Lenalidomide is an orally active immunomodulatory drug that has direct antineoplastic activity and indirect effects mediated through multiple types of immune cells found in the tumor ...microenvironment, including B, T, natural killer (NK), and dendritic cells. Recently, the E3 ubiquitin ligase cereblon was identified as a molecular target that may underlie the effects of lenalidomide on tumor cells, as well as on cells in the tumor microenvironment. Decreases in cereblon attenuate these effects and also confer resistance to lenalidomide. Tumoricidal effects of lenalidomide are associated with reduced interferon regulatory factor 4, a downstream target of cereblon. Lenalidomide stimulates proliferation and activation of NK cells, thereby enhancing NK cell-mediated cytotoxicity and antibody-dependent cellular cytotoxicity. These effects appear to be secondary to cytokine production from T cells. Lenalidomide has been shown to produce synergistic effects in experimental models when evaluated in combination with rituximab, dexamethasone, bortezomib, and B-cell receptor signaling inhibitors, consistent with mechanisms complementary to these agents. These experimental findings have translated to the clinic, where single-agent use displays durable responses in relapsed/refractory non-Hodgkin lymphoma, and combination with rituximab and other agents leads to improved responses at first line and in relapsed/refractory disease. The activity of lenalidomide is evident across multiple lymphoma subtypes, including indolent and aggressive forms. The interaction among cell types in the immune microenvironment is increasingly recognized as important to tumor cell recognition and destruction, as well as to protection of normal immune cells, as reflected by lenalidomide studies across multiple types of B-cell lymphomas.
Allogenic stem cell transplantation (allo-SCT) has been considered the treatment of choice for high-risk patients with chronic lymphocytic leukemia (CLL) and the only approach offered with curative ...intent in this disease. The availability novel agents, including the B-cell receptor inhibitors ibrutinib, acalabrutinib, and idelalisib, as well as venetoclax, which targets the BCL2 pathway, and the success of these agents in treating high-risk disease patients have made it more difficult to assess who should be considered for allo-SCT and when in the treatment course. In this review, I will discuss the different treatment options available for the treatment of high-risk CLL and how allo-SCT fits into the treatment algorithm in the era of novel agents.
How I treat CLL up front Gribben, John G.
Blood,
01/2010, Letnik:
115, Številka:
2
Journal Article
Recenzirano
Odprti dostop
Although chronic lymphocytic leukemia (CLL) remains incurable, over the past decade there have been major advances in understanding the pathophysiology of CLL and in the treatment of this disease. ...This has led to greatly increased response rates and durations of response but not yet improved survival. Advances in the use of prognostic factors that identify patients at high risk for progression have led us to the question whether there is still a role for a “watch and wait” approach in asymptomatic high-risk patients or whether they should be treated earlier in their disease course. Questions remain, including, what is the optimal first-line treatment and its timing and is there any role of maintenance therapy or stem cell transplantation in this disease? CLL is a disease of the elderly and not all patients are eligible for aggressive up-front chemoimmunotherapy regimens, so what is the optimal treatment approach for more frail elderly patients? It is highly likely that our treatment approaches will continue to evolve as the results of ongoing clinical trials are released and that further improvements in the outcome of this disease will result from identification of therapies that target the underlying pathophysiology of CLL.
The B7 family consists of structurally related, cell-surface proteins that regulate immune responses by delivering costimulatory or coinhibitory signals through their ligands. Eight family members ...have been identified to date including CD80 (B7-1), CD86 (B7-2), CD274 (programmed cell death-1 ligand PD-L1), CD273 (programmed cell death-2 ligand PD-L2), CD275 (inducible costimulator ligand ICOS-L), CD276 (B7-H3), B7-H4, and B7-H6. B7 ligands are expressed on both lymphoid and nonlymphoid tissues. The importance of the B7 family in regulating immune responses is clear from their demonstrated role in the development of immunodeficiency and autoimmune diseases. Manipulation of the signals delivered by B7 ligands shows great potential in the treatment of cancers including leukemias and lymphomas and in regulating allogeneic T-cell responses after stem cell transplantation.
