Bone Marrow Reserve Research Articles

Matched-pair analysis of mCRPC patients receiving 177Lu-labeled PSMA-targeted radioligand therapy in a 4-week versus 6-week treatment interval

BackgroundThe optimal regimen for 177Lu-labeled prostate-specific membrane antigen-targeted radioligand therapy, including treatment intervals, remains under study, with evidence suggesting shorter intervals could benefit patients with high disease volume and rapid progression. This retrospective analysis evaluated treatment toxicity, PSA response, PSA-progression-free survival (PSA-PFS), and overall survival (OS) in matched cohorts of mCRPC patients receiving 177Lu-PSMA-RLT at 4-week versus 6-week intervals.ResultsA PSA response (PSA decline ≥ 50%) was achieved in 47.8% and 21.7% of patients in the 4-week and 6-week treatment interval groups, respectively (p = 0.12). There was a trend towards longer PSA-PFS in the 4-week group compared to the 6-week group (median PSA-PFS, 26.0 weeks vs. 18.0 weeks; HR 0.6; p = 0.2). Although not statistically significant, there was a trend towards shorter OS in the 4-week group compared to the 6-week group (median OS, 15.1 months vs. 18.4 months; HR 1.3; p = 0.5). The 4-week group had a significantly greater decrease in leucocyte and platelet counts compared to the 6-week group (38.5% vs. 18.2% and 26.7% vs. 10.7%; p = 0.047 and p = 0.02). Severe adverse events were modest in both groups.ConclusionsIntensifying treatment intervals from 6 weeks to 4 weeks showed some improvements in PSA response and PSA-PFS for mCRPC patients, but did not significantly affect OS. Additionally, bone marrow reserve was significantly reduced with the intensified regimen. Therefore, the overall benefit remains uncertain, and further prospective studies are needed to compare 4-week and 6-week intervals regarding toxicity, treatment response, and outcome.

Rejuvenating bone marrow hematopoietic reserve prevents regeneration failure and hepatic decompensation in animal model of cirrhosis.

Bone marrow stem cells (BM-SCs) and their progeny play a central role in tissue repair and regeneration. In patients with chronic liver failure, bone marrow (BM) reserve is severally compromised and they showed marked defects in the resolution of injury and infection, leading to liver failure and the onset of decompensation. Whether BM failure is the cause or consequence of liver failure during cirrhosis is not known. In this study, we aimed to determine the underlying relationship between BM failure and regeneration failure in cirrhosis. C57Bl/6(J) mice were used to develop chronic liver injury through intra-peritoneal administration of carbon tetrachloride (CCl4) for 15 weeks (0.1-0.5 ml/kg). Animals were sacrificed to study the transition of cirrhosis and BM defects. To restore the BM-SC reserve; healthy BM cells were infused via intra-BM infusion and assessed for changes in liver injury, regeneration, and BM-SC reserve. Using a CCl4-induced animal - model of cirrhosis, we showed the loss of BM-SCs reserve occurred before regeneration failure and the onset of non-acute decompensation. Intra-BM infusion of healthy BM cells induced the repopulation of native hematopoietic stem cells (HSCs) in cirrhotic BM. Restoring BM-HSCs reserve augments liver macrophage-mediated clearance of infection and inflammation dampens neutrophil-mediated inflammation, accelerates fibrosis regression, enhances hepatocyte proliferation, and delays the onset of non-acute decompensation. These findings suggest that loss of BM-HSCs reserve underlies the compromised innate immune function of the liver, drives regeneration failure, and the onset of non-acute decompensation. We further provide the proof-of-concept that rejuvenating BM-HSC reserve can serve as a potential therapeutic approach for preventing regeneration failure and transition to decompensated cirrhosis.

Neutropenia in Childhood-A Narrative Review and Practical Diagnostic Approach.

Neutropenia refers to a decrease in the absolute neutrophil count according to age and race norms and poses a common concern in pediatric practice. Neutrophils serve as host defenders and act crucially in acute inflammation procedures. In this narrative review, we systematically present causes of neutropenia in childhood, mainly adopting the pathophysiological classification of Frater, thereby studying (1) neutropenia with reduced bone marrow reserve, (2) secondary neutropenia with reduced bone marrow reserve, and (3) neutropenia with normal bone marrow reserve. Different conditions in each category are thoroughly discussed and practically approached from the clinician's point of view. Secondary mild to moderate neutropenia is usually benign due to childhood viral infections and is expected to resolve in 2-4 weeks. Bacterial and fungal agents are also associated with transient neutropenia, although fever with severe neutropenia constitutes a medical emergency. Drug-induced and immune neutropenias should be suspected following a careful history and a detailed clinical examination. Cytotoxic chemotherapies treating malignancies are responsible for severe neutropenia and neutropenic shock. Rare genetic neutropenias usually manifest with major infections early in life. Our review of taxonomies clinical findings and associates them to specific neutropenia disorders. We consequently propose a practical diagnostic algorithm for managing neutropenic children.

Hematologic toxicity in 177lu-PSMA-617 treatment for mCRPC: Unraveling the impact of PSMA PET bone tumor volume (PSMA-bTTV).

5075 Background: Lutetium-177 prostate-specific membrane antigen (177Lu-PSMA-617) is a life-prolonging treatment approved by the FDA in metastatic castration-resistant prostate cancer (mCRPC), at a very late stage when there frequently reduced bone marrow reserve. We aim to report the incidence of hematologic toxicity during treatment and potential risk factors in a single-center study. Methods: This retrospective single-institution case series included mCRPC patients who underwent at least one cycle of 177Lu-PSMA-617 treatment between June 2022 and January 2024. Hematological parameters were documented at baseline, 3 weeks after each treatment, and before each subsequent treatment administration. Then, we captured the nadir values for each parameter during treatment. Hematologic toxicities were assessed using the Common Terminology Criteria for Adverse Events v5.0, with Grades 3 and 4 considered significant. Multivariable logistic regression analyses were conducted to investigate the association between hematological adverse events and baseline characteristics including PSMA-bTTV, measured by semi-automatic contouring of the PSMA-expressing whole-body bone metastases on pre-treatment PSMA PET. Results: Our study included 138 mCRPC patients (median age: 73y, prior chemotherapy: 92%, prior radiation: 43.5%, bone involvement: 89.1%), who underwent a median of 3 cycles (IQR: 2-5) of 177Lu-PSMA-617 treatment. At baseline, 8 (5.8%) patients had grade 3 anemia, 2 (1.4%) patients had grade 3 leukopenia, and 1 (0.7%) patient had grade 3 thrombocytopenia. Nadir values during treatment indicated that 23 (16.7%) had grade 3 anemia, 5 (3.6%) had grade 3 leukopenia, and 11 (8%) had grade 3 and 4 thrombocytopenia. Multivariable analysis of predisposing factors for hematologic adverse events showed that the PSMA-bTTV was significantly associated with occurrence of any grade ≥3 hematologic toxicity, anemia, and thrombocytopenia after adjusting for other baseline clinical variables (Table). Conclusions: Over 1 in 5 patients with mCRPC experienced significant hematologic adverse events during treatment with 177Lu-PSMA-617. Bone tumor volume is a possible risk factor for developing significant hematologic toxicity. [Table: see text]

