Transplant versus no transplant in myelodysplastic syndrome and acute myeloid leukemia with TP53 mutation; a referral center experience.

A remarkably high rate of post-transplant relapse in patients with TP53-mutated myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) calls to question the utility of allogeneic stem cell transplant (HSCT). We, therefore, performed a retrospective analysis to compare the outcomes between HSCT (N = 38) versus non-HSCT (N = 45) approaches. Patients in the HSCT cohort were younger (median age 63 vs. 72) while patients in the non-HSCT cohort more commonly had complex karyotype with chromosome 17 aberrancy and 5q deletion (p < .01). A total of 69 TP53 variants including 64 pathogenic variants, and 5 variants of undetermined significance were detected. Nine patients (4 in HSCT and 5 in non-HSCT) had multi-hit TP53 variants. After induction: 57.9% versus 56.6% in the HSCT versus non-HSCT cohort achieved morphologic complete remission. Median time to HSCT was 6 months and median follow-up was 15.1 months for HSCT and 5.7 months for non-HSCT. Median disease-free survival (DFS) and overall survival (OS) were 11.7 and 15.9 months for HSCT, and 4.1 and 5.7 months for non-HSCT cohorts, respectively. Non-relapse mortality at 12 months was 22% versus 44% for HSCT versus non-HSCT. In the HSCT cohort, the rate of grade II-IV acute and chronic graft-versus-host disease (GVHD) was 55% and 18%, respectively. None of the patients from the non-HSCT cohort were alive while four patients from the HSCT cohort were alive, in remission, and without GVHD (GRFS) at the time of abstraction. Better treatment strategies for patients with TP53-mutated MDS/AML remain an area of unmet clinical need.

Impact of bortezomib-based versus lenalidomide maintenance therapy on outcomes of patients with high-risk multiple myeloma.

BACKGROUND: Lenalidomide maintenance after autologous stem cell transplant (ASCT) in multiple myeloma (MM) results in superior progression-free survival and overall survival. However, patients with high-risk multiple myeloma (HRMM) do not derive the same survival benefit from lenalidomide maintenance compared with standard-risk patients. The authors sought to determine the outcomes of bortezomib-based maintenance compared with lenalidomide maintenance in patients with HRMM undergoing ASCT. METHODS: In total, the authors identified 503 patients with HRMM who were undergoing ASCT within 12 months of diagnosis from January 2013 to December 2018 after receiving triplet novel-agent induction in the Center for International Blood and Marrow Transplant Research database. HRMM was defined as deletion 17p, t(14;16), t(4;14), t(14;20), or chromosome 1q gain. RESULTS: Three hundred fifty-seven patients (67%) received lenalidomide alone, and 146 (33%) received bortezomib-based maintenance (with bortezomib alone in 58%). Patients in the bortezomib-based maintenance group were more likely to harbor two or more high-risk abnormalities and International Staging System stage III disease (30% vs. 22%; p = .01) compared with the lenalidomide group (24% vs. 15%; p < .01). Patients who were receiving lenalidomide maintenance had superior progression-free survival at 2 years compared with those who were receiving either bortezomib monotherapy or combination therapy (75% vs. 63%; p = .009). Overall survival at 2 years was also superior in the lenalidomide group (93% vs. 84%; p = .001). CONCLUSIONS: No superior outcomes were observed in patients with HRMM who received bortezomib monotherapy or (to a lesser extent) in those who received bortezomib in combination as maintenance compared with lenalidomide alone. Until prospective data from randomized clinical trials are available, post-transplant therapy should be tailored to each patient with consideration for treating patients in clinical trials that target novel therapeutic strategies for HRMM, and lenalidomide should remain a cornerstone of treatment.

Matching-adjusted indirect comparison from the Lymphoma Epidemiology of Outcomes Consortium for Real World Evidence (LEO CReWE) study to a clinical trial of mosunetuzumab in relapsed or refractory follicular lymphoma.

