Evolution from an antecedent chronic myeloid malignancy does not impact survival outcomes in NPM1-mutated AML.

Nucleophosmin-1 (NPM1)-mutated AML is a molecularly defined subtype typically associated with favorable treatment response and prognosis; however, its prognostic significance in AML evolving from an antecedent chronic myeloid malignancy is unknown. This study's primary objective was to determine the impact of mutated NPM1 on the prognosis of AML evolving from an antecedent chronic myeloid malignancy. We conducted a retrospective chart review including patients with NPM1-mutated de novo and sAML. sAML was defined as those with a preceding chronic-phase myeloid malignancy before diagnosis of AML. Of 575 NPM1-mutated patients eligible for inclusion in our study, 51 (8.9%) patients were considered to have sAML. The median time from diagnosis of NPM1-mutated chronic myeloid malignancy to sAML evolution was 3.6 months (0.5-79.3 months). No significant differences in leukemia-free (2-year LKFS 52.0% vs. 51.2%, p = .9922) or overall survival (2-year OS 56.3% vs. 49.4%, p = .4246) were observed between patients with NPM1-mutated de novo versus sAML. Our study suggests that evolution from a preceding myeloid malignancy is not a significant predictor of poor prognosis in the setting of an NPM1 mutation. Our study demonstrated a short time to progression to sAML in most patients, which further supports the consideration of NPM1 as an AML-defining mutation.

Novel insights and therapeutic approaches in secondary AML.

Secondary acute myeloid leukemia (sAML) presents as a complex and multifaceted ensemble of disorders, positioning itself as both a challenge and an intriguing frontier within hematologic oncology. Its origins are diverse, stemming from antecedent hematologic conditions, germline predisposing mutations, or the sequelae of cytotoxic therapies, and its development is driven by intricate genetic and epigenetic modifications. This complexity necessitates a diverse array of therapeutic strategies, each meticulously tailored to address the distinctive challenges sAML introduces. Such strategies require a personalized approach, considering the variegated clinical backgrounds of patients and the inherent intricacies of the disease. Allogeneic stem cell transplantation stands as a cornerstone, offering the potential for curative outcomes. This is complemented by the emergence of innovative treatments such as CPX-351, venetoclax, and glasdegib, which have demonstrated promising results in enhancing prognosis. The evolving landscape of sAML treatment underscores the importance of continued research and innovation in the field, aiming not only to improve patient outcomes but also to deepen our understanding of the disease's biological underpinnings, thereby illuminating pathways toward more effective and individualized therapies.

FLAG/FLAG-Ida Regimen in Secondary and Relapsed/Refractory Acute Myeloid Leukemia-Even in the Era of New Treatment Modalities Still a Significant Player.

(1) Background: Relapsed/refractory (r/r) and secondary acute myeloid leukemia are highlighted by chemoresistance and poor outcomes. The aim of the study was to assess the efficacy and toxicity of fludarabine, cytarabine, and granulocyte-colony stimulation factor (FLAG) with or without idarubicin (-Ida) and to discuss novel therapies in this setting. (2) Methods: Clinical and cytogenetic data on 130 consecutive patients with r/r and secondary AML treated at our center were retrospectively analyzed. (3) Results: There were 48, 56, and 26 patients with relapsed, refractory, and secondary AML, respectively. The median age was 60 years. The overall response was achieved in 70% of patients. The median overall survival (OS) time for the whole group was 9.4 months. In total, 47% of patients proceeded to allogeneic hematopoietic stem cell transplantation (aHSCT) and these patients had significantly prolonged OS compared to the others (63 months vs. 4.2 months; p < 0.001). Among the variables, including age, FLT3 mutation status, European LeukemiaNet (ELN) 2022 classification risk, FLAG vs. FLAG-Ida, and aHSCT, a multivariate analysis revealed that only aHSCT significantly influenced overall survival. (4) Conclusions: FLAG(-Ida) chemotherapy remains an effective salvage chemotherapy for patients with r/r and secondary AML with a plan of proceeding to aHSCT.

