Roy, Vivek

Objective Systemic sclerosis (SSc) is an autoimmune disease marked by immune dysregulation, leading to progressive fibrosis and multiorgan dysfunction. Autologous hematopoietic cell transplantation (autoHCT) has demonstrated superiority over conventional immunosuppression in randomized trials yet remains underused in the United States. We report outcomes following implementation of autoHCT as a standard‐of‐care strategy at our institution. Methods We performed a retrospective analysis of consecutive patients with severe SSc undergoing autoHCT between April 1, 2020, and December 31, 2023. Eligibility required progressive disease despite standard immunosuppressive therapy. Primary endpoints were overall survival (OS) and event free survival (EFS). Secondary endpoints included cumulative incidence of relapse and nonrelapse mortality (NRM), organ‐specific outcomes, and transplant‐related complications. Results Twenty‐five patients underwent autoHCT. Median age was 46 years; 80% were female. At a median follow‐up of 23 (interquartile range 16.4–31.9) months, two‐year OS was 91.67% (95% confidence interval [CI] 81.25–100.0) and EFS was 74.51% (95% CI 58.78–94.45). Two‐year cumulative incidence of relapse was 23.93% (95% CI 4.27 –43.59), and NRM was 8.33% (95% CI 2.97–19.64). Significant improvement in Modified Rodnan Skin Score was observed at day +90 and +180 ( P < 0.05), whereas pulmonary function stabilized. Infectious complications occurred in 56% of patients, primarily viral reactivations. Conclusion Implementation of autoHCT for severe SSc in a multidisciplinary care model was associated with favorable survival and meaningful improvement in skin disease, with acceptable toxicity. Earlier referral and optimization of conditioning strategies may further reduce relapse and treatment‐related morbidity.

Abstract Solitary bone plasmacytoma (SBP) and SBP with minimal marrow involvement (SBPmm) are treated similarly with definitive radiation therapy (RT) followed by observation. However, differences in the natural disease course after RT between the two, are not well described. We performed a multicenter study assessing outcomes after RT in 141 patients with SBP and 102 with SBPmm diagnosed between January 2010 and December 2024. About 92% of patients with SBPmm progressed to multiple myeloma (MM) vs 76% of those with SBP (P = .01). Among patients with SBP, 21% progressed with a second solitary bone lesion vs 4% with SBPmm (P&lt; .01). Patients with longer time to progression (TTP) after initial RT could achieve durable responses with RT to a second solitary plasmacytoma in the absence of other myeloma-defining events (MDE). Multifocal lytic bone lesions were the most common MDE, occurring in 89% and 81% of patients with SBPmm and SBP, respectively. Patients with SBPmm had a median TTP of 15 months (95% confidence interval [CI], 14-21) compared to 43 months (95% CI, 34-55) for those with SBP (P&lt; .0001); 67% with SBPmm progressed within 2 years of diagnosis. Del(17p) and 1q+ (gain or amplification) were associated with shorter TTP to MM in SBPmm, with 2-year progression rates of 100% and 82%, respectively. We report significant differences in risk and modes of progression between SBP and SBPmm. Patients with SBPmm are at particularly high risk for early progression to MM, with most developing bone disease as the MDE. These findings support prospective studies incorporating frontline systemic therapy for SBPmm.

Measurable residual disease (MRD) has established prognostic significance in patients with myeloid disorders; however, there is limited data regarding its prognostic and predictive value and the optimal technique for measurement in the setting of post allogeneic hematopoietic cell transplantation (allo-HCT). A multi-gene next generation sequencing (NGS) panel can overcome the limitations of conventional techniques for measurement of MRD and can shed light onto the longitudinal evolution and genomic complexity of patients undergoing allo-HCT for acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). In this study, patients with AML or MDS who underwent their first allo-HCT and completed NGS testing at day +100 and were in a state of morphological remission were identified from the transplant registry of Mayo Clinic in Florida. The primary aim was to evaluate the prognostic impact of somatic variants detected via NGS at day +100 post allo-HCT on long-term outcomes. In total, 105 patients who underwent allo-HCT for AML and MDS and completed NGS testing on day +100 were included in the study population. Seventeen patients were found to have detectable variants, and 88 patients were without a detectable variant. At a median follow up of 1.4 years (0.1–5.5), presence of any variant at day +100 was associated with inferior 4-year overall survival (OS) (32% vs. 69%, P < 0.001), decreased progression free survival (PFS) (34% vs. 61%, P < 0.001), and a higher incidence of relapse (64% vs. 23%, P < 0.001). In univariate models, a lower Karnofsky performance score and presence of variants post allo-HCT remained significantly associated with inferior OS, higher relapse incidence, and a decreased PFS. The presence of variants at day +100 post allo-HCT remained significant in multivariate models for relapse ( P = 0.002) but not for OS ( P = 0.06) and PFS ( P = 0.08). These results indicate that the presence of detectable somatic variants at day +100 is associated with poor long-term outcomes and are predictive of a higher incidence of relapse.

