Highlights from EHA 2020

From 11^th to 21^st June, the Acute Leukemia Advocates Network (ALAN) attended the 25^th European Hematology Association (EHA) congress.

Samantha Nier, Network Manager reports on the sessions she attended and this comes in addition to what was posted on social media (https://twitter.com/AcuteLeuk)

Acute Myeloid Leukemia (AML)

AML is a heterogeneous malignancy characterized by recurrent genetic, epigenetic and metabolic abnormalities. There are at least 50 genes in which mutations have been identified in AML (Figure 1).

Figure 1: Genomic landscape of AML reveals distinct molecular subgroups informing disease classification and prognosis stratification.

Evaluating for cytogenetic and molecular abnormalities is important for two main reasons:

• Prognosis: mutations that are detected can predict outcomes with conventional therapies, treatment resistance and long-term outcomes
• Targeted therapies: mutated proteins are a drug target themselves and rapidly detecting the mutation is important to guide treatment decisions.

Guidelines recommend rapid turnaround and molecular testing at diagnosis and at relapse (Figure 2)

Figure 2: Recommendations for mutation testing in AML according to guidelines

As a result of the increased knowledge of the underlying biology of AML leading to rational drug development, several new targeted agents have been added to the therapeutic arsenal (Figure 3 and 4)

Figure 3: Major advances in AML over the past five decades

Figure 4: Many potential targets, several with proven clinical benefit

Treatment options for newly diagnosed

Standard treatment with intensive induction chemotherapy for AML induces complete remission in 60%–80% of patients aged ≤60 years and in 40%–60% of patients aged > 60 years. However, about two-thirds of patients relapse after frontline therapy and most relapses occur within the first 18 months.

Effective, well-tolerated maintenance treatment is needed to reduce risk of relapse and prolong survival for older patients in remission, who are less likely than younger ones to be candidates for HSCT:

• CC-486 is an oral hypomethylating agent that allows for extended dosing schedules to sustain therapeutic activity and is well tolerated.
• Alvocidib, a potent cyclin-dependent kinase 9 (CDK9) inhibitor, used prior to 7+3 induction is showing an acceptable safety profile and encouraging clinical activity, particularly in adverse-risk disease in newly diagnosed
• CPX-351, a dual-drug liposomal encapsulation of cytarabine and daunorubicin, is approved for the treatment of adults with newly diagnosed therapy-related AML and is showing significantly improved median overall survival versus the conventional 7+3 regimen of cytarabine and daunorubicin, with a comparable safety profile. The major benefit with CPX-351 was observed among patients achieving complete response undergoing HSCT
• In newly diagnosed AML or high-risk MDS, glasdegib in combination with low-dose cytarabine shows to have an acceptable safety profile and improved overall survival compared to low-dose cytarabine alone.

Treatment options for older patients ineligible for intensive chemotherapy

Older patients with AML who are ineligible for intensive chemotherapy have limited therapeutic options and poor outcomes. Even without clinical trial evidence for improved overall survival (only effective in about half of the patients), hypomethylating agents (HMAs) as monotherapy namely azacitidine (AZA) and decitabine (DEC), have been the standard of care in this population for more than a decade and were approved in Europe for patients not candidates for intensive chemotherapy or patients not candidates for hematopoietic cell transplant.

Recent studies are investigating new combinations of HMA with various agents:

• Combination of DEC with all-trans retinoic acid (ATRA) is also showing improved the response rate and, particularly overall survival.
• Combination enasidenib (inhibitor of mutant IDH2) + AZA resulted in significantly improved response rates versus AZA monotherapy and was generally well-tolerated.
• Combination of magrolimab (antibody blocking CD47) with AZA is well-tolerated and effective.

But even in HMA responders, treatment failure by secondary resistance poses a major limitation to long-term disease control. Hence, HMA with BCL-2 inhibitors (venetoclax*) has emerged as a new standard for older patients with AML.

*Venetoclax is a selective, potent, orally bioavailable BCL-2 inhibitor that is approved in combination with hypomethylating agents (HMAs) or with low dose cytarabine (LDAC) for treating older or co-morbid patients with newly-diagnosed acute myeloid leukemia and who are unfit for intensive chemotherapy.

Venetoclax-based combinations have demonstrated rapid median response times with responses obtained earlier on therapy with median time to first response of less than 2 months. In particular Venetoclax + AZA shows CR/CRi 68 % vs 28% AZA only, median OS 14.7 months vs 9.6

The acquisition of resistance to venetoclax in AML is known to be main cause of treatment failure in venetoclax-based AML treatment approaches (mechanisms of acquired resistance in AML cell lines are still under investigation).

Treatment options for patients with FLT3 mutations relapsed/refractory (R/R) AML

FLT3 mutations occur in approximately 25% of cases of AML and predict for increased relapse and reduced survival. Few options are approved (Figure 5)

Figure 5: Approved FLT3 inhibitors

Midostaurin (a multi-kinase inhibitor) and gilteritinib have been recently approved respectively in combination with chemotherapy and as single agent for use in relapsed or refractory (R/R) AML patients and represent a new standard of care for patients with FLT3 mutations in both, first line or salvage settings.