Survival difference between secondary and de novo acute myeloid leukemia by age, antecedent cancer types, and chemotherapy receipt.

BACKGROUND: This study compared the survival of persons with secondary acute myeloid leukemia (sAML) to those with de novo AML (dnAML) by age at AML diagnosis, chemotherapy receipt, and cancer type preceding sAML diagnosis. METHODS: Data from Surveillance, Epidemiology, and End Results 17 Registries were used, which included 47,704 individuals diagnosed with AML between 2001 and 2018. Multivariable Cox proportional hazards regression was used to compare AML-specific survival between sAML and dnAML. Trends in 5-year age-standardized relative survival were examined via the Joinpoint survival model. RESULTS: Overall, individuals with sAML had an 8% higher risk of dying from AML (hazard ratio [HR], 1.08; 95% confidence interval [CI], 1.05-1.11) compared to those with dnAML. Disparities widened with younger age at diagnosis, particularly in those who received chemotherapy for AML (HR, 1.14; 95% CI, 1.10-1.19). In persons aged 20-64 years and who received chemotherapy, HRs were greatest for those with antecedent myelodysplastic syndrome (HR, 2.04; 95% CI, 1.83-2.28), ovarian cancer (HR, 1.91; 95% CI, 1.19-3.08), head and neck cancer (HR, 1.55; 95% CI, 1.02-2.36), leukemia (HR, 1.45; 95% CI, 1.12-1.89), and non-Hodgkin lymphoma (HR, 1.42; 95% CI, 1.20-1.69). Among those aged ≥65 years and who received chemotherapy, HRs were highest for those with antecedent cervical cancer (HR, 2.42; 95% CI, 1.15-5.10) and myelodysplastic syndrome (HR, 1.28; 95% CI, 1.19-1.38). The 5-year relative survival improved 0.3% per year for sAML slower than 0.86% per year for dnAML. Consequently, the survival gap widened from 7.2% (95% CI, 5.4%-9.0%) during the period 2001-2003 to 14.3% (95% CI, 12.8%-15.8%) during the period 2012-2014. CONCLUSIONS: Significant survival disparities exist between sAML and dnAML on the basis of age at diagnosis, chemotherapy receipt, and antecedent cancer, which highlights opportunities to improve outcomes among those diagnosed with sAML.

Updates in molecular genetics of therapy-related myeloid neoplasms.

Therapy-related myeloid neoplasms (t-MN) are a heterogeneous group of aggressive myeloid neoplasms that arise following exposure to various cytotoxic therapeutic agents and/or ionizing radiation for treatment of prior non-myeloid malignancy or autoimmune disease. Each therapeutic group has been associated with varying latency intervals from the time of therapy exposure to onset of t-MN, as well as certain recurrent genetic alterations. This review will focus on the molecular genetic alterations that have been described in t-MNs, as well as recent updates regarding diagnostic classification.

Reversal of malignant ADAR1 splice isoform switching with Rebecsinib.

Adenosine deaminase acting on RNA1 (ADAR1) preserves genomic integrity by preventing retroviral integration and retrotransposition during stress responses. However, inflammatory-microenvironment-induced ADAR1p110 to p150 splice isoform switching drives cancer stem cell (CSC) generation and therapeutic resistance in 20 malignancies. Previously, predicting and preventing ADAR1p150-mediated malignant RNA editing represented a significant challenge. Thus, we developed lentiviral ADAR1 and splicing reporters for non-invasive detection of splicing-mediated ADAR1 adenosine-to-inosine (A-to-I) RNA editing activation; a quantitative ADAR1p150 intracellular flow cytometric assay; a selective small-molecule inhibitor of splicing-mediated ADAR1 activation, Rebecsinib, which inhibits leukemia stem cell (LSC) self-renewal and prolongs humanized LSC mouse model survival at doses that spare normal hematopoietic stem and progenitor cells (HSPCs); and pre-IND studies showing favorable Rebecsinib toxicokinetic and pharmacodynamic (TK/PD) properties. Together, these results lay the foundation for developing Rebecsinib as a clinical ADAR1p150 antagonist aimed at obviating malignant microenvironment-driven LSC generation.

