Successful salvage therapy of irinotecan for relapsed Hodgkin's lymphoma

A 30-year-old man, who had a repeated history of relapsed Hodgkin's lymphoma over 7 years, developed bilateral pleural effusion and chest wall involvement. He was treated with weekly irinotecan hydrochloride (CPT-11; 80 mg/m2/week). Partial response was observed after two cycles of irinotecan. Neutropenia and diarrhea were tolerable. This case demonstrated that irinotecan has a therapeutic effect in patients with relapsed Hodgkin's lymphoma.     

Long-term outcomes after high dose therapy and autologous haematopoietic cell rescue for refractory/relapsed Hodgkin lymphoma

The standard treatment for patients with refractory or relapsed Hodgkin lymphoma (HL) is high-dose chemotherapy and/or radiation with autologous haematopoietic cell rescue (AHCR). In this study, we assessed quality of life and evaluated the risk of late morbidity and mortality for HL patients who underwent AHCR. One hundred and fifty-four patients who underwent AHCR at Stanford University from 1988 to 2002 and survived ≥2 years were evaluated. Median follow-up was 10·2 years. There were 54 deaths, 34 from HL, 20 from other causes. The 10-year cumulative incidence of death from HL or other causes was 21·7% and 12·7%, respectively. Thirteen deaths were from second malignancies. The risk ratio of second malignancies was 8·0 [95% confidence interval (CI), 4·7–12·6] compared with the general population, and 3·0 (95% CI, 1·8–4·8) compared with HL patients not undergoing AHCR. The risk ratio of second malignancies was 1·5 (95% CI, 0·9–2·4) compared with HL patients receiving non-AHCR therapy. Overall quality of life did not differ from the general population, but AHCR survivors did note reduced functioning and some worse symptoms. AHCR survivors may be at increased risk of death from HL and other causes compared with the general population, but not compared with the HL population as a whole.     

Successful salvage therapy of continuous low-dose irinotecan for a patient with relapsed and refractory diffuse large B-cell lymphoma

A 46-year-old man with relapsed and refractory diffuse large B-cell lymphoma after salvage therapy (EPOCH and ESHAP regimens) was treated with continuous low-dose CPT-11 (irinotecan hydrochloride) at 30 mg/day (20 mg/m2/day) for three consecutive days every week. The patient's general condition and both LDH and CRP, tumor related markers, improved dramatically. Complete remission was achieved after a 10-week cycle of therapy without severe adverse effects. Unfortunately, the lymphoma relapsed after allogeneic hematopoietic stem cell transplantation, low-dose CPT-11 therapy was used again to palliate tumor symptoms for 12 months. This therapy may be a useful salvage and palliative chemotherapy for relapsed and refractory lymphoma.     

Bendamustine combined with rituximab for patients with relapsed or refractory diffuse large B cell lymphoma

Patients with relapsed or refractory diffuse large B cell lymphoma (DLBCL) are treated with salvage regimens and may be considered for high-dose chemotherapy and autologous stem cell transplantation if disease is chemosensitive. Bendamustine is active in indolent B cell lymphomas and chronic lymphocytic leukemia but has not been extensively studied in aggressive lymphomas. This trial examines the combination of bendamustine and rituximab in patients with relapsed and refractory DLBCL. Patients received bendamustine at 90 mg/m² (n?=?2) or 120 mg/m² (n?=?57) on days 1 and 2 and rituximab at 375 mg/m² on day 1 every 28 days for up to 6 cycles. The study evaluated objective response rate (ORR), duration of response (DOR), progression-free survival (PFS), and treatment safety. Fifty-nine patients were treated, and 48 were evaluable for response. Median age was 74; 89 % had stage III or IV disease, and 63 % had high revised International Prognostic Index scores; the median number of prior therapies was 1. Based on analysis using the intent-to-treat population, the ORR was 45.8 % (complete response, 15.3 %; partial response, 30.5 %). The median DOR was 17.3 months, and the median PFS was 3.6 months. Grade 3 or 4 hematological toxicities included neutropenia (36 %), leukopenia (29 %), thrombocytopenia (22 %), and anemia (12 %). The combination of bendamustine and rituximab showed modest activity in patients with relapsed and refractory DLBCL and has an acceptable toxicity profile.     

