Pre‐transplant comorbidity burden and post‐transplant chronic graft‐versus‐host disease

The Haematopoietic Cell Transplantation‐Comorbidity Index (HCT‐CI) was designed as a predictor of non‐relapse mortality after HCT. Chronic graft‐versus‐host disease (GVHD) contributes to mortality after HCT. Here, we investigated whether the HCT‐CI could predict development of chronic GVHD or post‐chronic GVHD mortality. We retrospectively analysed data from 2909 patients treated with allogeneic HCT for malignant and non‐malignant haematological conditions at four institutions. In Cox regression models adjusted for potential confounders, increasing HCT‐CI was not statistically significantly associated with the development of chronic GVHD [hazard ratio (HR) = 1·02, P = 0·34]. Yet, the index was associated with an increased risk of non‐relapse mortality (HR = 1·29, P < 0·0001) as well as overall mortality (HR = 1·25, P < 0·001) following the development of chronic GVHD. The association between HCT‐CI and post‐chronic GVHD mortality was similar regardless of donor type or stem cell source. HCT‐CI scores could be incorporated in the design of clinical trials for treatment of chronic GVHD.     

Occurrence of graft‐versus‐host disease increases mortality after umbilical cord blood transplantation for acute myeloid leukaemia: a report from Eurocord and the ALWP of the EBMT

Background

The efficacy of umbilical cord blood transplantation (UCBT) as treatment for acute myeloid leukaemia (AML) relies on immune‐mediated graft‐versus‐leukaemia effects. Previous studies have suggested a strong association between graft‐versus‐host disease (GVHD) occurrence and graft‐versus‐leukaemia effects after allogeneic hematopoietic cell transplantation.

Methods

Here, we evaluated the kinetics of relapse rate in correlation with GVHD occurrence after UCBT. The kinetics of relapse rate over time in correlation to GVHD occurrence were assessed by calculating the relapse rate per patient‐year within sequential 90‐day intervals. The impact of GVHD on relapse and mortality was further studied in multivariate Cox models handling GVHD as a time‐dependent covariate.

Results

The study included data from 1068 patients given single (n  = 567) or double (n  = 501) UCBT. The proportion of patients with grade II, III and IV acute GVHD was 20%, 7% and 4%, respectively. At 2 years, the cumulative incidence of chronic GVHD was 42%, the cumulative incidence of relapse was 32%, and overall survival was 32% as well. Relapse rates declined gradually over time during the first 30 months after transplantation. There was a possible suggestion that grade II–IV acute (HR = 0.8, P  = 0.1) and chronic (HR = 0.65, P  = 0.1) GVHD decreased relapse risk. However, grade II–IV acute GVHD significantly increased early (the first 18 months after UCBT) mortality (HR = 1.3, P  = 0.02), whilst chronic GVHD increased each early (HR = 2.7, P  < 0.001) and late (HR = 4.9, P  < 0.001) mortality after UCBT.

Conclusions

The occurrence of grade II–IV acute or chronic GVHD each increases overall mortality after UCBT for AML mitigating the possible graft‐versus‐leukemia effect of GVHD.

     

The association of histologic grade with acute graft‐versus‐host disease response and outcomes

Consensus criteria are routinely used to clinically grade acute graft‐versus‐host disease (GVHD). A histologic grading system for acute GVHD is available, but there are limited data on its correlation with clinical grade and hematopoietic cell transplantation (HCT) outcomes. Among 503 patients who underwent allogeneic HCT from 2005 to 2013, we identified 300 biopsy episodes of the skin and gastrointestinal (GI) tract in 231 patients. Histologic grade was correlated with clinical grade of GVHD, day 28 treatment response, and outcome. Both skin (R = 0.32) and GI (R = 0.61) histologic grade correlated with clinical grade (P < 0.001). On multivariable analysis, histologic grade (HR 0.87, P = 0.011) and clinical grade (HR 0.86, P = 0.008) were significantly associated with day 28‐treatment response. A histologic grade lower than its associated clinical grade predicted for better response (HR 1.26, P = 0.027), while a histologic grade higher than associated clinical grade had no correlation with response (P = 0.89). Both clinical and histologic GVHD grade were significant predictors of non‐relapse mortality (HR 1.47, P = 0.04 and HR 1.67, P = 0.002, respectively) and all‐cause mortality (HR 1.57, P = 0.001 and HR 1.29, P = 0.046, respectively). Histologic GVHD grade thus is correlated with clinical grading and treatment response, and may play a role in further predicting severity and treatment response of acute GVHD.     

