Minimal residual disease-driven treatment intensification with sequential addition of ibrutinib to venetoclax in R/R CLL.

Undetectable measurable residual disease (uMRD) is achievable in patients with chronic lymphocytic leukemia (CLL) with the BCL2-inhibitor venetoclax alone or combined with the Bruton's tyrosine kinase inhibitor ibrutinib. This phase 2, multicenter, MRD-driven study was designed to discontinue treatment upon reaching uMRD4 (<10-4) in patients with relapsed/refractory CLL receiving venetoclax monotherapy or after the addition of ibrutinib. Primary end point of the study was proportion of uMRD4 with venetoclax ± ibrutinib. Secondary end points were overall response rate, partial response, complete response, progression-free survival, duration of response, overall survival, and safety of venetoclax ± ibrutinib. Patients with uMRD4 at Cycle 12 Day 1 discontinued venetoclax. MRD+ patients added ibrutinib and continued both drugs up to Cycle 24 Day 28/uMRD4/progression/toxicity. After Cycle 24 Day 28, MRD+ patients continued ibrutinib. Thirty-eight patients (29% with TP53 aberrations; 79% with unmutated IGHV) started venetoclax. Overall response rate with venetoclax was 36 (95%) of 38 patients (20 complete; 16 partial response). Seventeen patients (45%) with uMRD4 at Cycle 12 Day 1 discontinued venetoclax. Nineteen (55%) MRD+ subjects added ibrutinib. After a median of 7 months (range, 3-10 months) of combined treatment, 16 (84%) of 19 achieved uMRD4, thus stopping both drugs. Two MRD+ patients at Cycle 24 Day 28 continued ibrutinib until progression/toxicity. After a median follow-up of 36.5 months, median progression-free survival was not reached; 10 patients progressed (4 restarted venetoclax, 3 without treatment need, 2 developed Richter transformation, and 1 dropped out). Seven (22%) of 32 patients remain uMRD4 after 3 years of follow-up. Neutropenia was the most frequent grade 3 to 4 adverse event; no grade 5 events occurred on study. This sequential MRD-guided approach led to uMRD4 in 33 (87%) of 38 patients, with venetoclax monotherapy or combined with ibrutinib, delivering treatment combination only in a fraction, and ultimately identifying the few patients benefiting from continuous therapy. This trial was registered at www.clinicaltrials.gov as # NCT04754035.

Are we finally getting personal? Moving towards a personalized approach in chronic lymphocytic leukemia.

With its heterogeneous biological features and clinical course, chronic lymphocytic leukemia (CLL), the most frequent adult leukemia in the Western world, is a paradigmatic condition requiring a tailored approach and a precise knowledge of the biology behind each individual patient. This personalized management is becoming even more crucial, since, after decades of preclinical work unravelling the key role of the B-cell receptor (BcR) signalling pathways and the anti-apoptotic mechanisms in CLL cell survival and proliferation, we have now BcR and BCL2 inhibitors available in clinical practice. Thanks to this, we are now able to exploit specific biomarkers to tailor our treatment strategies and improve long-term disease control, patient outcome and quality of life. That notwithstanding, as the disease itself remains incurable, novel challenges and unmet clinical needs have risen from the introduction of novel targeted agents, including mechanisms of resistance at both genetic and epigenetic levels. In this review, we summarize the currently established predictive biomarkers (i.e. IGHV mutation status and TP53 gene disruption) that should be applied in clinical practice to inform treatment decision in 2021 but also discuss the most promising prognostic biomarkers (B-cell receptor stereotypy, complex karyotype, somatic gene mutations, measurable residual disease - MRD) that might become key to define the management of our patients in a near future.

Preexisting and treatment-emergent autoimmune cytopenias in patients with CLL treated with targeted drugs.

