twice daily: complete cytogenetic response (CCgR) rates at 12 and 24 months were 88% and 91%; moreover, at 12 and 24 months 56% and 73% of CCgR patients achieved a major molecular response. The incidence of adverse events was slightly higher than reported by the most important standard-dose trials. With a median follow-up of 24 months, 3 patients progressed to advanced phase. In intermediate Sokal risk newly diagnosed CML patients, high-dose imatinib induced rapid and high response rates, apparently faster than those documented in the International Randomized Study of IFN and Imatinib for the same risk category. These clinical trials are registered at www.clinicaltrials.gov as no. NCT00510926.

Reduction of antithrombin III, protein C, and protein S levels and activated protein C resistance in polycythemia vera and essential thrombocythemia patients with thrombosis

Patients with polycythemia vera (PV) or essential thrombocythemia (ET) show a high frequency of thrombosis. The reduction of hematocrit after phlebotomy and normalization of platelet counts do not completely eliminate thrombotic risk. Some preliminary studies reported a reduction in the concentration of natural anticoagulants (NA) in this group of patients. For this reason we evaluated protein S (PS) total antigen, antithrombin III (AT III), and protein C (PC) activity in 81 patients with chronic myeloproliferative disorders (33 with PV and 48 with ET). Data were compared with those obtained in 70 healthy sex‐ and age‐matched subjects. Fifty‐seven percent of patients (46 out of 81) showed one or more thrombotic episodes at diagnosis or during follow‐up. Interestingly, we found a NA deficit in 43.5% of patients with thrombosis versus only 5.7% in the group of patients without thrombosis. These results may suggest new interpretations about the pathogenesis of thrombosis in PV or ET patients.

“Fludarabine Containing-Regimens May Adversely Affect Peripheral Blood Stem Cell Collection in Low-Grade Non Hodgkin Lymphoma Patients”

Fludarabine (FLUDA) based chemotherapy has shown promise in both initial and salvage treatment of low-grade non Hodgkins lymphomas (LG-NHL). Recently, more aggressive therapies followed by autologous hemopoietic progenitor cell rescue, have also been successfully employed in these patients. However, this procedure, due to several factors including previous therapeutic regimens, is often limited by an inadequate collection of peripheral blood stem cell (PBSC). At present, very little data is available on the effect of FLUDA containing regimens in PBSC collection. We report our preliminary experience showing a possible correlation between FLUDA based chemotherapy regimens employed before mobilization and inability to collect an adequate number of blood derived hematopoietic progenitors for autologous PBSC transplantation in LG-NHL patients.

Prognostic value of serum IL-10 and soluble IL-2 receptor levels in aggressive non-Hodgkin's lymphoma.

Summary We investigated the prognostic significance of interleukin‐10 (IL‐10) and soluble interleuckin‐2 receptor (sIl‐2r) levles in the pretreatment serum of 105 individuals with newly‐diagnosed aggressive non‐Hodgkins lymphoma (NHL). Commercially available enzyem‐linked immunoassay kits were used for cytokine and receptor measurements. Detectable levels of IL‐10 were found in 42 (40%) patients at diagnosis, with no correlation with clinico‐haematological parameters, but in no control samples (P < 0.001).

Clinical implications of cytokine and soluble receptor measurements in patients with newly-diagnosed aggressive non-Hodgkin's lymphoma

Abstract:  Serum levels of 13 different cytokines and receptors were measured serially in 78 patients with aggressive non‐Hodgkins lymphoma (NHL) treated by 4 cycles of an intensive multi‐agent chemotherapy regimen. Recombinant human granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) was administered subcutaneously in 36 of these patients from day + 5 to day + 18 after each chemotherapy. Statistically significantly higher pretreatment levels of interleukin‐2 (IL‐2), interleukin‐6 (IL‐6), interleukin‐8 (IL‐8), interleukin‐10 (IL‐10), the soluble IL‐2 receptor (sIL‐2r), the soluble transferrin receptor (sTf‐r), and neopterin, were observed in NHL patients as compared to controls (p< 0.001 for all molecules). sIL‐2r and sTf‐r levels correlated with tumor burden (p< 0.001 and p = 0.003, respectively) whereas IL‐6 was higher in patients presenting B symptoms (p< 0.001). Cytokine levels progressively declined to normal ranges in responding patients, while they remained elevated in non‐responders. Relapsed patients also presented increased concentrations of several molecules. During the administration of GM‐CSF, we observed the drastic increase of sIL‐2r, while lower elevations were recorded for a number of cytokines, including IL‐8, tumor necrosis factor‐α, interleukin‐1β, IL‐6, and IL‐2. However, upon completion of the induction treatment, cytokine/receptor levels were comparable among individuals with the same type of response, whether or not they had received GM‐CSF. No single parameter was found to be of prognostic significance, but the combination of elevated IL‐10 and of sIL‐2r greater than 3000 U/ml selected a subgroup of 7 patients who failed induction treatment (p = 0.002). These results demonstrate that cytokine and soluble receptor measurements can provide valuable informations for a better management of NHL, in terms both of markers to monitor disease activity and of prognostic indicators.

Detection of soluble interleukin-2 receptor and interleukin-10 in the serum of patients with aggressive non-Hodgkin's lymphoma.Identification of a subset at high risk of treatment failure

Background. This study explores the ability of the combined detection of soluble IL‐2 receptor (sIL‐2r) and interleukin‐10 (IL‐10) to predict treatment failure in patients with aggressive non‐Hodgkins lymphoma (NHL) and to evaluate the modifications in cytokine measurements induced by the therapeutic administration of recombinant human granulocyte‐macrophage colony‐stimulating factor (GM‐CSF).

Immunoglobulin gene rearrangement analysis in composite hodgkin disease and large B-cell lymphoma: evidence for receptor revision of immunoglobulin heavy chain variable region genes in Hodgkin-Reed-Sternberg cells?

Immunoglobulin heavy chain gene (IgH) rearrangement was studied in a patient showing the occurrence of classical Hodgkin disease and large B-cell lymphoma (LBCL) in the same lymph node. The VHDHJH region was amplified by polymerase chain reaction, the template being the DNA extracted from single Hodgkin and Reed-Sternberg and LBCL cells, microdissected on hematoxylin-eosin–stained sections by laser capture. A repeated VH4DH3JH4 segment was found in Reed-Sternberg cells, whereas a repeated VH3DH3JH4 segment was observed in LBCL cells. Rearranged VH genes carried somatic mutations in both populations, indicating a common germinal center cell origin. The IgH rearrangement found in clonally related Reed-Sternberg cells differed from the one of LBCL cells in the VH region but showed the same JH and DH segments with no variation from the respective germline sequence. The DH–JH junction is the first immunoglobulin gene segment rearranged in precursor B cells. Because the possibility of secondary Ig gene rearrangement in peripheral lymphoid organs has recently been reported, in the patient described here Reed-Sternberg and LBCL cells might originate from a common precursor in which secondary VH replacement took place during the germinal center reaction, giving rise to two different clonally related lymphomas.