Highlights from EHA – Report

June 18, 2024

The 2024 European Hematology Association (EHA) Congress took place both virtually and in person in Madrid, Spain, from June 13-16. ALAN participated in both formats, engaging in the packed agenda filled with groundbreaking research findings. Here, we share key insights from selected clinical studies presented at the congress.

REPORT ON SESSIONS

Promising first results of the APOLLO trial in newly-diagnosed high-risk APL
  • Treatment with ATRA-ATO significantly improved event-free survival rates at both 2 years and 5 years compared with the standard ATRA-CHT treatment
  • The ATRA-ATO regimen was associated with fewer hematological side effects compared with ATRA-CHT

Acute promyelocytic leukemia (APL) is a rare subtype of acute myeloid leukemia (AML). For patients with low- or intermediate-risk APL, the standard treatment involves a combination of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO). However, patients with high-risk APL are typically treated with ATRA plus chemotherapy (ATRA-CHT). The combination of ATRA and ATO had not been studied for its effectiveness in high-risk patients with APL.

Uwe Platzbecker from University Hospital Leipzig, Germany, presented the first results of the Phase III APOLLO trial at EHA 2024. The objective of the trial was to compare the effectiveness of the ATRA-ATO regimen versus the standard treatment (ATRA-CHT) in patients with high-risk APL.

A total of 133 patients received treatment with either ATRA-ATO or ATRA-CHT:

  • ATRA-ATO group: Patients received two doses of idarubicin (12 mg/m2) on Days 1 and 3, plus ATO (0.15 mg/kg) and ATRA (45 mg/m2) daily until they achieved complete response. Consolidation therapy (given after initial chemotherapy to kill the remaining cancer cells) included four courses of ATO 5 days/week, 4 weeks on 4 weeks off, for a total of four courses, in parallel with ATRA 2 weeks on and 2 weeks off, for a total of seven our courses.
  • ATRA-CHT group: Patients received the standard AIDA (ATRA + idarubicin) induction followed by 3 cycles of CHT-based consolidation as well as maintenance.

The study met its primary end point, showing a 2-year event-free survival (EFS) rate of 88% in the ATRA-ATO group compared with 70% in the ATRA-CHT group. This trend continued with a 5-year EFS rate of 87% for the ATRA-ATO group versus 55% for the ATRA-CHT group.

The 2-year overall survival rates were 93% with ATRA-ATO and 87% with ATRA-CHT. The 5-year overall survival rate was also higher for patients receiving the ATRA-ATO regimen, at 93%, compared with 82% for those on ATRA-CHT. Complete and partial response rates were slightly higher in the ATRA-ATO group (93%) compared with the ATRA-CHT group (90%). However, Dr Platzbecker highlighted that the differences in overall survival and response rates were not significant enough to definitively confirm the effectiveness of the ATRA-ATO regimen.

In terms of safety, hematological side effects were significantly lower in the ATRA-ATO group compared to the ATRA-CHT group. The occurrence of thrombocytopenia (low platelet levels) was 0% in the ATRA-ATO group versus 56% in the ATRA-CHT group during the first consolidation cycle, and 0% versus 52% during the second consolidation cycle. Similarly, the occurrence of neutropenia (low neutrophil levels) was 1% in the ATRA-ATO group versus 19% in the ATRA-CHT group during the first consolidation cycle, and 1% versus 52% during the second consolidation cycle.

Other reported side-effects between the two treatment groups included a slightly higher rate of corrected QT prolongation (a test to measure the heart’s electrical activity) with ATRA-ATO at 4.4% compared with 0% in the ATRA-CHT group. Liver-related side effects and differentiation syndrome (a severe reaction to cancer treatment) were similar between both groups. Dr. Platzbecker expressed optimism about the potential to change future clinical practice in managing high-risk APL as he concluded his presentation.

What does this mean for patients?

The APOLLO trial showed that treatment with ATRA-ATO significantly improved EFS rates at both 2 years and 5 years compared with the standard ATRA-CHT treatment in patients with newly-diagnosed high-risk APL. Additionally, the ATRA-ATO regimen was associated with fewer hematological side effects, with substantially reduced rates of thrombocytopenia and neutropenia compared with ATRA-CHT. These results suggest that the ATRA-ATO regimen not only enhances survival outcomes compared with ATRA-CHT, but also offers a more tolerable safety profile, potentially leading to fewer side effects and a better quality of life during treatment. For patients, this could mean a more effective and more tolerable treatment option for managing high-risk APL. However, further analysis of the APOLLO trial is still needed to support the implementation of ATRA-ATO as the new standard of care in patients with high-risk APL.

