Frontline Therapy in Chronic Lymphocytic Leukemia.

BACKGROUND: The treatment landscape of chronic lymphocytic leukemia (CLL) has tremendously evolved in the last decades, thanks to the introduction of more effective therapies. SUMMARY: Frontline therapy for patients with CLL includes chemoimmunotherapy (CIT) and pathway inhibitors (PIs) (i.e., bruton tyrosine kinase inhibitors and BCL2 inhibitors); the latter has proved to be more effective than CIT mainly in patients with high-risk features (e.g., TP53 aberrations and unmutated IGHV) with acceptable toxicity. Combinations of PIs are playing the protagonist role as frontline therapy for CLL. KEY MESSAGES: In this article, the management of treatment-naïve patients with CLL is discussed.

Evolution in the frontline treatment of patients with chronic lymphocytic leukemia: experience from one European center.

Treatment of chronic lymphocytic leukemia (CLL) has dramatically evolved over the last decades thanks to the introduction of targeted therapies. We aimed to describe retrospectively the evolution in the frontline prescription in the CLL patients from our institution. As a secondary objective, the impact of frontline therapy on the time-to-next-treatment (TTNT) and overall survival (OS). After a median of 6.4 years (0.1-36.4) of follow-up from diagnosis, 323 of 780 CLL patients (41.4%) required therapy. Alkylating agents in monotherapy (chlorambucil) were the most used until 2012, and from then, chemoimmunotherapy. Since 2018, targeted therapies were the most common therapeutic strategy (74.1%). Patients who received targeted therapies had significantly longer TTNT compared to other regimens. In the multivariable analyses, mutated IGHV genes targeted therapies and chemoimmunotherapy regimens were related to longer TTNT, and sex female, age younger than 65, and mutated IGHV genes were associated with better OS.

mRNA-1273 SARS-CoV-2 vaccine in recently transplanted allogeneic hematopoietic cell transplant recipients: Dynamics of cellular and humoral immune responses and booster effect.

Allogeneic hematopoietic stem cell transplant (HCT) recipients are at high risk of severe COVID-19 despite vaccination. Little is known about cellular response to SARS-CoV-2 vaccine in this population, especially in recently transplanted patients (RTP). In this single-center study we examined cellular and humoral response to the mRNA-1273 (Spikevax®) vaccine in recently transplanted patients (RTP, n = 49), and compared them to long-term transplanted patients (LTTP, n = 19) and healthy controls (n = 20) at three different timepoints: one and three months after the second dose (T1 and T2, respectively, 28 days apart), and one month after the third dose (T3). Controls did not receive a third dose. RTPs showed lower IgG anti-S1 titers than healthy controls at both T1 (mean 0.50 vs 0.94 arbitrary units -AU-, p < 0.0001) and T2 (0.37 vs 0.79 AU, p < 0.0001). They also presented lower titers than LTTPs at T1 (0.50 vs 0.66, p = 0.01), but no differences at T2 (0.37 vs 0.40 AU, p = 0.55). The rate of positive T-cell responses was lower in RTPs than in controls at both T1 and T2 (61.2 % vs 95 %, p = 0.007; 59.2 % vs 100 %, p = 0.001, respectively), but without statistically significant differences between transplanted groups. At T3 no differences were seen between RTPs and LTTPs as well, neither in IgG antibodies (p = 0.82) nor in cellular responses (p = 0.15), although a third dose increased the rate of positive cellular and humoral responses in approximately 50 % of recently transplanted patients. However, active immunosuppressive treatment severely diminished their chances to produce an adequate response.

mRNA-1273 SARS-CoV-2 vaccine safety and COVID-19 risk perception in recently transplanted allogeneic hematopoietic stem cell transplant recipients.

