ALAN reports back from ASH 2019 (Orlando, USA)

AML is a heterogeneous malignancy characterized by recurrent genetic, epigenetic and metabolic abnormalities. 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.

• Hypomethylating agents (HMAs)

While HMAs have a limited efficacy as single agents and even if not definitive, a study shows compiling results in the use of maintenance therapy with decitabine and improved survival in older adults with acute myeloid leukemia (video here: https://www.ashclinicalnews.org/multimedia/meeting-coverage/ash-annual-meeting-meeting-coverage/james-foran-decitabine-maintenance-improve-survival-older-patients-aml/).

• FLT3 inhibitors

Midostaurin 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 is also showing a broad activity against most TKI mutation.

Investigational strategies that incorporates FLT3 inhibitors in combination with HMAs and as maintenance therapy after allogeneic SCT have shown promises by improving survival in FLT3 mutated patients.

Other novel combination strategies are also currently under clinical investigation.

• BCL-2 inhibitors

Venetoclax in combination with low-dose cytarabine (LDAC) or HMAs is safe and effective in older and unfit patients with newly diagnosed AML, ineligible for intensive chemotherapy and demonstrates significant quality-adjusted survival benefits.

• Hedgehog pathway inhibitors

Glasdegib with LDAC appears to be a reasonable combination for in older, difficult to treat adult patients with newly diagnosed AML, not eligible for intensive chemotherapy and is well tolerated and improves survival compared with LDAC alone.

• IDH inhibitors

The presence of IDH1 or IDH2 mutation seen in approximately 20% of AML patients can be effectively targeted by ivosidenib or enasidenib respectively.

A Phase I study has also shown that IDH1 inhibitor olutasidenib, as a single agent and in combination with azacitidine, demonstrated “favorable safety and clinical activity” in patients with IDH1-mutated AML (video here: https://www.ashclinicalnews.org/on-location/ash-annual-meeting/another-idh-inhibitor-option-acute-myeloid-leukemia/)

• Other hot topics in AML:

The liposome-encapsulated combination of daunorubicin and cytarabine (CPX-351) has shown superiority over the 7+3 regimen in new diagnosed, fit, older patients with therapy-related AML. CPX-351 induction therapy in low risk AML patients show a good tolerability.

Gemtuzumab ozogamicin improves event-free survival in CD33+ patients with favorable or intermediate-risk cytogenetics.

Combination APR-246 (P53 activator) with Azacitidine is currently being investigated.

BST-236 (Aspacytarabine) is safe and effective as single agent in first line treatment for unfit for standard induction.

Vosaroxin, a quinolone derivative is active on leukemia cells in combination with infusional cytarabine in front line AML.

Oral Azacitidine Maintenance Improves Survival in Transplant-Ineligible AML https://www.ashclinicalnews.org/on-location/ash-annual-meeting/quazar-oral-azacitidine-maintenance-improves-survival-transplant-ineligible-aml/

In children, clinical outcomes have improved minimally during the past four decades despite maximally intensive chemotherapy, hematopoietic stem cell transplantation and optimized supportive care. Chemo-resistance and relapse remain major source of mortality and highlight the need of alternative treatment approaches. The biologic and immune-phenotypic heterogeneity of childhood AML and the significant potential for on-target/off-tumor immunotherapeutic toxicity due to target antigen expression on nonmalignant cells remain a unique challenge.

Some studies are showing that BCL2 inhibitor (venetoclax) in combination with high dose chemotherapy is active and well tolerated in children. Also a correlation between CD123 expression level with disease characteristics and outcomes in pediatric AML has been demonstrated.

Antibody-based and cellular immunotherapies are currently under clinical evaluation with active or soon-to-open phase I trials.

Other resources to check

ASH Guidelines: https://www.hematology.org/Clinicians/Guidelines-Quality/Guidelines.aspx

VJHemOnc (a video journal of all the latest AML updates from ASH): https://www.vjhemonc.com/event/ASH-2019/?showAllVideos&taxonomy_name=subject&term_name=acute-myeloid-leukemia/

The landscape of ALL has evolved significantly over the last few years. Identification of specific recurrent genetic alterations and of minimal residual disease (MRD) guides prognostic classification and management. Novel agents (e.g. blinatumomab, a CD19/CD3 targeting bi-specific T cells) have demonstrated encouraging results in combination with standard chemotherapy in relapsed/refractory (R/R) and MRD+ (minimal residual disease positive) patients and are currently incorporated into upfront treatment in specific settings. It also shows better response than standard of care in elderly patients not eligible for intensive chemotherapy. Blinatumomab is currently being investigated in de novo Ph+ALL in chemotherapy free combination with dasatinib and ponatinib.

