Jose Mario Mariz

Review of therapy for relapsed/refractory multiple myeloma: focus on lenalidomide.

Purpose of review Multiple myeloma is a malignant neoplasm of plasma cells, for which there is no known cure. This article examines the efficacy and tolerability of lenalidomide, a potent structural analogue of thalidomide, for the treatment of patients with relapsed/refractory multiple myeloma. Recent findings Lenalidomide, a thalidomide analogue, was designed to provide increased efficacy, while avoiding the adverse effects associated with thalidomide therapy. Studies assessing lenalidomide as therapy for relapsed/refractory multiple myeloma have shown promising beneficial effects. Lenalidomide–dexamethasone is associated with significantly longer median time to disease progression and overall survival, as well as a significantly higher proportion of patients who respond to treatment compared with dexamethasone alone. Lenalidomide (with dexamethasone) was associated with a high rate of myelosuppression in clinical trials; neutropenia, infection, thrombocytopenia, and venous thromboembolism were common grade 3–4 adverse events. However, appropriate management of these adverse events maximizes the clinical benefit of lenalidomide. Summary Lenalidomide in combination with dexamethasone is approved by the US Food and Drug Administration and the European Medicines Agency for the treatment of patients with relapsed/refractory multiple myeloma. Lenalidomide is recommended as a treatment option for patients with multiple myeloma in both United States and European treatment guidelines.

Expression pattern of the septin gene family in acute myeloid leukemias with and without MLL-SEPT fusion genes

Septins are proteins associated with crucial steps in cell division and cellular integrity. In humans, 14 septin genes have been identified, of which five (SEPT2, SEPT5, SEPT6, SEPT9, and SEPT11) are known to participate in reciprocal translocations with the MLL gene in myeloid neoplasias. We have recently shown a significant down-regulation of both SEPT2 and MLL in myeloid neoplasias with the MLL-SEPT2 fusion gene. In this study, we examined the expression pattern of the other 13 known septin genes in altogether 67 cases of myeloid neoplasia, including three patients with the MLL-SEPT2 fusion gene, four with MLL-SEPT6 fusion, and three patients with the MLL-SEPT9 fusion gene. When compared with normal controls, a statistically significant down-regulation was observed for the expression of both MLL (6.4-fold; p=0.008) and SEPT6 (1.7-fold; p=0.002) in MLL-SEPT6 leukemia. Significant down-regulation of MLL was also found in MLL-MLLT3 leukemias. In addition, there was a trend for SEPT9 down-regulation in MLL-SEPT9 leukemias (4.6-fold; p=0.077). Using hierarchical clustering analysis to compare acute myeloid leukemia genetic subgroups based on their similarity of septin expression changes, we found that MLL-SEPT2 and MLL-SEPT6 neoplasias cluster together apart from the remaining subgroups and that PML-RARA leukemia presents under-expression of most septin family genes.

Detection of prognostic significant translocations in childhood acute lymphoblastic leukaemia by one-step multiplex reverse transcription polymerase chain reaction.

The search for chromosomal translocations in de novo cases of childhood acute lymphoblastic leukaemia (ALL) is crucial for the selection of the appropriate therapeutic protocol. In this work, we describe a new method – one‐step multiplex reverse transcription polymerase chain reaction (RT‐PCR) – to screen for prognostic significant translocations in childhood ALL. Our approach involves a single PCR reaction for the simultaneous detection of the molecular rearrangements resulting from the t(9;22), t(12;21), t(4;11) and t(1;19), with a turnaround time of less than 24 h. This assay proved to be highly sensitive, specific, reproducible and easy to implement in a routine genetics laboratory.

Genetic and clinical characterization of 45 acute leukemia patients with MLL gene rearrangements from a single institution

