Donor T-cell chimerism and early post-transplant cytomegalovirus viremia in patients treated with myeloablative allogeneic hematopoietic stem cell transplant.

BACKGROUND: Cytomegalovirus (CMV) is a common infection after myeloablative allogeneic hematopoietic stem cell transplant (M-alloHSCT). Achievement of complete donor T-cell chimerism (CDC-T) post transplant is a measure of immune reconstitution. We investigated the association between CDC-T post M-alloHSCT and the incidence of CMV viremia. METHODS: We retrospectively reviewed all CMV and chimerism results of 47 patients for the first 6 months post M-alloHSCT. CDC-T was analyzed as a time-varying covariate for association with post M-alloHSCT CMV viremia. RESULTS: CMV viremia occurred in 15 (32%) and CDC-T was achieved in 38 (81%) recipients within the first 6 months post M-alloHSCT. On univariable analysis, increased CMV viremia was seen among patients with CDC-T (hazard ratio 2.81 [P = 0.07, 95% confidence interval = 0.93-8.52]). A 30-day landmark analysis showed that the incidence of CMV viremia at 6 months (regardless of recipient CMV serostatus) was 50% among those who had achieved CDC-T by day 30, and 23% among those who had not (P = 0.06). CONCLUSION: We conclude that shorter time to CDC-T may be associated with higher risk of CMV viremia. If confirmed in a larger cohort, this might be a marker for risk stratification in the management of CMV in this population.

Double-negative regulatory T cells induce allotolerance when expanded after allogeneic haematopoietic stem cell transplantation.

Double-negative (DN) regulatory T cells (Tregs) are specialized T lymphocytes involved in the down-modulation of immune responses, resulting in allotolerance after allogeneic haematopoietic stem cell transplantation (HSCT). Most of the properties of DN Tregs were identified in murine models, including the unique ability to suppress alloreactive syngeneic effector T cells in an antigen-specific manner via Fas/Fas-ligand interactions. We investigated the behaviour of DN Tregs following human allogeneic HSCT with regard to occurrence of graft-versus-host disease (GvHD) and restoration of T-cell receptor repertoire in a cohort of 40 patients. The frequency of DN Tregs and CD4/CD8 TCR repertoire was measured serially and at the time of diagnosis of GvHD by flow cytometry. Analysis demonstrated a positive correlation between degree of alloreactivity, as measured by grade of GvHD, and the number of variable beta chain (Vbeta) family expansions in both T-cell populations. We also found that a deficiency of DN Tregs was associated with an increased number of Vbeta family expansions, and most importantly, with the occurrence of GvHD. All individuals who demonstrated more than 1% DN Tregs did not develop GvHD, providing evidence that DN Tregs participate in peripheral tolerance to prevent GvHD when expanded after allogeneic HSCT.

Influence of killer immunoglobulin-like receptor/HLA ligand matching on achievement of T-cell complete donor chimerism in related donor nonmyeloablative allogeneic hematopoietic stem cell transplantation.

Achievement of complete donor chimerism (CDC) after allogeneic nonmyeloablative hematopoietic stem cell transplantation (NMHSCT) is important for preventing graft rejection and for generating a graft-vs-malignancy effect. The alloreactivity of NK cells and some T-cell subsets is mediated through the interaction of their killer immunoglobulin-like receptors (KIRs) with target cell HLA/KIR ligands. The influence of KIR matching on the achievement of T-cell CDC after NMHSCT has not been previously described. We analyzed 31 patients undergoing T-cell replete related donor NMHSCT following fludarabine and 200 cGy TBI. Recipient inhibitory KIR genotype and donor HLA/KIR ligand matches were used to generate an inhibitory KIR score from 1 to 4 based upon the potential number of recipient inhibitory KIRs that could be engaged with donor HLA/KIR ligands. Patients with a score of 1 were less likely to achieve T-cell CDC (P=0.016) and more likely to develop graft rejection (P=0.011) than those with scores greater than 1. Thus, patients with lower inhibitory KIR scores may have more active anti-donor immune effector cells that may reduce donor chimerism. Conversely, patients with greater inhibitory KIR scores may have less active NK cell and T-cell populations, which may make them more likely to achieve CDC.

Elevated lactate dehydrogenase is an adverse predictor of outcome in HLA-matched sibling bone marrow transplant for acute myelogenous leukemia.

