Characteristics of Health Care Settings Where Adolescents and Young Adults Receive Care for ALL.

PURPOSE: Individuals diagnosed with cancer between 15 and 39 years (adolescent and young adult [AYA]) face unique vulnerability. Detail is lacking about care delivery for these patients, especially those with ALL. We address these knowledge gaps by describing AYA ALL care delivery details at National Cancer Institute Community Oncology Research Program (NCORP) (sub)affiliates by model of care. METHODS: Participating institutions treated at least one AYA with ALL from 2012 to 2016. Study-specific criteria were used to determine the number of unique clinical facilities (CFs) per NCORP and their model of care (adult/internal medicine [IM], pediatric, mixed [both]). Surveys completed by NCORPs for each CF by model of care captured size, resources, services, and communication. RESULTS: Among 84 participating CFs (adult/IM, n=47; pediatric, n=15; mixed, n=24), 34% treated 5-10 AYAs with ALL annually; adult/IM CFs more often treated <5 (adult/IM, 60%; pediatric, 40%; mixed, 29%). Referral decisions were commonly driven by an age/diagnosis combination (58%), with frequent ALL-specific age minimums (87%) or maximums (80%). Medical, navigational, and social work services were similar across models while psychology was available at more pediatric CFs (pediatric, 80%; adult/IM, 40%; mixed, 46%-54%). More pediatric or mixed CFs reported oncologists interacting with pediatric/adult counterparts via tumor boards (pediatric, 93%; adult/IM, 26%; mixed, 96%) or initiating contact (pediatric, 100%; adult/IM, 77%; mixed 96%); more pediatric CFs reported an affiliated counterpart (pediatric, 53%; adult, 19%). Most CFs reported no AYA-specific resources (79%) or meetings (83%-98%). CONCLUSION: System-level aspects of AYA ALL care delivery have not been examined previously. At NCORPs, these characteristics differ by models of care. Additional work is ongoing to investigate the impact of these facility-level factors on guideline-concordant care in this population. Together, these findings can inform a system-level intervention for diverse practice settings.

Impact of prior therapies and subsequent transplantation on outcomes in adult patients with relapsed or refractory B-cell acute lymphoblastic leukemia treated with brexucabtagene autoleucel in ZUMA-3.

BACKGROUND: Brexucabtagene autoleucel (brexu-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved in the USA for adults with relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL) and in the European Union for patients ≥26 years with R/R B-ALL. After 2 years of follow-up in ZUMA-3, the overall complete remission (CR) rate (CR+CR with incomplete hematological recovery (CRi)) was 73%, and the median overall survival (OS) was 25.4 months in 78 Phase 1 and 2 patients with R/R B-ALL who received the pivotal dose of brexu-cel. Outcomes by prior therapies and subsequent allogeneic stem cell transplantation (alloSCT) are reported. METHODS: Eligible adults had R/R B-ALL and received one infusion of brexu-cel (1×106 CAR T cells/kg) following conditioning chemotherapy. The primary endpoint was the CR/CRi rate per central review. Post hoc subgroup analyses were exploratory with descriptive statistics provided. RESULTS: Phase 1 and 2 patients (N=78) were included with median follow-up of 29.7 months (range, 20.7-58.3). High CR/CRi rates were observed across all prior therapy subgroups examined: 1 prior line of therapy (87%, n=15) and ≥2 prior lines (70%, n=63); prior blinatumomab (63%, n=38) and no prior blinatumomab (83%, n=40); prior inotuzumab (59%, n=17) and no prior inotuzumab (77%, n=61); and prior alloSCT (76%, n=29) and no prior alloSCT (71%, n=49). The frequency of Grade ≥3 cytokine release syndrome, neurological events, and treatment-related Grade 5 adverse events were largely similar among prior therapy subgroups.Median duration of remission (DOR) in responders with (n=14) and without (n=43) subsequent alloSCT was 44.2 (95% CI, 8.1 to not estimable (NE)) and 18.6 months (95% CI, 9.4 to NE); median OS was 47.0 months (95% CI, 10.2 to NE) and not reached (95% CI, 23.2 to NE), respectively. Median DOR and OS were not reached in responders without prior or subsequent alloSCT (n=22). CONCLUSIONS: In ZUMA-3, adults with R/R B-ALL benefited from brexu-cel, regardless of prior therapies and subsequent alloSCT status, though survival appeared better in patients without certain prior therapies and in earlier lines of therapy. Additional studies are needed to determine the impact prior therapies and subsequent alloSCT have on outcomes of patients who receive brexu-cel.

