Rituximab-based Chemoimmunotherapy Research Articles

Durable ibrutinib responses in relapsed/refractory marginal zone lymphoma: long-term follow-up and biomarker analysis

AbstractAdvanced marginal zone lymphoma (MZL) is an incurable B-cell malignancy dependent on B-cell receptor signaling. The phase 2 PCYC-1121 study demonstrated the safety and efficacy of single-agent ibrutinib 560 mg/d in 63 patients with relapsed/refractory MZL treated with prior rituximab (RTX) or rituximab-based chemoimmunotherapy (RTX-CIT). We report the final analysis of PCYC-1121 with median follow-up of 33.1 months (range: 1.4-44.6). Overall response rate (ORR) was 58%; median duration of response (DOR) was 27.6 months (95% confidence interval [CI]: 12.1 to not estimable [NE]); median progression-free survival (PFS) was 15.7 months (95% CI: 12.2-30.4); and median overall survival (OS) was not reached (95% CI: NE to NE). Patients with prior RTX treatment had better outcomes (ORR: 81%; median DOR: not reached [95% CI: 12.2 to NE]; median PFS: 30.4 months [95% CI: 22.1 to NE]; median OS: not reached [95% CI: 30.3 to NE]) vs those with prior RTX-CIT treatment (ORR: 51%; DOR: 12.4 months [95% CI: 2.8 to NE]; PFS: 13.8 months [95% CI: 8.3-22.5]; OS: not reached [95% CI: NE to NE]). ORRs were 63%, 47%, and 62% for extranodal, nodal, and splenic subtypes, respectively. With up to 45 months of ibrutinib treatment, the safety profile remained consistent with prior reports. The most common grade ≥3 event was anemia (16%). Exploratory biomarker analysis showed NF-κB pathway gene mutations correlated with outcomes. Final analysis of PCYC-1121 demonstrated long-term safety and efficacy of ibrutinib in patients with relapsed/refractory MZL, regardless of prior treatment or MZL subtype. This trial was registered at www.clinicaltrials.gov as #NCT01980628.

Abstract IA05: Microenvironmental signatures reveal biologic and clinical subtypes of diffuse large B-cell lymphoma

Abstract Diffuse large B-cell lymphoma (DLBCL) is a biologically and clinically heterogenous disease almost invariably treated with combinatorial chemoimmunotherapy resulting in a ~65% cure rate in first line. Further improvement of treatment outcome relies on elucidating the biology that underlies the clinical behavior of this heterogenous disease. Transcriptomic and genetic characterization of DLBCL have increased our understanding of its pathogenesis and provided potential novel therapeutic targets. Over the past few years, the role of the microenvironment in DLBCL biology has been increasingly recognized. A guiding framework is necessary to effectively and safely translate research evidence into clinical practice. Towards this goal, we characterized the DLBCL microenvironment based on the transcriptional footprint of microenvironment cells and processes in a large cohort of patients. We first developed transcriptional signatures reflecting distinct cellular subtypes of the microenvironment, biologic processes, and canonical signaling pathway activation. We then used these signatures to virtually reconstruct the lymphoma microenvironment (LME) by applying an unsupervised community detection algorithm in 4,656 DLBCL cases. As a result, we described four classes of LMEs that reflect distinct enrichment of associated signatures. 1. “Germinal center-like” (GC-like) due to the presence of signatures from cell types commonly found in germinal centers including follicular dendritic cells, lymphatic endothelial cells, total T cells, and several CD4+ T-cell subpopulations. 2. “Mesenchymal” (MS) for the abundance of signatures from stromal cells such as cancer-associated fibroblasts, fibroblastic reticular cells, vascular endothelial cells, and extracellular matrix pathways. The MS-LME class was enriched in mutations affecting antigen presentation. These lymphomas also presented with high activity of the TGFB/SMAD and HIF pathways, previously associated with favorable prognosis in DLBCL. 3. “Inflammatory” (IN) for the presence of signatures from macrophages, neutrophils, NK cells, and cytotoxic T cells. The IN-LME class was enriched for immune suppressive/pro-lymphoma cytokines, expression of the immune checkpoint molecules PD-L1 and IDO1, and higher activity of the NF-kB, JAK/STAT, and TNF signaling pathways. 4. A “depleted” (DP) form that, contrasting with the other LMEs, was characterized by an overall lower presence of microenvironment-derived signatures. We analyzed the association of LME classes with overall survival (OS) and progression-free survival (PFS) in patient cohorts of, respectively, 2,646 and 2,189 DLBCLs treated with rituximab-based chemoimmunotherapy. Analysis of OS by LME indicated significant differences in prognosis from better to poor as follows: GC-like, MS (p =0.03, vs. GC-like), IN (p = 0.006, vs. MS), and DP (p = 0.008, vs. IN) LMEs, whereas GC-like and MS have similarly favorable PFS curves (p = 0.9) followed by IN (p < 0.01) and DP (p = 0.03, vs. IN), which presented with the poorest PFS. In multivariate Cox-proportional hazard analysis controlled for C.O.O. and I.P.I., the LME subtypes remained informative with GC-like and MS LMEs associated with better outcome. When segregated by C.O.O., the DP-LME retained the poorest OS and PFS in both C.O.O. subtypes. However, in ABC-DLBCL, the LME with the best PFS and OS was MS, and in GCB-DLBCL, the best LME was GC-like, suggesting that the biologic impact of the microenvironment may be different depending on the lymphoma subtype. DHL and high-grade lymphomas (HGL) modified their outcome when LME was considered. DHL/HGL with the favorable prognosis LMEs GC-like and MS had significantly better PFS and OS than DHL/HGL with the unfavorable prognosis LMEs IN and DP. DLBCLs with a DP-LME were characterized by a minimal presence of LME signatures and tumor cells exhibited higher clonality, were enriched for mutations affecting TP53 and cell proliferation genes, as well as presented higher levels of aberrant hypermethylation of immune-related and TGFB/SMAD1 genes. Preclinical murine models and patient data demonstrated that some of these features can be pharmacologically reversed with hypomethylating agents, indicating that cytosine methylation patterning of lymphoma cells may contribute to a depleted LME. In summary, we categorized the DLBCL LME into four major transcriptionally defined subtypes with distinct biologic properties and clinical behavior, which complement genetically defined subtypes of DLBCL in guiding the development of rational therapeutic approaches for these patients. Citation Format: Leandro Cerchietti. Microenvironmental signatures reveal biologic and clinical subtypes of diffuse large B-cell lymphoma [abstract]. In: Proceedings of the AACR Virtual Meeting: Advances in Malignant Lymphoma; 2020 Aug 17-19. Philadelphia (PA): AACR; Blood Cancer Discov 2020;1(3_Suppl):Abstract nr IA05.

