The c.480C>G polymorphism of hOCT1 influences imatinib clearance in patients affected by chronic myeloid leukemia.

The aim of the study was to investigate any possible influence of polymorphisms of transmembrane transporters human organic cation transporter 1 (hOCT1), ABCB1, ABCG2 on imatinib pharmacokinetics in 33 men and 27 women (median age and range, 56 and 27-79 years, respectively) affected by chronic myeloid leukemia. A population pharmacokinetic analysis was performed to investigate imatinib disposition in every patient and the role of transporter polymorphisms. Results showed that the α1-acid glycoprotein and the c.480C>G genotype of hOCT1 had a significant effect on apparent drug clearance (CL/F) being responsible, respectively, for a 20% and 10% decrease in interindividual variability (IIV) of CL/F (from 50.1 up to 19.6%). Interestingly, 25 patients carrying at least one polymorphic c.480 G allele had a significant lower CL/F value with respect to the 35 c.480CC individuals (mean±s.d., 9.6±1.6 vs 12.1±2.3 l h(-1), respectively; P<0.001). In conclusion, the hOCT1 c.480C>G SNP may significantly influence imatinib pharmacokinetics, supporting further analyses in larger groups of patients.

Significant efficacy of 2-chlorodeoxyadenosine{+/-} rituximab in the treatment of splenic marginal zone lymphoma (SMZL): extended follow-up.

BACKGROUND: Splenic marginal zone lymphoma with or without villous lymphocytes (SLVL/SMZL) is an indolent lymphoma that typically affects elderly patients and that has a median survival >10 years. It presents with marked splenomegaly. Treatment is required in symptomatic cases. Splenectomy remains one of the first-line options in patients fit for surgery. The best pharmacological strategy has not yet been identified for poor surgical risk cases. Among different possible chemotherapeutic approaches, purine analogs, alone or in association with Rituximab, seem to be a valid therapeutic choice. PATIENTS AND METHODS: Fifty SMZL patients were treated with Cladribine ± anti-CD20 monoclonal antibody. RESULTS: Forty-seven of 50 patients were evaluable for response. ORR was 87%: 24 of 47 patients (51%) achieved a complete hematological response (CR), 17 of 47 (36%) a partial response (PR) and 6 (13%) resulted unresponsive. Interestingly, 15 of 24 cases (62%) in CR achieved also a molecular remission. After a median follow-up of 48 months, 7 of 41 responsive cases relapsed and the 5-year PFS was 80%. CONCLUSIONS: These data confirm the efficacy of this schedule emphasizing the impact of minimal residual disease even in the outcome of SMZL patients.

Significant efficacy of 2-CdA with or without rituximab in the treatment of splenic marginal zone lymphoma (SMZL).

BACKGROUND: Splenic marginal zone lymphoma (SMZL) with or without villous lymphocytes is an indolent lymphoma that typically affects elderly patients. Treatment is required in symptomatic cases. Splenectomy remains one of the first-line options in patients fit for surgery. The best therapeutic strategy has not yet been identified. Among different possible chemotherapeutic approaches, purine analogues, alone or in association with rituximab, seem to be a valid therapeutic choice. PATIENTS AND METHODS: Fifty SMZL patients were treated with cladribine with or without anti-CD20 mAb. RESULTS: Forty-six of 50 patients were assessable for response. Overall response rate was 87%: 24 of 46 patients (52%) achieved a complete hematological response (CR), 16 of 46 (35%) a partial response and 6 (13%) were unresponsive. Interestingly, 15 of 24 cases (62%) in CR also achieved a molecular remission. CONCLUSIONS: The present results indicate that this schedule is a valid therapeutic approach in SMZL. Addition of rituximab significantly improved quality of response and consequently the outcome of the disease.

Cell clonality in hypereosinophilic syndrome: what pathogenetic role?

