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Robust CD4+ T-cell recovery in adults transplanted with cord blood and no antithymocyte globulin

Robust CD4+ T-cell recovery in adults transplanted with cord blood and no antithymocyte globulin Downloaded from http://ashpublications.org/bloodadvances/article-pdf/4/1/191/1556118/advancesadv2019000836.pdf by guest on 12 October 2021 REGULAR ARTICLE Robust CD4 T-cell recovery in adults transplanted with cord blood and no antithymocyte globulin 1,2 3 3 1,2 1 1 1,2 Ioannis Politikos, Jessica A. Lavery, Patrick Hilden, Christina Cho, Taylor Borrill, Molly A. Maloy, Sergio A. Giralt, 1,2 1,2, 1,2, Marcel R. M. van den Brink, Miguel-Angel Perales, * and Juliet N. Barker * 1 2 Adult Bone Marrow Transplantation Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY; Department of Medicine, Weill Cornell Medical College, New York, NY; and Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY Quality of immune reconstitution after cord blood transplantation (CBT) without Key Points antithymocyte globulin (ATG) in adults is not established. We analyzed immune recovery in � ATG-free CBT in adults 106 engrafted adult CBT recipients (median age 50 years [range 22-70]) transplanted for is associated with rapid hematologic malignancies with cyclosporine/mycophenolate mofetil immunoprophylaxis CD4 -biased, thymus- and no ATG. Patients were treated predominantly for acute leukemia (66%), and almost all independent, T-cell 1 1 (96%) underwent myeloablation. Recovery of CD4 T cells was faster than CD8 T cells with reconstitution. 1 3 median CD4 T-cell counts exceeding 200/mm at 4 months. Early post-CBT, effector memory � Recovery of CD4 (EM), and central memory cells were the most common CD4 subsets, whereas effector and T cells and T-cell func- 1 EM were the most common CD8 T-cell subsets. Naive T-cell subsets increased gradually tion is associated with after 6 to 9 months post-CBT. A higher engrafting CB unit infused viable CD3 cell dose was improved survival in 1 1 1 associated with improved CD4 and CD4 CD45RA T-cell recovery. Cytomegalovirus adult CBT recipients. reactivation by day 60 was associated with an expansion of total, EM, and effector CD8 T cells, but lower CD4 T-cell counts. Acute graft-versus-host disease (aGVHD) did not significantly compromise T-cell reconstitution. In serial landmark analyses, higher CD4 T-cell counts and phytohemagglutinin responses were associated with reduced overall mortality. In contrast, CD8 T-cell counts were not significant. Recovery of natural killer and 3 3 B cells was prompt, reaching medians of 252/mm and 150/mm by 4 months, respectively, although B-cell recovery was delayed by aGVHD. Neither subset was significantly associated with mortality. ATG-free adult CBT is associated with robust thymus-independent CD4 T-cell recovery, and CD4 recovery reduced mortality risk. Introduction Cord blood (CB) is a valuable alternative hematopoietic stem cell (HSC) source for patients who lack 1,2 suitable adult donors, especially racial and ethnic minorities. Double-unit CB grafts have successfully extended cord blood transplantation (CBT) to larger children and adults, and both single- and double- 4,5 unit CBT has been associated with potent graft-versus-leukemia (GVL) effects, low rates of chronic 6-8 graft-versus-host disease (GVHD), and high rates of disease-free survival in patients with hematologic 4-6,8,9 malignancies. CBT, however, has also been associated with delayed immune reconstitution compared with T-cell replete HLA-matched adult donor allografts with multiple reports of high infection 10-13 rates early posttransplant. CB grafts contain low numbers of progenitor stem and immune cells compared with adult donor HSC grafts. In addition, CB-derived lymphocyte populations have unique phenotypic and immunological Submitted 14 August 2019; accepted 18 November 2019; published online 14 To request original data, contact corresponding author, Ioannis Politikos (politiki@ January 2020. DOI 10.1182/bloodadvances.2019000836. mskcc.org). The full-text version of this article contains a data supplement. © 2020 by The American Society of Hematology *M.-A.P. and J.N.B. contributed equally to this study. 14 JANUARY 2020 x VOLUME 4, NUMBER 1 191 Downloaded from http://ashpublications.org/bloodadvances/article-pdf/4/1/191/1556118/advancesadv2019000836.pdf by guest on 12 October 2021 properties, including almost exclusively naive T cells that do not Table 1. Patient and graft characteristics (n 5 106) 15,16 transfer immune memory. Although these CB graft attributes Variable Value could contribute to delayed immune reconstitution, many pre- Median age (range), y 50 (22-70) vious CBT series have included antithymocyte globulin (ATG), Male, n (%) 55 (52) a platform that has detrimental effects on both immune recon- 17-22 Median weight (range), kg 80 (36-138) stitution and survival after CBT. Notably, low ATG exposure or omission of ATG has been associated with rapid thymus- Recipient CMV , n (%) 59 (56) independent T-cell expansion and robust immune reconstitution Diagnosis, n (%) 19,22-25 in pediatric CBT recipients. In contrast to children, however, Acute leukemia (AML/ALL/other) 70 (66) relatively little is known about immune reconstitution after ATG-free MDS/MPN 14 (13) 12,26-30 CBT in adults. Lymphoma (NHL/HD) 22 (21) Herein, we report the kinetics of immune reconstitution in a large Conditioning, n (%)* cohort of adult CBT recipients transplanted for hematologic High intensity 1 (1) malignancies at a single center without ATG. We also analyzed Intermediate intensity 101 (95) the impact of patient, graft, and early posttransplant factors on immune recovery, as well as the immune variables associated Nonmyeloablative 4 (4) with improved survival. Our hypothesis was that, similar to Donor-recipient 8-allele HLA match,† median (range) 5 (3 to 7) pediatric series, ATG-free adult CBT is associated with prompt Infused TNC dose 3 10 /kg,† median (range) 2.35 (1.23-5.31) immune reconstitution and that early T-cell recovery improves 1 5 Infused viable CD34 dose 3 10 /kg,† median (range) 1.18 (0.18-4.08) survival post-CBT. 1 6 Infused viable CD3 dose 3 10 /kg,† median (range) 3.34 (0.45-10.61) Methods Graft composition, n (%)‡ dCB 45 (42) Patient and transplant characteristics dCB-haploCD34 59 (56) All consecutive adult patients #70 years old who underwent first sCB-haploCD34 2(2) allogeneic transplantation using single- or double-unit CB grafts for the treatment of hematologic malignancies at Memorial ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; HD, Hodgkin disease; MDS, myelodysplastic syndrome; MPN, myeloproliferative neoplasm; NHL, non-Hodgkin Sloan Kettering Cancer Center (MSKCC) between April 2012 lymphoma. and May 2016 were eligible for analysis (n 5 114). Those who *High-intensity myeloablative conditioning was with cyclophosphamide 120 mg/kg, did not achieve CB-derived engraftment (n 5 4) or had no fludarabine 75 mg/m , and total body irradiation (TBI) 1320 cGy; intermediate-intensity myeloablative was with cyclophosphamide 50 mg/kg, fludarabine 150 mg/m , thiotepa 5 to immune reconstitution assays performed due to development 10 mg/kg, and TBI 400 cGy ; nonmyeloablative included cyclophosphamide 50 mg/kg, 2 2 of fatal early posttransplant complications before day 30 fludarabine 150 mg/m , and TBI 200 cGy (n 5 3), or fludarabine 150 mg/m and TBI 400 cGy (n 5 1). (n 5 4) were excluded. Of the 106 evaluable patients, 93 were †Engrafting CB unit. treated on Institutional Review Board (IRB)–approved protocols ‡Fifty-nine double-unit CB (dCB) grafts and 2 single-unit CB (sCB) grafts were (#NCT00739141, #NCT01682226, and #NCT00387959). The supplemented with haploidentical CD34 cells to provide a myeloid bridge prior to CB engraftment. remaining 13 patients were treated off protocol due to either protocol ineligibility (n 5 8) or insurance denial for clinical trials in otherwise eligible patients (n 5 5). CB units were at least 4/6 HLA-A, -B antigen, -DRB1 allele immunophenotyping for the monitoring of absolute lymphocyte matched to the recipient, and each unit had a cryopreserved total count (ALC) and lymphocyte subset recovery was performed nucleated cell (TNC) dose $1.5 3 10 /kg. High-resolution HLA prospectively on fresh whole blood samples at the MSKCC typing, CD34 cell dose, CB quality, and bank of origin were Clinical Immunology Laboratory using BD FACS Canto II and BD also considered in unit selection as previously detailed. Some FACS Canto 10 color flow cytometers. Until April 2014, analyzed 1 1 patients also received mobilized peripheral blood-derived hap- lymphocyte subsets included total T cells (CD3 ), total CD4 , 1 1 1 2 1 loidentical CD34 cells as a myeloid bridge prior to CB engraftment CD4 45RA ,and CD8 T cells, natural killer (NK; CD3 CD56 1 1 (#NCT01682226). CD16 ), and B cells (CD19 ). Since May 2014, subset analysis 1 1 1 1 of CD4 and CD8 naive (CCR7 CD45RA ), central memory Most patients received myeloablative conditioning (outlined in 1 2 2 2 (CM; CCR7 CD45RA ), effector memory (EM; CCR7 CD45RA ), Table 1). GVHD prophylaxis was with cyclosporine-A/mycophenolate 2 1 1 effector (CCR7 CD45RA1), and activated (CD38 HLADR ) mofetil, and no patient received ATG. Granulocyte colony-stimulating 2 1 1 T cells, and naive (CD27 IgD ), nonswitched memory (CD27 factor was given starting day 17. Cytomegalovirus (CMV)-seropositive 1 1 2 1 IgD ), switched memory (CD27 IgD ), transitional (CD24 patients were monitored by quantitative polymerase chain reaction 1 1 2 1 CD38 ), and plasmablast (CD27 CD20 CD38 ) B cells was as of day 114 posttransplant. Preemptive antiviral therapy was performed. T-cell proliferative responses to mitogen phytohemag- given upon detection of any level of CMV viremia. glutinin (PHA) were assessed by measuring 3H-thymidine incor- This study was performed with MSKCC IRB approval. poration. Assessments were usually performed at days 30, 60, 120, 180, 270, 1 year, 18 months, and 2 years post-CBT. Immune Immune reconstitution monitoring recovery data were censored at the time of second allogeneic Immune reconstitution monitoring was per standard MSKCC clinical transplantation (n 5 1) or after infusion of viral-specific cytotoxic practice and not influenced by protocol enrollment. Flow cytometric T cells (n 5 5; 4 CMV specific, 1 Epstein-Barr virus specific). 