Myeloablative allogeneic versus autologous stem cell transplantation in adult patients with acute lymphoblastic leukemia in first remission: a prospective sibling donor versus no-donor comparison

While commonly accepted in poor-risk acute lymphoblastic leukemia (ALL), the role of allogeneic hematopoietic stem cell transplantation (allo-SCT) is still disputed in adult patients with standard-risk ALL. We evaluated outcome of patients with ALL in first complete remission (CR1), according to a sibling donor versus no-donor comparison. Eligible patients (433) were entered in 2 consecutive, prospective studies, of whom 288 (67%) were younger than 55 years, in CR1, and eligible to receive consolidation by either an autologous SCT or an allo-SCT. Allo-SCT was performed in 91 of 96 patients with a compatible sibling donor. Cumulative incidences of relapse at 5 years were, respectively, 24 and 55% for patients with a donor versus those without a donor (hazard ratio [HR], 0.37; 0.23-0.60; P < .001). Nonrelapse mortality estimated 16% (+/- 4) at 5 years after allo-SCT. As a result, disease-free survival (DFS) at 5 years was significantly better in the donor group: 60 versus 42% in the no-donor group (HR: 0.60; 0.41-0.89; P = .01). After risk-group analysis, improved outcome was more pronounced in standard-risk patients with a donor, who experienced an overall survival of 69% at 5 years (P = .05). In conclusion, standard-risk ALL patients with a sibling donor may show favorable survival following SCT, due to both a strong reduction of relapse and a modest nonrelapse mortality. This trial is registered with http://www.trialregister.nl under trial ID NTR228.     

Common variants in NLRP2 and NLRP3 genes are strong prognostic factors for the outcome of HLA-identical sibling allogeneic stem cell transplantation

The inflammasomes are macromolecular cytosolic complexes involved in the production of interleukin-1beta (IL-1beta) and IL-18 in response to several pathogen-derived stimuli. Such interleukins have been implicated in the origin of severe allogeneic stem cell transplant (allo-SCT) complications. We analyzed the relationship between the interindividual variability in inflammasome protein-encoding genes in donors and patients and clinical outcome after allo-SCT. Fourteen common genetic variants in 5 genes of the inflammasome, namely, NLRP1, NLRP2, NLRP3, CARD8, and CASP5, were genotyped in 133 human leukocyte antigen-identical sibling pairs undergoing allo-SCT. In the multivariate analysis, donor variants in NLRP2 and NLRP3 were the most important prognostic factors for the clinical outcome after allo-SCT. Thus, donor TT genotype at rs10925027 in NLRP3 was associated with disease relapse (odds ratio (OR) = 6.3, P = 1 x 10(-7)), and donor GG genotype at rs1043684 in NLRP2 was associated with nonrelapse mortality (OR = 4.4, P = 6 x 10(-4)) and overall survival (OR = 3.1, P = .001). In addition, patient AA genotype at rs5862 in NLRP1 was associated with nonrelapse mortality (OR = 2.8, P = .005) and overall survival (OR = 2.0, P = .009). These results suggest that inflammasome genetic variants are important prognostic factors for the outcome of allo-SCT. If validated in larger studies, including unrelated allo-SCT, NLRPs genotype would become an important factor in donor selection.     

A constitutional variant in the transcription factor EP300 strongly influences the clinical outcome of patients submitted to allo-SCT

An adequate response of the innate immune system after allo-SCT is crucial for the clinical outcome of patients submitted to this procedure. EP300 is one of the key genes of the innate immune system (IIS). We evaluated the influence of gene variant A>G rs20551 in EP300 in donor and/or recipient on clinical results after HLA-identical sibling allo-SCT. Patients with AA gene variant had a lower relapse incidence (31 vs 48%, P=0.025; odds ratio (OR)=1.6, P=0.05), attained better disease-free survival (AA: 53% vs AG+GG: 24%, P=0.001; OR=1.8, P=0.01), and better OS (AA: 53% vs AG+GG: 34%, P=0.001; OR=1.9, P=0.007). This beneficial association was more evident when AA gene variant was present in both donor and patient. In healthy individuals, AA gene variant was associated with lower IL2 production after a mitogenic stimuli, higher CD4+ cell response after CMV infection, and higher expression of innate immune genes (IRF-3 and MIF), cell cycle genes (AURKB, CCNA2 and CCNB1), lymphocyte survival genes (NFAT5 and SLC38A2), and with a lower expression of P53 compared with recessive GG gene variant. These findings suggest a beneficial effect of the AA gene variant in rs20551 on clinical outcome after allo-SCT.     

