Phase II study of novel CXCR2 agonist and Plerixafor for rapid stem cell mobilization in patients with multiple myeloma.

MGTA-145 or GROßT, a CXCR2 agonist, has shown promising activity for hematopoietic stem cell (HSC) mobilization with plerixafor in pre-clinical studies and healthy volunteers. Twenty-five patients with multiple myeloma enrolled in a phase 2 trial evaluating MGTA-145 and plerixafor for HSC mobilization (NCT04552743). Plerixafor was given subcutaneously followed 2 h later by MGTA-145 (0.03 mg/kg) intravenously with same day apheresis. Mobilization/apheresis could be repeated for a second day in patients who collected <6 ×106 CD34+ cells/kg. Lenalidomide and anti-CD38 antibody were part of induction therapy in 92% (n = 23) and 24% (n = 6) of patients, respectively. Median total HSC cell yield (CD34+ cells/kg × 106) was 5.0 (range: 1.1-16.2) and day 1 yield was 3.4 (range: 0.3-16.2). 88% (n = 22) of patients met the primary endpoint of collecting 2 ×106 CD34+ cells/kg in ≤ two days, 68% (n = 17) in one day. Secondary endpoints of collecting 4 and 6 × 106 CD34+ cells/kg in ≤ two days were met in 68% (n = 17) and 40% (n = 10) patients. Grade 1 or 2 adverse events (AE) were seen in 60% of patients, the most common AE being grade 1 pain, usually self-limited. All 19 patients who underwent transplant with MGTA-145 and plerixafor mobilized HSCs engrafted successfully, with durable engraftment at day 100. 74% (17 of 23) of grafts with this regimen were minimal residual disease negative by next generation flow cytometry. Graft composition for HSCs and immune cells were similar to a contemporaneous cohort mobilized with G-CSF and plerixafor.

ASTCT and USCLC Clinical Practice Recommendations for Allogeneic Stem Cell Transplant in Mycosis Fungoides and Sézary Syndrome.

Mycosis fungoides (MF) and Sézary syndrome (SS) are the most common subtypes of cutaneous T-cell lymphoma (CTCL). While MF generally follows an indolent course, a subset of patients will experience progressive and/or treatment-refractory disease; Sézary syndrome is an aggressive lymphoma associated with high morbidity and mortality. Although allogeneic hematopoietic cell transplant (allo-HCT) is the only currently available potentially curative treatment modality for MF/SS there is no published guidance on referral criteria, transplant timing orallo-HCT approach. To develop consensus clinical practice recommendations, we performed a Delphi survey of 32 specialists in dermatology (n = 9), transplant hematology/oncology (n = 10), non-transplant hematology/oncology (n = 8), and radiation oncology (n = 5) from across the United States. Consensus required agreement of ≥75% of participants. Sixteen consensus statements were generated on four topics: (1) criteria for referral for consideration for allo-HCT, (2) allo-HCT preparative regimens and procedures (3) disease status at the time of allo-HCT, and (4) multidisciplinary management in the pre- and post-transplant settings. These clinical practice guidelines provide a framework for decision-making regarding allo-HCT for MF/SS and highlight areas for future prospective investigation.

Bendamustine is a safe and effective lymphodepletion agent for axicabtagene ciloleucel in patients with refractory or relapsed large B-cell lymphoma.

BACKGROUND: Fludarabine in combination with cyclophosphamide (FC) is the standard lymphodepletion regimen for CAR T-cell therapy (CAR T). A national fludarabine shortage in 2022 necessitated the exploration of alternative regimens with many centers employing single-agent bendamustine as lymphodepletion despite a lack of clinical safety and efficacy data. To fill this gap in the literature, we evaluated the safety, efficacy, and expansion kinetics of bendamustine as lymphodepletion prior to axicabtagene ciloleucel (axi-cel) therapy. METHODS: 84 consecutive patients with relapsed or refractory large B-cell lymphoma treated with axi-cel and managed with a uniform toxicity management plan at Stanford University were studied. 27 patients received alternative lymphodepletion with bendamustine while 57 received FC. RESULTS: Best complete response rates were similar (73.7% for FC and 74% for bendamustine, p=0.28) and there was no significant difference in 12-month progression-free survival or overall survival estimates (p=0.17 and p=0.62, respectively). The frequency of high-grade cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome was similar in both the cohorts. Bendamustine cohort experienced lower proportions of hematological toxicities and antibiotic use for neutropenic fever. Immune reconstitution, as measured by quantitative assessment of cellular immunity, was better in bendamustine cohort as compared with FC cohort. CAR T expansion as measured by peak expansion and area under the curve for expansion was comparable between cohorts. CONCLUSIONS: Bendamustine is a safe and effective alternative lymphodepletion conditioning for axi-cel with lower early hematological toxicity and favorable immune reconstitution.

