Pre-engraftment graft-versus-host disease after allogeneic hematopoietic cell transplantation for acute leukemia

Objectives: Acute graft‐versus‐host disease (GVHD) usually occurs with neutrophil engraftment following allogeneic hematopoietic cell transplantation (HCT), but it can also occur before engraftment. We intended to analyze the effects of timing of acute GVHD on leukemia relapse and mortality. Methods: The outcomes of pre‐ and postengraftment GVHD were investigated in 384 patients who underwent allogeneic HCT for acute leukemia. Results: Acute GVHD occurred in 100 patients, pre‐engraftment in 22 and postengraftment in 78. Compared with postengraftment GVHD, pre‐engraftment GVHD was more severe, as assessed by overall grade, with more frequent and more severe skin involvement and higher incidences of non‐infectious fever, diarrhea, hepatic dysfunction, renal insufficiency, and weight gain. Compared with patients without acute GVHD, those with postengraftment GVHD had lower cumulative incidence of relapse [CIR; hazard ratio (HR), 0.470; P = 0.006] and higher cumulative incidence of non‐relapse mortality (CINRM; HR, 2.568; P < 0.001), while those with pre‐engraftment GVHD had similar CIR (HR, 0.815; P = 0.059) and higher CINRM (HR, 2.872; P = 0.036). Overall survival of patients with pre‐engraftment GVHD was lower than that of those without acute GVHD (HR, 1.976; P = 0.017), which was similar to that of those with postengraftment GVHD (HR, 0.969; P = 0.878). Separate analyses of the effects of timing of acute GVHD on post‐transplant outcomes in patients with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) showed similar trends. Conclusion: Pre‐engraftment GVHD might be a ‘cytokine storm’ type syndrome rather than ‘real’ GVHD, indicating the need for separate analyses of pre‐ and postengraftment GVHD in future trials.     

Maintenance therapy after allogeneic hematopoietic cell transplantation for acute myeloid leukemia

With improvements in the safety of allogeneic hematopoietic cell transplantation, disease recurrence following the procedure is now the most frequent reason for treatment failure. Administration of maintenance therapy after transplantation is one way to try and prevent recurrence. This paper provides a brief review of the topic.     

Factors affecting antibody levels after allogeneic hematopoietic cell transplantation

To obtain insight into the mechanism(s) of posttransplantation humoral immunodeficiency, we evaluated factors affecting serum antibody levels against polio, tetanus, Haemophilus influenzae, and Streptococcus pneumoniae in 87 patients. Patients with hematologic malignancies were randomized to receive marrow versus blood stem cells, which contain approximately 10 times more lymphocytes than marrow. Blood stem cell recipients did not have higher antibody levels than marrow recipients. Recipient pretransplantation antibody levels were correlated with the posttransplantation levels, especially in the first 6 months after transplantation when the correlation coefficients typically exceeded 0.6. Donor pretransplantation antibody levels had less of a correlation with posttransplantation levels in the recipient. Patient or donor age, total body irradiation, and graft-versus-host disease or its treatment appeared to have no effect. In conclusion, antibody levels in the first year after transplantation are affected primarily by pretransplantation antibody levels in the recipient and, to a lesser degree, in the donor. These findings suggest that immunization of the recipient and the donor before transplantation may be more effective in improving antibody immunity after transplantation than manipulating graft-versus-host disease, changing conditioning, or increasing the number of lymphocytes in the graft.     

Encephalopathy in pediatric patients after allogeneic hematopoietic stem cell transplantation is associated with a poor prognosis

Summary:Encephalopathy is a poorly characterized complication of hematopoietic stem cell transplantation (HSCT). No comprehensive report of encephalopathy exists for children, and the literature contains only a few for adults. We analyzed a large cohort of 405 pediatric patients who underwent allogeneic HSCT during a 10-year period and identified 26 patients (6.4%) who experienced encephalopathy. Identifiable causes of encephalopathy included infection (n=5), single or multiorgan failure (n=4), medication-related complications (n=3), nonconvulsive seizures (n=4), acute disseminated encephalomyelitis (n=2), thrombotic thrombocytopenic purpura (n=2), and stroke (n=1). We were unable to identify the etiology of encephalopathy in five (19%) patients. The prognosis for pediatric patients with encephalopathy was poor: only four (15%) experienced complete neurologic recovery, and 10 (38%) patients experienced partial recovery with residual neurologic deficits. Nine (35%) patients with complete or partial recovery survive long term. A total of 17 patients died; one died of progressive encephalopathy, and 16 died of either relapse of primary disease or toxicity. MRI, CSF analysis including molecular testing for infectious pathogens, and brain biopsy were helpful in obtaining a diagnosis in most of our patients. However, a standardized approach to accurate and timely diagnosis and treatment is needed to improve outcome in these patients.     

