Case Report of Succesful Multidisiplinary Treatment for Patient with Metastatic Lung Cancer and Relapsed/Refractory Chronic Lymphatic Leukemia/Small Lymphocytic Lymphoma

Introduction: Croatian National Cancer Registry of Croatian Institute for Public Health reported that in year 2020 lung cancer was the second most common cancer site diagnosed in men with 16% and the third most common in women with 10% incidence among all cancer sites. Unfortunatelly lung cancer has the highest mortality in both men and women. Haematological malignancies had 7% share in all malignancies in both male and female cances cases. In 2020 190 newly diagnosed cases of lymphatic leukemia in men and 128 cases in women were reporeted, meaning 1.5 and 1.2% of all malignancies, respectively. Chronic lymphatic leukemia (CLL) is an advanced age disease and incidence increases with age. Impaired immunity, T and B cell dysfunction in CLL, chromosomal aberations, long-term immunosuppressive therapy and genetic factors can all cause secondary malignancies. Co- occurence of solid tumors and CLL is very rare. Although patiens with CLL have an increased risk of developing second primary malignancies including lung carcinoma, the data about their clinical outcomes are lacking. Parekh et al. retrospectively analyzed patients with simultaneous CLL and lung carcinoma over a 20-year period, and they found that ~2% of patients with CLL actually developed lung carcinoma. The authors claimed that up to 38% of patients will also develop a third neoplasm more likely of the skin (melanoma and basal cell carcinoma), larynx (laryngeal carcinoma) or colon. Currently there are no specific guidelines for concurrent CLL and non-small cell lung carcinoma (NSCLC) treatment. Usually, when the tumors are diagnosed simultaneously, treatment is based to target the most aggressive malignancy, as the clinical outcomes depend on the response of the tumor with the poorest prognosis. For this reason, a multidisciplinary approach is mandatory. Case report: A patient with history of coronary heart disease, myocardial infarction and paroxysmal atrial fibrillation was diagnosed in 2019 (at the age of 71) with B chronic lymphocytic leukemia with bulky tumor (inguinal lymph nodes 8x5 cm), stage B according to Binet, intermediate risk. He was treated with 6 cycles of chemoimmunotherapy (rituximab/cyclofosfamid/fludarabine). In 10/2019 remission was confirmed, but MSCT described tumor in the posterior segment of upper right lung lobe measuring 20x17 mm and bilateral metastases up to 11 mm. Bronchoscopy and biopsy were performed, and EGFR neg, ALK neg, ROS 1 neg, PD-L1>50% adenocarcinoma was confirmed. He was referred to Clinical Hospital Center Osijek where monotherapy with pembrolizumab in a standard dose of 200 mg intravenously was started in 01/2020. Partial remission was confirmed in October 2020. Immunotherapy was discontinued due to development of pneumonitis, dysphagia and severe weight loss (20kg), but without radiologically confirmed disease progression. At that time he was referred to our hospital for further treatment. Gastroscopy has shown erosive gastritis with active duodenal ulcus, Forrest III. Supportive therapy and proton pump inhibitor were introduced. After complete regression of pneumonitis, improvement of general condition and resolution of dysphagia, no signs of lung cancer progression were found and pembrolizumab was reintroduced in 12/2021. Hypothyroidism was diagnosed in 01/2021 and levothyroxine replacement ther apy was started. In 03/2021 he underwent surgical removal of basal cell carcinoma of skin on the right temporal region with lobe reconstruction. From 02/2021, when pembrolizumab was reintroduced, regression in tumor size was continously confirmed with complete recovery of general condition. He was hospitalized for COVID 19 infection in 09/2021, and due to complications pembrolizumab was discontinued till 11/2021. Lung cancer immunotherapy proceeded till 11/2022, when Multidisciplinary team decided to finish pembrolizumab because of CLL relapse. CLL was in remission till August 2022 when due to B symptoms, lymphcytosis, anemia and generalized lymphadenopathy, hematological workup including biopsy of cervical lymph node was performed and CLL/SLL relapse was confirmed. Initially chlorambucil was introduced, but disease was refractory. Based on cytogenetic test results (IGHV unmutated, negative TP53) and due to cardiovascular comorbidity (contraindication for BTK inhibitors) venetoclax and rituximab were started in 01/2023. After just 1 cycle of treatment normal blood count as well as regression of B symptoms and peripheral lymphadenopathy occured, indicating the probability of complete disease remission. In our patient with metastatic lung adenocarcinoma excellent disease control is achieved during 41 month of treatment in first line setting. Furthermore, relapsed/refractory CLL/SLL is currently in confirmed remission. Conclusion(s): Successful treatment of patients with multiple primary malignancies is based on multidisciplinarity, early recognition and management of side effects, treatment of comorbidities with the aim of prolonging life, controlling symptoms of disease and preserving quality of life.

A single centre experience of using venetoclax and azacitidine in the treatment of AML

Background: The combination of venetoclax and azacitidine was licensed as a treatment regime for AML during the COVID-19 pandemic and has only been available for a short period of time. It has been widely adopted, including by our centre, for use in older adults and those with multiple co-morbidities, for whom intensive treatment might not be appropriate, but where low-intensity treatment or palliative care is also considered inappropriate. We feel that our patient cohort has been experiencing a lot of cytopaenias with the regime and thus treatment has been de-escalated more commonly than seen in the VIALE-A trial1 and so decided to carry out an audit of our practice. Method(s): Patients were identified by our pharmacy colleagues as having had Blueteq forms completed for venetoclax-azacitidine treatment. We then looked at their electronic medical records to ascertain their age, co-morbidities, treatment received, any treatment modifications made (and reasons for these adjustments), disease course and time until death. Result(s): We identified 22 patients who have received treatment with venetoclax and azacitidine, since October 2020. Eleven of these patients are now deceased (50%), with causes of death attributable to progressive disease or infection. The median age of our patient population was 72 years old (range of 51-84). The maximal number of cycles of venetoclax-azacitidine that have been delivered to a single patient is 12 (with cessation following disease progression). 9/22 patients had no dose modifications made to treatment, but of these, six patients only received one cycle of treatment (prior to progressive disease or death from sepsis). The rest of the patients (13) have had dose reductions to shorter courses of venetoclax (to between 21 days and 7 days) or have been changed to azacitidine alone (5/13 patients). One of our 22 patients has now received an allograft. Conclusion(s): Our patients routinely receive posaconazole prophylaxis, and thus a dose of 100 mg venetoclax (due to the known interaction), rather than the 400 mg dose used in the VIALE-A trial1-it may be that this, (and that it is equivalent to an actual dose of greater than 400 mg), is the reason behind the increased incidence of cytopaenias and increased need to de-escalate treatment. In the future it would be helpful and informative to compare our practice to that of other centres.