A phase 1 clinical trial of NKTR-255 with CD19-22 CAR T-cell therapy for refractory B-cell acute lymphoblastic leukemia.

ABSTRACT: Although chimeric antigen receptor (CAR) T-cell (CAR-T) therapy has revolutionized the treatment of B-cell malignancies, many patients relapse and therefore strategies to improve antitumor immunity are needed. We previously designed a novel autologous bispecific CAR targeting CD19 and CD22 (CAR19-22), which was well tolerated and associated with high response rates but relapse was common. Interleukin-15 (IL15) induces proliferation of diverse immune cells and can augment lymphocyte trafficking. Here, we report the results of a phase 1 clinical trial of the first combination of a novel recombinant polymer-conjugated IL15 receptor agonist (NKTR-255), with CAR19-22, in adults with relapsed/refractory B-cell acute lymphoblastic leukemia. Eleven patients were enrolled, 9 of whom successfully received CAR19-22 followed by NKTR-255. There were no dose-limiting toxicities, with transient fever and myelosuppression as the most common possibly related toxicities. We observed favorable efficacy with 8 of 9 patients (89%) achieving measurable residual disease-negative remission. At 12 months, progression-free survival for NKTR-255 was double that of historical controls (67% vs 38%). We performed correlative analyses to investigate the effects of IL15 receptor agonism. Cytokine profiling showed significant increases in IL15 and the chemokines CXCL9 and CXCL10. The increase in chemokines was associated with decreases in absolute lymphocyte counts and CD8+ CAR T cells in the blood and 10-fold increases in cerebrospinal fluid CAR-T cells, suggesting lymphocyte trafficking to tissue. Combining NKTR-255 with CAR19-22 was safe, feasible, and associated with high rates of durable responses. This trial was registered at www.clinicaltrials.gov as #NCT03233854.

Tabelecleucel for EBV+ PTLD after allogeneic HCT or SOT in a multicenter expanded access protocol.

ABSTRACT: Patients with Epstein-Barr virus (EBV)-positive posttransplant lymphoproliferative disease (EBV+ PTLD) in whom initial treatment fails have few options and historically low median overall survival (OS) of 0.7 months after allogeneic hematopoietic cell transplant (HCT) and 4.1 months after solid organ transplant (SOT). Tabelecleucel is an off-the-shelf, allogeneic EBV-specific cytotoxic T-lymphocyte immunotherapy for EBV+ PTLD. Previous single-center experience showed responses in patients with EBV+ PTLD after HCT or SOT. We now report outcomes from a multicenter expanded access protocol in HCT (n = 14) and SOT (n = 12) recipients treated with tabelecleucel for EBV+ PTLD that was relapsed/refractory (R/R) to rituximab with/without chemotherapy. The investigator-assessed objective response rate was 65.4% overall (including 38.5% with a complete and 26.9% with a partial response), 50.0% in HCT, and 83.3% in SOT. The estimated 1- and 2-year OS rates were both 70.0% (95% confidence interval [CI], 46.5-84.7) overall, both 61.5% (95% CI, 30.8-81.8) in HCT, and both 81.5% (95% CI, 43.5-95.1) in SOT (median follow-up: 8.2, 2.8, and 22.5 months, respectively). Patients responding to tabelecleucel had higher 1- and 2-year OS rates (94.1%) than nonresponders (0%). Treatment was well tolerated, with no reports of tumor flare, cytokine release syndrome, or rejection of marrow and SOT. Results demonstrate clinically meaningful outcomes across a broad population treated with tabelecleucel, indicating a potentially transformative and accessible treatment advance for R/R EBV+ PTLD after HCT or SOT. This trial was registered at www.ClinicalTrials.gov as #NCT02822495.