Mosunetuzumab is a novel bispecific antibody targeting epitopes on CD3 on T cells and CD20 on B cells with the goal of inducing T-cell mediated elimination of malignant B cells. A recent pivotal phase I/II clinical trial (GO29781) demonstrated that mosunetuzumab induced an overall response rate of 80%, complete response rate of 60%, and a median progression-free survival of 17.9 months in patients with relapsed/refractory (r/r) follicular lymphoma (FL) following at least two prior lines of systemic therapy, including alkylator and anti-CD20 antibody-based therapy. Historical data from cohorts receiving therapy for r/r FL can provide some context for interpretation of single-arm trials. We compared the results from the mosunetuzumab trial to outcomes from a cohort of patients with r/r FL from the LEO Consortium for Real World Evidence (LEO CReWE). We applied clinical trial eligibility criteria to the LEO CReWE cohort and utilized matching-adjusted indirect comparison weighting to balance the clinical characteristics of the LEO CReWE cohort with those from the mosunetuzumab trial. Overall response rates (73%, 95% CI:65-80%) and complete response rates (53%, 95% CI:45-61%) observed in the weighted LEO CReWE cohort were lower than those reported on the mosunetuzumab trial (ORR=80%, 95% CI:70-88%; CR=60%, 95% CI:49-70% respectively). Progression-free survival at 12 months was similar in the weighted LEO CReWE (60%, 95% CI:51-69%) and the mosunetuzumab trial (PFS 58%, 95% CI:47-68%). Sensitivity analyses examining the impact of matching variables, selection of line of therapy, and application of eligibility criteria, provide context for best practices in this setting.

Older patients with primary central nervous system lymphoma: Survival and prognostication across 20 U.S. cancer centers.

There is a paucity of large-scale data delineating outcomes and prognostication of older patients with primary central nervous system lymphoma (PCNSL). We retrospectively analyzed 539 newly-diagnosed PCNSL patients ages ≥60 years across 20 U.S. academic centers. The median age was 70 years (range 60-88); at least one geriatric syndrome was present in 46%; the median Cumulative Index Ratings Scale-Geriatrics (CIRS-G) score was 6 (range, 0-27); and 36% had impairment in activities of daily living (ADL). The most common induction regimens were high-dose methotrexate (HD-MTX) ± rituximab; methotrexate, temozolomide, rituximab (MTR); and rituximab, methotrexate, procarbazine, vincristine (R-MPV). Overall, 70% of patients achieved remission, with 14% undergoing consolidative autologous stem cell transplant (ASCT) and 24% receiving maintenance. With 58-month median follow-up, median progression-free survival (PFS) and overall survival (OS) were 17 months (95% CI 13-22 months) and 43 months (95% CI 31-56 months), respectively. Three-year PFS and OS were highest with MTR (55% and 74%, respectively). With single-agent methotrexate ± rituximab, 3-year PFS and OS were 30% (p = .0002) and 47% (p = .0072). On multivariate analysis, increasing age at diagnosis and Cooperative Oncology Group (ECOG) performance status (PS) was associated with inferior PFS; age, hypoalbuminemia, higher CIRS-G score, and ECOG PS adversely affected OS. Among patients receiving maintenance, 3-year PFS was 65% versus 45% without maintenance (p = 0.02), with 3-year OS of 84% versus 61%, respectively (p = .0003). Altogether, outcomes in older PCNSL patients appeared optimized with HD-MTX combination induction regimens and maintenance therapy. Furthermore, several prognostic factors, including geriatric measures, were associated with inferior outcomes.

Acute auto-aggression syndrome following autologous hematopoietic stem cell transplant and lenalidomide for multiple myeloma.

INTRODUCTION: Autologous hematopoietic stem cell transplant is an important treatment modality used to achieve long-term remission in people with multiple myeloma. Complications include chemotherapy-related toxicity or infection. Rarely, clinical features consistent with autologous graft-versus-host disease, otherwise known as auto-aggression syndrome, is possible. Auto-aggression syndrome appears more commonly in patients with multiple myeloma, hypothesized to be a result of underlying immune dysregulation, conditioning chemotherapy, or treatment with immunomodulating agents. CASE REPORT: A 66-year-old female with multiple myeloma underwent an autologous stem cell transplant with melphalan conditioning chemotherapy followed by maintenance therapy with lenalidomide. Transplant was complicated by engraftment syndrome versus auto-aggression syndrome. After lenalidomide maintenance therapy initiation, she required hospitalization for auto-aggression syndrome. MANAGEMENT AND OUTCOME: Auto-aggression syndrome with gastrointestinal, hepatic, and dermatologic involvement as demonstrated by skin punch biopsy, elevated reg3α, ST2, elafin, eosinophilia, transaminitis, and persistent diarrhea beyond the engraftment period were noted. Topical and systemic steroids with a prolonged taper resulted in symptom resolution. DISCUSSION: Acute graft-versus-host disease is a complication once considered unique to allogeneic stem cell transplant recipients, but a similar syndrome termed "auto-aggression syndrome" may be seen following autologous transplant. Auto-aggression syndrome should be suspected when complications extend beyond the normal engraftment syndrome period following autologous transplant, particularly in people with multiple myeloma, and/or those who have received prior immunomodulating therapy. There should be a low threshold for obtaining biopsies in the setting of suspected auto-aggression syndrome. Early recognition and prompt initiation of corticosteroids with prolonged tapers may prevent auto-aggression syndrome relapse and readmissions.

