A prospective study of posttransplant cyclophosphamide for unrelated donor peripheral blood stem cell transplant with special attention to graft content and the impact of a higher γδ T cell dose.

Posttransplant cyclophosphamide (PtCy) has been shown to decrease post-hematopoietic stem cell transplant acute and chronic graft-versus-host disease (GVHD). In this study, PtCy was used in 44 patients along with mycophenolate and tacrolimus with HLA matched (29) and mismatched (15) unrelated donors to determine the impact of graft content on outcome; thus, all patients had flow cytometric analysis of their graft content including the number of B cells, NK cells, and various T cell subsets. Higher γδ T cell dose was associated with the development of acute GVHD (p = .0038). For PtCy, further studies of the cell product along with further graft manipulation, such as selective γδ T cell depletion, could potentially improve outcomes.

Brentuximab vedotin in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone as frontline treatment for patients with CD30-positive B-cell lymphomas.

We conducted a phase I/II multicenter trial using 6 cycles of brentuximab vedotin (BV) in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHP) for treatment of patients with CD30-positive (+) B-cell lymphomas. Thirty-one patients were evaluable for toxicity and 29 for efficacy including 22 with primary mediastinal B-cell lymphoma (PMBCL), 5 with diffuse large B-cell lymphoma (DLBCL), and 2 with gray zone lymphoma (GZL). There were no treatment-related deaths; 32% of patients had non-hematological grade 3/4 toxicities. The overall response rate was 100% (95% CI: 88-100) with 86% (95% CI: 68-96) of patients achieving complete response at the end of systemic treatment. Consolidative radiation following end of treatment response assessment was permissible and used in 52% of all patients including 59% of patients with PMBCL. With a median follow-up of 30 months, the 2-year progression-free survival (PFS) and overall survival (OS) were 85% (95% CI: 66-94) and 100%, respectively. In the PMBCL cohort, 2-year PFS was 86% (95% CI: 62-95). In summary, BV-R-CHP with or without consolidative radiation is a feasible and active frontline regimen for CD30+ B-cell lymphomas (NCT01994850).

Low Nonrelapse Mortality after HLA-Matched Related 2-Step Hematopoietic Stem Cell Transplantation Using Cyclophosphamide for Graft-versus-Host Disease Prophylaxis and the Potential Impact of Non- Cyclophosphamide-Exposed T Cells on Outcomes.

The use of cyclophosphamide (CY) for bidirectional tolerization of recipient and donor T cells is associated with reduced rates of graft-versus-host disease (GVHD) and nonrelapse mortality (NRM) after HLA-matched hematopoietic stem cell transplantation (HSCT). However, recurrent disease remains the primary barrier to long-term survival. We extended our 2-step approach to HLA-matched related HSCT using a radiation-based myeloablative conditioning regimen combined with a high dose of T cells in an attempt to reduce relapse rates while maintaining the beneficial effects of CY tolerization. After conditioning, patients received their grafts in 2 components: (1) a fixed dose of 2 × 108/kg T cells, followed 2 days later by CY, and (2) a CD34-selected graft containing a small residual amount of non-CY-exposed T cells, at a median dose of 2.98 × 103/kg. Forty-six patients with hematologic malignancies were treated. Despite the myeloablative conditioning regimen and use of high T cell doses, the cumulative incidences of grade II-IV acute GVHD, chronic GVHD, and NRM at 1 year and 5 years were very low, at 13%, 9%, and 4.3%, respectively. This contributed to a high overall survival of 89.1% at 1 year and 65.8% at 5 years. Relapse was the primary cause of mortality, with a cumulative incidence of 23.9% at 1 year and 45.7% at 5 years. In a post hoc analysis, relapse rates were significantly lower in patients receiving greater than versus those receiving less than the group median of non-CY-exposed residual T cells in the CD34 product (19.3% versus 58.1%; P = .009), without a concomitant increase in NRM. In its current form, this 2-step regimen was highly tolerable, but strategies to reduce relapse, potentially the addition of T cells not exposed to CY, are needed.

Autologous Stem Cell Transplantation for Multiple Myeloma: Growth Factor Matters.

