Craniospinal irradiation for CNS leukemia: rates of response and durability of CNS control.

PURPOSE: Management of CNS involvement in leukemia may include craniospinal irradiation (CSI), though data on CSI efficacy are limited. METHODS: We retrospectively reviewed leukemia patients who underwent CSI at our institution between 2009 and 2021 for CNS involvement. CNS local recurrence (CNS-LR), any recurrence, progression-free survival (PFS), CNS PFS, and overall survival (OS) were estimated. RESULTS: Of thirty-nine eligible patients treated with CSI, most were male (59%) and treated as young adults (median 31 years). The median dose was 18 Gy to the brain and 12 Gy to the spine. Twenty-five (64%) patients received CSI immediately prior to allogeneic hematopoietic cell transplant, of which 21 (84%) underwent total body irradiation conditioning (median 12 Gy). Among 15 patients with CSF-positive disease immediately prior to CSI, all 14 assessed patients had pathologic clearance of blasts (CNS-response rate 100%) at a median of 23 days from CSI start. With a median follow-up of 48 months among survivors, 2-year PFS and OS were 32% (95% CI 18-48%) and 43% (95% CI 27-58%), respectively. Only 5 CNS relapses were noted (2-year CNS-LR 14% (95% CI 5-28%)), which occurred either concurrently or after a systemic relapse. Only systemic relapse after CSI was associated with higher risk of CNS-LR on univariate analysis. No grade 3 or higher acute toxicity was seen during CSI. CONCLUSION: CSI is a well-tolerated and effective treatment option for patients with CNS leukemia. Control of systemic disease after CSI may be important for CNS local control. CNS recurrence may reflect reseeding from the systemic space.

Acute Myeloid Leukemia, Version 3.2023, NCCN Clinical Practice Guidelines in Oncology.

Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy characterized by the clonal expansion of myeloid blasts in the peripheral blood, bone marrow, and/or other tissues. It is the most common form of acute leukemia among adults and accounts for the largest number of annual deaths from leukemias in the United States. Like AML, blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a myeloid malignancy. It is a rare malignancy characterized by the aggressive proliferation of precursors of plasmacytoid dendritic cells that frequently involves the bone marrow, skin, central nervous system, and other organs and tissues. This discussion section focuses on the diagnosis and management of BPDCN as outlined in the NCCN Guidelines for AML.

Hyper-CVAD versus dose-adjusted EPOCH as initial treatment for adults with acute lymphoblastic leukemia.

OBJECTIVES: We recently performed a single-arm phase II trial of DA-EPOCH in adults with acute lymphoblastic leukemia (ALL). We sought to compare these results to those with standard Hyper-CVAD. METHODS: We created a retrospective matched cohort of patients who received Hyper-CVAD (n = 69) at our center and otherwise met eligibility criteria for the DA-EPOCH trial (n = 53). RESULTS: Our outcomes support the use of Hyper-CVAD over DA-EPOCH in Ph- disease for both overall survival (OS; HR 0.18, p = .004) and event-free survival (EFS; HR 0.51, p = .06). In contrast, outcomes were similar in Ph+ disease (OS HR 0.97, p = .96; EFS HR 0.65, p = .21). Rates of morphologic remission and measurable residual-disease negativity were similar between the regimens. Hyper-CVAD was associated with significantly more febrile neutropenia (OR 1.9, p = .03) and a greater incidence of Grade 4 or 5 adverse events (20% vs. 6%). Average transfusions per cycle of both red blood cells (p < .001) and platelets (p < .001) were five-fold higher with Hyper-CVAD. CONCLUSIONS: Our findings support continued use of Hyper-CVAD for Ph- ALL but suggest that DA-EPOCH may be a reasonable alternative for Ph+ ALL. These data also highlight a potential role for DA-EPOCH in resource-limited settings or when more intense therapy is not feasible.

