Results In Chronic Lymphocytic Leukemia Research Articles

The complexities of T-cell dysfunction in chronic lymphocytic leukemia

Chronic lymphocytic leukemia (CLL) is a B-cell malignancy characterized by profound alterations and defects in the T-cell compartment. This observation has gained renewed interest as T-cell treatment strategies, which are successfully applied in more aggressive B-cell malignancies, have yielded disappointing results in CLL. Despite ongoing efforts to understand and address the observed T-cell defects, the exact mechanisms and nature underlying this dysfunction remain largely unknown. In this review, we examine the supporting signals from T cells to CLL cells in the lymph node niche, summarize key findings on T-cell functional defects, delve into potential underlying causes, and explore novel strategies for reversing these deficiencies. Our goal is to identify strategies aimed at resolving CLL-induced T-cell dysfunction which, in the future, will enhance the efficacy of autologous T-cell-based therapies for CLL patients.

NK Cell Dysfunction in CLL Is Mediated through SHP-1 Signaling and Is Associated with Poor Prognosis

Chronic lymphocytic leukemia (CLL) is a heterogeneous disease, presenting with a highly variable clinical course, outcome and response to therapy. This variability has been linked to a complex tumor microenvironment and genetic/epigenetic modifications that lead to immunosuppression. Indeed, the clinical hallmark of this disease is the susceptibility to infections and secondary malignancies. While T cell dysfunction in CLL has been well described, conflicting information exists on NK cell changes in CLL and their role in CLL immunosurveillance. Here, we analyzed samples from 75 untreated (or completed treatment >2 years ago) CLL patients and 30 healthy controls. We discovered a substantial variation in NK cell function compared with healthy controls, which we further classified into hyperfunctional, normofunctional and dysfunctional based on their ability to degranulate, and produce IFN- γ in response to K562 targets ( Figure 1). NK cells from ‘dysfunctional’ CLL samples also displayed impaired cytotoxicity against K562 targets, weaker synapse formation and Syk/Zap70 signaling in response to antibody-dependent cellular cytotoxicity (ADCC) compared to those from ‘functional’ samples. The NK functional status was strongly associated with multiple prognostic markers, including cytogenetics, IgVH mutation status, ZAP-70 expression and disease stage, with patients with dysfunctional NK cells having significantly higher rates of secondary malignancies and viral infections ( Table 1). Using multispectral flow cytometry we discovered high phenotypic heterogeneity with unique NK cell clusters present in the dysfunctional samples. Those clusters express a pattern of activation-induced exhaustion, with upregulation of multiple checkpoint molecules such as PD-1, TIGIT, LAG-3, KLRG-1, TIM-3 but not evidence of terminal differentiation (CD57 negative). Those clusters also showed concomitant expression of activating molecules such as NKG2D and DNAM-1, suggesting reversibility of their dysfunctional status. We subsequently found significantly higher (p<0.0001) constitutive phosphorylation of SHP-1 protein, a phosphatase downstream of multiple inhibitory NK cell receptors, in NK cells from dysfunctional samples. Treatment with a SHP-1 inhibitor NSC-87877 (EMD Millipore) or use of siRNA targeting SHP-1 (ThermoFisher scientific), resulted in reversal of NK dysfunction with full restoration of their functional capacity. Taken together, our data suggest that NK cells functional status plays an important role in CLL disease progression and secondary complications. The novel mechanism of NK cell immune dysfunction in CLL described here has the potential to improve outcomes with novel immunotherapies such as chimeric antigen receptors, checkpoint inhibitors and bi-specific antibody therapy that have shown disappointing results in CLL to date when compared with other B cell malignancies.

Poor Neutralizing Antibody Responses in Patients with CLL, NHL and HL after Vaccination Against Sars-Cov-2; A Prospective Study in 132 Patients