Alleviation of palmoplantar pustulosis associated with adult T cell leukemia/lymphoma after allogeneic hematopoietic stem cell transplantation

A 68-year-old female with palmoplantar pustulosis was referred to our hospital in July, 2009 because of liver dysfunction, a positive test for HTLV-1, and circulating abnormal lymphocytes with irregularly shaped nuclei. A diagnosis of acute type adult T cell leukemia/lymphoma (ATLL) was made based on generalized lymph node swelling and high levels of serum LDH, in addition to the findings described above. The associated palmoplantar pustulosis responded to some extent to antibiotics, steroid ointment, and narrow band UBV light irradiation. For ATLL, she was serially treated with CHOP chemotherapy, an LSG 15 protocol, and CytaBOM protocol with consequent partial remission. These chemotherapies did not affect the palmoplantar pustulosis. For ATLL in partial remission, we performed allogeneic peripheral blood stem cell transplantation (allo-PBSCT) from a related donor (HTLV-1-negative) with a conditioning regimen consisting of fludarabine, melphalan, and total body irradiation with 3 Gy in February, 2010. After the engraftment of donor hematopoietic cells, ATLL cells disappeared and the patient currently (as of April, 2012) remains in complete remission (CR). The residual palmoplantar pustulosis was further improved soon after allo-PBSCT and disappeared on Day 84 after transplantation. This refractory skin disease has also been in CR to date.     

Factors affecting thymic function after allogeneic hematopoietic stem cell transplantation

Hematopoietic stem cell transplantation (HSCT) is followed by profound immunodeficiency. Thymic function is necessary for de novo generation of T cells after HSCT. Circulating CD45RA(+) naive T-cell levels are predictive of antigen-specific T-cell responses in the absence of graft-versus-host disease (GVHD). These T cells may not represent recent thymic emigrants, since naive T cells may maintain this phenotype if not antigen-activated. To accurately measure thymic output after HSCT and determine the factors that influence thymic function, T-cell receptor excision circles (TRECs) were examined in CD4(+) and CD8(+) cells from a cross-section of patients following HSCT. TREC levels rose weeks after HSCT and could be detected in patients 6 years after HSCT. TREC levels correlated with the frequency of phenotypically naive T cells, indicating that such cells were not expanded progeny of naive T cells present in the donor graft. Chronic GVHD was the most important factor that predicted low TREC levels even years after HSCT. Patients with a history of resolved GVHD had decreased numbers of TREC, compared with those with no GVHD. Because few adults had no history of GVHD, it was not possible to determine whether age alone inversely correlated with TREC levels. Recipients of cord blood grafts had no evidence of decreased TREC induced by immunosuppressive prophylaxis drugs. Compared with unrelated donor grafts, recipients of matched sibling grafts had higher TREC levels. Collectively, these data suggest that thymopoiesis is inhibited by GVHD. Larger studies will be needed to determine the independent contributions of age and preparative regimen to post-transplant thymopoietic capacity.     

The graft versus leukemia response after allogeneic hematopoietic stem cell transplantation

It is now well established that the efficacy of allogeneic hematopoietic stem cell transplant for eradicating a variety of hematologic malignancies is related to antitumor activity mediated by donor immune cells contained in the stem cell graft. Recent studies have provided fundamental insights into the nature of the effector cells and target molecules that are responsible for the graft versus tumor effect. T cells specific for minor histocompatibility antigens can mediate potent antitumor activity but are also responsible for graft versus host disease (GVHD). The molecular characterization of minor antigens has suggested ways of potentially separating antitumor activity from GVHD. The challenge for the future is to continue to build on our understanding of the allogeneic graft versus tumor effect and develop strategies that can be incorporated into clinical practice to augment this effect without GVHD.     

Factors influencing B lymphopoiesis after allogeneic hematopoietic cell transplantation.