Cerebrospinal fluid flow cytometry and risk of central nervous system relapse after hyperCVAD in adults with acute lymphoblastic leukemia.

BACKGROUND: Potential involvement of the central nervous system (CNS) by acute lymphoblastic leukemia is typically evaluated by a conventional cytospin (CC) of cerebrospinal fluid (CSF). Multiparameter flow cytometry (MFC) is generally more sensitive and specific than morphology, but data to guide its use versus CC are limited. METHODS: This study identified 92 patients who had MFC performed on their initial CSF specimen and received at least 4 cycles of hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with methotrexate and cytarabine (hyperCVAD) as their initial treatment. RESULTS: Eighteen (20%) were CSF+ by MFC at the baseline, and only 6 of these patients were positive by CC. In contrast, 0 of 51 patients who were negative by MFC and had CC available were positive by CC. Despite the receipt of significantly more intra-CSF chemotherapy (P < .001), the cumulative incidence of CNS relapse by MFC was 22% among CSF+ patients versus 5% among those who were CSF- (P = .044). No such association was observed between CNS relapse and CC results (P = .42). None of the 74 CSF- patients became CSF+ during their initial treatment despite being tested a median of 5 times (range, 2-10). CSF positivity by MFC was the factor most strongly associated with CNS relapse in a series of univariate Cox models (hazard ratio, 3.7; P = .067). The initial CSF status by MFC had no significant impact on overall or event-free survival. CONCLUSIONS: MFC of CSF is superior to CC of CSF in identifying adults at high risk for CNS relapse after treatment with hyperCVAD. Surveillance of CSF by MFC has limited utility.

Survival of patients with newly diagnosed high-grade myeloid neoplasms who do not meet standard trial eligibility.

Few patients with cancer, including those with acute myeloid leukemia and high-grade myeloid neoplasms, participate in clinical trials. Broadening standard eligibility criteria may increase clinical trial participation. In this retrospective single-center analysis, we identified 442 consecutive newly diagnosed patients from 2014 to 2016. Patients were considered eligible if they had performance status 0-2, normal renal and hepatic function, no recent solid tumor, left ventricular ejection fraction (EF) ≥ 50%, and no history of congestive heart failure (CHF) or myocardial infarction (MI); ineligible patients failed to meet one or more of these criteria. We included 372 patients who received chemotherapy. Ineligible patients represented 40% of the population and had a 1-79-fold greater risk of death (95% CI 1.37, 2.33) than eligible patients. Very few patients had cardiac co-morbidities, including 2% with low EF, 4% with prior CHF, and 5% with prior MI. In multivariable analysis, ineligibility was associated with decreased survival [HR 1-44 (95% CI 1-07, 1-93)]. Allogeneic transplantation, performed in 150 patients (40%), was associated with improved survival [HR 0-66, 95% CI (0-48, 0-91)]. Therefore, standard eligibility characteristics identify a patient population with improved survival. Further treatment options are needed for patients considered ineligible for clinical trials.

Hypoalbuminemia as a prognostic biomarker for higher mortality and treatment complications in acute myeloid leukemia.

Older age and poor performance status lead to worse outcomes in acute myeloid leukemia (AML) patients. Hypoalbuminemia is a negative predictor of morbidity and mortality in several malignancies. We evaluated the relationship between baseline serum albumin levels on treatment-related complications, as well as short-term mortality and overall survival (OS) in 756 newly diagnosed AML patients. We conducted a retrospective multicenter study to examine treatment-related complications and OS according to pretreatment serum albumin levels: normal albumin ≥3.5 g/dl, marked hypoalbuminemia <2.5 g/dl, and hypoalbuminemia 2.5-3.4 g/dl. In an adjusted multivariate analysis, a lower baseline albumin was independently associated with a higher number of grade ≥3 complications when adjusting for age, secondary AML, sex and intensive treatment. When comparing normal to markedly low albumin levels, the estimated mean number of complications increases by a factor of 1.35. Patients who had a normal baseline albumin had a 30 day-mortality rate of 4.8%, which was significantly lower compared with patients with hypoalbuminemia (16.5%) and marked hypoalbuminemia (33.9%; p < 0.01). Similarly, 60-day mortality rate was significantly higher in the hypoalbuminemia group (24.0%) and marked hypoalbuminemia group (45%) compared with normal albumin group (8.3%; p < 0.01). Patients with lower baseline albumin levels have increased treatment-related morbidity and mortality, suggesting that pre-treatment serum albumin is an important independent prognostic marker.

