Molecular annotation of extramedullary acute myeloid leukemia identifies high prevalence of targetable mutations.

BACKGROUND: Genomic landscape of extramedullary acute myeloid leukemia (EM-AML), including myeloid sarcoma (MS) and leukemia cutis (LC), is not well characterized. The potential utility of next-generation sequencing (NGS) using EM tissue is not established. METHODS: In this multicenter retrospective study, clinical and NGS data were collected on patients with EM-AML. All statistical analyses were performed in SPSS Statistics (v 26). RESULTS: Our study included 58 patients with EM-AML. The median age at diagnosis was 62 years; 59% of patients had MS and 33% had LC. EM-AML was isolated (i.e., without blood or marrow involvement) in 31% and was first noted at relapse in 60% of patients. Median overall survival in our cohort was 18.2 months overall, with 19.1 months and 11.6 months in the newly diagnosed and the relapsed/refractory patients, respectively. At least one targetable or potentially targetable alteration was present in 52% of patients with EM-site NGS, with 26% IDH1, 21% NPM1, 11% IDH2, 6% FLT3, and 13% KMT2A-PTD. Mutations in IDH1 were significantly more prevalent on NGS from EM tissue than non-EM (blood or marrow) samples (26% vs. 3%; p = .030). Three of four patients treated with IDH inhibitors based on EM-site NGS experienced a complete response. CONCLUSIONS: Targetable mutations are frequent in EM-AML and EM-site NGS is warranted for selecting potential targeted therapies for patients with EM-AML.

Acquisition of IDH2 mutations in relapsed/refractory AML is associated with worse patient outcomes.

OBJECTIVES: The presence of targeted therapy, Enasidenib, for IDH2-mutated AML underscores the importance of understanding the clonal dynamics of IDH2 mutations, which has not been elucidated. In the largest study of IDH2 clonal dynamics, we detail the IDH2-evolutionary patterns and their clinical significance. METHODS: We analyzed ~6000 patients with NGS results to identify 120 AML patients with IDH2 mutations and longitudinal NGS testing. IDH2 mutation status was recorded at diagnosis, remission, relapse, and persistent disease. RESULTS: One hundred and five patients were IDH2-positive at the initial diagnosis, and 15 acquired the mutation later. Of those 15 patients, 7 patients gained the mutation during persistent disease, 6 during relapse, and 2 at remission. Twenty-one patients (18%) who were IDH2-positive in a prior test remained IDH2-positive in remission. Twenty-four patients with IDH2-positive AML were IDH2-positive at relapse. IDH2-positive at diagnosis had better survival than IDH2 mutation acquired later in disease (P = .024). Patients who were IDH2-negative in remission had significantly improved survival (P = .002). Also, loss-of-IDH2 mutation with persistent disease had better OS (P = .035). CONCLUSIONS: There are 70% that clear IDH2 in disease remission. 12% gain IDH2 mutation later, usually in the setting of refractory/relapsed AML. These patients fared worse. Longitudinal IDH2 testing may be helpful in prognostic stratification.

Tumor protein 53 mutations in acute myeloid leukemia: conventional induction chemotherapy or novel therapeutics.

PURPOSE OF REVIEW: Tumor protein 53 (TP53) protein is involved in fundamental processes of cancer, aging, and DNA repair. Thus, TP53 dysfunction is implicated in malignant processes and remains the most commonly mutated gene in cancer but represents a relatively small proportion in acute myeloid leukemia (AML). Patients with TP53-mutated AML attain inferior responses to therapy resulting in poor overall outcomes. RECENT FINDINGS: Traditional treatment approaches with conventional chemotherapy yields suboptimal responses for patients with TP53 mutant AML compared with wildtype TP53. In recent years, there is increasing interest in understanding the role and underlying biology of TP53 mutations in AML with efforts to harness the physiological tumor suppressive function of TP53 protein. Novel combination and targeted therapies may contribute to improved outcomes; however, responses to therapy may be short-lived and ongoing research is indicated to evaluate relapse-risk reduction strategies. These patients may benefit from consideration of enrollment in clinical trials or lower intensity therapy approaches in lieu of intensive chemotherapy. SUMMARY: Pharmacological treatments targeting the TP53 pathway in addition to novel emerging therapeutics and immunotherapy-based approaches hold promise for treatment of TP53 mutant AML.

