Eligibility For Stem Cell Transplantation Research Articles

Does Socioeconomic Status Have an Impact on Light Chain (AL) Amyloidosis Disease Characteristics and Outcomes?

Background: Evidence suggests that low socioeconomic status leads to unequal access to care and outcomes. This can be particularly problematic for rarer diseases such as light chain (AL) amyloidosis. Using the Area Deprivation Index (ADI) as a proxy for socioeconomic status (SES), we hypothesized that persons living in areas with greater deprivation will exhibit differences in AL disease characteristics at diagnosis and worse post-diagnosis outcomes. Methods: We conducted an IRB-approved, retrospective chart review of patients with systemic AL amyloidosis seen between January 1, 2010 and December 31, 2022 at a large and diverse health system in Milwaukee, Wisconsin. Patients with localized amyloidosis were excluded. Patients were identified using electronic health records. Demographic information (age, sex, race, zip code of residence, insurance, and marital status), disease characteristics (amyloid stage at diagnosis, type, and number of organs involved), and treatment indicators (stem cell transplant eligibility and utilization, time to first chemotherapy) were extracted for all eligible patients. The 2020 Area Deprivation Index (0-100, higher scores equating to higher deprivation) was calculated through the Neighborhood Atlas ® database using zip code and analyzed in quartiles. Spearman correlation was used to describe differences in sociodemographic and clinical characteristics across ADI quartiles and a Cox regression analysis was conducted for overall survival testing the association of ADI controlling for age, sex, race, disease stage, and number of involved organs. A p-value of <0.05 was considered statistically significant. Results: Of the 200 patients with systemic AL amyloidosis who met our inclusion criteria, 8 patients were excluded due to missing/other race. Of the remaining 192 patients which comprised our final cohort, 171 (89%) were White, 21 (11%) were Black. Over half of all patients (51.5%) lived in neighborhoods in the two highest ADI quartiles. Patients in different ADI quartile categories differed significantly by race (Black and White, p<0.001), age at diagnosis (p=0.012), marital status (p<0.001), and Medicaid insurance (p<0.001) (Table 1). Differences in diagnostic and treatment characteristics were not observed across ADI quartiles (Table 1). There were also no differences in overall survival at 1, 5, and 8 years across ADI quartiles (p=0.48). Multivariable analyses revealed that older age at diagnosis, but not ADI, were associated with worse survival (Table 2). Interestingly, while stage 4 diagnosis alone was significant for worse survival (p=<0.001), in general there was no significant correlation between staging and survival (overall p-value=0.497) (Table 2). Controlling for ADI and other factors, Black AL patients were twice as likely as White AL patients to die (OR=2.10; 95% CI: 0.98-4.51), with a p-value of 0.058, marginally short of statistical significance. Conclusion: Socioeconomic status, as measured by the Area Deprivation Index of the neighborhood of residence, was not associated with disease characteristics, treatment, and outcomes among patients with AL amyloidosis. Controlling for SES, however, Black AL patients had worse survival outcomes then their White counterparts. While there was no significant correlation between ADI and clinical characteristics, a substantial proportion of the cohort was living in highly socioeconomically disadvantaged neighborhoods. Given the nature of our study, we were only able to analyze patients who were seen at our institution and our sample size was small. Studies of larger, multicenter populations are needed to better assess the effects of socioeconomic status and other social determinants of health on outcomes among patients with AL amyloidosis.

Comparison of Time to Next Treatment or Death between Front-Line Daratumumab, Lenalidomide, and Dexamethasone (DRd) and Bortezomib, Lenalidomide, and Dexamethasone (VRd) in Transplant Ineligible Patients with Multiple Myeloma

Introduction: Daratumumab, lenalidomide, and dexamethasone (DRd) and bortezomib, lenalidomide, and dexamethasone (VRd) are the only two regimens that are considered as preferred per the National Comprehensive Care Network for transplant ineligible (TIE) patients with newly diagnosed multiple myeloma (NDMM). While there are no head-to-head studies comparing clinical outcomes of DRd and VRd in this population, an indirect comparison (PEGASUS study [Durie et al., 2020]) has shown that DRd was associated with significantly lower risk of disease progression or death compared with VRd and Rd. This study aims at supplementing this information by comparing real-world time-to-next-treatment (TTNT) or death between NDMM TIE patients treated with front-line (FL) DRd or VRd. Methods: A retrospective cohort study was conducted for patients with NDMM who initiated FL DRd or VRd in Acentrus (1/1/2018 - 5/31/2023), an electronic medical record (EMR) database from academic and non-teaching hospitals in the United States. Patients were included if they had ≥2 records with an ICD-10-CM diagnosis code for MM, ≥6 months of data availability prior to first record with MM diagnosis (without use of antineoplastic agent), initiated FL treatment (initiation of DRd or VRd; index date) within 12 months of first record of MM diagnosis, and ≥90 days of data availability post-index. Patients with pre-index diagnosis of amyloidosis or other cancers and those who participated in a clinical trial before or during FL treatment were excluded. To limit the analysis to the TIE population, patients who had a record of a stem-cell transplant (SCT) before or during FL treatment and those who were <65 years old (used as proxy to SCT eligibility) were excluded. Patient characteristics were evaluated up to 12-months pre-index (baseline period). Patients were followed from the index date until earliest of date of initiation of a next line of treatment, death, or end of data availability. Medications received within 60 days from the date of the first MM antineoplastic agent were considered as FL therapy regimen. Next line of treatment was identified as initiation of a new antineoplastic agent (excluding corticosteroids) outside of FL therapy or re-treatment of FL after >90-day gap. Inverse probability of treatment weighting (IPTW) was used to balance baseline characteristics between study cohorts, with variables with standardized differences <10% considered balanced. Weighted Kaplan-Meier (KM) curves and a doubly-robust Cox proportional hazards model adjusting for baseline variables remaining imbalanced after IPTW were used compare TTNT or death between study cohorts. Results: Overall, 149 and 494 patients were identified in the DRd and VRd cohorts, respectively. After weighting (N DRd weighted = 302, N VRd weighted = 341), most baseline characteristics in both cohorts were similar, including mean age (DRd: 75.3, VRd: 74.5), female sex (DRd: 48.9%, VRd: 45.8%), white race (DRd: 55.8%, VRd: 58.7%), black race (DRd: 8.8%, VRd: 11.3%), Medicare insurance coverage (DRd: 62.7%, VRd: 65.9%), and mean Quan-Charlson comorbidity index (DRd: 3.8, VRd: 3.6; Table 1). Some imbalances remained for mean age, race, ethnicity, and index year, thus they were additionally adjusted for in doubly-robust Cox model. The median duration of follow-up was 20.2 months and 21.5 months among DRd and VRd patients, respectively. A total of 98 (32.4%) DRd patients and 175 (51.2%) VRd patients received a subsequent line of therapy or died, with the median TTNT or death being 37.8 and 18.7 months in the DRd and VRd cohorts, respectively (hazard ratio: 0.58, 95% CI: 0.35, 0.81; p<0.001; Figure 1). KM estimates for patients remaining on FL therapy were significantly higher for DRd than VRd at 6 months (93.0% vs. 80.1%), 12 months (80.0% vs. 61.0%), 18 months (64.9% vs. 51.3%), and 24 months (60.2% vs. 42.9%). Conclusion: In this retrospective cohort study using EMR data, TIE NDMM patients who initiated DRd had a significantly longer time to next treatment or death than patients who initiated VRd. Results from this real-world study fills an unmet data gap by providing information on the comparative effectiveness evidence for DRd versus VRd among TIE NDMM patients. These findings support the use of DRd as an effective treatment option in the TIE NDMM patient population.

