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Summary: Although the unfavourable prognostic role of complex karyotype (CK) in chronic lymphocytic leukaemia (CLL) patients treated with chemoimmunotherapy has been clarified, its impact on the outcome of patients being treated with novel targeted agents, and especially with venetoclax‐based regimens, remains to be resolved. In fact, only few studies, utilizing data derived from clinical trials (e.g. MURANO, CLL14, GAIA‐CLL13), specifically focus on this topic while real‐word evidence is missing. In our real‐life retrospective study conducted on 61 patients with CLL and treated with venetoclax‐based regimens in any therapeutic line, we documented a remarkable lower progression‐free survival in patients harbouring both CK and high CK, while overall response rate (including complete remissions and partial remissions) and overall survival are not affected by CK in our population. [ABSTRACT FROM AUTHOR]

Chronic lymphocytic leukemia (CLL) is the most common leukemia in western societies, recognized by clinical and molecular heterogeneity. Despite the success of targeted therapies, acquired resistance remains a challenge for relapsed and refractory CLL, as a consequence of mutations in the target or the upregulation of other survival pathways leading to the progression of the disease. Research on proteins that can trigger such pathways may define novel therapies for a successful outcome in CLL such as the receptor tyrosine kinase‐like orphan receptor 1 (ROR1). ROR1 is a signaling receptor for Wnt5a, with an important role during embryogenesis. The aberrant expression on CLL cells and several types of tumors, is involved in cell proliferation, survival, migration as well as drug resistance. Antibody‐based immunotherapies and small‐molecule compounds emerged to target ROR1 in preclinical and clinical studies. Efforts have been made to identify new prognostic markers having predictive value to refine and increase the detection and management of CLL. ROR1 can be considered as an attractive target for CLL diagnosis, prognosis, and treatment. It can be clinically effective alone and/or in combination with current approved agents. In this review, we summarize the scientific achievements in targeting ROR1 for CLL diagnosis, prognosis, and treatment. [ABSTRACT FROM AUTHOR]

Clinical or biological parameters useful to predict progression during treatment in real‐life setting with ibrutinib, idelalisib and venetoclax in relapsed/refractory chronic lymphocytic leukemia (CLL) are still debated. We conducted a multi‐center retrospective study on CLL patients treated with ibrutinib and/or idelalisib who were switched to venetoclax for progression or due to adverse events to identify any clinical and/or biological parameters useful to predict progression during treatment with venetoclax. Of all the 128 evaluable patients, 81 had received ibrutinib prior to switching to venetoclax, 35 had received idelalisib and 12 both. When comparing the three subgroups, we did not notice any statistical difference in terms of clinical or biological features. No variable at baseline and at different time points during the follow‐up (at 6, 12, 18 and 24 months) was found to predict progression nor to have significance for Progression Free Survival (PFS) in the ibrutinib group and in the idelalisib group and in subgroups according to the line of treatment. Analyzing the data of the venetoclax treatment, after a median follow up of 14.3 months, median PFS was not reached and estimated 3‐year PFS was 54%. Of the 128 patients treated with venetoclax, 28 (22%) experienced progressive disease. At multivariate analysis for predictive factors for progression, lymph node diameter >56.5 mm before starting treatment emerged as an independent risk factor for progression. The lymph node predictive role for progression during venetoclax treatment could be a new parameter that deserves to be investigate in future studies. [ABSTRACT FROM AUTHOR]

Summary: Signalling events downstream the B‐cell receptor (BCR) are central for the survival and progression of chronic lymphocytic leukaemia (CLL) cells. Focal adhesion kinase (FAK), regulated through calpain, interacts with molecules of BCR signalling, cytoskeletal modelling and disease progression, such as Src/Lyn, cortactin and HS1. Hypothesizing that FAK might play a key role in CLL pathogenesis, we observed a down‐modulation of FAK whole form, associated with FAK cleavage due to calpain activity upon BCR stimulation. Patients, whose cells were able to release Ca++ after BCR stimulation, had less amount of full‐length FAK, which translated into a higher presence of cleaved/activated form of the protein phosphorylated at Y397, these features being mostly shown by immunoglobulin heavy chain (IGHV)‐unmutated poor‐prognosis patients. Moreover, we found that cortactin and HS1 proteins were overexpressed in those cells, suggesting a possible interplay with FAK. Treatment with the FAK inhibitor Defactinib was able to induce apoptosis in CLL cells. In conclusion, the malignant phenotype in unfavourable‐prognosis patients seems to be encouraged by the overexpression of cortactin and HS1, that, together with FAK, may be involved in a druggable pathogenetic pathway in CLL. [ABSTRACT FROM AUTHOR]

