Older Pts Research Articles

P1126: MOSUNETUZUMAB IS EFFICACIOUS AND WELL TOLERATED IN PATIENTS AGED <65 AND ≥65 YEARS WITH RELAPSED/REFRACTORY FOLLICULAR LYMPHOMA AND ≥2 PRIOR THERAPIES: SUBGROUP ANALYSIS OF A PIVOTAL PHASE II STUDY

Background: Advancing age is associated with a decline in immune function and an increase in the incidence of comorbidity (Castellino et al. 2017). Vulnerability to treatment-related toxicities may also increase with age. Mosunetuzumab is a T-cell engaging CD20xCD3 bispecific monoclonal antibody (Ab) that redirects T cells to eliminate malignant B cells. In a pivotal Phase II study (NCT02500407), mosunetuzumab induced deep and durable remissions and had a favorable safety profile in patients (pts) with relapsed/refractory (R/R) follicular lymphoma (FL) and ≥2 prior therapies (Budde et al. ASH 2021). Aims: In the current study, we evaluated the efficacy and safety of mosunetuzumab in pts aged <65 and ≥65 years (age stratification per ESMO Clinical Practice Guidelines for management of newly diagnosed and R/R FL; Dreyling et al. 2021) in the pivotal Phase II study. Methods: All pts had Grade (Gr) 1–3a FL and ECOG performance status (PS) 0–1, and were R/R to ≥2 prior therapies, including an anti-CD20 Ab and an alkylating agent. Intravenous mosunetuzumab was given in 21-day cycles with Cycle (C) 1 step-up dosing: C1 Day (D) 1: 1mg; C1D8 2mg; C1D15 and C2D1: 60mg; D1 of C3+: 30mg. Pts with a complete response (CR) by C8 completed therapy; pts with a partial response or stable disease continued treatment for up to 17 cycles, unless disease progression or unacceptable toxicity occurred. The primary endpoint was CR (as best response) rate by PET/CT assessed by Independent Review Committee using standard response criteria (Cheson et al. 2007). Cytokine release syndrome (CRS) was graded using ASTCT criteria (Lee et al. 2019). All pts provided informed consent. Results: As of August 27, 2021, 90 pts had received mosunetuzumab; 67% were aged <65 years and 33% were aged ≥65 years. Of 30 pts aged ≥65 years, median age was 71 years (range: 65–90) and 43% had ECOG PS 1 at entry, 53% had FLIPI 3–5, and 70% had Ann Arbor stage III/IV disease. Median number of prior therapies in the older age group was 3 (range: 2–8); 77% were refractory to a prior anti-CD20 Ab and 43% were double-refractory to a prior anti-CD20 Ab and an alkylating agent. Compared with younger pts, those aged ≥65 years had a numerically higher objective response rate (87% [95% CI: 69–96] vs 77% [95% CI: 64–87]) and CR rate (70% [95% CI: 51–85] vs 55% [95% CI: 42–68]). The 18-month event-free rate for duration of response was 54% (95% CI: 31–76) in pts aged ≥65 years and 59% (95% CI: 43–74) in those aged <65 years. The rate of Gr 3–4 adverse events (AEs) was comparable in the older and younger age groups (73% vs 68%, respectively). A lower rate of serious AEs of any Gr was observed in pts aged ≥65 years (37% vs 52%). One patient in each age group discontinued treatment due to mosunetuzumab-related AEs. CRS occurred less frequently in pts aged ≥65 years than in those aged <65 years (30% vs 52%), while CRS events were predominantly low-Gr in both groups (age ≥65 vs <65 years: Gr 1, 20% vs 28%; Gr 2, 7% vs 22%); high-Gr CRS was uncommon (one patient in each group). All CRS events resolved. No cases of aphasia, seizures, encephalopathy or cerebral edema occurred. Rates of serious AEs of infection (any Gr) were comparable in pts aged ≥65 and <65 years (17% vs 22%, respectively). The PK disposition of mosunetuzumab was also comparable in pts aged ≥65 and <65 years. Summary/Conclusion: Mosunetuzumab is efficacious and well tolerated in older and younger pts with R/R FL and ≥2 prior therapies. In older pts (aged ≥65 years), numerically lower rates of CRS and serious AEs were observed.

P355: MINI-HYPER-CVD PLUS INOTUZUMAB OZOGAMICIN, WITH OR WITHOUT BLINATUMOMAB, IN OLDER ADULTS WITH NEWLY DIAGNOSED B-CELL ACUTE LYMPHOBLASTIC LEUKEMIA: UPDATES FROM A PHASE II TRIAL

Background: Blinatumomab (Blina) and inotuzumab ozogamicin (INO) improve the outcomes of patients (pts) with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL). These drugs may allow for use of less chemotherapy and improve remission durations and overall survival (OS) in older pts with newly diagnosed B-ALL. Aims: To evaluate the combination of low-intensity chemotherapy and INO with or without Blina, in older pts with newly diagnosed B-ALL. Methods: Pts ≥60 years with newly diagnosed Philadelphia chromosome (Ph)-negative B-ALL were eligible to receive mini-hyper-CVD for up to 8 cycles. Initially, INO was given at 1.3-1.8mg/m2 on day (D) 3 of cycle 1 and 0.8-1.3mg/m2 on D3 of cycles 2-4. Rituximab (if CD20+) and prophylactic IT chemotherapy were given for the first 4 cycles. POMP maintenance was given for up to 3 years. Starting with pt #50, the protocol was amended and INO was administered in fractionated doses with each of the 4 cycles of hyper-CVD (0.6 mg/m2 on D2 and 0.3 mg/m2 on D8 of cycle 1; 0.3 mg/m2 on D2 and 8 of cycles 2-4) followed by 4 cycles of blina. The cumulative doses of INO given before and after this amendment were 4.3 mg/m2 and 2.7 mg/m2, respectively. Maintenance was also amended to include 12 cycles of POMP and 4 cycles of blina (1 cycle of blina after every 3 cycles of POMP). Results: 80 pts have been treated with a median age of 68 years (range, 60-87); 30 pts (38%) were ≥70 years. 6 pts were in complete remission (CR) at enrollment and unevaluable for morphological response. Pt characteristics are summarized below (Figure 1A). The overall response rate (ORR) among 74 evaluable pts was 99% (CR, n=66; CRi, n=7). MRD negativity by flow cytometry was achieved in 61/76 pts (80%) after 1 cycle and 74/79 pts (94%) overall. The 30-day and 60-day mortality rates were 0% and 3%, respectively. Among 79 pts who achieved remission, 33 (42%) are still in ongoing remission without stem cell transplant (SCT), 31 (39%) died in remission, 11 (14%) relapsed without SCT, and 4 (5%) proceeded to SCT in first remission (1 of whom subsequently relapsed). Notably, 9 pts (11%) later developed MDS/AML, 7 of whom had a TP53 mutation. Overall, 6 pts (8%) developed VOD, 1 after allogeneic SCT. With a median follow-up of 55 months (range, 3-119), the 5-year continuous remission and OS rates were 76% and 47%, respectively (Figure 1B). Pts aged 60-69 years had better outcomes compared with pts ≥70 years (5-year OS rates: 59% vs 27%, respectively; P=0.04) and as did those without poor cytogenetics (i.e. complex, KMT2A-rearranged, low-hypodiploidy/near-triploidy) compared with poor cytogenetics (5-year OS rates: 54% and 25%, respectively; P=0.02). Deaths in remission were more frequent in pts ≥70 years compared with those 60-69 years (70% vs 35%; P=0.005). The 5-year OS rates for pts age 60-69 without poor-risk cytogenetics (n=37), age 60-69 with poor-risk cytogenetics (n=13), age ≥70 without poor-risk cytogenetics (n=24), and age ≥70 with poor-risk cytogenetics (n=6) were 69%, 39%, 36% and 0% respectively (Figure 1C). Presence of a TP53 mutation did not significantly impact OS (P=0.22). Image:Summary/Conclusion: Reduced-intensity chemotherapy plus INO, with or without blina, resulted in an ORR of 99% and a 5-year OS rate of 47% in older pts with newly diagnosed Ph-negative B-ALL. Outcomes were particularly favorable in those 60-69 years of age without poor-risk cytogenetics. Pts ≥70 years were at a higher risk of death in remission. A chemotherapy-free approach, with INO plus blina only, is therefore now being explored in this population.

