Current Approaches for the Prevention and Treatment of Acute and Chronic GVHD
Abstract
:1. Introduction
2. Pathophysiology of Acute and Chronic GVHD
3. GVHD Prevention
4. Therapy of aGVHD
5. Treatment of SR-aGVHD
6. Treatment of cGVHD
7. SR-cGVHD
8. Management of Patients with Lung Involvement
9. Management and Topical Treatment of Specific cGVHD Localizations (Skin, Oral, Ocular and Genital cGVHD)
10. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Type of GVHD | Classical or Late aGVHD | Classic cGVHD | Overlap cGVHD | Indefinite Other cGVHD |
---|---|---|---|---|
Characteristics and Organs involved | Skin: maculopapular rash Liver: elevated bilirubin GIT: anorexia with weight loss, nausea, vomiting, diarrhea, severe pain, GI bleeding and/or ileus | Skin, nails, scalp and body hair Mouth Eyes Esophagus Lungs Muscles, joints and fascia Genitalia | Simultaneous presence of acute and chronic GVHD manifestations | Atypical signs and symptoms of alloreactivity outside NIH diagnostic criteria |
Risk Factor | aGVHD | cGVHD | References |
---|---|---|---|
Stem cell source (PBSC) | Debated Yes | Yes | [10,11,12] [13] |
Donor characteristics: Female-to-male graft Older donor Mismatched and unrelated donors | Yes Yes Yes | Yes Yes Not significant | [10,11,14,15,16] |
Patient age | Not significant | >12 years | [17] |
DLI | Yes | // | [11,15] |
Severe infections during the peri-transplant period | Yes | Yes | [10,11,18] |
Conditioning (Myeloablative regimen TBI/irradiation-based regimen) | Yes | Yes | [11,15,16,17,18,19] |
Strategy/Transplant Setting | Agent/Mechanism | Results | References |
---|---|---|---|
Donor selection/MUD | Matching based on high-definition HLA-typing | Mismatches at HLA-DQB1, HDRB3/4/5 increases the risk of aGVHD HLA-B dimorphisms associated with higher GVHD Non-permissive HLA-DPB1 mismatch increases NRM | [48,49,50] |
Inactivate alloreactive T-cells MRD/MUD | CNI; MMF Inhibition of TCR Inhibition of alloreactive T-cell proliferation | CyA/MTX: aGVHD II–IV: 44–76%; cGVHD 56% Tac/MTX: aGVHD II–IV: 56% (III–IV 18%); cGVHD 2y 76% Tac/MTX: aGVHD II–IV 31.9% (III–IV 13%); cGVHD 56% Tac/MTX: aGVHD II–IV 74% (III–IV 4%); cGVHD 1y 45% Tac/MMF: aGVHD II–IV 79% (III–IV 19%); cGVHD 1y 38% | [32,53,54] [53] [54] [55] |
In vivo T-cell depletion and modulation after HSCT Haploidentical_NMA/MAC Haploidentical_PTCy/Tac/MMF vs. Tac/MTX (RIC/NMA) Haploidentical vs. MUD vs. MRD Haploidentical vs. MUD (RIC/MAC) Haploidentical_BM vs. PBSC (RIC/MAC) Haploidentical_BM vs. PBSC (NMA) Haploidentical MAC vs. RIC_BM vs. PB vs. BM | PTCy Elimination/inhibition of alloreactive T cells; peripheral tolerance; central deletion of alloreactive T cells in the thymus | PTCy with bone marrow source aGVHD II–IV: 34% (III–IV: 6%); cGVHD extensive: 5 *–25% ** (NMA) aGVHD II–IV 17% (III–IV 5%); cGVHD moderate/severe: 15% (MAC) aGVHD II–IV 37.6% (III–IV 10.1%); cGVHD severe 2y: 27% (MAC) PTCy with peripheral blood stem cells source aGVHD II–IV: 53.8% (III–IV: 6.3%); cGVHD 1y: 21.9% vs. aGVHD II–IV: 51.9% (III–IV: 14.7%); cGVHD 1y: 35.1% PTCy with bone marrow or blood stem cells source aGVHD II–IV: 41% (III–IV: 17%); cGVHD mod/sev 2y: 31% vs. aGVHD II–IV: 48% (III–IV: 