Engraftment syndrome (ES) is a known complication of autologous hematopoietic stem cell transplant during neutrophil recovery. There is a limited amount of data available comparing the incidence of ES with post-transplant granulocyte colony-stimulating factor versus granulocyte macrophage colony-stimulating factor (GM-CSF), specifically in patients with multiple myeloma. Our retrospective review of 156 patients at a single center showed that GM-CSF was associated with a higher incidence of ES compared with G-CSF (32% versus 8% of patients, P < .001) and that development of ES was associated with a 32.9% (P < .001) longer hospital stay. This suggests that the choice of growth factor could possibly contribute to the development of ES and the associated costs of increased medical care.

Sirolimus enhances remission induction in patients with high risk acute myeloid leukemia and mTORC1 target inhibition.

Background Mammalian Target of Rapamycin Complex 1 (mTORC1) inhibitors enhance chemotherapy response in acute myelogenous leukemia (AML) cells in vitro. However whether inhibiting mTORC1 enhances clinical response to AML chemotherapy remains controversial. We previously optimized measurement of mTORC1's kinase activity in AML blasts during clinical trials using serial phospho-specific flow cytometry of formaldehyde-fixed whole blood or marrow specimens. To validate mTORC1 as a therapeutic target in AML, we performed two clinical trials combining an mTORC1 inhibitor (sirolimus) and MEC (mitoxantrone, etoposide, cytarabine) in patients with relapsed, refractory, or untreated high-risk AML. Methods Flow cytometric measurements of ribosomal protein S6 phosphorylation (pS6) were performed before and during sirolimus treatment to determine whether mTORC1 inhibition enriched for chemotherapy response. Results In 51 evaluable subjects, the overall response rate (ORR) to the combination regimen was 47% (95% confidence interval 33-61%, 33% CR, 2% CRi, 12% PR) and similar toxicity to historic experience with MEC alone. 37 subjects had baseline pS6 measured pre-sirolimus, of whom 27 (73%) exhibited mTORC1 activity. ORR was not significantly different between subjects with and without baseline mTORC1 activity (52% vs 40%, respectively, p = 0.20). The ORR among subjects with baseline target activation and mTORC1 inhibition during therapy was 71% (12/17) compared to 20% (2/10) in subjects without target inhibition. Conclusions Fixed, whole blood pS6 by flow cytometry may be a predictive biomarker for clinical response to mTORC1 inhibitor-based regimens. These data provide clinical confirmation that mTORC1 activation mediates chemotherapy resistance in patients with AML.

A Two-Step Haploidentical Versus a Two-Step Matched Related Allogeneic Myeloablative Peripheral Blood Stem Cell Transplantation.

Haploidentical stem cell transplantation (SCT) offers a transplantation option to patients who lack an HLA-matched donor. We developed a 2-step approach to myeloablative allogeneic hematopoietic stem cell transplantation for patients with haploidentical or matched related (MR) donors. In this approach, the lymphoid and myeloid portions of the graft are administered in 2 separate steps to allow fixed T cell dosing. Cyclophosphamide is used for T cell tolerization. Given a uniform conditioning regimen, graft T cell dose, and graft-versus-host disease (GVHD) prophylaxis strategy, we compared immune reconstitution and clinical outcomes in patients undergoing 2-step haploidentical versus 2-step MR SCT. We retrospectively compared data on patients undergoing a 2-step haploidentical (n = 50) or MR (n = 27) peripheral blood SCT for high-risk hematological malignancies and aplastic anemia. Both groups received myeloablative total body irradiation conditioning. Immune reconstitution data included flow cytometric assessment of T cell subsets at day 28 and 90 after SCT. Both groups showed comparable early immune recovery in all assessed T cell subsets except for the median CD3/CD8 cell count, which was higher in the MR group at day 28 compared with that in the haploidentical group. The 3-year probability of overall survival was 70% in the haploidentical group and 71% in the MR group (P = .81), while the 3-year progression-free survival was 68% in the haploidentical group and 70% in the MR group (P = .97). The 3-year cumulative incidence of nonrelapse mortality was 10% in the haploidentical group and 4% in the MR group (P = .34). The 3-year cumulative incidence of relapse was 21% in the haploidentical group and 27% in the MR group (P = .93). The 100-day cumulative incidence of overall grades II to IV acute GVHD was higher in the haploidentical group compared with that in the MR group (40% versus 8%, P < .001), whereas the grades III and IV acute GVHD was not statistically different between both groups (haploidentical, 6%; MR, 4%; P = .49). The cumulative incidence of cytomegalovirus reactivation was also higher in the haploidentical group compared to the MR group (haploidentical, 68%; MR, 19%; P < .001). There were no deaths from GVHD in either group. Using an identical conditioning regimen, graft T cell dose, and GVHD prophylaxis strategy, comparable early immune recovery and clinical outcomes were observed in the 2-step haploidentical and MR SCT recipients.

