Background
The standard first‐line treatment for primary mediastinal B‐cell lymphoma (PMBCL) patients is rituximab‐based immunochemotherapy; however, this is not due to the result of randomized ...clinical trials.
Aims
We retrospectively investigated 53 PMBCL patient outcomes treated either with R‐CHOP‐21 or DA‐EPOCH‐R‐28. The primary endpoint was overall survival (OS). Secondary endpoints were complete remission (CR), overall response rate (ORR), progression‐free survival (PFS), and treatment‐related complications.
Results
Treatment with R‐CHOP‐21 resulted in a 92.0% ORR (60% CR), while DA‐EPOCH‐R yielded a 92.6% ORR (70.4% CR). There were no differences in the occurrence of grade 3‐4 hematological adverse events, but grade 1‐2 cardiologic complications (P = .003) were observed more frequently in the DA‐EPOCH‐R arm. Median PFS and OS were not achieved. The differences in estimated 12‐month PFS in R‐CHOP and DA‐EPOCH‐R group (87% vs 73.9%) and OS (100% vs 92%) were insignificant. Patients treated with R‐CHOP‐21 and autologous hematopoietic stem cell transplantation (auto‐HSCT) had an improved OS (P = .03) but not PFS (P = .43) compared to those treated solely with R‐CHOP‐21. No differences in PFS or OS were observed between patients treated with R‐CHOP‐21/auto‐HSCT and DA‐EPOCH‐R.
Conclusion
The results of this study suggest that R‐CHOP‐21 may be an alternative to DA‐EPOCH‐R treatment for PMBCL patients.
Patients with hematologic malignancies are particularly vulnerable to severe infectious complications. SARS‐CoV‐2 infection is associated with a high risk of severe course and death in this patient ...population. In addition, immune deficits associated with both the blood cancer and the treatment used make vaccination against SARS‐CoV‐2 less effective than in immunocompetent individuals. Molnupiravir is one of the first oral antiviral drugs to demonstrate a significant benefit in reducing hospitalisation and death in COVID‐19 in the general population. In this context, 175 haematology patients with diagnosed COVID‐19, and treated with MOL between January and April 2022, came under our scrutiny with a view to defining their clinical characteristics and outcomes. The most common underlying conditions were lymphomas (45%), multiple myelomas (21%) and acute leukaemias or myelodysplastic syndrome (35%). Of all, 77% of the patients were vaccinated, and half of them received a booster. At 28 days after the breakthrough COVID‐19 diagnosis, 35 (20%) subjects required hospital admission. Out of those patients, seven (4%) died during the follow‐up due to the progression of COVID. Our results corroborate what has been established to date with regard to the positive clinical and safety outcomes of MOL in haematology patients with mild or moderate COVID‐19.
What's new?
SARS‐CoV‐2 infection is associated with a high risk of severe disease and death in patients with haematological malignancies, who are also less responsive to vaccination. Molnupiravir has been one of the first oral antiviral drugs to demonstrate a significant benefit in reducing hospitalisation and death due to COVID‐19 in the general population. However, the efficacy and drug tolerability of molnupiravir in patients with haematological cancer during the Omicron wave remain understudied. The results of our study corroborate the positive clinical and safety outcomes of molnupiravir in patients with haematological malignancies with mild or moderate COVID‐19 in daily clinical practice.
There is a rising number of evidence indicating the increased risk of cancer development in association with congenital metabolic errors. Although these diseases represent disorders of individual ...genes, they lead to the disruption of metabolic pathways resulting in metabolite accumulation or their deficiency. Gaucher disease (GD) is an autosomal recessive sphingolipidosis. It is a rare lysosomal storage disease. A strong correlation between GD and different types of cancers, such as multiple myeloma, leukemia, and hepatocellular carcinoma, has been reported. Common features for all types of GD include spleen and liver enlargement, cytopenia, and a variety of bone defects. Overall, the molecular bases leading to the association of GD and cancers are not clearly understood. Here, we describe the role of ceramides in GD, discuss the potential implications of immune cells activation and show how the disturbances in their metabolism might promote blood cancer development.
