Use Of Reduced-intensity Conditioning Research Articles

Posttransplant complications in patients with marrow failure syndromes: are we improving long-term outcomes?

Inherited bone marrow failure syndromes (IBMFS) encompass a group of rare genetic disorders characterized by bone marrow failure, non-hematologic multisystemic comorbidities, disease defining congenital anomalies, and a susceptibility to myelodysplastic syndrome, acute myeloid leukemia, and in some instances solid tumors. The most common IBMFS include Fanconi anemia, Shwachman-Diamond syndrome, Diamond-Blackfan anemia, and telomere biology disorders/ dyskeratosis congenita. Allogeneic hematopoietic stem cell transplant (HCT) is a well-established curative treatment to correct the hematological manifestations but does not halt or reverse the nonhematological complications and may hasten them. With advances in HCT and in our ability to care for patients with IBMFS, an increasing number of survivors are making it imperative to not only diagnose but also treat late effects from the pre-, peri-, and post-HCT course and complications relating to the natural history of the syndrome. As the field of HCT evolves to allow for the incorporation of alternate graft sources, for expansion of donor options to include unrelated and mismatched donors, and for use of reduced-intensity conditioning or reduced toxicity myeloablative regimens, we have yet to determine if these advances modify the disease-specific course. While long-term outcomes of these patients are often included under one umbrella, this article seeks to address disease-specific post-HCT outcomes within IBMFS.

How to improve the outcomes of elderly acute myeloid leukemia patients through allogeneic hematopoietic stem cell transplantation.

In recent years, with the gradual advancement of haploidentical transplantation technology, the availability of donors has increased significantly, along with the widespread use of reduced-intensity conditioning and the improvement of nursing techniques, giving more elderly acute myeloid leukemia (AML) patients the chance to receive allogeneic hematopoietic stem cell transplantation. We have summarized the classic and recently proposed pre-transplant assessment methods and assessed the various sources of donors, conditioning regimens, and post-transplant complication management based on the outcomes of large-scale clinical studies for elderly AML patients.

Conditioning Regimen Intensity and Donor Choice Do Not Impact Outcomes of Patients (pts) with Acute Myeloid Leukemia (AML) after Allogeneic Hematopoietic Cell Transplantation (Allo-HCT) in First Complete Remission (CR1): An EBMT Analysis

Allo-HCT is a curative treatment for fit pts with intermediate and adverse risk AML who achieve CR1. The presence of minimal residual disease (MRD) before allo-HCT has been shown to increase risk of relapse and decrease survival. Here, we describe outcomes of pts with AML who received allo-HCT in CR1 and the impact of MRD before allo-HCT on outcomes. We identified 1032 pts with AML who received allo-HCT in CR1 between 2015 and 2020 from the EBMT registry. The median age was 53.6 (range, 18.1-82.5) years and 526 (51%) were male. Most (94%) pts had de novo AML. FLT3-ITD and NPM1 mutations were detected in 46% and 44% of pts, respectively and high-risk cytogenetics were present in 20%. >1 course of induction therapy was required by 18% of pts to achieve CR1 and 39% were MRD positive at time of allo-HCT. The median time from diagnosis to allo-HCT was 4.9 months. Of pts with FTL3-wild type (FLT3-wt) disease, 33% were MRD negative and 22% were MRD positive at time of allo-HCT. In pts with FTL3-ITD mutation, 29% were MRD negative and 17% were MRD positive at time of allo-HCT. Donor type was matched sibling donor (MSD) in 29% of pts (n=297), matched unrelated donor (MUD) in 47% (n=481), mismatched unrelated donor (MMUD 9/10) in 8% (n=88), or haploidentical donor (haplo) in 16% (n=166). HCT-specific comorbidity index (HCT-CI) was >3 in 22% of pts (n=190). Myeloablative conditioning (MAC) was administered to 45% of pts (n=470), while reduced intensity conditioning (RIC) was used in 55% (n=562). The most common conditioning regimen was fludarabine/busulfan in MSD (n=148, 50%), MUD (n=272, 57%) and MMUD (n=38, 43%) recipients, while thiotepa/fludarabine/busulfan was the most used in haplo-HCT (n=99, 60%). Total body irradiation (TBI) was given to only 8% of pts (n=84), mainly in haplo-HCT (n=29). Most (n=1002, 98%) pts received calcineurin inhibitors (CNI), tacrolimus or cyclosporine A, for graft-versus-host disease (GVHD) prophylaxis in addition to mycophenolate mofetil (43%) or methotrexate (38%). Post-transplant cyclophosphamide was used in 18% (n=191) of pts, with 71% (n=136) having received haplo-HCT, and anti-thymocyte globulin was given to 67% (n=689). The median follow-up was 24 months. At day 60, the cumulative incidence of neutrophil engraftment was 99%. The cumulative incidence of grade III-IV acute GVHD (aGVHD) was 9% at day 180. At 2 years, the cumulative incidence of extensive chronic GVHD (cGVHD) was 17%. At 2 years, relapse incidence (RI), NRM, overall survival (OS), leukemia-free survival (LFS), and GVHD-free, relapse-free survival (GRFS) were 26%, 13%, 69%, 61%, and 48%, respectively. The main cause of death was primary disease in 55% of pts (n=157). Other causes of NRM were infections in 16% (n=45), and GVHD in 17% (n=47). In the multivariate analysis, compared to MSD, the use of MUD increased NRM (hazard ratio (HR) 1.86, p=0.02), GRFS (HR 1.28, p=0.039), aGVHD (HR 2.17, p<0.0001), and cGVHD (HR 1.36, p=0.044). The use of MMUD was associated with worse OS (HR 1.6, p=0.042) and higher risk of aGVHD (HR 2.11, p=0.003). Haplo-HCT was associated with higher incidence of aGVHD (HR 1.69, p=0.021) but lower risk of cGHVD (HR 0.63, p=0.033). Older age, lower performance status (PS), requiring >1 induction to achieve CR1, and FLT3-MRD positivity before allo-HCT were associated with worse LFS. Factors associated with lower OS were MMUD 9/10, older age, poor PS, >1 induction to achieve CR1, adverse cytogenetics, and FLT3-MRD positivity before transplant. In vivo TCD was associated with improved GRFS and lower risk of acute and cGVHD without increase of relapse. The use of RIC compared with MAC did not affect relapse, NRM or any other outcome. In conclusion, in pts with AML transplanted in CR1, those requiring >1 induction or with persistent FLT3-MRD positivity at time of allo-HCT had lower OS. Strategies to improve induction therapy, possibly through the addition of targeted agents, aiming to improve CR rates and deepening responses could potentially improve OS after allo-HCT. The use of RIC was associated with similar outcomes compared to MAC. This finding is particularly important for older pts or those with high HCT-CI scores unlikely to tolerate MAC. Survival after MSD allo-HCT is comparable to MUD and haplo, a finding that is in accordance with previous results for haplo and MUD as valid alternative donors in the absence of MSD. The use of MMUD was associated with lower OS compared to MSD and should be used as a last resort donor in this setting.