A two-step approach to myeloablative haploidentical transplantation: low nonrelapse mortality and high survival confirmed in patients with earlier stage disease.

Haploidentical hematopoietic stem cell transplantation (HSCT) is an attractive alternative donor option based on the rapid availability of an acceptable donor for most patients and decreased cost compared with costs of other alternative donor strategies. The safety of haploidentical HSCT has increased in recent years, making it ethically feasible to offer to patients with earlier stage disease. We developed a 2-step approach to haploidentical HSCT that separates the lymphoid and myeloid portions of the graft, allowing fixed T cell dosing to improve consistency in outcome comparisons. In the initial 2-step trial, the subset of patients without morphologic disease at HSCT had high rates of disease-free survival. To confirm these results, 28 additional patients without evidence of their disease were treated and are now 15 to 45 (median, 31) months past HSCT. To date, the 2-year cumulative incidence of nonrelapse mortality is 3.6%, with only 1 patient dying of nonrelapse causes, confirming the safety of this approach. Based on low regimen toxicity, the probabilities of disease-free and overall survival at 2 years are 74% and 77%, respectively, consistent with the findings in the initial trial and supporting the use of this approach in earlier stage patients lacking a matched related donor.

Clostridium difficile colonization and disease in patients undergoing hematopoietic stem cell transplantation.

There was an increase in the Clostridium difficile infection (CDI) rate in our bone marrow transplantation unit. To evaluate the role of unit-based transmission, C. difficile screening was performed on adult patients admitted for hematopoietic stem cell transplantation (HSCT) over a 2-year period, and C. difficile isolates were typed. C. difficile testing was performed using a 2-step C. difficile glutamate dehydrogenase antigen plus toxin A/B enzyme immunoassay (EIA) and cytotoxin assay (or molecular toxin assay). Multilocus sequence typing (MLST) was performed on toxin-positive whole stool samples. A retrospective chart review was performed on all patients with a positive toxin assay. Sixteen of 150 patients (10.7%) had toxigenic C. difficile colonization (CDC) on admission. The overall incidence of CDI within 100 days after HSCT was 24.7% (37 of 150). The median time to diagnosis of CDI was 3.5 days after HSCT. In an adjusted logistic regression model, CDC on admission was a significant risk factor for CDI (odds ratio, 68.5; 95% confidence interval, 11.4 to 416.2). MLST on 22 unit patient toxin-positive stool specimens revealed 15 distinct strain types. Further analysis identified at least 1 potential cross-transmission event; some events may have been missed because of incomplete typing from other specimens. Despite aggressive infection control interventions, there was no decline in the number of CDI cases during the study period. These data suggest that prior CDC plays a major role in CDI rates in this high-risk patient population. It remains unclear if CDI was cross-transmitted in the unit.

A Tender Reduced-Intensity Conditioning for the Unfit: A Novel 4 Gy Total Body Irradiation-Based Conditioning Followed by Two-Step Haploidentical Stem Cell Transplant, Results of a Prospective Trial.