In 93 allograft recipients, the numbers of marrow B-cell precursors on days 80 and 365 correlated with the counts of circulating B cells, suggesting that the posttransplantation B-cell deficiency is at least in part due to insufficient B lymphopoiesis. Factors that could affect B lymphopoiesis were evaluated. The number of marrow B-cell precursors on days 30 and 80 was at least 4-fold lower in patients with grade 2 to 4 acute graft-versus-host disease (GVHD) compared with patients with grade 0 to 1 acute GVHD. The number of B-cell precursors on day 365 was 18-fold lower in patients with extensive chronic GVHD compared with patients with no or limited chronic GVHD. The number of B-cell precursors was not related to CD34 cell dose, type of transplant (marrow versus blood stem cells), donor age, or patient age. It was concluded that posttransplantation B-cell deficiency results in part from inhibition of B lymphopoiesis by GVHD and/or its treatment.     

Factors associated with early molecular remission after T cell-depleted allogeneic stem cell transplantation for chronic myelogenous leukemia

Eighty patients with chronic myeloid leukemia (CML) underwent T cell-depleted stem cell transplantation from an HLA-identical sibling, with add-back of donor T cells on days 30 to 45 and days 60 to 100 in patients in whom grade 2 or greater acute graft-versus-host disease (GVHD) developed. The outcomes for 54 patients with chronic-phase (CP) and 26 with advanced-phase (AP) disease were as follows: overall survival, 85% +/- 5% versus 36% +/- 10%; transplantation-related mortality (TRM), 13% +/- 5% versus 43% +/- 11%; and current leukemia-free survival, 76% +/- 6% versus 34% +/- 9%. The day-30 lymphocyte count (LC30) was strongly associated with outcome. For patients in CP with counts greater than the median of 0.30 x 10(9)/L, survival was 100% versus 70% +/- 9% (P = .003); current LFS 100% versus 56% +/- 9% (P = .002); and TRM 0% versus 26% +/- 8% (P = .006). Higher-than-median LC30 correlated significantly with molecular remission (MR) at 3, 6, and 12 months and with higher CD34 doses. Lymphocyte subset analysis performed in 20 patients available for phenotyping showed that LC30 was highly correlated with absolute CD56+CD3- natural killer cell numbers (NK30), which also predicted for survival and MR. CD34 cell dose, LC30, and NK30, but not day-30 CD3+ cell count, were highly correlated and were significant predictors of transplantation outcome. These results suggest that transplanted CD34 cell doses greater than 5 x 10(6)/kg may improve outcomes by increasing the early recovery of NK cells.     

Favorable outcome of allogeneic hematopoietic stem cell transplantation for relapsed or refractory acute promyelocytic leukemia in childhood

The optimal therapy for children with relapsed or refractory acute promyelocytic leukemia (APL) is unclear. We therefore reviewed our institutional outcomes for children undergoing allogeneic hematopoietic stem cell transplantation (HSCT) for advanced APL. Between 1986 and 2003, 12 allogeneic HSCTs (five related donor, seven unrelated donor) were performed for 11 patients (median age, 13 years) with relapsed (n = 8) or refractory (n = 3) APL. All patients engrafted, after a median of 18.5 days. Grade B-D acute graft-versus-host disease (GVHD) developed after five transplants (42%; 90% CI, 18-68%), and the cumulative incidence of chronic GVHD was 45% (90% CI, 19-71%). The cumulative incidence of overt relapse post-HSCT was 10% (90% CI, 0-28%). The overall 5-year survival was 73% (90% confidence interval (CI), 51-95%), with a median post-HSCT follow-up of 64 months. The Lansky/Karnofsky performance scores are 100% in six of eight survivors. In view of the low risk of subsequent relapse and favorable survival suggested by other reports and our own experience, we continue to recommend allogeneic HSCT for children with advanced APL for whom a suitably HLA-matched donor is identified.     

