Publications by authors named "Sally Arai"

87 Publications

Initial therapy of chronic graft vs. host disease: Analysis of practice variation and failure-free survival.

Blood Adv 2021 Sep 17. Epub 2021 Sep 17.

Fred Hutchinson Cancer Research Center, SEATTLE, Washington, United States.

Prior clinical trials largely considered prednisone 1mg/kg/day with or without calcineurin inhibitor as standard initial therapy for chronic graft vs. host disease (cGVHD) but uncertainty remains regarding the extent of practice variation and whether this affects subsequent outcomes. We assembled a cohort of 745 cGVHD patients treated with initial systemic immune suppressive (IS) therapy from three prior Chronic GVHD Consortium observational studies. Initial therapy was defined as first IS therapy started for cGVHD or prednisone increased to ≥ 0.4mg/kg/day from lower doses within 30 days before cGVHD diagnosis to any time afterward. Initial therapies were non-prednisone IS therapies (n=137, 18%), prednisone alone (n=411, 55%), or prednisone plus other IS therapy (n=197, 26%). In multivariate analysis, initial therapy group was not associated with FFS (failure-free survival, a composite of death, relapse, new IS therapy), overall survival (OS) or non-relapse mortality (NRM). Among the prednisone-based approaches, steroid dose (mg/kg/day) was <0.25 (9%), 0.25-0.74 (36%), 0.75-1.25 (42%), or >1.25 (13%). Prednisone dose within the steroid-treated patients was not significantly associated with FFS, OS, or NRM. No significant interactions were detected between overall cGVHD severity and either initial therapy group or prednisone dose for the outcomes of FFS, OS, or NRM. These observational data document heterogeneity in more contemporary cGVHD initial treatment practices, including prednisone dose and use of non-steroid approaches. This variation was not associated with FFS, OS, or NRM. Prospective trials are needed to verify efficacy of reduced-dose prednisone or prednisone-free initial therapy approaches.
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http://dx.doi.org/10.1182/bloodadvances.2021005286DOI Listing
September 2021

Non-relapse mortality among patients diagnosed with chronic GVHD: An updated analysis from The Chronic GVHD Consortium.

Blood Adv 2021 Sep 14. Epub 2021 Sep 14.

Cleveland Clinic, Cleveland, Ohio, United States.

Chronic graft-versus-host disease (GVHD) is the leading cause of late morbidity and mortality after allogeneic hematopoietic cell transplantation. To better understand patients at highest risk for non-relapse mortality (NRM), we analyzed patient, transplant, and chronic GVHD-related variables, risk factors, and causes of non-relapse deaths in an updated cohort of 937 subjects enrolled on two prospective, longitudinal observational studies through the Chronic GVHD Consortium. The median follow-up of survivors was 4 years (0.1 months - 12.5 years). Relapse accounted for 25% of the 333 deaths. The cumulative incidence of NRM was 22% at 5 years and increased over time with a projected 40% (95%CI, 30-50) at 12 years. Centers reported that chronic GVHD (37.8%) was the commonest cause of NRM and was associated with organ failure, infection, or additional cause not otherwise specified. The next most frequent causes without mention of chronic GVHD were infection (17%) and respiratory failure (10%). In multivariate analysis, an increased risk for NRM was significantly associated with the use of reduced intensity conditioning, higher total bilirubin, NIH skin score 2-3, NIH lung score 1-3, worse modified HAP adjusted activity score, and decreased distance on walk test. In conclusion, chronic GVHD NRM does not plateau but increases over time and is most commonly attributed to GVHD or infection, presumably associated with immunocompromised status. Severe skin and lung chronic GVHD remain challenging manifestations associated with increased NRM, for which novel therapeutic options are needed that do not predispose patients to infections.
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http://dx.doi.org/10.1182/bloodadvances.2021004941DOI Listing
September 2021

Incidence and Risk Factors Associated with Bleeding and Thrombosis Following Chimeric Antigen Receptor T Cell Therapy.

Blood Adv 2021 Sep 14. Epub 2021 Sep 14.

Stanford University, Stanford, California, United States.

Bleeding and thrombotic events are an emerging toxicity associated with chimeric antigen receptor (CAR) therapies. To determine their incidence, we retrospectively analyzed consecutive adult patients (n=127) with large B-cell lymphoma (LBCL) or B-cell acute lymphoblastic leukemia (B-ALL) treated between 2017-2020 with axicabtagene ciloleucel (axi-cel) (N=89) or a bispecific CD19/CD22 CAR (N=38). 12 (9.4%) and 8 (6.3%) patients developed bleeding and thrombosis within first 3 months, respectively. In the axi-cel subgroup, these occurred in 11.2% and 6.7%, respectively. Bleeding occurred between days 8-30 (median 17.5), and thrombosis between days 2-91 (median 29). Bleeding sites included genitourinary (N=6), soft tissue (N=2), intracranial (N=2), gastrointestinal (N=1), pulmonary (N=1), and were associated with features of consumptive coagulopathy. On univariate analysis, patients with bleeding were older (median 72 vs. 60 yrs, P<0.01), had lower baseline platelets (86 vs. 178 K/uL, P<0.01), lower platelet nadir after CAR-T (median 17.5 vs. 48 K/uL; P<0.01), lower fibrinogen nadir (median 122 vs. 340 ug/mL; P<0.01) and elevated LDH (P=0.01). ICANS grade ≥3 was associated with increased bleeding (50% vs. 15%; P=0.01), thrombosis (50% vs. 16%; P=0.04), PT prolongation, hypofibrinogenemia and elevated D-dimer. A paucity of events limited multivariate analysis, however low pre-treatment platelets were associated with bleeding in a multivariate logistic regression model. Patients with thrombocytopenia or severe ICANS are at increased risk of bleeding complications and should be closely monitored particularly within the first month after CAR therapy. Future studies in larger cohorts should assess risk factors for systemic coagulopathies in CAR-T therapy, including their association with neurotoxicity.
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http://dx.doi.org/10.1182/bloodadvances.2021004716DOI Listing
September 2021

Concordance of peripheral blood and bone marrow measurable residual disease in adult acute lymphoblastic leukemia.

Blood Adv 2021 08;5(16):3147-3151

Division of Blood and Marrow Transplantation.

