Q2 2021 : Additional information and data in acute leukemia
Here is a retrospective on additional data and information published in the second quarter of 2021.
On May 25, 2021, the European Commission approved venetoclax with a hypomethylating agent for adult patients with newly diagnosed AML who are ineligible for intensive chemotherapy. Venetoclax is a first-in-class B-cell lymphoma-2 (BCL-2) selective inhibitor that promotes leukemic cell apoptosis, and it is administered in combination with azacitidine, decitabine, or low‑dose cytarabine. (Source: https://news.abbvie.com/news/press-releases/abbvie-receives-european-commission-approval-venclyxto-venetoclax-in-combination-with-hypomethylating-agent-for-patients-with-newly-diagnosed-acute-myeloid-leukemia-who-are-ineligible-for-intensive-chemotherapy.html )
The antibody CLN-049 received investigational new drug clearance from the U.S. FDA, to test a differentiated treatment approach by targeting extracellular FLT3, for the treatment of relapsed/refractory AML. (Source: https://markets.businessinsider.com/news/stocks/cullinan-oncology-receives-investigational-new-drug-ind-clearance-from-the-fda-for-cln-049-a-flt3-x-cd3-bispecific-antibody-for-the-treatment-of-relapsed-refractory-aml-1030499485)
The FDA has cleared an IND application for GDX012 to be examined as a therapy for patients with hematologic malignancies. GDX012 is an allogeneic variable delta 1 gamma delta T-cell therapy based on Vδ1 γδ T cells, a subset of T cells that recognize and are activated by molecular patterns of dysregulation on cancer cells. GDX012 also received FDA orphan drug designation for the treatment of AML. (Source: GammaDelta press release, May 20, 2021)
On 29th June, FDA grants fast track designation to SNDX-5613, an oral menin inhibitor for the treatment of adult & pediatric patients with R/R acute leukemias who have mixed lineage leukemia rearranged or an NPM1 mutation.
Hypomethylating agents (HMA) in combination with venetoclax have been widely adopted as the standard of care for patients who cannot tolerate induction chemotherapy and for patients who have relapsed/refractory AML. A recent showed that HMA + venetoclax can lead to impressive response rates with moderately durable remissions and survival. However, the benefits of this combination are diminished by the significant toxicities from infection, persistent cytopenias, and transfusion requirements. These findings require further investigation, including corroboration with larger cohorts of HMA + VEN treated patients, and need to be more systematically studied. (Ref. Feld et al. https://journals.lww.com/hemasphere/subjects/Myeloid%20Malignancies/Fulltext/2021/04000/Safety_and_Efficacy__Clinical_Experience_of.1.aspx)
A recent spate of approvals of targeted treatments, such as FLT3 and IDH1/2 inhibitors for AML, introduced major changes in the treatment of myeloid malignancies. Recently, across the spectrum of hematologic malignancies, cellular therapies are gaining traction. Now, as scientists better understand the biology of myeloid malignancies, cellular approaches are poised to overtake targeted treatments as the “next big thing” in myeloid malignancies. Read the full article: https://www.ashclinicalnews.org/spotlight/feature-articles/cellular-therapies-hold-promise-myeloid-malignancies/
What is the real-world experience of relapsed/refractory AML treatment with venetoclax and hypomethylating agents (HMAs)? In this video, DiNardo explains how the response rate of this regimen compares to other salvage chemotherapy options. She highlights that patients in the relapse setting have a higher chance of responding to this HMA regimen, including patients with diploid cytogenetics or MPN1, IDH1, and IDH2 mutations.
“There is hope that these cellular therapies will improve outcomes, but development is still in early stages.”
Patients over 65 who are newly diagnosed with AML currently have a poor prognosis, due to the toxicity and limited efficacy associated with high-intensity chemotherapy. A recent study has shown data demonstrating potential use of azacitidine as a backbone in induction and consolidation therapy combinations for elderly patients with AML, as opposed to LDAC. (Source: https://aml-hub.com/medical-information/flugaza-trial-azacitidine-vs-semi-intensive-chemotherapy-for-older-patients-with-newly-diagnosed-aml)
In patients with isocitrate dehydrogenase (IDH)–mutated AML treated by intensive chemotherapy, prognostic significance of co-occurring genetic alterations and allogeneic hematopoietic stem cell transplantation are of particular interest with the advent of IDH1/2 mutant inhibitors. A retrospective study is showing that the presence of NPM1 mutation is the primary prognostic factor for OS in IDH1– or IDH2R140-mutated AML treated by IC. Findings would need to be confirmed by additional trials. (Ref. Duchmann et al, 2021, https://doi.org/10.1182/blood.2020010165).