Two children with differing outcomes after treatment for pulmonary tuberculosis diagnosed after allogeneic hematopoietic stem cell transplantation

J.W. Lee, H.‐J. Kwon, P.‐S. Jang, N.‐G. Chung, B. Cho, D.‐C. Jeong, J.‐H. Kang, H.‐K. Kim. Two children with differing outcomes after treatment for pulmonary tuberculosis diagnosed after allogeneic hematopoietic stem cell transplantation.
Transpl Infect Dis 2011: 13: 520–523. All rights reserved. Abstract: Tuberculosis (TB) is a rare infectious complication after hematopoietic stem cell transplantation (HSCT), but may be more significant in areas where the disease is endemic. Here, we present the clinical course of 2 children with acute lymphoblastic leukemia who were diagnosed with pulmonary TB after allogeneic HSCT. Both patients were treated for either probable or possible invasive fungal infection, as well as TB. One patient, diagnosed with TB 3 months after HSCT, showed remittent fever and symptoms that progressed to acute respiratory distress syndrome and death, despite 3 modifications to the anti‐TB regimen. In contrast, another patient who was diagnosed with TB 8 months after transplantation, responded well to anti‐TB medication and completed 1 year of treatment with resolution of lung lesions. Co‐morbid opportunistic infections, profound host immunosuppression early after transplantation, and potential risk of multi‐drug resistant‐TB may act as major barriers to effective treatment of TB after HSCT despite appropriate anti‐TB medication.     

Infectious complications and outcomes after allogeneic hematopoietic stem cell transplantation in Korea

We reviewed 242 allogeneic hematopoietic stem cell transplantation (HSCT) recipients retrospectively over a 2-year period (January 1998-December 1999) in order to analyze the characteristics and assess the outcomes of infectious complications in patients after HSCT in Korea. Bacteria were the major pathogens before engraftment, and viral and fungal infections predominated during the post-engraftment period. Varicella zoster virus was the most common viral pathogen after engraftment. Cytomegalovirus disease occurred mainly in the late-recovery phase. The frequency of mold infection was higher than that of yeast. There was a relatively high incidence of tuberculosis (3.0%) and Pneumocystis carinii pneumonia (6.5%). One case of death by measles confirmed by autopsy was also noted. Overall, cumulative mortality was 43% (104/242), and 59.6% of these deaths (62/104) were infection-related. Allogeneic HSCT recipients from unrelated donors were prone to infectious complication and higher mortality than those from matched sibling (17/39 (43.6%) vs 45/203 (22.2%), respectively; P<0.01; odd ratio 2.5; 95% confidence interval 1.2-5.1). As infection was the main post-HSCT complication in our data, more attention should be given to the management of infections in HSCT recipients.     

Donor leukocyte infusions for the treatment of relapsed acute leukemia after allogeneic stem cell transplantation

Allogeneic stem cell transplantation (SCT) offers the only hope for cure for many adults with acute leukemia. Unfortunately, many patients relapse and die of their disease even after transplantation. Although in some cases, allogeneic SCT is effective because the intensive conditioning therapy eradicates all malignant cells, it has long been recognized that the adoptive transfer of donor immunity plays a critically important role in the induction and maintenance of remission. Recognition of the graft-versus-leukemia (GVL) effect of allogeneic SCT has prompted attempts at remission re-induction by adoptive immunotherapy with donor lymphocyte infusions (DLIs) in patients with relapsed disease after allogeneic SCT. In some cases, DLI-induced remissions are sustained and patients cured when no other treatment modality was effective. This review discusses the rationale, biology, complications and future applications of DLI in acute leukemia patients after allogeneic SCT.     

Bronchiolitis obliterans following pediatric allogeneic hematopoietic stem cell transplantation

Bronchiolitis obliterans (BrOb) is a well-recognized complication of allogeneic hematopoietic stem cell transplantation (HSCT). It is associated with substantial morbidity and mortality in adult patients. However, the incidence and morbidity of this complication have not been well described in the pediatric population. We report our experience of BrOb in 216 pediatric allogeneic HSCT patients between 1 January 2001 and 31 December 2005. In total 18 of 216 patients developed BrOb during this time. The diagnosis of BrOb was based on pulmonary function abnormalities, radiographic findings or lung biopsy. In total 14 of 18 patients with BrOb received stem cells from unrelated donors. In total 17 of 18 patients received bone marrow as a stem cell source, and 1 received peripheral blood stem cells. All pediatric patients in this report had a known risk factor for BrOb, most commonly chronic GVHD (l8 of 18 patients). Additionally, 7 of 18 patients had either toxic lung injury or virally mediated pulmonary disease before the diagnosis of BrOb. With a median of 45.1 months of follow-up, the outcomes were 5 of 18 patients died of lung disease, 2 died of other causes, 3 had progressive lung disease, 6 achieved partial resolution of disease and 2 had stable disease. BrOb, while uncommon, is associated with considerable morbidity and mortality in pediatric HSCT.     