Abstract Background: MM is the second most common hematologic malignancy, which despite significant therapeutic advancements, remains incurable. The complexity of MM and its intricate management creates substantial informational demands for patients navigating their care. Methods: A cross-sectional survey study (Mayo Clinic IRB # 25-004671) was conducted to assess MM patients’ awareness about disease basics. A voluntary English language survey (47 questions) encompassing multiple domains of patient MM awareness was administered (REDCap) via the patient EMR portal (Mayo Clinic) and MM support groups nationally. Responses were analyzed using descriptive and inferential statistics (R; Bluesky Statistics, V 10.3.4). Multiple model logistic regression was used for multivariate analysis using age (≤70 or &gt;70 yrs), gender, education (high school or less vs bachelor's and above), income (≤$74999 vs ≥$75000) and insurance status (private vs public). Results: The survey was completed by 2353 patients (pts) with 2177 MM (83.4% active, 16.6% smoldering) and 176 MGUS. Among MM pts median age was 63 yrs with 52.5% males, 91.5% white and 95.7% non-Hispanic. 17.5% had a prior diagnosis of MGUS and 20.2% of smoldering MM prior to MM, and 79.5% were not aware of MM prior to their own diagnosis. Majority (77%) depended most on their doctors to gain MM information but 24.3% reported not having sufficient discussion about MM at diagnosis. 31.2% were not sure what type of MM they had, 22.9% could not correctly report the cell of MM origin (plasma cell), 40.6% did not receive MM stage information at diagnosis, 45.4% were either unsure or reported wrong risk factors for MM and 22% were unsure or mistaken about MM symptoms. Majority (62.9%) did not understand genetic risk categories of MM, 32.3% did not report adequate understanding of MM tests and 31.9% did not understand the difference between response and remission. 57.5% reported not understanding about MRD status and 57.1% never had MRD testing. Majority (86.8%) felt they got adequate opportunity to participate in treatment decisions but only 54.2% felt confident in managing MM with their current knowledge and 28.2% had not discussed their prognosis although 77.7% wanted to know about it. Majority (64.4%) felt they had knowledge gaps about MM and its management. Multivariate analysis showed that females were less likely (OR 0.67) while those with public insurance were more likely (OR 1.35) to report receiving adequate information at diagnosis. Older pts (OR 0.55), males (OR 0.43), with lower education (OR 0.5), lower income (OR 0.5) and public insurance (OR 0.72) were less likely to identify the cell of MM origin correctly. These same groups were significantly less likely to be aware of types of MM as well. Older pts (OR 0.73), with lower education (OR 0.6), lower income (OR 0.77) and public insurance (OR 0.76) were less likely to be aware of MM genetic risk categories. Females (OR 0.81), with lower education (OR 0.68) and lower income (OR 0.63) were less likely to understand MM lab tests. Females and those with lower income were significantly less likely to report receiving adequate information about treatment options. Females reported that they did not get adequate opportunities to participate in treatment decisions (OR 0.65). Older pts, and those with lower income, lower education or public insurance were less likely to understand minimal residual disease (MRD) and all these groups were less likely to have had MRD testing. Those with lower income (OR 0.75) and lesser education (OR 0.72) felt less confident in managing MM with current knowledge. Older pts, females and those with lesser education, lower income and public insurance were also significantly less likely to have discussed about MM prognosis. Conclusion: This study demonstrates substantial basic knowledge deficits integral to managing and prognosticating MM among patients. Patients from unfavorable sociodemographic-economic groups were more likely to have awareness gaps and report lack of information which is integral to having adequate understanding of MM being provided to them. These findings highlight the critical need for structured, comprehensive educational interventions that address fundamental disease concepts to empower pts, overcome healthcare disparities, and engage pts in shared decision-making.

