Angela Gueli

Risk Factors for the Development of Secondary Malignancy After High-Dose Chemotherapy and Autograft, With or Without Rituximab: A 20-Year Retrospective Follow-Up Study in Patients With Lymphoma

PURPOSE High-dose chemotherapy with peripheral blood progenitor cell (PBPC) autograft is effective in high-risk lymphoma, particularly with the addition of rituximab; however, it is associated with risk of secondary malignancy. These issues have been addressed in a series of 1,347 patients with lymphoma treated with a high-dose sequential (HDS) program. PATIENTS AND METHODS A total of 1,024 patients with B-cell lymphoma, 234 patients with Hodgkins lymphoma, and 89 patients with T-cell lymphoma were treated with HDS between 1985 and 2005 at 11 Gruppo Italiano Terapie Innovative Linfomi centers. HDS was given as salvage treatment to 707 patients (52%); 655 patients (49%) received a modified HDS, with high-dose cytarabine and two consecutive PBPC harvests. Rituximab-supplemented HDS was given to 523 patients (39%). RESULTS At a median follow-up of 7 years, the median overall survival (OS) was 16.2 years; in B-cell lymphoma the OS was significantly superior with rituximab HDS compared to HDS alone. The cumulative incidence at 5 and 10 years of secondary myelodysplasia/acute leukemia (sMDS/AL) were 3.09% and 4.52%, respectively, that of solid tumors were 2.54% and 6.79%, respectively. Factors associated with sMDS/AL were male sex and use of the second harvest PBPC for the graft; factors found to be associated with solid tumor were advanced age, post-HDS radiotherapy, and rituximab addition to HDS. Despite the increased risk of solid tumors, rituximab addition to HDS was still associated with survival advantages. CONCLUSION This analysis has relevant implications for the design and use of intensive chemoimmunotherapy with autograft. In addition, it offers useful insights toward the understanding and prevention of tumor development.

The lymphocyte to monocyte ratio improves the IPI‐risk definition of diffuse large B‐cell lymphoma when rituximab is added to chemotherapy

The peripheral blood lymphocyte to monocyte ratio (LMR) at diagnosis can be clinically relevant in patients with diffuse large B‐cell lymphoma (DLBCL). We reviewed the outcome of 1,057 DLBCL patients followed from 1984 to 2012 at four centers. LMR was analyzed as a clinical biomarker by receiver‐operating characteristic (ROC) analysis and Harrells C‐statistics. Patients were characterized by a median age of 61 years, International Prognostic Index (IPI) score of >2 in 39%, and were treated with a rituximab‐containing chemotherapy in 66%. LMR proved strongly predictive for survival in patients treated with rituximab‐based programs, but not in those receiving chemotherapy alone. Additionally, an LMR value of ≤2.6 (as determined by ROC analysis) was associated with a worst performance status, a higher lactate dehydrogenase (LDH) level, an advanced clinical stage, and a higher IPI score (P = 0.000). In patients treated with rituximab‐supplemented chemotherapy programs, an LMR value of <2.6 was found in most of the primary refractory patients (75%) which proved as the best cutoff to predict both response and survival (P = 0.018). Finally, multivariate analysis and Harrells C‐statistics confirmed the IPI‐independent role of LMR on survival (P = 0.0000). In conclusion, LMR is a potent predictor of clinical response and survival in DLBCL treated with rituximab‐containing chemotherapy. Am. J. Hematol. 88:1062–1067, 2013.