Severe mucormycosis is a fatal disease rarely complicating chronic lymphoproliferative disorders. We present a fulminant and fatal case of a 74-year-old Caucasian woman suffering from CLL treated with second-generation BTK inhibitor zanubrutinib. After a first septic episode a month prior, originating from the lung with later systemic involvement by an unidentified agent and treated with large-spectrum antibiotics and fluconazonle, a slow-onset enlarging tender warm and erythematous nodular swollen cutaneous lesion appeared in her lower limbs and spread subsequently to her upper limbs, progressing towards central ulceration with a necrotic core. Suspecting a mycotic dissemination from an unknown agent, a skin punch biopsy was performed, and intraconazole was started. Due to spread of the skin lesions, the patient was hospitalized and intravenous liposomal ampthotericin B was started. Histopathology showed an atypical sporangium-rich mycotic angioinvasion of the small vessels. Only the increase of BDG and GM could corroborate the hypothesis of mycotic infection. However, long-term CLL, immunosuppressive therapies, neutropenia, and prior use of azoles and other antimycotic agents were risk factors for mucormycosis; BTK inhibitor could also be added as another novel risk factor. Despite all therapeutic efforts, the patient died. Post-mortem molecular exams confirmed the diagnosis of disseminated mucormycosis. [ABSTRACT FROM AUTHOR]

This article, published in Hematological Oncology, explores the role of karyotype in predicting the need for therapy in chronic lymphocytic leukemia (CLL) with 13q deletion. The study analyzed the karyotype of 106 CLL cases with isolated 13q deletion and found that the presence of additional chromosomal abnormalities increased the risk of requiring treatment. The study also confirmed the predictive role of immunoglobulin heavy variable (IGHV) gene mutation status in therapy requirement. The authors propose a classification system based on both IGHV status and karyotype to better predict the need for therapy in low-risk CLL patients. [Extracted from the article]

Pre-exposure prophylaxis with tixagevimab/cilgavimab in patients with chronic lymphocytic leukaemia treated with targeted agents At the time of tixagevimab/cilgavimab administration, 70 (79%) patients had not reported symptoms suggesting prior COVID-19, and most of them (46/70 [66%]) had not developed an antibody response to the last SARS-CoV-2 vaccine (Table 2). 8 d No patients diagnosed with coronavirus disease 2019 (COVID-19) before receiving tixagevimab/cilgavimab developed a new COVID-19 event. [Extracted from the article]

Thirty-seven patients were alive at the last follow-up, 13 had died (two dementia-related causes, one pneumonia, one warfarin-related bleeding, one ovarian cancer, eight because of unknown causes); no patient died due to CLL progression. Of the five patients initially categorized as in partial SR, three have subsequently converted to SR, one remains in partial SR and in one patient who achieved a partial SR after 19 years from diagnosis the lymphocyte count started to increase five years later. Of the four patients in stage B/II at diagnosis, two converted to A/0 and one to A/I. In the five patients with a partial SR, the median lymphocyte count at regression was 6.3 × 10 SP 9 sp /L, with a median lymphocyte decrease of 75.1% (69-89%), and at the last follow-up a median lymphocyte count of 5.6 × 10 SP 9 sp /L (5.3-11.8) (Figure 1). [Extracted from the article]

