Dose-Adjusted EPOCH Plus Inotuzumab Ozogamicin in Adults With Relapsed or Refractory B-Cell ALL: A Phase 1 Dose-Escalation Trial.

Importance: Options for adults with relapsed or refractory B-cell acute lymphoblastic leukemia or lymphoma (B-ALL) are limited, and new approaches are needed. Inotuzumab ozogamicin (InO) has been combined with low-intensity chemotherapy, with modest improvements over historical controls, and dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (DA-EPOCH) treatment is safe and active for newly diagnosed ALL. Objective: To assess the safety and clinical activity of DA-EPOCH and InO in adults with relapsed or refractory B-ALL. Design, Setting, and Participants: This single-center, single-arm, nonrandomized, phase 1 dose-escalation trial included adults with relapsed or refractory CD22+ B-ALL and was conducted between September 2019 and November 2022. At least 5% blood or marrow blasts or measurable extramedullary disease (EMD) was required for enrollment. Interventions: DA-EPOCH was given on days 1 to 5, while InO was given on day 8 and day 15 of a 28-day cycle. Three dose levels were studied using a bayesian optimal interval design. Main Outcomes and Measures: The primary outcome was the maximum tolerated dose of InO when combined with DA-EPOCH, defined as the highest dose level that produced a rate of dose-limiting toxicity below 33%. Secondary objectives included response rates, survival estimates, and descriptions of toxic effects. Results: A total of 24 participants were screened and enrolled (median age, 46 [range, 28-76] years; 15 [62%] male). The median number of lines of prior therapy was 3 (range, 1-12). Three of 11 participants (27%) treated at the highest dose level (InO, 0.6 mg/m2, on day 8 and day 15) experienced dose-limiting toxicity, making this the maximum tolerated dose. No deaths occurred during the study, and only 1 patient (4%; 95% CI, 0.1%-21%) developed sinusoidal obstructive syndrome after poststudy allograft. The morphologic complete response rate was 84% (95% CI, 60%-97%), 88% (95% CI, 62%-98%) of which was measurable residual disease negative by flow cytometry. Five of 6 participants with EMD experienced treatment response. The overall response rate was 83% (95% CI, 63%-95%). Median overall survival, duration of response, and event-free survival were 17.0 (95% CI, 8.4-not reached), 15.0 (95% CI, 6.7-not reached), and 9.6 (95% CI, 4.5-not reached) months, respectively. Conclusions: In this study, adding InO to DA-EPOCH in adults with relapsed or refractory B-ALL was feasible, with high response rates and sinusoidal obstructive syndrome occurring rarely in a heavily pretreated population. Many patients were able to proceed to poststudy consolidative allogeneic hematopoietic cell transplant and/or chimeric antigen receptor T-cell therapy. Further investigation of this combination is warranted. Trial Registration: ClinicalTrials.gov Identifier: NCT03991884.

Optimizing Autologous Stem Cell Transplantation in Multiple Myeloma: The Impact of Intensive Chemomobilization.

