Q4 2021: Additional information and data in acute leukemia
On October 9, the U.S. FDA placed a clinical hold on a trial assessing AstraZeneca’s AZD5991 in combination with venetoclax and as monotherapy for patients with relapsed or refractory AML. Source: BioSpace, October 21, 2021.
The U.S. FDA has placed a partial clinical hold on the phase Ib KOMET-001 study of Menin-KMT2A inhibitor KO-539 for the treatment of patients with relapsed or refractory AML. The agency’s decision follows a recent report by KO-539’s manufacturer, Kura Oncology, of a grade 5 serious adverse event resulting in a patient’s death. Source: Kura Oncology press release, November 24, 2021.
In an analysis of the phase III RATIFY trial published in Leukemia, researchers examined the molecular landscape of FLT3 internal tandem duplication (ITD) mutations in AML, confirming this subtype’s distinct heterogeneity and the negative prognostic impact of the tyrosine kinase domain-1 (TKD1) insertion site. The data also show that the negative impact of TKD1 insertions might not be overcome by treatment with the multikinase inhibitor midostaurin. This clinical observation “does not only confirm the known resistance to chemotherapy of patients with TKD1 insertions, but also to tyrosine kinase inhibitor (TKI) treatment, which is in line with preclinical data,”. (Ref. Rücker FG, Du L, Luck TJ, et al. Molecular landscape and prognostic impact of FLT3-ITD insertion site in acute myeloid leukemia: RATIFY study results [published online ahead of print, 2021 Jul 28]. Leukemia. doi: 10.1038/s41375-021-01323-0).
A prospective study demonstrated that low dose decitabine + venetoclax is as safe and efficacious as maintenance therapy following allo-HSCT in patients with high-risk AML/MDS. There were no reported irreversible regimen-related toxicities. One important note is that the authors hypothesized that decitabine + venetoclax may influence the graft-versus-leukemia effect, though no evidence of this was observed, potentially due to the small sample size. Further investigation of this maintenance regimen in larger cohorts is required. (Ref. Wei Y, Xiong X, Li X, et al. Low-dose decitabine plus venetoclax is safe and effective as post-transplant maintenance therapy for high-risk acute myeloid leukemia and myelodysplastic syndrome. Cancer Sci. 2021;112(9):3636-3644. DOI: 1111/cas.15048).
What are the future prospects for FLT3 mutated AML?
Venetoclax with azacitidine (ven/aza) has emerged as a promising regimen for AML, with a high percentage of clinical remissions in newly diagnosed patients. However, approximately 30% of newly diagnosed and the majority of relapsed patients do not achieve remission with ven/aza. It was previously reported that ven/aza efficacy is based on eradication of AML stem cells through a mechanism involving inhibition of amino acid metabolism, a process which is required in primitive AML cells to drive oxidative phosphorylation. Herein we demonstrate that resistance to ven/aza occurs via up-regulation of fatty acid oxidation (FAO). Studies are needed to confirm inhibition of FAO as a therapeutic strategy to address ven/aza resistance. (https://pubmed.ncbi.nlm.nih.gov/33884374/)
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. https://www.ashclinicalnews.org/on-location/ash-annual-meeting/azacitidine-venetoclax-magrolimab-shows-promise-newly-diagnosed-high-risk-aml/)
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 (vHR/HR-MDS) 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. https://www.ashclinicalnews.org/on-location/ash-annual-meeting/sabatolimab-combined-hypomethylating-agents-appears-safe-effective-mds-aml/)
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. However, patients with AML harboring TP53 mutations had an inferior survival versus those with wild-type TP53 when treated with the combination. (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. https://www.ashclinicalnews.org/on-location/ash-annual-meeting/venetoclax-plus-flag-ida-shows-promising-responses-newly-diagnosed-aml/)
