Survival benefits from reduced-intensity conditioning in allogeneic stem cell transplantation for young lower-risk MDS patients without significant comorbidities

Objective: The aim of this study was to determine the optimum conditioning intensity for allogeneic stem cell transplantation (SCT) in young (age ≤50), lower‐risk (INT‐1 by IPSS) Myelodysplastic syndrome (MDS) patients without significant comorbidities (hematopoietic cell transplantation‐comorbidity index score ≤3). Methods: Transplant outcomes from 46 consecutive patients were retrospectively analyzed according to the conditioning intensity: reduced‐intensity conditioning (RIC; n = 14), intensified RIC by adding low‐dose total body irradiation (iRIC; n = 15), and myeloablative conditioning (MAC; n = 17). Results: After a median follow‐up of 73.7 months, RIC had a better 4‐yr overall survival (OS) (92.9%) compared with the iRIC (64.2%) or MAC (70.6%). Multivariate analysis showed that RIC was associated with improved OS compared with the MAC [relative risk (RR) of 0.08, P = 0.022] because of a lower transplant‐related mortality (TRM) (RR, 0.08, P = 0.035). iRIC failed to show survival benefits over the MAC (RR of 0.77, P = 0.689) because of similarly high TRM (RR of 0.41, P = 0.480). Cumulative incidence of acute and chronic graft‐versus‐host disease (GVHD) after RIC was higher, but GVHD‐specific survival was significantly better (RIC 100% vs. iRIC 45.7% vs. MAC, P = 0.018). Relapse rate was not different among the three groups, but in the RIC group, azacitidine was available and useful for inducing remission in two patients. Conclusion: This study shows that RIC improved OS by directly lowering TRM and indirectly giving an additional chance for relapsed MDS in the era of hypomethylating treatment. RIC–SCT should be considered for relative healthy lower‐risk MDS patients.     

Conventional versus reduced-intensity conditioning regimen for allogeneic stem cell transplantation in patients with hematological malignancies

BACKGROUND: Allogeneic hematopoietic stem cell transplantation (HSCT) from human leukocyte antigen (HLA)-compatible sibling donors is a potential curative treatment for hematological and non-hematological malignancies. Nevertheless, high mortality rates may be associated with this therapy, especially in older patients, those with other comorbidities or who receive a second HSCT. PATIENTS AND METHODS: We analyzed the factors associated with transplant-related mortality (TRM) and overall survival in 157 consecutive adult patients (104 males and 53 females) who received a HSCT [29 bone marrow (BM) transplantation and 128 peripheral blood (PB) transplantation] from a HLA-identical sibling between January 1995 and March 2002 in our institution. One hundred patients received a standard conditioning prior to HSCT (STAND) and 57 patients received a reduced-intensity conditioning (RIC) HSCT. Fifty-eight patients were in an early phase at transplant and 99 in a non-early phase. Median age was 46 yr (16-66), and 90 patients (57%) were >45 yr of age. RESULTS: Patients in the RIC group were older than those in the STAND group, and had a higher proportion of non-early disease phases including a prior autologous HSCT in 39%. Median follow-up for survivors was 28 and 15 months in the STAND and RIC groups (P < 0,001), respectively. Cumulative incidence of TRM at 2 yr was 30% [95% confidence interval (CI) 22-41%] for the STAND group and 22% (95% CI 13-37%) for the RIC group [non-significant (NS)]. Factors associated with a higher TRM in multivariate analysis were: STAND vs. RIC conditioning regimen [relative risk (RR) 5.4; 95% CI 2.3-12.8; P < 0.001]; age > or =45 yr vs. <45 yr (RR 5; 95% CI 2.4-10.8, P < 0.001); second vs. first HSCT (RR 2.8, 95% CI 1.3-6.3, P = 0.01) and non-T-cell-depleted vs. T-cell-depleted graft (RR 2.7, 95% CI 1.3-5.8, P = 0.009). Overall survival (OS) at 2 yr was 52.5 +/- 10.4% for STAND group and 59 +/- 16.8% in RIC group. Factors associated with poorer OS in multivariate analysis were: STAND vs. RIC conditioning regimen (RR 3.4, 95% CI 1.7-6.9, P = 0.001); age > or =45 vs <45 yr (RR 2.5, 95% CI 1.4-4.5, P = 0.002) and diagnosis [other than chronic myeloid leukemia (CML) vs. CML] (RR 2.6, 95% CI 1.2-5.7 P = 0.02). CONCLUSIONS: Our results indicate that the introduction of RIC allogeneic HSCT for patients at high risk for TRM (advanced age, prior HSCT and non-T-cell depletion) leads to a reduction in the TRM and improvement in the OS.     