Secondary Acute Myeloid Leukemia in a Chronic Myeloid Leukemia Patient in Deep Molecular Response-An Unusual Case Report.

Perumal Kalaiyarasi Jayachandran Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder that develops from the stem cell compartment. The classical translocation ( BCR-ABL1 ) is present in approximately 95% of CML patients. Through disease progression, clonal evolution with additional chromosomal abnormalities (ACAs) start appearing. Although relatively rare, chromosomal abnormalities can exist or develop in the Philadelphia (Ph)-negative clones, which may lead to the evolution of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). We hereby present a case of AML which emerged from a Ph-negative clone in a patient with a history of CML who was in deep molecular response. The possible mechanisms of ACAs have been discussed.

Navigating the contested borders between myelodysplastic syndrome and acute myeloid leukemia.

Myelodysplastic syndrome and acute myeloid leukemia are heterogeneous myeloid neoplasms which arise from the accumulation of mutations in a myeloid stem cell or progenitor that confer survival or growth advantages. These disease processes are formally differentiated by clinical, laboratory, and morphological presentations, especially with regard to the preponderance of blasts in the peripheral blood or bone marrow (AML); however, they are closely associated through their shared lineage as well as their existence on a spectrum with some cases of MDS displaying increased blasts, a feature that reflects more AML-like behavior, and the propensity for MDS to transform into AML. It is increasingly recognized that the distinctions between these two entities result from the divergent patterns of genetic alterations that drive each of them. Mutations in genes related to chromatin-remodeling and the spliceosome are seen in both MDS and AML arising out of antecedent MDS, while mutations in genes related to signaling pathways such as RAS or FLT3 are more typically seen in AML or otherwise are a harbinger of transformation. In this review, we focus on the insights into the biological and genetic distinctions and similarities between MDS and AML that are now used to refine clinical prognostication, guide disease management, and to inform development of novel therapeutic approaches.

Durable remission of acute myeloid leukemia in an elderly patient following a limited course of azacitidine and venetoclax.

Acute myeloid leukemia (AML) is a heterogeneous hematological malignancy characterized by clonal expansion of myeloid blasts. It is the most common type of acute leukemia in adults, including elderly patients, and has historically been associated with poor outcomes in this age group. Here, we present the case of an 80-year-old woman with newly diagnosed AML with myelodysplasia-related changes. She was treated with a total of five cycles of azacitidine, two cycles as monotherapy followed by three cycles in combination with venetoclax. Therapy was stopped due to cytopenias and declining performance status. Bone marrow aspirate and biopsy immediately following treatment and again approximately four months later did not show any morphologic, immunophenotypic, or cytogenetic evidence of leukemia. The patient's clinical and performance status improved significantly with time. Follow-up labs more than three years following the completion of treatment reveal continued hematologic remission. A short treatment course of azacitidine and venetoclax with close monitoring may lead to durable responses in some patients. Further studies are necessary to determine which patients might be appropriate for treatment suspension or discontinuation while in remission.

[Hypernatremia and polyuria in a female patient with an initial diagnosis of secondary acute myeloid leukemia]. / Hypernatriämie und Polyurie bei einer Patientin mit Erstdiagnose einer sekundären akuten myeloischen Leukämie.

A 66-year-old female patient with the initial diagnosis of acute myeloid leukemia is reported. Paraneoplastic syndrome manifested as hypernatremia due to central diabetes insipidus (CDI), which could be controlled with the administration of desmopressin. After initiation of the induction therapy, the required desmopressin administration could be reduced and terminated. In the further course, the early increasing polyuria and hypernatremia indicated the primary refractory acute myeloid leukemia.

In Pursuit of Genetic Prognostic Factors and Treatment Approaches in Secondary Acute Myeloid Leukemia-A Narrative Review of Current Knowledge.

