Code Status Transitions in Patients with High-Risk Acute Myeloid Leukemia (AML)

Abstract Background: Patients with high-risk AML often experience intensive medical care at the end of life (EOL) such as hospitalization and intensive care unit (ICU) admission. Despite their poor prognosis, patients with AML and their caregivers often have substantial misperceptions of their prognosis, which may lead to difficult code status transitions near the end of life. However, studies examining code status transitions in patients with AML are lacking. Methods: We conducted a mixed-methods study of 200 patients with high-risk AML enrolled in supportive care studies at Massachusetts General Hospital between 2014-2021. High-risk AML was defined as: 1) new diagnosis ≥ 60 years, or 2) relapsed/refractory AML. Two physicians used consensus-driven medical record review to characterize code status transitions from time of diagnosis to death and identify patient, family, and palliative care involvement. Code status was coded as 'full' (confirmed or presumed), 'restricted' (i.e., do not resuscitate), or 'comfort measures only' (CMO). We used logistic regression to explore whether patient factors or features of the code status discussion were associated with the time between the last code status transition and death. Results: At diagnosis of high-risk AML, 86.0% of patients were 'full code' (38.5% presumed, 47.5% confirmed) and 8.5% had restrictions on life-sustaining therapies. Overall, 57% (114/200) of patients experienced a code status transition, with a median of two transitions (range 1-8) during their illness course. Overall, a total of 206 code status transitions were described across the cohort. Median time from diagnosis to first code status transition was 212 days (range 7-4507), and from last transition to death was 2 days (range 0-350). Most of these final code status transitions (71.1%, 81/114) were transitions to CMO near the end of life. Only 60.5% of patients (69/114) who underwent a code status transition participated in their last code status change. In contrast, patients and families participated in 87.7% (100/114) of the last code status transitions and palliative care was involved in 42.1% (48/114). A substantial minority of last code status transitions occurred in the ICU or emergency department (26.3%, 30/114). We identified three processes leading to code status transitions (Table 1): 1) pre-emptive conversations prior to any clinical change (15.6%, 32/206); 2) anticipatory conversations at the time of acute clinical deterioration (32.2%, 66/206); and 3) futility conversations after acute clinical deterioration, focused on withdrawing life-sustaining therapies (51.0%, 105/206). Older age (B = 0.07, P < 0.001), and receipt of non-intensive chemotherapy (B = 1.42, P = 0.003) were associated with a longer time from the last code status transition to death (Table 2). In contrast, futility conversations were associated with shorter time from last code status transition to death (B = -2.84, P < 0.001) compared to pre-emptive or anticipatory conversations. Conclusions: Almost half of patients were "presumed full code" at the time of diagnosis of high-risk AML and most experienced code status transitions at the end of life focused on futility of life-sustaining therapies after acute clinical deterioration. These results suggest that goals of care discussions occur too late in the typical illness course of patients with poor prognosis, high-risk AML. Interventions focused on enhancing patient engagement in timely discussions regarding their end of life care preferences are warranted. Figure 1 Figure 1. Disclosures LeBlanc: AbbVie: Consultancy, Honoraria, Other: Advisory board; Travel fees, Speakers Bureau; BMS/Celgene: Consultancy, Honoraria, Other: Travel fees, Research Funding, Speakers Bureau; Pfizer: Consultancy, Other: Advisory Board; Daiichi-Sankyo: Consultancy, Honoraria, Other: Advisory board; Flatiron: Consultancy, Other: Advisory board; Astellas: Consultancy, Honoraria, Other: Advisory board; American Cancer Society: Research Funding; Jazz Pharmaceuticals: Research Funding; AstraZeneca: Consultancy, Honoraria, Other: Advisory board, Research Funding; Agios: Consultancy, Honoraria, Other: Advisory board; Travel fees, Speakers Bureau; Duke University: Research Funding; Otsuka: Consultancy, Honoraria, Other; NINR/NIH: Research Funding; CareVive: Consultancy, Other, Research Funding; Helsinn: Consultancy, Research Funding; Heron: Consultancy, Honoraria, Other: advisory board; Amgen: Consultancy, Other: travel; UpToDate: Patents & Royalties; Seattle Genetics: Consultancy, Other: Advisory board, Research Funding.

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Code status transitions in patients with high-risk acute myeloid leukemia (AML).

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e19009 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e19009-e19009

Author(s):

Hannah Rebeccah Abrams ◽

Ryan David Nipp ◽

Lara Traeger ◽

Mitchell W. Lavoie ◽

Matthew J. Reynolds ◽

...

