Lenalidomide in Relapsed or Refractory Diffuse Large B-Cell Lymphoma: Is It a Valid Treatment Option?

BACKGROUND: Despite the advent of new treatment strategies, many patients with diffuse large B-cell lymphoma (DLBCL) relapse or die of the disease. Prospective clinical trials have demonstrated that lenalidomide is an effective and safe treatment option, especially for non-germinal center B-cell (non-GCB) DLBCL. However, routine clinical data are lacking, which is why we provide the results of the so-far largest relapsed/refractory (R/R) DLBCL real-life analysis. METHODS: We retrospectively assessed 123 R/R DLBCL patients who received either 15 or 25 mg/day of lenalidomide from January 2006 to January 2015. RESULTS: During a median follow-up period of 4.5 years, complete remission was achieved in 32% and a partial remission in 33% non-GCB patients compared with 0% and 3% in the GCB group (p < .001 and .001, respectively), with median response durations of 15 and 5 months, respectively (p < .001). Lenalidomide at 25 mg was superior to 15 mg in terms of response (complete remission 21% and partial remission 23% vs. 0% and 8%; p = .007 and .05) and median response duration (10 vs. 4 months; p = .03). Toxicity was limited and reversible. Median progression-free survival differed between non-GCB and GCB patients (37 vs. 30 months; p < .001) and between the two dosages (24 vs. 34 months; p = .002). However, overall survival was similar between the subgroups (38-42 months). CONCLUSION: We provide evidence that lenalidomide is a valid treatment option for R/R DLBCL, with limited and reversible toxicity, and is more efficient in non-GCB DLBCL and at higher doses. IMPLICATIONS FOR PRACTICE: Despite the advent of new treatment strategies, many patients with diffuse large B-cell lymphoma (DLBCL) relapse or die of the disease; hence, novel therapeutic approaches are urgently needed. This study confirms that lenalidomide is a valid and well-tolerated treatment option for relapsed/refractory (R/R) DLBCL. Superior outcomes were observed in non-germinal center B-cell (GCB) DLBCL, probably because of inhibition of the nuclear factor-κB pathway. Similarly, high drug doses resulted in greater clinical benefits. Overall, lenalidomide is a suitable therapeutic option for R/R DLBCL, especially in non-GCB DLBCL, and 25 mg/day dosing should be preferred.

Patients with myeloid malignancies bearing PDGFRB fusion genes achieve durable long-term remissions with imatinib.

Myeloid neoplasms and eosinophilia with rearrangements of PDGFRB are uncommon Philadelphia-negative myeloproliferative neoplasms. Patients are typically male, with morphologic features of a Philadelphia-negative chronic myeloproliferative syndrome or chronic myelomonocytic leukemia with eosinophilia. Reciprocal translocations involving PDGFRB result in fusion genes with constitutively activated receptor tyrosine kinase sensitive to inhibition with imatinib. We present an updated and expanded analysis of a cohort of 26 such patients treated with imatinib. After a median follow-up of 10.2 years (range, 1.8-17 years), the 10-year overall survival rate was 90% (95% confidence interval, 64%-97%); after median imatinib duration of 6.6 years (range, 0.1-12 years), the 6-year progression-free survival rate was 88% (95% confidence interval, 65%-96%). Of the patients, 96% responded; no patients who achieved a complete cytogenetic (n = 13) or molecular (n = 8) remission lost their response or progressed to blast crisis. Imatinib is well-tolerated and achieves excellent long-term responses in patients with PDGFRB rearrangements.

Bendamustine plus rituximab versus R-CHOP as first-line treatment for patients with indolent non-Hodgkin's lymphoma: evidence from a multicenter, retrospective study.

