Olga Salamero

Genomic and Gene Expression Profiling Defines Indolent Forms of Mantle Cell Lymphoma

Mantle cell lymphoma (MCL) is typically a very aggressive disease with poor outcomes, but some cases display an indolent behavior that might not necessitate treatment at diagnosis. To define molecular criteria that might permit recognition of such cases, we compared the clinicopathologic features, gene expression, and genomic profile of patients who had indolent or conventional disease (iMCL or cMCL). Patients with iMCL displayed nonnodal leukemic disease with predominantly hypermutated IGVH and noncomplex karyotypes. iMCL and cMCL shared a common gene expression profile that differed from other leukemic lymphoid neoplasms. However, we identified a signature of 13 genes that was highly expressed in cMCL but underexpressed in iMCL. SOX11 was notable in this signature and we confirmed a restriction of SOX11 protein expression to cMCL. To validate the potential use of SOX11 as a biomarker for cMCL, we evaluated SOX11 protein expression in an independent series of 112 cases of MCL. Fifteen patients with SOX11-negative tumors exhibited more frequent nonnodal presentation and better survival compared with 97 patients with SOX11-positive MCL (5-year overall survival of 78% versus 36%, respectively; P = 0.001). In conclusion, we defined nonnodal presentation, predominantly hypermutated IGVH, lack of genomic complexity, and absence of SOX11 expression as qualities of a specific subtype of iMCL with excellent outcomes that might be managed more conservatively than cMCL.

Rituximab, Fludarabine, Cyclophosphamide, and Mitoxantrone: A New, Highly Active Chemoimmunotherapy Regimen for Chronic Lymphocytic Leukemia

PURPOSE The addition of monoclonal antibodies to chemotherapy has significantly improved treatment of chronic lymphocytic leukemia (CLL). Based on excellent results with the chemotherapy-only regimen fludarabine, cyclophosphamide, and mitoxantrone (FCM), we built a new chemoimmunotherapy combination--rituximab plus FCM (R-FCM). We report a phase II clinical trial consisting of an initial treatment with R-FCM followed by rituximab maintenance. PATIENTS AND METHODS Seventy-two untreated CLL patients age 70 years or younger received rituximab 500 mg/m(2) on day 1 (375 mg/m(2) the first cycle), fludarabine 25 mg/m(2) IV on days 1 to 3, cyclophosphamide 200 mg/m(2) on days 1 to 3, and mitoxantrone 6 mg/m(2) IV on day 1, given at 4-week intervals with up to six cycles supported with colony-stimulating factor. Patients achieving response received maintenance with rituximab 375 mg/m(2) every 3 months for 2 years. RESULTS The overall response, minimal residual disease (MRD) -negative complete response (CR), MRD-positive CR, and partial response rates were 93%, 46%, 36%, and 11%, respectively. Severe neutropenia developed in 13% of patients. Major and minor infections were reported in 8% and 5% of cycles, respectively. Advanced clinical stage, del(17p), or increased serum beta2-microglobulin levels correlated with a lower CR rate. CONCLUSION R-FCM is highly effective in previously untreated CLL, with an 82% CR rate and a high proportion of MRD-negative CRs (46%). Treatment toxicity is acceptable. Parameters correlating with a lower response rate were advanced clinical stage, high serum beta2-microglobulin levels, and del(17p). Based on these results, R-FCM warrants further investigation in randomized clinical trials.

MYC protein expression and genetic alterations have prognostic impact in patients with diffuse large B-cell lymphoma treated with immunochemotherapy.

MYC alterations influence the survival of patients with diffuse large B-cell lymphoma. Most studies have focused on MYC translocations but there is little information regarding the impact of numerical alterations and protein expression. We analyzed the genetic alterations and protein expression of MYC, BCL2, BCL6, and MALT1 in 219 cases of diffuse large B-cell lymphoma. MYC rearrangement occurred as the sole abnormality (MYC single-hit) in 3% of cases, MYC and concurrent BCL2 and/or BCL6 rearrangements (MYC double/triple-hit) in 4%, MYC amplifications in 2% and MYC gains in 19%. MYC single-hit, MYC double/triple-hit and MYC amplifications, but not MYC gains or other gene rearrangements, were associated with unfavorable progression-free survival and overall survival. MYC protein expression, evaluated using computerized image analysis, captured the unfavorable prognosis of MYC translocations/amplifications and identified an additional subset of patients without gene alterations but with similar poor prognosis. Patients with tumors expressing both MYC/BCL2 had the worst prognosis, whereas those with double-negative tumors had the best outcome. High MYC expression was associated with shorter overall survival irrespectively of the International Prognostic Index and BCL2 expression. In conclusion, MYC protein expression identifies a subset of diffuse large B-cell lymphoma with very poor prognosis independently of gene alterations and other prognostic parameters.