Outcomes of Allogeneic Hematopoietic Stem Cell Transplantation from Different Donor Types in Primary Refractory Acute Myeloid Leukemia: A Report from the ALWP of the EBMT

Background Primary refractory acute myeloid leukemia (prAML) is a poor prognosis disease for which allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative option currently available. We aimed to estimate outcomes in the recent period, to analyze how different donor types may have impacted survival outcomes and to identify the most relevant predictive factors for allo-HSCT in prAML. Methods We conducted a retrospective multicenter study of adult patients reported to the European Society for Blood and Marrow Transplantation (EBMT) registry who received an allo-HSCT between 2015 and 2020 for prAML. We considered HSCT performed from matched sibling donors (MSD), 10/10 unrelated donors (UD 10/10), 9/10 unrelated donors (UD 9/10) and haploidentical donors. Primary endpoint was leukemia-free survival (LFS), secondary endpoints were overall survival (OS), relapse incidence (RI) and non-relapse mortality (NRM). A Cox proportional hazards model was used for multivariate analysis. Results We included 1574 patients. Median age was 56.9 years (range 18.1-77.9). Cytogenetic risk was intermediate in 855 (54.3%), adverse in 679 (43.2%) and favorable in 40 (2.5%) patients. Donor type was distributed as follows: MSD n = 521 (33.1%), UD 10/10 n = 540 (34.3%), UD 9/10 n = 153 (9.7%), haploidentical n = 360 (22.9%). Table 1 summarizes patient and transplant characteristics. Patients allografted from an MSD were younger, allografted faster after diagnosis, more often received myeloablative conditioning (MAC) (details in Table 1) and had less secondary AML. Use of post-transplant cyclophosphamide, and bone marrow as a stem cell source were more frequent in haploidentical transplants. LFS at 2 years was significantly lower in haploidentical transplants (27% [95%CI: 22-32.2]) compared to MSD (35.2% [95%CI: 30.6-39.9]), to UD 10/10 (37.6% [95%CI: 33.2-42.1]) and to UD 9/10 (35.2% [95%CI: 27.1-43.5]) (p=0.003). Haploidentical transplants also showed inferior OS at 2 years: 31.2% (95%CI: 25.8-36.8) compared to 40.9% (95%CI: 35.9-45.8) in MSD, to 45.7% (95%CI: 41.1-50.2) in UD 10/10 and to 43% (95%CI: 34.5-51.3) in UD 9/10 (p=0.001). In the UD 9/10 group we observed the lowest RI (33.5% [95%CI: 25.6-41.6], 46.7% [95%CI: 41.8-51.4] in MSD, 42.7% [95%CI: 38.2-47.1] in UD 10/10, 46.8% [95%CI: 41.1-52.3] in haploidentical) (p=0.013), and the highest NRM (31.2% [95%CI: 23.6-39.2], 18.1% [95%CI: 14.6-21.9] in MSD, 19.7% [95%CI: 16.3-23.3] in UD 10/10, 26.2% [95%CI: 21.6-31.1] in haploidentical) (p=0.001). Of note, LFS at 2 years was reduced for adverse cytogenetic risk (26.1% for adverse, 39.8% for intermediate and 51.9% for favorable risk) (p=0.001) and significantly differed between reduced intensity conditioning (RIC) and MAC (37.4% and 29.8%, respectively) (p=0.033). In multivariate analysis, factors predicting poor LFS were haploidentical donor (hazard ratio [HR] 1.22 [95%CI: 1.01-1.48], p=0.043), adverse cytogenetic risk (HR 1.73 [95%CI: 1.51-1.99], p<0.0001) and time from diagnosis to HSCT (HR 1.03 [95%CI: 1.01-1.06], p=0.009), whereas factors associated with a better LFS were RIC conditioning (HR 0.85 [95%CI: 0.73-0.98], p=0.025) and good Karnofsky performance status (KPS) ≥ 80 (HR 0.74 [95%CI: 0.62-0.88], p=0.0009). Haploidentical transplant correlated with lower OS (HR 1.3 [95%CI: 1.06-1.61], p=0.014) and higher NRM (HR 1.69 [95%CI: 1.18-2.41], p=0.004) and adverse cytogenetic risk was associated with higher RI (HR 1.9 [95%CI: 1.6-2.24], p<0.0001), higher NRM (HR 1.47 [95%CI: 1.15-1.87], p=0.002) and lower OS (HR 1.82 [95%CI: 1.57-2.11], p<0.0001). Moreover, increased age predicted higher NRM (HR 1.31 [95%CI: 1.17-1.47], p<0.0001) and lower OS (HR 1.09 [95%CI: 1.02-1.16], p=0.006). Conclusions Our study identified risk factors for survival outcomes in the challenging setting of allo-HSCT for prAML. The most relevant factors are adverse cytogenetic risk and haploidentical donor, both associated with worse outcomes. Of note, the group of haploidentical transplants presented the highest rate of bone marrow used as a stem cell source, with a possible impact on survival outcomes. Longer time from diagnosis to HSCT negatively impacted LFS, whereas use of RIC and KPS ≥ 80 showed a higher LFS. As concerns secondary endpoints, unrelated donors achieved better OS compared to other donors, and UD 9/10 showed the lowest RI at the expense of the highest NRM. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

The effect of intensity of conditioning regimen on the outcome of HSCT in children with sickle cell disease.

Allogeneic hematopoietic stem cell transplantation (HSCT) provides a cure for patients with sickle cell disease (SCD). This study describes the effect of conditioning regimen intensity on HSCT outcomes among children younger than 14 years with SCD. Transplants from HLA-matched related donors (MRD) and unrelated donors (MUD) using either myeloablative conditioning (MAC) regimens or reduced intensity conditioning (RIC) regimens were considered. Event-free survival (EFS) was the primary endpoint. Secondary endpoints included overall survival (OS) and occurrence of GVHD. 48 SCD patients underwent HSCT, 45 (93.8%) patients had MRD, 1 (2.1%) had 9/10 related donor, and 2 (4.1%) had MUD. The median age at transplant was 8.6 years (range, 3.1-13.8). Conditioning regimens were myeloablative (MAC) in 41 (85.4%) patients and of reduced intensity in 7 (14.6%) patients. EFS at 2 years was 100% among MAC group compared to 29% in the RIC group (p<.001). The median follow-up was 43.4 months (range 26.8-134). All events in the RIC group were secondary graft failure. However, OS was 100% in both groups at 2 years. Acute GVHD II-IV was diagnosed in 2 (4.1%) patients. Chronic GVHD occurred in 2 (4.1%) patients. GVHD did not occur in patients who underwent MUD HSCT. MAC in children with SCD is well tolerated and associated with an excellent outcome for HLA-matched HSCT in SCD. There was a high rate of secondary graft failure with the use of RIC. Future studies are needed to optimize RIC regimens in HSCT of children with SCD.