A Clinico-Genotypic Prognostic Index for De Novo Composite Diffuse Large B-Cell Lymphoma Arising from Follicular Lymphoma in Asian patients treated in the Rituximab Era

Composite follicular lymphoma with diffuse large B-cell lymphoma (FL/DLBCL) is uncommonly found on lymph node biopsy and represents a rare haematological malignancy. We aim to examine clinico-pathological features of patients with FL/DLBCL and investigate predictors of survival outcome. We included in our retrospective study patients with histologically-proven FL/DLBCL at diagnosis (n = 106) and who were subsequently treated with rituximab-based chemoimmunotherapy from 2002–2017 at the National Cancer Centre. The cohort consisted of 34 women and 72 men with a median age of 59 years (range, 24–82). In a multivariate model inclusive of known clinico-pathological parameters at diagnosis, advanced stage (p = 0.0136), presence of MYC and/or BCL6 rearrangement (p = 0.0376) and presence of B symptoms (p = 0.0405) were independently prognostic for worse overall survival (OS). The only remaining independent prognostic variables for worse OS after including first-line treatment data in the model were use of chemotherapy regimens other than R-CHOP (p = 0.0360) and lack of complete response to chemotherapy (p < 0.0001) besides the presence of B symptoms (p = 0.0022). We generated a Clinico-Genotypic Index by point-wise addition of all five adverse parameters (score of 0–1, 2, 3, 4–5) which revealed four prognostic risk groups with a predicted 5-year OS of 100%, 62%, 40% and 0% (p < 0.0001) accounting for 50.0%, 24.5%, 18.9% and 6.6% of the cohort respectively. We propose that R-CHOP should be the recommended first-line regimen for composite FL/DLBCL.

Influence of obesity and gender on treatment outcomes in patients with chronic lymphocytic leukemia (CLL) undergoing rituximab-based chemoimmunotherapy

Influence of obesity and gender on treatment outcomes in patients with chronic lymphocytic leukemia (CLL) undergoing rituximab-based chemoimmunotherapy

Evaluation of subcutaneous rituximab administration on Canadian systemic therapy suites.

