Idelalisib plus rituximab versus ibrutinib in the treatment of relapsed/refractory chronic lymphocytic leukaemia: A real-world analysis from the Chronic Lymphocytic Leukemia Patients Registry (CLLEAR).

Idelalisib (idela), a phosphatidylinositol 3-kinase inhibitor, and ibrutinib, a Bruton tyrosine kinase inhibitor, were the first oral targeted agents approved for relapsed/refractory (R/R) chronic lymphocytic leukaemia (CLL). However, no randomised trials of idelalisib plus rituximab (R-idela) versus ibrutinib have been conducted. Therefore, we performed a real-world retrospective analysis of patients with R/R CLL treated with R-idela (n = 171) or ibrutinib (n = 244). The median age was 70 versus 69 years, with a median of two previous lines. There was a trend towards higher tumour protein p53 (TP53) aberrations and complex karyotype in the R-idela group (53% vs. 44%, p = 0.093; 57% vs. 46%, p = 0.083). The median progression-free survival (PFS) was significantly longer with ibrutinib (40.5 vs. 22.0 months; p < 0.001); similarly to overall survival (OS; median 54.4 vs. 37.7 months, p = 0.04). In multivariate analysis, only PFS but not OS remained significantly different between the two agents. The most common reasons for treatment discontinuation included toxicity (R-idela, 39.8%; ibrutinib, 22.5%) and CLL progression (27.5% vs. 11.1%). In conclusion, our data show significantly better efficacy and tolerability of ibrutinib over R-idela in patients with R/R CLL treated in routine practice. The R-idela regimen may still be considered a reasonable option in highly selected patients without a suitable treatment alternative.

COVID-19 in patients with chronic lymphocytic leukemia: a multicenter analysis by the Czech CLL study group.

Patients with chronic lymphocytic leukemia (CLL) have a high risk of poor outcomes related to coronavirus disease 2019 (COVID-19). This multicenter cohort study evaluated the impact of COVID-19 infection on the population of CLL patients in the Czech Republic. Between March 2020 and May 2021, 341 patients (237 males) with CLL and COVID-19 disease were identified. The median age was 69 years (range 38-91). Out of the 214 (63%) patients with the history of therapy for CLL, 97 (45%) were receiving CLL-directed treatment at diagnosis of COVID-19: 29% Bruton tyrosine kinase inhibitor (BTKi), 16% chemoimmunotherapy (CIT), 11% Bcl-2 inhibitor, and 4% phosphoinositide 3-kinase inhibitor. Regarding the severity of COVID-19, 60% pts required admission to the hospital, 21% pts were admitted to the intensive care unit (ICU), and 12% received invasive mechanical ventilation. The overall case fatality rate was 28%. Major comorbidities, age over 72, male gender, CLL treatment in history, CLL-directed treatment at COVID-19 diagnosis were associated with increased risk of death. Of note, concurrent therapy with BTKi compared to CIT was not associated with better outcome of COVID-19.

Management of Treatment-Related Infectious Complications in High-Risk Hemato-Oncological Patients via Telemedicine.

Background: Infectious complications, especially febrile neutropenia, in hemato-oncological patients are associated with considerable morbidity, mortality and expenses. Remote monitoring of physiological functions and thus early detection of adverse events via telemedicine could improve the safety of these high-risk patients and save financial resources by shortening the time-to-antibiotics. Methods: Patients undergoing active cancer treatment in high risk of acquiring severe infection are selected and enrolled in this project. Each patient receives a digital blood pressure monitor, an infrared thermometer and a mobile hub (cell phone). In the comfort of their homes, patients measure their blood pressure/pulse and body temperature regularly or whenever they feel unwell. The obtained data are encrypted and forwarded via the mobile hub to the password-protected portal. The values registered outside the set-up range trigger the alarms, which are immediately sent to the designated physician who can check the portal in real-time from any device with an Internet connection, contact the patient, if need be, and initiate the anti-infective therapy almost instantly after the first symptoms occur. Results: Fifty hemato-oncological patients were recruited between March 1, 2018 and August 1, 2020. Two hundred ninety-seven alarms of body temperature were registered and checked by the physician and patients were contacted in 18.5% of the cases (55/297). Among these 55 events, 13 required medical assistance, which makes it approximately one-quarter of all conducted telephone interventions (23.4%) and neither septic shock nor death due to treatment-related toxicity occurred. Conclusion: Telemedicine seems like a useful tool to improve the safety of high risk hemato-oncological patients when treatment-related infectious complications are concerned.

Promising Immunotherapeutic Modalities for B-Cell Lymphoproliferative Disorders.