Azacitidine (AZA) is recognized as a vital drug used in the therapy of myelodysplastic syndromes (MDS) due to its beneficial effect on survival and quality of life. Nevertheless, many patients fail ...to respond to AZA treatment, as prognostic factors still are not identified. The present retrospective analysis included 79 patients with MDS treated with AZA as first-line therapy in a real-life setting. The percentage of patients with good, intermediate, and poor cytogenetics was 46.8%, 11.4%, and 34.2%, respectively. The overall response rate (complete remission CR, partial remission PR, and hematological improvement HI) was 24%. The CR, PR, and HI rates were 13.9%, 2.5%, and 7.6%, respectively. Stable disease (SD) was documented in 40.5% of patients. The median overall survival (OS) and progression-free survival (PFS) were 17.6 and 14.96 months, respectively. Patients with ORR and SD had a significantly longer median OS (23.8 vs. 5.7 months,
= 0.0005) and PFS (19.8 vs. 3.5 months,
< 0.001) compared to patients who did not respond to AZA. In univariate analysis, only an unfavorable cytogenetic group was a prognostic factor of a lower response rate (
= 0.03). In a multivariate model, older age (
= 0.047), higher IPSS (International Prognostic Scoring System) risk (
= 0.014), and higher IPSS-R cytogenetic risk (
= 0.004) were independent factors of shorter OS. Independent prognostic factors for shorter PFS were age (
= 0.001), IPSS risk (
= 0.02), IPSS cytogenetic risk (
= 0.002), and serum ferritin level (
= 0.008). The safety profile of AZA was predictable and consistent with previous studies. In conclusion, our study confirms the efficacy and safety of AZA in a real-world population and identifies potential biomarkers for response and survival.
Introduction
Patients with hematological malignancies (HM) require intensive chemotherapy with curative intent, especially in case of AML that results in more frequent admissions to Intensive Care ...Units (ICU). Due to our knowledge, this study is the first multicenter retrospective analysis in Polish population.
Methods
A total of 200 patients with HM hospitalized in 4 Polish hematological centers. Data concerning clinical indices and outcomes during admission and ICU stay were collected retrospectively.
Results
The most common hematological malignancy was acute leukemia (55%). The main cause of ICU admission was respiratory failure (88.5%), often accompanied by sepsis (58.5%) and acute renal failure (51.5%). In patients with hematological malignancies, the following factors were associated with ICU mortality: prolonged ICU stay
(odd ratio OR = 6.98, 95% confidence interval CI: 1.38-35.33,
χ
2
= 5.61,
p
= 0.02), the presence of acute respiratory failure (odd ratio OR = 5.35, 95% confidence interval CI: 1.01–28.46, χ
2
= 3.93,
p
= 0.04), and the need for renal replacement therapy (odd ratio OR = 8.75, 95% confidence interval CI: 1.23–62.11, χ
2
= 4.78,
p
= 0.03). There were following associations with in-hospital mortality in patients with hematological malignancies: prolonged ICU stay (odd ratio OR = 10.12, 95% confidence interval CI: 1.85–55.37, χ
2
= 7.21,
p
= 0.008), the presence of acute respiratory failure (odd ratio OR =5.24, 95% confidence interval CI: 1.36–20.16, χ
2
= 5.87,
p
= 0.02), the need for catecholamine support (odd ratio OR =3.43, 95% confidence interval CI: 1.06–11.05, χ
2
= 4.32,
p
= 0.04), and renal replacement therapy (odd ratio OR =5.55, 95% confidence interval CI: 1.14–26.92, χ
2
= 4.59,
p
= 0.03).