Financial Implications of Early Hospital Discharge After AML-Like Induction Chemotherapy: A 4-Year Retrospective Analysis.

BACKGROUND: Early hospital discharge (EHD) after intensive acute myeloid leukemia (AML) induction chemotherapy has become routine at the University of Washington/Seattle Cancer Care Alliance over the past several years. We assessed the financial implications of EHD over the first 4 years after its broad adoption for patients with AML and other high-grade myeloid neoplasms undergoing AML-like induction chemotherapy. PATIENTS AND METHODS: We retrospectively compared charges between 189 patients with EHD who received all postinduction inpatient/outpatient care within our care system between August 2014 and July 2018 and 139 medically matched control patients who remained hospitalized for logistical reasons. Charges from the day of initial discharge (patients with EHD) or end of chemotherapy (control patients) until blood count recovery, additional chemotherapy or care transition, hospital discharge (for control patients only), an elapse of 42 days, or death were extracted from financial databases and separated into categories: facility/provider, emergency department, transfusions, laboratory, imaging, pharmacy, and miscellaneous. RESULTS: Combined charges averaged $4,157/day (range, $905-$13,119/day) for patients with EHD versus $9,248/day (range, $4,363-$48,522/day) for control patients (P<.001). The EHD cohort had lower mean facility/provider, transfusion, laboratory, and pharmacy charges but not imaging or miscellaneous charges. During readmissions, there was no statistically significant difference in daily inpatient charges between the EHD and control cohorts. After multivariable adjustment, average charges were $3,837/day lower for patients with EHD (P<.001). CONCLUSIONS: Together with previous data from our center showing that EHD is safe and associated with reduced healthcare resource utilization, this study further supports this care approach for AML and other high-grade myeloid neoplasms if infrastructure is available to enable close outpatient follow-up.

NCCN Guidelines Insights: Acute Myeloid Leukemia, Version 2.2021.

The NCCN Guidelines for Acute Myeloid Leukemia (AML) provide recommendations for the diagnosis and treatment of adults with AML based on clinical trials that have led to significant improvements in treatment, or have yielded new information regarding factors with prognostic importance, and are intended to aid physicians with clinical decision-making. These NCCN Guidelines Insights focus on recent select updates to the NCCN Guidelines, including familial genetic alterations in AML, postinduction or postremission treatment strategies in low-risk acute promyelocytic leukemia or favorable-risk AML, principles surrounding the use of venetoclax-based therapies, and considerations for patients who prefer not to receive blood transfusions during treatment.

Current treatment strategies for measurable residual disease in patients with acute myeloid leukemia.

Patients with acute myeloid leukemia (AML) who achieve a morphologic complete remission still can have measurable residual disease (MRD) detected by multiparametric flow cytometry, molecular methods, or cytogenetics. Such patients with MRD have a high risk of disease recurrence over a short timeframe, but optimal treatment strategies are unknown. Outcomes with conventional treatment, including allogeneic hematopoietic cell transplantation, are worse than those for patients without MRD. Herein, the authors review current strategies, including novel clinical trials, targeted toward patients with MRD.

Emerging treatments in acute myeloid leukemia: current standards and unmet challenges.