Bortezomib: an effective agent in extramedullary disease in multiple myeloma

Abstract:  Bortezomib is a potent and selective proteasome inhibitor recently introduced in the treatment of multiple myeloma (MM). This drug produces significant responses in about one‐third of patients with relapsed/refractory disease. We first recognized the lack of efficacy of thalidomide in soft‐tissue plasmacytomas. There is little information on the effect of bortezomib on extramedullary myeloma. Four of 23 patients treated with bortezomib at our institution had extramedullary involvement at the time of relapse. In three of these patients large soft‐tissue plasmacytomas disappeared. This indicates that bortezomib may be useful in clinical situations of extramedullary disease in which other agents, such as thalidomide, may not be effective.

Favorable outcome of patients with acute myeloid leukemia harboring a low-allelic burden FLT3-ITD mutation and concomitant NPM1 mutation: relevance to post-remission therapy

Risk associated to FLT3 internal tandem duplication (FLT3-ITD) in patients with acute myeloid leukemia (AML) may depend on mutational burden and its interaction with other mutations. We analyzed the effect of FLT3-ITD/FLT3 wild-type (FLT3wt) ratio depending on NPM1 mutation (NPM1mut) in 303 patients with intermediate-risk cytogenetics AML treated with intensive chemotherapy. Among NPM1mut patients, FLT3wt and low ratio (<0.5) subgroups showed similar overall survival, relapse risk, and leukemia-free survival, whereas high ratio (≥0.5) patients had a worse outcome. In NPM1wt AML, FLT3-ITD subgroups showed a comparable outcome, with higher risk of relapse and shortened overall survival than FLT3wt patients. Allogeneic stem cell transplantation in CR1 was associated with a reduced relapse risk in all molecular subgroups with the exception of NPM1mut AML with absent or low ratio FLT3-ITD. In conclusion, effect of FLT3 burden is modulated by NPM1 mutation, especially in patients with a low ratio.

Bone marrow WT1 levels at diagnosis, post-induction and post-intensification in adult de novo AML.

We retrospectively assessed whether normalized bone marrow WT1 levels could be used for risk stratification in a consecutive series of 584 acute myeloid leukemia (AML) patients. A cutoff value of 5065 copies at diagnosis identified two prognostic groups (overall survival (OS): 44±3 vs 36±3%, P=0.023; leukemia-free survival (LFS): 47±3 vs 36±4%, P=0.038; and cumulative incidence of relapse (CIR): 37±3 vs 47±4%, P=:0.043). Three groups were identified on the basis of WT1 levels post-induction: Group 0 (WT1 between 0 and 17.5 copies, 134 patients, OS: 59±4%, LFS:59±4% and CIR: 26±4%); Group 1 (WT1 between 17.6 and 170.5 copies, 160 patients, OS: 48±5%, LFS:41±4% and CIR: 45±4%); and Group 2 (WT1 >170.5 copies, 71 patients, OS: 23±6%, LFS: 19±7% and CIR: 68±8%) (P<0.001). Post-intensification samples distinguished three groups: patients with WT1 >100 copies (47 patients, 16%); an intermediate group of patients with WT1 between 10 and 100 copies (148 patients, 52%); and a third group with WT1 <10 copies (92 patients, 32%). Outcomes differed significantly in terms of OS (30±7%, 59±4%, 72±5%), LFS (24±7%, 46±4%, 65±5%) and relapse probability (CIR 72±7%, 45±4%, 25±5%), all P<0.001. WT1 levels in bone marrow assayed using the standardized ELN method provide relevant prognostic information in de novo AML.

Herpes simplex and Epstein-Barr virus lymphadenitis in a patient with chronic lymphocytic leukemia treated with fludarabine

Abstract:  Multiple herpes virus co‐infection is a very rare complication in patients with chronic lymphocytic leukemia (CLL). We describe a patient with a CLL who developed an herpes virus lymphadenitis. Inmunohistochemical study was positive for HSV‐1, HSV‐2, and Epstein‐Barr Virus (EBV). The coinfection of EBV with a profile of expresion of viral latent genes type III, is usually seen in inmunodepressed patients. To the best of our knowledge, this is the first reported case of a multiple human herpes virus infection mimicking Richter syndrome.

