How I use next-generation sequencing-MRD to plan approach and prevent relapse after HCT for children and adults with ALL.

ABSTRACT: Measurable residual disease (MRD) evaluation by multiparameter flow cytometry (MFC) or quantitative polymerase chain reaction methods is an established standard of care for assessing risk of relapse before or after hematopoietic cell transplantation (HCT) for acute lymphoblastic leukemia (ALL). Next-generation sequencing (NGS)-MRD has emerged as a highly effective approach that allows for the detection of lymphoblasts at a level of <1 in 106 nucleated cells, increasing sensitivity of ALL detection by 2 to 3 logs. Early studies have shown superior results compared with MFC and suggest that NGS-MRD may allow for the determination of patients in whom reduced toxicity transplant preparative approaches could be deployed without sacrificing outcomes. Many centers/study groups have implemented immune modulation approaches based on MRD measurements that have resulted in improved outcomes. Challenges remain with NGS-MRD, because it is not commercially available in many countries, and interpretation of results can be complex. Through patient case review, discussion of relevant studies, and detailed expert opinion, we share our approach to NGS-MRD testing before and after HCT in pediatric and adult ALL. Improved pre-HCT risk classification and post-HCT monitoring for relapse in bone marrow and less invasive peripheral blood monitoring by NGS-MRD may lead to alternative approaches to prevent relapse in patients undergoing this challenging procedure.

A Phase 1 Clinical Trial of NKTR-255 with CD19-22 CAR-T Cell Therapy for Refractory B-cell Acute Lymphoblastic Leukemia.

While chimeric antigen receptor T-cell (CAR-T) therapy has revolutionized the treatment of B-cell malignancies, many patients relapse and therefore strategies to improve antitumor immunity are needed. We previously designed a novel autologous bispecific CAR targeting CD19 and CD22 (CAR19-22), which was well tolerated and associated with high response rates but relapse was common. Interleukin-15 (IL15) induces proliferation of diverse immune cells and can augment lymphocyte trafficking. Here, we report the results of a phase 1 clinical trial of the first combination of a novel recombinant polymer-conjugated IL15 receptor agonist (NKTR-255), with CAR19-22, in adults with relapsed / refractory B-cell acute lymphoblastic leukemia. Eleven patients were enrolled, nine of whom successfully received CAR19-22 followed by NKTR-255. There were no dose limiting toxicities, with transient fever and myelosuppression as the most common possibly related toxicities. We observed favorable efficacy with eight out of nine patients (89%) achieving measurable residual disease negative remission. At 12 months, progression-free survival for NKTR-255 was double that of historical controls (67% vs 38%). We performed correlative analyses to investigate the effects of IL15 receptor agonism. Cytokine profiling showed significant increases in IL15 and the chemokines CXCL9 and CXCL10. The increase in chemokines was associated with decreases in absolute lymphocyte counts and CD8+ CAR T-cells in blood and ten-fold increases in CSF CAR-T cells, suggesting lymphocyte trafficking to tissue. Combining NKTR-255 with CAR19-22 was safe, feasible and associated with high rates of durable responses (NCT03233854).

CD22-directed CAR T-cell therapy for large B-cell lymphomas progressing after CD19-directed CAR T-cell therapy: a dose-finding phase 1 study.