Over the last few years, treatment principles have been changed towards more targeted therapy for many B-cell lymphoma subtypes and in chronic lymphocytic leukemia (CLL). Immunotherapeutic modalities, namely monoclonal antibodies (mAbs), bispecific antibodies (bsAbs), antibody-drug conjugates (ADCs), and chimeric antigen receptor T (CAR-T) cell therapy, commonly use B-cell-associated antigens (CD19, CD20, CD22, and CD79b) as one of their targets. T-cell engagers (TCEs), a subclass of bsAbs, work on a similar mechanism as CAR-T cell therapy without the need of previous T-cell manipulation. Currently, several anti-CD20xCD3 TCEs have demonstrated promising efficacy across different lymphoma subtypes with slightly better outcomes in the indolent subset. Anti-CD19xCD3 TCEs are being developed as well but only blinatumomab has been evaluated in clinical trials yet. The results are not so impressive as those with anti-CD19 CAR-T cell therapy. Antibody-drug conjugates targeting different B-cell antigens (CD30, CD79b, CD19) seem to be effective in combination with mAbs, standard chemoimmunotherapy, or immune checkpoint inhibitors. Further investigation will show whether immunotherapy alone or in combinatory regimens has potential to replace chemotherapeutic agents from the first line treatment.

Selinexor, selective inhibitor of nuclear export: Unselective bullet for blood cancers.

Exportin 1 (XPO1), also known as chromosome maintenance 1 protein (CRM1), is the main transporter for hundreds of proteins like tumor suppressors, growth regulatory factors, oncoprotein mRNAs and others. Its upregulation leads to the inactivation of the tumor suppressor anti-neoplastic function in many cancers and logically is associated with poor prognosis. Selective inhibitors of nuclear export (SINE) are a new generation of XPO1 inhibitors that are being investigated as a promising targeted anti-cancer therapy. Selinexor is the first generation of SINE compounds that is being evaluated in many clinical trials involving solid tumors and hematological malignancies with its two approved indications for relapsed multiple myeloma and relapsed diffuse large B-cell lymphoma. Here, we comprehensively review the current knowledge of selinexor and next generations of the SINE compounds in lymphoid and myeloid malignancies.

External validation of International Prognostic Score for asymptomatic early stage chronic lymphocytic leukaemia and proposal of an alternative score.

Most patients with chronic lymphocytic leukaemia (CLL) are nowadays diagnosed without any symptoms and do not require therapy. A prognostic score identifying patients within this large group who are at high risk of disease progression would be highly beneficial. The recently published International Prognostic Score for Early asymptomatic patients (IPS-E) uses combination of absolute lymphocyte count (ALC) >15 × 109 /l, palpable lymphadenopathy, and unmutated immunoglobulin heavy-chain variable-region (IGHV) gene to predict the time to first-line therapy (TTFT). Patients at low, intermediate, and high risk had estimated 5-year TTFT of 8%, 28%, and 61%. We performed an external validation of the IPS-E score using an unselected, consecutive group of 130 Binet A patients. The 5-year TTFT was 11%, 36%, and 78% (C-statistic 0·74). Furthermore, we propose an alternative system (AIPS-E) using cytogenetic aberrations instead of palpable lymphadenopathy. This system yielded 5-year TTFT of 14%, 40%, and 72%. These results were externally validated in 388 Binet A patients from five Czech centres; the 5-year TTFT was 16%, 37%, and 80% (C-statistic 0·74). In conclusion, we have successfully validated the IPS-E score for patients with early stage CLL. In addition, we propose a modified scoring system, the AIPS-E, combining IGHV, fluorescence in situ hybridisation, and ALC.

Osteolytic bone lesions, hypercalcemia and paraprotein, but not a myeloma: case report and review of literature.

In June 2018, 77-year-old man was referred to The Department of Haematooncology, University Hospital Ostrava, for suspicion of multiple myeloma. This was supported by laboratory findings of hypercalcemia, paraprotein IgA κ in serum and by the presence of multiple osteolytic skeletal lesions. Low number of plasma cells in bone marrow sample - cytologically (3.6 %) as well as in flow cytometry (less than 95 % clonal plasma cells out of total bone marrow plasma cells) - pointed at the direction of monoclonal gammopathy of undetermined significance (MGUS). In the course of differential diagnosis of hypercalcemia, elevated level of parathormone had been found which led to the performance of 99mTc-MIBI scintigraphy where parathyroid adenoma was discovered and later histologically verified. The final diagnosis was determined as a coincidence of MGUS and primary hyperparathyroidism. This case report also contains brief differential diagnosis of hypercalcemia and osteolytic skeletal lesions and suggestions for their diagnostic algorithms.

Cytarabine + G-CSF is more effective than cyclophosphamide + G-CSF as a stem cell mobilization regimen in multiple myeloma.

Cyclophosphamide (Cy) plus granulocyte-colony stimulating factor (G-CSF) is currently a standard regimen for hematopoietic stem cell (HSC) mobilization in patients with multiple myeloma (MM). However, cytarabine (AraC) in intermediate doses plus G-CSF seems to have a higher mobilization efficacy. The aim of this study was to retrospectively compare mobilization using AraC and Cy. Thirty consecutive MM patients were mobilized by Cy + G-CSF, and the subsequent 40 patients by AraC + G-CSF. Both groups were comparable. The target yield of 10 × 106 CD34+ cells/kg (for tandem and 2 additional transplantations) was achieved in 98% (AraC) and 57% (Cy) of patients (p < 0.0001) by 1.2 and 2.1 apheresis (means), and by single apheresis in 83 and 17% of patients, respectively. AraC mobilization resulted in higher peak concentration of CD34+ cells in blood (median 238.0 vs. 87.9/µL, p < 0.0001) and higher CD34+ yield (median 28.6 × 106 vs. 10.4 × 106/kg, p < 0.0001) compared to Cy mobilization. Toxicities were comparable except for thrombocytopenia gr. 4, observed in 50% of patients after AraC (Cy 7%). In view of these results, we conclude that mobilization with AraC plus G-CSF is very effective with acceptable toxicity and could be considered in MM patients with planned or expected higher numbers of transplantations.