Evolution of Clinical Trials in Oncohematology in a Reference Center: Does It Worth a Dedicated Structure?

Introduction: As part of the reorganization of our outpatient activity in onco-hematology (OH), questions were raised about the relevance of dedicating a specific structure to clinical research in this field. These questions arise all the more so as the proportion of OH clinical trials (CT) in our center has increased from 10% to 45% of all CT between 2000 and 2020. The aim of this study is to assess the evolution of this activity and thus to consider the interest of such a structure. Material(s) and Method(s): A retrospective data review of new CT related to OH in our center from 2016 to 2021 was performed. The evolution of 3 key indicators was assessed: distribution of OH CT among all CT, main OH indications and preferred routes of administration. Results and discussion: Over the period 2016-2021, OH CT represented an average of 32% of newly activated CT corresponding to 34% in 2016 and 48% in 2021 (approximately 90 CT start each year for a total of 420 CT in our center). A short decrease was observed in 2019 and 2020, 25% and 24% respectively, probably related to Covid-19. In terms of sterile preparations, OH represented steadily more than 60% of our activity over the period. The main indications were lymphomas (30%), acute myeloid leukemias (AML - 19%), myelodysplastic syndromes (12%) and CT related to transplant center (12%) in steady distribution overtime. Only new CT in myeloma increased from 7% to 18% in relation with increased subcutaneous (SC) use of daratumumab. Regarding preferred routes of administration, an increased trend in oral and SC routes is observed (respectively 53% and 7% in 2016 vs. 69%and 28% in 2021). The increasing use of SC intensified in 2017 as part of the arrival of AML treatments combining azacitidine (SC) with venetoclax (oral). New CT using the intravenous route decreased from 70% in 2016 to 51% in 2021 even if bispecific antibodies araised in 2021. Focusing in 2021, 1359 visits (772 in day hospital for protocol chemotherapy and 597 for oral treatment) were observed, i.e. 6 patients per day. Conclusion(s): This review showed OH's activity growth in our center. The increasingly frequent use of SC and oral routes requires that patients be fully informed and trained about their own management. In this context, a pharmacist has its place and could best inform patients about the adverse effects of new complex therapies (antibodies, targeted therapy). A unique place, organized and dedicated to clinical research in OH, would allow patients benefiting from a structured and exhaustive support as well as meeting all the healthcare professionals involved and finally ensuring the conditions for optimal care.

Venetoclax: a promising repurposed drug against SARS-CoV-2 main protease.

Global health care emergency caused by a new coronavirus (severe acute respiratory syndrome coronavirus 2 or SARS-CoV-2) demands urgent need to repurpose the approved pharmaceutical drugs. Main protease, Mpro of SARS-CoV-2 draws significant attention as a drug target. Herein, we have screened FDA approved organosulfur drugs (till 2016) and our laboratory synthesized organosulfur and organoselenium compounds (L1-L306) against Mpro-apo using docking followed by classical MD simulations. Additionally, a series of compounds (L307-L364) were chosen from previous experimental studies, which were reported to exhibit inhibitory potentials towards Mpro. We found several organosulfur drugs, particularly Venetoclax (FDA approved organosulfur drug for Leukemia) to be a high-affinity binders to the Mpro of SARS-CoV-2. The results reveal that organosulfur compounds including Venetoclax preferentially bind (non-covalently) to the non-catalytic pocket of the protein located in the dimer interface. We found that the ligand binding is primarily favoured by ligand-protein van der Waals interaction and penalized by desolvation effect. Interestingly, Venetoclax binding alters the local flexibility of Mpro and exerts pronounced effect in the C-terminal as well as two loop regions (Loop-A and Loop-B) that play important roles in catalysis. These findings highlighted the importance of drug repurposing and explored the non-catalytic pockets of Mpro in combating COVID-19 infection in addition to the importance of catalytic binding pocket of the protein.Communicated by Ramaswamy H. Sarma.

Real-world evidence on venetoclax in chronic lymphocytic leukemia: The Italian experience.

Chronic lymphocytic leukemia (CLL) is the most common form of adult leukemia in the western world. In Italy, venetoclax was approved for use in patients with CLL as monotherapy in 2017 and in combinations in 2019. As a result of this delayed approval, there are relatively few real-world studies from Italian clinical practice and much of the data are in heavily pretreated patients. We have collected the available studies in Italian routine practice. Three studies confirm the effectiveness and tolerability of this agent in patients with relapsed/refractory CLL and high-risk disease characteristics, many of whom had received prior B-cell receptor signaling treatment. Addition of rituximab to venetoclax produced more complete responses in patients with relapsed/refractory CLL, while higher disease burden and progression while receiving a prior Bruton's tyrosine kinase inhibitor were both associated with poorer outcomes in patients treated with venetoclax. Venetoclax was well-tolerated with low discontinuation rates. No studies of venetoclax plus obinutuzumab for the first-line treatment of patients with CLL were available due to the short time since approval in Italy. Several cohorts addressed the impact of COVID-19 on patient management and outcomes, suggesting that treated patients and those in clinical observation had similar rates of COVID-19-related hospital admission, intensive care unit admission, and mortality. Overall, the responses and tolerance to venetoclax observed in the Italian real-world setting confirm the tolerability and effectiveness of venetoclax regimens in high-risk patients.