Secondary acute myeloid leukemia can be divided into two categories: AML evolving from the antecedent hematological condition (AHD-AML) and therapy related AML (t-AML). AHD-AML can evolve from hematological conditions such as myelodysplastic syndromes, myeloproliferative neoplasms, MDS/MPN overlap syndromes, Fanconi anemia, and aplastic anemia. Leukemic transformation occurs as a consequence of the clonal evolution-a process of the acquisition of mutations in clones, while previous mutations are also passed on, leading to somatic mutations accumulation. Compared de novo AML, secondary AML is generally associated with poorer response to chemotherapy and poorer prognosis. The therapeutic options for patients with s-AML have been confirmed to be limited, as s-AML has often been analyzed either both with de novo AML or completely excluded from clinical trials. The treatment of s-AML was not in any way different than de novo AML, until, that is, the introduction of CPX-351-liposomal daunorubicin and cytarabine. CPX-351 significantly improved the overall survival and progression free survival in elderly patients with s-AML. The only definitive treatment in s-AML at this time is allogeneic hematopoietic cell transplantation. A better understanding of the genetics and epigenetics of s-AML would allow us to determine precise biologic drivers leading to leukogenesis and thus help to apply a targeted treatment, improving prognosis.

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.

Mutational landscape of chronic myelomonocytic leukemia in Chinese patients.

BACKGROUND: Chronic myelomonocytic leukemia (CMML) is a rare and heterogeneous hematological malignancy. It has been shown that the molecular abnormalities such as ASXL1, TET2, SETBP1, and SRSF2 mutations are common in Caucasian population. METHODS: We retrospectively analyzed 178 Chinese CMML patients. The targeted next generation sequencing (NGS) was used to evaluate 114 gene variations, and the prognostic factors for OS were determined by COX regression analysis. RESULTS: The CMML patients showed a unique mutational spectrum, including TET2 (36.5%), NRAS (31.5%), ASXL1 (28.7%), SRSF2 (24.7%), and RUNX1 (21.9%). Of the 102 patients with clonal analysis, the ancestral events preferentially occurred in TET2 (18.5%), splicing factors (16.5%), RAS (14.0%), and ASXL1 (7.8%), and the subclonal genes were mainly ASXL1, TET2, and RAS. In addition, the secondary acute myeloid leukemia (sAML) transformed from CMML often had mutations in DNMT3A, ETV6, FLT3, and NPM1, while the primary AML (pAML) demonstrated more mutations in CEBPA, DNMT3A, FLT3, IDH1/2, NPM1, and WT1. It was of note that a series of clones were emerged during the progression from CMML to AML, including DNMT3A, FLT3, and NPM1. By univariate analysis, ASXL1 mutation, intermediate- and high-risk cytogenetic abnormality, CMML-specific prognostic scoring system (CPSS) stratifications (intermediate-2 and high group), and treatment options (best supportive care) predicted for worse OS. Multivariate analysis revealed a similar outcome. CONCLUSIONS: The common mutations in Chinese CMML patients included epigenetic modifiers (TET2 and ASXL1), signaling transduction pathway components (NRAS), and splicing factor (SRSF2). The CMML patients with DNMT3A, ETV6, FLT3, and NPM1 mutations tended to progress to sAML. ASXL1 mutation and therapeutic modalities were independent prognostic factors for CMML.

Secondary Acute Myeloid Leukemia (sAML): Similarly Dismal Outcomes of AML After an Antecedent Hematologic Disorder and Therapy Related AML.

Therapy related acute myeloid leukemia (tAML) and secondary AML after an antecedent hematologic disorder (sAML-AHD) are often addressed together, blurring any clinical and prognostic differences. Among 516 AML patients, we compared characteristics and outcomes of 149 patients with "sAML" (sAML-AHD: 104, tAML: 45), uniformly and intensively treated during the last 2 decades at 1 center. Clinical outcomes of the whole "sAML" cohort were significantly inferior compared to de novo AML and in both intermediate and poor cytogenetic risk groups. Adverse karyotype had no effect on survival in tAML, while it was a negative predictor in sAML-AHD. Both groups showed similarly dismal outcome, with low complete remission rates (CR 44% vs. 41%) and median overall survival (OS 7 vs. 10.5 months). Allogeneic hematopoietic cell transplantation (alloHCT) recipients in CR1 had superior median OS (24 vs. 8 months). By multivariate analysis, alloHCT was an independent predictor of outcome, while karyotype was for sAML-AHD only. In conclusion, both "sAML" groups have inferior outcomes after chemotherapy, with adverse karyotype affecting primarily sAML-AHD. Until new treatment approaches are available, only alloHCT offers a survival advantage.