Prognostic factors for survival following allogeneic BMT for AML include age, disease status and cytogenetic risk classification. Lactate dehydrogenase (LDH) levels have not been studied as a potential risk factor. We reviewed our experience with BMT for AML and included LDH at the time of admission in an analysis of prognostic factors for survival. We found that LDH >330 U/l (1.5 times the upper limit of normal at our institution), older age, active disease, peripheral stem cell graft and male-to-male transplant were significant adverse predictors of survival. After accounting for LDH, other factors such as disease status and cytogenetics were not significantly associated with the outcome of BMT. All but one patient with an LDH >330 U/l had active disease. However, when patients in CR were excluded, LDH >330 U/l remained a significant adverse predictor of overall survival (hazard ratio 2.70, 95% confidence interval 1.41-5.16, P=0.003). We conclude that LDH is an important adverse risk factor for survival and should be included in future studies of risk performed on larger patient cohorts.

Survival of AML patients receiving HLA-matched sibling donor allogeneic bone marrow transplantation correlates with HLA-Cw ligand groups for killer immunoglobulin-like receptors.

The reactivity of natural killer cells and some T-cell populations is regulated by killer immunoglobulin-like receptors (KIR) interactions with target cell HLA class I molecules. Such interactions have been suggested to influence outcomes after allogeneic hematopoietic stem cell transplantation, particularly for myeloid malignancies and with T-cell depletion. Donor KIR genotypes and recipient HLA KIR ligands were analyzed in 60 AML patients receiving T-cell replete, HLA-matched-related donor allogeneic bone marrow transplants. Patients were categorized according to their HLA inhibitory KIR ligand groups by determining whether or not they expressed: HLA-A3 or -A11; HLA-Bw4 and HLA-Cw groups (homozygous C1, homozygous C2 or heterozygous C1/C2). Heterozygous C1/C2 patients had significantly worse survival than those homozygous for C1 or C2 (5.8 vs 43.5 months, respectively, P=0.018) and the C1/C2 group had a higher relapse rate (47 vs 31%, respectively, P=0.048). Multivariate analysis found C1/C2 status to be an independent predictor for mortality (P=0.007, HR 2.54, confidence interval 1.29-5.00). C1/C2 heterozygosity was also associated with a delayed time to platelet engraftment, particularly for those with concurrent HLA-Bw4 expression (P=0.003). Since C1/C2 heterozygotes have a greater opportunity to engage inhibitory KIRs than do C1 or C2 homozygotes, they may more effectively inhibit KIR-positive NK- and T-cell populations involved in graft vs leukemia responses.

Patients mobilizing large numbers of CD34+ cells ('super mobilizers') have improved survival in autologous stem cell transplantation for lymphoid malignancies.

The cellular composition of an autologous graft may influence autologous stem cell transplantation (ASCT) outcome. Etoposide (VP) plus filgrastim (G) frequently mobilizes high numbers of CD34+ cells for autologous transplantation. We investigated whether patients collecting high numbers of CD34+ cells ('super mobilizers') have a better outcome than other patients. We reviewed 350 consecutive adult patients with NHL or Hodgkin's lymphoma receiving an ASCT from January 1994 to December 2005, mobilized with VP+G. Super mobilizers were defined as collecting a minimum of 8 x 10(6) CD34+ cells/kg. Two hundred and three patients were super mobilizers, while 147 collected between 2.0 and 7.95 CD34+ cells/kg. Super mobilizers were younger and more likely to have received two or fewer prior chemotherapy regimens (80 versus 63%, P<0.001). Median CD34+ cell dose for the super mobilizing group was 13.7 x 10(6) versus 4.4 x 10(6)/kg in the standard collecting group. The super mobilizer group had a superior overall survival (P=0.006). In multivariable analysis, favorable disease status and younger age at transplant, and super mobilization were associated with improved survival. We conclude that patients had an improved ASCT outcome if large numbers of CD34+ cells were mobilized and infused. The explanation for this observation is unknown.

Autologous hematopoietic stem cell transplantation in peripheral T-cell lymphoma using a uniform high-dose regimen.