Comparable long‐term outcomes after reduced‐intensity conditioning versus myeloablative conditioning allogeneic stem cell transplantation for adult high‐risk acute lymphoblastic leukemia in complete remission

The role of reduced‐intensity conditioning (RIC) in adult acute lymphoblastic leukemia (ALL) remains unclear because of the small sample size, short follow‐up duration, various regimens for conditioning and graft‐versus‐host disease (GVHD) prophylaxis, and the heterogeneity of selection criteria for transplantation. We compared long‐term outcomes of 60 consecutive RIC transplants (fludarabine plus melphalan) with 120 myeloablative conditioning (MAC) transplants (total body irradiation plus cyclophosphamide) for adult high‐risk ALL in first or second complete remission. All transplants received a uniform strategy of pretransplant chemotherapy and GVHD prophylaxis. Compared to MAC transplants, RIC transplants had older age (46 years vs. 33 years, P < 0.001) and higher proportions of transplantation using peripheral blood (93.3% vs. 13.3%; P < 0.001) but otherwise showed similar characteristics. After a median follow‐up of 67 months, RIC transplants showed comparable nonrelapse mortality (21.2% vs. 24.3%) and disease‐free survival (50.8% vs. 54.9%) to MAC transplants, although relapse risk was higher (34.2% vs. 26.4%; HR, 2.07; P = 0.019) in multivariate analysis. Other independent factors associated with better outcomes were the presence of chronic GVHD and transplantation in first complete remission. Interestingly, the negative impact of RIC on relapse risk was seen only for Philadelphia‐positive ALL transplants (32.7% vs. 19.6%; HR, 3.46; P = 0.020), while no difference was found between RIC and MAC for Philadelphia‐negative ALL transplants (35.0% vs. 32.1%; HR, 1.39; P = 0.429). RIC can be considered as a reasonable choice for providing a sufficient long‐term graft‐versus‐leukemia effect for adult high‐risk ALL patients ineligible for MAC. Am. J. Hematol. 88:634–641, 2013. © 2013 Wiley Periodicals, Inc.     

Primary treatment of leukemia relapses after allogeneic hematopoietic stem cell transplantation with reduced‐intensity conditioning second transplantation from the original donor

Acute leukemia relapsing after allogeneic hematopoietic stem cell transplantation (HSCT) has dismal outcome. Consecutive consenting patients (acute myeloid leukemia: N = 71; acute lymphoblastic leukemia: N = 37), at a median age of 37 (16–57) years, who had relapsed 7.9 (1.3–132) months post‐HSCT, were treated with three cytarabine‐based intensive regimens as reduced‐intensity conditioning (RIC), followed by infusion of mobilized HSC from the original donors. There were four treatment‐related mortalities (TRMs). Of 104 evaluable cases, 72 patients (67%) achieved complete remission (CR)/CR with incomplete hematologic recovery (CRi). The median overall survival (OS) of the entire cohort was 11.6 months. The OS of patients achieving CR/CRi after the first RIC/HSCT was 18.8 months, as compared with 3.9 months for those not (P < 0.01). For 32 patients with nonremission, 11 received a repeat RIC‐HSCT, leading to CR/CRi in three cases. Therefore, 75/108 (69%) of patients achieved CR/CRi after one or two courses of RIC‐HSCT. Among CR/CRi patients, 48 cases relapsed again after 6.1 (1.0–64.4) months. Thirty cases received a repeat RIC‐HSCT, leading to CR/CRi in 22 patients. Multivariate analyses showed a significant impact of remission duration after initial HSCT (P = 0.026) and the presence of acute graft‐versus‐host disease after RIC‐HSCT (P = 0.011) on CR/CRi. RIC‐HSCT as primary treatment for acute leukemic relapses post‐HSCT induced a high CR rate with low TRM. Optimal postremission treatment remains to be defined. Am. J. Hematol. 88:485–491, 2013. © 2013 Wiley Periodicals, Inc.     