OBJECTIVE: Idiopathic hypereosinophilic syndrome (HES) is a heterogeneous disorder, including either a myeloproliferative or a lymphoproliferative variant (l-HES). In l-HES, T-lymphocytes could be involved in the pathogenesis through several cytokines, including IL5. METHODS: We assayed both TCR Beta- and delta-rearrangements by fluorescent PCR, characterizing 14 patients affected by HES. Lyn activation (a src-kinase involved in the IL5 pathway) was also tested in 6 cases. RESULTS: FIP1L1-PDGFRa was detected in 4 cases (28.6%); a clonal TCR was found in 10 cases (71.4%), including cases FIP1L1-PDGFRalpha-positive; four cases did not show any molecular marker. In this series, levels of IL5, IL4, IL2 and gammaIFN were measured, without any significant difference among different subgroups. All pathological samples tested did not show Lyn activation. Immunophenotype was also characterized: only one case showed an atypical CD3-/CD4+ population in the bone marrow. CONCLUSION: This study would suggest that a real distinction between m- and l-HES is not wholly convincing and that clonal T-cell expansion could not be the "primum movens" but an epiphenomenon in HES.

High efficacy of Rituximab in indolent HCV-related lymphoproliferative disorders associated with systemic autoimmune diseases.

OBJECTIVE: The evidence of an increased frequency of B-non Hodgkin's lymphomas (NHL) in patients with HCV and systemic autoimmune diseases suggests a close relationship between infection, autoimmunity and cancer. Choosing the best therapy for patients affected either by HCV-related lymphoma or autoimmune disorders is not easy; in fact, some treatments may be accompanied by an excessive hepatic toxicity and may be followed by a reactivation of hepatitis. There is growing interest in the search for an ideal therapy for this kind of patient. Thanks to its mechanism of action and good toxicity profile, Rituximab could prove to be an attractive therapeutic option: it has been reported to be highly active in low-grade NHLs and has been proposed for the management of autoimmune diseases. RESULTS: In this paper we evaluate the role of anti-CD20 monoclonal antibody in mono-therapy in 10 patients with either indolent HCV-related lymphoma or autoimmune disease. A very high rate of response, of both NHL and of the associated autoimmune disease, was observed (100% of clinical response), with no significant hepatic and extra-hepatic toxicity. CONCLUSION: Thus, although the number of patients was small, our data strongly support the use of anti-CD20 in this patient setting.

Quantitative molecular evaluation in autotransplant programs for follicular lymphoma: efficacy of in vivo purging by Rituximab.

The main aim of this paper was to compare results of Genescan and real-time PCR methods in order to detect contamination in harvests from patients with follicular lymphoma. The secondary goal was to evaluate the efficacy of Rituximab as an in vivo purging agent. A total of 23 patients had been treated with CHOP followed by either high-dose therapy (12 patients) or high-dose plus Rituximab (11 patients), both followed by autologous transplantation. Results show that 86% of harvests from patients treated with Rituximab were PCR-negative compared to 14.3% from controls. Real-time PCR was more sensitive than Genescan PCR; quantitative analysis revealed a correlation between the amount of contamination in the harvests and relapse after transplantation. Whereas all patients reinfused with negative aphereses achieved complete remission and showed a significantly better 5-year PFS (100%) compared to those reinfused with contaminated samples (41%), a very low amount of contamination does not appear to negatively affect outcome, suggesting that determination of a cutoff in the contamination level of harvests could be useful. Results suggest that real-time PCR is superior to Genescan PCR to select transplantable harvests and confirm the ability of Rituximab as an in vivo purging tool for follicular lymphoma.

Oral cyclophosphamide therapy for patients with residual or relapsed indolent-type lymphoma after initial treatment for aggressive lymphomas. A sub-group of patients with apparent transformed indolent lymphoma.