Acute myeloid leukemia (AML) is rare and difficult to treat. Although remission is achieved in most patients with newly diagnosed disease, relapse occurs in most cases. For more than 40 years, the standard up-front induction treatment has been a combination of continuous-infusion cytarabine and an anthracycline. Risk stratification by molecular and cytogenetic characteristics and measurable residual disease (MRD) status informs decisions regarding referral to consolidative allogeneic hematopoietic cell transplant. In 2017, for the first time in years, 4 drugs are under consideration for approval by the US Food and Drug Administration. One of these agents, the multikinase inhibitor midostaurin, has already been approved for the treatment of patients with FLT3-mutated AML. The heterogeneity of AML suggests that single-target agents are unlikely to succeed at curing large numbers of patients, and that combinations of novel agents and traditional chemotherapy will be required to achieve this goal. Additionally, the 2017 European LeukemiaNet criteria suggest that treating physicians should strive for the new, stringent remission category (ie, complete remission without MRD). How the new drug approvals in 2017 will change practice is not clear, and further work remains to be done in treating and curing patients with AML.

Improvements in the early death rate among 9380 patients with acute myeloid leukemia after initial therapy: A SEER database analysis.

BACKGROUND: Acute myeloid leukemia (AML) is treated with conventional induction chemotherapy shortly after diagnosis for the majority of patients aged ≤ 65 years. A recent report suggested a substantial decline in the early, or 1-month, mortality rate in patients treated on clinical trials over the past 2 decades. It is unknown whether a similar improvement has been observed in the general population. METHODS: The authors examined the 1-month mortality rate in a large population-based series of 9380 patients with AML who were aged ≤ 65 years and were diagnosed and treated with chemotherapy between 1973 and 2010. RESULTS: A significant decline was observed in the 1-month mortality rate from 18.7% among patients diagnosed from 1973 through 1977 (95% confidence interval [95% CI], 16.4%-21.2%) to 5.8% for those diagnosed between 2008 and 2010 (95% CI, 4.5%-7.6%) (P <.001). The median overall survival improved significantly from 6 months (95% CI, 5 months-7 months) in 1973 to 1977 to 23 months (95% CI, 16 months-20 months) in 2008 to 2010 (P <.001). Although age and geographic variation were found to significantly influence the 1-month mortality for the period between 1973 and 1977, these differences in 1-month mortality were no longer significant among patients with AML who were treated more recently (2008-2010). CONCLUSIONS: Over the past 4 decades, early mortality has become uncommon in younger patients (aged ≤ 65 years) with newly diagnosed AML undergoing induction chemotherapy. It is encouraging that the improvements noted in 1-month mortality rate among a selective cohort of patients in clinical trials have also been observed in a population-based analysis.

Association between class III obesity and overall survival in previously untreated younger patients with acute myeloid leukemia enrolled on SWOG S1203.

There has been ongoing debate on the association between obesity and outcomes in acute myeloid leukemia (AML). Currently few studies have stratified outcomes by class I obesity, class II obesity, and class III obesity, and a more nuanced understanding is becoming increasingly important with the rising prevalence of obesity. We examined the association between body mass index (BMI) and outcomes in previously untreated AML in younger patients (age ≤60) enrolled in SWOG S1203 (n = 729). Class III obesity was associated with an increased rate of early death (p = 0.004) and worse overall survival (OS) in multivariate analysis (hazard ratio (HR) 2.48, 95% confidence interval (CI) 1.62-3.80 versus normal weight). Class III obesity was also associated with worse OS after allogeneic hematopoietic cell transplant (HR 2.37, 95% CI 1.24-4.54 versus normal weight). These findings highlight the unique risk of class III obesity in AML, and the importance of further investigation to better characterize this patient population.

Association between class III obesity and overall survival in previously untreated younger patients with acute myeloid leukemia enrolled on SWOG S1203.

