Q3 2023: Additional information and data in acute leukemia

September 27, 2023
AML

Olutasidenib (FT-2102) induces durable complete remissions in patients with relapsed or refractory IDH1-mutated AML: 

Olutasidenib is a new, selective small molecule inhibitor of IDH1 recently approved by the FDA; thus, it has become the second approved IDH1-targeted agent for the treatment of relapsed/refractory IDH1 mutant acute myeloid leukemia (AML). Overall response rate was 48% with complete remission/incomplete blood count recovery of 35%, and, importantly, response rates were similar in patients who had and who had not received prior venetoclax. (Ref: https://doi.org/10.1182/bloodadvances.2022009411)

FLT3-ITD does not predict inferior prognosis in AML patients aged ≥60 years

FLT3 internal tandem duplications (ITD) mutations are found in 25% of patients with AML. In younger patients, FLT3-ITD is associated with increased relapse and decreased survival. However, there are limited data on the prognostic implication of FLT3-ITD+ in older patients (aged ≥60 years) who received treatment, particularly, after the approval of FLT3 inhibitors and venetoclax.

Findings from a recent study suggest that among older patients, the presence of FLT3-ITD+ may not be of major prognostic value and that allo-SCT should be pursued, when possible, irrespective of initial therapy in older patients with AML, including in those with FLT3-ITD+. (Ref. https://doi.org/10.1182/bloodadvances.2023009748)

Impact of type of induction therapy on outcomes in older adults with AML after allogeneic stem cell transplantation:

Although venetoclax-based lower-intensity regimens have greatly improved outcomes for older adults with AML who are unfit for intensive chemotherapy, the optimal induction for older patients with newly diagnosed AML who are suitable candidates for hematopoietic stem cell transplant (HSCT) is controversial. A single site study analyzed the post HSCT outcomes of 127 patients ≥60 years of age who received induction therapy with intensive chemotherapy (IC; n = 44), lower-intensity therapy (LIT) without venetoclax (n = 29), or LIT with venetoclax (n = 54) and who underwent allogeneic HSCT in the first remission. The 2-year relapse-free survival (RFS) was 60% with LIT with venetoclax vs 54% with IC, and 41% with LIT without venetoclax; the 2-year overall survival (OS) was 72% LIT with venetoclax vs 58% with IC, and 41% with LIT without venetoclax. The benefit of LIT with venetoclax induction was greatest in patients with adverse-risk AML (2-year OS: 74%, 46%, and 29%, respectively). Induction with LIT, with or without venetoclax, was associated with the lowest rate of nonrelapse mortality (NRM) (2-year NRM: 17% vs 27% with IC; P = .04). Using multivariate analysis, the type of induction therapy did not significantly affect any of the post HSCT outcomes evaluated; hematopoietic cell transplantation-specific comorbidity index was the only factor that independently predicted RFS and OS. LIT plus venetoclax followed by HSCT is a feasible treatment strategy in older, fit, HSCT-eligible patients with newly diagnosed AML and may be particularly beneficial for those with adverse-risk disease. (ref: https://doi.org/10.1182/bloodadvances.2022009632)

Phase 2 study of PD-1 blockade following autologous transplantation for patients with AML ineligible for allogeneic transplant

Allogeneic transplant remains the best postremission therapy for patients with nonfavorable risk AML. However, some patients are ineligible because of psychosocial barriers, such as lack of appropriate caregiver support. A phase 2 study of autologous transplantation followed by administration of pembrolizumab (8 cycles starting day +1) was conducted.

Twenty patients with nonfavorable AML in complete remission were treated (median age, 64 years; CR1, 80%); 55% were non-White and adverse-risk AML was present in 40%. Treatment was well tolerated, with only 1 nonrelapse death. Immune-related adverse events occurred in 9 patients. After a median follow-up of 80 months, 14 patients remain alive, with 10 patients in continuous remission. The estimated 2-year LFS was 48.4%, which met the primary end point of 2-year LFS >25%; the 2-year overall survival (OS), nonrelapse mortality, and cumulative incidences of relapse were 68%, 5%, and 46%, respectively. In comparison with a propensity score–matched cohort group of patients with AML receiving allogeneic transplant, the 3-year OS was similar (73% vs 76%). Patients in the study had inferior LFS (51% vs 75%) but superior postrelapse survival (45% vs 14%).

