Q3 2021: Additional information and data in acute leukemia
With increasing diversity of advances in the treatment of AML, the need for anti-fungal prophylaxis against infection has also evolved. In the updated 2021 EHA guidelines, the recommendations are to follow the existing guidelines and where the evidence is limited, consideration should be given to individual patient factors and the clinical setting to decide on the appropriate antifungal agents. The risk of potential toxicity and drug-drug interaction in the specific patient population and whether a strong inhibitor is present should also be considered. (Ref Stemler J, Skoetz N, de Jonge N, et al. Antifungal prophylaxis in acute myeloid leukemia treated with novel agents. Oral abstract #S281. European Hematology Association 2021 Virtual Congress; Jun 11; Virtual https://library.ehaweb.org/eha/2021/eha2021-virtual-congress/324689/jannik.stemler.eha.guideline.antifungal.
A recent study shown that although the use of less-intensive therapies is associated with an increased risk of mortality in older patients with AML patients treated with these therapies also spend fewer days in the hospital. This study is the first step of reevaluating the role of intensity of therapy in AML and older patients that eventually could lead to improvement in the overall outcomes. It also highlights the importance of considering geriatric assessment for older patients with AML “to get a better sense of their overall health and not to rely on standard measures such as performance status scales or merely age”. (Ref: Sorror ML, Storer BE, Fathi AT, et al. Multi-site 11-year experience of less-intensive versus intensive therapies in acute myeloid leukemia. [published online ahead of print, 2021 Apr 28]. Blood. doi: 10.1182/blood.2020008812).
The use of combination chemotherapy, hypomethylating agents and/or hematopoietic stem cell transplantation are the current standard of treatment for AML. However, despite the many clinical benefits conferred by treatments for AML, health practitioners are facing challenges in managing associated toxicities that impact on the quality of life of patients. Treatment-related adverse events such as cardiotoxicity, hepatotoxicity, gastrointestinal toxicity, hematologic toxicity, immunological and pulmonary toxicity are common in patients with AML and contribute to treatment discontinuation and failure. Ravandi et al. provided updates on the phase III QUAZAR AML-001 trial, with a focus on onset of treatment-related gastrointestinal (GI) adverse events in older patients with AML in first remission receiving oral azacitidine, along with the toxicity management criteria. Awareness about the possibility for GI events during early oral azacitidine treatment will facilitate patients and clinicians to pre-plan and introduce prophylaxis and symptomatic interventions, which in turn will increase treatment adherence and better outcomes. (Ref. Ravandi F, Pocock C, Selleslag D, et al. Gastrointestinal events and management strategies for patients with acute myeloid leukemia in first remission receiving oral azacitidine (CC-486) maintenance therapy in the randomized, placebo-controlled, phase III QUAZAR® AML-001 trial. Presentation #1036. ASH 2020; Dec 5−8, 2020; Virtual)
A phase III study has recently shown that Oblimersen (G3139) can be safely added to conventional chemotherapy for older patients with AML. The addition of G3139 to chemotherapy failed to improve outcomes of older AML patients, but patients with secondary AML had improved disease-free survival. (Ref. Walker AR, Marcucci G, Yin J, et al. Phase 3 randomized trial of chemotherapy with or without oblimersen in older AML patients: CALGB 10201 (Alliance). Blood Adv. 2021;5(13):2775-2787. DOI: 10.1182/bloodadvances.2021004233)
In a study presented at EHA2021 Virtual, 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. (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)
IDH1 inhibitor ivosidenib in combination with azacitidine, showed improved survival compared to azacitidine monotherapy for treatment of IDH1-mutated AML in global phase 3 trial AGILE.
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. (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)
The FDA grants clearance for investigational new drug application for SYK inhibitor lanraplenib allowing for a phase I/II trial for combination therapy with FLT3 inhibitor gilteritinib in patients with R/R, FLT3-positive AML.
Less-intensive induction therapies are increasingly used in older patients with AML. Using an AML composite model. A study showed that in 2 cohorts, less-intensive therapies increased mortality in each of 3 risk groups defined by age, comorbidities, and cytogenetics. (Ref. https://doi.org/10.1182/blood.2020008812).
A recent trial showed that mutations in 7 genes independently predict overall survival in distinct cytogenetic groups of patients with AML aged ≥60 years and treated intensively. This led to report and validate a simple genetic model to identify older patients with AML with very good, intermediate, or poor outcome with 7 + 3. (Ref. https://doi.org/10.1182/blood.2021011103)
A novel tumor suppressor in AML called gene gamma GADD45g has been caracterized and shown to exert selective and potent antileukemic activities. GADD45g activation may be exploited therapeutically for treatment of FLT3-ITD+ and MLL-AF9+ AML by combining romidepsin with AC220 or JQ1. (Source: https://doi.org/10.1182/blood.2020008229)
First-in-Human study finds FF-10101-01 has clinical activity associated with high relapse and low survival/remission rates in relapsed/refactory FLT3-mutated AML. 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).
