Search

Introduction: Lymphodepleting chemotherapy (LDC) is critical to CAR T-cell expansion and efficacy. Despite this, there is not a consensus in the literature regarding the optimal LDC regimen, including dose and frequency. Methods: We retrospectively reviewed consecutive patients at a single institution that received LDC prior to treatment with the CD19 directed CAR T-cell products axicabtagene ciloleucel and tisagenlecleucel. Patients treated at our center received fludarabine 30 mg/m2 and cyclophosphamide 500 mg/m2 for 3 consecutive days prior to May 2019. After this timepoint patients routinely received fludarabine 40 mg/m² and cyclophosphamide 500 mg/m² for 2 consecutive days. Clinical data from each cohort were obtained from the electronic medical record and compared for differences in CAR T-cell efficacy and toxicity. Results: From June 2018 to August 2023, LDC was given to 92 patients prior to CD19 directed CAR T-cell therapy for relapsed non-Hodgkin's lymphoma. Twenty-eight patients received a 3-day regimen, and 64 patients received a 2-day regimen. In the total cohort, 75% of patients received axicabtagene ciloleucel and 25% received tisagenlecleucel. The overall response rates in both the 2-day regimen group and the 3-day regimen group were similar (69% vs 75%, p= 0.21) as were the complete response rates (50% vs 54%, p=0.82). There were no significant differences between the 2-day and 3-day regimens for grade 2-4 cytokine release syndrome (55% vs 50%, p=0.82), grade 2-4 immune effector cell associated-neurotoxicity syndrome (42% vs 29%, p=0.25), or time to resolution of neutropenia or thrombocytopenia. The rate of prolonged platelet recovery lasting greater than 60 days was higher with the 3-day regimen (9% vs 27%, p=0.026). Discussion: As the number of patients eligible for CAR T-cell therapy continues to increase, optimizing each component of therapy is necessary. We show that a 2-day regimen of LDC with fludarabine and cyclophosphamide is feasible without significant impact on CAR T-cell efficacy or toxicity. Prospective studies are necessary to further determine the most effective LDC regimen. [ABSTRACT FROM AUTHOR]

Background: Late complications of chemotherapy include treatment‐related secondary leukemias. We describe an unusual case of a new treatment‐related acute lymphoblastic leukemia (t‐ALL) that was unmasked and mobilized by G‐CSF during autologous hematopoietic progenitor cell collection (HPCC) in a young man with testicular cancer. Methods: Electronic chart review of the patient medical history and pertinent laboratory findings. Patient CD34 and blast results were compared to 4249 autologous and 437 allogeneic HPCC performed between 2004 and 2022. In autologous donors, the %blast and %CD34 were compared by linear regression and paired t‐test using commercial software. Results: The patient was a 21‐year‐old male with relapsed testicular cancer referred for G‐CSF cytokine‐only mobilization and autologous HPCC. His pre‐mobilization WBC count and differential were normal. On the day of HPCC, his WBC = 37.9 K/mcL with 12% blasts and 9.75% circulating CD34+ cells. The patient was admitted 9 days after HPCC with a normal WBC count and 15% blasts. He was diagnosed with a pro‐B t‐ALL bearing an t(4:11)(q21:q23) translocation and KMT2A‐AF4 rearrangement. Upon review, this patient had the highest %CD34 among 4686 HPCC and was the only donor with %CD34 > 1% after a cytokine‐only mobilization. Conclusion: We report a case of t‐ALL that mimicked CD34+ HPC and was mobilized by high‐dose G‐CSF. Up to 70% of secondary leukemias bear 11q23/KMT2A rearrangements, which occur at the multipotent stem cell stage and can result in myeloid and lymphoid leukemias. Donors who have received past chemotherapy, especially with topoisomerase II inhibitors, are at increased risk for 11q23/KMT2A leukemias. [ABSTRACT FROM AUTHOR]