Early developments and successes in AML clinical trials with novel menin inhibitors
  • Despite the availability of targeted treatments, the overall outcomes for patients with R/R AML remain very poor
  • Menin inhibitors are new treatments that are currently in clinical development and show promise for R/R AML with KMT2A rearrangements or NPM1 mutations

Several presentations were given on a new group of drugs called menin inhibitors. These are targeted drugs that come in the form of oral pills. Menin inhibitors are in development for AML, specifically for patients with AML who show changes in their genes KMT2A and NPM1. Up to 35% of patients with AML have these changes in their genes. These patients experience known side effects and develop changes in the genes (mutation) that make treatment less effective, also known as resistance mutations.

Naval Daver from the University of Texas, MD Anderson Cancer Center discussed the results of first-in-human Phase I/II study of menin inhibitor DSP-5336 in 57 patients with relapsed/refractory (R/R) AML. Phase I was to check the safety, tolerability, and determine the dose for Phase II. Phase II looked at the activity of the drug. The Phase I dose escalation part of the study had two parallel arms:

  • Arm A was given DSP-5336 without antifungal (azole) therapy
  • Arm B was given DSP-5336 with antifungal therapy

The study tested different doses of DSP-5336 and the positive news is that no side effects such as dose-limiting toxicity, deaths, or cardiac toxicity were seen at any of the dose levels. Among the treatment-related side effects that occurred, most were mild with vomiting (17.5%) and nausea (12.3%) being the most common. Importantly, these side effects did not lead to any patients stopping treatment with DSP-5336. Differentiation syndrome, which is a severe reaction to cancer drug, occurred in 3 (5.7%) patients, however, did not result in deaths or patients stopping treatment. Two patients had severe Q3 prolongation (measure of electrical activity of heart), and in one of them, it was thought to be related to DSP-5336. The amount of drug remaining in the bloodstream after previous doses and the impact of antifungal therapy on DSP-5336 was minimal. Of the 57 patients, 21 were treated at the therapeutic dose DSP-5336 140 mg twice daily. Among them 57% of patients, achieved treatment responses. Patients responded to treatment within an average duration of 1.4 months. A study to identify the recommended dose of DSP-5336 for the Phase II part of the study is on-going and evaluation of DSP-5336 in combination with other standard AML treatment is being planned.

Andrew Wei from Peter MacCallum Cancer Centre, Royal Melbourne Hospital discussed the results of a Phase 1b dose finding study of menin inhibitor bleximenib (JNJ-75276617). The study investigated the effectiveness of bleximenib in combination with venetoclax (Ven) and azacitidine (Aza) in patients with R/R AML with KMT2Ar and mutated NMP1. Oral bleximenib was given at different doses (15, 30, 50, 80, 100 mg twice a day) starting at Day 4 continuously in combination with Ven (28-day cycle) + Aza (7 days/cycle).

The efficacy of bleximenib was evaluated in 34 patients who received bleximenib dose levels ≥50 mg twice a day. A reduction of more than 50% in bone marrow blast or cancer cells was seen in 93% of patients. Overall treatment response was seen in 79% of patients. 41% of patients achieved either a complete response (CR) or CR with partial hematological recovery (CRh) or CR with incomplete recovery (CRi). The first treatment response was seen on Day 21. Patients who hadn’t received Ven previously achieved a higher response rate of 94% compared with 65% of patients who had been treated with Ven before. Twenty-six percent of patients stopped treatment after receiving stem cell transplantation from a matched donor (allogeneic). A combination of bleximenib with other therapies in patients with newly diagnosed AML is currently underway.

Safety was evaluated in 60 patients. Differentiation syndrome was seen in 3% of patients at 50 mg and 100 mg. No corrected QT prolongation was reported. Tumor lysis syndrome (cancer cells break down rapidly releasing their content in the bloodstream) was not reported except in one patient during Ven-Aza dosing and before bleximenib was administered.

Other menin-inhibitors like balomenib are also in development as presented by Erin Hertlein from the University of Cincinnati Cancer Center. Dr Hertlein explained that their study was developing balomenib to limit the side effects and also to reduce the likelihood of developing resistance mutations. The early pre-clinical work shows that balomenib is effective in controlling mutations and preventing side effects. Further work is underway to understand the effects of balomenib in healthy human volunteers.