Abstract Background: The phase II and III GRIFFIN and PERSEUS studies evaluated DVRd vs. VRd in NDMM pts that were transplant eligible (TE). These studies included consolidation (cons) and dual agent maintenance (maint) with dara and len (DR). Little is known about the efficacy of DVRd in RW practice including frequency of bor use, use of cons, use of DR maint, and subsequent treatment after progression (PD) on DVRd. We aim to evaluate the RW efficacy of NDMM pts treated with DVRd across the tri-site Mayo Clinic Comprehensive Cancer (MCCC). Methods: We retrospectively analyzed the medical records of pts treated with DVRd between June 2018 and June 2024 at the MCCC. Outcomes were estimated using the Kaplan-Meier method. Results: 464 pts were included; 278 pts were male, and the median (m) age of MM diagnosis was 64 years (yr). 114 pts had ISS III, 205 pts had R-ISS III, 266 pts had high risk (HR) FISH, 80 pts had extramedullary disease, 165 pts had ultra HR disease (dz) (as per 2025 IMS/IMWG consensus), and 47 pts had renal insufficiency (RI) with creatinine &gt;2 mg/dL. Starting len dose was 25mg in 356 pts, 15 mg in 40 pts and ≤10mg in 65 pts. 399 pts received bor 1x per week and 63 2x per week, 91 pts received 1-2 cycles of a different regimen prior to DVRd due to hospitalization (n=23), RI (n=38), poor performance status (n=6), other (n=34). 315 (67.9%) pts underwent autologous transplant (ASCT). The m number of induction cycles was 5; 4 for pts who underwent ASCT and 6 for pts who did not. The best ORR to induction for pts who underwent ASCT was 98% with 247 (79%) achieving ≥VGPR, and 82 (26%) achieving minimal residual disease negativity (MRD-) to at least 10-5. The best ORR for pts who did not undergo ASCT was 87%. For those who underwent ASCT, (96% with melphalan 200mg/m2), the ORR at day 100 was 97% with 56% achieving MRD-. At 1-yr post ASCT, 30% (93/312) were MRD-. 42 pts (13%) received post ASCT cons with DVRd for a m of 2 cycles. 281 pts received post ASCT maint including 107 (38%) len, 53 (19%) bor-len, 91 (32%) dara-len, 14 (5%) dara, 16 (6%) other. 61(13%) pts had change in treatment, due to change to second line therapy (35; 55%), discontinuation (d/c) of len (11; 17%), d/c of dara (3; 5%), d/c of bor (15; 23%), d/c of dex (0; 0%). The m follow-up time for all pts was 26 months (mo) (17-39). The m PFS of pts who underwent ASCT was not reached (NR), and was 57 mo (52-NA) for pts who did not undergo ASCT. For pts who underwent ASCT, the PFS at 24mo for pts who did not have HR FISH was 93% (88-99%) compared to 80% (73-88%) for pts with HR FISH (p=0.12) and 77% (68-87%) for pts with ultra-HR dz (p=0.013).The PFS at 24mo of pts with RI who underwent ASCT was 81% (66-98%) compared to 86% (82-92%) for those without RI, p=0.57. The PFS at 24mo of pts with RI who did not undergo ASCT was 53% (28-100%) compared to 64% (55-75%) for those without RI, p=0.42. The ORR and MRD- rate for pts who received once-weekly bor was 94% and 24%, compared to 94% and 27% for pts who received 2x weekly bor (p=0.85, p=0.93). For pts who underwent ASCT, the PFS at 24mo for pts who received len maint was 91% vs. 83% for pts who receive dual agent maint (DR or VR) (p=0.25), although pts who got dual agent maint were more likely to have HR FISH than pts who received len maint (p&lt;0.001). The PFS at 24mo for pts that received post-ASCT cons was 91% compared to 85% for those that did not (p=0.53); pts who got post-ASCT cons were more likely to have HR FISH (p=0.07). For pts that underwent ASCT, the 3 yr PFS rate is 85% and the 3 yrs OS rate is 96%. For pts that did not undergo ASCT the 3 yrs PFS rate is 60% and the 3 yr OS rate is 85%. 55 pts had functional HR (FHR) MM (relapse within 18 mo) and m PFS for FHR pts who underwent ASCT was 15 mo (11-NA), while m PFS was NR for pts without FHR MM (p&lt;0.001). 79 pts relapsed after 1st line DVRd. The most common 2nd line therapies (tx) were dara-carfilzomib (K)-D, dara-pomalidomide(P)-D, KPD, and other. The m follow-up time from 2nd line tx was 10 mo, the best ORR to 2nd line tx was 76%, and the m PFS with 2nd line tx was 18 mo (7-NA). Conclusion: In this RW analysis, the efficacy and survival outcomes of NDMM pts treated with DVRd was comparable to that reported in the PERSEUS and GRIFFIN trials, although MRD- rates appear lower. DR maint and post-ASCT cons use was not common and was used more frequently in pts with HR FISH. Pts can be effectively salvaged following PD on front-line DVRd with available tx.