Keyword(s):

High Risk ◽

Myeloid Leukemia ◽

Massachusetts General Hospital ◽

Clinical Deterioration ◽

Do Not Resuscitate ◽

Code Status ◽

Day Range ◽

Status Transition ◽

New Diagnosis ◽

Record Review

e19009 Background: Patients with high-risk AML often experience aggressive medical care at the end of life (EOL) such as hospitalization and intensive care unit (ICU) admission. Despite this, studies examining code status transitions in this population are lacking. Methods: We conducted a mixed methods study of 107 patients with high-risk AML enrolled in supportive care studies at Massachusetts General Hospital between 2014-2019. High-risk AML was defined as 1) new diagnosis > 60 years or 2) relapsed/refractory AML. Two physicians used consensus-driven medical record review to characterize code status transitions. Code statuses were coded as ‘full’ (confirmed or presumed), ‘restricted’ (i.e., do not resuscitate), or ‘comfort measures only’ (CMO); confirmations of presumed status were not coded as transitions. Results: At diagnosis of high-risk AML, 91.9% of patients were ‘full code’ (48.5% presumed, 43.4% confirmed) and 8.1% had restrictions on life-sustaining therapies. Overall, 55.1% (59/107) of patients experienced a code status transition, with a median of two transitions (range 1-4). Median time from first to last transition was 11 days (range 1-306) and from last transition to death was 1 day (range 0-11). Most of these transitions (79.6%; 48/59) were transitions to CMO near EOL. We identified three processes leading to code status transitions (Table): 1) pre-emptive conversations prior to any clinical change (15.3%; 9/59); 2) anticipatory conversations at the time of acute clinical deterioration (15%; 9/59); and 3) futility conversations after acute clinical deterioration, focused on withdrawing life-sustaining therapy (64.4%; 38/59). Only 55.9% (33/59) of patients participated in their last code status transition and 22.0% (13/59) of these transitions occurred in the ICU or Emergency Room. Conclusions: Most patients with high-risk AML had code status transitions at EOL, often following clinical deterioration that limited their ability to engage in EOL discussions. Interventions to promote earlier and more specific code status conversations are needed to improve patients’ ability to voice their EOL preferences.[Table: see text]

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A Case–Control Study Evaluating the Impact of Dedicated Palliative Care Training on Critical Care Interventions at the end of Life

Journal of Palliative Care ◽

10.1177/08258597211037436 ◽

2021 ◽

pp. 082585972110374

Author(s):

Jee Y. You ◽

Lie D. Ligasaputri ◽

Adarsh Katamreddy ◽

Kiran Para ◽

Elizabeth Kavanagh ◽

...

Keyword(s):

Palliative Care ◽

Critical Care ◽

High Risk ◽

End Of Life ◽

Poor Prognosis ◽

Medical Interventions ◽

Risk Of Death ◽

Before And After ◽

The Difference ◽

The Impact

Many patients admitted to intensive care units (ICUs) are at high risk of dying. We hypothesize that focused training sessions for ICU providers by palliative care (PC) certified experts will decrease aggressive medical interventions at the end of life. We designed and implemented a 6-session PC training program in communication skills and goals of care (GOC) meetings for ICU teams, including house staff, critical care fellows, and attendings. We then reviewed charts of ICU patients treated before and after the intervention. Forty-nine of 177 (28%) and 63 of 173 (38%) patients were identified to be at high risk of death in the pre- and postintervention periods, respectively, and were included based on the study criteria. Inpatient mortality (45% vs 33%; P = .24) and need for mechanical ventilation (59% vs 44%, P = .13) were slightly higher in the preintervention population, but the difference was not statistically significant. The proportion of patients in whom the decision not to initiate renal replacement therapy was made because of poor prognosis was significantly higher in the postintervention population (14% vs 67%, P = .05). There was a nonstatistically significant trend toward earlier GOC discussions (median time from ICU admission to GOC 4 vs 3 days) and fewer critical care interventions such as tracheostomies (17% vs 4%, P = .19). Our study demonstrates that directed PC training of ICU teams has a potential to reduce end of life critical care interventions in patients with a poor prognosis.

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Full Code to Do-Not-Resuscitate: Culturally Adapted Palliative Care Consultations and Code Status Change Among Seriously Ill Hispanic Patients

American Journal of Hospice and Palliative Medicine® ◽

10.1177/10499091211042305 ◽

2021 ◽

pp. 104990912110423

Author(s):

Neela K. Patel ◽

Stacey A. Passalacqua ◽

Kylie N. Meyer ◽

Gabriel A. de Erausquin

Keyword(s):

Palliative Care ◽

End Of Life ◽

Palliative Care Service ◽

Do Not Resuscitate ◽

Code Status ◽

Palliative Care Consultation ◽

Culturally Adapted ◽

Hispanic Patients ◽

The Impact ◽

Seriously Ill

Background: Palliative care and hospice services are disproportionately underutilized by ethnic minority patients. Addressing barriers to utilization of these services is critical to reducing disparities. The purpose of this study was to assess the impact of a culturally adapted palliative care consultation service for Hispanics on end-of-life decisions, specifically likelihood of changing from full code to do-not-resuscitate (DNR) status during index admission for serious illness. Methods: A cross-sectional study design was applied to data extracted from electronic health records (EHR) of patients seen by a Geriatric Palliative Care service during inpatient stays between 2018 and 2019. The majority of referrals came from critical care sites. Culturally adapted palliative care consultations using the SPIKES tool featured a Spanish-speaking team member leading discussions, involvement of multiple and key family members, and a chaplain who is a Catholic Priest. Results: The analytic sample included 351 patients who were, on average, 72 years old. 54.42% were female, 59.54% were Hispanic, and of Hispanic patients, 47.37% spoke primarily Spanish. Culturally adapted consults resulted in higher rates of conversion to DNR status in palliative cases of the target population. Both primary language and ethnicity were associated with likelihood of change from full code to DNR status, such that Spanish speakers and those of Hispanic ethnicity were more likely to switch to DNR than non-Hispanics and English-Speakers. Conclusion: This study illustrates how culturally adapted palliative care consultations can help reduce barriers and improve end-of-life decision-making, and can be applied with similar populations of seriously ill Hispanic patients.