Allogeneic hematopoietic stem cell transplant (HSCT) remains the only potentially curative treatment for many hematologic malignancies (HM). We previously developed a two-step approach that separates the lymphoid and myeloid portions of the graft, allowing a consistent T cell dosing and sparing the stem cells from the effect of post-transplant cyclophosphamide (CY). The two-step approach demonstrated safety and efficacy in patients treated with myeloablative and reduced-intensity conditioning. Here, we extended our two-step platform to older and less fit patients and explored the effects of using a high dose of T cells on disease relapse and transplant outcomes. Thirty-four patients with HM were treated. Median age was 68 years old and included a minority population constituting 32%. Eighty-two percent had a hematopoietic cell transplantation comorbidity index score ≥3. Ninety-one percent were haploidentical, and the rest were matched-related donor HSCT. Following administration of fludarabine and 2 Gy total body irradiation (TBI) (13 patients) or 4 Gy TBI (21 patients) conditioning regimen, a fixed dose of 2 × 108/kg CD3+ T cells was given, followed 2 days later by CY, then infusion of CD34-selected stem cells. Overall survival (OS) was 70% at 1 year and 48% at 3 years. The cumulative incidence (CI) of non-relapse mortality (NRM) and relapse were 22% and 33% at 3 years. However, the CI of relapse was much lower for patients treated with 4 Gy TBI versus those treated with 2 Gy TBI (11% versus 54%, P = .045), while NRM was similar (23% versus 15%, P = .399). This contributed to a high OS of 64% in patients who received 4 Gy TBI-based conditioning at 3 years, with median OS not reached, although this was not statistically significant (P = .68). The median time to neutrophil and platelet recovery was 12 and 17 days, respectively. The CI of grade II acute graft-versus-host-disease (aGVHD) was 22% and 26% at 100 days and 6 months, respectively. The CI of chronic GVHD (cGVHD) was 7.5% at 3 years. There was no grade III or IV aGVHD, no severe cGVHD, and no deaths attributable to GVHD. In conclusion, the two-step approach HSCT demonstrated a low disease relapse rate and high survival in patients treated with 4 Gy TBI-based conditioning, despite a generally older and more medically compromised patient population.

A 2-step approach to myeloablative haploidentical stem cell transplantation: a phase 1/2 trial performed with optimized T-cell dosing.

Studies of haploidentical hematopoietic stem cell transplantation (HSCT) have identified threshold doses of T cells below which severe GVHD is usually absent. However, little is known regarding optimal T-cell dosing as it relates to engraftment, immune reconstitution, and relapse. To begin to address this question, we developed a 2-step myeloablative approach to haploidentical HSCT in which 27 patients conditioned with total body irradiation (TBI) were given a fixed dose of donor T cells (HSCT step 1), followed by cyclophosphamide (CY) for T-cell tolerization. A CD34-selected HSC product (HSCT step 2) was infused after CY. A dose of 2 × 10(8)/kg of T cells resulted in consistent engraftment, immune reconstitution, and acceptable rates of GVHD. Cumulative incidences of grade III-IV GVHD, nonrelapse mortality (NRM), and relapse-related mortality were 7.4%, 22.2%, and 29.6%, respectively. With a follow-up of 28-56 months, the 3-year probability of overall survival for the whole cohort is 48% and 75% in patients without disease at HSCT. In the context of CY tolerization, a high, fixed dose of haploidentical T cells was associated with encouraging outcomes, especially in good-risk patients, and can serve as the basis for further exploration and optimization of this 2-step approach. This study is registered at www.clinicaltrials.gov as NCT00429143.

A Phase I Trial of Sirolimus with "7&3" Induction Chemotherapy in Patients with Newly Diagnosed Acute Myeloid Leukemia.