Non-Hodgkin lymphoma (nhl) is the most common hematologic malignancy. Diffuse large B-cell lymphoma (dlbcl) and follicular lymphoma (fl) constitute 55% of new nhl cases and are initially treated with rituximab-based chemoimmunotherapy. Relative to intravenous (IV) rituximab, a subcutaneous (sc) formulation approved in 2016 has comparable pharmacokinetics, efficacy, and safety, and a greatly reduced administration time; it is also preferred by patients. The objective of the present study was to estimate the effect (on systemic therapy suite time and on the costs of drug acquisition and administration) of implementing sc rituximab in the initial chemoimmunotherapy for fl and dlbcl over 3 years in the Canadian market. An Excel (Microsoft Corporation, Redmond, WA, U.S.A.)-based model was created with a population size based on epidemiologic data and current rituximab use, duration of use considering initial therapy, time savings for sc rituximab administration from published studies, costs from standard Canadian sources, and assumed uptake in implementing provinces of 65%, 75%, and 80% over 3 years. Key parameters and sensitivity analysis values were validated by clinical experts located in various Canadian jurisdictions. Costs are reported in 2017 Canadian dollars from the perspective of the health care system. More than 3 years after implementation of sc rituximab, we estimated that 5762 Canadians would be receiving sc rituximab, resulting in savings of 128,715 hours in systemic therapy suite time and approximately $40 million in drug and administration costs. Sensitivity analyses suggest that the model is most sensitive to sc market uptake, number of induction therapy cycles, and eligible patients. Subcutaneous administration of rituximab can significantly reduce systemic therapy suite time and achieve substantial savings in drug and administration costs.

PSY33 - Evaluation of Subcutaneous Rituximab Administration Impacts on Canadian Systemic Therapy Suites

Non-Hodgkin lymphoma (NHL) is the most common hematologic malignancy. Diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) comprise 55% of new NHL cases and are initially treated with rituximab-based chemoimmunotherapy. Relative to intravenous (IV) rituximab, a subcutaneous (SC) formulation approved in 2016 has comparable pharmacokinetics, efficacy and safety, with greatly reduced administration time, and is preferred by patients. The objective of this study was to estimate the impact of implementing rituximab SC with initial chemoimmunotherapy for FL and DLBCL over three years in the Canadian market on systemic therapy suite time and costs of drug acquisition and administration. An excel-based model was used with population size based on epidemiologic data and current rituximab use; duration of use considering initial therapy; time savings for rituximab SC administration from published studies; costs from standard Canadian sources; and uptake for implementing provinces assumed to be 65%, 75% and 80% over the 3 years. Key parameters and sensitivity analysis values were validated by clinical experts located in various jurisdictions of Canada. Costs are reported in 2017 Canadian dollars using a healthcare system perspective. Over 3 years after rituximab SC implementation, we estimated 5,762 Canadians using rituximab SC, with savings of 128,715 hours in systemic therapy suite time and approximately $40 million in drug and administration costs. Sensitivity analysis suggests the model is most sensitive to SC market uptake values, number of induction therapy cycles and eligible patients. SC administration of rituximab with initial chemoimmunotherapy can significantly reduce systemic therapy suite time and substantially save drug and administration costs.

Impact of obinutuzumab alone and in combination for follicular lymphoma.

Although rituximab-based chemoimmunotherapy prolongs the survival of patients with follicular lymphoma (FL), this disease is considered incurable in most patients. Thus, new therapies are needed not only for those in the relapsed/refractory setting, but also for initial treatment. Obinutuzumab (G, GA101) is a third-generation, fully humanized type II glycoengineered, anti-CD20 monoclonal antibody that results in increased direct cell death and antibody-dependent, cell-mediated cytotoxicity/phagocytosis compared to rituximab. Obinutuzumab has significant antitumor activity when used alone or in combinations in untreated or relapsed refractory FL patients. Studies have demonstrated its ability to prolong progression-free survival and, in some cases, overall survival, and to eliminate minimal residual disease. Several ongoing trials are investigating combinations with chemotherapy, immunomodulators, targeted drugs, and immunotherapy agents. G is generally well tolerated, with associated adverse effects including infusion-related reactions, neutropenia, thrombocytopenia, and reactivation of hepatitis B virus. Future studies with this antibody should focus on identifying predictive markers and developing chemotherapy-free combinations that will improve the outcome of patients with FL.

Current challenges in the management of follicular lymphoma.