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Impact of palliative care consultation on end-of-life care measures: A retrospective analysis of patients in the Oncology Care Model.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.27_suppl.45 ◽

2019 ◽

Vol 37 (27_suppl) ◽

pp. 45-45

Author(s):

Alison Greidinger ◽

Maria Vershvovsky ◽

Evan Lapinsky ◽

Alison Rhoades ◽

Amy Leader ◽

...

Keyword(s):

Palliative Care ◽

End Of Life ◽

Acute Care ◽

Advanced Cancer ◽

Cancer Center ◽

Do Not Resuscitate ◽

Care Model ◽

Code Status ◽

Palliative Care Consultation ◽

Oncology Care

45 Background: Despite a 2016 ASCO recommendation that patients with advanced cancer receive dedicated palliative care (PC) services, many patients are not referred and continue to receive chemotherapy and utilize high-acuity services near the end of life (EOL). Studies suggest that early PC involvement is associated with lower spending, acute care utilization, and chemotherapy administration at the EOL. The Sidney Kimmel Cancer Center participates in the Oncology Care Model (OCM), a CMS episode-based alternative payment model promoting high-value care. Using OCM-generated data, we evaluated the effect of PC visits on EOL outcomes. Methods: We identified OCM patients with episodes starting April 1, 2016-July 1, 2018 with GI and head & neck malignancies who had died, and determined whether patients who saw a PC provider had greater documentation of a code status (CS) before death, as well as lower spending and utilization of chemotherapy or acute care in the last 30 days of life. CMS spending data and dates of death were derived from OCM quarterly feedback, while all other data was compiled via chart review. CS was recorded at the start of the episode and at the time of death. Results: The study included 126 patients (median age 66 years), of whom 38% had a PC visit. 24% had only an inpatient (IP) PC consult, 6% only an outpatient (OP) visit, and 9% both IP & OP visits. More patients who saw PC had an initial CS documented (85%, vs 46% for no PC), and had a greater proportional increase in CS documentation before death (96% vs 53%). Despite similar rates at baseline, the final CS was significantly more likely to be “Do Not Resuscitate/Intubate” (DNR/DNI) among PC patients (79%, vs 28% for no PC). An initial CS of DNR/DNI was associated with lower mean ICU and total non-hospice spending in the last 30 days of life. Conclusions: This retrospective study in OCM patients found that PC intervention is associated with improved documentation of a CS and higher rates of DNR/DNI documentation before death. There is an association between an initial DNR/DNI CS and lower acute care spending. This data suggests a beneficial effect of early PC on utilization at the EOL in advanced cancer patients.

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Health Care Utilization and End of Life Care for Older Patients with Acute Myeloid Leukemia Receiving Supportive Care Alone

Blood ◽

10.1182/blood.v126.23.2126.2126 ◽

2015 ◽

Vol 126 (23) ◽

pp. 2126-2126

Author(s):

Areej El-Jawahri ◽

Sean F. Heavey ◽

Thomas W. LeBlanc ◽

Harry Vandusen ◽

Gregory Abel ◽

...

Keyword(s):