How I manage patients with relapsed/refractory diffuse large B cell lymphoma

Despite progress in the upfront treatment of diffuse large B cell lymphoma (DLBCL), patients still experience relapses. Salvage chemotherapy followed by autologous stem cell transplantation (ASCT) is the standard second‐line treatment for relapsed and refractory (R/R) DLBCL. However, half of the patients will not be eligible for transplantation due to ineffective salvage treatment, and the other half will relapse after ASCT. In randomized studies, no salvage chemotherapy regimen is superior to another. The outcomes are affected by the secondary International Prognostic Index at relapse and various biological factors. The strategy is less clear in patients who require third‐line treatment. A multicohort retros pec tive non‐Hodgkin lymphoma research (SCHOLAR‐1) study conducted in 636 patients with refractory DLBCL showed an objective response rate of 26% (complete response 7%) to the next line of therapy with a median overall survival of 6·3 months. In the case of a response followed by transplantation, long‐term survival can be achieved in DLBCL patients. There is clearly a need for new drugs that improve salvage efficacy. Encouraging results have been reported with chimeric antigen receptor ‐T cell engineering, warranting further studies in a well‐defined control group of refractory patients. The Collaborative Trial in Relapsed Aggressive Lymphoma (CORAL) was used as a handy framework to build the discussion.     

Diffuse large B cell lymphoma: molecular targeted therapy

Diffuse large B cell lymphoma (DLBCL) is a biologically heterogeneous disease and the most common subtype of B cell non-Hodgkin??s lymphoma in the USA. Even though it is a curable lymphoma in advanced stages, up to 40?% of patients eventually relapse or fail to achieve remission. Improved understanding of the biologic complexity of DLBCL reveals a diverse range of oncogenic driver mutations and signaling pathways that are essential for growth and survival of malignant cells. Since many of these signaling pathways can be targeted by small-molecule inhibitors, the therapy for DLBCL is currently undergoing a paradigm shift away from conventional chemotherapy and toward targeted agents that capitalize on an improved biologic understanding of the subsets with the highest risk of treatment failure. Participation in well-conducted and rationally designed clinical trials will be essential to realize the potential of these targeted agents and realize the goal of improving overall outcomes in the most common B cell lymphoma in the world.     

Successful salvage therapy with cladribine and rituximab for a patient with a relapsed Asian variant of intravascular large B-cell lymphoma

The Asian variant of intravascular large B-cell lymphoma (AIVL) is a rare aggressive lymphoma characterized by various clinical symptoms, hemophagocytic syndrome and predominant growth within vessels. We present a 73-year-old man with relapsed AIVL who had been treated with six courses of CHOP regimen. A half year later, he presented with high fever, sweat, dementia and hepatosplenomegaly without lymphadenopathy. A bone marrow biopsy showed prominent hemophagocytosis and immunological staining disclosed an augmented intrasinusal pattern of atypical large lymphocytes characteristic of the CD20+ and CD5+ phenotypes. As salvage therapy, CND-R (rituximab, cladribine, mitoxantrone, dexamethasone) was performed, and the clinical symptoms immediately and dramatically improved. Subsequently, CND-R therapy was repeated every 4 weeks. No serious adverse events were observed with the exception of grade 4 neutropenia and grade 3 thrombocytopenia. After completion of the fifth course, a bone marrow biopsy pathologically confirmed complete remission, leading to termination of this therapy. The patient has remained in remission for more than 15 months. CND-R therapy, which is effective for indolent lymphoma, may be one of the candidates in salvage therapy for relapsed AIVL.     

Bendamustine plus rituximab for relapsed or refractory diffuse large B cell lymphoma: a multicenter retrospective analysis

Bendamustine plus rituximab (BR) showed efficacy and safety in indolent lymphomas and mantle cell lymphoma. However, there were limited experiences of real-world practice of BR in diffuse large B cell lymphoma (DLBCL). In this study, we report the Korean experiences with BR in relapsed or refractory DLBCL who are not eligible for intensive chemotherapy and autologous stem cell transplantation. This is an observational, multicenter, retrospective analysis. Between December 2011 and December 2015, a total of 58 patients with relapsed or refractory DLBCL were treated with BR in 11 tertiary hospitals in Korea. Patients received an intravenous (IV) infusion of rituximab at a dose of 375 mg/m² on day 1. On days 2 and 3, patients received an IV infusion of bendamustine at doses of 120 or 90 mg/m². Median age was 69 (range 18–86), 74.1% had stage III or IV disease, and 67.2% showed high-intermediate or high International Prognostic Index scores at diagnosis. In an intention-to-treat analysis, 18 patients (31.0%) showed a complete response and 14 (24.1%) showed a partial response, resulting in an overall response rate of 55.1%. The median duration of the response was 3.7 months (range 1.0–47.2 months). The median progression-free survival was 3.9 months (95% confidence interval [CI], 2.4–5.4 months), and the median overall survival was 6.7 months (95% CI, 4.7–8.7 months). The most common grade 3/4 adverse event was neutropenia (n?=?40; 68.9%). Febrile neutropenia was observed in 11 patients (18.9%). Grade 3/4 thrombocytopenia was observed in 34 patients (58.6%). Our study confirmed the high efficacy and acceptable toxicity profile of BR in relapsed or refractory DLBCL patients. However, we need to closely observe the higher tendency of grade 3/4 hematological toxicities in Korean patients.     