18%); cGVHD mod/sev 2y: 47% vs. aGVHD II–IV: 28% (III–IV: 9%); cGVHD mod/sev 2y: 44% aGVHD II–IV: 29–33% (III–IV: 9–10%); cGVHD 2y: 27–33% vs. aGVHD II–IV: 29–32% (III–IV: 4%); cGVHD 2y: 29–25% aGVHD II–IV: 27.9% (III–IV: 7.7%); cGVHD extensive 2y: 14% vs. aGVHD II–IV: 38.3% (III–IV: 15.9%); cGVHD extensive 2y: 14% aGVHD II–IV: 33% (III–IV: 0%); cGVHD 1y: 21; 2y: 23% vs. aGVHD II–IV: 40% (III–IV: 5%); cGVHD 1y: 14; 2y: 19% HR aGVHD II–IV 1.01 (III–IV: 1.38); cGVHD: 1.05; extensive 1.11 HR aGVHD II–IV 1.67 (III–IV: 1.82); cGVHD: 1.46; extensive 1.44 | [76] [79] [26] [80] [54] [52] [57] [51] [26] |
Immunomediated in vivo T-cell depletion MRD/MUD MUD_RIC | ATG: polyclonal heterologous antibodies Targets: CD2,CD3,CD4, CD8, CD11a, CD107a, CD28 Alemtuzumab (humanized anti-CD-3 monoclonal antibody) | aGVHD II–IV 18% (range 7–34%) cGVHD 28% (range 16–28%)
Alemtuzumab/CyA vs. TMS: severe cGVHD 1y 0% vs 10.3%, 5y 4.5% vs. 28.5% | [32] [67] [68] [69] [70] [71] [75] |
Blocking alloreactivity and augmenting TReg MRD/MAC_Tac/Sir vs. Tac/MTX MRD/MUD_RIC TMS vs. CyA/MMF MUD_NMA Sir/CyA/MMF vs. CyA/MMF | Sirolimus mTOR inhibition | Tac/Sir: GVHD II–IV 26%; cGVHD: 53% vs. Tac/MTX: GVHD II–IV 34%; cGVHD: 45% TMS aGVHD II–IV: 9% (III–IV: 3%); cGVHD 2y 59% CyA/MMF aGVHD II–IV: 25% (III–IV: 4%) cGVHD 2y 63% Sir/CyA/MMF aGVHD II–IV: 26% (III–IV: 2%); cGVHD 1y: 49% vs. CyA/MMF aGVHD II–IV: 52%; (III–IV: 8%); cGVHD 1y: 50% | [58] [59] [60] |
Ex-vivo alloreactive T-Cell Depletion Haploidentical | selection of CD34+ cells Immune depletion of alpha/beta T cells | aGVHD III–IV 3%; cGVHD 0% aGVHD II–IV: 18% (range 11–28%); cGVHD: 8% aGVHD I–II: 26%; III–IV: 6%; cGVHD: 6% | [81] [85] [86] |
Ex-vivo alloreactive T-Cell Depletion Pediatric patients | selection of CD34+ cells CD34+ Megadose (19–21 × 106/kg) + higher T cell dose (1.4–4.7 × 104/kg) | aGVHD 0%; cGVHD 0% aGVHD II–IV: 17%; cGVHD: 35% | [82] [83] |
Selective depletion of alloreactive T cells Matched related (adults) Haploidentical (pediatrics) Developmental | Depletion of CD45RA naïve T cells, preserving the CD34+ and CD45RO fractions (better activity vs. infections and GVL) | aGVHD II–IV 66%; cGVHD 7–9% aGVHD II–IV 18%; cGVHD 35% | [84] |
↓ T-Cell Co-stimulatory/ Co-inhibitory signal MUD_ CNI/MTX + ABA vs. CNI/MTX + placebo Mismatched CNI/MTX + ABA vs. control IBMTR | Abatacept (CD28/CTLA-4 inhibitor) blockade of costimulatory T cell signaling and inhibition of T cell activation | aGVHD II–IV: 43.1% (III–IV: 6.8%); cGVHD moderate–severe 1y: 44.8% vs. aGVHD II–IV: 62.1% (III–IV: 14.8%) cGVHD moderate–severe 1y: 36% aGVHD II–IV: 41.9% (III–IV: 2.3%); cGVHD moderate–severe: 57.9% vs. aGVHD II–IV: 53.2% (III–IV: 30.2%) | [89] |
Blocking T-Cell trafficking (anti-homing compounds) MUD or Mismatched | Vedolizumab α4β7integrins inhibitor: mediates migration of T-cells to intestinal mucosa | aGVHD II–IV: 19% (III–IV: 5%) Lower GI aGvHD: 7.1% vs. 18.8% in the placebo group | [35] [95] |
Blocking T-Cell trafficking MRD/MUD RIC | Maraviroc CCR5 inhibitor blocks alloreactive lymphocyte chemotaxis to intestinal mucosa | 3 prophylaxis regimens compared in 273 randomized patients 1-TAC + MMF + PTCy; 2-TAC + MTX + BOR; 3-TAC + MTX + Maraviroc No sign of reduction of both acute and cGVHD with Maraviroc | [93] |