Treatment with mesenchymal stromal cells is a risk factor for pneumonia-related death after allogeneic hematopoietic stem cell transplantation

We performed a retrospective cohort study to find out whether the use of reduced‐intensity conditioning (RIC) might reduce the risk of early death from pneumonia. Pneumonia‐associated deaths were evaluated in 691 hematopoietic stem cell transplantation (HSCT) patients. The majority had a hematological malignancy (n = 504) and an HLA‐matched donor (n = 584). RIC was given to 336 patients and myeloablative conditioning (MAC) to 355. Data concerning radiology, culture and autopsy results were evaluated together with risk factors for death related to pneumonia within or after 100 d after HSCT (early and overall pneumonia). In 60 patients, pneumonia contributed to death (early n = 17). The cumulative incidence of early pneumonia‐related death was 2.8% and 2.1% in MAC and RIC patients, respectively. The cumulative incidence of overall pneumonia‐related death was 8.2% and 10.5%, respectively. In 40 patients, (67%) an etiology could be established, with 19 patients having proven or probable mold infection. In the multivariate analyses, acute graft‐versus‐host disease (GVHD) grades II–IV, cytomegalovirus (CMV) infection and having received mesenchymal stromal cells (MSCs) were factors associated with overall pneumonia‐related death. Bacteremia and a previous HSCT were associated with early pneumonia‐related death. RIC did not reduce the incidence of early death associated with pneumonia. Acute GVHD II–IV, CMV infection and MSC treatment were factors associated with pneumonia‐related death. Mold infection was the most common contributor to pneumonia‐related death in HSCT patients.     

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.     

The addition of sirolimus to the graft‐versus‐host disease prophylaxis regimen in reduced intensity allogeneic stem cell transplantation for lymphoma: a multicentre randomized trial

Inhibition of the mechanistic target of rapamycin (mTOR) pathway has clinical activity in lymphoma. The mTOR inhibitor sirolimus has been used in the prevention and treatment of graft‐versus‐host disease (GVHD) after allogeneic haematopoietic stem cell transplantation (HSCT). A retrospective study suggested that patients with lymphoma undergoing reduced intensity conditioning (RIC) HSCT who received sirolimus as part of their GVHD prophylaxis regimen had a lower rate of relapse. We therefore performed a multicentre randomized trial comparing tacrolimus, sirolimus and methotrexate to standard regimens in adult patients undergoing RIC HSCT for lymphoma in order to assess the possible benefit of sirolimus on HSCT outcome. 139 patients were randomized. There was no difference overall in 2‐year overall survival, progression‐free survival, relapse, non‐relapse mortality or chronic GVHD. However, the sirolimus‐containing arm had a significantly lower incidence of grade II‐IV acute GVHD (9% vs. 25%, P = 0·015), which was more marked for unrelated donor grafts. In conclusion, the addition of sirolimus for GVHD prophylaxis in RIC HSCT is associated with no increased overall toxicity and a lower risk of acute GVHD, although it does not improve survival; this regimen is an acceptable option for GVHD prevention in RIC HSCT. This trial is registered at clinicaltrials.gov (NCT00928018).     