Autoimmune cytopenias (AICs) affect 5% to 9% of patients with chronic lymphocytic leukemia (CLL). Targeted drugs-ibrutinib, idelalisib, and venetoclax-have a prominent role in the treatment of CLL, but their impact on CLL-associated AICs is largely unknown. In this study, we evaluated the characteristics and outcome of preexisting AICs and described the incidence, quality, and management of treatment-emergent AICs during therapy with targeted drugs in patients with CLL. We collected data from 572 patients treated with ibrutinib (9% in combination with an anti-CD20 monoclonal antibody), 143 treated with idelalisib-rituximab, and 100 treated with venetoclax (12% in combination with an anti-CD20 monoclonal antibody). A history of preexisting AICs was reported in 104 (13%) of 815 patients. Interestingly, 80% of patients whose AICs had not resolved when treatment with a targeted drug was started experienced an improvement or a resolution during therapy. Treatment-emergent AICs occurred in 1% of patients during ibrutinib therapy, in 0.9% during idelalisib therapy, and in 7% during venetoclax therapy, with an estimated incidence rate of 5, 6, and 69 episodes per 1000 patients per year of exposure in the 3 treatment groups, respectively. The vast majority of patients who developed treatment-emergent AICs had unfavorable biological features such as an unmutated IGHV and a del(17p) and/or TP53 mutation. Notably, despite AICs, 83% of patients were able to continue the targeted drug, in some cases in combination with additional immunosuppressive agents. Overall, treatment with ibrutinib, idelalisib, or venetoclax seems to have a beneficial impact on CLL-associated AICs, inducing an improvement or even a resolution of preexisting AICs in most cases and eliciting treatment-emergent AICs in a negligible portion of patients.

Prognostic impact of tumor-associated macrophages, lymphocyte-to-monocyte and neutrophil-to-lymphocyte ratio in diffuse large B-cell lymphoma.

INTRODUCTION: Microenvironment has a prognostic influence in diffuse large B-cell lymphoma (DLBCL); among its components, tumor-associated macrophages (TAM) play a leading role. TAM can be classified into M1 (anti-tumor) and M2 (pro-tumor). Another prognostic factor could be represented by lymphocyte-to-monocyte and neutrophil-to-lymphocyte ratio (LMR and NLR). OBJECTIVE: The aim of the study is to evaluate the prognostic impact of M1 and M2 TAM subtypes, LMR and NLR in DLBCL. METHODS: We analyzed 37 consecutive patients between 2009 and 2013. Out of 37 patients, 28/37 (75.6%) received R-CHOP/CHOP-like regimens, 9/37 (24.4%) less intensive therapies. Immunohistochemistry was performed with antibodies against CD68 and CD163. We divided our cohort into 2 categories according to the Steidl score. TAM who coexpressed CD68 and CD163 were considered as M2. For LMR and NLR we used previously published cut-offs of 2.71 and 2.81. RESULTS: CR rate was 70.3%; we did not record a significant correlation between CD68+ TAM, CD163+ TAM, CD68+/CD163+ TAM, LMR, NLR and CR. We observed a reduced PFS in patients with IPI ≥ 2 and high M2 TAM expression and a trend between higher expression of CD68+ TAM and improved PFS. CONCLUSION: M2 TAM could have a prognostic role for IPI ≥ 2 DLBCL patients receiving R-CHOP, which thus warrants further investigation.

The evolving treatment landscape of chronic lymphocytic leukemia.

PURPOSE OF REVIEW: This review provides guidance in the rapidly changing scenario of chronic lymphocytic leukemia (CLL) treatment. New studies as well as updates of other seminal ones have been recently presented and are likely to change the management of patients with CLL in everyday clinical practice. RECENT FINDINGS: Kinase inhibitors (e.g. ibrutinib and idelalisib) have transformed the treatment paradigm in CLL in both front-line and relapsed/refractory patients. Longer follow-up data are now available supporting the safety of ibrutinib and the continuous administration required per current label. Novel studies show the superiority of the drug alone or in combination with monoclonal antibodies compared with standard chemoimmunotherapy. The combination of venetoclax and obinutuzumab (treatment-naïve, only in United States) or rituximab (relapsed/refractory) has granted approval from the regulatory authorities in United States and Europe, based on phase 3 randomized studies. These novel chemo-free combinations allow for fixed-duration treatment and undetectable minimal residual disease. Novel targeted strategies including second and third generation BTK and PI3K inhibitors are currently under investigation and promise to further improve the CLL treatment armamentarium. The chimeric-antigen receptor (CAR) T cells are coming to the stage with promising efficacy and new challenges. SUMMARY: A bright chemo-free era for CLL patients is just around the corner. A deep knowledge of currently available evidences is key to tailor treatment choice and optimize long-term tolerability and disease control. Fixed-duration combinations are investigated to allow treatment holidays and avoid the emergence of resistant clones under the selective pressure of continuous treatment.