Combinacao Bem Sucedida De Azacitidina E Venetoclax: Mudando Paradigmas No Tratamento De Leucemia Mieloide Aguda E Sindrome Mielodisplasica

Objetivos: O Venetoclax tem como alvo a proteina BCL-2. Aprovado para LLC, mostrou eficacia tambem LMA em combinacao com agentes hipometilantes como a Azacitidina. No ultimo ano, tivemos experiencias bem-sucedidas com a utilizacao desta associacao. Selecionamos 4 casos representativos de LMA e SMD para relatar nossa experiencia com este protocolo e desfechos obtidos. Material e Metodos: As informacoes foram obtidas por meio de revisao do prontuario. Resultados: Caso 1 - E.Q.O., 42 anos, sexo feminino, diagnosticada em janeiro de 2019 com LMA, evoluiu com 3 recidivas, quando foi optado pela associacao de Azacitidina e Venetoclax. Realizou ciclos com boa evolucao. Caso 2 - F.G.S., 72 anos, sexo feminino, historico de Linfoma Folicular EIIA em 2003. Em janeiro de 2021 recebeu diagnostico de LMA. Houve associacao de Azacitidina e Venetoclax como tratamento. Foram realizados 2 ciclos sem intercorrencias. Entretanto, antes do terceiro ciclo, a paciente relatou sindrome gripal, com diagnostico de COVID-19 e evoluiu a obito. Caso 3 - J.W.L.L., 37 anos, sexo masculino, em agosto de 2020 foi diagnosticado com SMD. Evolui com remissao e melhora significativa das citopenias de base. Foi submetido a TCTH nao aparentado com sucesso em julho de 2021, com enxertia no D+16 e internacao sem intercorrencias. Caso 4 - Paciente de 72 anos, sexo masculino, com diagnostico de SMD com excesso de blastos. Iniciou protocolo com Azacitidina associado a Venetoclax, persistia com elevada necessidade transfusional. Houve reducao das dosagens no segundo ciclo. O paciente evoluiu com melhor tolerabilidade, mantendo padrao transfusional. Manteve dose de Azacitidina e ajustada novamente dose de Venetoclax. Apos o quarto e quinto ciclos, paciente retornou com melhora significativa de indices hematimetricos O mielograma estava normal, bem como a imunofenotipagem e o cariotipo. Discussao: Apresentamos aqui 4 casos distintos de indicacao bem-sucedida da associacao entre Azacitidina e Venetoclax. A dose padrao utilizada foi de 75 mg/m2/dia de Azacitidina, do D1 ao D7 e 100 mg/dia de Venetoclax, com escalonamento progressivo ate atingir 400 mg/dia, do D1 ao D28. O caso 1 descreve paciente com doenca refrataria. Na literatura, esse perfil de pacientes tem beneficio importante com essa combinacao. Em nossa pratica clinica, o ajuste de dose ou duracao do Venetoclax e/ou espacamento entre os ciclos tem se mostrado uma alternativa viavel para minimizar os impactos da neutropenia. O caso 2 refere-se a paciente idosa, com mutacao do NPM1, sem status performance para quimioterapia intensiva, em primeira linha de tratamento. O impacto favoravel da mutacao NPM1 tende a reduzir em pacientes idosos (>65 anos). Nos casos 3 e 4 relatamos pacientes com SMD. Os bons resultados de Azacitidina e Venetoclax em LMA levaram os pesquisadores a avaliar a combinacao em pacientes com SMD de alto risco. Conclusao: A escolha do tratamento depende em grande parte da idade do paciente, status performance, remissao, caracteristicas geneticas e moleculares.A quimioterapia de baixa intensidade, em especial a associacao de Azacitidina com Venetoclax e uma opcao viavel, mesmo em pacientes com recidiva multipla/doenca refrataria ou naqueles com baixo status performance. Tambem aparenta ser promissora nos casos de SMD de alto risco. Os efeitos adversos mais frequentes dizem respeito as infeccoes decorrentes da neutropenia prolongada, mas nos 4 casos relatados, os pacientes evoluiram com estabilidade. Copyright © 2022

Eficacia Do Tratamento Baseado Em Venetoclax Em Paciente Jovem Com Leucemia Mieloide Aguda Recidivada Candidato a Transplante De Medula Ossea Alogenico

Introducao: A Leucemia Mieloide Aguda (LMA) e uma doenca agressiva, e em geral, de prognostico reservado. O tratamento com intuito curativo e realizado com altas doses de quimioterapia, seguido ou nao por transplante de medula ossea (TMO) alogenico. Porem, a recidiva ainda representa um desafio a ser superado, levando a busca de novas opcoes terapeuticas, como o inibidor de bcl-2, Venetoclax. Objetivo: Relatar o caso de um paciente jovem com LMA recidivada com resposta ao tratamento baseado em Venetoclax, seguido por TMO alogenico. Metodo: Levantamento de dados do prontuario e revisao da literatura. Relato do caso: VSV, sexo masculino, 21 anos, diagnosticado com LMA em 18/02/2020, mielograma com 60,4% blastos, com fenotipo CD45+ intermediario;CD34+;CD13+;CD33 parcial;CD64 parcial;HLA-DR parcial;MPO parcial e cariotipo 46, XY [20]. Sem possibilidade de avaliacao molecular da doenca. O paciente recebeu tratamento de inducao padrao (D3A7) atingindo remissao completa apos um ciclo e seguindo com consolidacao com 3 ciclos de ARA-C 3g/m2 ate maio de 2020 (optou-se por nao realizar o 4ciclo devido a pandemia por COVID19). Apresentava doenca residual minima (DRM) negativa em reavaliacao medular de agosto de 2020, mantendo-se ate junho de 2021, quando apresentou recidiva com 33,8% de blastos em imunofenotipagem de reavaliacao. Internado em julho de 2021 para QT de resgate com FLAG, evoluiu com choque septico e insuficiencia respiratoria, sendo necessario suporte em unidade de terapia intensiva. Apos recuperacao clinica, obteve novamente DRM negativa, sendo encaminhado para TMO alogenico aparentado (irma "full match"). Entretanto, enquanto aguardava o transplante, apresentou nova recidiva (IF com 5,4% de blastos), sendo optado por tratamento com Venetoclax + Azacitidina, com reducao de DRM para 1,5%. Recebeu o segundo ciclo de Venetoclax combinado com citarabina, devido a indisponibilidade da Azacitidina, seguido por DRM negativa. O paciente foi submetido ao TMO alogenico em 31/03/22, com avaliacao medular no D+60 com quimerismo de 100%, mantendo DRM negativa no D+120. Discussao: O uso do inibidor de BCL-2 (Venetoclax), em combinacao com agentes hipometilantes ou doses baixas de citarabina, foi aprovado para pacientes recem-diagnosticados com LMA inelegiveis para quimioterapia intensiva, revolucionando o tratamento da doenca. Publicacoes recentes vem demonstrando novos beneficios dessa associacao, tanto previamente ao TMO (em primeira linha ou com doenca recidivada), como na terapia de resgate para recidiva pos-TMO. Tambem tendo sido evidenciado sucesso terapeutico em faixas etarias menores (incluindo criancas). Esses novos estudos motivaram o uso de terapia baseada em venetoclax nesse paciente jovem, com doenca recidivada, conseguindo atingir e manter DRM negativa. Conclusao: O caso relatado demonstra eficacia do Venetoclax (em combinacao com hipometilante ou citarabina) em promover remissao profunda da doenca, tornando o paciente habil para o transplante e aumentando a probabilidade de sobrevida a longo prazo. Copyright © 2022