There has been ongoing debate on the association between obesity and outcomes in acute myeloid leukemia (AML). Currently there are few studies that have stratified outcomes by class I obesity, class II obesity, and class III obesity; and a more nuanced understanding is becoming increasingly important with the rising prevalence of obesity. We examined the association between body mass index (BMI) and outcomes in previously untreated AML in younger patients (age ≤60) enrolled in SWOG S1203 (n=729). Class III obesity was associated with an increased rate of early death (p=0.004) and worse overall survival (OS) in multivariate analysis (hazard ratio (HR) 2.48, 95% confidence interval (CI) 1.62-3.80 versus normal weight). Class III obesity was also associated with worse OS after allogeneic hematopoietic cell transplant (HR 2.37, 95% CI 1.24-4.54 versus normal weight). These findings highlight the unique risk of class III obesity in AML, and the importance of further investigation to better characterize this patient population.

Dose-Adjusted EPOCH Plus Inotuzumab Ozogamicin in Adults With Relapsed or Refractory B-Cell ALL: A Phase 1 Dose-Escalation Trial.

Importance: Options for adults with relapsed or refractory B-cell acute lymphoblastic leukemia or lymphoma (B-ALL) are limited, and new approaches are needed. Inotuzumab ozogamicin (InO) has been combined with low-intensity chemotherapy, with modest improvements over historical controls, and dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (DA-EPOCH) treatment is safe and active for newly diagnosed ALL. Objective: To assess the safety and clinical activity of DA-EPOCH and InO in adults with relapsed or refractory B-ALL. Design, Setting, and Participants: This single-center, single-arm, nonrandomized, phase 1 dose-escalation trial included adults with relapsed or refractory CD22+ B-ALL and was conducted between September 2019 and November 2022. At least 5% blood or marrow blasts or measurable extramedullary disease (EMD) was required for enrollment. Interventions: DA-EPOCH was given on days 1 to 5, while InO was given on day 8 and day 15 of a 28-day cycle. Three dose levels were studied using a bayesian optimal interval design. Main Outcomes and Measures: The primary outcome was the maximum tolerated dose of InO when combined with DA-EPOCH, defined as the highest dose level that produced a rate of dose-limiting toxicity below 33%. Secondary objectives included response rates, survival estimates, and descriptions of toxic effects. Results: A total of 24 participants were screened and enrolled (median age, 46 [range, 28-76] years; 15 [62%] male). The median number of lines of prior therapy was 3 (range, 1-12). Three of 11 participants (27%) treated at the highest dose level (InO, 0.6 mg/m2, on day 8 and day 15) experienced dose-limiting toxicity, making this the maximum tolerated dose. No deaths occurred during the study, and only 1 patient (4%; 95% CI, 0.1%-21%) developed sinusoidal obstructive syndrome after poststudy allograft. The morphologic complete response rate was 84% (95% CI, 60%-97%), 88% (95% CI, 62%-98%) of which was measurable residual disease negative by flow cytometry. Five of 6 participants with EMD experienced treatment response. The overall response rate was 83% (95% CI, 63%-95%). Median overall survival, duration of response, and event-free survival were 17.0 (95% CI, 8.4-not reached), 15.0 (95% CI, 6.7-not reached), and 9.6 (95% CI, 4.5-not reached) months, respectively. Conclusions: In this study, adding InO to DA-EPOCH in adults with relapsed or refractory B-ALL was feasible, with high response rates and sinusoidal obstructive syndrome occurring rarely in a heavily pretreated population. Many patients were able to proceed to poststudy consolidative allogeneic hematopoietic cell transplant and/or chimeric antigen receptor T-cell therapy. Further investigation of this combination is warranted. Trial Registration: ClinicalTrials.gov Identifier: NCT03991884.

Intensive Reinduction Chemotherapy Followed by Early Allogeneic Hematopoietic Cell Transplantation for Relapsed/Refractory High-Grade Myeloid Neoplasms.