PURPOSE: This study aims to describe the incidence and severity of adverse events (AEs) following the mRNA-1273 SARS-CoV-2 vaccine and explore the risk perception of COVID-19 in allogeneic hematopoietic stem cell transplant (HCT) recipients. METHODS: We performed a single-center prospective study including recently transplanted (< 2 years post-infusion) allogeneic HCT recipients. AEs were assessed through phone calls and graded from 0 to 4, while COVID-19 risk perception was measured using the Brief Illness Perception Questionnaire (BIP-Q5). RESULTS: Fifty-four HCT recipients were evaluated. Incidence and grades of AE (94.4% and 85.2% after the first and second dose, respectively) were similar to those described in the general population. The most common AE was pain at the site of injection. Three patients (5.6%) developed a grade ≥ 3 AE. Vaccine-related cytopenias and graft-versus-host disease flares were not observed. Female sex (OR 3.94, 95% CI 1.14-13.58, p = 0.03) and time since HCT (per month since HCT: OR 1.09, 95% CI 1.01-1.18, p = 0.04) were associated with the occurrence of any AE. The patients' risk perception level of COVID-19 decreased over time (p < 0.05). CONCLUSION: Our study confirms that the mRNA-1273 SARS-CoV-2 vaccine is safe in recent HCT recipients and suggests that the perceived risk of COVID-19 decreases over time.

The road to chemotherapy-free treatment in chronic lymphocytic leukaemia.

PURPOSE OF REVIEW: The treatment landscape of chronic lymphocytic leukaemia (CLL) has tremendously evolved in the last decades, from chemo to chemoimmunotherapy (CIT) and, eventually, to pathway inhibitors that target critical pathways for leukaemic cells survival. Also, treatment goals are moving towards achieving undetectable minimal residual disease with little toxicity. RECENT FINDINGS: We performed a thorough review of the history of treatment approvals by both the Food and Drug Administration (FDA) and the European Medicines Agency (EMA). This review especially focuses on therapies that are currently approved by both agencies. The indications and particular characteristics of each drug are examined. SUMMARY: Currently available treatment approaches for CLL offer the opportunity to individualize therapy for every single patient with CLL. Inhibitors of B-cell receptor (BCR) signalling pathways and antiapoptotic proteins are nowadays the treatment of choice for most CLL patients, but CIT can be an option for younger and fit patients with low-risk disease [mutated IGHV, no del(11q) or del(17p)/TP53 mutations].

Autoimmune Cytopenia in CLL: Prognosis and Management in the Era of Targeted Therapies.

ABSTRACT: Chronic lymphocytic leukemia (CLL) is frequently associated with autoimmune hemolytic anemia and immune thrombocytopenia and, less frequently, with pure red cell aplasia and immune neutropenia. The emergence of these complications is related to an intertwined and complex relationship between patient, disease, and treatment characteristics. The prognostic repercussion of autoimmune cytopenia (AIC) in patients with CLL mainly depends on its response to therapy. For patients with AIC and nonactive CLL, treatment is as in primary, uncomplicated AIC, keeping in mind that no response is an indication for CLL therapy. The success of treating active CLL-related AIC widely relies on a flexible strategy that should include initial therapy with corticosteroids and a rapid shift to effective CLL therapy in nonresponding patients. Targeted therapies (e.g., ibrutinib) that have already demonstrated to be effective in CLL-related AIC will likely offer a unique possibility of treating both AIC and CLL as a single target.

Venetoclax in relapsed/refractory blastic plasmacytoid dendritic cell neoplasm with central nervous system involvement: a case report and review of the literature.

BACKGROUND: We describe a patient with blastic plasmacytoid dendritic cell neoplasm with central nervous system involvement and the outcome of venetoclax use in this setting. CASE PRESENTATION: A 54-year-old Caucasian male was referred to the Haematology Unit with an enlarged inguinal lymph node which was diagnostic of a blastic plasmacytoid dendritic cell neoplasm. The staging revealed disseminated disease (skin, visceral, lymph nodes, and bone marrow). He received chemotherapy with an acute myeloid leukaemia-like regime. Afterwards, he underwent allogeneic haematopoietic stem cell transplantation, though it was not successful, showing a relapse 14 months later with hepatic and central nervous system dissemination. Intrathecal chemotherapy was administered, and venetoclax (anti-bcl2 agent) was started in an off-label indication based on most recent literature. The disease halted its course for 3 months. In the end, the patient's disease progressed and so he succumbed due to infectious complications. CONCLUSIONS: Venetoclax monotherapy seems not enough to control the disease progression under CNS involvement and other treatments should be investigated.