Reduced-intensity Stem Cell Transplantation Research Articles

Reduced Intensity Stem Cell Transplantation for Accelerated-Phase Myelofibrosis

Reduced Intensity Stem Cell Transplantation for Accelerated-Phase Myelofibrosis

Haploidentical Natural Killer Cell Therapy As an Adjunct to Stem Cell Transplantation for Refractory Acute Myeloid Leukemia

Refractory acute myeloid leukemia (AML), defined as failure of 2 cycles of induction therapy at diagnosis or of 1 cycle at relapse, represents a subgroup with poor clinical outcomes. In our transplant cohort, the 5-year overall survival in this subgroup was 16% (Ganapule at al. JGO 2017). Haploidentical natural killer cell (NK) therapy is a strategy that is being explored in refractory malignancies. Our in-vitro and animal model data suggest that exposure to arsenic trioxide (ATO) results in enhanced NK cytotoxicity (Alex AA et al. Front. Immunol 2018). Historically, at our center, patients with refractory AML have been treated with cytoreductive therapy (FLAG ± idarubicin or mitoxantrone + etoposide for 3 to 5 days) followed by 1-week rest and then a reduced-intensity transplant with fludarabine + melphalan conditioning while in peak cytopenia. From February 2019, we initiated a phase II single arm clinical trial (CTRI/2019/02/017505) enrolling patients with refractory AML planned for a stem cell transplant in peak cytopenia. Patients received CD56-positive cells from an HLA haploidentical related family donor (other than the stem cell donor, wherever feasible) following cytoreductive chemotherapy. The NK cell donor preference strategy included presence of KIR ligand mismatch, greater number of KIR B motifs (or the B score), lower donor age, and negative donor specific antibodies tested using flowcytometry crossmatch (Figure 1a). CD56-positive selection was done using CliniMACS prodigy system. This was followed by overnight incubation of the CD56 positive cells in autologous plasma with 2 micromolar ATO and 500 U/mL of interleukin-2. The CD56 positive cells were then infused to the patient 1-day after the completion of cytoreductive chemotherapy. This was followed by a reduced intensity stem cell transplant (Figure 1b). The primary outcome variable was 1-year relapse free survival. From February 2019, 14 patients with median age 28 years (IQR: 15.75-31.5) were enrolled in this trial. Six were females. Six had primary-refractory AML while 8 had relapsed-refractory AML. The cytoreductive chemotherapy was FLAG ± idarubicin (n=7), Mitoxantrone + Etoposide (n=6) and GCLAC (n=1). The median blast percentage on flowcytometry MRD testing prior to NK infusion was 15.9% (IQR: 9.1%-54.5%) (n=11). The median B score for the NK cell donors was 2 (IQR: 1-3). The median age of the NK cell donor was 43 years (IQR: 36-49.5). KIR ligand mismatch with the patient was noted in 2 donors. The median CD56-cell dose infused was 46.16 x 10 6/kg (IQR: 25.06-70.36) (Figure 1c). Pre-defined release criteria, including sterile cultures, and endotoxin negativity were met in all cases. There was no infusion related toxicity. The median blast percentage on flowcytometry MRD testing done following NK cell infusion was 11.9% (IQR: 4.9%-47.6%) (n=8). One patient withdrew consent after NK cell infusion and did not undergo transplant. For the remaining 13 patients, the stem cell donor was HLA matched (n=4), HLA 9/10 matched (n=1) or HLA haplomatched (n=8). The median CD34 cell dose infused was 10 x 10 6/kg (IQR:7.51-11.6). Five (38.5%) patients died of immediate post-transplant complications (sepsis (n=3) on days 1, 2 and 28, cerebral venous sinus thrombosis (n=1) on day 1 in a patient treated with hormonal contraceptives for menorrhagia, and veno-occlusive disease (n=1) on day 15 in a patient undergoing a second transplant) while 2 (15.4%) did not engraft (both subsequently died of infective complications following engraftment post-second transplant). Of the remaining 6 (46.2%) patients who engrafted and survived beyond 1 month of the transplant, the day 28 post-transplant MRD was negative for 5 patients while it was positive in 1 patient (0.13%). On follow up, 2 (15.4%) patients developed disease relapse (on days 54 and 218 respectively) and died. The remaining 4 (30.8%) patients are alive and relapse free at last follow up (mean follow up of surviving patients is 16 months). One patient received a CD34 cell boost on day 96 (cell dose - 8.55 x 10 6/kg) for poor graft function. For the entire cohort, the estimated 1-year event free survival is 28.8% ± 13.1%(Figure 1d). Whereas, acute GVHD was noted in 3 patients (50%; out of 6 evaluable patients) and chronic GVHD was noted in 3 patients (50%; out of the 6 evaluable patients). Thus, haploidentical NK cell therapy as an adjunct to transplant is safe and merits further evaluation in patients with AML. [Display omitted] DisclosuresMathews: Christian Medical College: Patents & Royalties: US 2020/0345770 A1 - Pub.Date Nov.5, 2020; AML: Other: Co-Inventor.

