Emanuela Merla

Oral melphalan and prednisone chemotherapy plus thalidomide compared with melphalan and prednisone alone in elderly patients with multiple myeloma: randomised controlled trial

BACKGROUNDnSince 1960, oral melphalan and prednisone (MP) has been regarded as the standard of care in elderly multiple myeloma patients. This multicentre randomised trial compared oral MP plus thalidomide (MPT) with MP alone in patients aged 60-85 years.nnnMETHODSnPatients with newly diagnosed multiple myeloma were randomly assigned to receive oral MP for six 4-week cycles plus thalidomide (n=129; 100 mg per day continuously until any sign of relapse or progressive disease) or MP alone (n=126). Analysis was intention-to-treat. This study is registered at , number NCT00232934.nnnRESULTSnPatients treated with thalidomide had higher response rates and longer event-free survival (primary endpoints) than patients who were not. Combined complete or partial response rates were 76.0% for MPT and 47.6% for MP alone (absolute difference 28.3%, 95% CI 16.5-39.1), and the near-complete or complete response rates were 27.9% and 7.2%, respectively. 2-year event-free survival rates were 54% for MPT and 27% for MP (hazard ratio [HR] for MPT 0.51, 95% CI 0.35-0.75, p=0.0006). 3-year survival rates were 80% for MPT and 64% for MP (HR for MPT 0.68, 95% CI 0.38-1.22, p=0.19). Rates of grade 3 or 4 adverse events were 48% in MPT patients and 25% in MP patients (p=0.0002). Introduction of enoxaparin prophylaxis reduced rate of thromboembolism from 20% to 3% (p=0.005).nnnCONCLUSIONnOral MPT is an effective first-line treatment for elderly patients with multiple myeloma. Anticoagulant prophylaxis reduces frequency of thrombosis. Longer follow-up is needed to assess effect on overall survival.

Bortezomib as salvage treatment for heavily pretreated relapsed lymphoma patients: a multicenter retrospective study

Current treatments for non‐Hodgkin lymphomas are not optimally effective. Among new agents, bortezomib seems to play a pivotal role in the regulation of several cell pathways involved in the development of lymphomas. After results were obtained with clinical trials, we aimed to observe treatment with bortezomib in everyday clinical practice. We performed a multicenter retrospective analysis to assess the efficacy of bortezomib in heavily pretreated (median number of previous therapies 4, range 2–6) lymphoma patients in an off‐label setting. Bortezomib therapy was scheduled for 4–6 cycles (1.3u2009mg/m2 biweekly). Data from 50 patients were collected: 22% had a complete remission, 26% obtained a partial response and the remaining 52% was non‐responder. According to histotype, we observed an overall response rate (ORR) of 51.6% in mantle cell lymphomas, an ORR of 60% among follicular lymphoma patients, and an ORR of 50% in the indolent nonfollicular lymphomas. None of diffuse large B‐cell lymphoma patients obtained a response. Extra‐hematological toxicity was really mild, and peripheral neuropathy occurred in only 5 patients; hematological toxicity was grades 3–4 thrombocytopenia in nine patients and grades 3–4 neutropenia in only three patients. In conclusion, treatment with bortezomib as single agent resulted safe and effective in a subset of heavily pretreated lymphoma patients with usually poor outcome. New future hypotheses of investigation are indicated. Copyright

Minimal residual disease after allogeneic stem cell transplant: a comparison among multiparametric flow cytometry, Wilms tumor 1 expression and chimerism status (Complete chimerism versus Low Level Mixed Chimerism) in acute leukemia

Abstract Relapse represents the main cause of treatment failure after allogeneic stem cell transplant (allo-SCT). The detection of minimal residual disease (MRD) by multiparametric flow cytometry (MFC), chimerism, cytogenetics and molecular analysis may be critical to prevent relapse. Therefore, we assessed the overall agreement among chimerism (low level mixed chimerism [LL-MC] vs. complete chimerism [CC]), MFC and Wilms tumor 1 (WT1) mRNA to detect MRD and investigated the impact of MRD obtained from the three methods on patient outcome. Sixty-seven fresh bone marrow (BM) samples from 24 patients (17 acute myeloid leukemia [AML], seven acute lymphoblastic leukemia [ALL]) in complete remission (CR) after allo-SCT were investigated at different time points. A moderate agreement was found among the three techniques investigated. A higher concordance between positive results from MFC (75.0% vs. 32.7%, p = 0.010) and WT1 (58.3% vs. 29.1%, p = 0.090) was detected among LL-MC rather than CC samples. Relapse-free survival (RFS) and overall survival (OS) were found to be higher in MRD negative patients than in MRD positive patients analyzed with MFC and WT1. Our results discourage the use of low autologous signals as the only marker of MRD, and suggest the usefulness of MFC and WT1 real-time quantitative polymerase chain reaction (RQ-PCR) in stratifying patients with respect to risk of relapse.