P499: THE PHASE 1B OMNIVERSE TRIAL OF ORAL AZACITIDINE IN COMBINATION WITH VENETOCLAX FOR TREATMENT OF RELAPSED/REFRACTORY OR NEWLY DIAGNOSED ACUTE MYELOID LEUKEMIA (TRIAL IN PROGRESS)

Background: For older patients (pts) with acute myeloid leukemia (AML) who are ineligible for standard intensive chemotherapy (IC) regimens, traditional lower-intensity AML treatment (Tx) options include low-dose cytarabine (LDAC) or hypomethylating agents (HMAs; azacitidine [AZA] and decitabine), which are generally well tolerated but associated with suboptimal outcomes vs IC [Vey 2020]. Therefore, there remains a need for less toxic and more efficacious lower-intensity AML Tx regimens, especially agents that can be administered in the outpatient setting, which may increase convenience and reduce resource utilization. Venetoclax (VEN) is an oral, selective, small-molecule BCL2 inhibitor that has demonstrated considerable activity when combined with LDAC or HMAs in older pts with AML. In a recent phase 3 trial, VEN + injectable AZA significantly improved response and survival vs AZA alone in IC-ineligible pts with newly diagnosed (ND) AML [DiNardo 2020]. In the USA, VEN is approved in combination with an HMA or LDAC for Tx of pts with ND AML ≥ 75 years (y) of age or who cannot use IC due to comorbidities. Oral-AZA (CC-486) is approved for pts with AML in first remission (CR1) after IC who are ineligible for transplant or other curative therapies. In the randomized, phase 3 QUAZAR AML-001 trial of Oral-AZA in pts with AML in CR1 after IC, Oral-AZA 300 mg QD for 14 days (d)/28d Tx cycle was generally well tolerated and associated with significantly improved overall survival vs placebo. Gastrointestinal symptoms were the most common adverse events reported with Oral-AZA [Wei 2020]. Oral-AZA has also shown clinical activity in pts with active AML [Savona 2015]. As incorporation of AZA into DNA is S-phase-restricted, extended Oral-AZA dosing regimens (> 7d/28d Tx cycle) increase drug incorporation into cycling tumor cells to prolong epigenetic activity throughout the Tx cycle [Laille 2015]. An all-oral VEN + Oral-AZA combination regimen allows for outpatient administration and thus improves pt adherence [Eek 2016]. Aims: Describe the study design and objectives of the OMNIVERSE trial of Oral-AZA + VEN in older pts with ND AML or pts with AML relapsed/refractory (R/R) to prior Tx. Methods: OMNIVERSE (NCT04887857) is a multicenter, open-label, 2-part phase 1b trial (Figure). The key objectives of the trial are to assess safety and determine the maximum tolerated dose of Oral-AZA + VEN in pts with R/R AML (WHO 2016 criteria) ineligible to receive further IC (part I), and then in pts with ND AML ≥ 75 y of age, or those ≥ 18–74 y of age ineligible for IC or HSCT due to comorbidities (part 2). Main eligibility criteria include an ECOG performance status of 0–2 (ECOG 3 is allowed for pts ≥ 18–74 y of age with comorbidities) and an unfavorable cytogenetic risk profile for pts with ND AML. The initial dose of Oral-AZA is 300 mg QD × 14d/28d cycle, with de-escalation to 200 mg × 14d/28d cycle allowed for dose-limiting toxicities. VEN 400 mg is taken orally QD in continuous 28d cycles (or for 21d/cycle for dose level –2). A modified toxicity probability interval-2 design is used to evaluate the planned dose levels. The sample size is dependent on the dose levels included in the study (≤ 18 pts/part). Results: N/A Image:Summary/Conclusion: Study enrollment began in 2021. The trial is ongoing at clinical sites in the United States and Australia.

S209: PRIMARY RESULTS FROM THE PHASE 3 SHINE STUDY OF IBRUTINIB IN COMBINATION WITH BENDAMUSTINE-RITUXIMAB (BR) AND R MAINTENANCE AS A FIRST-LINE TREATMENT FOR OLDER PATIENTS WITH MANTLE-CELL LYMPHOMA

Background: Elderly patients (pts) with mantle-cell lymphoma (MCL) are unsuitable for intensive chemotherapy or transplantation due to excessive toxicities. Single-agent ibrutinib (Ibr), a first-in-class, oral Bruton’s tyrosine kinase inhibitor (BTKi), has transformed the care of pts with relapsed or refractory MCL with durable activity. Aims: We conducted a phase III trial (SHINE; NCT01776840) to evaluate combining Ibr with a standard chemoimmunotherapy (BR) and R maintenance in older pts with untreated MCL. Methods: Pts aged ≥ 65 years, enrolled between May 2013 and November 2014 from 183 sites across all geographical regions, were stratified by simplified MIPI score (low vs intermediate vs high risk) and were randomized 1:1 to Ibr (560 mg orally daily) or placebo (Pbo), plus 6 cycles of B (90 mg/m2) and R (375 mg/m2). Pts who achieved an objective response received R maintenance, administered every 8 weeks for up to 12 additional doses in both arms. Ibr and Pbo were administered until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS) assessed by the investigators. Results: A total of 523 pts were randomized to Ibr + BR (n = 261) or Pbo + BR (n = 262). Median age was 71 years (range, 65–87), 65.6% of pts had low/intermediate simplified MIPI, and 8.6% had blastoid/pleiomorphic histology. At the primary analysis, median follow up was 84.7 months. The primary endpoint was met as PFS was significantly improved in the Ibr arm vs the Pbo arm (hazard ratio, 0.75; one-sided P = 0.011) (Figure). Median PFS was 80.6 months with Ibr in combination with BR and R maintenance, a 50% improvement over Pbo in combination with BR and R maintenance (median PFS of 52.9 months). The complete response rate was 65.5% in the Ibr arm and 57.6% in the Pbo arm (P = 0.0567). There was no difference in overall survival between treatment arms (P = 0.648). Time to next treatment was longer in the Ibr arm compared with the Pbo arm (P < 0.001). Fifty-two (19.9%) and 106 (40.5%) pts received subsequent anti-lymphoma therapy in the Ibr and Pbo arms, respectively; 41/106 (38.7%) received a second-line BTKi in the Pbo arm. Rates of grade 3 or 4 treatment-emergent adverse events were 81.5% and 77.3% in the Ibr and Pbo arms, respectively. Of adverse events of clinical interest for BTKis, atrial fibrillation was reported in 13.9% and 6.5% of pts in the Ibr and Pbo arms, respectively. Rates of major hemorrhage, hypertension, arthralgia, and secondary primary malignancies were similar in both arms. Quality of life was also similar in both arms. Image:Summary/Conclusion: This phase III study in untreated MCL demonstrated that Ibr combined with BR and R maintenance significantly improved PFS compared with standard chemoimmunotherapy, with a median PFS of 6.7 years. The safety profile was consistent with the known profiles of the individual drugs.