Although typically indolent in nature, follicular lymphoma remains an ongoing challenge for practicing oncologists. While response rates >90% can be achieved with rituximab-based chemoimmunotherapy in advanced stage patients, the complete remission rates are substantially lower and patients inevitably relapse. The inability to achieve a complete remission and an early progression of disease have recently been determined to be indicative of poorer long-term outcomes. A greater understanding of the pathogenesis of follicular lymphoma has enabled the development of targeted therapies, which may improve standard treatment approaches. Examples include lenalidomide and obinutuzumab, which are currently in front-line Phase III investigation. Other therapies of interest include small molecule inhibitors, immune checkpoint inhibitors and chimeric antigen receptor T cells.

Peripheral blood T cell alterations in newly diagnosed diffuse large B cell lymphoma patients and their long-term dynamics upon rituximab-based chemoimmunotherapy.

The importance of T cell-dependent immune responses in achieving long-term cure of chemoimmunotherapy-treated cancer patients is underscored by the recently described "vaccinal effect" exerted by therapeutic mAbs. In accordance, pre- and post-therapy peripheral blood lymphopenia represents a well-established negative prognostic factor in DLBCL. We analyzed the phenotypic and functional (IFNγ production, and Granzyme B (GrzB) cytotoxic granule marker expression) profile of peripheral blood T lymphocyte subsets ("conventional" CD4+ and CD8+, FOXP3+CD25bright Treg, and "innate-like" CD56+) in DLBCL patients at diagnosis, and assessed the long-term impact of R-CHOP chemoimmunotherapy, in a prospective study. At diagnosis, DLBCL patients showed lower lymphocyte counts, due to selective decrement of CD4+ T (including Treg) and B lymphocytes. While all T cell subsets transiently decreased during therapy, CD4+ T cell and Treg remained significantly lower than controls, up to 1year after R-CHOP. Phenotypically skewed profile of CD4+ and CD8+ T cell subsets associated with higher frequencies of IFNγ+ and GrzB+ cells at diagnosis, that transiently decreased during therapy, and re-attained persistently elevated levels, till up to 1year after therapy. Differently, the pre-therapy elevated levels of circulating monocytes, and of plasma IL-6 and IL-10 rapidly normalized upon R-CHOP. In sum, we describe a quantitatively and functionally altered status of the peripheral blood T cell compartment in DLBCL patients at diagnosis, that persists long-term after tumor eradication, and it is only transiently perturbed by R-CHOP chemoimmunotherapy. Moreover, data suggest the association of selected T cell functional features with DLBCL phenotype, and with therapy outcome.

Skeletal muscle density is an independent predictor of diffuse large B-cell lymphoma outcomes treated with rituximab-based chemoimmunotherapy.

BackgroundWhile much cancer research focuses on tumours and their microenvironment, malignancies cause widespread physiologic changes. Cancer and treatment‐related sarcopenia, measured with quantitative imaging or as a decrease in overall body mass, are indicative of poor prognosis in elderly diffuse large B‐cell lymphoma (DLBCL) patients, skeletal muscle radiodensity (SMD) may be a better prognostic marker. SMD, a measure of muscle radiation attenuation on CT imaging, is more prognostic than sarcopenia or International Prognostic Index (IPI) scores in follicular lymphoma and multiple solid organ malignancies. Low SMD appears to correlate with fat accumulation in muscle and is associated with inflammation. This study set out to examine SMD's prognostic ability in DLBCL.MethodsAll DLBCL patients treated with rituximab‐containing therapy between 2004 and 2009 were compared to determine SMD's prognostic ability in this single centre, retrospective study. Pre‐treatment CT scans were used to measure SMD and muscle cross‐sectional area. Primary endpoints included progression free (PFS) and overall survival (OS) while objective response rates (ORR) were secondary.ResultsOf 224 evaluable patients, 116 were identified as having low SMD. Low SMD predicted poorer 5 year PFS, 60 vs. 81% (p = 0.001) and OS, 58 vs. 86% (p < 0.0001). SMD's prognostic ability retained significance in multivariate analysis taking into consideration the Revised International Prognostic Index (R‐IPI) and sex. Although high SMD was not predictive of ORR (95.4 vs. 91.4%, p = 0.17), it was strongly associated with radiographic complete response (85 vs. 66%, p = 0.0007). Contrary to previous findings, sarcopenia did not predict for poorer OS but suggested improved OS in elderly DLBCL patients (HR 0.38, p = 0.01).ConclusionsSMD is a novel prognostic (and potentially treatment predictive) marker independent of R‐IPI in DLBCL. It presents an inexpensive yet complementary assessment to R‐IPI for prognosticating DLBCL outcomes.