How could new treatment combinations improve outcomes in TP53 mutant AML?
How has acute myeloid leukemia treatment in elderly people changed in 2021?
Treatment outcomes for pediatric patients with AML have continued to lag behind outcomes reported for children with ALL, in part because of the heterogeneity of the disease, a paucity of targeted therapies, and the relatively slow development of immunotherapy compared with ALL. In addition, we have reached the limits of treatment intensity, and, even with outstanding supportive care, it is highly unlikely that further intensification of conventional chemotherapy alone will impact relapse rates. However, comprehensive genomic analyses and a more thorough characterization of the leukemic stem cell have provided insights that should lead to tailored and more effective therapies in the near future. In addition, new therapies are finally emerging, including the BCL-2 inhibitor venetoclax, CD33- and CD123-directed chimeric antigen receptor T-cell therapy, CD123-directed antibody therapy, and menin inhibitors. Here, we present 4 cases to illustrate some of the controversies regarding the optimal treatment of children with newly diagnosed or relapsed AML.
Hematopoietic stem cell transplant (HSCT) in patients with AML is often followed by maintenance therapy to prolong remission. Currently, there are no universally accepted standard maintenance therapies, leaving patients and physicians to determine which treatment to use by assessing the risk/benefit of the different options available. Manasee Shah and colleagues, investigated these preferences for post-HSCT treatment of AML using a discrete choice experiment. The study showed that there were differences between the attributes deemed to be important between patients and physicians when selecting post-HSCT maintenance therapy. Although both groups valued QoL, physicians valued duration of hospitalization less than patients, it also highlighted the importance of conversations between physicians and patients to fully understand patient treatment goals and preferences when determining the post-HSCT maintenance treatment. Acknowledging the differences between physician and patient treatment preferences will enable physicians to better select patient-centered treatments. (Ref. Zhou M, Yang H, Song Y, et al. Patient and physician preferences for post–hematopoietic stem cell transplantation maintenance treatment of acute myeloid leukemia. Oral abstract #S313. EHA2021; Jun 11, 2021; Virtual).
How are transplant options evolving for patients with ALL ?
In next-generation sequencing (NGS)-based MRD monitoring, the use of non-DNMT3A, TET2, or ASXL1 (non-DTA) mutations may predict relapse and survival following allogeneic hematopoietic cell transplantation (alloHCT) for patients with AML, according to findings published. (Ref. Heuser M, Heida B, Büttner K, et al. Posttransplantation MRD monitoring in patients with AML by next-generation sequencing using DTA and non-DTA mutations. Blood Adv. 2021;5(9):2294-2304)
Patients with newly diagnosed AML treated with Ven+Aza who achieved CRc and an MRD response <10−3 had a longer DoR, EFS, and OS compared with those who did not achieve an MRD response (≥10−3). Higher rates of neutropenia were observed in patients that achieved an MRD response compared with those who did not. MRD response was also a significant predictor of OS, however, further studies are required to investigate the role of MRD response in clinical management. (Ref. Pratz KW, Jonas BA, Pullarkat V, et al. Measurable residual disease response in acute myeloid leukemia treated with venetoclax and azacitidine. Oral abstract #S137. European Hematology Association (EHA)2021 Virtual Congress; Jun 11, 2021; Virtual).
NGS has shown reliability in the detection of specific mutations at both time of diagnosis and complete remission in patients with AML. However, NGS-based MRD detection, has its limitations related to sensitivity and specificity, and its inability to differentiate between residual and clonal hematopoiesis. There is limited evidence on the role of NGS-MRD in patients with AML receiving allogeneic hematopoietic cell transplantation (allo-HSCT). A recent shown that the prognostic impact of detectable mutations at each pre-specified time point was correlated to the conditioning intensity. Persistent mutations were associated with higher risks of relapse and mortality both at pre-HSCT and post-HSCT-1m, and there was an advantage of serial NGS-MRD monitoring after allo-HSCT. The practicality of NGS-MRD monitoring will enable future studies investigating the feasibility of MRD-based approaches to reduce relapse in patients with AML. (Ref. Kim HJ, Kim Y, Kang D, et al. Prognostic value of measurable residual disease monitoring by next-generation sequencing before and after allogeneic hematopoietic cell transplantation in acute myeloid leukemia. Blood Cancer J. 2021;11(6):109. DOI: 1038/s41408-021-00500-9)
In this video, Chiaretti discusses the feasibility of improving the results of a chemotherapy-free regimen with dasatinib for patients with newly diagnosed Ph+ ALL.
