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.     

Graft-versus-myeloma effect following antithymocyte globulin-based reduced intensity conditioning allogeneic stem cell transplantation

In all, 41 multiple myeloma (MM) patients received an antithymocyte globulin (ATG), fludarabine, and busulfan-based reduced intensity conditioning (RIC) for allogeneic stem cell transplantation (allo-SCT) from HLA-identical siblings. In total, 29 patients (70%) were in partial remission, one patient in complete remission, and 11 (27%) with progressive disease at the time of allo-SCT. Median time between diagnosis and allo-SCT was 24 months. The cumulative incidences of grade II-IV and grade III-IV acute graft-versus-host disease (GVHD) were 36% (95% CI, 21-51%) and 7% (95% CI, 2-20%), respectively. Overall, 10 patients developed limited chronic GVHD, whereas seven developed an extensive form (cumulative incidence, 41% (95% CI, 26-56%) at 2 years). With a median follow-up of 389 days, the overall cumulative incidence of transplant-related mortality (TRM) was 17% (95% CI, 6-28%). In all, 11 patients (27%) are in continuous complete remission, and the Kaplan-Meier estimates of overall survival (OS) and progression-free survival (PFS) at 2 years were 62% (95% CI, 47-76%) and 41% (95% CI, 23-62%), respectively. PFS and OS were significantly higher in patients with chronic GVHD as compared to patients without chronic GVHD (P=0.006 for PFS and P=0.01 for OS). Collectively, these data demonstrate that RIC allo-SCT can mediate a potentially curative graft-versus-myeloma effect with an acceptable incidence of toxicity and TRM.     

CD8+ T cell dose affects development of acute graft-vs-host disease following reduced-intensity conditioning allogeneic peripheral blood stem cell transplantation

OBJECTIVE: Acute graft-vs-host disease (aGVHD) remains an important cause of morbidity after reduced-intensity conditioning (RIC) allogeneic transplantation (allo-SCT). It has been shown that antithymocyte globulin (ATG) dose infused during RIC is a major determinant for the likelihood of developing aGVHD. The ATG modulation on aGVHD is likely related to in vivo T-cell depletion. PATIENTS AND METHODS: We therefore investigated the relationship between the cellular composition of the allograft and clinical outcome in 57 patients who received allogeneic peripheral blood stem cells from HLA-identical siblings following an ATG-based RIC. RESULTS: In a multivariate analysis, the CD8+ T cell dose infused was the only parameter associated with the risk of aGVHD (p=0.031; RR=1.96; 95% CI, 1.1-3.6). When looking at the extremes, patients experiencing grade III-IV aGVHD received a median of 143 x 10(6)/kg CD8+ T cells, while patients without aGVHD received a median of 96 x 10(6)/kg CD8+ T cells (p=0.021). None of the different cell subtypes contained in the allograft was associated with a significant probability of developing chronic GVHD. Patients with grade II aGVHD who received an intermediate dose of CD8+ T cells (median, 111 x 10(6)/kg) had a significantly better overall survival in comparison to patients with grade 0-I or grade III-IV aGVHD (p=0.009). CONCLUSION: In comparison to myeloablative allo-SCT, these results demonstrate that a cautious monitoring of the number of cells infused, at least in the context of ATG-based RIC, may represent an important predictive indicator of early transplant-related events and outcome after RIC allo-SCT.     

Effect of acute and chronic GVHD on relapse and survival after reduced-intensity conditioning allogeneic transplantation for myeloma

