Maintenance Cohort Research Articles

Mirikizumab Sustained Impact on Fatigue in Patients with Moderately to Severely Active Crohn's Disease in the Phase 2 AMAG Study.

Fatigue is a burdensome,under-recognized, multidimensional symptom experienced by patients with Crohn's disease (CD). We evaluated the impact of mirikizumab on fatigue and the association between changes in select patient-reported outcomes and clinical measures with changes in fatigue from baseline to week 104 (W104). Patients (N = 191) were randomized (2:1:1:2) to receive placebo (PBO), 200mg, 600mg, or 1000mg of mirikizumab, administered intravenously (IV) every 4 weeks at W0, W4, and W8. Patients who achieved ≥1 point improvement in Simple Endoscopic Score for Crohn's Disease (SES-CD) and received mirikizumab at W12 (rerandomized maintenance cohort) were rerandomized to continue induction IV treatment assignment (IV-C) or received 300mg of mirikizumab subcutaneously (SC) until W52. Nonrandomized maintenance cohort had endoscopic nonimprovers (1000mg) and PBO patients (PBO/1000mg) who received 1000mg of mirikizumab until W52. Subjects from the maintenance period with clinical benefit received 300mg SC Q4W from W52 to W104. The Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) questionnaire was used to assess fatigue, and the FACIT-F associations were assessed using Pearson correlation coefficient. At W12, mirikizumab groups reported improved FACIT-F scores compared with PBO, and improvement was maintained through W52 and W104. Changes in FACIT-F at W52 and W104 had strong correlations with changes at the same time point in quality of life (QoL) scores but lacked correlations with changes in inflammatory biomarkers. Mirikizumab treatment significantly improved fatigue in patients with moderately to severely active CD, which was sustained to W104. The improvement in fatigue was correlated with improvement in clinical measures and was strongly correlated with improvement in QoL.

Catheter ablation of atrial arrhythmias in cardiac amyloidosis: Impact on heart failure and mortality.

Atrial arrhythmias (AA) commonly affect patients with cardiac amyloidosis (CA) and are a contributing risk factor for the development of heart failure (HF). This study sought to investigate the long-term efficacy and impact of catheter ablation on HF progression in patients with CA and AA. Thirty-one patients with CA and AA undergoing catheter ablation were retrospectively included (transthyretin-ATTR CA 61% and light chain-AL CA 39%). AA subtypes included atrial fibrillation (AFib) in 22 (paroxysmal in 10 and persistent in 12), atrial flutter (AFl) in 17 and atrial tachycardia (AT) in 11 patients. Long-term AA recurrence rates were evaluated along with the impact of sinus rhythm (SR) maintenance on HF and mortality. AA recurrence was observed in 14 patients (45%) at a median of 3.5 months (AFib n = 8, AT n = 6, AFl = 0). Post-cardioversion, medical therapy or catheter ablation, 10 patients (32%) remained in permanent AA. Over a median follow-up of 19 months, all-cause mortality was 39% (n = 12): 3 with end-stage HF, 5 due to late complications of CA, 1 sudden cardiac death, 1 stroke, 1 COVID 19 (and one unknown). With maintenance of SR following catheter ablation, significant reductions in serum creatinine and natriuretic peptide levels were observed with improvements in NYHA class. Two patients required hospitalization for HF in the SR maintenance cohort compared to 5 patients in the AA recurrence cohort (p = 0.1). All 3 patients with deaths secondary to HF had AA recurrence compared to 11 out of the 28 patients whom were long-term survivors or deaths not related to HF (p = 0.04). All-cause mortality was not associated with AA recurrence. This study demonstrates moderate long-term efficacy of SR maintenance with catheter ablation for AA in patients with CA. Improvements in clinical and biological status with positive trends in HF mortality are observed if SR can be maintained.

Comparison of Methotrexate Maintenance Versus Autologous Stem Cell Transplant Consolidation after High-Dose Methotrexate-Based Induction Therapy in Primary Central Nervous System Lymphoma

Background: Primary central nervous system lymphoma (PCNSL) is a rare form of non-Hodgkin lymphoma with historically poor outcomes. Induction therapy with high-dose methotrexate (HD-MTX)-based regimens followed by consolidation with autologous stem cell transplant (auto-SCT) has become the mainstay of treatment with overall response rates (ORR) of 69-87% and two-year overall survival (OS) of 66-70% reported in prospective clinical trials. Limited data are available regarding a maintenance approach with single-agent HD-MTX, particularly in patients who are not auto-SCT candidates. Herein, we describe a comparison of outcomes in patients with PCNSL who underwent HD-MTX-based induction followed by either HD-MTX maintenance or auto-SCT consolidation at Mayo Clinic, Rochester. Methods: Patients with a diagnosis of PCNSL who received HD-MTX as part of induction therapy at Mayo Clinic between October 2010 and June 2022 were identified. Patients with prior or concurrent diagnosis of systemic lymphoma were excluded. Primary endpoints were progression-free survival (PFS) defined as time from post-induction treatment initiation to relapse, progression, or death due to any cause; and OS defined as time from post-induction treatment initiation to death due to any cause. We compared baseline characteristics by post-induction therapy using descriptive statistics. The primary endpoints PFS and OS were evaluated using Kaplan-Meier curves and compared by risk scores using a log-rank test. Results: A total of 148 patients were identified (51% female, 95% white) with median age at diagnosis of 66 years (range 29-85), with 48 patients (32%) age > 70. Most patients had multifocal disease (n=89, 60%) and deep brain involvement (n=100, 70%) at diagnosis. Few had vitreoretinal (n=15, 10%) or CSF involvement (n=9, 6%) at diagnosis. Using the Memorial Sloan Kettering (MSKCC) prognostic score for PCNSL, 35 patients (26%) scored class 3 (poor prognosis), 85 (62%) scored class 2, and 17 (12%) scored class 1. In total, 117 patients (79%) received methotrexate, rituximab, and temozolomide (MRT) induction therapy, and the remaining 31 patients (21%) received methotrexate and rituximab (MR) induction therapy (Table 1). A total of 70 patients (47%) underwent consolidation with auto-SCT and 37 patients (25%) received maintenance methotrexate. The patients who received maintenance methotrexate had higher median age of 72 versus 62 years, higher proportion of patients older than 70 (54% versus 16%, p<0.001), higher proportion of MSKCC prognostic score class 3 patients (33% versus 17%, p=0.026), and trend towards higher proportion of patients ECOG 2 or higher (41% versus 29%, p=0.109). A higher proportion of patients who underwent auto-SCT received MRT (vs MR) induction (n=64, 91%) compared to those who received maintenance methotrexate (n=24, 65%, p=0.004) (Table 1). The median follow-up for all patients was 4.5 years. At 1-, 3-, and 5-years post-induction treatment initiation, the PFS in the auto-SCT cohort was 85.8% (95% CI 77.7-94.9), 81.0% (95% CI 72.0-91.0), and 74.6% (95% CI 63.3-87.9), respectively; and the PFS in the HD-MTX maintenance cohort was 88.6% (95% CI 78.7-99.8), 72.6% (95% CI 58.8-89.8), and 72.6% (95% CI 58.8-89.8), respectively. At the same time points, the OS in the auto-SCT cohort was 94.0% (95% CI 88.4-99.9), 81.3% (95% CI 71.8-92.0), and 76.0% (95% CI 65.0-89.0), respectively; and the OS in the HD-MTX maintenance cohort was 94.3% (95% CI 86.9-100.0), 87.5% (76.8-99.8%), and 82.4% (69.0-98.4), respectively. Overall, there was no significant difference in PFS (p=0.64) or OS (p=0.95) based on post-induction treatment (Figure 1). Conclusions: Our study demonstrates comparable outcomes in PCNSL between a post-induction treatment approach with maintenance HD-MTX and consolidation auto-SCT, even though baseline characteristics indicate that patients who went on to receive auto-SCT were younger and had overall better performance status. This suggests that maintenance HD-MTX is a reasonable, time-limited strategy for patients with PCNSL responding to initial induction therapy, particularly in patients who are not candidates for auto-SCT.

