The most important European meeting of hematologists is held annually in June. Renowned experts will gather at the EHA Annual Congress to present and discuss current research data on various hematologic diseases. Recent results in leukemia, lymphoma, hemophilia, anemia, and thrombosis were discussed.
Primary mediastinal B-cell lymphoma (PMBCL) has a good prognosis when remission is achieved rapidly with dose-intensive immunochemotherapy. In these patients, mediastinal radiotherapy (RT) may consolidate response; however, it increases the risk of second malignancies and coronary or valvular heart disease. Therefore, we investigated whether sufferers who achieve a complete metabolic response (CMR) after immunochemotherapy could forgo RT [1]. 530 patients with newly diagnosed PMBCL were enrolled and initial rituximab and anthracycline therapy was selected according to local practice. CMR was defined as Deauville score 1 to 3 according to the Lugano classification after central review of positron emission computed tomography (PET/CT). The 268 patients who responded were randomized and assigned to the observation (OBS) or consolidation (RT) group. The primary endpoint was progression-free survival (PFS).
An interim analysis after a median follow-up of 30 months showed a much lower number of observed events than expected, so the independent data monitoring committee recommended that the size or duration of the study not be increased. Analysis of the primary end point was performed according to the IDMC recommendation, with ≥80% of patients having a follow-up of at least 30 months. PFS 30 months after randomization was 98.5% in the RT group and 96.2% in the OBS arm. The estimated relative effect of radiotherapy versus observation in terms of hazard ratio (HR) was 0.47 (0.12-1.88) without adjustments and 0.68 (0.16-2.91) after stratification for variables. At 30 months, the absolute risk reduction by RT was 2.3% without adjustment and 1.2% after adjustment. The 5-year overall survival rate was 99% in both groups. To date, three grade 3-4 cardiac events and three second cancers have been recorded – all in patients randomized to radiation.
This is the largest prospective study of PMBCL ever conducted. Although the event rate did not reach the expected level and a longer follow-up period is needed to properly evaluate late toxicities, the results provide solid evidence for not using RT in patients who achieve CMR after immunochemotherapy.
Age-related variations of hematopoietic stem cells.
Examination of complete blood counts of large cohorts of healthy individuals of different ages reveals a large interindividual heterogeneity across all age decimals as well as specific age-related patterns, such as the development of macrocytic anemia with high RDW and a decrease in absolute lymphocyte count. The mechanisms underlying these variations are unclear. Therefore, a study aimed to deepen the understanding of natural and age-related variations [2]. For this, cRNAseq was performed on CD34+ circulating HSPCs from fresh samples of 99 healthy individuals aged 25 to 95 years. All sample donors were considered healthy, their CBC levels were within the normal range, and ARCH-defining mutations were not known. Longitudinal CBCs were collected from all individuals up to 5 years before sampling and deep targeted somatic mutation analysis was performed to identify cases of CH. After quality control and filtering, 360,000 single cell profiles remained from which a model of circulating HSPCs could be constructed.
The size of the cohort allowed characterization of rare populations of HSPCs that could not previously be studied in depth. These included circulating HLF/AVP-positive HSCs known to have extensive self-renewal capacity and a common NK/T/DC progenitor that does not decrease with age. Interindividual heterogeneity in the frequency of specific cellular states was strongly correlated with certain blood indices, particularly the association of CLP frequency with lymphocytes and of MEP frequency with hematocrit. Interestingly, low CLP frequencies, high RDW, and the presence of CH were all individually associated. Composition-controlled analysis of interindividual transcriptional variation in HSPCs revealed a lamin A (LMNA) signature that was also correlated with CH and a reduction in CLP abundance, as well as an age-correlated S-phase signature observed in late MEP progression. Divergent synchronization in closing stem cell programs and opening erythroid programs in MEP differentiation was associated with both erythrocytes and MCV, such that subjects who closed their stem cell program too early had higher MCV and lower erythrocyte values and vice versa.
Metabolic plasticity is weak point in leukemia
T-cell acute lymphoblastic leukemia (T-ALL/T-LL) is a class of highly aggressive cancers in children and young adults characterized by aggressive behavior and poor clinical response, especially in refractory and relapsed (R/R) cases. As in many cancers, genetic lesions that result in abnormal PI3K signaling (PI3KSALT) are common in T-ALL and lead to unfavorable outcomes ranging from limited response to therapy to early relapse and poor survival. The aim of one study was to explore the metabolic plasticity of PI3K-driven leukemia and to decipher targets suitable for novel strategies to improve the treatment and outcomes of this aggressive disease [3].
Patients’ primary samples were analyzed by pan-exome sequencing, arrayCGH, MLPA, and RNA sequencing. Patient-derived xenografts (PDX) were used for in vivo experiments. PI3K signaling activity, glucose consumption, and cell survival were evaluated by flow cytometry cytometry.
PI3KSALT patients responded poorly to corticosteroids, had shorter overall survival (5y-OS: 58% vs. 74%, p=0.007) and shorter event-free survival (5y-EFS: 49% vs. 65%, p=0.008), and a higher incidence of relapse (5y-CIR: 39% vs. 27%, p=0.01). PI3KSALT define a subclass of aggressive T-ALL with a poor prognosis, so innovative therapies for these patients are urgently needed.