We evaluated the effect of acute and chronic GVHD on relapse and survival after allogeneic hematopoietic SCT (HSCT) for multiple myeloma using non-myeloablative conditioning (NMA) and reduced-intensity conditioning (RIC). The outcomes of 177 HLA-identical sibling HSCT recipients between 1997 and 2005, following NMA (n=98) or RIC (n=79) were analyzed. In 105 patients, autografting was followed by planned NMA/RIC allogeneic transplantation. The impact of GVHD was assessed as a time-dependent covariate using Cox models. The incidence of acute GVHD (aGVHD; grades I-IV) was 42% (95% confidence interval (CI), 35-49%) and of chronic GVHD (cGVHD) at 5 years was 59% (95% CI, 49-69%), with 70% developing extensive cGVHD. In multivariate analysis, aGVHD (≥ grade I) was associated with an increased risk of TRM (relative risk (RR)=2.42, P=0.016), whereas limited cGVHD significantly decreased the risk of myeloma relapse (RR=0.35, P=0.035) and was associated with superior EFS (RR=0.40, P=0.027). aGVHD had a detrimental effect on survival, especially in those receiving autologous followed by allogeneic HSCT (RR=3.52, P=0.001). The reduction in relapse risk associated with cGVHD is consistent with a beneficial graft-vs-myeloma effect, but this did not translate into a survival advantage.     

Reduced-intensity conditioning allogeneic SCT as salvage treatment for relapsed multiple myeloma

The aim of this retrospective analysis was to assess the benefit of reduced-intensity conditioning allo SCT (RIC allo-SCT) in a cohort of 32 relapsed multiple myeloma (MM) patients. A total of 19 patients had an HLA-identical sibling donor ('donor' group), while 13 patients had no donor ('no-donor' group). There were no significant differences between these two groups as for prognosis risk factors. Eighteen patients from the 'donor' group could actually proceed to RIC allo-SCT. With a median follow-up of 36 (range, 21-60) months, six patients died from transplant-related toxicity (cumulative incidence, 33% (95% CI, 11-55%)). Only 4 patients from the 18 transplanted patients (22%; 95% CI, 7-48%) progressed after RIC allo-SCT, as compared to 12 (86%; 95% CI, 56-98%; P=0.0003) among the nontransplanted patients. In an 'intention-to-treat' analysis, the Kaplan-Meier estimate of PFS was significantly higher in the 'donor' group as compared to the 'no-donor' group (P=0.01; 46 versus 8% at 3 years). There was no difference in terms of overall survival. However, in multivariate analysis, actual performance of RIC allo-SCT was associated with better PFS (relative risk, 0.35; 95% CI, 0.15-0.82; P=0.01). These data suggest a potential benefit for RIC allo-SCT in the management of relapsed MM warranting further prospective investigations.     

High-dose weekly liposomal amphotericin B antifungal prophylaxis following reduced-intensity conditioning allogeneic stem cell transplantation

The use of high-dose corticosteroids for graft-versus-host disease (GVHD) treatment represents a major risk factor for long-term invasive fungal infections. The aim of this study was to investigate the safety and tolerance of weekly prophylactic administration of once-weekly high-dose (7.5 mg/kg) of liposomal amphotericin B (L-AmB) therapy in 21 adult patients receiving high-dose prednisone (2 mg/kg/day) for acute GVHD therapy after reduced intensity conditioning (RIC) allogeneic stem cell transplantation (allo-SCT). Patients received a median of 4 (range, 1-8) infusions of L-AmB. Seven patients (33%; 95% confidence intervals (CI), 13-53%) discontinued taking the study drug owing to study drug-related adverse events, including elevated serum creatinine (>1.5 times from baseline values; n=5), hypotension and pain (n=1), and violent chest pain and arrhythmia (n=1). The overall frequency of infusion-related reactions was 29% (n=6; 95% CI, 10-48%), but these reactions were always transient and relieved by stopping the infusion. This safety data provide support for an efficacy study of this prophylaxis strategy, because this may help further improving the outcome of RIC or nonmyeloablative allo-SCT.     

