Disease characteristics of diffuse large B-cell lymphoma predicting relapse and survival after autologous stem cell transplantation: A single institution experience

While various tools such as the International Prognostic Index (IPI) and its derivatives exist for risk-stratification of diffuse large B-cell lymphoma (DLBCL) at diagnosis, patient and disease characteristics capable of predicting outcome after high-dose chemotherapy followed by autologous stem cell transplantation (HDC/ASCT) are not clearly defined. We retrospectively analyzed medical records of 111 DLBCL patients (78 relapsed and 33 refractory) who underwent HDC/ASCT at our institution from 2010-2015. After a median follow-up time of 4.6 years (interquartile range [IQR] 2.2-8.1), the likelihood of 5-year progression-free survival (PFS) was 62.2% (95% CI, 53.4%-72.4%) and the likelihood of 5-year overall survival (OS) was 68.9% (95% CI, 60.7%-78.2%). More than three chemotherapy regimens prior to ASCT was the only variable associated with lower likelihood of PFS (P = .004) and OS (P = 0.026). Male gender and high IPI score at time of ASCT were also associated with lower likelihood of PFS (P = .043; P = .013). NCCN IPI and age-adjusted IPI at time of ASCT were not predictive of outcome following ASCT. Patients with refractory and relapsed disease had similar outcomes post-ASCT (P = .207 for PFS, P = .073 for OS).     

Impact of the introduction of rituximab in first‐line follicular lymphoma: a retrospective study of 247 unselected patients referred to a single institution with a long‐term follow‐up

Rituximab was approved in France in 2004, following randomized trials that demonstrated efficacy in newly diagnosed high tumour burden follicular lymphoma (FL). This retrospective study compared the management and outcome of FL in unselected patients treated in a single institution before and after rituximab approval. Two hundred and forty‐seven adult patients were referred with first‐line FL between 1996 and 2010 and are included in this study. The 103 pre‐rituximab patients comprising cohort 1 were diagnosed between January 1996 and December 2003; cohort 2 includes the 144 patients diagnosed after the approval of rituximab between January 2004 and December 2010. Baseline clinical and biological data, type of therapy, treatment response, progression‐free survival (PFS) and overall survival (OS) rates were compared. There were no statistically significant differences between the two cohorts with respect to baseline clinical and disease characteristics, including FL International Prognostic Index score. The major difference between the two cohorts is the use of rituximab in first line. Seventy‐one per cent of patients in cohort 2 received rituximab (19% alone, 52% with chemotherapy) versus 10% in cohort 1 (2% alone, 8% with chemotherapy; p < 0.0001). The objective response rate (ORR) was significantly higher for cohort 2 (ORR 84% compared with 72% for cohort 1; p = 0.03). The PFS and OS rates were also significantly better: 3‐year PFS 72% [95% confidence interval (CI) 64–80%] versus 55% (95% CI 45–64%), p = 0.0039 and 3‐year OS 98% (95% CI 94–99%) versus 83% (95% CI 74–90%), p = 0.0007. Effect of period of study is significant when using multivariate analysis on PFS and OS and lactate dehydrogenase level (PFS and OS) and age (OS). These data from everyday practice confirm the benefit for patients with FL treated in the last decade through availability of rituximab in first line used alone or in association with various chemotherapy regimens. Copyright © 2014 John Wiley & Sons, Ltd.     

Post Salvage Therapy Autologous Transplant for Relapsed Myeloma,Ongoing Relevance within Modern Treatment Paradigms?

BackgroundSalvage transplant has been historically considered effective therapy for myeloma patients relapsing after first transplant, if they achieved adequate remission duration. However, the efficacy of novel agent combinations has called this paradigm into question.Materials and MethodsWe performed a retrospective analysis in a homogeneously treated cohort of 106 patients undergoing ASCT2 at our institution, all of whom received novel agent-based chemotherapy (immunomodulatory agent [IMiD] and/or proteasome inhibitor [PI]) for both induction and relapse. As an exploratory objective we assessed whether predictive thresholds of progression free survival post first transplant (ASCT1) for benefit post ASCT2 vary with use of IMiD maintenance post ASCT1.ResultsThe overall response rate (ORR) was 98% post-ASCT2 and treatment-related mortality (TRM) was low at 1.8%. With a median follow-up of 26 months (range 0.5-85) from ASCT2, median overall survival (OS) is estimated at 80 months (95% CI: ≥ 49-months) and median progression-free survival after ASCT2 (PFS2) at 24 months (95% CI 19-39). PFS post first transplant (PFS1) at >/= 50 months was associated with improved OS. Predictors of PFS2 included PFS1 ≤42 months and progression on IMiD-based maintenance post- ASCT1.ConclusionASCT2 continues to offer acceptable outcomes for most patients treated within modern day treatment paradigms, with longer PFS after ASCT1 and IMiD non-refractory disease being associated with improved outcomes     

