The introduction of high-dose therapy in the 1990s as well as the development of drugs such as thalidomide, lenalidomide, and bortezomib in the 2000s led to an impressive improvement in outcome of ...patients with multiple myeloma (MM) eligible for autologous stem cell transplantation (ASCT). Clinical trials conducted in the first ten years of the twenty-first century established as standard therapy for these patients a therapeutic approach including induction, single or double ASCT, consolidation, and maintenance therapy. More recently, incorporating second-generation proteasome inhibitors carfilzomib and monoclonal antibody daratumumab into each phase of treatment significantly improved the efficacy of ASCT in terms of measurable residual disease (MRD) negativity, Progression Free Survival (PFS), and Overall Survival (OS). The availability of techniques such as multiparameter flow cytometry (MFC) and next-generation sequencing (NGS) for MRD assessment allowed the design of MRD-based response-adjusted trials that will define, in particular, the role of consolidation and maintenance therapies. In this review, we will provide an overview of the most recent evidence and the future prospects of ASCT in MM patients.
Real-world data in clinical practice are needed to confirm the efficacy and safety that ibrutinib has demonstrated in clinical trials of patients with chronic lymphocytic leukemia (CLL). We described ...the real-world persistence rate, patterns of use, and clinical outcomes in 309 patients with CLL receiving single-agent ibrutinib in first line (1L,
= 118), 2L (
= 127) and ≥3L (
= 64) in the prospective, real-world, Italian EVIdeNCE study. After a median follow-up of 23.9 months, 29.8% of patients discontinued ibrutinib (1L: 24.6%, 2L: 29.9%, ≥3L: 39.1%), mainly owing to adverse events (AEs)/toxicity (14.2%). The most common AEs leading to discontinuation were infections (1L, ≥3L) and cardiac events (2L). The 2-year retention rate was 70.2% in the whole cohort (1L: 75.4%, 2L: 70.1%, ≥3L: 60.9%). The 2-year PFS and OS were, respectively, 85.4% and 91.7% in 1L, 80.0% and 86.2% in 2L, and 70.1% and 80.0% in ≥3L. Cardiovascular conditions did not impact patients' clinical outcomes. The most common AEs were infections (30.7%), bleeding (12.9%), fatigue (10.0%), and neutropenia (9.7%), while grade 3-4 atrial fibrillation occurred in 3.9% of patients. No new safety signals were detected. These results strongly support ibrutinib as a valuable treatment option for CLL.
Despite the recent dramatic progress in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) therapy, allogeneic transplant remains a mainstay of treatment for patients with acute ...leukemia. The availability of novel compounds and low intensity chemotherapy regimens made it possible for a significant proportion of elderly and comorbid patients with AML or ALL to undergo curative treatment protocols. In addition, the expansion of donor availability and the recent dramatic progress in haploidentical stem cell transplant, allow the identification of an available donor for nearly every patient. Therefore, an increasing number of transplants are currently performed in elderly and frail patients with AML or ALL. However, allo-Hematopoietic stem cell transplant (HSCT) in this delicate setting represents an important challenge, especially regarding the selection of the conditioning protocol. Ideally, conditioning intensity should be reduced as much as possible; however, in patients with acute leukemia relapse remains the major cause of transplant failure. In this article we present modern tools to assess the patient health status before transplant, review the available data on the outcome of frail AML an ALL patients undergoing allo-HSCT, and discuss how preparatory regimens can be optimized in this setting.
Gastrointestinal complications (GICs) represent the major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Differential diagnosis of GICs is of ...paramount importance since early and reliable identification of graft-versus-host disease (GVHD) is essential for a correct management of the patients. The aim of the present retrospective study was to evaluate the occurrence of GICs after allo-HSCT and to assess the diagnostic performance of a quick endoscopic and histological assessment in the differential diagnosis between GVHD and other GI conditions. Between January 2015 and August 2019, 122 consecutive patients receiving an allo-HSCT were managed by an interdisciplinary team, supported by a dedicated endoscopic service. Clinical, therapeutic, endoscopic and histological data were analyzed for each patient. Collectively, 94 of the patients developed GICs (77%). A moderate—severe mucositis was the most frequent complication, occurring in 79 patients (84%). Acute GI-GVHD was diagnosed in 35 patients (37% of whom with GICs) and 19 of them with a moderate–severe grade. Infective acute colitis developed in eight patients, mainly due to Clostridium difficile (CD) and Cytomegalovirus infections (8.5%). Rectal biopsy showed the highest sensitivity and specificity (80% and 100%, respectively). However, when biopsy procedures were guided by symptoms and performed on apparently intact mucosa, upper histology also provided a high negative predictive value (80%). Our multidisciplinary approach with a quick endoscopic/histologic investigation in the patients receiving an allo-HSCT and who suffered GICs could improve diagnostic and therapeutic management in this challenging setting.