Evidence-Based Recommendations for Induction Treatment of Newly Diagnosed Transplant-Eligible Multiple Myeloma Patients; A Scoping Review

Introduction Multiple myeloma is a hematological malignancy characterized by the uncontrolled proliferation of plasma cells within the bone marrow, with an increasing incidence and mortality in the last decade. Eligibility for stem cell transplantation plays a crucial role in determining the approach to treatment, with transplant eligible patients undergoing triple induction therapy with an immunomodulatory agent, a proteasome inhibitor, and steroid. We aimed to review the recent data on the available treatment options for newly diagnosed multiple myeloma (NDMM) in transplant eligible patients. Methods A scoping review was conducted according to the PRISMA 2020 guidelines utilizing the PubMed and Embase databases. The inclusion criteria was phase II or III clinical trials pertaining to the use of triple and quadruple therapy in NDMM patients, from the year 2010 onwards. A total of 2377 search results were screened, with 510 undergoing full-text screening against the inclusion criteria. Covidence was used to facilitate the screening process (Figure 1). Results Forty studies were included in the analysis. Eleven trials were based on Daratumumab induction. Additionally, two trials each utilized Isatuximab and Carfilzomib-based induction. One trial employed induction therapy containing Elotuzumab, and another utilized Cyclophosphamide. Addition of Daratumumab to the triplet regimen resulted in significant improvements in response rates and depth of responses. CASSIOPEIA trial demonstrated a notable improvement in minimal residual disease (MRD), with VTd treatment yielding 44% MRD, while Dara-VTd regimens achieved 64% MRD. Similarly, complete response (CR) rates increased from 26% to 39%, respectively. GRIFFIN trial revealed a remarkable 55% reduction in the risk of disease progression for patients with Dara-RVd . Moreover, the estimated 48-month progression-free survival (PFS) rate was 87.2% in the Dara-RVd group, compared to 70% in the RVd group. Notably, the median PFS was not reached in either treatment arm. The Lyra trial, which analyzed Dara-CyBorD followed by Dara maintenance, demonstrated a CR rate of 48.7% for transplant patients and 29.8% for non-transplant patients, respectively. Additionally, the MASTER trial revealed that Dara-KRd/autologous hematopoietic cell transplant (AHCT) led to a high rate of MRD negativity, with 80% of patients achieving MRD negativity. The two-year PFS was 87%. Furthermore, the addition of Isatuximab and Carfilzomib to the treatment regimen demonstrated favorable outcomes in terms of MRD and PFS (Table 1). The addition of Elotuzumab did not lead to a significant improvement in outcomes. Moreover, caution is warranted when using Cyclophosphamide, given its less favorable safety profile and limited additional benefit in survival outcomes (MRD: 27% in +Cyclophosphamide arm vs. 35% without), including a temporary decline in health-related quality of life. Conclusion In conclusion, this scoping review underscores the significance of individualized treatment approaches for multiple myeloma based on clinical trial results. Each induction regimen has shown varying levels of efficacy and safety, offering clinicians flexibility to tailor treatments for different patient populations. The results from these trials will serve as valuable benchmarks and inform future research in the quest for improved therapies for NDMM patients.

Assessment of Stem Cell Transplant Eligibility in Recipients with Oral Foci of Infection: Appropriate Conditioning Regimens.

It is unclear whether patients with oral foci of infection should be approved for hematopoietic stem cell transplant with or without posttransplant cyclophosphamide. We compared the presence of oral foci of infection status on the effects of various conditioning regimens for such patients. Three groups were classified as autologous (carmustine-etoposide-cytarabinemelphalan, mitoxantrone-melphalan, and melphalan 200 mg/m² groups; n = 502 patients), and 6 groups were classified as allogeneic (busulfan-fludarabinerabbit anti-T-lymphocyte globulin, busulfanfludarabine-posttransplant cyclophosphamide, fludarabine-cyclophosphamide-anti-T-lymphocyte globulin, busulfan-fludarabine-anti-T-lymphocyte globulin-posttransplant cyclophosphamide, total body irradiation-posttransplant cyclophosphamide, and other; n = 428 patients). Data were collected from a database that met international accreditation requirements. We evaluated dental radiological findings and calculated interobserver reliability. Oral foci of infections increased febrile neutropenia and bacterial infection frequencies in both groups but only increased mucositis frequency in patients with allogeneic treatment. The frequencies of oral foci of infection-related complications were similar in both the autologous and allogeneic groups. Rate of graft-versus-host disease was not affected by oral foci of infection status. Periodontitis/cysts and periapical lesions increased the risk of infections at day 100 in the mitoxantrone-melphalan group versus the melphalan 200 mg/m² group. We observed no differences among the autologous transplant groups in terms of early mortality. Similarly, no differences in early mortality were observed among the allogeneic groups. Transplant is a valid option in patients with oral foci of infections undergoing various autologous and allogeneic transplant protocols when time is of the essence, even at myeloablative dose intensities.

