Enrico Orciuolo

Unexpected cardiotoxicity in haematological bortezomib treated patients

Bortezomib is an antitumor compound that inhibits proteasome activity. It is able to impair the activation of nuclear factor (NF)-jB, blocking the degradation of inhibitory jB (IjB), which is required for NF-jB translocation into the nucleus and activation of target genes. NF-jB is important for cell survival, regulating the expression of genes involved in apoptosis, such as BCL2 and BCL2L1, cell cycle progression, inflammation and angiogenesis (Richardson et al, 2003). In 2006, we treated 69 patients with bortezomib, either alone or as combination therapy. Bortezomib therapy is known to be associated with neurological side effects and thrombocytopenia (Richardson et al, 2003); however, we noticed an unexpected increase of cardiac complications, ranging from heart failure to onset of arrhythmias. Only one single case of heart failure (Voortman & Giaccone, 2006) and one asymptomatic arrhythmia (Berenson et al, 2007) following bortezomib therapy have been reported to date. All except one of our bortezomib-treated patients were receiving at least a second line therapy, and some of them had previously received anthracycline-containing regimens. Eight (11Æ6%) of the 69 patients developed serious cardiac side effects requiring medication, hospitalisation or the implant of a pacemaker (see Table I). All patients underwent cardiovascular screening before receiving bortezomib and no clinically significant abnormalities were present. The only conditions that were identified as common to all the patients were bortezomib administration and age >60 years. All eight patients who experienced cardiotoxicity underwent at least four cycles of bortezomib, strengthening the hypothesis of a direct connection with the drug. Each cycle included bortezomib 1Æ3 mg/m on days 1, 4, 8 and 11 and the recycling period was 3 weeks. The onset of cardiac symptoms was never recorded before a cumulative dose of 20Æ8 mg/m of bortezomib. The ubiquitin-proteasome system is responsible for nonlysosomal degradation of intracellular proteins, including key regulators of cell cycle, angiogenesis and apoptosis, and transcription factors, which regulate crucial mechanisms of plaque formation and rupture. Additionally, the presence of a reduced proteasome activity is associated with an increased rate of apoptosis in smooth muscle cells, determining atherosclerotic plaque instability by weakening of the fibrous cap and enlargement of the necrotic core (Versari et al, 2006). Furthermore, NF-jB activation plays an essential role in the intracellular signal transduction of the second window of protection of delayed ischaemic preconditioning in the myocardium, leading to myocardial cytoprotection (Jancso et al, 2005). Therefore, bortezomib may simultaneously cause atherosclerotic plaque progression and tendency to rupture, and facilitate ischaemic heart complications by reducing/abrogating myocardial preconditioning. Additionally, although bortezomib was found to reduce the onset of delayed arrhythmias following coronary ligation in the canine model by upregulating

Radioimmunotherapy with Radretumab in Patients with Relapsed Hematologic Malignancies

We present here a systematic analysis of lymphoma and MM patients recruited into 2 clinical trials or treated with radretumab according to compassionate use, describing the biodistribution, dosimetry, safety, and clinical activity of radretumab. Methods: Uptake in lymphoma lesions, safety, and clinical activity of radretumab radioimmunotherapy (R-RIT) were evaluated in 18 relapsed lymphoma or multiple myeloma patients. Results: In 14 of 18 patients, selective tumor uptake was found; 11 of 15 lymphoma patients, including 9 of 11 with Hodgkin lymphoma (HL), were eligible for R-RIT (a priori criteria–based target-to-bone marrow ratio > 10:1 for EudraCT no. 2005-000545 or > 4:1 for EudraCT no. 2007-007241-12 at dosimetric imaging). Two HL and 1 diffuse large B cell lymphoma patient achieved complete response; 1 HL patient had partial response. Both multiple myeloma patients receiving R-RIT experienced stabilization of disease. Therefore, the overall objective response rate was 40%. Uncomplicated grade 3–4 thrombocytopenia or leukocytopenia was observed in 5 R-RIT patients, lasting 4–129 d. Conclusion: R-RIT showed a favorable benefit and risk profile in advanced relapsed lymphoma patients and induced complete response in 2 heavily pretreated, relapsed HL patients and in 1 diffuse large B cell lymphoma patient. These results warrant further exploration of R-RIT in larger phase II clinical trials.