Durable response after VNCOP-B and rituximab in an elderly patient with high-grade B-cell lymphoma.

OBJECTIVES AND METHODS:  High-grade B-cell lymphoma, NOS (HGBL) have an aggressive clinical behavior and poor outcome using regimens currently employed for diffuse large B-cell lymphoma (DLBCL) such as rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Promising results have been reported with more intensive regimens but this strategy is not suitable for elderly or unfit patients. Rituximab in association with cyclophosphamide, mitoxantrone, vincristine, etoposide, bleomycin, and prednisone (R-VNCOP-B) demonstrated high efficacy and manageable toxicity as first-line treatment for elderly aggressive non-Hodgkin lymphoma patients. RESULTS AND CONCLUSION: In this case study, we report the rapid improvement, long-lasting complete remission, and mild toxicity of R-VNCOP-B regimen in an elderly, triple-expressor HGBL patient, with aggressive disease and poor-risk profile.

Therapeutic Use of Brentuximab Vedotin in CD30+ Hematologic Malignancies.

The CD30 antigen is strongly expressed on neoplastic cells in classical Hodgkin lymphoma (HL), anaplastic large cell lymphoma (ALCL) and other hematologic malignancies (such as DLBCL and cutaneous TCL), while is almost undetectable on healthy tissues, representing an ideal immunotherapeutic target. Since unconjugated anti-CD30 antibody (SGN-30) demonstrated limited clinical activity, researchers' effort aimed to create an antibody-drug conjugate (ADC), leading to discovery of SGN-35 (brentuximab vedotin), in which an anti-CD30 antibody is linked to the antimitotic agent monomethyl auristatin E (MMAE). In the first phase I study in CD30+ hematologic malignancies (the majority of patients with HL), the maximum tolerated dose was fixed respectively at 1.8mg/Kg every 3 weeks, overall response rate (ORR) and complete response (CR) rate were 38% and 24%. In 2 subsequent phase II studies, amazing results were reported, that permitted accelerated FDA approval for relapsed/refractory patients and led to the development of many clinical trials including BV as first-line HL and ALCL treatment. Moreover, as CD30 antigen may be expressed by other malignancies, the potential therapeutic application is increasing, including at least diffuse large B-cell lymphoma, T-cell lymphomas other than ALCL and cutaneous lymphoproliferative disorders. BV is administrated as outpatient regimen and is usually well tolerated; sensorial peripheral neuropathy represents the most common toxic effect, although it is dose-dependent and at least partially reversible in most cases, after dose reduction and/or treatment ending.

Chemoimmunotherapy with oral low-dose fludarabine, cyclophosphamide and rituximab (old-FCR) as treatment for elderly patients with chronic lymphocytic leukaemia.

Median age at diagnosis for chronic lymphocytic leukaemia (CLL) patients is now 72 years, thus a consistent number of patients may not tolerate standard doses i.v. of fludarabine, cyclophosphamide and rituximab (FCR), the best available therapy, due to unacceptable myelotoxicity and risk of severe infections. We studied safety and efficacy of the addition of rituximab to the oral low-dose FC regimen (old-FCR) in a selected population of 30 elderly (median age 75, 15 untreated, 15 treated with 1 prior therapy) CLL patients. Complete remission (CR) rate was 80% in the untreated patients (overall response rate, ORR 93%), and 30% in pretreated patients (ORR 74%). Progression free survivals (PFS) were 45 months and 30 months in the untreated and treated patients, respectively. In patients achieving CR, old-FCR led to PFS of 67 months. Moreover, haematological toxicity was mild (grade 3-4: 15%) and patients were treated mostly in outpatient clinic. Old-FCR could be a good therapy option for elderly CLL patients outside clinical trials, larger studies are needed to confirm our findings.