Olutasidenib for the Treatment of mIDH1 Acute Myeloid Leukemia in Patients Relapsed or Refractory to Hematopoietic Stem Cell Transplant, Prior mIDH1 Inhibitor, or Venetoclax

Introduction. Olutasidenib is a small molecule, oral, mutated-IDH1 (mIDH1) inhibitor approved for the treatment of relapsed/refractory (R/R) acute myeloid leukemia (AML). In the pivotal cohort of the registrational phase 1/2 trial, 51/147 (35%) patients achieved a complete remission (CR) or CR with partial hematologic recovery (CRh) to olutasidenib, with a duration of response of 25.9 months and an overall response rate (ORR) of 48%. The phase 1/2 study included 10 cohorts for a total of 335 patients, and there were patient subsets that were R/R to previous hematopoietic stem cell transplant (HSCT), ivosidenib (IVO) or venetoclax (VEN). We conducted post hoc analyses to better understand the response to olutasidenib in these poor-prognosis subgroups of mIDH1 AML. Methods. This Phase 1/2, open-label, multi-center study enrolled patients with confirmed AML or intermediate, high-, or very high-risk myelodysplastic syndromes/neoplasms (MDS). Patients received olutasidenib 100mg QD, 150mg QD or 150mg BID monotherapy or the combination of olutasidenib 150mg BID plus azacitidine. Patients were grouped by prior therapy. Baseline demographics and disease characteristics are shown in Table 1. The study was not powered to statistically evaluate subpopulations; descriptive statistics are provided. Data cutoff date is June 2021. Results. The post-HSCT group (n=31) had a relatively high median baseline bone marrow blast count (58%) and a median of 4 prior treatment regimens ( Table 1). Six (19%) of these patients had a CR (including the 1 patient with MDS), and 3 (10%) patients had a CR with incomplete count recovery (CRi) resulting in a 29% composite complete remission (CRc) rate. One patient had a morphologic leukemia-free status, resulting in a 32% ORR. Half the responders received monotherapy, and half received a combination of olutasidenib and azacitidine. Two patients were enrolled in the monotherapy maintenance cohort while in CR to prior HSCT; one of these patients maintained a CR for 13 months before progressing, and the other patient progressed and discontinued due to a new central nervous system disease ( Table 2). For the 10 patients with responses (ORR), the median duration of response was 7.1 months (range 1-23.4+). At data cutoff, 2 patients were ongoing responders, 3 patients proceeded to a second HSCT, and 3 to donor lymphocyte infusion (DLI). The post-IVO group (n=9) had a high median baseline bone marrow blast count (83%) and a median of 4 prior treatment regimens ( Table 1). Two patients (22%) achieved a CR; both CRc and ORR were 22% ( Table 2). Both responders had received olutasidenib in combination with azacitidine. One responder proceeded to HSCT after 3.1 months, and one responded for 5.6 months and then had disease progression. Response rates in the post-VEN group (n=20) included CR in 6 patients (30%), CRh in 1 (5%), and CRi in 2 (10%) resulting in a CRc of 9 (45%) and an ORR of 45% ( Tables 1 and 2). One responder received combination olutasidenib and azacitidine. Two patients were enrolled in the monotherapy maintenance cohort while in CRi to prior treatment; both improved their response to a CR. Median duration of response was not reached and ongoing at 28.5 months. At data cutoff, 5 patients continued treatment, and 15 had discontinued. Conclusions. This descriptive analysis suggests that olutasidenib alone or in combination with azacitidine may induce complete remissions in patients with mIDH1 AML or MDS that is R/R to VEN, IVO or even HSCT. Further investigation of these difficult-to-treat subpopulations is needed. Although only a small number of patients receiving maintenance therapy were included in this analysis, the data show that maintenance of a CR and even improvement of response from CRi to CR is possible with olutasidenib.