A new extranodal scoring system based on the prognostically relevant extranodal sites in diffuse large B-cell lymphoma, not otherwise specified treated with chemoimmunotherapy.

Extranodal involvement is a well-known prognostic factor in patients with diffuse large B-cell lymphomas (DLBCL). Nevertheless, the prognostic impact of the extranodal scoring system included in the conventional international prognostic index (IPI) has been questioned in an era where rituximab treatment has become widespread. We investigated the prognostic impacts of individual sites of extranodal involvement in 761 patients with DLBCL who received rituximab-based chemoimmunotherapy. Subsequently, we established a new extranodal scoring system based on extranodal sites, showing significant prognostic correlation, and compared this system with conventional scoring systems, such as the IPI and the National Comprehensive Cancer Network-IPI (NCCN-IPI). An internal validation procedure, using bootstrapped samples, was also performed for both univariate and multivariate models. Using multivariate analysis with a backward variable selection, we found nine extranodal sites (the liver, lung, spleen, central nervous system, bone marrow, kidney, skin, adrenal glands, and peritoneum) that remained significant for use in the final model. Our newly established extranodal scoring system, based on these sites, was better correlated with patient survival than standard scoring systems, such as the IPI and the NCCN-IPI. Internal validation by bootstrapping demonstrated an improvement in model performance of our modified extranodal scoring system. Our new extranodal scoring system, based on the prognostically relevant sites, may improve the performance of conventional prognostic models of DLBCL in the rituximab era and warrants further external validation using large study populations.

Superior efficacy of rituximab-based chemoimmunotherapy as an initial therapy in newly diagnosed patients with B cell indolent lymphomas: long-term results from a single center in China

BackgroundRituximab has been confirmed to improve the survival of patients with B cell indolent non-Hodgkin lymphomas (B-iNHLs) in Western world as previously reported, however, it is rarely reported in Chinese cohort. This study is to investigate the efficacy and safety of rituximab-based chemoimmunotherapy and select subpopulations most sensitive to the regimen in Chinese B-iNHL patients.Methods334 B-iNHL patients from our center were retrospectively assessed.ResultsPatients received R-based chemoimmunotherapy showed significantly higher rates of overall response (OR) (93.0 % vs. 53.4 %, P < 0.001) and complete response (CR) (63.3 % vs. 16.0 %, P < 0.001) compared with the patients received other therapies. Survival analysis showed that rituximab-based chemoimmunotherapy could obviously improve the progression-free survival (PFS) (110 vs. 49 months, P = 0.001) and overall survival (OS) (120 vs. 72 months, P < 0.001) in patients with B-iNHLs. Interestingly, in chronic lymphocytic leukemia (CLL) patients, we found that the patients with β2-microglobulin (β2-MG) < 3.5 mg/L, lactate dehydrogenase (LDH) < 220 U/L, zeta-chain-associated protein kinase 70 (ZAP-70) negative, and non high-risk genetic abnormality could achieve more benefits from R-based regimens with higher CR rate (P = 0.003, 0.029, 0.013 and 0.038, respectively). Meanwhile, more CLL patients achieved minimal residual disease (MRD) negative after rituximab-based treatment (46.5 % vs. 10.3 %, P < 0.001). Moreover, CLL patients with MRD < 1 %, LDH < 220 U/L, complete remission (CR) or partial remission (PR), β2-MG < 3.5 mg/L and non high-risk cytogenetic abnormality showed superior outcome compared to the controls (P = 0.001, 0.000, 0.000, 0.001 and 0.013, respectively). No other side-effects increased in chemoimmunotherapy group except the elevation of grade 3–4 neutropenia.ConclusionsOur results demonstrate the superior efficacy of rituximab–based chemoimmunotherapy as an initial therapy in Chinese cohort with newly diagnosed B-iNHLs and further identify subpopulations that are more sensitive to R-based chemoimmunotherapy in CLL group.

Non-Hodgkin's lymphomas, version 4.2014.

Non-Hodgkin's lymphomas (NHL) are a heterogeneous group of lymphoproliferative disorders originating in B lymphocytes, T lymphocytes, or natural killer cells. Mantle cell lymphoma (MCL) accounts for approximately 6% of all newly diagnosed NHL cases. Radiation therapy with or without systemic therapy is a reasonable approach for the few patients who present with early-stage disease. Rituximab-based chemoimmunotherapy followed by high-dose therapy and autologous stem cell rescue (HDT/ASCR) is recommended for patients presenting with advanced-stage disease. Induction therapy followed by rituximab maintenance may provide extended disease control for those who are not candidates for HDT/ASCR. Ibrutinib, a Bruton tyrosine kinase inhibitor, was recently approved for the treatment of relapsed or refractory disease. This manuscript discusses the recommendations outlined in the NCCN Guidelines for NHL regarding the diagnosis and management of patients with MCL.