Health Care ◽

Intensive Care Unit ◽

Palliative Care ◽

Health Care Utilization ◽

Supportive Care ◽

End Of Life ◽

Older Patients ◽

Research Funding ◽

Advisory Board ◽

Care Utilization

Abstract Introduction: Many older adults (≥ 60) with AML treated with intensive or non-intensive chemotherapy have a poor prognosis and spend a significant portion of their life from diagnosis until death in the hospital. We hypothesized that the burden of illness, rather than its treatment, plays a major role in increasing health care utilization. Therefore, we examined health care utilization and end-of-life (EOL) outcomes for older adults with AML receiving supportive care alone. Methods: We conducted a retrospective analysis of 98 consecutive older patients diagnosed with AML between 9/9/1993 and 12/23/2011 and treated with supportive care alone at two tertiary care hospitals. We examined their health care utilization including frequency of hospitalizations, clinic visits, and intensive care unit admissions and their place of death. We also assessed health care utilization during the last 30 days of life including palliative care consultations, hospice referrals, hospitalizations, and blood transfusions. Results: The study included mostly white (n= 93/98, 95%) and male (n=52/98, 53%) patients with a median age of 77 (range 60-94). Supportive care treatments included transfusions (n=59/98, 60%), hydroxurea and transfusions (n=23/98, 24%), hydroxyurea without transfusion support (n=9/98, 9%), transfusions and growth factor support (n=7/98, 7%), or growth factor support alone (n=1/98, 1%). The median number of hospitalizations for the entire cohort was 1 (range 0-5). All patients died with a median number of days from diagnosis until death of 36.0 days (range 1-389). Patients spent a mean of 36% of their life from diagnosis in the hospital and 8% of their life attending outpatient clinic appointments. Only 18% (n=18/98) and 30% (n=29/98) of patients utilized palliative care or hospice services, respectively. A minority of patients (n=13/98, 13%) were admitted to the intensive care unit with 11% (n=11/98) having an intensive care unit stay during the last 30 days of life. Within 30 days of death, 88% (n=87/98) of patients were hospitalized with 46% (N=45/98) dying in the hospital. The majority (n=89/98, 92%) of patients received a blood transfusion within the last 30 days of life and 64% (n=58/91) received a transfusion in the last 7 days of life. Conclusion: Despite a decision to not receive chemotherapy, older patients with AML receiving supportive care alone have high health care utilization reflecting the burden of this disease. Despite this populations' poor prognosis, palliative care and hospice services are rarely utilized. Future work should study novel health-care delivery models designed to meet the needs of this population, such as transfusion support and other intensive supportive care measures at home toward the EOL. Figure 1. Proportion of life spent in hospital, clinic, or home Figure 1. Proportion of life spent in hospital, clinic, or home Figure 2. Health Care Utilization near the end of life Figure 2. Health Care Utilization near the end of life Figure 3. Place of death Figure 3. Place of death Disclosures LeBlanc: Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees; Flatiron: Consultancy; Epi-Q: Consultancy; Helsinn Therapeutics: Honoraria, Research Funding. Steensma:Incyte: Consultancy; Amgen: Consultancy; Celgene: Consultancy; Onconova: Consultancy. Fathi:Seattle Genetics: Other: Advisory Board participation, Research Funding; Agios Pharmaceuticals: Other: Advisory Board participation; Merck: Other: Advisory Board participation. DeAngelo:Celgene: Consultancy; Amgen: Consultancy; Ariad: Consultancy; Bristol Myers Squibb: Consultancy; Agios: Consultancy; Incyte: Consultancy; Novartis: Consultancy; Pfizer: Consultancy. Stone:Merck: Consultancy; Agios: Consultancy; AROG: Consultancy; Roche/Genetech: Consultancy; Pfizer: Consultancy; Karyopharm: Consultancy; Sunesis: Consultancy, Other: DSMB for clinical trial; Abbvie: Consultancy; Celator: Consultancy; Amgen: Consultancy; Celgene: Consultancy; Novartis: Research Funding; Juno: Consultancy. Chen:Bayer: Consultancy, Research Funding.

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Do Hispanics prefer to be full code at the end of life? The impact of palliative care consults on clarifying code status preferences and hospice referrals in Spanish-speaking patients

Palliative & Supportive Care ◽

10.1017/s1478951520000425 ◽

2020 ◽

pp. 1-5

Author(s):

Fernando Kawai ◽

Cynthia X. Pan ◽

John Zaravinos ◽

Min Min Maw ◽

Gary Lee

Keyword(s):

Palliative Care ◽

End Of Life ◽

Do Not Resuscitate ◽

Code Status ◽

Spanish Speaking ◽

Significant Difference ◽

Hispanic Patients ◽

English Speaking ◽

The Impact ◽

Hispanic White

Abstract Background Hispanics often have disparities at the end of life. They are more likely to die full code and less likely to have discussions regarding prognosis and do not resuscitate (DNR)/do not intubate (DNI), despite studies showing Hispanic values comfort over the extension of life. Barriers to patient-centered care include language,socioeconomic status and health literacy. Context We evaluated the impact of palliative care (PC) consults on the change of code status and hospice referrals, comparing seriously ill Hispanic and non-Hispanic white patients. Method A retrospective cohort study of all white and Hispanic patients referred to the PC service of a county hospital from 2006 to 2012. We evaluated ethnicity, language, code status at admission and after PC consult, and hospice discharge. Chi-squared tests were used to analyze characteristics among three groups: non-Hispanic white, English-speaking Hispanic, and Spanish-speaking Hispanic patients. Results Of 925 patients, 511 (55%) were non-Hispanic white, 208 (23%) were English-speaking Hispanic, and 206 (22%) were Spanish-speaking Hispanic patients. On admission, there was no statistically significant difference in code status among the three groups (57%, 64%, and 59% were full code, respectively, p = 0.5). After PC consults, Spanish-speaking Hispanic patients were more likely to change their code status to DNR/DNI when compared with non-Hispanic white and English-speaking Hispanic patients (44% vs. 32% vs. 28%, p = 0.05). Spanish-speaking Hispanic patients were more likely to be discharged to hospice when compared with English-speaking Hispanics and non-Hispanic whites (33%, 29%, and 23%, respectively, p = 0.04). Significance of results Spanish-speaking Hispanic patients were more likely to change from full code to DNR/DNI compared with non-Hispanic white and English-speaking Hispanic patients, despite similar code status preferences on admission. They were also more likely to be discharged to hospice. PC consults may play an important role in helping patients to align their care with their values and may prevent unwanted aggressive interventions at the end of life.

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Abstract 68: Palliative Care Is Underutilized in Patients with Severe Intracerebral Hemorrhage

Stroke ◽

10.1161/str.46.suppl_1.68 ◽

2015 ◽

Vol 46 (suppl_1) ◽

Author(s):

April Sisson ◽

Karen C Albright ◽

Michelle Peck ◽

Linh M Nguyen ◽

Michael Lyerly ◽

...