Allogeneic hematopoietic stem cell transplantation for adult T-cell leukemia-lymphoma with special emphasis on preconditioning regimen: a nationwide retrospective study

Adult T-cell leukemia-lymphoma (ATL) is an intractable mature T-cell neoplasm. We performed a nationwide retrospective study of allogeneic hematopoietic stem cell transplantation (HSCT) for ATL in Japan, with special emphasis on the effects of the preconditioning regimen. This is the largest study of ATL patients receiving HSCT. Median overall survival (OS) and 3-year OS of bone marrow or peripheral blood transplantation recipients (n = 586) was 9.9 months (95% confidence interval, 7.4-13.2 months) and 36% (32%-41%), respectively. These values for recipients of myeloablative conditioning (MAC; n = 280) and reduced intensity conditioning (RIC; n = 306) were 9.5 months (6.7-18.0 months) and 39% (33%-45%) and 10.0 months (7.2-14.0 months) and 34% (29%-40%), respectively. Multivariate analysis demonstrated 5 significant variables contributing to poorer OS, namely, older age, male sex, not in complete remission, poor performance status, and transplantation from unrelated donors. Although no significant difference in OS between MAC and RIC was observed, there was a trend indicating that RIC contributed to better OS in older patients. Regarding mortality, RIC was significantly associated with ATL-related mortality compared with MAC. In conclusion, allogeneic HSCT not only with MAC but also with RIC is an effective treatment resulting in long-term survival in selected patients with ATL.     

Hematopoietic stem cell transplantation in patients with severe Langerhans cell histiocytosis and hematological dysfunction: experience of the French Langerhans Cell Study Group

The aim of this study was to assess the results of hematopoietic stem cell transplantation (HSCT) in refractory Langerhans cell histiocytosis (LCH). Among 85 patients with LCH and hematological dysfunction diagnosed in France between 1987 and 2000, eight received HSCT in six institutions. Median age at diagnosis was 0.54 years. The median LCH activity score at diagnosis was 10 (range 3-20). All patients responded poorly to initial chemotherapy. At the time of HSCT, the median activity score was 16.5 (range 7-18). HSCT was autologous in three cases and allogeneic in five cases. The conditioning regimen consisted of TBI in two cases and chemotherapy alone in six cases. Conditioning had to be attenuated in two patients. All patients had persistent active disease after autologous HSCT, which was fatal in two cases and controlled by chemotherapy in one case. After allogeneic HSCT, two patients died from toxicity and three had complete responses; two patients had had no recurrences after 21 months and 7 years of follow-up, while the other patient relapsed and died from sepsis related to splenectomy. HSCT for refractory LCH can thus be highly toxic but can also achieve sustained disease control.     

Reduced-intensity allografting in patients with therapy-related myeloid neoplasms and active primary malignancies

Therapy-related myeloid neoplasms (t-MNs) are severe long-term consequences of cytotoxic treatments for a primary, often, malignant disorder. So far, the majority of patients eligible for transplantation have undergone myeloablative allo haematopoietic SCT (HSCT) as a potentially curative treatment, but it has been associated with high transplantation-related mortality (TRM) rates. In this retrospective study, we analysed the outcome of patients with t-MNs undergoing HSCT with reduced-intensity conditioning (RIC). Of 55 patients, seen at a single centre over a 10-year period, 17 underwent RIC HSCT with related or unrelated donors. The estimated overall survival was 53% at 1 year and 47% at 3 years, and disease-free survival was 47% at 1 year. At 1 year, the cumulative incidence of relapse and TRM were 24% and 30%, respectively. Of five patients with active primary neoplasms who underwent transplantation, two are alive beyond 1 year and show CR of both t-MNs and the primary malignancy. These data indicate that RIC HSCT is an encouraging approach for patients with t-MNs. The issue of primary malignancies not being in remission at the time of transplantation should be explored in further studies.     