Monitoring of measurable residual disease (MRD) is essential to the management of acute lymphoblastic leukemia (ALL) and is typically performed through repeated bone marrow (BM) assessments. Using a next-generation sequencing (NGS) MRD platform, we performed a prospective observational study evaluating the correlation between peripheral blood (PB) and BM MRD in adults with ALL receiving cellular therapies (hematopoietic cell transplantation [HCT] and chimeric antigen receptor T-cell [CAR-T] therapies). Among the study cohort (N = 69 patients; 126 paired PB/BM samples), we found strong correlation between PB and BM MRD (r = 0.87; P < .001), with a sensitivity and specificity of MRD detection in the PB of 87% and 90%, respectively, relative to MRD in the BM. MRD became detectable in the PB in 100% of patients who subsequently relapsed following HCT, with median time from MRD+ to clinical relapse of 90 days, and in 85% of patients who relapsed following CAR T, with median time from MRD+ to clinical relapse of 60 days. In adult patients with ALL undergoing cellular therapies, we demonstrate strong concordance between NGS-based MRD detected in the PB and BM. Monitoring of ALL MRD in the PB appears to be an adequate alternative to frequent invasive BM evaluations in this clinical setting.
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http://dx.doi.org/10.1182/bloodadvances.2021004234DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8405199PMC
August 2021

CAR T cells with dual targeting of CD19 and CD22 in adult patients with recurrent or refractory B cell malignancies: a phase 1 trial.

Nat Med 2021 08 26;27(8):1419-1431. Epub 2021 Jul 26.

Division of Blood and Marrow Transplantation and Cellular Therapy, Stanford University School of Medicine, Stanford, CA, USA.

Despite impressive progress, more than 50% of patients treated with CD19-targeting chimeric antigen receptor T cells (CAR19) experience progressive disease. Ten of 16 patients with large B cell lymphoma (LBCL) with progressive disease after CAR19 treatment had absent or low CD19. Lower surface CD19 density pretreatment was associated with progressive disease. To prevent relapse with CD19 or CD19 disease, we tested a bispecific CAR targeting CD19 and/or CD22 (CD19-22.BB.z-CAR) in a phase I clinical trial ( NCT03233854 ) of adults with relapsed/refractory B cell acute lymphoblastic leukemia (B-ALL) and LBCL. The primary end points were manufacturing feasibility and safety with a secondary efficacy end point. Primary end points were met; 97% of products met protocol-specified dose and no dose-limiting toxicities occurred during dose escalation. In B-ALL (n = 17), 100% of patients responded with 88% minimal residual disease-negative complete remission (CR); in LBCL (n = 21), 62% of patients responded with 29% CR. Relapses were CD19 in 50% (5 out of 10) of patients with B-ALL and 29% (4 out of 14) of patients with LBCL but were not associated with CD22 disease. CD19/22-CAR products demonstrated reduced cytokine production when stimulated with CD22 versus CD19. Our results further implicate antigen loss as a major cause of CAR T cell resistance, highlight the challenge of engineering multi-specific CAR T cells with equivalent potency across targets and identify cytokine production as an important quality indicator for CAR T cell potency.
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http://dx.doi.org/10.1038/s41591-021-01436-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8363505PMC
August 2021

A Fructo-Oligosaccharide Prebiotic Is Well Tolerated in Adults Undergoing Allogeneic Hematopoietic Stem Cell Transplantation: A Phase I Dose-Escalation Trial.

Transplant Cell Ther 2021 Jul 16. Epub 2021 Jul 16.

Department of Genetics, Department of Medicine, Stanford University, Stanford, California; Division of Blood and Marrow Transplantation and Cellular Therapy, Department of Medicine, Stanford University, Stanford, California. Electronic address:

Alterations of the gut microbiota after allogeneic hematopoietic cell transplantation (allo-HCT) are a key factor in the development of transplant-related complications such as graft-versus-host disease (GVHD). Interventions that preserve the gut microbiome hold promise to improve HCT-associated morbidity and mortality. Murine models demonstrate that prebiotics such as fructo-oligosaccharides (FOSs) may increase gut levels of short-chain fatty acids (SCFAs) such as butyrate and consequently induce proliferation of immunomodulatory FOXP3CD4 regulatory T cells (Tregs), which impact GVHD risk. We conducted a pilot phase I trial to investigate the maximum tolerated dose of FOS in patients undergoing reduced-intensity allo-HCT (n = 15) compared with concurrent controls (n = 16). We administered the FOS starting at pretransplant conditioning and continuing for a total of 21 days. We characterized the gut microbiome using shotgun metagenomic sequencing, measured stool short-chain fatty acids (SCFAs) using liquid chromatography-mass spectrometry, and determined peripheral T cell concentrations using cytometry by time-of-flight. We found that FOS was safe and well-tolerated at 10 g/d without significant adverse effects in patients undergoing allo-HCT. Community-level gut microbiota composition differed significantly on the day of transplant (day 0) between patients receiving FOS and concurrent controls; however, FOS-associated alterations of the gut microbiota were not sustained after transplant. Although the impact of FOS was fleeting, transplantation itself impacted a substantial number of taxa over time. In our small pilot trial, no significant differences were observed in gut microbial metabolic pathways, stool SCFAs, or peripheral Tregs, although Tregs trended higher in those patients who received FOS. A marker of CD4 T cell activation (namely, CTLA4) was significantly higher in patients receiving FOS, whereas a non-significant trend existed for FOP3CD4 Treg cells, which were higher in those receiving FOS compared with controls. FOS is well tolerated at 10 g/d in patients undergoing reduced-intensity allo-HCT. Although the alterations in gut microbiota and peripheral immune cell composition in those receiving FOS are intriguing, additional studies are required to investigate the use of prebiotics in HCT recipients.
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http://dx.doi.org/10.1016/j.jtct.2021.07.009DOI Listing
July 2021

Belumosudil for Chronic Graft-versus-Host Disease (cGVHD) After 2 or More Prior Lines of Therapy: The ROCKstar Study.

Blood 2021 Jul 15. Epub 2021 Jul 15.

Kadmon Corporation, West Chicago, Illinois, United States.