Intensive chemotherapy regimens have been the mainstay of newly diagnosed AML induction therapy for several decades. During this time, alterations to the standard backbone therapy have yielded improved response rates, longer remissions, and improved survival in those who are fit and <60 years. Such regimens include the cladribine with higher dose cytarabine and idarubicin (CLIA) regimen which has been shown to achieve high complete response or partial response rates in a small study of patients with a mean age of 54. Further, the addition of the BCL2 inhibitor venetoclax, improves CR and PR rates in older patients (≥75 years) or unfit patients treated with a lower intensity treatment regimen using hypomethylating agents. In a recent study, it has been reported that the addition of venetoclax to the CLIA high intensity chemotherapy regimen resulted in durable complete responses in patients with newly diagnosed AML and high-risk MDS, with high rates of MRD-negativity. The authors considered that these data compared favorably with other published studies in similar patient groups without venetoclax. (Ref. Kadia TM, Reville PK, Borthakur G, et al. Venetoclax plus intensive chemotherapy with cladribine, idarubicin, and cytarabine in patients with newly diagnosed acute myeloid leukaemia or high-risk myelodysplastic syndrome: A cohort from a single-centre, single-arm, phase 2 trial. Lancet Haematol. 2021;8(8):e552-e561. DOI: 10.1016/S2352-3026(21)00192-7)
Poly(ADP‐ribose) polymerase 1 (PARP1) is a key mediator of various forms of DNA damage repair and plays an important role in the progression of several cancer types. The enzyme is activated by binding to DNA single-strand and double-strand breaks. Its contribution to chromatin remodeling makes PARP1 crucial for gene expression regulation. Inhibition of its activity with small molecules leads to the synthetic lethal effect by impeding DNA repair in the treatment of cancer cells. A recent study suggested that the positive correlation of PARP1, PARP2, PARP3, and TRPM2 genes in physiological cells, is disturbed in patients with AML and consequently, the need for further research of the mutual expression and regulation of different PARP family members is mandatory (ref. Gil-Kulik P, Dudzińska E, Padzikowska-Büchner E, et al. Different regulation of PARP1, PARP2, PARP3 and TRPM2 genes expression in acute myeloid leukemia cells. BMC Cancer. 2020; 20(1):435).
The U.S. FDA has approved CD19-directed chimeric antigen receptor (CAR) T-cell therapy brexucabtagene autoleucel for the treatment of adult patients with relapsed or refractory B-cell precursor ALL. Source: FDA press release, October 1, 2021.
A retrospective study demonstrated that haploidentical HCT using posttransplant cyclophosphamide (PTCy) could be a preferred alternative donor HCT approach in adult patients with ALL, with superior OS . Although the OS was similar with haploidentical HCT compared to traditional MDS and MUD HCT, the risk of GvHD was reduced in the haploidentical HCT cohort. Further research aiming to prevent relapse, reduce death by infections, and establishing the role of haploidentical HCT using PTCy at different stages of ALL remission with a longer-term follow-up are warranted. (Ref. Wieduwilt MJ, Metheny L, Zhang M-J, et al. Haploidentical vs. sibling, unrelated, or cord blood hematopoietic cell transplantation for acute lymphoblastic leukemia. Blood Adv. 2021;bloodadvances.2021004916. DOI: 1182/bloodadvances.2021004916)
A recent study showed that patients with APL treated with ATRA-ATO reported better long-term quality of life outcomes than patients treated with chemotherapy. Also, late comorbidity and health problem prevalence was similar between patients with APL previously treated with ATRA-ATO or chemotherapy. The main objective of this study was to compare the long-term health-related quality of life of patients with APL treated with all-trans retinoic acid (ATRA) plus arsenic trioxide (ATO) vs ATRA plus standard chemotherapy. Findings also suggest that, in the long term, the health status of patients with APL previously treated with ATRA-ATO may be comparable to that of the general population. (ref. Fabio Efficace et al. https://doi.org/10.1182/bloodadvances.2021004649)
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 – full article here: https://journals.lww.com/hemasphere/Fulltext/2022/01000/Technical_Aspects_of_Flow_Cytometry_based.5.aspx
A single-cell multi-omic analysis of the genetic, cellular, and molecular landscape of TP53-driven transformation can provide unique insights into the evolution of chronic hematologic malignancies towards an aggressive acute leukemia. TP53 is the most commonly mutated gene in human cancer. Presence of “multi-hit” TP53 mutations is associated with lack of response to conventional treatments and poor outcomes, the authors explained. (Ref. Rodriguez-Meira A, Rahman H, Norfo R, et al. Single-cell multi-omics reveals the genetic, cellular and molecular landscape of TP53 mutated leukemic transformation in MPN. Abstract #9. Presented at the 2021 American Society of Hematology Annual Meeting, December 11, 2021.)