BACKGROUND: Outcomes are poor for patients with large B-cell lymphoma who relapse after CD19-directed chimeric antigen receptor (CAR) T-cell therapy (CAR19). CD22 is a nearly universally expressed B-cell surface antigen and the efficacy of a CD22-directed CAR T-cell therapy (CAR22) in large B-cell lymphoma is unknown, which was what we aimed to examine in this study. METHODS: In this single centre, open-label, dose-escalation phase 1 trial, we intravenously administered CAR22 at two dose levels (1 million and 3 million CAR22-positive T cells per kg of bodyweight) to adult patients (aged ≥18 years) who relapsed after CAR19 or had CD19-negative large B-cell lymphoma. The primary endpoints were manufacturing feasibility, safety measured by the incidence and severity of adverse events and dose-limiting toxicities, and identification of the maximum tolerated dose (ie, the recommended phase 2 dose). This study is registered with ClinicalTrials.gov (NCT04088890) and is active, but closed for enrolment. FINDINGS: From Oct 17, 2019, to Oct 19, 2022, a total of 41 patients were assessed for eligibility; however, one patient withdrew. 40 patients underwent leukapheresis and 38 (95%) had CAR T-cell products manufactured successfully. The median age was 65 years (range 25-84), 17 (45%) were women, 32 (84%) had elevated pretreatment lactate dehydrogenase, 11 (29%) had refractory disease to all previous therapies, and patients had received a median of four lines of previous therapy (range 3-8). Of the 38 patients treated, 37 (97%) had relapsed after previous CAR19. The identified maximum tolerated dose was 1 million CAR T cells per kg. Of 29 patients who received the maximum tolerated dose, no patients developed a dose-limiting toxicity or grade 3 or higher cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, or immune effector cell-associated haemophagocytic lymphohistiocytosis-like syndrome. INTERPRETATION: This trial identifies CD22 as an immunotherapeutic target in large B-cell lymphoma and demonstrates the durable clinical activity of CAR22 in patients with disease progression after CAR19 therapy. Although these findings are promising, it is essential to recognise that this is a phase 1 dose-finding study. Further investigations are warranted to establish the long-term efficacy and to delineate the patient subgroups that will derive the most benefit from this therapeutic approach. FUNDING: National Cancer Institute, National Institutes of Health, Stanford Cancer Institute, Leukemia & Lymphoma Society, Parker Institute for Cancer Immunotherapy, Lymph & Co, and the European Hematology Association.

Improved outcomes for relapsed/refractory Hodgkin lymphoma after autologous transplantation in the era of novel agents.

The treatment landscape of relapsed/refractory (R/R) classic Hodgkin lymphoma (cHL) has evolved significantly over the past decade after the approval of brentuximab vedotin (BV) and the programmed death-1 (PD-1) inhibitors. We evaluated how outcomes and practice patterns have changed for patients with R/R cHL who underwent autologous hematopoietic cell transplantation (AHCT) at our institution from 2011 to 2020 (N = 183) compared with those from 2001 to 2010 (N = 159) and evaluated prognostic factors for progression-free survival (PFS) and overall survival (OS) in both eras. OS was superior in the modern era with a trend toward lower nonrelapse mortality beyond 2 years after transplant. Among patients who progressed after AHCT, 4-year postprogression survival increased from 43.3% to 71.4% in the modern era, reflecting increasing use of BV and the PD-1 inhibitors. In multivariable analysis for patients that underwent transplant in the modern era, age ≥45 years, primary refractory disease, and lack of complete remission pre-AHCT were associated with inferior PFS, whereas receipt of a PD-1 inhibitor-based regimen pre-AHCT was associated with superior PFS. Extranodal disease at relapse was associated with inferior OS. Our study demonstrates improved survival for R/R cHL after AHCT in the modern era attributed to more effective salvage regimens allowing for better disease control pre-AHCT and improved outcomes for patients who progressed after AHCT. Excellent outcomes were observed with PD-1 inhibitor-based salvage regimens pre-AHCT and support a randomized trial evaluating immunotherapy in the second line setting.

Management of post-autologous transplant relapse in patients with T-cell lymphomas.

Autologous hematopoietic cell transplantation (AHCT) is often used as a consolidation for patients with peripheral T-cell lymphomas (PTCLs) due to the poor prognosis associated with this heterogenous group of disorders. However, a significant number of patients will experience post-AHCT disease relapse. Here, we report a retrospective study of consecutive 124 patients with PTCLs who underwent AHCT from 2008 to 2020. With a median follow-up of 6.01 years following AHCT, 49 patients (40%) experienced disease relapse. As expected, more patients who were not in first complete remission experienced post-AHCT relapse. Following relapse, majority of the patients (70%) receiving systemic therapies intended as bridging to curative allogeneic HCT. However, only 18 (53%) patients eventually underwent allogeneic HCT. The estimated 3-year OS among patients proceeding to allogeneic HCT was 72% (95% CI 46%-87%). Our report details the pattern of post-AHCT relapse and the management of relapsed disease using different therapeutic modalities.