BACKGROUND: Most transplant-eligible multiple myeloma (MM) patients undergo autologous peripheral blood stem cell collection (PBSC) using G-CSF with on-demand plerixafor (G±P). Chemomobilization (CM) can be used as a salvage regimen after G±P failure or for debulking residual tumor burden ahead of autologous peripheral blood stem cell transplantation (ASCT). Prior studies utilizing cyclophosphamide-based CM have not shown long-term benefit. OBJECTIVES: At our center, intensive CM (ICM) using a PACE- or HyperCVAD-based regimen has been used to mitigate "excessive" residual disease based on plasma cell burden or MM-related biomarkers. Given the lack of efficacy of non-intensive CM, we sought to determine the impact of ICM on event-free survival (EFS), defined as death, progressive disease, or unplanned treatment escalation. STUDY DESIGN: We performed a retrospective study of newly diagnosed MM patients who collected autologous PBSCs with the intent to proceed immediately to ASCT at our center between 7/2020 and 2/2023. Patients were excluded if they underwent a tandem autologous or sequential autologous-allogeneic transplant, had primary plasma cell leukemia, received non-ICM treatment (i.e., cyclophosphamide and/or etoposide), or had previously failed G±P mobilization. To appropriately evaluate the impact of ICM among those who potentially could have received it, we utilized a propensity score matching (PSM) approach whereby ICM patients were compared to a cohort of non-CM patients matched on pre-ASCT factors most strongly associated with the receipt of ICM. RESULTS: Of 451 patients identified, 61 (13.5%) received ICM (PACE-based, n=45; hyper-CVAD-based, n=16). Post-ICM/pre-ASCT, 11 patients (18%) required admission for neutropenic fever and/or infection. Among 51 evaluable patients, the overall response rate was 31%; however, 46 of 55 evaluable patients (84%) saw a reduction in M-spike and/or involved FLCs. Among those evaluated with longitudinal peripheral blood flow cytometry (n=8), 5 patients (63%) cleared circulating blood PCs post-ICM. Compared to patients mobilized with non-CM, ICM patients collected a slightly greater median number of CD34+ cells (10.8 vs 10.2 × 106/kg, p=.018). The median follow-up was 30.6 months post-ASCT. In a PSM multivariable analysis, ICM was associated with significantly improved EFS (HR 0.30, 95% CI 0.14 to 0.67, p=.003), but not improved OS (HR 0.38, 95% CI 0.10 to 1.44, p=.2). ICM was associated with longer post-ASCT inpatient duration (+4.1 days, 95% CI, 2.4 to 5.8, p<.001), more febrile days (+0.96 days, 95% CI 0.50 to 1.4, p<.001), impaired platelet engraftment (HR 0.23, 95% CI 0.06 to 0.87, p=.031), more bacteremia (OR 3.41, 95% CI 1.20 to 9.31, p=.018), and increased antibiotic usage (cefepime: +2.3 doses, 95% CI 0.39 to 4.1, p=.018; vancomycin: +1.0 doses, 95% CI 0.23 to 1.8, p=.012). CONCLUSIONS: ICM was independently associated with improved EFS in a matched analysis involving MM patients with excessive disease burden at pre-ASCT workup. This benefit came at the cost of longer inpatient duration, more febrile days, greater incidence of bacteremia, and increased antibiotic usage in the immediate post-ASCT setting. Our findings suggest that ICM could be considered for a subset of MM patients, but its use must be weighed carefully against additional toxicity.

HA-1-targeted T cell receptor (TCR) T cell therapy for recurrent leukemia after hematopoietic stem cell transplantation.

Relapse is the leading cause of death after allogeneic hematopoietic stem cell transplantation (HCT) for leukemia. T cells engineered by gene transfer to express T cell receptors (TCR; TCR-T) specific for hematopoietic-restricted minor histocompatibility (H) antigens may provide a potent selective anti-leukemic effect post-HCT. We conducted a phase I clinical trial employing a novel TCR-T product targeting the minor H antigen HA-1 to treat or consolidate treatment of persistent or recurrent leukemia and myeloid neoplasms. The primary objective was to evaluate the feasibility and safety of administration of HA-1 TCR-T post-HCT. CD8+ and CD4+ T cells expressing the HA-1 TCR and a CD8-co-receptor were successfully manufactured from HA-1 disparate HCT donors. One or more infusions of HA-1 TCR-T following lymphodepleting chemotherapy were administered to nine HCT recipients who had developed disease recurrence post-HCT. TCR-T cells expanded and persisted in vivo after adoptive transfer. No dose-limiting toxicities occurred. Although the study was not designed to assess efficacy, four patients achieved or maintained complete remissions following lymphodepletion and HA-1 TCR-T, with one ongoing at >2 years. Single-cell RNA sequencing of relapsing/progressive leukemia after TCR-T therapy identified upregulated molecules associated with T cell dysfunction or cancer cell survival. HA-1 TCR-T therapy appears feasible and safe and shows preliminary signals of efficacy. This clinical trial is registered at clinicaltrials.gov as NCT03326921.

Hypertension treatment for patients receiving ibrutinib: a multicenter retrospective study.

ABSTRACT: Although Bruton tyrosine kinase inhibitors (BTKis) are generally well tolerated and less toxic than chemotherapy alternatives used to treat lymphoid malignancies, BTKis like ibrutinib have the potential to cause new or worsening hypertension (HTN). Little is known about the optimal treatment of BTKi-associated HTN. Randomly selected patients with lymphoid malignancies on a BTKi and antihypertensive drug(s) and with at least 3 months of follow-up data were sorted into 2 groups: those diagnosed with HTN before BTKi initiation (prior-HTN), and those diagnosed with HTN after BTKi initiation (de novo HTN). Generalized estimating equations assessed associations between time varying mean arterial pressures (MAPs) and individual anti-HTN drug categories. Of 196 patients included in the study, 118 had prior-HTN, and 78 developed de novo HTN. Statistically significant mean MAP reductions were observed in patients with prior-HTN who took ß blockers (BBs) with hydrochlorothiazide (HCTZ), (-5.05 mmHg; 95% confidence interval [CI], 10.0 to -0.0596; P = .047), and patients diagnosed with de novo HTN who took either an angiotensin converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) with HCTZ (-5.47 mmHg; 95% CI, 10.9 to -0.001; P = .05). These regimens also correlated with the greatest percentages of normotensive MAPs. Treatment of HTN in patients taking a BTKi is challenging and may require multiple antihypertensives. Patients with prior-HTN appear to benefit from combination regimens with BBs and HCTZ, whereas patients with de novo HTN appear to benefit from ACEi/ARBs with HCTZ. These results should be confirmed in prospective studies.