 What does this mean for patients?

Menin inhibitors are new and promising drugs currently in development. Menin inhibitors may offer the hope of potential new treatment for patients with specific genetic changes such as KMT2A rearrangement and NPM1 mutations. These mutations are present in nearly 35% of patients with AML, making them particularly sensitive to menin inhibitors. Menin inhibitors have been tested in Phase I and II clinical trials, both alone and in combination with other drugs showing promising results in terms of response rates and safety in heavily pre-treated patients. This development can potentially lead to better treatment outcomes for patients who face poor outcomes due to changes in specific genes.

Latest findings from PhALLCON trial comparing ponatinib vs imatinib in the treatment of Ph+ ALL
  • Tyrosine kinase inhibitors like ponatinib have shown encouraging results in patients with Ph+ ALL; however, it is unclear if ponatinib promotes longer survival, deeper responses, and reduces the need for transplant
  • Ponatinib leads to higher rates of MRD negativity, longer PFS, and reduced need for allogeneic HSCT

The standard of care for patients with recently diagnosed Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL) is tyrosine kinase inhibitors (TKIs) in combination with chemotherapy or steroids. Ponatinib and imatinib are both TKIs. PhALLCON was the first study to compare two different TKI’s in patients with newly diagnosed (ND) Ph+ ALL. Results were better with ponatinib which led to its US Food and Drug Administration approval in March 2024.

While ponatinib achieves better results than imatinib, it is unclear if it can achieve deeper responses and longer survival rates. Josep Ribera from the Josep Carreras Leukemia Research Institute, Spain presented a detailed assessment of deeper responses with ponatinib. The updated findings from the PhALLCON trial looked at measurable residual disease (MRD) responses.

Adult patients with newly diagnosed Ph+ ALL with the following criteria were included in the study:

  • Eastern Co-operative Oncology Group performance status of 0–2
  • Confirmed BCR::ABL1 dominant variant p190 or p210

Overall, 154 patients received ponatinib 30 mg once daily plus reduced intensity chemotherapy and 78 patients received imatinib 600 mg once daily plus reduced intensity chemotherapy.

The primary endpoint of the trial was MRD negativity, which refers to no cancer cells remaining after treatment. A higher number of patients treated with ponatinib achieved MRD negativity, measured at any time during the study period compared with those treated with imatinib (68% vs 50%). The trend of MRD negativity rates was also higher in ponatinib vs imatinib group for the following patient subgroups:

  • Aged younger than 65 years (69% vs 49%)
  • Aged older than 65 years (62% vs 53%)
  • With BCR::ABL1 p190 (70% vs 57%)
  • With BCR::ABL1 p210 (60% vs 36%)

However, Dr Ribera highlighted that the results for these subgroups were not significant enough to confirm the effectiveness of ponatinib.

Progression-free survival or PFS was defined as the time from receiving treatment to disease progression, relapse, or death due to any cause. The average duration of PFS was nearly three times longer at 20.2 months with ponatinib vs 7.5 months with imatinib. A similar trend was observed across age and dominant BCR::ABL1 variants subgroups.

The need to receive hematopoietic stem cell transplantation (HSCT) from a matched donor (allogeneic HSCT) was reduced in patients receiving ponatinib compared with those receiving imatinib (35% vs 47%). This also applied to patients who achieved MRD negativity and received ponatinib versus those with MRD negativity receiving imatinib (32% vs 56%). It is worth noting that the study investigator made the decision regarding who received allogeneic HSCT. In patients who did not receive a HSCT, the average exposure to treatment in the ponatinib group was more than two-times longer than in the imatinib group (12.8 months vs 5.1 months). In terms of safety, the treatment-related side effects were similar across both ponatinib and imatinib groups, however, dose interruptions were more frequent with ponatinib (73% vs 41%).

What does this mean for patients?

Ponatinib has emerged as a significant treatment option for patients with ND Ph+ ALL, since its approval in March 2024. This drug, used in combination with chemotherapy, has demonstrated superior outcomes compared with imatinib. Ponatinib led to a higher rate of patients achieving no detectable cancer cells (MRD negativity) and nearly tripled the average PFS duration (20.2 months versus 7.5 months). Fewer patients needed allogeneic HSCT with ponatinib. The side effects profile was similar across both ponatinib and imatinib groups. Overall, ponatinib, combined with reduced-intensity chemotherapy, offers better disease control and may reduce the need for transplants, making it a promising frontline treatment for Ph+ ALL.