Characteristics and prognostic impact of IDH mutations in AML: a COG, SWOG, and ECOG analysis.

Somatic mutations in isocitrate dehydrogenase (IDH) genes occur frequently in adult acute myeloid leukemia (AML) and less commonly in pediatric AML. The objective of this study was to describe the prevalence, mutational profile, and prognostic significance of IDH mutations in AML across age. Our cohort included 3141 patients aged between <1 month and 88 years treated on Children's Cancer Group/Children's Oncology Group (n = 1872), Southwest Oncology Group (n = 359), Eastern Cooperative Oncology Group (n = 397) trials, and in Beat AML (n = 333) and The Cancer Genome Atlas (n = 180) genomic characterization cohorts. We retrospectively analyzed patients in 4 age groups (age range, n): pediatric (0-17, 1744), adolescent/young adult (18-39, 444), intermediate-age (40-59, 640), older (≥60, 309). IDH mutations (IDHmut) were identified in 9.2% of the total cohort (n = 288; IDH1 [n = 123, 42.7%]; IDH2 [n = 165, 57.3%]) and were strongly correlated with increased age: 3.4% pediatric vs 21% older, P < .001. Outcomes were similar in IDHmut and IDH-wildtype (IDHWT) AML (event-free survival [EFS]: 35.6% vs 40.0%, P = .368; overall survival [OS]: 50.3% vs 55.4%, P = .196). IDH mutations frequently occurred with NPM1 (47.2%), DNMT3A (29.3%), and FLT3-internal tandem duplication (ITD) (22.4%) mutations. Patients with IDHmut AML with NPM1 mutation (IDHmut/NPM1mut) had significantly improved survival compared with the poor outcomes experienced by patients without (IDHmut/NPM1WT) (EFS: 55.1% vs 17.0%, P < .001; OS: 66.5% vs 35.2%, P < .001). DNTM3A or FLT3-ITD mutations in otherwise favorable IDHmut/NPM1mut AML led to inferior outcomes. Age group analysis demonstrated that IDH mutations did not abrogate the favorable prognostic impact of NPM1mut in patients aged <60 years; older patients had poor outcomes regardless of NPM1 status. These trials were registered at www.clinicaltrials.gov as #NCT00070174, #NCT00372593, #NCT01371981, #NCT00049517, and #NCT00085709.

Association of crystalloid fluid infusion with intravascular hemolysis and organ dysfunction in hematopoietic stem cell transplant patients.

Endothelial cell activation and injury is common after hematopoietic stem cell transplant (HSCT) and is associated with many post-transplant complications. An underexplored mechanism of endothelial cell damage in this population is the infusion of normal saline (NS, 0.9 % sodium chloride) and other crystalloids, as NS use is associated with adverse outcomes in other patient populations. We hypothesized that the infusion of unbalanced crystalloids during HSCT may lead to changes in biomarkers commonly associated with red blood cell (RBC) hemolysis in patients before and after infusion, and that markers of endothelial and end-organ damage during admission may be associated with markers of hemolysis and total crystalloid use. Samples were collected from 97 patients. From pre-fluid infusion to post-fluid infusion, mean haptoglobin decreased (11.7 ug/ml vs 8.4 ug/ml; p < 0.0001), hemopexin decreased (549 vs 512 µg/ml; p = 0.005), and red cell distribution width (RDW) decreased (15.7 vs 15.6; p = 0.0009). During admission (mean 19.4 days, SD 9.9), all markers of tissue and organ damage, including mean creatinine, lactate dehydrogenase (LDH), blood urea nitrogen (BUN), total bilirubin, AST, and ALT, increased from admission to peak levels (p < 0.0001). On linear regression, fluid volume (ml/kg) of crystalloid infusion positively predicted post-fluid infusion cell-free hemoglobin (r(96) = 0.34, p < 0.0001), free heme (r(96) = 0.36, p < 0.0001), and peak LDH during admission (r(75) = 0.23, p = 0.041), and negatively predicted post-fluid infusion hemopexin (r(96) = - 0.34, p < 0.0001). Unbalanced crystalloids may contribute to hemolysis and endothelial damage in HSCT patients. Alternatives such as buffered crystalloid solutions (PlasmaLyte, Lactated Ringer's) may be worth investigating in this population.