P502: CLINICAL IMPLEMENTATION OF GERMLINE GENETIC TESTING FOR HEMATOLOGIC DISORDERS

Background: Up to 18% of adult hematology patients (pts) suspected of having an inherited predisposition are found to have a germline mutation leading to a hereditary hematologic disorder (HHD). Timely identification of these disorders leads to heightened surveillance for malignancies, specific treatment regimens, donor selection, transplant conditioning regimens, cascade testing in family members and supportive care. Unlike solid tumour hereditary cancer syndromes, the investigations in HHD are more complex and there is no formal consensus of referral criteria or genetic testing criteria. We describe our initial experience in this patient population at our centre, the Princess Margaret Cancer Centre (PM). We have established a workflow to initiate germline genetic testing in pts under suspicion for a HHD. This involves a collaboration with a genetics clinic to 1) capture pts based on their personal/family history of cancer and suggestive genetic findings identified on bone marrow/blood, 2) procure a skin biopsy for fibroblast culture and germline DNA extraction and 3) provide follow-up counselling and management for positive results. Aims: Our goal is to evaluate the positivity rate of germline mutations in adult hematology pts who were referred for genetics assessment. Methods: The PM is the largest leukemia Centre in Canada, and has seen over 3000 adult pts with a malignant disorder from 2015-2021 (AML:1597, MDS:472, ALL:286, MPN:664 and marrow failure:22). We performed a retrospective chart review of all adult hematology pts referred to cancer genetics service for HHD workup during this time period. Results: 116 pts (66 male, 50 female) were suspected for a HHD and referred for germline genetic testing on fibroblast DNA. 52 pts (45%) were ≤40y old and 64 pts (55%) >40y old (age range 18-86y, median 53y). 71 pts (61%) were referred with a positive family history of hematologic disorders (HD). In addition, 61 pts presented with a myeloid malignancy (46 with MDS, AML, or CML, and 15 with a MPN), 42 presented with a lymphoid malignancy (ALL, CLL, or lymphoma), 8 presented with bone marrow failure, and 5 presented with other HD. 40 pts were found to have a germline genetic mutation, 7 of which were associated with carrier status. In total, 33 (28.4%) referred pts were found to have at least one actionable germline mutation. This corresponds to a positive genetic result found in 30% of pts referred with MDS/AML, 33% of pts referred with a lymphoid malignancy, and 18% of pts referred with bone marrow failure, MPN, or other HD. Additionally, 18 (55%) of these pts had a positive family history of HD, while 15 (45%) presented with no family history of HD. Of these 33 positive cases, 13 (11.2% of all referrals) occurred in a gene associated with a hematologic malignancy and resulted in a HHD diagnosis. 20 pts were found to have a mutation in a gene associated with a non-hematologic hereditary cancer syndrome. After the implementation of a HHD genetics workflow in 2018, we saw an increase in the total number of referrals to a genetics clinic over the past seven years, with 25 pts (6 positive cases) referred between 2015-2018, and 91 pts (27 positive cases) referred between 2019-2021. Image:Summary/Conclusion: Our overall positivity rate was 28.4% which includes mutations in any hereditary cancer gene, and 11.2% for HHDs. Our high pickup rate across all age groups and the increase in the number of referrals to genetics service suggests that more pts with HD, including older pts, would benefit from consultation with specialized centres that are experienced in the evaluation and treatment of these disorders.

Primary results from the double-blind, placebo-controlled, phase III SHINE study of ibrutinib in combination with bendamustine-rituximab (BR) and R maintenance as a first-line treatment for older patients with mantle cell lymphoma (MCL).

LBA7502 Background: Elderly patients (pts) with MCL are unsuitable for intensive chemotherapy or transplantation due to excessive toxicities. Single-agent ibrutinib (Ibr), a first-in-class, oral Bruton’s tyrosine kinase inhibitor (BTKi), has transformed the care of pts with relapsed or refractory MCL with durable activity. We conducted a phase III trial (SHINE; NCT01776840) to evaluate combining Ibr with a standard chemoimmunotherapy (BR) and R maintenance in older pts with untreated MCL. Methods: Pts aged ≥ 65 years, enrolled between May 2013 and November 2014 from 183 sites across all geographical regions, were stratified by simplified MIPI score (low vs intermediate vs high risk) and were randomized 1:1 to Ibr (560 mg orally daily) or placebo (Pbo), plus 6 cycles of B (90 mg/m2) and R (375 mg/m2). Pts who achieved an objective response received R maintenance, administered every 8 weeks for up to 12 additional doses in both arms. Ibr and Pbo were administered until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS) assessed by the investigators. Results: A total of 523 pts were randomized to Ibr + BR (n = 261) or Pbo + BR (n = 262). Median age was 71 years (range, 65–87), 65.6% of pts had low/intermediate simplified MIPI, and 8.6% had blastoid/pleiomorphic histology. At the primary analysis, median follow up was 84.7 months. The primary endpoint was met as PFS was significantly improved in the Ibr arm vs the Pbo arm (hazard ratio, 0.75; one-sided P = 0.011). Median PFS was 80.6 months with Ibr in combination with BR and R maintenance, a 50% improvement over Pbo in combination with BR and R maintenance (median PFS of 52.9 months). The complete response rate was 65.5% in the Ibr arm and 57.6% in the Pbo arm ( P = 0.0567). There was no difference in overall survival between treatment arms ( P = 0.648). Time to next treatment was longer in the Ibr arm compared with the Pbo arm ( P &lt; 0.001). Fifty-two (19.9%) and 106 (40.5%) pts received subsequent anti-lymphoma therapy in the Ibr and Pbo arms, respectively; 41/106 (38.7%) received a second-line BTKi in the Pbo arm. Rates of grade 3 or 4 treatment-emergent adverse events were 81.5% and 77.3% in the Ibr and Pbo arms, respectively. Of adverse events of clinical interest for BTKis, atrial fibrillation was reported in 13.9% and 6.5% of pts in the Ibr and Pbo arms, respectively. Rates of major hemorrhage, hypertension, arthralgia, and secondary primary malignancies were similar in both arms. Quality of life was also similar in both arms. Conclusions: This phase III study in untreated MCL demonstrated that Ibr combined with BR and R maintenance significantly improved PFS compared with standard chemoimmunotherapy, with a median PFS of 6.7 years. The safety profile was consistent with the known profiles of the individual drugs. Clinical trial information: NCT01776840.

Disparities in speed to BMT consult and allograft in 279 adults with AML.

6523 Background: Whether patient (pt) ancestry impacts the time to BMT is not established. Methods: We hypothesized that non-European (non-EURO) ancestry AML pts are at increased risk of delayed time to transplant. Thus, we analyzed time to allograft (Allo) by ancestry defining delayed (late) times as: Allo Indication to BMT Consult (Ind. – Consult) &gt; 90 days, Consult – BMT &gt; 120 days &amp; Allo Indication to BMT (Ind. - BMT) &gt; 180 days. We studied pts &lt; 70 yrs transplanted 1/2016-7/2021. Results: In 279 AML pts (median 56 yrs, range 19-69), BMT indication was date of diagnosis if ELN 2017 intermediate/ high risk &amp;/or high risk mutations &amp;/or sAML in 261 (94%) pts, or date of refractory/ relapsed disease in 18 (6%) pts. European (EURO) pts (n = 195, 70%; median 60 yrs) were older than non-EURO pts (n = 84, 30%; median 49 yrs), p &lt;.001. Most HLA-matched sibling (SIB) (27/33, 82%) &amp; 8/8 HLA-matched unrelated donor (mURD, 113/138, 82%) recipients were EURO; more non-EURO pts received HLA-disparate grafts [cord blood (CB)/ haplo/ mmURD]: 48/84 (57%) vs 55/195 (28%), p &lt;.001. Overall, median (range) times for BMT Ind. - Consult, Consult - BMT, &amp; Ind. - BMT were 45 (1-1127), 86 (13-1628), &amp; 135 (23-1683) days. 15% of pts had late BMT Ind. - Consult, 27% late Consult – BMT, &amp; 28% late Ind. - BMT. In multivariate analysis (significant variables in Table), more older pts had late Consult - BMT &amp; Ind. - BMT; more non-EURO pts had late Ind. - Consult, Consult - BMT &amp; Ind. – BMT; &amp; despite mostly being non-EURO (35/67, 52%), fewer CB recipients had late Consult - BMT. In mURD pts, BMT Ind. - BMT time was delayed in non-EURO (median 182 days) vs EURO (median 128 days) pts (p = 0.04); there was no difference in CB pts (BMT Ind. - BMT EURO pt median 118 vs non-EURO pt median 108 days, p = 0.42). During the pandemic, as compared with EURO pts BMT delays were further exacerbated in non-EURO pts (Ind. - Consult median 13 &amp; Ind. - BMT median 33 days). Conclusions: Few older non-EURO pts are allografted. Matched SIB &amp; 8/8 mURD transplants predominantly serve EURO pts; the majority of non-EURO pts receive HLA-disparate grafts. Older age &amp; non-EURO ancestry are associated with delayed BMT. CB transplants (CBT) are the fastest regardless of ancestry. Finally, the pandemic further exacerbated delays for non-EURO pts. Strategies to mitigate referral barriers (esp. for older non-EURO pts), prompt adult donor evaluations, efficient URD searches, &amp; utilization of all alternative donors are critical to ensure timely BMT for all. Given the rapid availability, CBT should have high priority in high-risk or urgent pts &amp; speedy graft procurement can compensate for late referral. [Table: see text]