Second chronic phase before transplantation is crucial for improving survival of blastic phase chronic myeloid leukaemia

Because successful outcome after transplantation seems to depend in acute myeloid leukaemia (AML) and in chronic phase chronic myeloid leukaemia (CML) on disease status at the time of transplantation, we investigated whether FLAN (fludarabine, cytosine arabinoside, mitoxantrone) induction before allogeneic stem cell transplantation (allo-SCT) may be useful in blastic phase (BP)-CML. Twenty patients with BP-CML were studied: 10 patients received FLAN induction chemotherapy before proceeding to early allo-SCT, whereas 10 patients were submitted to bone marrow transplantation (BMT) without remission induction. Eight out of 10 (80%) patients achieved second chronic phase after one course of therapy with FLAN and seven patients (six in second chronic phase and one with partial response) were then submitted to allo-SCT. Of the six patients transplanted in the second chronic phase, all achieved molecular remission, four are still in second chronic phase, with intervals ranging from 10 to 54 months, whereas one patient died from infection having relapsed 14 months after SCT and one died of transplant-related complications in the second chronic phase. Mean durations of second chronic phase and survival after allo-SCT were both significantly longer than in the group of 10 BP-CML patients submitted to allo-SCT without FLAN remission induction treatment [22.4 (range 1-61) vs. 3.5 months (range 1-10) with FLAN and 22.7 (range 2-61) vs. 6.4 (range 1-16) months without FLAN]. We conclude that FLAN induction therapy followed by early allo-SCT appears to be effective in the treatment of BP-CML and could provide a curative possibility for BP-CML patients.     

Patient socioeconomic status as a prognostic factor for allo-SCT

The aim of the present study was to assess the influence of socioeconomic status (SeS) on the outcome of allo-SCT at a Brazilian SCT center. In total, 201 patients receiving HLA-identical related allo-SCTs were studied. The median age was 30 years. Overall, 163 patients had malignancies (CML 68, ALL/AML 63, myelodysplastic syndrome 12 and others 20). SeS was defined according to the Brazilian Association of Market Research Agencies classification, where people are clustered in groups A-E (richest to poorest). In total, 146 patients (72%) were classified as richest (A+B+C) and 55 (28%) as poorest (D+E). The D+E SeS group was associated with a higher incidence of chronic GVHD and acute GVHD (hazard ratio (HR)=2.61; P=0.001 and HR=2.62; P=0.001, respectively), better platelet and neutrophil engraftment (HR=1.94; P=<0.001 and HR=2.12; P=0.001) and with a higher TRM in multivariate analysis (HR=1.92; P=0.039). Estimated overall survival at 5 years was 55.2%. A D+E SeS (HR=2.13; P=0.001) was associated with a worse survival on multivariate analysis. In conclusion, a lower SeS is a strong prognostic factor in patients undergoing allo-SCT in Brazil, influencing engraftment, TRM and overall survival.     

Choice of pretransplant treatment and timing of transplants for chronic myelogenous leukemia in chronic phase [see comments]

We analyzed the outcome of 450 HLA-identical sibling bone marrow transplants for chronic myelogenous leukemia (CML) in chronic phase performed between 1985 and 1990 and reported to the International Bone Marrow Transplant Registry (IBMTR). All patients received either hydroxyurea (n = 292) or busulfan (n = 158) to treat their CML before transplant. The median interval between diagnosis and transplant was 10 months (range, 1 to 191). Patients treated with hydroxyurea had a higher probability (95% confidence interval) of leukemia-free survival (LFS) at 3 years than those treated with busulfan (61% [51% to 70%] v 45% [36% to 55%], P < .0003). Probability of LFS was also higher in patients transplanted within 1 year of diagnosis (61% [53 to 68%] v 47% [38% to 57%], P < .001). After adjustment for patient and transplant covariables in a multivariate analysis, prior chemotherapy and duration of disease pretransplant were independently associated with LFS. These data support the use of hydroxyurea rather than busulfan and transplant within 1 year of diagnosis for patients with CML and an HLA-identical sibling.     