In conclusion, programmed cell death protein–1 blockade after autologous transplant is a safe and effective alternative postremission strategy in patients with nonfavorable risk AML who are ineligible for allogeneic transplant, a context in which there is significant unmet need. (Ref. https://doi.org/10.1182/bloodadvances.2023010477)

ENHANCE 2 study discontinued

Following review by the independent data monitoring committee, Gilead has stopped its ENHANCE 2 study in AML with TP53 mutations as Gilead concluded that magrolimab is unlikely to demonstrate a survival benefit for these patients compared to standard of care. www.gilead.com

ALL

Lenalidomide-associated B-cell ALL: clinical and pathologic correlates and sensitivity to lenalidomide withdrawal

Lenalidomide is an integral component of current therapy for multiple myeloma but carries a risk of secondary malignancies, even in the absence of traditional cytotoxic therapies. This study by Geyer and colleagues examines therapy-related acute lymphoblastic leukemia (ALL) arising in the context of multiple myeloma treated with lenalidomide and highlights the need to understand leukemogenic effects of prolonged lenalidomide maintenance and the potential of lenalidomide to act as a driver even after initiation of lymphoblastic neoplasia. (Ref: https://doi.org/10.1182/bloodadvances.2022009212)

CAR T-cell therapy for adult B-cell ALL: state-of-the-(C)ART and the road ahead

The introduction of CD19 CAR T-cell therapy has revolutionized the field of B-ALL and other CD19+ B-cell malignancies. With the current generation of approved CAR products, we are seeing very encouraging clinical activity in multiply R/R B-ALL. The toxicities associated with CAR T cells are manageable and most institutions have developed clinical practice algorithms to manage these toxicities. The field of CAR T-cell therapy continues to evolve with several novel constructs, novel targets, and combination targets in clinical development, including trials with allogeneic CARs. In the next few years, we expect to see trials incorporating CAR T cells in earlier lines of therapy with the eventual goal of providing long-term disease control for the majority of the patients with B-ALL. (Ref: https://doi.org/10.1182/bloodadvances.2022009462)

Next-generation sequencing–based MRD in adults with ALL undergoing hematopoietic cell transplantation

MRD is an adverse prognostic factor in adult patients with ALL undergoing hematopoietic cell transplant (HCT). Next-generation sequencing (NGS) can detect MRD with a sensitivity of 10–6, but the prognostic value of NGS-based MRD in adult patients with ALL undergoing HCT remains minimally studied. In a recent study, MRD was assessed before HCT (MRDpre) and up to 1 year after HCT (MRDpost). Patients were followed up for leukemia relapse and survival for up to 2 years after HCT. In total, 158 patients had a trackable clonotype for MRD monitoring. The cumulative incidence of relapse was increased at all levels of MRDpre, including in patients who had low MRDpre of <10–4 (hazard ratio [HR], 3.56; 95% confidence interval [95% CI], 1.39-9.15). In multivariable analysis, MRDpre level remained significantly prognostic; however, detectable MRDpost was the strongest predictor of relapse (HR, 4.60; 95% CI, 3.01-7.02). In exploratory analyses limited to patients with B-cell ALL, the detection of post-HCT immunoglobulin H (IgH) MRD clonotypes, rather than non-IgH MRD clonotypes, was associated with relapse. In this analysis across 2 large transplant centers, we found that the detection of MRD by NGS at a level of 10–6 offers significant prognostic value in adults with ALL undergoing HCT. (Ref: https://doi.org/10.1182/bloodadvances.2023009856)

Effect of BMI on toxicities and survival among adolescents and young adults treated on DFCI Consortium ALL trials

Adolescent and young adults (AYAs) with ALL reated with asparaginase-containing pediatric regimens are commonly overweight or obese. A recent study looked at the association of body mass index (BMI) on outcomes of 388 AYAs aged 15 to 50 years treated on Dana-Farber Cancer Institute (DFCI) consortium regimens (2008-2021). BMI was normal in 207 (53.3%) and overweight/obese in 181 (46.7%). Patients who were overweight or obese experienced higher nonrelapse mortality (NRM; 4-year, 11.7% vs 2.8%, P = .006), worse event-free survival (4-year, 63% vs 77%, P = .003), and worse overall survival (OS; 4-year, 64% vs 83%, P = .0001). Because younger (aged 15-29 years) AYAs more frequently had a normal BMI (79% vs 20%, P < .0001), we conducted separate analyses in each BMI group. An excellent OS was found among younger and older (30-50 years) AYAs with normal BMI (4-year OS, 83% vs 85%, P = .89). Conversely, in AYAs who were overweight/obese, worse outcomes were seen in older AYAs (4-year OS, 55% vs 73%, P = .023). Regarding toxicity, AYAs who were overweight/obese experienced higher rates of grade 3/4 hepatotoxicity and hyperglycemia (60.7% vs 42.2%, P = .0005, and 36.4% vs 24.4%, P = .014, respectively) but had comparable rates of hypertriglyceridemia (29.5% vs 24.4%, P = .29). In a multivariable analysis, higher BMI was associated with worse OS, hypertriglyceridemia was associated with improved OS, and age was not associated with OS.