CD22-directed CAR T-cell therapy induces complete remissions in CD19-directed CAR-refractory large B-cell lymphoma.

The prognosis of patients with large B-cell lymphoma (LBCL) that progresses after treatment with chimeric antigen receptor (CAR) T-cell therapy targeting CD19 (CAR19) is poor. We report on the first 3 consecutive patients with autologous CAR19-refractory LBCL who were treated with a single infusion of autologous 1 × 106 CAR+ T cells per kilogram targeting CD22 (CAR22) as part of a phase 1 dose-escalation study. CAR22 therapy was relatively well tolerated, without any observed nonhematologic adverse events higher than grade 2. After infusion, all 3 patients achieved complete remission, with all responses continuing at the time of last follow-up (mean, 7.8 months; range, 6-9.3). Circulating CAR22 cells demonstrated robust expansion (peak range, 85.4-350 cells per microliter), and persisted beyond 3 months in all patients with continued radiographic responses and corresponding decreases in circulating tumor DNA beyond 6 months after infusion. Further accrual at a higher dose level in this phase 1 dose-escalation study is ongoing and will explore the role of this therapy in patients in whom prior CAR T-cell therapies have failed. This trial is registered on clinicaltrials.gov as #NCT04088890.

Sequencing antigen-targeting antibodies and cellular therapies in adults with relapsed/refractory B-cell acute lymphoblastic leukemia.

The recent approvals of four CD19-or CD22-targeted therapies for B-cell acute lymphoblastic leukemia (B-ALL) have transformed the treatment of relapsed/refractory (r/r) disease. Adults with r/r B-ALL are usually eligible for all options, but there are no studies directly comparing these agents, and the treating physician must decide which to select. Each therapy has notable activity as a single agent but has limitations in particular settings, and the optimal choice varies. These therapies can be complementary and used either sequentially or concomitantly. Here, we review the current landscape of antigen-targeted therapies for r/r B-ALL and discuss considerations for their use.

Frontline treatment patterns and outcomes among older adults with acute myeloid leukemia: A population-based analysis in the modern era.

BACKGROUND: Traditionally, conventional induction chemotherapy has been the primary frontline treatment for acute myeloid leukemia (AML); however, older adults are often poor chemotherapy candidates. Recently, several nonconventional frontline AML regimens, including hypomethylating agents, the BCL-2 inhibitor venetoclax, and targeted therapies, have emerged, and they may offer new options for older adults. This study was aimed at describing treatment patterns and outcomes of older adult AML in a modern population-based cohort. METHODS: This study evaluated patients aged ≥60 years with a first primary diagnosis of AML (2014-2017) in the California Cancer Registry linked to inpatient hospitalizations. Multivariable regression examined factors associated with the frontline treatment regimen and survival. RESULTS: In all, 3068 patients were included; 36% received frontline therapy with a conventional chemotherapy backbone, 42% received nonconventional therapy, and 22% received no treatment. The use of nonconventional therapy increased over time from 38% of patients in 2014 to 47% in 2017 (P < .001). In multivariable analyses, receipt of treatment was associated with an age younger than 80 years, fewer than 2 comorbidities, and care at a National Cancer Institute-designated cancer center (NCI-CC). Compared with conventional chemotherapy, nonconventional therapy was associated with Black race/ethnicity, public health insurance, fewer hospital admissions, and fewer inpatient days. Receiving frontline therapy at an NCI-CC was independently associated with superior overall survival. CONCLUSIONS: Using a population-based approach, this study has demonstrated that patterns of care for frontline AML treatment in older adults are changing, with increasing use of nonconventional therapies. A significant proportion of older adults remain untreated. At the population level, there remain opportunities to increase therapy access for older adults with AML.

Measurable residual disease in acute lymphoblastic leukemia: methods and clinical context in adult patients.