Busulfan-containing conditioning regimens in allogeneic hematopoietic stem cell transplantation for acute lymphoblastic leukemia: A Taiwan observational study.

BackgroundAllogeneic stem cell transplantation (allo‐HSCT) is the ultimate cure for acute lymphoblastic leukemia (ALL).AimThis study was performed to compare the outcomes of ALL patients receiving busulfan (Bu) with cyclophosphamide (Cy)‐based or total body irradiation (TBI)‐based regimen in a Chinese population.MethodsWe enrolled 224 adult patients with ALL who received allo‐HSCT at National Taiwan University Hospital between 1997 and 2016.ResultsThe median age at transplantation was 33 years. Before allo‐HSCT, 75.9% of patients attained first or late complete remission. A total of 141 patients (62.9%) received Bu/Cy‐based conditioning, either myeloablative (MA) or reduced‐intensity stem cell transplantation (RIST), and 83 patients received a TBI‐based regimen (MA‐TBI). Patients receiving the MA‐Bu regimen had longer relapse‐free survival (RFS) than those receiving the MA‐TBI regimen (median, 24.1 vs. 6.7 months, p = .044). There was no difference in overall survival (OS, MA‐Bu vs. MA‐TBI vs. RIST‐Bu: 39.4 vs. 28.2 vs. 13.1 months, p = .276), treatment‐related mortality (TRM), or incidences of grade 3–4 acute graft‐versus‐host disease (GvHD). Among patients receiving identical GvHD prophylactic regimens, there was no difference between MA‐Bu and MA‐TBI groups regarding the incidence of grade 3–4 acute GvHD, grade 2–4, and all‐grade chronic GvHD. In subgroup analysis, patients receiving oral busulfan had comparable RFS and OS to the intravenous busulfan group (p = .436 and p = .236, respectively), but a higher TRM (25% vs. 9.8%, p = .016). In the multivariable analysis, disease status before allo‐HSCT was the only risk factor impacting RFS and OS.ConclusionIn summary, patients receiving Bu/Cy‐based or TBI‐based regimens as conditioning had similar results in terms of OS, TRM, and acute GvHD, whereas the use of myeloablative Bu/Cy resulted in a better RFS. A Bu‐based regimen could be an alternative conditioning choice for patients who are ineligible to receive TBI. Prospective and randomized controlled trials are warranted to validate the long‐term outcomes.

Reduced Intensity Stem Cell Transplantation Followed By Adjunctive Lenalidomide Is Tolerable and Safe and Improves Complete Response Rate in Multiple Myeloma:a UK NCRI Phase 2 Feasibility Study (LenaRIC)