Adaptation of Serious Illness Care Program to be delivered via telehealth for older patients with hematologic malignancy.

Older patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) experience intense inpatient health care at the end-of-life stage. Early advance care planning may improve care at the end of life for patients with AML or MDS. The Serious Illness Care Program (SICP) is a multicomponent, communication intervention developed to improve conversations about values for patients with serious illnesses. The SICP has been shown to improve the quality and frequency of advance care planning discussions. We adapted the SICP for delivery via telehealth to older patients with AML or MDS. We conducted a single-center qualitative study of 45 participants (25 clinicians, 15 older patients with AML or MDS, and 5 caregivers). Participants, whether clinicians, patients, or caregivers, agreed that the SICP would help older patients with AML or MDS to share their personal values with their care team. Four qualitative themes emerged from our data: (1) serious illness conversations can be conducted via telehealth, (2) older patients have limited experience using technology but are willing and able to learn, (3) patients feel that serious illness conversations will help them understand their AML or MDS diagnosis and prognosis better, and (4) serious illness conversations should be common and routine, not extraordinary. The adapted SICP may provide older patients with AML or MDS an opportunity to share what matters most to them with their care team and may assist oncologists in aligning patient care with patient values. The adapted SICP is the subject of an ongoing single-arm pilot study at the Wilmot Cancer Institute (clinicaltrials.gov identifier: NCT04745676).

Patient-centered communication tool for older patients with acute myeloid leukemia, their caregivers, and oncologists: A single-arm pilot study.

BACKGROUND: In a single-arm pilot study, we assessed the feasibility and usefulness of an innovative patient-centered communication tool (UR-GOAL tool) that addresses aging-related vulnerabilities, patient values, and prognostic awareness for use in treatment decision making between older adults with newly diagnosed acute myeloid leukemia (AML), their caregivers, and oncologists. METHODS: Primary feasibility metric was retention rate; >50% was considered feasible. We collected recruitment rate, usefulness, and outcomes including AML knowledge (range 0-14) and perceived efficacy in communicating with oncologists (range 5-25). Due to the pilot nature and small sample size, hypothesis testing was performed at α = 0.10. RESULTS: We included 15 patients (mean age 76 years, range 64-88), 12 caregivers, and 5 oncologists; enrollment and retention rates for patients were 84% and 73%, respectively. Patients agreed that the UR-GOAL tool helped them understand their AML diagnosis and treatment options, communicate with their oncologist, and make more informed decisions. From baseline to post-intervention, patients and caregivers scored numerically higher on AML knowledge (patients: +0.6, p = 0.22; caregivers: +1.1, p = 0.05) and perceived greater efficacy in communicating with their oncologists (patients: +1.5, p = 0.22; caregivers: +1.2, p = 0.06). CONCLUSION: We demonstrated that it is feasible to incorporate the UR-GOAL tool into treatment decision making for older patients with AML, their caregivers, and oncologists.

Advance care planning in older patients with acute myeloid leukemia and myelodysplastic syndromes.