Treatment patterns and outcomes by age in metastatic urothelial carcinoma (mUC): A retrospective tertiary cancer center analysis.

582 Background: Older adults with locally advanced or mUC often do not receive optimal first-line (1L) therapy (Rx) and subsequent treatments (Lara et al. ASCO 2016). There are limited randomized data for age-appropriate Rx in older mUC adults. Through our real-world study, we describe the clinical characteristics, treatment patterns, and outcomes among pts with mUC, comparing older to younger adults receiving 1L systemic Rx. Methods: This retrospective IRB-approved study included pts receiving care between 2014 and 2023 at the University of Utah, Huntsman Cancer Institute, a tertiary care National Cancer Institute-Designated Comprehensive Cancer Center. Eligible pts had a confirmed diagnosis of mUC and received 1L chemotherapy or 1L immunotherapy-based regimens. Based on age at receipt of 1L Rx, pts aged 70 years or above were grouped in the ‘older’ group, while rest were included in the ‘younger’ cohort. Survival and Rx-related outcomes of those enrolled inwere excluded. Overall survival (OS) between the two groups was compared using Kaplan-Meier and Cox Regression analysis. All statistical analyses were implemented in R-Studio (v.4.2). Results: We identified 212 eligible mUC pts (103 older vs. 109 younger). Older pts received more immunotherapy-based Rx in the 1L (52.4% vs 35.7%, p=0.02), were more likely to be (73.6% vs. 45.4%, p<0.001), less likely to receive subsequent lines of Rx (median; range: 0 (0-3) vs 1 (0-5), p=0.005) and had lower clinical trial participation (69.9% vs 81.6%, p=0.04)compared to younger pts. For survival outcomes and treatment-related analysis, 160 patients (72 older vs. 88 younger) undergoing approved standard of care were included. Among mUC treated with 1L chemotherapy (n=108), more pts required dose adjustments in older group (23/43 vs 15/65 younger). Older adults received less number of cycles of chemotherapy (median; range: 4 (0-6) vs 5 (1-12), p= 0.03). Older pts had OS comparable to younger pts (11.2 mos vs. 14 mos, p=0.06). Pts from both age groups had similar rates of Rx-related toxicity and healthcare visits, independent of the type of systemic Rx. Conclusions: Older pts with mUC tend to be cis-ineligible and have lower bone marrow reserve. Nevertheless, select pts can be treated with risk-adjusted regimens of chemotherapy and with immunotherapy with comparable outcomes to younger mUC pts in terms of toxicity and outcomes. Validated tools to predict vulnerabilities and excessive chemotherapy-related toxicity in older adults with mUC are available and may help mitigate toxicity by informing Rx adjustments.

Inflammatory Marker Levels, Age, Race and Prior Treatment Burden Independently Predict Delayed Hematologic Recovery after BCMA-Directed CART Therapy in Multiple Myeloma

Inflammatory Marker Levels, Age, Race and Prior Treatment Burden Independently Predict Delayed Hematologic Recovery After BCMA-directed CART Therapy in Multiple Myeloma Introduction: With the advent of two approved anti-BCMA products and several additional investigational cellular therapies, the use of BCMA-directed chimeric antigen receptor T-cell therapy (CART) is expanding for the treatment of multiple myeloma (MM). Prolonged cytopenias have been observed in a subset of CART recipients across products. The etiology and natural history of these cytopenias has not been thoroughly evaluated in the literature. We present a comprehensive multivariable model of hematologic recovery post-CART in an analysis of 140 MM CART recipients from a large academic center. Methods: We retrospectively reviewed electronic health record data for relapsed/refractory MM patients from our institution who received a BCMA-directed CART product between 2017 & 2022. For each patient, all available lab values of hemoglobin (Hgb), platelet count (Plt) and absolute neutrophil count (ANC) were recorded and graded according to CTCAE v5.0 criteria. Missing lab values were linearly interpolated between available measurements. We defined time to recovery for each blood count as the number of days from CART infusion (day 0) until the first day of a 30-day-long period without any grade 3 or 4 (G3/4) values. Time to recovery from any G3/4 myeloid cytopenia (i.e., anemia, thrombocytopenia, and neutropenia) was also calculated. Next, we classified patients according to the CAR-HEMATOTOX scoring system (Rejeski et al, ASH 2022), a tool which incorporates baseline blood counts and inflammatory parameters such as C-reactive protein and ferritin prior to lymphodepletion to predict the risk of post-CART hematotoxicity. Kaplan-Meier curves were generated treating recovery from G3/4 cytopenia as the ‘event’ and censoring patients at the time of PD. A Cox proportional hazards model was used for multivariate analysis. Results: A total of 140 MM patients who received a BCMA-directed CART product at ISMMS were included in the study. 107 patients (76%) received CART as part of a clinical trial and 33 (24%) commercially. Median age at CART infusion was 62 (range 35-83) and median number of prior lines of therapy was 5 (range 1-18). 102/140 patients (73%) were previously treated with high-dose melphalan and autologous stem cell transplantation, of which 23 had more than one prior transplant. Median CAR-HEMATOTOX score was 1 (range 0-6), with 45 patients (33%) classified as HT high (higher inflammatory marker levels prior to lymphodepletion) and 91 (67%) as HT low (lower inflammatory marker levels). Median time to recovery from G3/4 anemia, thrombocytopenia, neutropenia, and any myeloid cytopenia were as follows: 11.5 days, 10 days, 32 days and 40 days, respectively. After censoring 28 patients who had PD before day +120, 112/140 patients (80%) remained evaluable at that time point, of which 105 (94%) had achieved recovery from G3/4 anemia, 94 (84%) from G3/4 thrombocytopenia, 99 (88%) from G3/4 neutropenia, and 88 (79%) from any G3/4 myeloid cytopenia. Four variables were significantly associated with delayed recovery from any G3/4 myeloid cytopenia as compared to others: HT high score (median 63 vs 31 days, p<0.01, Fig. 1A), age at CART infusion ≥50 (42 vs 29 days, p<0.01, Fig. 1B), ≥3 prior lines of therapy (44 vs 14 days, p<0.01, Fig. 1C), and Black race (68 vs 35 days, p=0.02, Fig. 1D). In a multivariate Cox proportional hazards model, all four variables maintained their significance in predicting delayed hematologic recovery after CART. Conclusion: Systemic inflammation and reduced bone marrow reserve due to aging and/or prior therapies were independently associated with delayed recovery from G3/4 myeloid cytopenias in a large, single-center cohort of MM patients treated with BCMA-directed CART therapy. Our study reinforces the predictive capability of CAR-HEMATOTOX in assessing the risk of delayed hematologic recovery after CART. However, we suggest that this tool could be further refined for MM by factoring in variables such as patient age, race, and number of prior lines of therapy.