Measurable residual disease (MRD) is the most powerful independent predictor of risk of relapse and long-term survival in adults and children with acute lymphoblastic leukemia (ALL). For almost all patients with ALL there is a reliable method to evaluate MRD, which can be done using multi-color flow cytometry, quantitative polymerase chain reaction to detect specific fusion transcripts or immunoglobulin/T-cell receptor gene rearrangements, and high-throughput next-generation sequencing. While next-generation sequencing-based MRD detection has been increasingly utilized in clinical practice due to its high sensitivity, the clinical significance of very low MRD levels (<10-4) is not fully characterized. Several new immunotherapy approaches including blinatumomab, inotuzumab ozogamicin, and chimeric antigen receptor T-cell therapies have demonstrated efficacy in eradicating MRD in patients with B-ALL. However, new approaches to target MRD in patients with T-ALL remain an unmet need. As our MRD detection assays become more sensitive and expanding novel therapeutics enter clinical development, the future of ALL therapy will increasingly utilize MRD as a criterion to either intensify or modify therapy to prevent relapse or de-escalate therapy to reduce treatment-related morbidity and mortality.

Controversies in the Treatment of Adolescents and Young Adults with Philadelphia Chromosome-Negative B-Cell Acute Lymphoblastic Leukemia.

PURPOSE OF THE REVIEW: The incidence of acute lymphoblastic leukemia (ALL) has been increasing steadily in the adolescent and young adult (AYA) population. In this review article focused on the management of AYAs with Philadelphia chromosome-negative (Ph-) B-ALL, we examine topics of clinical interest and identify areas of controversy in need of further investigation. RECENT FINDINGS: We explore four areas of active investigation: pediatric-inspired front-line treatment regimens, the optimal time of measurable residual disease (MRD) assessment, the role of hematopoietic stem cell transplant and the optimal salvage therapy for relapsed/refractory B-ALL in AYAs. There has been rapid advancement in the management of ALL in the AYA patient population, which has resulted in improved outcomes. We must build on the successes by continuing to promote multi-center innovative clinical research with clinical trial populations reflecting the AYA ALL patient spectrum. The incorporation of novel targeted immunotherapy into front-line treatment will be transformative and redefine treatment paradigms in the coming years.

Outcomes with Autologous or Allogeneic Stem Cell Transplantation in Patients with Plasma Cell Leukemia in the Era of Novel Agents.

Plasma cell leukemia (PCL) is a rare and very aggressive plasma cell disorder. The optimal treatment approach, including whether to pursue an autologous (auto) or allogeneic (allo) stem cell transplantation (SCT) is not clear, given the lack of clinical trial-based evidence. This single-center retrospective study describes the outcomes of 16 patients with PCL (n = 14 with primary PCL) who underwent either autoSCT (n = 9) or alloSCT (n = 7) for PCL in the era of novel agents, between 2007 and 2019. The median age of the cohort was 58 years. High-risk cytogenetics were found in 50% of the patients. All patients received a proteasome inhibitor and/or immunomodulatory drug-based regimen before transplantation. At the time of transplantation, 10 patients (62%) obtained at least a very good partial response (VGPR). The response after autoSCT (3 months) was at least a VGPR in 6 patients (67%; complete response [CR] in 5). All patients undergoing alloSCT achieved a CR at 3 months. Maintenance therapy was provided to 5 patients (56%) after autoSCT. The median progression-free survival after transplantation was 6 months in the autoSCT group, compared with 18 months in the alloSCT group (P = .09), and median overall survival (OS) after transplantation in the 2 groups was 19 months and 40 months, respectively (P = .41). The median OS from diagnosis was 27 months and 49 months, respectively (P = .50). Of the 11 deaths, 10 patients (91%) died of relapsed disease. AlloSCT was not observed to offer any significant survival advantage over autoSCT in PCL, in agreement with recent reports, and relapse remains the primary cause of death in these patients.