Autologous Stem Cell Transplantation in Central Nervous System Lymphoma: A Multicenter Retrospective Series and a Review of the Literature

BackgroundCentral nervous system (CNS) lymphoma is associated with poor outcomes. Autologous stem cell transplantation (ASCT) has been reported to improve outcomes when used as a consolidation strategy in primary CNS lymphoma (PCNSL) and as a salvage strategy in patients with disease relapse limited to the CNS. Herein, we describe our experience of using ASCT in PCNSL and secondary CNS lymphoma (SCNSL).Patients and MethodsWe evaluated clinical outcomes of 18 patients from 2 major academic centers with a median age of 55 (range, 46-72) years. Thirteen patients had PCNSL and 5 patients had SCNSL. Most of the cases were in the first (CR1) or second (CR2) complete remission (CR1 = 7, CR2 = 7) at the time of ASCT. Carmustine with thiotepa (n = 12, 67%) was the most commonly prescribed preparative regimen.ResultsThe median follow-up from ASCT for surviving patients was 12 (range, 0.9-115) months. The 2-year progression-free survival (PFS) and overall survival (OS) were 74% (95% confidence interval [CI], 48%-99%) and 80% (95% CI, 55%-100%), respectively. Two-year non-relapse mortality was 0%. The 2-year cumulative incidence of relapse/progression was 27% (95% CI, 10%-72%). In subgroup analysis of PCNSL patients, 2-year PFS, OS, and relapse were 71% (95% CI, 38%-100%), 71% (95% CI, 38%-100%), and 29% (95% CI, 9%-92%), respectively.ConclusionIn this retrospective study of patients with CNS lymphoma, consolidation with ASCT after high-dose methotrexate-based chemotherapy is safe and effective in reducing disease relapse.     

Late Relapses After High-dose Chemotherapy and Autologous Stem Cell Transplantation in Patients With Diffuse Large B-cell Lymphoma in the Rituximab Era

BackgroundThe standard of care for diffuse large B-cell lymphoma (DLBCL) relapsing after front-line therapy is high-dose chemotherapy and autologous stem cell transplantation (ASCT). Evidence has suggested that early relapses (ie, within 1 year) after this approach portends exceptionally poor outcomes. However, data examining relapses > 1 year after ASCT for patients with refractory or relapsed DLBCL are limited, in particular, in the rituximab era. We sought to examine the effect of early (≤ 1 year) and late (> 1 year) relapse after ASCT in a single-institution cohort of patients with relapsed and refractory DLBCL treated with chemoimmunotherapy.Materials and MethodsA retrospective analysis was performed on the data from 85 consecutive patients who had undergone ASCT for biopsy-confirmed relapsed or refractory DLBCL from 2001 to 2010 at the University of Rochester Medical Center. All patients had received rituximab as a part of treatment. Of the 85 patients, 35 developed relapse after ASCT. These 35 patients were divided into 2 groups according to the timing of the relapse (≤ 1 year and > 1 year after ASCT).ResultsThe median follow-up period was 6.4 years. For all patients, the overall survival (OS) from post-ASCT relapse was 5.2 years. For the 27 patients developing relapse at ≤ 1 year after ASCT, the median OS was 0.6 year and progression-free survival was 0.4 year. For the 8 patients developing relapse at > 1 year after ASCT, the median OS was 5.9 years and progression-free survival was 2.9 years.ConclusionPatients with relapsed or refractory DLBCL experiencing relapse > 1 year after ASCT had good outcomes. Despite the relative rarity in incidence, a significant risk of relapse of DLBCL after ASCT remains, suggesting the need for continued monitoring because of the possibility of later progression.     