Azacitidine Plus Venetoclax Maintenance in Acute Myeloid Leukemia Produces Sustained Remissions with Low Toxicity: Results of a Phase 2 Study

Background: Most patients diagnosed with acute myeloid leukemia (AML) achieve remission following induction therapy. However, disease relapse remains a major clinical concern. The QUAZAR AML-001 study demonstrated improved overall and relapse-free survival with oral azacitidine (CC-486) maintenance. We designed a phase 2 study (NCT04062266) to evaluate low doses of azacitidine plus venetoclax as maintenance therapy following both intensive and low-intensity induction in AML. We present updated results of this study with close to 2 years of median follow-up. Methods: Patients ≥ 18 years of age with non-APL AML in first complete remission (CR) or CR with incomplete count recovery (CRi) not immediately eligible for allogeneic stem cell transplantation (SCT) were eligible. Cohort 1 enrolled patients who had received at least 2 cycles of intensive therapy (defined as containing intermediate to high-dose cytarabine). Cohort 2 enrolled patients who had received at least 3 cycles of low-intensity therapy (defined as hypomethylating agent or low-dose cytarabine-based). Patients with positive measurable residual disease (MRD) by flow cytometry were eligible in CR1 or beyond. Other inclusion requirements were ECOG ≤ 3, adequate hepatic/renal function, and adequate bone marrow reserve (defined as absolute neutrophil count > 0.5 x 10 9/L and platelets > 30 x 10 9/L). Treatment consisted of azacitidine 50 mg/m 2 SQ/IV on D1-5 and venetoclax 400 mg PO (adjusted for concomitant CYP3A inhibitors) on D1-14 in 28-day cycles, up to 24 cycles. Venetoclax duration could be reduced to D1-7 per physician discretion to mitigate myelosuppression and dose modifications during subsequent cycles were allowed. Antibacterial, antifungal, and antiviral prophylaxis were recommended in all patients. The primary objective was relapse-free survival (RFS, defined as time from enrollment to progression or death). Secondary objectives included overall survival (OS), safety/toxicity, and MRD clearance. Patients subsequently becoming eligible for SCT were taken off study and censored for analyses at the time of SCT. Results: 35 patients have been enrolled (25 in cohort 1 and 10 in cohort 2). The median age was 47 years in cohort 1 and 71 years in cohort 2. The baseline characteristics are shown in table 1. The median number of cycles given was 9 (range 1-24). 22/35 (63%) patients had 7 days of venetoclax during cycle 1. Median follow-up is currently 20.9 months (m). For the full cohort, the median RFS was not reached (NR; 2-year 60%) and the median OS was NR (2-year 75%). In cohort 1, the median RFS and OS were NR (2-year 71%) and NR (2-year 77%), respectively. In cohort 2, the median RFS and OS were 23.5 m (2-year 34%) and NR (2-year 67%), respectively. When stratified by ELN 2017, patients who were favorable (n=16), intermediate (n=11), and adverse (n=8) had a median RFS of NR (2-year 85%), NR (2-year 64%), and 4.0 m (2-year 0%), respectively. Corresponding median OS were NR (2-year 91%), NR (2-year 76%), and 14.9 m (2-year 27%), respectively. 4/8 (50%) of the ELN adverse patients had complex cytogenetics and/or TP53 mutations. Patients who were MRD-positive at enrollment (n=7, 3 with prior venetoclax exposure) had significantly shorter RFS compared to those who were MRD-negative (median 4.0 m versus NR, p<0.01). Only 2/7 (29%) MRD-positive patients converted to MRD-negative while on maintenance. As mutations in NPM1, IDH1, or IDH2 may sensitize AML to venetoclax, we analyzed RFS based on the presence or absence of these mutations (figure 1). Patients with sensitizing mutations had a trend towards longer RFS (median RFS NR versus 23.5 m, 2-year RFS 79% vs 36%, p=0.08). The most common grade 3/4 adverse events were infections (26%), neutropenia (17%), thrombocytopenia (17%), hypotension (6%), and neutropenic fever (6%). 4 (11%) patients required cycle 2 venetoclax dose reductions. 8 (23%) of patients went off protocol to receive SCT. All observed deaths (n=8) occurred following AML relapse (n=7) or SCT-related complications (n=1). Conclusions: Lower dose azacitidine plus venetoclax is a feasible and safe maintenance strategy in AML. This approach yields encouraging results in MRD-negative patients with non-adverse ELN risk (favorable or intermediate risk). A genetic-guided strategy may help select patients who benefit the most from this combination (i.e. those with NPM1, IDH1, or IDH2 mutations).