INTRODUCTION: Older patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) have worse survival rates compared to younger patients, and experience more intense inpatient healthcare at the end of life (EOL) compared to patients with solid tumors. Advance care planning (ACP) has been shown to limit aggressive and burdensome care at EOL for patients with AML and MDS. The purpose of this study was to better understand ACP from the perspective of clinicians, older patients with AML and MDS, and their caregivers. MATERIALS AND METHODS: We conducted semi-structured interviews with 45 study participants. Interviews were audio-recorded and transcribed. Open coding and focused content analysis were used to organize data and develop and contextualize categories and subcategories. RESULTS: Guided by our specific aims, we developed four themes: (1) The language of ACP and medical order for life-sustaining treatment (MOLST) does not resonate with patients, (2) There is no uniform consensus on when ACP is currently happening, (3) Oncology clinician-perceived barriers to ACP (e.g., patient discomfort, patient lack of knowledge, and lack of time), and (4) Patients felt that they are balancing fear and hope when navigating their AML or MDS diagnosis. DISCUSSION: The results of this study can be used to develop interventions to promote serious illness conversations for patients with AML and MDS and their caregivers to ensure that patient care aligns with patient values.

Referral to and receipt of allogeneic hematopoietic stem cell transplantation in older adults with acute myeloid leukemia.

INTRODUCTION: Recent data have shown improved outcomes in selected older adults with acute myeloid leukemia (AML) following allogeneic hematopoietic stem cell transplantation (HSCT). Nonetheless, practice patterns for referring and performing HSCT vary. We aimed to evaluate referral, utilization, and reasons for not referring/proceeding to HSCT in older adults with AML. MATERIALS AND METHODS: This is a single center retrospective analysis of patients aged ≥60 years diagnosed with AML evaluating rates of HSCT referral and utilization. Fisher's exact test was used to compare rates of referral and utilization across age groups and years of diagnosis. RESULTS: Median age of the 97 patients was 70 years (range 61-95); 30% (29/97) were referred for HSCT and of these, 69% (20/29) received HSCT. Common documented reasons (can be multiple) for not referring were performance status (n = 21), advanced age (n = 16), patient refusal (n = 15), refractory disease (n = 14), and prohibitive comorbidity (n = 6). Among patients who were referred but did not receive HSCT (n = 9/29), documented reasons for not proceeding with HSCT were refractory disease (n = 5), advanced age (n = 2), and prohibitive comorbidity (n = 2). HSCT referral and utilization rates significantly decreased with age (p < 0.01) but were generally stable over time from 2014 to 2017 (p = 0.40 for referral and p = 0.56 for utilization). DISCUSSION: Despite improvements in supportive care and HSCT techniques, HSCT referral and utilization rates remained low among older adults with AML but stable over time.

Dasatinib/prednisone induction followed by blinatumomab/dasatinib in Ph+ acute lymphoblastic leukemia.

Novel treatment strategies are needed for the treatment of Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) in older patients. This trial evaluated the feasibility and outcomes with the anti-CD19 bispecific T-cell-engaging antibody, blinatumomab, in combination with dasatinib and steroids. Patients 65 years of age or older with Ph+ or Ph-like ALL (with dasatinib-sensitive fusions/mutations) were eligible and could be newly diagnosed or relapsed/refractory. Induction therapy consisted of dasatinib/prednisone. Patients not achieving response by day 56 proceeded to blinatumomab reinduction therapy. Patients achieving response with induction or reinduction therapy proceeded to blinatumomab/dasatinib postremission therapy for 3 cycles followed by dasatinib/prednisone maintenance. All patients received central nervous system prophylaxis with intrathecal methotrexate for a total of 8 doses. Response was assessed at days 28, 56, and 84 and at additional time points based on response parameters. Measurable residual disease was assessed centrally by 8-color flow cytometry at day 28. A total of 24 eligible patients with newly diagnosed Ph+ ALL were enrolled with a median age of 73 years (range, 65-87 years). This combination was safe and feasible. With a median of 2.7 years of follow-up, 3-year overall survival and disease-free survival were 87% (95% confidence interval [CI], 64-96) and 77% (95% CI, 54-90), respectively. Although longer follow-up is needed, these results are encouraging, and future trials are building on this backbone regimen. This trial was registered at www.clinicaltrials.gov as #NCT02143414.