Chemotherapy remains a primary treatment for younger AML patients, though many relapse. Data from our group have shown that highly phosphorylated S6 in blasts may predict response to sirolimus given with chemotherapy. We report the results of a phase I study of this combination in newly diagnosed AML and the pharmacodynamic analysis of pS6 before and after treatment. Subjects received sirolimus (12 mg on day 1, 4 mg daily, days 2-10), then idarubicin and cytarabine (days 4-10). Response was assessed at hematologic recovery or by day 42 using a modified IWG criteria. Fifty-five patients received sirolimus. Toxicity was similar to published 7 + 3 data, and 53% had high-, 27% intermediate-, and 20% favorable-risk disease. Forty-four percent of the high-risk patients entered into CR/CRp. Seventy-nine percent of the intermediate-risk subjects had a CR/CRp. All favorable-risk patients had a CR by day 42; 9/11 remained alive and in remission with a median follow-up of 660 days. Additionally, 41/55 patients had adequate samples for pharmacodynamic analysis. All patients demonstrated activation of S6 prior to therapy, in contrast to 67% seen in previous studies of relapsed AML. mTORC1 inhibition was observed in 66% of patients without enrichment among patients who achieved remission. We conclude that sirolimus and 7 + 3 is a well-tolerated and safe regimen. mTORC1 appears to be activated in almost all patients at diagnosis of AML. Inhibition of mTORC1 did not differ based on response, suggesting that AML cells may have redundant signaling pathways that regulate chemosensitivity in the presence of mTORC1 inhibition.

The Two-Step Allogeneic Stem Cell Transplantation Approach Results in Rapid Engraftment and Excellent Outcomes in Patients with Lymphoid Malignancies.

The 2-step graft engineering approach has been the main platform for allogeneic hematopoietic cell transplantation (allo-HCT) at Thomas Jefferson University since 2005. We have previously described separating donor lymphocyte infusion followed by cyclophosphamide for bidirectional tolerization from CD34-selected hematopoietic grafts in haploidentical and matched related donors. Here we analyzed 60 patients with high-risk lymphoid malignancies who underwent a 2-step allo-HCT between 2008 and 2020. The majority of patients received haploidentical stem cell grafts (82%), and 20% of patients received matched related donor stem cell grafts. The patients underwent allo-HCT for diffuse large C cell lymphoma (n = 17; 28%), chronic lymphoblastic leukemia (n = 10; 17%), follicular lymphoma (n = 8; 13%), and Hodgkin lymphoma (n = 7; 12%). Eight patients (13%) had received prior high-dose chemotherapy. Thirty patients (50%) had a Hematopoietic Cell Transplantation Comorbidity Index ≥3, and 20 patients (33%) had a Center for International Blood & Marrow Transplant Research Revised Disease Risk Index of high risk or very high risk. The median patient age was 56 years (range, 24 to 75 years). Neutrophils engrafted at a median of 11 days (range, 9 to 16 days), and platelets engrafted at a median of 16 days (range, 13 to 37 days). With a median follow-up of 6 years, the 3-year probability of overall survival was 62.9% (95% confidence interval [CI], 49.3% to 73.8%), and that of disease-free survival was 60.2% (95% CI, 46.4% to 71.6%). The cumulative incidence of relapse at 3 years was 11.9% (95% CI, 5.2% to 21.6%). The cumulative incidence of nonrelapse mortality at 3 years was 30.1% (95% CI, 1.91% to 42.0%). The cumulative incidence of grade II-IV acute graft-versus-host disease (GVHD) at 1 year was 45% (95% CI, 32.2% to 57.0%), and that of grade III-IV acute GVHD at 1 year was 5% (95% CI, 1.3% to 12.6%). The cumulative incidence of cGVHD at 3 years was 15.2% (95% CI, 7.5% to 25.4%). The 2-step approach achieved excellent outcomes in high-risk lymphoid malignancies, with rapid neutrophil and platelet recovery.

Outcomes of two-step haploidentical allogeneic stem cell transplantation in elderly patients with hematologic malignancies.

Allogeneic hematopoietic stem cell transplantation (allo-SCT) remains the best curative option for the majority of patients with hematologic malignancies (HM); however, many elderly patients are excluded from transplant and outcome data in this population is still limited. The novel two-step graft engineering approach has been the main platform for allo-SCT at Thomas Jefferson University since 2006. Following administration of the preparative regimen, we infuse donor lymphocytes, followed by cyclophosphamide to induce bidirectional tolerance, then infusion of CD34-selected cells. A total of 76 patients ≥ 65 years old with HM underwent haploidentical (haplo) allo-SCT on the two-step transplant platform between 2007 and 2021. The median time to neutrophil engraftment was 11 days and platelet engraftment was 18 days. With a median follow up of 44 months, the 3-year overall survival (OS) and progression-free survival (PFS) were 36.3% and 35.6%, respectively. The cumulative incidences of non-relapse mortality (NRM) and relapse at 3 years were 43.5% and 21.0% at 3 years, respectively. The cumulative incidence of grade III-IV acute graft-versus-host-disease (GVHD) was 11.1% at 6 months, and chronic GVHD requiring treatment was 15.1% at 2 years. The two-step haplo allo-SCT is a novel alternative platform for high-risk older HM patients, achieving fast engraftment, low relapse rates and promising survival.