Outcomes in patients with acute lymphoblastic leukemia who underwent second allogeneic hematopoietic cell transplantation for relapse after first transplantation.

Outcomes in patients with acute lymphoblastic leukemia (ALL) who experience relapse after allogeneic hematopoietic cell transplantation (HCT) are unsatisfactory. This study aimed to evaluate the outcomes of patients with ALL who underwent second HCT (HCT2) for relapse after first HCT. It was a single-center retrospective study including adult patients with ALL who underwent HCT2 between 1991 and 2020. The cohort was stratified according to the transplant year, and included 39 patients with a median age of 29years. A more recent transplant year was associated with achievement of complete remission (CR) and use of reduced-intensity conditioning (RIC), compared with an earlier transplant year. The overall survival (OS) rate and 2-year cumulative incidence of non-relapse mortality (recent vs. earlier) were 55% vs. 8% (P < 0.001) and 26% vs. 75% (P < 0.001), respectively. In multivariate analysis, non-CR (vs. CR; HR 3.6, 95% CI 1.2-11.3, P = 0.025) and myeloablative conditioning (vs. RIC; HR 3.5, 95% CI 1.3-9.4, P = 0.011) were negative prognostic factors for OS. Outcomes of the recent cohort from real-world data are promising, and achieving CR and using the RIC regimen at HCT2 may be an important therapeutic strategy.

Phase II Trial of Allogeneic Transplantation Plus Novel Drugs in Multiple Myeloma: Effect of Intensifying Reduced-Intensity Conditioning with Bortezomib and Adding Maintenance Treatment

The use of reduced-intensity conditioning (RIC) regimens has decreased the risk of nonrelapse mortality (NRM) after allogeneic stem cell transplantation (alloSCT). In contrast, disease relapse remains the most frequent cause of treatment failure and death. Owing to both their antimyeloma effect and immunomodulatory properties, novel drugs could improve outcomes after alloSCT. This phase II European Myeloma Network trial was designed to evaluate the combination of alloSCT with novel agents. The study was conducted to evaluate the toxicity and efficacy of RIC intensified with bortezomib (Bz) prior to alloSCT for high-risk (HR) multiple myeloma (MM) patients, as well as the efficacy of post-transplantation maintenance with Bz and lenalidomide (Len). Patients received RIC with Bz on days -9 and -2, fludarabine on days -6 to -4, and melphalan on day -3. Patients who were in complete response (CR) or near CR at day +100 post-transplantation received 6 cycles of Bz every 56 days, and the remaining received Bz, Len, and dexamethasone. Len maintenance was started on day +180 at a dose of 5 mg and continued until relapse or toxicity occurred. Of the 24 patients included, 21 were evaluable on day +100, including 12 in CR, 4 in very good partial response, 3 in partial response, and 2 with relapse or progression. The cumulative incidence (CuI) of relapse was 13.6% (95% confidence interval [CI], 3.2% to 31.3%) at 1 year and 28.5% (95% CI, 11.1% to 48.9%) at 2 years. The CuI of NRM was 21.1% (95% CI, 7.4% to 39.4%) at 2 years. With a median follow-up of 39 months (range, 1 to 67 months), the median event-free survival (EFS) was 29 months, and median overall survival (OS) was not reached. EFS and OS at 3 years were 42.5% (95% CI, 21.9% to 61.7%) and 74.01% (95% CI, 50.9% to 87.5%), respectively. The use of Bz within an RIC regimen allows for a high response rate after alloSCT. Maintenance with Bz and Len is feasible and provides remarkable results in terms of EFS and OS in HR MM patients.

Haploidentical Allogeneic Stem Cell Transplantation in Sickle Cell Disease: A Systematic Review and Meta-Analysis

▪BackgroundAllogeneic hematopoietic stem cell transplantation (SCT) is the only established curative treatment option for patients with sickle cell disease (SCD). Transplantations with an HLA-identical matched sibling donor (MSD) have resulted in excellent disease-free survival of >90% and overall survival (OS) of >95%. However, lack of HLA-identical siblings is a limiting factor. The chance of finding a potential matched unrelated donor is low for patients with a non-Western ethnic background (< 20%). Haploidentical related donors are a promising pool of donors potentially extending SCT as a curative treatment to a larger group of SCD patients with no other meaningful treatment options. Myeloablative conditioning regimens (MAC) are not recommended for adult SCD patients, as cumulative SCD-related organ damage renders these patients susceptible to increased toxicity and higher risk of transplant-related mortality. Using reduced-intensity conditioning (RIC) or non-myeloablative conditioning (NMC) in both adult and pediatric patients has resulted in decreased transplant-related toxicity and mortality. However, while successful in hematologic malignancies, NMC has been associated with significant risk of graft failure in hemoglobinopathies. In the present study, we aimed to systematically review (1) the outcomes of haploidentical SCT (Haplo-SCT), (2) the effects of conditioning intensity and modes of T-cell depletion on Haplo-SCT outcomes and (3) comparative outcomes between matched sibling donor SCT (MSD-SCT) and Haplo-SCT in selected studies.MethodsA comprehensive search was performed in MEDLINE/PubMed and Embase up to May 2021. Data was extracted by two reviewers independently and the Newcastle-Ottawa Quality Assessment Scale was used to assess the quality of the studies. Only studies reporting at least one of the outcomes: graft failure, OS, transplant-related mortality, and acute/chronic graft-versus-host disease (GvHD) were included. Fourteen studies met the inclusion criteria. To have an overview of the results of Haplo-SCT, we divided the included studies in four groups according to the conditioning intensity (MAC versus NMC/RIC) and the T-cell depletion method (in vivo (post-transplant cyclophosphamide (PTCy)) vs. in vitro).ResultsAll included studies were observational cohort studies. A subgroup meta-analysis of the results of Haplo-SCT showed relatively low overall pooled proportions of graft failure (7%, 95% CI: 2 - 20), acute (4%, 95% CI: 2 - 12) and chronic (11%, 95% CI: 7 - 16) GvHD. Overall survival was high (91%, 95% CI: 85 - 94). Graft failure in MAC-in vitro, MAC-in vivo, NMC/RIC-in vitro and NMC/RIC-in vivo groups was 4% (95% CI: 1 - 14), 0% (95% CI: 0 - 100), 25% (95% CI: 10 - 51) and 11% (95% CI: 3 - 36) respectively (Figure 1). OS was 100% and 93% for MAC and NMC/RIC groups with PTCy (in vivo T-cell depletion) respectively. In patients with in vitro T-cell depletion, OS was 87% and 81% in MAC and NMC/RIC groups respectively (Figure 2). Based on a comparative meta-analysis of the three studies that included both haploidentical and MSD transplantation, graft failure was significantly higher in the haploidentical group than in the MSD group (odds ratio 5.3, 95% CI: 1.0 - 27.6). Overall survival, transplant-related mortality and acute/chronic GvHD were not significantly different between the groups.ConclusionsThis systematic review shows that modifications in the intensity of the conditioning regimen and improved T-cell depletion approaches in Haplo-SCT in SCD have led to reduced transplantation-related toxicity while keeping graft failure rates low. Both in vitro and in vivo (PTCy) T-cell depletions result in very low transplantation-related mortality, though in vitro T-cell depletion is associated with a higher incidence of viral reactivations and other infectious complications.Haploidentical stem cell transplantation is becoming a viable alternative curative option for SCD, extending the availability of allogeneic SCT as a treatment option to many more transplant eligible SCD patients. Novel immunosuppression (immunoablation) and improvement in supportive care have allowed the use of RIC or NMC regimens, resulting in low risk of transplantation-related complications and improvement in engraftment rates. [Display omitted] DisclosuresBiemond: Global Blood Therapeutics: Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau; CSL Behring: Honoraria; Sanquin: Research Funding; Novo Nordisk: Honoraria; Celgene: Honoraria. Nur: Celgene: Speakers Bureau; Roche: Speakers Bureau; Novartis: Research Funding, Speakers Bureau.