Prophylactic CNS directed therapy in systemic diffuse large B cell lymphoma

Overall survival in diffuse large B-cell lymphoma (DLBCL) has significantly improved in the last decade, especially after the incorporation of rituximab. Involvement of the central nervous system (CNS) at presentation or at recurrence is an uncommon event, but carries a dismal prognosis with median survival of less than 6 months. Although prophylactic CNS directed therapy is a widely used approach to prevent this complication, randomized clinical trials have been very limited. CNS prophylaxis has inherent toxicities; therefore, identifying the population of patients who would receive most benefit is of utmost importance. From an extensive review of current literature, we report the incidence of CNS relapse in DLBCL and describe the role of CNS prophylaxis in the post-rituximab compared to the pre-rituximab era. We also review the current modalities of CNS prophylaxis and attempt to identify the high-risk patients who would benefit. Lastly, we present a treatment algorithm that defines the role of CNS prophylaxis in the management of patients with DLBCL.     

Primary cutaneous diffuse large B cell lymphoma relapsed solely as a huge lung tumor mimicking a primary pulmonary lymphoma

Primary cutaneous large B cell lymphoma, leg type (PCLBCL-leg) has recently been identified and recognized as a specific entity. Patients with PCLBCL-leg have a higher relapse rate and a poorer prognosis than the other types of primary cutaneous B cell lymphomas, and disease relapse is confined to the skin in the majority of cases with rare exclusive extracutaneous progression. The late occurrence of lymphoma in patients with a prior history of lymphoma may represent a relapse/progression or a distinct tumor unrelated to the original one. The distinction is of important clinical and therapeutic implications. Here, we report the case of a 90-year-old lady with a history of PCLBCL-leg in complete remission after radiotherapy that developed a huge, solitary pulmonary lymphoma without lymphadenopathy 14 months later. The latter was initially considered as stage IE primary pulmonary lymphoma and was treated with combination chemotherapy resulting in complete remission. Retrospective pathologic review and B cell clonality study revealed that the pulmonary tumor was a diffuse large B cell lymphoma of the same clonal origin as the PCLBCL-leg. This case is unique in the exclusive pulmonary relapse and illustrates the importance of expert pathological review and molecular study in the management of lymphoma patients with unusual clinical features.     

Electrocardiographic changes following surgical repair of ostium primum defect.

A four-year-old boy had an OPD with an ECG showing a LAH pattern. After surgical repair the ECG changed to a pattern of LBBB with right axis deviation. This case suggests that early activation of the posterior left ventricular wall associated with partial impairment in the anterior portion of the left bundle, and abnormal hemodynamics, accounts for the superiorly oriented frontal plane QRS axis in patients with OPD.     

同种异体胸骨移植修复胸骨肿瘤切除后胸壁缺损

目的观察同种异体胸骨移植修复胸骨肿瘤切除后胸壁缺损的效果。方法对21例胸骨肿瘤患者行胸骨部分或全部切除,用经深低温冷冻处理后的同种异体胸骨重建骨性胸壁,用胸大肌肌瓣、胃网膜右或左动脉为蒂的大网膜重建胸壁软组织。分别于术前4 d及术后14、28 d空腹抽取外周血,检测外周血T淋巴细胞亚群(CD4、CD8、CD3)及血清补体(C3、C4)和循环免疫复合物(CIC),观察宿主的免疫反应;分别于术后1、4、6、9、12、24、48个月行胸部X线检查,观察异体胸骨愈合情况;术后3、6、9、12、24、48个月行99mTe SPECT骨扫描,观察宿主的免疫反应及与异体骨的成活替代或吸收情况。结果本组重建后胸廓外形良好,无感染,无排异反应,呼吸动度良好;仅1例皮肤愈合延迟。外周血T淋巴细胞亚群及血清C3、C4、CIC手术前后比较,P均>0.05。胸部X线检查结果显示,异体胸骨愈合率为94.7%(18/19)。术后3～6个月SPECT骨扫描显示,移植的异体胸骨两端及髓腔内同位素浓集明显低于正常,而异体胸骨两端所对应的自体骨端同位素浓集明显高于正常;此现象于移植后9个月开始逐渐减弱。结论采用同种异体胸骨移植修复胸骨肿瘤切除后胸壁缺损,不仅确保了胸廓的完整性与稳定性,且排异反应轻、不良反应少。     

Intravascular large B cell lymphoma with migratory local high density shadow by chest CT and diagnosed by transbronchial lung biopsy