Molecular and genomic landscapes in secondary & therapy related acute myeloid leukemia.

Acute myeloid leukemia (AML) is a complex, aggressive myeloid neoplasm characterized by frequent somatic mutations that influence different functional categories' genes, resulting in maturational arrest and clonal expansion. AML can arise de novo (dn-AML) or can be secondary AML (s-AML) refers to a leukemic process which may arise from an antecedent hematologic disorder (AHD-AML), mostly from a myelodysplastic syndrome (MDS) or myeloproliferative neoplasm (MPN) or can be the result of an antecedent cytotoxic chemotherapy or radiation therapy (therapy-related AML, t-AML). Clinical and biological features in secondary and therapy-related AML are distinct from de novo AML. Secondary and therapy-related AML occurs mainly in the elderly population and responds worse to therapy with higher relapse rates due to resistance to cytotoxic chemotherapy. Over the last decade, advances in molecular genetics have disclosed the sub-clonal architecture of secondary and therapy-related AML. Recent investigations have revealed that cytogenetic abnormalities and underlying genetic aberrations (mutations) are likely to be significant factors dictating prognosis and critical impacts on treatment outcome. Secondary and therapy-related AML have a poorer outcome with adverse cytogenetic abnormalities and higher recurrences of unfavorable mutations compared to de novo AML. In this review, we present an overview of the clinical features of secondary and therapy-related AML and address the function of genetic mutations implicated in the pathogenesis of secondary leukemia. Detailed knowledge of the pathogenetic mechanisms gives an overview of new prognostic markers, including targetable mutations that will presumably lead to the designing and developing novel molecular targeted therapies for secondary and therapy-related AML. Despite significant advances in knowing the genetic aspect of secondary and therapy-related AML, its influence on the disease's pathophysiology, standard treatment prospects have not significantly evolved during the past three decades. Thus, we conclude this review by summarizing the modern and developing treatment strategies in secondary and therapy-related acute myeloid leukemia.

Emerging therapies for AML with myelodysplasia-related changes: slowly but surely moving the needle.

Introduction: Patients with acute myeloid leukemia with myelodysplasia-related changes (AML-MRC) have historically poor outcomes with conventional chemotherapy regimens. Current treatment strategies focus on intensive induction therapy followed by allogeneic stem cell transplant or a less intensive approach with hypomethylating agents with or without venetoclax. CPX-351 is a liposomal formulation of cytarabine and daunorubicin that has been shown to significantly improve response rates and survival compared with 7 + 3 (continuous infusion cytarabine plus anthracyclines). Despite the approval of CPX-351 for AML-MRC, overall prognosis remains poor with an unmet need to develop novel therapeutic strategies for this patient population.Areas covered: This article reviews the data for existing therapeutic options for patients with AML-MRC and the emerging therapies undergoing clinical trial development for this patient population.Expert opinion: The development of CPX-351 as a more effective induction therapeutic backbone for patients with AML-MRC presents an opportunity to investigate novel combination regimens in order to further improve outcomes. Promising emerging therapeutic modalities include immunotherapeutic strategies, small-molecule inhibitors and targeted agents. Unfortunately, there have been few clinical trials focusing on patients with AML-MRC with reliance instead on subgroup analyses. Clinical trials focused specifically on this patient population are urgently needed.

Multicenter comparison of high-dose cytarabine-based regimens versus liposomal daunorubicin and cytarabine (CPX-351) in patients with secondary acute myeloid leukemia.

