Andrea Nozza

Bortezomib-thalidomide-dexamethasone is superior to thalidomide-dexamethasone as consolidation therapy after autologous hematopoietic stem cell transplantation in patients with newly diagnosed multiple myeloma

In a randomized, phase 3 study, superior complete/near-complete response (CR/nCR) rates and extended progression-free survival were demonstrated with bortezomib-thalidomide-dexamethasone (VTD) versus thalidomide-dexamethasone (TD) as induction therapy before, and consolidation after, double autologous stem cell transplantation for newly diagnosed myeloma patients (intention-to-treat analysis; VTD, n = 236; TD, n = 238). This per-protocol analysis (VTD, n = 160; TD, n = 161) specifically assessed the efficacy and safety of consolidation with VTD or TD. Before starting consolidation, CR/nCR rates were not significantly different in the VTD (63.1%) and TD arms (54.7%). After consolidation, CR (60.6% vs 46.6%) and CR/nCR (73.1% vs 60.9%) rates were significantly higher for VTD-treated versus TD-treated patients. VTD consolidation significantly increased CR and CR/nCR rates, but TD did not (McNemar test). With a median follow-up of 30.4 months from start of consolidation, 3-year progression-free survival was significantly longer for the VTD group (60% vs 48% for TD). Grade 2 or 3 peripheral neuropathy (8.1% vs 2.4%) was more frequent with VTD (grade 3, 0.6%) versus TD consolidation. The superior efficacy of VTD versus TD as induction was retained despite readministration as consolidation therapy after double autologous transplantation. VTD consolidation therapy significantly contributed to improved clinical outcomes observed for patients randomly assigned to the VTD arm of the study. The study is registered at www.clinicaltrials.gov as #NCT01134484.

High-Dose Chemotherapy in Poor-Prognosis Adult Small Round-Cell Tumors: Clinical and Molecular Results From a Prospective Study

PURPOSE The prognosis of metastatic/high-risk localized small round-cell tumors (SRCTs) treated conventionally is dismal. In this phase II study, we explored a high-dose chemotherapy (HD-CT) approach and analyzed the clinical significance of fusion transcripts detection. PATIENTS AND METHODS From June 1997 to November 1999, 28 SRCT patients (median age, 26 years; 14 peripheral primitive neuroectodermal tumors [pPNETs], seven rhabdomyosarcomas [RMSs], and seven desmoplastic small round-cell tumors [DSRCTs]) received induction chemotherapy with ifosfamide, epirubicin, and vincristine followed by HD-CT. Local treatment (radiotherapy and/or surgery) was performed when possible. Molecular analysis was performed on peripheral-blood and leukapheresis products by reverse-transcriptase polymerase chain reaction. RESULTS Overall response (OR) was 65% (18 of 28), with 40% complete response and 25% partial response. According to histology, the OR rate was 86% in pPNET and 43% in both RMS DSRCT. With a median follow-up of 35 months, median overall survival was 16 months and median progression-free survival (PFS) was 10 months. PFS was statistically better in pPNET than other histologic types (P =.0045). No correlation was found between the fusion transcript and clinical outcome during follow-up. Furthermore, transcript detection in leukapheretic products was not of prognostic significance. CONCLUSION Intensive HD-CT seems to enhance the response rate and survival when compared with conventional treatment in poor-prognosis pPNET. The poor results of this treatment in RMS and DSRCT do not support the inclusion of such an approach in these patient subsets. No definitive conclusions can currently be drawn concerning the clinical implications of the detection of fusion transcripts during treatment or follow-up.

Allogeneic Stem Cell Transplantation in Multiple Myeloma Relapsed after Autograft: A Multicenter Retrospective Study Based on Donor Availability.