Diagnosis and evaluation of intestinal graft-versus-host disease after allogeneic hematopoietic stem cell transplantation following reduced-intensity and myeloablative conditioning regimens

Colonoscopic evaluation of mucosal tissues after allogeneic hematopoietic stem cell transplantation (HSCT) is very useful in evaluating pathogenesis and diagnosis of intestinal graft-versus-host disease (GVHD). However, information on the timing and sites of biopsies and the immunohistological evaluation of mucosal tissues for diagnosing intestinal GVHD, especially following reduced-intensity (RIC) regimens, remains very limited. A total of 33 patients with histologically proven GVHD after allogeneic HSCT with RIC (n = 23) and myeloablative conditioning (MAC, n = 10) regimens were enrolled in the present study. Colonoscopy was performed due to gastrointestinal symptoms, especially diarrhea and anorexia. Sites of biopsies with the worst histopathological grading were the terminal ileum in 67 % of patients. In the RIC group, the onset of diarrhea prior to colonoscopy examination was later (median: RIC, 57 vs. MAC, 27 days) and the number of patients who developed abdominal pain tended to be higher (RIC, 70 % vs. MAC, 30 %). A lower number of CD4+ cells and a higher ratio of Foxp3+ cells to CD4+ cells were detected in the involved lesions of intestinal GVHD following RIC. These differences in the RIC and MAC groups suggest that regimen-specific therapeutic strategies are required for diagnosing intestinal GVHD.     

Outcome of conditioning intensity in acute myeloid leukemia with monosomal karyotype in patients over 45 year‐old: A study from the acute leukemia working party (ALWP) of the European group of blood and marrow transplantation (EBMT)

Acute myeloid leukemia with monosomal karyotype (MK AML) carries a very poor prognosis, even after allogeneic stem cell transplantation (SCT). However, SCT remains the only curative option in this high‐risk population. Because myeloablative conditioning regimen (MAC) is associated with less relapse, we hypothesized that more intensive conditioning regimen might be beneficial for MK AML patients. We reviewed 303 patients over age 45 diagnosed with either de novo or secondary MK AML. One hundred and five patients received a MAC and 198 a reduced‐intensity conditioning (RIC). The median age at SCT was 57‐year‐old, significantly lower in the MAC (53‐year‐old) than in the RIC group (59‐year‐old). The median follow‐up was 42 months (range, 3 ? 156 months). The 3‐year overall survival (OS), leukemia‐free survival (LFS), and relapse rate (RR) were not significantly different between both groups with overall values of 34%, 29%, and 51%, respectively. On the contrary, the 3‐year nonrelapse mortality (NRM) was significantly higher in MAC recipients (28%) compared with RIC patients (16%, P = 0.004). The incidence of Grades II to IV acute graft‐versus‐host disease (GvHD) was significantly higher after a MAC (30.5%) than after a RIC (19.3%, P = 0.02). That of chronic GvHD was comparable between both groups (35%) and did not impact on LFS. Interestingly, within our MK AML cohort, hypodiploidy was significantly associated with worse outcomes. Due to reduced toxicity and comparable OS, LFS, and RR, RIC appears as a good transplant option in the very high‐risk population, including older patients, diagnosed with MK AML. Am. J. Hematol. 90:719–724, 2015. © 2015 Wiley Periodicals, Inc.     

Factors associated with bronchiolitis obliterans syndrome and chronic graft‐versus‐host disease after allogeneic hematopoietic cell transplantation

Bronchiolitis obliterans syndrome (BOS) is a form of chronic graft vs. host disease (cGVHD) and a highly morbid pulmonary complication after allogeneic hematopoietic stem cell transplantation (HSCT). We assessed the prevalence and risk factors for BOS and cGVHD in a cohort of HSCT recipients, including those who received reduced intensity conditioning (RIC) HSCT. Between January 1, 2000 and June 30, 2010, all patients who underwent allogeneic HSCT at our institution (n = 1854) were retrospectively screened for the development of BOS by PFT criteria. We matched the BOS cases with two groups of control patients: (1) patients who had concurrent cGVHD without BOS and (2) those who developed neither cGVHD nor BOS. Comparisons between BOS patients and controls were conducted using t‐test or Fisher's exact tests. Multivariate regression analysis was performed to examine factors associated with BOS diagnosis. All statistical analyses were performed using SAS 9.2. We identified 89 patients (4.8%) meeting diagnostic criteria for BOS at a median time of 491 days (range: 48–2067) after HSCT. Eighty‐six (97%) of our BOS cohort had extra‐pulmonary cGVHD. In multivariate analysis compared to patients without cGVHD, patients who received busulfan‐based conditioning, had unrelated donors, and had female donors were significantly more likely to develop BOS, while ATG administration was associated with a lower risk of BOS. Our novel results suggest that busulfan conditioning, even in RIC transplantation, could be an important risk factor for BOS and cGVHD. Am. J. Hematol. 89:404–409, 2014. © 2013 Wiley Periodicals, Inc.     