Durable Survival Outcomes in Primary and Secondary Central Nervous System Lymphoma After High-dose Chemotherapy and Autologous Stem Cell Transplantation Using a Thiotepa,Busulfan, and Cyclophosphamide Conditioning Regimen

BackgroundHigh-dose chemotherapy (HDC) with autologous stem cell transplantation (ASCT) has been investigated in patients with primary central nervous system lymphoma (PCNSL) and non-Hodgkin lymphoma (NHL) with CNS involvement and has shown promising results.Patients and MethodsA retrospective analysis was performed of 48 consecutive patients who had undergone HDC/ASCT with TBC (thiotepa, busulfan, cyclophosphamide) conditioning for PCNSL (27 patients), secondary CNS lymphoma (SCNSL) (8 patients), or relapsed disease with CNS involvement (13 patients) from July 2006 to December 2017. Of the 27 patients with PCNSL, 21 had undergone ASCT at first complete remission (CR1).ResultsThe 2-year progression-free survival (PFS) rate was 80.5% (95% confidence interval [CI], 69.9-92.9) and the 2-year overall survival (OS) rate was 80.1% (95% CI, 69.2%-92.7%) among all patients. The 2-year PFS and OS rate for patients with PCNSL in CR1 was 95.2% (95% CI, 86.6%-100%) and 95.2% (95% CI, 86.6%-100%), respectively. On univariate analysis of the patients with PCNSL, ASCT in CR1 was the only variable statistically significant for outcome (P = .007 for PFS; P = .008 for OS). Among patients with SCNSL or CNS relapse, the 2-year PFS and OS rate were comparable at 75.9% (95% CI, 59.5%-96.8%) and 75.3% (95% CI, 58.6%-98.6%), respectively. The most common side effects were febrile neutropenia (89.6%; of which 66.7% had an infectious etiology identified), nausea/vomiting (85.4%), diarrhea (93.8%), mucositis (89.6%), and electrolyte abnormalities (89.6%). Four patients (8.3%) died of treatment-related overwhelming infection; of these patients, 3 had SCNSL.ConclusionHDC and ASCT using TBC conditioning for both PCNSL and secondary CNS NHL appears to have encouraging long-term efficacy with manageable side effects.     

Maintenance rituximab after autologous stem cell transplantation in patients with mantle cell lymphoma

BackgroundHigh-dose therapy and autologous stem cell transplantation (ASCT) improves outcomes for patients with mantle cell lymphoma (MCL), but relapse ultimately occurs in most patients. Recently presented interim results from a phase III prospective trial suggest maintenance rituximab (MR) after ASCT for MCL improves progression-free survival (PFS). The maturation of these data and any benefit of MR on overall survival (OS) remain to be defined.Patients and methodsIn this retrospective study, we examined a cohort of consecutive patients with MCL that underwent ASCT for MCL at our center and evaluated their outcomes according to whether they received MR after ASCT (n = 50) or did not (n = 107). MR was treated as a time-dependent covariate to account for variation in timing of its initiation.ResultsMR was associated with an improved PFS [hazard ratio (HR) 0.44; confidence interval (CI) (0.24–0.80), P = 0.007] and overall survival (OS; HR 0.46; CI 0.23–0.93, P = 0.03) following a multivariate adjustment for confounding factors with a median follow-up of ∼5 years. Grade 4 neutropenia was increased (34% versus 18%, P = 0.04) in the MR group, but no effect on the rate of mortality unrelated to relapse was observed.ConclusionsThese data support that MR after ASCT for MCL confers a benefit in PFS and additionally suggest it may improve OS. General application of this strategy will require confirmation of benefit in prospective randomized trials.     

Long-term outcome of autologous stem-cell transplantation in relapsed or refractory Hodgkin's lymphoma

BackgroundThe purpose of this study was to assess prognostic factors and outcome of patients with relapsed/refractory Hodgkin's lymphoma (HL) who received high-dose chemotherapy and autologous stem-cell transplant (ASCT).Patients and methodsData on 195 patients who received ASCT between 1985 and June 2005 were reviewed. Median time from first treatment to ASCT was 2.6 years (0.4–27.3). Demography at ASCT was 61% stage IV, median age 31 years (18–69), median prior treatment (tx) regimens 3 (2–7), median Hasenclever index 3 (0–6); 150 patients had responding disease [54 complete remission (CR), 96 partial remission (PR)], and 45 patients had untested relapse/refractory disease.ResultsPost-ASCT, 61% (119/195) patients attained CR with an overall response (CR + PR) of 85%. Twelve patients had nonrelapse mortality. Of 119 patients attaining CR, 27 relapsed: 3 after attaining CR for >5 years and 1 after attaining CR for >10 years. Median overall survival (OS)/progression-free survival (PFS) from ASCT was 9 years/2.9 years. Five-year OS/PFS was 55% of 44% and 10-year OS/PFS was 49.4% of 37% for whole group. Twenty (10%) patients developed second cancer (seven secondary acute myeloid leukaemia (AML)/myelodysplastic syndrome (MDS)). Probability of developing second cancer at 10 years was 14.7% (95% confidence interval 8.9% to 23.8%) and 24.8% at 19 years.ConclusionThese data provide the longest follow-up reported for patients receiving ASCT for relapsed/refractory HL. In addition to previously described prognostic factors, our data show that Hasenclever index <3 influences outcome favorably and attaining CR at ASCT leads to a better outcome.     