A Prospective, Randomized Trial Examining the Use of G-CSF Versus No G-CSF in Patients Post-Autologous Transplantation.

Contemporary, prospective data regarding the impact of granulocyte-colony stimulating factor (G-CSF) on outcomes after autologous hematopoietic stem cell transplantation (Auto-HSCT) in an era when stem cell grafts are more qualitatively robust are limited. Recent retrospective analyses have not supported a beneficial effect of post-transplantation G-CSF use on major outcomes after Auto-HSCT leading to strategies to delay or eliminate the use of G-CSF altogether in this context. To test the hypothesis that the infusion of consistently higher doses of stem cells (defined as ≥4 × 106/kg) in Auto-HSCT will obviate the need for post-transplantation G-CSF. If so, the impact of withholding G-CSF will be noninferior to the use of G-CSF in terms of length of stay (LOS). The specific objectives were to conduct a prospective, randomized clinical trial primarily examining the impact of post-transplantation G-CSF on LOS, and secondarily on engraftment, infectious complications, antibiotic usage, and incidence of engraftment syndrome after Auto-HSCT in patients receiving versus not receiving G-CSF after Auto-HSCT. Patients with multiple myeloma or non-Hodgkin lymphoma (NHL) who underwent Pegfilgrastim plus Plerixafor-primed stem cell collection followed by Auto-HSCT were randomized to the G-CSF group (receive G-CSF starting at day 3 after Auto-HSCT) or the no G-CSF group (G-CSF withheld after Auto-HSCT). Seventy patients per arm were planned to demonstrate the primary endpoint of noninferiority in LOS between the G-CSF and the no G-CSF groups. Patient outcomes in the two groups were followed up and compared after Auto-HSCT, and an interim analysis for futility was planned when accrual reached 50%.The primary finding of this study was that despite only a 2-day longer median absolute neutrophil count (ANC) recovery in the no G-CSF arm (median 11 versus 13 days; P = .001), LOS was 4 days longer in patients not treated with G-CSF (median 11 days versus 15 days; P = .001). G-CSF use was associated with more robust incremental daily increases in ANC once recovered (P = .001), fewer days of febrile neutropenia (P = .001), and fewer days on antibiotics (P = .001), potentially contributing to this disproportionate finding. Inferiority in LOS in the no G-CSF group was demonstrated on the interim analysis, and the study was closed at the half-way point. There were no significant group differences in platelet recovery, documented infections, hospital readmissions, or overall survival at 1 year. Engraftment syndrome occurred in 54.3% of patients and was not related to G-CSF use. These results suggest that the increased LOS associated with the omission of G-CSF is largely due to concerns regarding the potential for infection in patients without a stable, recovered ANC in a hospital setting. Engraftment syndrome represented a significant source of febrile neutropenia further contributing to patient safety concerns and requires strategies to decrease its incidence. Infectious complications and death were not affected by the omission of G-CSF supporting a carefully monitored outpatient approach to Auto-HSCT in which white blood cell growth factor is eliminated or given as needed for documented infection. © 2023 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Inpatient versus outpatient hypomethylating agent induction for acute myeloid leukemia as a predictor for survival.