Bendamustine with or without rituximab for the treatment of heavily pretreated non-Hodgkin's lymphoma patients : A multicenter retrospective study on behalf of the Italian Lymphoma Foundation (FIL).

Bendamustine is an alkylating agent with a nitrogen mustard group and a purine-like benzimidazole group. The aim of this study was to collect all the Italian experiences with this drug in order to evaluate the results in term of response to therapy and toxicities. We analyzed lymphoma patients treated in 24 Italian haematological centres with bendamustine alone or in combination with anti-CD20 antibody. One hundred seventy-five relapsed or refractory lymphoma patients were enrolled. The median age was 69 years (range 26–87). Seventy-nine patients were relapsed, 35 were refractory and 61 presented a progressive disease after partial response. The diagnoses were 60 indolent non-follicular lymphomas, 34 diffuse large B-cell lymphomas, 48 follicular lymphomas, 30 mantle cell lymphomas and three peripheral T-cell lymphomas. All patients were evaluable for response: 52 (29%) with complete remission, 72 (43%) with partial response with an overall response rate of 71%, and 51 non-responders. With a median observation period of 10 months (1–43), 70% of patients are alive. In summary, this retrospective study shows that treatment with bendamustine alone or in combination with rituximab is a safe and effective regimen in a subset of multi-resistant 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.

MDR1 diplotypes as prognostic markers in multiple myeloma

Objective The aim of this study was to evaluate the effect of diplotypes of MDR1 polymorphisms at positions 2677 and 3435 on the clinical outcome of multiple myeloma, in terms of response to the therapy and overall survival (OS). Methods G2677T/A SNP was analysed by RFLP-PCR assay on 110 patients, treated with dexamethasone, doxorubicin (adryamicin) and vincristine regimen, followed by autologous stem cell transplantation. Results Treatment efficacy was not related to G2677T/A SNP, whereas the OS of G/G carriers was significantly shorter than that of T/T or G/T patients. Similar results were previously reported for MDR1 C3435T polymorphism. Given that these two single nucleotide polymorphisms are in strong linkage disequilibrium, we analyzed the effects of the most frequent haplo/diplotypes and the survival probability was lower for GC/GC patients (55%) than for GC/TT and TT/TT carriers (>80%; log-rank test, P=0.03). Interestingly, the effect of MDR1 diplotype on the OS seems to be confined to autologous stem cell transplantation nonresponders. Conclusion These results support the hypothesis that genetic variability of MDR1 should be considered as an important factor that influences the clinical outcome of multiple myeloma.

2CdA chemotherapy and rituximab in the treatment of marginal zone lymphoma

Standard chemotherapic approach for MZL is missing. We are presenting our monocenter experience with 2CdA+/-rituximab. Patients received 2CdA, 5mg/m(2), weekly, for 6 weeks. Patients receiving rituximab underwent to antibody administration in association with 2CdA, or after the end of chemotherapy. Global ORR was 89.3%, with 53.6% CR, with 60 months of median of TTF. 2CdA and rituximab led to 96.5% ORR, with 60.3% CR, while 2CdA alone to 73.1% ORR, with 38.5% CR. TTF median was reached at 35 months with 2CdA alone; not reached yet in the combination arm. Considering subgroups of MZL, combination therapy has a more favorable outcome in SMZL and NMZL, while MALT does not differ. However, all subgroups present a delayed relapse. Considering minimal residual disease (MRD), adding of rituximab converted 65.0% to negativity versus 15.4% of 2CdA alone, with TTF in positive patients reached after 34 months; not reached yet in negatives. Concomitant use of rituximab with 2CdA allowed an ORR of 98.0%, with 68% CR and 56.3% of MRD conversion, while consequent use 100%, 54.6%, and 70.8%, respectively. TTF does not differ. 2CdA therapy is effective in the treatment of MZL. Adding rituximab allows increasing ORR and CR, prolonging TTF.

Genetics and molecular epidemiology of multiple myeloma: The rationale for the IMMEnSE consortium (Review)

There is strong evidence suggesting the presence of a genetic component in the aetiology of multiple myeloma (MM). However no genetic risk factors have been unequivocally established so far. To further our understanding of the genetic determinants of MM risk, a promising strategy is to collect a large set of patients in a consortium, as successfully done for other cancers. In this article, we review the main findings in the genetic susceptibility and pharmacogenetics of MM and present the strategy of the IMMEnSE (International Multiple Myeloma rESEarch) consortium in contributing to determine the role of genetic variation in pharmacogenetics and in MM risk.