Graft‐versus‐host disease (GVHD) is a common complication of hematopoietic stem cell transplant, which is known to be mediated by cytotoxic T‐cell effectors and dysregulated inflammatory cytokines. ...Similarly, the lung injury observed in severe COVID‐19 cases appears to be related to a massive production of pro‐inflammatory cytokines. The selective JAK1/2 inhibitor ruxolitinib has shown promising results in the context of GVHD, and different trials are currently underway in patients with severe COVID‐19; nevertheless, no clinical observation of safety or efficacy of treatment with ruxolitinib in this context has been published yet. We describe a first case of severe COVID‐19 developed after hematopoietic stem cell transplantation in a patient with a concomitant chronic GVHD (cGVHD), in which a treatment with ruxolitinib was administered with good tolerance and positive outcome.
Introduction. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), responsible for coronavirus disease 19 (COVID-19), has led to a significant increase of morbidity worldwide. A recent ...meta-analysis showed a high case fatality rate in hospitalized patients with hematological malignancies and published reports indicated high rates also in chronic lymphocytic leukemia patients (CLL) patients. The aim of our study was to evaluate the impact of COVID-19 in CLL patients treated with venetoclax. Methods. The retrospective multicenter study included CLL patients treated since 2017 with venetoclax single agent until progression or toxicity or venetoclax plus anti-CD20 antibody (mainly rituximab as part of VR protocol for 24 months in relapsed/refractory patients or obinutuzumab as part of VO protocol for 12 months in untreated patients). Results. We found 128 infections from SARS-CoV-2 in 104 patients out of 287 patients with CLL who received venetoclax. Basal characteristics of the 104 patients who experienced COVID-19 were compared to those of the 183 patients who did not experience the infection (Table 1). Patients of the first group did not show more comorbidities in terms of CIRS, nor renal and pulmonary impairment. Unexpectedly patients without COVID-19 experienced more previous infections in the 12 months before the beginning of venetoclax but a similar low rate of previous SARS-CoV-2 infection. They received a median of 2 different previous lines of treatment whereas patients with COVID-19 were exposed to a median of a single line of therapy. No significant differences were noted for prophylaxis with immunoglobulin, antiviral and antibacterial drugs. In the group of COVID-19 a higher rate of patients received venetoclax plus anti-CD20 antibody (62.9% vs 38.5% of the group without COVID-19, p<0.001). The rate of vaccination was higher than 66% in both the groups with a median of 3 doses each. Prophylaxis with tixagevimab/cilgavimab was administered in less than 20% of the patients. Analyzing the characteristics of the 128 infections we distinguished 73 grade 1-2 COVID-19 and 55 grade 3-4 COVID-19. Patients with grade 1-2 COVID-19 were positive for a median time of 10 days (range 5-97). No treatment was administered in 29.1% of the cases, nirmatrelvir/ritonavir was used in 23.6%, remdesivir in 18.2%. Regarding patients with grade 3-4 COVID-19 resulted positive for a median time of 21 days (range 5-120). Remdesivir was chosen as treatment in 48.9%, nirmatrelvir/ritonavir in 21.3%. Univariate and multivariate analysis found that association to anti-CD20 was a risk factor for COVID-19 of any grade (OR 1.93) and of grade 3-4 (OR 2.96), conversely previous infection in the 12 months before the beginning of venetoclax was a protective factor for COVID-19 any grade (OR 0.42) and grade 1-2 (OR 0.32). During COVID-19 Venetoclax was withdrawn in 38 (36.5%) patients, in 32 of whom venetoclax was administered together to anti-CD20 antibody; in 25/38 the discontinuation was only temporary. Thirty-five (33.6%) patients required hospitalization due to COVID-19, the median time of recovery was 15 days, and 8 (7.7%) patients needed intensive care unit admission. Among the 104 patients with COVID-19, 18 patients died, 10 deaths were due to COVID-19: 7 were exposed to anti-CD20 antibody, 3 had a previous grade 1-2 COVID-19, but none experienced a SARS-CoV-2 infection before treatment with venetoclax. All were vaccinated with at least 3 doses except one patient who was not vaccinated but was infected and died in 2020. The rate of mortality due to COVID-19 was 9.6% considering patients who were infected by SARS-CoV-2, but 18.2% among patients with severe grade 3-4 COVID-19. Conclusions. This is a real-life study on 287 patients affected by CLL treated with venetoclax with the aim to describe COVID-19 in this cohort. The analysis found over a third of patients infected by SARS-CoV-2, in 57% of the cases the infection was grade 1-2 with a mortality rate of almost 10%, but higher if COVID-19 was of grade 3-4 (18.2%). We confirmed the association of anti-CD20 antibody to venetoclax as a risk factor for SARS-CoV-2 infection and mortality rate in patients with CLL and severe COVID-19.
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