Final Results of Ruxopeg, a Phase 1/2 Adaptive Randomized Trial of Ruxolitinib (Rux) and Pegylated Interferon Alpha (IFNa) 2a in Patients with Myelofibrosis (MF)

Background MF is characterized by splenomegaly, anemia, debilitating symptoms and bone marrow (BM) fibrosis. Rux is the current standard of care improving symptoms and splenomegaly but with little impact on the malignant clone and BM fibrosis. IFNa can reduce mutant allele burden and fibrosis but is poorly tolerated in highly symptomatic patients (pts). The RUXOPEG study was designed to assess the efficacy and safety of different doses combinations of Rux + pegylated IFNa 2a in both JAK inhibitor and IFNa-naïve MF pts (NCT02742324). Methods RUXOPEG is a multi-center Bayesian Phase 1/2 adaptive trial. Phase 1 (P1) evaluated 9 possible combinations of doses of Rux, and IFNa (10, 15 and 20 mg BID, and 45, 90 and 135 mcg/week, respectively) and included 6 cohorts of 3 pts. Phase 2 (P2) randomized the 2 best dose combinations selected from P1. Primary tolerance criterion was the occurrence of dose limiting toxicities (DLT) within 45 days in P1. Primary efficacy criterion was >50% reduction in spleen length (SL) by palpation within 24 weeks (W). Secondary objectives included molecular response, quality of life and symptoms evolution, reduction of BM fibrosis, event-free and overall survival. Key inclusion criteria: diagnosis of MF (WHO), Intermediate (Int) or high risk (HR) (IPSS), need of active therapy. Key exclusion criteria: prior treatment with Rux or IFNa, eligibility for stem cell transplantation, autoimmune disease, history of depression. Enrolment in P1 was completed in Nov 2018 and in P2 in Nov 2020. We report the data collected after last pt last visit after 12 months in the study (Nov 2021). Results A total of 37 pts (18 in P1, 19 in P2) were included from 6 centers. Median (range) age was 63.5 years (37-71), 21 had primary MF, 16 post ET or post PV MF. Median (range) SL was 9 cm (0-20) by palpation and 19.5 cm (10.6-30) by imaging. Mean (range) hemoglobin was 12.2 g/dL (7.8-16.2), WBC 12.2 G/L (3.5- 36.1), platelets 372 G/L (150-1304). IPSS at inclusion: Int-1 in 23, Int-2 or HR in 14 pts. Mean number of mutations (mut) per pt was 3.4.; 21 pts had JAK2V617F, 11 CALR and 4 MPL mut; NGS identified 90 additional mut in 17 genes in 33 pts, including mut in HR genes: ASXL1 (n= 21), EZH2 (5), SRSF2 (2), IDH1 (1), and TP53 (5). Safety: No DLT occurred among the 18 pts included in 6 cohorts of P1 (primary safety criterion), and 19 pts were randomized between the 2 dose combinations selected for P2: IFNa 135 mcg/w + Rux 15 (level 6, 9 pts) or 20 (level 9, 10 pts) mg BID. Over 24W, a total of 363 AEs (59% gr1, 33% gr2, 7.5% gr3, 0.5% gr4) including 6 SAE (2 skin cancers, 2 anemias, 1 urinary infection, 1 Raynaud's phenomenon) were reported. Only 2.5% of them resulted in treatment interruption. Most frequent AEs were anemia (18.7%), thrombocytopenia (13.7%), GI (7%), musculoskeletal (6.8%) and asthenia (6.6%). During the 12-month period of the study, 1 patient died of AML transformation after 10.4 months. Efficacy: Primary efficacy endpoint (reduction by at least 50% of SL within 24 W) was reached in 70% (IC95%: 53;84) of pts (26/37 pts in ITT, 67% in P1, 74% in P2) with a clear decrease in SL at W24 (median 3.5 cm by palpation, range 0-12) (Fig 1), maintained at 12 months (median SL of 3 cm, range 0-12) (Fig 2) including complete resolution of palpable splenomegaly in 38% of pts. The best response rate (83%) was seen in patients receiving dose level 6. JAK2V617F allele burden decreased from a median (range) of 84% (23-96) at baseline to 65% (16-95), and 53% (16-92) after 6, and 12 months. Genotyping of progenitor-derived colonies performed in 10 patients showed that the combination of drugs clearly targets in 12 months committed (CD34+CD38+), immature (CD34+CD38-) and HSC-enriched progenitors (CD90+CD34+CD38-) carrying homozygous or heterozygous JAK2V617F. BM biopsies at inclusion and after 12 months are currently centrally reviewed (preliminary results show reduction of BM cellularity and grade of fibrosis in selected pts), and results of additional exploratory endpoints including evolution of clonal architecture with single cell and NGS sequencing, cytokine array and changes in immune effector cells will be presented. Conclusion RUXOPEG is the first study to formally assess the safety and efficacy of Rux + pegylated IFNa 2a combination in patients with MF never exposed to either drug before. Final results show that the combination provided high rates of important reductions in SL and JAK2V617F allele burden due to selective targeting of mutated progenitors. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Real-World Treatment Patterns and Outcomes of Patients with Newly Diagnosed Multiple Myeloma: An Analysis Using National Health Insurance Service Database

Introduction: Available treatments for multiple myeloma (MM) have improved rapidly in recent years. However, due to huge disparities in economy, healthcare infrastructure, and accessibility to new drugs, there are big barriers to provide optimal treatment for MM patients in Asian countries. Until now, there are few data on treatment patterns for MM in real practice setting of Asian countries. In terms of continuous improvement of MM management, it is necessary to ascertain the treatment patterns for achieving optimal treatment. Therefore, we investigated the actual treatment patterns and outcomes of MM patients in Korea using the National Health Insurance Service (NHIS) database. Methods: Newly diagnosed MM patients were identified from the Korean NHIS database between 1st January 2010 to 31st December 2018. Patients had diagnosis with MM (ICD-10 codes C90.0) confirmed with rare and intractable disease registration program. Patients that received at least one stem cell transplantation (SCT) were classified into SCT patients and those without SCT to non-SCT patients. SCT patients and non SCT patients were divided into before and after 1st October 2015 (reimbursement date of bortezomib/dexamethasone [Vd], bortezomib/thalidomide/dexamethasone [VTd] regimens), and 1st December 2017 (reimbursement date of lenalidomide/dexamethasone [Rd] regimen) respectively. MM treatment was defined to start from the first prescription claim including MM treatment following the diagnosis index date, and the therapies within 14-days period from the first date of each line of therapy (LOT) were considered to constitute the treatment regimen of the respective LOT. When a new MM therapy that was not part of the prior LOT appeared in the prescription claim, LOT was considered to advance to the next LOT. Treatment duration, and treatment-free interval times between LOTs were estimated up to 5th LOT. Median overall survival (OS) was assessed by Kaplan Meier. Comparison between groups was evaluated by Log rank and Wilcoxon test. Results: The study population included total of 9,986 newly diagnosed MM patients, 7,501 non-SCT and 2,485 SCT for baseline analyses. Incidence of MM gradually increased by 5.7% of an average annual percent change, from 841 in 2010 to 1,309 in 2018. The mean age of the non-SCT group was older than the SCT group (71.6±9.4 vs 56.7±6.7). The proportion of patients aged <65 was 36.9% and ≥65 was 63.1%. Regardless of SCT eligibility (<65 years), 24.9% of MM patients received SCT. Of the patient eligible for SCT, 62.0% received SCT. Those 8,367 patients (non-SCT:5,925 / SCT:2,442) with at least ≥1 prescription claims with MM treatment after index date were included for treatment pattern analyses. The proportion of patients advancing to each subsequent LOT was higher across all LOT for SCT patients (range, 44%-58%) than non-SCT patients (range, 35%-44%) and decreased with each line. Higher proportion of patients remained to receive 5th LOT in SCT patients than non-SCT (8% vs 3%). Treatment duration and treatment-free interval between LOTs decreased as the LOTs advanced in both SCT and non-SCT patients. Treatment-free interval was the longest after the 1st LOT in SCT patients which was 17.7 months (Fig. 1). The most common 1st LOT treatment regimen for the non-SCT patients was bortezomib/melphalan/prednisolone and for the SCT patients, thalidomide/dexamethasone was mostly used for induction therapy in the 1st LOT. This trend changed as new regimens were available by reimbursement in the 1st LOT: for SCT patients, to VTd; and for non-SCT patients, to Rd. The median OS of all patients was 3.36 years (95% CI: 3.22-3.50). The median OS of the SCT patients was significantly longer with median OS of 7.04 years (95% CI: 6.49-8.11) compared to 2.32 years (95% CI: 2.22-2.44) for the non-SCT patients (p<0.0001). When stratified by age and SCT, SCT patients of younger age (< 65 years) had the longest median OS of 7.10 years (95% CI: 6.56-8.20) (Fig. 2). OS was significantly improved for the SCT group after the reimbursement of Vd and VTd in the 1st LOT (p=0.0019). Conclusions: This real-world data suggests that MM treatment evolves rapidly following the reimbursement of new novel drugs, to treat patients with the most optimal treatment available. And these results show that the OS improves as new novel drugs are incorporated to the treatment. Also, SCT remains an essential treatment providing OS benefit. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Fixed Duration Daratumumab, Ixazomib, Lenalidomide, and Dexamethasone Quadruplet for Newly Diagnosed Multiple Myeloma - MRD Negativity and Survival Outcomes