192 POLITIKOS et al 14 JANUARY 2020 x VOLUME 4, NUMBER 1 Downloaded from http://ashpublications.org/bloodadvances/article-pdf/4/1/191/1556118/advancesadv2019000836.pdf by guest on 12 October 2021 (range 0.18-4.08) 3 10 /kg, respectively. The median 8-allele Statistical analysis engrafting unit-recipient HLA match was 5/8 (range 3/8-7/8). Acute graft-versus-host disease (aGVHD) was diagnosed clini- cally with histologic confirmation when possible and was graded Transplant outcomes according to International Bone Marrow Transplant Registry crite- 32 In all of the 106 patients (including all 61 recipients of CB grafts ria. CMV reactivation was defined as detection of CMV DNA by supplemented with haploidentical CD34 cells), long-term hema- quantitative polymerase chain reaction regardless of the viremia topoiesis was mediated by 1 CB unit (termed the engrafting unit), level. Transplant-related mortality (TRM) was defined as death from with no contribution from the host. Of the 59 CMV-seropositive any cause other than disease relapse or progression. The cumu- patients, 44 reactivated CMV by day 60 for a cumulative incidence lative incidence of aGVHD, CMV reactivation, relapse, and TRM of 75% (95% CI, 61-84). The cumulative incidence of grade II to IV was calculated in the competing risks framework considering and III to IV aGVHD by day 100 was 77% (95% CI, 68-84) and 17% relapse/death without developing aGVHD, death without CMV (95% CI, 11-25), respectively. Of the 64 patients with grade II day reactivation, TRM, and relapse as the competing events, respec- 100 aGVHD, 22 (34%) were treated with systemic corticosteroids tively. Overall survival (OS) and progression-free survival estimates by day 100; remaining patients were treated with nonabsorbable were calculated using Kaplan-Meier methodology. oral or topical corticosteroids. Loess-smoothed curves were estimated to visually inspect immune With a median survivor follow-up of 2 years (range 7 months to recovery trends over time. The association between baseline or 4.7 years), the 2-year estimates of OS and progression-free early posttransplant factors and immune variables was investi- survival for the 106 patients evaluable for immune recovery gated with linear mixed effects models. Immune recovery data (8 nonevaluable patients with graft failure or early death excluded) were natural log transformed before the analysis. The mixed effects were 73% (95% CI, 62-81) and 69% (95% CI, 58-78), respectively. models contained linear and quadratic terms for time, as well as Two-year TRM was 19% (95% CI, 12-28) and 2-year relapse was random intercepts for each patient and fixed effects for variables of 12% (95% CI, 6-20). interest. From the mixed effects models, the slopes and the 95% confidence intervals (CIs) of the baseline and early posttransplant T-, NK-, and B-cell immune reconstitution factors were estimated. Models for day 60 CMV reactivation and The median ALC surpassed 500/mm by 2 months. The speed of day 100 aGVHD considered only immune recovery data beyond 60 recovery varied markedly between lymphocyte subsets. NK cells and 100 days, respectively. were the most common lymphocyte population early posttrans- 1 1 plant, followed by CD3 T cells, and B cells. However, CD3 Landmark analyses at 2, 4, and 6 months were performed to T cells comprised the largest lymphocyte subset beyond 4 months investigate the association between each of the immune variables (Table 2; Figure 1). and OS. For the 2-, 4-, and 6-month landmark analyses, the most recent immune parameter values prior to day 65, 130, and 195 were 1 1 Of CD3 T-cell subsets, CD4 lymphocytes recovered faster than used, respectively. Univariable OS analyses were first performed for 1 1 CD8 lymphocytes (Table 2; Figure 2A). The median CD4 T-cell each immune variable, baseline factors, and early posttransplant 3 1 1 count surpassed 200/mm by 4 months. CD4 CD45RA T cells, factors. Exploratory analyses were also performed to potentially 1 considered to represent naive CD4 T cells, remained low in the identify an optimal CD4 T-cell count based on its univariable 1 first 6 to 9 months post-CBT (Figure 2A). CD8 T cells increased association with OS at each of the landmark time points. Multivari- steadily until 15 to 18 months post-CBT, followed by a relative able Cox regression models were built for each immune variable contraction of the CD8 T-cell compartment (Figure 2A). T-cell that was statistically significant controlling for significant baseline function, as assessed by PHA responses, increased rapidly and and/or posttransplant covariates. Immune variables were highly remained relatively stable beyond 6 months (Figure 2B). correlated with each other and therefore could not be included in Eighty-eight patients had 1 or more time points assayed with the the same models (correlations were assessed using Spearman’s extended lymphocyte subset immunophenotyping panel. EM rank correlation coefficient). and CM cells were the most prevalent CD4 subsets post-CBT, Tests with P , .01 were considered statistically significant, to account followed by naive and effector subsets (Figure 2C). EM and CM for multiple comparisons. All statistical analyses were performed in R CD4 T-cell numbers increased rapidly in the first 6 months and version 3.5.3 (The R Foundation for Statistical Computing). remained relatively stable between 9 and 24 months. Naive CD4 T cells increased steadily beyond 6 months. In contrast to 1 1 Results CD4 T-cell subsets, effector CD8 T cells comprised the 1 1 majority of CD8 T cells post-CBT, followed by the EM CD8 Patient and graft characteristics subset (Figure 2D). Following their marked initial increase, The characteristics of the 106 analyzed patients (median 50 years, effector CD8 T cells decreased beyond 18 months posttrans- range 22 to 70) and their grafts are summarized in Table 1. The plant. Recovery of naive CD8 T cells paralleled that of naive most common diagnosis was acute leukemia (66%), followed CD4 T cells beyond 6 months post-CBT (Figure 2D). by lymphoma (21%), or myelodysplasia/myeloproliferative disease NK cells increased rapidly in the first 2 months post-CBT and (13%). The majority of patients (95%) received intermediate-intensity 33 remained stable thereafter (Table 2; Figure 1). B cells also rose myeloablative conditioning. rapidly with the median B-cell count reaching normal range by Nearly all patients (n 5 104) received double-unit CB grafts. The 4 months posttransplant (Table 2; Figure 1). This was explained by median infused TNC and infused viable CD34 cell doses of the a marked increase of naive B cells in the first 6 months post-CBT. engrafting unit were 2.35 (range 1.23-5.31) 3 10 /kg and 1.18 Naive B cells continued to be the most prevalent B-cell subset 14 JANUARY 2020 x VOLUME 4, NUMBER 1 IMMUNE RECONSTITUTION AFTER ATG-FREE ADULT CBT 193 Downloaded from http://ashpublications.org/bloodadvances/article-pdf/4/1/191/1556118/advancesadv2019000836.pdf by guest on 12 October 2021 Table 2. Recovery of lymphocyte subsets and PHA responses after CBT Posttransplant time point Immune variable, median (range) 2mo 4 mo 6mo 1 y ALC, cells/mm 608 745 933 1554 (NR: 500-5300) (85-7200) (145-2025) (173-6287) (384-4774) 1 3 CD3 T cells, cells/mm 171 252 380 669 (NR: 822-1825) (7-3024) (8-1112) (38-1572) (148-3246) 1 3 CD4 T cells, cells/mm 120 203 294 420 (NR: 429-1131) (5-1584) (8-912) (30-1069) (22-891) 1 3 CD8 T cells, cells/mm 22 25 47 204 (NR: 209-768) (0-1440) (0-761) (0-909) (11-2574) B cells, cells/mm 22 150 201 324 (NR: 87-441) (0-3024) (0-1357) (0-3960) (0-1968) NK cells, cells/mm 222 252 221 220 (NR: 78-424) (41-1333) (29-717) (65-1519) (70-896) PHA, CPM 66 816 76 319 86 944 86 091 (NR: 109 576-256 486) (231-156 128) (667-162 912) (14 590-161 140) (6724-164 435) CPM, counts per minute; NR, normal range. through 2 years post-CBT (Figure 3). Transitional B cells were the higher engrafting unit infused viable CD3 cell dose was 1 1 1 next most common B-cell subset, whereas nonswitched memory, associated with higher CD4 and CD4 CD45RA T-cell counts switched memory, and plasmablast B-cell subsets remained low after CBT, although these associations were not significant at the (Figure 3). 0.01 level (Table 4). Conversely, CMV reactivation was associated with lower CD4 T cells (Figure 4A) and PHA responses post-CBT Association of patient, graft, and posttransplant (Table 4). In contrast, CMV reactivation was the only factor significantly associated with higher CD8 T-cell counts posttrans- variables with immune reconstitution plant (Table 4; Figure 4B). The association of baseline and early posttransplant variables with The association of transplant variables with the recovery of CD4 recovery of lymphocyte subsets and PHA responses is shown in T-cell subsets is shown in supplemental Table 1. A higher engrafting Tables 3 and 4. No patient, graft (including the addition of 1 1 unit CD34 cell dose was associated with higher EM CD4 T-cell haploidentical CD34 cells), or early posttransplant variables were counts, whereas a higher engrafting unit CD3 dose was associ- significantly associated with ALC or CD3 T-cell recovery (Table 3). ated with higher naive CD4 T-cell counts post-CBT, although Patient characteristics, including age, sex, or diagnosis, were not these associations did not reach significance at the 0.01 level. CMV 1 1 significantly associated with CD4 or CD8 T-cell recovery. A reactivation was associated with lower CM and, to a lesser extent, naive CD4 T-cell counts (supplemental Figure 1). No transplant factors were associated with effector CD4 T-cell reconstitution. Increased numbers of activated CD4 T cells were observed in ALC association with a higher engrafting unit CD34 cell dose, whereas lower activated CD4 T-cell counts were seen in patients with aGVHD, especially corticosteroid-requiring aGVHD (data not shown). These associations, however, did not reach the prespecified level of statistical significance. The association of transplant variables with the recovery of CD8 T-cells T-cell subsets is shown in supplemental Table 2. A higher engrafting unit CD34 cell dose was associated with higher EM and, to 1000 1 a lesser extent, effector CD8 T-cell counts after CBT. In addition, B-cells a marked expansion of EM and effector CD8 T cells was observed in patients with CMV reactivation (supplemental Figure 2). No transplant factors were significantly associated with CM or naive NK-cells 1 1 CD8 T-cell reconstitution. A higher number of activated CD8 T cells were observed in association with higher CD34 dose of the engrafting CB unit and CMV reactivation. 0 3 6 9 12 15 18 21 24 Older recipient age and higher CD34 cell dose of the engrafting Months post-CBT CB unit were associated with NK-cell recovery early posttransplant (Table 3). B-cell reconstitution was adversely affected by the Figure 1. ALC and lymphocyte subset recovery in adult CBT recipients. ALC, development of grade II to IV aGVHD (Table 3), especially aGVHD CD3 cells, NK cells, B cells. Curves are Loess-smoothed averages. requiring systemic corticosteroids (data not shown). The negative 194 POLITIKOS et al 14 JANUARY 2020 x VOLUME 4, NUMBER 1 Lymphocyte count (cells/mm ) Downloaded from http://ashpublications.org/bloodadvances/article-pdf/4/1/191/1556118/advancesadv2019000836.pdf by guest on 12 October 2021 A B CD3+ CD4+ 600 50000 CD8+ CD4+CD45RA+ 0 3 6 9 12 15 18 21 24 0 3 6 9 12 15 18 21 24 Months post-CBT Months post-CBT C D CD4+ CD8+ Effector CD8+ EM CD4+ 200 EM CD8+ CM CD4+ Naïve CD4+ Naïve CD8+ CM CD8+ Effector CD4+ 0 0 0 3 6 9 12 15 18 21 24 0 3 6 9 12 15 18 21 24 Months post-CBT Months post-CBT 1 1 1 1 1 1 Figure 2. Recovery of T-cell subsets and T-cell function in adult CBT recipients. (A) CD3 ,CD4 ,CD8 ,CD4 CD45RA T cells. (B) PHA responses. (C) CD4 and 1 1 1 CD4 T-cell subsets (naive, CM, EM, effector). (D) CD8 and CD8 T-cell subsets (naive, CM, EM, effector). Curves are Loess-smoothed averages. In panels C and D, Loess- 1 1 smoothed curves for total CD4 and total CD8 T cells, respectively, are based on values from the time points of which the extended immunophenotyping panel was also performed. effect of aGVHD was also observed in naive, transitional, nonswitched In the 4-month landmark analysis (Table 6), recipient age was again memory, and to a lesser extent, switched memory and plasmablast the only baseline factor impacting OS. In addition, there was no B-cell subset recovery (data not shown). No other transplant association of day 100 aGVHD grade with OS. In univariable 1 1 factors were associated with B-cell recovery. analysis, 4-month ALC, total CD3 and CD4 T cells, and PHA responses were significantly associated with OS beyond 4 months. Although an association of higher B-cell counts with improved Association of immune variables with OS OS was also observed, it was not significant at the 0.01 level. In Next, we investigated the association of immune reconstitution multivariable analyses controlling for age, each of the variables with OS in serial landmark analyses. At 2 months, recipient age 1 1 of ALC, CD3 and CD4 T cells, and PHA remained significant. was the only baseline factor associated with OS (Table 5). A As expected, CD4 T-cell counts and PHA responses at 4 months higher PHA response was the only immune variable