Azacitidine/Venetoclax Combination as First-Line Therapy in Elderly Patients with Acute Myeloid Leukemias: A First Step

Background. The treatment of elderly patients with acute myeloid leukemias (AML) is one of the most formidable challenges in oncohematology. Hypomethylating drugs combined with venetoclax show relatively high efficacy and lower toxicity in elderly AML patients. Aim. To retrospectively analyze the efficacy and tolerability of the combined azacitidine/venetoclax therapy in AML primary patients of older age as well as to determine a spectrum of issues related to the implementation of this regimen in real-world clinical practice. Materials & Methods. The retrospective analysis enrolled a cohort of patients followed-up at the Botkin City Clinical Hospital (n = 35). The median age was 73 years (range 60-90 years), 57 % of patients were over 70 years of age. The median follow-up duration was 5.2 months (range 1.6-42.6 months). By the time of final analysis 15 patients were still receiving the therapy. The median of overall survival was 11.1 months (95% confidence interval [95% CI] 8.1-14.1 months). The causes of death in 20 patients were AML progression (n = 3), non-COVID-19 infectious complications (n = 3), and COVID-19 (n = 10). In 4 patients the cause of death remained unidentified. Results. Complete remission (CR) was documented in 17 (48.5 %) patients;CR with incomplete hematologic recovery was identified in 9 (26 %) patients. The median time before achieving remission was 67 days (range 27-120 days). In 96 % of patients CR was achieved after 3 azacitidine/venetoclax cycles. The mean CR duration was 9.2 months (95% CI 5.7-12.6 months);the median time before loss of response was 19 months. Relapses were diagnosed in 5 patients. Neutropenia > grade 3 was identified in patients who achieved remission on subsequent therapy cycles in 100 % of cases (n = 26), anemia > grade 2 was reported in 9 (34 %) patients, and thrombocytopenia > grade 3 was detected in 13 (50 %) patients. Despite frequent neutropenia, patients with remission did not show any severe infectious complications. Conclusion. The combined azacitidine/venetoclax therapy in elderly patients yields remission in more than 70 % of cases and is not marked by any severe infectious complications, despite developing neutropenia. Due to its ease of administration and low toxicity, this regimen can be performed in outpatient units. © 2022 Practical Medicine Publishing House. All rights reserved.

Immunogenicity of a third dose of the BNT162b2 COVID-19 vaccine in patients with CLL: effects on treatment selection.

Patients with chronic lymphocytic leukemia (CLL) show suboptimal responses to the vaccines against SARS-CoV-2; it has been shown though that a booster dose of the BNT162b2 vaccine may lead to a significant increase in the seroconversion rates of immunocompromised patients. We conducted a prospective, non-interventional study to evaluate the immunogenicity of a third dose of the BNT162b2 vaccine in adult patients with CLL. Sera were tested before the first, after the second, and before and after the third dose for anti-SARS-CoV-2 receptor binding domain (RBD) spike protein IgG (anti-RBD). Thirty-nine patients with CLL were included in the study. The seroconversion rate increased from 28.2% before the third dose to 64.1% after the third dose and was higher in treatment-naïve patients (72.7% versus 47.1% in actively treated patients, p = 0.042). All but one patient achieving a seroconversion after the second dose retained after the third, while eight patients not achieving a seroconversion after the second dose (38.1%), did so after the third. Moreover, patients actively treated with venetoclax had a higher seroconversion rate than those treated with ibrutinib (87.5% versus 14.3%, p = 0.001). This study confirms the beneficial effect of a third dose of the BNT162b2 vaccine on the seroconversion rate in patients with CLL. Our results also strongly suggest that the use of venetoclax is correlated with higher immunogenicity/seroconversion rates than that of ibrutinib, a finding that has been reported by another study. A treatment strategy change during the pandemic favoring the use of venetoclax may be suggested based on our results, although these results should be validated in larger studies.

A CASE OF REFRACTORY CHRONIC LYMPHOCYTIC LEUKEMIA INDUCED IMMUNE THROMBOCYTOPENIC PURPURA SUCCESSFULLY TREATED WITH VENETOCLAX

Background: Chronic lymphocytic leukemia (CLL) is the most common adult leukemia. Approximately 2% of patients with CLL develop immune thrombocytopenic purpura (ITP) during the course of the disease. When resistant to steroids, this constitutes as indication for treatment of the CLL. Here we report a patient with refractory ITP secondary to CLL successfully treated with venetoclax. Aims: To present an interesting case with CLL related refractory ITP treated successfully with novel agent venetoclax. Methods: Patient data was taken from the patient herself and Hospital records. Informed consent to publish the case is obtained from patient. Permission for off-label venetoclax and eltrombopag was obtained from Ministry of Health of Turkey. Results: 46-year-old female patient presented with lumps on her neck that were present for the last 9 months in November 2020. She has a history of frequent pneumonia and otitis but no constitutional symptoms. Her physical examination reveals multiple 2cm lymphadenopathies on her neck and no organomegaly or other pathological features. Blood work shows mild lymphocytosis (6800/mm3) with no serious cytopenias. Peripheral blood smear, flow cytometry and bone marrow biopsy were all compatible with CLL. She was classified as Binet A CLL and was followed up with no treatment after appropriate vaccinations against capsulated pathogens. In July and August 2021 she received two doses of mRNA vaccination against COVID-19. On 1st November 2021 she experienced excessive menstrual bleeding and blood work showed platelet count of 23000/mm3, she was started on steroids (1 mg/kg/day) and after 4 days platelet count has risen to 55000/mm3, she discontinued steroids on her own against medical advice. On 13th of November she presented with extensive petechiae and purpura and was again started on steroids and was given the courses of intravenous immunoglobulins (IVIG) without any sustained response. She was refractory to platelet transfusions too. She was transferred to our clinic. She was found to have del11q and del13q. She refused bone marrow examination. She was treated with rituximab, steroids, vincristine, IVIG and eltrombopag for ITP without success (Fig. 1). She had a minimal response to IVIG only. She received two courses of bendamustine (90 mg/kg for two days) also without success. Three courses of plasmapheresis yielded no response either. After mild success with immunadsorbtion apharesis she was started on venetoclax plus rituximab with ramp-up. Sustained response was achieved within the first week of venetoclax therapy. (Figure Presented ) Summary/Conclusion: Gordon et al. reported 2 CLL cases one with ITP and other with Evans syndrome successfully treated with venetoclax. We think, this treatment should be considered in patients with refractory immune cytopenias secondary to CLL and assessed with prospective clinical trials.