Keyword(s):

Palliative Care ◽

Poor Prognosis ◽

Care Service ◽

Care Center ◽

Symptom Relief ◽

Tertiary Care ◽

Palliative Care Service ◽

Code Status ◽

Ich Score ◽

Expected Mortality

Background and Purpose: Palliative care is an essential part of ICH care, particularly in patients with high ICH scores given their poor prognosis. Palliative care involves consultation by the Palliative Care Service and includes de-escalation of care, changing code status, and making pain and symptom relief the central goal of management. Methods: We performed a retrospective review of consecutive patients presenting to our tertiary care center from 2008-2013 with primary ICH. Demographic and clinical data were collected. Our sample included only patients who died or were transferred to hospice. We examined the proportion of patients that received an inpatient palliative care consult and compared this group to patients who did not receive an inpatient palliative care consult. Patients were categorized by ICH score. Results: Of the 99 ICH patients who died or were discharged to hospice, only 23% received a palliative care consult. Figure 1 displays death, predicted death, and palliative care consult proportions by ICH score. Patients that received a Palliative Care consult were older (mean age 65 vs. 73, p=0.018) and more frequently had evidence of infection (32% vs. 13%, p=0.038); no other significant differences were found between groups. Conclusions: In our sample of ICH patients, 23% of patients received a palliative care consult. In those with high ICH scores utilization was only 28%, despite 30 day expected mortality of 97% or greater. This raises concern that palliative care may be underutilized in patients who may benefit from it the most.

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Multicenter Analysis of Treatment and Outcomes for Patient with TP53 Mutated AML in the Era of Novel Therapies; Significant Impact of Allogeneic Stem Cell Transplantation on Survival

Blood ◽

10.1182/blood-2021-147639 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 797-797

Author(s):

Talha Badar ◽

Mark R. Litzow ◽

Rory M. Shallis ◽

Jan Philipp Bewersdorf ◽

Antoine Saliba ◽

...

Keyword(s):

Stem Cell ◽

High Risk ◽

Stem Cell Transplantation ◽

Board Of Directors ◽

Research Funding ◽

Univariate Analysis ◽

Advisory Board ◽

Novel Therapies ◽

Advisory Committees ◽

Tp53 Mutations

Abstract Background: TP53 mutations occur in 10-20% of patients with AML, constitute high-risk disease as per ELN criteria, and confer poorer prognosis. Venetoclax combination therapies and CPX-351 were recently approved for AML treatment and lead to improved outcomes in subsets of high-risk AML, however the most effective approach for treatment of TP53-mutated (m) AML remains unclear. In this study we explored the clinical outcome of TP53m AML patients treated over the last 8 years as novel therapies have been introduced to our therapeutic armamentarium. Methods: We conducted a multicenter observational study in collaboration with 4 U.S. academic centers and analyzed clinical characteristics and outcome of 174 TP53m AML patients diagnosed between March 2013 and February 2021. Mutation analysis was performed on bone marrow specimens using 42, 49, 199, or 400 gene targeted next generation sequencing (NGS) panels. Patients with an initial diagnosis of AML were divided into 4 groups (GP) based on the progressive use of novel therapies in clinical trials and their approvals as AML induction therapy during different time periods: 2013-2017 (GP1, n= 37), 2018-2019 (GP2, n= 53), 2019-2020 (GP3, n= 48) and 2020-2021 (GP4, n= 36) to analyze difference in outcome. Results: Baseline characteristics were not significantly different across different GP, as shown in Table 1. Median age of patients was 68 (range [R], 18-83), 65 (R, 29-88), 69 (R, 37-90) and 70 (R, 51-97) years in GP1-4, respectively (p=0.40). The percentage of patients with de novo AML/secondary AML/therapy-related AML in GP1-4 was 40/40/20, 36/29/24, 37.5/37.5/25 and 28/52/20, respectively (p=0.82). The