Circulating cancer-specific CD8 T cell frequency is associated with response to PD-1 blockade in Merkel cell carcinoma.

Understanding cancer immunobiology has been hampered by difficulty identifying cancer-specific T cells. Merkel cell polyomavirus (MCPyV) causes most Merkel cell carcinomas (MCCs). All patients with virus-driven MCC express MCPyV oncoproteins, facilitating identification of virus (cancer)-specific T cells. We studied MCPyV-specific T cells from 27 patients with MCC using MCPyV peptide-HLA-I multimers, 26-color flow cytometry, single-cell transcriptomics, and T cell receptor (TCR) sequencing. In a prospective clinical trial, higher circulating MCPyV-specific CD8 T cell frequency before anti-PD-1 treatment was strongly associated with 2-year recurrence-free survival (75% if detectable, 0% if undetectable, p = 0.0018; ClinicalTrial.gov: NCT02488759). Intratumorally, such T cells were typically present, but their frequency did not significantly associate with response. Circulating MCPyV-specific CD8 T cells had increased stem/memory and decreased exhaustion signatures relative to their intratumoral counterparts. These results suggest that cancer-specific CD8 T cells in the blood may play a role in anti-PD-1 responses. Thus, strategies that augment their number or mobilize them into tumors could improve outcomes.

Craniospinal irradiation for CNS leukemia: rates of response and durability of CNS control.

PURPOSE: Management of CNS involvement in leukemia may include craniospinal irradiation (CSI), though data on CSI efficacy are limited. METHODS: We retrospectively reviewed leukemia patients who underwent CSI at our institution between 2009 and 2021 for CNS involvement. CNS local recurrence (CNS-LR), any recurrence, progression-free survival (PFS), CNS PFS, and overall survival (OS) were estimated. RESULTS: Of thirty-nine eligible patients treated with CSI, most were male (59%) and treated as young adults (median 31 years). The median dose was 18 Gy to the brain and 12 Gy to the spine. Twenty-five (64%) patients received CSI immediately prior to allogeneic hematopoietic cell transplant, of which 21 (84%) underwent total body irradiation conditioning (median 12 Gy). Among 15 patients with CSF-positive disease immediately prior to CSI, all 14 assessed patients had pathologic clearance of blasts (CNS-response rate 100%) at a median of 23 days from CSI start. With a median follow-up of 48 months among survivors, 2-year PFS and OS were 32% (95% CI 18-48%) and 43% (95% CI 27-58%), respectively. Only 5 CNS relapses were noted (2-year CNS-LR 14% (95% CI 5-28%)), which occurred either concurrently or after a systemic relapse. Only systemic relapse after CSI was associated with higher risk of CNS-LR on univariate analysis. No grade 3 or higher acute toxicity was seen during CSI. CONCLUSION: CSI is a well-tolerated and effective treatment option for patients with CNS leukemia. Control of systemic disease after CSI may be important for CNS local control. CNS recurrence may reflect reseeding from the systemic space.

Differential Association between Blood Glucose Levels and Nonrelapse Mortality after Allogeneic Hematopoietic Cell Transplantation Based on Presence or Absence of Preexisting Diabetes.

Malglycemia, defined as hyperglycemia, hypoglycemia, or increased glycemic variability, has been associated with increased mortality after allogeneic hematopoietic cell transplantation (HCT). Among critically ill non-HCT recipients with diabetes and poor glycemic control, compared to those without diabetes, stringent blood glucose control has been associated with increased mortality. This study investigated whether a pre-HCT diagnosis of diabetes and the type of pre-HCT diabetes treatment modulate the previously reported negative impact of malglycemia on post-HCT nonrelapse mortality (NRM). We performed a single-institution retrospective analysis of mortality outcomes after allogeneic HCT as a function of post-HCT blood glucose levels, pre-HCT diagnosis of diabetes, and type of pre-HCT diabetes treatment (insulin, no insulin). A total of 1062 patients who underwent allogeneic HCT between 2015 and 2020 were included in this study. Among these patients, 84 (8%) had a pre-HCT diagnosis of diabetes, of whom 38 (4%) used insulin and 46 (4%) used a noninsulin antiglycemic agent. Post-HCT blood glucose values measured within 100 days from HCT, modeled as a continuous nonlinear time-varying covariate, were associated with day-200 NRM, with both lower and higher glycemic values associated with higher NRM compared to normoglycemic values (adjusted P < .0001). The association between post-HCT blood glucose and NRM varied, however, depending on the presence or absence of a pre-HCT diagnosis of diabetes; that is, there was evidence of a statistical interaction between blood glucose levels and diabetes (adjusted P = .008). In particular, the detrimental impact of hyperglycemic values was more pronounced in patients without a pre-HCT diagnosis of diabetes compared to those with a pre-HCT diagnosis of diabetes. As reported previously, higher and lower blood glucose levels measured within 100 days after allogeneic HCT were associated with an increased risk of NRM; however, this association was more pronounced among patients without a pre-HCT diagnosis of diabetes compared to those with a pre-HCT diagnosis of diabetes, suggesting that patients with diabetes are relatively protected from the downstream effects of hyperglycemia. These data support the notion that patients with pre-HCT diabetes may need a different approach to blood glucose management after transplantation compared to those without diabetes. © 2024 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.