Lymph node or bone marrow biopsy from sixty-one patients affected by aggressive non-Hodgkin lymphomas (NHL) were retrospectively evaluated to assess the histology at relapse. Eighteen cases (29.5%) were proven to have relapsed or persistent low-grade lymphoma after conventional therapy. In 5/18 patients association of low and high-grade lymphoma was detectable at diagnosis by bone marrow biopsy. In the remaining 13/18 no evidence of follicular lymphoma was detected at diagnosis. The outcome of these patients was compared to that of 43 patients relapsed without change in histology and treated by a second line therapy. Of these 43 patients, 13 were not responders (NR), 10 achieved a partial remission (PR) and 18 complete remission (CR). Two were lost during follow-up. The 18 patients with residual/relapsed indolent subtype received oral cyclophosphamide (100 mg/day for 15 days every month for six months): 3 of them had NR, 5 CR, and 10 PR. The overall survival (OS) median time was 39 months in low-grade resistant/relapsed patients and 20 months in patients with aggressive histology. OS at 24 months was 71 and 41%, respectively, (p < 0.02). Most of the patients with high-grade disease were refractory or relapsed after a median of five months, whereas cases with low-grade NHL showed a long lasting stable PR. We suggest that the higher grade patients with residual or relapsed low grade lymphoma were, in fact, transformed low-grade at diagnosis and, after removing the more aggressive component by chemotherapy, it is possible to manage these patients by conventional therapy for indolent lymphomas.

Role of low-dose 2-CdA in refractory or resistant lymphoplasmocytic lymphoma.

Cladribrine (2-CdA), a purine analogue active on both dividing and resting lymphocytes, plays an important role in the treatment of indolent lymphoproliferative malignancies such as Hairy Cell Leukemia (HCL), Chronic Lymphocytic Leukemia (CLL), Lymphoplasmocytic Lymphoma (LPL), Waldenström's Macroglobulinemia (WM). With the aim of evaluating the efficacy and toxicity of low dose 2-CdA, 15 lymphoplasmocytic lymphoma patients, not eligible for more aggressive or standard therapies, because of age or poor performance status, were treated with the drug at a dose of 5 mg/m2, once a week for six total courses. All patients showed disease progression. Fourteen patients were valuable for response. In eleven out of these 14 (85.7%) disease progression stopped, with 21% having good hematological responses (one CR and two PR). The treatment was generally well tolerated, without serious infectious events. This schedule may be appropriate for the management of patients where the aim of the treatment is control of disease progression.

[Proposal for the treatment of cervix dysplasia with immunomodulators]. / Proposta di terapia con immunomodulanti nelle displasie cervicali.

The study included 60 patients: 43 suffered from slight portio dysplasia (12 had HPV infection also), while 17 had moderate dysplasia (7 had HPV infections also). The treatment was carried out by self-administration in 3 stages: attack (50 mg of thymopentin by s.c. injection every day for two weeks); maintenance (50 mg of thymopentin by s.c. injection every other day for ten weeks); recall 6 months after (50 mg of thymopentin every day for 4 weeks). The drug was well tolerated by all of the patients and the recovery rate in a 9-months follow-up period was significantly higher versus an historical control group.

A rare case of primary systemic amyloidosis of the neck with massive cervical lymph node involvement: a case report and review of the literature.

Amyloidosis is a term applied to a diverse group of disorders that share the deposition of amyloid protein in various extracellular tissues. Systemic amyloidosis may involve almost any organ system in the body including regions in the head and neck; however, neck lymph node involvement is rare, with only five previous cases reported. We present the case of a primary systemic AL amyloidosis with hepatic, cervical, retroperitoneal, axillary and inguinal lymphnode localizations, unresponsive to medical therapy and treated with a surgical approach followed by autologous bone marrow transplantation. We review the pertinent literature with exclusive attention to the otorhinolaryngologic aspect.

Is lithium able to reverse neurological damage induced by vinca alkaloids? (Short communication).

Lithium (Li) actively antagonises the inhibiting action of vinca alkaloids on human leukocyte chemotaxis; it proved to be related to the activation of microtubular system, possibly mediated by its inhibiting effect on cyclic AMP. Vinca alkaloids induce peripheral neuropathy and muscle damage. The molecular basis of this neurotoxicity has not been fully explained, but a possible role of neurofibrillary degeneration has been reported. We studied both in animals and in humans, whether Li is able to antagonise vinca alkaloid neurotoxicity.