proportion of patients with complex cytogenetics (CG) was 92%, 89%, 96% and 94% in GP1-4, respectively (p=0.54). The median TP53m variant allele frequency (VAF) was 48% (range [R], 5-94), 42% (R, 5-91), 45% (R, 10-94) and 60% (R, 8-82) in GP1-4, respectively (p=0.38). Four (11%), 13 (24.5%), 10 (21%) and 9 (25%) patients had multiple TP53 mutations in GP1-4, respectively (p=0.33). The proportion of patients who received 3+7 (30%, 16%, 6% & 8%; p=0.01), HMA only (11%, 18%, 2% & 8%; p=0.06), venetoclax-based (2.5%, 12%, 48%, & 61%; p <0.01) and CPX-351 induction (16%, 40%, 28% & 5%; p<0.001) were varied in GP1-4, respectively. The rate of CR/CRi was 22%, 26%, 28% and 18% in GP1-4, respectively (p=0.63). Treatment related mortality during induction was observed in 3%, 7%, 10% and 17% of patients in GP1-4, respectively (p=0.18). Overall, 28 (16%) patients received allogeneic hematopoietic stem cell transplantation (alloHCT) after induction/consolidation: 22%, 15%, 17% and 11% in GP1-4, respectively (p=0.67). In subset analysis, there was no difference in the rate of CR/CRi with venetoclax-based regimens vs. others (39% vs 61%, p=0.18) or with CPX-351 vs. others (25% vs 75%, p=0.84). The median progression-free survival was 7.7, 7.0, 5.1 and 6.6 months in GP1-4, respectively (p=0.60, Fig 1A). The median overall survival (OS) was 9.4, 6.1, 4.0 and 8.0 months in GP1-4, respectively (p=0.29, Fig 1B). In univariate analysis for OS, achievement of CR/CRi (p<0.001) and alloHCT in CR1 (p<0.001) associated with favorable outcome, whereas complex CG (p=0.01) and primary refractory disease (p<0.001) associated with poor outcome. Multiple TP53 mutations (p=0.73), concurrent ASXL1m (p=0.86), extra-medullary disease (p=0.92), ≥ 3 non-TP53m mutations (p=0.72), TP53m VAF ≥ 40% vs. < 40% (p=0.25), induction with CPX-351 vs. others (p=0.59) or venetoclax-based regimen vs. others (p=0.14) did not show significance for favorable or poor OS in univariate analysis. In multivariable analysis, alloHCT in CR1 (hazard ratio [HR]=0.28, 95% CI: 0.15-0.53; p=0.001) retained an association with favorable OS and complex CG (HR 4.23, 95%CI: 1.79-10.0; p=0.001) retained an association with dismal OS. Conclusion: We present the largest experience with TP53m AML patients analyzed by NGS. Although outcomes were almost universally dismal, alloHCT appears to improve the long-term survival in a subset of these patients. Effective therapies are warranted to successfully bridge patients to alloHCT and to prolong survival for transplant ineligible patients. Figure 1 Figure 1. Disclosures Badar: Pfizer Hematology-Oncology: Membership on an entity's Board of Directors or advisory committees. Litzow: Omeros: Other: Advisory Board; Pluristem: Research Funding; Actinium: Research Funding; Amgen: Research Funding; Jazz: Other: Advisory Board; AbbVie: Research Funding; Astellas: Research Funding; Biosight: Other: Data monitoring committee. Shallis: Curis: Divested equity in a private or publicly-traded company in the past 24 months. Goldberg: Celularity: Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Aprea: Research Funding; Arog: Research Funding; DAVA Oncology: Honoraria; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding; Prelude Therapeutics: Research Funding; Aptose: Consultancy, Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Atallah: BMS: Honoraria, Speakers Bureau; Takeda: Consultancy, Research Funding; Amgen: Consultancy; Abbvie: Consultancy, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Research Funding. Foran: revolution medicine: Honoraria; gamida: Honoraria; bms: Honoraria; pfizer: Honoraria; novartis: Honoraria; takeda: Research Funding; kura: Research Funding; h3bioscience: Research Funding; OncLive: Honoraria; servier: Honoraria; aptose: Research Funding; actinium: Research Funding; abbvie: Research Funding; trillium: Research Funding; sanofi aventis: Honoraria; certara: Honoraria; syros: Honoraria; taiho: Honoraria; boehringer ingelheim: Research Funding; aprea: Research Funding; sellas: Research Funding; stemline: Research Funding.