Background Peripherally inserted central catheters (PICCs) are associated with an increased risk of venous thromboembolism. However, the size of this risk relative to that associated with other central venous catheters (CVCs) is unknown. We did a systematic review and meta-analysis to compare the risk of venous thromboembolism associated with PICCs versus that associated with other CVCs. Methods We searched several databases, including Medline, Embase, Biosis, Cochrane Central Register of Controlled Trials, Conference Papers Index, and Scopus. Additional studies were identified through hand searches of bibliographies and internet searches, and we contacted study authors to obtain unpublished data. All human studies published in full text, abstract, or poster form were eligible for inclusion. All studies were of adult patients aged at least 18 years who underwent insertion of a PICC. Studies were assessed with the Newcastle-Ottawa risk of bias scale. In studies without a comparison group, the pooled frequency of venous thromboembolism was calculated for patients receiving PICCs. In studies comparing PICCs with other CVCs, summary odds ratios (ORs) were calculated with a random effects meta-analysis. Findings Of the 533 citations identified, 64 studies (12 with a comparison group and 52 without) including 29 503 patients met the eligibility criteria. In the non-comparison studies, the weighted frequency of PICC-related deep vein thrombosis was highest in patients who were critically ill (13.91%, 95% CI 7.68-20.14) and those with cancer (6.67%, 4.69-8-64). Our meta-analysis of 11 studies comparing the risk of deep vein thrombosis related to PICCs with that related to CVCs showed that PICCs were associated with an increased risk of deep vein thrombosis (OR 2- 55, 1.54-4.23, p<0.0001) but not pulmonary embolism (no events). With the baseline PICC-related deep vein thrombosis rate of 2.7% and pooled OR of 2.55, the number needed to harm relative to CVCs was 26 (95% CI 13-71). Interpretation PICCs are associated with a higher risk of deep vein thrombosis than are CVCs, especially in patients who are critically ill or those with a malignancy. The decision to insert PICCs should be guided by weighing of the risk of thrombosis against the benefit provided by these devices. Funding None. [ABSTRACT FROM AUTHOR]

Analysis of culled arthropod prey parts collected from beneath four feeding perches was used to assess prey taken by Nycteris grandis from November 1987 to May 1988. The perches were located along the Zambezi River in Mana Pools National Park in Zimbabwe. With the exception of an occasional solifugid, N. grandis ate mainly insects in addition to frogs and other small vertebrates. Three species of katydids and many species of moths were the most common prey. While hats using one feeding perch fed heavily on two species of cicadas at times, those at the other perches rarely did. There also were differences in the incidences of antlions, mantids and beetles in the diets of bats using different perches. Extensive samples from two feeding roosts about 2 km apart showed significant differences in prey composition. Smaller samples from two sites closer to one another showed similar patterns of the incidence of different prey. [ABSTRACT FROM AUTHOR]