Findings from a first-in-human study show promising clinical activity for patients with relapsed and/or refractory FLT3-mutated AML treatment with the selective and irreversible FLT3 inhibitor. The findings of this early-phase study need to be confirmed in larger trials. (Ref. Levis MJ, Smith C, Perl AE, et al. Phase 1 first-in-human study of irreversible FLT3 inhibitor FF-10101-01 in relapsed or refractory acute myeloid leukemia. Abstract #7008. Presented at the 2021 American Society of Clinical Oncology Annual Meeting, June 4-8, 2021).
Olutasidenib, an investigational IDH1 inhibitor selective for mutant IDH1, was well tolerated and associated with durable complete remissions in patients with high-risk, relapsed/refractory IDH1-mutated AML according to interim findings from a phase II trial. (Ref. De Botton S, Yee KWL, Recher C, et al. Effect of olutasidenib (FT-2102) on complete remissions in patients with relapsed/refractory (R/R) mIDH1 acute myeloid leukemia (AML): Results from a planned interim analysis of a phase 2 clinical trial. Abstract #7006. Presented at the 2021 American Society of Clinical Oncology Annual Meeting, June 4-8, 2021).
In a small study of patients with IDH1-mutated myeloid malignancies, treatment with ivosidenib plus venetoclax, with or without azacitidine, had an acceptable safety profile and led to high rates of complete responses in patients with AML.The study is continuing to enroll patients and these initial results will need to be confirmed in larger studies. (Ref. Lachowiez CA, Borthakur G, Loghavi S, et al. A phase Ib/II study of ivosidenib with venetoclax +/- azacitidine in IDH1-mutated myeloid malignancies. Abstract #7012. Presented at the 2021 American Society of Clinical Oncology Annual Meeting, June 4-8, 2021)
Initial findings from a proof-of-concept study suggest that UniCAR, a universal, rapidly switchable second-generation chimeric antigen receptor (CAR) T-cell therapy platform, could offer a new treatment option for patients with relapsed/refractory AML. (Ref. Mareschal S, Palau A, Lindberg J, et al. Challenging conventional karyotyping by next-generation karyotyping in 281 intensively treated patients with AML. Blood Adv. 2021;5:1003-1016. https://doi:10.1182/bloodadvances.2020002517 )
Compared with conventional cytogenetic analysis (CCA), next generation sequencing (NGS)–based karyotyping offered greater insight into the prognosis of patients with intensively treated AML particularly through its ability to better detect copy number alterations (CNAs). Preliminary findings suggest that NGS-based approaches, given their increased precision and sensitivity, could replace CCA for karyotyping. but also emphasize the need for future research to investigate and develop new NGS-based prognostic markers. This may also improve individualized AML treatment. (Ref. Mareschal S, Palau A, Lindberg J, et al. Challenging conventional karyotyping by next-generation karyotyping in 281 intensively treated patients with AML. Blood Adv. 2021;5:1003-1016. http://doi:10.1182/bloodadvances.2020002517)
In the international randomized phase 3 RATIFY (Randomized AML Trial In FLT3 in patients less than 60 Years old) trial, the multikinase inhibitor midostaurin significantly improved overall and event-free survival in patients 18 to 59 years of age with FLT3-mutated AML. However, only 59% of patients in the midostaurin arm achieved protocol-specified complete remission (CR), and almost half of patients achieving CR relapsed. A recent study explored the mechanisms of resistance and the patterns of clonal evolution and had shown that at the time of disease resistance or progression, ∼50% of patients treated with midostaurin become FLT3-ITD negative and that FLT3-ITD persistence can be caused by selection of resistant FLT3 clones, mechanisms bypassing FLT3 inhibition, or insufficient drug activity. (Ref. Schmalbrock et al., https://doi.org/10.1182/blood.2020007626)
Patients’ negative perception of the side effects of intensive chemotherapy for AML may be associated with undertreatment and worse outcomes, according to results of an international study. It shows There is a need for more patient education and resources about the lived treatment experience, to enhance understanding and mitigate pre-conceived notions of side effects. (Ref. Maze D, Walter RB, Merino DM, et al. A mixed methods study exploring the role of perceived side effects on treatment decision-making in older adults with acute myeloid leukemia (AML). Abstract #7016. Presented at the 2021 American Society of Clinical Oncology Annual Meeting, June 4-8, 2021).