Early Failure of Frontline Rituximab-Containing Chemo-immunotherapy in Diffuse Large B Cell Lymphoma Does Not Predict Futility of Autologous Hematopoietic Cell Transplantation

The poor prognosis for patients with diffuse large B cell lymphoma (DLBCL) who relapse within 1 year of initial diagnosis after first-line rituximab-based chemo-immunotherapy has created controversy about the role of autologous transplantation (HCT) in this setting. We compared autologous HCT outcomes for chemosensitive DLBCL patients between 2000 and 2011 in 2 cohorts based on time to relapse from diagnosis. The early rituximab failure (ERF) cohort consisted of patients with primary refractory disease or those with first relapse within 1 year of initial diagnosis. The ERF cohort was compared with those relapsing >1 year after initial diagnosis (late rituximab failure [LRF] cohort). ERF and LRF cohorts included 300 and 216 patients, respectively. Nonrelapse mortality (NRM), progression/relapse, progression-free survival (PFS), and overall survival (OS) of ERF versus LRF cohorts at 3 years were 9% (95% confidence interval [CI], 6% to 13%) versus 9% (95% CI, 5% to 13%), 47% (95% CI, 41% to 52%) versus 39% (95% CI, 33% to 46%), 44% (95% CI, 38% to 50%) versus 52% (95% CI, 45% to 59%), and 50% (95% CI, 44% to 56%) versus 67% (95% CI, 60% to 74%), respectively. On multivariate analysis, ERF was not associated with higher NRM (relative risk [RR], 1.31; P = .34). The ERF cohort had a higher risk of treatment failure (progression/relapse or death) (RR, 2.08; P < .001) and overall mortality (RR, 3.75; P < .001) within the first 9 months after autologous HCT. Beyond this period, PFS and OS were not significantly different between the ERF and LRF cohorts. Autologous HCT provides durable disease control to a sizeable subset of DLBCL despite ERF (3-year PFS, 44%) and remains the standard-of-care in chemosensitive DLBCL regardless of the timing of disease relapse.

Improved survival with rituximab-based chemoimmunotherapy in older patients with extranodal diffuse large B-cell lymphoma

Using the Surveillance, Epidemiology, and End Results (SEER)–Medicare database, we investigated the relative benefits of adding rituximab to CHOP chemotherapy in diffuse large B-cell lymphoma (DLBCL) of extranodal origin, and found similar advantage for nodal and extranodal lymphomas. Hazard ratio for overall survival was 0.64 for nodal, and 0.70 for extranodal DLBCL. Hazard ratios for lymphoma-related death were 0.62 and 0.57, respectively. The advantage was largest for DLBCL of the spleen, liver and lung. Conversely, it was not evident for thyroid or testicular lymphomas. Compared with nodal DLBCL, spleen was the only site with significantly better prognosis after R-CHOP.

Chemoimmunotherapy resistant follicular lymphoma: predictors of resistance, association with transformation and prognosis

Follicular lymphoma (FL) is characterized by an initial response to treatment with inevitable relapse. We evaluated chemoimmunotherapy resistance (CIR resistance) including transformation. We identified patients who received rituximab combination therapy for symptomatic FL. CIR resistance was defined as disease progression during rituximab-based chemoimmunotherapy, rituximab maintenance or within 6 months of treatment completion. Our primary outcome was time to early progression (CIR resistance). Between July 2006 and April 2010, 132 patients met the inclusion criteria and 22 (16.7%) demonstrated CIR resistance with a median follow-up of 33 months. High-risk Follicular Lymphoma International Prognostic Index (FLIPI) score was predictive of CIR resistance (hazard ratio [HR] 2.43; 95% confidence interval [CI], 1.4–4.1; p = 0.001). Overall, eight patients (36.3%) transformed (biopsy-proven), with no transformation in the chemoimmunotherapy responder group. Median overall survival in the CIR resistant group was 47 months. Patients with CIR resistance had high rates of histologic transformation and shorter survival with poor response to next therapy.