Management of post-autologous transplant relapse in patients with T-cell lymphomas.

Autologous hematopoietic cell transplantation (AHCT) is often used as a consolidation for patients with peripheral T-cell lymphomas (PTCLs) due to the poor prognosis associated with this heterogenous group of disorders. However, a significant number of patients will experience post-AHCT disease relapse. Here, we report a retrospective study of consecutive 124 patients with PTCLs who underwent AHCT from 2008 to 2020. With a median follow-up of 6.01 years following AHCT, 49 patients (40%) experienced disease relapse. As expected, more patients who were not in first complete remission experienced post-AHCT relapse. Following relapse, majority of the patients (70%) receiving systemic therapies intended as bridging to curative allogeneic HCT. However, only 18 (53%) patients eventually underwent allogeneic HCT. The estimated 3-year OS among patients proceeding to allogeneic HCT was 72% (95% CI 46%-87%). Our report details the pattern of post-AHCT relapse and the management of relapsed disease using different therapeutic modalities.

CAR19 monitoring by peripheral blood immunophenotyping reveals histology-specific expansion and toxicity.

ABSTRACT: Chimeric antigen receptor (CAR) T cells directed against CD19 (CAR19) are a revolutionary treatment for B-cell lymphomas (BCLs). CAR19 cell expansion is necessary for CAR19 function but is also associated with toxicity. To define the impact of CAR19 expansion on patient outcomes, we prospectively followed a cohort of 236 patients treated with CAR19 (brexucabtagene autoleucel or axicabtagene ciloleucel) for mantle cell lymphoma (MCL), follicular lymphoma, and large BCL (LBCL) over the course of 5 years and obtained CAR19 expansion data using peripheral blood immunophenotyping for 188 of these patients. CAR19 expansion was higher in patients with MCL than other lymphoma histologic subtypes. Notably, patients with MCL had increased toxicity and required fourfold higher cumulative steroid doses than patients with LBCL. CAR19 expansion was associated with the development of cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, and the requirement for granulocyte colony-stimulating factor 14 days after infusion. Younger patients and those with elevated lactate dehydrogenase (LDH) had significantly higher CAR19 expansion. In general, no association between CAR19 expansion and LBCL treatment response was observed. However, when controlling for tumor burden, we found that lower CAR19 expansion in conjunction with low LDH was associated with improved outcomes in LBCL. In sum, this study finds CAR19 expansion principally associates with CAR-related toxicity. Additionally, CAR19 expansion as measured by peripheral blood immunophenotyping may be dispensable to favorable outcomes in LBCL.

A US Multicenter Collaborative Study on Outcomes of Hematopoietic Cell Transplantation in Hepatosplenic T-Cell Lymphoma.

Hepatosplenic T-cell lymphoma (HSTCL) is a rare and aggressive type of peripheral T-cell lymphoma with median overall survival (OS) of approximately 1 year. Data on the effectiveness of hematopoietic cell transplantation (HCT) is limited, as is the choice between autologous HCT (auto-HCT) and allogeneic HCT (allo-HCT) in the treatment of this disease. To evaluate the outcome of patients with HSTCL who underwent either auto-HCT or allo-HCT, we performed a multi-institutional retrospective cohort study to assess outcomes of HCT in HSTCL patients. Fifty-three patients with HSTCL were included in the study. Thirty-six patients received an allo-HCT and 17 received an auto-HCT. Thirty-five (66%) were males. Median age at diagnosis was 38 (range 2 to 64) years. Median follow-up for survivors was 75 months (range 8 to 204). The median number of prior lines of therapy was 1 (range 1 to 4). Median OS and progression-free survival (PFS) for the entire cohort were 78.5 months (95% CI: 25 to 79) and 54 months (95% CI: 18 to 75), respectively. There were no significant differences in OS (HR: 0.63, 95% CI: 0.28 to 1.45, P = .245) or PFS (HR: 0.7, 95% CI: 0.32 to 1.57, P = .365) between the allo-HCT and auto-HCT groups, respectively. In the allo-HCT group, the 3-year cumulative incidence of relapse was 35% (95% CI: 21 to 57), while 3-year cumulative incidence of NRM was 16% (95% CI: 7 to 35). In the auto-HCT group, the 3-year cumulative incidence of relapse and NRM were 43% (95% CI: 23 to 78) and 14% (95% CI: 4 to 52), respectively. Both Auto-HCT and Allo-HCT are effective consolidative strategies in patients with HSTCL, and patients should be promptly referred for HCT evaluation.

