Therapeutic Leukapheresis: Experience of a Single Oncologic Centre.

Introduction: Leukostasis refers to clinical symptoms caused by hyperleukocytosis seen in some haematological diseases such as leukaemia. Cytoreduction can be achieved by therapeutic leukapheresis. The aim of this study was to retrospectively analyse the procedures performed in our Centre and to evaluate their efficacy and safety. Methods: This was a retrospective study of all the therapeutic leukapheresis procedures carried out in our Centre between January 1998 and December 2020. The sample collection was obtained through the review of the clinical files of the respective patients. Statistical analysis was performed using the software R v.4.0.1. A total of 54 therapeutic leukapheresis procedures were performed in 31 patients in our Centre. Results: After these procedures clinical improvement was observed in 16 patients and we verify that there was a significant difference in survival between the group that improved and the group that maintained the same clinical condition or worsened. The lack of immediate clinical improvement was a sign of a poor prognosis. Laboratory efficacy occurred in 16 patients who had a reduction in white blood cell count, with a 39.1% reduction after 24 h, and did not succeed in 15 patients, who had no reduction. However, in this case there is no significant difference in survival between the two groups. There was some complication in 53.9% of the procedures, with hypocalcaemia being the most frequent, which was observed in 22 procedures. Only 4 patients experienced serious side effects but these adverse reactions cannot be attributed to the procedures carried out. The overall survival rate 6 months after this treatment was 51.6%. Conclusion: Despite the reduced number of patients, we conclude that therapeutic leukapheresis is a safe and effective option that may still have a therapeutic role in some cases.

Efficacy and safety of oral panobinostat plus subcutaneous bortezomib and oral dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma (PANORAMA 3): an open-label, randomised, phase 2 study.

BACKGROUND: Improved therapeutic options are needed for patients with relapsed or relapsed and refractory multiple myeloma. Subcutaneous bortezomib has replaced intravenous bortezomib as it is associated with a more favourable toxicity profile. We investigated the activity and safety of three different dosing regimens of oral panobinostat in combination with subcutaneous bortezomib and oral dexamethasone for this indication. METHODS: PANORAMA 3 is an open-label, randomised, phase 2 study being done at 71 sites (hospitals and medical centres) across 21 countries. Patients aged 18 years or older with relapsed or relapsed and refractory multiple myeloma (as per International Myeloma Working Group 2014 criteria), who had received one to four previous lines of therapy (including an immunomodulatory agent), and had an Eastern Cooperative Oncology Group performance status of 2 or lower, were randomly assigned (1:1:1) to receive oral panobinostat 20 mg three times weekly, 20 mg twice weekly, or 10 mg three times weekly, plus subcutaneous bortezomib and oral dexamethasone. All study drugs were administered in 21-day cycles. Randomisation was done by an interactive response technology provider, and stratified by number of previous treatment lines and age. The primary endpoint was overall response rate after up to eight treatment cycles (analysed in all randomly assigned patients by intention to treat). Safety analyses included all patients who received at least one dose of any study drug. No statistical comparisons between groups were planned. This trial is ongoing and registered with ClinicalTrials.gov, NCT02654990. FINDINGS: Between April 27, 2016, and Jan 17, 2019, 248 patients were randomly assigned (82 to panobinostat 20 mg three times weekly, 83 to panobinostat 20 mg twice weekly, and 83 to 10 mg panobinostat three times weekly). Median duration of follow-up across all treatment groups was 14·7 months (IQR 7·8-24·1). The overall response rate after up to eight treatment cycles was 62·2% (95% CI 50·8-72·7; 51 of 82 patients) for the 20 mg three times weekly group, 65·1% (53·8-75·2; 54 of 83 patients) for the 20 mg twice weekly group, and 50·6% (39·4-61·8; 42 of 83 patients) for the 10 mg three times weekly group. Grade 3-4 adverse events occurred in 71 (91%) of 78 patients in the 20 mg three times weekly group, 69 (83%) of 83 patients in the 20 mg twice weekly group, and 60 (75%) of 80 patients in the 10 mg three times weekly group; the most common (≥20% patients in any group) grade 3-4 adverse events were thrombocytopenia (33 [42%] of 78, 26 [31%] of 83, and 19 [24%] of 83 patients) and neutropenia (18 [23%], 13 [16%], and six [8%]). Serious adverse events occurred in 42 (54%) of 78 patients in the 20 mg three times weekly group, 40 (48%) of 83 patients in the 20 mg twice weekly group, and 35 (44%) of 83 patients in the 10 mg three times weekly group; the most common serious adverse event (≥10% patients in any group) was pneumonia (nine [12%] of 78, ten [12%] of 83, and nine [11%] of 80 patients). There were 14 deaths during the study (five [6%] of 78 patients in the 20 mg three times weekly group, three [4%] of 83 in the 20 mg twice weekly group, and six [8%] of 80 in the 10 mg three times weekly group); none of these deaths was deemed treatment related. INTERPRETATION: The safety profile of panobinostat 20 mg three times weekly was more favourable than in previous trials of this regimen with intravenous bortezomib, suggesting that subcutaneous bortezomib improves the tolerability of the panobinostat plus bortezomib plus dexamethasone regimen. The overall response rate was highest in the 20 mg three times weekly and 20 mg twice weekly groups, with 10 mg three times weekly best tolerated. FUNDING: Novartis Pharmaceuticals and Secura Bio.