The intravascular large B cell lymphoma (IVL) is a rare subtype characterized by the presence of lymphoma cells in the lumina of small vessels. Reported here is the case of a 68-year-old woman with a high-grade fever uncontrolled by antibiotics or antipyretic drugs, and elevation of the serum LDH and sIL-2R levels. After she was admitted, dyspnea, hypoxia, and severe body weight gain with leg edema gradually developed. Chest computed tomography (CT) revealed a characteristic migratory local high density area typical of atelectasis. A diagnosis of IVL was made with a transbronchial lung biopsy (TBLB) and immunohistochemical analysis. The patient was treated with combination chemotherapy (modified CHOP), and her symptoms of dyspnea, hypoxia, pyrexia and leg edema were quickly resolved. The level of LDH and sIL-2R returned to normal, and a complete response was obtained. Although diagnosis of IVL is difficult, an early and appropriate diagnostic procedure (biopsy of tissue with vessels, such as lung and skin, is required) will improve the prognosis of IVL.     

Outcomes for patients who fail high dose chemoradiotherapy and autologous stem cell rescue for relapsed and primary refractory Hodgkin lymphoma

Most patients with Hodgkin lymphoma (HL) are cured with first and second-line treatment; however, the outcome is unknown for those who fail high dose chemoradiotherapy with autologous stem cell transplant (HDT-ASCT). This report is an analysis of patients with relapsed and primary refractory HL who were treated with HDT-ASCT and failed due to progression of disease (POD). Two hundred and two patients received HDT-ASCT at Memorial Sloan Kettering Cancer Center for relapsed or refractory HL between December 1994 and 2005 and 71 failed due to POD. The median survival following HDT-ASCT failure was 25 months. Only 16 (23%) of the 71 patients are currently alive, nine of whom are in remission. Multivariate analysis revealed two factors associated with poor outcome: relapse within 6 months of HDT-ASCT and primary refractory disease. The only factor associated with improved survival was the ability to receive a second transplant, in particular, reduced intensity allogeneic transplant (RIT). Novel therapies are needed for patients who fail HDT-ASCT, particularly those with primary refractory disease and those who relapse within 6 months of HDT-ASCT. Future studies should focus on prospectively evaluating RIT following HDT-ASCT failure in patients with remission duration from HDT-ASCT of >6 months.     

Lymphopenia following the completion of first-line therapy predicts early relapse in patients with diffuse large B cell lymphoma

Early relapse is a parameter that affects clinical outcomes in relapsed diffuse large B cell lymphoma (DLBCL). The prognostic value of lymphopenia following the completion of first-line therapy and the relationship between lymphopenia and early relapse are unknown. Therefore, we studied the role of absolute lymphocyte count (ALC) on early relapse. We retrospectively analyzed de novo DLBCL patients who were treated with rituximab-containing treatment between 2003 and 2010. The median age at the time of diagnosis of 59 DLBCL patients was 71 years. We identified no association between ALC at diagnosis and ALC following the completion of first-line therapy. Among all patients analyzed, 13 (22%) patients were confirmed to exhibit early relapse. Low ALC following the completion of first-line therapy was significantly associated with early relapse by univariate analysis [hazard ratio (HR) = 4.05; 95% confidence interval (CI), 1.11–14.73; P = 0.02] and multivariate analysis (HR = 4.66; 95% CI, 1.24–17.48; P = 0.023). The low ALC group tended to have worse outcomes than the high ALC group with lower rates of progression-free survival (66% and 74%, respectively; P = 0.13) and overall survival (74% and 86%, respectively; P = 0.09), but these differences did not reach statistically. Lymphopenia following the completion of first-line therapy can be used as a marker to predict early relapse.     

Pathogenesis of diffuse large B cell lymphoma

Substantial additional insight has been obtained in the past decade regarding the pathogenesis of diffuse large B cell lymphoma (DLBCL). Distinct subtypes of DLBCL have been defined by gene expression profiling (GEP) and they differ not only in GE profiles but also in the pattern of genetic abnormalities. The ability to correlate corresponding genetic and GEP data markedly facilitates the identification of target genes in regions with copy number abnormalities. Oncogenic pathways are often differentially activated in these different subtypes of DLBCL, suggesting that therapy should be targeted according to these differences. The tumor microenvironment plays a significant role in determining outcome and may be a novel target for therapy. The role of microRNA in lymphomagenesis is increasingly being recognized and mutation of key genes has been demonstrated to drive the activation of the NF-κB pathway and B cell receptor signaling. The pace of discovery will be even more rapid in the near future with the convergence of data from multiple complementary genome-wide studies and technological innovations including the rapid advance in the technology of high-throughput sequencing.