Allogeneic stem cell transplantation (allo-SCT) using reduced-intensity conditioning (RIC) is a feasible procedure in selected patients with relapsed multiple myeloma (MM), but its efficacy remains a matter of debate. The mortality and morbidity related to the procedure and the rather high relapse risk make the use of allo-SCT controversial. In addition, the availability of novel antimyeloma treatments, such as bortezomib and immunomodulatory agents, have made allo-SCT less appealing to clinicians. We investigated the role of RIC allo-SCT in patients with MM who relapsed after autologous stem cell transplantation and were then treated with a salvage therapy based on novel agents. This study was structured similarly to an intention-to-treat analysis and included only those patients who underwent HLA typing immediately after the relapse. Patients with a donor (donor group) and those without a suitable donor (no-donor group) were compared. A total of 169 consecutive patients were evaluated retrospectively in a multicenter study. Of these, 75 patients found a donor and 68 (91%) underwent RIC allo-SCT, including 24 from an HLA-identical sibling (35%) and 44 from an unrelated donor (65%). Seven patients with a donor did not undergo allo-SCT for progressive disease or concomitant severe comorbidities. The 2-year cumulative incidence of nonrelapse mortality was 22% in the donor group and 1% in the no-donor group (P < .0001). The 2-year progression-free survival (PFS) was 42% in the donor group and 18% in the no-donor group (P < .0001). The 2-year overall survival (OS) was 54% in the donor group and 53% in the no-donor group (P = .329). In multivariate analysis, lack of a donor was a significant unfavorable factor for PFS, but not for OS. Lack of chemosensitivity after salvage treatment and high-risk karyotype at diagnosis significantly shortened OS. In patients who underwent allo-SCT, the development of chronic graft-versus-host disease had a significant protective effect on OS. This study provides evidence for a significant PFS benefit of salvage treatment with novel drugs followed by RIC allo-SCT in patients with relapsed MM who have a suitable donor.

Melphalan 200 mg/m 2 versus melphalan 100 mg/m 2 in newly diagnosed myeloma patients: a prospective, multicenter phase 3 study

High-dose (200 mg/m(2), MEL200) and intermediate-dose melphalan (100 mg/m(2), MEL100) showed significant activity in myeloma. In a phase 3 study, 298 patients were randomly assigned to receive 2 autologous transplantations after conditioning with MEL200 or MEL100. Ninety-six of 149 (64%) completed MEL200 and 103 of 149 (69%) MEL100. Best response to MEL200 was: complete remission 22 of 149 (15%); partial remission 95 of 149 (64%), for an overall response rate of 79%. Best response to MEL100 was: complete remission 12 of 149 (8%); partial remission 95 of 149 (64%), for an overall response rate of 72%. Overall survival did not differ (P = .13); median progression-free survival (31.4 vs 26.2 months, P = .01), median time to progression (34.4 vs 27.0 months, P = .014) were longer in the MEL200. Treatment-related mortality was 3.1% in the MEL200 and 2.9% in the MEL100 group. Severe neutropenia and infections were marginally superior, whereas severe thrombocytopenia, mucositis, gastrointestinal adverse events, and the overall occurrence of at least 1 nonhematologic grade 3 or 4 adverse event were significantly higher in the MEL200 cohort. We conclude that MEL200 leads to longer remission duration and should be considered the standard conditioning regimen for autologous transplantation. This study was registered at www.clinicaltrials.gov as #NCT00950768.

Predictive value of early 18F‐fluorodeoxyglucose positron emission tomography (FDG‐PET) during salvage chemotherapy in relapsing/refractory Hodgkin lymphoma (HL) treated with high‐dose chemotherapy

This retrospective study evaluated whether early 2‐[fluorine‐18]fluoro‐2‐deoxy‐D‐glucose positron emission tomography (FDG‐PET) after two cycles of salvage chemotherapy (PET2) could predict survival after high‐dose chemotherapy (HDC). Twenty‐four Hodgkin lymphoma (HL) patients were included. PET2 was negative in 58% and positive in 42% of patients. Ninety per cent of patients (9/10) with positive PET2 relapsed after HDC while all but one patient with negative PET2 maintained a complete remission. The 2‐year progression‐free survival was 93% vs. 10% for patients with negative and positive PET2, respectively (P < 0.001). This study shows that interim PET can predict the outcome after high‐dose chemotherapy in HL patients.

Melphalan, Prednisone, and Lenalidomide for Newly Diagnosed Myeloma: Kinetics of Neutropenia and Thrombocytopenia and Time-to-Event Results