Outcomes for adults with relapsed/refractory (R/R) high-grade myeloid neoplasms remain poor, with allogeneic hematopoietic cell transplantation (HCT) the sole therapy likely to result in cure. We conducted the present study to determine the feasibility of early HCT-within 60 days of beginning reinduction chemotherapy-to see whether getting patients to HCT in an expeditious manner would expand the number of patients being offered this curative option. In this proof-of-principle feasibility study, we included adults age 18 to 75 years with R/R myeloid malignancies with ≥10% blood/marrow blasts at diagnosis who were eligible for a reduced-intensity HCT. Subjects received reinduction chemotherapy with cladribine, cytarabine, mitoxantrone, and filgrastim (CLAG-M) and proceeded to HCT with reduced-intensity conditioning (fludarabine/ melphalan). We enrolled 30 subjects, all of whom received CLAG-M reinduction, although only 9 underwent HCT within 60 days (<15, the predetermined threshold for feasibility "success"), with a median time to HCT of 48 days (range, 42 to 60 days). Eleven additional subjects received HCT beyond the target 60 days (off-study), with a median time to transplantation of 83 days (range, 53 to 367 days). Barriers to early HCT included infection, physician preference, lack of an HLA-matched donor, logistical delays, and disease progression, all of which may limit the real-world uptake of such early-to-transplantation protocols.

Impact of polymorphisms in drug pathway genes on disease-free survival in adults with acute myeloid leukemia.

Acute myeloid leukemia (AML) is a clinically heterogeneous disease, with a 5-year disease-free survival (DFS) ranging from under 10% to over 70% for distinct groups of patients. At our institution, cytarabine, etoposide and busulfan are used in first or second remission patients treated with a two-step approach to autologous stem cell transplantation (ASCT). In this study, we tested the hypothesis that polymorphisms in the pharmacokinetic and pharmacodynamic pathway genes of these drugs are associated with DFS in AML patients. A total of 1659 variants in 42 genes were analyzed for their association with DFS using a Cox-proportional hazards model. One hundred and fifty-four genetically European patients were used for the primary analysis. An intronic single nucleotide polymorphism (SNP) in ABCC3 (rs4148405) was associated with a significantly shorter DFS (hazard ratios (HR)=3.2, P=5.6 × 10(-6)) in our primary cohort. In addition, a SNP in the GSTM1-GSTM5 locus, rs3754446, was significantly associated with a shorter DFS in all patients (HR=1.8, P=0.001 for 154 European ancestry; HR=1.7, P=0.028 for 125 non-European patients). Thus, for the first time, genetic variants in drug pathway genes are shown to be associated with DFS in AML patients treated with chemotherapy-based autologous ASCT.

Prognostic impact of secondary versus de novo ontogeny in acute myeloid leukemia is accounted for by the European LeukemiaNet 2022 risk classification.

Secondary AML (sAML), defined by either history of antecedent hematologic disease (AHD) or prior genotoxic therapy (tAML), is classically regarded as having worse prognosis than de novo disease (dnAML). Clinicians may infer a new AML diagnosis is secondary based on a history of antecedent blood count (ABC) abnormalities in the absence of known prior AHD, but whether abnormal ABCs are associated with worse outcomes is unclear. Secondary-type mutations have recently been incorporated into the European LeukemiaNet (ELN) 2022 guidelines as adverse-risk features, raising the question of whether clinical descriptors of ontogeny (i.e., de novo or secondary) are prognostically significant when accounting for genetic risk by ELN 2022. In a large multicenter cohort of patients (n = 734), we found that abnormal ABCs are not independently prognostic after adjusting for genetic characteristics in dnAML patients. Furthermore, history of AHD and tAML do not confer increased risk of death compared to dnAML on multivariate analysis, suggesting the prognostic impact of ontogeny is accounted for by disease genetics as stratified by ELN 2022 risk and TP53 mutation status. These findings emphasize the importance that disease genetics should play in risk stratification and clinical trial eligibility in AML.