Lenalidomide Maintenance in Multiple Myeloma: A Retrospective, Nationwide, Real-World Study

Introduction: Lenalidomide maintenance (LM) has shown progression-free (PFS) and overall survival (OS) benefit in clinical trials and is the recommended standard of care in patients with newly diagnosed multiple myeloma (MM) after high-dose melphalan and autologous stem cell transplantation (HDM-ASCT). In Denmark, LM has been approved for all patients treated with HDM-ASCT since June 2019 and is publicly funded. That LM was made available nationwide simultaneous across all regions creates a unique opportunity to study the real-world use pattern, efficacy, and adverse effects of LM in an unselected, population-based cohort without referral bias. Methods: Patients with newly diagnosed MM treated with their first HDM-ASCT between June 2019 and March 2022 were included and followed until data cut-off in June 2023. To compare outcomes, a historical pre-LM cohort from the Danish MM Registry, consisting of MM patients treated with HDM-ASCT between June 2015 and June 2019, was used. Baseline clinical characteristics were acquired from the Danish MM Registry. To avoid the risk of guarantee-time bias, several strategies were applied. Early discontinuation of LM was studied using landmark analysis at 6 months after initiation of LM. For comparison with the pre-LM cohort, survival time was calculated from date of ASCT to progression or death for PFS and death of any cause for OS. Cox proportional hazards regression was used to calculate hazard ratios. Multivariate adjustment was made for age and sex as well as known risk factors for worse outcome: ISS and high-risk cytogenetics. Results: Lenalidomide maintenance cohort: Among 364 patients treated with HDM-ASCT after June 2019, 22.3% received consolidation therapy, and 3.7% underwent tandem HDM-ASCT. During follow-up, 297 patients (81.6%) initiated maintenance therapy, with 277 (76.1%) receiving LM. Overall, 145 patients (52.3%) discontinued LM most commonly due to toxicity 75 (51.7%), with fatigue (30.7%), cytopenia (25.3%), and neuropathy (17.3%) being the main reasons. During follow up, 119 (32.7%) patients had an event of progressive disease or death and 38 died. Only 1 death was related to Covid-19. To study the impact of early discontinuation of LM on clinical outcomes a 6-month landmark analysis was conducted. Early discontinuation did not negatively impact PFS, HR 0.92 (95% CI: 0.50, 1.70) or OS, HR 1.12 (0.25, 5.12). Results were similar in a 12-month landmark analysis. Comparison to the pre-lenalidomide maintenance cohort: A cohort of 364 multiple myeloma patients treated before the introduction of lenalidomide maintenance was used as comparison (pre-LM cohort). In that we take advantage of the randomness in being treated for MM in the years before and after the approval of lenalidomide. As the inclusion to either cohort was solely defined by the date of HDM-ASCT baseline characteristics were well balanced as expected with a median age of 61.1 vs 61.8 in the LM cohort and pre-LM cohort, respectively. By chance the dates of inclusion resulted in equal numbers of participants in both cohorts. We confirmed that lenalidomide maintenance was not routinely used before the approval in June 2019 by reviewing the electronic records of all patients treated with HDM-ASCT between January and June 2019. Of these, only 3 (7%) received LM, and in each case, LM was initiated just prior to approval. The LM cohort had similar PFS, HR 0.82 (0.65, 1.04), and OS HR 1.22 (0.78, 1.89) compared to the pre-LM cohort in unadjusted analysis, Figure 1. Results were similar after multivariate adjustment. The 3-year PFS and OS rates in the LM cohort were 61% (95 CI: 55%, 67%) and 86% (95 CI: 82%, 91%), respectively, while the pre-LM cohort had a 3-year PFS of 55% (50%, 60%) and a 3-year OS of 89% (86%, 93%). Conclusion: In this study encompassing all Danish patients with MM treated with HDM-ASCT since the introduction LM, we found that LM was initiated in approximately three out of four patients. One third of patients treated with LM discontinued this treatment within the first year, mainly due to toxicity. Early discontinuation of LM was not associated with worse clinical outcomes. When comparing post-transplantation PFS and OS in two cohorts of patients treated before and after the approval of LM, respectively, we found no differences.

Real-World Immunosuppressant Treatment Patterns for Patients with Lupus Nephritis in the United States.

Lupus nephritis (LN) treatment aims to control and prevent flares and irreversible kidney damage. Around 30% of patients are unresponsive to treatment; however, real-world LN treatment patterns have not been reported. Objectives of this retrospective cohort study (GSK 209758) were to quantify the time to switching/re-initiating induction therapy in patients with LN initiating immunosuppressant therapy and conversion from induction to maintenance immunosuppressant therapy, and to assess corticosteroid use. Patients with LN initiating induction or maintenance immunosuppressant therapy were identified using claims data. Patients were followed up from the index date (immunosuppressant initiation date) until treatment discontinuation, death, disenrollment, administrative censoring, or the end of follow-up period. The cumulative incidence of switching/re-initiating induction therapy and conversion to maintenance therapy was estimated using outpatient pharmacy claims and procedure codes. Corticosteroid use was estimated using pharmacy claims; a mean daily dose of ≥ 7.5mg/day was considered high. In total, 5000 patients with LN contributed 5516 treatment episodes (induction cohort, N = 372; maintenance cohort, N = 5144). In the induction cohort, the cumulative incidence (95% confidence interval) of switching between induction therapies was 24.6% (20.1-30.0) at 12months, while 59.6% (52.4-66.1) of patients converted to maintenance therapy at 12months. In the maintenance cohort, 21.2% (19.9-22.5) re-initiated induction therapy at 12months. Oral corticosteroid use decreased during the follow-up in both cohorts, but 21.5% of patients remained on a high dose at 12months in the induction cohort, while 15.8% in the maintenance cohort were taking a high dose at 24months. Around a quarter of patients with LN initiating immunosuppressant therapy switched within 12months, while a fifth re-initiated induction therapy within 12months. Use of high corticosteroid doses were observed during 24months of follow-up. These data suggest that many patients do not respond to existing standard LN therapies.

Benchmarking Maintenance Therapy Survival in First-Line Platinum-Based Chemotherapy-Treated Patients with Advanced Urothelial Carcinoma Using Simulated Disease Modeling.

First-line (1L) maintenance avelumab prolonged overall survival (OS) in patients with advanced urothelial carcinoma (aUC) in JAVELIN Bladder 100. OS was measured from maintenance initiation in patients with disease control following 1L platinum-based therapy (PBT). The OS impact of maintenance for the 1L PBT-treated population is unknown since it was not measured from 1L initiation, nor can it be benchmarked with other 1L therapies. To characterize the OS impact of maintenance avelumab, we used an oncology simulation model to estimate the OS of maintenance-eligible and -ineligible patients with aUC from 1L PBT initiation. We developed a simulated cohort of 1L PBT-treated patients with aUC, including those who did and did not receive maintenance avelumab. Eligibility was assessed at 5.6 months post 1L PBT initiation based on the JAVELIN trial design. Among the 1L-treated population, 58% (95% credible interval [CrI] 49-67%) were projected to be eligible (calculated from contemporary phase 3 trials); of those, 85% were assumed to receive maintenance. The model estimated median OS (mOS) among a maintenance-ineligible simulated cohort which when combined with the maintenance-eligible cohort yielded an estimated OS in the overall maintenance- intended population from 1L PBT initiation. Approximately half of the modeled 1L PBT-treated population received maintenance. Estimated mOS was 10.1 months (95% CrI 7.5-13.5) for the maintenance-ineligible cohort, 29.3 months (95% CrI 24.8-33.9) for the maintenance-eligible, received maintenance cohort, and 15.9 months (95% CrI 13.2-19.1) in the overall maintenance-intended, 1L PBT-treated population, including those eligible and ineligible for maintenance. The model shows that maintenance avelumab has a modest impact on OS in the overall 1L PBT-treated population of patients with aUC. While maintenance avelumab improves OS for eligible patients, a large proportion of the maintenance-intended population may not receive maintenance due to ineligibility or physician/patient choice.