Liposomal daunorubicin/cytarabine (CPX-351) gained FDA approval for secondary AML after demonstrating improved outcomes over daunorubicin and cytarabine (7 + 3). A number of study limitations prompted a comparison of safety/efficacy of CPX-351 against regimens containing a purine analogue and high-dose cytarabine (HIDAC). This retrospective study compared complete response rates with/without count recovery (CR/CRi) between HIDAC-based regimens and CPX-351 in 169 patients with newly diagnosed sAML. The CR/CRi rate was 62.7% in the HIDAC-based therapy arm vs. 47.9% in the CPX-351 arm (p = 0.002 [one-sided for non-inferiority]). Median time to absolute neutrophil and platelet count recovery was shorter after HIDAC-based therapy (18 and 23 days, respectively) compared to CPX-351 (36 and 38 days; p < 0.001). Median overall survival was 9.8 months in the HIDAC-based group and 9.14 months in the CPX-351 group. 30-day mortality was greater with CPX-351 (8.5%) compared to HIDAC-based (1.3%; p = 0.039). These results reveal comparable efficacy and favorable safety with HIDAC-based regimens.

Secondary AML Emerging After Therapy with Hypomethylating Agents: Outcomes, Prognostic Factors, and Treatment Options.

PURPOSE OF REVIEW: Secondary AML (s-AML) encompasses a distinct subgroup of AML with either therapy-related AML or AML arising from preexisting myeloid neoplasms. Despite recent advances in the treatment armamentarium of AML, outcomes remain poor in s-AML. The purpose of this review is to highlight distinct characteristics, prognostic factors, and treatment options for patients with s-AML. Further, we focus on a distinctly poor-risk subgroup of s-AML with previous exposure to hypomethylating agents (HMAs) and describe ongoing clinical trials in this patient population. RECENT FINDINGS: CPX-351 (liposomal daunorubicin and cytarabine) is the first drug approved for s-AML and represents an advancement in the management of fit patients with this subtype of AML. Despite incremental improvement in remission rates and survival, long-term survival remains poor. Patients who have received prior HMAs for antecedent MDS rarely benefit from CPX-351 or other cytotoxic chemotherapy regimens. The approval of venetoclax in combination with azacitidine has led to a paradigm shift in the management of newly diagnosed older unfit AML patients; however, patients with s-AML and prior HMA therapy were excluded from the landmark randomized phase 3 study. Several early phase clinical trials with both low- and high-intensity therapies are ongoing for s-AML patients, though prior HMA exposure limits inclusion in many of these studies that include HMAs. Patients with s-AML previously treated with an HMA have dismal outcomes with standard therapeutic options and are under-represented in clinical trials. Trials investigating novel therapeutic options in this population are critically needed.

AML with Myelodysplasia-Related Changes: Development, Challenges, and Treatment Advances.

Acute myeloid leukemia (AML) with myelodysplasia-related changes (AML-MRC) is a distinct biologic subtype of AML that represents 25-34% of all AML diagnoses and associates with especially inferior outcomes compared to non-MRC AML. Typically, patients with AML-MRC experience low remission rates following intensive chemotherapy and a median overall survival of merely 9-12 months. In light of these discouraging outcomes, it has become evident that more effective therapies are needed for patients with AML-MRC. Liposomal daunorubicin-cytarabine (CPX-351) was approved in 2017 for adults with newly diagnosed AML-MRC and those with therapy-related AML (t-AML), and remains the only therapy specifically approved for this patient population. Other studies have also demonstrated the efficacy of the hypomethylating agent (HMA) azacitidine as upfront therapy for AML-MRC patients, which, to date, is the most common treatment employed for patients unable to tolerate the more intensive CPX-351. HMAs and venetoclax combinations have also been evaluated, but additional studies utilizing these agents in this specific subgroup are needed before conclusions regarding their role in the therapeutic armamentarium of AML-MRC patients can be reached. Currently, many studies are ongoing in attempts to further improve outcomes in this historically ill-fated patient group.