Reverse Autologous Peripheral Blood Stem Cell Transplantation after Allogeneic Transplantation to Restore Immune Function and Pancytopenia

Despite advances in multiple myeloma treatment the disease remains challenging to treat with repeated relapses in most. For high-risk younger patients, allogeneic transplants are occasionally performed. While curative in some, complications can include the development of opportunistic infections and secondary malignancies. Furthermore, patients relapsing after an allogeneic transplant may have poor bone marrow reserve limiting the ability to use subsequent therapies. We describe two patients who underwent a “reverse” autologous peripheral blood stem cell rescue using stem cells banked prior to allogeneic transplantation. The outcomes were successful and led to full engraftment and correction of their immunodeficiencies and pancytopenia respectively. Case 1: A 37-year-old woman was diagnosed with multiple myeloma during routine testing for an in-vitro fertilization assessment. She had ISS stage 2 disease and was treated with CyBorD, followed by an autologous stem cell transplantation. Lenalidomide plus dexamethasone was used as maintenance. She relapsed after just one year then progressed through single agent carfilzomib and then bendamustine. After responding to 2 cycles of DCEP she had a 10/10 matched unrelated donor CD34-selected allogeneic transplant. The patient was EBV positive, but the donor was not. Four months post-transplant she developed tonsillar PTLD with a rising EBV DNA titer and was treated with rituximab. Her CD4 count was 46. Her multiple myeloma relapsed thereafter necessitating treatment with daratumumab. She then developed rituximab-resistant monomorphic PTLD which then responded to brentuximab-vedotin and donor lymphocyte infusions. The multiple myeloma relapsed again and was treated with daratumumab + pomalidomide + dexamethasone. After a rising EBV DNA titer, brentuximab-vedotin was restarted but the lymphoma progressed again with a 5 x 3 cm anterior mediastinal mass biopsy proven to be monomorphic PTLD. R-CHOP was given for 4 cycles but resulted in only a partial response. Due to subsequent rapidly symptomatic and progressive disease a decision was made to use high-dose melphalan (200 mg/m2) followed by a reinfusion of her previously collected autologous stem cells to restore her T-cell immunity and hopefully control her lymphoma. She engrafted uneventfully at Day + 12 with chimerism studies showing autologous hematopoiesis and a CD4 count of 856. Her post-transplant course was complicated by renal thrombotic microangiopathy treated successfully with eculizumab. After further myeloma relapses, she is currently alive and well and in remission while on teclistamab over 4 yrs after her 2 nd autologous PBSC transplant. Her lymphoma has resolved. Case 2: A 37-year-old-male with beta-thalassemia was noted to have an elevated total protein on routine blood testing for a life insurance policy. Work up revealed multiple myeloma with a t(4:14) abnormality and complex cytogenetics. After initial observation he was started on KRD for progressive anemia. A VGPR was obtained and consolidated with an autologous PBSC transplant. He was maintained on Ixazomib+lenalidomide+dexamethasone but relapsed 2 years later with a sacral mass. After progressions though daratumumab+pomalidomide+dexamethasone then carfilzomib and then XRT to a large chest mass followed by DCEP as salvage, he underwent a 9/10 mismatched allogeneic transplant. He developed Grade 2 skin GVH but had disease progression again after just 6 months. Salvage treatment with elotuzumab+pomalidomide+dexamethasone then DCEP and subsequently ciltacabtagene autoleucel were unsuccessful with progression after just 6 weeks from the latter. He was treated again with DCEP but became transfusion dependent after the 2 nd cycle and had progressive disease again. Due to symptomatic myeloma and pancytopenia he underwent a reverse autologous PBSC transplant using banked stem cells. He engrafted uneventfully on Day +11 and despite recurrent multiple myeloma, he is currently in remission while on talquetamab. His beta-thalassemia returned. These cases demonstrate the ability to reverse an allogeneic transplant successfully using previously stored autologous peripheral blood stem cells. The recovery allowed for resumption of effective anti-cancer treatment that became lifesaving. Whether this approach could correct patients with unrelenting GVH issues should be contemplated as well.

Proliferation and apoptosis after whole-body irradiation: longitudinal PET study in a mouse model

PurposeA reliable method for regional in vivo imaging of radiation-induced cellular damage would be of great importance for the detection of therapy-induced injury to healthy tissue and the choice of adequate treatment of radiation emergency patients in both civilian and military events. This study aimed to investigate in a mouse model if positron emission tomography (PET) imaging with proliferation and apoptosis markers is potentially suitable for this purpose.MethodsFour groups, including twenty mice (wild-type C57BL/6) each, were whole-body irradiated with 0 Gy, 0.5 Gy, 1 Gy, and 3 Gy and examined by PET over a six-month period at defined time points. 3'-[18F]fluoro-3'-deoxythymidine ([18F]FLT) and 2-(5-[18F]fluoropentyl)-2-methyl malonic acid ([18F]ML-10) were used to visualise proliferation and apoptosis. Regional standard uptake values were compared with respect to irradiation dose over time. Histologic data and peripheral blood cell values were correlated with the PET results.ResultsThe hematopoietic bone marrow showed a significantly increased [18F]FLT signal at early time points after radiation exposure (day 3 and day 7). This correlated with blood parameters, especially leukocytes, and histological data. A significantly increased [18F]FLT signal also occurred in the gastrointestinal tract and thymus at early time points. An increased [18F]ML-10 signal related to irradiation doses was observed in the bone marrow on day 8, but there was a high variability of standard uptake values and no correlation with histological data.Conclusion[18F]FLT showed potential to visualise the extent, regional distribution and recovery from radiation-induced cellular damage in the bone marrow, gastrointestinal tract and thymus. The potential of [18F]FLT imaging to assess the extent of bone marrow affected by irradiation might be especially useful to predict the subsequent severity of hematopoietic impairment and to adapt the therapy of the bone marrow reserve. [18F]ML-10 PET proved to be not sensitive enough for the reliable detection of radiation induced apoptosis.

Dose reduction and toxicity of lenalidomide-dexamethasone in multiple myeloma: A machine-learning prediction model.