Expression of nuclear transcription factor interferon consensus sequence binding protein in chronic myeloid leukemia correlates with pretreatment risk features and cytogenetic response to interferon-alpha

Recently, it was shown that interferon consensus sequence binding protein (ICSBP), a member of the interferon regulatory factor (IRF) family, has a potential role in chronic myeloid leukemia (CML). Deletion of ICSBP gene in mice leads to a CML-like syndrome and samples from CML patients exhibited impaired ICSBP expression. The present study found that ICSBP expression correlated with risk features determined by Sokal score in untreated CML (P =.007 for high versus low risk). In addition, analyzing ICSBP expression during interferon-alpha (IFN-alpha) therapy in "good" (n = 27) versus "poor" (n = 15) cytogenetic responders, high ICSBP levels were only observed in "good" responders (P =.0002). Together, these data suggest that ICSBP levels are related to initial presentation of CML and the therapeutic response of CML to IFN-alpha, indicating an important role of ICSBP in CML. (Blood. 2001;97:3648-3650)     

Graft-versus-host disease following allogeneic transplantation from HLA-identical sibling with antithymocyte globulin-based reduced-intensity preparative regimen

Reduced-intensity conditioning (RIC) regimens are increasingly used for allogeneic stem cell transplantation (allo-SCT). RIC has been shown to allow engraftment with minimal early transplantation-related mortality (TRM). However, in the context of RIC, predictive factors for acute and chronic graft-versus-host disease (aGVHD and cGVHD, respectively) and their effect on outcome remain unknown. In this report, we analyzed the outcome of 101 high-risk patients (70 hematologic and 31 nonhematologic malignancies) who received an HLA-identical sibling allo-SCT after RIC, including fludarabine, busulfan, and antithymocyte globulin (ATG). The cumulative incidence of grade II-IV aGVHD was 36% (95% confidence interval [CI], 27%-45%), whereas the cumulative incidence of cGVHD at 2 years was 43% (95% CI, 33%-53%). In multivariate analysis, the incidence of aGVHD was significantly associated with the ATG dose infused during conditioning (P =.0005), whereas peripheral blood as stem cell source was the only predictive factor for the development of cGVHD (P =.0007). The 1-year cumulative incidences of disease progression or relapse in patients with (n = 69) and without (n = 31) GVHD (whatever its form or grade) were 30% (95% CI, 19%-41%) and 55% (95% CI, 37%-72%), respectively (P =.02), suggesting that a potent graft-versus-tumor (GVT) effect can be achieved in high-risk patients following RIC. Moreover, the GVT effect was closely associated with GVHD without an increased risk of TRM (cumulative incidence of TRM, 18% [95% CI, 10%-25%]). Collectively, these results provide a framework for the refinement of RIC approaches designed to enhance the GVT effect with an acceptable risk of GVHD.     

Vascular endothelial growth factor (VEGF) is associated with reduced severity of acute graft-versus-host disease and nonrelapse mortality after allogeneic stem cell transplantation

This study investigated whether or not there is a correlation between the changes in the serum levels of vascular endothelial growth factor (VEGF) and the outcome of allogeneic stem cell transplantation (allo-SCT). Eighty-five patients undergoing allo-SCT were prospectively studied. The serum VEGF levels were measured on days 0, +7 and +14 after transplantation. The VEGF levels decreased significantly on day +7 and recovered on day +14. The highest levels from day +7 through day +14 were categorized by cluster analysis, which were then correlated with the nonrelapse mortality (NRM). There was a significant correlation between a low VEGF level and the occurrence of severe acute graft-versus-host disease (GVHD) including grade III-IV (P=0.029). The 1-year probability of NRM in patients with a low VEGF level was 22.5% compared with 3.5% for those with a high VEGF level (P=0.024). Multivariate analysis revealed clinically defined infections (P=0.011), advanced disease (P=0.014) and a low VEGF cluster (P=0.05) to be significantly associated with the occurrence of NRM in the cohort. In conclusion, low VEGF levels after allo-SCT are associated with NRM with an exacerbated severity of acute GVHD. VEGF monitoring after a transplant might identify those patients at risk of severe transplant-related mortality.     