How can venetoclax combinations be used in preparation for transplant?
Sociodemographic factors are associated with survival in acute leukaemia in studies across different countries. The potential causal links are multiple and suggest many relatively simple interventions that have received inadequate research and attention. Most clinical and scientific writing and discussion assume that a small number of biological factors should accurately predict outcome: cytogenetic and molecular genetic abnormalities, presenting white cell count and patient fitness for treatment. The reality is more complex.
Multiple sociodemographic factors affect outcomes and are inadequately addressed by the balance scale model. Consider ethnic differences—a recent study of over 25 000 adult AML patients in the United States demonstrated a 3-year survival of 34% in Black patients compared with 43% in White patients, despite no significant difference in baseline genetic risk categorisation and a “younger” median age in the Black patient group. Poverty has also been shown to strongly predict poorer outcomes in acute leukaemia. Limited English proficiency (LEP) describes people who are not fluent in spoken English but who will often speak other languages proficiently. Having LEP is associated with reduced survival in pancreatic cancer and higher risk of treatment failure in head and neck cancers. There are no published studies on LEP and acute leukaemia mortality, but a US study of Hispanic families in a paediatric stem cell transplant setting showed that parental LEP was significantly associated with prolonged hospitalisation.
Fundamentally, health systems and haemato-oncology departments have been mostly developed and operated by people with relative financial security, with advanced language proficiency and health literacy, and who are often from the majority ethnic group of their country. Even with the best intentions, we will not have sufficient collective imagination to address sociodemographic disparities until our practice is led and informed by people of varied ethnic, socioeconomic, and linguistic backgrounds. (Ref. Hibbs, Stephen, The Fragile Web of Care: Ethnicity, Poverty, and Language in Acute Leukaemia, HemaSphere: November 2021 – Volume 5 – Issue 11 – p e652, doi: 10.1097/HS9.0000000000000652)
Using technology to monitor outpatients undergoing cancer treatments at home was feasible and led to improvements in care, according to results of a pilot study. From January 2020 to August 2021, patients who were planning to start an intravenous anti-cancer treatment plan at Ochsner Health System, had an active patient portal account, and had a smart phone with the Ochsner portal application installed were asked to voluntarily participate in the Chemotherapy Care Companion program. The pilot program monitored patients’ vital signs to identify issues related to or exacerbated by their treatment. It is to be noted that This pilot study was limited by its requirements of smartphone access, basic technology skills, and collection of patient feedback, as well as its small sample size. (Ref: Pierce E, Stott C, Larned Z, et al. Ochsner Health System’s Chemotherapy Care Companion: Technology for monitoring outpatient Oncology patients at home. Clinical poster JL913. Presented at JADPRO Live Virtual, October 7-17, 2021.)
Grand rounds provide an opportunity for oncology advanced practitioners to discuss quality and safety across disciplines and may have positive effects on patient outcomes. This formal discussion group created a “new forum for oncology APs who were otherwise siloed within their own subspecialty. (Ref. Dryden C and Bazzell A. Oncology advanced practice provider quality and safety grand rounds: Development, implementation, and improving patient outcomes. Clinical poster JL914. Presented at JADPRO Live Virtual, October 7-17, 2021.)