Allogeneic bone marrow vs. peripheral blood stem cell transplantation: a long-term retrospective single-center analysis in 329 patients

Objectives: Granulocyte colony‐stimulating factor‐mobilized peripheral blood hematopoietic stem cell transplantation (HSCT) provides a valuable and increasingly used alternative to bone marrow transplantation (BMT). This retrospective study aimed at determining whether the stem cell source is predictive for outcome, relapse incidence, non‐relapse mortality, and severity and incidence of both, acute and chronic graft‐versus‐host disease (GVHD) in patients undergoing allogeneic HSCT. Patients and methods: Between 1983 and 2007, 329 adult patients (median age 40, range 18–76) received a first allogeneic HSCT from either sibling (n = 203) or volunteer unrelated donors (n = 126) at our institution. The source of stem cells was bone marrow in 177 (54%) and peripheral blood in the remaining 152 (46%) patients. Results: Overall survival was 37% (31–43%, 95% confidence interval, CI), the relapse incidence was 30% (25–36%, 95% CI), and the non‐relapse mortality was 43% (38–49%, 95% CI) for the entire cohort with no significant differences between peripheral blood stem cell or BMT. In patients receiving myeloablative conditioning, peripheral blood stem cell transplantation (PBSCT) was associated with a significantly lower non‐relapse mortality (32% vs. 46%, P = 0.05), which, however, was restricted to standard‐risk disease (23% vs. 42%, P = 0.02). The overall cumulative incidences of acute GVHD II–IV were 51% and 54% following bone marrow and PBSCT, respectively. Severe acute GVHD III–IV was significantly more frequent after BMT (24% vs. 14%, P = 0.04), whereas chronic GVHD was significantly more frequent following PBSCT (48% vs. 24%, P = 0.0001). By multivariate analysis, PBSCT was only predictive for chronic GVHD (RR 2.29, P = 0.02). Conclusion: Although we failed to demonstrate any advantage of PBSCT over conventional BMT with regard to overall survival, relapse incidence and non‐relapse mortality PBSCT were associated with a significantly higher incidence of chronic graft‐versus‐host disease. Therefore, and by virtue of observations, that some patient groups might benefit from either stem cell source, there is still need for prospective randomized trials with special emphasize on quality of life in long‐term survivors.     

Activating killer immunoglobulin‐like receptor incompatibilities enhance graft‐versus‐host disease and affect survival after allogeneic hematopoietic stem cell transplantation

Objectives: Killer immunoglobulin‐like receptors (KIRs) regulate function of natural killer (NK) cells and a subset of T cells. In this study, we prospectively evaluated the impact of donor and recipient activating KIR genes on outcome of allogeneic hematopoietic stem cell transplantation (alloHSCT) for patients with hematological malignancies. Methods: One‐hundred consecutive recipients of myeloablative transplantation and their donors were tested for KIR genotype as well as for immune reconstitution, including activating KIR expression on NK cells and T cells. Results: In a multivariate analysis, mismatches of particular activating KIRs such that the patient was negative and the donor was positive (P^?D⁺) resulted in increased risk of acute (KIR2DS1) and chronic (KIR2DS3) graft‐versus‐host disease (GVHD) as well as relapse (KIR2DS5). KIR2DS1 incompatibility in the same direction in the presence of HLA‐C‐group 2 ligand in recipient was associated with reduced overall (risk ratio, RR = 3.01; P = 0.01) and disease‐free survival (RR = 2.92, P = 0.03). Activating mismatches in P^?D⁺ direction resulted in decreased CD4⁺ : CD8⁺ T‐cell ratio up to 1 yr after alloHSCT, as a consequence of decreased CD3⁺CD4⁺ number within the first 100 d and increased CD3⁺CD8⁺ number in later time‐points. Among six evaluated patients, expression of activating KIRs on NK cells and T cells was particularly prominent for those developing intestinal GVHD. Conclusion: Our findings indicate that the presence of particular activating KIRs in donor with their absence in recipient enhances GVHD, which is not accompanied by graft‐versus‐leukemia effect. Evaluation of activating KIR genotype may allow optimization of both donor selection and transplantation procedure in order to avoid GVHD.     

