Adverse outcome in follicular lymphoma is associated with MYC rearrangements but not MYC extra copies.

Follicular lymphomas (FLs) with MYC rearrangements (MYC-R) and extra copies of MYC (MYC-EC) are rare and the prognosis impact is uncertain. We conducted a retrospective study including 321 FL patients, among whom 259 (81%) had no 8q24 alterations and 62 (19%) were assigned to 8qAlt. Forty-five cases were classified as MYC-EC and six as MYC-R. MYC-R patients were significantly older (P = 0·008), had higher follicular lymphoma international prognostic index (FLIPI) stage (P = 0·05) and ß2-microglobulin (ß2m; P = 0·05). Among patients treated with immuno-chemotherapy, four presented a MYC-R and 25 a MYC-EC. Univariate analysis showed the absence of significant difference between MYC-EC and normal MYC (MYC-NL) regarding progression-free survival (PFS; HR1·3; 95% CI [0·4-1·6]) and specific overall survival (SOS; HR 1·6; 95% CI [0·4-5·7]). Those results were compared to data from the PRIMA trial. This confirmed that MYC-EC had no impact on PFS (P = 0·86) or SOS (P = 0·9). Conversely, MYC-R was associated with a trend to inferior outcome regarding PFS (HR : 6·1; 95% CI [2·2-17·1]; P = 0·00026), lymphoma-related death (SOS; HR 13·6; 95% CI [2·9-65]; P = 0·00014) and risk of transformation (transformation-free survival (TFS); HR 82·7; 95% CI [14·8-463·4]; P < 0·0001). In conclusion, MYC-EC has no prognostic impact in FL but MYC-R FL tended to be associated with an increased risk of transformation and poorer outcome.

Prognostic value of PINI index in patients with multiple myeloma.

BACKGROUND: The Prognostic Inflammatory and Nutritional Index (PINI) is a simple scoring system that aggregates two blood markers of inflammatory [C-reactive protein (CRP) and orosomucoid] and of nutritional (albumin and prealbumin) states. It is used in routine practice in geriatric medicine, especially in hospitalized elderly patients. This study was undertaken to evaluate the usefulness of PINI index in multiple myeloma (MM), a malignancy of the elderly. METHOD: The PINI score was determined in 231 previously untreated patients with MM, of whom 112 were ≥65 yrs old. The serum albumin, prealbumin, orosomucoid (human α1-acid glycoprotein), and hsCRP are measured routinely by immunonephelometry. RESULTS: In the overall population and the elderly subset, PINI ≥ 4 ('high PINI') was correlated with a shorter median survival, 26 vs. 65 months in the high and low PINI groups, respectively. The prognostic impact of PINI index was dramatic in the elderly MM subgroup, 6 and 45 months, respectively. The high PINI index also predicted for shorter survival in various groups with good prognostic, such as low International Staging System (ISS) stages, low b2m, and absence of del17p and t(4;14), further demonstrating its prognostic impact on overall survival. In multivariate analysis, PINI index provided additional survival prognostic information to b2m in a b2m/PINI model. CONCLUSION: PINI index appears to be a useful and easy-to-perform marker in routine to determine the prognosis of patients with MM, especially in the elderly population. PINI might represent an alternative to ISS score, especially in elderly patients, in the future.

Targeted treatment and new agents in diffuse large B cell lymphoma.

The outcome of patients with diffuse large B cell lymphoma (DLBCL) has completely changed with the introduction of rituximab in combination with chemotherapy. This was the first targeted therapy, and it led the way to new antibodies targeting cell surface receptors and to small molecules targeting one or several key proteins of the cellular machinery. Those new therapeutic small molecules are targeting the different pathways of apoptosis, proteasome inhibitors, immunomodulators, histone deacetylase inhibitors, mammalian target of rapamycin inhibitors, heat shock protein inhibitors, PKC inhibitors, antiangiogenic agents, Syk inhibitors, and farnesyl transferase inhibitors. The new monoclonal antibodies target CD20, CD22, CD19, CD40, CD74, and HLA Drbeta. Although the majority of them have been studied in mixed subtypes of B cell lymphoma, the aim of this review was to present major results in clinical studies for these new agents in DLBCL patients, and for those that have just entered clinical evaluation, the results of pre-clinical studies in DLBCL lines.

In vivo model of follicular lymphoma resistant to rituximab.