Hypomethylating Agent Maintenance for Favorable and Intermediate Risk Acute Myeloid Leukemia

Background: Acute myeloid leukemia (AML) is a heterogenous disease with variable outcomes among different risk groups. Favourable risk group AML after consolidation chemotherapy have long-term- leukemia-free survival of 60-70% [1]. Also, many patients in India in the intermediate risk group do not opt for allogenic hematopoietic stem cell transplant due to financial constraints, non-availability of fully matched donors and due to reservations regarding non relapse mortality associated with transplant. Previous studies have shown the value of azacytidine maintenance in prolonging overall survival and relapse free survival in older patients of AML [2]. We conducted this study to assess the results of hypomethylating agents as maintenance in non-adverse risk, younger AML patients who did not receive allogeneic stem cell transplant. Methods: Adults with de-novo AML (>18 years) who received treatment at our centre from January 2021 to December 2021 were included in our retrospective analysis. Induction therapies used were out of these 4 as per physician's choice- 3days x daunorubicin+7 x cytarabine; 2days x daunorubicine + 5 x cytarabine +venetoclax; azacytidine+venetoclax; Fludarabine+Cytarabine+venetoclax. Complete remission was defined as per the ELN 2017 criteria [3]. Measureable residual disease assessment was done by multiparametric flowcytometry or by PCR for patients who had NPM1 mutation or inversion 16. Consolidation chemotherapy comprised of received 3-4 cycles of intermediate dose cytarabine at a dose of 1500mg/m2 twice daily on days 1, 3 and 5. Midostaurin was administered at a dose of 50mg twice daily on day 8 through 21 in FLT3 mutated patients. Patients who were in remission after consolidation therapy received maintenance using hypomethylating agents such as Azacytidine or decitabine alone or in combination (Venetoclax 100mg x 4 days with Voriconazole 200mg twice daily). Midostaurin 50mg twice daily or Sorafenib 200mg twice daily was given if FLT3-ITD/TKD mutated in addition to the hypomethylating agents. Our aim was to asses the tolerability and results of maintenance azacytidine in a non-selected cohort. Results Fifty-three AML patients received induction therapy during the study period and out of which 23 patients went on to receive consolidation with cytarabine. Seven patients were consolidated with allogeneic bone marrow transplant, 7 had refractory AML and 3 were induction deaths, (1) relapsed post consolidation, (1) did not receive maintenance. These were excluded from the analysis. Seventeen patients were lost to follow up after induction. Nineteen patients were started on hypomethylating agent maintenance. Baseline characteristics of the cohort are shown in Table 1. The median consolidation chemotherapy cycles were 3 (range 1-4). The cumulative doses of Daunorubicin used was 261mg (range-170 to345), cytarabine 1078mg (range 840 to 1351) and venetoclax 1200mg (range 600 to 3500mg). Post induction measurable residual disease MRD was positive in 01 out of 16 patients and post consolidation MRD was positive for 03 out of 08 patients. These 3 patients who were MRD positive post consolidation received azacytidine and venetoclax as maintenance. Table 2 showing the distribution of maintenance and the grade ¾ adverse events in patients who were on maintenance. Two patients in the maintenance cohort relapsed belonging to the MRD negative group. Both these patients received salvaged chemotherapies and are awaiting allogenic transplant. Conclusion Azacytidine maintenance is feasible option for preventing relapses in patients with favourable and intermediate risk AML who do not choose bone marrow transplant as consolidative therapy, however further studies are warranted. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Maintenance with Hypomethylating Agents Post-Transplant in Acute Myeloid Leukemia Patients: Safe and Affordable Way to Induce Graft Versus Leukemia Effect