associ- were highly correlated (r 5 0.35). Therefore, they could not be ated with improved OS in univariable and multivariable analysis concurrently included in a multivariable model. controlling for age. This was due to decreased TRM in patients with higher PHA responses, whereas relapse risk was unaffected At 6 months (Table 7), the association of recipient age with OS was (data not shown). no longer significant at the 0.01 level (P5 .025), but was retained in 14 JANUARY 2020 x VOLUME 4, NUMBER 1 IMMUNE RECONSTITUTION AFTER ATG-FREE ADULT CBT 195 T-cells (cells/mm ) CD4+ T-cells & subsets (cell/mm ) PHA response (CPM) CD8+ T-cells & subsets (cells/mm ) Downloaded from http://ashpublications.org/bloodadvances/article-pdf/4/1/191/1556118/advancesadv2019000836.pdf by guest on 12 October 2021 addition, due to the limited number of events in assayed patients, 1 1 800 B-cells the prognostic value of specific CD4 and CD8 T-cell subsets could not be evaluated. Finally, in exploratory analyses, no optimal Naïve CD4 T-cell count cutoff for OS could be identified at any time point post-CBT. Discussion This study represents the largest analysis of immune reconstitution after ATG-free CBT in adults to date. In contrast to the protracted T-cell lymphopenia reported after ATG-based CBT, we show Transitional Non-switched rapid early thymus-independent CD4 T-cell recovery consistent Switched memory Memory 23,24 with that reported in pediatric ATG-free CBT. In this adult 0 Plasmablasts population with a median age of 50 years, the median CD4 0369 12 15 18 21 24 T-cell count already exceeded 200/mm by 4 months and increased Months post-CBT steadily through 2 years posttransplant. EM and CM T cells were 1 11,34 the most prevalent CD4 subsets early post-CBT, whereas Figure 3. Recovery of B cells and subsets in adult CBT recipients. Curves are naive CD4 T-cell counts gradually increased beyond 6 to 9 months Loess-smoothed averages. Loess-smoothed curves for total B-cell counts are based post-CBT. on values from the time points of which the extended immunophenotyping panel was 1 1 Recovery of CD8 T cells was initially slow, but marked CD8 T-cell also performed. expansion was noted beyond 6 months post-CBT. Effector and 1 11,34 EM were the most common CD8 T-cell subsets early post-CBT. multivariable modeling because it is a clinically important factor. Of 1 1 As with naive CD4 T cells, naive CD8 T-cell counts increased 1 1 the immune variables, higher ALC, total CD3 and CD4 T cells, steadily beyond 6 to 9 months, suggesting thymus-dependent and PHA responses were significantly associated with subsequent recovery from this time point, even despite the relatively advanced improved OS in univariable and age-adjusted analyses. As with 15 age of this patient cohort. Recovery of T-cell function, as the 4-month landmark, CD4 T-cell counts and PHA responses at assayed by PHA responses, was also prompt. 6 months were highly correlated (r 5 0.39); therefore, their indepen- Of factors associated with T-cell reconstitution, a notable finding dent prognostic significance could not be examined. was the lack of an adverse effect of recipient age on total, CD4 , 1 1 1 1 CD4 CD45RA T-cell, CD8 T-cell, or NK-cell counts were not CD8 , and subset T-cell recovery. It is possible that the relatively associated with OS at any time point post-CBT (Tables 5-7). In older age of this patient cohort did not allow the detection of such Table 3. Association of transplant variables with the recovery of ALC and total T, NK, and B cells ALC CD3 T cells NK cells B cells Variable Slope (95% CI) P Slope (95% CI) P Slope (95% CI) P Slope (95% CI) P Age (10 y) 0.01 (20.08, 0.09) .897 20.06 (20.16, 0.04) .260 0.15 (0.07, 0.23) .001 20.20 (20.46, 0.07) .146 8-allele HLA-match* .135 .733 .327 .465 ,5/8 reference reference reference reference $5/8 0.17 (20.05, 0.39) 0.05 (20.22, 0.31) 0.12 (20.12, 0.35) 0.26 (20.44, 0.96) Infused viable CD34 cell dose* .099 .840 .018 .245 ,1.18 3 10 /kg reference reference reference reference $1.18 3 10 /kg 0.17 (20.03, 0.37) 0.03 (20.22, 0.27) 0.25 (0.05, 0.46) 0.38 (20.25, 1.01) Infused viable CD3 cell dose* .727 .185 .093 .612 ,3.34 3 10 /kg reference reference reference reference $3.34 3 10 /kg 0.04 (20.16, 0.24) 0.16 (20.08, 0.40) 20.18 (20.39, 0.03) 0.164 (20.47, 0.80) CMV reactivation by day 60 .783 .391 .577 .488 No CMV reactivation reference reference reference reference CMV reactivation 20.03 (20.23, 0.17) 0.12 (20.15, 0.38) 0.06 (20.15, 0.27) 20.26 (21.01, 0.48) Day 100 aGVHD grade .313 .960 .708 <.001 0-I reference reference reference reference II 20.16 (20.43, 0.11) 20.05 (20.41, 0.31) 0.09 (20.19, 0.38) 21.15 (22.04, 20.26) III-IV 20.26 (20.60, 0.08) 20.02 (20.47, 0.43) 20.01 (20.37, 0.35) 22.38 (23.50, 21.25) There was no association with the variables of recipient sex, diagnosis (acute leukemia vs MDS/MPD vs lymphoma), or the addition of haploidentical CD34 cells (data not shown). P values significant at the .01 level are indicated in bold. *Engrafting CB unit. 196 POLITIKOS et al 14 JANUARY 2020 x VOLUME 4, NUMBER 1 B-cells & subsets (cells/mm ) Downloaded from http://ashpublications.org/bloodadvances/article-pdf/4/1/191/1556118/advancesadv2019000836.pdf by guest on 12 October 2021 Table 4. Association of transplant variables with the recovery of T-cell subsets and function 1 1 1 1 CD4 T cells CD4 CD45RA T cells CD8 T cells PHA Variable Slope (95% CI) P Slope (95% CI) P Slope (95% CI) P Slope (95% CI) P Age (10 y) 20.09 (20.20, 0.01) .087 20.05 (20.22, 0.12) .539 0.01 (20.15, 0.16) .924 20.08 (20.21, 0.04) .205 8-allele HLA-match* .200 .545 .105 .565 ,5/8 reference reference reference reference $5/8 0.19 (20.10, 0.47) 0.14 (20.30, 0.58) 20.33 (20.73, 0.07) 0.09 (20.22, 0.41) Infused viable CD34 cell dose* .646 .333 .245 .574 ,1.18 3 10 /kg reference reference reference reference $1.18 3 10 /kg 20.06 (20.32, 0.20) 20.20 (20.60, 0.20) 0.22 (20.15, 0.58) 0.08 (20.21, 0.37) Infused viable CD3 cell dose* .045 .020 .893 .065 ,3.34 3 10 /kg reference reference reference reference $3.34 3 10 /kg 0.26 (0.01, 0.52) 0.47 (0.08, 0.87) 0.03 (20.34, 0.39) 0.27 (20.01, 0.56) CMV reactivation by day 60 .005 .171 <.001 <.001 No CMV reactivation reference Reference reference reference CMV reactivation 20.39 (20.66, 20.13) 20.31 (20.75, 0.13) 1.15 (0.77, 1.52) 20.58 (20.86, 20.29) Day 100 aGVHD grade .651 .386 .630 .435 0-I reference reference reference reference II 20.16 (20.52, 0.20) 20.05 (20.62, 0.51) 0.29 (20.32, 0.90) 20.20 (20.61, 0.21) III-IV 20.19 (20.65, 0.27) 0.37 (0.36, 1.10) 0.30 (20.48, 1.07) 20.33 (20.83, 0.17) *Engrafting CB unit. There was no association with the variables of recipient sex, diagnosis (acute leukemia vs MDS/MPD vs lymphoma), or the addition of haploidentical CD34 cells (data not shown). P values significant at the .01 level are indicated in bold. 36-38 an effect. Alternatively, early thymus-independent T-cell recovery reconstitution, overall grade II to IV aGVHD did not significantly after ATG-free CBT may not be significantly influenced by advanced affect T-cell recovery in our series, with the exception of activated recipient age, in contrast to the thymus-dependent pathway of T-cell CD4 T-cell counts. reconstitution. Data concerning the potential impact of CB graft 23,35,36 CMV reactivation significantly impacts quantitative and qualita- characteristics on T-cell recovery after CBT are limited. We 39,40 tive T-cell recovery after HSC transplantation (HSCT). CMV observed a notable trend for a higher engrafting CB unit infused reactivation after HSCT has been associated with a rapid viable CD3 cell dose being associated with higher total and naive 1 1 increase of CD8 T cells due to EM and effector CD8 subset CD4 T cells post-CBT. In addition, higher engrafting CB unit 39-45 1 expansion. Theimpactontotal CD4 T-cell and subset infused viable CD34 cell dose was associated with higher EM and 39-43 recovery, however, is less clear, with a previous report suggesting activated CD8 T-cell counts, and a similar trend was observed 1 39 for the same CD4 T-cell subsets. Interestingly, despite high levels that CMV reactivation may compromise thymopoiesis. These of engrafting CB unit-recipient HLA-mismatch, such mismatch effects lead to contraction of the naive T-cell compartment and 39,43,46 had no discernible effect on total T-cell and subset recovery. TCR repertoire diversity. In our analysis, a marked expan- 1 1 In addition, despite concerns that aGVHD may hamper immune sion of total CD8 ,EMand effector CD8 T-cell subsets, and A B 8 8 6 6 4 4 Figure 4. Association of CMV reactivation 1 1 with CD4 and CD8 T-cell recovery in adult 2 2 CBT recipients. (A) CD4 T-cell recovery accord- No CMV reactivation No CMV reactivation ing to CMV reactivation by day 60 post-CBT. CMV reactivation CMV reactivation 1 0 0 (B) CD8 T-cell recovery according to CMV reac- tivation by day 60 post-CBT. Individual patient time 0369 12 15 18 21 24 0369 12 15 18 21 24 points are color coded according to CMV reac- Months post-CBT Months post-CBT tivation. Curves are Loess-smoothed averages. 14 JANUARY 2020 x VOLUME 4, NUMBER 1 IMMUNE RECONSTITUTION AFTER ATG-FREE ADULT CBT 197 log(CD4+ T-cells) log(CD8+ T-cells) Downloaded from http://ashpublications.org/bloodadvances/article-pdf/4/1/191/1556118/advancesadv2019000836.pdf by guest on 12 October 2021 Table 5. Two-month landmark analysis for OS Table 6. Four-month landmark analysis for OS Immune variable* n HR (95% CI) P Immune variable* n HR (95% CI) P ALC 90 0.67 (0.34-1.31) .246 ALC 93 0.20 (0.08-0.51)† .004 1 1 CD3 T cells 90 0.73 (0.45-1.18) .219 CD3 T cells 93 0.41 (0.24-0.71)† .006 1 1 CD4 T cells 90 0.69 (0.43-1.12) .150 CD4 T cells 93 0.43 (0.25-0.73)† .006 1 1 1 1 CD4 CD45RA T cells 90 1.11 (0.75-1.64) .587 CD4 CD45RA T cells 93 1.03 (0.70-1.51) .887 1 1 CD8 T cells 90 1.00 (0.66-1.49) .984 CD8 T cells 93 0.86 (0.60-1.24) .434 NK cells 78 1.34 (0.63-2.84) .439 NK cells 91 0.71 (0.32-1.60) .420 B cells 90 0.85 (0.68-1.07) .163 B cells 93 0.80 (0.66-0.97) .029 PHA 88 0.56 (0.40-0.78)† .009 PHA 89 0.43 (0.26-0.71)† .008 P values significant at the .01 level are indicated in bold. P values significant at the .01 level are indicated in bold. *In univariable analysis of patient and graft variables, only recipient age was significantly *In univariable analysis of patient, graft, and posttransplant variables, only recipient age associated with OS (hazard ratio [HR], 2.11 [95% CI, 1.30-3.43] per decade, P 5 .001). was significantly associated with OS (HR, 2.21 [95% CI, 1.31-3.75] per decade, P 5 Patient sex, diagnosis, CMV seropositivity, engrafting CB unit–recipient HLA-match, .001). Patient sex, diagnosis, CMV seropositivity, engrafting CB unit–recipient HLA match, 1 1 1 1 engrafting CB unit infused viable CD34 and CD3 cell doses, addition of haploidentical engrafted CB unit infused viable CD34 and CD3 cell doses, addition of haploidentical 1 1 CD34 cells were not significant. CD34 cells, and day 100 aGVHD grade were not significant. †HR adjusted for age. †HR adjusted for age. 1 44 activated CD8 Tcells was observed in patients with CMV advanced recipient age was associated with higher NK-cell counts, 47 36,55 reactivation post-CBT. Because CB T cells are exclusively naive, as has previously been suggested in some HSCT studies, and this CMV-driven CD8 T-cell expansion reflects the emergence may represent a compensatory mechanism as recovery of adap- of CMV effectors from naive CB-derived T cells. Although T-cell tive immunity may be delayed in older HSCT recipients. We also specificity was not examined, our findings are supported by reports observed an association of a higher engrafting unit infused viable that CMV effectors with memory phenotype are generated from naive CD34 cell dose with higher NK-cell counts post-CBT. In contrast, 48-50 CB-derived T cells early post-CBT and after CMV infection in NK-cell counts tended to be lower in recipients of a higher engrafting 51 1 neonates. We also observed that CMV reactivation was associated unit infused viable CD3 cell dose, a finding possibly explained by 1 1 57 with lower total and CM CD4 T-cell counts. Although naive CD4 NK- and T-cell competition for homeostatic cytokines. Similar 58,59 T cells were also numerically lower, this difference was not significant findings have been reported in adult donor HSCT. Importantly, in 54,58,60-62 at the prespecified significance threshold. Therefore, although we contrast to multiple HSCT series, we found no association demonstrate a negative impact of CMV reactivation on CD4 T-cell between NK-cell counts and CBT outcomes. recovery after CBT, whether thymopoiesis is impaired is uncertain. B-cell counts normalized by 4 months and were primarily charac- A critical finding of this analysis is that early T-cell recovery, terized by naive immunophenotype. Development of grade II to IV especially CD4 counts and T-cell function, was associated with aGVHD by day 100, and especially corticosteroid-requiring GVHD, improved survival. Although an association of CD4 counts with was the only factor that adversely affected B-cell and subset OS was not observed at 2 months, .75% of assayed patients already recovery. Whether B-cell recovery has any prognostic value for 1 3 had CD4 T cells .50/mm by that time, a threshold previously CBT outcomes remains unclear, as the prespecified statistical associated with protection against infections and improved survival significance threshold in our analysis was not achieved. 