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Conventional Immunochemotherapy (R-CHOEP) Vs High-Dose Immunochemotherapy (R-MegaCHOEP) in Younger Patients with High-Risk Aggressive B-Cell Lymphoma: 10-Year Long-Term Follow-up of a German Lymphoma Alliance (GLA) Study

Blood ◽

10.1182/blood-2019-123637 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1589-1589

Author(s):

Fabian Frontzek ◽

Marita Ziepert ◽

Maike Nickelsen ◽

Bettina Altmann ◽

Bertram Glass ◽

...

Keyword(s):

High Risk ◽

Board Of Directors ◽

Research Funding ◽

Advisory Board ◽

High Dose ◽

Advisory Committees ◽

Scientific Advisory Board ◽

Scientific Advisory

Introduction: The R-MegaCHOEP trial showed that dose-escalation of conventional chemotherapy necessitating autologous stem cell transplantation (ASCT) does not confer a survival benefit for younger patients (pts) with high-risk aggressive B-cell lymphoma in the Rituximab era (Schmitz et al., Lancet Oncology 2012; 13, 1250-1259). To describe efficacy and toxicity over time and document the long-term risks of relapse and secondary malignancy we present the 10-year follow-up of this study. Methods: In the randomized, prospective phase 3 trial R-MegaCHOEP younger pts aged 18-60 years with newly diagnosed, high-risk (aaIPI 2-3) aggressive B-cell lymphoma were assigned to 8 cycles of CHOEP (cyclophosphamide, doxorubcine, vincristine, etoposide, prednisone) or 4 cycles of dose-escalated high-dose therapy (HDT) necessitating repetitive ASCT both combined with Rituximab. Both arms were stratified according to aaIPI, bulky disease, and center. Primary endpoint was event-free survival (EFS). All analyses were calculated for the intention-to-treat population. This follow-up report includes molecular data based on immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH) for MYC (IHC: 31/92 positive [40-100%], FISH: 14/103 positive), BCL2 (IHC: 65/89 positive [50-100%], FISH: 23/111 positive) and BCL6 (IHC: 52/86 positive [30-100%], FISH: 34/110 positive) and data on cell of origin (COO) classification according to the Lymph2CX assay (GCB: 53/88; ABC: 24/88; unclassified: 11/88). Results: 130 pts had been assigned to R-CHOEP and 132 to R-MegaCHOEP. DLBCL was the most common lymphoma subtype (~80%). 73% of pts scored an aaIPI of 2 and 27% an aaIPI of 3. 60% of pts had an initial lymphoma bulk and in 40% more than 1 extranodal site was involved. After a median observation time of 111 months, EFS at 10 years was 57% (95% CI 47-67%) in the R-CHOEP vs. 51% in the R-MegaCHOEP arm (42-61%) (hazard ratio 1.3, 95% CI 0.9-1.8, p=0.228), overall survival (OS) after 10 years was 72% (63-81%) vs. 66% (57-76%) respectively (p=0.249). With regard to molecular characterization, we were unable to detect a significant benefit for HDT/ASCT in any subgroup analyzed. In total, 16% of pts (30 pts) relapsed after having achieved a complete remission (CR). 23% of all relapses (7 pts) showed an indolent histology (follicular lymphoma grade 1-3a) and 6 of these pts survived long-term. In contrast, of 23 pts (77%) relapsing with aggressive DLBCL or unknown histology 18 pts died due to lymphoma or related therapy. The majority of relapses occurred during the first 3 years after randomization (median time: 22 months) while after 5 years we detected relapses only in 5 pts (3% of all 190 pts prior CR). 11% of pts were initially progressive (28 pts) among whom 71% (20 pts) died rapidly due to lymphoma. Interestingly, the remaining 29% (8 pts) showed a long-term survival after salvage therapy (+/- ASCT); only 1 pt received allogeneic transplantation. The frequency of secondary malignancies was very similar in both treatment arms (9% vs. 8%) despite the very high dose of etoposide (total 4g/m2)in the R-MegaCHOEP arm. We observed 2 cases of AML and 1 case of MDS per arm. In total 70 pts (28%) have died: 30 pts due to lymphoma (12%), 22 pts therapy-related (11 pts due to salvage therapy) (9%), 8 pts of secondary neoplasia (3%), 5 pts due to concomitant disease (2%) and 5 pts for unknown reasons. Conclusions: This 10-year long-term follow-up of the R-MegaCHOEP trial confirms the very encouraging outcome of young high-risk pts following conventional chemotherapy with R-CHOEP. High-dose therapy did not improve outcome in any subgroup analysis including molecular high-risk groups. Relapse rate was generally low. Pts with aggressive relapse showed a very poor long-term outcome while pts with indolent histology at relapse survived long-term. Secondary malignancies occurred; however, they were rare with no excess leukemias/MDS following treatment with very high doses of etoposide and other cytotoxic agents. Supported by Deutsche Krebshilfe. Figure Disclosures Nickelsen: Roche Pharma AG: Membership on an entity's Board of Directors or advisory committees, Other: Travel Grants; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant; Janssen: Membership on an entity's Board of Directors or advisory committees. Hänel:Amgen: Honoraria; Celgene: Other: advisory board; Novartis: Honoraria; Takeda: Other: advisory board; Roche: Honoraria. Truemper:Nordic Nanovector: Consultancy; Roche: Research Funding; Mundipharma: Research Funding; Janssen Oncology: Consultancy; Takeda: Consultancy, Research Funding; Seattle Genetics, Inc.: Research Funding. Held:Roche: Consultancy, Other: Travel support, Research Funding; Amgen: Research Funding; Acrotech: Research Funding; MSD: Consultancy; Bristol-Myers Squibb: Consultancy, Other: Travel support, Research Funding. Dreyling:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: scientific advisory board, Research Funding, Speakers Bureau; Bayer: Consultancy, Other: scientific advisory board, Speakers Bureau; Celgene: Consultancy, Other: scientific advisory board, Research Funding, Speakers Bureau; Mundipharma: Consultancy, Research Funding; Gilead: Consultancy, Other: scientific advisory board, Speakers Bureau; Novartis: Other: scientific advisory board; Sandoz: Other: scientific advisory board; Janssen: Consultancy, Other: scientific advisory board, Research Funding, Speakers Bureau; Acerta: Other: scientific advisory board. Viardot:Kite/Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; F. Hoffmann-La Roche Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees. Rosenwald:MorphoSys: Consultancy. Lenz:Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Research Funding; Agios: Research Funding; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bayer: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Roche: Employment, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy. Schmitz:Novartis: Honoraria; Gilead: Honoraria; Celgene: Equity Ownership; Riemser: Consultancy, Honoraria.

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Dose-Adjusted EPOCH and Rituximab (DA-EPOCH-R) Treatment in Dual Expressor Diffuse Large B-Cell and Double/Triple Hit Lymphomas: TP53 Mutations Influence on Clinical Outcome

Blood ◽

10.1182/blood-2019-124350 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4116-4116

Author(s):

Anna Dodero ◽

Anna Guidetti ◽

Fabrizio Marino ◽

Cristiana Carniti ◽

Stefania Banfi ◽

...