INTRODUCTION Allogenic stem cell transplantation (ASCT) is the only optimistic therapy for poor risk, relapse and/or refractory acute myeloid leukemia (AML) patients for better survival outcome. However, 40% of the patients relapse after ASCT translating into 2-year survival rates below 20% and majority of relapses occurs within 12-18 months of transplant (Devillier, Leukemia & Lymphoma 2013). Hence, it's reasonable to start maintenance therapy as early as possible for such high risk AML. Azacytidine, an hypomethylating agent (HMA) has been shown previously as a potential maintenance drug to be used in post transplant setting (Oran, Blood advances 2020). Recently Keruakous (Hematology/Oncology and Stem Cell Therapy, 2021) had showed that the relapse rate was significantly higher in the control cohort (66.67%) versus in the azacytidine maintenance cohort (25.81%). On the similar concept, we analyzed our AML patients who received maintenance with HMA post transplant. OBJECTIVE To analyze the Relapse free survival (RFS) and overall survival( OS) in AML patients post-transplant with the use of HMA maintenance therapy. METHODS It's a retrospective analysis of AML patients who have undergone ASCT at our centre between May 2020 and April 2022. Maintenance was given to all patients post ASCT irrespective of MRD status post transplant and risk classification pre-transplant. Patients who received maintenance with HMA (either azacytidine@ at 32 mg/m2 daily for 5 days 4 weekly or decitabine @10mg/m2/day for 5 days 6 weekly) and had completed at-least one cycle were included (Oran, Blood advances 2020 and Pusic, Biol of Blood Marrow Transplant 2015). Maintenance was planned for minimum of one year. OS and RFS was calculated by the Kaplan-Meier curves. Events included relapses and deaths. RESULTS Twenty-six patients (AML=24, MDS=1, CMML=1) received maintenance with HMA during the study period. Mean age was 31.5 (14-51) years and 15 (57.69%) patients were male. As per European Leukemia Net (ELN) 2017 classification 5 (19.2%), 12 (46.1%) and 7 (26.9%) patients were categorized into favorable risk, intermediate risk and adverse risk respectively. There were 14 (53.8%) patients in Complete remission (CR1) group, 10 (38.4%) in CR2 group and two(7.6%) were refractory disease. Source of graft was peripheral blood stem cell for all patients. Conditioning regimen was myelo-ablative in 22 (84.6%) patients, whereas 4 (15.3%) patients received reduced intensity. Donors were matched sibling (n=15, 57.69%), haplo-identical (n=6, 23.07%), matched unrelated (n=4, 15.38%) and mismatched unrelated(n=1,3.8%). Azacytidine was started within 100 days of transplant in 22(84.61%) patients. The median of number of cycles of HMA received were 6. The median duration of follow up was 13 months. Seven (26.9%) patients completed 12 cycles. Acute Graft versus host disease (GVHD) was seen in 7 patients (26.9%) involving skin and liver whereas 3 (11.5%) patients had chronic GVHD involving skin and eye. Three (30%) patients developed GVHD prior and 7(70%) developed GVHD post initiation of maintenance. Six (85.7%) patients who relapsed on HMA maintenance had no prior acute or chronic GVHD. Out of all the 7(26.9%) patients who relapsed, 6 patients relapsed within a year and one patient relapsed after a year. One year RFS was 71% (Figure1), Event Free Survival was 67.9% and OS was 81.4% (Figure 2) Only 1 (3.8%) patient had Transplant Related Mortality (TRM), who died of COVID-19 infection. OS at 1 year for those in CR1 and CR2 was 84.6% and 88.9% respectively and it was not statistically significant (P = 0.95). There was no substantial hematological toxicity and resulting drug interruptions during the maintenance. CONCLUSION Early HMA maintenance seems to be an effective strategy post ASCT in AML patients to prevent early relapses and improving overall survival. Development of GVHD for patients on HMA had probably synergistic effect to prevent relapses by mediating graft versus leukemia effect without additional toxicity. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Etrolizumab as induction and maintenance therapy in patients with moderately to severely active Crohn's disease (BERGAMOT): a randomised, placebo-controlled, double-blind, phase 3 trial

Etrolizumab as induction and maintenance therapy in patients with moderately to severely active Crohn's disease (BERGAMOT): a randomised, placebo-controlled, double-blind, phase 3 trial

LBA31 Randomized phase III trial of maintenance chemotherapy with tegafur-uracil versus observation following concurrent chemoradiotherapy for locally advanced cervical cancer, GOTIC-002 LUFT trial

Maintenance chemotherapy with oral tegafur-uracil (UFT) after surgery was shown to prolong survival in lung, breast, gastric and colon cancer. Aim of this trial is to elucidate the efficacy of maintenance chemotherapy using UFT following concurrent chemoradiotherapy (CCRT) for locally advanced cervical cancer. Eligible patients (pts) are those with FIGO (2008) stage Ib2 -IVa cervical cancer, who have squamous cell carcinoma, adenocarcinoma or adenosquamous carcinoma. Pts must have completed curative treatment of CCRT with a response of CR or PR. Pts were randomized to observation only (Arm O) or UFT maintenance cohort (Arm UFT) with 1:1 ratio. Dose of oral UFT was 400 mg /day for pts with body surface area (BSA)≥ 1.25 m2 and 300 mg/day for pts with BSA < 1.25 m2. Pts received UFT for 2 years without interruption unless disease progression or unacceptable toxicities happened. Primary endpoint was PFS and secondary endpoints included OS, safety and QOL. Significant level was 0.05 (one-side). Enrollment started in 2010 and completed in 2018. A total of 351 pts from 55 institutions in Japan were randomized either to Arm O (178 pts) or Arm UFT (173 pts). Safety data was analyzed in 176 pts in Arm O and 168 pts in Arm UFT. Pts characteristics were well balanced between two arms. Most of pts were stage IIb or IIIb, and received CCRT using weekly cisplatin. Median PFS did not reach for both arms. Five-year PFS rates were 61.3% (90%CI: 54.8-67.1) for Arm O and 62.0% (90%CI: 55.4-67.8) for Arm UFT (p=0.634). Hazard ratio (HR) of PFS for Arm UFT vs. Arm O was 0.92 (90%CI: 0.69-1.22). Five-year OS rates were 77.6% (90%CI: 71.8-82.4) for Arm O and 76.1% (90%CI: 70.1-81.1) for Arm UFT (p=0.869). HR of OS for Arm UFT vs. Arm O was 1.04 (90%CI: 0.73-1.47). All grade adverse events (AEs) occurred significantly more in Arm UFT (93.5%) than Arm O (73.9%) (Odds ratio = 5.05, 95%CI: 2.51, 10.15) but most of them were grade 1 or 2. Incidence of AEs ≥ grade 3 were 15.9% in Arm O and 22.6% in Arm UFT. Maintenance chemotherapy using UFT for 2 years after definitive chemoradiation therapy for locally advanced cervical cancer was well tolerated. However, it did not improve either PFS or OS.

Phase I dose escalation and expansion study of defactinib, pembrolizumab, and gemcitabine in patients with advanced treatment-refractory pancreatic cancer.

4146 Background: Targeting focal adhesion kinase (FAK) renders checkpoint immunotherapy effective in pancreatic ductal adenocarcinoma (PDAC) mouse models. Defactinib is a highly potent oral FAK inhibitor shown to have a tolerable safety profile. We evaluated the safety and recommended phase 2 dose (RP2D) of defactinib in combination with pembrolizumab and gemcitabine for PDAC patients. Methods: We conducted a multicenter, open-label, phase I study with dose escalation and expansion phases. In 3x3 dose escalation, patients with refractory solid tumors were treated at five escalating dose levels of defactinib and gemcitabine to identify a RP2D. In expansion phase, patients with metastatic PDAC who progressed on frontline treatment (refractory cohort) or had treatment response or stable disease (SD) on standard gemcitabine/nab-paclitaxel (maintenance cohort) were treated at RP2D. Pre- and post-treatment tumor biopsies were performed to evaluate changes in tumor immunity. Results: The triple drug combination was well-tolerated with no dose-limiting toxicities. Among 17 treated patients with refractory PDAC, the disease control rate (DCR) was 58.8% with one partial response (PR) and nine SDs and the median progression-free survival (PFS) and overall survival (OS) were 4.2 months and 9.1 months, respectively. Among the evaluable patients in the maintenance cohort, DCR was 63.6% with one PR and six SD. Three patients with SD came off study due to treatment- or disease-related complications. The median PFS and OS were 5.0 months and 8.3 months, respectively. Conclusions: The combination of defactinib, pembrolizumab, and gemcitabine was well-tolerated, had promising preliminary efficacy, and showed increased infiltrative T lymphocytes in post-treatment tumor biopsies. Incorporation of a more potent chemotherapy backbone should be considered to achieve better clinical response in future trial design. Clinical trial information: NCT02546531.