Background: The combination of a proteasome inhibitor (PI), an immunomodulatory drug (IMiD), and dexamethasone is the current standard induction therapy for myeloma. Daratumumab (Dara), a monoclonal antibody directed against CD38, is highly effective in treating myeloma and improves response rates and progression free survival (PFS) when added to a PI or IMiD. Recent studies have shown high efficacy rates with quadruplet regimens that contain these three drug classes, potentially allowing for limited duration therapy as well as reduction in the steroid doses. We designed this trial to examine the efficacy of the quadruplet regimen containing daratumumab, ixazomib (an oral proteasome inhibitor), lenalidomide and dexamethasone (Dara-IRd) given for fixed duration, and to evaluate impact of early discontinuation of steroids. Patients and Methods: Patients with previously untreated MM who had measurable disease and adequate organ function were enrolled, irrespective of their autologous stem cell transplant eligibility (NCT03012880). The primary objective was to determine the rate of complete response to Dara-IRD combination. Treatment involved 28-day cycles consisting of ixazomib 4 mg days 1, 8, 15; lenalidomide 25 mg days 1-21, dexamethasone 40 mg, weekly and Dara 16 mg/kg, weekly for two cycles, every other week during cycles 3-6 and then every 4 weeks thereafter during induction (12-cycles) followed by Dara-ixazomib maintenance (maximum 24 cycles). Patients were enrolled into two sequential cohorts: Cohorts A (n=38) and B (N=40), with dexamethasone discontinued after two cycles in Cohort B. Transplant eligible patients were allowed to collect stem cells for future transplant anytime after 4 cycles. Serum immunofixation was assessed with mass spectrometry (MASS-FIX) and marrow MRD negativity by Euro flow (sensitivity of 1 in 105). Results: Seventy-eight patients were enrolled; median age was 63.5 (range 33, 81), 55% were male. A third of the patients were high risk by mSMART criteria and ISS stage 1, 2, and 3 had 41%, 35%, and 24% of patients respectively. All patients have completed the treatment phase and those who have not gone off study continue on observation. Among the 40 patients who have gone off study, the reasons for discontinuation among patients in Cohorts A and B, respectively were: progression, 9 and 12; alternate therapy (most often transplant), 11 and 8. The best overall response on therapy was 96% including 31% CR, 39% VGPR. For the entire cohort, time to response was fast, median time to VGPR, CR or minimal residual disease negative (MRD) negativity was 4 cycles. Responses deepened over the duration of treatment as shown in the figure; 31% of patients achieved a marrow MRD negative status (28% CR and MRDneg). After a median follow up was 37.8 months, median PFS or OS has not been reached. Five patients enrolled on the study have died. A grade 3 or higher adverse event at least possibly attributed to the study drugs was seen in 56% of patients. The most common toxicities included fatigue, neutropenia, lymphopenia, peripheral neuropathy, diarrhea, and nausea. Stem cells were collected in 60 patients; median (range) of CD34 cells/kg 7.8 (2.8, 15.9) x 106, with plerixafor used in 88% of patients as per our standard of care "on-demand” approach based on blood CD34 count. Conclusion: Dara-IRd is an active regimen in newly diagnosed MM, with high overall rates of response and deep and durable responses with nearly a third of the patients being MRDneg (Mass Spec based blood testing and flow based MRD), that improved over time with therapy. The toxicities were manageable, with dose modifications. All patients were able to collect stem cells when required, though the majority needed plerixafor. This study demonstrates excellent outcomes with limited duration quadruplet regimen without planned upfront autologous stem cell transplant and no maintenance till progression. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

An Epidemiology Model for Estimating the Numbers of US Patients With Multiple Myeloma by Line of Therapy and Treatment Exposure

ObjectivesEstimates on the distribution of patients with multiple myeloma (MM) by line of therapy (LOT) are scarce and get outdated quickly as new treatments become available. The objective of this study was to estimate the number of patients with MM by LOT and the number of patients who have received at least 4 previous LOTs including proteasome inhibitors, immunomodulatory agents, and anti-CD38 monoclonal antibodies (mAbs). MethodsA compartmental model was developed to calculate the number of patients by LOT. Two pathways were considered based on stem cell transplant eligibility, and at each pathway, treatments were stratified in 2 types: anti-CD38 mAbs or other. The model population was stratified into 4 subgroups based on age and cytogenetic risk. Model inputs were informed from real-world evidence. ResultsThe model estimated that, in 2020, 126 869 patients were living with MM in the United States. Of these, 105 701 received treatment in any LOT, with 56 959, 27 252, 11 258, and 5217 in lines 1 to 4, respectively, and 5015 in line 5 or beyond. The model estimated that 3497 patients received at least 4 previous LOTs including proteasome inhibitors, immunomodulatory agents, and anti-CD38 mAbs. The model overall prevalence predictions aligned well with publicly available estimates. ConclusionsThis study proposes a novel framework to estimate MM prevalence. It can assist clinicians to understand future trends in MM epidemiology, healthcare systems to plan for future resource use allocation, and payers to quantify the budget impact of new treatments.