Positive impact of chronic graft‐versus‐host disease on the outcome of patients with de novo myelodysplastic syndrome after allogeneic hematopoietic cell transplantation: a single‐center analysis of 115 patients

To evaluate the impact of graft‐versus‐host disease (GVHD) and prognostic factors for patients with myelodysplastic syndrome (MDS) after allogeneic hematopoietic cell transplantation (allo‐HCT), we retrospectively reviewed 115 patients with MDS or acute myeloid leukemia with multilineage dysplasia (AML‐MLD) after allo‐HCT at our center. Eighty one patients received reduced‐intensity conditioning (RIC) regimens, whereas 34 received myeloablative conditioning regimens. Although the RIC group was significantly older and included more patients with poor cytogenetic risk, no difference in 4‐yr overall survival (OS) was seen between the two groups. In a multivariate analysis, covariates associated with a worse OS were the French‐American‐British stage of refractory anemia excess blasts in transformation/AML‐MLD at peak, poor cytogenetic risk, bone marrow blasts of 20% or higher at HCT and the absence of chronic GVHD (cGVHD). By using semi‐landmark analyses, we found that the presence of cGVHD significantly improved OS in high‐risk patients or the RIC group. However, there was no difference in OS between those with and without cGVHD among low‐risk MDS patients. These findings suggest that the graft‐versus‐leukemia effect may be more beneficial in high‐risk patients who do not receive intensive preparative regimens.     

Measurable residual disease,conditioning regimen intensity,and age predict outcome of allogeneic hematopoietic cell transplantation for acute myeloid leukemia in first remission: A registry analysis of 2292 patients by the Acute Leukemia Working Party European Society of Blood and Marrow Transplantation

Patients with acute myeloid leukemia (AML) in morphological first complete remission (CR1) pre‐allogeneic hematopoietic cell transplantation (HCT) may have measurable residual disease (MRD) by molecular and immunophenotyping criteria. We assessed interactions of MRD status with HCT conditioning regimen intensity in patients aged <50 years (y) or ≥50y. This was a retrospective study by the European Society for Blood and Marrow Transplantation registry. Patients were >18y with AML CR1 MRD NEG/POS and recipients of HCT in 2000‐2015. Conditioning regimens were myeloablative (MAC), reduced intensity (RIC) or non‐myeloablative (NMA). Outcomes included leukemia free survival (LFS), overall survival (OS), relapse incidence (RI), non‐relapse mortality (NRM), chronic graft‐vs‐host (cGVHD), and GVHD‐free and relapse‐free survival (GRFS). The 2292 eligible patients were categorized into four paired groups: <50y MRD POS MAC (N = 240) vs RIC/NMA (N = 58); <50y MRD NEG MAC (N = 665) vs RIC/NMA (N = 195); ≥50y MRD POS MAC (N = 126) vs RIC/NMA (N = 230), and ≥50y MRD NEG MAC (N = 223) vs RIC/NMA (N = 555). In multivariate analysis RIC/NMA was only inferior to MAC for patients in the <50y MRD POS group, with worse RI (HR 1.71) and LFS (HR 1.554). Patients <50Y MRD NEG had less cGVHD after RIC/NMA HCT (HR 0.714). GRFS was not significantly affected by conditioning intensity in any group. Patients aged <50y with AML CR1 MRD POS status should preferentially be offered MAC allo‐HCT. Prospective studies are needed to address whether patients with AML CR1 MRD NEG may be spared the toxicity of MAC regimens. New approaches are needed for ≥50y AML CR1 MRD POS.     