Introduction: Recent data suggest a suboptimal antibody response to COVID-19 vaccination in patients with hematological malignancies, especially under therapy with monoclonal antibodies targeting B-cells. Herein, we evaluated the development of neutralizing antibodies (NAbs) against SARS-CoV-2 in patients with chronic lymphocytic leukemia (CLL), Non-Hodgkin Lymphoma (NHL) and Hodgkin's Lymphoma (HL) after vaccination with the mRNA BNT162b2 vaccine, up to 50 days post their first vaccine dose.Methods: This is a large prospective study (NCT04743388) evaluating the kinetics of anti-SARS-CoV-2 antibodies after COVID-19 vaccination in healthy subjects and patients with hematological malignancies. We report here the results in CLL, NHL and HL patients in comparison to age- and gender-matched controls who were vaccinated at the same time period (January to May 2021).After vein puncture, the serum of both patients and controls was collected on day 1 (D1; before the first BNT162b2 dose), on day 22 (D22; before the second dose of the BNT162b2) and on day 50 (D50; 3 weeks post second dose of the BNT162b2). Serum was separated within 4 hours from blood collection and stored at -80°C until the day of measurement. NAbs against SARS-CoV-2 were measured using FDA approved methodology (ELISA, cPass™ SARS-CoV-2 NAbs Detection Kit; GenScript, Piscataway, NJ, USA) on the abovementioned timepoints. A NAb titer of at least 30% is considered as positive, according to manufacturer, whereas a NAb titer of at least 50% has been associated with clinically relevant viral inhibition [Walsh et al. N Engl J Med 2020, 383, 2439-50]. Samples of the same individual were measured in the same ELISA plate.Results: We evaluated 132 patients with CLL/Lymphomas after vaccination with the BNT162b2. Patient population included 53 with CLL, 57 with NHL and 22 with HL, while 214 healthy controls, of similar age and gender, were also studied. At the time of vaccination, 30% (n=40) of patients had asymptomatic disease and out of 92 symptomatic patients, 49% (n=45) were on active treatment. Vaccination with two doses of the BNT162b2 led to lower production of NAbs against SARS-CoV-2 in patients compared with controls, both on day 22 and on day 50 (P<0.001 for all comparisons) for all subgroups. After the first dose of the vaccine, on D22, the patient group had lower NAb titers compared with controls: the median NAb inhibition titer was 18% (IQR: 8.5-29%) for patients versus 41.6% (IQR: 25.3-59%) for controls; p<0.001. On D50, the median NAb inhibition titer was 32.5% (IQR: 13.5-93%) for patients versus 94.7% (IQR: 89-97%) for controls; p<0.001. More specifically, only 50.8% (67/132) of the patients versus 98.1% (210/214) of the controls developed NAb titers ≥30% and 43.9% (58/132) of patients versus 95.3% (204/214) titers ≥50% (high protective titers) at day 50 (p<0.0001 for all comparisons; Figure-left part). Importantly, active treatment (which included anti-CD antibodies, Bruton's tyrosine kinase inhibitors, a combination of the above, chemotherapy-only regimens or Bcl-2 inhibitors) was an independent prognostic factor for suboptimal antibody response at day 50 (<50%) in the patient subgroup (p<0.001). Rituximab administration in the last 12 months correlated with decreased antibody response at day 50 (p<0.01). Patients with HL were more likely to achieve humoral responses (>50% at day 50) compared to other disease types (p<0.05; Figure-right part). Disease-related immune dysregulation and therapy-related immunosuppression were therefore involved in the low humoral responses seen in patients. Regarding adverse events, 9% and 9.8% patients reported mild reactions after the first and second dose of the BNT162b2 vaccine, respectively.Conclusion: Patients with CLL/NHL/HL have a low humoral response following SARS-CoV-2 vaccination, particularly patients who are on active treatment with rituximab or BTK inhibitors. These patient subgroups therefore should continue utilizing protective measures against SARS-CoV-2 (masks, social distancing, etc) as they are at high risk for COVID-19. Further studies on the kinetics of immune subpopulations following COVID-19 vaccination will elucidate the underlying immune landscape and determine the potential need for additional booster vaccine doses or protective administration of antibodies against SARS-CoV-2 in CLL/NHL/HL patients with poor response after full vaccination. [Display omitted] DisclosuresTerpos: Sanofi: Consultancy, Honoraria, Research Funding; Novartis: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Janssen-Cilag: Consultancy, Honoraria, Research Funding; GSK: Honoraria, Research Funding; Genesis: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; BMS: Honoraria; Amgen: Consultancy, Honoraria, Research Funding. Gavriatopoulou: Janssen: Honoraria; GSK: Honoraria; Genesis: Honoraria; Takeda: Honoraria; Sanofi: Honoraria; Amgen: Honoraria; Karyopharm: Honoraria. Baltadakis: Amgen: Honoraria; Bristol-Myers Squibb: Honoraria; Alexion: Honoraria; Astellas: Honoraria; Pfizer: Honoraria, Other: Travel Grants; Gilead: Honoraria; Novartis: Honoraria; Abbvie: Honoraria; Genesis Pharma: Other: Travel Grants; Gilead: Other: Travel Grants; WinMedica: Other: Travel Grants; Baxalta Hellas: Other: Travel Grants. Dimopoulos: BMS: Honoraria; Amgen: Honoraria; Janssen: Honoraria; Takeda: Honoraria; Beigene: Honoraria.