Introduction Genomic minimal residual disease (MRD) detected in complete remission using droplet digital PCR (ddPCR) is associated with inferior survival in AML patients when measured after induction chemotherapy and before and after allogeneic HSCT. However, the utility of high sensitivity genomic MRD detection in the context of allogeneic HSCT for patients with myelodysplastic syndrome (MDS) is unclear. Here we present data evaluating the association of genomic MRD with survival in HSCT recipients with MDS. Methods Peripheral blood mononuclear cells (PBMC) from 72 MDS patients sampled prior to HSCT were enriched for CD34+ cells and CD3+ cells using MACS columns. Genomic DNA extracted from CD34+ fractions underwent targeted next generation sequencing of 49 genes recurrently mutated in MDS. Variants were confirmed in the CD34+ fraction and germline polymorphisms excluded in the CD3+ fraction using Sanger resequencing. To date, mutations identified in 43 cases have been quantified with ddPCR in unfractionated PBMC genomic DNA prior to conditioning and at day 30 post-transplant with a sensitivity as low as 0.002%. Results A median of 2 mutations per case (range 1-4) was identified with NGS and subsequently measured with ddPCR. Prior to HSCT, 70% of cases had mutations with a variant allele frequency (VAF) ≥10% and had inferior OS compared to those with <10% VAF (HR 2.7 [1.2-5.7], p=0.04). At Day 30 after HSCT, 65% of patients still had detectable mutations in circulating PBMC (≥0.002% VAF) (MRDpos) and had inferior DFS (median 347d vs not reached; HR 3.6 [1.6-8.1], p<0.01) and OS (median 560d vs not reached; HR 4.0 [1.7-9.2], p<0.01) compared to patients with undetectable mutations (MRDneg). TP53 mutations remained detectable in all cases (8 of 8) along with most DNMT3A (4 of 7), RUNX1 (3 of 4), ASXL1 (3 of 5) and spliceosome gene mutations (5 of 8). The 1-year relapse rate was 35% in the MRDpos group and 5% in the MRDneg group (p=0.02). Non-relapse mortality in the MRDpos and MRDneg groups was 44% and 31%, respectively (p=0.99). In bivariate analyses, DFS and OS remained significantly inferior in MRDpos patients versus MRDneg patients when controlled for age, cytogenetics, IPSS-R at diagnosis or pre-HSCT, or presence of adverse gene mutations. In addition, MRDpos patients with mutations detected at <0.1% VAF (58% of MRDpos cases; median 0.009%, range 0.002-0.082% VAF) had equally inferior DFS and OS as MRDpos patients with mutations detected at ≥0.1% (42% of MRDpos cases; median 0.48%, range 0.12-16.1% VAF). Conclusion Ultrasensitive genomic MRD detection in PBMC of MDS patients 30 days after HSCT is feasible and is associated with increased relapse risk and inferior DFS and OS. The gene mutations of most MRDpos patients were detected at <0.1% VAF, suggesting ultrasensitive genomic MRD detection in peripheral blood identifies patients with very low level MRD at high risk for relapse and death post-HSCT. [ABSTRACT FROM AUTHOR]

INTRODUCTION The composite endpoint of GVHD-free, relapse-free survival (GRFS), defined as survival free from grade 3–4 acute GVHD (aGVHD), chronic GVHD (cGVHD) requiring systemic immunosuppressive therapy (IST), or relapse has emerged as an outcome to capture clinically meaningful events. In the present study, we validated GRFS as a useful surrogate endpoint by examining the relative importance of individual events and the GRFS composite itself on overall survival (OS) at 5-years after allogeneic HCT. METHODS We conducted an IRB-approved retrospective cohort study on 565 consecutive patients (age ≥18 years) undergoing first-time allogeneic HCT for hematologic malignancy (January 2007–March 2013). Data abstraction of GRFS events was performed through chart review of the EHR. To determine the impact of each event of the GRFS composite endpoint, we accounted for competing risks using Fine and Gray methods, and correlated each event with OS using Kaplan-Meier methods. Using statistical simulations, the relative consequences of successfully modulating individual or composite endpoints on OS were examined to further elucidate the role of GRFS in clinical trials research. RESULTS The median age of the cohort was 54 years (18–73 years), comprised predominantly of males (58%) and Caucasians (94%). The most common indication for transplant was AML (41%), followed by lymphoma (21%) and MDS/MPD (14%). Patients received HLA-matched related (47%), and matched unrelated (53%) donors, and mostly peripheral blood stem cells (90%) and myeloablative conditioning (68%). Relapse conferred the greatest risk for death (HR 7.89; 95% CI:5.83–10.69). Grade 3–4 aGVHD was associated with HR 6.16 (95%CI:4.42–8.56), while cGVHD requiring IST was associated with lower HR 1.69 (95%CI:1.16–2.46). Indeed, the GRFS composite correlated with less HR 4.81 (95% CI:3.61–6.41) compared with either relapse or grade 3–4 aGVHD events. To determine the impact of hypothetical improvements on individual events or combined events (composite) on OS, we next performed Monte Carlo simulations. Compared with individual events, modulating composite endpoints predicted the greatest change in 5-year OS (Figure 1). The greatest gain in OS was seen by proportionally reducing both grade 3–4 aGVHD and relapse (modified GRFS). Reducing chronic GVHD requiring IST proportionally with grade 3–4 aGVHD and relapse events (conventional GRFS) did not change 5-year OS. CONCLUSION These findings highlight the importance of influencing OS by targeting the major early adverse post-HCT events (i.e., grade 3–4 acute GVHD and relapse). Moreover, the simulations herein suggest that GRFS as currently defined may be less optimal for predicting OS than using early grade 3–4 aGVHD and relapse as composite endpoints. Importantly, further refinement of these endpoints will depend on the a priori defined study population as well as intervention. [ABSTRACT FROM AUTHOR]