Building immune function after CD7 CAR T-cell therapy in patients with refractory/relapsed acute T-ALL or LBL
  • CD19, a CAR T-cell therapy offers excellent efficacy and has no major impact on immune function
  • CD7, another CAR T-cell therapy also offers improved efficacy but it’s impact on immune function is not well understood
  • CD7 therapy shows a similar efficacy, safety profile and impact on immune function as CD19 with no increase in overall rate of infections

CAR T-cell therapy, also known as chimeric antigen receptor T-cell therapy, is a type of immunotherapy that can modify a patient’s own T cells to recognize and kill cancer cells. CD19 CAR T-cell therapy has an excellent efficacy and safety profile with no significant impact on immune function. Another CAR T-cell therapy called CD7, has also shown effectiveness in treating patients with relapsed/refractory (R/R) T-cell acute lymphoblastic leukemia/lymphoma (T-ALL/LBL). However, while the side effects of CD19 CAR T-cell therapy are well-documented, the impact of CD7 CAR T-cell therapy on immune function, particularly its effect on T cells, is uncertain.

Xian Zhang from the Hebei Yanda Lu Daopei Hospital, China presented the comparison of the effectiveness, safety, and impact of CD7 and CD19 therapy on immune function. The study included 120 patients who previously received CD7 or CD19 therapy. Patients in both groups were similar in age and gender with similar Eastern Co-operative Oncology Group performance status scores.

Complete response rates were high in CD7 as well as CD19 group (94.4% vs 98.3%). Similarly, measurable residual disease (MRD) negativity (no cancer cells remaining after treatment) with complete or partial treatment response rates were also higher in both CD7 and CD19 groups (94.4% vs 96.6%). Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) are known side effects of CAR T-cell therapy. CD7 resulted in mild to moderate CRS in 88% of patients while CD19 in 95% of patients. Mild to moderate ICANS were seen in 3.3% of patients receiving CD7 vs 0% in those receiving CD19. In the CD7 group, no deaths were observed within 30 days of treatment while one death was seen in the CD19 group due to infection and heart failure. Zhang further talked about the rate of infections after CD7 and CD19 therapy. Infections were seen in 36.7% of patients in the CD7 group compared with 28.3% in the CD19 group. Interestingly of all the infections, fungal infections were more common in patients treated with CD7 than with CD19 (10% vs 1.6%). Severe hematological side effects such as immune effect cell-associated hematotoxicity within 30 days of treatment were seen in 33.3% of patients in the CD7 group compared with 18.3% of patients in CD19 group. T-cells help your body fight against infections. Before patients received CD7 therapy, they had a low level of CD7 negative T-cells. After treatment with CD7, the level of non-treatment related CD7 negative T-cells increased significantly. This suggests that the immune function was restored after CD7 therapy. However, these results need further confirmation in studies with a larger number of patients and a longer period of follow-up.

 What does this mean for patients?

CD7 CAR T-cell therapy shows high response rates similar to CD19 therapy. Patients experienced known side effects of CAR T-cell therapy such as CRS and ICANS, which were mild to moderate and comparable across both CD7 and CD19. The rate of severe or life-threatening CRS or ICANS was low in both groups. Infection rates were similar in patients receiving CD7 and CD19 therapy. Non-treatment related CD7 negative T-cells increased significantly in patients receiving CD7 therapy suggesting immune function restoration. CD7 shows comparable effectiveness, and safety profile along with the ability to restore immune function making it another feasible CAR T-cell therapy option for patients with R/R T-ALL/LBL.

Hypomethylating agent as a combination therapy in the treatment of AML with FLT3 mutation: Latest development from EHA
  • FLT3 mutated AML is associated with poor outcomes, particularly in older patients
  • FLT3 inhibitors in combination with hypomethylating agents and venetoclax have shown improved outcomes
  • A fully oral treatment with decitabine/cedazuridine in combination with venetoclax and gilteritinib shows encouraging response rates in patients with newly diagnosed and R/R AML

For patients with acute myeloid leukemia (AML) who cannot receive intensive chemotherapy due to age, other health conditions, AML subtypes etc., the standard of care is hypomethylating agents (HMA) in combination with venetoclax (Ven). Changes in gene (mutated) FLT3 such as FLT3-ITD are common in AML and occur in nearly 20–25% of patients. FLT3 mutations are associated with poor treatment responses, particularly in older patients. The addition of agents that control FLT3 mutations to HMA plus Ven have shown encouraging results. Gilteritinib is a FLT3 inhibitor and decitabine/cedazuridine (DEC-C) is an oral, fixed dose formulation approved in Europe for treatment of AML.