Despite the availability of novel therapies, clinical outcomes remain poor in the 10‒20% of pediatric and adolescent patients with B-cell acute lymphoblastic leukemia (B-ALL) who relapse after initial therapy. The autologous CART-cell therapy KTE-X19 is currently being evaluated for the treatment of children, adolescents, and adults with other B-cell malignancies. The phase I ZUMA-4 study (NCT02625480) is investigating KTE-X19 in pediatric and adolescent patients with R/R B-ALL, and the long-term results elicited that no dose-limiting toxicities were reported, and that reported AEs were consistent with those known to be associated with CAR T-cell therapy. The 40 mL dose of 1 × 106 CAR T cells/kg was shown to be the optimal formulation of KTE-X19 for the treatment of children and adolescents with R/R B-ALL, as this formulation was associated with an improved safety profile compared with the other dose formulations, while maintaining high rates of minimal residual disease negativity and CR + CRi rates in this patient population. Therefore, this dose was selected for the phase II ZUMA-4 trial, which is currently enrolling pediatric patients with R/R B-ALL. (Ref. Wayne AS. ZUMA-4 phase 1 long-term results: KTE-X19 chimeric antigen receptor T-cell therapy in pediatric/adolescent patients with relapsed/refractory B-cell acute lymphoblastic leukemia. E-Poster #EP341. 26th European Hematology Association Annual Congress; Jun 11, 2021; Virtual).
How are transplant options evolving for patients with ALL?
Asparaginase Erwinia chrysanthemi (recombinant)-rywn has been approved by the FDA as part of a treatment regimen for adult and pediatric patients with ALL who have developed hypersensitivity to E. coli-derived asparaginase. Source: FDA press release, June 30, 2021.
A recent study showed that genomic testing leads to improved risk assignment in most adult patients with BCR-ABL1− B-ALL and antigen profiles affect outcome in B-ALL when considered in conjunction with genomic subtype. This prognostic importance of genomic analyses, which may translate into future therapeutic benefits. (Ref. https://doi.org/10.1182/blood.2020010144)
APL is a subtype of AML involving complex coagulopathy resulting in early mortality due to hemorrhagic events. Currently, all-trans retinoic acid (ATRA) with arsenic trioxide (ATO) is used as a frontline treatment in low-risk APL patients with excellent cure rates. The use of ATRA with ATO for high-risk APL patients is also under investigation. Despite the benefits offered by ATRA + ATO therapy, there are reports of varicella-zoster virus (VZV)—the causative agent of herpes zoster (HZ)—reactivation in APL patients treated with ATO.
There is a variety of effective therapeutic agents in use to treat AML where each one of them has a distinctive mechanism of action and unique toxicity profile. However, awareness about the impact of adverse events of any treatment, and knowledge about the extent to which a patient can bear the treatment, allows to maintain a balance between prolonging survival and the quality of life of patients.
Strategies to stimulate normal production of CD4+ T cells and/or balance Tregs during the first 6 months of ATO therapy are needed to effectively control herpes zoster reactivation risk. (Ref. Glass JL, Derkach A, Hilden P. Arsenic trioxide therapy predisposes to herpes zoster reactivation despite minimally myelosuppressive therapy. Leuk Res. 2021;106:106569. DOI: 1016/j.leukres.2021.106569)
Despite therapeutic advances, early death (ED) remains a major factor curtailing survival of APL. A recent study showed that early death after hospital admission remains one of the major determinants of outcome in APL in the modern era and that delays in administration of ATRA and hypofibrinogenemia are major predictors of early death. (Ref. https://doi.org/10.1182/bloodadvances.2021004789)
COVID-19 and Vaccination
In an amendment to its emergency use authorization for the Pfizer-BioNTech and Moderna COVID-19 vaccines, the U.S. FDA authorized a third dose of the shots for certain immunocompromised individuals.
People who have received solid organ transplants or who are considered to have an equivalent level of immunocompromise due to medical conditions are especially vulnerable to severe COVID-19 infection and may not have gotten adequate protection from the two-dose vaccine regimen. The FDA determined that a third dose may increase protection in these patients, but recommends they continue physical precautions to prevent infection. Those who are eligible for a booster shot are authorized to receive a third dose at least 28 days following the two-dose regimen of the same vaccine.
Source: FDA press release, August 12, 2021.