Prophylaxis regimens for GVHD: systematic review and meta-analysis

Opinions are divided regarding the best prophylactic regimen for GVHD. The aim of this study was to evaluate potential survival benefit of different prophylactic regimens for acute GVHD (aGVHD). We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) including patients undergoing Allo-SCT. We included trials that assessed the addition of MTX, compared CsA and tacrolimus and evaluated the addition of steroids. Outcomes assessed were all-cause mortality (ACM) at the longest follow-up, aGVHD, chronic GVHD, TRM, relapse rate and regimen-specific adverse events. Relative risks (RRs) with 95% confidence intervals (CIs) were estimated and pooled. The regimen of MTX-CsA vs CsA alone (four trials) yielded no statistically significant difference in ACM (RR=0.84 (0.61-1.14)), but a significant decrease in aGVHD (RR=0.52 (0.39-0.7)). There was no difference in ACM for the comparison of MTX-CsA and MTX-tacrolimus (three trials); however, MTX-tacrolimus was superior to MTX-CsA in the reduction of aGVHD (RR=0.62 (0.52-0.75)) and severe aGVHD (RR=0.67 (0.47-0.95)). The addition of steroids did not affect the outcomes (four trials). We conclude that MTX-CsA and MTX-tacrolimus are both acceptable alternatives for GVHD prophylaxis, although MTX-tacrolimus may be superior in terms of aGVHD reduction.     

Influence of the intensity of the conditioning regimen on the characteristics of acute and chronic graft-versus-host disease after allogeneic transplantation

The graft-versus-host disease (GVHD) characteristics of 150 consecutive patients undergoing reduced intensity conditioning allogeneic (allo-RIC) transplants and 88 patients undergoing myeloablative conditioning regimen were analysed. All patients received the same GVHD prophylaxis and peripheral blood stem cells from a human leucocyte antigen identical sibling. The cumulative incidence of acute GVHD (aGVHD) was 67% and 44% in the myeloablative and allo-RIC regimen groups, respectively (P < 0.001), and was 39% vs. 29%, respectively (P = 0.043), for grades 2-4 aGVHD. Only conditioning type (myeloablative versus allo-RIC) significantly influenced the incidence of aGVHD in multivariate analysis: Hazard ratio (HR) = 2.16 [95% confidence interval (CI): 1.52-3.07], P < 0.0001. The cumulative incidence of chronic GVHD (cGVHD) was 63% and 71% among myeloablative and allo-RIC patients respectively (P = 0.084). This trend was because of the higher incidence of limited cGVHD, but not extensive cGVHD among allo-RIC recipients [HR = 3.3 (95% CI: 1.42-8.08), P = 0.0017]. Moreover, among patients who developed cGVHD, the cumulative incidence of limited cGVHD was significantly lower in the myeloablative group than in the allo-RIC group (7% vs. 25%, P = 0.007). Duration of immunosuppression was shorter among allo-RIC patients (35.5% vs. 68.8% required systemic immunosuppression 36 months after transplant, P = 0.028). Although prospective controlled trials are required to further evaluate the effect of the conditioning regimen on GVHD, our results suggest that RIC modifies the incidence and characteristics of both acute and cGVHD after allogeneic transplantation, and decreases the immunosuppression requirements in long-term follow up when compared with myeloablative conditioning.     

Predictors of prolonged survival after allogeneic hematopoietic stem cell transplantation for multiple myeloma

A total of 149 patients with multiple myeloma (MM) who received allogeneic hematopoietic stem cell transplantation (allo-HCT) with myeloablative (MAC; n = 38) or reduced-intensity conditioning (RIC; n = 110) regimens at MD Anderson Cancer Center were evaluated. Of the total, 120 (81%) patients had relapsed or had refractory disease. Median age of MM patients was 50 (28-70) years with a followup time of 28.5 (3-164) months. The 100-day and 5-year treatment related mortality (TRM) rates were 17% and 47%, respectively. TRM was significantly lower with RIC regimens (13%) vs. 29% for MAC at 100 days (P = 0.012). The cumulative incidence of Grade II-IV acute graft-versus-host disease (GVHD) was 35% and chronic GVHD was 46%. PFS and OS at 5 years were 15% and 21%, respectively. In multivariate analysis, allo-HCT for primary remission consolidation was associated with longer PFS (HR 0.35; 95% CI, 0.18-0.67) and OS (HR 0.29; 95% CI 0.15-0.55), while absence of high-risk cytogenetics was associated with longer PFS only (HR 0.59; 95% CI 0.37-0.95). We observe that TRM has decreased with the use of RIC regimens, and long-term disease control can be expected in a subset of MM patients undergoing allo-HCT. Further studies should be conducted in carefully designed clinical trials in this patient population.     