19,22,52,53 in pediatric CBT. Importantly, we observed a continuous A striking finding of our study is that T-cell recovery after ATG-free reduction in overall mortality with increasing CD4 T-cell counts at CBT in adults is robust, thymus independent, and CD4 biased. 4 and 6 months post-CBT. Because CD4 T cells were the most These results add to the growing literature supporting an under- prevalent CD3 subset at these time points, this lymphocyte 19,22-24,28 appreciated prompt T-cell recovery after T-replete CBT. population likely also accounted for the prognostic significance of They suggest that the reconstituting neonatal immune system in 1 1 CD3 T-cell counts and ALC on survival. In contrast, CD8 T-cell adult CBT recipients has unique biology as previously demon- counts were not associated with survival, as previously reported 24 1 strated in children. The observed CD4 bias is in contrast to 38,54 after adult donor HSCT. Early recovery of T-cell function as 1 1 the inversion of the CD4 /CD8 T-cell ratio after adult donor assessed by PHA responses was also associated with improved HSCT. Moreover, our study demonstrates that early CD4 T-cell survival, as has previously been reported in CD34 selected HSCT recovery after adult CBT, as well as T-cell function, is associated 55 1 recipients, and was highly correlated with CD4 T-cell counts. with reduction in overall mortality, corroborating previous HSCT and 22,28,38,53-55,63,64 Notably, in contrast to previous reports supporting an important role primarily pediatric CBT studies. 15,30,48 of thymopoiesis on CBT outcomes, we did not observe an We acknowledge that not all patients had early T-cell recovery. 1 1 association of CD4 CD45RA T-cell count recovery with improved Therefore, as with adult donor HSCT, strategies to further survival. A possible explanation is that ATG omission may decrease augment immune reconstitution are needed. Notably, we found reliance on thymopoiesis for CD4 T-cell reconstitution due to early that increased cell dose improved T-cell recovery, whereas HLA thymus-independent T-cell recovery. mismatch was not detrimental. If these findings are confirmed, Previous CBT studies have reported prompt posttransplant NK- they would support prioritizing cell dose over HLA match in CB 12,28,29,56 and B-cell recovery, regardless of ATG use. Similarly, unit selection as a potentially modifiable factor to promote both we observed early NK-cell recovery in our cohort. Unexpectedly, myeloid engraftment and T-cell recovery. In addition, although grade II 198 POLITIKOS et al 14 JANUARY 2020 x VOLUME 4, NUMBER 1 Downloaded from http://ashpublications.org/bloodadvances/article-pdf/4/1/191/1556118/advancesadv2019000836.pdf by guest on 12 October 2021 22,53 Table 7. Six-month landmark analysis for OS with myeloid malignancies. Thus, further research should focus on the impact of T-cell recovery on TRM and relapse risk separately, Immune variable* n HR (95% CI) P as well as the unique immune biology of CB-mediated GVL. ALC 92 0.20 (0.07-0.54)† .003 CD3 T cells 93 0.34 (0.19-0.61)† .001 Acknowledgments CD4 T cells 93 0.30 (0.16-0.56)† <.001 The authors thank Theodore and Laura Hromadka for their generous 1 1 CD4 CD45RA T cells 93 0.90 (0.59-1.39) .651 support. CD8 T cells 93 0.74 (0.45-1.21) .221 This research was supported in part by the National Institutes of Health, National Cancer Institute grants P01 CA23766 and P30 NK cells 93 0.85 (0.31-2.34) .757 CA008748. B cells 93 0.80 (0.64-0.99) .054 PHA 89 0.34 (0.17-0.68)† .004 Authorship P values significant at the .01 level are indicated in bold. Contribution: I.P., M.-A.P., and J.N.B. designed the study and as- *In univariable analysis of patient, graft, and posttransplant variables, only recipient age sembled and analyzed the data; I.P. and J.N.B. wrote the manuscript; was associated with OS, although not at the 0.01 significance level (HR, 1.78 [95% CI, 1.04-3.03] per decade, P 5 .025). Patient sex, diagnosis, CMV seropositivity, engrafting J.A.L. and P.H. performed the statistical analysis; T.B. and M.A.M. 1 1 CB unit–recipient HLA-match, engrafting CB unit infused viable CD34 and CD3 cell doses, maintained the patient database and procured data for the study; I.P., addition of haploidentical CD34 cells, and day 100 aGVHD grade were not significant. J.A.L., P.H., C.C., S.A.G., M.R.M.v.d.B., M.-A.P., and J.N.B. inter- †HR adjusted for age. preted the data and reviewed and edited the manuscript; and all authors have approved the final version of the manuscript. to IV aGVHD did not significantly affect overall T-cell recovery or Conflict-of-interest disclosure: I.P. serves on a data and safety mortality, severe aGVHD is often associated with significant morbidity monitoring board for ExcellThera. S.A.G. has served as a consultant and opportunistic infections. Moreover, mitigation of aGVHD burden for Amgen, Actinium, Celgene, Johnson & Johnson, Jazz Pharma- may further speed thymus-dependent T-cell recovery due to the ceutical, Takeda, Novartis, Kite, and Spectrum Pharma and has 37,65 deleterious effect of aGVHD on thymopoiesis. Therefore, based received research funding from Amgen, Actinium, Celgene, John- 66,67 on the promising results reported in adult donor HSCT, our son & Johnson, Miltenyi, and Takeda. M.R.M.v.d.B. has received center is now investigating enhanced aGVHD prophylaxis with the research support from Seres Therapeutics; has consulted, received addition of tocilizumab (#NCT03434730) as a nonlymphodepleting honorarium from or participated in advisory boards for Seres strategy. Finally, although CMV-specific immunity ultimately develops, Therapeutics, Flagship Ventures, Novartis, Evelo, Jazz Pharma- most seropositive CBT recipients reactivate CMV early posttrans- ceuticals, Therakos, Amgen, Magenta Therapeutics, Merck & Co, plant. Therefore, our center has adopted letermovir prophylaxis Inc, Acute Leukemia Forum, and DKMS Medical Council (Board); starting day 17 for all adult CMV-seropositive CBT recipients. It is has IP Licensing with Seres Therapeutics, Juno Therapeutics, possible that reduction in CMV reactivation could in turn improve and has stock options from Smart Immune. M.-A.P. has received CD4 T-cell recovery in these patients. honoraria from AbbVie, Bellicum, Bristol-Myers Squibb, Incyte, Merck, Novartis, Nektar Therapeutics, and Takeda; serves on data Our study could have benefited from an even larger patient sample and safety monitoring boards for Servier and Medigene and the size and more frequent lymphocyte subset immunophenotyping scientific advisory boards of MolMed and NexImmune; and has re- assessments. In addition, detailed evaluation of thymopoiesis, 15 ceived research support for clinical trials from Incyte, Kite (Gilead), including T-cell receptor excision circles and T-cell repertoire 43,46 29,39,48-50 and Miltenyi Biotec. J.N.B. has received clinical trial funding from diversity, virus-specific T-cell responses, and analysis of 62,70,71 Angiocrine Bioscience and unrestricted educational grants from phenotypic or functional NK-cell reconstitution, were not Gamida Cell and Merck. The remaining authors declare no com- routinely performed. These should be investigated in the future to peting financial interests. further elucidate the biology of immune recovery after CBT. Future correlation of quantitative and qualitative T-cell reconstitution with The current affiliation for P.H. is RWJ Barnabas Health, functional immune competence, as evidenced by protection against St. Barnabas Medical Center, Livingston, NJ. 52,72 viral infections, will also be critically important. Such studies ORCID profiles: J.A.L., 0000-0002-2746-5647; S.A.G., 0000- could identify immune milestones that may inform the duration of 0003-1944-5053. needed viral monitoring and the safe cessation of antiviral prophylaxis, including letermovir. Correlation of B-cell recovery with vaccine Correspondence: Ioannis Politikos, Adult Bone Marrow Trans- responses will also be of great interest. 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Origin and evolution of the T cell repertoire after posttransplantation cyclophosphamide. JCI Insight. 2016; 1(5):e86252. 44. Itzykson R, Robin M, Moins-Teisserenc H, et al. Cytomegalovirus shapes long-term immune reconstitution after allogeneic stem cell transplantation. Haematologica. 2015;100(1):114-123. 45. Jeljeli M, Guerin-El ´ Khourouj V, Porcher R, et al. Relationship between cytomegalovirus (CMV) reactivation, CMV-driven immunity, overall immune recovery and graft-versus-leukaemia effect in children. Br J Haematol. 2014;166(2):229-239. 46. van Heijst JW, Ceberio I, Lipuma LB, et al. Quantitative assessment of T cell repertoire recovery after hematopoietic stem cell transplantation. Nat Med. 2013;19(3):372-377. 47. Garderet L, Dulphy N, Douay C, et al. The umbilical cord blood alphabeta T-cell repertoire: characteristics of a polyclonal and naive but completely formed repertoire. Blood. 1998;91(1):340-346. 48. Brown JA, Stevenson K, Kim HT, et al. Clearance of CMV viremia and survival after double umbilical cord blood transplantation in adults depends on reconstitution of thymopoiesis. Blood. 2010;115(20):4111-4119. 49. McGoldrick SM, Bleakley ME, Guerrero A, et al. Cytomegalovirus-specific T cells are primed early after cord blood transplant but fail to control virus in vivo. Blood. 2013;121(14):2796-2803. 50. Cohen G, Carter SL, Weinberg KI, et al. Antigen-specific T-lymphocyte function after cord blood transplantation. Biol Blood Marrow Transplant. 2006; 12(12):1335-1342. 51. Marchant A, Appay V, Van Der Sande M, et al. Mature CD8(1) T lymphocyte response to viral infection during fetal life. J Clin Invest. 2003;111(11): 1747-1755. 52. Admiraal R, de Koning CCH, Lindemans CA, et al. Viral reactivations and associated outcomes in the context of immune reconstitution after pediatric hematopoietic cell transplantation. J Allergy Clin Immunol. 2017;140(6):1643-1650.e1649. 53. Admiraal R, van Kesteren C, Jol-van der Zijde CM, et al. Association between anti-thymocyte globulin exposure and CD41 immune reconstitution in paediatric haemopoietic cell transplantation: a multicentre, retrospective pharmacodynamic cohort analysis. Lancet Haematol. 