CD38 targeted treatment for multiple myeloma.

CD38 antigen is highly and uniformly expressed on plasma cells and thus represents an ideal target for the treatment of multiple myeloma (MM) with anti-CD38 monoclonal antibodies (mAbs). Daratumumab is the most advanced anti-CD38 mAb in the clinical development with approval in several indications, nevertheless isatuximab that targets completely different epitope of CD38 molecule is also very promising drug. Anti-CD38 possess pleiotropic mechanism of action that have been described also in other mAbs, but quite specific, novel and very important seems to be the immunomodulatory effect provided by depletion of several CD38+ immunosuppressive immune cell populations. CD38-targeted mAbs induce partial response or better in approximately 30 % of heavily pre-treated myeloma patients as monotherapy. Based on their favourable toxicity profile and distinct mechanism of action, anti-CD38 mAbs represents very attractive partner to back-bone anti-myeloma drugs. Indeed, daratumumab is already approved as a part of three distinct combination regimens in relapsed setting. The combination of daratumumab with lenalidomide and dexamethasone is considered to be the best treatment option in relapsed myeloma with unprecedented prolongation of median PFS, including high rate of good quality responses. CD38 targeted therapy is rapidly moving toward the first line treatment. Anti-CD38 mAbs have been also successfully tested in other plasma cell dyscrasias (such as AL amyloidosis), and they are examined in other hematological malignancies (such as CLL, ALL, AML, etc.) and even in solid oncology as well as in autoimmune disorders. Implementation of CD38 targeted mAbs have been significant milestone in the treatment of MM, similar to that of CD20 targeted mAbs in CLL or non-Hodgkin lymphomas. We believe that this drug may eventually help to reach the cure at least in a subset of MM patients in the near future. Key words: acute myeloid leukemia - CD38 - daratumumab - isatuximab - multiple myeloma.

Venetoclax: A new wave in hematooncology.

Inhibitors of antiapoptotic proteins of the BCL2 family can successfully restart the deregulated process of apoptosis in malignant cells. Whereas nonselective agents have been limited by their affinity to different BCL2 members, thus inducing excessive toxicity, the highly selective BCL2 inhibitor venetoclax (ABT-199, Venclexta™) has an acceptable safety profile. To date, it has been approved in monotherapy for the treatment of relapsed or refractory chronic lymphocytic leukemia (CLL) with 17p deletion. Extension of indications can be expected in monotherapy and in combination regimens. Sensitivity to venetoclax is not common in lymphomas, but promising outcomes have been achieved in the mantle cell lymphoma group. Venetoclax is also active in multiple myeloma patients, especially in those with translocation t(11;14), even if high-risk features such as del17p are also present. Surprisingly, positive results are being obtained in elderly acute myeloid leukemia patients, in whom inhibition of BCL2 is able to substantially increase the efficacy of low-dose cytarabine or hypomethylating agents. Here, we provide a summary of available results from clinical trials and describe a specific mechanism of action that stands behind the efficacy of venetoclax in hematological malignancies.

PD-1/PD-L1 inhibitors in haematological malignancies: update 2017.

The introduction of PD-1/PD-L1 pathway inhibitors is an important landmark in solid oncology with unprecedented practice-changing activity in various types of solid tumours. Among haematological malignancies, PD-1/PD-L1 inhibitors have been successful, so far, only in the treatment of classical Hodgkin lymphoma, which typically exhibits an over-expression of PD-1 ligands (PD-L1, PD-L2) due to alterations in chromosome 9p24.1. Such positive outcomes led to the US Food and Drug Administration approval of nivolumab use in relapsed Hodgkin lymphoma in 2016 as the first haematological indication. Although the results in other lymphoid malignancies have not been so striking, blockade of the PD-1/PD-L1 axis has led to meaningful responses in other lymphoma types such as diffuse large B-cell lymphoma, follicular lymphoma or several T-cell lymphomas. Monotherapy with PD-1/PD-L1 inhibitors in chronic lymphocytic leukaemia and multiple myeloma has been unsatisfactory, suggesting that a combinational approach with other synergistic drugs is needed. In the case of multiple myeloma, immunomodulatory agents together with corticosteroids represent the most promising combinations. Among myeloid malignancies, the anti-PD-1 monoclonal antibodies are examined dominantly in acute myeloid leukaemia and myelodysplastic syndromes in combination with potentially synergistic hypomethylating drugs such as 5-azacitidine, resulting in promising outcomes that warrant further investigation. We have described all available clinical results of PD-1/PD-L1 inhibitors in haematological malignancies and discussed related toxicities, as well as highlighted crucial preclinical studies in this review.