Clinical features of neurotoxicity after CD19 CAR T-cell therapy in mantle cell lymphoma.

ABSTRACT: CD19 chimeric antigen receptor (CAR) T-cell therapy has proven highly effective for treating relapsed/refractory mantle cell lymphoma (MCL). However, immune effector cell-associated neurotoxicity syndrome (ICANS) remains a significant concern. This study aimed to evaluate the clinical, radiological, and laboratory correlatives associated with ICANS development after CD19 CAR T-cell therapy in patients with MCL. All patients (N = 26) who received standard-of-care brexucabtagene autoleucel until July 2022 at our institution were evaluated. Laboratory and radiographic correlatives including brain magnetic resonance imaging (MRI) and electroencephalogram (EEG) were evaluated to determine the clinical impact of ICANS. Seventeen (65%) patients experienced ICANS after treatment, with a median onset on day 6. Ten (38%) patients experienced severe (grade ≥3) ICANS. All patients with ICANS had antecedent cytokine release syndrome (CRS), but no correlation was observed between ICANS severity and CRS grade. Overall, 92% of EEGs revealed interictal changes; no patients experienced frank seizures because of ICANS. In total, 86% of patients with severe ICANS with postinfusion brain MRIs demonstrated acute neuroimaging findings not seen on pretreatment MRI. Severe ICANS was also associated with higher rates of cytopenia, coagulopathy, increased cumulative steroid exposure, and prolonged hospitalization. However, severe ICANS did not affect treatment outcomes of patients with MCL. Severe ICANS is frequently associated with a range of postinfusion brain MRI changes and abnormal EEG findings. Longer hospitalization was observed in patients with severe ICANS, especially those with abnormal acute MRI or EEG findings, but there was no discernible impact on overall treatment response and survival.

Single-center randomized trial of T-reg graft alone vs T-reg graft plus tacrolimus for the prevention of acute GVHD.

ABSTRACT: Allogeneic hematopoietic cell transplantation (HCT) is a curative therapy for hematological malignancies for which graft-versus-host disease (GVHD) remains a major complication. The use of donor T-regulatory cells (Tregs) to prevent GVHD appears promising, including in our previous evaluation of an engineered graft product (T-reg graft) consisting of the timed, sequential infusion of CD34+ hematopoietic stem cells and high-purity Tregs followed by conventional T cells. However, whether immunosuppressive prophylaxis can be removed from this protocol remains unclear. We report the results of the first stage of an open-label single-center phase 2 study (NCT01660607) investigating T-reg graft in myeloablative HCT of HLA-matched and 9/10-matched recipients. Twenty-four patients were randomized to receive T-reg graft alone (n = 12) or T-reg graft plus single-agent GVHD prophylaxis (n = 12) to determine whether T-reg graft alone was noninferior in preventing acute GVHD. All patients developed full-donor myeloid chimerism. Patients with T-reg graft alone vs with prophylaxis had incidences of grade 3 to 4 acute GVHD of 58% vs 8% (P = .005) and grade 3 to 4 of 17% vs 0% (P = .149), respectively. The incidence of moderate-to-severe chronic GVHD was 28% in the T-reg graft alone arm vs 0% with prophylaxis (P = .056). Among patients with T-reg graft and prophylaxis, CD4+ T-cell-to-Treg ratios were reduced after transplantation, gene expression profiles showed reduced CD4+ proliferation, and the achievement of full-donor T-cell chimerism was delayed. This study indicates that T-reg graft with single-agent tacrolimus is preferred over T-reg graft alone for the prevention of acute GVHD. This trial was registered at www.clinicaltrials.gov as #NCT01660607.