Sustained remission of MDS overt leukemia associated with abrupt discontinuation of immunosuppression following relapse after the second course of allogeneic hematopoietic stem cell transplantation

The case of a 32-year-old female with relapsed myelodysplastic syndrome (MDS) after second course of allogeneic transplantation is described. The peripheral blood stem cell transplantation was performed as early as 3 months after the initial bone marrow transplantation because of rejection and relapse; however, the patient again relapsed 2 months later. Immediate discontinuation of cyclosporine resulted in the progression of pancytopenia and the development of high fever, liver dysfunction and skin eruption. The patient was then treated with dexamethasone, which successfully stabilized these symptoms. After these clinical events, a dramatic hematological response was obtained; the blast rate was reduced from 10.6 to 0% in bone marrow aspiration, and pancytopenia was restored to normal levels. Moreover, fluorescence in situ hybridization analyses with X and Y chromosome-specific probes revealed that hematopoietic precursor cells were predominantly of donor origin. The patient subsequently received donor lymphocyte infusion (DLI) from the original donor. Currently, 2 years after DLI, the patient continues to be in remission.     

Nephrotic syndrome associated with chronic graft-versus-host disease after allogeneic hematopoietic stem cell transplantation

Chronic graft-versus-host disease (cGVHD) is the most common late complication of allogeneic hematopoietic cell transplantation (HCT) causing significant morbidity and mortality. The kidneys are not considered a target organ for cGVHD in humans, although animal models show renal damage. Renal involvement in patients with cGVHD, presenting as nephrotic syndrome (NS), has rarely been reported in patients who received allogeneic transplantation. Herein we describe, by far, the largest series of nine patients with NS associated with cGVHD, including two patients who received a reduced-intensity regimen. Pathological features of membranous nephropathy were the most common finding on renal biopsy. The clinical course of the NS was temporally associated with the classical features of cGVHD in all but one of the nine cases. The clinicopathologic features of NS in our series as well as reports in the literature demonstrate an immunopathologic process typical of antibody-mediated damage consistent with cGVHD. Treatment directed against antibody-mediated damage, such as anti-B-cell antibody may play an important role in ameliorating NS associated with cGVHD.     

Disease burden may identify patients more likely to benefit from second allogeneic hematopoietic stem cell transplantation to treat relapsed acute myelogenous leukemia

The major cause of failure after allogeneic hematopoietic stem cell transplantation (HSCT) for acute myelogenous leukemia (AML) is disease relapse or progression. We analyzed the outcome of second HSCT for treatment of patients with relapsed, refractory AML/myelodysplastic syndrome (MDS) at our institution. A total of 72 patients were eligible for this analysis. In all, 25 (35%) patients received salvage chemotherapy prior to the second transplant procedure and only two (3%) patients were in complete remission at the time of the second transplant. A total of 20 patients (28%) had low leukemia burden as measured by the absence of peripheral blood blasts and 相似文献   

Effect of race on outcomes after allogeneic hematopoietic cell transplantation for severe aplastic anemia

We compared outcomes after hematopoietic cell transplantation in patients of African American (n = 84) and Caucasian (n = 215) descent with severe aplastic anemia. African Americans and Caucasians were matched for age, donor–recipient human leukocyte antigen match, graft type, and transplantation year. The median follow‐up of surviving patients was 5 years. In multivariate analysis, overall mortality risks were higher for African Americans compared to Caucasians (relative risk 1.73, P = 0.01). The 5‐year probabilities of overall survival adjusted for interval from diagnosis to transplantation, and performance score was 58% for African Americans and 73% for Caucasians. The day‐100 cumulative incidence of grade III–IV, but not grade II–IV acute graft‐versus‐host disease (GVHD), was higher in African Americans compared to Caucasians (29% vs. 13%, P = 0.006). Although the 5‐year cumulative incidence of chronic GVHD was not significantly different between the racial groups, African Americans were more likely to have extensive chronic GVHD compared to Caucasians (72% vs. 49%, P = 0.06). Survival differences between Caucasians and African Americans can be attributed to multiple factors. Our data suggest that some of the observed survival differences between Caucasians and African Americans may be explained by higher rates of acute GVHD and severity of chronic GVHD. Am. J. Hematol. 89:125–129, 2014. © 2013 Wiley Periodicals, Inc.