Outcome and surveillance pattern in older GIST population.

e24016 Background: Recent studies of patients (pts) with gastrointestinal stromal tumor (GIST) have included an older patient population. The majority of these have focused on treatment, but little is known regarding the optimal duration of surveillance following surgery for localized disease. Methods: We conducted a retrospective study of pts age 70 years (yrs) and above (≥) at diagnosis (dx), who underwent surgery for their localized GIST. Charts were reviewed of GIST diagnosed between 1992 to 2016, to allow at least 5 yrs for surveillance, if performed. Demographics were analyzed and pts were risk stratified using modified NIH criteria. Results: We identified 42 pts with a median age of 74 yrs (70 to 89 yrs) at dx. The majority of pts were male (31, 74%) and non-Hispanic White (37, 88%). Most pts had gastric GIST (25, 60%). The median resected tumor was 47 mm (range 6 to 190). Thirty-nine of 42 pts had margin status documented R0 resection. The median overall survival for all pts was 7.9 yrs (1.1 to 17.7), with median recurrence free survival 5.6 yrs (1.1 to 13.7). Only 4 of 16 (25%) pts died from GIST recurrence, and all were detected under 5 yrs from surgery. Fourteen of 34 pts (41%) who survived over 5 yrs from resection had extended surveillance imaging. Demographics and risk stratification are shown in Table. None of the 16 low risk pts developed recurrence, including 6 (38%) whose surveillance imaging continued beyond 5 yrs. Among 7 intermediate risk pts, only 1 pt (14%) extended surveillance imaging beyond 5 yrs. Two intermediate risk pts (29%) developed recurrence and were symptomatic at dx. One intermediate risk pt died from GIST metastasis within 1 yr from surgery. Seven of 19 (37%) high risk pts had surveillance imaging beyond 5 yrs following surgical resection. Seven high risk pts (37%) developed recurrence within median 5.6 yrs (1.6 to 13.7) from surgery; five of these were detected on imaging. In the high risk pts with recurrence, 5 had received adjuvant imatinib and 2 declined any systemic therapy. Three pts (16%) in the high risk cohort died from GIST. Conclusions: In this cohort of pts age ≥ 70 yrs with resected GIST, the majority of pts were symptomatic at relapse. Older pts who undergo surgery for low risk GIST may not require extended surveillance. Fit, older pts with high risk GIST may benefit from extended surveillance imaging, even if they received adjuvant imatinib.[Table: see text]

COVID-19 vaccine uptake in patients with cancer and Sars-Cov-2 infection in 2020: Results from the ASCO registry.

e18713 Background: The availability of safe and effective COVID-19 vaccines has enabled protections against serious outcomes from SARS-CoV-2 infection. The ASCO Registry provides an opportunity to study the rate of vaccine uptake among patients (pts) with cancer who had SARS-CoV-2 infection prior to availability of vaccines. Methods: Participating US medical oncology practices identify pts eligible for inclusion: pts with a positive SARS-CoV-2 test and, at the same time, either (a) or (b) cancer-free less than 12 months (i.e., in complete remission or post-resection) and receiving adjuvant treatment. Registry data were extracted on 2/4/22. Pts in this analysis had a SARS-CoV-2 positive test between 3/1/2020 and 12/31/2020 and at least one clinical encounter on or after 1/1/21, documenting receipt or not of 1st and 2nd vaccine shots. Pts lacking data on vaccination status in their medical records were excluded from analysis. When the exact date of 1st vaccine shot was known, the primary endpoint was number of days from 1/1/21 to 1st shot date. If the exact date of 1st shot was unknown, date was categorized as within 7 days from the clinical encounter, 2-4 weeks, or more than 1 month prior. Summary statistics and 95% confidence intervals (CIs) were calculated using Kaplan-Meier methods. Results: The Registry included 1260 pts with SARS-CoV-2 infection in 2020. Time to vaccination (described using cumulative incidence) across age categories is shown in Table, with 1/1/21 as the baseline. Median time to vaccination ranged from 63 days in the oldest pts (&gt; 80 years of age) to 220 days in the youngest pts (&lt; 45 years of age). Differences in rates of vaccination uptake were most pronounced in the early months (Jan – Mar) and diminished in April and beyond. Conclusions: Older pts with cancer who were infected with SARS-CoV-2 in 2020 received COVID-19 vaccinations in 2021 at higher rates than those of younger ages. Delayed uptake by younger aged pts at outset could be related to lack of clarity on pts with cancer qualifying for early vaccine access and state policies on availability.[Table: see text]

Increased Dependence on Food Assistance Programs and Changes in Food Purchasing Patterns in Inner-City Dialysis Patients During the COVID-19 Pandemic

ObjectivesThe COVID-19 pandemic created nutritional stressors in indigent patients, especially those with diets prescribed for chronic disease. We studied use of SNAP benefits and how food purchasing behavior was affected in a cohort of inner-city dialysis patients during the past year. Methods33 dialysis patients were surveyed face to face about use of grocery stores, restaurants, take-out, and use of SNAP or other benefits over 12 months prior to the summer of 2021. The survey also assessed patient attitudes and fears relating to food purchasing due to COVID-19. ResultsMean age was 57.1 ± 17.9 yrs, 20 (61%) men, 91% identified as Black. 9/20 pts (27%) reported yearly income under $20,000 with 70% less than $40,000. The number of pts using SNAP, WIC, or Greenmarket Bucks to buy groceries increased from 21% before the pandemic to 33% after (p = 0.019). Age correlated inversely with feeling safe eating at a restaurant indoors (r = –0.47, p = 0.008), or outdoors (r = –0.58, p = < 0.001) and increased use of take-out since the start of the pandemic (r = –0.39, p = 0.032). There was a significant difference in pts who purchased breakfast (45.9 ± 4.0 vs 65.3 ± 3.6, p < .001), lunch (49.7 ± 4.1 vs 65.3 ± 4.0, p = .006) and dinner compared to those who didn’t (48.5 ± 4.9 vs 60.9 ± 3.9, p = 0.031). There was a positive correlation between income and the frequency that pts purchased breakfast (r = 0.45, p = 0.048) and lunch (r = 0.45, p = 0.046) and a negative correlation between age and the statement “I wish I could cook more meals at home” (r = –0.497, p = 0.004) and a positive correlation with income (r = 0.60, p = 0.006). There was no association between age and income. Only 6% (2) pts were employed and both were <60 yrs old. ConclusionsUse of food assistance programs increased in our dialysis population after the start of the pandemic. Older pts felt less safe eating at restaurants regardless of whether it was indoors or outdoors and more likely to make meals at home. Younger patients were more likely to eat take-out food and reported they wished they could cook more meals at home. Increased use of food programs suggests that more patients may be at risk for food scarcity. In addition to increased use of take out food by younger or lower income patients, this suggests that dietary habits have changed since the pandemic and nutritional counseling for dietary restrictions will be even more important. Funding SourcesUnfunded.