CLINICAL EFFICACY AND TOLERABILITY OF VENETOCLAX PLUS RITUXIMAB IN RELAPSED OR REFRACTORY CHRONIC LYMPHOCYTIC LEUKEMIA - REAL WORLD ANALYSIS OF POLISH ADULT LEUKEMIA STUDY GROUP

Background: The introduction of venetoclax into clinical practice has improved the outcome of patients with relapsed/refractory chronic lymphocytic leukemia (RR-CLL). The results of the MURANO trial published in March 2018 showed significantly longer progression-free survival (PFS) and overall survival (OS) in RR-CLL patients treated with venetoclax and rituximab (VEN-R) comparing to bendamustine and rituximab (BR) and resulted in the approval of VEN-R in the therapy of RR-CLL in the European Union and the United States. It should be noted that the results of registration studies often do not correspond with the data from real-life observations. Aims: To study the clinical efficacy and safety profile of VEN-R treatment in RR-CLL patients outside clinical trials. Methods: We performed retrospective analysis of RR-CLL patients treated with VEN-R in hematology centers of the Polish Adult Leukemia Study Group (PALG) from 2019 to 2021. Results: Clinical data of 117 RR-CLL patients treated with VEN-R were collected. Median patient age upon initiation of VEN-R therapy was 67 years (range 33 - 84 years). Seventy-two patients (61.5%) were men. Median Cumulative Illness Rating Scale (CIRS) was 6 (range 2 -16). Patients were treated with a median of 2 (range 1-9) previous lines of therapy, whereas 32 patients (27.4%) had relapsed following the first line of treatment. Overall, 25 patients (21.4%) had 17p deletion, whereas TP53 mutation was identified in 13 patients (11.1%). The median follow-up was 9.96 months (range 0.27 -29.13). The overall response rate (ORR) was 95.2%. Seventeen patients (14.5%) achieved complete remission (CR), 83 (70.9%) partial remission (PR), while in 5 patients (4.3%) disease progression was noted. In the patients with 17p deletion (n=22) or TP53 mutation (n=11), CR and PR were observed in 4 (12.1%) and 29 (87.9%) patients, respectively. The median PFS in the whole cohort was 20.8 (95% CI 18.43 -not reached) months and the median OS was not reached. In our study none of the analyzed clinico-pathological factors had significant impact on ORR, PFS and OS. During the follow-up time four (3.4%) cases of Richter transformation were diagnosed. There were 18 deaths recorded during the course of observation;3 (16.7%) due to disease progression and 7 (38.9%) due to COVID-19 infection. The others were due to infections other than SARS-CoV-2 (n=3, 16.7%) and the cause of death could not be specified in five cases (27.8%). Eighty-three patients (70.9%) remain on treatment, while treatment was discontinued in thirty-four cases (29.1%). Reasons for therapy discontinuation included patient's death (52.9%), treatment-related cytopenias (17.6%), disease progression (14.7%), Richter's transformation (11.8%), autoimmune hemolytic anemia (5.9%), diarrhea (2.9%) and infections (8.8%). In one case treatment discontinuation was due to consent withdrawal and one patient was lost to follow-up. The following adverse events of VEN-R treatment were reported during the study: all grade neutropenia (71.8% with grade 3/4 in 55.6%), anemia (51.3%), thrombocytopenia (47%), pneumonia (9.4%), neutropenic fever (6.8%), autoimmune hemolytic anemia (4.3%), immune thrombocytopenic purpura (1.7%), diarrhea (4.3%) and in one case exacerbation of heart failure was observed. Summary/Conclusion: In this retrospective analysis the outcomes of treatment with the VEN-R regimen in real-life setting were worse than those reported in the MURANO trial.

DEPLETION AND RECOVERY OF NORMAL B-CELLS DURING AND AFTER TREATMENT WITH CHEMOIMMUNOTHERAPY, IBRUTINIB OR VENETOCLAX

Background: Infectious complications are a major cause of morbidity and mortality in Chronic Lymphocytic Leukaemia (CLL). Therapeutic approaches that deplete CLL cells also affect normal B-cells. Optimal treatment would result in eradication of CLL cells and recovery of normal immune function. FLAIR (ISRCTN01844152) is a phase III trial for previously untreated CLL comparing ibrutinib plus rituximab (IR) with fludarabine, cyclophosphamide and rituximab (FCR) and subsequently amended to also compare ibrutinib plus venetoclax (I+V) and ibrutinib alone (I) with FCR. Measurable residual disease (MRD) and normal B-cell levels were assessed at multiple timepoints. Aims: To assess the depletion of normal B-cells during treatment and recovery after end of treatment. Methods: Participants aged under 75 years with <20% TP53-deleted cells were initially randomised to FCR or IR and subsequently to FCR, IR, I+V or I with the IR arm closed after randomisation of 771 participants to FCR/IR. FCR was given for 6 cycles, while treatment in the IR, I and I+V arms continued for up to 6 years except in participants attaining <0.01% MRD who continued treatment for the time taken to achieved MRD <0.01% and then stopped if MRD remained <0.01%. Month (M) 24 was earliest permitted stopping point. MRD flow cytometry was performed according to ERIC guidelines (panel: CD19/5/20/43/79/81+ROR1, acquisition of 0.5-2.2 million cells, BD Biosciences Lyric). Additional analysis of normal B-cell subsets was performed in a cohort of >500 patients (panel: CD19 to identify B-cells, CD20/5/79b+ROR1 and CD3 to exclude CLL & contaminating cells, with CD27/ 38/IgD/IgM to characterise normal B-cell subsets using a Coulter Cytoflex LX). Results: Normal B-cells were undetectable during FCR treatment and only rarely detectable until 12 months after last FCR cycle. Circulating normal B-cells were reduced in number or undetectable in participants receiving ibrutinibcontaining regimens with greater depletion in the I+V and IR arms relative to I monotherapy. B-progenitors persist through FCR treatment but were depleted during I, I+R or I+V treatment. Normal B-cell levels at 24 and 36 months after randomisation, with time off-treatment if applicable, are shown in Figure 1. In the ibrutinib-containing arms (IR, I, and I+V), there was a trend towards fewer COVID-associated SAE at any time point for participants with detectable B-cells at 24M (4/181, 2.2%) compared to those with no detectable B-cells (14/344, 4.1%) and COVID-associated SAEs were not observed in FCR-treated participants who had recovered any level of normal B-cells by 24M (0/215). However, the data on COVID infections are limited and there was no apparent association between normal B-cell levels at 24M with the proportion of participants experiencing an infectious SAE overall. Assessment of normal B-cell subsets during ibrutinib-based treatment demonstrated a mix of naïve and memory B-cells. Serological response to COVID infection/vaccination in this cohort is currently being performed. Participants stopping I+V treatment at 24-30 months post-randomisation due to MRD eradication showed rapid recovery of normal naive B-cells within 6-12 months after end of treatment in the vast majority (>95%) of evaluable cases. Summary/Conclusion: Normal circulating B-cells are depleted during treatment with rituximab but can persist at a low level during I, IR or I+V treatment. Most patients in remission after treatment with FCR or I+V show recovery of normal B-cells at 12 months of stopping treatment.