Time to unrelated donor leukocyte infusion is longer,but incidence of GVHD and overall survival are similar for recipients of unrelated DLI compared to matched sibling DLI

Donor leukocyte infusion (DLI) is used to treat relapsed leukemia after allogeneic hematopoietic stem cell transplant (HCT). Data comparing outcomes after unrelated DLI (uDLI) to matched sibling DLI (msDLI) are scant. We performed a retrospective analysis to assess differences in time to administer uDLI versus msDLI, and impact on outcomes. Fifty three patients with relapsed acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), or myelodysplastic syndrome (MDS) after allogeneic HCT received uDLI (n = 18) or msDLI (n = 35) from 2000 to 2011. Median time from relapse to uDLI request was 15 days (range 0–66). Median time from relapse to uDLI was 56 days versus 40 days for msDLI patients (p = 0.034). 35% of msDLI and 44% of uDLI patients developed acute GVHD (p = 0.50). There was no significant difference in Grade C/D GVHD among uDLI and msDLI (28% and 21%, p = 0.58) or median OS after DLI between uDLI and msDLI (95 versus 75 days, p = 0.76). For patients with relapsed acute leukemia and MDS after allogeneic HCT, time from relapse to uDLI was longer than to msDLI, but incidence of GVHD and overall survival were similar. Access to uDLI does not appear to be a barrier to DLI administration. Outcomes unfortunately remain poor regardless of donor source. Am. J. Hematol. 91:426–429, 2016. © 2016 Wiley Periodicals, Inc.     

Growth factor-associated graft-versus-host disease and mortality 10 years after allogeneic bone marrow transplantation

This study analysed the effects of growth factor on outcome after haematopoietic stem‐cell transplantation (HSCT) with >9 years follow‐up. Of 1887 adult patients with acute leukaemia who received bone marrow from human leucocyte antigen (HLA)‐identical siblings and were treated with myeloablative conditioning, 459 (24%) were treated with growth factor. Growth factor hastened engraftment of neutrophils (P < 0·0001), but reduced platelet counts (P = 0·0002). Graft‐versus‐host disease (GVHD)‐free survival (no acute GVHD grade II–IV or chronic GVHD) at 10 years was 12 ± 2% (±SE) in the growth factor group, as opposed to 17 ± 2% in the controls [hazard ratio (HR) 0·81, P = 0·001]. Similar differences in GVHD‐free survival were seen in patients with or without conditioning with total body irradiation (TBI). Non‐relapse mortality (NRM) was higher in the growth factor group irrespective of whether or not TBI conditioning was included [HR = 1·48; 95% confidence interval (CI): 1·15–1·9; P = 0·002; HR = 1·59; 95% CI: 1·07–2·37; P = 0·02, respectively]. Both groups had similar probabilities of leukaemic relapse (HR = 0·96; 95% CI: 0·78–1·18; P = 0·71). Leukaemia‐free survival (LFS) at 10 years was 35 ± 2% in those receiving growth factor prophylaxis, as opposed to 44 ± 1% in the controls (HR = 0·70; 95% CI: 0·60–0·82; P = 0·00001). Prophylaxis with growth factor increases the risk of GVHD, does not affect relapse, increases NRM and reduces LFS > 10 years after HSCT, regardless of conditioning with TBI.     