How well do patients cope with intensive induction therapy? LeBlanc discusses a mediation analysis on data from a randomized trial investigating coping strategies in patients with AML who received integrated palliative care, alongside intensive induction therapy.
A study analyzing genetic data from more than 3,000 patients with AML identified 14 distinct molecular subgroups of the disease, each associated with distinct clinical presentation and outcomes. The investigators used this information to develop a unified framework for disease classification and risk stratification that could be adopted in the clinic and incorporated cytogenetic data and the 32 identified genes into an open-access online calculator that considers molecular, clinical, and demographic parameters to guide individualized patient management. (Ref. Tazi Y, Arango JE, Zhou Y, et al. A unified classification and risk stratification algorithm to support clinical decisions in acute myeloid leukemia. Abstract #S133. Presented at the EHA2021 Virtual Congress, June 9-17, 2021)
For older patients with AML who are ineligible for intensive treatment, the standard of care includes venetoclax incorporated into a low-intensity regimen of low-dose cytarabine or hypomethylating agents (HMA + Ven). Some molecular subgroups (NPM1, IDH1/2, TP53) have been identified as predictive of venetoclax sensitivity or resistance, but outcomes in other molecular subgroups remain to be defined and, though spliceosome mutations have historically been linked to poor outcomes, venetoclax-based therapy may attenuate these negative prognostic effects. (Source: https://aml-hub.com/medical-information/hma-venetoclax-may-improve-outcomes-in-patients-with-splicing-mutations?fbclid=IwAR0_049Q9dVpZGG5axaX-ayYS1nalvgNCmPAUo2_ia0HCevS3M-87BBG0xQ)
Patients with relapsed or refractory (r/r) AML have a poor prognosis and treatment remains challenging. For the majority of r/r patients, allogeneic hematopoietic stem cell transplantation is the only curative treatment approach. Salvage therapy is given in order to reduce the leukemia load prior to transplantation. Here is a complete review from Thol et al. https://journals.lww.com/hemasphere/Fulltext/2021/06000/Treatment_for_Relapsed_Refractory_Acute_Myeloid.2.aspx?context=LatestArticles
A recent study shown that adding short-term venetoclax to an intensive FLA-IDA chemotherapy regimen proved safe and led to high rates of overall response and MRD negativity in patients with relapsed/refractory AML.The findings from this report are promising, they concluded, although they are limited by the small patient population. (Ref. Shahswar R, Beutel G, Gabdoulline R, et al. FLAVIDA chemotherapy induces MRD-negative remission in patients with relapsed/refractory acute myeloid leukemia. Abstract #S139. Presented at the EHA2021 Virtual Congress, June 9-17, 2021).
Which R/R AML subgroups would benefit from enasidenib treatment?DiNardo begins by explaining the importance of an IDH2 mutation for the efficacy of this targeted inhibitor. She then reports on promising results from the enasidenib versus conventional care regimens trial.
The FDA has approved a revised label for liposomal daunorubicin and cytarabine, CPX 351, to include a new indication for the treatment of newly diagnosed secondary AML or AML with myelodysplasia-related changes in children aged one year and older. (Source; Source: Jazz Pharmaceuticals press release, March 30, 2021)
For patients with MDS or low-blast secondary AML, allogeneic hematopoietic cell transplantation (AHCT) is the only potentially curative treatment option. However, debate persists around the balance of benefits and risks associated with disease reduction using hypomethylating agents or induction chemotherapy prior to transplantation. Experts agree to say that we need proper randomized studies using an active agent. The UniCAR platform uses targeting molecule TM123 and a single-chain variable fragment that is directed against the CD123 antigen. Since the time of the study’s publication, all patients have demonstrated a clinical response to treatment. A partial remission was observed in one patient, while two patients had complete remission with incomplete hematologic recovery (CRi). In one patient with CRi, the disease was still under control approximately 100 days after administration of treatment, while the other patient with CRi experienced regrowth after one month. (Ref: Wermke M, Kraus S, Ehninger A, et al. Proof-of-concept for Rapidly Switchable Universal CAR-T Platform with UniCAR-T-CD123 in relapsed/refractory AML. Blood. 2021 Feb 23. [Epub ahead of print])
The standard treatment for pediatric de novo AML treatment includes intensive chemotherapy for remission induction, followed by remission maintenance with intensive chemotherapy and/or hematopoietic stem cell transplantation. Although progress has been made in reducing early death rates and overall treatment-related mortality, long-term effects of intensive chemotherapy in conjunction with deficient supportive care and stagnant overall survival rates remain a cause of concern, especially in low- and middle-income countries.