Comparisons of commonly used front-line regimens on survival outcomes in patients aged 70 years and older with acute myeloid leukemia.

In older patients with acute myeloid leukemia, the more frequent presence of biologically inherent therapy-resistant disease and increased comorbidities translate to poor overall survival and therapeutic challenges. Optimal front-line therapies for older patients with acute myeloid leukemia remain controversial. We retrospectively evaluated survival outcomes in 980 elderly (≥70 years) acute myeloid leukemia patients from a single institution between 1995 and 2016. Four treatment categories were compared: high-intensity (daunorubicin/cytarabine or equivalent), hypomethylating agent, low-intensity (low-dose cytarabine or similar without hypomethylating agents), and supportive care therapy (including hydroxyurea). At a median follow up of 20.5 months, the median overall survival for the entire cohort was 7.1 months. Multivariate analysis identified secondary acute myeloid leukemia, poor-risk cytogenetics, performance status, front-line therapy, age, white blood cell count, platelet count, and hemoglobin level at diagnosis as having an impact on survival. High-intensity therapy was used in 360 patients (36.7%), hypomethylating agent in 255 (26.0%), low-intensity therapy in 91 (9.3%), and supportive care in 274 (28.0%). Pairwise comparisons between hypomethylating agent therapy and the three other treatment groups demonstrated statistically significant superior median overall survival with hypomethylating agent [14.4 months) vs high-intensity therapy 10.8 months, hazard ratio 1.35, 95% confidence interval (CI): 1.10-1.65; P =0.004], low-intensity therapy (5.9 months, hazard ratio 2.01, 95%CI: 1.53-2.62; P<0.0001), and supportive care (2.1 months, hazard ratio 2.94, 95%CI: 2.39-3.61; P<0.0001). Our results indicate a significant survival benefit with hypomethylating agents compared to high-intensity, low-intensity, or supportive care. Additionally, high-intensity chemotherapy resulted in superior overall outcomes compared to low-intensity therapy and supportive care. Results from this study highlight the need for novel therapeutic approaches besides utilization of intensive chemotherapy in this specific aged population.

How I treat newly diagnosed acute myeloid leukemia in an outpatient setting: a multidisciplinary team perspective.

Historically, patients with acute myeloid leukemia received intensive chemotherapy requiring hospitalization, which can diminish quality of life and increase healthcare costs. The introduction of new therapies facilitated a shift toward outpatient therapy, which requires coordination of a multidisciplinary team, thorough patient evaluation, careful preparation and rigorous patient monitoring. Many patients are candidates for multiple treatment approaches; we generally employ CPX-351 (Vyxeos®) as an intensive outpatient approach and venetoclax (Venclyxto/Venclexta®) plus hypomethylating agents as a lower-intensity approach, with 2-3 visits/week during treatment. Treatment infusions are scheduled in the morning to leave sufficient time for transfusions and other supportive care later the same day, to prevent additional visits. With careful planning and patient monitoring, acute myeloid leukemia treatment can be successfully administered in the outpatient setting.

Genetically inspired prognostic scoring system (GIPSS) outperforms dynamic international prognostic scoring system (DIPSS) in myelofibrosis patients.