Improved outcomes for relapsed/refractory Hodgkin lymphoma after autologous transplantation in the era of novel agents.

The treatment landscape of relapsed/refractory (R/R) classic Hodgkin lymphoma (cHL) has evolved significantly over the past decade after the approval of brentuximab vedotin (BV) and the programmed death-1 (PD-1) inhibitors. We evaluated how outcomes and practice patterns have changed for patients with R/R cHL who underwent autologous hematopoietic cell transplantation (AHCT) at our institution from 2011 to 2020 (N = 183) compared with those from 2001 to 2010 (N = 159) and evaluated prognostic factors for progression-free survival (PFS) and overall survival (OS) in both eras. OS was superior in the modern era with a trend toward lower nonrelapse mortality beyond 2 years after transplant. Among patients who progressed after AHCT, 4-year postprogression survival increased from 43.3% to 71.4% in the modern era, reflecting increasing use of BV and the PD-1 inhibitors. In multivariable analysis for patients that underwent transplant in the modern era, age ≥45 years, primary refractory disease, and lack of complete remission pre-AHCT were associated with inferior PFS, whereas receipt of a PD-1 inhibitor-based regimen pre-AHCT was associated with superior PFS. Extranodal disease at relapse was associated with inferior OS. Our study demonstrates improved survival for R/R cHL after AHCT in the modern era attributed to more effective salvage regimens allowing for better disease control pre-AHCT and improved outcomes for patients who progressed after AHCT. Excellent outcomes were observed with PD-1 inhibitor-based salvage regimens pre-AHCT and support a randomized trial evaluating immunotherapy in the second line setting.

Radiation Therapy for Primary Cutaneous Gamma Delta Lymphoma Prior to Stem Cell Transplantation.

We present a patient with widespread PCGD-TCL of the bilateral arms and legs, who underwent radiotherapy with 34 Gy in 17 fractions using circumferential VMAT and 3-D printed bolus to the four extremities prior to planned stem cell transplant, who was then found to have progression in the liver, lung, and skin, followed by drastic regression of all in and out-of-field lesions on imaging 1.5 months later. The cause of regression may be related to a radiation-induced abscopal effect from the immunomodulatory effects of radiation, or related to immune reactivation in the setting of cessation of systemic immunosuppressive agents.

Allogeneic Hematopoietic Cell Transplantation for Adult Acute Lymphoblastic Leukemia in the Modern Era.

Allogeneic hematopoietic cell transplantation (HCT) remains an important treatment for adults with acute lymphoblastic leukemia (ALL). We hypothesized that advances in ALL and transplantation have resulted in improved HCT outcomes in recent years. In this study, we evaluated the characteristics and outcomes of adult ALL patients undergoing allogeneic HCT over the last decade. Patients with ALL aged 18 years and older who underwent allogeneic HCT at Stanford University between 2008 and 2019 were included in this study. Patients were divided into 2 eras based on year of HCT: 2008 to 2013 (earlier era) and 2014 to 2019 (later era). A total of 285 patients were included: 119 patients underwent HCT in the earlier era and 166 in the later era. Patients who underwent transplantation in the later era were more likely to be Hispanic (38% versus 21%) and to have an HCT-comorbidity index ≥3 (31% versus 18%). Donor source for HCT also differed with an increase in the use of HLA-mismatched donor sources (38% versus 24%), notably umbilical cord blood in the later era (16% versus 0%). Patients in the later era were less likely to undergo transplantation with active disease (4% versus 16%); pre-HCT rates of measurable residual disease were similar across the eras (38% versus 40%). In unadjusted analyses, overall survival (OS) improved across eras, with 2-year estimates for the later and earlier eras of 73% (95% confidence interval [CI], 66%-80%) versus 55% (95% CI, 46%-64%), respectively. Multivariable analysis confirmed the association between later era and OS (hazard ratio = 0.52, 95% CI, 0.34-0.78). Finally, among patients relapsing after HCT (25% in later era and 33% in earlier era), the use of novel immunotherapies increased in the later era (44% versus 3%), as did the median OS after post-HCT relapse (16 months versus 8 months, P< .001). OS after HCT for adult ALL has improved in recent years. This is due, in part, to a significant improvement in the ability to effectively salvage adults with ALL relapsing after HCT.