Safety and efficacy of 90Yttrium‐Ibritumomab‐Tiuxetan for untreated follicular lymphoma patients. An Italian cooperative study

90Yttrium (90Y)‐Ibritumomab‐Tiuxetan combines the targeting advantage of a monoclonal antibody with the radiosensitivity of Follicular Lymphoma (FL). Previous studies showed that 90Y‐IT is safe and effective in relapsed/refractory indolent FL, irrespective of prior treatment with rituximab. This multicentre trial aimed to evaluate the safety and the efficacy of “upfront” single‐agent (90Y)‐Ibritumomab‐Tiuxetan in advanced‐stage FL. The primary objective was the incidence of responses in terms of complete (CR) and partial remission (PR). Fifty patients with stage II “bulky”, III or IV FL received a single treatment course with (90Y)‐Ibritumomab‐Tiuxetan as initial therapy. The median age was 60 years. Bone marrow involvement (<25%) was observed in 24 patients (48%) and 7 (14%) had an elevated lactate dehydrogenase level. The overall response (ORR) and CR rates were 94% and 86%, respectively with a median follow‐up of 38·8 months. The median progression‐free survival (PFS) was not reached, whereas the 3‐year estimated PFS and overall survival (OS) rate was 63·4% and 90%, respectively. Grade 3/4 neutropenia and thrombocytopenia occurred in 30% and 26% of patients respectively; none experienced grade 3/4 non‐haematological toxicity. No cases of secondary haematological malignancies were observed. (90Y)‐Ibritumomab‐Tiuxetan was demonstrated to be highly effective and safe as first‐line treatment for advanced‐stage FL.

Vascular Endothelial Growth Factor Polymorphisms in Mantle Cell Lymphoma

In this study, we determined the allele and genotype frequencies of vascular endothelial growth factor (VEGF) G+405C, C–460T, C+936T and C–2578A single nucleotide polymorphisms (SNPs) in 32 patients affected by mantle cell lymphoma (MCL) and 58 healthy controls. Real-time PCR combined with melting curve analysis was used for the determination of SNP alleles. A significant difference in the allele frequency of VEGFC–460T and C+936T SNPs in MCL and healthy cases was not observed. On the contrary, VEGF G+405C and C–2578A SNP allele distribution was significantly lower in the patient group than among normal controls (p = 0.014, p = 0.001). This observation suggests that further investigation is warranted, both in vitro and in a larger series of patients, to further examine the role of VEGF polymorphisms in the pathogenesis of MCL. In addition, the use of quantitative real-time PCR combined with a melting curve analysis method in the detection of the 4 VEGF SNPs may have the potential to replace older and more time-consuming PCR-RFLP methods and bears further investigation.

Impact of polymorphic variation at 7p15.3, 3p22.1 and 2p23.3 loci on risk of multiple myeloma

whole of the UK. Wales has been a pioneer in the process of haematology harmonization, as a result of the introduction of a national laboratory information management system for Wales, and is represented on the Pathology Harmony Haematology Sub-Group. Scotland is represented on the Pathology Harmony Committee and the Scottish representatives have supported the earlier changes in Clinical Chemistry. The process to date has not been as easy as might be envisaged; it has taken much effort to reach this stage of the project. The haematology sub-group is also working closely with the DH advisor for the National Laboratory Medicine Catalogue (NLMC) on the incorporation of the changes of nomenclature and units into the NLMC, the standard for pathology test requests and results reporting, under collaborative development by the RCPath, the Department of Health and NHS Connecting for Health. The future challenges will be to move on to other areas of standardization including the development of consensus reference intervals for FBC and expansion to other areas of haematology, e.g., Hb A2, haematinic assays, coagulation factor assays and leucocyte immunophenotyping. The issue of harmonized reference intervals for the extended FBC is not expected to be straightforward, given the variation seen with age, ethnic differences and physiological state, e.g., pregnancy. For harmonized reference intervals to be effective, they must be widely adopted and this will not happen without a pragmatic approach and majority agreement within haematology.