A prospective randomized trial comparing cyclosporine and short course methotrexate with cyclosporine and mycophenolate mofetil for GVHD prophylaxis in myeloablative allogeneic bone marrow transplantation

Cyclosporine (CSP) and short course methotrexate (MTX) have been the gold standard for GVHD prophylaxis for decades. Problems associated with MTX include increased time to hematopoietic engraftment, mucositis, and other organ toxicities. The combination of CSP with mycophenolate mofetil (MMF) has been used successfully for the prevention of graft rejection and GVHD in nonmyeloablative transplantation. We performed a prospective randomized trial comparing CSP and MTX with CSP and MMF in myeloablative (busulfan based) allogeneic 6/6 matched sibling bone marrow transplantation (BMT). The group receiving MMF (n = 21) had significantly less severe mucositis than did the group receiving MTX (n = 19) (21 vs 65%, P = 0.008). Median time to neutrophil engraftment was more rapid in the MMF group (11 vs 18 days, P < 0.001). The incidence of acute GVHD, as well as 100 day survival, was similar for both groups. The reduced toxicity of the CSP and MMF arm resulted in premature study closure. We conclude that a GVHD prophylaxis regimen of CSP and MMF after a myeloablative allogeneic preparative regimen is associated with faster hematopoietic engraftment, decreased incidence of mucositis, similar incidence of aGVHD, and comparable survival as compared to CSP and MTX.     

Early administration of recombinant erythropoietin improves hemoglobin recovery after reduced intensity conditioned allogeneic stem cell transplantation

The use of recombinant human erythropoietin (rHuEPO) has been controversial after myeloablative allogeneic Stem cell transplantation (allo-SCT). Reduced intensity conditioning regimens (RIC) offer a novel approach that might translate into a different profile of erythropoietic recovery. We treated 20 consecutive patients with rHuEPO early after matched sibling RIC allo-SCT. Conditioning included fludarabine, busulfan and antithymocyte globulin. EPO treatment was analyzed in terms of toxicity, impact on the frequency of Red blood cell transfusions (RBCT) and kinetics of Hemoglobin recovery within the 60 days post-allo-SCT. Results were compared with 27 matched patients who did not receive rHuEPO. In the first 2 months after allo-SCT all patients receiving rHuEPO (100%) achieved an Hb level > 11 g/dl at a median of 30 (15-35) days post-allo-SCT, as compared to only 63% of the patients not receiving rHuEPO (P = 0.007) at a median of 35 (20-55) days (P = 0.03). A total of 70% (95% CI, 50-90) of rHuEPO patients maintained an Hb over 11 g/dl in the second month as compared to only 19% (95% CI, 4-34) in the other group (P = 0.0004). For patients receiving RBCT, the use of rHuEPO was associated with a trend towards reduced RBCT requirements. This pilot study suggests a potential benefit of early administration of rHuEPO after RIC allo-SCT on early erythropoietic recovery.     

Higher CD3(+) and CD34(+) cell doses in the graft increase the incidence of acute GVHD in children receiving BMT for thalassemia