The role of high-dose therapy and autologous stem cell transplantation (ASCT) for patients with peripheral T-cell lymphoma (PTCL) is poorly defined. Comparisons of outcomes between PTCL and B-cell non-Hodgkin's lymphoma (NHL) have yielded conflicting results, in part due to the rarity and heterogeneity of PTCL. Some retrospective studies have found comparable survival rates for patients with T- and B-cell NHL. In this study, we report our single-center experience of ASCT over one decade using a uniform chemotherapy-only high-dose regimen. Thirty-two patients with PTCL-unspecified (PTCL-u; 11 patients) and anaplastic large-cell lymphoma (21 patients) underwent autologous stem cell transplant, mostly for relapsed or refractory disease. The preparative regimen consisted of busulfan, etoposide and cyclophosphamide. Kaplan-Meier 5-year overall survival (OS) and relapse-free survival (RFS) are 34 and 18%, respectively. These results suggest a poor outcome for patients with PTCL after ASCT, and new therapies for T-cell lymphoma are needed.

Effect of prior rituximab on high-dose therapy and autologous stem cell transplantation in follicular lymphoma.

Autologous stem-cell transplantation (ASCT) has been used in follicular lymphoma (FL) to achieve durable responses in first remission or in the relapsed or refractory settings. Addition of rituximab to chemotherapy for FL has been shown to improve survival. The impact of prior therapy with rituximab upon the effectiveness of high-dose therapy (HDT) and ASCT in patients with FL is unknown. We retrospectively reviewed consecutive patients with FL who underwent HDT and ASCT. Patients were categorized according to prior therapy with rituximab. Outcomes were compared between groups in all patients and in a well-matched subset. In all 35 patients received prior rituximab and 71 rituximab-naive patients were analyzed. The rituximab-naive group had a median overall survival (OS) that was not reached during follow-up, with a median relapse-free (RFS) survival of 49.9 months. The prior rituximab group also did not reach median OS and had a median RFS of 24.6 months. Survivals were not significantly different in this group or in the well-matched subset. In conclusion, these results suggest that the use of rituximab-based regimens for the treatment of FL does not compromise the effectiveness of HDT and ASCT as a salvage strategy in patients with FL.

Association of socioeconomic status with autologous hematopoietic cell transplantation outcomes for lymphoma.

Socioeconomic status (SES) is an important determinant of disparities in health care. The association of SES with outcomes in autologous hematopoietic cell transplantation (AHCT) has not been described previously. We conducted a retrospective cohort study of 687 AHCT recipients with lymphoma transplanted between 2003 and 2013. Patients were categorized into low (<$50 000/year) and high SES (⩾$50 000/year). A greater proportion of low SES patients lived farther away from our center (median 54 vs 28 miles), belonged to a racial minority (12 vs 3%), had poorer performance status (4 vs 1%) and had high-risk disease at AHCT (9 vs 5%). Median follow-up was 53 months. In univariable analysis, low SES patients had significantly higher relapse mortality and lower OS and PFS. This was confirmed on multivariable analysis for relapse mortality (HR for high vs low SES: 0.74 (95% confidence interval (CI), 0.54-0.99), P=0.05), OS (HR 0.74 (0.58-0.95), P=0.02) and PFS (HR 0.77 (0.63-0.95), P=0.02). In multivariable analysis of ⩾1-year progression-free survivors, high SES patients had better OS (HR 0.73, P=0.05 vs low SES) that was primarily driven by a trend toward lower risk of non-relapse mortality (HR 0.62, P=0.06). SES is associated with outcomes of AHCT in patients with lymphoma.

Imidazole antifungals Miconazole and Econazole induce apoptosis in mouse lymphoma and human T cell leukemia cells: regulation by Bcl-2 and potential role of calcium.

We have recently reported that thapsigargin (TG), a specific endoplasmic reticulum (ER)-associated Ca(2+)-ATPase inhibitor, induces apoptosis in mouse lymphoma cells. In view of recent evidence that the imidazole antifungals econazole (EC) and miconazole (MC) inhibit TG-sensitive Ca(2+)-ATPase activity in normal rat thymocytes, we investigated the effect of these agents on intracellular Ca(2+) homeostasis and cell survival in WEHI7.2 mouse lymphoma cells and human CEMT-cell leukemia cells. In this report, we demonstrate that MC treatment releases Ca(2+) from the TG-sensitive ER pool of WEHI7.2 cells. MC induced apoptosis, based on morphological and biochemical criteria, and on inhibition by the Bcl-2 oncogene. Moreover, intracellular Ca(2+) changes induced by MC treatment were inhibited by overexpression of Bcl-2. In addition to inducing cell death in WEHI7.2 cells, MC induced apoptosis in the glucocorticoid sensitive and resistant human T-cell leukemia lines, CEM-C7 and CEM-C1 respectively, in normal thymocytes and in normal lymphocytes. Based on their apoptosis-inducing activity, imidazole derivatives should be explored as potential immunosuppressive and/or chemotherapeutic agents.

