Long-term repair of T-cell synapse activity in a phase II trial of chemoimmunotherapy followed by lenalidomide consolidation in previously untreated chronic lymphocytic leukemia (CLL)

Key Points• Maintenance rituximab attained a prolonged PFS and improved the quality of response in patients with detectable disease after R-FCM.The effectiveness of rituximab maintenance therapy in the treatment of chronic lymphocytic leukemia has been investigated in a phase 2 clinical trial that included an initial treatment with rituximab 500 mg/m2 on day 1 (375 mg/m2 the first cycle), fludarabine 25 mg/m2 on days 1 to 3, cyclophosphamide 200 mg/m2 on days 1 to 3, and mitoxantrone 6 mg/m2 on day 1 (R-FCM), for 6 cycles, followed by a maintenance phase with rituximab 375 mg/m2 every 3 months for 2 years. Sixty-seven patients having achieved complete response (CR) or partial response (PR) with R-FCM were given maintenance therapy. At the end of maintenance, 40.6% of patients were in CR with negative minimal residual disease (MRD), 40.6% were in CR MRD-positive, 4.8% remained in PR, and 14% were considered failures. Six of 29 patients (21%) who were in CR MRD-positive or in PR after R-FCM improved their response upon rituximab maintenance. The 4-year progression-free survival (PFS) and overall survival rates were 74.8% and 93.7%, respectively. MRD status after R-FCM induction was the strongest predictor of PFS. Maintenance with rituximab after R-FCM improved the quality of the response, particularly in patients MRD-positive after initial treatment, and obtained a prolonged PFS. This trial was registered at www.clinicaltrialsregister.eu as identifier #2005-001569-33. (Blood. 2013122(24):3951-3959)

Section: Discussionmentioning

confidence: 71%

Section: Introductionmentioning

confidence: 99%

Rituximab maintenance after first-line therapy with rituximab, fludarabine, cyclophosphamide, and mitoxantrone (R-FCM) for chronic lymphocytic leukemia

Abrisqueta

Villamor

Terol

et al. 2013

“…Moreover, an indirect effect on leukemic cell trafficking may contribute to the efficacy of lenalidomide, an immunomodulatory agent that is currently under investigation as salvage therapy for patients with relapsed or refractory CLL 106 and as a consolidation strategy in progressive cases. 107 Lenalidomide treatment reduced the chemokine response of CLL cells in vitro and down-modulated the expression of RHOH, 80 which, in the Em-TCL1 model, is indispensable for the homing of malignant B cells to the bone marrow. 80 Inhibition of tumor-microenvironmental interactions.…”

Section: Em-tcl1 Transgenic Mouse Model As a Preclinical Model For Nomentioning

confidence: 99%

Mouse models in the study of chronic lymphocytic leukemia pathogenesis and therapy

Simonetti

Bertilaccio

Ghia

et al. 2014

Mouse models that recapitulate human malignancy are valuable tools for the elucidation of the underlying pathogenetic mechanisms and for preclinical studies. Several genetically engineered mouse models have been generated, either mimicking genetic aberrations or deregulated gene expression in chronic lymphocytic leukemia (CLL). The usefulness of such models in the study of the human disease may potentially be hampered by species-specific biological differences in the target cell of the oncogenic transformation. Specifically, do the genetic lesions or the deregulated expression of leukemia-associated genes faithfully recapitulate the spectrum of lymphoproliferations in humans? Do the CLL-like lymphoproliferations in the mouse have the phenotypic, histological, genetic, and clinical features of the human disease? Here we compare the various CLL mouse models with regard to disease phenotype, penetrance, and severity. We discuss similarities and differences of the murine lymphoproliferations compared with human CLL. We propose that the Eμ-TCL1 transgenic and 13q14-deletion models that have been comprehensively studied at the levels of leukemia phenotype, antigen-receptor repertoire, and disease course show close resemblance to the human disease. We conclude that modeling CLL-associated genetic dysregulations in mice can provide important insights into the molecular mechanisms of disease pathogenesis and generate valuable tools for the development of novel therapies.

“…Other potential lenalidomiderelated biomarkers include components of PI3K signaling (eg, GSK3b) 50 and the T-cell immune synapse with granzyme B expression. 51,52 AITL, angioimmunoblastic T-cell lymphoma; autoSCT, autologous stem cell transplantation; CHOP, cyclophosphamide, doxorubicin, oncovin, and prednisone; CR, complete remission; d, days; DLBCL, diffuse large B-cell lymphoma; FL, follicular lymphoma; FLG3, follicular lymphoma grade 3; GCB, germinal center B-cell; ICE, ifosfamide carboplatin, etoposide; Len, lenalidomide; maint, maintenance; MF, mycoses fungoides; mo, months; MZL, marginal zone lymphoma; NR, not reached; ORR, overall response rate; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PR, partial remission; PTCL NOS, peripheral T-cell lymphoma not otherwise specified; pts, patients; R, rituximab; rel/ref: relapsd/refractory; SLL, small lymphocytic lymphoma; TCL, T-cell lymphoma; TL, transformed lymphoma; yr, year.…”

Section: Future Directions Biomarkersmentioning

confidence: 99%

Lenalidomide in non-Hodgkin lymphoma: biological perspectives and therapeutic opportunities

Kritharis

Coyle

Sharma

et al. 2015

Lenalidomide is an immunomodulatory drug (IMiD) with activity in lymphoid malignancies occurring primarily through immune modulation (eg, T-cell immune synapse enhancement and NK-cell/T-cell effector augmentation) and antiproliferative effects. Food and Drug Administration–approved for bortezomib-resistant, relapsed/refractory mantle-cell lymphoma, lenalidomide has demonstrated efficacy in several additional lymphoma subtypes. There are many ongoing clinical trials examining the use of lenalidomide alone or in combinatorial therapy. It will be important in these studies to delineate reliable, predictive biomarkers to optimally integrate lenalidomide into lymphoma treatment paradigms.