Belumosudil, an investigational oral selective inhibitor of rho-associated coiled-coil-containing protein kinase-2 (ROCK2), reduces type 17 and follicular helper T cells via downregulation of signal transducer and activator of transcription 3 (STAT3) and enhances regulatory T cells via upregulation of signal transducer and activator of transcription 5 (STAT5). Belumosudil may effectively treat patients with cGVHD, a major cause of morbidity and late nonrelapse mortality after an allogeneic hematopoietic cell transplant. This phase 2, randomized, multicenter registration study evaluated belumosudil 200 mg QD (n=66) and 200 mg BID (n=66) in subjects with cGVHD who had received 2 to 5 prior lines of therapy. The primary end point was best overall response rate (ORR). Duration of response (DOR), changes in Lee Symptom Scale score, failure-free survival, corticosteroid dose reductions and overall survival were also evaluated. Overall median follow-up was 14 months. The best ORR (95% CI) of belumosudil 200 mg QD and 200 mg BID was 74% (62%-84%) and 77% (65%-87%), respectively, with high response rates observed in all subgroups. All affected organs demonstrated complete responses. The median DOR was 54 weeks; 44% of subjects have remained on therapy for ≥1 year. Symptom reduction with belumosudil 200 mg QD and 200 mg BID was reported in 59% and 62% of subjects, respectively. Adverse events (AEs) were consistent with those expected in patients with cGVHD receiving corticosteroids and other immunosuppressants. Sixteen subjects (12%) discontinued belumosudil due to possible drug-related AEs. Belumosudil, a promising therapy for cGVHD, was well tolerated with clinically meaningful responses. (Funded by Kadmon Corporation, LLC; ClinicalTrials.gov number, NCT03640481.).
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http://dx.doi.org/10.1182/blood.2021012021DOI Listing
July 2021

Outcomes after delayed and second autologous stem cell transplant in patients with relapsed multiple myeloma.

Bone Marrow Transplant 2021 Jun 23. Epub 2021 Jun 23.

Department of Medicine, Stanford University, Stanford, CA, USA.

We evaluated the outcomes of 168 patients undergoing delayed or second autologous stem cell transplant (ASCT) for relapsed multiple myeloma (MM) from 2010 to 2019. Overall, 21% (n = 35) patients had received a prior transplant and 69% (n = 116) underwent transplant at first relapse. Overall, 27% patients had high-risk cytogenetics and 15% had ISS stage III disease. Stem cell collection was performed after relapse in 72% and 35% of patients received maintenance therapy. Median PFS from salvage treatment and transplant were 28 and 19 months, respectively. Median OS from salvage treatment and transplant was 69 and 55 months. Multivariate analysis revealed that ASCT in first relapse was associated with superior PFS (HR 0.63, p = 0.03) and OS (HR 0.59, p = 0.04) compared to later lines of therapy. In addition, PFS of ≥36 months with prior therapy was associated with improved PFS (HR 0.62, p = 0.04) and OS (HR 0.41, p = 0.01). Ninety-five patients underwent delayed transplant at first relapse, median PFS and OS from start of therapy was 30 and 69 months, and median OS from diagnosis was 106 months. These data may serve as a guide when counseling patients undergoing ASCT for relapsed MM and provide a benchmark in designing clinical trials of transplantation/comparative treatments for relapsed MM.
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http://dx.doi.org/10.1038/s41409-021-01371-1DOI Listing
June 2021

Stem Cell Mobilization in Multiple Myeloma: Comparing Safety and Efficacy of Cyclophosphamide +/- Plerixafor versus Granulocyte Colony-Stimulating Factor +/- Plerixafor in the Lenalidomide Era.

Transplant Cell Ther 2021 07 26;27(7):590.e1-590.e8. Epub 2021 Apr 26.

Stanford Cancer Institute, Stanford, California; Division of Blood and Marrow Transplantation and Cellular Therapy, Department of Medicine, Stanford University, Stanford, California. Electronic address:

Growth factor and chemotherapy-based stem cell mobilization strategies are commonly used to treat patients with multiple myeloma. We retrospectively compared 398 patients mobilized between 2017 and 2020 using either cyclophosphamide (4 g/m) plus granulocyte colony-stimulating factor (G-CSF) or G-CSF alone, with on demand plerixafor (PXF) in both groups. Although total CD34 yield was higher after chemomobilization compared with G-CSF +/- PXF (median, 13.6 × 10/kg versus 4.4 × 10/kg; P < .01), achievement of ≥2 × 10 CD34 cells (95% versus 93.7%; P = .61) and rates of mobilization failure (5% versus 6.3%; P = .61) were similar. Fewer patients required PXF with chemomobilization (12.3% versus 49.5%; P < .01), and apheresis sessions were fewer (median, 1 [range, 1 to 4] versus 2 [range, 1 to 5]). The rate of complications, including neutropenic fever, emergency department visits, and hospitalizations, was higher after chemomobilization (30% versus 7.4%; P < .01). Previous use of ≤6 cycles of lenalidomide did not impair cell yield in either group. The median cost of mobilization was 17.4% lower in the G-CSF +/- PXF group (P = .01). Between group differences in time to engraftment were not clinically significant. Given similar rates of successful mobilization, similar engraftment time, and less toxicity and lower costs compared with chemomobilization, G-CSF with on-demand PXF may be preferable in myeloma patients with adequate disease control and limited lenalidomide exposure.
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http://dx.doi.org/10.1016/j.jtct.2021.04.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8378276PMC
July 2021

Use of Backup Stem Cells for Stem Cell Boost and Second Transplant in Patients with Multiple Myeloma Undergoing Autologous Stem Cell Transplantation.

Transplant Cell Ther 2021 05 25;27(5):405.e1-405.e6. Epub 2021 Feb 25.

Department of Medicine, Division of Blood and Marrow Transplantation and Cellular Therapy, Stanford University School of Medicine, Stanford, California.. Electronic address:

Autologous hematopoietic stem cell transplantation (ASCT) is a standard treatment for multiple myeloma (MM). Consensus guidelines recommend collecting sufficient stem cells in case there is a need for stem cell boost for delayed/poor engraftment or for future second ASCT. However, collecting and storing backup stem cells in all patients requires significant resources and cost, and the rates of backup stem cell utilization are not well studied. We sought to examine the utilization of backup stem cells (BSCs) in patients with MM undergoing ASCT. Patients with MM aged ≥18 years old who underwent first ASCT at our institution from January 2010 through December 2015 and collected sufficient stem cells for at least 2 transplants were included in this single-center retrospective study. This timeframe was selected to allow for adequate follow-up. A total of 393 patients were included. The median age was 58 years (range, 25-73). After a median follow-up of 6 years, the median progression-free survival (PFS) of the cohort was 3 years. Sixty-one percent (n = 240) of patients progressed or relapsed. Chemotherapy-based mobilization was used in almost all patients (98%). The median total CD34+ cells collected was 18.2 × 10/kg (range, 3.4-112.4). A median of 5.7 × 10 CD34+ cells/kg (range, 1.8-41.9) was infused during the first ASCT, and a median of 10.1 × 10 CD34+ cells/kg (range, 1.5-104.5) was cryopreserved for future use. Of the patients, 6.9% (n = 27) used backup stem cells, with 2.3% (n = 10) using them for stem cell boost, 4.6% (n = 18) for a second salvage ASCT, including 1 patient for both stem cell boost and second ASCT. Rates of backup stem cell use among patients aged <60, 60-69, and ≥70 years were 7.8%, 5.7%, and 5.9%, respectively. There was a trend toward higher rates of backup stem cell use for second ASCT in patients who were younger, had suboptimal disease control at time of first ASCT, and longer PFS. The median dose of stem cell boost given was 5.6 × 10 CD34+ cells/kg (range, 1.9-20). The median time from stem cell boost to neutrophil, hemoglobin, and platelet engraftment was 4 (range, 2-11), 15 (range, 4-34), and 12 (range, 0-34) days, respectively. Lower CD34+ dose and older age at time of ASCT predicted need for stem cell boost. With new salvage therapies for relapsed MM, the rates of second ASCT are very low. The low rates of use suggest that institutional policies regarding universal BSC collection and long-term storage should be reassessed and individualized. However, need for stem cell boost in 2.3% of patients may present a challenge to that.
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http://dx.doi.org/10.1016/j.jtct.2021.02.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8113075PMC
May 2021