Long-Term Immune Recovery After Hematopoietic Stem Cell Transplantation for ADA Deficiency: a Single-Center Experience

Unconditioned hematopoietic stem cell transplantation (HSCT) is the recommended treatment for patients with adenosine deaminase (ADA)-deficient severe combined immunodeficiency with an HLA-matched sibling donor (MSD) or family donor (MFD). Improved overall survival (OS) has been reported compared to the use of unrelated donors, and previous studies have demonstrated that adequate cellular and humoral immune recovery can be achieved even in the absence of conditioning. Detailed insight of the long-term outcome is still limited. We aim to address this by studying a large single-center cohort of 28 adenosine deaminase-deficient patients who underwent a total of 31 HSCT procedures, of which more than half were unconditioned. We report an OS of 85.7% and event-free survival of 71% for the entire cohort, with no statistically significant differences after procedures using related or unrelated HLA-matched donors. We find that donor engraftment in the myeloid compartment is significantly diminished in unconditioned procedures, which typically use a MSD or MFD. This is associated with poor metabolic correction and more frequent failure to discontinue immunoglobulin replacement therapy. Approximately one in four patients receiving an unconditioned procedure required a second procedure, whereas the use of reduced intensity conditioning (RIC) prior to allogeneic transplantation improves the long-term outcome by achieving better myeloid engraftment, humoral immune recovery, and metabolic correction. Further longitudinal studies are needed to optimize future management and guidelines, but our findings support a potential role for the routine use of RIC in most ADA-deficient patients receiving an HLA-identical hematopoietic stem cell transplant, even when a MSD or MFD is available.

Graft Failure Post Allogeneic Stem Cell Transplant: Conditioning Regimen Improves Engraftment and Survival

▪Introduction- Untreated Graft Failure (GF) post allogeneic stem cell transplant (allo-SCT) is potentially lethal. Salvage stem cells with or without additional conditioning regimen can be curative but concerns about toxicity and the need for adequate immunosuppression needs to be balanced in the therapeutic decisions. Due to the rarity of GF and paucity of data no consensus exists on the most preferred combinations to opt at the time of intervention. To address this unmet scenario we performed a large single institution retrospective study.Methods- From January 1996- February 2016, 97 patients received treatment for GF following an allo-SCT. We excluded from the analysis patients (n-15) who received autologous cells as their sole rescue and those who developed GF after progression of the underlying malignancy. Both primary GF (48%) and secondary GF (52%) post 1st allo-SCT were included. Median time from 1st allo-SCT to GF rescue intervention was 56 (range 21-738) days. Conditioning regimen prior to allogeneic rescue cell infusions was categorized as : 1) no preparative regimen (21%) 2) single agent antithymocyte globulin (ATG) or Campath (6%) 3) Reduced intensity conditioning (RIC) chemotherapy or low dose total body irradiation (TBI) (200cGY) (28%) (4) Fludarabine (Flu) + ATG (41%) and 5) miscellaneous other combinations (4%). Engraftment (absolute neutrophil count ≥ 500 for 3 consecutive days) and overall survival (OS) from the time of intervention were the main outcomes of interest. The following factors were considered for their association with primary outcomes following GF rescue intervention: 1) donor/ patient demographics, 2) disease status, 3) graft- source (related, unrelated donors, peripheral blood, bone marrow and umbilical cord blood), cell dose, graft modification (t cell deplete vs replete), level of human leucocyte antigen (HLA)/ABO matching between donor and recipient and 4) treatment related metrics (conditioning regimens and graft versus host disease prophylaxis).Results- Among patients (n=82) who received GF rescue intervention, 56 (68%) engrafted, 10 (12%) failed to engraft and 16 (20%) had early death (< 28 days). With a median follow up of 61 (range 11-242) months, 5-y OS was 18%. Only conditioning regimen correlated with engraftment with a significantly higher proportion of patients engrafting after Flu/Mel (92%) or TBI (91%) based preparative regimens (Table 1). In comparison, 38%, 40%, 67%, and 33% engrafted following no preparative regimen, and conditioning with ATG or Campath, Flu/ATG, and miscellaneous other group, respectively. Change of donor, graft source and graft modification were not significant predictors for engraftment. On multivariate Classification and Regression Tree (CART) analysis, use of 1 HLA antigen mismatched related or unrelated donor was associated with poor overall survival (HR 3.7, 95 % CI 1.5-8.9 P value 0.004). In the absence of 1 antigen related or unrelated donor the use of 2nd allo-SCT was associated with better survival compared with boost only (i.e. no preparative regimen prior to cell infusion) (HR- 0.5, 95 % CI 0.3-0.9, p value 0.03)(Figure-1). Graft rejection/failure (39.7%) and infections (23.5%) were the commonest primary causes of death.Conclusions- GF post allo-SCT is a rare entity with sparse long term survivors despite interventions. For patients eligible to receive conditioning, use of RIC portends better engraftment and survival prior to cell rescue. [Display omitted] DisclosuresOran:Celgene: Research Funding; AROG: Research Funding; Astex: Research Funding. Khouri:Novartis: Research Funding.