The optimal first-line treatment for advanced low-grade non-Hodgkin lymphomas (LG-NHL) is still highly debated. Recently, the StiL and the BRIGHT trials showed that the combination of rituximab and bendamustine (R-B) is non-inferior to rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) with a better toxicity profile. Utilizing a retrospective analysis, we compared the efficacy and safety of both regimens in clinical practice. From November 1995 to January 2014, 263 LG-NHL patients treated with either R-B or R-CHOP were retrospectively assessed in seven European cancer centers. Ninety patients were treated with R-B and 173 with R-CHOP. Overall response rate was 94 and 92 % for the R-B and the R-CHOP group, respectively. The percentage of complete response was similar for both groups (63 vs. 66 % with R-B and R-CHOP, respectively; p = 0.8). R-B was better tolerated and less toxic than R-CHOP. The median follow-up was 6.8 and 5.9 years for the R-CHOP and the R-B group, respectively. Overall, no difference in progression-free survival (PFS) (108 vs. 110 months; p = 0.1) was observed in the R-B group compared to the R-CHOP cohort. Nevertheless, R-B significantly prolonged PFS in FL patients (152 and 132 months in the R-B and R-CHOP group, respectively; p = 0.05). However, this result was not verified in multivariate analysis probably due to the limits of the present study. We confirm that the R-B regimen administered in patients with LG-NHL is an effective and less toxic therapeutic option than R-CHOP in clinical practice.

Cancer cachexia syndrome: pathogenesis, diagnosis, and new therapeutic options.

Cancer anorexia-cachexia syndrome (CACS) is the most frequent paraneoplastic syndrome occurring in half of all oncologic patients and is considered as a poor prognosticator. Patients usually present with weight loss, lipolysis, muscle wasting, anorexia, chronic nausea, inflammation, and asthenia. The etiopathogenesis of CACS is still poorly understood, although several factors and biological pathways are known to be involved. Because of the complexity of this multifactorial condition, a single agent therapy may not be sufficient. Indeed, there is a tendency toward an integrated multiple approach including nonpharmacological and pharmacological treatments. However, despite encouraging preliminary results, currently there is not enough evidence to support a change in clinical practice. This review provides a brief and practical summary of the diagnosis, pathogenesis, and treatment of CACS. Future perspectives will also be discussed.

Personalized treatment of early-stage non-small-cell lung cancer: the challenging role of EGFR inhibitors.

Adjuvant cisplatin-based chemotherapy significantly improves outcomes of completely resected early-stage non-small-cell lung cancer (NSCLC) patients. However, its effect on overall survival is limited and may be unsuitable for many patients due to toxicity. Targeted therapies and individualization of adjuvant treatment offer the potential to improve curability and extend survival of these patients while decreasing toxicity. Here we review Phase II and III studies examining the role of EGF receptor inhibitors, including tyrosine kinase inhibitors and the monoclonal antibody cetuximab, as adjuvant therapy in resected patients or as part of multimodality treatment for stage III NSCLC. Recent results from genotype-directed adjuvant tyrosine kinase inhibitors trials including early-stage NSCLC patients with EGFR mutations are promising, but more data are needed to support their use in this setting.

Emerging markers of cachexia predict survival in cancer patients.

BACKGROUND: Cachexia may occur in 40% of cancer patients, representing the major cause of death in more than 20% of them. The aim of this study was to investigate the role of leptin, ghrelin and obestatin as diagnostic and predictive markers of cachexia in oncologic patients. Their impact on patient survival was also evaluated. METHODS: 140 adults with different cancer diagnoses were recruited. Thirty healthy volunteers served as control. Serum ghrelin, obestatin and leptin were tested at baseline and after a follow-up period of 18 months. RESULTS: Ghrelin levels were significantly higher in cancer patients than in healthy subjects (573.31 ± 130 vs 320.20 ± 66.48 ng/ml, p < 0.0001), while obestatin (17.42 ± 7.12 vs 24.89 ± 5.54 ng/ml, p < 0.0001) and leptin (38.4 ± 21.2 vs 76.28 ± 17.48 ng/ml, p < 0.0001) values were lower. At ROC analyses the diagnostic profile of ghrelin (AUC 0.962; sensitivity 83%; specificity 98%), obestatin (AUC 0.798; sensitivity 74.5%; specificity 81.5%) and leptin (AUC 0.828; sensitivity 79%; specificity 73%) was superior to that of albumin (AUC 0.547; sensitivity 63%, specificity 69.4%) for detecting cachexia among cancer patients. On Cox multivariate analyses ghrelin (HR 1.02; 95% CI 1.01 - 1.03; p < 0.0001) and leptin (HR 0.94; 95% CI 0.92 - 0.96; p < 0.0001) were significant predictors of death even after correction for other known risk factors such as presence of metastasis and chronic kidney disease. CONCLUSION: Ghrelin and leptin are promising biomarkers to diagnose cachexia and to predict survival in cancer patients.