Merkel cell carcinoma recurrence risk estimation is improved by integrating factors beyond cancer stage: A multivariable model and web-based calculator.

BACKGROUND: Merkel cell carcinoma (MCC) recurs in 40% of patients. In addition to stage, factors known to affect recurrence risk include: sex, immunosuppression, unknown primary status, age, site of primary tumor, and time since diagnosis. PURPOSE: Create a multivariable model and web-based calculator to predict MCC recurrence risk more accurately than stage alone. METHODS: Data from 618 patients in a prospective cohort were used in a competing risk regression model to estimate recurrence risk using stage and other factors. RESULTS: In this multivariable model, the most impactful recurrence risk factors were: American Joint Committee on Cancer stage (P < .001), immunosuppression (hazard ratio 2.05; P < .001), male sex (1.59; P = .003) and unknown primary (0.65; P = .064). Compared to stage alone, the model improved prognostic accuracy (concordance index for 2-year risk, 0.66 vs 0.70; P < .001), and modified estimated recurrence risk by up to 4-fold (18% for low-risk stage IIIA vs 78% for high-risk IIIA over 5 years). LIMITATIONS: Lack of an external data set for model validation. CONCLUSION/RELEVANCE: As demonstrated by this multivariable model, accurate recurrence risk prediction requires integration of factors beyond stage. An online calculator based on this model (at merkelcell.org/recur) integrates time since diagnosis and provides new data for optimizing surveillance for MCC patients.

Targeted Radiation Delivery before Haploidentical HCT for High-risk Leukemia or MDS Patients Yields Long-term Survivors.

PURPOSE: Hematopoietic cell transplantation (HCT) has curative potential for myeloid malignancies, though many patients cannot tolerate myeloablative conditioning with high-dose chemotherapy alone or with total-body irradiation (TBI). Here we report long-term outcomes from a phase I/II study using iodine-131 (131I)-anti-CD45 antibody BC8 combined with nonmyeloablative conditioning prior to HLA-haploidentical HCT in adults with high-risk relapsed/ refractory acute myeloid or lymphoid leukemia (AML or ALL), or myelodysplastic syndrome (MDS; ClinicalTrials.gov, NCT00589316). PATIENTS AND METHODS: Patients received a tracer diagnostic dose before a therapeutic infusion of 131I-anti-CD45 to deliver escalating doses (12-26 Gy) to the dose-limiting organ. Patients subsequently received fludarabine, cyclophosphamide (CY), and 2 Gy TBI conditioning before haploidentical marrow HCT. GVHD prophylaxis was posttransplant CY plus tacrolimus and mycophenolate mofetil. RESULTS: Twenty-five patients (20 with AML, 4 ALL and 1 high-risk MDS) were treated; 8 had ≥ 5% blasts by morphology (range 9%-20%), and 7 had previously failed HCT. All 25 patients achieved a morphologic remission 28 days after HCT, with only 2 patients showing minimal residual disease (0.002-1.8%) by flow cytometry. Median time to engraftment was 15 days for neutrophils and 23 days for platelets. Point estimates for overall survival and progression-free survival were 40% and 32% at 1 year, and 24% at 2 years, respectively. Point estimates of relapse and nonrelapse mortality at 1 year were 56% and 12%, respectively. CONCLUSIONS: 131I-anti-CD45 radioimmunotherapy prior to haploidentical HCT is feasible and can be curative in some patients, including those with disease, without additional toxicity.

Cryopreservation of Growth Factor-Mobilized Peripheral Blood Stem Cells Does Not Compromise Major Outcomes after Allogeneic Hematopoietic Cell Transplantation: A Single-Center Experience.