Evaluation of Functional and Cytogenetic High-Risk Multiple Myeloma Using Real-World Data

Introduction: Multiple myeloma (MM) is a heterogeneous disease with wide variability in outcomes. The presence of cytogenetic abnormalities in MM is of critical importance for prognosis and risk stratification. However, patients who may or may not have sufficient cytogenetic abnormalities to classify as high-risk can still experience rapid disease progression despite therapy, or functional high risk (FHR) disease. These two high risk cohorts comprise vulnerable subpopulations who have a significant burden of disease, and it is critical that we understand the underlying patient characteristics and optimal treatment sequence. We sought to investigate these two high risk patient populations treated in the contemporary real-world practice setting.Methods: A total of 1719 patients were identified in the COTA real-world database as having been diagnosed with active MM on or after January 1, 2015 and classified as either FHR, cytogenetic high risk (CHR), or both. The COTA real-world database is a USA-based real-world evidence database comprised of longitudinal, Health Insurance Portability and Accountability Act (HIPAA)-compliant, data on the diagnosis, clinical management, and outcomes of patients with cancer. Of the 1719 patients, 1260 were identified to be FHR, defined as relapse <18 months from initial active MM diagnosis. A total of 459 patients were identified as CHR, among which 347 were both FHR and CHR. CHR was defined as a patient having at least one of the following abnormalities: t(4;14), t(14;16), t(14;20), del(17p), 1q gain, or hypoploid. Line of therapy was applied programmatically using an algorithm based on International Myeloma Working Group criteria and clinical guidance. The primary outcome was time to next treatment (TTNT) calculated using the Kaplain Meier method. Univariate and multivariate analyses were conducted to understand predictors of rapid disease progression among high-risk patients.Results: In our real-world population, FHR patients tended to be slightly younger, African American, and treated predominantly in the academic setting (Table 1). First-line (1L) and second-line (2L) treatment patterns by category are shown in Table 2. A lower proportion of FHR patients received 1L immunomodulators as compared to the other high-risk groups, while almost half of the CHR patients received 1L stem cell transplant (SCT). In 2L, among patients not receiving 2L SCT, a higher proportion of CHR patients received a daratumamab-based treatment as compared to FHR (23.2% vs. 12.0%, respectively). We observed a longer median (95% CI) TTNT for high-risk patients receiving 2L daratumamab-based treatment as compared to patients who did not: 8.5 months (6.4-13.0) vs. 6.0 months (5.3-6.9), p=0.07 (Figure 1). Univariate and multivariate analyses showed age at diagnosis (HR: 0.98, CI: 0.97, 0.99), normal cytogenetics (HR: 0.78, CI: 0.63, 0.97), 1L immunomodulator (HR: 0.39, CI: 0.22, 0.69), 1L proteasome inhibitor (HR: 1.4, CI: 1.1, 1.8), and 1L SCT (HR: 0.22, CI: 0.15, 0.32) as significant predictors of rapid disease progression.Conclusions: Our study provides important insights comparing high risk populations with MM treated in the real-world setting. A higher proportion of CHR patients received 1L SCT and this provided the longest 1L TTNT as compared to other treatments. In 2L, among patients not receiving 2L SCT, we observed a trend towards significantly longer TTNT provided by dara-based treatment as compared to non-dara based treatment; however, our TTNT is lower than progression-free survival results observed in pivotal trials. We identified potential underlying differences in our patient populations that may be driving the predictors of rapid disease progression, including 1L SCT eligibility and renal disease, and these will be further investigated in propensity score matched populations. Future research will continue to explore optimal treatment sequences in high-risk populations with multiple myeloma to improve patient outcomes. These data highlight an urgent need to better predict FHR patients at diagnosis and develop clinical trials incorporating novel compounds in high risk patients. [Display omitted] DisclosuresHansen: COTA, Inc.: Current Employment. Belli: COTA, Inc.: Current Employment, Other: Equity ownership. Goran: COTA, Inc.: Current Employment. Wang: COTA, Inc.: Current Employment, Other: Equity ownership.

Front‐line treatment patterns in multiple myeloma: An analysis of U.S.‐based electronic health records from 2011 to 2019

Multiple myeloma (MM) treatment options have evolved rapidly, but how new agents are incorporated into treatment decisions in current practice is not well understood. This study examined prescribing trends of physicians treating newly diagnosed MM and treatment outcomes in the United States. Electronic health record data from 6271 adult patients diagnosed with MM and receiving initial treatment between 1 January 2011 and 31 January 2020 were derived from the Flatiron Health electronic‐health record de‐identified database. The number/types of agents included in therapy regimens, time to next treatment (TTNT), and overall survival (OS) were assessed. Subgroups were analyzed by the International Staging System (ISS) disease stage at diagnosis, stem cell transplant eligibility and timing, and practice type. Exploratory prognostic models evaluated the association between baseline covariates and time‐to‐event outcomes. The proportion of patients receiving triplet therapies increased from 2011 (36%) to 2019 (72%) as those receiving initial monotherapy or doublet therapy decreased. Overall, the most prevalent triplet regimen consisted of an immunomodulatory drug (IMiD), a proteasome inhibitor, and a steroid. From 2017 to 2019, median TTNT from front‐line to second‐line was longer in patients with ISS stage I versus stages II/III, and in those receiving IMiD‐containing doublet or triplet therapies versus other combinations. Overall median OS was 56 months and increased from 2011 to 2014, after which median OS was not yet reached. Age, ISS stage, and high‐risk status were prognostic for both OS and TTNT, while sex, practice type, and ECOG status were prognostic for OS only.

Associations between Socioeconomic Status and Health-Related Quality of Life in Patients with AL Amyloidosis

