Serious Acute or Chronic Graft-Versus-Host Disease after Hematopoietic Cell Transplantation: A Comparison of Myeloablative and Non-Myeloablative Conditioning Regimens.

Abstract We have previously described serious graft-versus-host disease (GVHD) as a highly undesirable outcome after allogeneic hematopoietic cell transplantation (HCT). Serious GVHD encompasses death, lengthy hospitalization, major disability, or recurrent major infections related to either acute or chronic GVHD. In a previous study, we found a 25% incidence of serious GVHD among 171 consecutive patients who had HCT after non-myeloablative (NMA) conditioning between January 1998 and May 2002. To put this observation into perspective, we applied the same criteria for serious GVHD in a cohort of 264 consecutive patients who had HCT after myeloablative (MA) conditioning during the same period of time and compared results with those of the previous study. The overall incidence of serious GVHD was 17% (44/264) in the MA group, compared to 25% (43/171) in the NMA group. There were no statistically significant differences in the incidence of grades III–IV GVHD, extensive chronic GVHD or nonrelapse mortality between the two groups (Table). Patients in the NMA group were older and had higher comorbidity scores than those in the MA group. In the univariate analysis, the hazard ratio (HR) of serious GVHD for the NMA group compared to the MA group was 1.71 (95% C.I., 1.1–2.6) (p = 0.01). After adjusting for patient age, patient and donor gender, donor type, HLA-mismatch, aggressive versus indolent malignancy at HCT, remission versus relapse at HCT, myeloid versus non–myeloid malignancy, HCT co–morbidity index, and prior donor lymphocyte infusion, the HR of serious GVHD was 1.50 (95% C.I., 0.8–2.7) (p = 0.17). After censoring for recurrent or progressive malignancy after HCT, the cumulative incidence of serious GVHD at 3 years was 21% for the NMA group and 14% for the MA group, and the HR was 1.33 (95% C.I., 0.7–2.6) (p = 0.40). Reasons for categorization of GVHD as serious (i.e., death, lengthy hospitalization, major disability, or recurrent major infections) were similar between the MA and NMA cohorts. Among the 44 patients with serious GVHD in the MA group, 19 (43%) had serious acute GVHD, and 25 (57%) had serious chronic GVHD. Among the 43 patients with serious GVHD in the NMA group, 20 (46%) had serious acute GVHD, and 30 (70%) had serious chronic GVHD. Among the 264 MA patients, 28 (11%) had grade III–IV acute GVHD and 147 (56%) had extensive chronic GVHD that did not meet the criteria for serious GVHD, compared to 7 (4%) and 84 (49%) of the 171 NMA patients, respectively. We conclude that the type of pretransplant conditioning regimen does not have a large effect on the incidence of serious GVHD after HCT. Assessment of serious GVHD provides additional useful information to acute GVHD grades and the classification of limited and extensive chronic GVHD in describing overall GVHD-related outcomes after HCT. MA NMA Outcome, n (%) n = 264 n = 171 Serious GVHD 44 (17) 43 (25) Grades III–IV acute GVHD 54 (20) 27 (16) Extensive chronic GVHD 174 (66) 114 (68) 2-year nonrelapse mortality 66 (25) 43 (25)

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Prognostic Relevance of “Early-Onset” Graft-Versus-Host Disease Following Nonmyeloablative Hematopoietic Cell Transplantation.

Blood ◽

10.1182/blood.v104.11.423.423 ◽

2004 ◽

Vol 104 (11) ◽

pp. 423-423

Author(s):

Marco Mielcarek ◽

Lauri Burroughs ◽

Wendy Leisenring ◽

Paul Martin ◽

Razvan Diaconezcu ◽

...

Keyword(s):