Immune Reconstitution after Allogeneic Stem Cell Transplantation - a Systematic Single Center Survey

The renewal of the immune system after allogeneic hematopoietic stem cell transplantation (HSCT) is a complex process not fully understood. Recently, the use of reduced intensity conditioning (RIC) regimens, new anti-viral drugs and intensified GvHD treatment changed the landscape of allogeneic transplantation. Here, the influence of several parameters on the development of the cellular and humoral immunity of 136 patients consecutively transplanted in a single center was analyzed.All adult patients transplanted during a period of three years (September 2010 to August 2013), were analyzed in respect of immunoglobulin levels with the turbidimetric method, serum electrophoresis, immunofixation and lymphocyte subset counts by flow cytometry. Also the occurrence of a monoclonal/biclonal gammopathy was reported. In addition, we looked for donor chimerism, B and T cell receptor repertoire of peripheral blood samples. Most patients received a reduced conditioning regimen; nearly all patients received either anti-thymoglobulin (ATG) or alemtuzumab (25/136 matched related donors) leading to a relatively low rate of chronic GvHD (40%). The immune parameters obtained one year after stem cell transplantation were correlated with relevant factors of stem cell transplantation, namely the conditioning regimen, diagnosis, relapse rate, age, sex and history of CMV infection, acute and chronic GvHD using Pearson correlation, t-test and regression analysis (SPSS).A normal CD4/CD8 ratio at day 360 after HSCT was only seen in 14% of evaluable patients, while it was reduced in 83%. This was mainly due by an impaired CD4 cell count while the CD8 cell count was even increased in 42%. The CD8 cell count was significantly higher in patients after CMV infection (p<0.001) and in those not receiving alemtuzumab as part of the conditioning regimen (p=0.003). The IgG level was normal in 51%, reduced in 31% and increased in 17 % of tested patients. The IgG level correlated with a history of CMV infection, NK, CD4, and CD8 cell count (all p≤0.025); but age, sex, diagnosis, relapse, use of RIC, acute and chronic GvHD had no significant impact. The development of a new clonal gammopathy was found in 18 patients after undergoing a HSCT and was in nearly all cases reversible. Interestingly, this was associated with chronic GvHD (p=0.034), but not any of the other parameters.Almost all patients show a compromised immune system one year after allogeneic stem cell transplantation mainly characterized by an inverted CD4/CD8 ratio. Whether an increased CD8 cell count may not only reflect the response to viral infections but in some cases improved immunosurveillance, is hard to document. Interestingly, the immunoglobulin levels are highly variable ranging from antibody deficiency to hypergammaglobulinemia positively correlating with CMV reactivation. Continuous disbalanced immunoreactivity indicated by clonal gammopathy was associated with chronic GvHD. The systematic evaluation of these basic immune parameters may lead to better therapeutic guidance in patients after allogeneic HSCT. DisclosuresNo relevant conflicts of interest to declare.

Incidence, Management, and Prognosis of Graft Failure and Autologous Reconstitution after Allogeneic Hematopoietic Stem Cell Transplantation.

BackgroundThis study presents outcomes of management in graft failure (GF) after allogeneic hematopoietic stem cell transplantation (HCT) and provides prognostic information including rare cases of autologous reconstitution (AR).MethodsWe analyzed risk factors and outcomes of primary and secondary GF, and occurrence of AR in 1,630 HCT recipients transplanted over period of 18 years (January 2000–September 2017) at our center.ResultsPrimary and secondary GF occurred in 13 (0.80%), and 69 patients (10-year cumulative incidence, 4.5%) respectively. No peri-transplant variables predicted primary GF, whereas reduced intensity conditioning (RIC) regimen (relative risk [RR], 0.97–28.0, P < 0.001) and lower CD34+ cell dose (RR, 2.44–2.84, P = 0.002) were associated with higher risk of secondary GF in multivariate analysis. Primary GF demonstrated 100% mortality, in the secondary GF group, the 5-year Kaplan-Meier survival rate was 28.8%, relapse ensued in 18.8%, and AR was observed in 11.6% (n = 8). In survival analysis, diagnosis of aplastic anemia (AA), chronic myeloid leukemia and use of RIC had a positive impact. There were 8 patients who experienced AR, which was rarely reported after transplantation for acute leukemia. Patient shared common characteristics such as young age (median 25 years), use of RIC regimen, absence of profound neutropenia, and had advantageous survival rate of 100% during follow period without relapse.ConclusionPrimary GF exhibited high mortality rate. Secondary GF had 4.5% 10-year cumulative incidence, median onset of 3 months after HCT, and showed 5-year Kaplan-Meier survival of 28.8%. Diagnosis of severe AA and use of RIC was both associated with higher incidence and better survival rate in secondary GF group. AR occurred in 11.6% in secondary GF, exhibited excellent prognosis.

Umbilical cord blood transplantation: a maturing technology.

The use of umbilical cord blood (CB) as a source of hematopoietic progenitor cells for patients with high-risk hematologic disorders receiving allogeneic hematopoietic cell transplantations (HCTs) has increased significantly. Single-institution and registry studies have shown a decreased relapse rate and an increased transplantation-related mortality rate with similar overall survival rates after allogeneic HCT with CB compared with other donor sources. The transplantation of double CB units has overcome the dose limitation inherent in a single CB unit and thus has markedly extended the use of CB to larger children and adults. Similarly, the use of reduced intensity conditioning in the CB transplantation setting has allowed the treatment of older patients who would be unable to tolerate the myeloablative regimens used in the original CB transplantation protocols.