We evaluated the incidence of GVHD, risk factors and the impact of graft composition on acute GVHD (aGVHD) in 92 children who underwent BMT for thalassemia following busulfan/cyclophosphamide (BUCY)-based conditioning regimens and GVHD prophylaxis with CSA/short-MTX and methylprednisolone. The incidence of grade 2-4 and 3-4 aGVHD was 35% (95% confidence interval (CI) 25-44) and 9% (95% CI 4-16), respectively. We found that CD3(+) and CD34(+) cell doses above the median were associated with high incidence of grade 2-4 aGVHD (49 vs 20%, P=0.005 and 46 vs 23%, P=0.021, respectively). In multivariate analysis, high CD3(+) (hazard ratio (HR) 4.6; 95% CI 1.4-14.7; P=0.010) and CD34(+) (HR 4.3; 95% CI 1.4-12.7; P=0.011) cell doses were associated with grade 2-4 aGVHD. We further examined the effect of CD3(+) and CD34(+) cell doses on aGVHD using quartile cutoff points and found a minimum threshold for CD3(+) (38 × 10(6)/kg) and CD34(+) (4 × 10(6)/kg) cells above which the incidence of grade 2-4 aGVHD is significantly increased. This study shows for the first time a positive correlation between the number of CD3(+) and CD34(+) cells and aGVHD in children receiving sibling BMT, and indicates that using tailored and more intensive post transplant immunosuppression may permit to better control aGVHD.     

Allogeneic hematopoietic stem cell transplantation following reduced-intensity conditioning regimen in children: a single-center experience

This single-center retrospective study reported the outcome of 19 children treated with a reduced-intensity conditioning (RIC) regimen prior to allogeneic stem cell transplantation (allo-SCT), for hematologic malignancies (n = 17), bone marrow failure (n = 1), and neuroblastoma (n = 1). Children were ineligible for standard myeloablative conditioning because of severe comorbidities (n = 9), a previous auto or allo-SCT (n = 7) or a prior history of extensive chemotherapy (n = 3). All patients underwent a fludarabine-based RIC regimen, and received grafts from matched-related donors (n = 5), match-unrelated donors (n = 6), or unrelated cord blood (UCB, n = 8). In this series, two patients treated with UCB failed to engraft and 63% achieved full donor chimerism at day 100 after allo-SCT. With a median follow-up of 537 d (range, 115-4136), treatment-related mortality was 16% and overall survival was 47%. The principal cause of death was disease relapse (n = 7). Acute graft versus host disease (GVHD) occurred in 53% of patients, while only 10% developed extensive chronic GVHD. Overall, results from this series suggest that RIC allo-SCT can be a valid alternative treatment option in unfit children with malignant hematological diseases. Prospective studies are needed to enlarge pediatric experience in this domain and better identify those children more suitable for a RIC allo-SCT approach.     

Increased incidence of acute graft-versus-host disease with the continuous infusion of cyclosporine A compared to twice-daily infusion

We retrospectively compared the incidence of acute graft-versus-host disease (GVHD) before and after September 1999, when we changed the mode of cyclosporine A (CsA) administration from twice-daily infusions (TD) (n=58) to continuous infusion (CIF) (n=71). The incidence of grade II-IV acute GVHD in the CIF group (56%) was significantly higher than that in the TD group (27%, P=0.00022). Multivariate analysis identified only two independent significant risk factors for the development of grade II-IV acute GVHD; CIF of CsA (relative risk 2.59, 95% CI 1.46-4.60, P=0.0011) and the presence of HLA mismatch (2.01, 95% CI 1.15-3.53, P=0.014). The incidence of relapse was significantly lower in the CIF group when adjusted for disease status before transplantation (0.41, 95% CI 0.18-0.95, P=0.038), which resulted in better disease-free survival in high-risk patients (43 vs 16% at 2 years, P=0.039), but not in standard-risk patients (72 vs 80%, P=0.45). CIF of CsA with a target level of 250-400 ng/ml may not be appropriate for GVHD prophylaxis in standard-risk patients.     

Bone marrow as stem cell source for allogeneic HLA-identical sibling transplantation following reduced-intensity preparative regimen