2015;2(5):e194-e203. 54. Buhlman ¨ n L, Buser AS, Cantoni N, et al. Lymphocyte subset recovery and outcome after T-cell replete allogeneic hematopoietic SCT. Bone Marrow Transplant. 2011;46(10):1357-1362. 55. Goldberg JD, Zheng J, Ratan R, et al. Early recovery of T-cell function predicts improved survival after T-cell depleted allogeneic transplant. Leuk Lymphoma. 2017;58(8):1859-1871. 56. Nakatani K, Imai K, Shigeno M, et al. Cord blood transplantation is associated with rapid B-cell neogenesis compared with BM transplantation. Bone Marrow Transplant. 2014;49(9):1155-1161. 57. Bunting MD, Varelias A, Souza-Fonseca-Guimaraes F, et al. GVHD prevents NK-cell-dependent leukemia and virus-specific innate immunity. 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Letermovir prophylaxis for cytomegalovirus in hematopoietic-cell transplantation. N Engl J Med. 2017;377(25): 2433-2444. 70. Pical-Izard C, Crocchiolo R, Granjeaud S, et al. Reconstitution of natural killer cells in HLA-matched HSCT after reduced-intensity conditioning: impact on clinical outcome. Biol Blood Marrow Transplant. 2015;21(3):429-439. 71. Nguyen S, Achour A, Souchet L, et al. Clinical impact of NK-cell reconstitution after reduced intensity conditioned unrelated cord blood transplantation in patients with acute myeloid leukemia: analysis of a prospective phase II multicenter trial on behalf of the Societ ´ e´ Française de Greffe de Moelle Osseuse et Therapie Cellulaire and Eurocord. Bone Marrow Transplant. 2017;52(10):1428-1435. 72. Camargo JF, Wieder ED, Kimble E, et al. Deep functional immunophenotyping predicts risk of cytomegalovirus reactivation after hematopoietic cell transplantation. Blood. 2019;133(8):867-877. 73. Shah GL, Shune L, Purtill D, et al. Robust vaccine responses in adult and pediatric cord blood transplantation recipients treated for hematologic malignancies. Biol Blood Marrow Transplant. 2015;21(12):2160-2166. 74. Hiwarkar P, Qasim W, Ricciardelli I, et al. Cord blood T cells mediate enhanced antitumor effects compared with adult peripheral blood T cells. Blood. 2015;126(26):2882-2891. 202 POLITIKOS et al 14 JANUARY 2020 x VOLUME 4, NUMBER 1 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Blood Advances Unpaywall

Robust CD4+ T-cell recovery in adults transplanted with cord blood and no antithymocyte globulin

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Downloaded from http://ashpublications.org/bloodadvances/article-pdf/4/1/191/1556118/advancesadv2019000836.pdf by guest on 12 October 2021 REGULAR ARTICLE Robust CD4 T-cell recovery in adults transplanted with cord blood and no antithymocyte globulin 1,2 3 3 1,2 1 1 1,2 Ioannis Politikos, Jessica A. Lavery, Patrick Hilden, Christina Cho, Taylor Borrill, Molly A. Maloy, Sergio A. Giralt, 1,2 1,2, 1,2, Marcel R. M. van den Brink, Miguel-Angel Perales, * and Juliet N. Barker * 1 2 Adult Bone Marrow Transplantation Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY; Department of Medicine, Weill Cornell Medical College, New York, NY; and Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY Quality of immune reconstitution after cord blood transplantation (CBT) without Key Points antithymocyte globulin (ATG) in adults is not established. We analyzed immune recovery in � ATG-free CBT in adults 106 engrafted adult CBT recipients (median age 50 years [range 22-70]) transplanted for is associated with rapid hematologic malignancies with cyclosporine/mycophenolate mofetil immunoprophylaxis CD4 -biased, thymus- and no ATG. Patients were treated predominantly for acute leukemia (66%), and almost all independent, T-cell 1 1 (96%) underwent myeloablation. Recovery of CD4 T cells was faster than CD8 T cells with reconstitution. 1 3 median CD4 T-cell counts exceeding 200/mm at 4 months. Early post-CBT, effector memory � Recovery of CD4 (EM), and central memory cells were the most common CD4 subsets, whereas effector and T cells and T-cell func- 1 EM were the most common CD8 T-cell subsets. Naive T-cell subsets increased gradually tion is associated with after 6 to 9 months post-CBT. A higher engrafting CB unit infused viable CD3 cell dose was improved survival in 1 1 1 associated with improved CD4 and CD4 CD45RA T-cell recovery. Cytomegalovirus adult CBT recipients. reactivation by day 60 was associated with an expansion of total, EM, and effector CD8 T cells, but lower CD4 T-cell counts. Acute graft-versus-host disease (aGVHD) did not significantly compromise T-cell reconstitution. In serial landmark analyses, higher CD4 T-cell counts and phytohemagglutinin responses were associated with reduced overall mortality. In contrast, CD8 T-cell counts were not significant. Recovery of natural killer and 3 3 B cells was prompt, reaching medians of 252/mm and 150/mm by 4 months, respectively, although B-cell recovery was delayed by aGVHD. Neither subset was significantly associated with mortality. ATG-free adult CBT is associated with robust thymus-independent CD4 T-cell recovery, and CD4 recovery reduced mortality risk. Introduction Cord blood (CB) is a valuable alternative hematopoietic stem cell (HSC) source for patients who lack 1,2 suitable adult donors, especially racial and ethnic minorities. Double-unit CB grafts have successfully extended cord blood transplantation (CBT) to larger children and adults, and both single- and double- 4,5 unit CBT has been associated with potent graft-versus-leukemia (GVL) effects, low rates of chronic 6-8 graft-versus-host disease (GVHD), and high rates of disease-free survival in patients with hematologic 4-6,8,9 malignancies. CBT, however, has also been associated with delayed immune reconstitution compared with T-cell replete HLA-matched adult donor allografts with multiple reports of high infection 10-13 rates early posttransplant. CB grafts contain low numbers of progenitor stem and immune cells compared with adult donor HSC grafts. In addition, CB-derived lymphocyte populations have unique phenotypic and immunological Submitted 14 August 2019; accepted 18 November 2019; published online 14 To request original data, contact corresponding author, Ioannis Politikos (politiki@ January 2020. DOI 10.1182/bloodadvances.2019000836. mskcc.org). The full-text version of this article contains a data supplement. © 2020 by The American Society of Hematology *M.-A.P. and J.N.B. contributed equally to this study. 14 JANUARY 2020 x VOLUME 4, NUMBER 1 191 Downloaded from http://ashpublications.org/bloodadvances/article-pdf/4/1/191/1556118/advancesadv2019000836.pdf by guest on 12 October 2021 properties, including almost exclusively naive T cells that do not Table 1. Patient and graft characteristics (n 5 106) 15,16 transfer immune memory. Although these CB graft attributes Variable Value could contribute to delayed immune reconstitution, many pre- Median age (range), y 50 (22-70) vious CBT series have included antithymocyte globulin (ATG), Male, n (%) 55 (52) a platform that has detrimental effects on both immune recon- 17-22 Median weight (range), kg 80 (36-138) stitution and survival after CBT. Notably, low ATG exposure or omission of ATG has been associated with rapid thymus- Recipient CMV , n (%) 59 (56) independent T-cell expansion and robust immune reconstitution Diagnosis, n (%) 19,22-25 in pediatric CBT recipients. In contrast to children, however, Acute leukemia (AML/ALL/other) 70 (66) relatively little is known about immune reconstitution after ATG-free MDS/MPN 14 (13) 12,26-30 CBT in adults. Lymphoma (NHL/HD) 22 (21) Herein, we report the kinetics of immune reconstitution in a large Conditioning, n (%)* cohort of adult CBT recipients transplanted for hematologic High intensity 1 (1) malignancies at a single center without ATG. We also analyzed Intermediate intensity 101 (95) the impact of patient, graft, and early posttransplant factors on immune recovery, as well as the immune variables associated Nonmyeloablative 4 (4) with improved survival. Our hypothesis was that, similar to Donor-recipient 8-allele HLA match,† median (range) 5 (3 to 7) pediatric series, ATG-free adult CBT is associated with prompt Infused TNC dose 3 10 /kg,† median (range) 2.35 (1.23-5.31) immune reconstitution and that early T-cell recovery improves 1 5 Infused viable CD34 dose 3 10 /kg,† median (range) 1.18 (0.18-4.08) survival post-CBT. 1 6 Infused viable CD3 dose 3 10 /kg,† median (range) 3.34 (0.45-10.61) Methods Graft composition, n (%)‡ dCB 45 (42) Patient and transplant characteristics dCB-haploCD34 59 (56) All consecutive adult patients #70 years old who underwent first sCB-haploCD34 2(2) allogeneic transplantation using single- or double-unit CB grafts for the treatment of hematologic malignancies at Memorial ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; HD, Hodgkin disease; MDS, myelodysplastic syndrome; MPN, myeloproliferative neoplasm; NHL, non-Hodgkin Sloan Kettering Cancer Center (MSKCC) between April 2012 lymphoma. and May 2016 were eligible for analysis (n 5 114). Those who *High-intensity myeloablative conditioning was with cyclophosphamide 120 mg/kg, did not achieve CB-derived engraftment (n 5 4) or had no fludarabine 75 mg/m , and total body irradiation (TBI) 1320 cGy; intermediate-intensity myeloablative was with cyclophosphamide 50 mg/kg, fludarabine 150 mg/m , thiotepa 5 to immune reconstitution assays performed due to development 10 mg/kg, and TBI 400 cGy ; nonmyeloablative included cyclophosphamide 50 mg/kg, 2 2 of fatal early posttransplant complications before day 30 fludarabine 150 mg/m , and TBI 200 cGy (n 5 3), or fludarabine 150 mg/m and TBI 400 cGy (n 5 1). (n 5 4) were excluded. Of the 106 evaluable patients, 93 were †Engrafting CB unit. treated on Institutional Review Board (IRB)–approved protocols ‡Fifty-nine double-unit CB (dCB) grafts and 2 single-unit CB (sCB) grafts were (#NCT00739141, #NCT01682226, and #NCT00387959). The supplemented with haploidentical CD34 cells to provide a myeloid bridge prior to CB engraftment. remaining 13 patients were treated off protocol due to either protocol ineligibility (n 5 8) or insurance denial for clinical trials in otherwise eligible patients (n 5 5). CB units were at least 4/6 HLA-A, -B antigen, -DRB1 allele immunophenotyping for the monitoring of absolute lymphocyte matched to the recipient, and each unit had a cryopreserved total count (ALC) and lymphocyte subset recovery was performed nucleated cell (TNC) dose $1.5 3 10 /kg. High-resolution HLA prospectively on fresh whole blood samples at the MSKCC typing, CD34 cell dose, CB quality, and bank of origin were Clinical Immunology Laboratory using BD FACS Canto II and BD also considered in unit selection as previously detailed. Some FACS Canto 10 color flow cytometers. Until April 2014, analyzed 1 1 patients also received mobilized peripheral blood-derived hap- lymphocyte subsets included total T cells (CD3 ), total CD4 , 1 1 1 2 1 loidentical CD34 cells as a myeloid bridge prior to CB engraftment CD4 45RA ,and CD8 T cells, natural killer (NK; CD3 CD56 1 1 (#NCT01682226). CD16 ), and B cells (CD19 ). Since May 2014, subset analysis 1 1 1 1 of CD4 and CD8 naive (CCR7 CD45RA ), central memory Most patients received myeloablative conditioning (outlined in 1 2 2 2 (CM; CCR7 CD45RA ), effector memory (EM; CCR7 CD45RA ), Table 1). GVHD prophylaxis was with cyclosporine-A/mycophenolate 2 1 1 effector (CCR7 CD45RA1), and activated (CD38 HLADR ) mofetil, and no patient received ATG. Granulocyte colony-stimulating 2 1 1 T cells, and naive (CD27 IgD ), nonswitched memory (CD27 factor was given starting day 17. Cytomegalovirus (CMV)-seropositive 1 1 2 1 IgD ), switched memory (CD27 IgD ), transitional (CD24 patients were monitored by quantitative polymerase chain reaction 1 1 2 1 CD38 ), and plasmablast (CD27 CD20 CD38 ) B cells was as of day 114 posttransplant. Preemptive antiviral therapy was performed. T-cell proliferative responses to mitogen phytohemag- given upon detection of any level of CMV viremia. glutinin (PHA) were assessed by measuring 3H-thymidine incor- This study was performed with MSKCC IRB approval. poration. Assessments were usually performed at days 30, 60, 120, 180, 270, 1 year, 18 months, and 2 years post-CBT. Immune Immune reconstitution monitoring recovery data were censored at the time of second allogeneic Immune reconstitution monitoring was per standard MSKCC clinical transplantation (n 5 1) or after infusion of viral-specific cytotoxic practice and not influenced by protocol enrollment. Flow cytometric T cells (n 5 5; 4 CMV specific, 1 Epstein-Barr virus specific). 