Optimal approach to T-cell ALL.

T-lineage acute lymphoblastic leukemia (T-ALL) is curable for most children and adolescent and young adult patients with contemporary frontline chemotherapy regimens. During the past decade, improved survival rates have resulted from the optimization of frontline chemotherapy regimens, the use of minimal residual disease (MRD) assessment for evaluating a patient's risk for relapse, and the intensification of treatment based on the persistence of MRD. Optimization of initial therapy is critical because relapsed T-ALL after initial intensive chemotherapy is incurable for most adult patients. Current T-ALL salvage chemotherapy regimens are minimally effective, and unlike in B-cell ALL, there are no approved antibody therapies or chimeric antigen receptor T-cell therapies for relapsed disease. Immunotherapy and small-molecule inhibitors are beginning to be tested in relapsed T-ALL and have the potential to advance the treatment. Until effective salvage strategies are discovered, however, intensive frontline therapy is required for cure. In this article I review the current frontline chemotherapy regimens for adult patients with T-ALL, summarize the novel targeted and immune therapeutics currently in early-phase clinical trials, and outline how these therapies are helping to define an optimal approach for T-ALL.

Two-year follow-up of KTE-X19 in patients with relapsed or refractory adult B-cell acute lymphoblastic leukemia in ZUMA-3 and its contextualization with SCHOLAR-3, an external historical control study.

BACKGROUND: Brexucabtagene autoleucel (KTE-X19) is an autologous anti-CD19 CAR T-cell therapy approved in the USA to treat adult patients with relapsed or refractory B-precursor acute lymphoblastic leukemia (R/R B-ALL) based on ZUMA-3 study results. We report updated ZUMA-3 outcomes with longer follow-up and an extended data set along with contextualization of outcomes to historical standard of care. METHODS: Adults with R/R B-ALL received a single infusion of KTE-X19 (1 × 106 CAR T cells/kg). Long-term post hoc subgroup assessments of ZUMA-3 were conducted. Outcomes from matched patients between historical clinical trials and ZUMA-3 patients were assessed in the retrospective historical control study SCHOLAR-3. RESULTS: After 26.8-months median follow-up, the overall complete remission (CR) rate (CR + CR with incomplete hematological recovery) among treated patients (N = 55) in phase 2 was 71% (56% CR rate); medians for duration of remission and overall survival (OS) were 14.6 and 25.4 months, respectively. Most patients responded to KTE-X19 regardless of age or baseline bone marrow blast percentage, but less so in patients with > 75% blasts. No new safety signals were observed. Similar outcomes were observed in a pooled analysis of phase 1 and 2 patients (N = 78). In SCHOLAR-3, the median OS for treated patients from ZUMA-3 (N = 49) and matched historical controls (N = 40) was 25.4 and 5.5 months, respectively. CONCLUSIONS: These data, representing the longest follow-up of CAR T-cell therapy in a multicenter study of adult R/R B-ALL, suggest that KTE-X19 provides a clinically meaningful survival benefit with manageable toxicity in this population. TRIAL REGISTRATION: NCT02614066.

SWOG 1318: A Phase II Trial of Blinatumomab Followed by POMP Maintenance in Older Patients With Newly Diagnosed Philadelphia Chromosome-Negative B-Cell Acute Lymphoblastic Leukemia.