Impact of cytogenetic abnormalities on outcomes of adult Philadelphia-negative acute lymphoblastic leukemia after allogeneic hematopoietic stem cell transplantation: a study by the Acute Leukemia Working Committee of the Center for International Blood and Marrow Transplant Research.

Cytogenetic risk stratification at diagnosis has long been one of the most useful tools to assess prognosis in acute lymphoblastic leukemia (ALL). To examine the prognostic impact of cytogenetic abnormalities on outcomes after allogeneic hematopoietic cell transplantation, we studied 1731 adults with Philadelphia-negative ALL in complete remission who underwent myeloablative or reduced intensity/non-myeloablative conditioning transplant from unrelated or matched sibling donors reported to the Center for International Blood and Marrow Transplant Research. A total of 632 patients had abnormal conventional metaphase cytogenetics. The leukemia-free survival and overall survival rates at 5 years after transplantation in patients with abnormal cytogenetics were 40% and 42%, respectively, which were similar to those in patients with a normal karyotype. Of the previously established cytogenetic risk classifications, modified Medical Research Council-Eastern Cooperative Oncology Group score was the only independent prognosticator of leukemia-free survival (P=0.03). In the multivariable analysis, monosomy 7 predicted post-transplant relapse [hazard ratio (HR)=2.11; 95% confidence interval (95% CI): 1.04-4.27] and treatment failure (HR=1.97; 95% CI: 1.20-3.24). Complex karyotype was prognostic for relapse (HR=1.69; 95% CI: 1.06-2.69), whereas t(8;14) predicted treatment failure (HR=2.85; 95% CI: 1.35-6.02) and overall mortality (HR=3.03; 95% CI: 1.44-6.41). This large study suggested a novel transplant-specific cytogenetic scheme with adverse [monosomy 7, complex karyotype, del(7q), t(8;14), t(11;19), del(11q), tetraploidy/near triploidy], intermediate (normal karyotype and all other abnormalities), and favorable (high hyperdiploidy) risks to prognosticate leukemia-free survival (P=0.02). Although some previously established high-risk Philadelphia-negative cytogenetic abnormalities in ALL can be overcome by transplantation, monosomy 7, complex karyotype, and t(8;14) continue to pose significant risks and yield inferior outcomes.

Clinical actionability of measurable residual disease (MRD) assessment in the management of patients with hematologic malignancies: a case-based monograph.

New treatments for hematologic malignancies have led to outcomes that are outpacing the ability of traditional measures of response to accurately capture a patient's depth of response and risk of relapse. Assessment of measurable residual disease (MRD) offers a high-sensitivity evaluation for remaining disease present in a patient. MRD is not a surrogate marker for the detection of cancer cells, but rather a direct measure of them. MRD has quickly become an important measurement of response in patients with multiple myeloma and acute lymphocytic leukemia. Retrospective and prospective studies indicate that MRD-negative patients have better outcomes, particularly progression-free and overall survival, compared with patients who are MRD-positive. Two methods have emerged as the primary strategies for assessing MRD: next-generation sequencing (NGS) and next-generation flow (NGF). Both methods measure detectable disease in the bone marrow. The clonoSEQ® Assay, which uses NGS technology, is cleared by the US Food and Drug Administration for the detection and monitoring of MRD in bone marrow samples from patients with multiple myeloma or B-cell acute lymphoblastic leukemia. This monograph discusses the supporting research and clinical use of MRD assessment among patients with multiple myeloma and acute lymphoblastic leukemia.

The Current Genomic and Molecular Landscape of Philadelphia-like Acute Lymphoblastic Leukemia.

Philadelphia (Ph)-like acute lymphoblastic leukemia (ALL) is a high-risk B-cell Acute Lymphoblastic Leukemia (B-ALL) characterized by a gene expression profile similar to Ph-positive B-ALL but lacking the BCR-ABL1 translocation. The molecular pathogenesis of Ph-like B-ALL is heterogenous and involves aberrant genomics, receptor overexpression, kinase fusions, and mutations leading to kinase signaling activation, leukemogenic cellular proliferation, and differentiation blockade. Testing for the Ph-like signature, once only a research technique, is now available to the clinical oncologist. The plethora of data pointing to poor outcomes for this ALL subset has triggered investigations into the role of targeted therapies, predominantly involving tyrosine kinase inhibitors that are showing promising results.