T cells, particularly activated CD4+ cells, maintain anti-CD20-mediated NK cell viability and antibody dependent cellular cytotoxicity.

Anti-CD20 monoclonal antibody (mAb) therapy is a mainstay of therapy for B cell malignancies, however many patients fail to respond or eventually develop resistance. The current understanding of mechanisms responsible for this resistance is limited. When peripheral blood mononuclear cells of healthy donors were cultured with Raji cells for 7 days, rituximab (RTX) induced NK cell-mediated antibody-dependent cellular cytotoxicity (ADCC), enhanced NK cell viability and increased or maintained NK expression of CD56, CD16, CD57 and KIR. T cells, mainly CD4+, mediated these changes in a contact-dependent manner, with local T cell production of IL2 playing a central role. Similar findings were found when autologous B cells were used as target cells demonstrating the need for T cell help was not due to allogenic reaction. Results with other anti-CD20 and anti-EGFR antibodies were consistent. Small numbers of T cells activated by anti-CD3/CD28 beads or bispecific antibody enhanced RTX-mediated NK cell ADCC, viability and phenotypical changes. Pathway analysis of bulk NK cell mRNA sequencing after activation by RTX with and without T cells was consistent with T cells maintaining the viability of the activated NK cells. These findings suggest T cell help, mediated in large part by local production of IL2, contributes to NK cell ADCC and viability, and that activating T cells in the tumor microenvironment, such as through the use of anti-CD3 based bispecific antibodies, could enhance the efficacy of anti-CD20 and other mAb therapies where NK-mediated ADCC is a primary mechanism of action.

Surveillance imaging during first remission in follicular lymphoma does not impact overall survival.

BACKGROUND: Although many patients with follicular lymphoma (FL) undergo routine radiographic surveillance during their first remission, no consensus exists on the modality, duration, frequency, or need for routine imaging studies. The authors retrospectively examined the effect of surveillance imaging on relapse detection and overall survival (OS) in patients with FL. METHODS: Patients with newly diagnosed FL who had a response to induction therapy were identified from the Lymphoid Malignancies Enterprise Architecture Database (LEAD) at Emory University and from the Molecular Epidemiology Resource (MER) of the University of Iowa/Mayo Clinic. Patients were evaluated for both relapse and method of relapse detection (ie, clinical concerns vs radiologic detection through surveillance imaging in an asymptomatic patient). RESULTS: Of 148 patients in the LEAD cohort, 55 (37%) relapsed, and the majority (n = 35; 64%) of relapses were detected clinically. In the MER cohort, 63 of 177 relapses (54%) were detected clinically. There was no significant difference in OS from the date of diagnosis between the 2 methods of relapse detection in the LEAD (hazard ratio [HR], 0.61; 95% CI, 0.13-2.94; P = .54) and MER (HR, 1.02; 95% CI, 0.47-2.21; P = .96) cohorts. Similarly, there was no significant difference in OS from the date of relapse between the 2 methods of relapse detection in the LEAD (HR, 0.47; 95% CI, 0.10-2.27; P = .35) and MER (HR, 1.02; 95% CI, 0.47-2.21; P = .96) cohorts. CONCLUSIONS: These findings suggest a limited role for routine surveillance imaging in patients with FL who complete front-line therapy. Future studies should evaluate which patients may benefit from a more aggressive surveillance approach and should explore novel methods of relapse detection.

Risk Score for the Development of Veno-Occlusive Disease after Allogeneic Hematopoietic Cell Transplant.