Confidence Interval ◽

Cell Transplantation ◽

Graft Versus Host Disease ◽

Early Onset ◽

Hematopoietic Cell Transplantation ◽

Chronic Gvhd ◽

Hematopoietic Cell ◽

Host Disease ◽

Graft Versus Host ◽

Unrelated Donors

Abstract We have shown that graft-versus-host disease (GVHD) after nonmyeloablative hematopoietic cell transplantation (HCT) occurs a median of 2 months later than after myeloablative HCT (Blood 102:756, 2003). Here, we asked whether there was an association between the time of onset of GVHD and survival after nonablative HCT. We retrospectively analyzed outcomes among 395 patients with hematologic diseases who had nonmyeloablative HCT from HLA-matched related (n=297) or unrelated donors (n=98). The nonablative regimen consisted of 2 Gy total body irradiation with or without fludarabine followed by postgrafting immunosuppression with mycophenolate mofetil and cyclosporine. The cumulative incidences of grades II-IV acute GVHD and extensive chronic GVHD were 45% and 47%, respectively, with grafts from related donors, and 68% and 68%, respectively, with those from unrelated donors. The median time to prednisone initiation, a marker for the onset of both acute and chronic GVHD, was 79 (range, 8–799) days among patients with sibling donors and 28 (range, 5–104) days among patients with unrelated donors. Among patients with GVHD following related grafts (n=187), the cumulative incidence of non-relapse mortality (NRM) at 4 years was 55% among the tertile of patients who initiated prednisone before day 50 (“early initiation”), and 29% when prednisone was initiated on or after day 50 (“late initiation”; p<0.001). After controlling for patient age, diagnosis, type of preparative regimen, number of previous chemotherapies and donor/recipient gender combinations in multivariate analysis, early initiation of prednisone was identified as an independent predictor of increased NRM (Table). The presence of comorbidid conditions at the time of transplant (Charlson Comorbidity Index >=1) was neither predictive for the time of onset nor the overall incidence of GVHD. Among patients who initiated prednisone for the treatment of GVHD, those with pretransplant comorbidities had a significantly greater hazard of NRM than those without comorbidities (hazard ratio, 2.6; 95% confidence interval, 1.2–5.4; p=0.01). There was no association between time to prednisone initiation and survival after nonmyeloablative HCT from unrelated donors. In conclusion, early-onset GVHD (prednisone initiation before day 50) was associated with increased NRM and poor survival after nonmyeloablative HCT from HLA-identical related donors and identified a subgroup of patients who might benefit from more aggressive primary therapy of GVHD. Hazard of Non-Relapse Mortality According to Time to Prednisone Initiation (HLA-Matched Related Transplants) Prednisone Initiation for Treatment of GVHD [Day] Hazard Ratio† 95% Confidence Interval P* P** †Cox proportional hazards model treating “early vs. late prednisone initiation” as a time-dependent covariate; *compared to “not initiated”; **comparison of prednisone initiation <day 50 vs.≥day 50 Not initiated 1.0 --- --- --- <50 11.4 5.3–24.4 <0.001 --- ≥50 6.3 2.8–14.5 <0.001 0.04

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Association of IL-10 and IL-10 Receptor Gene Polymorphisms and Graft-Versus-Host Disease Following Hematopoietic Cell Transplantation.

Blood ◽

10.1182/blood.v104.11.421.421 ◽

2004 ◽

Vol 104 (11) ◽

pp. 421-421 ◽

Cited By ~ 1

Author(s):

Li-Hui Tseng ◽

Ming-Tseh Lin ◽

Barry Storer ◽

Paul J. Martin ◽

Bryan Grogan ◽

...

Keyword(s):

Cell Transplantation ◽

Graft Versus Host Disease ◽

Lower Risk ◽

Acute Gvhd ◽

Hematopoietic Cell Transplantation ◽

Multivariable Analysis ◽

Hematopoietic Cell ◽

P Value ◽

Host Disease ◽

Graft Versus Host

Abstract Polymorphisms in cytokine genes can influence immune responses and may affect the outcome of hematopoietic cell transplantation (HCT). We have shown that the IL-10/-592*A allele of the recipient is a marker for less severe acute graft-versus-host disease (GVHD) and a lower risk of non-relapse mortality (NRM) after HCT from an HLA-identical sibling (N Engl J Med, 2003). To further test the hypothesis that IL-10 pathway is important in the intensity of acute GVHD, we undertook a study of variation in the IL-10 receptor β gene. A single nucleotide polymorphism (A/G) at cDNA position 238 of the IL-10 receptor β gene (IL-10RB/1304) was genotyped in 953 HCT recipients and their HLA-identical sibling donors. IL-10/-592 and IL-10RB alleles and genotypes were tested for association with GVHD by multivariable analysis. The IL-10/-592*A allele of the recipient and IL-10RB/238*G allele of the donor were significantly associated with a lower risk of acute grades III-IV GVHD (trend p value 0.0008 and 0.02, respectively). None of the 16 cases with a patient IL-10 A/A genotype and donor IL-10RB G/G genotype developed grades III-IV acute GVHD (HR = 0.0 and p value = 0.007), compared to pairs with a patient IL-10 C/C genotype and donor IL-10RB A/A genotype. The hazard ratios were 0.4–0.6 among pairs with a patient IL-10 A/A genotype and donor IL-10RB A/G or A/A genotype and among pairs with a patient IL-10 A/C genotype and donor IL-10RB G/G or A/G genotype. The effect of donor IL-10RB genotype on GVHD was observed only among pairs with a patient IL-10 A/C or A/A genotype (trend p value = 0.005 and 0.06 respectively), but not among pairs with a patient IL-10 C/C genotype (trend p value = 0.82). These data suggest an interaction in the effect of the patient IL-10/-592 and donor IL-10RB/1304 genotypes on GVHD, further supporting the hypothesis that the IL-10 pathway plays an important role in controlling the severity of acute GVHD.