Chromosomal rearrangements affecting the MLL gene are associated with high‐risk pediatric, adult and therapy‐associated acute leukemia. In this study, conventional cytogenetic, fluorescence in situ hybridization, and molecular genetic studies were used to characterize the type and frequency of MLL rearrangements in a consecutive series of 45 Portuguese patients with MLL‐related leukemia treated in a single institution between 1998 and 2011. In the group of patients with acute lymphoblastic leukemia and an identified MLL fusion partner, 47% showed the presence of an MLL–AFF1 fusion, as a result of a t(4;11). In the remaining cases, a MLL–MLLT3 (27%), a MLL–MLLT1 (20%), or MLL–MLLT4 (7%) rearrangement was found. The most frequent rearrangement found in patients with acute myeloid leukemia was the MLL–MLLT3 fusion (42%), followed by MLL–MLLT10 (23%), MLL–MLLT1 (8%), MLL–ELL (8%), MLL–MLLT4 (4%), and MLL–MLLT11 (4%). In three patients, fusions involving MLL and a septin family gene (SEPT2, SEPT6, and SEPT9), were identified. The most frequently identified chromosomal rearrangements were reciprocal translocations, but insertions and deletions, some cryptic, were also observed. In our series, patients with MLL rearrangements were shown to have a poor prognosis, regardless of leukemia subtype. Interestingly, children with 1 year or less showed a statistically significant better overall survival when compared with both older children and adults. The use of a combined strategy in the initial genetic evaluation of acute leukemia patients allowed us to characterize the pattern of MLL rearrangements in our institution, including our previous discovery of two novel MLL fusion partners, the SEPT2 and CT45A2 genes, and a very rare MLL–MLLT4 fusion variant.

Coexistence of alternative MLL–SEPT9 fusion transcripts in an acute myeloid leukemia with t(11;17)(q23;q25)

We present the characterization at the RNA level of an acute myeloid leukemia with a t(11;17)(q23;q25) and a MLL rearrangement demonstrated by FISH. Molecular analysis led to the identification of two coexistent in-frame MLL-SEPT9 fusion transcripts (variants 1 and 2), presumably resulting from alternative splicing. Real-time quantitative RT-PCR analysis showed that the relative expression of the MLL-SEPT9 fusion variant 2 was 1.88 fold higher than the relative expression of MLL-SEPT9 fusion variant 1. This is the first description of a MLL-SEPT9 fusion resulting in coexistence of two alternative splicing variants, each of which previously found isolated in myeloid leukemias.

POU1F1 is a novel fusion partner of NUP98 in acute myeloid leukemia with t(3;11)(p11;p15).

BackgroundNUP98 gene rearrangements have been reported in acute myeloid leukemia, giving rise to fusion proteins that seem to function as aberrant transcription factors, and are thought to be associated with poor prognosis.FindingsA patient with treatment-related acute myeloid leukemia presented a t(3;11)(p11;p15) as the only cytogenetic abnormality. FISH and molecular genetic analyses identified a class 1 homeobox gene, POU1F1, located on chromosome 3p11, as the fusion partner of NUP98. In addition, we have found that the patient harbored an FLT3-ITD mutation, which most likely collaborated with the NUP98-POU1F1 fusion gene in malignant transformation.ConclusionsWe have identified POU1F1 as the NUP98 fusion partner in therapy-related AML with a t(3;11)(p11;p15). This is the first POU family member identified as a fusion partner in human cancer.

Both SEPT2 and MLL are down-regulated in MLL-SEPT2 therapy-related myeloid neoplasia

BackgroundA relevant role of septins in leukemogenesis has been uncovered by their involvement as fusion partners in MLL-related leukemia. Recently, we have established the MLL-SEPT2 gene fusion as the molecular abnormality subjacent to the translocation t(2;11)(q37;q23) in therapy-related acute myeloid leukemia. In this work we quantified MLL and SEPT2 gene expression in 58 acute myeloid leukemia patients selected to represent the major AML genetic subgroups, as well as in all three cases of MLL-SEPT2-associated myeloid neoplasms so far described in the literature.MethodsCytogenetics, fluorescence in situ hybridization (FISH) and molecular studies (RT-PCR, qRT-PCR and qMSP) were used to characterize 58 acute myeloid leukemia patients (AML) at diagnosis selected to represent the major AML genetic subgroups: CBFB-MYH11 (n = 13), PML-RARA (n = 12); RUNX1-RUNX1T1 (n = 12), normal karyotype (n = 11), and MLL gene fusions other than MLL-SEPT2 (n = 10). We also studied all three MLL-SEPT2 myeloid neoplasia cases reported in the literature, namely two AML patients and a t-MDS patient.ResultsWhen compared with normal controls, we found a 12.8-fold reduction of wild-type SEPT2 and MLL-SEPT2 combined expression in cases with the MLL-SEPT2 gene fusion (p = 0.007), which is accompanied by a 12.4-fold down-regulation of wild-type MLL and MLL-SEPT2 combined expression (p = 0.028). The down-regulation of SEPT2 in MLL-SEPT2 myeloid neoplasias was statistically significant when compared with all other leukemia genetic subgroups (including those with other MLL gene fusions). In addition, MLL expression was also down-regulated in the group of MLL fusions other than MLL-SEPT2, when compared with the normal control group (p = 0.023)ConclusionWe found a significant down-regulation of both SEPT2 and MLL in MLL-SEPT2 myeloid neoplasias. In addition, we also found that MLL is under-expressed in AML patients with MLL fusions other than MLL-SEPT2.