OBJECTIVE: Reduced-intensity conditioning regimens (RIC) and peripheral blood stem cells (PBSC) are increasingly used for allogeneic stem cell transplantation (allo-BMT). RIC has been shown to allow engraftment with minimal early transplant-related mortality (TRM). However, in the context of RIC, the use of bone marrow (BM) as stem cell source is still little evaluated. PATIENTS AND METHODS: In this report, we analyzed the outcome of 32 high-risk patients with hematological malignancies who received an HLA-identical sibling allo-BMT after RIC including fludarabine, busulfan, and anti-thymocyte globulin (ATG). RESULTS: Sustained neutrophil and platelet recovery occurred at a median of 13 days (range, 10-19) and 17 days (range, 0-45) respectively. Early and durable full donor chimerism could be established as soon as the first month after allo-BMT. Also, a sustained and early CD8(+) T-cell recovery was observed, but the CD4(+) T-cell compartment remained profoundly low. The cumulative incidences of grade II-IV acute GVHD and chronic GVHD were 26% (95% CI, 11-41%) and 31% (95% CI, 15-47%) respectively. The overall cumulative incidence of TRM was 28% (95% CI, 12-44%) occurring mainly in patients aged over 50. In this setting, GVHD showed a protective effect on disease progression or relapse with better progression-free survival for patients with GVHD as compared to patients without GVHD (p=0.03). CONCLUSIONS: Collectively, these results confirm that the use of BM grafts for RIC is feasible with durable donor engraftment and no detrimental GVHD.     

Mycophenolate mofetil combined with tacrolimus and minidose methotrexate after unrelated donor bone marrow transplantation with reduced-intensity conditioning

We evaluated the efficacy of a post-grafting immunosuppressive regimen consisting of tacrolimus, methotrexate, and mycophenolate mofetil (MMF) in 21 adults (median age, 55 years) with poor-risk hematologic malignancy who underwent unrelated bone marrow transplantation after fludarabine-based reduced-intensity conditioning (RIC). In combination with intravenous tacrolimus and minidose methotrexate (5 mg/m² on days 1, 3, and 6), MMF was orally administered at 30 mg/kg daily in three divided doses between days 7 and 27. All patients achieved neutrophil recovery with donor-type chimerism at a median of 19 days (range, 13–35). Cumulative incidences of grades II–IV and III–IV acute graft-versus-host disease (GVHD) were 33% (95% CI, 15–53%) and 5% (95% CI, 0.3–20%), respectively. Five of 20 evaluable patients developed extensive chronic GVHD. Toxicities associated with the use of MMF were acceptable, although one patient experienced intractable GVHD immediately after the cessation of MMF. With a median follow-up of 24 months, overall survival at 3 years was 38% (95% CI, 14–63%). No late graft failure was observed. In conclusion, post-transplant MMF combined with tacrolimus and methotrexate was well tolerated and conferred stable donor cell engraftment, low risk of severe acute GVHD, and encouraging overall survival in unrelated donor marrow transplantation after RIC regimens.     

Comparable incidence and severity of cytomegalovirus infections following T cell-depleted allogeneic stem cell transplantation preceded by reduced intensity or myeloablative conditioning

Reports on infectious complications following reduced intensity conditioning (RIC) before allogeneic stem cell transplantation (allo-SCT) are equivocal. This prospective follow-up study compared the impact of cytomegalovirus (CMV) infections following RIC with fludarabine, ATG and busulphan or conventional myeloablative conditioning (MAC). Forty-eight RIC and 59 MAC patients were enrolled. The occurrence and severity of CMV infections within 100 days following allo-SCT were assessed, using plasma CMV DNA load kinetics. CMV DNAemia was observed in 21 RIC (60%) and in 19 MAC (44%) patients at risk for CMV. The mean CMV DNAemia free survival time was comparable following RIC and MAC: 70 days (95% (confidence interval) CI: 59-80 days) and 77 days (95% CI: 68-86 days), respectively (P=0.24). Parameters indicative for the level of CMV reactivation, including the area under the curve of CMV DNA load over time as well as the onset, the peak values and duration of CMV infection episodes, the numbers and duration of CMV treatment episodes and recurrent infections, were not different in both groups. During follow-up, none of the patients developed CMV disease. RIC with fludarabine, ATG and busulphan demonstrated safety comparable to conventional MAC with regard to frequency and severity of CMV infections within 100 days following T cell-depleted allo-SCT.     