Introduction: Socioeconomic status (SES) can affect health-related quality of life (HRQoL) through a variety of mechanisms, including poor access to healthcare, physical and mental health comorbidities, low levels of health literacy or health activation, and consequent negative health behaviors. The impact of low SES on HRQoL of patients with AL amyloidosis, however, has not been well described. AL amyloidosis is a rare, complex disease associated with significant organ dysfunction, disability, and death. Although patients with AL amyloidosis report significant HRQoL impairments, it is likely that patients in lower SES groups report even greater deficits. The aim of this study was to assess the impact of SES on HRQoL in AL amyloidosis patients.Methods: This was a cross-sectional, observational study. A total of 1,289 patients with AL amyloidosis were evaluated at the Amyloidosis Center at Boston University between 1994 and 2014 and completed the SF-36v1 Health Survey within seven days of their initial evaluation. The SF-36v1 assessed HRQoL across eight domains and two component summary measures: physical functioning (PF); role limitations due to physical health problems (RP); bodily pain (BP); general health (GH); vitality (VT); social functioning (SF); role limitations due to emotional health problems (RE); mental health (MH); and physical (PCS) and mental (MCS) component summaries. SES was based on patients' occupation type (ie, professional/managerial positions vs. other occupations, including administrative/clerical, service, blue-collar, and farming positions vs. retired vs. disability) and educational attainment (≤ high school diploma versus > a high school diploma). Regression models using each SF-36v1 domain or summary score as a dependent variable were fit to examine whether there was an association between SES and HRQoL, independent of other demographic and clinical characteristics including type of organ involvement, multi-organ involvement, eligibility for stem cell transplantation, and time since diagnosis. Adjusted least-square means for each SF-36v1 domain and summary were obtained from two sets of models using educational or occupational group as the measure of SES. Established minimally important differences (MIDs) were used to determine whether differences in adjusted mean scores across groups were also clinically meaningful.Results: The mean age of the population was 61.6 years and the average time since diagnosis was 7.3 months. Based on multivariable models, patients with fewer years of education reported worse HRQoL impairment (i.e., significantly worse scores for all SF-36v1 domain and summary scores) compared to patients with more education (p < 0.05 for all) [Figure 1]. With the exception of GH, MH, and MCS, differences by educational attainment all exceeded the threshold of 1 MID.In multivariable models using occupation as the independent variable for SES, SF-36v1 scores also differed significantly by occupation (Figure 2). Relative to scores among patients with professional/managerial occupations: •Patients in other occupations reported statistically (p < 0.05 for all) and clinically (i.e. exceeding 1 MID) significant deficits on all SF-36v1 scores.•Patients on disability also exhibited significantly worse SF-36v1 scores (p < 0.05 for all). Deficits exceeded 1 MID for all scores. For PF, VT, and PCS, these differences exceeded 2 MIDs.•Retired patients reported only significant deficits for PF and RP (p < 0.05 for both); however these differences did not meet the threshold for an MID.Conclusions: Patients from lower SES groups, defined in terms of education or employment, had poorer HRQoL as compared to those with more years of education or professional/managerial positions. These relationships were independent of other clinical variables that served as proxies for disease severity. Outreach efforts designed to increase the understanding of the disease among community-based clinicians should highlight the additional HRQoL burden and potential need for more comprehensive care among patients in lower SES groups. As treatments of AL amyloidosis and healthcare resource utilization can be costly, future research should examine whether SES is associated with costs associated with treatment, type of health care received, and consequently HRQoL.Supported by Amyloid Research Fund at BUMC and a grant from Prothena Biosciences Inc. [Display omitted] DisclosuresMcCausland:Optum: Employment; Prothena Biosciences: Research Funding. White:Prothena Biosciences: Research Funding; Optum: Employment. Yokota:Optum: Employment; Prothena Biosciences: Research Funding. Quock:Prothena Biosciences Inc: Employment, Other: Stockholder. Bayliss:Optum: Employment; Prothena Biosciences: Research Funding.

Real-world (RW) treatment (tx) patterns and outcomes of 3,455 previously untreated mantle cell lymphoma (MCL) patients (pts) in U.S. routine clinical practice.

7504 Background: MCL is a non-Hodgkin lymphoma with heterogeneous biology and outcomes. We characterized RW tx patterns and outcomes of MCL pts to identify factors associated with outcomes in the US. Methods: This retrospective study included adult MCL pts diagnosed Jan 2011-Nov 2020 in the nationwide Flatiron Health EHR-derived deidentified database. Pt characteristics, tx patterns, time to next tx (rwTTNT, defined as start of first-line [1L] tx to subsequent tx or death) and rwOS were evaluated. Results: 3455 pts were included, 85.3% from a community oncology setting. In 2946 (85.2%) pts with documented 1L MCL tx, median age was 69.5 y (range 27.7-85.3); 9.5% had blastoid/pleomorphic MCL. 262 (39.6%) and 235 (35.6%) of 661 pts with available MCL international prognostic index (MIPI) had intermediate and high risk, respectively. 150/1253 pts (12.0%) with available ECOG PS had PS ≥ 2. Chemoimmunotherapy was the most common 1L tx, including BR in 1223 (41.5%), R-CHOP in 512 (17.4%) and cytarabine (ara-C)-containing tx in 414 (14.1%). 667 pts received R maintenance (MR). In 1036 pts &lt; 65 y, 243 pts received 1L stem cell transplant (SCT), mainly autologous. In 1L-treated pts, with median follow-up of survivors of 45.3 mos (range 0.03-117.2), median rwTTNT was 24 mos; 36-mo rwOS was 67%. The Table shows tx received and outcomes by age and SCT status. MVA analyses showed age ≥ 65 y, ECOG PS ≥ 2, LDH/ULN ≥ 1, WBC ≥ 10 × 109/L, bulky disease (≥ 5 cm) and blastoid/pleomorphic morphology were associated with shorter rwTTNT and rwOS; MR was independently associated with longer rwTTNT and rwOS. In pts &lt; 65 y who were alive and did not initiate subsequent tx within 6 mos of 1L tx (“SCT-eligible”), 36-mo rwTTNT and rwOS were similar between pts treated with vs without SCT: 65% vs 59% and 86% vs 85%, respectively. Conclusions: In this large RW cohort of primarily community-based US practices, median 1L rwTTNT for MCL pts was ̃ 2 y. BR was the most commonly used 1L tx. SCT was uncommon even in pts &lt; 65 y, suggesting RW considerations may influence SCT eligibility and availability. Also, SCT was not clearly associated with rwOS. As with other reports, older age and high-risk disease features were predictive of worse outcome in RW, while MR appeared to be associated with better outcomes. Outcomes across the board appear worse than prospective trials, suggesting a need to focus on developing tx that can be delivered effectively in the community setting.[Table: see text]

Monitoring treatment with 5-Azacitidine by flow cytometry predicts duration of hematological response in patients with myelodysplastic syndrome.

5-Azacitidine (AZA) therapy is used in high-risk myelodysplastic syndrome (MDS) patients who often show abnormalities in their immunophenotype. We explored the potential impact of AZA on these immunophenotypic abnormalities in serial bone marrow studies performed in 81 patients from five centers. We compared the immunophenotypic features before and after therapy with AZA, established definitions consistent with flow cytometry immunophenotyping (FCI) improvement, and explored its clinical significance. After a median of 6 cycles of AZA, 41% of patients showed a FCI improvement and this finding associated with best possible clinical response (P < 0.001). FCI improvement also correlated with hematological improvement (HI) (53/78 patients; 68%), independently of their eligibility for stem cell transplantation. Among patients who achieved a HI after 6 cycles of AZA, the probability of maintaining this response at 12 cycles of AZA was twice as large (67%) for those patients who also achieved a FCI improvement after 6 cycles of AZA as compared to patients who did not (33%, P < 0.01). These findings support that monitoring of the immunophenotypic abnormalities during therapy with AZA may assist in redefining the quality of response in patients with MDS.