Abstract Background: Allogeneic hematopoietic cell transplantation (allo-HCT) is the only curative option for myelofibrosis (MF) but carries significant non-relapse mortality (NRM). Splenomegaly in MF patients undergoing allo-HCT is linked to delayed engraftment, poor graft function, and worse overall survival (OS). Strategies to reduce spleen size pre-HCT have been explored. Splenic irradiation (SI) offers a non-invasive approach for rapid spleen size reduction, though data on transplant outcomes are limited. Retrospective studies suggest SI just before HCT may reduce relapse and effectively shrink spleens with acceptable toxicity. Methods: We conducted a single-center observational study on MF patients with splenomegaly undergoing allo-HCT between 2022–2024. SI (100 cGy in 5 fractions) was delivered within 6 weeks pre-HCT. Primary endpoints: engraftment kinetics (including primary engraftment failure), time to neutrophil/platelet engraftment, and transfusion independence. Secondary endpoints: OS, progression-free survival (PFS), relapse, NRM, and rates of acute/chronic GVHD. Kaplan–Meier methods were used for OS/PFS; cumulative incidence functions with competing risks were used for relapse/NRM. Results: Thirteen patients were analyzed. Median age was 63 (range 40–74) years, and 54% were male. Eight (62%) patients had primary MF, 3 (23%) post-essential thrombocytosis, and 2 (17%) post-polycythemia vera. Eleven (94.6%) patients had prior Ruxolitinib therapy, and 10 (76.9%) harbored a JAK2 mutation with a median variant allele frequency of 51% (range 34%–94%). DIPSS risk at transplant was low in 1 (7.7%), intermediate-1 in 8 (61.5%), and intermediate-2 in 4 (30.8%) patients. Median pretransplant spleen size was 22.4 (range 14.5–28) cm. Two patients had a history of thrombosis, including 1 with portal vein thrombosis. The median interval between SI and stem cell infusion was 14 (range 10–43) days. The median HCT-CI score was 2 (range 0–6), and the median KPS was 80% (range 80–100%). Most patients (76.9%) received a HLA-matched unrelated donor transplantation, while 3 (23.1%) received haploidentical donor grafts. All grafts used peripheral blood stem cells. Reduced-intensity conditioning (RIC) was used in 11 (84.6%) patients, while 2 (15.4%) received myeloablative conditioning (MAC). Five (38.5%) patients received total body irradiation (TBI) as part of conditioning, with all receiving a TBI dose of 200 cGy. All patients received post-transplant cyclophosphamide (PTCy)-based GVHD prophylaxis. With a median follow-up of 17.1 months, median neutrophil engraftment occurred at 18 (range 14–45) days, platelet engraftment at 30 (range 15–434) days, red blood cell transfusion independence at 35 (range 11–341) days, and platelet transfusion independence at 24 (range 10–312) days. Median hospital stay was 26 (range 14–86) days. Primary engraftment failure occurred in 1 (8.3%) patient. One (7.7%) patient developed veno-occlusive disease. Four (33.3%) patients experienced CMV reactivation, and 3 developed CMV disease requiring systemic therapy. Median post-transplant spleen size was 16.6 (range 12.2–25.2) cm, and 30% of patients achieved &gt;50% spleen size reduction, with a median time of 114 (range 45–212) days, with none having a normal spleen at day 30 post-transplant but 2 (15%) patients having a normal spleen at day 100 post-transplant. At 1 year, OS was 73.3% (95%CI, 51.5–100%), and PFS was 66% (95%CI, 44%–100%). The 1-year cumulative incidence of relapse was 7.6%, while 1-year NRM was 25.7%. Seven (53%) patients developed acute GVHD, with 1 