Reduced-Intensity Versus Myeloablative Conditioning for Allogeneic Hematopoietic Cell Transplantation in Patients with Myelodysplastic Syndrome: A Systematic Review and Meta-Analysis of Randomized Clinical Trials & Cohort Studies

Background: Conditioning regimen given before allogeneic hematopoietic stem cell transplantation (allo-HSCT) contributes significantly to the outcomes following transplant for myelodysplastic syndrome (MDS). Myeloablative conditioning (MAC) regimens are often associated with a lower risk of relapse; however, their use is often limited by toxicity and a higher risk of non-relapse mortality (NRM). Reduced-intensity conditioning (RIC) regimens are associated with a higher risk of relapse, a lower NRM, a lower incidence of graft versus host disease (GVHD), and hence is feasible in patients with advanced age or comorbidities. This study highlights the importance of the difference between the two interventions used in allo-HSCT for myelodysplastic syndrome (MDS). Methods: We conducted a comprehensive literature search using PubMed, Clinicaltrial.gov, Embase, Cochrane, and Web of Science on 5th May 2020 with no restriction of language or period. Initial research revealed 1698 articles. After excluding review articles, duplicates, and non-relevant articles, we included two randomized clinical trials and three cohort studies, which reported overall survival (OS), relapse-free survival (RFS), relapse incidence (RI), and incidence of acute and chronic (GVHD). Based on inclusion criteria, two randomized clinical trials (BMT CTN 0901 Trial Scott et al. 2017 &amp; EBMT RICMAC Trial Kroger et al. 2017) and three cohort studies (BBMT 55226 Park et al. 2018, BBMT Orozco et al. 2019, BMT Alatrash et al. 2019) were included. Results: Among combined MDS and acute myeloid leukemia (AML) patients (n=1188) enrolled in 5 studies, 651 patients had MDS. Patients underwent MAC (n=484) or RIC (n=692) followed by either a matched related donor (MRD), n=236, or matched unrelated donor (MUD), n=236, allo-HCT. The median age range at the time of transplant was 50-54 years The use of RIC causes statistically non-significant trend of improved overall survival (OS) (OR 1.11: 95% CI: 0.74-1.67, p-value= 0.61) along with more risk of relapse incidence (RI) (R 1.34: 95% CI: 0.56-3.18, p value= 0.51), and reduced relapse free survival (RFS) (OR 0.88, 95% CI: 0.55-1.44: p value= 0.59). Differences were found in terms of safety of both conditioning regimens. MAC allo-HCT have more acute GVHD, grade 3 and 4 (OR 0.66: 95% CI: 0.29-1.52, p value= 0.33) and chronic GVHD, grade 3 and 4 (OR 0.72: 95% CI: 0.41-1.27: p value= 0.26) and treatment-related mortality (TRM) (OR 0.83, 95% CI: 0.37-1.86, p value= 0.65). The meta-analysis results are shown in figure-1. Conclusion: In adult MDS patients undergoing allo-HSCT, RIC is associated with improved overall survival, but at the cost of reduced RFS, and a higher risk of relapse. MAC, on the other hand, is associated with more treatment-related mortality and GVHD. Results of our analysis point out these trends but these are not statistically significant Figure 1 Disclosures Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.: Honoraria, Research Funding, Speakers Bureau.

Clinical Impact of Cytokine Release Syndrome on Outcomes of Peripheral Blood Stem Cell Haploidentical Hematopoietic Cell Transplantation with Post-Transplant Cyclophosphamide

Peripheral blood stem cell (PBSC) as a graft source compared to bone marrow has been reported to result in lower risk of relapse after haploidentical hematopoietic cell transplantation (haplo-HCT) with use of post-transplant cyclophosphamide (PTCy) as a graft-versus-host-disease (GvHD) prophylaxis. However, cytokine release syndrome (CRS) is a common complication of this platform that can affect the outcomes of patients after PBSC haplo-HCT. CRS occurs due to rapid activation and proliferation of alloreactive donor T cells resulting in the elevated secretion of inflammatory cytokines. In this study, we sought to examine the risk factors for CRS and the effect of CRS severity on outcomes of PBSC haplo-HCT. We identified total of 271 consecutive patients with hematological malignancies who received their first PBSC haplo-HCT with PTCy-based GVHD prophylaxis at City of Hope (n=157) or Moffitt (n=114) Cancer Centers between 2014 and 2019. The median patient age at HCT was 54 years (INQ range, 37-64) for the entire cohort and 48% of the patients had HCT-CI ³3. Close to 70% of the study cohort had acute leukemia and 33% of all patients had high/very high-risk disease risk index. Myeloablative conditioning was used in 52% of the cases and 81% of all HCT recipients were CMV seropositive. The median donor age at HCT was 33 years (INQ range, 26-43). The HLA -A, -B, -C, -DRB1, -DQB1, or -DPB1 mismatch between the recipient and the donor in the GVH direction was 5/10 in 51%, 4/10 in 29% and £3/10 in 20% of cases. Offspring donors were used in 54% of the patients, sibling donors in 35%, and parent/other relative donors in 11%. Female donors to male recipients were used in only 22% of patients. The median infused CD34 dose was 5.25 x106 cells/kg (range, 2.3-22.4x106) and the CD3 dose was 2.48x108 cells/kg (range, 0.002-8.88 x108). CRS of any grade by ASTCT criteria was observed in 92% of study patients within first 7 days of HCT: 54% had grade 1, 39% grade 2, and 5.2% grade 3-4. Infused cell doses of CD34 &amp;gt;5x106 cells/kg and of CD3 &amp;gt;2.5x108 cells/kg had no significant effect on grade 3-4 CRS. On multivariable analysis, the use of reduced-intensity conditioning (RIC) was associated with increased grade 2-4 CRS (HR = 1.6, 95% CI: 1.11.-2.33, p=0.01) and grade 3-4 CRS (HR = 14.7, 95% CI: 1.97-109.5, p=0.009) compared with the myeloablative conditioning. Donor 5/10 HLA-mismatch was also associated with increased grade 2-4 CRS (HR = 1.5, 95% CI: 1.05-2.18; p=0.03) and grade 3-4 CRS (HR = 3.50, 95% CI: 1.00-12.32; p=0.05) compared with £4/10 HLA-mismatch. Non-relapse mortality (NRM) at day 100, and 1-year overall survival (OS) by CRS severity is shown in Figure. Comparing with the grade 0-1 CRS in multivariable analysis (Table), increase in CRS severity was associated with lower probability of neutrophil engraftment (HR = 0.9 for grade 2 and HR = 0.4 for grade 3-4; p=0.03). Increased CRS severity as compared to the grade 0-1 was also predictive of higher risks of NRM (HR = 1.6, 95% CI: 0.95-2.79 for grade 2 and HR = 6.6, 95% CI: 3.12-13.78 for grade 3-4; p&amp;lt;0.001), lower disease-free survival (DFS; HR = 1.3 for grade 2 and HR = 4.5 for grade 3-4; p&amp;lt;0.001) and lower OS (HR = 1.2 for grade 2 and HR = 4.1 for grade 3-4; p&amp;lt;0.001) after HCT. We observed no association between CRS severity and risk of relapse or the incidence and severity of acute GvHD after transplant. We conclude that CRS is a common complication after PB haplo-HCT/PTCy. CRS severity is associated with post-HCT outcomes with grade 3-4 CRS associated with the highest risk of NRM and overall mortality after HCT. Infused CD34 or CD3 cell doses effect on CRS is unclear. RIC and higher degree of HLA-mismatch are predictive of higher-grade CRS. Identification of modifiable risk factors can help to mitigate the risk for serious CRS and subsequent mortality after PB haplo-HCT/PTCy. Figure 1 Disclosures Nishihori: Karyopharm: Other: Research support to institution; Novartis: Other: Research support to institution. Pidala:CTI Biopharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Takeda: Research Funding; Janssen: Research Funding; Johnson and Johnson: Research Funding; Pharmacyclics: Research Funding; Abbvie: Research Funding; BMS: Research Funding; Syndax: Consultancy, Membership on an entity's Board of Directors or advisory committees. Nakamura:Merck: Other: advisory board meeting; Alexion: Other: Support on a meeting presentation; Kyowa-Kirin: Other: Support on a meeting presentation; Celgene: Other: Support on seminar; Magenta Therapeutics: Other: Advisory board meeting; Viracor: Consultancy; Kadmon Corporation: Other: Advisory board meeting; NapaJen Pharma: Consultancy. Al Malki:Rigel Pharma: Consultancy; Jazz Pharmacuticals, Inc: Consultancy; Neximmune: Consultancy. Bejanyan:Kiadis Pharma: Membership on an entity's Board of Directors or advisory committees.