BACKGROUND A recent U.S. Food and Drug Administration (FDA) safety communication (Aug 2018) warned prescribers of the risk of relapse in patients receiving azithromycin as prophylaxis for bronchiolitis obliterans syndrome (BOS) following hematopoietic cell transplant (HCT). However, the FDA warning was based upon a single multicenter trial, in which patients were randomized to receive azithromycin for 2 years, starting at the time of conditioning. We now examine relapse rates in a cohort of patients treated with azithromycin for management of moderate-severe CGVHD. PATIENT POPULATION A retrospective review of our HCT database (2010-2017) identified 239 patients (median age 55 years, range 4-72) with moderate-severe CGVHD following an allogeneic HCT for a primary hematologic malignancy. NIH consensus criteria (2015) were used for CGVHD grading. Patients were divided into 2 cohorts, a) those receiving an extended course of azithromycin (≥ 14 days) for CGVHD management (cohort 1, n=86) and b) those who did not (cohort 2, n=153). Patients in cohort 2 either did not receive any azithromycin (n=122) or had received an abbreviated (<14 day) course (n=31) of azithromycin post-HCT. For cohort 1, the median time to initiation of azithromycin therapy was 15 months post-HCT (range 3-68), with a 26 month median duration of azithromycin therapy (range 1-77). All patients in cohort 1 met NIH consensus criteria for BOS. Patients in cohort 2 did not exhibit BOS, but still met NIH criteria for moderate-severe CGVHD. Hematologic conditions included acute leukemia (n=139), MDS/MPD (n=44), malignant lymphomas (n=26), chronic leukemia (n=24), and multiple myeloma (n=6). Ninety-one patients exhibited moderate and 148 patients exhibited severe CGVHD. The two cohorts were balanced for CGVHD severity, with severe CGVHD noted in 69% and 63% of patients in cohorts 1 and 2 respectively. RESULTS Decreased rates of relapse and improved survival were noted for patients treated with azithromycin for CGVHD. At 2 years, the cumulative incidence of relapse was 2% (95% CI:1-9%) for patients in cohort 1 vs 16% (95% CI: 11-23%) in cohort 2, p=0.001. Overall survival (2-year OS) in cohort 1 was 93% (95%CI: 88-99%) vs 78% (95% CI:72-85%) for cohort 2, p=0.003. Overall, 7 of 86 (8.1%) CGVHD patients treated with an extended course of azithromycin (cohort 1) have relapsed, the median time to relapse 876 days (range 379-1303) post-HCT. In comparison, 28 of 153 (18.3%) in cohort 2 have relapsed, a median 371 days (range 98-1252) post-HCT. CONCLUSION The use of azithromycin for the management of moderate to severe CGVHD was not associated with an increased risk of relapse in patients undergoing HCT for a hematologic malignancy. Azithromycin therapy for patients with CGVHD should not be contra-indicated in this patient population. [ABSTRACT FROM AUTHOR]