The hypomethylating agents (HMA) decitabine and azacitidine are used in acute myeloid leukemia (AML) for induction therapy in select patients. They are given on either inpatient (IP) or outpatient (OP) services and the decision where to administer them is complex but ultimately depends on the risk for neutropenic infections, hyperleukocytosis and other complications. In our study, we investigated 100-day survival differences between IP and OP HMA induction. This study reviewed 68 patients, 29 of whom received HMA as an IP while 39 received it as an OP. Using a logistic regression model, we found that IP induction was associated with a significantly lower odds of survival at 100-days (Odds Ratio 5.90; p=0.005). Given these results, we hypothesize the survival difference was related to the inherent risk associated with being admitted for chemotherapy, whether it be neutropenic fever, hyperleukocytosis or other reasons. We advise physicians who are administering IP HMA to consider its' inherent risk associated with its' administration.

An Examination of Cytomegalovirus, Socioeconomic Status, Race, and Ethnicity on Outcomes after Haploidentical Hematopoietic Transplantation.

Previous analyses of the effects of race and socioeconomic status (SES) on outcomes after hematopoietic stem cell transplantation (HSCT) have suggested that minority populations and those in disadvantaged groups have inferior outcomes. However, the results of these studies have been inconsistent, potentially due to a multitude of factors, both medical and nonmedical, that have confounded results. In haploidentical (HI) HSCT, an expanding approach with the potential to enfranchise more minority patients, data on the effect of race and SES on outcomes are very limited. To identify and potentially correct factors that negatively impact outcomes after HI HSCT in disadvantaged groups at our institution, we performed a retrospective, multivariable analysis of the impact of race and SES as single and combined variables on HI HSCT outcomes of relapse, transplantation-related mortality, acute and chronic graft-versus-host disease (GVHD), and overall survival (OS). In addition to controlling for race and SES, all patients had HI donors and were treated with the same 2-step approach, with consistent T cell dosing and GVHD prophylaxis to further reduce the impact of confounders in this complex area. The study cohort of 239 patients was 71% Caucasian, 19.7% African American, 4.6% Hispanic, and 4.2% Asian. The majority of minority patients were in areas of higher deprivation (P = .001) and had the highest incidence of cytomegalovirus (CMV) seropositivity (P = .001) and the lowest likelihood of possessing a CMV immunodominant (IMD) allele (P = .001), which was previously associated with an OS benefit. Positive CMV serostatus was highly linked to post-transplantation CMV reactivation (P = .001) which was associated with higher relapse rates (hazard ratio [HR], 1.56; 95% confidence interval [CI], 1.06 to 2.30; P = .026), higher TRM (HR, 2.10; 95% CI, 1.09 to 4.05; P = .027), and lower OS (HR, 1.77; 95% CI, 1.18 to 2.65; P = .006). The lack of a CMV IMD allele largely replicated the results of CMV reactivation on HSCT results. Although race and SES did not directly correlate with either OS or relapse incidence, non-Caucasians in a more disadvantaged group had a higher incidence of chronic GVHD (HR, 2.55; 95% CI, 1.08 to 6.01; P = .033) compared with Caucasians and minorities in less disadvantaged groups. Regardless of SES, minorities had a lower incidence of acute GVHD than Caucasians in a more advantaged SES group (HR, 0.52; 95% CI, 0.30 to 0.90; P = .020). The primary finding of this study is that CMV reactivation was the major driver of mortality after HI HSCT. CMV reactivation may have be associated with poor HSCT outcomes in HI HSCT recipients in disadvantaged areas, most of whom were minorities. The data suggest that the prevention of post-transplantation CMV reactivation possibly could have a major impact on HI HSCT outcomes, especially in minority recipients. The finding of different GVHD manifestations between races are intriguing and merits further study.

Overlap between in vitro donor antihost and in vivo posttransplantation TCR Vbeta use: a new paradigm for designer allogeneic blood and marrow transplantation.

Following allogeneic blood and marrow transplantation (BMT), mature donor T cells can enhance engraftment, counteract opportunistic infections, and mount graft-versus-tumor (GVT) responses, but at the risk of developing graft-versus-host disease (GVHD). With the aim of separating the beneficial effects of donor T cells from GVHD, one approach would be to selectively deplete subsets of alloreactive T cells in the hematopoietic cell inoculum. In this regard, TCR Vbeta repertoire analysis by CDR3-size spectratyping can be a powerful tool for the characterization of alloreactive T-cell responses. We investigated the potential of this spectratype approach by comparing the donor T-cell alloresponses generated in vitro against patient peripheral blood lymphocytes (PBLs) with those detected in vivo posttransplantation. The results indicated that for most Vbeta families that exhibited alloreactive CDR3-size skewing, there was a robust overlap between the in vitro antipatient and in vivo spectratype histograms. Thus, in vitro spectratype analysis may be useful for determining the alloreactive T-cell response involved in GVHD development and, thereby, could serve to guide select Vbeta family depletion for designer transplants to improve outcomes.