Clinical value of serum HMGB1 in diagnosis and prognosis of laryngeal squamous cell carcinoma

Autologous hematopoietic stem cell transplantation (AHSCT) is a treatment option for relapsed and recurrent follicular lymphoma (R/R FL); however, its value in the rituximab era remains to be elucidated. To evaluate the safety and clinical outcome of AHSCT for relapsed FL, we present a retrospective series of AHSCT for 30 FL patients (17 male and 13 female) at median age of 49 years. Patients were transplanted in second or subsequent complete or partial response after at least one therapeutic line including chemotherapy and rituximab. Overall, seven patients achieved second or higher complete response (CR) at AHSCT, whereas 23 were transplanted in partial response. Median overall survival (OS) was not reached, whereas progression-free survival (PFS) was 4.8 years. The estimated 10-year OS and PFS were found to be 60 and 33 %, respectively. There was no significant difference in OS and PFS in terms of FLIPI score and disease status at transplant. Median follow-ups from diagnosis and from AHSCT were 4.9 years (range 1.5–18.4 years) and 1.7 years (range 0.03–16.5 years), respectively. Fifteen patients relapsed, and 11 out of them (73 %) died of disease recurrence and chemoresistance. At the last contact, 19 patients are alive: 12 are in CR, whereas seven patients receive salvage regimens due to active lymphoma. AHSCT for relapsed FL patients who were pretreated with rituximab remains a safe procedure with low transplant-related mortality and long-term progression-free survival in about one-third of transplanted patients.     

Prolonged survival after second autologous transplantation and lenalidomide maintenance for salvage treatment of myeloma patients at first relapse after prior autograft

Autologous stem cell transplantation (ASCT) as part of the primary therapy in multiple myeloma (MM) is standard practice. In contrast, the role of a second ASCT (ASCT2) and subsequent lenalidomide maintenance for relapsed disease remains unclear. In this study, we analysed 86 consecutive MM patients with a first relapse after prior ASCT receiving either a second ASCT or conventional chemotherapy. After a median follow‐up of 37.7 months since first relapse, 54 (62.8%) patients were still alive and 29 (33.7%) without progression. Sixty‐one (71.0%) patients received ASCT2 and had better progression‐free survival (PFS) (30.2 versus 13.0 mo; P = .0262) and overall survival (OS) rates (129.6 versus 33.5 mo; P = .0003) compared with 25 (29.0%) patients with conventional treatment. Patients relapsing later than 12 months after ASCT1 benefitted from a second ASCT with better PFS2 (P = .0179) and OS2 (P = .0009). Finally, lenalidomide maintenance after ASCT2 was associated with longer PFS (41.0 vs 21.6 mo; P = .0034) and better OS (not yet reached vs 129.6 mo; P = .0434) compared with patients without maintenance. Our data suggest that a second ASCT and lenalidomide maintenance given at first relapse in MM after prior ASCT are associated with better survival rates.     

Transformed follicular lymphoma in the rituximab era: A report from the Spanish Lymphoma Oncology Group

Follicular lymphoma (FL) is the second most common non‐Hodgkin lymphoma (NHL) subtype. The histological transformation (HT) of FL is an event considered frequent in the natural history of this tumor. We studied the transformation rates, predictive factors, and treatment characteristics that may impact in the survival of patients with FL and HT. A total of 1074 patients diagnosed with FL were prospectively enrolled from 1990 to 2016 in a Spanish registry. Sixty‐four HTs were recorded based on clinical criteria (55%) or histological confirmation (45%). The cumulative incidence rate of transformation at 5 years is 7.3%. The 5‐year overall survival (OS) without HT was 85% (95% confidence interval [CI], 70%‐90%) vs 66% (95% CI, 51%‐76%; P = 0.0012) with HT. Factors associated with HT were elevated lactate dehydrogenase (LDH) (odds ratio [OR] 1.83), intermediate‐high Follicular lymphoma international prognostic index (FLIPI) (OR 2.16‐OR 3.21), B symptoms (OR 2.46), or Eastern Cooperative Oncology Group (ECOG) 1 (OR 2.35). Treatment options related to HT were “watch and wait” or no rituximab or anthracyclines initially. A 5‐year OS for patients treated with chemotherapy before HT was 55% (95% CI, 38%‐69%) versus 81% (95% CI, 53%‐93%; P = 0.009) for those who had not received it. The HT rate has decreased after the introduction of rituximab, as has been previously described. The timing of this treatment had an impact on the survival of these patients.     