Introduction Relapse remains a significant challenge towards improving survival after allogeneic hematopoietic transplantation (HCT) for Acute Myeloid Leukemia (AML) not in remission or possessing poor cytogenetic/molecular features. Insights from murine pre-clinical studies demonstrate a central role for CD8+ dendritic cells in cross-presentation of leukemia associated antigens (LAA) in mediating GVL without aggravating acute Graft-versus-Host Disease (aGVHD)(Toubai, Blood 2013). We posited that enhancing LAA cross-presentation with exogenous Type I Interferon (pegIFNα) would promote GVL response and reduce rates of relapse after HCT. Methods We initiated a prospective, phase I/II, clinical trial of pegIFNα administration after myeloablative conditioning for prevention of relapse in pts with detectable AML at time of HCT (resistant to induction) or with cytogenetic/molecular features conferring high relapse risk and poor survival. Pts received up to four doses of 90mcg or 180mcg pegIFNα SubQ on d -1 and d 14, 28, 42 after PBSC or BMT. aGVHD prophy was tacrolimus + MTX or MMF. The primary endpoint was to determine the incidence of relapse in pts receiving the phase II dosage of pegIFNα. We hypothesized that 30 pts assigned to the same dose would provide 80% power to detect a difference between a promising day 180 relapse rate of 40% versus a rate of 60%. Results A total of 30 pts received study treatment at a median age of 60 years (17-72). Conditioning was myeloablative FluBu (n=9), CloBu (n=20) or FluCyTBI (n=1). At time of HCT, AML was detected in 28 pts and 2 pts enrolled for poor cytogenetic/molecular risk, complex/monosomal karyotype (n=1) and FLT3-ITD+ (n=1). There was no DLT at 90mcg (n=3) and one DLT (graft failure) after escalation to 180mcg (n=27). pegIFNα was well tolerated with ≥3 doses administered to 87% of pts. ≥Grade 3 SAEs during treatment include acute kidney injury(n=1), engraftment failure(n=1), bone pain/weakness(n=1), hypotension(n=1) and hypoxemia (n=1). 29 pts (97%) experienced primary engraftment and bone marrow exam at d 30 revealed CR in 100% of pts. Thirteen pts (43%) experienced infection. Grade II-IV aGVHD and grade III-IV aGVHD occurred in 35% (20 – 56%) and 11% (4 – 30%) by day 180. The incidence of TRM was 11% (3-30%) at day 180 and 19% (8-41%) at 1-yr. The day 180 (and 1-yr) incidence of relapse was 39% (24 – 60%) in the overall cohort and 36% (20 – 58%) in 27 pts treated at the phase II dose. At a median follow up of 19 months, the 1-yr OS was 42% (27 – 65%). Conclusion These data provide initial evidence of clinical translation for pegIFNα when administered prophylactically in an AML cohort at high risk for relapse. Type I Interferon did not significantly alter toxicity or aGVHD risk and produced relatively low rates of relapse suggesting a robust GVL response. The role of type 1 IFN in reducing clinical relapse and its underlying biological mechanisms warrants additional study. [ABSTRACT FROM AUTHOR]