A genetically inspired prognostic scoring system (GIPSS) that stratifies primary myelofibrosis (PMF) patients by genetic variants alone was recently proposed. While non-inferior to the dynamic international prognostic scoring system (DIPSS), the lack of overlapping prognostic variables between the models leads to increased risk for disagreement between two valid prognostic models and presents a challenging clinical situation. In an external cohort of 266 molecularly annotated myelofibrosis (MF) patients, we demonstrated that the GIPSS model significantly differentiated between four risk groups (low, int-1, int-2, high) with median OS that was not reached, not reached, 60.5 and 28.9 months, respectively. High-risk patients had significantly inferior leukemia-free survival (LFS) (P < 0.0001). We identified a cohort of prognostically ambiguous patients (n = 39) in which GIPSS and DIPSS models differed by ≥2 risk groups. Among these patients, a similar proportion were up-staged by DIPSS (n = 19) and GIPSS (n = 20). Patients upstaged by GIPSS (genetically high-risk) had a trend toward inferior OS compared with patients upstaged by DIPSS (clinically high-risk) (P = .08) and significantly worse LFS (P = .04). Patients deemed intermediate-2 and high-risk by GIPSS who underwent allogeneic transplant had improved OS compared with those that did not (P = .04). GIPSS is a valid disease-specific prognostic system and outperforms DIPSS in patients where the two models disagree. Additionally, while GIPSS was developed for PMF; the current study shows, however, that the contemporary genetic model performs equally well for both primary and secondary myelofibrosis.

Ponatinib in the treatment of chronic myeloid leukemia and philadelphia chromosome positive acute lymphoblastic leukemia.

Philadelphia chromosome, reciprocal translocation between chromosome 9 and 22, leading to a constitutively active fusion protein BCR-ABL1 is the common feature among Philadelphia positive acute lymphoblastic leukemia (Ph+ ALL) and chronic myeloid leukemia (CML). The discovery of tyrosine kinase inhibitors (TKIs) has led to significant improvement in the treatment of CML and Ph+ ALL. Ponatinib is a third-generation TKI that is currently approved as per label when no other TKIs are indicated for the treatment of patients with CML and Ph+ ALL after failing treatment with second-generation TKIs or if presence of T315I mutation is discovered. This review summarizes the ponatinib development, approved indications as well as ongoing clinical studies in CML and Ph+ ALL.

Resistance in chronic myeloid leukemia: definitions and novel therapeutic agents.

PURPOSE OF REVIEW: Chronic myeloid leukemia (CML) is hallmarked by the presence of fusion protein kinase derived from a reciprocal translocation between chromosome 9 and 22, breakpoint cluster region (BCR)-Abelson leukemia virus (ABL) 1, causing aberrant regulation of the downstream pathways leading to unchecked CML leukemia stem cells (LSCs) proliferation. Since the discovery of tyrosine kinase inhibitors (TKI), CML, once a fatal disease, has become a chronic illness if managed appropriately. Changing treatment landscape has unsurfaced the challenge of TKI resistance that is clinically difficult to overcome. RECENT FINDINGS: In this review, we discuss the concept of TKI resistance and pathways leading to the resistance which allows for a survival advantage to CML LSCs. Aside from BCR-ABL-dependent mechanisms of resistance which involves aberrant expression in the regulatory pumps involving efflux and influx of the TKI affecting drug bioavailability, activation of alternate survival pathways may be accountable for primary or secondary resistance. Activation of these pathways, intrinsically and extrinsically to LSCs, may be mediated through various upstream and downstream signaling as well as conditions affecting the microenvironment. Several therapeutic approaches that combine TKI with an additional agent that inhibits the activation of an alternate pathway have been studied as part of clinical trials which we will discuss here. SUMMARY: We categorize the resistance into BCR-ABL-dependent and BCR-ABL-independent subgroups to further describe the complex molecular pathways which can potentially serve as a therapeutic target. We further discuss novel combination strategies currently in early or advanced phase clinical trials aimed to overcome the TKI resistance. We further highlight the need for further research despite the tremendous strides already made in the management of CML.

Between a rux and a hard place: evaluating salvage treatment and outcomes in myelofibrosis after ruxolitinib discontinuation.