Dr Alex Bataller from the MD Anderson Cancer Center, USA, presented the results of a Phase I/II study exploring the effectiveness and safety of a fully oral combination of DEC-C, Ven and gilteritinib. The study included 26 patients with newly diagnosed (ND) AML or relapsed/refractory (R/R) AML or high-risk myelodysplastic syndrome (MDS) with mutated FLT3. Patients received DEC-C 100 mg plus Ven 400 mg in combination with gilteritinib 80 or 120 mg.

Response rates to treatment were almost double in ND AML compared with R/R AML and MDS groups (86% vs 44%). In both groups, patients needed an average of one treatment cycle to achieve their first response. At the time of study presentation, treatment response in ND AML group were still being followed. Patients in the R/R AML and MDS group showed improvement with treatment for an average of 7.6 months. Despite continuing to achieve treatment response in the ND AML group, 43% of patients received stem cell transplantation from a matched donor (allogeneic transplantation) compared with 17% in R/R AML and MDS group. Survival outcomes could not be determined in the ND AML group as patients were still responding to treatment. In the R/R AML and MDS group, the average overall survival period was 6.8 months, event-free survival period was 3.7 months and relapse-free survival period was 7.6 months.

Severe side effects from DEC-C in combination with Ven and gilteritinib were seen in 58% of patients. Severe to life-threatening sepsis was the most common side effect seen in 38% of patients. Two patients died due to septic shock in the R/R AML and MDS group. The duration of blood count recovery was 38 days for platelets and 48 days for neutrophils after treatment Cycle 1. Bataller concluded by highlighting that DEC-C in combination with Ven and gilteritinib offers encouraging overall response rates and prolonged survival rates in patients with ND AML, R/R AML and MDS with FLT3 mutations. But he also pointed out that low blood cell counts and the time it takes to recover blood cell counts were the main problems restricting the use of this combination, requiring regular dose modifications.

What does this mean for patients?

This study explored a fully oral treatment combination for patients with ND AML, R/R AML or MDS with FLT3 mutations. DEC-C in combination with Ven and gilteritinib showed excellent response rates in both ND AML, and R/R AML and MDS groups. These responses were achieved in the first two cycles of treatment. The combination also showed prolonged survival outcomes in both groups. The side effects profile was acceptable for this population. This combination offers patients the ease of receiving an oral formulation and therefore, holds promise for patients with ND AML, R/R AML or MDS FLT3 mutations. However, low blood cell counts and delay in recovering blood cell count were the primary limitation of DEC-C, Ven and gilteritinib combination, requiring regular dose adjustments. The results of this study need to be further validated in a larger study with a greater number of patients and a longer follow-up period.

First-in-human study of CD123 NK cell engager – SAR443579 in the treatment of R/R AML
  • CD123 is associated with poor response rates in several blood cancers
  • SAR443579 is a NK cell engager that facilitates the activation of NK cells leading to death of cancer cells
  • Phase I part of a first-in-human study show manageable safety profile of SAR443579 up to dose level 6 mg/kg in patients with R/R AML

CD123 protein is often produced in abundance in cancer (leukemic) cells and is associated with poor treatment response in several blood cancers. SAR443579 is a natural killer (NK) cell engager that helps in the stimulation of NK cell leading to death of cancer cells.

Sylvian Garciaz from Aix-Marseille University, France, presented the findings of the first-in-human, Phase I part of the study investigating the safety and establishing the recommended dose of SAR443579 for the Phase II part. The Phase 1 or dose escalation part explored a range of dose levels from 0.01 to 6 mg/kg in multiple patient groups to check for any dose-limiting toxicity.

The study included 58 patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) and one patient with myelodysplastic syndrome (MDS). Patients were older than 12 years and confirmed positive for CD123. The maximum treatment response was seen at dose level 1 mg/kg. Complete or partial response to treatment was achieved by 33.3% of patients treated with 1 mg/kg of SAR443579. Patients needed an average number of 2 treatment cycles to achieve a response. The treatment response achieved lasted for an average of 7.9 weeks. Of the patients achieving a treatment response, 2 patients continued to receive treatment. Examination of the blood and bone marrow showed that the cancer (blast) cell count was reduced across all dose levels.