Predictors of Unsuccessful Hydroxychloroquine Tapering and Discontinuation: Can We Personalize Decision-Making in Systemic Lupus Erythematosus Treatment?

ObjectiveHydroxychloroquine (HCQ) is a key systemic lupus erythematosus (SLE) drug, making concerns of drug shortages grave. Our objective was to evaluate factors associated with poor outcomes after HCQ taper or discontinuation in SLE.MethodsWe studied 5 Canadian SLE cohorts between 1999 and 2019, following patients from the date of HCQ tapering (cohort 1) or discontinuation (cohort 2). A composite outcome was defined as any of the following: a need for therapy augmentation, an increase (of at least 4 points) in the Systemic Lupus Erythematosus Disease Activity Index 2000 score, or hospitalization for SLE. In each cohort, multivariable Cox regression was used to identify demographic and clinical factors associated with time to the earliest of these events. A third cohort continuing to receive HCQ was also studied, to assess whether the same factors influenced the outcome even when the HCQ dose was unchanged.ResultsThe poor outcome rate, per 100 person‐years, was 35.7 (95% confidence interval [95% CI] 31.6–40.3) in the HCQ taper cohort (n = 398), 29.0 (95% CI 25.5–33.0) in the discontinuation cohort (n = 395), and 16.1 (95% CI 13.2–19.6) in the maintenance cohort (n = 395). In patients tapering HCQ, baseline prednisone use was independently associated with greater risk of poor outcomes. In the discontinuation cohort, the risk of poor outcomes was greater for Black patients and those diagnosed with SLE at age ≤25 years. Among those maintaining HCQ, baseline immunosuppressive use and First Nations ethnicity were associated with poor outcomes.ConclusionWe identified demographic and clinical factors associated with poor outcomes after HCQ taper/discontinuation. This information is critical in the current setting of potential shortages, but over the long term, such information could inform personalized therapies.

A prospective study of switching asthma patients from a Fixed-Dose Combination (FDC) Inhaled Corticosteroid [ICS]/Long-Acting Beta Agonist [LABA] therapy delivered by Dry Powder Inhaler (DPI) to ICS/LABA delivered by pressurised Metered Dose Inhaler (pMDI)

BackgroundPrevious real-world studies have suggested that in comparison to a dry powder inhaler (DPI), the rate of critical errors is lower with a pressurised metered dose inhaler (pMDI), and inhaled corticosteroid/long-acting bronchodilator (ICS/LABA) delivered by pMDI is more likely to achieve asthma control. ObjectivesTo evaluate the acceptability, efficacy, safety and cost-effectiveness of switching asthma patients from an ICS/LABA DPI to an ICS/LABA pMDI in a real-world population in Kuwait. MethodsThis was a 12-month, observational, nonblinded, prospective, real world study. Patients with asthma for ≥1 year with 2 or more asthma exacerbations in the last year were assigned to either switch to ICS/LABA pMDI, or to continue with ICS/LABA DPI. ResultsA total of 239 patients were treated with either ICS/LABA pMDI (Switch cohort; n = 119) or ICS/LABA DPI (Maintenance cohort; n = 120). The majority of patients (99/119; 83.2%) in the Switch cohort remained on ICS/LABA pMDI over 12 months of follow-up. Both cohorts experienced an improvement in their FEV1 levels, with mean values in the Switch group reaching normal levels (>80% predicted). On average, at 3 and 12 months, the Switch cohort had significantly better FEV1 values than patients in the Maintenance cohort (p = 0.001). At 12 months, the proportion of patients with controlled asthma increased in the Switch group, but did not change significantly in the Maintenance group. ConclusionsIn patients with asthma symptoms that are not well controlled with an ICS/LABA DPI, switching to an ICS/LABA pMDI provides an alternative choice that may improve asthma control.

OP07 Exploring disease control by combining clinical, biological, and health-related quality of life remission with endoscopic improvements among Ulcerative Colitis patients treated with filgotinib: A post-hoc analysis from the SELECTION trial

Abstract Background For patients with ulcerative colitis (UC), both subjectively and objectively reported measures are equally important treatment goals. We explored clinical, biological, HRQoL remission and endoscopic improvements as a combined endpoint (CE) from SELECTION (NCT02914522), a phase 2b/3 double-blind trial which assessed the efficacy and safety of filgotinib, a once-daily, oral, Janus 1 kinase preferential inhibitor, for the treatment of UC. Methods In SELECTION, patients with moderately to severely active UC were randomized 2:2:1 to 200mg filgotinib (FIL200), 100mg filgotinib, or placebo (PBO) for an 11-week induction phase followed by a 47-week maintenance period in patients who achieved clinical remission or response.1 We defined a CE as achieving all of the following: 1) clinical remission defined as partial Mayo Score (excluding endoscopy domain) ≤2 and no sub-score &amp;gt;1), 2) biological remission defined as faecal calprotectin &amp;lt;150 µg/g endoscopic improvement defined as Mayo endoscopic sub-score ≤1), 3) Inflammatory Bowel Disease Questionnaire (IBDQ) remission defined as IBDQ &amp;gt;170 and 4) endoscopic improvement defined as Mayo endoscopic sub-score ≤1). We evaluated the CE among patients treated with FIL200 vs placebo in induction (week 10) and maintenance (week 58) phases. Among those achieving the CE, we analysed MCID improvement during induction and decline during maintenance on generic QoL instruments (36-item short-form questionnaire and EuroQol 5-dimension [EQ5D]).2,3,4 Results Overall population included 381 biologic-naïve and 401 biologic-experienced patients undergoing induction, of which 297 subsequently entered maintenance. A higher proportion of patients receiving FIL200 achieved CE than PBO by week 10 in the biologic-naïve induction cohort (17.6% vs 4.41%, p&amp;lt;0.001) and by week 58 in the maintenance cohort (22.1% vs 7.14%, p=0.002) (Table 1). Biologic-naïve CE achievers had higher MCID improvement across all generic QoL scales and domains (Table 2). Patients achieving CE in maintenance experienced a lower proportion of MCID decline in EQ5D utility, and visual analogue scale. Conclusion Treatment with filgotinib resulted in a higher proportion of patients with combined clinical, biological, HRQoL remission and endoscopic improvements. Among patients achieving this combined composite endpoint, clinically meaningful improvements were observed in their overall quality of life. Holistic assessment of several subjective and objective measures may help achieve better outcomes in UC.