Healthcare Utilization is High in Adult Patients Relapsing after Allogeneic Hematopoietic Cell Transplantation.

Disease relapse is the leading cause of death for patients with acute leukemia (AL) and myelodysplastic syndrome (MDS) who undergo allogeneic hematopoietic cell transplantation (HCT). Relapse post-HCT is associated with poor prognosis; however, inpatient healthcare utilization of this population is unknown. Here we describe survival, intensity of healthcare utilization, and characteristics associated with high resource use at the end of life (EOL). Adult patients with AL/MDS who underwent HCT at a large regional referral center with subsequent relapse between 2005 and 2015 were included in this retrospective study. We compared the distribution of demographic and clinical characteristics of patients as well as healthcare utilization over 2 years postrelapse and at EOL by postrelapse disease-directed therapeutic interventions. We created a composite score for EOL healthcare utilization intensity by summing the presence of any of the following criteria: death in the hospital, use of chemotherapy, emergency department, hospitalization, intensive care unit, intubation, cardiopulmonary resuscitation, or hemodialysis in the last month of life. Higher scores indicate more intense healthcare use at EOL. Multivariable linear regression analysis was used to determine variables (demographic characteristics, postrelapse treatment group, advance directives documentation, palliative care referral, time to relapse) associated with EOL healthcare utilization intensity. One hundred fifty-four patients were included; median age at relapse was 56 years (interquartile range [IQR], 39 to 63), 55% were men, 79% had AL, and median time from HCT to relapse was 6 months (IQR, 3 to 10). After relapse, 28% received supportive care only, 50% received chemotherapy only, and 22% received chemotherapy plus cell therapy (either donor lymphocyte infusion, second HCT, or donor lymphocyte infusion plus second HCT). With the exception of time until relapse and Karnofsky Performance Status, baseline characteristics (gender, age, race, graft-versus-host disease, year of treatment) did not significantly differ by postrelapse treatment group. One hundred thirty-six patients (88%) died within 2 years of relapse; survival differed significantly by postrelapse treatment group, with those receiving disease-directed treatment showing lower risk of death. Healthcare use in AL/MDS patients after post-HCT relapse was high overall, with 44% visiting the emergency department at least once (22% at least 2 times), 93% hospitalized (55% at least 2 times, 16% at least 5 times), and 38% using the intensive care unit (median length of stay 5, days; IQR, 3 to 10). Use was high even among those receiving only supportive care. For those patients who died, the mean intensity score for EOL healthcare use was 1.8 (standard deviation, 1.8). Most patients (70%) had a marker of high-intensity healthcare utilization at the EOL or died in hospital. In multivariable analysis, an increase in age (estimate -.03 (95% CI, -.06 to -.003) and having AL versus MDS were significantly associated with a decreased EOL healthcare intensity score; no other variables were associated with intensity of EOL healthcare use. Healthcare utilization after post-HCT relapse is associated with receipt of disease-directed therapy but remains high across all groups despite known poor prognosis. Interventions are needed to minimize nonbeneficial treatments and promote goal-concordant EOL care in this seriously ill patient population.

Comparison of High Doses of Total Body Irradiation in Myeloablative Conditioning before Hematopoietic Cell Transplantation.