192 POLITIKOS et al 14 JANUARY 2020 x VOLUME 4, NUMBER 1 Downloaded from http://ashpublications.org/bloodadvances/article-pdf/4/1/191/1556118/advancesadv2019000836.pdf by guest on 12 October 2021 (range 0.18-4.08) 3 10 /kg, respectively. The median 8-allele Statistical analysis engrafting unit-recipient HLA match was 5/8 (range 3/8-7/8). Acute graft-versus-host disease (aGVHD) was diagnosed clini- cally with histologic confirmation when possible and was graded Transplant outcomes according to International Bone Marrow Transplant Registry crite- 32 In all of the 106 patients (including all 61 recipients of CB grafts ria. CMV reactivation was defined as detection of CMV DNA by supplemented with haploidentical CD34 cells), long-term hema- quantitative polymerase chain reaction regardless of the viremia topoiesis was mediated by 1 CB unit (termed the engrafting unit), level. Transplant-related mortality (TRM) was defined as death from with no contribution from the host. Of the 59 CMV-seropositive any cause other than disease relapse or progression. The cumu- patients, 44 reactivated CMV by day 60 for a cumulative incidence lative incidence of aGVHD, CMV reactivation, relapse, and TRM of 75% (95% CI, 61-84). The cumulative incidence of grade II to IV was calculated in the competing risks framework considering and III to IV aGVHD by day 100 was 77% (95% CI, 68-84) and 17% relapse/death without developing aGVHD, death without CMV (95% CI, 11-25), respectively. Of the 64 patients with grade II day reactivation, TRM, and relapse as the competing events, respec- 100 aGVHD, 22 (34%) were treated with systemic corticosteroids tively. Overall survival (OS) and progression-free survival estimates by day 100; remaining patients were treated with nonabsorbable were calculated using Kaplan-Meier methodology. oral or topical corticosteroids. Loess-smoothed curves were estimated to visually inspect immune With a median survivor follow-up of 2 years (range 7 months to recovery trends over time. The association between baseline or 4.7 years), the 2-year estimates of OS and progression-free early posttransplant factors and immune variables was investi- survival for the 106 patients evaluable for immune recovery gated with linear mixed effects models. Immune recovery data (8 nonevaluable patients with graft failure or early death excluded) were natural log transformed before the analysis. The mixed effects were 73% (95% CI, 62-81) and 69% (95% CI, 58-78), respectively. models contained linear and quadratic terms for time, as well as Two-year TRM was 19% (95% CI, 12-28) and 2-year relapse was random intercepts for each patient and fixed effects for variables of 12% (95% CI, 6-20). interest. From the mixed effects models, the slopes and the 95% confidence intervals (CIs) of the baseline and early posttransplant T-, NK-, and B-cell immune reconstitution factors were estimated. Models for day 60 CMV reactivation and The median ALC surpassed 500/mm by 2 months. The speed of day 100 aGVHD considered only immune recovery data beyond 60 recovery varied markedly between lymphocyte subsets. NK cells and 100 days, respectively. were the most common lymphocyte population early posttrans- 1 1 plant, followed by CD3 T cells, and B cells. However, CD3 Landmark analyses at 2, 4, and 6 months were performed to T cells comprised the largest lymphocyte subset beyond 4 months investigate the association between each of the immune variables (Table 2; Figure 1). and OS. For the 2-, 4-, and 6-month landmark analyses, the most recent immune parameter values prior to day 65, 130, and 195 were 1 1 Of CD3 T-cell subsets, CD4 lymphocytes recovered faster than used, respectively. Univariable OS analyses were first performed for 1 1 CD8 lymphocytes (Table 2; Figure 2A). The median CD4 T-cell each immune variable, baseline factors, and early posttransplant 3 1 1 count surpassed 200/mm by 4 months. CD4 CD45RA T cells, factors. Exploratory analyses were also performed to potentially 1 considered to represent naive CD4 T cells, remained low in the identify an optimal CD4 T-cell count based on its univariable 1 first 6 to 9 months post-CBT (Figure 2A). CD8 T cells increased association with OS at each of the landmark time points. Multivari- steadily until 15 to 18 months post-CBT, followed by a relative able Cox regression models were built for each immune variable contraction of the CD8 T-cell compartment (Figure 2A). T-cell that was statistically significant controlling for significant baseline function, as assessed by PHA responses, increased rapidly and and/or posttransplant covariates. Immune variables were highly remained relatively stable beyond 6 months (Figure 2B). correlated with each other and therefore could not be included in Eighty-eight patients had 1 or more time points assayed with the the same models (correlations were assessed using Spearman’s extended lymphocyte subset immunophenotyping panel. EM rank correlation coefficient). and CM cells were the most prevalent CD4 subsets post-CBT, Tests with P , .01 were considered statistically significant, to account followed by naive and effector subsets (Figure 2C). EM and CM for multiple comparisons. All statistical analyses were performed in R CD4 T-cell numbers increased rapidly in the first 6 months and version 3.5.3 (The R Foundation for Statistical Computing). remained relatively stable between 9 and 24 months. Naive CD4 T cells increased steadily beyond 6 months. In contrast to 1 1 Results CD4 T-cell subsets, effector CD8 T cells comprised the 1 1 majority of CD8 T cells post-CBT, followed by the EM CD8 Patient and graft characteristics subset (Figure 2D). Following their marked initial increase, The characteristics of the 106 analyzed patients (median 50 years, effector CD8 T cells decreased beyond 18 months posttrans- range 22 to 70) and their grafts are summarized in Table 1. The plant. Recovery of naive CD8 T cells paralleled that of naive most common diagnosis was acute leukemia (66%), followed CD4 T cells beyond 6 months post-CBT (Figure 2D). by lymphoma (21%), or myelodysplasia/myeloproliferative disease NK cells increased rapidly in the first 2 months post-CBT and (13%). The majority of patients (95%) received intermediate-intensity 33 remained stable thereafter (Table 2; Figure 1). B cells also rose myeloablative conditioning. rapidly with the median B-cell count reaching normal range by Nearly all patients (n 5 104) received double-unit CB grafts. The 4 months posttransplant (Table 2; Figure 1). This was explained by median infused TNC and infused viable CD34 cell doses of the a marked increase of naive B cells in the first 6 months post-CBT. engrafting unit were 2.35 (range 1.23-5.31) 3 10 /kg and 1.18 Naive B cells continued to be the most prevalent B-cell subset 14 JANUARY 2020 x VOLUME 4, NUMBER 1 IMMUNE RECONSTITUTION AFTER ATG-FREE ADULT CBT 193 Downloaded from http://ashpublications.org/bloodadvances/article-pdf/4/1/191/1556118/advancesadv2019000836.pdf by guest on 12 October 2021 Table 2. Recovery of lymphocyte subsets and PHA responses after CBT Posttransplant time point Immune variable, median (range) 2mo 4 mo 6mo 1 y ALC, cells/mm 608 745 933 1554 (NR: 500-5300) (85-7200) (145-2025) (173-6287) (384-4774) 1 3 CD3 T cells, cells/mm 171 252 380 669 (NR: 822-1825) (7-3024) (8-1112) (38-1572) (148-3246) 1 3 CD4 T cells, cells/mm 120 203 294 420 (NR: 429-1131) (5-1584) (8-912) (30-1069) (22-891) 1 3 CD8 T cells, cells/mm 22 25 47 204 (NR: 209-768) (0-1440) (0-761) (0-909) (11-2574) B cells, cells/mm 22 150 201 324 (NR: 87-441) (0-3024) (0-1357) (0-3960) (0-1968) NK cells, cells/mm 222 252 221 220 (NR: 78-424) (41-1333) (29-717) (65-1519) (70-896) PHA, CPM 66 816 76 319 86 944 86 091 (NR: 109 576-256 486) (231-156 128) (667-162 912) (14 590-161 140) (6724-164 435) CPM, counts per minute; NR, normal range. through 2 years post-CBT (Figure 3). Transitional B cells were the higher engrafting unit infused viable CD3 cell dose was 1 1 1 next most common B-cell subset, whereas nonswitched memory, associated with higher CD4 and CD4 CD45RA T-cell counts switched memory, and plasmablast B-cell subsets remained low after CBT, although these associations were not significant at the (Figure 3). 0.01 level (Table 4). Conversely, CMV reactivation was associated with lower CD4 T cells (Figure 4A) and PHA responses post-CBT Association of patient, graft, and posttransplant (Table 4). In contrast, CMV reactivation was the only factor significantly associated with higher CD8 T-cell counts posttrans- variables with immune reconstitution plant (Table 4; Figure 4B). The association of baseline and early posttransplant variables with The association of transplant variables with the recovery of CD4 recovery of lymphocyte subsets and PHA responses is shown in T-cell subsets is shown in supplemental Table 1. A higher engrafting Tables 3 and 4. No patient, graft (including the addition of 1 1 unit CD34 cell dose was associated with higher EM CD4 T-cell haploidentical CD34 cells), or early posttransplant variables were counts, whereas a higher engrafting unit CD3 dose was associ- significantly associated with ALC or CD3 T-cell recovery (Table 3). ated with higher naive CD4 T-cell counts post-CBT, although Patient characteristics, including age, sex, or diagnosis, were not these associations did not reach significance at the 0.01 level. CMV 1 1 significantly associated with CD4 or CD8 T-cell recovery. A reactivation was associated with lower CM and, to a lesser extent, naive CD4 T-cell counts (supplemental Figure 1). No transplant factors were associated with effector CD4 T-cell reconstitution. Increased numbers of activated CD4 T cells were observed in ALC association with a higher engrafting unit CD34 cell dose, whereas lower activated CD4 T-cell counts were seen in patients with aGVHD, especially corticosteroid-requiring aGVHD (data not shown). These associations, however, did not reach the prespecified level of statistical significance. The association of transplant variables with the recovery of CD8 T-cells T-cell subsets is shown in supplemental Table 2. A higher engrafting unit CD34 cell dose was associated with higher EM and, to 1000 1 a lesser extent, effector CD8 T-cell counts after CBT. In addition, B-cells a marked expansion of EM and effector CD8 T cells was observed in patients with CMV reactivation (supplemental Figure 2). No transplant factors were significantly associated with CM or naive NK-cells 1 1 CD8 T-cell reconstitution. A higher number of activated CD8 T cells were observed in association with higher CD34 dose of the engrafting CB unit and CMV reactivation. 