Obinutuzumab (GA101) Plus CHOP Or FC In Relapsed/Refractory Follicular Lymphoma: Final Data From The Maintenance Phase Of The Phase 1b GAUDI Study (BO21000)

Rituximab-based chemoimmunotherapy is standard treatment for non-Hodgkin's lymphoma (NHL), but some patients relapse or do not respond to treatment. GA101, the first glycoengineered, humanized, anti-CD20 monoclonal antibody, was developed to induce increased direct cell death and antibody-dependent cellular cytotoxicity relative to rituximab. Phase 1 and 2 studies of patients with NHL have shown that GA101 monotherapy has promising activity. The phase 1b GAUDI study (NCT00825149, BO21000) evaluated the safety and efficacy of induction treatment with GA101 plus chemotherapy in patients with relapsed/refractory follicular lymphoma (FL). GA101 was partnered with cyclophosphamide, doxorubicin, vincristine, and prednisone (G-CHOP) or with fludarabine and cyclophosphamide (G-FC). The end-of-induction overall response rate was 96% for G-CHOP and 93% for G-FC (Radford et al. Blood. 2013). Here we report results from the cohort of patients who received GA101 maintenance monotherapy after responding to induction treatment.During induction, patients with relapsed/refractory FL received G-CHOP (every 3 weeks, 6–8 cycles) or G-FC (every 4 weeks, 4–6 cycles). Chemotherapy backbone was selected by the investigator on the basis of patient characteristics and treatment history. Patients were randomized to either high-dose GA101 (1600 mg on days 1 and 8 of cycle 1, 800 mg on day 1 of subsequent cycles) or to low-dose GA101 (400 mg on days 1 and 8 of cycle 1 and day 1 of subsequent cycles). Patients with complete response (CR) or partial response after induction were eligible to receive GA101 monotherapy (at the same dose used for induction) as maintenance treatment every 3 months for 2 years or until disease progression. Patients who completed maintenance therapy were followed for 2 years after the last GA101 dose or until progression/initiation of a new antilymphoma treatment. The primary end point was safety. Progression-free survival (PFS) was a secondary end point.Median observation time from study start in the G-CHOP and G-FC cohorts was 31.8 and 37.5 months, respectively. In the G-CHOP cohort, 82% (23/28) and 65% (15/23) of patients started and completed maintenance therapy, respectively. There were 7 discontinuations due to stable disease (SD) or progressive disease (PD) and 1 due to an adverse event (AE; hepatosplenic T-cell lymphoma). In the G-FC cohort, 61% (17/28) and 53% (9/17) of patients started and completed maintenance therapy, respectively. There were 4 discontinuations due to AEs (pancytopenia/septicemia, n=1; diarrhea/weight loss, n=1; neutropenia, n=2), 2 due to SD or PD, 1 due to administrative/other (patient moved away), and 1 due to death (chronic obstructive pulmonary disease, which was considered unrelated to GA101). During the maintenance period, 3 and 6 patients in the G-CHOP and G-FC cohorts, respectively, experienced a serious AE. No grade ≥3 AEs occurred in >1 patient in the G-CHOP cohort; in the G-FC cohort, the most common grade ≥3 AE was neutropenia (n=3). The proportion of patients with CR as a best overall response increased between the end of induction and the end of maintenance in the G-CHOP (39% [9/23] to 52% [12/23]) and G-FC cohorts (59% [10/17] to 82% [14/17]). Median PFS was not reached for G-CHOP; median PFS in the G-FC cohort was 46.0 months (95% CI: 24.4–46.0 months). Pharmacokinetic data will be presented.In this phase 1b study, maintenance treatment with GA101 monotherapy was well tolerated and CR rates increased compared with the end of the induction phase. This suggests that GA101 could be used to sustain and extend the clinical response achieved after induction with GA101 plus chemotherapy in patients with relapsed/refractory FL. The majority of responders completed maintenance treatment. No new safety signals emerged during maintenance treatment with GA101 monotherapy. In summary, data from the GAUDI study show that GA101 maintenance monotherapy is well tolerated and confers clinical benefit after induction with GA101 plus chemotherapy. Disclosures:Davies:Roche: Consultancy, Honoraria, Research Funding. Off Label Use: GA101 is a novel, glycoengineered, type II anti-CD20 monoclonal antibody that is designed to enhance direct cell death and antibody-dependent cellular cytotoxicity. It is being investigated in chronic lymphocytic leukemia, Non-Hodgkin's Lymphoma and other hematologic indications. Cartron:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Morschhauser:Roche, Celgene, Mundipharma, Spectrum: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Salles:Roche: Consultancy, Honoraria, Research Funding. Marcus:Roche: Consultancy, Honoraria. Wenger:Genentech: Employment. Lei:Roche: Employment. Wassner-Fritsch:Roche: Employment. Vitolo:Roche, Celgene, Takeda: Membership on an entity's Board of Directors or advisory committees.