In terms of safety, dose-limiting toxicity in the form of severe cytokine release syndrome (CRS) was seen in one patient at dose level 0.75 mg/kg. In total, 98.3% of patients experienced treatment-related side effects. Serious treatment-related side effects were experienced by 59.3% of patients. Infusion-related reaction was the most common treatment-related side effect seen in 57.6% of patients. Infusion-related reactions were mild and manageable. Three patients developed mild CRS while one patient experienced severe CRS. No neurological side effects were seen. The US Food and Drug Administration has granted a fast-track status to SAR443579. This accelerates the development of SAR443579, ensuring that the drug becomes available to patients sooner.

What does this mean for patients?

SAR443579 shows a manageable safety profile up to a dose level of 6 mg/kg. The most common side effect was mild to moderate infusion-related reaction. Mild CRS was seen in 3 patients and severe CRS in 1 patient. No neurological side effects were seen in patients. SAR443579 also showed a good response rate at dose level 1 mg/kg. SAR443579 has received fast-track status by the US FDA. Fast Track status allows the drug to be developed faster. This means that SAR443579 can be made available to patients earlier. Phase II part of the study is currently underway and is looking into selection of the most effective dose of SAR443579.

Role of secondary type mutations in the prognosis of AML: Highlights from EHA
  • The ELN 2022 risk classification system helps clinicians predict the prospect of patients with AML
  • The impact of secondary type mutations in patients who are in the ELN favorable risk category is uncertain
  • Poor overall survival rates and reduced treatment responses are associated with secondary type of mutations in patients with AML favorable risk group

The European LeukemiaNet (ELN) 2022 risk classification system classifies patients with acute myeloid leukemia (AML) into 3 risk groups: favorable, intermediate, and adverse. Although this classification helps clinicians to understand the outlook of the disease, the impact of secondary changes in genes (mutations) in patients who are in the favorable risk category is not clearly understood. Dimitrios Kotsos from Erasmus MC, Netherlands, provided some insights on this topic at the EHA 2024 Congress.

The study looked at 549 patients with newly-diagnosed AML who were classified as favorable risk to investigate the potential impact of secondary type mutation (SMT). STMs were specified as having at least one mutation in the following genes:

  • SRSF2
  • SF3B1
  • U2AF1
  • ZRSR2
  • ASXL1
  • EZH2
  • BCOR
  • STAG2

STMs were found in 14.5% of patients. The proportion of male patients was higher (67.5% vs 49%) as was the average age (60 vs 52 years) in the STM group compared to no STM group.

Patients with STM had significantly lower complete remission (CR) and CR with incomplete count recovery (CRi) rates to induction therapy compared with patients without STMs (85% vs 93.8%). Patients in the STM group had significantly poorer overall survival than their counterpart in the no STM group (48.8% vs 68.7%). Overall survival was particularly poor for patients aged over 60 years with NPM1 mutation without FLT3-ITD and those with CEBPα_bZIP mutations in the STM group. The AML risk stratification should consider STM particularly, in patients with NPM1 mutated without FLT3-ITD and CEBPα_bZIP mutations. The role of measurable residual disease (MRD) in STMs may provide further knowledge of how STMs affect the outlook of patients with AML favorable disease characteristics.

 What does this mean for patients?

Patients with ELN 2022 favorable risk with the presence of STM showed significantly lower rates of response to the induction therapy compared to those without STM. The overall survival was also significantly poor in the STM group compared with no STM group. The trend in poor overall survival was also prominent in patients aged older than 60 years with NPM1 mutations without FLT3-ITD and those with CEBPα_bZIP mutations in the STM group. Therefore, AML risk stratification should consider STM particularly, in patients with NPM1 mutations without FLT3-ITD and CEBPα_bZIP mutations. Further knowledge on the impact of STM may be gained by understanding the role of MRD in STM which may help to improve treatment approaches in these patients.

Initial results of ALLTogether1 DS trial in the treatment of Down Syndrome B-cell ALL
  •  Children with DS-ALL have higher rates of treatment-related deaths and poor survival
  • A Phase II study looking into replacing consolidation chemotherapy with blinatumomab in patients with DS-ALL shows excellent MRD negativity and reduced treatment related deaths

The risk of acute lymphoblastic leukemia (ALL) is highly increased in patients with Down Syndrome accounting for 2–3% of cases in children. Children with Down Syndrome ALL (DS-ALL) experience higher rates of treatment-related deaths and poor survival. A new innovative approach of replacing consolidation chemotherapy with blinatumomab in these patients is currently being studied in a Phase II ALLTogether1 DS (A2G DS) study. Blinatumomab is a CD3-/CD19-directed bispecific T-cell engager that has shown promising results in frontline setting for both children and adult patients with relapsed/refractory B cell ALL (B-ALL).