0 3 6 9 12 15 18 21 24 Older recipient age and higher CD34 cell dose of the engrafting Months post-CBT CB unit were associated with NK-cell recovery early posttransplant (Table 3). B-cell reconstitution was adversely affected by the Figure 1. ALC and lymphocyte subset recovery in adult CBT recipients. ALC, development of grade II to IV aGVHD (Table 3), especially aGVHD CD3 cells, NK cells, B cells. Curves are Loess-smoothed averages. requiring systemic corticosteroids (data not shown). The negative 194 POLITIKOS et al 14 JANUARY 2020 x VOLUME 4, NUMBER 1 Lymphocyte count (cells/mm ) Downloaded from http://ashpublications.org/bloodadvances/article-pdf/4/1/191/1556118/advancesadv2019000836.pdf by guest on 12 October 2021 A B CD3+ CD4+ 600 50000 CD8+ CD4+CD45RA+ 0 3 6 9 12 15 18 21 24 0 3 6 9 12 15 18 21 24 Months post-CBT Months post-CBT C D CD4+ CD8+ Effector CD8+ EM CD4+ 200 EM CD8+ CM CD4+ Naïve CD4+ Naïve CD8+ CM CD8+ Effector CD4+ 0 0 0 3 6 9 12 15 18 21 24 0 3 6 9 12 15 18 21 24 Months post-CBT Months post-CBT 1 1 1 1 1 1 Figure 2. Recovery of T-cell subsets and T-cell function in adult CBT recipients. (A) CD3 ,CD4 ,CD8 ,CD4 CD45RA T cells. (B) PHA responses. (C) CD4 and 1 1 1 CD4 T-cell subsets (naive, CM, EM, effector). (D) CD8 and CD8 T-cell subsets (naive, CM, EM, effector). Curves are Loess-smoothed averages. In panels C and D, Loess- 1 1 smoothed curves for total CD4 and total CD8 T cells, respectively, are based on values from the time points of which the extended immunophenotyping panel was also performed. effect of aGVHD was also observed in naive, transitional, nonswitched In the 4-month landmark analysis (Table 6), recipient age was again memory, and to a lesser extent, switched memory and plasmablast the only baseline factor impacting OS. In addition, there was no B-cell subset recovery (data not shown). No other transplant association of day 100 aGVHD grade with OS. In univariable 1 1 factors were associated with B-cell recovery. analysis, 4-month ALC, total CD3 and CD4 T cells, and PHA responses were significantly associated with OS beyond 4 months. Although an association of higher B-cell counts with improved Association of immune variables with OS OS was also observed, it was not significant at the 0.01 level. In Next, we investigated the association of immune reconstitution multivariable analyses controlling for age, each of the variables with OS in serial landmark analyses. At 2 months, recipient age 1 1 of ALC, CD3 and CD4 T cells, and PHA remained significant. was the only baseline factor associated with OS (Table 5). A As expected, CD4 T-cell counts and PHA responses at 4 months higher PHA response was the only immune variable associ- were highly correlated (r 5 0.35). Therefore, they could not be ated with improved OS in univariable and multivariable analysis concurrently included in a multivariable model. controlling for age. This was due to decreased TRM in patients with higher PHA responses, whereas relapse risk was unaffected At 6 months (Table 7), the association of recipient age with OS was (data not shown). no longer significant at the 0.01 level (P5 .025), but was retained in 14 JANUARY 2020 x VOLUME 4, NUMBER 1 IMMUNE RECONSTITUTION AFTER ATG-FREE ADULT CBT 195 T-cells (cells/mm ) CD4+ T-cells & subsets (cell/mm ) PHA response (CPM) CD8+ T-cells & subsets (cells/mm ) Downloaded from http://ashpublications.org/bloodadvances/article-pdf/4/1/191/1556118/advancesadv2019000836.pdf by guest on 12 October 2021 addition, due to the limited number of events in assayed patients, 1 1 800 B-cells the prognostic value of specific CD4 and CD8 T-cell subsets could not be evaluated. Finally, in exploratory analyses, no optimal Naïve CD4 T-cell count cutoff for OS could be identified at any time point post-CBT. Discussion This study represents the largest analysis of immune reconstitution after ATG-free CBT in adults to date. In contrast to the protracted T-cell lymphopenia reported after ATG-based CBT, we show Transitional Non-switched rapid early thymus-independent CD4 T-cell recovery consistent Switched memory Memory 23,24 with that reported in pediatric ATG-free CBT. In this adult 0 Plasmablasts population with a median age of 50 years, the median CD4 0369 12 15 18 21 24 T-cell count already exceeded 200/mm by 4 months and increased Months post-CBT steadily through 2 years posttransplant. EM and CM T cells were 1 11,34 the most prevalent CD4 subsets early post-CBT, whereas Figure 3. Recovery of B cells and subsets in adult CBT recipients. Curves are naive CD4 T-cell counts gradually increased beyond 6 to 9 months Loess-smoothed averages. Loess-smoothed curves for total B-cell counts are based post-CBT. on values from the time points of which the extended immunophenotyping panel was 1 1 Recovery of CD8 T cells was initially slow, but marked CD8 T-cell also performed. expansion was noted beyond 6 months post-CBT. Effector and 1 11,34 EM were the most common CD8 T-cell subsets early post-CBT. multivariable modeling because it is a clinically important factor. Of 1 1 As with naive CD4 T cells, naive CD8 T-cell counts increased 1 1 the immune variables, higher ALC, total CD3 and CD4 T cells, steadily beyond 6 to 9 months, suggesting thymus-dependent and PHA responses were significantly associated with subsequent recovery from this time point, even despite the relatively advanced improved OS in univariable and age-adjusted analyses. As with 15 age of this patient cohort. Recovery of T-cell function, as the 4-month landmark, CD4 T-cell counts and PHA responses at assayed by PHA responses, was also prompt. 6 months were highly correlated (r 5 0.39); therefore, their indepen- Of factors associated with T-cell reconstitution, a notable finding dent prognostic significance could not be examined. was the lack of an adverse effect of recipient age on total, CD4 , 1 1 1 1 CD4 CD45RA T-cell, CD8 T-cell, or NK-cell counts were not CD8 , and subset T-cell recovery. It is possible that the relatively associated with OS at any time point post-CBT (Tables 5-7). In older age of this patient cohort did not allow the detection of such Table 3. Association of transplant variables with the recovery of ALC and total T, NK, and B cells ALC CD3 T cells NK cells B cells Variable Slope (95% CI) P Slope (95% CI) P Slope (95% CI) P Slope (95% CI) P Age (10 y) 0.01 (20.08, 0.09) .897 20.06 (20.16, 0.04) .260 0.15 (0.07, 0.23) .001 20.20 (20.46, 0.07) .146 8-allele HLA-match* .135 .733 .327 .465 ,5/8 reference reference reference reference $5/8 0.17 (20.05, 0.39) 0.05 (20.22, 0.31) 0.12 (20.12, 0.35) 0.26 (20.44, 0.96) Infused viable CD34 cell dose* .099 .840 .018 .245 ,1.18 3 10 /kg reference reference reference reference $1.18 3 10 /kg 0.17 (20.03, 0.37) 0.03 (20.22, 0.27) 0.25 (0.05, 0.46) 0.38 (20.25, 1.01) Infused viable CD3 cell dose* .727 .185 .093 .612 ,3.34 3 10 /kg reference reference reference reference $3.34 3 10 /kg 0.04 (20.16, 0.24) 0.16 (20.08, 0.40) 20.18 (20.39, 0.03) 0.164 (20.47, 0.80) CMV reactivation by day 60 .783 .391 .577 .488 No CMV reactivation reference reference reference reference CMV reactivation 20.03 (20.23, 0.17) 0.12 (20.15, 0.38) 0.06 (20.15, 0.27) 20.26 (21.01, 0.48) Day 100 aGVHD grade .313 .960 .708 <.001 0-I reference reference reference reference II 20.16 (20.43, 0.11) 20.05 (20.41, 0.31) 0.09 (20.19, 0.38) 21.15 (22.04, 20.26) III-IV 20.26 (20.60, 0.08) 20.02 (20.47, 0.43) 20.01 (20.37, 0.35) 22.38 (23.50, 21.25) There was no association with the variables of recipient sex, diagnosis (acute leukemia vs MDS/MPD vs lymphoma), or the addition of haploidentical CD34 cells (data not shown). P values significant at the .01 level are indicated in bold. *Engrafting CB unit. 196 POLITIKOS et al 14 JANUARY 2020 x VOLUME 4, NUMBER 1 B-cells & subsets (cells/mm ) Downloaded from http://ashpublications.org/bloodadvances/article-pdf/4/1/191/1556118/advancesadv2019000836.pdf by guest on 12 October 2021 Table 4. Association of transplant variables with the recovery of T-cell subsets and function 1 1 1 1 CD4 T cells CD4 CD45RA T cells CD8 T cells PHA Variable Slope (95% CI) P Slope (95% CI) P Slope (95% CI) P Slope (95% CI) P Age (10 y) 20.09 (20.20, 0.01) .087 20.05 (20.22, 0.12) .539 0.01 (20.15, 0.16) .924 20.08 (20.21, 0.04) .205 8-allele HLA-match* .200 .545 .105 .565 ,5/8 reference reference reference reference $5/8 0.19 (20.10, 0.47) 0.14 (20.30, 0.58) 20.33 (20.73, 0.07) 0.09 (20.22, 0.41) Infused viable CD34 cell dose* .646 .333 .245 .574 ,1.18 3 10 /kg reference reference reference reference $1.18 3 10 /kg 20.06 (20.32, 0.20) 20.20 (20.60, 0.20) 0.22 (20.15, 0.58) 0.08 (20.21, 0.37) Infused viable CD3 cell dose* .045 .020 .893 .065 ,3.34 3 10 /kg reference reference reference reference $3.34 3 10 /kg 0.26 (0.01, 0.52) 0.47 (0.08, 0.87) 0.03 (20.34, 0.39) 0.27 (20.01, 0.56) CMV reactivation by day 60 .005 .171 <.001 <.001 No CMV reactivation reference Reference reference reference CMV reactivation 20.39 (20.66, 20.13) 20.31 (20.75, 0.13) 1.15 (0.77, 1.52) 20.58 (20.86, 20.29) Day 100 aGVHD grade .651 .386 .630 .435 0-I reference reference reference reference II 20.16 (20.52, 0.20) 20.05 (20.62, 0.51) 0.29 (20.32, 0.90) 20.20 (20.61, 0.21) III-IV 20.19 (20.65, 0.27) 0.37 (0.36, 1.10) 0.30 (20.48, 1.07) 20.33 (20.83, 0.17) *Engrafting CB unit. There was no association with the variables of recipient sex, diagnosis (acute leukemia vs MDS/MPD vs lymphoma), or the addition of haploidentical CD34 cells (data not shown). P values significant at the .01 level are indicated in bold. 36-38 an effect. Alternatively, early thymus-independent T-cell recovery reconstitution, overall grade II to IV aGVHD did not significantly after ATG-free CBT may not be significantly influenced by advanced affect T-cell recovery in our series, with the exception of activated recipient age, in contrast to the thymus-dependent pathway of T-cell CD4 T-cell counts. reconstitution. Data concerning the potential impact of CB graft 23,35,36 CMV reactivation significantly impacts quantitative and qualita- characteristics on T-cell recovery after CBT are limited. We 39,40 tive T-cell recovery after HSC transplantation (HSCT). CMV observed a notable trend for a higher engrafting CB unit infused reactivation after HSCT has been associated with a rapid viable CD3 cell dose being associated with higher total and naive 1 1 increase of CD8 T cells due to EM and effector CD8 subset CD4 T cells post-CBT. In addition, higher engrafting CB unit 39-45 1 expansion. Theimpactontotal CD4 T-cell and subset infused viable CD34 cell dose was associated with higher EM and 39-43 recovery, however, is less clear, with a previous report suggesting activated CD8 T-cell counts, and a similar trend was observed 1 39 for the same CD4 T-cell subsets. Interestingly, despite high levels that CMV reactivation may compromise thymopoiesis. These of engrafting CB unit-recipient HLA-mismatch, such mismatch effects lead to contraction of the naive T-cell compartment and 39,43,46 had no discernible effect on total T-cell and subset recovery. TCR repertoire diversity. In our analysis, a marked expan- 1 1 In addition, despite concerns that aGVHD may hamper immune sion of total CD8 ,EMand effector CD8 T-cell subsets, and A B 8 8 6 6 4 4 Figure 4. Association of CMV reactivation 1 1 with CD4 and CD8 T-cell recovery in adult 2 2 CBT recipients. (A) CD4 T-cell recovery accord- No CMV reactivation No CMV reactivation ing to CMV reactivation by day 60 post-CBT. CMV reactivation CMV reactivation 1 0 0 (B) CD8 T-cell recovery according to CMV reac- tivation by day 60 post-CBT. Individual patient time 0369 12 15 18 21 24 0369 12 15 18 21 24 points are color coded according to CMV reac- Months post-CBT Months post-CBT tivation. Curves are Loess-smoothed averages. 