Ruxolitinib is a JAK1/2 inhibitor that is effective in managing symptoms and splenomegaly related to myelofibrosis (MF). Unfortunately, many patients must discontinue ruxolitinib, at which time treatment options are not well defined. In this study, we investigated salvage treatment options and clinical outcomes among MF patients who received and discontinued ruxolitinib outside the context of a clinical trial. Among 145 patients who received ruxolitinib, 23 died while on treatment, 58 remained on treatment at time of analysis, leaving 64 people available for analysis. Development of cytopenias was the most common reason for discontinuation (38%) after median treatment time of 3.8 months (mo). The majority of patients received some form of salvage therapy after ruxolitinib discontinuation (n = 42; 66%), with allogeneic hematopoietic stem cell transplant (alloHSCT) (n = 17), being most commonly employed. Lenalidomide, thalidomide, hydroxyurea, interferon, and danazol were used with similar frequency. The response rate to salvage treatment was 26% (8 responses) and responses were most often seen with lenalidomide or thalidomide. Improved outcomes were observed in patients who underwent alloHSCT or received salvage therapy compared to those who did not receive additional therapy. Median overall survival (OS) after ruxolitinib discontinuation was 13 months. These findings show that salvage therapy can provide clinical responses after ruxolitinib discontinuation; however, these responses are rare and outcomes in this patient population are poor. This represents an area of unmet clinical need in MF.

CPX-351: changing the landscape of treatment for patients with secondary acute myeloid leukemia.

Multiple novel therapeutic agents against acute myeloid leukemia (AML) have been evaluated in the past several decades without meaningful clinical improvement in outcomes, especially for AML patients age ≥60, where the overall incidence of AML is highest. Therapeutic options mainly consist of hypomethylating agents, ongoing clinical trials and, less commonly, intensive cytotoxic chemotherapy. CPX-351, a novel liposomal formulation which encapsulates cytarabine and daunorubicin in 5:1 molar ratio, has shown promising efficacy, leading to recent US FDA approval for front-line therapy for patients with therapy-related AML and AML with myelodysplasia-related changes based on a large multicenter Phase III clinical trial. This review summarizes the clinical development of CPX-351 as induction therapy.

Mutations highly specific for secondary AML are associated with poor outcomes in ELN favorable risk NPM1-mutated AML.

ABSTRACT: Acute myeloid leukemia (AML) is a heterogeneous malignancy with outcomes largely predicted by genetic abnormalities. Mutations of NPM1 are common in AML, occurring in ∼30% of cases, and generally considered a favorable risk factor. Mutations highly specific for secondary AML (sMut) have been shown to confer poor prognosis, but the overall impact of these mutations in the setting of favorable-risk AML defined by mutant NPM1 remains unclear. In this multicenter study of patients with AML (n = 233) with NPM1 mutation at diagnosis, we observed that patients with sMut had worse overall survival (OS) than those without sMut (15.3 vs 43.7 months; P = .002). Importantly, this finding persisted in the European LeukemiaNet (ELN) 2017-defined favorable risk subset (14.7 months vs not reached; P < .0001). Among patients who achieved NPM1 measurable residual disease (MRD) negativity, longer OS was observed in the entire cohort (P = .015) as well as in both the sMut subset (MRD negative: median OS (mOS) 73.9 months vs MRD positive: 12.3 months; P = .0170) and sMut ELN 2017-favorable subset (MRD negative: mOS 27.3 vs MRD positive: 10.5 months; P = .009). Co-occurrence of sMut and mutant NPM1 confers a poor prognosis in AML.

Allogeneic hematopoietic stem cell transplant outcomes in adults with inherited myeloid malignancies.