patient experiencing grade III acute GVHD that progressed to sepsis and death at day 248 post-transplant. Two additional deaths occurred (graft failure=1, multiorgan failure=1). Two (15%) patients developed moderate chronic GVHD Conclusion: In this single-center cohort, SI pre-allo-HCT was feasible, tolerated, and associated with promising OS and PFS. Engraftment occurred in &gt;90%, with one case of primary engraftment failure and most achieving transfusion independence within reasonable time frames. SI reduced spleen size in &gt;30%, though acute GVHD was frequent. It remains uncertain whether the incidence and severity of GVHD may be influenced using TBI as part of the conditioning regimen (albeit reduced in intensity) in addition to splenic irradiation. Larger prospective studies are needed to clarify SI's impact on engraftment, transfusion dependence, GVHD, and outcomes in MF patients.

Abstract Background In patients with myelofibrosis (MF) undergoing allogeneic hematopoietic cell transplantation (allo-HCT), graft-versus-host disease (GVHD) prophylaxis has traditionally included a calcineurin inhibitor (CNI) plus methotrexate (MTX). We conducted a retrospective study comparing the safety and efficacy of post-transplant cyclophosphamide (PTCy)-based GVHD prophylaxis to CNI-based regimens. Methods This study was approved by the Mayo Clinic IRB. Patients with myelofibrosis who underwent allo-HCT after 2016 at Mayo Clinic in Arizona and Florida were included. Categorical variables were compared using Chi-square or Fisher's exact tests. Overall survival (OS) was defined from transplant to death, and progression-free survival (PFS) from transplant to relapse or death. OS and PFS were estimated using Kaplan-Meier methods; univariate differences were assessed with log-rank tests. The cumulative incidence of acute and chronic GVHD and time to neutrophil and platelet engraftment were analyzed using competing risk models, with death as a competing event; differences were tested using Gray's test. Cox proportional hazards models were used to estimate adjusted hazard ratios (HRs). Results A total of 110 patients were included. 53 patients received PTCy-based prophylaxis (43 PTCy/Tac/MMF, 1 PTCy/CSA/MMF, 9 PTCy/Siro/MMF), while 57 received non-PTCy regimens (54 Tac/MTX +/- 39 T-cell depletion, 2 CSA/MMF, 1 Tac/MMF). Median age at transplant was 63 (range: PTCy 40-76; others 38-74) years in both groups; 59 were male (58.5% PTCy vs 49.1% others). Median Karnofsky Performance Status (KPS) and HCT–Comorbidity Index (HCT-CI) in patients receiving PTCy vs non-PTCy were 90 vs 80 and 1 vs 3, respectively. Conditioning intensity was similar: 22.6% myeloablative vs 21.7%, and 77.4% reduced-intensity vs 76.7% in PTCy and non-PTCy, respectively (p=1.000). Stem cell source was peripheral blood in all patients except one in the non-PTCy group who received bone marrow. 58 patients had primary MF (54.7% PTCy vs 50.9% others), and 52 had secondary MF (45.3% PTCy vs 49.1% others), including essential thrombocythemia (28.3% PTCy vs 31.6% others), polycythemia vera (17.0% vs 15.8%), and MPN-NOS (0% vs 1.8%). Median follow-up was 26.2 months (95% CI: 20.7-52.7) in the PTCy and 60.6 months (95% CI: 53.1-70.6) in the non-PTCy cohort. CD3 and CD33 donor chimerism ≥95% at day +100 was 66.7% and 86.7% in PTCy vs 63.6% and 92.7% in others, respectively (p=0.50); day +100 driver molecular mutations were present in 32.1% of PTCy and 32.0% of others (p&gt;0.99). Rates of acute GVHD grades ≥2 and ≥3 were not statistically significant, in the PTCy group (37.7% vs 49.1% p=0.229 