Early vancomycin-resistant enterococcus (VRE) bacteremia after allogeneic bone marrow transplantation is associated with a rapidly deteriorating clinical course.

Vancomycin-resistant enterococcal (VRE) infection is a growing threat. We studied the incidence, risk factors, and clinical course of early-onset VRE bacteremia in allogeneic hematopoietic stem cell transplant recipients. We carried out a chart review of 281 allogeneic hematopoietic stem cell transplant recipients from 1997-2003, including preparative regimen, diagnosis, status of disease, graft-versus-host disease prophylaxis, antimicrobial therapy, and survival. VRE bacteremia developed in 12/281 (4.3%) recipients; 10 (3.6%) were within 21 days of transplant. Diagnoses were acute leukemia (7), NHL (2), and MDS (1). In all, 70% had refractory/relapsed disease; 30% were in remission. In total, 50% had circulating blasts. Nine of 10 had matched unrelated donors (7/9 with CD8+ T-cell depletion). The average time to positive VRE cultures was 15 days; average WBC was 0.05, and 80% had concomitant infections. Despite treatment, all patients died within 73 days of VRE bacteremia. Intra-abdominal complications were common. Causes of death included bacterial or fungal infection, multiorgan failure, VOD, ARDS, and relapse. A total of 60% of patients engrafted neutrophils, but none engrafted platelets. Early VRE bacteremia after allogeneic bone marrow transplant is associated with a rapidly deteriorating clinical course, although not always directly due to VRE. Early VRE may be a marker for the critical condition of these high-risk patients at the time of transplant.

Steroids prevent engraftment syndrome after autologous hematopoietic stem cell transplantation without increasing the risk of infection.

Engraftment syndrome (ES) following autologous hematopoietic stem cell transplantation (AHSCT) is characterized by fever and rash. In January 2002, we instituted steroid prophylaxis for ES from day +4 to +14. This study was conducted to assess whether this practice increased the risk of infection. In total, 194 consecutive patients were reviewed, 111 did not receive steroid prophylaxis (group A), and 83 did (group B). Initial antimicrobial prophylaxis was the same in both groups. There were no significant differences between groups in age, gender, race, prior radiation therapy, number of prior chemotherapy regimens, disease status at transplant, mobilization regimen, days of leukopheresis, CD34(+) cell dose, and days to platelet and neutrophil engraftment. Group B had significantly fewer patients with non-Hodgkin's lymphoma and multiple myeloma, shorter median duration from diagnosis to transplant, lower risk of ES, and shorter mean length of hospital stay. The incidence of early and late microbiologically confirmed infections was not significantly different between groups. Types of infections and types of organisms identified were similar in both groups. Hospital readmission rates were similar in both groups. Steroid prophylaxis significantly decreases the risk of ES following AHSCT, and is associated with shortened hospitalization, without increasing risk of infection.

CD8+ T-cell-depleted, matched unrelated donor, allogeneic bone marrow transplantation for advanced AML using busulfan-based preparative regimens.

The role of T-cell depletion (TCD) to prevent graft-versus-host disease (GVHD) after matched unrelated donor allogeneic bone marrow transplant (MUD BMT) remains undefined. Most studies employ total body irradiation and pan TCD. Between March 1993 and June 2002, we treated 33 relapsed acute myelogenous leukemia (AML) patients with busulfan-based preparative regimens and selective TCD. The preparative regimen consisted of busulfan 14 mg/kg, cyclophosphamide 120 mg/kg and VP-16 50 mg/kg in all but one patient who only received busulfan and cyclophosphamide. Donor marrow was depleted of CD8+ T cells by immunomagnetic bead separation. The patients were also treated with cyclosporine and methylprednisolone or FK-506 and mini-dose methotrexate. Four (15%) of 33 patients developed graft failure or rejection. However, three of these patients were serologically mismatched at HLA-Cw. Although 67% of evaluable patients developed acute GVHD, severe grade III-IV acute GVHD only developed in 19%. The severity of acute GVHD correlated with the degree of CD8+ TCD. Median relapse-free survival was 5 months among 20 patients treated with active AML, and 28 months among 13 patients treated in complete remission. Our results confirm that MUD BMT with CD8+ TCD for AML is a potentially curative treatment option.