Anemia Associated with Impaired Erythropoietin Secretion after Allogeneic Stem Cell Transplantation: Incidence, Risk Factors, and Response to Treatment

After allogeneic stem cell transplantation (allo-SCT) some patients develop persistent anemia in association with an inadequate erythropoietin (Epo) secretion. We determined the frequency and risk factors for this complication and the response to treatment with erythropoiesis stimulating proteins (ESP). Of 83 evaluable allo-SCT patients, 63 (76%) developed persistent anemia at a median of 34 (range: 30-244) days after allo-SCT. Forty-one (49%) patients had anemia considered as primary, and in all of them inadequate serum Epo levels (median 43.3, range: 2.5-134, mU/mL) were found. A high creatinine level during the first month after allo-SCT was associated with primary anemia (relative risk [RR] 2.5, P = .01). Of the 41 patients, 35 received ESP. Transfusion independence and an Hb level higher than 10 g/dL was achieved in 29 of 30 (97%) evaluable patients. Median ferritin levels at the beginning and at the end of the ESP treatment was 1628 (range: 168-5208) and 805 (range: 14-7443) ng/mL, respectively (P = .04). In conclusion, anemia associated with impaired Epo secretion after allo-SCT is more frequent than usually recognized and it is associated to early postransplantation renal damage. This complication easily reverts with ESP, which seems to contribute to reduce iron overload.

Autologous stem cell transplantation for patients with active Hodgkin's lymphoma: long-term outcome of 61 patients from a single institution.

Sixty-one patients with refractory or relapsed Hodgkins lymphoma (HL) underwent high-dose chemotherapy and autologous stem cell transplantation (ASCT). All patients had active HL at the time of ASCT: 13 patients had partial remission, 14 refractory disease, 18 sensitive relapse, 4 resistant relapse, and 12 nontreated relapse. Overall transplant-related mortality (TRM) was 16.4% at 1 year. Twenty-eight patients (46%) achieved complete remission (CR). Actuarial 5-year overall survival (OS) and progression-free survival (PFS) were 51% and 47%, respectively. Patients with positive gallium-67 scintigraphy at 3 – 6 months after transplantation had a worse PFS at 5 years (28%) than those with negative 67Ga scan (80%) (p = 0.016), whereas no statistical differences were observed between patients with residual mass and those in CR according to computed tomography scan. In multivariate analysis, bulky disease at diagnosis, bone marrow stem cells, and stage IV at transplant were the only adverse prognostic factors significantly influencing OS. Bulky disease at diagnosis and stage IV at transplant adversely influenced PFS. Although long-term outcome of patients with active HL at the time of ASCT is poor due to a high TRM and a low CR after transplantation, a subgroup of patients with no adverse prognostic factors at ASCT gain benefit from this treatment.

The expression level of BAALC-associated microRNA miR-3151 is an independent prognostic factor in younger patients with cytogenetic intermediate-risk acute myeloid leukemia.

Acute myeloid leukemia (AML) is a heterogeneous disease whose prognosis is mainly related to the biological risk conferred by cytogenetics and molecular profiling. In elderly patients (⩾60 years) with normal karyotype AML miR-3151 have been identified as a prognostic factor. However, miR-3151 prognostic value has not been examined in younger AML patients. In the present work, we have studied miR-3151 alone and in combination with BAALC, its host gene, in a cohort of 181 younger intermediate-risk AML (IR-AML) patients. Patients with higher expression of miR-3151 had shorter overall survival (P=0.0025), shorter leukemia-free survival (P=0.026) and higher cumulative incidence of relapse (P=0.082). Moreover, in the multivariate analysis miR-3151 emerged as independent prognostic marker in both the overall series and within the unfavorable molecular prognostic category. Interestingly, the combined determination of both miR-3151 and BAALC improved this prognostic stratification, with patients with low levels of both parameters showing a better outcome compared with those patients harboring increased levels of one or both markers (P=0.003). In addition, we studied the microRNA expression profile associated with miR-3151 identifying a six-microRNA signature. In conclusion, the analysis of miR-3151 and BAALC expression may well contribute to an improved prognostic stratification of younger patients with IR-AML.