Lenalidomide remains an effective drug for multiple myeloma, but it is often associated with adverse events and requires dose adjustments. The objective of this study was to propose a model for predicting whether a patient would require dose adjustment. This retrospective observational study included patients treated with lenalidomide and dexamethasone from June 2014 to September 2018 at a tertiary hospital. Demographic variables, patient functional status, disease, analytical data specific to myeloma, and treatment-related variables were collected. Univariate and machine learning (logistic regression and classification and regression trees model) analyses were also performed. Kaplan-Meier analysis was used to determine the time of toxicity onset. Only lenalidomide (and not dexamethasone) related dose reductions are included. A total of 64 patients received lenalidomide-dexamethasone. 69% (44) required dose reduction or discontinuation of treatment due to lenalidomide-related adverse events. The median time between treatment beginning and lenalidomide dose reduction or discontinuation was 8.0 months (95% CI: 6.0-17.0). Age, platelet count, and neutrophil count were related to dose reduction in the univariate model. In the multivariate models, age and neutrophil count were significant in the logistic regression model, renal clearance, and neutrophil count in the classification and regression trees model. Elderly patients and those with low bone marrow reserves are prone to dose-limiting adverse events. This study can aid in making follow-up, prophylaxis, and dosing decisions to achieve better pharmacotherapeutic results.

Association between IDEAL-IQ MRI fat fraction quantification and pelvic bone marrow reserve function in concurrent chemoradiotherapy for cervical cancer

ObjectiveTo analyze the association between iterative decomposition of water and fat with echo asymmetry and least-squares estimation quantification sequence (IDEAL-IQ) magnetic resonance imaging (MRI) of bone marrow fat fraction and bone marrow reserve function during concurrent chemoradiotherapy for cervical cancer. MethodsThe study retrospectively analyzed twenty-six patients with stage IB1 to IVA cervical cancer treated between February 2020 and November 2020. All patients received concurrent chemoradiotherapy that included platinum alone or combined paclitaxel and platinum. Pelvic IDEAL-IQ MRI (plain and enhanced) was performed before and after treatment. Regions of interest, including the fifth lumbar vertebra, sacrum, ilium, ischium, and femoral neck, were manually delineated, and the bone marrow fat fraction was measured. Peripheral blood cell counts were recorded during treatment, and the relationship between the fat fraction values and changes in the blood cell counts was explored. ResultsIDEAL-IQ MRI bone marrow fat fraction was associated with platelet nadir and platelet decline during treatment. The average pelvic bone marrow fat fraction before chemoradiotherapy was moderately negatively correlated with platelet count nadir during concurrent chemoradiotherapy (r ​= ​−0.450, P ​= ​0.021). The change in average pelvic bone marrow fat fraction through chemoradiotherapy was moderately positively correlated with the degree of thrombocytopenia (r ​= ​0.399, P ​= ​0.044). ConclusionBone marrow fat content quantified by IDEAL-IQ was associated with platelet count nadir and the degree of thrombocytopenia in patients with cervical cancer undergoing concurrent chemoradiotherapy.

Tolerability of lutetium-177–PSMA-617 in men with prostate cancer and baseline cytopenia.

e17057 Background: Results from the VISION trial (NCT03511664) led to the approval of lutetium-177 (177Lu)–PSMA-617 for the treatment of metastatic castration-resistant prostate cancer (mCRPC). This trial excluded patients with baseline cytopenias, thus safety in this frequently encountered patient population is unknown. We aimed to use real-world data to describe the tolerability of radioligand therapy in those with poorer bone marrow reserve. Methods: We retrospectively reviewed the records of all patients, who received a first dose of 177Lu–PSMA-617 at Mayo Clinic in the interval of April 26, 2022, to December 1, 2022. Patients were categorized as having poor marrow reserve on the basis of pre-treatment hematologic parameters, including: (1) an anemia cohort with hemoglobin (Hg) less than 9 g/dL, (2) a thrombocytopenia cohort with platelets (Plt) less than 100 x 109/L, (3) a leukopenia cohort with white blood cell count (WBC) less than 2.5 x 109/L, and (4) a multiple cytopenia cohort. These were exclusionary parameters from the VISION trial. Longitudinal laboratory data and clinical outcomes were collected and analyzed using descriptive statistics. Results: At data cutoff, 185 patients had received one or more doses of 177Lu, including 26 (14%) with at least one baseline cytopenia prior to their first cycle of treatment. In total, there were 19 (73%) patients with anemia, 3 (12%) with thrombocytopenia, 2 (8%) with leukopenia, and 2 (8%) with multiple cytopenias at baseline. The median number of cycles received thus far is 3, including 14 (54%) who are still receiving therapy and 12 (46%) who have permanently discontinued treatment. Median longitudinal changes in blood counts for the anemia cohort are presented in Table 1. Reasons for treatment discontinuation include: toxicity (n = 2), disease progression (n = 5), death (n = 4), or other (n = 1). Dose reductions or treatment delays for worsening myelosuppression were utilized in 3 (12%) and 5 (19%) patients, respectively. Transfusions of packed red blood cells or platelets were required for 16 (62%) patients. A total of 6 (23%) received care in the emergency department or were hospitalized. Conclusions: Treatment discontinuation for toxicity was rare among men with mCRPC and baseline cytopenias, while receiving 177Lu; however, these patients have an overall poor prognosis. [Table: see text]

Recovery-model: A model for CAR T-cell-related thrombocytopenia in relapsed/refractory multiple myeloma

BackgroundPatients with multiple myeloma (MM) treated with anti-B cell maturation antigen (BCMA) and chimeric antigen receptor (CAR) T-cell therapy tend to show delayed platelet recovery. Patients and methodsThis single-center retrospective observational study included a cohort of patients with MM treated with anti-BCMA CAR-T cells in ChiCTR-OPC-16009113, ChiCTR1800018137, and ChiCTR1900021153. ResultsFifty-eight patients with MM treated with anti-BCMA CAR-T cells were included. Delayed platelet recovery (platelet count not recovering to 50 × 109/L within 28 days) was observed in 36 % of patients. Regression analysis identified several factors that influenced platelet recovery, and accordingly, a Recovery-Model was developed. A high Recovery-Model score indicates a greater risk of delayed platelet recovery after CAR-T cell infusion and reflects the risk of hematologic toxicity. The model's predictive biomarkers included baseline platelet count, baseline hemoglobin level, logarithm of baseline Ferritin level, and cytokine release syndrome grade. Finally, survival analysis showed a significant relationship between overall survival, delayed platelet recovery (p = 0.0457), and a high Recovery-Model score (p = 0.0011). ConclusionsInflammation-related factors and bone marrow reserves are associated with delayed platelet recovery. Therefore, we developed a model to predict the risk of delayed platelet recovery and hematological toxicity in relapsed/refractory patients with MM after anti-BCMA CAR-T cell treatment.