Temozolomide-induced shrinkage of a pituitary carcinoma causing Cushing's disease--report of a case and literature review.

Temozolomide (TMZ) is an alkylating chemotherapeutic agent that has recently been used in some cases as a new therapeutic tool for pituitary carcinomas and aggressive pituitary adenomas. In this report, we present the case of effective TMZ treatment in a 42-year-old man with ACTH-secreting carcinoma. The tumor grew progressively over 4 years, from 2.2 to 31.1 cm³, despite three surgical approaches and γ-knife treatment. Ki-67 increased from 2 to 18%. An intradural metastasis at the foramen magnum was detected by MRI after the third operation. Thereafter, four cycles of 5-day TMZ administration (200 mg/m²/day during the first, and 150 mg/m²/day during the following cycles) induced dramatic tumor size reduction (>90%). Clinical conditions improved progressively and, after 17 months from the beginning of TMZ administration, the patient is still alive. The treatment was well tolerated except for a transient thrombocytopenia (grade 4 WHO).

Interferon Alpha Has a Strong Anti-tumor Effect in Philadelphia-negative Myeloproliferative Neoplasms.

BACKGROUND: Despite the important progress in the research of myeloproliferative neoplasms (MPN), treatment options are still limited. Currently, a cytoreductive approach is the backbone treatment, with hydroxyurea (HU) being the most important agent. However, this drug is not always well-tolerated and has been questionably linked to a potential leukemogenic effect. A valid alternative is interferon alfa (IFN-α), but it is reserved for selected patients owing to the more frequent side effects and the lack of final results from the studies directly comparing IFN-α with HU, which is why we provided the results of the so far largest real-life analysis. PATIENTS AND METHODS: From 2000 to 2016, 63 patients with Philadelphia-negative MPN prospectively received either HU or IFN-α. RESULTS: During a median follow-up period of 121 months (range, 88-168 months), 97% of the patients treated with IFN-α achieved a hematologic response (60% complete, 37% partial) compared with 78% in the HU group (56% complete, 20% partial; P < .01). Molecular responses were limited to patients treated with IFN-α. IFN-α was well-tolerated with no secondary malignancy, whereas HU was associated with more toxic events and cases of leukemic transformation. A significantly longer progression-free survival (5.0 vs. 3.1 years; P < .001) and overall survival (7.8 vs. 5.8 years; P = .006) were observed in the IFN-α group compared with the HU cohort. CONCLUSION: Our data support IFN-α as a more valid therapeutic option owing to its more profound hematologic responses, durable molecular remissions, long-term disease control, and reduced risk of leukemic transformation with a favorable toxicity profile.

Bisphosphonate-associated osteonecrosis of the jaw: a review of 35 cases and an evaluation of its frequency in multiple myeloma patients.