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Randomized Phase III BMT CTN Trial of Calcineurin Inhibitor–Free Chronic Graft-Versus-Host Disease Interventions in Myeloablative Hematopoietic Cell Transplantation for Hematologic Malignancies

Journal of Clinical Oncology ◽

10.1200/jco.21.02293 ◽

2021 ◽

Author(s):

Leo Luznik ◽

Marcelo C. Pasquini ◽

Brent Logan ◽

Robert J. Soiffer ◽

Juan Wu ◽

...

Keyword(s):

Cell Transplantation ◽

Graft Versus Host Disease ◽

Hematopoietic Cell Transplantation ◽

Chronic Gvhd ◽

Single Agent ◽

Hematopoietic Cell ◽

Phase Iii ◽

Host Disease ◽

Graft Versus Host ◽

Cd34 Selection

PURPOSE Calcineurin inhibitors (CNI) are standard components of graft-versus-host disease (GVHD) prophylaxis after hematopoietic cell transplantation (HCT). Prior data suggested that CNI-free approaches using donor T-cell depletion, either by ex vivo CD34 selection or in vivo post-transplant cyclophosphamide (PTCy) as a single agent, are associated with lower rates of chronic GVHD (cGVHD). METHODS This multicenter phase III trial randomly assigned patients with acute leukemia or myelodysplasia and an HLA-matched donor to receive CD34-selected peripheral blood stem cell, PTCy after a bone marrow (BM) graft, or tacrolimus and methotrexate after BM graft (control). The primary end point was cGVHD (moderate or severe) or relapse-free survival (CRFS). RESULTS Among 346 patients enrolled, 327 received HCT, 300 per protocol. Intent-to-treat rates of 2-year CRFS were 50.6% for CD34 selection (hazard ratio [HR] compared with control, 0.80; 95% CI, 0.56 to 1.15; P = .24), 48.1% for PTCy (HR, 0.86; 0.61 to 1.23; P = .41), and 41.0% for control. Corresponding rates of overall survival were 60.1% (HR, 1.74; 1.09 to 2.80; P = .02), 76.2% (HR, 1.02; 0.60 to 1.72; P = .95), and 76.1%. CD34 selection was associated with lower moderate to severe cGVHD (HR, 0.25; 0.12 to 0.52; P = .02) but higher transplant-related mortality (HR, 2.76; 1.26 to 6.06; P = .01). PTCy was associated with comparable cGVHD and survival outcomes to control, and a trend toward lower disease relapse (HR, 0.52; 0.28 to 0.96; P = .037). CONCLUSION CNI-free interventions as performed herein did not result in superior CRFS compared with tacrolimus and methotrexate with BM. Lower rates of moderate and severe cGVHD did not translate into improved survival.

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Genetic variation in the IL-10 pathway modulates severity of acute graft-versus-host disease following hematopoietic cell transplantation: synergism between IL-10 genotype of patient and IL-10 receptor β genotype of donor

Blood ◽

10.1182/blood-2004-11-4338 ◽

2005 ◽

Vol 106 (12) ◽

pp. 3995-4001 ◽

Cited By ~ 60

Author(s):

Ming-Tseh Lin ◽

Barry Storer ◽

Paul J. Martin ◽

Li-Hui Tseng ◽

Bryan Grogan ◽

...