Case Report: Tocilizumab for the Treatment of SARS-CoV-2 Infection in a Patient With Aplastic Anemia.

While cytokine storm develops in a minority of patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, novel treatment approaches are desperately needed for those in whom it does. Tocilizumab, an interleukin-6 receptor antibody, has been utilized for the treatment of cytokine storm in a number of severe inflammatory conditions, including in patients with severe coronavirus disease 2019 (COVID-19). Here, we present the first published case utilizing this therapy in a patient with underlying immunodeficiency. Our patient with aplastic anemia developed cytokine storm due to COVID-19 manifested by fever, severe hypoxia, pulmonary infiltrates, and elevated inflammatory markers. Following treatment with tocilizumab, cytokine storm resolved, and the patient was ultimately safely discharged from the hospital.

Antiviral responses following L-leucyl-L-leucine methyl esther (LLME)-treated lymphocyte infusions: graft-versus-infection without graft-versus-host disease.

Although allogeneic hematopoietic progenitor cell transplant (HPCT) is curative therapy for many disorders, it is associated with significant morbidity and mortality, which can be related to graft-versus-host disease (GVHD) and the immunosuppressive measures required for its prevention and/or treatment. Whether the immunosuppression is pharmacologic or secondary to graft manipulation, the graft recipient is left at increased risk of the threatening opportunistic infection. Refractory viral diseases in the immunocompromised host have been treated by infusion of virus-specific lymphotyces and by unmanipulated donor lymphocyte infusion (DLI) therapy. L-leucyl-L-leucine methyl ester (LLME) is a compound that induces programmed cell death of natural killer (NK) cells, monocytes, granulocytes, most CD8(+) T cells, and a small fraction of CD4(+) T cells. We have undertaken a study of the use of LLME-treated DLI following T cell-depleted allogeneic HPCT, specifically to aid with immune reconstitution. In this ongoing clinical trial, we have demonstrated the rapid emergence of virus-specific responses following LLME DLI with minimal associated GVHD. This paper examines the pace of immune recovery and the rapid development of antiviral responses in 6 patients who developed viral infections during the time period immediately preceding or coincident with the administration of the LLME DLI.

The Presence of a CMV Immunodominant Allele in the Recipient Is Associated With Increased Survival in CMV Positive Patients Undergoing Haploidentical Hematopoietic Stem Cell Transplantation.

Specific major histocompatibility (MHC) class I alleles dominate anti-CMV responses in a hierarchal manner. These CMV immunodominant (IMD) alleles are associated with a higher magnitude and frequency of cytotoxic lymphocyte responses as compared to other human leukocyte antigen (HLA) alleles. CMV reactivation has been associated with an increased incidence of graft-vs.-host disease and non-relapse mortality, as well as protection from relapse in HLA-matched HSCT settings. Less is known about the impact of CMV reactivation on these major outcomes after haploidentical (HI) HSCT, an increasingly applied therapeutic option. In HI HSCT, the efficiency of the immune response is decreased due to the immune suppression required to cross the MHC barrier as well as MHC mismatch between presenting and responding cells. We hypothesized that the presence of a CMV IMD allele would increase the efficiency of CMV responses after HI HSCT potentially impacting CMV-related outcomes. In this retrospective, multivariable review of 216 HI HSCT patients, we found that CMV+ recipients possessing at least 1 of 5 identified CMV IMD alleles had a lower hazard of death (HR = 0.40, p = 0.003) compared to CMV+ recipients not possessing a CMV IMD allele, and an overall survival rate similar to their CMV- counterparts. The analysis delineated subgroups within the CMV+ population at greater risk for death due to CMV reactivation.