IACH NEWS OF THE WEEK: Highlights 29th European Hematology Association Hybrid Congress (EHA2024; 13 to 16 June, Madrid, Spain). 

Last weekend we were at EHA2024, a great event that brought together hematologists (trainees, juniors, and seniors) from different parts of the world, as well as nurses, research assistants, pharmaceutical companies and institutions/societies/associations related to our field, where we shared the advances in hematology in sunny Madrid.

Phase 3 study (IMROZ) results of isatuximab, bortezomib, lenalidomide, and dexamethasone (Isa-VRD) versus VRD for transplant-ineligible patients with newly diagnosed multiple myeloma (NDMM).  

In the IMROZ study (NCT03319667), Isa-VRD showed a significantly reduced risk of progression or death by 40.4% versus VRD while providing deep and sustained responses. 

446 patients (265 Isa-VRD versus 181 VRD) were randomized (3:2) and stratified by age, R-ISS stage, and Chinese versus non-Chinese, to receive Isa-VRD or VRD. The primary endpoint was progression-free survival (PFS). Patients’ characteristics were well balanced. Median treatment duration was 53.2 (Isa-VRD) versus 31.3 (VRD) months. At a median follow-up of 59.7 months, median PFS was not reached (Isa-VRD) versus 54.3 months (VRD) (hazard ratio [HR] 0.596 (98.5% confidence interval [CI]: 0.406–0.876), log-rank p=0.0005). PFS benefit was consistent across subgroups and maintained through the subsequent line of therapy (PFS2 HR 0.697; 95% CI: 0.51-0.952). Isa-VRD led to deep and sustained responses and was well-tolerated.

Glofitamab (CD20:CD3 bispecific antibody) plus gemcitabine and oxaliplatin (Glofit-GemOx) versus Rituximab(R)-GemOx for Relapsed/Refractory (R/R) Difusse Large B-Cell Lymphoma (DLBCL): results of a global randomized phase III trial (STARGLO).  

Glofit-GemOx demonstrated statistically significant and clinically meaningful benefit in overall survival (OS) over R-GemOx in autologous stem cell transplant (ASCT)-ineligible patients with R/R DLBCL (NCT04408638). We previously discussed this abstract on April 21, 2024.

274 patients with DLBCL were randomized 2:1 to receive either Glofit-GemOx (8 cycles, plus 4 cycles glofitamab monotherapy) or R-GemOx (8 cycles) and stratified by number of prior therapies (1 versus ≥2), and refractoriness to last treatment. Primary endpoint was OS. 

There was a significant OS benefit with Glofit-GemOx, a fixed-duration, off-the-shelf regimen (25.5 versus 12.9 months, hazard ratio 0.62, 95% confidence interval: 0.43–0.88; p=0.006) after a median follow-up of 20.7 months. Glofit-GemOx was well tolerated with a safety profile consistent with known risks of each individual agent. Comparable results were observed in clinically relevant stratified subgroups. 

First results of the APOLLO trial: a randomized phase III study to compare arsenic trioxide (ATO) plus all-trans retinoic acid (ATRA [arm A]) versus standard ATRA plus Idarubicin (AIDA regimen [arm B])  for patients with newly diagnosed, high-risk acute promyelocytic leukemia (HR-APL).  

First-line therapy with ATRA-ATO with two initial doses of idarubicin results in superior event-free survival (EFS) compared to conventional AIDA in patients with HR-APL (NCT0268840).

The APOLLO trial is an open label, randomized European intergroup trial. The study was prematurely discontinued in August 2022, due to slow recruitment during the COVID-19 pandemic, and expiration of study-drug reserved for the trial. Maintenance treatment and observational period are still ongoing. Overall, 131 patients are evaluable for outcome, 68 in Arm A and 63 in arm B.  A total of 120 out of 131 patients are currently evaluable for disease status following induction. After a median follow-up of 31 months (range 1.7 –71.5 months), the 2-year EFS was 89% and 72% in the ATRA-ATO and ATRA-CHT groups, respectively (p= 0.02). Molecular relapse was observed in 0 and 6 patients in the ATRA-ATO and AIDA arm, respectively. The 2-year OS rate was 93% versus 87% (p= 0.33) for ATRA-ATO versus AIDA, respectively. Analysis of safety is ongoing.

ENERGIZE: a global phase 3 double-blind, randomized, placebo-controlled study of mitapivat demonstrating efficacy and safety in adults with alpha- or beta-non-transfusion-dependent thalassemia (α- or β-NTDT).  

Mitapivat (a first-in-class, oral, allosteric activator of pyruvate kinase that increases ATP production) significantly increased hemoglobin (Hb) and improved fatigue versus placebo in ENERGIZE (NCT04770753).