Keyword(s):

Cell Transplantation ◽

Graft Versus Host Disease ◽

Lower Risk ◽

Acute Gvhd ◽

Hematopoietic Cell Transplantation ◽

Multivariable Analysis ◽

Hematopoietic Cell ◽

Host Disease ◽

Graft Versus Host ◽

Acute Graft

We have previously shown that the interleukin 10 (IL-10)/-592*A allele of the recipient is associated with less severe acute graft-versus-host disease (GVHD) and a lower risk of nonrelapse mortality after hematopoietic cell transplantation (HCT) from an HLA-identical sibling. In the present study, we examined variation in the IL-10 receptor β gene as a further test of the hypothesis that the IL-10 pathway regulates the risk of acute GVHD. A single nucleotide polymorphism (A/G) at cDNA position 238 of the IL-10 receptor β gene (IL10RB/c238) was genotyped in 953 HC transplant recipients and their HLA-identical sibling donors. IL-10/-592 and IL10RB/c238 genotypes were tested for association with GVHD by multivariable analysis. The IL-10/-592*A allele of the recipient and IL10RB/c238*G allele of the donor were significantly associated with a lower risk of grades III-IV acute GVHD (trend P < .001 and P = .02, respectively). The donor IL10RB/c238*G allele provided protection among patients with the IL-10/-592 A/C or A/A genotypes but not among patients with the high-risk IL-10/-592 C/C genotype. These data suggest an interaction of the patient IL-10/-592 and donor IL10RB/c238 genotypes on risk of GVHD, further supporting the hypothesis that the IL-10 pathway plays an important role in controlling the severity of acute GVHD.

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Blockade of TIM-1 on the donor graft ameliorates graft-versus-host disease following hematopoietic cell transplantation

Blood Advances ◽

10.1182/bloodadvances.2019000286 ◽

2019 ◽

Vol 3 (21) ◽

pp. 3419-3431

Author(s):

Bettina P. Iliopoulou ◽

Katie Hsu ◽

Magdiel Pérez-Cruz ◽

Sai-Wen Tang ◽

Wendy W. Pang ◽

...

Keyword(s):

T Cells ◽

Cell Transplantation ◽

Graft Versus Host Disease ◽

Acute Gvhd ◽

Hematopoietic Cell Transplantation ◽

Hematopoietic Cell ◽

Host Disease ◽

Graft Versus Host ◽

Key Points ◽

Donor Graft

Key Points Administration of anti–TIM-1 blocking mAb ameliorates acute GVHD while preserving graft-versus-tumor effects. Treatment with anti–TIM-1 blocking mAb does not affect proliferation of donor allogeneic T cells.

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Graft-Versus-Host Disease and Graft-Versus-Tumor Effects After Allogeneic Hematopoietic Cell Transplantation

Journal of Clinical Oncology ◽

10.1200/jco.2012.45.0247 ◽

2013 ◽

Vol 31 (12) ◽

pp. 1530-1538 ◽

Cited By ~ 140

Author(s):

Rainer Storb ◽

Boglarka Gyurkocza ◽

Barry E. Storer ◽

Mohamed L. Sorror ◽

Karl Blume ◽

...

Keyword(s):

Cell Transplantation ◽

Graft Versus Host Disease ◽

Hematopoietic Cell Transplantation ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Hematopoietic Cell ◽

Allogeneic Hematopoietic Cell Transplantation ◽

High Dose ◽

Host Disease ◽

Graft Versus Host

Purpose We designed a minimal-intensity conditioning regimen for allogeneic hematopoietic cell transplantation (HCT) in patients with advanced hematologic malignancies unable to tolerate high-intensity regimens because of age, serious comorbidities, or previous high-dose HCT. The regimen allows the purest assessment of graft-versus-tumor (GVT) effects apart from conditioning and graft-versus-host disease (GVHD) not augmented by regimen-related toxicities. Patients and Methods Patients received low-dose total-body irradiation ± fludarabine before HCT from HLA-matched related (n = 611) or unrelated (n = 481) donors, followed by mycophenolate mofetil and a calcineurin inhibitor to aid engraftment and control GVHD. Median patient age was 56 years (range, 7 to 75 years). Forty-five percent of patients had comorbidity scores of ≥ 3. Median follow-up time was 5 years (range, 0.6 to 12.7 years). Results Depending on disease risk, comorbidities, and GVHD, lasting remissions were seen in 45% to 75% of patients, and 5-year survival ranged from 25% to 60%. At 5 years, the nonrelapse mortality (NRM) rate was 24%, and the relapse mortality rate was 34.5%. Most NRM was a result of GVHD. The most significant factors associated with GVHD-associated NRM were serious comorbidities and grafts from unrelated donors. Most relapses occurred early while the immune system was compromised. GVT effects were comparable after unrelated and related grafts. Chronic GVHD, but not acute GVHD, further increased GVT effects. The potential benefit associated with chronic GVHD was outweighed by increased NRM. Conclusion Allogeneic HCT relying on GVT effects is feasible and results in cures of an appreciable number of malignancies. Improved results could come from methods that control progression of malignancy early after HCT and effectively prevent GVHD.

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