Q1 2022: Additional information and data in acute leukemia
AML
A recent study published showed that patients with high-risk AML used both approach-oriented and avoidant coping strategies at the time of diagnosis, but that using more approach-oriented coping techniques was linked to less psychological distress and better quality of life. (Ref. Amonoo HL, Bodd MH, Reynolds MJ, et al. Coping strategies in patients with acute myeloid leukemia [published online ahead of print, 2021 Nov 12]. Blood Adv. doi: 10.1182/bloodadvances.2021005845.)
Sabatolimab, an immunotherapeutic therapy targeting TIM-3 on immune and myeloid cells, was well-tolerated and led to durable clinical responses when combined with hypomethylating agents in patients with very high/high-risk myelodysplastic syndrome and newly diagnosed AML. (Ref. Brunner AM, Esteve J, Porkka K, et al. Efficacy and Safety of Sabatolimab (MBG453) in Combination with Hypomethylating Agents (HMAs) in Patients (Pts) with Very High/High-Risk Myelodysplastic Syndrome (vHR/HR-MDS) and Acute Myeloid Leukemia (AML): Final Analysis from a Phase Ib Study. Abstract #244. Presented at the 2021 American Society of Hematology Annual Meeting, December 11, 2021.)
Patients with newly diagnosed, IDH2-mutated AML had significantly improved overall response rates with the combination of enasidenib plus azacitidine compared with azacitidine alone, according to results of the phase Ib/II AG221-AML-005 trial. Enasidenib is an oral IDH2 inhibitor, and IDH2 mutations occur in about 8-19% of patients with AML. Enasidenib is currently approved in the U.S. as a single agent for adult patients with relapsed or refractory IDH2-mutated AML. (Ref. DiNardo CD, Schuh AC, Stein EM, et al. Enasidenib plus azacytidine versus azacytidine alone in patients with newly diagnosed, mutant-IDH2 acute myeloid leukaemia (AG221-AML-005): a single-arm, phase 1b and randomized, phase 2 trial. Lancet Oncol. 2021;22(11):1597-1608.)
Mutations of the isocitrate dehydrogenase-1 (IDH1) and IDH2 genes are among the most frequent alterations in AML and can be found in ∼20% of patients at diagnosis. A recent study analyzed a large cohort of patients with AML for the prevalence and prognostic impact of IDH mutations. A detailed analysis of different mutations revealed distinct clinical and comutational features of the IDH1-R132C mutation, and providing additional evidence in support of delineating the IDH2-R172K mutation as a distinct entity based on its comutational landscape and significant impact on outcome. The differences in outcome of distinct mutations of IDH must be considered in future trials. Our analysis serves as a benchmark for future studies incorporating novel agents to show improvements compared with conventional intensive regimens. (Ref. https://doi.org/10.1182/bloodadvances.2021004934)
Induction and consolidation therapy comprising venetoclax plus fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin (FLAG-IDA) was highly effective for the treatment of newly diagnosed AML, according to research. (Ref. Lachowiez C, DiNardo CD, Takahashi K, et al. Venetoclax Combined with FLAG-IDA Induction and Consolidation in Newly Diagnosed Acute Myeloid Leukemia. Abstract #701. Presented at the 2021 American Society of Hematology Annual Meeting, December 13, 2021).
A combination regimen consisting of azacitidine with venetoclax and magrolimab showed clinical activity in older and high-risk patients with newly diagnosed AML. (Ref. Daver N, Konopleva M, Maiti A, et al. Phase I/II Study of Azacitidine (AZA) with Venetoclax (VEN) and Magrolimab (Magro) in Patients (pts) with Newly Diagnosed Older/Unfit or High-Risk Acute Myeloid Leukemia (AML) and Relapsed/Refractory (R/R) AML. Abstract #371. Presented at the 2021 American Society of Hematology Annual Meeting, December 12, 2021.)