Keyword(s):

High Risk ◽

B Cell ◽

Board Of Directors ◽

Research Funding ◽

Poor Prognosis ◽

Tp53 Mutation ◽

Advisory Committees ◽

Tp53 Mutations ◽

Travel Costs ◽

Large B Cell

Introduction: Diffuse Large B-Cell Lymphoma (DLBCL) is an heterogeneous disease: 30-40% of cases have high expression of MYC and BCL2 proteins (Dual Expressor, DE) and 5-10% have chromosomal rearrangements involving MYC, BCL2 and/or BCL6 (Double-/ Triple-Hit, DH/TH). Although the optimal treatment for those high-risk lymphomas remains undefined, DA-EPOCH-R produces durable remission with acceptable toxicity (Dunleauvy K, Lancet 2018). TP53 mutation is an independent marker of poor prognosis in patients (pts) with DLBCL treated with R-CHOP therapy. However, its prognostic value in poor prognosis lymphomas, receiving intensive therapy, has not been investigated yet. Methods: A series of consecutive pts (n=87) with biopsy proven diagnosis of DE DLBCL (MYC expression ≥40% and BCL2 expression ≥ 50% of tumor cells) or DE-Single Hit (DE-SH, i.e., DE-DLBCL with a single rearrangement of either MYC, BCL2 or BCL6 oncogenes) or DE-DH/TH (MYC, BCL2 and/or BCL6 rearrangements obtained by FISH) were treated with 6 cycles of DA-EPOCH-R and central nervous system (CNS) prophylaxis consisting of two courses of high-dose intravenous Methotrexate. Additional eligibility criteria included age ≥18 years and adequate organ functions. Cell of origin (COO) was defined according to Hans algorithm [germinal center B cell like (GCB) and non GCB)]. TP3 mutations were evaluated by next generation sequencing (NGS) based on AmpliseqTM technology or Sanger sequencing and considered positive when a variant allelic frequency ≥10% was detected. Results: Eighty-seven pts were included [n=36 DE only, n=32 DE-SH (n=8 MYC, n=10 BCL2, n=14 BCL6), n=19 DE-DH/TH] with 40 patients (46%) showing a non GCB COO. Pts had a median age of 59 years (range, 24-79 years). Seventy-three pts (84%) had advanced disease and 44 (50%) an high-intermediate/high-risk score as defined by International Prognostic Index (IPI). Only 8 of 87 pts (9%) were consolidated in first clinical remission with autologous stem cell transplantation following DA-EPOCH-R. After a median follow-up of 24 months, 73 are alive (84%) and 14 died [n=12 disease (n=2 CNS disease); n=1 pneumonia; n=1 suicide]. The 2-year PFS and OS were 71% (95%CI, 60-80%) and 76% (95%CI, 61%-85%) for the entire population. For those with IPI 3-5 the PFS and OS were not significant different for DE and DE-SH pts versus DE-DH/TH pts [64% vs 57% p=0.77); 78% vs 57% p=0.12)]. The COO did not influence the outcome for DE only and DE-SH [PFS: 78% vs 71% (p=0.71); 92% vs 86% (p=0.16) for GCB vs non -GCB, respectively]. Fourty-six pts (53%;n=18 DE only, n=18 DE-SH, n=10 DE-DH/TH ) were evaluated for TP53 mutations with 11 pts (24%) carrying a clonal mutation (n=6 in DE, n=3 in DE-SH, n=2 in DE-DH/TH). The 2-year PFS and OS did not significantly change for pts DE and DE-SH TP53 wild type as compared to DE and DE-SH mutated [PFS: 84 % vs 77%, (p=0.45); OS: 87% vs 88%, (p=0.92)]. The two pts DE-DH/TH with TP53 mutation are alive and in complete remission.Conclusions: High risk DLBCL pts treated with DA-EPOCH-R have a favourable outcome independently from high IPI score, DE-SH and DE-DH/TH. Also the presence of TP53 mutations does not negatively affect the outcome of pts treated with this intensive regimen. The efficacy of DA-EPOCH-R in overcoming poor prognostic genetic features in DLBCL should be confirmed in a larger prospective clinical trial. Disclosures Rossi: Daiichi-Sankyo: Consultancy; Roche: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Mundipharma: Honoraria; BMS: Honoraria; Sandoz: Honoraria. Carlo-Stella:Takeda: Other: Travel, accommodations; F. Hoffmann-La Roche Ltd: Honoraria, Other: Travel, accommodations, Research Funding; Rhizen Pharmaceuticals: Research Funding; Celgene: Research Funding; Amgen: Honoraria; AstraZeneca: Honoraria; Janssen Oncology: Honoraria; MSD: Honoraria; BMS: Honoraria; Genenta Science srl: Consultancy; Janssen: Other: Travel, accommodations; Servier: Consultancy, Honoraria, Other: Travel, accommodations; Sanofi: Consultancy, Research Funding; ADC Therapeutics: Consultancy, Other: Travel, accommodations, Research Funding; Novartis: Consultancy, Research Funding; Boehringer Ingelheim: Consultancy. Corradini:AbbVie: Consultancy, Honoraria, Other: Travel Costs; KiowaKirin: Honoraria; Gilead: Honoraria, Other: Travel Costs; Amgen: Honoraria; Celgene: Honoraria, Other: Travel Costs; Daiichi Sankyo: Honoraria; Janssen: Honoraria, Other: Travel Costs; Jazz Pharmaceutics: Honoraria; Kite: Honoraria; Novartis: Honoraria, Other: Travel Costs; Roche: Honoraria; Sanofi: Honoraria; Takeda: Honoraria, Other: Travel Costs; Servier: Honoraria; BMS: Other: Travel Costs.

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