Modulation of microbiota Developmental | Microbiota Transplantation induces modifications of alloreactivity against intestinal mucosa antigens | aGVHD III/IV: 0% vs. 25% in the control group | [96] |
Overall Glucksberg Criteria/MAGIC criteria | Original Glucksberg Criteria | Modified Glucksberg or Keystone Criteria | Minnesota Criteria | MAGIC Criteria | IBMTR Criteria | Overall IBMTR Grade |
---|---|---|---|---|---|---|
0 | no organ involvement (skin = 0; and liver = 0; and GI = 0) corresponds to the absence of aGVHD | O | ||||
I | Skin = stage 1–2, without liver/GI involvement or decrease in performance status/fever | skin = stage 1–2, without liver/GI involvement | Skin = stage 1–2, without liver/GI involvement | Skin = stage 1–2, without liver/GI involvement | Skin = stage 1–2, without liver/GI involvement | A |
II | Skin = stage 1–2 and (liver and/or GI involvement = stage 1–2) with a mild decrease in performance status | Skin = stage 3 and/or liver = 1 and/or GI = 1 | Skin = stage 3 and/or liver = stage 1 and/or GI = stage 1 | Skin = stage 3 and/or liver = stage 1 and/or GI = stage | Skin = stage 2 and/or liver = stage 1–2 and/or GI = stage 1–2 | B |
III | (skin and/or liver and/or GI = stage 2–4) with marked decrease in performance status | Liver = stage 2–3 and/or GI = 2–4 | Liver = stage 2–4 and/or GI = 2–3 | Liver = stage 2–3 and/or lower GI = 2–3, with skin stage 0–3 and/or upper GI stage 0–1 | Skin = stage 3 and/or liver = stage 3 and/or GI = stage 3 | C |
IV | (skin and/or liver and/or GI = stage 2–4) with Karnofsky < 30% | Skin = stage 4 and/or liver = stage 4 | Skin = stage 4 and/or GI = stage 4 | Skin = stage 4; and/or liver = stage 4; and/or lower GI = stage 4, with stage 0–1 upper GI | Skin = stage 4; and/or liver = stage 4; and/or GI = stage 4 | D |
Original Seattle Classification [144] | NIH 2005 [3] | NIH 2015 [4] |
---|---|---|
Limited One or both of: Localized skin involvement Hepatic dysfunction due to cGVHD Extensive One of: Generalized skin involvement Localized skin involvement and/or hepatic dysfunction due to GVHD, AND: Liver histology showing chronic aggressive hepatitis, bridging necrosis, or cirrhosis, or: Involvement of eye (Schirmer’s test with <5 mm wetting), OR: Involvement of minor salivary glands or oral mucosa demonstrated on labial biopsy, OR: Involvement of any other target organ | Mild cGVHD: only 1 or 2 organs (except the lung), with a score of 1 Moderate cGVHD:
| Mild cGVHD: 1 or 2 organs with a maximum score of 1 AND Lung score of 0 Moderate cGVHD
|
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Olivieri, A.; Mancini, G. Current Approaches for the Prevention and Treatment of Acute and Chronic GVHD. Cells 2024, 13, 1524. https://doi.org/10.3390/cells13181524
Olivieri A, Mancini G. Current Approaches for the Prevention and Treatment of Acute and Chronic GVHD. Cells. 2024; 13(18):1524. https://doi.org/10.3390/cells13181524
Chicago/Turabian StyleOlivieri, Attilio, and Giorgia Mancini. 2024. "Current Approaches for the Prevention and Treatment of Acute and Chronic GVHD" Cells 13, no. 18: 1524. https://doi.org/10.3390/cells13181524