A risk score identifying patients at high risk for veno-occlusive disease (VOD) may aid efforts to study preventive strategies for this uncommon complication of hematopoietic cell transplantation (HCT). Patients receiving a first allogeneic HCT between 2008 and 2013 as reported to the Center for International Blood and Marrow Transplant Research (N = 13,097) were randomly divided into training and validation sets. Independent prognostic factors for development of VOD by day +100 after HCT were identified with a multivariate logistic regression model. A risk score was constructed in the training set using the significant factors and confirmed in the validation set. Baseline characteristics of the training and validation sets were balanced. In total, 637 patients (4.9%) developed VOD by day +100. Younger age, positive hepatitis B/C serology, lower Karnofsky performance scale score, use of sirolimus, disease, disease status at transplant, and conditioning regimen were independent prognostic factors. Myeloablative conditioning regimens were associated with higher risk of VOD. Busulfan-based myeloablative conditioning regimens guided by pharmacokinetic monitoring were associated with higher risk than those without pharmacokinetic monitoring. Patients were stratified into 4 distinct, statistically significantly different groups by their risk score percentile. This pretransplant risk score successfully stratified allogeneic HCT patients by risk of developing VOD, was validated in an independent set, and demonstrated strong discriminatory ability to identify a high-risk cohort.

A rash diagnosis: Gemcitabine-associated pseudocellulitis.

Gemcitabine is an antitumor agent with broad clinical application. The most common cutaneous toxicities are mild rash and pruritus; however, a severe 'pseudocellulitis' rash, which resembles infectious cellulitis in clinical presentation, has increasingly been recognized as a rare complication of this agent. Though the specific pathophysiology related to this condition is not clear, it has been observed to occur primarily in regions of significant lymphadenopathy or prior radiation exposure typically after 24-48 h following administration of gemcitabine. It is a self-limiting reaction, with most cases resolving within two to seven days of onset without any specific treatment for the rash. Treatment with gemcitabine may be safely continued in patients with this complication, though recurrence of the rash is common following repeated doses. We report a case of biopsy confirmed gemcitabine associated pseudocellulitis in a patient treated for metastatic pancreatic adenocarcinoma. Knowledge of this complication is important to avoid unwarranted hospitalizations and antibiotic use in patients treated with gemcitabine.

Defibrotide for Treatment of Severe Veno-Occlusive Disease in Pediatrics and Adults: An Exploratory Analysis Using Data from the Center for International Blood and Marrow Transplant Research.

Veno-occlusive disease (VOD) is an early and serious complication of hematopoietic cell transplantation (HCT) that is associated with inferior survival, particularly when it is complicated by multiorgan failure (severe VOD). We evaluated the efficacy of defibrotide in the treatment of severe VOD using observational data from the Center for International Blood and Marrow Transplant Research (CIBMTR). Eight thousand three hundred forty-one patients treated by HCT between 2008 and 2011 were identified from the CIBMTR clinical database; 3.2% met criteria for VOD and 1.2% met criteria for severe VOD. Patients with a diagnosis of VOD as reported to the CIBMTR by their transplanting centers, who had no prior history of cirrhosis, and who had a maximum total bilirubin level > 2.0 mg/dL by day +100 post-HCT were selected for study. Severe VOD was defined as VOD occurring in the setting of renal impairment requiring dialysis or any noninfectious pulmonary abnormality. Patients with severe VOD were divided into 2 groups for analysis: those treated with defibrotide (n = 41) and those not treated with defibrotide (n = 55). Patients in the nondefibrotide group were older, were more likely to be male, were more likely to have a history of previous fungal infection, and had a higher proportion of clinically significant pre-existing disease or organ impairment. Survival rate at day +100 was 39% (95% CI, 24.8% to 54.3%) in patients receiving defibrotide and 30.9% (95% CI, 19.5% to 43.6%) in those not receiving defibrotide. Resolution rate of VOD at day +100 was 51% in the defibrotide group and 29% in the nondefibrotide group (difference, 22.1%; 95% CI, 2.6% to 42%). The results of our study are consistent with previously reported experiences with defibrotide, confirm the poor outcome of this syndrome, and suggest defibrotide is effective in the treatment of severe VOD.

Difficult to swallow: warm autoimmune hemolytic anemia in a Jehovah's Witness treated with hemoglobin concentrate complicated by achalasia.