Malignancy relapse is the most common cause of treatment failure among recipients of hematopoietic cell transplantation (HCT). Conditioning dose intensity can reduce disease relapse but is offset by toxicities. Improvements in radiotherapy techniques and supportive care may translate to better outcomes with higher irradiation doses in the modern era. This study compares outcomes of recipients of increasing doses of high-dose total body irradiation (TBI) divided into intermediate high dose (IH; 13-13.75 Gy) and high dose (HD; 14 Gy) with standard dose (SD; 12 Gy) with cyclophosphamide. A total of 2721 patients ages 18 to 60 years with hematologic malignancies receiving HCT from 2001 to 2013 were included. Cumulative incidences of nonrelapse mortality (NRM) at 5 years were 28% (95% confidence interval [CI], 25% to 30%), 32% (95% CI, 29% to 36%), and 34% (95% CI, 28% to 39%) for SD, IH, and HD, respectively (P = .02). Patients receiving IH-TBI had a 25% higher risk of NRM compared with those receiving SD-TBI (12 Gy) (P = .007). Corresponding cumulative incidences of relapse were 36% (95% CI, 34% to 38%), 32% (95% CI, 29% to 36%), and 26% (95% CI, 21% to 31%; P = .001). Hazard ratios for mortality compared with SD were 1.06 (95% CI, .94 to 1.19; P = .36) for IH and .89 (95% CI, .76 to 1.05; P = .17) for HD. The study demonstrates that despite improvements in supportive care, myeloablative conditioning using higher doses of TBI (with cyclophosphamide) leads to worse NRM and offers no survival benefit over SD, despite reducing disease relapse.

Increasing use of allogeneic hematopoietic cell transplantation in patients aged 70 years and older in the United States.

In this study, we evaluated trends and outcomes of allogeneic hematopoietic cell transplantation (HCT) in adults ≥70 years with hematologic malignancies across the United States. Adults ≥70 years with a hematologic malignancy undergoing first allogeneic HCT in the United States between 2000 and 2013 and reported to the Center for International Blood and Marrow Transplant Research were eligible. Transplant utilization and transplant outcomes, including overall survival (OS), progression-free survival (PFS), and transplant-related mortality (TRM) were studied. One thousand one hundred and six patients ≥70 years underwent HCT across 103 transplant centers. The number and proportion of allografts performed in this population rose markedly over the past decade, accounting for 0.1% of transplants in 2000 to 3.85% (N = 298) in 2013. Acute myeloid leukemia and myelodysplastic syndromes represented the most common disease indications. Two-year OS and PFS significantly improved over time (OS: 26% [95% confidence interval (CI), 21% to 33%] in 2000-2007 to 39% [95% CI, 35% to 42%] in 2008-2013, P < .001; PFS: 22% [16% to 28%] in 2000-2007 to 32% [95% CI, 29% to 36%] in 2008-2013, P = .003). Two-year TRM ranged from 33% to 35% and was unchanged over time (P = .54). Multivariable analysis of OS in the modern era of 2008-2013 revealed higher comorbidity by HCT comorbidity index ≥3 (hazard ratio [HR], 1.27; P = .006), umbilical cord blood graft (HR, 1.97; P = .0002), and myeloablative conditioning (HR, 1.61; P = .0002) as adverse factors. Over the past decade, utilization and survival after allogeneic transplant have increased in patients ≥70 years. Select adults ≥70 years with hematologic malignancies should be considered for transplant.

Acute leukemia in a patient with 15q overgrowth syndrome.

Overgrowth syndromes are rare genetic conditions which present as global or segmental hyperplasia and are sometimes associated with increased risk of malignancy. Trisomy of the terminal portion of 15q which includes the IGFR1 gene, produces a rare overgrowth phenotype that has been termed 15q overgrowth syndrome (15q OGS). Upregulation of IGF1R has long been implicated in oncogenesis of multiple cancer types, including acute leukemias, and has been shown to render cells more susceptible to other transforming events. To date, too few cases of 15q OGS have been reported to identify any cancer predisposition. We present a case of a 34-year-old female with intellectual disability, macrocephaly, and subtle dysmorphic features who was diagnosed with mixed phenotype acute leukemia (lymphoid and myeloid). Prior to initiation of therapy she was referred to medical genetics for further evaluation and was identified as having a chromosomal translocation resulting in a partial trisomy of chromosome 15q, consistent with 15q OGS. A review of the literature for cases of malignancy in individuals with increased copy number of 15q revealed only one other reported patient. Given the small number of reported individuals, we cannot rule out an increased risk of cancer associated with this chromosomal overgrowth syndrome. Although concerns have been raised regarding treatment feasibility in the setting of chromosomal disorders, the reported patient underwent successful treatment with allogeneic hematopoietic stem-cell transplant.