IBRUTINIB PLUS VENETOCLAX IN PATIENTS WITH COMPLEX KARYOTYPE AND CHRONIC LYMPHOCYTIC LEUKEMIA

Background: In the largest study of Baliakas et al. (2019) the presence of at least 5 abnormalities, was associated with dismal clinical outcome, independently of the somatic hypermutation status and TP53 status. The presence of 3 or 4 aberrations is defined as clinically relevant in the absence of TP53. Studies by Kittai (2021) and Al-Sawaf (2020) showed the impact of karyotypic complexity on survival in patients with chronic lymphocytic leukemia (CLL) treated with ibrutinib or venetoclax. The complex karyotype (CK) is a topic that is being intensively researched, both in the aspect of increasing karyotypic complexity stratification and clonal evolution. Optimal therapy for patients with CLL has not yet been developed. The combination therapy of ibrutinib and venetoclax was superior to chlorambucil and obinutuzumab in terms of undetectable minimal residual disease (MRD) responses according to data from the GLOW trial (Tunir, 2021). The importance of achieving a complete response with undetectable MRD as the goal of therapy in CLL was proposed (Montserrat, 2005). Aims: The aim of our study is to evaluate the effectiveness of therapy with ibrutinib and venetoclax in combination for the patients with CLL and CK. Methods: This ambilinear observational study included patients with CLL with high genetic complexity (high-CK), defined as >=5 aberrations or CK (>=3 aberrations) in combination with a 17p deletion (CK+del17p). The first retrospective cohort included patients treated with ibrutinib monotherapy (Imono) to progression or intolerable toxicity since May 2015. The second prospective cohort included patients receiving ibrutinib in combination with venetoclax (IVen) since July 2019. Venetoclax therapy was started at the 3rd month of ibrutinib (from the escalation phase). Combination therapy was continued until a complete response, defined as three consecutive PET-CT-negative and MRD-negative results 3 months apart. If this criterion was not achieved at 24th month of therapy, venetoclax was discontinued and ibrutinib continued indefinitely. Results: Seventy-nine patients are included in the study. Twenty-nine patients in the first cohort and 50 patients in the second cohort. The characteristic is presented in Table. At the current follow-up periods, there were no significant differences in PFS and OS regarding a follow-up period <= 24 months (with the exception of death from COVID-19, since patients were not observed at parallel time intervals). In the group of patients treated with Imono, the majority of patients achieved partial remission or partial remission with lymphocytosis by 12 months. In 21 patients from Iven group, with a median follow-up of 7.4 months, a complete remission was achieved (72.4%);of these, 8 had unmeasurable MRD. Four patients did not complete the escalation period. There was a significant difference in the median MRD response achieved between 3 (log10>10) and 12 (log10<0,1) months in IVen group (p=0,03). In 2 patient from the IVen group progression of the disease was noted. Summary/Conclusion: Combination therapy with ibrutinib and venetoclax is an effective oral regimen for high-risk patients with complex karyotype disorders. PFS in both groups is currently not significantly different, which is obviously due to the short follow-up period. Patients receiving the IVen regimen achieve a significantly better response, which paves the way for allogeneic transplantation in these patients.

SEROLOGIC RESPONSE TO THE SECOND AND THIRD DOSE OF THE SARS-COV-2 VACCINE IN PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA: RESULTS OF A PROSPECTIVE, CENTRALIZED, MULTICENTER STUDY