Treatment refusal and death as a result of toxicity account for most treatment failures among children with AML in resource-constrained settings. A recent study reported the results of treating children with AML with a combination of low-dose cytarabine and mitoxantrone or omacetaxine mepesuccinate with concurrent granulocyte colony-stimulating factor (G-CSF) (low-dose chemotherapy [LDC]) for remission induction followed by standard postremission strategies and provided long-term follow-up:
-Most children with de novo AML experience complete hematologic remission when treated with minimally myelosuppressive therapy plus G-CSF.
-Reduced-intensity induction decreases toxicity without adversely affecting the long-term outcomes in children with newly diagnosed AML.
(Ref. Hu Y, Chen A, Gao L, et al. Minimally myelosuppressive regimen for remission induction in pediatric AML: Long-term results of an observational study. Blood Adv. 2021;5(7):1837-1847. DOI: 1182/bloodadvances.202000345)
Being overweight or obese during B-cell ALL induction is associated with chemoresistance as quantified by minimal residual disease (MRD). A study shown that integrating caloric restriction into B-ALL induction is feasible, reduces fat gain in the overweight, and improves disease response. The IDEAL trial is the first prospective trial to test caloric and nutrient restriction plus exercise as a therapeutic modality to improve chemotherapy efficacy and disease response in a hematologic malignancy. (Ref. Ortan et al., 2021 https://doi.org/10.1182/bloodadvances.2020004018)
AUTO1 CAR T cells from pediatric ALL patients who still had CAR T cells detectable in the blood more than two years after their treatment were compared with patients who had lost their AUTO1 CAR T cells one to two months post treatment. The study shows that a subset of AUTO1 CAR T cells called Stem Cell Memory T-cells (TSCM) appear critical in both the initial anti-leukemic response and for long term immune surveillance. This suggests that this sub-group of AUTO1 CAR T cells contribute to the long-term durability of effect that AUTO1 has in these patients. (Source: https://autolus.gcs-web.com/news-releases/news-release-details/autolus-therapeutics-announces-additional-nature-publication)
Next-generation sequencing (NGS)-based measurable residual disease (MRD) monitoring in patients with AML is widely applicable and prognostic prior to allogeneic hematopoietic cell transplantation. A study shows that the use of multiple MRD markers per patient improves the diagnostic accuracy. (Ref. Heuser et al., 2021, https://doi.org/10.1182/bloodadvances.2021004367)
First results of a study shown that NGS MRD detected after the first consolidation might provide better prognostic insight than the one after induction chemotherapy. Further prospective and intervention trials are warranted to validate these findings. (Ref. https://doi.org/10.1182/bloodadvances.2020003738)
What advances have there been in biomarkers for AML? Dr Hourigan summarises advances including MRD testing for risk stratification, using a ‘mechanistic hubris’ that moves past using single mutations, and finally, understanding the host microenvironment instead of solely focusing on leukemia biology.
Should pre-transplant MRD be used to guide treatment in AML? Ossenkoppele begins by outlining emerging techniques in MRD, such as next-generation sequencing. He goes on to describe how risk category and MRD status can inform treatment decisions, such as for allogeneic stem cell transplant. Link to podcast: https://play.acast.com/s/8df04782-19f8-5575-9fa5-3d7a8cefad7e/60cb333616c352001ac64c4d
A recent study published in Leukemia & Lymphoma examined one-month mortality and overall survival (OS) data of patients diagnosed with acute promyelocytic leukemia (APL) between 2004 and 2015 who were treated in real-world practices across the U.S. The study sought to determine whether real-world outcomes mirrored those observed in clinical trials.
“Although outcomes have continued to improve over time, there are challenges associated with translating clinical trial findings to real-world practice,” the authors concluded. “Our findings highlight the need for continued research and studies aimed at improving outcomes of APL in the real world, particularly among older adults.” (Ref. Dhakal P, Lyden E, Rajasurya V, et al. Early mortality and overall survival in acute promyelocytic leukemia: Do real-world data match results of the clinical trials? [published online ahead of print, 2021 Mar 12]. Leuk Lymphoma. doi:10.1080/10428194.2021.1894651.)
Remote monitoring and treatment of cancer and treatment-related symptoms during the COVID-19 pandemic was associated with significant reductions in symptom burden and improvements in quality of life, at least during the first two months of remote monitoring.
How does COVID-19 affect outcomes in AML? Gavrilina evaluates treatment outcomes, risk factors, prognosis, and mortality rates related to patients with AML and SARS-CoV-2 infection in a real-world setting.