Advance Directive Utilization Is Associated with Less Aggressive End-of-Life Care in Patients Undergoing Allogeneic Hematopoietic Cell Transplantation.

Allogeneic hematopoietic cell transplantation (HCT) is associated with significant morbidity and mortality, making advance care planning (ACP) and management especially important in this patient population. A paucity of data exists on the utilization of ACP among allogeneic HCT recipients and the relationship between ACP and intensity of healthcare utilization in these patients. We performed a retrospective review of patients receiving allogeneic HCT at our institution from 2008 to 2015 who had subsequently died after HCT. Documentation and timing of advance directive (AD) completion were abstracted from the electronic medical record. Outcomes of interest included use of intensive care unit (ICU) level of care at any time point after HCT, within 30 days of death, and within 14 days of death; use of mechanical ventilation at any time after HCT; and location of death. Univariate logistic regression was performed to explore associations between AD completion and each outcome. Of the 1031 patients who received allogeneic HCT during the study period, 422 decedents (41%) were included in the analysis. Forty-four percent had AD documentation prior to death. Most patients (69%) indicated that if terminally ill, they did not wish to be subjected to life-prolonging treatment attempts. Race/ethnicity was significantly associated with AD documentation, with non-Hispanic white patients documenting ADs more frequently (51%) compared with Hispanic (22%) or Asian patients (35%; P = .0007). Patients with ADs were less likely to use the ICU during the transplant course (41% for patients with ADs versus 52% of patients without ADs; P = .03) and also were less likely to receive mechanical ventilation at any point after transplantation (21% versus 37%, P < .001). AD documentation was also associated with decreased ICU use at the end of life; relative to patients without ADs, patients with ADs were more likely to die at home or in hospital as opposed to in the ICU (odds ratio, .44; 95% confidence interval, .27 to .72). ACP remains underused in allogeneic HCT. Adoption of a systematic practice to standardize AD documentation as part of allogeneic HCT planning has the potential to significantly reduce ICU use and mechanical ventilation while improving quality of care at end of life in HCT recipients.

Decreased early mortality associated with the treatment of acute myeloid leukemia at National Cancer Institute-designated cancer centers in California.

BACKGROUND: To the authors' knowledge, few population-based studies to date have evaluated the association between location of care, complications with induction therapy, and early mortality in patients with acute myeloid leukemia (AML). METHODS: Using linked data from the California Cancer Registry and Patient Discharge Dataset (1999-2014), the authors identified adult (aged ≥18 years) patients with AML who received inpatient treatment within 30 days of diagnosis. A propensity score was created for treatment at a National Cancer Institute-designated cancer center (NCI-CC). Inverse probability-weighted, multivariable logistic regression models were used to determine associations between location of care, complications, and early mortality (death ≤60 days from diagnosis). RESULTS: Of the 7007 patients with AML, 1762 (25%) were treated at an NCI-CC. Patients with AML who were treated at NCI-CCs were more likely to be aged ≤65 years, live in higher socioeconomic status neighborhoods, have fewer comorbidities, and have public health insurance. Patients treated at NCI-CCs had higher rates of renal failure (23% vs 20%; P = .010) and lower rates of respiratory failure (11% vs 14%; P = .003) and cardiac arrest (1% vs 2%; P = .014). After adjustment for baseline characteristics, treatment at an NCI-CC was associated with lower early mortality (odds ratio, 0.46; 95% confidence interval, 0.38-0.57). The impact of complications on early mortality did not differ by location of care except for higher early mortality noted among patients with respiratory failure treated at non-NCI-CCs. CONCLUSIONS: The initial treatment of adult patients with AML at NCI-CCs is associated with a 53% reduction in the odds of early mortality compared with treatment at non-NCI-CCs. Lower early mortality may result from differences in hospital or provider experience and supportive care. Cancer 2018;124:1938-45. © 2018 American Cancer Society.