Gilteritinib significantly prolonged overall survival and resulted in higher remission rates compared with salvage chemotherapy. However, patients may develop resistance after an initial response to gilteritinib. Gilteritinib is also showing a broad activity against most TKI mutation.

Other agent is under investigation:

• AC220 is an orally-administered second-generation Class III receptor tyrosine kinase inhibitor (TKI) with potent and highly efficacious FLT3 inhibitory activity in vitro and in vivo. Early-phase trials of AC220 as monotherapy demonstrated acceptable toxicity, and potential activity in AML including patients with wild type FLT3.

Treatment options for patients with IDH1 mutation AML

IDH mutations are found in 20% of AML patients.

The combination of IDH1 inhibitor ivosidenib with venetoclax and azacitidine is well tolerated and highly effective for patients with IDH1 mutated AML. Additional follow up and accrual is ongoing to better define tolerability, efficacy, and biomarkers of response.

NPM1 mutation AML

NPM1 mutation is one of the most common genetic changes in AML and it is associated with favorable prognosis in absence of FLT3 internal tandem duplication in patient that achieve MRD negativity. Durable remissions in these patients can be achieved by intensive consolidation chemotherapy. MRD should be closely monitored, as persistent positivity or rise in the number of NPM1 copies increase the risk of relapse. Allogeneic SCT provides superior outcomes in NPM1+ patients with adverse prognostic features and persistent or growing MRD.

Pediatric

The incidence of AML increases with age and represents approximately one third of leukemias in adolescents and young adults (AYAs).

Younger AML patient present with more aggressive disease features, such as hyperleukocytosis and elevated serum LDH levels. Favorable cytogenetics are more common and response to treatment and outcomes for AYAs and especially adolescents are significantly superior compared to elderly patients

HSCT

The decision to perform HSCT depends on many factors (Figure 6).

Figure 6: HSCT for AML – ELN Guidelines

Measurable Residual Disease (MRD)

The proportion of residual leukemic cells detected in the bone marrow provides an independent post-diagnosis and prognostic indicator:

• provides an objective methodology to establish a deeper remission status,
• then refines outcome prediction and inform post-remission treatment,
• allows identification of impending relapses and enable early intervention,
• allows more robust post-transplant surveillance.

It should be used for risk stratification (Figure 7) and guide treatment decisions (Figure 8). It appears to be a highly anticipated surrogate endpoint in early phase clinical trials that evaluate novel drugs.

Figure 7: ELN 2017 AML risk stratification by genetics

Figure 8: MRD-guided treatment decisions

Acute Lymphoblastic Leukemia (ALL)

ALL is a malignant disease in which B-line or T-line cells originating from lymphocytes proliferate abnormally in bone marrow. Molecular biology and molecular genetics studies have revealed that ALL is a group of highly heterogeneous diseases. In recent years, high-throughput sequencing technology has enabled us to further understand the genetic diversity and more accurate clonal structure of ALL, which is helpful to deepen the biology understanding and the choice of treatment strategies. However, there are still many related problems that are not clear.

Lot of research is being undertaken to understand the biology in ALL e.g. investigation on the asparaginase resistance by inhibiting the GSK3-dependent protein, PRC2 alterations in T-ALL, mechanisms of relapse in T-ALL, recurrent PAX5 fusions in infant B-cell precursor ALL, use of second generation TKI after allogeneic hematopoietic stem cell transplantation (HSCT), and much more.

There is a lot going on, and clinical trials are needed to confirm the first findings.

In the treatment landscape, we witness a transformation of the approach to treatment of ALL as the existing shift away from intensive chemotherapy and HSCT to immune and targeted therapy gains further momentum (Figure 9).

Figure 9: Drugs active in lymphoid malignancies

Relapsed / Refractory ALL

The prognosis of R/R ALL is very poor, particularly in patients relapsing after allogeneic HSCT. New agents, such as inotuzumab (monoclonal antibody) or blinatumomab, constitute a major breakthrough and have improved the complete response rate in R/R ALL, but the progression-free survival is shorter than 6 months.

Inotuzumab ozogamycin (INO) was shown to be an effective treatment of relapsed ALL compared to standard treatment with complete response rate of about 80% observed but of short duration (median PFS of 5 months). Further data are required to evaluate the benefit-risk balance of INO in a real-life setting.

Blinatumomab was approved for use in patients with measurable residual disease (MRD)-positive, Philadelphia chromosome-negative ALL in either first or subsequent complete remission. Its use as consolidation in first complete remission patients with low-level MRD is under investigation.

Blinatumomab is shown to be effective within 2 cycles in relapsed/refractory Philadelphia chromosome-positive B-cell precursor ALL. Complete response is achieved in 40% of patients of which one third proceed to allogeneic HSCT without further therapy.

In the last decade, several chimeric antigen receptor anti-CD19 (CAR19) constructs have been developed and are looking promising.