Repertoire of Rearranged Immunoglobulin Heavy Chain Genes in Russian Patients With B-Cell Lymphoproliferative Diseases

IntroductionImmunoglobulin heavy chain variable region (IGHV) repertoire narrowing could be an evidence for the involvement of a limited set of antigens in the development of lymphomas. For chronic lymphocytic leukemia (CLL) the existence of more than 200 subgroups of tumor IGHV antigen-binding sites, so called “stereotypical” antigen receptors (SAR) has been shown. For others lymphomas the possibility of SARs is also suggested. The aim of this study is to compare the tumor IGHVs and possible SARs in various B-cell malignancies in Russia and other countries. Materials and MethodsThe study included samples of 1800 CLL patients, 52 patients with mantle cell lymphoma, 48 patients with hairy cell lymphoma and 37 patients with splenic marginal cell lymphoma. The nucleotide sequences of the IGHV genes were determined according to ERIC protocol. ResultsIn CLL most common IGHV genes were IGHV1-69, IGHV1-2, IGHV3-30 and IGHV4-34. The most common SARs were CLL#1, CLL#6, CLL#2, CLL#3. In MCL the most common genes were IGHV4-34, IGHV3-21, IGHV3-23. In 5 MCL patients CDR3 sequences were identified matching definitions of a stereotyped. In the half of SMZL patients was identified gene IGHV1-2. Other IGHV genes were much less common. Two pairs of SMZL patients have motives similar to each other. In HCL IGHV repertoire was the most variable, no trends for antigen receptor stereotypy were observed. It was found that SARs are highly disease-specific both at the level of nucleotide and amino acid sequences. ConclusionOur results suggest that antigens crucial for the pathogenesis of B-cell malignancies could be disease-specific. Further studies on extended samples of non-CLL patients concerning the role of SARs in pathogenesis of these diseases may also contribute to the development of new diagnostic and prognostic markers.

T Cell Defects and Immunotherapy in Chronic Lymphocytic Leukemia.

Simple SummaryThe treatment of chronic lymphocytic leukemia (CLL) is a rapidly evolving field; however, despite recent progress, CLL remains incurable. Different types of immunotherapy have emerged as therapeutic options for CLL, aiming to boost anti-tumor immune responses; that said, despite initial promising results, not all patients benefit from immunotherapy. Relevant to this, the tumor microenvironment (TME) in CLL has been proposed to suppress effective immune responses while also promoting tumor growth, hence impacting on the response to immunotherapy as well. T cells, in particular, are severely dysfunctional in CLL and cannot mount effective immune responses against the malignant cells. However, reinvigoration of their effector function is still a possibility under the proper manipulation and has been associated with tumor regression. In this contribution, we examine the current immunotherapeutic options for CLL in relation to well-characterized T cell defects, focusing on possible counteracts that enhance anti-tumor immunity through the available treatment modalities.In the past few years, independent studies have highlighted the relevance of the tumor microenvironment (TME) in cancer, revealing a great variety of TME-related predictive markers, as well as identifying novel therapeutic targets in the TME. Cancer immunotherapy targets different components of the immune system and the TME at large in order to reinforce effector mechanisms or relieve inhibitory and suppressive signaling. Currently, it constitutes a clinically validated treatment for many cancers, including chronic lymphocytic leukemia (CLL), an incurable malignancy of mature B lymphocytes with great dependency on microenvironmental signals. Although immunotherapy represents a promising therapeutic option with encouraging results in CLL, the dysfunctional T cell compartment remains a major obstacle in such approaches. In the scope of this review, we outline the current immunotherapeutic treatment options in CLL in the light of recent immunogenetic and functional evidence of T cell impairment. We also highlight possible approaches for overcoming T cell defects and invigorating potent anti-tumor immune responses that would enhance the efficacy of immunotherapy.