Background: Evidence guiding the pre-hematopoietic stem cell transplantation (HSCT) cardiovascular evaluation is limited. We sought to derive and validate a pre-HSCT score for the cardiovascular risk stratification of HSCT candidates., Methods and Results: We leveraged the CARE-BMT (Cardiovascular Registry in Bone Marrow Transplantation) study, a contemporary multicenter observational study of adult patients who underwent autologous or allogeneic HSCT between 2008 and 2019 (N=2435; mean age at transplant of 55 years; 4.9% Black). We identified the subset of variables most predictive of post-HSCT cardiovascular events, defined as a composite of cardiovascular death, myocardial infarction, heart failure, stroke, atrial fibrillation or flutter, and sustained ventricular tachycardia. We then developed a point-based risk score using the hazard ratios obtained from Cox proportional hazards modeling. The score was externally validated in a separate cohort of 919 HSCT recipients (mean age at transplant 54 years; 20.4% Black). The risk score included age, transplant type, race, coronary artery disease, heart failure, peripheral artery disease, creatinine, triglycerides, and prior anthracycline dose. Risk scores were grouped as low-, intermediate-, and high-risk, with the 5-year cumulative incidence of cardiovascular events being 4.0%, 10.3%, and 22.4%, respectively. The area under the receiver operating curves for predicting cardiovascular events at 100 days, 5 and 10 years post-HSCT were 0.65 (95% CI, 0.59-0.70), 0.73 (95% CI, 0.69-0.76), and 0.76 (95% CI, 0.69-0.81), respectively. The model performed equally well in autologous and allogeneic recipients, as well as in the validation cohort., Conclusions: The CARE-BMT risk score is easy to calculate and could help guide referrals of high-risk HSCT recipients to cardiovascular specialists before transplant and guide long-term monitoring.

Patients with chronic graft-versus-host disease (cGVHD) have increased B cell-activating factor (BAFF) levels, but whether BAFF promotes disease after allogeneic bone marrow transplantation (allo-BMT) remains unknown. In a major histocompatibility complex-mismatched model with cGVHD-like manifestations, we first examined B-lymphopenic μMT allo-BMT recipients and found that increased BAFF levels in cGVHD mice were not merely a reflection of B-cell number. Mice that later developed cGVHD had significantly increased numbers of recipient fibroblastic reticular cells with higher BAFF transcript levels. Increased BAFF production by donor cells also likely contributed to cGVHD, because BAFF transcript in CD4+ T cells from diseased mice and patients was increased. cGVHD manifestations in mice were associated with high BAFF/B-cell ratios and persistence of B-cell receptor (BCR)-activated B cells in peripheral blood and lesional tissue. By employing BAFF transgenic (Tg) mice donor cells, we addressed whether high BAFF contributed to BCR activation in cGVHD. BAFF increased NOTCH2 expression on B cells, augmenting BCR responsiveness to surrogate antigen and NOTCH ligand. BAFF Tg B cells had significantly increased protein levels of the proximal BCR signaling molecule SYK, and high SYK protein was maintained by BAFF after in vitro BCR activation or when alloantigen was present in vivo. Using T cell-depleted (BM only) BAFF Tg donors, we found that BAFF promoted cGVHD manifestations, circulating GL7+ B cells, and alloantibody production. We demonstrate that pathologic production of BAFF promotes an altered B-cell compartment and augments BCR responsiveness. Our findings compel studies of therapeutic targeting of BAFF and BCR pathways in patients with cGVHD., (© 2021 by The American Society of Hematology.)

Hematopoietic cell transplantation (HCT) involves the infusion of hematopoietic progenitor cells into patients with hematologic disorders with the goal of re-establishing normal hematopoietic and immune function. HCT is classified as autologous or allogeneic based on the origin of hematopoietic cells. Autologous HCT uses the patient's own cells while allogeneic HCT uses hematopoietic cells from a human leukocyte antigen-compatible donor. Allogeneic HCT is a potentially curative treatment option for patients with certain types of hematologic malignancies, and autologous HCT is primarily used to support patients undergoing high-dose chemotherapy. Advances in HCT methods and supportive care in recent decades have led to improved survival after HCT; however, disease relapse and posttransplant complications still commonly occur in both autologous and allogeneic HCT recipients. Allogeneic HCT recipients may also develop acute and/or chronic graft-versus-host disease (GVHD), which results in immune-mediated cellular injury of several organs. The NCCN Guidelines for Hematopoietic Cell Transplantation focus on recommendations for pretransplant recipient evaluation and the management of GVHD in adult patients with malignant disease., (© 2020 by the National Comprehensive Cancer Network.)