Lymphocyte transformation and autoimmune disorders

The many features that link autoimmune disorders (AD) and lymphoma are reviewed herein. Firstly, the epidemiology indicates the increased risk of non-Hodgkins lymphoma (NHL) development in many AD, and especially in Sjögrens syndrome, rheumatoid arthritis and systemic lupus erythematosus. In these AD, the relative risk of NHL occurrence varies between 2 and 4 up to 40 fold higher than in the general population, according to various surveys. Factors favouring or predicting NHL have been reported in detail. B-cell activation and proliferation are part of AD and are essential factors for the onset of malignant cell clones in a deregulated immunological environment. Targeting deregulated or malignant B-cells is the goal of some newly developed treatments. The prototype is anti-CD20 rituximab that has substantially modified the prognosis of B-cell NHL and is also an effective new treatment opportunity for some AD. Similarly, intensified treatments with autologous haematopoietic stem cell transplant (ASCT) that were developed for high-risk lymphoma are now under advanced investigation for use in some refractory AD. Thus, the successful use of rituximab and ASCT in both AD and NHL further emphasizes the close link between these two entities. This review provides details on the main epidemiological features regarding NHL incidence in AD, the pathogenetic factors that favour lymphoma onset and some recent advances in therapeutic approaches that are effective in both autoimmune and malignant lymphoproliferative disorders.

Efficacy of rituximab-bendamustine in cold agglutinin haemolytic anaemia refractory to previous chemo-immunotherapy: a case report

Primary cold agglutinin disease (CAD) is a haemolytic anaemia caused by high titres of cold antibodies, usually IgM, directed against red blood cells1,2. Cold agglutinins are present at low titres in all normal individuals, but at high concentrations, the agglutinins can have pathological consequences. In the cool peripheral circulation, cold agglutinin-coated red blood cells activate the complement cascade to the C3b/C3d stage and in the hepatic circulation C3b+ erythrocytes trigger phagocytosis by macrophages. An autoimmune disorder is responsible for the high titres of circulating cold antibodies and CAD accounts for approximately 13–15% of cases of autoimmune haemolytic anaemia3. Moreover, CAD has been found to be associated with a clonal lymphoproliferative disorder in many cases. Indeed, the cold agglutinins are monoclonal IgM in more than 90% of CAD patients and the presence of a lymphoid neoplasm, in particular B-cell non-Hodgkin’s lymphoma (NHL), has been observed in approximately 75% of patients with primary CAD4,5. Treatments, including corticosteroids or alkylating agents, which are effective in other forms of autoimmune haemolytic anaemia are usually ineffective in CAD. On the other hand, half of the patients with CAD respond to rituximab alone, a drug that has markedly improved the prognosis of patients with B-cell lymphomas. Moreover, combining rituximab with fludarabine has further improved the outcome of CAD patients, with a 75% overall response rate being achieved in a recent, prospective trial6. Most CAD patients are elderly and their advanced age makes the use of potentially harmful therapies questionable. It is, therefore, reasonable to search for less toxic regimens for CAD patients. Recently, bendamustine, a molecule analogous to fludarabine, has been successfully employed in the treatment of low-grade B-cell NHL7,8. Compared to fludarabine, bendamustine has fewer side effects and an excellent tolerability. Thus, bendamustine with rituximab might be an effective chemo-immunotherapy option for elderly patients with CAD. The case report here presented, gives support to the use of bendamustine in CAD.

Rate of primary refractory disease in B and T-cell non-Hodgkin's lymphoma: correlation with long-term survival.