Allogeneic transplantation after PD-1 blockade for classic Hodgkin lymphoma.

Leukemia 2021 09 3;35(9):2672-2683. Epub 2021 Mar 3.

Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, IL, USA.

Anti-PD-1 monoclonal antibodies yield high response rates in patients with relapsed/refractory classic Hodgkin lymphoma (cHL), but most patients will eventually progress. Allogeneic hematopoietic cell transplantation (alloHCT) after PD-1 blockade may be associated with increased toxicity, raising challenging questions about the role, timing, and optimal method of transplantation in this setting. To address these questions, we assembled a retrospective cohort of 209 cHL patients who underwent alloHCT after PD-1 blockade. With a median follow-up among survivors of 24 months, the 2-year cumulative incidences (CIs) of non-relapse mortality and relapse were 14 and 18%, respectively; the 2-year graft-versus-host disease (GVHD) and relapse-free survival (GRFS), progression-free survival (PFS), and overall survival were 47%, 69%, and 82%, respectively. The 180-day CI of grade 3-4 acute GVHD was 15%, while the 2-year CI of chronic GVHD was 34%. In multivariable analyses, a longer interval from PD-1 to alloHCT was associated with less frequent severe acute GVHD, while additional treatment between PD-1 and alloHCT was associated with a higher risk of relapse. Notably, post-transplant cyclophosphamide (PTCy)-based GVHD prophylaxis was associated with significant improvements in PFS and GRFS. While awaiting prospective clinical trials, PTCy-based GVHD prophylaxis may be considered the optimal transplantation strategy for this patient population.
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http://dx.doi.org/10.1038/s41375-021-01193-6DOI Listing
September 2021

Immune reconstitution and infectious complications following axicabtagene ciloleucel therapy for large B-cell lymphoma.

Blood Adv 2021 01;5(1):143-155

Division of Blood and Marrow Transplantation, Department of Medicine, Stanford University School of Medicine, Stanford, CA.

Chimeric antigen receptor (CAR) T-cell therapy targeting CD19 has significantly improved outcomes in the treatment of refractory or relapsed large B-cell lymphoma (LBCL). We evaluated the long-term course of hematologic recovery, immune reconstitution, and infectious complications in 41 patients with LBCL treated with axicabtagene ciloleucel (axi-cel) at a single center. Grade 3+ cytopenias occurred in 97.6% of patients within the first 28 days postinfusion, with most resolved by 6 months. Overall, 63.4% of patients received a red blood cell transfusion, 34.1% of patients received a platelet transfusion, 36.6% of patients received IV immunoglobulin, and 51.2% of patients received growth factor (granulocyte colony-stimulating factor) injections beyond the first 28 days postinfusion. Only 40% of patients had recovered detectable CD19+ B cells by 1 year, and 50% of patients had a CD4+ T-cell count <200 cells per μL by 18 months postinfusion. Patients with durable responses to axi-cel had significantly longer durations of B-cell aplasia, and this duration correlated strongly with the recovery of CD4+ T-cell counts. There were significantly more infections within the first 28 days compared with any other period of follow-up, with the majority being mild-moderate in severity. Receipt of corticosteroids was the only factor that predicted risk of infection in a multivariate analysis (hazard ratio, 3.69; 95% confidence interval, 1.18-16.5). Opportunistic infections due to Pneumocystis jirovecii and varicella-zoster virus occurred up to 18 months postinfusion in patients who prematurely discontinued prophylaxis. These results support the use of comprehensive supportive care, including long-term monitoring and antimicrobial prophylaxis, beyond 12 months after axi-cel treatment.
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http://dx.doi.org/10.1182/bloodadvances.2020002732DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7805341PMC
January 2021

CD22-directed CAR T-cell therapy induces complete remissions in CD19-directed CAR-refractory large B-cell lymphoma.

Blood 2021 Apr;137(17):2321-2325

Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University, Stanford, CA.

The prognosis of patients with large B-cell lymphoma (LBCL) that progresses after treatment with chimeric antigen receptor (CAR) T-cell therapy targeting CD19 (CAR19) is poor. We report on the first 3 consecutive patients with autologous CAR19-refractory LBCL who were treated with a single infusion of autologous 1 × 106 CAR+ T cells per kilogram targeting CD22 (CAR22) as part of a phase 1 dose-escalation study. CAR22 therapy was relatively well tolerated, without any observed nonhematologic adverse events higher than grade 2. After infusion, all 3 patients achieved complete remission, with all responses continuing at the time of last follow-up (mean, 7.8 months; range, 6-9.3). Circulating CAR22 cells demonstrated robust expansion (peak range, 85.4-350 cells per microliter), and persisted beyond 3 months in all patients with continued radiographic responses and corresponding decreases in circulating tumor DNA beyond 6 months after infusion. Further accrual at a higher dose level in this phase 1 dose-escalation study is ongoing and will explore the role of this therapy in patients in whom prior CAR T-cell therapies have failed. This trial is registered on clinicaltrials.gov as #NCT04088890.
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http://dx.doi.org/10.1182/blood.2020009432DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8085484PMC
April 2021

Outcomes with Autologous or Allogeneic Stem Cell Transplantation in Patients with Plasma Cell Leukemia in the Era of Novel Agents.

Biol Blood Marrow Transplant 2020 12 19;26(12):e328-e332. Epub 2020 Sep 19.