Increased regulatory T cell graft content is associated with improved outcome in haematopoietic stem cell transplantation: a systematic review

Allogeneic haematopoietic stem cell transplant (HSCT) recipients are at increased risk of morbidity and mortality, often due to the development of acute or chronic graft‐versus‐host disease (GVHD). Low numbers or proportions of regulatory T cells (Tregs) have been reported in patients who develop GVHD. We undertook a systematic review of studies that reported the Treg composition of HSCT grafts in patients with haematological malignancies. Fourteen eligible studies were identified, eight of which stratified patients by Tregs (absolute dose or ratio to CD3+ or CD4+ cells). Meta‐analyses showed that high levels of Tregs in the grafts were associated with improved overall survival [hazard ratio (HR) 0·42, 95% confidence interval (CI) 0·23–0·74, P  = 0·003, 2 studies], with a significant reduction in non‐relapse mortality (HR 0·30, 95% CI 0·14–0·64, P  = 0·002, 2 studies) and a reduced risk of acute GVHD (relative risk (RR) 0·59, 95% CI 0·40–0·89, P  = 0·01, 6 studies). The consistency of these findings strongly suggests that the Treg composition of HSCT grafts has a powerful effect on the success of allogeneic HSCT. The major challenge is to translate these findings into better selection of allografts and future donors to provide a substantial improvement in allogeneic HSCT outcomes and practice.     

Demodicidosis simulating acute graft‐versus‐host disease after allogeneic stem cell transplantation in one patient with acute lymphoblastic leukemia

One important differential diagnosis of facial erythema in a patient receiving an allogeneic bone marrow transplant (BMT) is acute graft‐versus‐host disease (GVHD). Demodex folliculorum has been rarely implicated in the development of facial rashes in immunosuppressed patients, including BMT recipients. We report the case of a patient, suffering from acute lymphoblastic leukemia, who after bone marrow transplantation developed a facial rash due to D. folliculorum mimicking GVHD. Differential diagnosis of facial rashes and demodicidosis after BMT is reviewed.     

Donor age determines outcome in acute leukemia patients over 40 undergoing haploidentical hematopoietic cell transplantation

Haploidentical hematopoietic cell transplantation (haplo‐HCT) is being increasingly used in acute leukemia patients as an alternative transplant modality when matched sibling or matched unrelated donors are unavailable. As several potential haploidentical relative donors are typically available for a given patient, optimizing donor selection to improve clinical outcome is crucial. The impact of donor age and kinship on the outcome of acute leukemia patients is not clearly established in this setting. Using the multinational registry of the acute leukemia working party of the European society for blood and marrow transplantation we retrospective analyzed the clinical outcome of 1270 acute myeloid leukemia and acute lymphoblastic leukemia patients who underwent haplo‐HCT between 2005 and 2015. Patients over the age of 40 were significantly affected by increasing donor age resulting in higher non‐relapse mortality (NRM) [Hazard ratio (HR)=1.86, confidence interval (CI) 95%, 1.18‐2.94; P = .007], inferior leukemia‐free survival (LFS) (HR = 1.59, CI 95%, 1.13‐2.24; P = .007), and overall survival (OS) (HR = 1.74, CI 95%, 1.22‐2.47; P = .002) when donors were over the age of 40. Additionally, kinship was found to be prognostically significant as patients transplanted from children donors over the age of 35 experienced an increased rate of NRM (HR = 1.82, CI 95%, 1.13‐2.9; P = .01), inferior LFS (HR = 1.5, CI 95%, 1.05‐2.13; P = .03), and OS (HR = 1.5, CI 95%, 1.04‐2.15; P = .03). For patients younger than 40 years, donor age and kinship were mostly not clinically impactful. Our data establish donor age and kinship as significant determinants of outcome following haplo‐HCT for acute leukemia patients.     

Comparison of transplant outcomes from matched sibling bone marrow or peripheral blood stem cell and unrelated cord blood in patients 50 years or older