Predictors of Healthcare Utilization in Newly Diagnosed Myeloma

Introduction The introduction of novel therapies has significantly improved outcomes in myeloma. However, the economic burden of enhanced healthcare utilization is significant and cannot be discounted. This study sought to identify baseline characteristics that may influence outcomes and subsequent healthcare utilization. Patients were also stratified by induction therapy to determine the impact newer combinations have on healthcare utilization. Methods This retrospective single-center study enrolled all newly diagnosed patients with myeloma between 2005 and 2020. Three outcome measures were used to determine healthcare utilization - total inpatient length of stay (LOS), number of admissions, and day ward attendances. Univariate and multivariable analyses were performed to identify significant covariates related to overall survival (OS) and healthcare utilization. Outcomes were subsequently adjusted for duration of follow-up and per patient year. Results There were 113 patients included; 60 (53.1%) female; median age at diagnosis was 67 years (IQR 62, 73 years) and 22.1% were high risk International Staging System (ISS). Further baseline demographics are presented in Table 1. Median duration of follow up was 3.2 years (IQR 1.50, 6.55). Sixty patients (53.1%) died, 91.7% attributable to myeloma or its treatment. Predictors of OS by multivariable analysis were advanced stage [ISS III (p&amp;lt;0.001)] and IgA idiotype [(IgA vs IgG) (p=0.0002)]. Stem cell transplant eligibility was associated with improved OS (p=0.003). The total number of admissions to hospital was 547 (median 4; IQR 2, 7), with 55.4% unplanned. In the multivariable analysis, younger age (p=0.020), higher paraprotein levels (p=0.045), dialysis (p=0.037), and SCT eligibility (p=0.0012) were predictive of greater number of admissions. During the study period, there were 7000 inpatient bed occupancy days (median 46; IQR 26, 80). Only younger age remained significant (p=0.0028) in the multivariable analysis. There were a total of 5987 day care attendances during the study period. Multivariable analysis identified younger age at diagnosis (p&amp;lt;0.0001), WBC (p=0.0072), and light chain (kLC vs lLC) (p=0.0027) as predictive of increased day ward attendance. Healthcare utilization correlated with increased survival, as depicted in figure 1. There was no significant relationship between treatment type and LOS (p=0.055); this remained unchanged when adjusted per patient year (p=0.24). There was significant relationship between treatment type and total number of admissions (p=0.015). Patients receiving anthracycline based therapy (p=0.003), Immunomodulatory (IMiD)/Proteasomal Inhibition (PI)/Steroid (p=0.020), or PI/Steroid (p=0.021) were more likely to have a greater number of admissions. However, when adjusted per patient year, this association was no longer evident (p=0.19). A highly significant relationship between treatment type and day ward attendances was identified (p&amp;lt;0.0001). Alkylator based (pp=0.005), alkylator/PI/Steroid (p=0.006), anthracycline based (p=0.0002), IMiD/PI/Steroid (p=0.0007), or PI/Steroid (0.0002) were more likely to have greater day ward attendance. When adjusted per patient year, this significant association between treatment type and day ward attendance remained (p=0.0002). Conclusion Studies assessing healthcare utilization in patients with myeloma are mostly limited to relapsed refractory setting. In this population, younger age at presentation was a significant predictor for all three measures of healthcare utility. Whilst treatment type did not demonstrate a significant impact of LOS, we did determine that novel triplet therapy combinations were associated with increased number of admissions and day care attendances. We also showed that healthcare utilization increased with survival time. While survival outcomes with novel agents have improved, given current financial and capacity limitations within which the majority of health systems function, resource demand implications must be considered when planning future service provision and novel treatment strategies. Disclosures No relevant conflicts of interest to declare.

Daratumumab, Ixazomib, Lenalidomide, and Dexamethasone for Newly Diagnosed Multiple Myeloma

Daratumumab, Ixazomib, Lenalidomide, and Dexamethasone for Newly Diagnosed Multiple Myeloma

Addition of Brentuximab Vedotin to Gemcitabine in Relapsed or Refractory T-Cell Lymphoma: Results of a Lysa Multicenter, Phase II Study. “the TOTAL Trial”

Addition of Brentuximab Vedotin to Gemcitabine in Relapsed or Refractory T-Cell Lymphoma: Results of a Lysa Multicenter, Phase II Study. “the TOTAL Trial”

MM-138: Estimating the Number of US Patients with Multiple Myeloma (MM) at Different Lines of Treatment (LOT)

Context: The MM patient journey by LOT evolves as new treatments become available. Numbers of patients with MM by LOT are important to inform coverage and resource allocation decisions, but current estimates are lacking. Objective: To estimate the number of US patients with MM at different LOTs and identify a subgroup on their ≥4 LOT (LOT4+), including prior exposure to a proteasome inhibitor (PI), an immunomodulatory agent, and/or an anti-CD38 antibody (i.e., daratumumab). Methods: Differential equations were used to develop a four-compartment model: LOT1 through LOT4+. Patients in LOT1–LOT3 could die or transition to the next LOT. Patients in LOT4+ could remain in that compartment or die. Each LOT included four sub-compartments based on stem-cell transplant eligibility (SCT; eligible/ineligible) and treatment type (daratumumab/other). Patients could change treatment type when they transitioned to the next LOT. The model evaluated patient numbers in four strata: age (≥65/ Results: The model predicted an MM prevalence of 128,083 US patients, with 106,043 receiving treatment (LOT1: 54% [n=56,738]; LOT2: 27% [n=28,287]; LOT3: 10% [n=10,629]; LOT4+: 10% [n=10,389]). An estimated 50% (5156/10,389) of patients in LOT4+ (standard deviation=1361) had prior exposure to PIs, immunomodulatory agents, and/or anti-CD38 antibodies. LOT4+ model results were most sensitive to mortality, TTNT, and daratumumab use. Conclusions: This is one of the first estimates of the current number of US patients with MM by LOT, including the number of patients in LOT4+, accounting for newly approved regimens. Funding: GlaxoSmithKline (213290). This abstract was previously presented at the 2020 EHA 25 Congress and is presented on behalf of and with the permission of the original authors and EHA (Nikolaou A, et al. EP963).

Bone marrow plasma cells 20% or greater discriminate presentation, response, and survival in AL amyloidosis.