There is increasing recognition that pathogenic germ line variants drive the development of hematopoietic cancers in many individuals. Currently, patients with hereditary hematologic malignancies (HHMs) receive similar standard therapies and hematopoietic stem cell transplant (HSCT) approaches as those with sporadic disease. We hypothesize that patients with myeloid malignancies and deleterious germ line predisposition variants have different posttransplant outcomes than those without such alleles. We studied 472 patients with myeloid neoplasms, of whom 26% had deleterious germ line variants and 34% underwent HSCT. Deleterious germ line variants in CHEK2 and DDX41 were most commonly seen in American and Australian cohorts, respectively. Patients with deleterious germ line DDX41 variants had a higher incidence of severe (stage 3-4) acute graft-versus-host disease (GVHD) (38%) than recipients with deleterious CHEK2 variants (0%), other HHM variants (12%), or patients without such germ line variants (9%) (P = .002). Importantly, the use of posttransplant cyclophosphamide reduced the risk of severe acute GVHD in patients receiving HSCT for deleterious germ line DDX41-associated myeloid neoplasms (0% vs 53%, P = .03). Based on these results, we advocate the use of posttransplant cyclophosphamide when individuals with deleterious germ line DDX41 variants undergo allogeneic HSCT for myeloid malignancies, even when transplantation has been performed using wild-type donors.

Molecular characteristics and outcomes in Hispanic and non-Hispanic patients with acute myeloid leukemia.

Hispanic patients have been reported to have an increased incidence of AML and possibly inferior outcomes compared to non-Hispanics. We conducted a retrospective study of 225 AML patients (58 Hispanic and 167 non-Hispanic) at two academic medical centers in Florida. Disease characteristics, cytogenetics, mutation profiles, and clinical outcomes were assessed. Hispanic patients were younger at presentation than non-Hispanics (p = 0.0013). We found associations between single gene mutations and ethnicity, with IDH1 mutations being more common in non-Hispanics (95.2% vs. 4.8%, p = 0.0182) and WT1 mutations more common in Hispanics (62.5% vs. 37.5%, p = 0.0455). We also found an emerging trend towards adverse risk cytogenetics in Hispanic patients (p = 0.1796), as well as high risk fusions such as MLL-r (70% vs. 30%, p = 0.004). There was no difference in overall survival (OS) between Hispanic and non-Hispanics patients. When examining only newly diagnosed patients (n = 105), there was improved OS in Hispanics (median 44.7 months vs. 14 months, p = 0.026) by univariate analysis and equivalent OS by multivariate analysis (hazard ratio = 1.52 [95% CI = 0.74-3.15]). Hispanics with a driver mutation not class-defining had improved survival compared to non-Hispanics. Our study demonstrates significant genetic differences between Floridian Hispanics and non-Hispanics, but no difference in OS in patients treated at an academic medical center.

CPX-351 Yields Similar Response and Survival Outcome in Younger and Older Patients With Secondary Acute Myeloid Leukemia.

BACKGROUND: CPX-351 was approved by the FDA in 2017 as frontline induction chemotherapy for patients aged ≥18 years with newly diagnosed acute myeloid leukemia (AML) which includes myelodysplasia-related changes (AML-MRC) and therapy-related acute myeloid leukemia (t-AML). The efficacy of CPX-351 among younger patients (aged <60 years) is currently unclear, as the large, randomized phase 3 study that led to approval of CPX-351 only included patients between the ages of 60 and 75 years. METHODS: We performed a retrospective study of clinical and molecular data from adult patients with newly diagnosed AML-MRC or t-AML treated with CPX-351. Patients were divided into 2 cohorts: aged <60 years (cohort A) and aged ≥60 years (cohort B). We compared overall response rate (ORR) and median overall survival (mOS) between the cohorts. RESULTS: Of 169 evaluable patients, 21.3% were in cohort A and 78.7% were in cohort B. ORR of the entire cohort was 53.3%; ORR of cohort A was 47.2% compared with 54.9% for cohort B (P = .46). Overall, 54.4% of responding patients proceeded to allogenic stem cell transplant (allo-SCT), including 52.9% of patients in cohort A and 54.8% in cohort B (P = 1.00). At a median follow-up of 24 months, mOS of the entire cohort was 16 months and was similar between cohorts A and B (18 vs. 15 months, respectively; P = .29). CONCLUSION: CPX-351 resulted in similar response rates and survival outcomes among both younger and older adult patients with newly diagnosed AML-MRC or t-AML.