Sujith Samarasinghe from the Great Ormond Hospital for Children, UK, discussed the initial findings. The study included 33 patients aged between 1–25 years with Down Syndrome and B-ALL. Patients received induction therapy (initial therapy to kill the cancer cells) with prednisolone, asparaginase, and vincristine. At the end of the induction therapy, patients who had measurable residual disease (MRD) positive status received consolidation therapy (therapy to kill remaining cancer cells). Patients in the experimental arm received blinatumomab during consolidation Cycles 1 and 2, while patients in the non-experimental arm received standard of care. The primary objective was to find the proportion of patients with MRD negativity at the end of the first consolidation cycle with blinatumomab.

Two of the 33 patients stopped treatment at consolidation Cycle 1 and three at Cycle 2 due to neurological side effects and infection. The primary objective of the study was met, with 91% of patients with MRD negativity at the end of consolidation Cycle 1. Patients were followed up for an average of 15 months at the time of study presentation. During this period there were no deaths, secondary cancers, or relapse. Results from the study were compared with a previous study – UKALL. The comparison showed that serious side effects was much lower in this trial compared with UKALL (39.4% vs 77.3%). However, the occurrence of seizures was higher in this trial compared with UKALL study (18.2% vs 4.5%). Further exploration of seizures showed that the rate was significantly higher in children older than 10 years vs those younger than 10 years (56.6% vs 4.2%). Although children received preventative treatment with levetiracetam, seizures still happened. Children experienced seizures more often in consolidation Cycle 1. Based on this information, the investigators changed the seizure prevention treatment by starting it one week before administering blinatumomab rather than receiving it with blinatumomab. Following the updated seizure prevention treatment, the severity of seizure was reduced in patients who experienced them. Samarasinghe concluded the presentation by stating that blinatumomab has shown impressive activity with over 90% rate of MRD negativity.

 What does this mean for patients?

Children with DS-ALL have worse survival outcomes and higher rates of treatment-related deaths. This trial explored a new way of replacing consolidation chemotherapy with blinatumomab to establish if blinatumomab provided greater MRD clearance and reduced treatment-related deaths. Remarkably 91% of patients had MRD negativity after blinatumomab Cycle 1. Side effects, particularly severe to life-threatening, were also lower in this trial compared with a previous study. Children older than 10 years experienced more episodes of seizures. Blinatumomab as replacement for standard consolidation chemotherapy may offer a new treatment option for patients with DS-ALL improving survival and reducing treatment-related deaths. However, to determine whether the improved results persist over time and if the seizure prevention treatment is beneficial, a larger study involving more patients is needed.

AND MORE… 

Harmony project

GENOMIC LANDSCAPE OF ADULT AML WITH T(8;21)(Q22;Q22.1) AND PROGNOSTIC IMPLICATIONS – RESULTS FROM THE HARMONY PLATFORM

OUTCOME PREDICTORS FOR PATIENTS AGED 55 YEARS AND OLDER WITH ACUTE LYMPHOBLASTIC LEUKEMIA: A RETROSPECTIVE STUDY FROM THE HARMONY BIG DATA PLATFORM

SEX DISPARITIES IN GENETIC LANDSCAPE OF ACUTE MYELOID LEUKEMIA: A COMPREHENSIVE ANALYSIS USING THE HARMONY CONSORTIUM DATASET

COMPARISON OF TWO HIERARCHICAL DIRICHLET MIXTURE MODELS FOR THE GENOMIC STRATIFICATION OF PATIENTS WITH ACUTE MYELOID LEUKEMIA

Other data published

CTX-001, A FIRST IN CLASS AUTOLOGOUS ANTI-IL-1RAP CAR T-CELL THERAPY FOR THE TREATMENT OF RELAPSED/REFRACTORY AML

OVERALL SURVIVAL IN NEWLY DIAGNOSED ACUTE MYELOID LEUKEMIA PATIENTS WITH MIDH1 OR MIDH2 IN THE US, FROM AN INTERNATIONAL REAL-WORLD DATABASE (REAL-IDH)