Older recipient and donor age were associated with higher incidences of severe graft‐versus‐host disease (GVHD) and mortality after allogeneic hematopoietic stem cell transplantation from matched sibling donors (MSDs) and matched unrelated donors. Since a lower incidence of severe GVHD is advantageous in unrelated cord blood transplantation (CBT), a higher incidence of GVHD using older MSDs could be overcome using cord blood for older patients. We retrospectively analyzed Japanese registration data of 2,091 patients with acute myeloid leukemia, acute lymphoblastic leukemia (ALL), and myelodysplastic syndrome aged 50 years or older who underwent MSD bone marrow transplantation (BMT) (n = 319), MSD peripheral blood stem cell transplantation (PBSCT) (n = 462), or unrelated CBT (n = 1,310) between 2007 and 2012. Median age of MSD was 56 (range, 38–74) years. Compared with CBT, the risk of developing extensive chronic GVHD was higher after BMT (hazard ratio [HR], 2.00; P = 0.001) or PBSCT (HR, 2.38; P < 0.001), and transplant‐related mortality was lower after BMT (HR, 0.61; P < 0.001) or PBSCT (HR, 0.63; P < 0.001). Relapse rates were not significant difference between three groups. Although overall mortality was lower after BMT (HR, 0.67; P < 0.001) or PBSCT (HR, 0.75; P = 0.002) compared with CBT, the rates of a composite endpoint of GVHD‐free, relapse‐free survival (GRFS) were not significant difference between three groups. These data showed that MSDs remain the best donor source for older patients, but CBT led to similar GRFS to BMT and PBSCT. Am. J. Hematol. 91:E284–E292, 2016. © 2016 Wiley Periodicals, Inc.     

Similar outcome of allogeneic stem cell transplantation after myeloablative and sequential conditioning regimen in patients with refractory or relapsed acute myeloid leukemia: A study from the Société Francophone de Greffe de Moelle et de Thérapie Cellulaire

Patients with acute myeloid leukemia (AML) in relapse or refractory to induction therapy have a dismal prognosis. Allogeneic hematopoietic stem cell transplantation is the only curative option. In these patients, we aimed to compare the results of a myeloablative transplant versus a sequential approach consisting in a cytoreductive chemotherapy followed by a reduced intensity conditioning regimen and prophylactic donor lymphocytes infusions. We retrospectively analyzed 99 patients aged 18‐50 years, transplanted for a refractory (52%) or a relapsed AML not in remission (48%). Fifty‐eight patients received a sequential approach and 41 patients a myeloablative conditioning regimen. Only 6 patients received prophylactic donor lymphocytes infusions. With a median follow‐up of 48 months, 2‐year overall survival was 39%, 95% confidence interval (CI) (24‐53) in the myeloablative group versus 33%, 95% CI (21‐45) in the sequential groups (P = .39), and 2‐year cumulative incidence of relapse (CIR) was 57% versus 50% respectively (P = .99). Nonrelapse mortality was not higher in the myeloablative group (17% versus 15%, P = .44). In multivariate analysis, overall survival, CIR and nonrelapse mortality remained similar between the two groups. However, in multivariate analysis, sequential conditioning led to fewer acute grade II‐IV graft versus host disease (GVHD) (HR for sequential approach = 0.37; 95% CI: 0.21‐0.65; P < .001) without a significant impact on chronic GVHD (all grades and extensive). In young patients with refractory or relapsed AML, myeloablative transplant and sequential approach offer similar outcomes except for a lower incidence of acute GvHD after a sequential transplant.     

FABC预处理异基因造血干细胞移植治疗难治未缓解急性白血病临床研究

目的观察FABC预处理异基因造血干细胞移植治疗未缓解急性白血病(AL)患者的疗效及安全性。方法收集2005年11月至2010年8月广东省人民医院采用FABC预处理方案进行异基因造血干细胞移植治疗18例难治未缓解AL患者。观察造血恢复、植入率、急慢性移植物抗宿主病发生率、移植相关病死率、复发、总存活率和无病存活率及预后因素分析。结果所有患者均于移植后14～21 d获得完全供者植入,中性粒细胞>0.5×109/L和血小板>20×109/L中位时间分别为12(7～72)d和13(7～60)d;急性移植物抗宿主病(GVHD)及慢性GVHD累积发生率分别为50%和73.3%。中位随访10.5(3.1～66.6)个月,移植相关病死率5.6%(1/18),复发率为36.8%(7/18)。1年的预期总生存(OS)率和无病生存(DFS)率分别是(58.9±13.2)%和(53.6±15.5%)。COX逐步回归模型分析显示,慢性GVHD是DFS独立有利因素。结论 FABC预处理异基因造血干细胞移植是治疗难治性未缓解AL安全有效的方法。     