Stanford Cancer Institute, Stanford University Medical Center, Stanford, California. Electronic address:

Plasma cell leukemia (PCL) is a rare and very aggressive plasma cell disorder. The optimal treatment approach, including whether to pursue an autologous (auto) or allogeneic (allo) stem cell transplantation (SCT) is not clear, given the lack of clinical trial-based evidence. This single-center retrospective study describes the outcomes of 16 patients with PCL (n = 14 with primary PCL) who underwent either autoSCT (n = 9) or alloSCT (n = 7) for PCL in the era of novel agents, between 2007 and 2019. The median age of the cohort was 58 years. High-risk cytogenetics were found in 50% of the patients. All patients received a proteasome inhibitor and/or immunomodulatory drug-based regimen before transplantation. At the time of transplantation, 10 patients (62%) obtained at least a very good partial response (VGPR). The response after autoSCT (3 months) was at least a VGPR in 6 patients (67%; complete response [CR] in 5). All patients undergoing alloSCT achieved a CR at 3 months. Maintenance therapy was provided to 5 patients (56%) after autoSCT. The median progression-free survival after transplantation was 6 months in the autoSCT group, compared with 18 months in the alloSCT group (P = .09), and median overall survival (OS) after transplantation in the 2 groups was 19 months and 40 months, respectively (P = .41). The median OS from diagnosis was 27 months and 49 months, respectively (P = .50). Of the 11 deaths, 10 patients (91%) died of relapsed disease. AlloSCT was not observed to offer any significant survival advantage over autoSCT in PCL, in agreement with recent reports, and relapse remains the primary cause of death in these patients.
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http://dx.doi.org/10.1016/j.bbmt.2020.08.035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8083942PMC
December 2020

Nonmyeloablative allogeneic transplantation achieves clinical and molecular remission in cutaneous T-cell lymphoma.

Blood Adv 2020 09;4(18):4474-4482

Department of Dermatology.

The majority of patients with refractory, advanced-stage mycosis fungoides (MF) or Sézary syndrome (SS) have a life expectancy of <5 years. Here, we report a phase 2 study of a novel nonmyeloablative allogeneic transplantation strategy tailored for this patient population. This study has completed the enrollment, and 35 patients (13 MF, 22 SS) have undergone transplant as planned. The majority (80%) of the patients had stage IV disease and received multiple previous systemic therapies. All patients had active disease at the time of conditioning using total skin electron beam therapy, total lymphoid irradiation, and antithymocyte globulin, and received allograft infusion as outpatients. Cyclosporine or tacrolimus and mycophenolate mofetil were used for graft-versus-host disease (GVHD) prophylaxis. Patients tolerated the transplant well, with 1- and 2-year nonrelapse mortality of 3% and 14%, respectively. The day +180 cumulative incidence of grade 2 to 4 acute GVHD was 16%, and the 2-year incidence of moderate/severe chronic GVHD was 32%. With a median posttransplant follow-up of 5.4 years, the 2-, 3-, and 5-year overall survival rates were 68%, 62%, and 56%. Using high-throughput sequencing of the T-cell receptor for minimal residual disease monitoring, we observed that 43% achieved molecular remission, which was associated with a lower incidence of disease progression or relapse (9% vs 87%; P = .02). Our study also showed that patients who were aged ≥65 years at the time of allotransplant had similar clinical outcomes compared with younger patients. Thus, we have developed an alternative and potentially curative nonmyeloablative allogeneic transplant regimen for patients with advanced stage MF/SS. This trial was registered at www.clinicaltrials.gov as #NCT00896493.
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http://dx.doi.org/10.1182/bloodadvances.2020001627DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7509879PMC
September 2020

Outcomes with autologous stem cell transplant vs. non-transplant therapy in patients 70 years and older with multiple myeloma.

Bone Marrow Transplant 2021 02 11;56(2):368-375. Epub 2020 Aug 11.

Stanford Cancer Institute, Stanford University Medical Center, Stanford, CA, USA.

We evaluated 79 patients with multiple myeloma (MM) ≥70 years referred to our blood and marrow transplant clinic, within 1 year of diagnosis from 2010 to 2019, for consideration of autologous stem cell transplant (ASCT). Thirty-eight (48%) of 79 patients underwent ASCT. ASCT was not pursued in 41 (52%) patients due to: patient or physician preference in 80% (n = 33) or ineligibility in 20% (n = 8). Baseline characteristics of patients in the two groups were similar. Median PFS from treatment start amongst patients undergoing ASCT (n = 38) vs. not (n = 41) was 41 months vs. 33 months, p = 0.03. There was no difference in OS, with estimated 5-year OS of 73% vs. 83%, respectively (p = 0.86). Day +100 transplant-related mortality (TRM) was 0%. ASCT was an independent favorable prognostic factor for PFS in multivariate analysis, after accounting for HCT-CI score, performance status, hematologic response, and maintenance. Finally, patients ≥70 years undergoing ASCT had similar PFS compared to a contemporaneous institutional cohort of patients <70 years (n = 631) (median PFS from transplant: 36 vs. 47 months, p = 0.25). In this retrospective analysis, ASCT was associated with low TRM and better PFS in fit older adults with MM compared to non-transplant therapy, with comparable benefits as seen in younger patients.
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http://dx.doi.org/10.1038/s41409-020-01026-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8019397PMC
February 2021

Outcomes in Patients With Cardiac Amyloidosis Undergoing Heart Transplantation.

JACC Heart Fail 2020 06 6;8(6):461-468. Epub 2020 May 6.

Stanford Amyloid Center, Stanford University School of Medicine, Stanford, California. Electronic address:

Objectives: The purpose of this study is to report outcomes after heart transplantation in patients with cardiac amyloidosis based on a large single-center experience.

Background: Cardiac amyloidosis causes significant morbidity and mortality, often leading to restrictive cardiomyopathy, progressive heart failure, and death. Historically, heart transplantation outcomes have been worse in patients with cardiac amyloidosis compared with other heart failure populations, in part due to the systemic nature of the disease. However, several case series have suggested that transplantation outcomes may be better in the contemporary era, likely in part due to the availability of more effective light chain suppressive therapies for light chain amyloidosis.

Methods: This study examined all patients seen between 2004 and 2017, either at the Stanford University Medical Center or the Kaiser Permanente Santa Clara Medical Center, who were diagnosed with cardiac amyloidosis and ultimately underwent heart transplantation. This study examined pre-transplantation characteristics and post-transplantation outcomes in this group compared with the overall transplantation population at our center.

Results: During the study period, 31 patients (13 with light chain amyloidosis and 18 with transthyretin [ATTR] amyloidosis) underwent heart transplantation. Patients with ATTR amyloidosis were older, were more likely to be male, had worse baseline renal function, and had longer waitlist times compared with both patients with light chain amyloidosis and the overall transplantation population. Post-transplantation, there were no differences in post-operative bleeding, renal failure, infection, rejection, or malignancy. There was no significant difference in mortality between patients who underwent heart transplantation for amyloid cardiomyopathy and patients who underwent heart transplantation for all other indications.