Rituximab consolidation after high-dose chemotherapy and autologous blood stem cell transplantation in follicular and mantle cell lymphoma: a prospective, multicenter phase II study.

BACKGROUND: Patients with follicular (FL) or mantle cell lymphoma (MCL) are incurable with conventional therapy. We investigated the safety and efficacy of rituximab consolidation after autologous stem cell transplantation (ASCT) in order to prevent relapse by clearance of minimal residual disease (MRD). METHODS: Rituximab was given approximately 8 weeks after CD34+ cell enriched ASCT at 375 mg/m2, weekly for 4 weeks. Monitoring of MRD was performed by repetitive PCR analyses. RESULTS: Thirty-one patients were included; one died early after ASCT before rituximab administration. Thirty patients (20 FL, 10 MCL) were evaluable after rituximab consolidation, and 27 of these were assessable for MRD detection. Rituximab consolidation post-ASCT was safe, the most common toxicity being infection. At a median follow-up of 42 months (range 13-96) after ASCT, 25 patients were censored with an actuarial event-free survival (EFS) of 81% at 4 and 5 years. Four patients (two FL, two MCL) relapsed, and one additional MCL patient died unexpectedly in complete remission. PCR-negativity was observed in 22% of the patients before ASCT, 53% post-ASCT (P=0.0547), 72% after rituximab (P=0.0018) and 100% at 6 months post-transplant (P < 0.001). CONCLUSIONS: One single course of rituximab consolidation given after ASCT is safe, may help to eliminate MRD and may translate into improved EFS in both FL and MCL patients.     

Factors influencing outcome in advanced stage,low-grade follicular lymphoma treated at MD Anderson Cancer Center in the rituximab era

BackgroundThe optimal initial therapy of follicular lymphoma (FL) remains unclear. The aims of this study were to compare primary treatment strategies and assess the impact of maintenance rituximab and patterns of treatment failure.Patients and methodsWe retrospectively analyzed patients with treatment-naive advanced stage, grade 1–2 FL treated at our center from 2004 to 2014. We included 356 patients treated on clinical trials or standard of care with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP, n = 119); R-CHOP with maintenance (R-CHOP + M, n = 65); bendamustine/rituximab (BR, n = 45); BR with maintenance (BR + M, n = 35); R² (n = 94). We compared baseline characteristics, progression-free survival (PFS), overall survival (OS) and analyzed prognostic factors using univariate and multivariate analysis adjusted for treatment.ResultsAfter a median follow-up of 4 years (range 0.2–15.0), the 3-year PFS was 60% [95% confidence interval (CI) 51% to 69%] for R-CHOP, 72% (59% to 82%) for R-CHOP + M, 63% (42% to 78%) for BR, 97% (80% to 100%) for BR + M and 87% (78% to 93%) for R². Patients treated with R-chemotherapy had more high-risk features than patients treated with R² but, by adjusted multivariate analysis, treatment with R² [hazard ratio (HR) 0.39 (0.17–0.89), P = 0.02] was associated with a superior PFS. Eastern Cooperative Oncology Group Performance status of one or more predicted inferior OS. Among patients treated with R-chemotherapy, maintenance was associated with the superior PFS [HR 0.38 (95% CI 0.21–0.68)]. By adjusted multivariate analysis, disease progression within 2 years [HR 5.1 (95% CI 1.57–16.83)] and histologic transformation (HT) [HR 11.05 (95% CI 2.84–42.93)] increased risk of death.ConclusionInduction therapy with R² may result in disease control which is comparable with R-chemotherapy. Early disease progression and HT are predictive of inferior survival.     