Risk Factors for Overall Survival in Children with High Risk Acute Myeloid Leukemia (HR AML) after Allogeneic Hematopoietic Stem Cell Transplantation (allo-HSCT) with Different Intensity of Conditioning Regimens

Background: Traditionally, children with AML undergo аllo-HSCT with myeloablative conditioning (MAC). It is known that MAC is associated with significant transplant-related morbidity and mortality. Reduced-intensity conditioning (RIC) is used in patients not eligible for conventional conditioning therapy due to poor performance status and severe toxic complications after previous chemotherapy. RIC is a well-established treatment strategy in adult patients with comorbidities. But there is no conclusive evidence to support efficacy of RIC allo-HSCT in children suffering from different malignant diseases including AML. The aim: To compare efficacy of different intensity conditioning regimens in children with high risk (HR) AML (according to AML-BFM protocols 1998 and 2004) and to identify factors which have a prognostic significance for overall survival (OS). Patients and methods: Retrospective analysis was performed in 192 patients (pts) with AML (median age of 10 years (0.5-18 y.o.), who received allo-HSCT at R.M. Gorbacheva Research Institute between 08/2000 and 09/2019. MAC (busulfan- or treosulfan-based) were used in 109 pts: 1st CR - 46 pts (MRD+ n=11), 2nd CR - 18 pts, 3rd CR - 1 pt, relapse - 44 pts. Allo-HSCT with RIC were performed in 83 pts: 1st CR - 32 pts (MRD+ n=13), 2nd CR -19 pts, 3rd CR - 4 pts, relapse -28 pts (p=0,674). RIC consisted of fludarabine (30 mg/m2/d x 5 days) + melphalan (70 mg/m2/d x 2 days) or fludarabine (30 mg/m2/d x 5 days) + busulfan (4 mg/kg/d x 2 days). Indication for RIC allo-HSCT was poor performance status (Lansky/Karnofsky score ≤70%), or organ dysfunction due to previous therapy, or infectious complications at the moment of allo-HSCT. Allo-HSCT from matched related donor was performed in 30 pts (16%), from matched unrelated donor - in 98 pts (51%), haploidentical - in 64 pts (33%) and the donor distribution was not different between groups (p=0,878). Post-transplant Cy was included in GVHD prophylaxis regimens in 102 pts (53%). OS were estimated using Kaplan-Meier curves. Univariate analyses were performed using the log rank test for OS, Grey test for cumulative incidences. Multivariate analyses were performed using the Cox proportional-hazard model. Results: Median follow-up was 5 years for МАС, 4.5 years for RIC. In both groups the median time to neutrophil engraftment &amp;gt;=0,5x109/l was D+16 (range D+8-52). Engraftment was observed in 67 pts (81%) after RIC and 94 pts (86%) after MAC (p=0,231). OS after RIC allo-HSCT in the 1st CR was 76% and after MAC - 68% (p=0,014), in 2nd CR 50% after RIC and 54% after MAC (p=0,058), in advanced disease 14% after RIC and 16% after MAC (p=0,394). The transplant-related mortality rate was 19% after RIC and 22% after MAC (p=0,546). Risk of relapse was 28% after RIC and 26% after MAC (p=0,456). Factors influencing OS after MAC were: 1) Remission status at the moment of allo-HSCT (р=0.001); 2) Presence of aGVHD grade I-II (р=0,005); 3) Relapse or MRD+ status after allo-HSCT (р=0.012); 4) Lansky score &amp;gt;70% (р=0,024). Factors influencing OS after RIC were: 1) Remission status at the moment of allo-HSCT (1st remission) (p=0,001); 2) Lansky score &amp;gt;70% (р=0,004). Conclusion: The effectiveness of RIC and MAC is comparable in children with HR AML, but RIC demonstrated better results in 1st CR. The presence of I-II grade aGVHD had positive effect in MAC. Factors influencing OS in both groups were disease status at the moment of allo-HSCT and performance status before allo-HSCT The use of RIC can be effective in patients, especially those who have undergone allo-HSCT in the 1st remission, while minimizing regimen-related toxicity in children who have undergone previous intensive treatment. Multicenter studies are warranted, especially for patients in the first CR, where long-term complications are of most importance. Disclosures No relevant conflicts of interest to declare.

Less Is More: Superior Graft-versus-Host Disease-Free/Relapse-Free Survival with Reduced-Intensity Conditioning and Dual T Cell Depletion in Acute Myelogenous Leukemia.

In this study, we compared the outcomes of patients with acute myelogenous leukemia (AML) in complete remission treated with myeloablative conditioning (MAC) and those treated with reduced-intensity conditioning (RIC) before allogeneic hematopoietic stem cell transplantation (allo-HCT). In addition, we explored the efficacy of dual T cell depletion using anti-thymocyte globulin (ATG) and post-transplantation cyclophosphamide (PTCy) for the prevention of graft-versus-host disease (GVHD) in patients undergoing RIC allo-HCT. Our study cohort comprised 356 adults with AML in complete remission who underwent allo-HCT between 2013 and 2018. One hundred eleven patients (31.2%) received a MAC regimen, and 245 (68.8%) received an RIC regimen. One hundred seventy-one of the patients who received an RIC regimen (68.4%) received ATG, PTCy, and cyclosporine (ATG-PTCY-CsA) for GVHD prophylaxis in accordance with our institutional protocol. Data were collected retrospectively and updated in July 2019. With a median follow-up of 14.5 months (range, 0 to 76 months), 161 patients (45.2%) died, and 66 (18.5%) relapsed. Two-year overall survival (OS), relapse-free survival (RFS), and GVHD-free/RFS (GRFS) were 55%, 52.6%, and 35%, respectively. The intensity of the conditioning regimen, with or without ATG-PTCY-CsA, did not have a significant impact on OS and RFS. However, RIC in combination with ATG-PTCY-CsA was associated with a significantly lower cumulative incidence of acute GVHD and chronic GVHD. The use of RIC with ATG-PTCy-CsA was a significant predictor for higher GRFS secondary to the reduction of clinically relevant GVHD (P= .0001). In patients with AML, RIC allografts and dual T cell modulation with ATG and PTCy led to superior GRFS. The use of this GVHD prophylaxis strategy, along with mitigation of conditioning toxicity using RIC, may result in better long-term quality of life for allo-HCT recipients.