Aspirin use and bleeding events during thrombocytopenia after autologous stem-cell transplantation for multiple myeloma.

In patients with cardiovascular (CV) comorbidities that necessitate antiplatelet therapy (APT), its optimal management during chemotherapy-induced thrombocytopenia remains elusive, as the risk of bleeding has to be balanced against the risk of CV events. The purpose of this study was to assess the risk for bleeding with APT during thrombocytopenia in patients with multiple myeloma undergoing high-dose chemotherapy and subsequent autologous stem-cell transplantation (ASCT) with and without acetylsalicylic acid (ASA) as comedication. We assessed patients who underwent ASCT at the Heidelberg University Hospital between 2011 and 2020 for bleeding events, management strategies for ASA intake during thrombocytopenia, transfusion requirements, and the occurrence of CV events. There were 57/1,113 patients who continued ASA until at least 1 day after ASCT; thus, a continuous platelet inhibition during thrombocytopenia was assumed. Most of the patients (41/57) continued ASA until they had a platelet count of 20-50/nl. This range reflects the kinetics of thrombocytopenia and nondaily measurements of platelets during ASCT. A tendency toward a higher risk for bleeding events in the ASA group was demonstrated (1.9% (control group) vs. 5.3% (ASA), p = 0.082). The risk factors for bleeding in multivariate analysis were the duration of thrombocytopenia < 50/nl, a history of gastrointestinal bleeding, and diarrhea. The factors predicting the duration of thrombocytopenia were age >60 years, a hematopoietic stem-cell transplantation comorbidity index ≥3, and an impaired bone marrow reserve at admission. CV events occurred in three patients; none of them took ASA or had an indication for APT. The intake of ASA until thrombocytopenia with a platelet count of 20-50/nl appears safe, although an elevated risk cannot be excluded. If ASA is indicated for the secondary prevention of CV events, the evaluation of risk factors for bleeding and a prolonged time of thrombocytopenia before conditioning is crucial to adapt the strategy for ASA intake during thrombocytopenia.

The CAR-Hematotox Score Identifies Patients at High Risk for Hematological Toxicity, Infections and Poor Clinical Outcomes Following Brexucabtagene Autoleucel in Relapsed/Refractory Mantle Cell Lymphoma

Background: Hematological toxicity and infectious complications drive the toxicity burden of CD19 CAR-T. We recently developed the CAR-HEMATOTOX (HT) score - a validated risk-stratification system of hematotoxicity, infections, and clinical outcomes in LBCL patients (Rejeski et al. Blood 2021/JITC 2022). The score integrates parameters associated with pre-CAR-T hematopoietic reserve (e.g. ANC, hemoglobin, platelet count) and inflammation (e.g. CRP, ferritin). Whether the HT score is of prognostic utility in relapsed/refractory mantle cell lymphoma (R/R MCL) remains unstudied. Methods: In this multicenter retrospective study, we characterized the influence of the HT score on toxicity and survival in 78 patients receiving standard-of-care brexucabtagene autoleucel (brexu-cel) across seven international sites. Patterns of hematopoietic recovery were defined as quick recovery vs. intermittent recovery vs. aplastic as previously described (Rejeski et al. Blood 2021). The duration of severe neutropenia was assessed as the total cumulative days with an ANC<500/µl between days 0-60. Early infection events (day 0-90) were defined as bacterial, viral or fungal based on microbiologic data or as a clinical syndrome of infection (e.g. pneumonia, cellulitis, cystitis) based on retrospective chart review. Severe (Grade ≥3) infections were defined as requiring intravenous anti-infectives and/or hospitalization. Kaplan-Meier estimates of progression-free (PFS) and overall survival (OS) were compared using the log-rank test. Results: The study cohort comprised a representative cohort of R/R MCL patients treated in a real-world setting: median age was 68 (range 49-89), median ECOG PS was 1, median LDH was 217 U/L (interquartile range 171-289 U/L), and patients had received a median of 3 prior treatment lines (IQR 2-4). Of note, 28% of patients had received a prior autologous stem cell transplant (ASCT) and >90% were BTKi exposed. The rate of severe (grade ≥3) CRS and ICANS was 2.6% and 27%, respectively. Tocilizumab was applied in 82% of patients, while glucocorticoids were used in 64% of all cases. Across all patients, the median duration of severe neutropenia was 8 days (IQR 5-15). The distribution of neutrophil recovery phenotypes was: 30% quick, 46% intermittent, and 24% aplastic. The cumulative 90-day incidence of any-grade and severe infections was 37% and 17%, respectively. The median CAR-HEMATOTOX score was 1 (IQR 1-3), including 42 HTlow (Score 0-1) and 36 HThigh (Score ≥2) patients. When comparing risk groups, we noted higher serum LDH levels in HThigh patients(median 261 vs. 209 U/L, p=0.07).In terms of toxicity, the incidence of severe CRS and ICANS was comparable between both groups. However, the duration of neutropenia was significantly increased in HThigh patients compared to their HTlow counterparts (15 vs. 7 days, p<0.001). Moreover, the proportion of patients displaying an aplastic phenotype of neutrophil recovery, defined by continuous severe neutropenia ≥14 days, was markedly increased in the HThigh group (53 vs. 0%, p<0.0001, Fig. 1A). This translated into a higher rate of severe infectious complications in the HThighgroup (28% vs. 7%, p=0.03), including 3 life-threatening (all bacterial), and 2 fatal infections (1 bacterial, 1 fungal).Notably, a high HT score was associated with markedly inferior PFS (median 7.5 months vs. not-reached, p=0.0006, Fig. 1B) and OS (median 15.3 months vs. not-reached, p=0.0004). Comparing the HThigh vs. HTlow groups, we observed 1-year PFS of 73% vs. 38% and 1-year OS of 88% vs. 51%. Conclusions: Taken together, these findings underline the importance of pre-CAR-T bone marrow reserve and systemic inflammation in driving immunotoxicity after CD19 CAR-T therapy. Importantly, they validate the utility of the HT score to risk-stratify patients for hematotoxicity, severe infections and poor survival outcomes prior to brexu-cel infusion. The score can be used to aid clinical decision-making concerning anti-infective prophylaxis and early or prophylactic G-CSF use. Considering that ASCT represents a mainstay of frontline MCL therapy, the HT score may also guide the use of stem cell rescue (obtained at time of remission) for the patients developing severe CAR-T-related aplasia. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Outcomes of Older Patients with Aplastic Anemia Treated with Frontline Anti-Thymocyte Globulin (ATG)-Based Immunosuppressive Therapy