Summary
The treatment landscape in relapsed/refractory chronic lymphocytic leukaemia (CLL) has rapidly evolved over the past five years, with one such emergent treatment being the BCL2 inhibitor, ...venetoclax. This oral treatment has demonstrated significant clinical advantages in indicated patients, but rapid tumour debulking can lead to a treatment‐related risk of the acute condition known as tumour lysis syndrome (TLS). Here, I present real patient cases to show how I have used the recommended predose monitoring and prophylactic procedures to mitigate the risk of TLS. I also used the ramp‐up dose escalation schedule of venetoclax therapy initiation to safely take patients through the treatment, successfully providing them with sustained clinical benefits.
Discovery of the enzymatic activity that catalyses oxidation of 5-methylcytosine (5mC) to generate 5-hydroxymethylcytosine (5hmC) mediated by the MLL (KMT2A) fusion partner TET1 has sparked intense ...research to understand the role this new DNA modification has in cancer. An unambiguous picture has emerged where tumours are depleted of 5hmC compared to corresponding normal tissue, but it is not known whether lack of 5hmC is a cause or a consequence of tumourigenesis. Experimental data reveals a dual tumour-suppressive and oncogenic role for TET proteins. Tet2 mutations are drivers in haematological malignancies but Tet1 had an oncogenic role in MLL-rearranged leukaemia, where Tet1 is overexpressed. Overexpression of Tet2 in melanoma cells re-established the 5hmC landscape and suppressed cancer progression but inhibiting Tet1 in non-transformed cells did not initiate cellular transformation. In this review we summarise recent findings that have shaped the current understanding on the role 5hmC plays in cancer.
Patients with indolent non-Hodgkin lymphoma typically respond well to first-line immunochemotherapy. At relapse, single-agent rituximab is commonly administered. Data suggest the immunomodulatory ...agent lenalidomide could increase the activity of rituximab.
A phase III, multicenter, randomized trial of lenalidomide plus rituximab versus placebo plus rituximab was conducted in patients with relapsed and/or refractory follicular or marginal zone lymphoma. Patients received lenalidomide or placebo for 12 cycles plus rituximab once per week for 4 weeks in cycle 1 and day 1 of cycles 2 through 5. The primary end point was progression-free survival per independent radiology review.
A total of 358 patients were randomly assigned to lenalidomide plus rituximab (n = 178) or placebo plus rituximab (n = 180). Infections (63%
49%), neutropenia (58%
23%), and cutaneous reactions (32%
12%) were more common with lenalidomide plus rituximab. Grade 3 or 4 neutropenia (50%
13%) and leukopenia (7%
2%) were higher with lenalidomide plus rituximab; no other grade 3 or 4 adverse event differed by 5% or more between groups. Progression-free survival was significantly improved for lenalidomide plus rituximab versus placebo plus rituximab, with a hazard ratio of 0.46 (95% CI, 0.34 to 0.62;
< .001) and median duration of 39.4 months (95% CI, 22.9 months to not reached) versus 14.1 months (95% CI, 11.4 to 16.7 months), respectively.
Lenalidomide improved efficacy of rituximab in patients with recurrent indolent lymphoma, with an acceptable safety profile.
The treatment of chronic lymphocytic leukemia (CLL) has been revolutionized by targeted therapies that either inhibit proliferation (ibrutinib) or reactivate apoptosis (venetoclax). Both ...significantly improve survival in CLL and replace chemoimmunotherapy for many patients. However, individually, they rarely lead to eradication of measurable residual disease (MRD) and usually are taken indefinitely or until progression. We present the CLARITY trial that combined ibrutinib with venetoclax to eradicate detectable CLL with the intention of stopping therapy.
CLARITY is a phase II trial that combined ibrutinib with venetoclax in patients with relapsed or refractory CLL. The primary end point was eradication of MRD after 12 months of combined therapy. Key secondary end points were response by International Workshop on CLL criteria, safety, and progression-free and overall survival.
In 53 patients after 12 months of ibrutinib plus venetoclax, MRD negativity (fewer than one CLL cell in 10,000 leukocytes) was achieved in the blood of 28 (53%) and the marrow of 19 (36%). Forty-seven patients (89%) responded, and 27 (51%) achieved a complete remission. After a median follow-up of 21.1 months, one patient progressed, and all patients were alive. A single case of biochemical tumor lysis syndrome was observed. Other adverse effects were mild and/or manageable and most commonly were neutropenia or GI events.
The combination of ibrutinib plus venetoclax was well tolerated in patients with relapsed or refractory CLL. There was a high rate of MRD eradication that led to the cessation of therapy in some patients. The progression-free and overall survival rates are encouraging for relapsed and refractory CLL.
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