Relapse after non-T-cell-depleted allogeneic bone marrow transplantation for chronic myelogenous leukemia: early transplantation, use of an unrelated donor, and chronic graft-versus- host disease are protective

We analyzed the incidence of posttransplant chronic myelogenous leukemia (CML) relapse in 283 consecutive related-donor (n = 177) and unrelated-donor (n = 106) allogeneic transplant recipients. Twenty-two of 165 related-donor recipients with stable or advanced disease at the time of transplant had hematologic relapse of CML following transplant (5-year Kaplan-Meier estimate of relapse, 20%; 95% confidence interval [CI], 11 to 30%). One of 12 patients transplanted in second stable phase following blast crisis also relapsed. Fifteen related-donor transplant recipients relapsed within 5 years of transplant; however, seven relapsed between 5 and 9 years after transplant. Factors independently associated with an increased risk of posttransplant relapse for related-donor recipients included prolonged interval between diagnosis and transplant (relative risk, [RR], 3.81; P = .009) and bone marrow basophilia (RR, 5.62; P = .01). Related-donor recipients with posttransplant chronic graft-versus-host disease (CGVHD) had a decreased risk of relapse (RR, 0.24; P = .005). Only two of 106 unrelated-donor transplant recipients relapsed following transplant (5-year Kaplan-Meier estimate of relapse, 3%; 95% CI, 0% to 7%). When both related- and unrelated-donor recipients were considered, the use of an unrelated donor was independently associated with a decreased risk of relapse (RR, 0.24; P = .07). Twelve of 16 relapsing patients who received further therapy (nine of 13 who underwent second transplant and three of three who received donor leukocyte infusions) remain alive. This analysis shows that relapse, sometimes occurring long after transplant, is an important adverse outcome in allogeneic transplantation for CML. Early transplant, posttransplant CGVHD, and use of an unrelated donor are associated with a reduced incidence of relapse, perhaps due to allogeneic disparities enhancing the graft- versus-leukemia effect.     

Coexpression of BMI-1 and EZH2 polycomb-group proteins is associated with cycling cells and degree of malignancy in B-cell non-Hodgkin lymphoma

Polycomb-group (PcG) proteins, such as BMI-1 and EZH2, form multimeric gene-repressing complexes involved in axial patterning, hematopoiesis, and cell cycle regulation. In addition, BMI-1 is involved in experimental lymphomagenesis. Little is known about its role in human lymphomagenesis. Here, BMI-1 and EZH2 expression patterns are analyzed in a variety of B-cell non-Hodgkin lymphomas (B-NHLs), including small lymphocytic lymphoma, follicular lymphoma, large B-cell lymphoma, mantle-cell lymphoma, and Burkitt lymphoma. In contrast to the mutually exclusive pattern of BMI-1 and EZH2 in reactive follicles, the neoplastic cells in B-NHLs of intermediate- and high-grade malignancy showed strong coexpression of BMI-1 and EZH2. This pattern overlapped with the expression of Mib-1/Ki-67, a marker for proliferation. Neoplastic cells in B-NHL of low-grade malignancy were either BMI-1(low)/EZH2(+) (neoplastic centroblasts) or BMI-1(low)EZH2(-) (neoplastic centrocytes). These observations show that low-, intermediate-, and high grade B-NHLs are associated with increased coexpression of the BMI-1 and EZH2 PcG proteins, whose normal expression pattern is mutually exclusive. This expression pattern is probably caused by a failure to down-regulate BMI-1 in dividing neoplastic cells, because BMI-1 expression is absent from normal dividing B cells. These observations are in agreement with findings in studies of Bmi-1 transgenic mice. The extent of BMI-1/EZH2 coexpression correlated with clinical grade and the presence of Mib-1/Ki-67 expression, suggesting that the irregular expression of BMI-1 and EZH2 is an early event in the formation of B-NHL. This points to a role for abnormal PcG expression in human lymphomagenesis. (Blood. 2001;97:3896-3901)     

Results of allogeneic hematopoietic stem cell transplantation for chronic myelogenous leukemia patients who failed tyrosine kinase inhibitors after developing BCR-ABL1 kinase domain mutations