Inflammatory cytokines and acute graft-versus-host disease after reduced-intensity conditioning allogeneic stem cell transplantation

This study investigated the role of inflammatory cytokines in acute graft-versus-host disease (aGVHD) incidence and severity in 113 patients who underwent reduced-intensity conditioning (RIC) allogeneic stem cell transplantation (allo-SCT). Among all tested cytokines in the first 3 months after allo-SCT, only interleukin-12 p70 (IL-12p70) levels in the first month were significantly associated with grades II to IV aGVHD development (P < .001). IL-12p70 levels were directly correlated with aGVHD severity grade (P < .001). Before aGVHD onset, blood monocytes, the main precursor pool of IL12p70-secreting dendritic cells, recovered more rapidly in patients with grades II to IV aGVHD (P = .005). Similarly, at the effector level, there was a more robust reconstitution of naive CD3+CD4+CD45RA+CD27+ T cells in patients developing grades II to IV aGVHD (P = .006). In multivariate analysis, IL-12p70 level measured in the first month was the strongest predictive factor for aGVHD development (P < .001). These findings, reconstituting a T(H)1 loop, support a model in which aGVHD reflects a type 1 alloreaction after RIC allo-SCT.     

Current status of reduced-intensity-conditioning allogeneic stem cell transplantation for acute myeloid leukemia

Allogeneic stem cell transplantation (allo-SCT) is the most efficient antileukemic treatment for acute myeloblastic leukemia (AML). However, elderly patients can rarely benefit from standard myeloablative allo-SCT because of an unacceptable rate of procedure-related toxicities. This point is critical when considering AML patients in first complete remission. The development of the so-called reduced-intensity conditioning (RIC) regimens appears to decrease allo-SCT-related toxicities, and has emerged as an attractive modality in AML patients not eligible for standard allo-SCT. Such RIC regimens aim primarily to provide the immune graft-versus-leukemia effect while causing little toxicity. Of note, treatment-related toxicity appears to be lower with RIC regimens as compared to standard myeloablative regimens. Nevertheless, toxicity might represent only one aspect of the problem, since AML encompasses a group of chemosensitive diseases, raising concerns that significant reduction of the intensity of the preparative regimen may have a negative impact on long-term leukemic control. Furthermore, no prospective studies have been reported thus far establishing RIC allo-SCT as the preferred option in AML. Investigators are currently faced with a dilemma on how to optimize the potential role of RIC allo-SCT in AML patients, while delivering minimal myeloablation and maximizing allogeneic immunotherapy. The aim of this review is to analyze the available research evidence in this field.     

Reduced-intensity allogeneic haemopoietic stem cell transplantation induces durable responses in patients with chronic B-lymphoproliferative disorders

Thirty-six patients with chronic B-lymphoproliferative disorders (B-LPD) underwent reduced-intensity allogeneic transplantation (RIT) from HLA-identical related donors. Diagnoses included follicular (n=17), mantle cell (n=9) and small lymphocytic lymphoma (n=2), and chronic lymphocytic leukaemia (n=8). Median age at transplant was 51 years (range, 30-66) and time from diagnosis was 3.4 years (range, 0.3-9.5). At transplant, 28% were in CR, 36% were in PR and 36% were chemorefractory. Conditioning therapy included fludarabine and either cyclophosphamide (n=27) or melphalan (n=9). Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporin (CsA)/methotrexate (n=21), CsA/mycophenolate mofetil (n=13) or CsA alone (n=2). Eight patients died owing to acute GVHD (n=3), infection in association with chronic GVHD (n=4) and intra-abdominal bleeding (n=1). Treatment-related mortality was 8% at day 100, and 17 and 20% at one and two years, respectively. The cumulative incidence of grade II-IV acute GVHD was 58%, whereas limited and extensive chronic GVHD occurred in 25 and 56%, respectively. No patient has relapsed or progressed. At a median follow-up of 48 months, overall survival probability is 80% (95% CI, 67-93%). We confirm that RIT in chronic B-LPD can result in high and durable CR rates but with significant incidences of acute and chronic GVHD.