High-dose chemotherapy followed by autologous stem cell transplantation for relapsed or refractory Hodgkin lymphoma: prognostic features and outcomes

Between January 1990 and April 2001, 115 patients received high-dose chemotherapy (HDT) followed by autologous stem cell transplantation (ASCT) for relapsed or refractory Hodgkin lymphoma (HL). With a median follow-up of 58 months (range, 1 - 175 months), 5-year progression-free survival (PFS) and overall survival (OS) were 46% and 58%, respectively. Twelve patients with primary refractory disease had a 5-year PFS of 41% and OS of 58%, not significantly different from those of the remaining cohort. Early and overall regimen related mortality were 7% and 16%, respectively. Male gender (P = 0.04) and a time to relapse (TTR) < 12 months (P = 0.03) were associated with decreased OS by univariate analysis. In multivariate analysis, TTR < 12 months remained statistically significant (P = 0.04). We have confirmed that HDT and ASCT result in long-term survival for a proportion of patients with relapsed or refractory HL. All patients, including those with primary refractory disease, benefited from HDT and ASCT.     

Autologous Stem-Cell Transplantation for Poor-Risk and Relapsed Intermediate- and High-Grade Non-Hodgkin's Lymphoma

The primary objective of this study was to evaluate the outcome of patients treated with high-dose chemo-/radiotherapy or high-dose chemotherapy and autologous stem-cell transplant (ASCT) for relapsed, refractory, or poor-risk intermediate-grade (IG) and high-grade (HG) non-Hodgkin's lymphoma (NHL). The secondary objectives were to determine prognostic factors for relapse and survival. Between February 1987 and August 1998, 264 patients, 169 (64%) IG and 95 (36%) HG, underwent high-dose therapy and ASCT at City of Hope National Medical Center (COHNMC). There were 157 (59%) males and 107 (41%) females with a median age of 44 years (range, 5–69 years). The median number of prior chemotherapy regimens was 2 (range, 1–4), and 71 (27%) had received prior radiation as part of induction or as salvage therapy. The median time from diagnosis to ASCT was 10.8 months (range, 3–158 months). Ninety-four patients (36%) underwent transplantation in first complete/partial remission (CR/PR), 40 (15%) in induction failure, and 130 (49%) in relapse or subsequent remission. Two preparative regimens were used: total body irradiation/high-dose etoposide/cyclophosphamide (TBI/VP/CY) in 208 patients (79%) and carmustine/etoposide/cyclophosphamide (BCNU/VP/CY) in 56 patients (21%). One hundred sixty-three patients (62%) received peripheral blood stem cells (PBSC) and 101 (38%) received bone marrow (BM) alone or BM plus PBSC. At a median follow-up of 4.43 years for surviving patients (range, 1–12.8 years), the 5-year Kaplan-Meier estimates of probability of overall survival (OS), progression-free survival (PFS), and relapse for all patients are 55% (95% confidence interval [CI]: 49%–61%), 47% (95% CI: 40%–53%), and 47% (95% CI: 40%–54%), respectively. There were 27 deaths (10%) from nonrelapse mortality, including seven (3%) patients who developed second malignancies (five with myelodysplasia/acute myelogenous leukemia and two with solid tumors). By stepwise Cox regression analysis, disease status at ASCT was the only prognostic factor that predicted for both relapse and survival. The 5-year probability of PFS for patients transplanted in first CR/PR was 73% (95% CI: 62%–81%) as compared to 30% (95% CI: 16%– 45%) for induction failure and 34% (95% CI: 26%–42%) for relapsed patients. Our results further support the role of high-dose therapy and ASCT during first CR/PR for patients with poor-risk intermediate- and high-grade NHL. Early transplant is recommended for patients failing initial induction therapy or relapsing after chemotherapy-induced remission. Relapse continues to be the most common cause of treatment failure. An alternative approach to prevent relapse, the incorporation of radioimmunotherapy into the high-dose regimen, is being investigated. The development of a second malignancy is a serious complication of high-dose therapy, which requires close surveillance.     

Rituximab monotherapy with eight weekly infusions for relapsed or refractory patients with indolent B cell non-Hodgkin lymphoma mostly pretreated with rituximab: a multicenter phase II study