Hematopoietic stem cell transplantation (HSCT) is effective therapy for patients with chronic myelogenous leukemia (CML) but is now mostly indicated for patients who develop resistance to tyrosine kinase inhibitors (TKIs), which can be associated with point mutations in BCR-ABL1. We reviewed the outcomes of imatinib-resistant CML patients (chronic phase, n = 34; accelerated phase [AP], n = 9; and blast phase [BP], n = 4) who underwent HSCT and had BCR-ABL1 sequencing. Mutations were found in 19 patients (40%); 15 of 19 had advanced CML (AP + BP + second chronic phase). Patients with mutations were more likely to transform to AP/BP at time of imatinib failure (69% vs 35%, P = .03). Forty-two patients (89%) responded to HSCT: 32 (68%) had at least a major molecular response. The 2-year event-free survival was 36% and 58% (P = .05) for the mutant and nonmutant groups, respectively; and the 2-year overall survival was 44% and 76% (P = .02), respectively. HSCT is an important salvage option for TKI-resistant patients with or without BCR-ABL1 mutations. Patients with mutations were more likely to develop advanced disease and had worse outcomes after HSCT. HSCT should be considered early for patients deemed to have a low probability of responding to second-generation TKI.     

Gene expression profiling of Polycomb, Hox and Meis genes in patients with acute myeloid leukaemia

The Polycomb group (PcG) of genes is important for differentiation and cell-cycle regulation and is aberrantly expressed in several cancers. To analyse the role of deregulated PcG genes in acute myeloid leukaemia (AML), we determined by RQ-PCR the expression of the PcG genes BMI-1 , MEL18 , SCML2 , YY1 and EZH2 , and the downstream PcG targets HOXA4 , HOXA9 and MEIS1 in diagnostic bone marrow samples from 126 AML patients. There was a general overexpression of the genes in AML patients compared to 20 healthy donors, except of HOXA4 and MEL18 , which both displayed a wide range of expression levels within the AML subgroups. Among the AML patients with normal karyotype, a low HOXA4 level was associated with a shorter overall survival ( P  = 0.005). In addition, expression levels of MEL18 and EZH2 were significantly ( P  < 0.025) higher in patients with complex karyotype and lower in CBF-mutated patients. The t (8;21) vs. inv(16) positive patients showed significantly different expression of SCML2 , BMI-1 , YY1 , HOXA9 and MEIS1 ( P  ≤ 0.01). Comparisons between the PcG and PcG-regulated genes and a number of clinical and molecular data revealed correlations to genes involved in DNA methylation ( DNMT1 , DNMT3B ), apoptosis ( BAX , CASPASE 3 ) and multidrug-resistance ( MDR1 , MRP ) ( P  < 0.01). In conclusion, our data suggest that the role of PcG and PcG-regulated genes in leukaemogenesis varies between, as well as within karyotypic subgroups.     

Improved outcome in HLA-identical sibling hematopoietic stem-cell transplantation for acute myelogenous leukemia predicted by KIR and HLA genotypes

Inhibitory killer immunoglobulin (Ig)-like receptors (KIRs) recognize HLA-C and -B epitopes on target cells, thereby regulating natural killer (NK) cell activity. In 178 patients receiving T-cell-depleted HLA-identical sibling transplants for acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), acute lymphoblastic leukemia (ALL), or myelodysplastic syndrome (MDS), analysis of donor KIR genotype with HLA genotype demonstrated that 62.9% of the patients lacked an HLA ligand for donor-inhibitory KIR. Lack of HLA ligand for donor-inhibitory KIR (missing KIR ligand) had no effect on disease-free survival (DFS), overall survival (OS), or relapse in patients receiving transplants for CML and ALL. In patients with AML and MDS, however, there was a significant missing KIR ligand effect on DFS (P = .014; hazard ratio [HR], 0.53; 95% confidence interval [95% CI], 0.28-0.88) and OS (P = .03; HR, 0.53; 95% CI, 0.3-0.93). Incidence of relapse was also lower in patients with AML and MDS who lacked the HLA ligand for donor-inhibitory KIR (P = .04; HR, 0.41; 95% CI, 0.18-0.97). AML and MDS patients lacking 2 HLA ligands for donor-inhibitory KIR had the highest DFS (P = .002) and OS (P = .003). There was no significant contribution of donor-activating KIR to transplantation outcome in these patients. These data indicate that the absence of class I ligand in the recipient for donor-inhibitory KIR can be a prognostic factor for transplantation outcome in HLA-identical sibling transplantation and that the lack of HLA-C or -B ligands for donor-inhibitory KIR can contribute to improved outcomes for patients with AML and MDS.     