Over a period of 28 months, we observed five cases of osteonecrosis of the jaw (ONJ) in cancer patients treated with bisphosphonates (BP) at our institution. This prompted us to undertake a retrospective, multicenter study to analyse the characteristics of patients who exhibited ONJ and to define the frequency of ONJ in multiple myeloma (MM). We identified 35 cases in Gruppo Italiano Studio Linfomi centers during the period 2002 - 05. The median time from cancer diagnosis to the clinical onset of ONJ was 70 months. In these 35 cases of ONJ, 24 appeared 20 - 60 months after starting BP treatment. The time for the onset of ONJ was significantly shorter for patients treated with zoledronic acid alone than for those treated with pamidronate followed by zoledronic acid. The frequency of ONJ in the MM group during the study period was 1.9%, although the nature of the present study may have resulted in an underestimation of ONJ cases. Our analysis strongly suggested an association between the use of BP and the occurrence of ONJ, although we were unable to identify any definite risk factors with a retrospective study. The most frequently ONJ-associated clinical characteristics were chemotherapy treatment, steroid treatment, advanced age, female sex, anemia, parodonthopaties/dental procedures and thalidomide (in the case of MM patients).

Pitfalls of positron emission tomography for assessing relapse in Hodgkin's disease: a case report.

FDG-PET imaging is more frequently being used to stage malignant Lymphoma and monitor response to therapy. However, FDG-PET is not a tumor specific substance and increased accumulation may be seen in a variety of benign entities, our case exemplifies this problem and underline the importance of a biopsy.

90Y-Ibritumomab-Tiuxetan Consolidation Therapy for Advanced-Stage Mantle Cell Lymphoma After First-Line Autologous Stem Cell Transplantation: Is It Time for a Step Forward?

BACKGROUND: Mantle cell lymphoma (MCL) is an aggressive lymphoma with a dismal prognosis because of numerous relapses. Because the most promising results have been obtained with immunochemotherapy followed by autologous cell stem transplantation (ASCT), we evaluated the efficacy of yttrium-90 ibritumomab ((90)Y-IT) consolidation after such an intensive treatment. PATIENTS AND METHODS: We retrospectively assessed 57 patients affected by intermediate or high-risk MCL in complete remission (CR) or partial remission (PR) after 3 cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin [hydroxydaunorubicin], vincristine [Oncovin], prednisolone) plus 3 cycles of R-DHAP (dexamethasone, cytarabine [Ara-C], cisplatin [platinum]) followed by ASCT and additional consolidation treatment with (90)Y-IT in 28 cases. All patients underwent 2 years of rituximab maintenance. RESULTS: After ASCT, 94% achieved CR and 4% achieved PR. The median follow-up was 6.2 years (range, 1.8-9.7 years). Treatment intensification was well tolerated and led to a significantly longer response duration in comparison to standard treatment. In contrast to the historical cohort, the addition of (90)Y-IT seems to overcome important risk factors such as Mantle Cell Lymphoma International Prognostic Index (MIPI) score and bone marrow infiltration. CONCLUSION: In the present retrospective analysis, immunochemotherapy followed by ASCT resulted in a very high response rate, and subsequent (90)Y-IT consolidation significantly reduced the number of relapses and increased survival, suggesting that (90)Y-IT consolidation might be a valid option in first-line treatment. However, a prospective confirmatory trial is warranted.

Thyroid function, autoimmunity and nodules in hematological malignancies.

OBJECTIVE: Hematological malignancies encompass a large spectrum of disease entities whose treatment by chemo/radiotherapy could lead to thyroid complications. To the best of our knowledge, no study has simultaneously addressed thyroid function, autoimmunity and nodularity. Therefore, we decided to conduct one. MATERIALS AND METHODS: We evaluated 82 Caucasian patients (36 women and 46 men), who were treated at our Oncology division for hematological malignancies (multiple myeloma, chronic myeloid leukemia, chronic lymphatic leukemia, non-Hodgkin lymphoma and polycythemia vera) and compared them with a control group of 104 patients. Patients who had received or were receiving external head/neck radiotherapy were excluded. All oncological patients and control individuals underwent thyroid ultrasonography and thyroid function and autoimmunity tests. RESULTS: A lower prevalence of enlarged thyroid and nodules were found in patients with respect to controls. The rate of thyroid nodules was the highest in multiple myeloma and polycythemia vera, and the lowest in chronic lymphatic leukemia. Non-Hodgkin lymphoma patients had the smallest thyroid nodules while men with multiple myeloma the biggest ones. No patient had hypothyroidism, while 5.6% of patients had subclinical hyperthyroidism. In contrast, within the control group the rates of hypothyroidism and hyperthyroidism, overt and subclinical, were 3.8%, 20.2%, 0% and 0% respectively. Moreover, the overall rate of thyroid autoantibody positiveness in patients was significantly lower than controls. CONCLUSION: In our experience, we found a significantly lower prevalence of thyroid abnormalities in hematologic patients who underwent chemotherapy, but not radiotherapy, with respect to controls.