Information regarding rituximab monotherapy with eight weekly infusions for relapsed or refractory indolent B cell non-Hodgkin lymphoma (B-NHL), in particular for patients pretreated with rituximab, is limited. To evaluate the efficacy and safety of eight doses of rituximab monotherapy, 52 patients with relapsed or refractory indolent B-NHL were enrolled in the present study. Forty of 45 eligible patients (89%) had follicular lymphoma and 24 (53%) were at intermediate or high risk group according to the Follicular Lymphoma International Prognostic Index. The median number of prior chemotherapy regimens was 1 (range 1-7). At the median follow-up of 12.2 months, the overall response rate (ORR), complete response rate (%CR), and median progression-free survival (PFS) were 69% (95% confidence interval [CI] 53%-82%), 47% (95% CI 32%-62%), and 15.6 months (95% CI 10.6- months), respectively. In the 33 patients pretreated with rituximab, the ORR, %CR, and median PFS were inferior compared with values for the 12 patients who had not received rituximab previously (64%vs 83% for ORR; 39%vs 67% for %CR; and 13.8 vs 17.5 months for median PFS, respectively). All mild-to-moderate infusion-related toxicities were reversible. Grade 3/4 non-hematologic adverse events occurred in six of the 52 patients. Two patients developed Grade 4 late-onset neutropenia and a decrease (>50%) in serum immunoglobulin was observed in six patients. In conclusion, rituximab monotherapy with eight weekly infusions is effective in relapsed patients with indolent B-NHL, with acceptable toxicities, including in patients pretreated with rituximab; however, careful monitoring is recommended for infections associated with late-onset neutropenia and hypogammaglobulinemia. (University Hospital Medical Information Network no. UMIN000002974.)     

Assessing the Effectiveness of Treatment Sequences for Older Patients With High-risk Follicular Lymphoma With a Multistate Model

BackgroundDisease progression within < 2 years of initial chemoimmunotherapy and patient age > 60 years have been associated with poor overall survival (OS) in follicular lymphoma (FL). No standard treatment exists for these high-risk patients, and the effectiveness of sequential therapies remains unclear.Patients and MethodsWe studied the course of FL with first-, second-, and third-line treatment. Using large population-based data, we identified 5234 patients with FL diagnosed in 2000 to 2009. Of these patients, 71% had received second-line therapy < 2 years, and 29% had received no therapy after first-line therapy, with a median OS of < 3 years. Treatment included rituximab, R-CVP (rituximab, cyclophosphamide, vincristine), R-CHOP (rituximab, cyclophosphamide, hydroxydaunorubicin, vincristine), R-Other (other rituximab-containing), and other regimens. The Aalen-Johansen estimator and Cox proportional hazards models were used to quantify the outcomes and assess the effects of the clinical and sociodemographic factors.ResultsR-CHOP demonstrated the most favorable 5-year OS among first- (71%), second- (55%), and third-line (61%) therapies. First-line R-CHOP improved OS (hazard ratio [HR], 0.57; 95% confidence interval [CI], 0.50-0.64) and reduced the mortality risks after first-line (HR, 0.60; 95% CI, 0.47-0.77), second-line (HR, 0.40; 95% CI, 0.29-0.53), and third-line (HR, 0.63; 95% CI, 0.53-0.76) treatments. B-symptoms, being married, and histologic grade 1/2 were associated with the use of earlier second-line therapy. Early progression from second- to third-line therapy was associated with poor OS. The repeated use of R-CHOP or R-CVP as first- and second-line treatment yielded high 2-year mortality rates (R-CHOP + R-CHOP, 17.3%; R-CVP + R-CVP, 21.1%).ConclusionOur multistate approach assessed the effect of sequential therapy on the immediate and subsequent treatment-line outcomes. We found that R-CHOP in any line improved OS for patients with high-risk FL.     

LACE‐conditioned autologous stem cell transplantation for relapsed or refractory diffuse large B‐cell lymphoma: treatment outcome and risk factor analysis from a single centre

High‐dose chemotherapy followed by autologous stem cell transplantation (ASCT) is a recognized treatment option for patients with relapsed diffuse large B‐cell lymphoma. We have analysed 51 patients who underwent ASCT after LACE (lomustine (CCNU), cytarabine (Ara‐C), cyclophosphamide, etoposide) conditioning for relapsed (n = 34, 67%) or primary refractory (n = 17, 33%) diffuse large B‐cell lymphoma. With a median follow‐up of 60 months (range 2–216) the probabilities of overall survival (OS) and progression‐free survival (PFS) at 5 years were 47 and 42%, respectively. The cumulative treatment‐related mortality was 10% (n = 5). Probabilities for OS and PFS at 5 years were 56 and 50% for patients with chemosensitive and 29 and 27% for patients with chemorefractory disease. In multivariate analysis abnormal pre‐ASCT levels of C‐reactive protein (>5 mg/L) were identified as a risk factor for worse OS, whereas abnormal pre‐ASCT levels of C‐reactive protein and chemoresistance predicted inferior PFS. LACE followed by ASCT is an effective treatment for approximately half of patients with chemosensitive relapsed diffuse large B‐cell lymphoma, and a proportion of chemorefractory patients also benefit. Copyright © 2010 John Wiley & Sons, Ltd.     