A phase II study of CPX-351 in younger patients &lt; 60 years old with secondary acute myeloid leukemia: Trial in progress.

TPS7073 Background: Patients (pts) with secondary acute myeloid leukemia (s-AML) and therapy-related AML (t-AML) have poor long-term outcomes following standard induction 7+3 chemotherapy. CPX-351, a liposomal formulation of cytarabine and daunorubicin fixed at the synergistic ratio of 5:1, is indicated for the treatment of pts with newly diagnosed s-AML and t-AML based on the results of a phase III trial favorably comparing CPX-351 to 7+3. Although the trial only enrolled pts aged 60-75 years (Y), CPX-351 is approved by the United States Food and Drug Administration for all adult pts with t-AML and AML with myelodysplasia-related changes (AML-MRC). In a prior retrospective analysis of CPX-351 in pts &lt;60 Y with s-AML, we noted that the outcomes of these younger pts appeared inferior to those reported in older pts (60-75 Y) in the phase III trial (Przespolewski et al. Blood 2018 p.2677). Therefore, we designed this prospective study to evaluate the efficacy of CPX-351 in pts &lt;60 Y with untreated s-AML and t-AML. Methods: In this phase II single-arm multi-institutional study, pts aged 18-59 Y with untreated t-AML or AML-MRC, adequate organ function, and ECOG performance status ≤ 2 are eligible. Pts with active central nervous system disease and infections were excluded. CPX-351 will be dosed at 100 mg/m2 cytarabine and 44 mg/m2 daunorubicin on days 1, 3, and 5 during induction. Bone marrow biopsy will be performed between days 14-21 to assess response. If needed, re-induction CPX-351 dose will be 44 mg/m2 daunorubicin/100 mg/m2 cytarabine on days 1 and 3. Pts achieving a complete remission (CR) following induction can receive up to 2 cycles of consolidation CPX-351 dosed as cytarabine 65 mg/m2 and daunorubicin 29 mg/m2 on days 1 and 3. The primary endpoint of the study is overall response rates defined as CR and CR with incomplete blood count recovery (CRi)) within 45 days of beginning therapy. Secondary endpoints are duration of response, event-free survival, overall survival, rate of allogeneic stem cell transplant, and adverse events. A maximum of 46 pts will be enrolled at 4 U.S. sites with 5-year follow-up from the start of CPX-351.The study is open and has enrolled 4 pts to date. Clinical trial information: NCT04269213.

Outcomes of patients with T1a,b N0 Her2-positive breast cancer treated with adjuvant trastuzumab in a prospective registry in Ontario, Canada.

533 Background: Multiple randomized trials of chemo +/- tras in early stage, Her 2 positive BrCa demonstrated improvement in survival, but patients (pts) with T1a,b N0 disease were mostly excluded. Given the uncertainty of benefit in this group and the toxicities of chemo + tras, treatment in Ontario was funded for these patients conditional upon data collection for toxicity and survival endpoints. We report the outcomes for 483 patients enrolled in this Evidence Building Program (EBP). Methods: Between 2011 and 2018, 483 eligible pts with Her 2 pos disease and adequate cardiac function were treated with chemo + tras in the EBP. Cardiac toxicity, febrile neutropenia (FN), event-free (EFS), and overall survival (OS) were determined for this cohort from administrative datasets, and compared retrospectively to controls of similar stage selected from the Ontario Cancer Registry who did not receive tras and/or chemo. For the EBP cohort, clinicians also reported changes in left ventricular ejection fraction (LVEF). Results: Pt characteristics are shown in the Table. EBP patients had improved OS when compared to controls who received no chemo or tras. The 3-year OS in the EBP pts was 99.1%, versus 96.9% in the controls [adjusted HR 0.59 (95% CI 0.29-1.20)]. Patients receiving EBP tras had a significantly longer EFS than controls with or without chemo [adjusted HR 0.54 (0.36-0.83), p=0.005]. Use of chemo + tras in EBP pts was associated with an increased risk of clinical congestive heart disease (CHD) and febrile neutropenia (FN). About 3.5% of pts experienced CHD during treatment with chemo + tras. About 6% of pts had an absolute reduction of LVEF &gt;10% or reached LVEF &lt;50%. In an adjusted analysis, the risk of CHD was higher in older pts [HR 1.06 (1.03-1.08) per 1-yr increase in age, p&lt;0.0001) and for pts who received anthracyclines [HR 5.00 (1.71-14.7). In a matched analysis, the crude frequency of FN during treatment was 20% in EBP pts vs. 3% among controls who did not receive chemo or tras (p&lt;0.001). Conclusions: Analysis of the Ontario EBP for pts with, T1a,b N0 HER2 pos BrCa revealed that the prognosis is excellent and is improved with the use of chemo + tras. The safety profile was expected and tolerable, especially when non anthracycline chemo was used. These results led to a funding policy change where prospective data collection has been discontinued and chemo + tras is now routinely funded in this population. [Table: see text]

Aflibercept-LV5FU2 as first-line treatment of non-resectable metastatic colorectal cancers: Results of the FOLFA randomized phase II trial.

3555 Background: Previous trials have demonstrated that bevacizumab and fluoropyrimidine combination is effective and well-tolerated in older patients (pts) with non-aggressive unresectable metastatic colorectal cancer. We evaluated in this trial safety and efficacy of aflibercept and infusional 5-fluorouracil/folinic acid (LV5FU2 regimen) combination versus LV5FU2 alone in older pts, asymptomatic and/or frail, deemed unsuitable for doublet cytotoxic chemotherapy. Methods: The main eligibility criteria for this randomized phase II trial were age ≥ 65 and WHO performance status &lt; 2. Randomization was stratified according to thymidylate synthase (TS)- 5’UTR germline polymorphism. Common (also called simplified) LV5FU2 regimen was preceded or not by aflibercept (4mg/kg). The primary endpoint was the 6-month progression-free survival (PFS) rate, achieved if &gt; 40% in the experimental arm. Secondary objectives were safety, quality of life, overall survival (OS), and the prognostic impact of TS -5’UTR polymorphism. Results: 117 patients (pts) were included, 59 in arm A (5FU-aflibercept), 58 in arm B (5FU alone), of median age 81 years (range 67-91; &gt; 75 years: 81%). RAS/ BRAF status (available in 112 pts [96%]) was mutated in 49% and 7%, respectively. The 6-month PFS was 54% in both arms (same 90% CI 42-65). The disease control rate was 83% in arm A and 87% in arm B. The median OS was 21.8 months in arm A and 25.1 months in arm B. The toxicities were more common in arm A: at least 1 grade 3-4 toxicity &gt; 2 in 82% versus (vs) 58.2% pts, hypertension grade &gt; 3 in 42% vs 18% pts, proteinuria (any grade) in 51% vs 11% pts, dysphonia (grade &lt; 3) in 19% vs 2%, 1 colic perforation in arm A. Treatment delays for toxicities were required for 4% of the 753 courses in arm A vs 2% of the 780 courses in arm B , 5FU bolus suppression was decided for 29.8% pts vs 20% (arm A vs arm B), median 29 days vs 73 days after the first course (arm A vs B), without difference in the doses of infusional 5FU. A second and third line of treatment were received in 41% and 14% of pts in arm A vs 67% and 29% of pts in arm B, respectively. The TS 5’UTR polymorphism (3R3R vs 2R2R or 2R3R) had no impact on PFS or OS. Regarding the quality of life (QLQ C30 score), the difference of overall health score was on average -6.39 (SD = 26.68) in arm A vs -4.91 (SD = 27.15) in arm B, and was very similar in all components. The median time to definitive deterioration in quality of life was 15 months (95% CI: 9-22.8) in arm A vs 9.6 (95% CI: 5.1-19.4) in arm B. Conclusions: FOLFA trial meets is primary endpoint with 53.6% of 6-month PFS with LV5FU2-aflibercept. Nevertheless, as compared with LV5FU2 alone we observed no increase in PFS or OS and more toxicities. These results do not argue for an evaluation of LV5FU2-aflibercept combination in a randomized phase III trial. Clinical trial information: EudraCT 2014-001837-10.