Other new strategies included the incorporation of tyrosine kinase-inhibitor based therapy for patients with Ph+ALL and the use of DOT inhibitors and bcl-2/bcl-x inhibitors in R/R disease. These innovations promise to improve management and outcome of this disease. NOTCH inhibitors, OBI-3424, CD38 antibody (daratumomab) are currently being investigated for T-ALL.

CD19-20-52-22 are expressed in B ALL and are usually associated with bad prognosis. CD22 directed antibody drug, inotuzumab ozogamicin demonstrated efficacy and safety as single agent versus standard chemotherapy in adult patients with Ph- or Ph+ relapsed and refractory (R/R) ALL. It is also investigated in upfront setting. Monoclonal anti CD20 antibody rituximab is recommended in the treatment of newly diagnosed CD20+, Ph- B ALL patient younger than 60 years in addition to chemotherapy and obinituzumab is currently being assessed for its effectiveness. Tandem CAR-T targeting CD19 and CD22 is a safe and efficacious treatment in R/R ALL patients (link here https://www.vjhemonc.com/event/ASH-2019/?showAllVideos&taxonomy_name=field&term_name=car-t-cellular-therapy/).

The understanding and treatment of Ph+ALL have changed rapidly in the past 10 years. The outcome is equally as good as for Ph-disease and with the TKI therapies in addition to chemotherapy, the novel immunotherapy approaches and the extension of allogeneic HCT to older individuals, there is the potential to exceed this outcome. This is particular interest in reducing chemotherapy exposure and considering for whom allogenic stem-cell transplant can be avoided. However, the available evidence is often derived from single-arm studies and patient population that can help test those options in clinical trials is limited in number. (Fielding A., 2019).

In children, current approaches incorporate the bispecific T-cell engager blinatumomab (video here https://www.ashclinicalnews.org/on-location/ash-annual-meeting/blinatumomab-new-standard-care-young-patients-b-cell/), the anti-body drug conjugate inotuzumab ozogamicin and the CD19-directed chimeric antigen receptor T cells in R/R B-cell ALL pediatric patients. Also the potential of using these immunotherapies in the treatment of newly diagnosed children is currently being investigated.

Studies have also confirmed that using pediatric-inspired protocols in adolescent and adult ALL is a superior approach (Muffly et al, 2019).

Other resources to check

ALL NCCN Guidelines for patients 2019 available www.NCCN.org/patients

According to ongoing discussions, MRD is a 1/ predictive factor and will become a tool to predict the treatment and 2/ prognostic factor and correlates with the prognosis (e.g. MRD negative patients have a longer progression-free survival).

MRD technologies increase the ability to measure response in AML. When applied in clinical trials, molecular and immune-phenotypic MRD assays have improved prognostic precision, providing a strong rational for their use to guide treatment as well as to measure its effectiveness.

Initiatives such as those from European Leukemia Network now provide a collaborative knowledge- based framework for selection (ELN Guidelines 2018) and implementation of MRD assays most appropriate for defined genetic subgroups. Different methods with different sensitivity are used and there is a need for standardization:

• For example, for patients mutated-NPM1 AML, quantitative PCR (qPCR) monitoring of mutated NPM1 transcripts post-induction and sequentially after treatment has emerged as a highly sensitive and selective tool to predict relapse and potential benefit from allogeneic transplant.
• Flow cytometric MRD after induction is prognostic across genetic risk groups and can identify those patients in the wild-type NPM1 intermediate AML subgroup with a very high risk for relapse.
• In parallel, advances in genetic profiling have extended understanding for MRD monitoring using next-generation sequencing (NGS). NGS AML MRD detection can stratify outcomes and has potential utility in the peri-allogeneic transplant setting. However there remain challenges inherent in the NGS approach and its relevance needs to be further clarify for routine clinical use.

VJHemOnc also have a thread on MRD from ASH: https://www.vjhemonc.com/event/ASH-2019/?s

We will continue to monitor the clinical advances as they come and share with you. For sure, there will be more to come at the European Hematology Association (EHA) meeting in June and again at ASH in December 2020. Stay tuned for more updates on what’s happening in the world of acute leukemia!