Idelalisib Given Front-Line for the Treatment of Chronic Lymphocytic Leukemia Results in Frequent and Severe Immune-Mediated Toxicities

Introduction: Idelalisib (idela) is a highly selective oral inhibitor of PI3Kδ that is currently FDA-approved in conjunction with rituximab for the treatment of relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL). In clinical trials performed in the R/R setting, the overall response rate was 70-80%, while the frequency of significant toxicity was easily manageable (grade ≥3 transaminitis 14%, pneumonitis 3%, grade ≥3 diarrhea 14%) (Coutre EHA 2015). Given the high efficacy of idela, we are evaluating the combination of idela plus ofatumumab (ofa) as first-line therapy for CLL in a phase II study. Surprisingly, we noted much higher rates of grade 3-4 transaminitis in particular, as well as more pneumonitis and colitis, than previously reported. Preclinical data and clinical response to corticosteroids suggest that these toxicities may be autoimmune in origin.Methods: These results describe the clinical characteristics and toxicities of the first 21 subjects enrolled in a single-arm phase II study of idela plus ofa in previously untreated CLL patients in need of therapy. Subjects received idela 150mg twice daily during a 2 month lead-in period prior to the addition of weekly ofa infusions x 8 followed by monthly infusions x 4. For the first 2 months, subjects were monitored for toxicities with weekly clinic visits and biweekly serum chemistries. Single cell mass cytometry (CyTOF) permits the simultaneous evaluation of up to 36 markers without marker emission overlap, allowing for a comprehensive phenotypic and functional analysis of T cell subsets. We used CyTOF to compare T cell subset number and function between subjects who experienced no toxicity (n=2) and a portion of subjects (n=5) who experienced grade ≥3 toxicity while on idela.Results: After a median follow-up of 8.1 months (range 0.7-10.8 months), sixteen subjects (76%) had experienced a grade 3 or higher toxicity. The most frequent grade ≥3 adverse events were transaminitis (n=12, 57%), enterocolitis (n=3, 14%), and pneumonitis (n=2, 10%). The subjects who experienced grade ≥3 toxicities, or who experienced multiple toxicities of at least grade 2 (n =13), were younger (median age 65 vs. 75 years, P =0.047) and had higher absolute lymphocyte counts (median 71466 vs. 19250 cells/µL, p =0.017) compared to subjects who experience no or low grade toxicity (n=7). The median time to onset of transaminase elevation was 28 days (range 14-274 days), with most occurring between days 20-30. Two subjects with ongoing elevation of grade 4 transaminitis after holding idela underwent liver biopsy. These biopsies showed increased activated cytotoxic T cells within the liver parenchyma compared to normal controls with CLL. In all cases, the organ toxicities have abated with the initiation of immunosuppressive therapy. Sixteen subjects (76%) required steroids and one subject (5%) required mycophenolate mofetil.Preclinical data suggest that PI3Kδ is critical to the function of regulatory T cells (Tregs), and inhibition of PI3Kδ leads to autoimmunity. Indeed, CyTOF analysis demonstrated that five out of six tested subjects (83%) had a decrease in the percentage of Tregs after one cycle of idela therapy. Tregs from subjects who experienced grade ≥3 toxicity had lower baseline expression level of functional markers (GITR, T-bet, TIM-3) and higher expression level of apoptotic markers (CD95) compared to subjects who experienced no toxicity. After one cycle of idela therapy, expression levels of the Treg effector markers granzyme β, HLA-DR, and PD-1 decreased in subjects who experienced toxicity, but increased in those subjects who did not.Conclusions: The use of idela as first-line therapy in CLL results in more frequent and severe toxicities than its use in the R/R setting. Multiple lines of evidence suggest that this toxicity is immune-mediated: the delayed time to onset, an immune cell infiltrate in biopsies of affected organs, and abatement of toxicity with immunosuppressants. Affected patients had depressed Treg functionality at baseline and lost markers of Treg activation after idela therapy, suggesting that they may be particularly sensitive to PI3Kδ blockade and Treg inhibition. In addition to elucidating the mechanisms of idelalisib, these studies will hopefully allow us to better screen and select patients in whom idela therapy will be well tolerated. DisclosuresNo relevant conflicts of interest to declare.