Also early clinical studies are showing that BCL-2 and BCL-XL inhibitors have synergistic anti-leukemic effects in ALL. The combination of venetoclax with low-dose navitoclax with chemotherapy appears to be well-tolerated, and efficacy is promising in heavily pretreated patients (including those with prior blinatumomab, inotuzumab, or CAR-T) with high rates of complete response. This would need to be investigated further.

Relapsed / Refractory T-ALL

T-ALL in adults is an aggressive malignancy with low long term remission rates and high relapse and mortality rates. The only evaluable effective, though quite toxic, therapeutic option is nelarabine combinations followed by allogeneic HSCT.

Some studies are showing:

• Preliminary studies showed efficacy and low toxicities of venetoclax with decitabine in the treatment of MRD persistent and relapsed/refractory T-cell acute lymphoblastic leukemia patients. This will need to be further investigated.
• CD7 is present on >95% T-ALL samples and has restricted expression on the lymphoid (T and NK) lineage. GC027 is a CD7 targeted universal CAR-T product demonstrating superior clinical efficacy and induced deep response in patients with acceptable safety profile.

B-ALL

In adults, prognosis for B-ALL is poor and there is currently no CD19 CAR therapeutic with acceptable toxicity and durable efficacy. Some early data with novel second generation CD19CAR shows high remission rates with 87% achieving MRD negative complete response.

Pediatric

The most common cancer in the childhood and adolescent age group is ALL. Despite the advances in treatment and an impressive cure rate, high treatment-associated morbidities persist. Severe short and long term side effects highlight the need for further research to discover and establish a more specific and benign therapy for children with ALL. New targeted combination are currently being investigated and hopefully some data could be shared in the near future.

Blinatumomab is approved for the treatment of pediatric patients with relapsed/refractory Philadelphia chromosome-negative B-cell precursor ALL. Blinatumomab is shown to be effective within 2 cycles, with more than half of patients in complete response and the majority of patients achieving MRD response. Most patients who are responding to blinatumomab proceed to HSCT and are alive 1 year after HSCT.

An interesting discovery has been made in mice. It is know that the majority of childhood leukemias are caused by the cooperation of prenatal genetic predisposition and oncogenic events taking place after birth. Genetic predisposition is frequent in children (>1-5%), but less than 1% of genetic carriers will develop the disease. Infectious stimuli are believed to play a major role, but the critical determinants leading to developing the disease in children are unknown. The results of this early stage research show that:  1/ the microbiome deprivation via antibiotic treatment as a risk factor for leukemia development (Figure 10) and 2/ the gut microbiome may serve as an integration hub for environmental signals that modulate the risk of developing B-cell ALL in children. We will keep an eye on this and share any developments.

Figure 10: Gut microbiome disturbance by antibiotic treatment in early life is sufficient to induce leukemia in predisposed mice

Minimal Residual Disease (MRD)

Molecular biology and MRD are currently essential parameters in the management of adult ALL.

COVID-19

ALL experts have expressed their opinion regarding ALL patients’ management during COVID-19 pandemic:

• Standard treatments should be modified as little as possible. This applies to first line and relapse including immunotherapies with rituximab, inotuzumab, blinatumomab and HSCT.
• Consider chemotherapy adaptations in patients with previous prolonged cytopenias.
• In case of delay to HSC, continue standard therapy and avoid interruptions.
• Any modification of these regimen could lead to poorer chances of cure. There is no evidence that any modification would reduce the risk of acquiring COVID-19.

General recommendations:

• Social distancing including in waiting rooms at hospital
• No visits on the ward
• Personal protection
• Testing of patients before admission
• Use of telemedicine when possible

Acute promyelocytic leukemia (APL)

Acute promyelocitic leukemia (APL) is characterized by abnormal proliferation of promyelocytes, acquisition of the PML-RARA gene and life-threatening coagulopathy. After introduction of all-trans retinoic acid (ATRA) + arsenic trioxide (ATO) into the practice, the prognosis of APL has improved dramatically.

For high-risk APL patients, ATRA and ATO plus chemotherapy is, however, still the alternative standard therapy.  Gemtuzumab ozogamicin is also the first line treatment for high-risk APL.

Nevertheless, the incidence of early death (ED) remains high, and subsequent relapses occur in a proportion of patients as well. Also differentiation syndrome or ATRA related severe adverse events are occasionally experienced. They can be life-threatening and leading to discontinuation of ATRA.

The use of ATO-based regimen as first line treatment in APL is associated with excellent and sustainable response rates. The low early death despite a high bleeding/hemorrhage rate at diagnosis as compared to reported historical data seems to be attributable to improved supportive care and awareness of APL as a medical emergency.

Prospective trials in children aimed to minimize the use of chemotherapy are ongoing. However, limited data are available about safety of ATO-ATRA in children.

More ressources

If you wish to dig more into science, there are some resources you can access:

• https://journals.lww.com/hemasphere/pages/default.aspx
• Educational Updates in hematology:
• https://ehaweb.org/congress/eha25/program/educational-updates-in-hematology-book/
• All abstracts presented during the congress: https://journals.lww.com/hemasphere/Documents/EHA25_Abstracts_2020.pdf

ALAN is planning to hold a webinar soon and present the EHA highlights in acute leukemia. Stay tuned for more details to come!