We explored the association between bone marrow plasma cells (BMPCs) and disease presentation and outcome among 1574 AL patients. Three BMPC groups were formulated: <5% (n = 231, 15% of study population), 5-19% (n = 1045, 66%), and ≥20% (n = 298, 19%). Heart and renal involvement were more and less prevalent, respectively, with increasing BMPCs. Patients with ≥20% BMPCs had higher likelihood for classic myeloma phenotype with less skewed lambda restriction, a higher rate of intact immunoglobulin secretion, a lower hemoglobin and higher rates of hypercalcemia and bone lytic lesions. High-risk cytogenetic abnormalities were more common in ≥20% BMPCs. Complete hematological response was less frequent with rising BMPCs. The median survival was inversely associated with the BMPC groups (81, 33, 12 months for <5%, 5-19%, and ≥20% BMPCs, respectively; P < 0.001). Survival discrimination was maintained at 1-year landmark and in those who achieved a complete response. Multivariate analysis accounting for known prognostic markers yielded an independent prognostic role for ≥20% BMPCs, but not for the other BMPC groups. AL patients with 20% or greater BMPCs have poorer outcome independent of their cardiac risk category and stem cell transplant eligibility. Distinct interventions in these patients should be explored to improve outcome.

Geriatric Assessment in Older Adults with Multiple Myeloma.

The incidence of myeloma in older adults is increasing, yet little is known about geriatric impairments in these patients. We aimed to examine the prevalence of geriatric impairments in older adults with myeloma and the association between geriatric assessment and autologous stem cell transplant eligibility. Prospective cohort study. Two academic medical centers. A total of 40 adults 65 years and older with newly diagnosed myeloma were enrolled. Participants completed a primarily self-administered geriatric assessment, including measures of functional status, comorbidities, polypharmacy, psychosocial status, social support, quality of life, cognition, and physical performance. Outcomes were autologous stem cell transplant eligibility and receipt. Forty patients enrolled; their mean age was 71 years. Geriatric impairments were common: 62% reported dependence in one or more instrumental activities of daily living (IADL), 76.9% had polypharmacy (four or more medications), and 47.5% had one or more comorbidities. Median time on the Timed Up and Go was 13.3 ± 4.9 seconds. Those considered candidates for autologous stem cell transplant (N = 26) were younger, with fewer comorbidities, better performance status, and faster performance on the Timed Up and Go test. Factors independently associated with receiving autologous stem cell transplant (N = 21) included age and IADL dependence. Impairments in geriatric domains are common in this population, even among those considered to have a good performance status. Geriatric assessment domains are associated with both transplant eligibility and receipt. J Am Geriatr Soc 67:987-991, 2019.

In Vivo Blockade of Beta-1 and Beta-2 Integrin Activity Inhibits Splenomegaly in JAK2-V617F Positive Myeloproliferative Disease

Introduction:Recently, we showed that in chronic myeloproliferative neoplasia (CMN), β1 and β2 integrins are overactivated on leukocytes in patients and in a JAK2-V617F knock-in mouse model (Gupta et al., Leukemia, 2017; Edelmann-Stephan et al., JCI, In-Press Preview) resulting in increased adhesion of leukocytes to vascular cell adhesion molecule 1 (VCAM-1) and to intercellular cell adhesion molecule 1 (ICAM-1). VCAM-1 and ICAM-1 are abundantly expressed on endothelial cells and in spleen tissue. In JAK2-V617F induced CMN, current therapeutic strategies for symptomatic splenomegaly as hydroxyurea, JAK inhibitors or allogeneic stem cell transplantation (SCT) are effective, however, often limited in duration of efficacy or in eligibility for SCT. Therefore, there is a need to deeper understand the pathophysiology of splenomegaly in CMN in order to develop novel therapeutic approaches. We sought to investigate the effects of in vivo blockade of β1 and β2 integrin overactivation on spleen size, cellular composition of spleen and peripheral blood counts.Material and Methods:11 weeks old Vav1-Cre x JAK2+/V617F mice were treated with a combination of 200µg neutralizing anti-α4β1-integrin (VLA4) antibody (BioXCell, USA) plus 200µg neutralizing anti-β2 integrin antibody (BD Pharmingen, USA) (N=6) and with isotype controls (each 200µg) (N=3), respectively. Animals were injected i.p. on day 1 and day 8. Small animal MRI was used to serially assess the development of spleen volume on days 1, 8, and 15. Abdominal MRI-images employing a slice thickness of 1-2 mm were obtained. The volume of spleens were computed according to radiology standards. Peripheral blood was collected via retro-orbital bleeding and blood counts were measured on days 1, 8, and 15. Thereafter, mice were sacrificed by cervical dislocation and spleens were removed for further analysis by FACS.Results and Discussion:The applied antibody injections were well tolerated and all animals survived the planned observation period. At the start of the experiments (day 1), splenomegaly was confirmed by MRI. As expected, the spleen volumes were similar in the cohorts of isotype and β1/β2 integrin antibody treated JAK2+/V617F mice: 550±76 mm3 (mean±SD) and 518±96 mm3, respectively (Fig. 1). At day 8, upon a single injection of β1/β2 integrin antibodies, a significant decrease in mean spleen volume from baseline 518±96 mm3 to 414±32 mm3 (p=0.0302) was observed (Fig. 1). The correspondent mean±SD for the isotype antibody treated animals was 594±63 mm3. Thus, on day 8, a 30.3% reduction in spleen volume was demonstrated upon β1/β2 integrin antibody treatment in comparison to isotype treatment (p=0.0006). On day 15, the mean spleen volumes of isotype-treated and β1/β2 integrin antibody-treated mice were 665±187 mm3 and 460±69 mm3 (p=0.0410). These results demonstrate that in JAK2-V617F induced disease, blocking of overactivated β1/β2 integrins reduces splenomegaly within a short period of time (8 days). Longer application schedules may build up even stronger and stable decrease in spleen size.In addition to MRI imaging, we also analyzed the composition of peripheral blood cells. At the start of the experiments on day 1, blood parameters showed the typical abnormalities of myeloproliferative disease in both cohorts. Mean counts in isotype treated animals were: WBC = 14,300/µL, hematocrit = 80.3 %, PLT = 1283/nL. Mean counts in β1/β2 integrin antibody treated animals were: WBC = 13,850/µL, hematocrit = 76.0 %, PLT = 1348/nL. This confirms that the JAK2-V617F mouse model used indeed resembles polycythemia vera. In general, the changes observed upon β1/β2 integrin antibody treatment in blood were subtle: the WBC slightly decreased from 13,850/µL to 12,520/µL on day 15, whereas RBC, HCT and PLT remained nearly unchanged. This indicates tolerability of β1/β2 integrin antibody treatment at the level of the hematopoietic system. In isotype treated mice, peripheral blood counts also stayed stable. Data obtained by FACS analysis of peripheral blood and of spleen tissue (composition in granulocytes, B-cells and T-cells) will be presented.Overall, our results indicate a novel role of JAK2-V617F induced overactivation of β1/β2 integrins in development of splenomegaly. Thus, modulation of integrin activity may have therapeutic potential to reduce the spleen volume in CMN patients insufficiently responding to standard treatment. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.