Allogeneic stem cell transplantation for chronic myeloid leukemia-status in 2007

Whereas until 2000 allo-SCT was the recommended treatment for all new patients with CML who were eligible on grounds of age and donor availability, approaches to initial therapy have changed very substantially since the introduction of imatinib mesylate. Today topical questions are (1) Should any newly diagnosed patient receive SCT as primary therapy? (2) How should imatinib failure be defined? (3) Should a patient who has failed imatinib but is still in chronic phase be offered an SCT or further treatment with a 'second-generation' TKI? (4) Would prior treatment with imatinib or concomitant delay to transplant adversely affect the subsequent results of allo-SCT? (5) Once the decision to proceed with allo-SCT is taken, how exactly should this be performed? (6) If a patient relapses after allo-SCT, how should he/she be treated? These questions will be addressed, but definitive answers may not yet be possible.     

Late-onset noninfectious pulmonary complications after allogeneic stem cell transplantation are significantly associated with chronic graft-versus-host disease and with the graft-versus-leukemia effect

Late-onset noninfectious pulmonary complications (LONIPCs) occurring beyond 3 months after allogeneic stem cell transplantation (allo-SCT) have become recognized as life-threatening complications, and they reduce the recipient's quality of life. However, the pathogenesis and optimal treatment for LONIPCs are still unclear. In this study, we retrospectively analyzed the incidence and outcome of LONIPCs among allo-SCT recipients. Between October 1993 and September 2001, 96 patients underwent allo-SCT and 76 patients who survived and were free of disease for more than 3 months after SCT were enrolled. Among the 76 patients, 18 patients (23.7%) developed LONIPCs at a median interval of 227 days after allo-SCT (range, 91-1105 days). The patients with LONIPCs were subclassified into those with bronchiolitis obliterans (BO) (6 patients), with interstitial pneumonia (IP) (11 patients), or with both BO and IP (1 patient). The presence of extensive chronic graft-versus-host disease (GVHD) was significantly associated with the development of LONIPCs (P =.0008). Liver or skin involvement in chronic GVHD was not associated, but sicca syndrome was significantly associated with the development of LONIPCs (P <.0001). Most of the IP patients (58.3%) responded well to immunosuppressive treatment, while BO patients did not respond to the therapy. Eight of the 18 patients with LONIPCs died. The major cause of death was respiratory failure (62.5%). The relapse rate of primary malignant disease in the LONIPC patients was significantly lower than that of non-LONIPC patients (1 of 17 [5.9%] versus 16 of 52 [30.8%]; P =.0387). These results indicate that the development of LONIPCs was strongly associated with chronic GVHD and especially with sicca syndrome and the graft-versus-leukemia (GVL) effect.     

Comparable results of umbilical cord blood and HLA-matched sibling donor hematopoietic stem cell transplantation after reduced-intensity preparative regimen for advanced Hodgkin lymphoma

We compared the safety and efficacy of allogeneic stem cell transplantation (allo-SCT) after reduced-intensity conditioning using either unrelated umbilical cord blood (UCB) donors or matched-sibling donors (MSDs) for 21 adults at high risk with advanced Hodgkin lymphoma (UCB, n = 9; MSD, n = 12). Both groups were comparable except for younger age in the UCB cohort (median, 28 vs 42 years; P = .02). Neutrophil recovery occurred earlier in the MSD group (median, 7 vs 10 days; P = .02). All patients had sustained donor engraftment by day 60. Cumulative incidence of acute severe graft-versus-host-disease (33% vs 33%; P = .99), chronic graft-versus-host-disease (11% vs 33%; P = .24), and 100-day treatment-related mortality (11% vs 17%; P = .80) were comparable. With median follow-up periods of 17 and 24 months, the 2-year progression-free survival rates were 25% (95% confidence interval [95% CI], 0%-55%) for UCB and 20% (95% CI, 0%-44%) for MSD allo-SCT (P = .67). Our results suggest comparable outcomes for reduced-intensity allo-SCT using UCB or MSD in adults at high risk with advanced Hodgkin lymphoma.