Conclusions
We have demonstrated that ICU and in-hospital mortalities among patients with hematological malignancies are still poor, but easier access to the intensive care unit and close cooperation between hematologists and intensivists may improve outcomes. We have found that acute failure of key organs (acute respiratory failure, end-stage renal failure requires renal replacement therapy) and length of ICU stay (but probably no comorbidities and illness severity) may have impact on mortality (both ICU and in-hospital).
Resistance to glucocorticosteroids (GCs) is a major adverse prognostic factor in B-ALL, but the molecular mechanisms leading to GC resistance are not completely understood. Herein, we sought to ...elucidate the molecular background of GC resistance in B-ALL and characterize the therapeutic potential of targeted intervention in these mechanisms. Using exploratory bioinformatic approaches, we found that resistant cells exhibited significantly higher expression of MEK/ERK (MAPK) pathway components. We found that GC-resistant ALL cell lines had markedly higher baseline activity of MEK and small-molecule MEK1/2 inhibitor selumetinib increased GCs-induced cell death. MEK inhibitor similarly increased in vitro dexamethasone activity in primary ALL blasts from 19 of 22 tested patients. To further confirm these observations, we overexpressed a constitutively active MEK mutant in GC-sensitive cells and found that forced MEK activity induced resistance to dexamethasone. Since recent studies highlight the role GC-induced autophagy upstream of apoptotic cell death, we assessed LC3 processing, MDC staining and GFP-LC3 relocalization in cells incubated with either DEX, SEL or combination of drugs. Unlike either drug alone, only their combination markedly increased these markers of autophagy. These changes were associated with decreased mTOR activity and blocked 4E-BP1 phosphorylation. In cells with silenced beclin-1 (BCN1), required for autophagosome formation, the synergy of DEX and SEL was markedly reduced. Taken together, we show that MEK inhibitor selumetinib enhances dexamethasone toxicity in GC-resistant B-ALL cells. The underlying mechanism of this interaction involves inhibition of mTOR signaling pathway and modulation of autophagy markers, likely reflecting induction of this process and required for cell death. Thus, our data demonstrate that modulation of MEK/ERK pathway is an attractive therapeutic strategy overcoming GC resistance in B-ALL patients.
Lymph node microenvironment provides chronic lymphocytic leukaemia (CLL) cells with signals promoting their survival and granting resistance to chemotherapeutics. CLL cells overexpress PIM kinases, ...which regulate apoptosis, cell cycle and migration. We demonstrate that BCR crosslinking, CD40 stimulation, and coculture with stromal cells increases PIMs expression in CLL cells, indicating microenvironment‐dependent PIMs regulation. PIM1 and PIM2 expression at diagnosis was higher in patients with advanced disease (Binet C vs. Binet A/B) and in those, who progressed after first‐line treatment. In primary CLL cells, inhibition of PIM kinases with a pan‐PIM inhibitor, SEL24‐B489, decreased PIM‐specific substrate phosphorylation and induced dose‐dependent apoptosis in leukaemic, but not in normal B cells. Cytotoxicity of SEL24‐B489 was similar in TP53‐mutant and TP53 wild‐type cells. Finally, inhibition of PIM kinases decreased CXCR4‐mediated cell chemotaxis in two related mechanisms‐by decreasing CXCR4 phosphorylation and surface expression, and by limiting CXCR4‐triggered mTOR pathway activity. Importantly, PIM and mTOR inhibitors similarly impaired migration, indicating that CXCL12‐triggered mTOR is required for CLL cell chemotaxis. Given the microenvironment‐modulated PIM expression, their pro‐survival function and a role of PIMs in CXCR4‐induced migration, inhibition of these kinases might override microenvironmental protection and be an attractive therapeutic strategy in this disease.
Background
Patients with relapsed/refractory multiple myeloma (RRMM) have poor prognosis. Pomalidomide is an immunomodulatory compound that has demonstrated activity in MM patients with disease ...refractory to lenalidomide and bortezomib.
Objectives
Participants of clinical trials are highly selected populations; therefore, the aim of this study was to present observations from real practice that might provide important information for practitioners.