Risk Factors for and Outcomes of Follicular Lymphoma Histological Transformation at First Progression in the GALLIUM Study

BackgroundAlthough advanced?stage follicular lymphoma (FL) is considered incurable, survival has improved with the introduction of the anti-CD20 antibodies, rituximab (R) and obinutuzumab (G). However, FL can undergo histological transformation (HT) to a more aggressive disease, and a validated model for predicting HT risk is not yet available.Patients and MethodsWe assessed HT incidence, risk factors and outcomes in the phase III, GALLIUM study evaluating R- or G-chemotherapy in patients with previously untreated, advanced-stage FL (ClinicalTrials.gov NCT01332968). HT rates were assessed by repeat tumour biopsy at disease progression or relapse, at the investigator's discretion.ResultsOf 1202 patients enrolled, 315 (26.2%) experienced progressive disease; 46 (14.6%) had a biopsy at first progression, 40 of whom had biopsy-confirmed HT. HT risk factors were male sex (subdistribution hazard ratio [sHR], 2.21; 95% confidence interval [CI], 1.16-4.20), elevated baseline serum lactate dehydrogenase (sHR, 3.97; 95% CI, 2.03-7.76), and elevated baseline serum β₂-microglobulin (sHR, 1.96; 95% CI, 1.02-3.79). Patients with HT at first progression had poorer post-progression survival than those with relapsed FL (2-year rate: 55.9% vs. 83.1%). Relapse with HT occurred earlier than FL relapse (median time from randomisation: 0.8 vs. 2.3 years).ConclusionHT was a low-frequency event associated with poor survival outcomes in the GALLIUM study. Male sex and elevated baseline levels of serum LDH and B2M were significant risk factors for HT. Further research is required to develop validated prognostic indices for HT risk and guide treatment decisions.     

A randomized study comparing yttrium-90 ibritumomab tiuxetan (Zevalin) and high-dose BEAM chemotherapy versus BEAM alone as the conditioning regimen before autologous stem cell transplantation in patients with aggressive lymphoma

BACKGROUND:

High‐dose chemotherapy combined with autologous stem‐cell transplantation (ASCT) is the standard therapy for refractory/relapsed aggressive lymphoma. In the era of rituximab‐containing frontline regimens, it is becoming more challenging to salvage patients in this setting, and novel approaches are required. This is a randomized study evaluating the safety and efficacy of standard‐dose ibritumomab tiuxetan (Zevalin) combined with high‐dose BEAM chemotherapy (Z‐BEAM) and ASCT in refractory/relapsed aggressive lymphoma.

METHODS:

Forty‐three patients with CD20⁺‐aggressive lymphoma were randomized to a treatment arm (Z‐BEAM, n = 22) or control arm (BEAM alone, n = 21). Ibritumomab tiuxetan was given at 0.4 mCi/kg on day ?14 before ASCT.

RESULTS:

Patient characteristics, engraftment kinetics, and toxicity profile were similar between the 2 groups. Two‐year progression‐free survival (PFS) for all patients was 48% (95% confidence interval, 32%‐64%): 59% and 37% after Z‐BEAM and BEAM alone, respectively (P = .2). Multivariate analysis identified advanced age (hazard ratio [HR], 8.3; P = .001), high‐risk disease (relapse within 12 months of diagnosis and/or secondary International Prognostic Index >2; HR, 2.8; P = .04), positive positron emission tomography‐computed tomography pretransplant (HR, 2.4; P = .07), and BEAM alone (HR, 2.8; P = .03) as poor prognostic factors. Intermediate‐risk patients with 1 or 2 risk factors had better PFS with Z‐BEAM compared with BEAM: 69% and 29%, respectively (P = .07). Two‐year overall survival was 91% and 62% after Z‐BEAM and BEAM, respectively (P = .05). Similar prognostic factors determined survival. The HR for BEAM alone in the multivariate analysis was 8.1 (P = .01).

CONCLUSIONS:

Standard‐dose ibritumomab tiuxetan combined with BEAM high‐dose chemotherapy is safe and possibly more effective than BEAM alone as a conditioning regimen for ASCT in the era of rituximab‐containing chemotherapy regimens. Cancer 2012. © 2012 American Cancer Society.