BACKGROUND Initial analysis of the combination melphalan, prednisone, plus lenalidomide (MPR) showed significant antimyeloma activity in patients with untreated multiple myeloma, with neutropenia and thrombocytopenia as the most frequent side effects. This updated analysis reassessed the kinetics of neutropenia and thrombocytopenia as well as the safety and efficacy of MPR. PATIENTS AND METHODS A total of 21 patients with newly diagnosed myeloma received melphalan 0.18 mg/kg on days 1-4, prednisone 2 mg/kg on days 1-4, and lenalidomide 10 mg daily on days 1-21 for nine 28-day cycles, followed by maintenance therapy with lenalidomide 10 mg daily on days 1-21. RESULTS Grade 3/4 neutropenia occurred in 52% of the patients, and granulocyte colonystimulating factor was administered in 43%. The mean neutrophil counts at the start of each MPR cycle, during nadir, and after 6 months of maintenance were 2.69 x 109/L, 1.43 x 109/L, and 2.11 x 109/L, respectively. Grade 3/4 thrombocytopenia occurred in 24% of the patients. Platelet transfusions were required by 1 patient (5%) with a platelet count of 16 x 109/L; however, no thrombocytopenia-associated bleeding was reported. The mean platelet counts at the start of each cycle, during nadir, and after 6 months of maintenance were 174 x 109/L, 121 x 109/L, and 158 x 109/L, respectively. Median follow-up was 29.6 months, median progression-free survival was 28.5 months, and 2-year overall survival was 91%. CONCLUSION MPR is a promising regimen with manageable hematologic toxicity.

Prospective study of high-dose chemotherapy and autologous peripheral stem cell transplantation in adult patients with advanced desmoplastic small round-cell tumour.

A total of 10 desmoplastic small round-cell tumour patients were treated by high-dose chemotherapy with stem cell support. After high-dose chemotherapy, no complete response conversion was obtained and EWS-WT1 fusion transcript detection was positive in the peripheral blood during follow-up in all patients. High-dose chemotherapy did not seem to change the results in desmoplastic small round-cell tumour.

Idiopathic Thrombocytopenic Purpura and Splenic Marginal-zone B-cell Lymphoma: A Casual Correlation?

Autoimmunity, defined as an abnormal immunological reactivity to self antigens, is commonly seen in lymphoproliferative disorders. Idiopathic thrombocytopenic purpura (ITP) is encountered in these particular settings. The two conditions are usually diagnosed simultaneously or ITP may follow the diagnosis of lymphoma [ 1,2]. There are only a few reports of ITP as the presenting feature of non-Hodgkins lymphoma or Hodgkins disease [3,4]. We describe two cases of splenic marginal-zone-cell lymphoma (SMZCL) discovered after splenectomy in patients treated for refractory ITP. Case 1: In March 2000, a 46-year-old woman was referred from another hospital because of steroid-resistant ITP. Hemoglobin and leucocyte levels were within the normal range and Hepatitis B and C markers were negative. No platelet clumping was detectable in peripheral blood, and serum antibodies targeted to specific antigens for platelet membrane were not found. Bone marrow aspiration revealed normal cellularity, increased megakaryocytes and neither major myelodysplastic features nor atypical lymphocyte infiltration. Finally, when steroid therapy failed to achieve an adequate platelet response, splenectomy was performed. A prominent marginal zone was present, containing small to intermediate-sized lymphoid cells with round to oval to slightly irregular nuclei and small nucleoli (Fig. 1). Residual germinal centers were present within some of these lymphoma nodules. Extensive tumor infiltration of the red pulp was also found. Immunohistochemistry showed neoplastic cells expressing CD20 and lacking reactivity for CD3, CD5, CD23 and CDlO, consistent with SMZCL. Complete staging assessment was performed without evidence of lymphoma. Following splenectomy, the platelet count rapidly increased. As of September 2002, the patient is alive and well with a normal number of platelets and no evidence of lymphoma. Case 2: A 73-year-old lady was found to be severely thrombocytopenic in September 2000 with a platelet count of 3 X 109/l. After biochemical, imaging and bone marrow work-up a diagnosis of ITP was performed. Treatment with prednisone was started and resulted in a slow but full platelet recovery. However, severe thrombocytopenia, with a platelet count of 20 x 109/1, recurred 11 months later, and splenectomy was then performed. The spleen showed infiltration by lymphocytes with morphologic and immunohistochemical features consistent with SMZCL, as detailed above (Fig. 2). All staging assessments were negative for lymphoma. Post operatively, she had an excellent platelet response, but this was short lived (1 month). Before restarting steroid therapy, a bone marrow aspirate was performed. This was again consistent with ITP and excluded lymphoma. At present, the patient requires chronic steroid therapy to maintain a satisfactory platelet count and rituximab is being considered. Several models have been proposed to explain the increased rate of autoimmunity in lymphoproliferative disorders. Rather than a specific autoantibody being produced by the monoclonal malignant cell population itself, it is more likely that the disease allows the emergence of clones which have autoantibody activity. According to this hypothesis, our two ITP cases can be interpreted as a para neoplastic phenomenon, potentially curable by specific therapy. The occurrence of ITP in our two cases could have been a consequence of the activity of the underlying lymphoma and thus represent the first manifestation of the active disease. As far as we are aware, these are the first described cases of ITP occurring as

Inhibition of chronic graft-vs-host disease with retention of anti-myeloma effects by the proteasome inhibitor bortezomib.