Early lymphocyte recovery at 28 d post‐transplant is predictive of reduced risk of relapse in patients with acute myeloid leukemia transplanted with peripheral blood stem cell grafts

Allogeneic hematopoietic cell transplantation (HCT) is potentially curative for acute myeloid leukemia (AML). Impact of lymphocyte recovery on post‐transplant outcomes has been suggested but reports are conflicting. We evaluated the impact of lymphocyte recovery at 28 d post‐HCT in 191 AML patients using peripheral blood stem cells as graft. Patients were divided into those with absolute lymphocyte count (ALC) ≥0.5 × 10⁹/L (n = 111, 58%; high ALC group) and those with ALC <0.5 × 10⁹/L (n = 80, 42%; low ALC group), at day 28 post‐transplant. With a median follow‐up of 49 months, overall survival (OS) was significantly improved in the high ALC group (59% at 3 yr) vs. patients with low ALC (40% at 3 yr, P = 0.03). Cumulative incidence of relapse (CIR) was significantly lower in the high ALC group (16% at 3 yr) vs. low ALC group (36% at 3 yr, P = 0.001). Multivariable analysis for CIR demonstrated high ALC group as an independent factor decreasing relapse risk (P = 0.03, HR = 0.49, 95% CI = 0.26–0.92). Multivariable analysis for OS and non‐relapse mortality did not demonstrate ALC ≥0.5 × 10⁹/L at 28 d post‐transplant to be predictive. We conclude that lymphocyte recovery with ALC ≥0.5 × 10⁹/L at day 28 post‐transplant is associated with less relapse in AML patients undergoing allogeneic peripheral blood HCT, but without survival benefit.     

Minimal residual disease status determined by multiparametric flow cytometry pretransplantation predicts the outcome of patients with ALL receiving unmanipulated haploidentical allografts

This study evaluated the effects of pretransplantation minimal residual disease (pre-MRD) on outcomes of patients with acute lymphoblastic leukemia (ALL) who underwent unmanipulated haploidentical stem cell transplantation (haplo-SCT). A retrospective study including 543 patients with ALL was performed. MRD was determined using multiparametric flow cytometry. Both in the entire cohort of patients and in subgroup cases with T-ALL or B-ALL, patients with positive pre-MRD had a higher incidence of relapse (CIR) than those with negative pre-MRD in MSDT settings (P < 0.01 for all). Landmark analysis at 6 months showed that MRD positivity was significantly and independently associated with inferior rates of relapse (HR, 1.908; P = 0.007), leukemia-free survival (LFS) (HR, 1.559; P = 0.038), and OS (HR, 1.545; P = 0.049). The levels of pre-MRD according to a logarithmic scale were also associated with leukemia relapse, LFS, and OS, except that cases with MRD <0.01% experienced comparable CIR and LFS to those with negative pre-MRD. A risk score for CIR was developed using the variables pre-MRD, disease status, and immunophenotype of ALL. The CIR was 14%, 26%, and 59% for subjects with scores of 0, 1, and 2-3, respectively (P < 0.001). Three-year LFS was 75%, 64%, and 42%, respectively (P < 0.001). Multivariate analysis confirmed the association of the risk score with CIR and LFS. The results indicate that positive pre-MRD, except for low level one (MRD < 0.01%), is associated with poor outcomes in patients with ALL who underwent unmanipulated haplo-SCT.     