A Phase I First-in-Human Study of ABBV-383, a B-Cell Maturation Antigen × CD3 Bispecific T-Cell Redirecting Antibody, in Patients With Relapsed/Refractory Multiple Myeloma.

PURPOSE: ABBV-383, a B-cell maturation antigen × CD3 T-cell engaging bispecific antibody, has demonstrated promising results in an ongoing first-in-human phase I study (ClinicalTrials.gov identifier: NCT03933735) in patients with relapsed/refractory multiple myeloma (RRMM). Herein, we report safety and efficacy outcomes of this phase I dose escalation/expansion study. METHODS: Patients with RRMM (≥ three prior lines including a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 monoclonal antibody) were eligible. ABBV-383 was administered intravenously over 1-2 hours once every 3 weeks, without any step dosing. A 3 + 3 design with backfilling for dose escalation was used (intrapatient escalation to highest safe dose permitted) followed by initiation of dose expansion. RESULTS: As of January 8, 2022, 124 patients (dose escalation [0.025-120 mg], n = 73; dose expansion [60 mg], n = 51) have received ABBV-383; median age was 68 years (range, 35-92 years). The most common hematologic treatment-emergent adverse events (TEAEs) were neutropenia (all grades: 37%) and anemia (29%). The most common nonhematologic TEAEs were cytokine release syndrome (57%) and fatigue (30%). Seven deaths from TEAEs were reported with all considered unrelated to study drug by the investigator. For all efficacy-evaluable patients (n = 122; all doses), the objective response rate (ORR) was 57% and very good partial response (VGPR) or better (≥ VGPR) rate was 43%. In the 60 mg dose expansion cohort (n = 49), the ORR and ≥ VGPR rates were 59% and 39%, respectively; and in the ≥ 40 mg dose escalation plus dose expansion cohorts (n = 79) were 68% and 54%, respectively. CONCLUSION: ABBV-383 in patients with RRMM was well tolerated with an ORR of 68% at doses ≥ 40 mg. This novel therapy's promising preliminary antitumor activity in heavily pretreated patients warrants further clinical evaluation.

Myelodysplastic/myeloproliferative neoplasms with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T): Mayo-Moffitt collaborative study of 158 patients.

The current World Health Organization (WHO) classification of myeloid malignancies includes myelodysplastic/myeloproliferative neoplasms with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T) as a distinct entity. Previous literature on predictors of survival was based on the provisional category of refractory anemia with ring sideroblast and thrombocytosis (RARS-T), which was not subject to MDS/MPN-RS-T exclusionary criteria such as PB blast% ≥1, BM blast% ≥5 or cytogenetic abnormalities such as t(3;3)(q21.2;q26.2), inv(3)(q21.23q26.2) or isolated del(5q). We examined overall (OS) and leukemia-free (LFS) survival and its predictors, among 158 patients with WHO-defined MDS/MPN-RS-T. In univariate analysis, age ≥70 years (P = 0.006), hemoglobin (Hb) ≤10 g/dL (P = 0.03) and abnormal karyotype (excluding -Y, P = 0.008) were associated with shortened OS, which was otherwise not affected by either ASXL1 (P = 0.7), SF3B1 (P = 0.4) or JAK2 V617F (P = 0.7) mutations; in multivariable analysis, Hb ≤ 10 g/dL (P = 0.03) and abnormal karyotype (P = 0.001) remained significant, and thus allowed the development of an operational survival model with low (0 risk factors, median OS 10.5 years), intermediate (1 risk factor, median OS 4.8 years) and high risk (2 risk factors, median OS 1.4 years) categories (P = 0.0009). Comparison of MDS/MPN-RS-T (n = 158) and MDS/MPN-U with BM RS ≥ 15% (MDS/MPN-U-RS; n = 25) did not reveal significant differences in frequency of thrombosis, OS, or LFS, although SF3B1 mutation frequency was higher in the former (93% versus 59%; P = 0.0005). These data suggest limited survival impact for molecular abnormalities and the morphological distinction between MDS/MPN-RS-T and MDS/MPN-U-RS.