Optimal time-points for minimal residual disease monitoring change on the basis of the method used in patients with acute myeloid leukemia who underwent allogeneic stem cell transplantation: A comparison between multiparameter flow cytometry and Wilms’ tumor 1 expression

Minimal residual disease (MRD) of 30 adult AML patients was monitored by multiparameter flow cytometry (MFC) and WT1 expression before and after allogeneic stem cell transplantation (allo-SCT). Diagnostic performance of pre-transplant MRD measured by MFC was higher than that obtained by WT1 expression. Comparable results were displayed at day +30 post-transplant, while better values by WT1 compared to MFC were found at day +90. Positive MRD by MFC predicted a shorter disease free survival (DFS) before and 1 month after transplant (p=0.006 and p=0.005), while only high WT1 levels at 1 month from the transplant significantly impacted on DFS (p=0.010). Our results support the idea that MRD monitoring by MFC should be suggested before and 30 days after the transplant, while WT1 expression should be preferred after this procedure. The assessment of MRD at day +30 from allo-SCT is recommended as post transplant check-point for the predictive role displayed, independently of the method used.

Gemtuzumab ozogamicin as maintenance therapy after autologous stem cell transplantation in elderly patients with acute myeloid leukaemia.

Acute myeloid leukaemia (AML) has a dismal prognosis, particularly in older patients who make up a large proportion of the AML population. Induction therapy, typically consisting of cytarabine and anthracycline combination regimens, is the cornerstone of treatment and achieves a complete remission (CR) rate of 45–55% in older patients and a median survival of only 8–12 months (Roboz, 2007). Unfortunately, aggressive, postremission consolidation chemotherapy does not appear to improve survival in older patients who are at increased risk of chemotherapy-related mortality (Stone, 2001). Gemtuzumab ozogamicin (GO) is a recombinant humanized monoclonal antibody conjugated to the antitumour antibiotic calicheamicin. The antibody component targets the CD33 cell surface marker that is expressed on cancerous cells in the majority of AML patients. GO is currently indicated for the treatment of AML in patients aged ‡60 years who are in their first relapse and are not considered suitable candidates for other types of chemotherapy. Gemtuzumab ozogamicin has also been investigated in the first-line treatment of AML, with more promising results seen when this agent is added to combination chemotherapy induction regimens (Fenton & Perry, 2005; Pagano et al, 2007). Clinical trials currently underway are investigating the role of GO in consolidation therapy. Studies evaluating the use of GO in conditioning regimens prior to haematopoietic SCT have indicated an increased risk of hepatic venoocclusive disease, though this risk appears to be greatly reduced if more than 3Æ5 months elapses between GO exposure and SCT (Wadleigh et al, 2003). Little or nothing is known about the usefulness of GO as maintenance therapy after autologous SCT (Tsimberidous et al, 2005) and no experience in this setting has been published to date. Gemtuzumab ozogamicin monotherapy has typically been administered as a 2-h infusion at a dose of 9 mg/m on days 1 and 15 of treatment. Favourable tolerability results following the administration of fractionated doses have recently been reported (Taksin et al, 2007). We hypothesized that GO could have beneficial effects as maintenance therapy after haematopoietic SCT in high-risk patients. Here, we report data on five elderly AML patients in CR who received four fractionated doses of GO as maintenance therapy following ASCT. This study was carried out under ethical approval. Our approach differs from previous reports in the literature in that, instead of using GO to induce a first remission or re-induce a second remission after relapse, we administered GO to patients while they remained in remission, 2 months after undergoing ASCT. Patient 1 was a 64-year-old male with 88% CD33 expression at diagnosis. He was in second CR following an induction regimen of two cycles of fludarabine + cytarabine + idarubicin. This patient had previously undergone an ASCT, using a conditioning regimen of busulphan + cyclophosphamide. Patient 2 was a female, aged 67 years and had 90% CD33 expression at diagnosis. She was in first CR following an induction regimen of two cycles of etoposide + cytarabine + idarubicin. Patients 3 and 4 were a 69-year-old male and a 68-year-old female with 95% and 93% CD33 expression at diagnosis respectively. They were in first CR following an induction regimen of two cycles of fludarabine + cytarabine. Patient 4 was still receiving maintenance therapy and, at that time, received two doses of GO. Finally, patient 5 was a 60-year-old male with 90% CD33 expression at diagnosis. He had an AML refractory to a standard induction chemotherapy (3 + 7 regimen) and was rescued with one MEC (mitoxantrone, etoposide and cytosine arabinoside) regimen. Histocompatible donors were not available for any of the patients. Three months after attaining CR, all the five patients received a myeloablative conditioning regimen and underwent ASCT. Two months after complete engraftment, patients initiated treatment with GO (see Table I for details of preASCT conditioning therapy and GO regimens). Disease outcomes and details of haematological adverse events are summarized in Table I. All the five patients remained alive and in CR at +21, +17, +15, +7, +13 months, respectively, while the overall survival at the time of reporting was +39, +19, +17, +8, +20 months. There were no cases of grade 3 or 4 liver toxicity and bleeding was not observed in any of the patients. Thrombocytopenia (50–100 · 10 cells/l) occurred in all the five patients and neutropenia (0Æ5– 1Æ0 · 10 cells/l) in two patients. In conclusion, despite the limited numbers, GO demonstrated good efficacy when administered in fractionated doses as maintenance therapy after ASCT in our series of older patients with CD33 AML in first or second CR. To our knowledge, this is the first report on the use of GO as maintenance therapy after ASCT. GO showed an acceptable tolerability profile, with no severe hepatotoxicity and no bleeding. Thrombocytopenia occurred in all the five patients Correspondence