Background Primary refractory disease is a main challenge in the management of non-Hodgkin’s Lymphoma (NHL). This survey was performed to define the rate of refractory disease to first-line therapy in B and T-cell NHL subtypes and the long-term survival of primary refractory compared to primary responsive patients. Methods Medical records were reviewed of 3,106 patients who had undergone primary treatment for NHL between 1982 and 2012, at the Hematology Centers of Torino and Bergamo, Italy. Primary treatment included CHOP or CHOP-like regimens (63.2%), intensive therapy with autograft (16.9%), or other therapies (19.9%). Among B-cell NHL, 1,356 (47.8%) received first-line chemotherapy with rituximab. Refractory disease was defined as stable/progressive disease, or transient response with disease progression within six months. Results Overall, 690 (22.2%) patients showed primary refractory disease, with a higher incidence amongst T-cell compared to B-cell NHL (41.9% vs. 20.5%, respectively, p<0.001). Several other clinico-pathological factors at presentation were variably associated with refractory disease, including histological aggressive disease, unfavorable clinical presentation, Bone Marrow involvement, low lymphocyte/monocyte ration and male gender. Amongst B-cell NHL, the addition of rituximab was associated with a marked reduction of refractory disease (13.6% vs. 26.7% for non-supplemented chemotherapy, p<0.001). Overall, primary responsive patients had a median survival of 19.8 years, compared to 1.3 yr. for refractory patients. A prolonged survival was consistently observed in all primary responsive patients regardless of the histology. The long life expectancy of primary responsive patients was documented in both series managed before and after 2.000. Response to first line therapy resulted by far the most predictive factor for long-term outcome (HR for primary refractory disease: 16.52, p<0.001). Conclusion Chemosensitivity to primary treatment is crucial for the long-term survival in NHL. This supports the necessity of studies aimed to early identify refractory disease and to develop different treatment strategies for responsive and refractory patients.

Results of a randomized trial comparing high-dose chemotherapy plus Auto-SCT and R-FC in CLL at diagnosis

The importance of early therapy intensification in B-cell CLL (B-CLL) patients remains to be defined. Even though several studies have been published, no randomized trials comparing directly autologous stem cell transplant (ASCT) and the accepted conventional therapy (that is, rituximab, fludarabine and CY; R-FC) have been reported so far. To assess the benefit of a first-line aggressive therapy, we designed a multicenter, randomized, phase 3 trial comparing R-FC and high-dose chemotherapy supported by ASCT in patients under 65 years of age, with stage B(II) or C B-CLL. Primary end point was CR: 96 patients were enrolled (48 in each arm). On an intent-to-treat basis, the CR rates in the ASCT and R-FC arms were 62.5% and 58%, respectively. After 5 years of follow-up, PFS was 60.4% in the ASCT arm and 65.1% in the R-FC arm, time to progression 65.8 and 70.5%, and overall survival 88% vs 88.1%, respectively. Our trial demonstrates, for the first time in a randomized manner, that frontline ASCT does not translate into a survival advantage when compared with benchmark chemoimmunotherapy in B-CLL patients; the possibility of its clinical benefit in certain subgroups remains uncertain.

Use of the novel thrombopoietin receptor-agonist romiplostim, in combination with steroids and immunoglobulins for the increase of platelets prior to splenectomy, in refractory immune thrombocytopenia: a case report.

This case report describes a patient with relapsed primary immune thrombocytopenic purpura (ITP), in which splenectomy was not possible due to the persistence of a low platelet count despite treatment with corticosteroids, intravenous immunoglobulins (IVIG) and platelet transfusion treatment. As an attempt to increase platelet count prior to performing splenectomy, the thrombopoietin receptor agonist, romiplostim, was administered in combination with steroids and IVIG. A single administration of romiplostim was found to be markedly effective, allowing a rapid and notable platelet increase, required for a well tolerated splenectomy. This case confirms the potent activity of romiplostim in ITP, and indicates that patients with recurrent primary ITP who are unresponsive to conventional immunosuppressive therapy may benefit from the addition of a short course of romiplostim.

The issue of refractory disease in follicular and other lymphoma subtypes

A evolucao dos linfomas tem sido definitivamente melhorada ao longo das ultimas decadas. Isto se deve principalmente devido a introducao e desenvolvimento de novas e efetivas abordagens terapeuticas. Apesar disto, uma pequena parcela deste notavel grupo de pacientes pode apresentar uma pobre resposta aos tratamentos, com uma verdadeira refratariedade, ou com resposta transitoria e precocemente uma recidiva. A presente revisao aborda este assunto da doenca refrataria nos pacientes com linfoma, enfocando sua incidencia global e os principais aspectos clinicos associados a refratariedade.