During the Coronavirus disease 2019 pandemic, cryopreservation of allogeneic donor stem cell products ensured the availability of products at the start of conditioning for hematopoietic cell transplantation (HCT). Following recommendations from unrelated donor registries, including the National Marrow Donor Program, many centers began to cryopreserve related donor peripheral blood stem cell (PBSC) products. Throughout this process, several centers have published outcomes with cryopreserved versus fresh products, some with conflicting results. Even though cryopreservation was initially considered only a temporary measure driven by the pandemic, potential advantages include greater flexibility of transplantation timing. However, concerns about detrimental effects of cryopreservation, including increased risk of graft rejection, relapse, and consequent mortality, remained. The primary objective of the present study was to describe our center's experience comparing outcomes following PBSC transplantation with cryopreserved versus fresh grafts. This was an observational case study with a retrospective review comparing cryopreserved grafts (n = 213) to a recent historical cohort (controls) using fresh grafts (n = 167). In multivariable analyses, the adjusted hazard ratio (HR) for fresh versus cryopreserved grafts was 1.20 (95% confidence interval [CI], .79 to 1.82; P = .40) for overall mortality, .99 (95% CI, .55 to 1.77; P = .98) for nonrelapse mortality, and .94 (95% CI, .60 to 1.48; P = .80) for relapse. The adjusted HR for platelet engraftment was 1.31 (95% CI, 1.05 to 1.63; P = .02) and the odds ratio of grade III-IV acute GVHD was 1.75 (95% CI, 1.01 to 3.04; P = .05) with fresh grafts compared to cryopreserved grafts. There was no demonstrable difference in the risk of chronic GHVD. Although longer-term follow-up is needed, these data provide preliminary reassurance that in the event of another pandemic or should the logistical need arise in individual patients, cryopreservation of PBSC products is a reasonably safe alternative.

Impact of Donor Statin Treatment on Graft-versus-Host Disease after Allogeneic Hematopoietic Cell Transplantation.

Some retrospective studies have suggested that long-term donor statin use may protect against graft-versus-host disease (GVHD) in patients receiving cyclosporine (CSP)-based immunosuppression after allogeneic hematopoietic cell transplantation (HCT), but prospective studies of short-term treatment of donors with statin have shown conflicting results. We conducted 2 consecutive prospective clinical trials to assess whether donor statin treatment was associated with protection against severe acute GVHD (aGVHD). In a single-arm phase II trial (study 1), we evaluated whether short-term statin treatment of HLA-matched related donors for 14 days before HCT prevented grade III-IV aGVHD. In a prospective observational cohort study (study 2), we evaluated whether longer-term (>14 days) donor statin use was required for GVHD-protective effects. Study 1 was terminated after 6 of the 35 recipients (17%) developed grade III-IV GVHD. For study 2, we identified 135 patients whose unrelated donors had received long-term treatment with statins up to the time of HCT and 4942 patients whose donors had not received long-term statin treatment. The adjusted odds ratio for grade III-IV aGVHD (statin versus no statin) was .83 (95% confidence interval [CI], .46 to 1.50; P = .54). Multivariable analysis showed no statistically significant differences between the 2 groups in the risk of grade II-IV aGVHD, chronic GVHD, nonrelapse mortality, recurrent malignancy, or overall mortality. Among patients receiving CSP-based immunosuppression, including 35 with donors receiving long-term statin treatment and 973 with donors who did not receive statins, the adjusted odds ratio of grade III-IV aGVHD was .30 (95% CI, .07 to 1.35; P = .12). In study 1, short-term statin treatment of donors was ineffective in preventing grade III-IV GVHD. In study 2, in the prespecified subgroup of recipients given CSP-based immunosuppression, nondefinitive evidence suggested that donor statin use was associated with a reduced risk of severe aGVHD.

Revisiting the Utility of Granulocyte Colony-Stimulating Factor Post-Autologous Hematopoietic Stem Cell Transplantation for Outpatient-Based Transplantations.