Nonmyeloablative allogeneic stem cell transplantation (NST) after truly nonmyeloablative and reduced intensity conditioning regimens

Nonmyeloablative allogeneic stem cell transplantation (NST) has been explored to overcome transplant-related mortality (TRM). From the review of 39 published reports, 50% of the 1484 treated patients had NSTs with truly nonmyeloablative conditioning (NMC) and 417 patients (29%) received an unrelated donor transplant (UDT). Median age was 49 years (range 17-59). A median dose of 4.74 x 10(6) CD34+ per kg (range 1.7-7.5) was administered. Hematological recovery was rapid with all the regimens used. Sustained engraftment was obtained in 1267/1355 assessable patients (94%, range 67-100%). Complete donor chimerism was observed in 707/948 assessable patients (75%, range 22-100%). Both were higher after reduced intensity conditioning (RIC) than after NMC regimens. Reject was more frequent after UDT and NMC regimens. Grades II-IV and III-IV acute graft versus host disease (GVHD) occurred in 580/1400 (41%; range 7-72%) and 188/1093 (17%; range 0-29%) assessable patients, respectively; grades II-IV and III-IV acute GVHD were more frequent after UDT and RIC regimens, respectively. Chronic GVHD occurred in 407/1046 assessable patients (39%; range 0-79%) and extensive chronic GVHD in 166/835 patients (20%; range 0-69%); they were more frequent after RIC regimens and less frequent after UDT. Transplant-related mortality (TRM) rate of 20.6%, without differences between RIC and NMC regimens, was observed; TRM was higher with UDTs. The most frequent causes of TRM were acute or chronic GVHD after RIC regimens and infections after NMC regimens and UDTs. Indolent lymphoid malignancies and some solid tumors appear sensitive to the graft versus malignancy (GVM) effect. NSTs could guarantee relatively low TRM and toxicity in patients not eligible for conventional allogeneic transplantation and could represent a platform for successive specific immunotherapy.     

Predictive value of risk assessment scores in patients with hematologic malignancies undergoing reduced‐intensity conditioning allogeneic stem cell transplantation

Reduced‐intensity conditioning allogeneic stem cell transplantation (RIC allo‐SCT) is associated with less toxicity and is used for older patients. We retrospectively studied the predictive value of two risk assessment scores, which were the hematopoietic cell transplantation‐specific comorbidity index (HCT‐CI) and the pre‐transplantation assessment of mortality (PAM) score, for assessing the outcome of RIC allo‐SCT. Seventy‐eight patients underwent transplantation between 2005 and 2013 at a single institution. RIC was performed with fludarabine and melphalan with/without total body irradiation. The 3‐year overall survival of patients with an HCT‐CI >3 was significantly worse than that of patients with an HCT‐CI 0–3 (31.6% vs. 59.6%, P = 0.020). Also, the 3‐year overall survival of patients with a PAM score >24 was significantly worse than that of those with a PAM score ≤24 (29.2% vs. 61.4%, P = 0.005). The present findings suggest that changing the cut‐off values of these risk assessment scores can improve prediction of outcomes in patients receiving RIC allo‐SCT with this conditioning regimen and we need validation by large‐scale study with other regimens. Am. J. Hematol. 89:E138–E141, 2014. © 2014 Wiley Periodicals, Inc.     