Conclusions: In carefully selected patients with cardiac amyloidosis, heart transplantation can be an effective therapeutic option with outcomes similar to those transplanted for other causes of heart failure.
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http://dx.doi.org/10.1016/j.jchf.2019.12.013DOI Listing
June 2020

Organ responses with daratumumab therapy in previously treated AL amyloidosis.

Blood Adv 2020 02;4(3):458-466

Deparment of Medicine, Stanford University School of Medicine, Stanford, CA and.

Immunoglobulin light chain amyloidosis (AL amyloidosis) involves deposition of abnormally folded light chains into a wide range of tissues causing organ dysfunction, including in the heart and kidney. Daratumumab, a CD38-targeted antibody, has recently demonstrated efficacy in producing hematologic responses in previously treated disease. However, data on survival outcomes and organ responses to daratumumab are lacking. Seventy-two patients with previously treated AL amyloidosis who received daratumumab monotherapy with dexamethasone were retrospectively evaluated. With a median follow-up of 27 months, 2-year overall survival (OS) was 86.9% (median OS, not reached) and 2-year time-to-next treatment or death (TTNT)-free survival was 62% (median TTNT, not reached). Forty of 52 evaluable patients achieved a hematologic response (77%), with >60% of patients achieving a very good partial response or better; median time-to-hematologic response was 1 month. Fifty-seven patients (79%) had cardiac involvement, and 55% of evaluable patients achieved a cardiac response, with a median response time of 3.2 months among responders. Cardiac responses were associated with an improvement in OS, with landmark analysis for cardiac responses at 3 months trending toward statistical significance (100% vs 55% at 30 months, P = .051). Forty-seven patients (65%) had renal involvement, and 52% of evaluable patients achieved a renal response, with a median response time of 6 months among responders; there was no significant difference in OS between renal responders and nonresponders. This study demonstrates that daratumumab is highly effective in the treatment of previously treated AL amyloidosis, and a significant proportion of patients can achieve deep hematologic responses, as well as improvements in organ function.
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http://dx.doi.org/10.1182/bloodadvances.2019000776DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7013253PMC
February 2020

A Changing Landscape of Mortality for Systemic Light Chain Amyloidosis.

JACC Heart Fail 2019 11 9;7(11):958-966. Epub 2019 Oct 9.

Stanford Amyloid Center, Stanford University School of Medicine, Stanford, California. Electronic address:

Objectives: The purpose of this study was to address the overall trends in mortality since the adoption of modern therapies for treatment of systemic amyloidosis, and to reconsider the prognostic significance of individual components of the current staging system.

Background: Systemic light chain (AL) amyloidosis involves deposition of immunoglobulin light chains in organs throughout the body and is known to have the highest mortality when significant cardiac involvement is present. Survival has historically been poor but may be improving as systemic therapies continue to advance. This study assesses whether recent advancements in light chain directed therapy have led to improved survival in patients with systemic AL amyloidosis.

Methods: We reviewed all cases of patients who were evaluated for a new diagnosis of AL amyloidosis at the Stanford Amyloid Center between 2009 and 2016. Patients' stage at diagnosis was determined according to the most commonly used staging system. Clinical data, overall survival from diagnosis, and the independent influence of each component of the staging system were analyzed.

Results: At total of 194 patients were identified with a new diagnosis of systemic AL amyloidosis. Median overall survival was 59 months and 6 months for stage 3 and 4 patients, respectively. Median overall survival was not reached in stage 1 and 2 groups, as survival was >50% by the end of the study. Mean overall survival was 118 months, 76 months, 64 months, and 27 months in Stages 1, 2, 3, and 4 patients, respectively. Although N-terminal pro-B-type natriuretic peptide and troponin I concentrations had large effects on prognosis, differences in serum free light chains (dFLC) on initial staging laboratory results ≥18 mg/dl, part of the current staging system, did not contribute significantly to prognosis for values ≥5 mg/dl.

Conclusions: Survival for patients with systemic AL amyloidosis has improved for patients at all stages of disease in the present era of rapid advancements in light chain-reducing therapies. Cardiac biomarkers at diagnosis, but not baseline dFLC ≥18 mg/dl, continue to provide important prognostic information.
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http://dx.doi.org/10.1016/j.jchf.2019.07.007DOI Listing
November 2019

Nonmyeloablative TLI-ATG conditioning for allogeneic transplantation: mature follow-up from a large single-center cohort.

Blood Adv 2019 08;3(16):2454-2464

Division of Blood and Marrow Transplantation, Department of Medicine.

Nonmyeloablative total lymphoid irradiation and antithymocyte globulin (TLI-ATG) conditioning is protective against graft-versus-host disease (GVHD), while retaining graft-versus-tumor activity across various hematologic malignancies. We report our comprehensive experience using TLI-ATG conditioning in 612 patients with hematologic malignancies who underwent allogeneic transplantation at Stanford University from 2001 to 2016. All patients received granulocyte colony-stimulating factor-mobilized peripheral blood grafts and cyclosporine and mycophenolate mofetil for GVHD prophylaxis. The median age was 60 years (range, 21-78), with a median follow-up of 6.0 years (range, 1.0-16.4). Common diagnoses included acute myeloid leukemia (AML; n = 193), myelodysplastic syndrome (MDS; n = 94), chronic lymphocytic leukemia (CLL; n = 80), non-Hodgkin lymphoma (NHL; n = 175), and Hodgkin lymphoma (HL; n = 35). Thirty-four percent of patients had a comorbidity index ≥3, 30% had a high to very high disease risk index, and 56% received unrelated donor grafts, including 15% with HLA-mismatched donors. Ninety-eight percent underwent transplant in the outpatient setting, and 57% were never hospitalized from days 0 through 100. The 1-year rates of nonrelapse mortality (NRM), grade II-IV acute GVHD, and extensive chronic GVHD were 9%, 14%, and 22%, respectively. The 4-year estimates for overall and progression-free survival were 42% and 32% for AML, 30% and 21% for MDS, 67% and 43% for CLL, 68% and 45% for NHL, and 78% and 49% for HL. Mixed chimerism correlated with the risk of relapse. TLI-ATG conditioning was well tolerated, with low rates of GVHD and NRM. Durable remissions were observed across hematologic malignancies, with particularly favorable outcomes for heavily pretreated lymphomas. Several efforts are underway to augment donor chimerism and reduce relapse rates while maintaining the favorable safety and tolerability profile of this regimen.
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http://dx.doi.org/10.1182/bloodadvances.2019000297DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6712526PMC
August 2019

Transplantation of donor grafts with defined ratio of conventional and regulatory T cells in HLA-matched recipients.