Positioning Ozanimod in Ulcerative Colitis: Restoring Leukocyte Traffic Under Control

Positioning Ozanimod in Ulcerative Colitis: Restoring Leukocyte Traffic Under Control

Efficacy and Safety of Mirikizumab in a Randomized Phase 2 Study of Patients With Crohn’s Disease

Mirikizumab is a humanized monoclonal antibody targeting interleukin 23p19 with demonstrated efficacy in psoriasis and ulcerative colitis. We investigated the safety and efficacy of mirikizumab in patients with moderate-to-severe Crohn's disease (CD). Patients (N= 191) were randomized (2:1:1:2) to receive placebo (PBO), 200, 600, or 1000 mg mirikizumab, administered intravenously (IV) every 4 weeks. Patients who received mirikizumab and achieved ≥1 point improvement in Simple Endoscopic Score-CD at Week 12 (rerandomized maintenance cohort) were rerandomized to continue their induction IV treatment (combined IV groups [IV-C]) or receive 300 mg mirikizumab subcutaneously (SC) every 4 weeks. Nonrandomized maintenance cohort included endoscopic nonimprovers (1000 mg) and PBO patients (PBO/1000 mg) who received 1000 mg mirikizumab IV from Week 12. The primary objective was to evaluate superiority of mirikizumab to PBO in inducing endoscopic response (50% reduction from baseline in Simple Endoscopic Score-CD) at Week12. At Week 12, endoscopic response was significantly higher by the predefined 2-sided significance level of 0.1 for all mirikizumab groups compared with PBO (200 mg: 25.8%, 8/31, 95% confidence interval [CI], 10.4-41.2, P= .079; 600 mg: 37.5%, 12/32, 95% CI, 20.7-54.3, P= .003; 1000 mg: 43.8%, 28/64, 95% CI, 31.6-55.9, P < .001; PBO: 10.9 %, 7/64, 95% CI, 3.3-18.6). Endoscopic response at Week 52 was 58.5% (24/41) and58.7% (27/46) in the IV-C and SC groups, respectively. Frequencies of adverse events (AE) in the mirikizumab groupswere similar to PBO. Through Week 52, frequencies oftreatment-emergent AEs were similar across all groups. Frequencies of serious AE and discontinuations due to AE werehigher in the nonrandomized maintenance cohort. Mirikizumab effectively induced endoscopic response after 12 weeks in patients with moderate-to-severe CD and demonstrated durable efficacy to Week 52. A detailed summary can be found in the Video Abstract. ClinicalTrials.gov, Number: NCT02891226.

AML-286: Intentional Azole Antifungals with Azacitidine-Venetoclax Based Combination in AML as an Outpatient Therapy: Experience from a Resource-Limited Setting in India

<h3>Introduction:</h3> Acute myeloid leukemia (AML) primarily warrants intensive induction therapy, followed by consolidation chemotherapy as a curative regimen. However, in elderly (>60 years) and unfit younger patients, less-intense regimens with targeted therapy have been effective. They have proven to be effective regimens for improving overall survival and remission rates while the world battles COVID-19. <h3>Patients and Methods:</h3> A retrospective study, where case files for all patients diagnosed with AML at a tertiary care center from 2016–2021 were reviewed. The study included patients who received a low-intensity regimen for remission induction, either in upfront or relapsed settings. The primary outcome was complete remission (CR) rates. <h3>Results:</h3> The median age of the study cohort (n=55) was 45 years (range: 17–75 years), with >60 years comprising 29%; 44.4% had baseline ECOG performance status of >3, which declined to 16.6% after completion of four cycles. The most commonly encountered subtypes were M2 (42.5%) and AML-not otherwise specified (46.3%), according to FAB and WHO classifications, respectively. Azacitidine was employed in 52.7%, azacitidine and venetoclax (aza-ven) in 32.7%, and low-dose cytarabine in 14.5%. In the aza-ven cohort, patients received itraconazole (n=14/18, 77.7%) and voriconazole (n= 4/18, 22.2%) as azoles. The dose of venetoclax varied from 100 to 200 mg and no ramp-up was used. No patients developed TLS. Patients were initiated with remission induction in an outpatient setting. The complete remission rates (CR+CRi) in the aza-ven cohort were 16.6% and 27.7% in treatment-naive and relapsed/refractory settings, respectively. The time to neutrophil and platelet recovery in those achieving CR were 84 days (range: 28–140 days) and 28 days (range: 28–60 days), respectively. The incidence of febrile neutropenia and fungal infection (probable/possible/proven) were 16.6% and 16%, respectively. In the maintenance cohort, azacitidine was primarily used. Interestingly, MRD+ patients (3/10) attained MRD negativity after two cycles, accounting for 100% remission status (10/10). It bridged the gap, allowing three previously unfit patients to receive intensive chemotherapy and two to receive haploidentical transplants. <h3>Conclusion:</h3> This retrospective study highlights the importance of low-intensity therapy, especially during COVID-19. Aza-ven-azole is a safe and feasible remission induction regimen in patients who are ineligible for intensive induction.