Long-term follow-up of allogeneic hematopoietic stem-cell transplantation with reduced-intensity conditioning for patients with chronic myeloid leukemia

Allogeneic hematopoietic stem-cell transplantation (HSCT) remains an effective strategy for inducing durable remission in chronic myeloid leukemia (CML). Reduced-intensity conditioning (RIC) regimens extend HSCT to older patients and those with comorbidities who would otherwise not be suitable candidates for HSCT. The long-term efficacy of this approach is not established. We evaluated outcomes of 64 CML patients with advanced-phase disease (80% beyond first chronic phase), not eligible for myeloablative preparative regimens due to older age or comorbid conditions, who were treated with fludarabine-based RIC regimens. Donor type was matched related (n =30), 1 antigen-mismatched related (n =4), or matched unrelated (n =30). With median follow-up of 7 years, overall survival (OS) and progression-free survival (PFS) were 33% and 20%, respectively, at 5 years. Incidence of treatment-related mortality (TRM) was 33%, 39%, and 48% at 100 days, and 2 and 5 years after HSCT, respectively. In multivariate analysis, only disease stage at time of HSCT was significantly predictive for both OS and PFS. RIC HSCT provides adequate disease control in chronic-phase CML patients, but alternative treatment strategies need to be explored in patients with advanced disease. TRM rates are acceptable in this high-risk population but increase over time.     

Similar outcomes using myeloablative vs reduced-intensity allogeneic transplant preparative regimens for AML or MDS

Although reduced-intensity conditioning (RIC) and non-myeloablative (NMA)-conditioning regimens have been used for over a decade, their relative efficacy vs myeloablative (MA) approaches to allogeneic hematopoietic cell transplantation in patients with AML and myelodysplasia (MDS) is unknown. We compared disease status, donor, graft and recipient characteristics with outcomes of 3731 MA with 1448 RIC/NMA procedures performed at 217 centers between 1997 and 2004. The 5-year univariate probabilities and multivariate relative risk outcomes of relapse, TRM, disease-free survival (DFS) and OS are reported. Adjusted OS at 5 years was 34, 33 and 26% for MA, RIC and NMA transplants, respectively. NMA conditioning resulted in inferior DFS and OS, but there was no difference in DFS and OS between RIC and MA regimens. Late TRM negates early decreases in toxicity with RIC and NMA regimens. Our data suggest that higher regimen intensity may contribute to optimal survival in patients with AML/MDS, suggesting roles for both regimen intensity and graft vs leukemia in these diseases. Prospective studies comparing regimens are needed to confirm this finding and determine the optimal approach to patients who are eligible for either MA or RIC/NMA conditioning.     

Reduced intensity conditioning prior to allogeneic stem cell transplantation in first complete remission is effective in patients with acute myeloid leukemia and an intermediate-risk karyotype

To evaluate the efficacy of reduced intensity conditioning (RIC) prior to allogeneic stem cell transplantation (alloSCT) in patients with acute myeloid leukemia (AML) in first complete remission (CR1), we retrospectively analyzed the outcome of 93 consecutive patients transplanted at our institution either following RIC (n = 37) or standard myeloablative conditioning (MAC) (n = 56) between 1999 and 2007. Projected overall survival (OS) or disease-free survival (DFS) for all patients at 1, 2, and 5 years was 78 or 70%, 65 or 57%, and 61 or 53% in the RIC group versus 73 or 70%, 68 or 62%, and 56 or 54% in the standard MAC group. In the subgroup of patients with an intermediate-risk karyotype projected OS at 1, 2, and 5 years was 86, 68, and 68% following RIC (n = 21) or 75, 69, and 66% following standard MAC (n = 36). Relapse or treatment-related mortality (TRM) was 15 or 17% (RIC group) and 26 or 14% (standard MAC group). Taken together, these data suggest that RIC-alloSCT may induce stable remissions in patients with AML transplanted in CR1. In particular, patients with an intermediate-risk karyotype ineligible to transplantation following standard MAC may benefit from RIC-alloSCT in CR1 at a low TRM.     

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.