In conclusion, among AYAs treated on DFCI Consortium ALL regimens, elevated BMI was associated with increased toxicity, increased NRM, and decreased OS. The deleterious effect of elevated BMI was more pronounced in older AYAs. (ref: https://doi.org/10.1182/bloodadvances.2023009976)

CAR-T

Longitudinal patient-reported outcomes in patients receiving chimeric antigen receptor T-cell therapy:

A study showed the longitudinal PROs of patients with relapsed/refractory hematologic malignancies, demonstrating a decline in QOL and an increase in depression symptoms early in treatment, followed by an improvement in QOL, psychological distress, and physical symptom burden 3 and 6 months after CAR-T infusion. A significant minority of patients report substantial psychological and physical symptom burdens throughout the treatment trajectory. Our findings highlight the ability of CAR-T to improve PROs and the unmet need for supportive care interventions to ameliorate the QOL, psychological distress, and physical symptoms throughout the continuum of patient experience. (ref: https://doi.org/10.1182/bloodadvances.2022009117)

GvHD

Late acute graft-versus-host disease (GVHD) is defined as de novo acute GVHD presenting beyond 100 days after allogeneic hematopoietic cell transplantation (HCT) without manifestations of chronic GVHD. A recent study has showed:

  • The cumulative incidence of classic acute GVHD that required systemic treatment was 35.2%, and an additional 5.7% of patients required treatment for late acute GVHD.
  • At the onset of symptoms, late acute GVHD was more severe than classic acute GVHD based on both clinical and MAGIC algorithm probability biomarker parameters and showed a lower overall response rate on day 28.
  • Both clinical and biomarker grading at the time of treatment stratified the risk of nonrelapse mortality (NRM) in patients with classic and late acute GVHD, respectively, but long-term NRM and overall survival did not differ between patients with classic and late acute GVHD.
  • Advanced age, female-to-male sex mismatch, and the use of reduced intensity conditioning were associated with the development of late acute GVHD, whereas the use of posttransplant cyclophosphamide–based GVHD prevention was protective mainly because of shifts in GVHD timing.

Because overall outcomes were comparable, the findings, although not definitive, suggest that similar treatment strategies, including eligibility for clinical trials, based solely on clinical presentation at onset are appropriate. (ref: https://doi.org/10.1182/bloodadvances.2023009885)

CAR-T

Anti-CD19 chimeric antigen receptor (CAR) T-cell therapy is a highly effective treatment option for patients with relapsed/refractory large B-cell lymphoma and ALL. However, widespread use is deterred by the development of clinically significant acute inflammatory toxicities, including cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS), that induce significant morbidity and require close monitoring. Identification of host biochemical signatures that predict the severity and time-to-onset of CRS and ICANS may assist patient stratification to enable timely mitigation strategies.

A study reports on pretreatment host metabolites that are associated with CRS and ICANS induced by axicabtagene ciloleucel or tisagenlecleucel therapy. Both untargeted metabolomics analysis and validation using targeted assays revealed a significant association between the abundance of specific pretreatment biochemical entities and an increased risk and/or onset of clinically significant CRS (q < .1) and ICANS (q < .25). Higher pretreatment levels of plasma glucose and lower levels of cholesterol and glutamate were associated with a faster onset of CRS. In contrast, low baseline levels of the amino acids proline and glycine and the secondary bile acid isoursodeoxycholate were significantly correlated with clinically significant CRS. Lower concentration of the amino acid hydroxyproline was associated with higher grade and faster onset of ICANS, whereas low glutamine was negatively correlated with faster development of ICANS.

Overall, data indicate that the pretreatment host metabolome has biomarker potential in determining the risk of clinically significant CRS and ICANS, and may be useful in risk stratification of patients before anti-CD19 CAR T-cell therapy. (ref. https://doi.org/10.1182/bloodadvances.2022007456)

MDS

Phase 3 ENHANCE (5F9009) study Magrolimab plus Azacitidine in Higher-Risk MDS: Gilead has announced that this study has been discontinued due to futility based on a planned analysis.

Other

Burnout in US hematologists and oncologists: impact of compensation models and advanced practice provider support

Burnout is a significant challenge in medicine, even more so since the beginning of the COVID-19 pandemic. With this in mind, Lee and colleagues questioned practicing hematologists and oncologists through a survey developed by members of the Fitzhugh Mullan Institute for Health Workforce Equity at George Washington University in collaboration with the American Society of Hematology Recruitment and Retention Working Group. The survey assessed practice activities, career satisfaction, participation in medical education and mentoring, compensation, practice setting, and practitioner demographics. Over one third of survey participants reported burnout. (Ref: https://doi.org/10.1182/bloodadvances.2021006140)