and 17.0% vs 22.8% p=0.445, respectively). Chronic GVHD (any grade) occurred in 42.3% of PTCy vs 38.2% of others (p=0.664), while moderate-to-severe cGVHD was lower with PTCy (21.2% vs 27.3% p=0.461). Platelet engraftment was significantly delayed in the PTCy group (median 33 vs 21 days, p=0.030). Median time to neutrophil engraftment was also delayed in the PTCy group (20 vs 17 days, adjusted p=0.025). Age-adjusted HR for time to platelet engraftment was 0.60 (95% CI: 0.41–0.90; p=0.014), and for neutrophil engraftment 0.65 (95% CI: 0.44–0.95; p=0.025), indicating significantly delayed hematopoietic recovery with PTCy. Graft failure occurred in 9.4% vs 5.3% (p = 0.48); primary 7.5% vs 3.5%, secondary 1.9% vs 1.8% in PTCy vs non-PTCy groups, respectively. Relapse or progression occurred in 11.3% of PTCy vs 17.5% of others (p=0.355); four patients in the non-PTCy group progressed to AML post-transplant, versus none in the PTCy group (p=0.119). 1-year TRM was 22.6% in the PTCy group and 14.0% in the non-PTCy group, p = 0.324. Median OS was 72.8 months in the PTCy group (95% CI: 49.9 months, upper limit not estimable [NE]) and 93.4 months in the non-PTCy group (95% CI: 48.5 months, upper limit NE), although the difference was not statistically significant (p=0.739). After adjusting for age and HCT-CI, there were no significant differences in PFS (adjusted HR 1.37; 95% CI: 0.73–2.56; p=0.331) or OS (adjusted HR 1.27; 95% CI: 0.64–2.51; p=0.498). Conclusions In myelofibrosis patients undergoing allo-HCT, PTCy-based GVHD prophylaxis showed similar rates of grade ≥2 acute and moderate-severe chronic GVHD compared to non-PTCy regimens. Engraftment was significantly delayed, while OS and PFS were comparable. PTCy appears to be a safe and viable alternative to CNI-based prophylaxis.

Abstract Allogeneic hematopoietic stem cell transplant (alloHCT) is considered for all patients with myeloid neoplasms (MNs) harboring TP53 mutations (TP53mut). The aim of this international study across 7 transplant centers in the United States and Australia was to identify factors associated with improved post-alloHCT survival. Of 134 TP53mut MN cases who underwent alloHCT, 80% harbored complex karyotype; 94% of TP53 variants were localized to the DNA-binding domain (DBD). Most common comutations were ASXL1 (7%), TET2 (7%), and DNMT3A (6%). Median post-HCT survival was 1.03 years, and overall survival (OS) at 1 year, 2 years, and 3 years was 51.4%, 35.1%, and 25.1%, respectively. A total of 103 cases (76.9%) met the International Consensus Classification (ICC) criteria for MN with mutated TP53 (referred to as ICC-defined TP53mut MN hereafter). The 3-year OS of ICC-defined TP53mut was significantly shorter compared with that of other TP53mut MNs (3-year OS, 16.9% vs 54.9%; P = .002). ICC-defined TP53mut MNs was independently associated with inferior OS (hazard ratio [HR], 2.62; P = .019). The presence of non-DBD TP53mut only (HR, 3.40; P = .005), DNMT3A comutation (HR, 2.64; P = .016), and pre-alloHCT bone marrow blasts ≥5% (HR, 2.76; P = .006) was independently associated with inferior relapse-free survival (RFS), whereas melphalan-based conditioning was associated with superior RFS (HR, 0.52; P = .005). Combining these variables, we constructed a hierarchical model that stratified patients into low-, intermediate-, and high-risk categories with 1-year RFS of 81.3%, 31.3%, and 6.7%, respectively (P &lt; .001). In conclusion, a subset of MN harboring TP53mut who have low blasts pre-alloHCT and received melphalan-based conditioning derived long-term benefit from alloHCT.