Extranodal diffuse large B-cell lymphoma with monoclonal gammopathy: an aggressive and primary refractory disease responding to an immunomodulatory agent.

BACKGROUND: Although the clinical outcome of patients with diffuse large B cell lymphoma (DLBCL) has been improved by the addition of rituximab to standard chemotherapy, almost one-third fails or relapses after first line treatment. The presence of monoclonal gammopathy (MG) is a known adverse prognostic factor for DLBCL. Because this subset of patients does not benefit from R-CHOP, new therapeutic options are required. Herein, we report the first case of extranodal DBCL of the lung with a concomitant MG who achieved a long lasting complete remission with lenalidomide. CASE PRESENTATION: The 73-year-old male patient presented with lateral cervical lymphadenopathy, B symptoms, lactate dehydrogenase and beta2-microglobulin elevation. Computed tomography (CT) showed mediastinal lymphadenopathy and bilateral lung involvement. Biopsy of both disease locations revealed the presence of DLBCL. Successive bone marrow trephine biopsy proved the presence of concordant DLBCL involvement. At the time of diagnosis, a MG was present as well. The patient did not respond to the standard treatments, and subsequently underwent lenalidomide 25 mg/m(2) days 1-21 q28 plus dexamethasone 40 mg days 1-4, 9-12 e 17-20. This therapeutic regimen was efficacious and safe as salvage therapy in extranodal DBCL with a MG. Furthermore, we observed a close association between DLBCL response to therapy and MG levels, suggesting that the amount of M-protein might be a surrogate marker of disease response. CONCLUSION: Although DLBCL associated with MG does not respond properly to the standard treatments, it is highly sensitive to lenalidomide, which is why we endorse its role as treatment of choice in this subset of patients. In addition, MG levels appear to correlate with tumor burden, suggesting that it might be a useful marker of disease response. Prospective trials to validate these observations are warranted.

Bendamustine in combination with rituximab for elderly patients with previously untreated B-cell chronic lymphocytic leukemia: A retrospective analysis of real-life practice in Italian hematology departments.

The front-line therapy for CLL young and fit patients is chemo-immunotherapy with fludarabine-cyclophosphamide-rituximab (FCR). FCR regimen results in a significant myelosuppression and high rates of early and late infections especially in elderly patients. German CLL study group compared FCR vs. bendamustine-rituximab (BR) in fit untreated patients. The response rates with BR or FCR were comparable, BR could be an alternative 1st-line treatment for elderly patients. Here we report retrospective data of 70 elderly (≥65 years) CLL patients from 12 Italian centers treated with BR as front-line therapy. The primary end points were overall response rate (complete remission/partial remission) and safety. Forty-seven males and 23 females, with a median age of 72 years, were included in the study. Eight patients were unfit for CIRS. The OR rate was 88.6% (31.4% CR and 57.2% PR). Progression free survival, treatment free survival and overall survival rates at 2-years were 79%, 90.3% and 89.6%, respectively. Only del17 was independent unfavorable parameter on the response rate and PFS. Our results indicate that BR front-line at standard dose provides a high response rate with a good safety profile, even if more than 50% of patients experienced a bendamustine dose reduction until 70 mg/m2.