Adults with α- or β-NTDT and baseline Hb ≤10 g/dL were randomized 2:1 to mitapivat 100 mg twice daily, or placebo for 24 weeks. 194 patients were randomized (mitapivat N=130; placebo N=64); 94.8% completed the 24-week trial. Baseline characteristics were similar between treatment arms. Mitapivat demonstrated statistically significant improvements (defined as ≥1.0 g/dL increase in average Hb concentration over weeks 12–24 compared with baseline; first endpoint) versus placebo for Hb response (42.3% versus 1.6%, respectively; 2-sided p<0.0001),  and weeks 12–24 average FACIT-Fatigue score (least-squares mean [LSM] difference, 95% confidence interval: 3.40 [1.21, 5.59]; 2-sided p<0.0026). Results favored mitapivat across all prespecified subgroups. Improvements in several markers of hemolysis and erythropoiesis were also observed, consistent with the proposed mechanism of mitapivat. The proportion of patients with treatment-emergent adverse events (TEAEs) of any grade was similar across treatment arms. The most common TEAEs (≥10% of pts) with mitapivat were headache, initial insomnia, nausea, and upper respiratory tract infection.

Asciminib (ASC) provides superior efficacy and excellent safety and tolerability versus tyrosine kinase inhibitors (TKI) in newly diagnosed chronic myeloid leukemia (ND-CML) in the pivotal ASC4FIRST study. 

ASC is the first BCR::ABL1 oral inhibitor to Specifically Target the ABL Myristoyl Pocket (STAMP). In this trial comparing ASC with investigator-selected TKIs and imatinib, ASC showed superior efficacy and a favorable safety profile in patients with newly diagnosed chronic-phase CML (NCT04971226).

In a phase 3 trial, patients with ND-CML were randomly assigned in a 1:1 ratio to receive either ASC (n=201) or an investigator-selected (IS) TKI (n=204), with randomization stratified by European Treatment and Outcome Study long-term survival score category and by IS TKI before randomization (including imatinib and second-generation TKIs). The primary endpoints were major molecular response (MMR) on the international scale at week 48, for comparisons between ASC and investigator-selected TKIs and between ASC and investigator-selected TKIs in the pre-randomization-selected (PRS) imatinib stratum. The median follow-up was 16.3 months in the ASC group and 15.7 months in the IS TKI group. The primary endpoint occurred in 67.7% of patients in the ASC group, as compared with 49.0% in the IS TKI group (difference: 18.9 percentage points; 95% confidence interval [CI], 9.6 to 28.2; adjusted two-sided p<0.001), and in 69.3% of patients in the ASC group as compared with 40.2% in the imatinib group within the imatinib stratum (difference: 29.6 percentage points; 95% CI, 16.9 to 42.2; adjusted two-sided p<0.001). The percentage of patients with an MMR at week 48 was 66.0% with ASC and 57.8% with TKIs in the second-generation TKI stratum (difference: 8.2 percentage points; 95% CI, −5.1 to 21.5). Adverse events of grade 3 or higher and events leading to discontinuation of the trial regimen were less frequent with ASC (38.0% and 4.5%, respectively) than with imatinib (44.4% and 11.1%) and second-generation TKIs (54.9% and 9.8%).

This study was published in the NEJM on May 31, 2024.

The landscape of TP53 mutations and their prognostic impact in Chronic Lymphocytic Leukemia (CLL). 

An analysis of 10051 patients (from 39 clinical trials and a single center) reveals key insights into the role of TP53 in CLL, especially on the prognostic significance of various mutations, co-occurrent risk factors and different therapies.

The authors identified 1824 TP53 alterations in 1368 patients. At a median observation time of 65.7 months, TP53 mutated patients had inferior progression free survival (PFS) (hazard ratio [HR] 2.1, p<0.001) and overall survival (OS) (HR 2.8, p<0.001) compared to wildtype. Gain/loss of function mutations, splice site or nonsense mutations as well as missense mutations with pathogenic prediction equally associated with shorter survival. In contrast, missense variants of unknown significance (n=26) and mutations leading to partial p53 activity (n=23) did not impair prognosis compared to TP53 wildtype. Minor TP53 mutations (variant allele fraction <10%) were associated with shorter OS (HR 1.8, p=0.02), but not PFS (HR 1.4, p=0.08).

The number of TP53 variants per patient (1, 2 or >2) affected survival only in absence of del(17p): here, compared to wildtype, patients with 2 TP53 mutations had an inferior outcome (PFS: HR 3,7, p<0.001, OS 4.4 p<0.001) than cases with one variant (HR 1.5, p<0.001, OS HR 1.6 p=0.001). Patients with del(17p) and unmutated TP53 also had a poor PFS, similar to deletion plus mutation (HR 1.0, p=1), but longer OS (HR 0.4, p<0.01).

TP53 mutations resulted in shorter PFS and OS in both modalities with higher HRs for chemoimmunotherapy (PFS: HR 2.6, p<0.001; OS: HR 3.0, p<0.001) than for targeted agents (PFS: HR 1.6, p=0.01; OS 2.5, p<0.01).

Acalabrutinib (acala) plus bendamustine and rituximab (BR) in untreated mantle cell lymphoma (MCL): results from the phase 3, double-blind, placebo-controlled ECHO trial. 

The addition of acala to BR (ABR) in the ECHO trial for elderly patients with untreated MCL demonstrated a statistically significant improvement in progression-free survival (PFS), which was more pronounced in patients not affected by COVID-19 (NCT02972840).  

