Nishitha Reddy

Immunomodulatory drugs stimulate natural killer‐cell function, alter cytokine production by dendritic cells, and inhibit angiogenesis enhancing the anti‐tumour activity of rituximab in vivo

The immunomodulatory drugs (IMiDs) lenalidomide and actimid (also known as CC‐4047) are thalidomide analogues which are more potent than their parental compound. In combination with rituximab, we have previously demonstrated that IMiDs have synergistic in vivo anti‐tumour activity in preclinical studies in a human lymphoma severe combined immunodeficiency mouse model. This report further explored the mechanisms by which IMiDs exert their anti‐lymphoma effects. Following exposure of subcutaneous lymphoma tumours in murine models to IMiDs, there was a significant increase in the recruitment of natural killer (NK) cells to tumour sites. This increase in NK cells was mediated via stimulation of dendritic cells and modification of the cytokine microenvironment associated with an increase in monocyte chemotactic protein‐1, tumour necrosis factor‐α and interferon‐γ and probably augmented rituximab‐associated antibody‐dependent cellular cytotoxicity. IMiDs also had significant anti‐angiogenic effects in our B‐cell lymphoma models. Thus, by modulation of the immune system mediated via dendritic cells and NK cells, changing the cytokine milieu, as well as by their anti‐angiogenic effects, IMiDs in combination with rituximab resulted in augmented in vivo anti‐tumour effects against B‐cell lymphoma. Our positive preclinical data adds additional support for the evaluation of IMiDs plus rituximab in patients with relapsed/refractory B‐cell lymphoma.

Immunomodulatory Drug CC-5013 or CC-4047 and Rituximab Enhance Antitumor Activity in a Severe Combined Immunodeficient Mouse Lymphoma Model

New thalidomide derivatives CC-5013 and CC-4047 (immunomodulatory drugs, IMiD) are up to 10,000 times more potent than Thalidomide. The biological effects of IMiDs are presumed to be mediated by (a) activation of some components of the innate [natural killer (NK) cells] or adoptive immune system (T cells), (b) modification of cytokine microenvironment in the tumor bed, or by (c) inhibition of angiogenesis. In this article, we tested an innovative combination strategy involving rituximab and IMiDs in aggressive lymphoma cell lines and human lymphoma xenografts. Treatment of non-Hodgkins lymphoma cells with CC-5013 resulted in a 40% to 70% growth inhibition when compared with controls (P < 0.05). Exposure of lymphoma cells to CC-4047 resulted in a lesser degree of growth inhibition. Induction of apoptosis was shown in 10% to 26% of lymphoma cells 24 hours following exposure to either IMiD. In vivo studies in severe combined immunodeficient mice showed synergistic activity between CC-4047 (and to a lesser degree, CC-5013) plus rituximab. Animals treated with the CC-4047/rituximab combination had a median survival of 74 days (P = 0.0012) compared with 58 days (P = 0.167) in CC-5013/rituximab-treated animals compared with 45 days in rituximab monotherapy–treated animals. The synergistic effect between IMiDs and rituximab in our mouse model was attributed to NK cell expansion. The enhancement of rituximab activity by IMiDs was abrogated by in vivo depletion of NK cells. Augmenting NK cell function by CC-4047 or CC-5013 exposure may increase the antitumor effects of rituximab against B-cell lymphomas and warrants further exploration in the context of a clinical trial.

Impact of induction regimen and stem cell transplantation on outcomes in double-hit lymphoma: A multicenter retrospective analysis

Patients with double-hit lymphoma (DHL), which is characterized by rearrangements of MYC and either BCL2 or BCL6, face poor prognoses. We conducted a retrospective multicenter study of the impact of baseline clinical factors, induction therapy, and stem cell transplant (SCT) on the outcomes of 311 patients with previously untreated DHL. At median follow-up of 23 months, the median progression-free survival (PFS) and overall survival (OS) rates among all patients were 10.9 and 21.9 months, respectively. Forty percent of patients remain disease-free and 49% remain alive at 2 years. Intensive induction was associated with improved PFS, but not OS, and SCT was not associated with improved OS among patients achieving first complete remission (P = .14). By multivariate analysis, advanced stage, central nervous system involvement, leukocytosis, and LDH >3 times the upper limit of normal were associated with higher risk of death. Correcting for these, intensive induction was associated with improved OS. We developed a novel risk score for DHL, which divides patients into high-, intermediate-, and low-risk groups. In conclusion, a subset of DHL patients may be cured, and some patients may benefit from intensive induction. Further investigations into the roles of SCT and novel agents are needed.

Management of relapse after allo-SCT for AML and the role of second transplantation

Relapse after allo-SCT for AML carries very poor prognosis. Second allo-SCT, although curative, is not an appropriate treatment option for a large number of relapsing patients (only 2–20% patients receive a second allo-SCT), and efforts to increase the number of patients who may benefit from a second allo-SCT are ongoing. In addition, understanding the varied biological processes that are operative in disease relapse has encouraged the development of novel therapies, and could be beneficial to patients who are currently managed conservatively with supportive care for relapsed disease. Incorporating novel combinations of drugs with immunomodulation, although theoretically attractive, should be tested in the setting of clinical trials. In this review, we discuss the currently available approaches for relapsed AML after allo-SCT.