Long-term results of a phase 2 trial of crenolanib combined with 7+3 chemotherapy in adults with newly diagnosed FLT3 mutant AML.

7007 Background: Crenolanib is a potent type I FLT3 inhibitor active against FLT3- ITD, TKD and variant mutations. We report the long-term outcomes of a phase II trial evaluating crenolanib combination therapy in patients (pts) with newly diagnosed FLT3 mutant AML. Methods: Pts (≥ 18 yrs) with newly diagnosed FLT3-AML received 7+3 induction with cytarabine 100 mg/m2/d for 7 days and daunorubicin (DNR) (&lt;60 yrs: 90 mg/m2; ≥60 yrs: 60 mg/m2) or idarubicin (IDA 12 mg/m2) for 3 days. Crenolanib 100 mg TID was administered starting on day 9 until 72 hrs prior to next chemotherapy. Re-induction was allowed. Up to 4 cycles of HiDAC consolidation (&lt;60 yrs: 3 g/m2; ≥60 yrs: 1g/m2) was allowed. Eligible pts could proceed to transplant. Crenolanib maintenance therapy was offered for 1 yr after HiDAC or transplant. Results: 44 pts (22 male) with a median age of 57 yrs (range 19-75) were treated; 15 (34%) pts were &gt;60 yrs. 7 pts had initial WBC &gt;100,000/μL (2 had WBC &gt;200,000). 4 pts had AML following MDS/MPN. 39 (89%) pts had intermediate risk cytogenetics, 3 (7%) had adverse risk, and 2 were unavailable. 33 (75%) pts had FLT3-ITD, 8 (18%) had TKD, and 3 (7%) had ITD and TKD mutations. 11 pts had concomitant NPM1/ DNMT3A mutations, 11 pts had secondary AML-type mutations, and 2 pts had TP53. 28 pts received DNR/crenolanib; 16 pts received IDA/crenolanib. Overall CRc (CR + CRi) was 73% (32/44) after one induction cycle; 86% (38/44) after two cycles. CRc rates &gt; 80% were noted in pts ≤ 60 yo, FLT3-ITD mutations, concomitant FLT3/DMT3A/NPM1 mutations, intermediate risk cytogenetics, and WBC ≥ 100,000/µL. Median time to count recovery was 30 days. MRD-negative CRc was achieved in 94% of evaluable pts (17); 22 pts underwent HSCT. The most common treatment related adverse events (AE) were diarrhea (66%), nausea (57%) and febrile neutropenia (52%). Grade ≥3 AE included febrile neutropenia (50% pts), diarrhea (18%), nausea (6%), and rash (6%). No QTC prolongation was observed. 6 pts required crenolanib dose reduction during induction. High levels of serum crenolanib were achieved and maintained throughout therapy. With a median follow-up of 45 mos (4.4-54.9), the median OS for all pts has not been reached with 57% of pts alive. Median EFS for all pts was 45 mos. In younger pts (≤ 60 yo) OS was 69% and EFS 62%. Cumulative incidence of relapse was 15%. In older pts (61-75), 80% achieved CR/CRi, and median OS was 20 mos. Mutational analysis demonstrated clearance of multiple variant FLT3 mutations and no new FLT3 clones at relapse in pts completing protocol therapy. Conclusions: Long-term outcomes of a phase 2 trial of crenolanib combined with 7+3 induction and consolidation in adults with newly diagnosed FLT3 mutant AML demonstrate high response rates (CRc 86%). With a median follow-up of 45 mos, median OS has not been reached. A phase 3 trial (NCT03258931) randomizing pts with newly diagnosed FLT3 mutant AML to crenolanib vs midostaurin with 7+3 is ongoing. Clinical trial information: NCT02283177.

An observational study of dose-optimization for fruquintinib in elderly patients (pts) with metastatic colorectal cancer (mCRC) who had failed standard therapy.

e15560 Background: As one of the third-line standard treatment regimens for advanced colorectal cancer, fruquintinib is widely used in clinical practice, but there are limited data on safety and efficacy of fruquintinib in elderly pts. Multiple studies have shown improved tolerability, reduced grade 3-4 adverse events, and comparable efficacy in pts treated with regorafenib through a first-cycle flexible dose optimization regimen. This method of drug administration is more practical especially in elderly pts, and is worthy of clinical adoption. This observational study aims to investigate the safety, tolerability, and efficacy of a dose-optimized regimen of fruquintinib in elderly mCRC pts who had failed previous standard therapy. Methods: Pts ≥65 years with mCRC refractory to fluoropyrimidine-based chemotherapy ± anti-VEGF/EGFR were enrolled. The primary endpoint was progression-free survival (PFS) (RECIST v1.1). All pts were administered with fruquintinib 3mg (po, qd) for one week. If tolerable, fruquintinib 4mg would be administered in the second week. In the third week, fruquintinib 5mg would be administered if 4mg is tolerable, followed by a week’s rest. The maximum tolerated dose (MTD) of fruquintinib confirmed in the first cycle would be administered from the second cycle. Adverse events were evaluated using CTCAE 5.0. Results: As of February 9, 2022, 29 pts were identified, with an median age of 69.59 (65-77) years and 16 males (55.2%) included. Of the 29 pts, the MTD was 3mg in 31% (9/29) pts, 4mg in 58.6% (17/29) pts and 5mg in 10.3% (3/29) pts. Among the 24 pts available for efficacy evaluation, 14 had stable disease (SD) and 10 had progressive disease (PD) as the best response. Disease control rate (DCR) of 3mg group, 4mg group and 5mg group were 33.33% (2/6), 68.75% (11/16) and 50.00% (1/2), respectively. At a median 4.93 months follow-up, the median (m) PFS was 3.73 months [95% CI, 2.32-5.14] and the mOS was 7.97 months [95% CI, 5.05-10.89]. In addition, the median PFS of 3mg group and 4mg group were 1.87 months and 3.73 months, respectively. And the median OS of 3mg group and 4mg group was 7.97 months and 11.0 months, respectively. Treatment-related adverse events (TRAEs) were observed in all 29 pts (100%). Common TRAEs (&gt; 40%) included fatigue (79.3%), anorexia (58.6%) and hand-foot syndrome (44.8%). The most common (&gt; 10%) grade≥3TRAEs were hand-foot syndrome (20.7%), hypertension (17.2%) and diarrhea (10.3%). No grade 5 TRAEs were observed. There were no correlations with efficacy, toxicity, and geriatric assessment scores. Conclusions: The dose-optimized strategy of fruquintinib in pts aged ≥ 65 years showed acceptable toxicities and anti-tumor activities consistent with the overall population in FRESCO study. The dose-optimized strategy of fruquintinib is a viable alternative in older pts with mCRC. Clinical trial information: NCT05025631.

Oral azacitidine plus venetoclax in patients with relapsed/refractory or newly diagnosed acute myeloid leukemia: The phase 1b OMNIVERSE trial.