Radioimmunotherapy in Allogeneic Nonmyeloablative Conditioning for B Cell Lymphoma: Should We Use It More Often?

In this issue of Biology of Blood and Marrow Transplantation, Cassaday and coworkers reported improved survival rates in patients with indolent B-cell lymphomas who underwent anti-CD-20 radioimmunotherapy using yttrium-90-ibrutinib tiuxetan (90YIT) with their nonmyeloablative transplant conditioning regimen.1 All these patients had been exposed to rituximab. The authors compared their results to those of a historical control group of patients who did not receive 90YIT.1 After adjusting for imbalances in patients’ characteristics including chemoresistant and bulky disease, thrombocytopenia and Hematopoietic Cell Transplant Comorbidity Index Scores of ≥ 3, favoring the control group, the 3-year adjusted estimates of overall survival and progression-free survival in the 90YIT were 87% and 71%, vs 59% and 44% in the non-90YIT group. The authors acknowledge the limitation of the small number of patients studied (n=18), which was even smaller after adjusting for high-risk disease features described above. Nevertheless, their findings further confirm that RIT improves the outcome of patients with relapsed or refractory high-risk indolent lymphoma who have been considered for nonmyeloablative allogeneic transplantation. They are also in agreement with those of an earlier report from our center of a 3-year progression-free survival rate of 80% in refractory follicular lymphoma patients after allogeneic transplantation and 90YIT.2 Nonmyeloablative conditioning has been the cornerstone of adoptive allogeneic immunotherapy for B-cell indolent lymphoma that has failed to respond to conventional treatment. Pre-transplantation chemosensitivity vs refractoriness has been an important determinant of outcomes,3 and how to treat refractory disease without inducing additional toxicity has been a challenge. One strategy to enhance initial disease control is to incorporate novel agents into allogeneic conditioning regimens that are effective against lymphoma; remission can later be sustained via the graft-versus-lymphoma effect. One of the most compelling of these agents is 90YIT, which is used as targeted therapy in indolent lymphomas. The known sensitivity of B-cell indolent lymphomas to conventional radiotherapy makes them an attractive target for RIT. In the United States, 90YIT (Zevalin; Spectrum Pharmaceuticals, Henderson, NV) has been approved for the treatment of relapsed low-grade and follicular lymphomas. In 2009, the drug received an additional indication for use as consolidation after initial chemotherapy.4 90YIT uses the antibody to mediate complement-mediated cytotoxicity, along with the delivery of high-energy, short path-length (5 mm) beta irradiation from 90Y to both CD20-lymphoma cells and neighboring tumor cells that are inaccessible to the antibody or have insufficient antigen expression as a result of a cross-fire effect, with little effect on other solid organs. Of note, positive results were found in this study in patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (10 of 18 patients), while the degree of marrow involvement and cytopenia were not factored into eligibility criteria to receive 90YIT. RIT is not known to be active as a single agent, without transplantation, in these histologic types. In a study at MD Anderson, 90YIT was administered to 14 patients with relapsed CLL that was in partial (but with 100,000/mm3. Of the 13 patients evaluable for response, only 1 patient achieved an MRD-negative remission but soon thereafter had Richter transformation. Grade ≥ 3 hematological toxicity was seen in 12 of the 13 evaluable patients. In view of this contrast in responses and safety, further exploration is needed of the mechanism of action of 90YIT in these diseases in the context of allogeneic transplantation. How can the information in the Cassaday et al study be used in clinical practice? The results of the current study confirm that the type of conditioning used in nonmyeloablative transplantation strategies matters and that one size does not fit all. The results of this study and the study at our center suggest that 90YIT should be more frequently administered to patients with active or refractory indolent lymphoma before transplantation. However, patients should be treated in clinical trials. The CLL results are intriguing and need to be confirmed in other studies. Contrary to previous findings in mouse models,6 it appears that prior exposure to rituximab does not affect the efficacy or safety of transplantation with 90YIT. Finally, this study does not address the lingering question in allogeneic transplantation: the incidence of graft-versus-host disease (GVHD). Over 70% of patients in this study developed acute II-IV GVHD. This incidence appears to be higher (23%) than the one observed in our transplantation study with 90YIT,2 suggesting that the difference is related to the GVHD prophylaxis used rather than to the innate conditioning regimen. In this era of novel B-cell receptor pathway-targeted agents such as ibrutinib and idelalisib, it is paramount that the safety of allogeneic transplantation be enhanced to encourage referrals from the community.