Primary samples and PDX of PI3KSALT leukemia exhibit a hyperglycolytic profile. PI3KSALT T-ALL cell lines mimic this glucose addiction. Surprisingly, the cell lines cannot survive glucose limitation, whereas PI3KSALT-PDX tolerate this starvation. This highlights their ability to switch their metabolism to adapt to a nutrient-poor microenvironment. PI3KSALT PDX were shown to exhibit unique metabolic plasticity in starvation. These blasts use glutaminolysis to cope with glucose limitation and maintain the TCA cycle, whereas wild-type PI3KS do not. Pharmaceutical inhibition of PI3KS-mTOR metabolism and glutamine metabolism resulted in marked cytotoxicity ex vivo. Therefore, a strategy targeting mTOR and glutamine was proposed. Erwinase, an L-asparaginase with glutaminase activity, synergizes efficiently with Torisel and shows tumor eradication and prolonged survival in vivo.
Infections in CLL
Infections are the biggest problem for patients with chronic lymphocytic leukemia (CLL). Severe infections (1-month mortality rate: 10%) occur more frequently than progression to CLL treatment. Therefore, the machine learning-based CLL Treatment Infection Model (CLL-TIM) was developed to identify newly diagnosed patients at high risk for severe infections and/or in need of early treatment [4]. The included CLL patients were prescreened by CLL-TIM. CLL-TIM assessed risk using +70 variables. Patients were classified as high or low risk for the combined endpoint of severe infection and/or CLL treatment. The algorithm provided a confidence estimate (low/high), resulting in four prediction groups: (1) high risk, high confidence; (2) high risk, low confidence; (3) low risk, low confidence; and (4) low risk, high confidence. Outcome in terms of infection (all grades, ≥grade 3, +/- COVID-19), CLL treatment, or death was recorded.
Of the 118 patients with available data, 12 (10%), 8 (7%), 62 (53%), and 36 (31%) were classified as high-risk and categorized as groups 1-4, respectively. High risk was more common in male patients, patients without IGHV mutation, patients with del(17p), and patients with Binet stage B/C. The high-risk group had lower hemoglobin, lower platelet count, and higher leukocyte count compared to the low-risk patients. For the combined outcome of infection (any grade), CLL treatment, or death within 1 year, the hazard ratio was 2.3 for the high-risk, high-confidence group compared with the low-risk, high-confidence group. Twenty-nine of the 56 infections were classified as COVID-related. Restricting the analysis to infections ≥ grade 3 and/or to non-COVID infections, the hazard ratios for the high-risk, high-confidence group compared with the low-risk group increased to 8.62 and 25.0, respectively, compared with the low-risk, high-confidence group.
This is the first prospective clinical validation of a machine learning-based predictive model in hematology. CLL-TIM performed well during COVID, although it was trained before the pandemic. Performance was improved when the outcome was restricted to ≥grade 3, non-COVID-19 infections. Thus, the robustness of CLL-TIM has been demonstrated in various clinical settings.
Prognostic factors in Hodgkin’s lymphoma
Hodgkin’s lymphoma (HL) is a highly curable malignant tumor. Risk-adapted treatment for children with HL aims to maximize survival while minimizing toxicity. The aim of the study was to investigate the outcomes and prognostic features of Egyptian pediatric patients with classic HL [5]. All newly diagnosed cases of classic HL (n=69) treated between January 2016 and December 2018 were included in this study.
18% of patients had an elevated ESR (>50), 42% had more than three affected lymph node groups, 18.8% had extensive disease, 52.2% were at an advanced stage, and 34% had B symptoms. Age older than 15 years, B symptoms, more than three affected lymph node groups, extra-nodal involvement, and advanced stages significantly affected survival. There was no statistically significant difference between patients who received combined modality therapy (CMT) and those who received chemotherapy alone (3-year OS and EFS were 95.5% and 87.6% versus 89.9% and 83.3%, respectively). Rapid early response (RER) is one of the most important prognostic factors. There was no statistically significant difference in survival between patients with negative PET-CT who received CMT and those who received chemotherapy alone. At the end of the study, OS and EFS at three years for the entire group were 91.9% and 83.6%, respectively.
The results indicate that treatment with risk- and response-adaptive therapy should be the standard of care for pediatric patients with HL. Omission of radiotherapy in patients with RER can be done safely without compromising treatment outcomes.
Congress: 28th Annual Congress of the European Hematology Association (EHA) 2023
Literature:
- Martelli M, Ceriani L, Zucca E, et al: Omission of radiotherapy in primary mediastial B-Cell Lymphoma patients following complete metabolic response to standard immunochemotherapy: results of the IELSG37 randomised trial. HemaSphere 2023; 7(S3): 5-7.
- Furer N, Rappoport N, Tanay A, Shlush L: Natural and age-relates variation in circulating human hematopoietic stem cells. HemaSphere 2023; 7(S3): 11-13.
- Andrieu G, Simonin M, Cabannes-Hamy A, et al: Metabolic plasticity reveals a targetable vulnerability in leukemia. HemaSphere 2023; 7(S3): 18-19.
- Niemann C, Levin MD, Österborg A et al. The CLL treatment infection model – clinical prospeltive validation a spart of the prevent-acall trial. HemaSphere 2023; 7(S3): 1126-1127.
- Ali N, Mansour M, Khalil E, Ebeid E: Outcome and prognostic factors of mediatric patients with hodgkin lymphoma: a single-center experience. HemaSphere 2023; 7(S3): 4303.
InFo ONCOLOGY & HEMATOLOGY 2023; 11(4): 20-21 (published 9/13-23, ahead of print).