PURPOSE: Chemotherapy outcomes in older patients with Philadelphia (Ph) chromosome-negative B-acute lymphoblastic leukemia (ALL) are very poor. Here, we evaluated blinatumomab as induction and consolidation therapy followed by prednisone, vincristine, 6-mercaptopurine, and methotrexate (POMP) maintenance chemotherapy in this patient population. PATIENTS AND METHODS: Patients were treated at National Clinical Trial Network sites. Eligibility criteria included age ≥ 65 years and newly diagnosed Ph chromosome-negative B-ALL. Patients received blinatumomab as induction for one-two cycles until attainment of response (complete remission (CR) and CR with incomplete count recovery). Patients then received three cycles of consolidation with blinatumomab followed by 18 months of POMP maintenance chemotherapy. Eight doses of intrathecal methotrexate were administered as central nervous system prophylaxis. RESULTS: Twenty-nine eligible patients were enrolled. The median age was 75 years, and the median bone marrow blast count at diagnosis was 87%. Cytogenetic risk was poor in 10 patients (34%), and five of 14 patients (36%) tested had the Ph-like ALL gene signature. Nineteen patients (66%; 95% CI, 46 to 82) achieved CR. Kaplan-Meier 3-year disease-free survival and overall survival estimates were 37% (95% CI, 17 to 57) and 37% (95% CI, 20 to 55), respectively. CONCLUSION: Blinatumomab was well tolerated and effective in the treatment of older patients with newly diagnosed Ph chromosome-negative B-ALL, including patients with poor-risk cytogenetics. The 3-year disease-free survival and overall survival results are encouraging and suggest that this approach should be further explored.

A phase II study of sequential decitabine and rapamycin in acute myelogenous leukemia.

A phase II study was conducted to ascertain whether sequential exposure to decitabine followed by rapamycin, an mTOR (mechanistic target of rapamycin) inhibitor would result in better responses than decitabine alone. Newly diagnosed acute myelogenous leukemia (AML) patients who were >65 years old and not eligible for intensive induction regimens or patients with relapsed or refractory AML received 10 days of decitabine followed by 12 days of rapamycin in cycle 1 and 5 days of decitabine followed by 17 days of rapamycin in subsequent cycles. The composite complete remission rate (CR) was 33 % (CR plus CR with incomplete count recovery). Median overall survival was 7.7 months in newly diagnosed elderly AML patients and 6.6 months in relapsed/refractory AML patients. Twenty-four evaluable patients were enrolled, and the study did not meet its primary endpoint of demonstrating a significant improvement in composite CR rate with the combination as compared to an established historical CR rate of 25 % with decitabine alone. Despite that, the survival rates in relapsed/refractory cases appear comparable to what is reported with other salvage regimens, and no significant patterns of non-hematologic toxicity were noted. 50 % of subjects in the de novo group achieved a composite CR which is significantly higher (p = 0.02) than the rate of 25 % with decitabine alone. This trial is registered at clinical trials.gov as NCT02109744.

Portable medical orders and end-of-life measures in acute myeloid leukemia and myelodysplastic syndromes.

Patients with acute myeloid leukemia (AML) or a myelodysplastic syndrome (MDS) experience high rates of hospitalization, intensive care unit (ICU) admission, and in-hospital death at the end of life. Early goals-of-care (GOC) discussions may reduce the intensity of end-of-life (EOL) care. Portable Medical Order forms, known as Medical Orders for Life-Sustaining Treatment (MOLST) forms in New York state, assist patients in translating GOC discussions into specific medical orders that communicate their wishes during a medical emergency. To determine whether the timing of completion of a MOLST form is associated with EOL care in patients with AML or MDS, we conducted a retrospective study of 358 adult patients with AML or MDS treated at a single academic center and its affiliated sites, who died during a 5-year period. One-third of patients completed at least 1 MOLST form >30 days before death. Compared with patients who completed a MOLST form within 30 days of death or never, those who completed a MOLST form >30 days before death were less likely to receive transfusion (adjusted odds ratio [AOR], 0.39; P < .01), chemotherapy (AOR, 0.24; P < .01), or life-sustaining treatments (AOR, 0.21; P < .01) or to be admitted to the ICU (AOR, 0.21; P < .01) at EOL. They were also more likely to use hospice services (AOR, 2.72; P < .01). Earlier MOLST form completion was associated with lower intensity of care near EOL in patients with MDS or AML.

KTE-X19 for relapsed or refractory adult B-cell acute lymphoblastic leukaemia: phase 2 results of the single-arm, open-label, multicentre ZUMA-3 study.