The use of granulocyte colony-stimulating factor (G-CSF) after autologous stem cell transplantation (ASCT) has been shown to reduce the time to neutrophil engraftment, as well as the duration of hospitalization post-transplantation. However, prior studies have focused on inpatient-based ASCT, where patients are routinely admitted for conditioning and frequently remain hospitalized until signs of neutrophil recovery. Given improvements in post-transplantation care, an increasing number of patients, particularly those receiving ASCT for multiple myeloma, are now undergoing transplantation in an outpatient setting. We hypothesized that the routine use of G-CSF for outpatient-based ASCT might not result in the same benefit with respect to a reduced duration of hospitalization and thus should be reconsidered in this setting. We performed a retrospective cohort study of 633 consecutive patients with multiple myeloma (MM; n = 484) or non-Hodgkin lymphoma (NHL; n = 149) who underwent ASCT between September 2018 and February 2023. Outpatient ASCT comprised 258 (53%) of combined MM and NHL cases. Starting in September 2021, post-transplantation G-CSF was incorporated into the supportive care regimen for all ASCTs. A total of 410 patients (309 with MM, 101 with NHL) underwent ASCT during the pre-G-CSF policy period and 223 (175 with MM, 48 with NHL) did so in the post-G-CSF policy period. The primary outcome focused on the duration of hospitalization within the first 30 days following graft infusion. As expected, after implementation of the G-CSF policy, the time to neutrophil engraftment was reduced in the patients with MM (mean, -2.8 days; P < .0001) and patients with NHL (mean, -2.9 days; P < .0001). However, among the patients with MM, roughly one-half of whom underwent outpatient-based ASCT, the inpatient duration during the first 30 days was not reduced after G-CSF implementation (P = .40). Comparatively, the inpatient duration (mean, -1.8 days; P = .030) was reduced among patients with NHL, all of whom were electively admitted for ASCT. For patients with MM at an outpatient-based transplant center, incorporation of G-CSF post-ASCT resulted in reduced time to neutrophil engraftment but did not significantly reduce the time spent in the inpatient setting through day +30.

Dental evaluation and clearance prior to allogeneic hematopoietic cell transplantation.

INTRODUCTION: Dental examination and stabilization are performed prior to allogeneic hematopoietic cell transplantation to decrease infection risk during neutropenia. Burden of dental disease and treatment need is not well characterized in this population. OBJECTIVES: This report describes the dental status of a cohort of patients within the Chronic Graft-versus-Host Disease Consortium and treatment rendered prior to transplant. METHODS: The cohort included 486 subjects (Fred Hutchinson: n = 245; Dana-Farber: n = 241). Both centers have institutional-based dental clearance programs. Data were retrospectively abstracted from medical records by calibrated oral health specialists. RESULTS: The median age at transplant was 55.9 years, 62.1% were male, and 88% were white. Thirteen patients were edentulous (2.7%). The mean teeth among dentate patients before clearance was 26.0 (SD, 4.6). Dental findings included untreated caries (31.2%), restorations (91.6%), endodontically treated teeth (48.1%), and dental implants (5.7%). Pretransplant procedures during clearance included endodontic therapy (3.6%; mean = 0.1 teeth), restorations (25.1%; mean = 0.7), dental prophylaxis (59.2%), scaling/root planing (5.1%), and extraction (13.2%; mean = 0.3). The mean teeth after clearance was 25.6 (SD, 5.0). CONCLUSIONS: Retrospective analysis of pre-AlloHCT dental data in subjects at two large transplant centers identified low levels of dental need. Findings suggest high access to care.

γ-Secretase inhibitor in combination with BCMA chimeric antigen receptor T-cell immunotherapy for individuals with relapsed or refractory multiple myeloma: a phase 1, first-in-human trial.

BACKGROUND: γ-Secretase inhibitors (GSIs) increase B cell maturation antigen (BCMA) density on malignant plasma cells and enhance antitumour activity of BCMA chimeric antigen receptor (CAR) T cells in preclinical models. We aimed to evaluate the safety and identify the recommended phase 2 dose of BCMA CAR T cells in combination with crenigacestat (LY3039478) for individuals with relapsed or refractory multiple myeloma. METHODS: We conducted a phase 1, first-in-human trial combining crenigacestat with BCMA CAR T-cells at a single cancer centre in Seattle, WA, USA. We included individuals aged 21 years or older with relapsed or refractory multiple myeloma, previous autologous stem-cell transplant or persistent disease after more than four cycles of induction therapy, and Eastern Cooperative Oncology Group performance status of 0-2, regardless of previous BCMA-targeted therapy. To assess the effect of the GSI on BCMA surface density on bone marrow plasma cells, participants received GSI during a pretreatment run-in, consisting of three doses administered 48 h apart. BCMA CAR T cells were infused at doses of 50 × 106 CAR T cells, 150 × 106 CAR T cells, 300 × 106 CAR T cells, and 450 × 106 CAR T cells (total cell dose), in combination with the 25 mg crenigacestat dosed three times a week for up to nine doses. The primary endpoints were the safety and recommended phase 2 dose of BCMA CAR T cells in combination with crenigacestat, an oral GSI. This study is registered with ClinicalTrials.gov, NCT03502577, and has met accrual goals. FINDINGS: 19 participants were enrolled between June 1, 2018, and March 1, 2021, and one participant did not proceed with BCMA CAR T-cell infusion. 18 participants (eight [44%] men and ten [56%] women) with multiple myeloma received treatment between July 11, 2018, and April 14, 2021, with a median follow up of 36 months (95% CI 26 to not reached). The most common non-haematological adverse events of grade 3 or higher were hypophosphataemia in 14 (78%) participants, fatigue in 11 (61%), hypocalcaemia in nine (50%), and hypertension in seven (39%). Two deaths reported outside of the 28-day adverse event collection window were related to treatment. Participants were treated at doses up to 450 × 106 CAR+ cells, and the recommended phase 2 dose was not reached. INTERPRETATIONS: Combining a GSI with BCMA CAR T cells appears to be well tolerated, and crenigacestat increases target antigen density. Deep responses were observed among heavily pretreated participants with multiple myeloma who had previously received BCMA-targeted therapy and those who were naive to previous BCMA-targeted therapy. Further study of GSIs given with BCMA-targeted therapeutics is warranted in clinical trials. FUNDING: Juno Therapeutics-a Bristol Myers Squibb company and the National Institutes of Health.