Patients aged ≥65 years with previously untreated MCL and ECOG performance status ≤2 were randomly assigned 1:1 to receive ABR or placebo plus BR (PBR). In total, 598 patients were included in this analysis, with 299 patients in each arm. Patient characteristics were well balanced between arms. With a median 45 months of follow-up, 31.8% and 25.8% of patients continued treatment in the ABR and PBR arms, respectively. Overall response/complete response rates were 91.0%/66.6% and 88.0%/53.5% with ABR and PBR, respectively. Median PFS was 66.4 months with ABR and 49.6 months with PBR (hazard ratio [HR] 0.73; 95% confidence interval [CI] 0.57, 0.94; p=0.0160). Overall survival was not significantly different between the two arms (HR 0.86; 95% CI 0.65, 1.13; p=0.27) despite 51 patients crossing over to acala after experiencing progressive disease with PBR. COVID-19 deaths had a relevant impact on the study outcome.  With respect to safety, grade ≥3 adverse events (AEs)/grade ≥3 serious AEs were comparable and well balanced between both arms.

Guidelines session: EHA-ESMO Clinical Practice Guideline on primary central nervous system lymphoma (PCNSL). 

Here is a summary of the main diagnosis and first-line treatment recommendations  of newly diagnosed PCNSL. For the rest of the recommendations, see the link to the full free “special article”. 

The guideline recommendations were based on advice from the GRADE working group accompanied by the proper levels of evidence (LOE) and grades of recommendations (GOR: that incorporates both the quality of evidence as well as the clinical significance/magnitude of benefit or harm given by following the recommendation) according to the adapted grading system. 

Diagnosis: 
•    Contrast-enhanced cranial MRI is the recommended imaging modality for patients with PCNSL [II, A].  
•    Corticosteroid therapy before tissue biopsy should be avoided whenever clinically possible [IV, D]. In case of clinical deterioration, urgent biopsy should be carried out before the start of corticosteroids [IV, A]. 
•    Tumor resection is not recommended, except in carefully selected patients with rapidly increasing intracranial pressure who may benefit from surgical debulking at the time of tumor biopsy [IV, D]. 
•    Diagnosis is based on morphology and immunohistochemistry (minimum stain panel includes CD20, CD3, CD10, Bcl-6, Bcl-2, MUM1 and Ki-67 antibodies). Molecular analysis of Ig heavy and light chain loci can be used in selected cases where diagnosis is difficult [V, A]. 
•    When brain biopsy is contraindicated, central system fluid (CSF) examination is a valid option. Flow cytometry, MYD88 L265P mutation analysis and IL-10 levels in CSF samples may support a diagnosis of PCNSL [IV, B]. 
•    Suspicion of primary vitro-retinal lymphoma (PVRL) should be confirmed by conventional cytology examination of the vitreous humor and, when possible, by flow cytometry. Although not diagnostic, MYD88 L265P mutation and IL-10 levels may be assessed in the vitreous and aqueous humors as indicators of ocular lymphoma [III, A]. 

Treatment (see Figure 2 of the full article): 
•    When a prospective trial is not available, induction chemotherapy (ChT) including high-dose methotrexate (HD-MTX) is recommended at a minimum dose of 3 g/m2 delivered in a 3-hour infusion [I, A]. 
•    Combinations of HD-MTX with other cytotoxic agents that cross the blood- brain barrier and have been tested in prospective (preferably randomized) trials are recommended (e.g. MATRix, R-MBVP, rituximab-HD-MTX- carmustine-etoposide-prednisone, R-MPV, R-MT) [I, A]. 
•    The benefit of adding rituximab to induction HD-MTX- based polyChT remains unclear. The balance between tolerability and efficacy should be discussed with patients and their carers [II, B]. 
•    Intrathecal ChT is not recommended in routine practice, except for patients with CSF dissemination who are unable to receive ChT including HD-MTX at 3 g/m2 or for patients with persistence of CSF or meningeal disease at the end of first-line treatment [III, D]. 
•    Intravitreal ChT is not recommended in routine practice, except for patients with persistent intraocular lymphoma at the end of first-line treatment [III, D]. 
•    High-dose chemotherapy and autologous stem cell transplantation  (HDC-ASCT) is recommended as consolidation in fit patients with responsive or stable disease after suitable induction ChT [I, A]. 
•    Thiotepa-based ASCT conditioning regimens should be used. The dose of thiotepa combined with either busulfan or carmustine should be based on established protocols and informed by patient fitness and comorbidities [III, A]. 
•    Consolidation whole-brain radiotherapy (WBRT) at a dose of 36-40 Gy/20 fractions is recommended in young patients who are not suitable candidates for ASCT [I, A]. 
•    Watchful waiting can be considered for elderly patients in complete remission after induction with an established drug combination [II, B]. Maintenance with oral drugs, such as alkylating agents or immunomodulators such as lenalidomide can be considered on an individual basis [IV, C].
•    There is no established standard of care for patients unfit for HD-MTX-based ChT. Valid (but incompletely investigated) palliative options include upfront WBRT [III, B], corticosteroids, oral alkylating agents with or without rituximab, BTK inhibitors, and immunomodulators [V, C].