BACKGROUND: Despite treatment with novel therapies and allogeneic stem-cell transplant (allo-SCT) consolidation, outcomes in adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia remain poor, underlining the need for more effective therapies. METHODS: We report the pivotal phase 2 results of ZUMA-3, an international, multicentre, single-arm, open-label study evaluating the efficacy and safety of the autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy KTE-X19 in adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia. Patients were enrolled at 25 sites in the USA, Canada, and Europe. Eligible patients were aged 18 years or older, with Eastern Cooperative Oncology Group performance status of 0-1, and morphological disease in the bone marrow (>5% blasts). After leukapheresis and conditioning chemotherapy, patients received a single KTE-X19 infusion (1 × 106 CAR T cells per kg bodyweight). The primary endpoint was the rate of overall complete remission or complete remission with incomplete haematological recovery by central assessment. Duration of remission and relapse-free survival, overall survival, minimal residual disease (MRD) negativity rate, and allo-SCT rate were assessed as secondary endpoints. Efficacy and safety analyses were done in the treated population (all patients who received a dose of KTE-X19). This study is registered with ClinicalTrials.gov, NCT02614066. FINDINGS: Between Oct 1, 2018, and Oct 9, 2019, 71 patients were enrolled and underwent leukapheresis. KTE-X19 was successfully manufactured for 65 (92%) patients and administered to 55 (77%). The median age of treated patients was 40 years (IQR 28-52). At the median follow-up of 16·4 months (13·8-19·6), 39 patients (71%; 95% CI 57-82, p<0·0001) had complete remission or complete remission with incomplete haematological recovery, with 31 (56%) patients reaching complete remission. Median duration of remission was 12·8 months (95% CI 8·7-not estimable), median relapse-free survival was 11·6 months (2·7-15·5), and median overall survival was 18·2 months (15·9-not estimable). Among responders, the median overall survival was not reached, and 38 (97%) patients had MRD negativity. Ten (18%) patients received allo-SCT consolidation after KTE-X19 infusion. The most common adverse events of grade 3 or higher were anaemia (27 [49%] patients) and pyrexia (20 [36%] patients). 14 (25%) patients had infections of grade 3 or higher. Two grade 5 KTE-X19-related events occurred (brain herniation and septic shock). Cytokine release syndrome of grade 3 or higher occurred in 13 (24%) patients and neurological events of grade 3 or higher occurred in 14 (25%) patients. INTERPRETATION: KTE-X19 showed a high rate of complete remission or complete remission with incomplete haematological recovery in adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia, with the median overall survival not reached in responding patients, and a manageable safety profile. These findings indicate that KTE-X19 has the potential to confer long-term clinical benefit to these patients. FUNDING: Kite, a Gilead Company.

KTE-X19 anti-CD19 CAR T-cell therapy in adult relapsed/refractory acute lymphoblastic leukemia: ZUMA-3 phase 1 results.

ZUMA-3 is a phase 1/2 study evaluating KTE-X19, an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, in adult relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL). We report the phase 1 results. After fludarabine-cyclophosphamide lymphodepletion, patients received a single infusion of KTE-X19 at 2 × 106, 1 × 106, or 0.5 × 106 cells per kg. The rate of dose-limiting toxicities (DLTs) within 28 days after KTE-X19 infusion was the primary end point. KTE-X19 was manufactured for 54 enrolled patients and administered to 45 (median age, 46 years; range, 18-77 years). No DLTs occurred in the DLT-evaluable cohort. Grade ≥3 cytokine release syndrome (CRS) and neurologic events (NEs) occurred in 31% and 38% of patients, respectively. To optimize the risk-benefit ratio, revised adverse event (AE) management for CRS and NEs (earlier steroid use for NEs and tocilizumab only for CRS) was evaluated at 1 × 106 cells per kg KTE-X19. In the 9 patients treated under revised AE management, 33% had grade 3 CRS and 11% had grade 3 NEs, with no grade 4 or 5 NEs. The overall complete remission rate correlated with CAR T-cell expansion and was 83% in patients treated with 1 × 106 cells per kg and 69% in all patients. Minimal residual disease was undetectable in all responding patients. At a median follow-up of 22.1 months (range, 7.1-36.1 months), the median duration of remission was 17.6 months (95% confidence interval [CI], 5.8-17.6 months) in patients treated with 1 × 106 cells per kg and 14.5 months (95% CI, 5.8-18.1 months) in all patients. KTE-X19 treatment provided a high response rate and tolerable safety in adults with R/R B-ALL. Phase 2 is ongoing at 1 × 106 cells per kg with revised AE management. This trial is registered at www.clinicaltrials.gov as #NCT02614066.