TPS7068 Background: For patients (pts) with acute myeloid leukemia (AML) who cannot undergo intensive chemotherapy (IC), lower-intensity treatment (Tx) regimens, including low-dose cytarabine (LDAC) and hypomethylating agents (HMAs; azacitidine [AZA], decitabine), are generally well tolerated but are associated with lower response rates than IC [Vey 2020]. Similarly, the BCL2 inhibitor, venetoclax (VEN), has shown antileukemic activity, although only modest clinical benefit as monotherapy [Konopleva 2016]. VEN + AZA shows synergistic activity in preclinical models, enhancing leukemic cell apoptosis in vitro and anti-tumor activity in vivo [Jin 2020]. In IC-ineligible pts with ND AML, VEN + injectable AZA significantly increased complete remission (CR)/CR with incomplete hematologic recovery (CRi) rates ( P &lt; 0.001) and prolonged overall survival (OS; P &lt; 0.001) vs AZA only [DiNardo 2020]. VEN, in combination with an HMA or LDAC, is approved in the US for Tx of pts with ND AML ≥ 75 years (y) of age or who cannot undergo IC due to comorbidities. Oral-AZA (CC-486) is approved for Tx of pts with newly diagnosed (ND) AML in first CR or CRi after IC who cannot receive curative therapy (eg, HSCT). In the phase 3 QUAZAR AML-001 trial, maintenance Tx with Oral-AZA 300 mg QD for 14 days (d)/28-d Tx cycle improved OS and relapse-free survival vs placebo in older pts in CR/CRi after IC [Wei 2020]. Incorporation of AZA into DNA is S-phase-restricted; thus, extending AZA exposure over a longer duration by using an oral formulation increases the opportunity for cycling tumor cells to incorporate the drug to sustain therapeutic activity [Laille 2015]. Additionally, an all-oral combination regimen allows for outpatient administration to optimize pt convenience and reduce resource utilization. Methods: OMNIVERSE (NCT04887857) is an open-label, multicenter, 2-part phase 1b trial. The main goals are to evaluate safety and establish the maximum tolerated dose of Oral-AZA + VEN in pts ≥ 18 y of age with relapsed/refractory AML who are ineligible for further IC ( part 1), and subsequently, in pts with ND AML ≥ 75 y of age, or pts 18–74 y of age with comorbidities that prevent use of IC or HSCT ( part 2). Key eligibility criteria include ECOG performance status of 0–2 (ECOG 3 is allowed for pts 18–74 y of age with comorbidities) and unfavorable-risk cytogenetics for pts with ND AML. The Oral-AZA starting dose is 300 mg QD × 14 d/28-d cycle, which can be de-escalated to 200 mg QD × 14 d depending on dose-limiting toxicities; oral VEN 400 mg QD is taken continuously (or 21 d/cycle for dose level −2). A modified toxicity probability interval-2 design is used to evaluate dose levels. Sample size depends on the dose levels utilized (≤ 18 pts/part). Enrollment began in 2021. The trial is ongoing at clinical sites in the United States and Australia. Clinical trial information: NCT04887857.

Health-related quality of life (HRQoL) with enasidenib versus conventional care regimens in older patients with late-stage mutant-IDH2 relapsed or refractory acute myeloid leukemia (R/R AML).

7032 Background: Enasidenib (ENA) is an oral inhibitor of mutant-IDH2 (mIDH2) proteins. In the phase 3 IDHENTIFY trial, ENA improved event-free survival (EFS), overall response, and complete remission rate vs conventional care regimens (CCR) ( P &lt; 0.01 for all) in patients (pts) ≥ 60 years of age with m IDH2 R/R AML with 2 or 3 prior treatments (Tx) (DiNardo 2021). Pt-reported HRQoL was a secondary trial endpoint. Methods: IDHENTIFY is an open-label, randomized trial (NCT02577406). Pts were preselected to a CCR (SC azacitidine, intermediate- or low-dose Ara-C, or supportive care) and then randomized 1:1 to ENA 100 mg/d or CCR in 28-d cycles. Key HRQoL endpoints were mean changes from baseline (CFB) overall and by clinical response in the Global Health Status/QoL, Physical Functioning, Role Functioning, Fatigue, and Dyspnea domains of the EORTC QLQ-C30 questionnaire, and in EQ-5D-5L utility index (UI) and visual analogue scale scores. The QLQ-C30 and EQ-5D-5L were assessed on D1 of each Tx cycle (C) and at end of Tx. Minimally important differences (MIDs) in CFB scores within or between Tx arms were based on accepted thresholds. Sensitivity analysis using imputed data on CFB was conducted using pattern mixture modeling. Results: HRQoL-evaluable cohorts included 118/158 (74.7%) pts in the ENA arm and 80/161 (49.7%) in the CCR arm; 40 ENA pts and 81 CCR pts were not evaluable due to missing data at baseline (BL; 22 ENA and 51 CCR) and/or at ≥1 post-BL visit (26 ENA and 69 CCR). Pts ineligible for HRQoL analyses had lower response rates and worse EFS and overall survival than HRQoL-evaluable pts. Overall QLQ-C30 completion rates in the ENA and CCR arms were 79% and 65%, respectively ( P &lt; 0.001). While there was no meaningful improvement or worsening from BL (ie, exceeding MID) within either Tx arm in the key QLQ-C30 domains, scores worsened during initial Tx cycles and then improved with continued Tx. Mean EQ-5D-5L scores also worsened during early cycles in both Tx arms, with meaningful UI deterioration in the ENA arm from C2 through C7. However, between-group comparisons showed no consistent differences between ENA and CCR in mean CFB. Sensitivity analysis with imputation of missing CFB data showed worsened HRQoL compared with non-imputed data in the CCR arm but not with ENA. In the ENA arm, clinical responders reported relatively stable mean HRQoL scores over time, and non-responders showed no meaningful differences in CFB vs the CCR arm. Conclusions: HRQoL measures tended to worsen during early cycles in both Tx arms and gradually improved with continued Tx. Data should be interpreted with caution as only approximately one-half of pts in the CCR arm were HRQoL-evaluable. ENA improved clinical efficacy measures vs CCR without compromising HRQoL in older pts with R/R AML. Clinical trial information: NCT02577406.

Evaluation of inpatient chemotherapy among patients with cancer.

6566 Background: Administration of inpatient chemotherapy (IC) is associated with more aggressive end of life care, reduced use of palliative care (PC) and decreased quality of life (QOL). This study aims to identify risk factors associated with overutilization of IC. Methods: We conducted a retrospective chart review of all admissions where IC was administered at an academic center between January 2016 and December 2017. Patients (pts) were stratified by solid tumors (ST) versus hematologic malignancies (HM) and urgency for IC was assessed. We evaluated other variables which can impact patient care such as length of stay (LOS), reason for admission and for IC. Descriptive statistics and odds ratios (OR) were estimated from logistic regression models with mixed-effect taking into account correlations from multiple admissions per patient. All tests were two-sided and statistical significance was considered when p&lt;.05. Results: We analyzed 880 admissions (17% ST). Table 1 summarizes outcomes. HM pts required frequent direct admission for IC compared to ST. ST pts (p&lt;.0001), pts &gt;65 years (p=0.004) and pts with KPS ≤50% (p&lt;.0001) were most likely admitted for cancer complications rather than for IC. LOS (&gt;7 days) was significantly longer in HM admissions (p=0.0001), among pts with stage 4 cancer (p=0.014) and KPS ≤50% (p=0.0001). ST (p=0.006) and pts with KPS ≤50% (p=0.0001) received IC for a non-urgent indication significantly more often than HM. In 20% of ST admissions, pts received IC because the admission coincided with a non-urgent planned cycle compared to 3% of HM. In the adjusted analysis, tumor type was the most important factor correlated with urgency of IC (OR 0.42, 95% CI: 0.25-0.72; p=0.001). ST pts (p=0.0001), older pts (p=0.004) and pts with KPS ≤50% (p=0.0001) were less likely to respond to chemotherapy. Only 15% of HM admissions and 46% of ST admissions had a PC consult. 60-day mortality was significantly higher in ST pts than HM (p=0.002). Conclusions: IC is associated with poorer outcomes for pts with advanced stage ST, pts with poor functional status and pts admitted for acute indications. Additionally, ST pts have a higher mortality after IC compared to HM. Utilization of IC should be standardized to account for different patient characteristics and to reduce the incidence of non-urgent administration. Based on this data, we created a standardized protocol to better assess the appropriateness of IC to improve patient care, QOL, and reduce chemotherapy and healthcare utilization at the end of life. [Table: see text]

Overall survival by IDH2 mutant allele (R140 or R172) in patients with late-stage mutant-IDH2 relapsed or refractory acute myeloid leukemia treated with enasidenib or conventional care regimens in the phase 3 IDHENTIFY trial.