BACKGROUND: The acute treatment of severe warm autoimmune hemolytic anemia (wAIHA) is focused on maximizing the oxygen delivery capacity of the patient's circulation and reversal of the underlying autoimmune process. The most effective means of preventing ischemic injury acutely is replacement of red blood cells (RBCs) via allogeneic RBC transfusion. However, in cases where this is not an option, other strategies must be considered including the use of hemoglobin-based oxygen carriers (HBOCs). CASE REPORT: Herein we present a case of a 70-year-old Jehovah's Witness with wAIHA who required emergent HBOC-201 to prevent life-threatening decompensation. The treatment was complicated by hypertension and achalasia likely related to the nitric oxide scavenging effects of HBOC-201. These side effects were managed appropriately, and the patient ultimately recovered. CONCLUSION: Early recognition of the need and ready familiarity with its properties on the part of the physician are critical to the utilization of HBOC-201 in a safe and timely fashion.

Plerixafor and abbreviated-course granulocyte colony-stimulating factor for mobilizing hematopoietic progenitor cells in light chain amyloidosis.

Cytokine-based mobilization in light chain (AL) amyloidosis is frequently complicated by fluid overload, weight gain, cardiac arrhythmias, and peri-mobilization mortality. We analyzed hematopoietic progenitor cells (HPC) mobilization outcomes in 49 consecutive AL amyloidosis patients at our institution between 2004 and 2013 with granulocyte colony-stimulating factor (G) (10 µg/kg/day) (n = 25) versus an institutional protocol to limit G exposure using plerixafor (P) (.24 mg/kg s.c. starting day 3 of G 10 µg/kg) (n = 24). G+P strategy yielded higher total CD34(+) cells/kg (12.8 × 10(6) versus 6.3 × 10(6); P < .001) and CD34(+) cells/kg collected on day 1 (10.8 × 10(6) versus 4.9 × 10(6), P = .004) compared with the G cohort. More G+P patients collected ≥5 × 10(6) CD34(+) HPCs/kg (22 versus 16, P = .02) and ≥ 10 × 10(6) CD34(+) HPCs/kg (13 versus 5, P = .01). Four patients (16%) had mobilization failure with G; none with G+P. Peri-mobilization weight gain was lower with G+P strategy (median weight gain 1 versus 7 pounds, P = .009). Numbers of apheresis sessions (median, 1 versus 1, P = .52), number of hospitalization days (median, 1.1 versus 1.6, P = .52), transfusions, use of intravenous antibiotics, and cardiac arrhythmias were similar. In conclusion, our study demonstrates that upfront use of G+P as a mobilization strategy results in superior HPC collection, no mobilization failures, and less weight gain than G alone.

Clinical outcomes of patients receiving three versus four doses of methotrexate with concomitant antithymocyte globulin in match unrelated donor allogeneic stem cell transplant: A single-center experience.

Methotrexate (MTX) doses on days +1, +3, +6, and +11 after match unrelated donor allogeneic stem cell transplant (MUD HSCT) is a common graft-versus-host disease (GVHD) prophylaxis regimen. However, the overlapping toxicity of MTX with conditioning chemotherapy sometimes warrants the omission of the fourth dose of MTX. Prior single-institution studies showed conflicting results comparing the outcomes of patients who received three versus four doses of MTX, but to our knowledge, the effect of concomitant antithymocyte globulin (ATG) has not been reported. Charts of patients who underwent MUD HSCT between 2009 and 2023 were reviewed. Patients received rabbit ATG (Thymoglobulin), given at 0.5 mg/kg on day -3, 2 mg/kg on day -2, and 2.5 mg/kg on day -1. MTX is given at 15 mg/m2 on day +1 and 10 mg/m2 on days +3, +6, and +11. Severe mucositis was the most common indication for day +11 MTX omission (82%). We identified 292 patients (116 in 3 dose cohort and 176 in 4 dose cohort). Median follow-up was 23 months (range 1-151). Patients in the 4 doses cohort were more frequently male (68% vs. 50%, p < 0.01), received a reduced intensity conditioning regimen (38.0% vs. 22%, p < 0.01), were older (median 58 vs. 54 years, p = 0.02), and received a transplant in the earlier era (median HSCT year 2014 vs. 2018, p < 0.01). A statistically significant difference was not evidenced between the cohorts for the following outcomes: acute GVHD (aGVHD) (HR 1.1, 95% CI 0.9-1.5), chronic GVHD (cGVHD) (HR 1.3, 95% CI 0.8-1.6), relapse-free survival (RFS) (HR 1.0, 95% CI 0.6-1.5), non-relapse mortality (NRM) (HR 1.4, 95% CI 0.9-2.2), and overall survival (OS) (HR 1.2, 95% CI 0.9-1.7). Both cohorts had similar median time to neutrophil engraftment at 14 days. When ATG is incorporated, omission of day +11 MTX does not significantly impact the rate of engraftment or cumulative incidence of aGVHD, cGVHD, RFS, NRM, and OS.