Infection with SARS-CoV-2 can be severe in patients receiving stem cell transplants especially for allo-HSCT recipients with a fatality rate of almost 30% in this group. In addition, severity of COVID-19 was linked to history of Grade 2–4 aGvHD and immunosuppression therapy.
In terms of vaccination, both vaccines examined in patients undergoing HSCT appear to be well tolerated with no new safety signals being recorded following at least one dose of the vaccination. There was an incidence of 9.7% of new cases of chronic GvHD and a low rate of worsening chronic GvHD symptoms (3.5%), though causality to the vaccines could not be established given the retrospective nature of the study.
While the efficacy of these vaccines remains unclear in this patient population, given the increased risk of severe or fatal COVID-19 in allo-HSCT recipients, vaccination is a good option for this group despite any potential activation of inflammatory pathways and immune-related adverse events. Vaccination in patients receiving allo-HSCT is supported by recommendations from the American Society of Hematology, the National Comprehensive Cancer Network and the American Society for Transplantation and Cellular Therapy.
- Mushtaq MU, Shahzad M, Chaudhary SG, et al. Impact of SARS-CoV-2 in hematopoietic stem cell transplantation and chimeric antigen receptor T cell therapy recipients. Transplant Cell Ther. 2021. Online ahead of print. DOI: 1016/j.jtct.2021.07.005
- Ali H, Ngo D, Aribi A, et al. Safety and tolerability of SARS-CoV-2 emergency-use authorized vaccines allogeneic hematopoietic stem cell transplant recipients. Transplant Cell Ther. Online ahead of print. DOI: 10.1016/j.jtct.2021.07.008
Acute leukemias and MDS
In patients with acute leukemias or myelodysplastic syndromes (MDS), those who underwent haploidentical relative hematopoietic cell transplantation (haploHCT) had higher rates of grade 3-4 graft-versus-host disease and mortality compared with those who underwent HCT with a matched unrelated donor (MUD), according to results recently published. These preliminary results would need to be investigated further. (Ref. Gooptu M, Romee R, St Martin A, et al. HLA Haploidentical versus matched unrelated donor transplants with post-transplant cyclophosphamide based prophylaxis. [published online ahead of print, 2021 Apr 13]. Blood. doi: 10.1182/blood.2021011281)
Open survey : Understanding patient’s burden, quality of life, and alignment of patient-reported outcome measures to capture changes in high-risk MDS/AML.
Link to participate to the survey: https://www.mdsqualityoflifestudy.com/delphi-contact-information
On July 21, 2021, the U.S. FDA granted breakthrough therapy designation to venetoclax (in combination with azacitidine) for the treatment of adult patients with previously untreated intermediate- to very high-risk myelodysplastic syndromes (MDS). This approval was based on the results of the phase Ib M15-531 study. (https://www.businesswire.com/news/home/20210720006307/en/FDA-Grants-Breakthrough-Therapy-Designation-for-Venclexta-in-Combination-With-Azacitidine-for-the-Treatment-of-Patients-With-Myelodysplastic-Syndromes. Published Jul 21, 2021)
End of life
Patients with AML and their caregivers generally defer end-of-life (EOL) transfusion decisions to clinicians without participating in shared decision-making. This tendency may delay hospice admission in patients who would benefit from this care the most, according to a new study published. This research adds to a multitude of other studies suggesting hematologists struggle to navigate care decisions for patients and families at the EOL. We know patients with blood cancers are more likely than those with solid tumors to die in the hospital, spend time in an intensive care unit or emergency department near the EOL, or to receive chemotherapy in the last two weeks of life. Hematologic patients are also less likely to use hospice care services overall. (Ref. Cripe LD, Cottingham AH, Martin CE, Hoffmann ML, Sargent K, Baker LB. Bereaved informal caregivers rarely recall a relationship between transfusions and hospice in acute myeloid leukemia [published online ahead of print, 2021 Apr 29]. Am J Hosp Palliat Care. doi: 10.1177/10499091211013290)
Discussions about possible infertility in young patients with cancer should happen early, and often.
Chemotherapy, radiation, and hematopoietic cell transplantation (HCT) are essential treatment options for patients with hematologic malignancies, but these therapies often harm patients’ reproductive health and future fertility. Nevertheless, a survey of nearly 7,000 patients of reproductive age who were diagnosed with cancer found that more than half did not receive counseling about the risk of infertility associated with cancer treatments.
With recent treatment advances for many cancers, survival rates have improved. Patients are living longer after a cancer diagnosis and conversations about future fertility are now considered an essential part of patient management and survivorship care for young adults, adolescents, and even prepubertal children.
“Several studies have found that, when you ask young adult survivors of cancer what they worry about related to their health, infertility is often one of the top concerns.”