Background: Patients with chronic lymphocytic leukemia (CLL) show high infection-related morbidity and mortality due to variable degree of humoral and cellular immune deficiency. High Covid-related mortality and reduced response to the SARS-Cov-2 vaccine have been reported in this patient population. Aims: We carried out a prospective multicenter study to define the rate of CLL patients with an appropriate immune response after the mRNA SARS-CoV2 vaccine (Pfizer-BioNTech;Moderna). Methods: Two-hundred patients with CLL received the first dose of the SARS-CoV-2 vaccine between February and August 2021. Centralized assessment of the anti-SARS-Cov-2 IgG levels (Sero Index, Kantaro Quantitative SARS-CoV-2 IgG Antibody, RUO-R&D System) was performed at the Istituto Superiore di Sanità of Rome, Italy. The median followup of this study is 10.7 months (range 1-12.9). Results: The median age of patients was 70 years, the median IgG level was 635 mg/dl, 61% of patients were IGHV unmutated, and 34% showed TP53 disruption. The majority of patients, 83.5%, were previously treated. Prior treatment included chemoimmunotherapy in 20 (10%) patients, ibrutinib-based therapy in 72 (36%;front-line, 21%;advanced line, 15%), venetoclax-based therapy in 75 (37.5%;front-line, 13.5%;advanced line, 24%). Overall, 135 (77.5%) patients had been previously treated with rituximab, 33 (16.5%) of them within 12 months before vaccination. We assessed the serologic response after the second dose of the SARS-CoV2 vaccine in 195 patients while five were excluded from the analysis (positive test before vaccination, 3 patients;lost to the follow-up, 1;Richter syndrome, 1). Adequate levels of anti-SARS-Cov-2 IgG were detected in 76/195 (39%) patients. Age (<70 vs.≥ 70 years;p <0.0001), CIRS value (<6 vs. ≥6;p=0.005), beta-2 microglobulin (<3.5 vs. ≥ 3.5mg/dl;p=0.04), IgG levels (<550 vs. ≤ 550 mg/dl;p <0.0001), prior treatment (p=0.0001), number of prior treatments (0+1 vs. ≥ 2;p=0.002) and the time between prior rituximab and vaccination (>12 vs. ≤12 month;p=0.001) showed a significant impact on the humoral response. In multivariate analysis only age (OR: 0.92 [95% CI: 0.92-0.97] p=0.0001), IgG levels (OR: 0.28 [95% CI: 0.13-0.58] p<0.001), and the time between prior rituximab and vaccination (OR: 0.10 [95% CI: 0.03-0.37] p=0.001), revealed a significant and independent impact on response. When the analysis was restricted to patients who received targeted therapy, in addition to the younger age (OR: 0.96 [95% CI: 0.92-0.99] p=0.04), higher IgG levels at baseline (OR: 0.31 [95% CI: 0.12-0.79] p=0.014), longer time between the start of ibrutinib or venetoclax-based therapy and vaccination (<18 vs.≥18 months;OR: 0.17 [95% CI: 0.06-0.44], p <0.0001) showed a favorable and independent impact on response. Ninety-three% (182/195) of patients received a third dose of the vaccine. A significant increase in the rate of serologic responses, 51.5% (85/165 evaluated patients, p=0.019), was observed after the booster dose. Moreover, a response was detected in 25% (26/103 evaluated patients) of previously seronegative patients. Summary/Conclusion: In this prospective, multicenter, centralized study, we recorded an effective immune response to the SARS-CoV-2 vaccine in about a third of patients with CLL. Younger age, higher IgG levels, no prior treatment, or stable disease after targeted therapy that suggest preserved immunocompetence were associated with a greater likelihood of achieving an effective immune response. A booster dose of the SARS-CoV-2 vaccine proved beneficial also in previously seronegative patients.

INHIBITION OF PROTEIN KINASE CK2 AND BCL-2: A NOVEL THERAPEUTIC STRATEGY TO ANTAGONIZE MANTLE CELL LYMPHOMA CELL GROWTH

Background: Mantle cell lymphoma (MCL) is a B-cell tumor which often relapses. BCR inhibitors (Ibrutinib, Acalabrutinib) and antiapoptotic BCL2-family members blockers BH3-mimetics (Venetoclax, ABT-199) are effective drugs to fight MCL. However, the disease remains incurable, due to therapy resistance, even to the promising Venetoclax and Ibrutinib combination. Therefore, there is a profound need to explore novel useful therapeutic targets. CK2 is a S/T kinase overexpressed in several solid and blood tumors. We demonstrated that CK2, operating through a 'non-oncogene addiction' mechanism promotes tumor cell survival, and counteracts apoptosis, by activating pro-survival signaling cascades, such as NF-κ B, STAT3 and AKT. CK2 could regulate also BCL2 family members. The CK2 chemical inhibitor CX-4945 (Silmitasertib, Sil) is already under scrutiny in clinical trials in relapsed multiple myeloma, solid tumors and COVID-19. Aims: In this work, we tested the effect of CK2 chemical inhibition or knock down on Venetoclax (Ven)-induced cytotoxicity in MCL pre-clinical models to effectively reduce MCL cell growth and clonal expansion. Methods: CK2 expression and BCR/BCL2 related signaling components were analyzed in MCL cells and control cells by Western blotting. CK2 and BCL2 inhibition was obtained with Sil and Ven, respectively and with CK2 gene silencing through the generation of anti-CK2 shRNA IPTG-inducible MCL cell clones. Survival, apoptosis, mitochondrial membrane depolarization and proliferation were investigated by FACS analysis of AnnexinV/PI and JC-10 staining. The synergic action of Ven and Sil was analyzed by the Chou-Talalay combination index (CI) method. CK2 knock down in vivo was obtained in xenograft NOD-SCID mouse models Results: CK2 inactivation (with Sil or CK2 silencing) determined a reduction in the activating phosphorylation of S529 p65/RelA and S473 and S129 AKT, important survival cascades for MCL. Sil or CK2 silencing caused BCL2 and related MCL1 protein reduction, causing cell death. Importantly, we confirmed these results also in an in vivo xenograft mouse model of CK2 knockdown in MCL. Sil +Ven combination increased MCL cell apoptosis, as judged by the augmented frequency of Annexin V positive cells and expression of cleaved PARP protein, and JC-10 mitochondrial membrane depolarization, with respect to the single treatments. Captivatingly, Sil or CK2 gene silencing led to a substantial reduction of the Ven-induced increase of MCL-1, potentially counteracting a deleterious Ven-induced drawback. Analysis of cell cycle distribution confirmed an increased frequency of apoptotic cells in the sub G1 phase in CK2-silenced cells and a modulation of the other phases of the cell cycle. Remarkably, the calculated CI less than 1 suggested a strong synergic cell-killing effect between Sil and Ven, on all the cell lines tested, including those less sensitive or resistant to Ven Summary/Conclusion: We demonstrated that the simultaneous inhibition/knock down of CK2 and BCL2 synergistically cooperates in inducing apoptosis and cell cycle arrest of MCL malignant B-lymphocytes and has the potential of reducing MCL clonal growth, also counterbalancing mechanism of resistance that may arise with Ven. Therefore, CK2 is a rational therapeutic target for the treatment of MCL to be tested in combination with Ibrutinib or Ven.