EASIX-1year and late mortality after allogeneic stem cell transplantation.

Patients with hematological malignancies who survive the first year after allogeneic stem cell transplantation (allo-SCT) without relapse have a substantial risk of nonrelapse mortality (NRM) and missing predictive markers. The Endothelial Activation and Stress Index (EASIX) predicts endothelial complications and NRM early after allo-SCT. We hypothesized that EASIX assessed 1 year after allo-SCT in survivors who were disease free may predict late NRM. Survivors who were relapse-free at 1 year after allo-SCT were retrospectively studied in 2 independent cohorts (training cohort, n = 610; merged validation cohort, n = 852). EASIX determined 1 year after allo-SCT correlated with the overall survival (OS), NRM, and relapse. Serum endothelial and inflammatory markers were measured in the training cohort and correlated with EASIX-1year, which predicted OS and NRM but not relapse risk in both the training and validation cohorts in univariable and multivariable Cox regression analyses. Brier score and c-index analyses validated the univariable EASIX effects. There was no significant interaction between EASIX-1year and incidence of chronic graft-versus-host disease (GVHD) on OS. EASIX-1year predicted the outcome irrespective of preexisting comorbidities. Principal causes of NRM in both training and validation cohorts were infections with and without GVHD as well as cardiovascular complications. EASIX-1year correlated with sCD141 and interleukin-18 but not with C-reactive protein, suppressor of tumorigenicity-2, angiopoietin-2, CXCL9, or CXCL8. To our knowledge, EASIX-1year is the first validated predictor of late overall and NRM. Patients who are high risk as defined by EASIX-1year might be considered for intensified surveillance and prophylactic measures.

Acute kidney injury and chronic kidney disease in umbilical cord blood transplant recipients.

Introduction: Acute kidney injury (AKI) is a frequent early complication post hematopoietic stem cell transplant (HSCT), associated with high morbidity and mortality. Cord blood transplant (CBT) recipients are potentially exposed to more nephrotoxic insults, compared to patients undergoing HSCT from other donor sources. We aimed to identify risk factors for AKI in patients undergoing CBT. We also aimed to identify the impact of AKI on chronic kidney disease (CKD) and survival outcomes by one-year post-CBT. Methods: Adults and children who underwent a first CBT at our Institution were retrospectively evaluated. AKI was staged according to Kidney Disease Improving Global Outcomes (KDIGO) definitions. Cox regression models were used to estimate the association of demographic factors and post-CBT parameters with the cause-specific hazard of AKI. Results: We identified 276 patients. Median age was 32 years, 28% (77/276) were children (<18 years) and 129 (47%) were white. A myeloablative conditioning regimen was administered to 243 patients (88%) and 248 (90%) received cyclosporine for GVHD prophylaxis. One-hundred and eighty-six patients (67%) developed AKI by day 60 post-transplant, with 72 (26%) developing severe AKI (stage 2 and 3). In a multivariable analysis, each increase in bilirubin level of 1 mg/dL was associated with a 23% increase in the risk of severe AKI (adjusted HR 1.23, 95% CI 1.13 - 1.34, p<.0001). Conversely, systemic steroid administration appeared to be protective of severe AKI (unadjusted HR 0.36, 95% CI 0.18 - 0.72, p=.004) in a univariate model . Two-hundred-forty-seven patients were evaluable at the one-year time point. Among those, 100 patients (40%) developed CKD one-year post-CBT. Severe AKI was associated with a higher hazard of non-relapse mortality (adjusted HR=3.26, 95% CI 1.65-6.45, p=.001) and overall mortality (adjusted HR=2.28, 95% CI 1.22-4.27, p=.01). Discussion: AKI is a frequent complication after CBT and is associated with worse outcomes. Questions remain as to the mechanism of the protective role of steroids on kidney function in the setting of CBT.