TREATMENT PATTERNS AND CLINICAL OUTCOMES IN NEWLY DIAGNOSED ACUTE MYELOID LEUKEMIA WITH AND WITHOUT MIDH1/MIDH2 TREATED WITHOUT INTENSIVE CHEMOTHERAPY: REAL-IDH A STUDY OF REALWORLD DATABASES

MUTATIONAL PATTERNS AND CLONAL HIERARCHY IN 430 PATIENTSWITH IDH1 MUTATED AML INDICATE PRACTICAL IMPLICATIONS FOR MOLECULAR TESTING AND TARGETED TREATMENT

QUANTUM-FIRST: EFFICACY BY AGE IN NEWLY DIAGNOSED (ND) PATIENTS (PT) WITH FMS-LIKE TYROSINE KINASE 3-INTERNAL TANDEM DUPLICATION–POSITIVE (FLT3-ITD+) ACUTE MYELOID LEUKEMIA (AML)

QUANTUM-FIRST: PATIENT-REPORTED OUTCOMES (PROS) IN NEWLY DIAGNOSED (ND) FLT3-ITD+ ACUTE MYELOID LEUKEMIA (AML) PATIENTS(PTS) RECEIVING STANDARD CHEMOTHERAPY (CTX) PLUS QUIZARTINIB (Q) OR PLACEBO (P)

QUANTUM-FIRST: SAFETY BY TREATMENT (TX) PHASE AND BY AGE IN NEWLY DIAGNOSED (ND) PATIENTS WITH FMS-LIKE TYROSINE KINASE 3–INTERNAL TANDEM DUPLICATION (FLT3-ITD) POSITIVE ACUTE MYELOID LEUKEMIA (AML)

VICEROY: A PHASE I/II STUDY OF GILTERITINIB, VENETOCLAX AND AZACITIDINE COMBINATION IN PATIENTS WITH NEWLY DIAGNOSED FLT3-MUTATED ACUTE MYELOID LEUKEMIA INELIGIBLE FOR INTENSIVE INDUCTION CHEMOTHERAPY

GILTERITINIB VERSUS SALVAGE CHEMOTHERAPY IN MAINLY ASIAN PATIENTS WITH RELAPSED/REFRACTORY FLT3-MUTATED ACUTE MYELOID LEUKEMIA: REGIONAL SUB-ANALYSIS OF COMMODORE IN CHINA, SOUTH-EAST ASIA, RUSSIA

OBECABTAGENE AUTOLEUCEL (OBE-CEL, AUTO1) FOR RELAPSED/REFRACTORY ADULT B CELL ACUTE LYMPHOBLASTIC LEUKEMIA (R/R B-ALL): THE IMPACT OF INOTUZUMAB-CONTAINING BRIDGING THERAPY ON TREATMENT OUTCOME

DROPLET DIGITAL PCR AND FLOW CYTOMETRY SENSITIVITY FOR MEASURING CAR-T CELL KINETICS IN ADULT PATIENTS WITH RELAPSED/REFRACTORY B CELL ACUTE LYMPHOBLASTIC LEUKEMIA TREATED WITH OBECABTAGENE AUTOLEUCEL

CLINICAL PHARMACOLOGY AND PHARMACOKINETIC PROFILE OF ZIFTOMENIB, A MENIN INHIBITOR, IN ADULTS WITH RELAPSED/REFRACTORY ACUTE MYELOID LEUKEMIA

SUSTAINED COST-EFFECTIVENESS OF BREXUCABTAGENE AUTOLEUCEL FOR THE TREATMENT OF RELAPSED/REFRACTORY B-CELL ACUTE LYMPHOBLASTIC LEUKEMIA IN PATIENTS AGED 26 YEARS OR OLDER IN ITALY

TREATMENT PATTERNS AND MOLECULAR TESTING ACROSS THE PATIENT JOURNEY: A REAL-WORLD ANALYSIS IN A U.S.-BASED COHORT OF NEWLY DIAGNOSED AND RELAPSED/REFRACTORY AML PATIENTS

PATIENT CHARACTERISTICS, BURDEN OF DISEASE AND HEALTHCAREUTILIZATION IN ACUTE MYELOID LEUKEMIA – AN ANALYSIS OF GERMAN CLAIMS DATA

SAFETY OUTCOMES IN ADULT PATIENTS WITH AML WHO ACHIEVED THEIR FIRST COMPLETE REMISSION WITH GO PRIOR TO HSCT