CHARACTERISTICS AND OUTCOMES OF PATIENTS WITH ACUTE MYELOID LEUKAEMIA TREATED WITH VENETOCLAX COMBINATION THERAPY: REAL-WORLD EXPERIENCE IN BOTH FRONTLINE AND RELAPSED/REFRACTORY SETTINGS

Background: Venetoclax (Ven) in combination with hypomethylating agents, such as azacitidine (Aza) and low dose cytarabine (LDAC) has been shown to be effective therapy in acute myeloid leukaemia (AML) and has become standard of care for newly-diagnosed patients unfit for intensive chemotherapy (DiNardo et al., 2020;Wei et al., 2019;Pollyea et al., 2020). Efficacy has also been shown in the relapsed/refractory (R/R) setting in more limited data sets (Báez-Gutiérrez et al., 2021;Pollyea et al., 2020, Stahl et al., 2020;DiNardo et al., 2019). Ven combination therapy has become widely used in newly-diagnosed patients in the UK since its approval during the COVID-19 pandemic as an alternative to intensive chemotherapy and subsequently for patients unfit for intensive therapy. Aims: We describe the characteristics and outcomes of patients with AML or high risk myelodysplastic syndrome (HRMDS) receiving Ven combinations in frontline and R/R settings to provide real-world insight into their use in UK clinical practice. Methods: A retrospective analysis was performed of all patients with AML or HR-MDS who received Ven combination therapy at University College London Hospital between April 2020 and September 2021. Patient demographics, treatment history and bone marrow results were obtained from electronic health care and laboratory records. Disease stratification and response assessments were made as per European LeukemiaNet (ELN) criteria (Döhner et al., 2017). Results: At the time of analysis, 95 patients received Ven combinations (61 as frontline treatment and 34 for R/R AML), with a median follow up of 14 months. The majority of patients in both groups had adverse risk ELN classification (70.5% of frontline patients, 64.7% of R/R) and received Ven-Aza (100% frontline and 91.1% R/R) (Table 1). The median ages were 72 and 59 years respectively. The incidence of composite CR/CRi was 70.5% in the frontline setting, with median duration of response (DoR) of 8.3 months and overall survival (OS) of 7.1 months. In R/R AML, the CR/CRi rate was 64.7%, median DoR 10.5 months and median OS 9.8 months. Four out of the 43 patients who achieved CR/CRi (9.3%) following frontline treatment and 9 of the 22 R/R (40.9%) patients proceeded to allogeneic stem cell transplant (alloSCT) post induction. The median survival for all patients who underwent alloSCT is not reached in this analysis. The highest CR/CRi rates were observed in intermediate risk patients (90.9% in frontline treatment, 71.4% in R/R), with lower rates in both favourable (80% and 66.7%) and adverse risk patients (65.1% and 59.1% respectively). The presence of NPM1 and IDH1/2 mutations were associated with high CR/CRi rates in both the frontline (85.7% and 84.6% respectively) and R/R groups (100% and 81.8%), with below average response rates seen in TP53 mutated AML (62% in frontline, 40% in R/R). Notable responses were seen in patients with RUNX1 mutations in both settings (77.8% frontline, 66.6% R/R). Summary/Conclusion: Our data describes real world effectiveness for venetoclax combinations as both frontline and salvage therapy in UK clinical practice, similar to that seen in clinical trials. This further contributes to our understanding of these therapies, in particular their use as a viable treatment option in R/R patients and as a bridge to alloSCT, and highlights the importance of further characterisation of genetic predictors of response to inform treatment decisions in real-world practice.

PROSPECTIVE MULTICENTRIC STUDY ON INFECTIOUS COMPLICATIONS AND CLINICAL OUTCOME IN 230 UNFIT AML PATIENTS TREATED IN FIRST-LINE WITH HYPOMETHYLATING AGENTS ALONE OR IN COMBINATION WITH VENETOCLAX

Background: The hypomethylating agents (HMAs) are an important therapeutic option for older patients (pts) with AML and have become the backbone for combination regimens (eg, with Venetoclax). However, there are very limited real-life prospective studies regarding clinical outcome of these pts, including infectious complications and infection related mortality (IRM) during treatment. Aims: To investigate the infectious complications and clinical outcome in AML patients treated with HMAs± Venetoclax (V) outside of clinical trials. Methods: The recruitment of this prospective multicentric study (CE-Id-study:2908) has been completed on December 31, 2020. We enrolled 230 AML pts with a median age of 75 years (range 25-94);157 pts (68%) had >2 relevant comorbidities. Of the 230 cases, 132 (57%) received a first-line therapy with a combination of HMAs+V while 98 (43%) were treated with HMAs monotherapy (azacitidine or decitabine). A total of 1550 cycles of HMAs have been administered (680/1550 with HMAs+V). Results: The best response achieved, with HMAs treatment, was: CR in 44% of cases (57,6% with HMAs+V and 25,5% with HMAs alone, P=0,0001), PR in 17% and SD in 14% of cases (ORR 61%;72% in HMAS+V and 46% in HMAs alone, P=0,0007). The microbiological or radiological proven infectious complications (almost one) occurred in 160/230 (70%) of pts, mainly pneumonia (in 42% of pts) and/or bacteremia/sepsis (one or more events in 29% of pts). Febrile neutropenia (one or more episodes) occurred in 38% of pts and 14 cases of Covid-19 (6%) were reported. After a median follow-up of 9 months (1-24) from the start of HMAs therapy, 144 (63%) pts died and 86 (37%) were alive. The 1 yr OS probability was 46% with a median OS of 10,3 months (11 months in HMAs+V and 9 months in HMAs alone;P=ns). The primary causes of death were: progression of AML (42%), Infection (26%-37/144), Infection+AML (24%), other causes (8%). The IRM was 26% and 19/144 (13%) pts died of infectious complication while in CR/PR (16 in HMAs+V group and only 3 in HMAs group;P=0,005). Data on antibiotic prophylaxis, hospitalization, drugdoses modulation, are available and analyzed in this study. Summary/Conclusion: The results of this real-life, multicentric, prospective study, confirm a higher CR rate in pts treated with HMAs+V compared to HMAs alone (P=0,0001). However, we found a high rate of infectious complications and IRM (26%) with a higher infection related deaths in patients in CR/PR who were treated with HMAs+V (P=0,005). Findings from this study highlight the critical relevance of infection prevention in reducing infectious mortality, which adversely impacts the OS of this frail AML population.

Clinical and Virological Response to Convalescent Plasma in a Chronic Lymphocytic Leukemia Patient with COVID-19 Pneumonia.

The burden of COVID-19 remains unchanged for immunocompromised patients who do not respond to vaccines. Unfortunately, Omicron sublineages are resistant to monoclonal antibodies authorized in Europe so far, and small chemical antivirals have contraindications and toxicities that have not been studied in these patients. We report here the successful treatment of COVID-19 pneumonia lasting for 4 months after the transfusion of COVID-19 convalescent plasma (CCP) in a patient with severe immunosuppression due to both chronic lymphocytic leukemia and venetoclax treatment. The patient achieved a complete clinical, radiological and virological response after six transfusions (600 mL each) of high-titer CCP collected from triple-vaccinated and convalescent donors. This dramatic case adds to the mounting evidence of CCP efficacy in immunocompromised patients, provided that high-titer and large volumes are infused.