The Survival Impact of Lenalidomide Maintenance Chemotherapy in Multiple Myeloma Patients Treated with Autologous Stem Cell Transplant and Bortezomib-Based Induction: An Analysis of Real World Data

IntroductionMultiple myeloma (MM) represents an incurable plasma cell malignancy. Success in the management of this disease requires a focus on prolonging disease control to positively impact survival. This is the rationale behind maintenance chemotherapy after frontline autologous stem cell transplant (ASCT). Recent large-scale phase 3 randomized trials have shown daily low dose lenalidomide, an oral immunomodulator (IMID), has led to markedly improved progression free survival (PFS) and an evolving benefit on overall survival (OS). We sought to evaluate the effect of lenalidomide maintenance in patients with MM undergoing bortezomib-based induction chemotherapy and ASCT in a real world setting.MethodsRetrospective review of patients with MM undergoing initial bortezomib-based induction chemotherapy and ASCT was completed in patients at our institution. Patients who began therapy up until June 30th, 2015 were included to ensure a minimum of 2-yrs follow-up. Patients were analyzed on an intention-to-treat basis. Maintenance chemotherapy included those on lenalidomide alone or lenalidomide plus bortezomib, the latter being a treatment option at our centre for high-risk patients. OS was measured from the time induction therapy was started until death or last follow-up. PFS was measured from the time of induction therapy initiation to relapse, death or last follow-up. Maximal response to treatment was assessed according to the IMWG consensus criteria although an additional endpoint of near CR (nCR) was included to account for patients where the monoclonal protein on electrophoresis disappeared and light chains normalized but where CR was not confirmed with immunofixation and a bone marrow biopsy was not done.Results198 patients were included in the analysis. 121 received lenalidomide based maintenance and 77 received no maintenance between December 2004 to June 30th, 2015. Median ISS score was 2 in both groups without significant difference between them (p=0.98) . In the maintenance and no maintenance groups respectively 32% and 36% had ISS stage 3 disease. The mean number of maintenance cycles received was 25 cycles (0.5 - 84). Sixty percent of patients required dose reductions or discontinuation due to adverse effects excluding relapse. Most commonly this was due to cytopenias (29.8%), rash (10.7%), infection (9.1%) and fatigue (5.8%). 15% discontinued therapy before relapse occurred. Though venous thromboembolism and second primary malignancies (SPMs) are a worry in patients treated long term with IMIDs these were only seen in 3.3% and 1.7% of patients respectively. Median follow-up in the maintenance group was 44 months and 60 months in the no maintenance group. Survival data is shown in figure 1. The median OS was not reached in the maintenance cohort and was 89 months in the no maintenance group (p = 0.01). Estimated 3-year OS was superior in the maintenance group at 88.4% versus 80.5% in the no maintenance cohort. A statistically significant difference in median PFS was also noted favouring the lenalidomide maintenance (55.0 months versus 32.9 months, p=0.002). Of patients treated with lenalidomide-based maintenance 95.0% achieved ≥ VGPR (53.7% ≥ nCR) while 77.9% (29.1% ≥ nCR) of those who did not receive maintenance therapy achieved these endpoints (p=0.03). Further characterization of therapy for relapsed disease as well as PFS after 1st relapse (2nd PFS) and time to second relapse (PFS2) will be presented at the meeting.ConclusionsOur retrospective analysis of lenalidomide maintenance therapy in MM patients treated with bortezomib-based induction chemotherapy and ASCT illustrates the positive impact lenalidomide has had on both PFS and OS. Patients treated with lenalidomide at our centre experienced a more prolonged and profound remission of their disease. The treatment was well tolerated with no unexpected adverse effects. Rates of thromboembolic disease and SPMs were low. Most importantly, the superior OS in the maintenance arm suggests that second line therapy for those not receiving maintenance could not overcome the negative impact of an earlier relapse. This data supports our ongoing approach incorporating lenalidomide-based maintenance continued until progression for all patients who have undergone an ASCT. Importantly, these real world results validate the phase 3 trial experience, helping to further establish this approach as a standard of care. [Display omitted] DisclosuresBelch:Amgen, Celgene, Takeda: Honoraria.

Real-world evidence costs of allergic rhinitis and allergy immunotherapy in the commercially insured United States population

Objective To assess total and allergic rhinitis (AR)-related healthcare costs among AR patients residing in the United States with a focus on patients persisting with AIT. Methods AR patients were identified in the IBM MarketScan database between 1 January 2014 to 31 March 2017. Patients receiving allergy immunotherapy (AIT) were identified with relevant billing codes (earliest AIT claim = index date); non-AIT patients were identified with claims containing a diagnosis code for AR (earliest AR claim = index date). AIT patients reaching 25+ injection claims were analyzed as a separate maintenance cohort. All patients were required to have continuous enrollment for 12 months preceding and following index. Results A total of 2,334,530 AR patients were included; 103,207 had at least 1 AIT claim, with 45,279 (43.9%) of these patients reaching maintenance, and 24,640 AIT patients (23.9%) never presenting a single injection claim. Compared to non-AIT patients, patients initiating AIT presented higher rates of baseline comorbidities, including asthma (30.1% vs. 7.5%) and conjunctivitis (21.7% vs. 4.4%). During the follow-up period, patients reaching the maintenance phase of AIT incurred lower total costs than the overall AIT cohort ($10,431±$16,606 vs. $11,612±$24,797), and also presented lower follow-up hospitalization costs ($698±$7,248 vs. $1,281±$12,991) and total medical costs ($7950±$13,844 vs. $8989±$22,019). Conclusions Continued efforts are needed to increase patient awareness of available options and adherence to AIT, along with reducing wastage. Despite AIT patients presenting fairly progressed disease at the time of treatment initiation, this therapy remains an economical treatment option, as it was not accompanied by substantial increases in overall healthcare expenditure, and may promote positive societal impacts beyond the direct medical costs. What is known on this topic The prevalence of allergic diseases has increased over the past 50 years and affects between 10–30% of the world population. Allergic rhinitis (AR) poses a significant economic burden in the form of both direct and indirect costs Allergy immunotherapy (AIT) is the only treatment option able to modify the underlying course of the disease. What this study adds Specific all-cause and AR-related healthcare costs decreased following the initiation of AIT among patients diagnosed with AR, with the largest decreases observed among AIT patients reaching the maintenance phase of treatment, while non-AIT patients showed increases in all categories assessed over a similar follow-up period. Cost decreases among AIT patients were observed despite increased levels of comorbidities compared to non-AIT patients, as the AIT cohort presented elevated rates of atopic dermatitis (7.1% vs. 2.7%), conjunctivitis (21.7% vs. 4.4%), asthma (30.1% vs. 7.5%), and chronic sinusitis (22.6% vs. 4.9%). An analysis of patients’ index subcutaneous AIT consultation revealed substantial variability in the initial treatment costs, with nearly 20% of paid amounts exceeding $1,000; given nearly 1 in 4 AIT patients who get AIT mixed never came back for their first injection, this highlights an opportunity to target frontloaded billing practices and the timing of mixing/injection as an area to minimize healthcare waste.