Hematopoietic Stem Cell Transplant Recipients Surviving at Least 2 Years from Transplant Have Survival Rates Approaching Population Levels in the Modern Era of Transplantation.

The health and outcomes of long-term survivors after hematopoietic cell transplant (HCT) are areas of evolving interest as short-term transplant outcomes improve. Because recent changes in transplant practice have likely changed the survivor population, we sought to assess the survival of a contemporary cohort of patients who were alive and free of disease 2 years after HCT. Data were extracted from first transplants documented between 2002 and 2011 in the Australasian Bone Marrow Transplant Recipient Registry on patients who received an allogeneic HCT for acute myeloid leukemia (AML), acute lymphoblastic leukemia, chronic myeloid leukemia (CML), non-Hodgkin lymphoma, and myelodysplastic syndromes or an autologous HCT for myeloma or lymphoma. Patients were included if they had survived at least 2 years without disease relapse or progression. Mortality rates were compared with standard Australian and New Zealand populations using relative-survival analysis. A total of 1562 allogeneic and 3822 autologous HCT patients were included, with a median follow-up of 5.6 years. Compared with a matched group of patients from our previous study from 1992 to 2001, the contemporary cohort of allogeneic HCT recipients was older and more likely to receive peripheral blood stem cells and from unrelated donors. Allogeneic HCT for AML increased, wheresa transplants for CML fell from 32% to 8%. Increasing use of reduced-intensity conditioning and unrelated donors was also seen. Long-term survival after allogeneic and autologous HCT were very similar to the previous 1992 to 2001 cohort despite changes in practice over time. Recipients of autologous HCT for myeloma demonstrated substantially lower overall survival than HCT for other indications with no clear plateau. Annual relative survival for survivors of allogeneic HCT was 96% to 99% of the general population but only 89% to 96% of the general population for recipients of autologous HCT. Late deaths were primarily due to nonrelapse causes after allogeneic HCT, but relapse or disease progression remained prominent for recipients of autologous HCT, particularly for myeloma. The management of late HCT effects is important to improve long-term survival of transplant recipients but should be tailored to the risks specific to the primary disease and transplant type. Future planning should account for the impact of the expected increase in transplant activity and number of survivors on resource utilization.

Hematopoietic Stem Cell Transplantation in Children with Sickle Cell Disease: Myeloablative Versus Reduced Intensity Conditioning

<h3>Background</h3> Sickle cell disease (SCD) is prevalent in Saudi Arabia. We reviewed transplant outcome among SCD patients who underwent HLA-matched related donor HSCT at our institution using either myeloablative or reduced intensity conditioning (RIC) <h3>Methods</h3> myeloablative conditioning (MAC) regimen was intravenous (IV) busulfan (Bu) 16mg/kg, cyclophosphamide (Cy) 200mg/kg, and rabbit anti-thymocyte globulin (ATG) 10mg/kg (BuCyATG) and recently we use TBF regimen (thiotepa 8mg/kg, IV Bu 16mg/kg, and fludarabine 160mg/m²). GVHD prophylaxis included calcineurin inhibitor (CNI) and methotrexate (10mg/m²) on day 1, 3, and 6. CNI was continued for one year post transplant then tapered slowly. Based on parental preference, we used RIC regimen that included alemtuzumab, fludarabine, and melphalan (AFM) in 4 patients as reported by (King et al. AJH 2015). Three patients participated in a pilot RIC study (NCT02776202) which included pre-conditioning hydroxyurea (40mg/kg) from day -60 to day -10 and intensive iron chelation if needed followed by conditioning that included ATG 10 mg/kg, fludarabine 175mg/m², and melphalan 140 mg/m² (ATGFM) with GVHD prophylaxis consisting of mycophenolate mofetil from day -3 to +45 and sirolimus from day -1 until at least one year post transplant. Bone marrow was the source of stem cells in all patients. SCD-specific supportive care was implemented <h3>Results</h3> A total of 41 SCD patients were transplanted, 34 received MAC and 7 RIC. Indications for HSCT were recurrent pain crisis (n=25), stroke or abnormal transcranial doppler (n=13), and other (n=3). Patient and transplant characteristics are shown in Table. All patients who underwent MAC are alive and free of SCD at a median follow up of 444 days. Among patients who received RIC, 4 had late graft failure with autologous recovery. Of those, two underwent successful second HSCT using MAC and 2 patients are alive with SCD. In addition, 2 patients who received RIC (1 AFM and 1 ATGFM) are off immunosuppressant with full donor chimerism more than 2 years post-transplant and one patient (ATGFM) is still on sirolimus at 351 days post-transplant with low donor chimerism. There was no mortality in our study <h3>Conclusions</h3> MAC HSCT in SCD is well tolerated and associated with excellent outcome. There is high rate of late graft failure with the use of RIC in SCD.

Current status of stem cell transplantation in paroxysmal nocturnal hemoglobinuria

Paroxysmal nocturnal hemoglobinuria (PNH) is a clonal, acquired hematopoietic stem cell disorder, which is caused by activation of the complement system leading to life-threatening manifestations such as hemolysis, thrombosis, and marrow failure. Eculizumab is a complement inhibitor of C5, which acts by blocking complement-mediated hemolysis. It needs to be administered lifelong to the patient; hence, there are major financial implications. This drug is easily available in the Western countries; however, in low resource countries, where its availability is limited, hematopoietic stem cell transplantation (HSCT) still remains the main modality for achieving cure in PNH. PNH being a rare disease, large prospective studies and guidelines are scarce. To choose the ideal candidate for transplant is the real challenge. This article aims to review the trends in HSCT for PNH, such as the use of reduced-intensity conditioning to attain the graft versus PNH effect or the use of haploidentical donors. In the era of complement inhibitor therapy, the role of transplantation still needs to be explored.