Background: Advances in the treatment of aplastic anemia (AA), such as the addition of eltrombopag (EPaG) to immunosuppressive therapy (IST) and the expanded use of unrelated and haploidentical stem cell transplant (SCT) have steadily improved outcomes. However, little is known about the characteristics and outcomes of patients (pts) ≥ 60 years (yrs) of age with newly diagnosed AA who have been treated with an ATG-based regimen. Presumed low bone marrow (BM) reserves, higher frequency of underlying clonal hematopoiesis, intolerance to therapy, comorbidities, and challenges in proceeding to salvage SCT have led to the speculation that response and survival of these pts to IST may be inferior than their younger counterparts. Methods: We retrospectively analyzed the characteristics and outcomes of pts ≥ 60 yrs of age (OLDER) at the time of diagnosis of AA treated with frontline (F/L) ATG based therapy at our center and compared them to pts < 60 yrs of age (YOUNG) treated with F/L ATG over the same time period. We captured their clinical characteristics, cytogenetic abnormalities, mutations in DNMT3A (D), ASXL1 (A) and TET2 (T), exposure to EPaG, response, time to response (TTR) and survival. Overall response included complete and partial response per the standard definitions. Relapse free survival (RFS) was tabulated from the time of best response to loss of response, 2nd ATG infusion, salvage SCT or death (whichever was earlier) and overall survival was tabulated from the time of response to death from any cause. Results: From Jan 2011-May 2012, 43 OLDER pts were treated as F/L for AA of whom 41 (95%) received ATG based therapy; 68 YOUNG pts were treated as F/L for AA over the same time period of whom 62 (91%) received ATG based regimen. Four YOUNG pts vs. no pts in the OLDER group received upfront SCT, and 2 pts in each group were treated with non ATG based therapy: single agent CSA, EPaG, or alemtuzumab. Comparative baseline characteristics are depicted in Table 1. There were no differences in the baseline WBC, peripheral blood lymphocyte percentage and platelet counts between the ATG treated OLDER and YOUNG groups. Both groups had similar frequencies of cytogenetic abnormalities and PNH clones, though OLDER pts had mutations in D-A-T genes compared to the YOUNG group (62% vs. 38%, p=0.05). Both groups had equal concurrent exposure to EPaG with ATG. Cumulatively 23/41 (56%) pts in the OLDER group had an overall response (OR) compared to 43/62 (70%) pts in the YOUNG group (p=0.1); 11/23 (48%) and 23/43 (53%) responders in each group attained CR respectively. There were no differences in OR rates in both groups based on concurrent EPaG exposure: 61% vs. 46% with and without EPaG, respectively, in the OLDER group (p=0.5) and 74% vs 60%, respectively, (p=0.38) in the YOUNG group. On logistic regression analysis using baseline platelet counts, PB lymphocyte (%), D-A-T mutations, karyotype, and EPaG use as covariates, none affected the odds of OR in the 2 groups. The median TTR was 111 days (range, 10-323 days) and 177 days (51-410) in YOUNG AND OLDER groups, respectively; and this was not affected by EPaG use in either group. At a median follow of 38 months (mos) from ATG initiation (53 mos for the OLDER group and 32 mos for the YOUNG group), the median RFS was 49 mos and 39 mos (p=0.6) and median OS 55 vs. not reached (NR) (p <0.0001) in OLDER and YOUNG groups respectively (Fig.1). Significantly more pts in the YOUNG group underwent a subsequent SCT (19% vs. 5%) due to loss of response/ no response, possibly accounting for the higher OS rates. Rates of transformation to MDS or AML was 5% in both groups. Conclusion: Frontline ATG based IST in older pts with AA is a feasible and safe treatment option with promising response rates of 56% and median RFS more than 4 years; figures which are comparable to younger pts with AA treated with IST. The overall risks of transformation to MDS/AML on long term follow-up remain low (≈5%). Further studies assessing the response of the ATG+EPaG combination in these pts and the possibilities of clonal evolution with time needs to be conducted. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Trial in Progress: A Phase II Window of Opportunity Study of the BCMAxCD3 Bispecific Antibody REGN5458 in Previously Untreated Patients with Symptomatic Multiple Myeloma

