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. 2023 Jul 25;7(14):3725-3734.
doi: 10.1182/bloodadvances.2022009478.

Alemtuzumab and CXCL9 levels predict likelihood of sustained engraftment after reduced-intensity conditioning HCT

Ashley V Geerlinks  1 , Brooks Scull  2 , Christa Krupski  3   4 , Ryan Fleischmann  2 , Michael A Pulsipher  5 , Mary Eapen  6 , James A Connelly  7 , Catherine M Bollard  8 , Sung-Yun Pai  9 , Christine N Duncan  10 , Leslie S Kean  10 , K Scott Baker  11 , Lauri M Burroughs  11 , Jeffrey R Andolina  12 , Shalini Shenoy  13 , Philip Roehrs  14 , Rabi Hanna  15 , Julie-An Talano  16 , Kirk R Schultz  17 , Elizabeth O Stenger  18 , Howard Lin  19 , Adi Zoref-Lorenz  20   21   22 , Kenneth L McClain  2   19 , Michael B Jordan  3   22 , Tsz-Kwong Man  2   19 , Carl E Allen  2   19 , Rebecca A Marsh  3   4
Affiliations

Alemtuzumab and CXCL9 levels predict likelihood of sustained engraftment after reduced-intensity conditioning HCT

Ashley V Geerlinks et al. Blood Adv. .

Abstract

Overall survival after reduced-intensity conditioning (RIC) allogeneic hematopoietic cell transplantation (HCT) using alemtuzumab, fludarabine, and melphalan is associated with high rates of mixed chimerism (MC) and secondary graft failure (GF). We hypothesized that peritransplantation alemtuzumab levels or specific patterns of inflammation would predict these risks. We assessed samples from the Bone Marrow Transplant Clinical Trials Network 1204 (NCT01998633) to study the impact of alemtuzumab levels and cytokine patterns on MC and impending or established secondary GF (defined as donor chimerism <5% after initial engraftment and/or requirement of cellular intervention). Thirty-three patients with hemophagocytic lymphohistiocytosis (n = 25) and other IEIs (n = 8) who underwent HCTs with T-cell-replete grafts were included. Patients with day 0 alemtuzumab levels ≤0.32 μg/mL had a markedly lower incidence of MC, 14.3%, vs 90.9% in patients with levels >0.32 μg/mL (P = .008). Impending or established secondary GF was only observed in patients with day 0 alemtuzumab levels >0.32 μg/mL (P = .08). Unexpectedly, patients with impending or established secondary GF had lower CXCL9 levels. The cumulative incidence of impending or established secondary GF in patients with a day 14+ CXCL9 level ≤2394 pg/mL (day 14+ median) was 73.6% vs 0% in patients with a level >2394 pg/mL (P = .002). CXCL9 levels inversely correlated with alemtuzumab levels. These data suggest a model in which higher levels of alemtuzumab at day 0 deplete donor T cells, inhibit the graft-versus-marrow reaction (thereby suppressing CXCL9 levels), and adversely affect sustained engraftment in the nonmyeloablative HCT setting. This trial was registered at www.clinicaltrials.gov as #NCT01998633.

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Conflict of interest statement

Conflict-of-interest disclosure: C.E.A. is on the advisory board for Sobi, Atara Biotherapeutics, and Electra Therapeutics. M.B.J. is a consultant for Sobi and received research funding from Sobi. K.L.M. is on the advisory board of Sobi. J.A.C. is a Consultant for X4 Consultancy and is on the advisory board for Sobi and Horizon. P.R. is a consultant for Sobi. C.M.B. owns stock in Mana Therapeutics, Cabaletta Bio, Catamaran Bio, Repertoire Immune Medicine, and Neximmune, is a Data and Safety Monitoring Board (DSMB) member for Sobi, and is on the ad hoc advisory board for BMS and Pfizer. S.S. is on the advisory board for Janssen Pharma Inc, Graphite Bio, and Bristol Myer Squibb, is a consultant for California Institute of Regenerative Medicine and on DSMB for Aruvant. The remaining authors declare no conflicts of interest. A.Z-L received consulting fees from Sobi.

Figures

None
Graphical abstract
Figure 1.
Figure 1.
Peritransplantation alemtuzumab levels. Box and whisker plots outline alemtuzumab levels measured on specific days in relation to HCT day 0. The boxes represent the 25th percentile, median, and 75th percentile on each specified day. The lines represent the minimum and maximum alemtuzumab levels on each specified day.
Figure 2.
Figure 2.
MC and impending or established secondary GF stratified based on day 0 alemtuzumab levels. (A) Cumulative incidence of MC, defined as donor chimerism <95%. (B) Cumulative incidence of impending or established secondary GF. Stratification using the first quartile day 0 alemtuzumab levels (level ≤ 0.32 μg/mL). D0, day 0.
Figure 3.
Figure 3.
MC and impending or established secondary GF stratified based on CXCL9 levels. (A) Grouped plasma proteomic expression in patients with and without intervention-free sustained engraftment. Five analytes were identified to be statistically significant (maximum false discovery proportion of 0.1 at an 80% confidence level). (B) Cumulative incidence of secondary GF, impending or established, stratified by median D+14 CXCL9 level, 2394 pg/mL. (C) Cumulative incidence of secondary GF, impending or established, stratified based on median D+28 CXCL9 level, 2867 pg/mL. D+14, day +14 after HCT; D+28, day +28 after HCT.
Figure 4.
Figure 4.
Peritransplantation CXCL9 levels stratified based on day 0 alemtuzumab levels. Peritransplantation CXCL9 median levels for all patients. Stratification using first quartile day 0 alemtuzumab levels (level ≤0.32 μg/mL). Light gray shading represents range (25th-75th percentile) of CXCL9 values in healthy pediatric controls. Dark gray shading represents range (25th-75th percentile) of CXCL9 values in pediatric patients with untreated HLH. D0, day 0 after HCT.
Figure 5.
Figure 5.
Overall survival and survival with intervention-free sustained engraftment stratified based on alemtuzumab and CXCL9 levels. Overall survival stratified based on day 0 alemtuzumab levels (A), day +14 CXCL9 levels (C), and day +28 CXCL9 levels (E). Probability of survival with intervention-free sustained engraftment stratified based on day 0 alemtuzumab levels (B), day +14 CXCL9 levels (D), and day +28 CXCL9 levels (F).
Figure 6.
Figure 6.
Proposed model in which higher peritransplantation alemtuzumab levels drive T-cell depletion of the stem cell graft, inhibit graft-versus-marrow effect, and facilitate secondary GF after RIC HCT.
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References

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