Bruton's tyrosine kinase (BTK) function is important to the development and expansion of chronic lymphocytic leukemia (CLL)

AbstractChronic lymphocytic leukemia (CLL) is characterized by constitutive activation of the B-cell receptor (BCR) signaling pathway, but variable responsiveness of the BCR to antigen ligation. Bruton's tyrosine kinase (BTK) shows constitutive activity in CLL and is the target of irreversible inhibition by ibrutinib, an orally bioavailable kinase inhibitor that has shown outstanding activity in CLL. Early clinical results in CLL with other reversible and irreversible BTK inhibitors have been less promising, however, raising the question of whether BTK kinase activity is an important target of ibrutinib and also in CLL. To determine the role of BTK in CLL, we used patient samples and the Eμ-TCL1 (TCL1) transgenic mouse model of CLL, which results in spontaneous leukemia development. Inhibition of BTK in primary human CLL cells by small interfering RNA promotes apoptosis. Inhibition of BTK kinase activity through either targeted genetic inactivation or ibrutinib in the TCL1 mouse significantly delays the development of CLL, demonstrating that BTK is a critical kinase for CLL development and expansion and thus an important target of ibrutinib. Collectively, our data confirm the importance of kinase-functional BTK in CLL.

Fludarabine plus cyclophosphamide and rituximab in Waldenstrom macroglobulinemia

The combination of fludarabine, cyclophosphamide, and rituximab (FCR) has produced promising results in chronic lymphocytic leukemia and other lymphoproliferative disorders. The authors report the final results from a multicenter, prospective study examining FCR in Waldenstrom macroglobulinemia (WM). Forty-three patients with symptomatic WM that was untreated or pretreated with 1 line of chemotherapy received rituximab 375 mg/m(2) intravenously on day 1 and fludarabine 25 mg/m(2) and cyclophosphamide 250 mg/m(2) intravenously on days 2 through 4. FCR was repeated every 28 days for up to 6 courses. The overall response rate was 79%, and the major response rate of 74.4%, including 11.6% complete remissions (CRs) and 20.9% very good partial remissions. An amelioration of the quality of responses was observed during follow-up, leading to 18.6% of CRs. No differences in terms of responses were observed among previously treated or untreated patients. Among the clinical and laboratory features that were considered, only the β2-microglobulin level had a significant impact in terms of achieving a major response. The major toxicity reported was grade 3/4 neutropenia, which occurred in 45% of courses and was the main reason for treatment discontinuation. After the end of treatment, 19 patients (44%) had long-lasting episodes of neutropenia. Three patients developed myelodysplastic syndrome during follow-up. The FCR regimen was capable of neutralizing adverse prognostic factors and proved to be active in patients with WM, leading to rapid disease control and good-quality responses. Because myelosuppression was the main concern, further studies are warranted to optimize dosages and treatment duration.

Lenalidomide for the Treatment of B-Cell Malignancies

Lenalidomide is a novel anticancer agent that has made a major impact in the treatment of patients with B-cell malignancies. A more potent analog of thalidomide, lenalidomide was developed to enhance immunomodulatory properties with improved safety profile. Its antitumor activity seems mediated through modulation of both the cytokine and cellular tumor cell microenvironment. Preclinical as well as clinical observations demonstrate that lenalidomide downregulates production of various critical prosurvival cytokines in the tumor microenvironment while concurrently promoting activation of T- and natural killer (NK) cell-mediated antitumor response. Early clinical investigations noted its efficacy in relapsed and/or refractory multiple myeloma patients. Subsequently, larger randomized studies confirmed the clinical benefit of lenalidomide when added to dexamethasone compared with dexamethasone alone in previously treated myeloma patients resulting in its recent approval by the US Food and Drug Administration. Consequently, the role of lenalidomide in other B-cell malignancies has been investigated, with impressive results in chronic lymphocytic leukemia and non-Hodgkin's lymphoma. This review summarizes the data from various clinical investigations and highlights the impact of lenalidomide in the management of patients with B-cell malignancies.