Posterior Reversible Encephalopathy Syndrome in Children With Hematologic Malignancies.

Since its original description 2 decades ago, posterior reversible encephalopathy syndrome has been reported in children with several predisposing conditions. Epidemiologic data of posterior reversible encephalopathy syndrome in children with hematologic malignancies is still scarce. Herein, we describe the clinical and radiologic features along with the outcome and follow-up of posterior reversible encephalopathy syndrome complicating the treatment of children with hematologic malignancies. Ten patients with a median age of 6.3 years were diagnosed with posterior reversible encephalopathy syndrome. Six of them were undergoing chemotherapy and the remaining 4 were at 37, 52, 78, and 857 days after allogenic hematopoietic stem cell transplant. The median follow-up was 27.6 months. Even though follow-up imaging showed complete resolution of abnormalities in those 10 children, 2 developed secondary epilepsy. Despite accurate diagnosis of posterior reversible encephalopathy syndrome and immediate intervention, neurologic sequelae may still develop. Thus, a close follow-up should be considered in all patients.

Enteropathy-associated T cell lymphoma as a complication of silent celiac disease

Celiac disease is an autoimmune disorder in which a genetic predisposition and the ingestion of wheat gluten triggers a deleterious immune response. This response is complex and may lead to manifestations other than enteropathyha: hepatitis, dermatitis and neuropathy. There is higher risk for neoplasia. We observed an atypical case, corresponding to a 69-year old female presenting with complicated celiac disease. The patient was referred following the histological examination of an enterectomy specimen, which unexpectedly revealed an enteropathy-associated T cell lymphoma in a background of celiac disease. Patient’s previous medical history comprised several abdominal surgical procedures, without other prior symptoms suggestive of celiac disease. Indeed, the patient was obese and no signs of malabsortion were apparent. This case draws our attention to clinically silent celiac disease, which represents a diagnostic challenge. Thus, this should be kept in mind whenever a patient presents with abdominal relapsing complications, otherwise unexplained.

Treatment Outcomes of Patients with Primary Mediastinal Diffuse Large B-CellLymphoma: A Single-Center Experience

Background: Primary mediastinal B-cell lymphoma (PMBCL) is a distinct clinicopathologic entity from diffuse large B-cell lymphoma. The optimal first-line therapy for PMBCL is subject of ongoing debate with no accepted standard of care. Patients and Methods: We searched retrospectively for adult patients with newly diagnosed PMBCL treated at our department between 2002 and 2014. Clinical, management and follow-up data were collected. Staging and response assessment of patients included PET and/or CT scan. Results: Twenty-nine patients with PMBCL (17 female and 12 male) were included. The median age at diagnosis was 36 years (18-79 years). Eighteen (62.1%) and 20 (69%) patients had limited-stage and bulky disease, respectively. All patients were treated with rituximab-based combination chemotherapy; 21 patients underwent consolidation radiotherapy. Seven patients (24.1%) were transplanted (six in first remission and the remaining in second remission). At the end of frontline therapy, 28 patients had responded (27 complete response and 1 partial response) and one patient showed progressive disease. Febrile neutropenia was the most frequent acute adverse event and three patients developed late toxicity. The median follow-up was 51,5 months. The 5-year overall progression-free survival was 83.8%. Four patients died, half of which died within the first year after diagnosis. Conclusion: Our study shows favorable prognosis of patients with PMBCL treated with rituximab-based chemotherapy and consolidation radiotherapy or autologous stem-cell transplant. While consolidation therapy continues to be commonly used, its role has become increasingly controversial.