High-dose busulfan, cyclophosphamide, and etoposide does not improve outcome of allogeneic stem cell transplantation compared to BuCy2 in patients with acute myeloid leukemia.

SUMMARY: To reduce relapse following allogeneic transplantation for AML, intensification of high-dose busulfan/cyclophosphamide using additional agents has been investigated but with few reported comparisons. We compared an intensified regimen of etoposide (60 mg/kg), busulphan (14 mg/kg), and cyclophosphamide (120 mg/kg) (BuCyVP) with BuCy2 in 237 AML patients. No significant difference in overall outcome was observed following BuCyVP (n=127) or BuCy2 (n=110). The 5-year survival was 27.3 and 30.1% following BuCyVP and BuCy2, respectively (P=0.48). Similarly, the 5-year cumulative incidence of relapse (CIR) was 28.3 and 34.8% with BuCyVP and BuCy2 (P=0.45), respectively. On multivariable analysis, patients transplanted in CR1 (P=0.002) and from related donors (P=0.013) had longer survival, while disease status at transplant was the only factor predicting CIR (P=0.002). In a separate analysis of CR1 patients (n=56), there was no significant difference in survival (P=0.37) or CIR (P=0.87) between the two regimens. However, for more advanced disease, there was a trend towards less relapse with BuCyVP (P=0.08), which was balanced by a higher cumulative incidence of transplant-related deaths (P=0.03) compared to BuCy2, resulting in similar survival. Overall, our results do not support the use of the more intensive BuCyVP regimen over BuCy2 in either early or more advanced disease AML patients.

Dendritic cells in autologous hematopoietic stem cell transplantation for diffuse large B-cell lymphoma: graft content and post transplant recovery predict survival.

Allograft dendritic cell (DC) content has been identified as a predictor of relapse and event-free survival after allogeneic bone marrow transplantation. However, the prognostic importance of DCs has not been evaluated in the setting of autologous hematopoietic stem cell transplantation (HSCT). We prospectively determined pre-transplant and post transplant DC levels, including DC1 and DC2 subset levels, in 53 patients with diffuse large B-cell non-Hodgkin's lymphoma (DLBC NHL) undergoing autologous HSCT. Pre-transplant DCs were measured in the collected stem cell products and were therefore indicative of cell numbers infused directly into patients; post transplant analysis of DCs was performed on the peripheral blood of patients 6 weeks after the infusion of autologous stem cells. Higher pre-transplant levels of DC1 cells and total DCs were significantly associated with improved survival. Similarly, greater post transplant levels of total DCs and both subsets were significantly associated with survival. These findings suggest a relationship between DC reconstitution and survival following autologous HSCT for DLBC NHL. Strategies to increase autograft DC content or accelerate DC recovery after autologous HSCT might improve outcomes in this setting.

Racial differences in allogeneic hematopoietic cell transplantation outcomes among African Americans and whites.

The impact of race on outcome has been identified in a number of cancers, with African Americans having poorer survival compared with whites. We conducted a study to investigate the association of race with allogeneic hematopoietic cell transplant (HCT) outcomes. We identified 789 patients (58 African Americans and 731 whites) who underwent allogeneic HCT for hematologic disorders. There were no significant differences between African Americans and white patients in gender, performance status or comorbidity score. However, African Americans were younger than whites (median 40 years versus 47 years, P=0.003) and were more likely to be in remission at HCT (74% versus 57%, P=0.011), to have an HLA-mismatched donor (36% versus 14%, P<0.001), to have positive donor or recipient CMV serostatus (90% versus 69%, P<0.001) and to have received a cord blood transplant (21% versus 6%, P<0.001). In univariate analysis, African Americans had worse overall survival (OS) (HR 1.41, P=0.026) compared with whites, with no significant differences in acute or chronic GvHD, non-CMV infection or relapse. However, after adjusting for several transplant and disease-related factors in multivariate analysis, the OS difference between African Americans and whites became nonsignificant (HR 1.27, P=0.18). These results suggest that race in and of itself does not lead to worse survival post HCT.

Prognostic significance of pre-transplant quality of life in allogeneic hematopoietic cell transplantation recipients.