JCI Insight 2019 05 16;4(10). Epub 2019 May 16.

Division of Blood and Marrow Transplantation, Stanford University, Stanford, California, USA.

BACKGROUNDIn preclinical murine and early clinical studies of hematopoietic cell transplantation, engineering of donor grafts with defined ratios of CD4+CD25+FoxP3+ Tregs to conventional T cells (Tcons) results in the prevention of graft-versus-host disease and improved immune reconstitution. The use of highly purified primary graft Tregs for direct cell infusion has potential advantages over impure immunomagnetic selection or culture expansion, but has not been tested clinically. We performed a phase I study of the timed addition of CD34-selected hematopoietic stem cells and Tregs, followed by Tcons for the treatment of patients with high-risk hematological malignancies.METHODSWe present interim evaluation of a single-center open phase I/II study of administration of human leukocyte-matched Tregs and CD34-selected hematopoietic cells, followed by infusion of an equal ratio of Tcons in adult patients undergoing myeloablative hematopoietic stem cell transplantation (HCT) for high-risk or active hematological malignancies. Tregs were purified by immunomagnetic selection and high-speed cell sorting.RESULTSHere we report results for the first 12 patients who received Tregs of between 91% and 96% purity. Greater than grade II GVHD was noted in 2 patients in the first cohort of 5 patients, who received cryopreserved Tregs, but neither acute nor chronic GVHD was noted in the second cohort of 7 patients, who received fresh Tregs and single-agent GVHD prophylaxis. Patients in the second cohort appeared to have normal immune reconstitution compared with patients who underwent transplantation and did not develop GVHD.CONCLUSIONOur study shows that the use of highly purified fresh Tregs is clinically feasible and supports continued investigation of the strategy.TRIAL REGISTRATIONClinicalTrials.gov NCT01660607.FUNDINGNIH NHBLI R01 HL114591 and K08HL119590.
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http://dx.doi.org/10.1172/jci.insight.127244DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6542607PMC
May 2019

Three prophylaxis regimens (tacrolimus, mycophenolate mofetil, and cyclophosphamide; tacrolimus, methotrexate, and bortezomib; or tacrolimus, methotrexate, and maraviroc) versus tacrolimus and methotrexate for prevention of graft-versus-host disease with haemopoietic cell transplantation with reduced-intensity conditioning: a randomised phase 2 trial with a non-randomised contemporaneous control group (BMT CTN 1203).

Lancet Haematol 2019 Mar;6(3):e132-e143

Blood and Marrow Transplant Program at Northside Hospital, Atlanta, GA, USA.

Background: Prevention of graft-versus-host disease (GvHD) without malignant relapse is the overall goal of allogeneic haemopoietic cell transplantation (HCT). We aimed to evaluate regimens using either maraviroc, bortezomib, or post-transplantation cyclophosphamide for GvHD prophylaxis compared with controls receiving the combination of tacrolimus and methotrexate using a novel composite primary endpoint to identify the most promising intervention to be further tested in a phase 3 trial.

Methods: In this prospective multicentre phase 2 trial, adult patients aged 18-75 years who received reduced-intensity conditioning HCT were randomly assigned (1:1:1) by random block sizes to tacrolimus, mycophenolate mofetil, and post-transplantation cyclophosphamide (cyclophosphamide 50 mg/kg on days 3 and 4, followed by tacrolimus starting on day 5 and mycophenolate mofetil starting on day 5 at 15 mg/kg three times daily not to exceed 1 g from day 5 to day 35); tacrolimus, methotrexate, and bortezomib (bortezomib 1·3 mg/m intravenously on days 1, 4, and 7 after HCT); or tacrolimus, methotrexate, and maraviroc (maraviroc 300 mg orally twice daily from day -3 to day 30 after HCT). Methotrexate was administered as a 15 mg/m intravenous bolus on day 1 and 10 mg/m intravenous bolus on days 3, 6, and 11 after HCT; tacrolimus was given intravenously at a dose of 0·05 mg/kg twice daily (or oral equivalent) starting on day -3 (except the post-transplantation cyclophosphamide, as indicated), with a target level of 5-15 ng/mL. Tacrolimus was continued at least until day 90 and was tapered off by day 180. Each study group was compared separately to a contemporary non-randomised prospective cohort of patients (control group) who fulfilled the same eligibility criteria as the trial, but who were treated with tacrolimus and methotrexate at centres not participating in the trial. The primary endpoint (GvHD-free, relapse-free survival [GRFS]) was defined as the time from HCT to onset of grade 3-4 acute GvHD, chronic GvHD requiring systemic immunosuppression, disease relapse, or death. The study was analysed by modified intention to treat. The study is closed to accrual and this is the planned analysis. This trial is registered with ClinicalTrials.gov, number NCT02208037.

Findings: Between Nov 17, 2014, and May 18, 2016, 273 patients from 31 US centres were randomly assigned to the three study arms: 89 to tacrolimus, methotrexate, and bortezomib; 92 to tacrolimus, methotrexate, and maraviroc; 92 to tacrolimus, mycophenolate mofetil, and post-transplantation cyclophosphamide; and six were excluded. Between Aug 1, 2014, and Sept 14, 2016, 224 controls received tacrolimus and methotrexate. Controls were generally well matched except for more frequent comorbidities than the intervention groups and a different distribution of types of conditioning regimens used. Compared with controls, the hazard ratio for GRFS was 0·72 (90% CI 0·54-0·94; p=0·044) for tacrolimus, mycophenolate mofetil, and post-transplantation cyclophosphamide, 0·98 (0·76-1·27; p=0·92) for tacrolimus, methotrexate, and bortezomib, and 1·10 (0·86-1·41; p=0·49) for tacrolimus, methotrexate, and maraviroc. 238 patients experienced grade 3 or 4 toxicities: 12 (13%) had grade 3 and 67 (73%) grade 4 events with tacrolimus, mycophenolate mofetil, and post-transplantation cyclophosphamide; ten (11%) had grade 3 and 68 (76%) had grade 4 events with tacrolimus, methotrexate, and bortezomib; and 18 (20%) had grade 3 and 63 (68%) had grade 4 events with tacrolimus, methotrexate, and maraviroc. The most common toxicities were haematological (77 [84%] for tacrolimus, mycophenolate mofetil, and post-transplantation cyclophosphamide; 73 [82%] for tacrolimus, methotrexate, and bortezomib; and 78 [85%] for tacrolimus, methotrexate, and maraviroc) and cardiac (43 [47%], 44 [49%], and 43 [47%], respectively).