Impact of graft-versus-host disease on outcomes after allogeneic hematopoietic cell transplantation for adult T-cell leukemia: a retrospective cohort study

Allogeneic hematopoietic cell transplantation (HCT) is an effective treatment for adult T-cell leukemia (ATL), raising the question about the role of graft-versus-leukemia effect against ATL. In this study, we retrospectively analyzed the effects of acute and chronic graft-versus-host disease (GVHD) on overall survival, disease-associated mortality, and treatment-related mortality among 294 ATL patients who received allogeneic HCT and survived at least 30 days posttransplant with sustained engraftment. Multivariate analyses treating the occurrence of GVHD as a time-varying covariate demonstrated that the development of grade 1-2 acute GVHD was significantly associated with higher overall survival (hazard ratio [HR] for death, 0.65; P = .018) compared with the absence of acute GVHD. Occurrence of either grade 1-2 or grade 3-4 acute GVHD was associated with lower disease-associated mortality compared with the absence of acute GVHD, whereas grade 3-4 acute GVHD was associated with a higher risk for treatment-related mortality (HR, 3.50; P < .001). The development of extensive chronic GVHD was associated with higher treatment-related mortality (HR, 2.75; P = .006) compared with the absence of chronic GVHD. Collectively, these results indicate that the development of mild-to-moderate acute GVHD confers a lower risk of disease progression and a beneficial influence on survival of allografted patients with ATL.     

Comparative outcomes of myeloablative and reduced-intensity conditioning allogeneic hematopoietic cell transplantation for therapy-related acute myeloid leukemia with prior solid tumor: A report from the acute leukemia working party of the European society for blood and bone marrow transplantation

Therapy-related acute myeloid leukemia (t-AML) arises as a late complication following antecedent solid tumors or hematologic diseases and their associated treatments. There are limited data regarding risk factors and outcomes following allogeneic hematopoietic cell transplantation (HCT) for t-AML following a prior solid tumor, and furthermore, the impact of myeloablative (MAC) vs reduced-intensity conditioning (RIC) on survival is unknown. The acute leukemia working party (ALWP) of the European society for blood and bone marrow transplantation (EBMT) performed a large registry study that included 535 patients with t-AML and prior solid tumor who underwent first MAC or RIC allogeneic HCT from 2000-2016. The primary endpoints of the study were OS and LFS. Patients receiving RIC regimens had an increase in relapse incidence (hazard ratio [HR], 1.52; 95% confidence interval [CI] 1.02-2.26; P = 0.04), lower LFS (HR, 1.52; 95% CI 1.12-2.05, P = 0.007), and OS (HR, 1.51; CI 1.09-2.09; P = 0.012 ) . There were no differences in NRM and GRFS. Importantly, LFS and OS were superior in patients receiving ablative regimens due to a decrease in relapse. As NRM continues to decline in the current era, it is conceivable that outcomes of HCT for t-AML with prior solid tumor may be improved by careful patient selection for myeloablative regimens.     

Engraftment syndrome after allogeneic hematopoietic cell transplantation in adults

We performed a retrospective study of the engraftment syndrome (ES) as defined by the Spitzer Criteria in adult patients undergoing allogeneic hematopoietic cell transplantation (HCT) for various hematological malignancies at a single institution, over a decade, and analyzed its relationship to acute GVHD; 217 patients underwent either myeloablative (38.7%) or reduced intensity (61.3%) HCT; 22.1% met the criteria for ES. Acute GVHD prophylaxis (P = 0.006) and transplants prior to 2006 (P < 0.0001) were significantly associated with a risk of ES in univariable analysis. Early aGVHD within 4 weeks of engraftment was significantly more common in the ES compared to the non ES cohort (21 vs. 8.3% respectively, P = 0.02). ES did not predict for future GVHD, as at day +180, the cumulative incidences of grades II–IV aGVHD (31 vs. 23%, P = 0.19) and of chronic GVHD at 2 years of engraftment (42 vs. 36%, P = 0.28) were not significantly different between the ES and non ES groups, respectively. No significant differences in NRM, overall survival and progression‐free survival were observed between the two groups. Although predictive of early aGVHD, ES occurred independently of GVHD in 79% of the patients. Survival outcomes should be evaluated in a larger randomized study to investigate if there is a correlation with ES. Am. J. Hematol. 89:698–705, 2014. © 2014 Wiley Periodicals, Inc.