A Risk Stratification System in Myeloma Patients with Autologous Stem Cell Transplantation.

Autologous stem cell transplantation (ASCT) has been a mainstay in myeloma treatment for over three decades, but patient prognosis post-ASCT varies significantly. In a retrospective study of 5259 patients with multiple myeloma (MM) at the University of Arkansas for Medical Sciences undergoing ASCT with a median 57-month follow-up, we divided the dataset into training (70%) and validation (30%) subsets. Employing univariable and multivariable Cox analyses, we systematically assessed 29 clinical variables, identifying crucial adverse prognostic factors, such as extended duration between MM diagnosis and ASCT, elevated serum ferritin, and reduced transferrin levels. These factors could enhance existing prognostic models. Additionally, we pinpointed significant poor prognosis markers like high serum calcium and low platelet counts, though they are applicable to a smaller patient population. Utilizing seven easily accessible high-risk variables, we devised a four-stage system (ATM4S) with primary stage borders determined through K-adaptive partitioning. This staging system underwent validation in both the training dataset and an independent cohort of 514 ASCT-treated MM patients from the University of Iowa. We also explored cytogenetic risk factors within this staging system, emphasizing its potential clinical utility for refining prognostic assessments and guiding personalized treatment approaches.

Safety and Efficacy of Teclistamab in Patients with Relapsed/Refractory Multiple Myeloma: A Real-World Experience.

Teclistamab is a B cell maturation antigen (BCMA)-directed bispecific antibody approved for relapsed/refractory multiple myeloma (RRMM) on the basis of the phase I/II MajesTEC-1 trial. Here we report clinical outcomes with standard-of-care teclistamab in a real-world RRMM population. A total of 106 patients from 5 academic centers who received teclistamab from August 2022 to August 2023 were included in this retrospective analysis, 83% of whom would have been considered ineligible for the MajesTEC-1 trial. All patients were triple-class exposed, 64% were penta-class refractory, and 53% had received prior BCMA-directed therapy. Cytokine release syndrome was observed in 64% of patients, and only 1 event was grade ≥3, whereas immune effector cell-associated neurotoxicity syndrome was observed in 14% of patients (3 events were grade 3 or 4). One-third (31%) of patients experienced at least 1 infection, with nearly half of these infections graded as severe (grade ≥3). The overall response rate (ORR) was 66%, and the complete or better response rate was 29%. The ORR was 47% for patients with extramedullary disease (EMD), 59% for patients with prior BCMA-directed therapy exposure, and 68% for patients with penta-refractory disease. At a median follow-up of 3.8 months, the median progression-free survival (PFS) was 5.4 months (95% CI, 3.4 months to not reached), while median overall survival was not reached. Patients with Eastern Cooperative Oncology Group Performance Status ≥2, EMD, and age ≤70 years had inferior PFS on multivariable analysis. Our study demonstrates reasonable safety and good efficacy of teclistamab in patients with RRMM treated in a real-world setting.

Prognostic Biomarkers for Hepatic Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome in Myeloablative Allogeneic Hematopoietic Cell Transplantation: Results from the Blood and Marrow Transplant Clinical Trials Network 1202 Study.

Hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a potentially life-threatening complication of hematopoietic cell transplantation (HCT). This study aimed to determine a blood biomarker signature early post-HCT that identifies patients at high risk for VOD/SOS. A set of 23 plasma biomarkers, selected from the VOD/SOS literature, was measured on days 0, 7, and 14 after myeloablative HCT using blood samples from patients enrolled in the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) Protocol 1202. Eligible cases were diagnosed with VOD/SOS in BMT CTN 1202 using the Baltimore criteria. Controls (without VOD/SOS) were matched to cases for conditioning regimen and age. Significant biomarkers were identified using the Bonferroni-adjusted Wilcoxon rank-sum test (P ≤ .002). Thirty-three patients with mild or severe VOD/SOS were identified (cases) and matched to 107 controls. Two, 8, and 5 biomarkers measured from the plasma of these patients were significantly associated with the development of VOD/SOS at days 0, 7, and 14, respectively, with the strongest associations on days 7 and 14. Biomarker associations were stronger for severe VOD/SOS risk and were stronger prognostic markers for VOD/SOS cases occurring within 28 days of HCT. Hyaluronan was most strongly associated with VOD/SOS risk, with an area under the receiver operating characteristic curve (AUC) of .81 on day 7 and .79 on day 14. Multivariate models of up to 5 biomarkers generated AUCs ranging from .82 to .85. All associations with VOD/SOS risk were independent of clinical risk factors. This study confirms previously identified biomarkers of VOD/SOS risk and identified novel prognostic biomarker signatures that identify patients at risk for VOD/SOS shortly after HCT. Multivariate analysis suggests that a combination of up to 5 of these protein biomarkers may provide a prognostic tool for identifying patients at risk for VOD/SOS.

Impact of Public Reporting of Center-Specific Survival Analysis Scores on Patient Volumes at Hematopoietic Cell Transplant Centers.

The Center for International Blood and Marrow Transplant Research reports the outcomes of allogeneic hematopoietic cell transplantation (alloHCT) at United States transplantation centers (TC) annually through its Center-Specific Survival Analysis (CSA). The CSA compares the actual 1-year overall survival (OS) and predicted 1-year OS rate after alloHCT at each TC, which is then reported as 0 (OS as expected), -1 (OS worse than expected), or 1 (OS better than expected). We evaluated the impact of public reporting of TC performance on their alloHCT patient volumes. Ninety-one TCs that serve adult or combined adult and pediatric populations and had CSA scores reported for 2012-2018 were included. We analyzed prior-calendar-year TC volume, prior-calendar-year CSA score, whether the CSA score had changed in the prior year from two years earlier, calendar year, TC type (adult only vs. combined adult and pediatric), and years of alloHCT experience for their impact on patient volumes. A CSA score of -1, as compared with 0 or 1, was associated with an 8% to 9% reduction in the mean TC volume (P < 0.001) in the subsequent year, adjusting for the prior year center volume. Additionally, being a TC neighboring an index TC with a -1 CSA score, was associated with a 3.5% increase in mean TC volume (P = 0.04). Our data show that public reporting of CSA scores is associated with changes in alloHCT volumes at TCs. Additional investigation into the causes of this shift in patient volume and the impact on outcomes is ongoing.

Impact of second primary malignancy post-autologous transplantation on outcomes of multiple myeloma: a CIBMTR analysis.

The overall survival (OS) has improved significantly in multiple myeloma (MM) over the last decade with the use of proteasome inhibitor and immunomodulatory drug-based combinations, followed by high-dose melphalan and autologous hematopoietic stem cell transplantation (auto-HSCT) and subsequent maintenance therapies in eligible newly diagnosed patients. However, clinical trials using auto-HSCT followed by lenalidomide maintenance have shown an increased risk of second primary malignancies (SPM), including second hematological malignancies (SHM). We evaluated the impact of SPM and SHM on progression-free survival (PFS) and OS in patients with MM after auto-HSCT using CIBMTR registry data. Adult patients with MM who underwent first auto-HSCT in the United States with melphalan conditioning regimen from 2011 to 2018 and received maintenance therapy were included (n = 3948). At a median follow-up of 37 months, 175 (4%) patients developed SPM, including 112 (64%) solid, 36 (20%) myeloid, 24 (14%) SHM, not otherwise specified, and 3 (2%) lymphoid malignancies. Multivariate analysis demonstrated that SPM and SHM were associated with an inferior PFS (hazard ratio [HR] 2.62, P < .001 and HR 5.01, P < .001, respectively) and OS (HR 3.85, P < .001 and HR 8.13, P < .001, respectively). In patients who developed SPM and SHM, MM remained the most frequent primary cause of death (42% vs 30% and 53% vs 18%, respectively). We conclude the development of SPM and SHM leads to a poor survival in patients with MM and is an important survivorship challenge. Given the median survival for MM continues to improve, continued vigilance is needed to assess the risks of SPM and SHM with maintenance therapy post-auto-HSCT.