Quality of life (QOL) is an important outcome for hematopoietic cell transplantation (HCT) recipients. Whether pre-HCT QOL adds prognostic information to patient and disease related risk factors has not been well described. We investigated the association of pre-HCT QOL with relapse, non-relapse mortality (NRM), and overall mortality after allogeneic HCT. From 2003 to 2012, the Functional Assessment of Cancer Therapy-Bone Marrow Transplant Scale instrument was administered before transplantation to 409 first allogeneic HCT recipients. We examined the association of the three outcomes with (1) individual QOL domains, (2) trial outcome index (TOI) and (3) total score. In multivariable models with individual domains, functional well-being (hazard ratio (HR) 0.95, P=0.025) and additional concerns (HR 1.39, P=0.002) were associated with reduced risk of relapse, no domain was associated with NRM, and better physical well-being was associated with reduced risk of overall mortality (HR 0.97, P=0.04). TOI was not associated with relapse or NRM but was associated with reduced risk of overall mortality (HR 0.93, P=0.05). Total score was not associated with any of the three outcomes. HCT-comorbidity index score was prognostic for greater risk of relapse and mortality but not NRM. QOL assessments, particularly physical functioning and functional well-being, may provide independent prognostic information beyond standard clinical measures in allogeneic HCT recipients.

Association of socioeconomic status with long-term outcomes in 1-year survivors of allogeneic hematopoietic cell transplantation.

The relationship of socioeconomic status (SES) with long-term outcomes in allogeneic hematopoietic cell transplantation (HCT) survivors has not been well described. We studied the association of SES with the outcomes of 283 consecutive allogeneic HCT recipients transplanted between 2003 and 2012 who had survived for at least 1 year in remission. Median annual household income was estimated using Census tract data and from ZIP code of residence. SES categories were determined by recursive partitioning analysis (low SES (<$51 000/year), N=203; high SES (⩾$51 000/year), N=80). In multivariable analyses, low SES patients had higher risks of all-cause mortality (hazard ratio (HR) 1.98, P=0.012) and non-relapse mortality (NRM) (HR 2.22, P=0.028), but similar risks of relapse mortality (HR 1.01, P=0.97) compared with high SES patients. A trend toward better survival and lower NRM for high SES patients with no chronic GVHD was observed; low SES patients without GVHD had similar survival as patients with chronic GVHD. In allogeneic HCT survivors who survive in remission for at least 1 year, SES is associated with long-term survival that is primarily mediated through higher risks of NRM. More research is needed to understand the mechanisms of health-care disparities and interventions to mitigate them.

High-dose chemotherapy with autologous stem-cell support for germ cell tumors: a critical review.

High-dose chemotherapy (HDC) with autologous stem-cell support (ASCS) has been investigated in patients with cisplatin-resistant, relapsed, or poor-prognosis germ cell tumor (GCT). Although some of these patients have benefited from this approach, it is unknown when best to administer such therapy. This review categorizes the HDC/ASCS trials into those performed as (1) salvage therapy for second or greater relapse, (2) salvage therapy for first relapse, and (3) first-line therapy. From the trials performed to date, earlier use of HDC/ASCS (first-line or salvage therapy in first relapse) achieved a higher durable remission rate than when used later as salvage therapy in second or greater relapse (approximately 50% v 15%, respectively). HDC/ASCS is not beneficial for relapsed or cisplatin-resistant primary extragonadal GCT patients, but may have a role in testicular GCT who are not "absolutely" cisplatin-resistant. Trial differences regarding the patients selected and the high-dose transplant preparative regimen used have made precise comparative analyses difficult. There has been only one phase III trial and it did not show a survival advantage to the HDC/ASCS arm, although this trial had significant methodological difficulties. In the future, more definitive treatment recommendations may be made upon completion of two ongoing phase III trials comparing HDC/ASCS with standard chemotherapy in the first salvage and front-line settings.

Syngeneic graft-versus-host disease: a report of two cases and literature review.

Rappeport et al first reported the clinical syndrome of graft-versus-host disease (GVHD) in syngeneic bone marrow transplant patients. Recently, there have been more reports of a GVHD-like syndrome in syngeneic bone marrow transplant patients (SGVHD) that may result in significant clinical morbidity. A total of 17 cases of SGVHD in syngeneic bone marrow transplant patients have been reported to date in the medical literature. The current report reviews these cases and presents two additional cases of severe SGVHD that have occurred at our institution.