Patients and Methods
We analyzed retrospectively 50 patients treated with pomalidomide in 12 Polish sites between 2014 and 2017. Median age was 63 years, median time since diagnosis 4.5 years and median number of prior regimens 4.
Results
The overall response rate was 39.1%. Median progression‐free survival (PFS) and overall survival (OS) were 10.0 and 14.0 months, respectively. Previous treatment with immunomodulatory drugs, bortezomib or stem cell transplant had no impact on PFS and OS. Most frequent grade 3/4 treatment‐emergent adverse events were hematologic (neutropenia 24.0%, thrombocytopenia 10.0%, anemia 8.0%). Most common grade 3/4 non‐hematologic toxicities were respiratory tract infection (14.0%) and neuropathy (4.0%).
Conclusions
This real‐world data have confirmed that pomalidomide is an active drug in RRMM and support results of published clinical trials and other real‐world studies.
B‐cell precursor acute lymphoblastic leukemia (BCP‐ALL) is a genetically heterogeneous blood cancer characterized by abnormal expansion of immature B cells. Although intensive chemotherapy provides ...high cure rates in a majority of patients, subtypes harboring certain genetic lesions, such as MLL rearrangements or BCR‐ABL1 fusion, remain clinically challenging, necessitating a search for other therapeutic approaches. Herein, we aimed to validate antioxidant enzymes of the thioredoxin system as potential therapeutic targets in BCP‐ALL. We observed oxidative stress along with aberrant expression of the enzymes associated with the activity of thioredoxin antioxidant system in BCP‐ALL cells. Moreover, we found that auranofin and adenanthin, inhibitors of the thioredoxin system antioxidant enzymes, effectively kill BCP‐ALL cell lines and pediatric and adult BCP‐ALL primary cells, including primary cells cocultured with bone marrow‐derived stem cells. Furthermore, auranofin delayed the progression of leukemia in MLL‐rearranged patient‐derived xenograft model and prolonged the survival of leukemic NSG mice. Our results unveil the thioredoxin system as a novel target for BCP‐ALL therapy, and indicate that further studies assessing the anticancer efficacy of combinations of thioredoxin system inhibitors with conventional anti‐BCP‐ALL drugs should be continued.
In B‐cell precursor acute lymphoblastic leukemia (BCP‐ALL), we observed oxidative stress along with increased expression of the enzymes of the thioredoxin antioxidant system. Inhibition of these enzymes with auranofin and adenanthin triggered oxidative and endoplasmic reticulum stress and effectively killed BCP‐ALL cells in vitro and in vivo. Our results unveil thioredoxin system as a novel target for BCP‐ALL therapy.
The severe acute respiratory syndrome coronavirus (SARS-CoV-2) has become the cause of a worldwide pandemic, and its clinical infection course in patients with hematological malignancies may be ...severe.
We performed a retrospective study on 188 chronic lymphocytic leukemia patients (CLL) with COVID-19 infection.
At the time of infection 51 patients (27.1%) were treated with Bruton tyrosine kinase inhibitor (BTKi), 46 (24.5%) with anti-CD20 antibodies while 37 patients (19.7%) received venetoclax. In total, 111 patients (59.0%) required hospitalization and 50 patients (26.5%) died due to COVID-19. Patients with poor performance status (ECOG >1;
= 0.02), advanced age (>65 years;
= 0.04), low hemoglobin concentration (≤10 g/dl;
= 0.0001), low platelets (<100 × 109/L;
= 0.003), and elevated lactate dehydrogenase level (LDH;
= 0.014) had an increased risk of death due to COVID-19. Neither CLL treatment status (treatment naïve vs. treated) nor the type of CLL-directed treatment had impact on the SARS-CoV-2 related risk of death. The multivariate survival analysis showed that advanced age (
= 0.009) and low platelet count (
= 0.0001) were associated with significantly shorter patients' overall survival.
SARS-CoV-2 infection in CLL patients is associated with poor outcome regardless of administered CLL-directed treatment.
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