14 JANUARY 2020 x VOLUME 4, NUMBER 1 IMMUNE RECONSTITUTION AFTER ATG-FREE ADULT CBT 197 log(CD4+ T-cells) log(CD8+ T-cells) Downloaded from http://ashpublications.org/bloodadvances/article-pdf/4/1/191/1556118/advancesadv2019000836.pdf by guest on 12 October 2021 Table 5. Two-month landmark analysis for OS Table 6. Four-month landmark analysis for OS Immune variable* n HR (95% CI) P Immune variable* n HR (95% CI) P ALC 90 0.67 (0.34-1.31) .246 ALC 93 0.20 (0.08-0.51)† .004 1 1 CD3 T cells 90 0.73 (0.45-1.18) .219 CD3 T cells 93 0.41 (0.24-0.71)† .006 1 1 CD4 T cells 90 0.69 (0.43-1.12) .150 CD4 T cells 93 0.43 (0.25-0.73)† .006 1 1 1 1 CD4 CD45RA T cells 90 1.11 (0.75-1.64) .587 CD4 CD45RA T cells 93 1.03 (0.70-1.51) .887 1 1 CD8 T cells 90 1.00 (0.66-1.49) .984 CD8 T cells 93 0.86 (0.60-1.24) .434 NK cells 78 1.34 (0.63-2.84) .439 NK cells 91 0.71 (0.32-1.60) .420 B cells 90 0.85 (0.68-1.07) .163 B cells 93 0.80 (0.66-0.97) .029 PHA 88 0.56 (0.40-0.78)† .009 PHA 89 0.43 (0.26-0.71)† .008 P values significant at the .01 level are indicated in bold. P values significant at the .01 level are indicated in bold. *In univariable analysis of patient and graft variables, only recipient age was significantly *In univariable analysis of patient, graft, and posttransplant variables, only recipient age associated with OS (hazard ratio [HR], 2.11 [95% CI, 1.30-3.43] per decade, P 5 .001). was significantly associated with OS (HR, 2.21 [95% CI, 1.31-3.75] per decade, P 5 Patient sex, diagnosis, CMV seropositivity, engrafting CB unit–recipient HLA-match, .001). Patient sex, diagnosis, CMV seropositivity, engrafting CB unit–recipient HLA match, 1 1 1 1 engrafting CB unit infused viable CD34 and CD3 cell doses, addition of haploidentical engrafted CB unit infused viable CD34 and CD3 cell doses, addition of haploidentical 1 1 CD34 cells were not significant. CD34 cells, and day 100 aGVHD grade were not significant. †HR adjusted for age. †HR adjusted for age. 1 44 activated CD8 Tcells was observed in patients with CMV advanced recipient age was associated with higher NK-cell counts, 47 36,55 reactivation post-CBT. Because CB T cells are exclusively naive, as has previously been suggested in some HSCT studies, and this CMV-driven CD8 T-cell expansion reflects the emergence may represent a compensatory mechanism as recovery of adap- of CMV effectors from naive CB-derived T cells. Although T-cell tive immunity may be delayed in older HSCT recipients. We also specificity was not examined, our findings are supported by reports observed an association of a higher engrafting unit infused viable that CMV effectors with memory phenotype are generated from naive CD34 cell dose with higher NK-cell counts post-CBT. In contrast, 48-50 CB-derived T cells early post-CBT and after CMV infection in NK-cell counts tended to be lower in recipients of a higher engrafting 51 1 neonates. We also observed that CMV reactivation was associated unit infused viable CD3 cell dose, a finding possibly explained by 1 1 57 with lower total and CM CD4 T-cell counts. Although naive CD4 NK- and T-cell competition for homeostatic cytokines. Similar 58,59 T cells were also numerically lower, this difference was not significant findings have been reported in adult donor HSCT. Importantly, in 54,58,60-62 at the prespecified significance threshold. Therefore, although we contrast to multiple HSCT series, we found no association demonstrate a negative impact of CMV reactivation on CD4 T-cell between NK-cell counts and CBT outcomes. recovery after CBT, whether thymopoiesis is impaired is uncertain. B-cell counts normalized by 4 months and were primarily charac- A critical finding of this analysis is that early T-cell recovery, terized by naive immunophenotype. Development of grade II to IV especially CD4 counts and T-cell function, was associated with aGVHD by day 100, and especially corticosteroid-requiring GVHD, improved survival. Although an association of CD4 counts with was the only factor that adversely affected B-cell and subset OS was not observed at 2 months, .75% of assayed patients already recovery. Whether B-cell recovery has any prognostic value for 1 3 had CD4 T cells .50/mm by that time, a threshold previously CBT outcomes remains unclear, as the prespecified statistical associated with protection against infections and improved survival significance threshold in our analysis was not achieved. 19,22,52,53 in pediatric CBT. Importantly, we observed a continuous A striking finding of our study is that T-cell recovery after ATG-free reduction in overall mortality with increasing CD4 T-cell counts at CBT in adults is robust, thymus independent, and CD4 biased. 4 and 6 months post-CBT. Because CD4 T cells were the most These results add to the growing literature supporting an under- prevalent CD3 subset at these time points, this lymphocyte 19,22-24,28 appreciated prompt T-cell recovery after T-replete CBT. population likely also accounted for the prognostic significance of They suggest that the reconstituting neonatal immune system in 1 1 CD3 T-cell counts and ALC on survival. In contrast, CD8 T-cell adult CBT recipients has unique biology as previously demon- counts were not associated with survival, as previously reported 24 1 strated in children. The observed CD4 bias is in contrast to 38,54 after adult donor HSCT. Early recovery of T-cell function as 1 1 the inversion of the CD4 /CD8 T-cell ratio after adult donor assessed by PHA responses was also associated with improved HSCT. Moreover, our study demonstrates that early CD4 T-cell survival, as has previously been reported in CD34 selected HSCT recovery after adult CBT, as well as T-cell function, is associated 55 1 recipients, and was highly correlated with CD4 T-cell counts. with reduction in overall mortality, corroborating previous HSCT and 22,28,38,53-55,63,64 Notably, in contrast to previous reports supporting an important role primarily pediatric CBT studies. 15,30,48 of thymopoiesis on CBT outcomes, we did not observe an We acknowledge that not all patients had early T-cell recovery. 1 1 association of CD4 CD45RA T-cell count recovery with improved Therefore, as with adult donor HSCT, strategies to further survival. A possible explanation is that ATG omission may decrease augment immune reconstitution are needed. Notably, we found reliance on thymopoiesis for CD4 T-cell reconstitution due to early that increased cell dose improved T-cell recovery, whereas HLA thymus-independent T-cell recovery. mismatch was not detrimental. If these findings are confirmed, Previous CBT studies have reported prompt posttransplant NK- they would support prioritizing cell dose over HLA match in CB 12,28,29,56 and B-cell recovery, regardless of ATG use. Similarly, unit selection as a potentially modifiable factor to promote both we observed early NK-cell recovery in our cohort. Unexpectedly, myeloid engraftment and T-cell recovery. In addition, although grade II 198 POLITIKOS et al 14 JANUARY 2020 x VOLUME 4, NUMBER 1 Downloaded from http://ashpublications.org/bloodadvances/article-pdf/4/1/191/1556118/advancesadv2019000836.pdf by guest on 12 October 2021 22,53 Table 7. Six-month landmark analysis for OS with myeloid malignancies. Thus, further research should focus on the impact of T-cell recovery on TRM and relapse risk separately, Immune variable* n HR (95% CI) P as well as the unique immune biology of CB-mediated GVL. ALC 92 0.20 (0.07-0.54)† .003 CD3 T cells 93 0.34 (0.19-0.61)† .001 Acknowledgments CD4 T cells 93 0.30 (0.16-0.56)† <.001 The authors thank Theodore and Laura Hromadka for their generous 1 1 CD4 CD45RA T cells 93 0.90 (0.59-1.39) .651 support. CD8 T cells 93 0.74 (0.45-1.21) .221 This research was supported in part by the National Institutes of Health, National Cancer Institute grants P01 CA23766 and P30 NK cells 93 0.85 (0.31-2.34) .757 CA008748. B cells 93 0.80 (0.64-0.99) .054 PHA 89 0.34 (0.17-0.68)† .004 Authorship P values significant at the .01 level are indicated in bold. Contribution: I.P., M.-A.P., and J.N.B. designed the study and as- *In univariable analysis of patient, graft, and posttransplant variables, only recipient age sembled and analyzed the data; I.P. and J.N.B. wrote the manuscript; was associated with OS, although not at the 0.01 significance level (HR, 1.78 [95% CI, 1.04-3.03] per decade, P 5 .025). Patient sex, diagnosis, CMV seropositivity, engrafting J.A.L. and P.H. performed the statistical analysis; T.B. and M.A.M. 1 1 CB unit–recipient HLA-match, engrafting CB unit infused viable CD34 and CD3 cell doses, maintained the patient database and procured data for the study; I.P., addition of haploidentical CD34 cells, and day 100 aGVHD grade were not significant. J.A.L., P.H., C.C., S.A.G., M.R.M.v.d.B., M.-A.P., and J.N.B. inter- †HR adjusted for age. preted the data and reviewed and edited the manuscript; and all authors have approved the final version of the manuscript. to IV aGVHD did not significantly affect overall T-cell recovery or Conflict-of-interest disclosure: I.P. serves on a data and safety mortality, severe aGVHD is often associated with significant morbidity monitoring board for ExcellThera. S.A.G. has served as a consultant and opportunistic infections. Moreover, mitigation of aGVHD burden for Amgen, Actinium, Celgene, Johnson & Johnson, Jazz Pharma- may further speed thymus-dependent T-cell recovery due to the ceutical, Takeda, Novartis, Kite, and Spectrum Pharma and has 37,65 deleterious effect of aGVHD on thymopoiesis. Therefore, based received research funding from Amgen, Actinium, Celgene, John- 66,67 on the promising results reported in adult donor HSCT, our son & Johnson, Miltenyi, and Takeda. M.R.M.v.d.B. has received center is now investigating enhanced aGVHD prophylaxis with the research support from Seres Therapeutics; has consulted, received addition of tocilizumab (#NCT03434730) as a nonlymphodepleting honorarium from or participated in advisory boards for Seres strategy. Finally, although CMV-specific immunity ultimately develops, Therapeutics, Flagship Ventures, Novartis, Evelo, Jazz Pharma- most seropositive CBT recipients reactivate CMV early posttrans- ceuticals, Therakos, Amgen, Magenta Therapeutics, Merck & Co, plant. Therefore, our center has adopted letermovir prophylaxis Inc, Acute Leukemia Forum, and DKMS Medical Council (Board); starting day 17 for all adult CMV-seropositive CBT recipients. It is has IP Licensing with Seres Therapeutics, Juno Therapeutics, possible that reduction in CMV reactivation could in turn improve and has stock options from Smart Immune. M.-A.P. has received CD4 T-cell recovery in these patients. honoraria from AbbVie, Bellicum, Bristol-Myers Squibb, Incyte, Merck, Novartis, Nektar Therapeutics, and Takeda; serves on data Our study could have benefited from an even larger patient sample and safety monitoring boards for Servier and Medigene and the size and more frequent lymphocyte subset immunophenotyping scientific advisory boards of MolMed and NexImmune; and has re- assessments. In addition, detailed evaluation of thymopoiesis, 15 ceived research support for clinical trials from Incyte, Kite (Gilead), including T-cell receptor excision circles and T-cell repertoire 43,46 29,39,48-50 and Miltenyi Biotec. J.N.B. has received clinical trial funding from diversity, virus-specific T-cell responses, and analysis of 62,70,71 Angiocrine Bioscience and unrestricted educational grants from phenotypic or functional NK-cell reconstitution, were not Gamida Cell and Merck. The remaining authors declare no com- routinely performed. These should be investigated in the future to peting financial interests. further elucidate the biology of immune recovery after CBT. Future correlation of quantitative and qualitative T-cell reconstitution with The current affiliation for P.H. is RWJ Barnabas Health, functional immune competence, as evidenced by protection against St. Barnabas Medical Center, Livingston, NJ. 52,72 viral infections, will also be critically important. Such studies ORCID profiles: J.A.L., 0000-0002-2746-5647; S.A.G., 0000- could identify immune milestones that may inform the duration of 0003-1944-5053. needed viral monitoring and the safe cessation of antiviral prophylaxis, including letermovir. Correlation of B-cell recovery with vaccine Correspondence: Ioannis Politikos, Adult Bone Marrow Trans- responses will also be of great interest. 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