The search for molecules to be targeted that are involved in apoptosis resistance/increased survival and pathogenesis of onco-hematological malignancies is ongoing since these diseases are still not completely understood. Over the years, a good candidate has been identified in the Heat Shock Protein of 70kDa (HSP70), a molecule defined as "the most cytoprotective protein ever been described". HSP70 is induced in response to a wide variety of physiological and environmental insults, allowing cells to survive lethal conditions. This molecular chaperone has been detected and studied in almost all the onco-hematological diseases and is also correlated to poor prognosis and resistance to therapy. In this review, we give an overview of the discoveries that have led us to consider HSP70 as a therapeutic target for mono- or combination-therapies in acute and chronic leukemias, multiple myeloma and different types of lymphomas. In this excursus, we will also consider HSP70 partners, such as its transcription factor HSF1 or its co-chaperones whose druggability could indirectly affect HSP70. Finally, we will try to answer the question asked in the title of this review considering that, despite the effort made by research in this field, HSP70 inhibitors never reached the clinic. [ABSTRACT FROM AUTHOR]

One of the main issues in the treatment of patients with chronic lymphocytic leukemia (CLL) deals with the choice between continuous or fixed-duration therapy. Continuous ibrutinib (IB), the first-in-class BTK inhibitor, and obinutuzumab-chlorambucil (G-CHL) are commonly used therapies for elderly and/or comorbid patients. No head-to-head comparison has been carried out. Within the Italian campus CLL network, we performed a retrospective study on CLL patients without TP53 disruption treated with IB or G-CHL as first-line therapy. Patients in the G-CHL arm had a higher CIRS score and the worst renal function. The overall response rates between the GCHL and IB arms were similar, but more complete remissions (CRs) were achieved with G-CHL (p = 0.0029). After a median follow-up of 30 months, the progression-free survival (PFS, p = 0.0061) and time to next treatment (TTNT, p = 0.0043), but not overall survival (OS, p = 0.6642), were better with IB than with G-CHL. Similar results were found after propensity score matching and multivariate analysis. While PFS and TTNT were longer with IB than with G-CHL in IGHV unmutated patients (p = 0.0190 and 0.0137), they were superimposable for IGHV mutated patients (p = 0.1900 and 0.1380). In the G-CHL arm, the depth of response (79% vs. 68% vs. 38% for CR, PR and SD/PD; p < 0.0001) and measurable residual disease (MRD) influenced PFS (78% vs. 53% for undetectable MRD vs. detectable MRD, p = 0.0203). Hematological toxicities were common in the G-CHL arm, while IB was associated with higher costs. Although continuous IB provides better disease control in CLL, IGHV mutated patients and those achieving an undetectable MRD show a marked clinical and economic benefit from a fixed-duration obinutuzumabbased treatment. [ABSTRACT FROM AUTHOR]

Summary: The relationship between chronic lymphocytic leukaemia (CLL) and qualitative/quantitative gammaglobulin abnormalities is well established. Nevertheless, in order to better understand this kind of connection, we examined 1505 patients with CLL and divided them into four subgroups on the basis of immunoglobulin (Ig) aberrations at diagnosis. A total of 73 (4·8%), 149 (10%), 200 (13·2%) and 1083 (72%) patients were identified with IgM monoclonal gammopathy (IgM/CLL), IgG monoclonal gammopathy (IgG/CLL), hypogammaglobulinaemia (hypo‐γ) and normal Ig levels (γ‐normal) respectively. IgM paraprotein was significantly associated with a more advanced Binet/Rai stage and del(17p)/TP53 mutation, while IgG abnormalities correlated with a higher occurrence of trisomy 12. Patients with any type of Ig abnormality had shorter treatment‐free survival (TFS) but no significant impact affecting overall survival (OS) compared to those with normal Ig levels. [ABSTRACT FROM AUTHOR]

A 76-year-old patient with a longstanding history of CLL presented with persistent massive splenomegaly and uMRD after venetoclax-based treatment. Persistent splenomegaly after treatment is a common finding in chronic lymphocytic leukemia (CLL). While uMRD is desirable in all CLL patients (especially for time-limited treatment schemes), the persistence of splenomegaly should prompt searching for additional conditions, whose treatment may be independent of CLL therapies. [Extracted from the article]