Management of older and frail patients with multiple myeloma in the Portuguese routine clinical practice: Deliberations and recommendations from an expert panel of hematologists.

The management of older patients with Multiple Myeloma (MM) is particularly challenging due to the highly heterogeneous nature of this population, both in terms of physical and cognitive functioning. Older patients may be divided into fit, intermediate and frail, with variable abilities to tolerate treatments. A careful and correct assessment of the frailty status is thus paramount for the success of therapy and for improving outcomes. With the aging of the European population, the number of older patients with MM is rapidly growing. We hereby present the deliberations and recommendations from an expert panel of Portuguese hematologists conducted to discuss the management of this population, including how to stratify and treat older patients with MM according to their frailty status. The use of frailty tools is critical for the development of individualized risk-adapted treatment strategies and to minimize the risk of under or overtreatment. Aggressive therapies should be used in fitter patients to improve survival outcomes, while frail patients should generally be treated with less toxic approaches to control symptoms while minimizing toxicity. In intermediate-fit patients, low-dose triplets are recommended to achieve a balance between improving survival and maintaining quality of life. The management of older patients with MM should be performed by a multidisciplinary team in view of their advanced age and high prevalence of comorbidities. The inclusion of older and frail patients in future clinical trials investigating treatment regimens for MM is crucial to evaluate treatment feasibility and to improve clinical decision making in this population.

Myeloid Disease with the CSF3R T618I Mutation after CLL.

Chronic lymphocytic leukemia (CLL) is frequently an indolent diagnosis, with most of the patients being under surveillance for long time. There is an increased risk of a second neoplasia in CLL, rarely hematological (in the myeloid lineage is even rarer). A 58-year-old male was diagnosed with CLL in 2012, remaining in regular surveillance until 2014. Then, the CLL progressed, and 6 cycles of rituximab, fludarabine, and cyclophosphamide were prescribed with partial response. He remained in surveillance and suffered 2 episodes of autoimmune hemolytic anemia until 2019. Then, the hemolytic anemia relapsed and a neutrophilia became evident (progressing slowly), as well as a thrombocytopenia and splenomegaly without adenopathy were found. The bone marrow aspirate showed a chronic myeloproliferative disease without dysplasia. A peripheral blood search for the CSF3R mutation (T618I) was positive, also suggesting Chronic Neutrophilic Leukemia (CNL). For a discrete monocytosis, a chronic myelomonocytic leukemia (CMML) was also considered. Hydroxyurea was then prescribed. The T618I CSF3R mutation is highly suggestive of CNL (being diagnostic criteria for CNL); however, this case may also suggest CMML as a possible diagnosis (there are other mutations in the CSF3R gene described for CMML, but not the T618I, which is highly exclusive of CNL according to the literature). To our knowledge, this is the first report of a possible CNL in a CLL patient (the opposite was already described in 1998).