Role of NKG2D ligands and receptor in haploidentical related donor hematopoietic cell transplantation.

The recurrence of malignancy after hematopoietic cell transplantation (HCT) is the primary cause of transplantation failure. The NKG2D axis is a powerful pathway for antitumor responses, but its role in the control of malignancy after HCT is not well-defined. We tested the hypothesis that gene variation of the NKG2D receptor and its ligands MICA and MICB affect relapse and survival in 1629 patients who received a haploidentical HCT for the treatment of a malignant blood disorder. Patients and donors were characterized for MICA residue 129, the exon 5 short tandem repeat (STR), and MICB residues 52, 57, 98, and 189. Donors were additionally defined for the presence of NKG2D residue 72. Mortality was higher in patients with MICB-52Asn relative to those with 52Asp (hazard ratio [HR], 1.83; 95% confidence interval [CI], 1.24-2.71; P = .002) and lower in those with MICA-STR mismatch than in those with STR match (HR, 0.66; 95% CI, 0.54-0.79; P = .00002). Relapse was lower with NKG2D-72Thr donors than with 72Ala donors (relapse HR, 0.57; 95% CI, 0.35-0.91; P = .02). The protective effects of patient MICB-52Asp with donor MICA-STR mismatch and NKG2D-72Thr were enhanced when all 3 features were present. The NKG2D ligand/receptor pathway is a transplantation determinant. The immunobiology of relapse is defined by the concerted effects of MICA, MICB, and NKG2D germ line variation. Consideration of NKG2D ligand/receptor pairings may improve survival for future patients.

Impact of GVHD prophylaxis on CMV reactivation and disease after HLA-matched peripheral blood stem cell transplantation.

The kinetics of early and late cytomegalovirus (CMV) reactivation after hematopoietic cell transplantation using various methods of graft-versus-host-disease (GVHD) prophylaxis are poorly defined. We retrospectively compared CMV reactivation and disease among 780 seropositive patients given HLA-matched peripheral blood stem cell (PBSC) grafts and calcineurin inhibitor plus posttransplantation cyclophosphamide (PTCy; n = 44), mycophenolate mofetil (MMF; n = 414), or methotrexate (MTX; n = 322). Transplantation occurred between 2007 and 2018; CMV monitoring/management followed uniform standard practice. Hazards of CMV reactivation at various thresholds were compared. Spline curves were fit over average daily viral load and areas under the curve (AUC) within 1 year were calculated. PTCy and MMF were associated with an increased risk of early (day ≤100) CMV reactivation ≥250 IU/mL after multivariate adjustment. The viral load AUC at 1 year was highest with MMF (mean difference = 0.125 units vs MTX group) and similar between PTCy and MTX (mean difference = 0.016 units vs MTX group). CMV disease risk was similar across groups. There was no interaction between GVHD prophylaxis and CMV reactivation on chronic GVHD risk. Despite PTCy-associated increased risk of early CMV reactivation, the CMV disease risk by 1 year was low in HLA-matched PBSC transplant recipients. In contrast, MMF was associated with higher overall CMV viral burden in the 1 year posttransplant. Although different mechanisms of immunosuppressive agents may affect CMV reactivation risk, effective prevention of GVHD may reduce corticosteroid exposure and mitigate infection risk over time.

Transplantation for myeloid neoplasms with antecedent solid tumor.

BACKGROUND: Definitive treatment of acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and myeloproliferative neoplasm (MPN) involves allogeneic hematopoietic stem cell transplantation (allo-HSCT), either with myeloablative (MAC) or reduced-intensity conditioning (RIC). These diseases may arise in patients with a prior solid tumor. The impact of antecedent solid tumor on transplantation decision-making and outcomes is not well defined. METHODS: The authors performed a retrospective cohort study to address this question. A total of 1193 patients who underwent allo-HSCT for AML, MDS, or MPN between January 1, 2010 and December 31, 2018 were included, 102 of whom had a history of prior solid tumor. RESULTS: Patients with prior solid tumor were older (median age, 62.5 vs. 54.9 years; p < .00001) and more frequently were conditioned with RIC (52.5% vs. 27.2%; p < .00001). A higher incidence of acute graft-versus-host disease was observed in patients with prior solid tumor (73.5% vs 66.4%; adjusted odds ratio, 1.65; 95% confidence interval, 1.03-2.65; p = .037), yet overall survival and relapse did not significantly differ. Cytogenetic risk was the dominant risk factor for survival. CONCLUSIONS: Analysis by the authors suggests that patients with antecedent solid tumor and respective therapy can be transplanted successfully. Although selection bias is likely to be a factor, the results are encouraging for patients who come to transplantation after surviving a prior cancer.