Treatment decision-making in acute myeloid leukemia: a qualitative study of older adults and community oncologists.

Little is known about the characteristics of patients, physicians, and organizations that influence treatment decisions in older patients with AML. We conducted qualitative interviews with community oncologists and older patients with AML to elicit factors that influence their treatment decision-making. Recruitment was done via purposive sampling and continued until theoretical saturation was reached, resulting in the inclusion of 15 patients and 15 oncologists. Participants' responses were analyzed using directed content analysis. Oncologists and patients considered comorbidities, functional status, emotional health, cognition, and social factors when deciding treatment; most oncologists evaluated these using clinical gestalt. Sixty-seven percent of patients perceived that treatment was their only option and that they had not been offered a choice. In conclusion, treatment decision-making is complex and influenced by patient-related factors. These factors can be assessed as part of a geriatric assessment which can help oncologists better determine fitness and guide treatment decision-making.

The challenge to further improvements in survival of patients with T-ALL: Current treatments and new insights from disease pathogenesis.

Survival rates for children and adult patients with T-cell acute lymphoblastic leukemia (T-ALL) have improved during the past decade due to optimization of frontline multiagent chemotherapy regimens. The outcome for relapsed T-ALL after initial intensive chemotherapy is frequently fatal, however, because no effective salvage regimens have been developed. Immunotherapy and small molecule inhibitors are beginning to be tested in T-ALL and have the potential to advance the treatment, especially the frontline regimen by eradicating minimal residual disease thus inducing more durable remissions. In this paper, I review the current chemotherapy regimens for adult patients with T-ALL and summarize the novel immunotherapies and small molecule inhibitors that are currently in early phase clinical trials.

American Society of Hematology 2020 guidelines for treating newly diagnosed acute myeloid leukemia in older adults.

BACKGROUND: Older adults with acute myeloid leukemia (AML) represent a vulnerable population in whom disease-based and clinical risk factors, patient goals, prognosis, and practitioner- and patient-perceived treatment risks and benefits influence treatment recommendations. OBJECTIVE: These evidence-based guidelines of the American Society of Hematology (ASH) are intended to support patients, clinicians, and other health care professionals in their decisions about management of AML in older adults. METHODS: ASH formed a multidisciplinary guideline panel that included specialists in myeloid leukemia, geriatric oncology, patient-reported outcomes and decision-making, frailty, epidemiology, and methodology, as well as patients. The McMaster Grading of Recommendations Assessment, Development and Evaluation (GRADE) Centre supported the guideline-development process, including performing systematic evidence reviews (up to 24 May 2019). The panel prioritized clinical questions and outcomes according to their importance to patients, as judged by the panel. The panel used the GRADE approach, including GRADE's Evidence-to-Decision frameworks, to assess evidence and make recommendations, which were subject to public comment. RESULTS: The panel agreed on 6 critical questions in managing older adults with AML, mirroring real-time practitioner-patient conversations: the decision to pursue antileukemic treatment vs best supportive management, the intensity of therapy, the role and duration of postremission therapy, combination vs monotherapy for induction and beyond, duration of less-intensive therapy, and the role of transfusion support for patients no longer receiving antileukemic therapy. CONCLUSIONS: Treatment is recommended over best supportive management. More-intensive therapy is recommended over less-intensive therapy when deemed tolerable. However, these recommendations are guided by the principle that throughout a patient's disease course, optimal care involves ongoing discussions between clinicians and patients, continuously addressing goals of care and the relative risk-benefit balance of treatment.