Byrd et al report on the impact of PTPN11 mutations on AML mutational characteristics and patient outcomes for 1725 patients with AML. Patients with N-terminal SH2 domain PTPN11 mutations had an early death (<30 days) more often than those with phosphatase domain mutations. And PTPN11 mutations are associated with inferior outcomes in AML patients with wild-type NPM1.
Highlights include the higher co-occurrence of PTPN11 with NPM1, DNMT3A, STAG2 and inv3 mutations, the higher median number of (driver) mutations in PTPN11-mutated AML, and the adverse impact of N-terminal SHP2 domain PTPN11 mutations in certain contexts. (Ref. https://doi.org/10.1182/bloodadvances.2021006242)
MRD
Measurable residual disease (MRD) quantified by multiparameter flow cytometry (MFC) is a strong and independent prognostic factor in AML. However, several technical factors may affect the final read-out of the assay. Experts from the MRD Working Party of the European LeukemiaNet evaluated which aspects are crucial for accurate MFC-MRD measurement. Here, we report on the agreement, obtained via a combination of a cross-sectional questionnaire, live discussions, and a Delphi poll. The recommendations consist of several key issues from bone marrow sampling to final laboratory reporting to ensure quality and reproducibility of results. Furthermore, the experiences were tested by comparing two 8-color MRD panels in multiple laboratories. The results presented here underscore the feasibility and the utility of a harmonized theoretical and practical MFC-MRD assessment and are a next step toward further harmonization.
ALL
The treatment of ALL has evolved rapidly during the recent decade. The expanding use of modern sequencing techniques has elaborated the genetic background of ALL and helped to define new subtypes, such as Philadelphia chromosome–like subtype of B-cell ALL (Ph-like ALL). Novel immunotherapeutic approaches, such as bispecific T-cell engaging antibodies, antibody-drug conjugates, and chimeric antigen receptor T-cell therapy, have achieved encouraging results in relapsed or refractory ALL. In addition, other novel targeted therapies, such as the third generation tyrosine kinase inhibitor ponatinib and allosteric inhibitor asciminib are being introduced to Ph-like ALL and Ph+ ALL. Despite this progress, a significant fraction of adult patients still succumbs to leukemia or treatment-related events. Especially the treatment of elderly ALL patients remains challenging, as intensive chemotherapy regimens or allogeneic hematopoietic stem cell transplantation are frequently not suitable for nonfit patients. There is an urgent need for less toxic, yet effective treatment alternatives. A new study showed that the combination of ex vivo drug testing and molecular profiling is a powerful tool for identifying novel effective and actionable therapies for ALL patients. Targeting the apoptosis pathway by inhibiting antiapoptotic proteins (BCL2, BCL-XL, BCL-W) and p53 with BCL2 and MDM2 inhibitors in combination with established ALL drugs is a highly promising strategy for improving survival and reducing treatment-related toxicity. (Source: https://journals.lww.com/hemasphere/Fulltext/2022/03000/Targeting_Apoptosis_Pathways_With_BCL2_and_MDM2.8.aspx)
Wudhikarn et al present a retrospective analysis of combination blinatumomab and inotuzumab therapy in relapse/refractory adult acute lymphoblastic leukemia. The authors evaluate the impact of dual therapy on remission, relapse, and overall survival. They also provide outcome metrics for the subset of patients who proceeded to transplant following sequential therapy. These data are clinically relevant as the use of these medications to induce remission and potentially bridge to transplant continues to expand. Therefore, knowledge about response rates and toxicities will be valuable for clinicians and researchers alike. (Ref. https://doi.org/10.1182/bloodadvances.2021005978).
ADDITIONAL RESOURCES
Why patients with AML ≥60 years of age should or should not be offered early allogeneic stem cell transplantation ?
In a Point-Counterpoint discussion, the question of whether all patients over the age of 60 with acute myeloid leukemia (AML) should be offered an allogeneic transplant is discussed by experts in the field. Tey and Lane argue yes while Deeg argues no. What do you do in your practice? We hope that these articles will help you make an informed decision that greatly benefits your patients.
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