The profile of the onco-hematology patient in the palliative care: 4 years of experience.

OBJECTIVES: Most of the palliative care (PC) patients have oncologic diseases, being hematologic tumors a small part of them. According to the literature, onco-hematologic (OH) patients should be individualized from those with solid tumors for the specialized care required along their disease course. This study aims to review the casuistry of OH patients referred to PC in a specialized oncologic hospital and help to understand better how hematologists can improve the care of these patients. METHODS: We analyzed all OH patients referred to the PC service in 1 oncologic hospital along 42 months, through consultation of their clinical files. RESULTS: A total of 179 patients were reviewed (52.% males, median age of 71 years): 48.6% had non-Hodgkin lymphoma, 26.3% had multiple myeloma, 10.6% had acute leukemia, 14.5% had other OH diseases; 88.2% were treated for their OH disease (96.2% with chemotherapy, 28.5% radiotherapy, and 21.5% hematopoietic stem cell transplant). The referral was heterogeneous among physicians (27.4% by 1 physician). Most patients were firstly observed as inpatients (55.3%) and 17.9% in the outpatient consult. At the end of the study, 98.9% of the patients died (88.7% in the hospital, 10.2% at home). The median time between the end of treatment and referral do PC was 46 days and between referral and death was 16 days. We also reviewed medical prescription in the last month of life and we noticed that most invasive orders were requested by hematologists (as antibiotic prescription, imaging, and biopsy studies). SIGNIFICANCE OF RESULTS: This study demonstrated that OH patients should be referred earlier to PC and that a more intensive team work needs to be practiced between PC and hematologists. More educational programs for healthcare workers on this issue are needed in order to guarantee a more effective assistance in the appropriate time.

Recommendations from a Portuguese Expert Group for Discontinuation of Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia Patients in Clinical Practice.

Until recently, the main goal of chronic myeloid leukemia therapy was disease control with the best overall survival, which required lifelong treatment. However, currently, the treatment-free remission concept is becoming an important goal in clinical practice, and several tyrosine kinase inhibitors discontinuation studies have shown that round 50% of patients with a durable deep molecular response beyond major molecular response successfully interrupt tyrosine kinase inhibitors for at least three years without loss of molecular response. However, and regardless of the existing evidence, the exact conditions for attempting treatment-free remission remain poorly defined. Different authors tried to guide the clinical decision regarding this topic but there are some points that differ, namely with respect to the recommended duration of tyrosine kinase inhibitors therapy and the appropriate molecular response prior to treatment-free remission. The goal of this article is to propose an algorithm to guide clinical practice in Portugal concerning chronic phase-chronic myeloid leukemia patients who wish to attempt treatment-free remission, since there are no national guidelines.

Até recentemente, o objectivo principal do tratamento da leucemia mielóide crónica era o controlo da doença com o maior tempo possível de sobrevivência, o que requeria tratamento durante toda a vida. No entanto, e actualmente, o conceito de remissão livre de tratamento está a tornar-se um objectivo importante na prática clínica, e vários estudos de descontinuação de inibidores de tirosina cinase mostraram que cerca de 50% dos doentes com uma resposta molecular profunda duradoura, para além da resposta molecular major, interrompem tratamento com inibidores de tirosina cinase com sucesso durante pelo menos três anos sem perda da resposta molecular. No entanto, e apesar da evidência existente, as condições concretas e exactas para tentar remissão livre de tratamento são ainda pouco conhecidas. Diferentes autores tentaram guiar a decisão clínica sobre este tópico mas alguns pontos permanecem não consensuais, nomeadamente no que respeita à duração recomendada de tratamento com inibidores de tirosina cinase e à resposta molecular apropriada antes de tentar remissão livre de tratamento. O objectivo desta publicação é propor um algoritmo que permita guiar a prática clínica em Portugal relativa a doentes com leucemia mielóide crónica ou em fase crónica que pretendam tentar remissão livre de tratamento, dada a ausência de recomendações nacionais.