Interpretation: Tacrolimus, mycophenolate mofetil, and post-transplantation cyclophosphamide was the most promising intervention, yielding the best GRFS; this regimen is thus being prospectively compared with tacrolimus and methotrexate in a phase 3 randomised trial.

Funding: US National Health, Lung, and Blood Institute; National Cancer Institute; National Institute of Allergy and Infectious Disease; and Millennium Pharmaceuticals.
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http://dx.doi.org/10.1016/S2352-3026(18)30221-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6503965PMC
March 2019

Grading cardiac response in AL amyloidosis: implications for relapse and survival.

Br J Haematol 2019 07 19;186(1):144-146. Epub 2018 Dec 19.

Department of Medicine, Stanford University Hospital, Stanford, CA, USA.

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http://dx.doi.org/10.1111/bjh.15717DOI Listing
July 2019

Donor-derived MDS/AML in families with germline mutation.

Blood 2018 11 19;132(18):1994-1998. Epub 2018 Sep 19.

Hematology Section, Department of Laboratory Medicine, Clinical Center, National Institutes of Health (NIH), Bethesda, MD.

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http://dx.doi.org/10.1182/blood-2018-07-861070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6213320PMC
November 2018

Amphiregulin modifies the Minnesota Acute Graft-versus-Host Disease Risk Score: results from BMT CTN 0302/0802.

Blood Adv 2018 08;2(15):1882-1888

National Marrow Donor Program, Minneapolis, MN.

Amphiregulin (AREG) is an epidermal growth factor receptor ligand that can restore integrity to damaged intestinal mucosa in murine models of acute graft-versus-host disease (aGVHD). We previously reported that circulating AREG is elevated in late-onset aGVHD (occurring after 100 days posttransplant), but its clinical relevance in the context of aGVHD risk is unknown. We measured AREG in 251 aGVHD onset blood samples from Blood and Marrow Clinical Trials Network (BMT CTN) primary treatment trials and determined their association with GVHD severity, day 28 complete or partial response (CR/PR) to first-line therapy, overall survival (OS), and nonrelapse mortality (NRM). Every doubling of plasma AREG was associated with a 33% decrease in the odds of day 28 CR/PR (odds ratio [OR], 0.67; < .01). An AREG threshold of 33 pg/mL or greater divided patients with Minnesota standard-risk (SR) aGVHD into a distinct group with a significantly lower likelihood of: day 28 CR/PR (72% vs 85%; = .02); greater 2-year NRM (42% vs 15%; < .01); and inferior OS (40% vs 66%; < .01). High AREG ≥ 33 pg/mL also stratified patients with Minnesota high-risk (HR) aGVHD: day 28 CR/PR (54% vs 83%; = .03) and 2-year NRM (53% vs 11%; < .01), with a trend toward inferior 2-year OS (37% vs 60%; = .09). High-circulating AREG (≥33 pg/mL) reclassifies patients into HR subgroups and thereby further refines the Minnesota aGVHD clinical risk score.
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http://dx.doi.org/10.1182/bloodadvances.2018017343DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6093743PMC
August 2018

Final results from a defibrotide treatment-IND study for patients with hepatic veno-occlusive disease/sinusoidal obstruction syndrome.

Br J Haematol 2018 06 16;181(6):816-827. Epub 2018 May 16.

Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.

Hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a potentially life-threatening complication of haematopoietic stem cell transplant (HSCT) conditioning and chemotherapy. Defibrotide is approved for treatment of hepatic VOD/SOS with pulmonary or renal dysfunction [i.e., multi-organ dysfunction (MOD)] after HSCT in the United States and severe VOD/SOS after HSCT in patients aged older than 1 month in the European Union. Defibrotide was available as an investigational drug by an expanded-access treatment programme (T-IND; NCT00628498). In the completed T-IND, the Kaplan-Meier estimated Day +100 survival for 1000 patients with documented defibrotide treatment after HSCT was 58·9% [95% confidence interval (CI), 55·7-61·9%]. Day +100 survival was also analysed by age and MOD status, and post hoc analyses were performed to determine Day +100 survival by transplant type, timing of VOD/SOS onset (≤21 or >21 days) and timing of defibrotide treatment initiation after VOD/SOS diagnosis. Day +100 survival in paediatric patients was 67·9% (95% CI, 63·8-71·6%) and 47·1% (95% CI, 42·3-51·8%) in adults. All patient subgroups without MOD had higher Day +100 survival than those with MOD; earlier defibrotide initiation was also associated with higher Day +100 survival. The safety profile of defibrotide in the completed T-IND study was similar to previous reports.
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http://dx.doi.org/10.1111/bjh.15267DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6032999PMC
June 2018

Infusion of donor-derived CD8 memory T cells for relapse following allogeneic hematopoietic cell transplantation.

Blood Adv 2018 03;2(6):681-690

Division of Blood and Marrow Transplantation and.

Murine models showed that CD8CD44 memory T (T) cells could eradicate malignant cells without inducing graft-versus-host disease (GVHD). We evaluated the feasibility and safety of infusing freshly isolated and purified donor-derived phenotypic CD8 T cells into adults with disease relapse after allogeneic hematopoietic cell transplantation (HCT). Phenotypic CD8 T cells were isolated after unmobilized donor apheresis using a tandem immunomagnetic selection strategy of CD45RA depletion followed by CD8 enrichment. Fifteen patients received CD8 T cells at escalating doses (1 × 10, 5 × 10, or 10 × 10 cells per kg). Thirteen received cytoreduction before CD8 T cell infusion, and 9 had active disease at the time of infusion. Mean yield and purity of the CD8 T infusion were 38.1% and 92.8%, respectively; >90% had CD8 T effector memory phenotype, cytokine expression, and secretion profile. No adverse infusional events or dose-limiting toxicities occurred; GVHD developed in 1 patient (grade 2 liver). Ten patients (67%) maintained or achieved response (7 complete response, 1 partial response, 2 stable disease) for at least 3 months after infusion; 4 of the responders had active disease at the time of infusion. With a median follow-up from infusion of 328 days (range, 118-1328 days), median event-free survival and overall survival were 4.9 months (95% confidence interval [CI], 1-19.3 months) and 19.6 months (95% CI, 5.6 months to not reached), respectively. Collection and enrichment of phenotypic CD8 T cells is feasible, well tolerated, and associated with a low incidence of GVHD when administered as a manipulated infusion of donor lymphocytes in patients who have relapsed after HCT. This trial was registered at www.clinicaltrials.gov as #NCT01523223.
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http://dx.doi.org/10.1182/bloodadvances.2017012104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5873230PMC
March 2018
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