Real-World Experience of Cryopreserved Allogeneic Hematopoietic Grafts during the COVID-19 Pandemic: A Single-Center Report.

In response to the widespread COVID-19 pandemic, cryopreservation of allogeneic donor apheresis products was implemented to mitigate the challenges of donor availability and product transport. Although logistically beneficial, the impact of cryopreservation on clinical outcomes and graft composition remains unclear. In this study, we compared outcomes and graft composition with cryopreserved versus fresh allografts in the setting of allogeneic hematopoietic cell transplantation (allo-HCT). We retrospectively analyzed the clinical outcomes of 30 consecutive patients who received cryopreserved allografts between March and August 2020 and 60 consecutive patients who received fresh allografts before the COVID-19 pandemic. Primary endpoints were hematopoietic engraftment and graft failure (GF), and secondary outcomes were overall survival (OS), relapse-free survival (RFS) and nonrelapse mortality (NRM). In addition, extended immunophenotype analysis was performed on cryopreserved and prospectively collected fresh apheresis samples. Compared with recipients of fresh allografts, both neutrophil and platelet recovery were delayed in recipients of cryopreserved reduced-intensity conditioning (RIC) allo-HCT, with a median time to engraftment of 24 days versus 18 days (P = .01) for neutrophils and 27 days versus 18 days (P = .069) for platelets. We observed primary GF in 4 of 30 patients in the cryopreserved cohort (13.3%) versus only 1 of 60 patients (1.7 %) in the fresh cohort (P = .03). Cryopreserved RIC allo-HCT was associated with significantly lower median total, myeloid, and T cell donor chimerism at 1 month. OS and RFS were inferior for cryopreserved graft recipients (hazard ratio [HR], 2.16; 95% confidence interval [CI], 1.00 to 4.67) and HR, 1.90; 95% CI, 0.95 to 3.79, respectively. Using an extended immunophenotype analysis, we compared 14 samples from the cryopreserved cohort to 6 prospectively collected fresh apheresis donor samples. These analyses showed both a decrease in total cell viability and a significantly reduced absolute number of natural killer cells (CD3-CD56+) in the cryopreserved apheresis samples. In this single-institution study, we found delayed engraftment and a trend toward clinical inferiority of cryopreserved allografts compared with fresh allografts. Further evaluation of the use of cryopreserved allografts and their impact on clinical and laboratory outcomes is warranted.

Incidence and risk factors associated with bleeding and thrombosis following chimeric antigen receptor T-cell therapy.

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 from 2017 through 2020 with axicabtagene ciloleucel (axi-cel; n = 89) or a bispecific CD19/CD22 CAR (n = 38). Twelve (9.4%) and 8 (6.3%) patients developed bleeding and thrombosis within the first 3 months, respectively. In the axi-cel subgroup, these occurred in 11.2% and 6.7%, respectively. Bleeding occurred between days 8 and 30 (median, 17.5) and thrombosis between days 2 and 91 (median, 29). Bleeding sites included genitourinary, soft tissue, intracranial, gastrointestinal, and pulmonary and were associated with features of consumptive coagulopathy. On univariate analysis, patients with bleeding were older, had lower baseline platelets (86 × 103/µL vs 178 × 103/µL; P < .01), lower platelet and fibrinogen nadirs , and elevated lactate dehydrogenase. Immune effector cell (IEC)-associated neurotoxicity syndrome (ICANS) grade ≥3 was associated with increased bleeding (50% vs 15%; P = .01), thrombosis (50% vs 16%; P = .04), prothrombin time prolongation, hypofibrinogenemia, and elevated D-dimer. Low pretreatment platelet counts were associated with bleeding in a multivariate logistic regression model. Patients with thrombocytopenia or severe ICANS are at increased risk of bleeding 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.

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

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.

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

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 CD19lo 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-/lo 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-/lo 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.

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

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.