7005 Background: IDH2 gene mutations (m IDH2) occur in up to ̃20% of patients (pts) with acute myeloid leukemia (AML), most commonly as R140Q (in ̃75% of cases) or R172K (̃25%) point mutations. The functional effects and prognostic relevance of m IDH2-R140 and m IDH2-R172 can vary (Papaemmanuil 2016). In the randomized, phase 3 IDHENTIFY trial, enasidenib (ENA), an oral mIDH2 inhibitor, did not significantly improve overall survival (OS) vs conventional care regimens (CCR) as salvage treatment (Tx) for older pts with m IDH2 relapsed/refractory (R/R) AML in ITT analysis, but a trend for improved OS with ENA was detected in pts with IDH2-R172 mutations. We further investigated OS and correlative biomarkers in IDHENTIFY pt subgroups defined by m IDH2 variant (R140/R172). Methods: This open-label trial (NCT02577406) enrolled pts ≥ 60 years of age who had received 2 or 3 prior AML Tx. Pts were preselected to a CCR (azacitidine, intermediate- or low-dose Ara-C, or supportive care), and were then randomized 1:1 to ENA 100 mg/d or CCR in 28d cycles. Co-occurring gene mutations were identified by targeted next-generation sequencing (37-gene panel) of bone marrow mononuclear cell (BMMC) DNA. Total 2-HG levels were determined by LC/MS. Results: Of 319 pts enrolled, 88 pts (28%; 43 ENA, 45 CCR) had m IDH2-R172 and 229 (72%; 115 ENA, 114 CCR) had m IDH2-R140. Median baseline (BL) 2-HG levels were similar between Tx arms and m IDH2 variant subgroups, as were IDH2 variant allele frequencies. Pts with m IDH2-R172 had fewer median BL co-mutations (4 [range 2–8]) than did pts with m IDH2-R140 (5 [1–11]) ( P &lt; 0.0001). The most frequently co-occurring mutations were SRSF2 and RUNX1 in the R140 cohort (59% each) and DNMT3A in the R172 cohort (57%). Compared with the R172 cohort, the R140 group was enriched with SRSF2, FLT3 (-ITD/-TKD), NPM1, RUNX1, and JAK2 mutations, whereas DNMT3A and TP53 mutations were more common in the R172 group. In Cox multivariate analysis including m IDH2 variant (R140/R172), DNMT3A mutation status, and number of gene mutations at BL, m IDH2-R172 was significantly ( P = 0.04) correlated with improved OS (vs. R140) in the ENA arm, whereas the number of BL gene mutations was significantly ( P &lt; 0.01) associated with OS in the CCR arm. Median OS in the R172 subgroup was 14.6 mo with ENA vs 7.8 mo with CCR (HR, 0.59 [95%CI 0.35-0.98]; P = 0.039) and 1-yr survival rates were 62% and 30%, respectively. In m IDH2-R140 pts, median OS was 5.7 mo in both Tx arms (0.93 [0.70-1.24]; P = 0.61), and 1-year survival rates were 29% and 25% with ENA and CCR, respectively. Conclusions: Mutational burden and co-mutational profiles differed between pts with m IDH2-R140 and m IDH2-R172 R/R AML. ENA improved survival outcomes for pts with IDH2-R172 mutations, with median OS and 1-year survival rate approximately double those in the CCR arm. Clinical trial information: NCT02577406.

Age-associated differences in transcriptional expression and tumor immune microenvironment composition among older patients with cancer.

2633 Background: Older patients (pts) with cancer are underrepresented in registrational clinical trials for immune checkpoint inhibitor (ICI) therapies. There may be relevant differences in the makeup of the tumor microenvironment (TME) and in genomic signatures of cancer in older pts. This analysis explores differences in the genomic makeup of common cancers and their TME in pts ≥ 80 years (yr) of age, compared to younger pts. Methods: Next-generation sequencing of DNA (592 gene panel, NextSeq or whole-exome sequencing, NovaSeq) and RNA (whole transcriptome sequencing, NovaSeq) was performed for non-small cell lung carcinoma (NSCLC; n = 19,891), melanoma (MEL n = 2,899), and renal cell carcinoma (RCC; n = 1,333) pt samples submitted to a CLIA-certified laboratory (Caris Life Sciences, Phoenix, AZ). PD-L1 expression was assessed by immunohistochemistry (IHC), and high tumor mutational burden (TMB-H) was defined as ≥10 mut/Mb. Pts were stratified into age subgroups of ≥80 and &lt; 80 yr for comparison of DNA damage response (DDR) gene alterations, gene expression profiling, and TME analysis (MCP-counter; Becht, 2016). P-values were adjusted for multiple hypotheses testing (Benjamini-Hochberg) unless noted as exploratory. Results: Pts ≥80 yr accounted for 16.0%, 19.9% and 5.3% of NSCLC, MEL and RCC pts, respectively. Compared to pts &lt; 80 yr, NSCLC and MEL pts ≥80 yr had similar DDR gene mutation rates, while BRCA1 mutations were more common in MEL pts ≥80 yr (2.1 vs 0.8%; exploratory- p &lt; 0.05). NSCLC ≥80 yr TMEs had increased abundance of fibroblasts (1.09-fold, p &lt; 0.01), dendritic cells (1.07-fold, p &lt; 0.01) and macrophages (1.04-fold, p &lt; 0.01), and MEL≥80 yr TMEs had fewer infiltrating T-lymphocytes (0.87-fold, p = 0.02). Increased expression of immune checkpoint (IC) genes PDCDL1G2 (PD-L2; 1.11-fold), HAVCR2 (TIM-3; 1.11-fold ), and CD80/86 (1.07/1.08-fold, p &lt; 0.05) was seen in NSCLC pts ≥80 yr, while IL-6 expression was decreased (0.88-fold; p &lt; 0.05). The largest change in IC gene expression was for IL-6 (1.24-fold, p = 0.78) in MEL, and GZMB (0.56-fold ; p = 0.17) in RCC ≥80 yr. TMB-H was less common in NSCLC (29.7 vs 36.5%, p &lt; 0.001) and more common in MEL pts ≥80 yr (65.7 vs 49.0%, p &lt; 0.01), and PD-L1 (IHC-SP142, ≥2+|5%) expression was less frequent in RCC pts ≥80 yr (9.1 vs 19.4%, exploratory p &lt; 0.05). Profiling of glutamine and glucose metabolism-related genes revealed increased SLC38A5 (1.17-fold; p &lt; 0.0001) and decreased G6PC (0.65-fold, p &lt; 0.01) expression in NSCLC ≥80 yr. While not statistically significant, MEL and RCC pts ≥80 yr had opposite trends for SLC38A5 and G6PC expression. Conclusions: Our analysis provides new insights to immune landscape of NSCLC, MEL, and RCC pts ≥80 yr. Differential gene expression and TME composition changes in this population suggest unique, cancer-specific therapeutic opportunities, and a potential to explore biomarkers of response to ICIs.