Strategies to Prevent EBV Reactivation and Posttransplant Lymphoproliferative Disorders (PTLD) after Allogeneic Stem Cell Transplantation in High-Risk Patients

Epstein-Barr virus (EBV)-associated postallogeneic stem cell transplantation (SCT) lymphoproliferative disorder (PTLD) is often life threatening. The risk of EBV reactivation is highest in older patients, T cell-depleted SCT (in vivo or vitro), and in unrelated or mismatched SCT. Cumulative numbers of patients with EBV reactivation and PTLD are rising as more patients at high risk for EBV reactivation and PTLD are receiving allo-SCT. Novel but easily applicable strategies are needed to prevent EBV reactivation and PTLD to serve the needs of the increasingly enlarging population of high-risk SCT recipients across the globe.

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.

Genetic and Functional Drivers of Diffuse Large B Cell Lymphoma

Diffuse large B cell lymphoma (DLBCL) is the most common form of blood cancer and is characterized by a striking degree of genetic and clinical heterogeneity. This heterogeneity poses a major barrier to understanding the genetic basis of the disease and its response to therapy. Here, we performed an integrative analysis of whole-exome sequencing and transcriptome sequencing in a cohort of 1,001 DLBCL patients to comprehensively define the landscape of 150 genetic drivers of the disease. We characterized the functional impact of these genes using an unbiased CRISPR screen of DLBCL cell lines to define oncogenes that promote cell growth. A prognostic model comprising these genetic alterations outperformed current established methods: cell of origin, the International Prognostic Index comprising clinical variables, and dual MYC and BCL2 expression. These results comprehensively define the genetic drivers and their functional roles in DLBCL to identify new therapeutic opportunities in the disease.

Allogeneic transplantation provides durable remission in a subset of DLBCL patients relapsing after autologous transplantation

For diffuse large B‐cell lymphoma (DLBCL) patients progressing after autologous haematopoietic cell transplantation (autoHCT), allogeneic HCT (alloHCT) is often considered, although limited information is available to guide patient selection. Using the Center for International Blood and Marrow Transplant Research (CIBMTR) database, we identified 503 patients who underwent alloHCT after disease progression/relapse following a prior autoHCT. The 3‐year probabilities of non‐relapse mortality, progression/relapse, progression‐free survival (PFS) and overall survival (OS) were 30, 38, 31 and 37% respectively. Factors associated with inferior PFS on multivariate analysis included Karnofsky performance status (KPS) <80, chemoresistance, autoHCT to alloHCT interval <1‐year and myeloablative conditioning. Factors associated with worse OS on multivariate analysis included KPS<80, chemoresistance and myeloablative conditioning. Three adverse prognostic factors were used to construct a prognostic model for PFS, including KPS<80 (4 points), autoHCT to alloHCT interval <1‐year (2 points) and chemoresistant disease at alloHCT (5 points). This CIBMTR prognostic model classified patients into four groups: low‐risk (0 points), intermediate‐risk (2‐5 points), high‐risk (6‐9 points) or very high‐risk (11 points), predicting 3‐year PFS of 40, 32, 11 and 6%, respectively, with 3‐year OS probabilities of 43, 39, 19 and 11% respectively. In conclusion, the CIBMTR prognostic model identifies a subgroup of DLBCL patients experiencing long‐term survival with alloHCT after a failed prior autoHCT.

Role of Cytotoxic Therapy with Hematopoietic Cell Transplantation in the Treatment of Hodgkin Lymphoma: Guidelines from the American Society for Blood and Marrow Transplantation

The role of hematopoietic cell transplantation (HCT) in the therapy of Hodgkin lymphoma (HL) in pediatric and adult patients is reviewed and critically evaluated in this systematic evidence-based review. Specific criteria were used for searching the published literature and for grading the quality and strength of the evidence and the strength of the treatment recommendations. Treatment recommendations based on the evidence are included and were reached unanimously by a panel of HL experts. Both autologous and allogeneic HCT offer a survival benefit in selected patients with advanced or relapsed HL and are currently part of standard clinical care. Relapse remains a significant cause of failure after both transplant approaches, and strategies to decrease the risk of relapse remain an important area of investigation.

Enhancing activity and overcoming chemoresistance in hematologic malignancies with bortezomib: preclinical mechanistic studies

BACKGROUND Proteasome inhibition results in antitumor activity through various mechanisms, including disruption of cell cycle progression and control, induction of apoptosis, and inhibition of proliferation. DESIGN This review assesses preclinical data on the ability of bortezomib, the first proteasome inhibitor approved for clinical use, to enhance antitumor activity of other agents and to overcome chemoresistance in hematologic malignancies and discusses mechanisms by which such activity arises. RESULTS Bortezomib has been shown to affect multiple cellular pathways and levels of numerous intracellular proteins, including targets of importance in hematologic malignancies. These mechanisms have shown additive or synergistic effects in vitro and in vivo with those of conventional therapeutic and novel targeted agents. Additionally, targets of proteasome inhibition are implicated in resistance or lack of sensitivity to different therapies. Bortezomib in combination with other agents has been shown to overcome resistance to those agents and to resensitize cells to agents to which they were previously unresponsive. CONCLUSIONS This review indicates the potential utility of proteasome inhibition for substantially enhancing activity of other therapeutic approaches. It explains the mechanisms responsible for the observed clinical activity of bortezomib-based regimens and elucidates novel therapeutic approaches through identification of combinations of agents with complimentary mechanisms of action.