Graft-vs-host-disease (GVHD) is a major complication of allogeneic stem cell transplantation (ASCT) [1]. Bortezomib is a proteasome inhibitor that has recently been approved for myeloma treatment. It has been shown to have numerous biological effects, including inhibition of NF-kB activation [2]. NF-kB is a transcription factor that has been detected in most cell types and that controls the expression of a number of genes involved in mediating immune and inflammatory responses [3]. A recent study on murine acute graft-vs-host disease (aGVHD) models has shown that bortezomib induces a selective depletion of alloreactive T lymphocytes by decreasing the production of Th1 cytokines [4]; it inhibits aGVHD and preserves graft-versus-tumor (GVT) effects [5]; and also that NF-kB is the target of bortezomib activity for aGVHD prevention [6]. However, there are only sparse data available on the effect of bortezomib on human GVHD [7]. We report a case of extensive chronic GVHD (cGVHD) and post-ASCT extramedullary myeloma progression, which were both responsive to bortezomib. A 49-year-old Caucasian patient with IgGk Stage III A multiple myeloma (Durie and Salmon) upon diagnosis, in partial remission because of a persistent positive immunofixation [8] after conventional chemotherapy and high-dose melphalan, received lenograstim-stimulated CD34þ cells from an HLAidentical sibling (on Day 0) after reduced-intensity conditioning with fludarabine 30 mg/m/die 73, 72, 71 i.v. and cyclophosphamide 300 mg/m/die 73, 72, 71 i.v. GVHD prophylaxis consisted of cyclosporine A and short-course methotrexate. Neutropenia and thrombocytopenia were not observed. Disease evaluation after ASCT showed stable disease. Full donor chimerism (revealed by PCR analysis) on total marrow and peripheral cells was reached six months after transplant and coincided with cyclosporine withdrawal. Eight months after ASCT the patient developed extensive cGvHD with involvement of the liver, skin, and bilateral conjunctiva and mouth mucosa, which was treated with cyclosporine and steroids until complete remission was reached. Sixteen months after ASCT the patient experienced extramedullary disease progression as revealed by a huge mass (12.56 9 cm) extending to the upper left chest wall, reappearance of monoclonal immunoglobulin (M component) by electrophoresis, and absence of bone marrow infiltration by plasma cells. The chest mass biopsy confirmed the presence of myelomatous cells. Cyclosporine was tapered and stopped, and loco-regional radiotherapy (total 20 Gy) was administered without any disease response. Then the patient received three monthly escalating doses of donor lymphocytes (DLIs, 16 10 kg; 56 10 kg; 16 10 kg) from his HLA-identical donor without any perceivable reduction of the extramedullary mass. Therefore, in June 2005, a few days after the third DLI, he was started on standard-dose bortezomib (1.3 mg/m i.v. for four times on Days þ1, þ4, þ8, þ11) to be

Lenalidomide and dexamethasone in patients with POEMS syndrome: results of a prospective, open-label trial

Given its anti‐angiogenic activity, lenalidomide may have a role in the treatment of POEMS (Peripheral neuropathy, Organomegaly, Endocrinopathy, Monoclonal plasma cell disorder and Skin changes) syndrome. This prospective, open‐label, pilot study evaluated the combination of lenalidomide + dexamethasone (RD) in 18 POEMS syndrome patients (13 pre‐treated, 5 newly‐diagnosed but ineligible for high‐dose therapy). Treatment consisted of six cycles of lenalidomide (25 mg/day for 21 days followed by 7 days rest) plus dexamethasone (40 mg/once a week). Patients responding after six cycles continued treatment until progression or unbearable toxicity. The primary endpoint was the proportion of patients with either neurological or clinical improvement. The RD combination was considered as deserving further evaluation if 9 of the first 15 patients responded. Ten responses were observed among the first 15 enrolled patients, meeting the primary endpoint. Fifteen of 18 patients (83%) completed six RD cycles: 13 (72%) patients responded and nine had both clinical and neurological improvement. Among the 15 patients who completed the six RD cycles, four were still on treatment after a 25‐month follow‐up. At 39 months of follow‐up, all patients were alive with a 3‐year progression‐free survival of 59%. No patient discontinued RD for toxicity. Overall, the RD regimen showed a high incidence of prolonged symptoms improvement and was well tolerated in most POEMS patients.