Rituximab-Based Chemoimmunotherapy Prolongs Survival of Patients With Chronic Lymphocytic Leukemia Independently of the Time of Administration

The combination of purine analogues (PA) and rituximab (chemoimmunotherapy) is considered the treatment of choice for CLL. The aim of this study was to determine whether chemoimmunotherapy prolonged the overall survival in patients with CLL from a single center. From 1980 to 2010, 273 patients with CLL received: (1) PA (n = 159); and (2) PA plus rituximab (PA+R) (n = 114). All treated patients were included in the analysis, regardless of time at which treatment was administered, duration of therapy, and response. Patients from the PA and PA+R groups were well balanced for demographic, clinical, and biologic features. At 8 years, the survival from diagnosis of the PA+R group was 88% (95% confidence interval [CI], 82-94%) compared with 68% (95% CI, 60-76%) for the PA group (P < .001). When survival of patients treated with PA+R was analyzed according to the time of treatment administration (first- [n = 55] vs. second or more lines [n = 59]), no significant differences were observed (8-year overall survival 89% vs. 87%, respectively; P = .8). Chemoimmunotherapy prolonged the survival of patients with CLL and this effect was independent of the phase of the disease at which treatment was given.

Ofatumumab‐based chemoimmunotherapy is effective and well tolerated in patients with previously untreated chronic lymphocytic leukemia (CLL)

Although rituximab-based chemoimmunotherapy (CIT) has substantially improved clinical outcomes in chronic lymphocytic leukemia (CLL), only 40% to 50% of patients achieve a complete remission (CR). There remains interest in identifying new approaches to improve the effectiveness of CIT. Ofatumumab is a fully human anti-CD20 monoclonal antibody with greater apparent single-agent activity than rituximab in CLL patients. Previously untreated CLL patients in need of therapy received 6 cycles of CIT induction with pentostatin, cyclophosphamide, and ofatumumab (PCO) followed by response assessment. Of the 48 patients enrolled, 77% completed PCO induction. Adverse events during induction included grade 3+ hematologic toxicity (27%) and grade 3+ nonhematologic toxicity (23%). Median CD4 count after induction and 6 months later were 186 × 10(6)/L and 272 × 10(6) /L. The overall response rate was 96% (46 of 48 patients), and the CR rate was 46% (22 of 48 patients). Among the 38 patients who underwent minimal residual disease evaluation, 7 (18%) were negative for minimal residual disease. After median follow-up of 24 months, 10 (21%) patients have progressed and 8 (17%) have required retreatment. The efficacy and toxicity of ofatumumab-based CIT compare favorably to our historical trials of rituximab-based CIT using an identical chemotherapy backbone (n = 64). Time to retreatment also appeared longer for ofatumumab-based CIT (free of retreatment at 24 months: 86% [95% confidence interval = 75-99] versus 68% [95% confidence interval = 56-81] for rituximab-based CIT). Ofatumumab-based CIT is well tolerated in patients with previously untreated CLL. The efficacy of ofatumumab-based CIT compares favorably to historical trials of rituximab-based CIT, suggesting randomized trials comparing ofatumumab-based CIT and rituximab-based CIT should be considered.

B- and T-cell prolymphocytic leukemia: antibody approaches.

B- and T-cell subtypes of prolymphocytic leukemia (PLL) are rare, aggressive lymphoid malignancies with characteristic morphologic, immunophenotypic, cytogenetic, and molecular features. Prognosis for these patients remains poor, with short survival times and no curative therapy. The advent of mAbs has improved treatment options. In B-PLL, rituximab-based combination chemoimmunotherapy is effective in fitter patients. TP53 abnormalities are common and, as for chronic lymphocytic leukemia, these patients should generally be managed using an alemtuzumab-based therapy. Currently, the best treatment for T-PLL is IV alemtuzumab, which has resulted in very high response rates of more than 90% when given as frontline treatment and a significant improvement in survival. Consolidation of remissions with autologous or allogeneic stem cell transplantation further prolongs survival times, and the latter may offer potential cure. The role of allogeneic transplantation with nonmyeloablative conditioning needs to be explored further in both T- and B-PLL to broaden the patient eligibility for what may be a curative treatment.