Background Treatment of multiple myeloma (MM) has advanced significantly in the last 20 years, resulting in improved survival. For patients with newly diagnosed MM (NDMM) who are fit with no comorbidities, currently recommended treatment includes induction with triplets such as bortezomib, lenalidomide, and dexamethasone (VRd), followed by high-dose chemotherapy (HDT) and autologous stem cell transplantation (ASCT), and maintenance therapy using predominantly immunomodulatory agents. Patients who are elderly or ineligible for HDT/ASCT receive multiple drug combination therapies such as VRd or daratumumab with Rd. Despite the availability of these combinations, induction therapy does not induce complete remission with minimal residual disease negativity in all patients, and triplet- or quadruplet-based regimens are expensive and associated with enhanced toxicities including to stem cells. Moreover, MM remains incurable and new therapies with alternative mechanisms may improve or maintain the safety profile while increasing or deepening responses for longer periods. B-cell maturation antigen (BCMA) is a cell surface protein expressed on malignant plasma cells (Lee, et al. Br J Haematol. 2016;176:911-22). Notably, BCMA is detected only at low levels on normal plasma cells, activated B cells, and plasmacytoid dendritic cells, making it an attractive therapeutic target for MM. REGN5458 is a BCMA×CD3 bispecific antibody capable of binding to BCMA on MM cells and CD3 on T cells, inducing T-cell mediated cytotoxicity of MM cells. REGN5458 monotherapy has demonstrated early, deep, and durable responses with a manageable safety and tolerability profile in patients with relapsed/refractory (R/R) MM (NCT03761108; Zonder, et al. EHA 2022. Abstract S189) with a response rate of 75% among patients treated at the 200-800 mg dose levels. Cytokine release syndrome was reported in 38% of patients and was mostly Grade 1, with no Grade ≥3 events. Given the single agent efficacy and tolerability of REGN5458 in heavily pre-treated patients with R/R MM, its use in patients with NDMM (who are thought to potentially have improved T-cell fitness versus R/R patients) is hypothesized to have enhanced therapeutic benefit. Study Design and Methods This open-label, Phase II study aims to assess the safety, tolerability, pharmacokinetics (PK), and preliminary efficacy of REGN5458 monotherapy in patients with NDMM who are eligible or ineligible for HDT/ASCT. Transplant-eligible patients will receive REGN5458 induction, HDT/ASCT, followed by REGN5458 consolidation, and standard of care maintenance therapy. Transplant-ineligible patients will receive REGN5458 until disease progression or other discontinuation criteria are met (Figure). The primary objectives during part 1 are to assess safety and tolerability and to determine a recommended regimen for expansion. The objective for dose expansion is to assess preliminary antitumor activity. Secondary objectives are to evaluate the PK properties and immunogenicity of REGN5458 as well as soluble BCMA concentrations in serum at baseline and over time. The primary endpoints for part 1 are: the incidence of dose-limiting toxicities (DLTs) from the first dose of study drug to the end of the DLT observation period; the incidence and severity of treatment-emergent adverse events and adverse events of special interest with REGN5458 through study completion; for expansion: the proportion of patients with a very good partial response or better as determined by the investigator using International Myeloma Working Group response criteria; and the proportion of patients achieving minimal residual disease-negative status (at 10-5). Patients will have a window of opportunity to benefit from treatment; patients who do not meet the specified efficacy thresholds will transition to standard of care therapies. Approximately 92 patients are planned for this study. Eligibility criteria include age ≥18 years; ECOG PS 0-2; histologically or cytologically confirmed symptomatic MM; measurable disease; no prior therapy for MM, except radiation on an emergency/palliative basis or 1 month of single-agent corticosteroid if the patient still has measurable disease; and adequate bone marrow reserves, hepatic, renal, and cardiac function. The study will take place in approximately 20 sites located in North America and Europe. There are no formal hypothesis tests for this study. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

PD-L1 negatively regulates antifungal immunity by inhibiting neutrophil release from bone marrow

Programmed death ligand 1 (PD-L1) has been shown to be inducibly expressed on neutrophils to suppress host immunity during polymicrobial sepsis, virus and parasite infections. However, the role of PD-L1 on neutrophil-mediated antifungal immunity remains wholly unknown. Here, we show that the expression of PD-L1 on murine and human neutrophils was upregulated upon the engagement of C-type lectin receptor Dectin-1 with its ligand β-glucans, exposed on fungal pathogen Candida albicans yeast. Moreover, β-glucan stimulation induced PD-L1 translocation into nucleus to regulate the production of chemokines CXCL1 and CXCL2, which control neutrophil mobilization. Importantly, C. albicans infection-induced expression of PD-L1 leads to neutrophil accumulation in bone marrow, through mediating their autocrine secretion of CXCL1/2. Furthermore, neutrophil-specific deficiency of PD-L1 impaired CXCL1/2 secretion, which promoted neutrophil migration from bone marrow into the peripheral circulation, thereby conferring host resistance to C. albicans infection. Finally, either PD-L1 blockade or pharmacological inhibition of PD-L1 expression significantly increased neutrophil release from bone marrow to enhance host antifungal immunity. Our data together indicate that activation of Dectin-1/PD-L1 cascade by β-glucans inhibits neutrophil release from bone marrow reserve, contributing to the negative regulation of antifungal innate immunity, which functions as a potent immunotherapeutic target against life-threatening fungi infections.

Neutropenia in Cynomolgus Monkeys With Anti-Drug Antibodies Associated With Administration of Afucosylated Humanized Monoclonal Antibodies.

Removal of the core fucose from the Fc region of humanized monoclonal antibodies (afucosylated antibodies) enhances their antibody-dependent cell cytotoxicity activities in killing cancer cells. Based on the authors' experience and literature, administrations of afucosylated antibodies have been associated with neutropenia in cynomolgus monkeys. However, in a recent general toxicology study conducted with an afucosylated antibody in cynomolgus monkeys, transient neutropenia was observed and correlated with the emergence of anti-drug antibodies (ADAs) in the affected animals. To further explore the relationship between neutropenia, afucosylated antibodies, and ADAs in cynomolgus monkeys, we performed an investigational retrospective meta-analysis of data from general toxicology studies conducted with Genentech's therapeutic antibodies administered to cynomolgus monkeys between 2005 and 2021. In this analysis, transient neutropenia strongly correlated with ADA-induced inflammation in cynomolgus monkeys administered afucosylated antibodies. This may reflect the simultaneous occurrence of two distinct processes of neutrophil elimination and utilization, thus overwhelming bone marrow reserve capacity leading to transient neutropenia. The integrated analysis of immunogenicity, and anatomic and clinical pathology results from these studies highlights the correlation of transient neutropenia in cynomolgus monkeys with ADA-related inflammation, potentially exacerbated by enhanced effector function of afucosylated antibodies.

796 ECRG4 regulates neutrophil responsiveness to proinflammatory signals during recruitment to infection

Rapid neutrophil recruitment to cutaneous injury is critical for controlling local infection and preventing systemic dissemination. Neutrophils are mobilized from bone marrow reserves and home to vasculature near the source of inflammation, where they extravasate and migrate to the site of injury. We found that Esophageal Cancer Related Gene 4 (ECRG4), a leukocyte surface protein, amplifies early neutrophil recruitment to injury and hypothesized that ECRG4 may be important for the inflammatory response to infection through its ability to regulate neutrophil recruitment.