PURPOSE: Follicular lymphoma (FL) is the most common subtype of indolent lymphomas. Rituximab is widely used alone or in combination therapy for the treatment of FL. Despite its well-established clinical efficacy, a subpopulation of patients does not respond to rituximab and most patients will relapse after therapy. The mechanisms of action and resistance to rituximab are not fully understood. EXPERIMENTAL DESIGN: To study these mechanisms we developed an in vivo model of FL resistant to rituximab. This model was developed using the human RL line, isolated from a patient with FL, grown as xenotransplants in severe combined immunodeficient mice, exposed weekly to rituximab in vivo, followed by serial reimplantation and reexposure to rituximab, until a resistant phenotype was obtained. RESULTS: RL-derived tumors unexposed to rituximab were grown as controls and compared with the resistant tumors. Although the expression of CD46 and CD55 antigens were not differently expressed in the resistant cells, the complement inhibitor CD59 was overexpressed in a subpopulation and CD20 was found to be expressed at a lower level in a minority of cells. Bcl-X(L) and YY1 were also found more highly expressed in rituximab-resistant cells. CONCLUSION: This model provides insight on potential in vivo resistance mechanisms to rituximab and could help contribute to the development of novel therapies in rituximab-refractory diseases.

Waldenstrom macroglobulinemia.

In the past years, new developments have occurred both in the understanding of the biology of Waldenstrom Macroglobulinemia (WM) and in therapeutic options for WM. WM is a B-cell disorder characterized primarily by bone marrow infiltration with lymphoplasmacytic cells, along with demonstration of an IgM monoclonal gammopathy. Despite advances in therapy, WM remains incurable, with 5-6 years median overall survival of patients in symptomatic WM. Therapy is postponed for asymptomatic patients, and progressive anemia is the most common indication for initiation of treatment. The main therapeutic options include alkylating agents, nucleoside analogues, and rituximab. Studies involving combination chemotherapy are ongoing, and preliminary results are encouraging. No specific agent or regimen has been shown to be superior to another for treatment of WM. As such, novel therapeutic agents are needed for the treatment of WM. In ongoing efforts, we and others have sought to exploit advances made in the understanding of the biology of WM so as to better target therapeutics for this malignancy. These efforts have led to the development of several novel agents including the proteasome inhibitor bortezomib, and several Akt/mTor inhibitors, perifosine and Rad001, and immunomodulatory agents such as thalidomide and lenalidomide. Studies with monoclonal antibodies are ongoing and promising including the use of alemtuzumab, SGN-70, and the APRIL/BLYS blocking protein TACI-Ig atacicept. Other agents currently being tested in clinical trials include the PKC inhibitor enzastaurin, the natural product resveratrol, as well as the statin simvastatin. This report provides an update of the current preclinical studies and clinical efforts for the development of novel agents in the treatment of WM.

Serum immunoglobulin free light chain correlates with tumor burden markers in Waldenstrom macroglobulinemia.

The serum IgM level has been utilised as a marker of tumor progression and to assess response to therapy in patients with Waldenstrom macroglobulinemia (WM). However, there are many limitations to the IgM protein level. The objective of this study was to evaluate the association of known tumor burden markers and prognostic factors with serum free light chain (sFLC) in 98 patients with WM. We demonstrated that sFLC measurement accurately differentiated IgM-MGUS compared with WM reflecting a measurement of tumor burden. In univariate and multivariate analysis, median sFLC at the cut-off at 60 mg/L was higher for WM patients with low hemoglobin and high beta2M, when we applied the WM-IPSS cut-offs, but showed no association with IgM level. This study demonstrates that sFLC is a new marker in WM disease. Further analysis is required to prospectively study the role of sFLC in monitoring response to therapy and as a prognostic marker in WM patients.

Long-term outcome in acquired aplastic anemia treated with an intensified dose schedule of horse antilymphocyte globulin in combination with androgens.

Aplastic anemia (AA) is a rare hematopoietic stem cell disease, which can be treated with horse antilymphocyte globulin (ALG) for patients not eligible for bone marrow transplantation. ALG gives about 60% overall survival rate (OS) after 5 years, a 30% of persistent complete remission and a 20% early death rate related to failure. ALG has been incriminated in the emergence of 10 to 20% therapy-related AML/MDS (t-AML/MDS) with the usual doses. Questions remain whether higher doses of ALG could improve the response and OS rates and whether the combination with androgens is able to protect patients from t-AML/MDS. We have carried out a single institutional retrospective study of 87 AA treated with higher doses of ALG, twice the usual posology (140 mg/kg instead of 75 mg/kg), combined to androgens. The overall response rate was 77% and the OS rate at 5 years was 78%. Androgens in combination with ALG improved response and OS rates. At diagnosis, 6% of AA had an abnormal karyotype using conventional cytogenetic not related to any time-to-event. Two patients displayed a cytogenetic conversion related to the occurrence of secondary malignancies. The incidence of t-AML/MDS was 2.3% with an estimated 10-year cumulative incidence of 3.1. Our results show that higher doses of ALG combined to androgens are feasible and give results close to those recently describe with the immunosuppressive treatments including ALG associated to cyclosporine, with a low SMD/AML incidence rate.