BackgroundThe role of allogeneic stem cell transplantation in the management of myeloma remains uncertain as it is a procedure with significant mortality and low long term rates of disease control. We sought to evaluate the feasibility of using adjunctive Lenalidomide (Revlimid®) to augment long term myeloma response following Reduced-Intensity Conditioned (RIC) allograft in the UK NCRI trial LenaRIC (Lenalidomide in Reduced Intensity Conditioned Transplant)-ISRCTN:16228367.Material & MethodsForty (40) patients were recruited in this single arm phase II trial at ten UK stem cell transplant centres from June 2011-June 2015. All patients were in CR/VGPR 1 or 2 and had undergone a Melphalan conditioned autologous transplant in the previous 6 months. They then underwent a RIC allograft using Fludarabine & 2Gy TBI with ATG (Fresenius) as in vivo T-cell depletion (planned tandem SCT programme). Patients were scheduled to receive Lenalidomide (10mg until 2013, reduced to 5mg thereafter on DMEC advice) from day +35 if stable donor engraftment was present in the absence of GvHD. Lenalidomide was planned to be discontinued 12 months post-transplant with donor lymphocyte infusions given to patients with evidence of residual disease, relapse or mixed chimerism.ResultsOf the thirty nine(39) patients transplanted within 42 days of study entry, 8 were in CR1, 16 in VGPR1, 7 in CR2 and 8 in VGPR2. The median age was 49 years (range 35-65) with peripheral blood as the graft source in the 39 patients, from either sibling (n=16) or 10/10 matched unrelated donor (n=23). 1 patient failed to proceed to transplant. Of thirty four (34) evaluable patients, 28 (82.4%) achieved full donor T-cell chimerism and 32 (94.1%) full donor in whole blood. 34 patients completed at least one cycle of Lenalidomide. Mean number of cycles received was 7.4 (range 1-12, median 9.0). Mean dose was 5.2mg, median 5mg. 16 patients completed at least 10 cycles and 5 patients completed 12 cycles as per protocol treatment; of those completing >= 10 cycles, 5/16 received DLI.Safety dataThere were eight (8) patients who had biopsy-proven aGVHD (4 of grade 1-2 and 4 of grade 3- all 4 within 3 cycles of Lenalidomide) and 3 patients with cGVHD (2 extensive and 1 limited). No Grade 3/4 aGVHD was seen following DMEC advice to reduce the Lenalidomide dose to 5mg daily. 8 patients experienced grade 3 or 4 non-Haem toxicity. The majority of AEs were grade 1-2. Significant (Grade 3/4) non-Haem SAEs in this transplant population included Gastro-intestinal (4 patients), metabolism (4 patients), infection (13 patients) and vascular (4 patients). One year relapse-free survival was 84.3%.Clinical OutcomesEfficacy was assessed at a median follow-up of 445 days. The pre-transplant CR rate of 38.4% was improved to 67.6% at best response post-transplant. PFS at 2 years was 43.1% (figure 1a), OS at years 75.7% with a 2 year disease-free survival of 59.1% (figure 1b). Of the 10 patients who have died, 6 have been recorded as disease-related.Conclusions1) Based on the pre-defined safety stopping rules, the LenaRIC study shows that post-graft Lenalidomide is safe and tolerated in a T-depleted RIC setting at a dose of 5mg daily- this results in a tolerable AE profile with an acceptable GVHD rate.2) Acute GVHD only occurred in the first 3 cycles of exposure to Lenalidomide- consideration should be given to examining the longer term use of Lenalidomide beyond 12 months following a T-depleted RIC allograft to augment long term outcomes3) CR rates were nearly doubled by this approach4) Further work correlating Lenalidomide exposure with clinical events and immune reconstitution is ongoing.An unrestricted educational grant was provided to support the trial & adjunctive science by Cancer Research UK and by Celgene. Lenalidomide provided free of charge by Celgene. Lenograstim provided free of charge by Chugai. The support and time of participating patients and their families is gratefully acknowledged. [Display omitted] DisclosuresCook:Janssen: Honoraria, Other: Travel support, Research Funding; Amgen: Honoraria, Other: Travel support; Takeda: Honoraria; Myeloma UK: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Other: Travel support, Research Funding; Jazz Pharmaceuticals: Honoraria. Brock:Merck: Other: travel expenses; Roche: Honoraria, Other: travel expenses; GlaxoSmithKline: Equity Ownership; Astra-Zeneca: Equity Ownership. Snowden:Sanofi: Honoraria. Hunter:Celgene: Other: Travel Support. Cavenagh:Takeda: Consultancy; Novartis: Consultancy; Janssen: Honoraria; Celgene: Consultancy. Cook:BMS: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; Glycomimetics: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau.

Reduced-intensity stem cell transplantation for acute myeloid leukemia with fludarabine-based conditioning with intravenous busulfan versus melphalan.

Reduced-intensity conditioning (RIC) has been facilitating allogeneic hematopoietic cell transplantation (allo-HCT) for patients originally considered ineligible for HCT with myeloablative conditioning. Fludarabine (Flu) with reduced doses of busulfan (Bu) (Flu + Bu) and Flu with reduced doses of melphalan (Mel) (Flu + Mel) are widely used RIC regimens for acute myeloid leukemia (AML). A nationwide retrospective study comparing clinical outcomes of adult patients with AML receiving first allo-HCT after RIC between 2001 and 2010 was performed. Cumulative incidences of relapse were not significantly different among the Flu + ivBu-based (FBiv), Flu + poBu-based (FBpo), and Flu + Mel-based (FM) groups (p = 0.29). Non-relapse mortality (NRM) was significantly lower in patients receiving FBiv compared with FBpo (p = 0.003) and FM (p < 0.001). On multivariate analysis, there was no significant difference in overall survival, but FM was associated with a significantly lower risk of relapse (hazard ratio (HR) = 0.65, 95% confidence interval (CI): 0.50-0.85, p = 0.002), higher NRM (HR = 1.60, 95% CI: 1.10-2.33, p = 0.013) and better leukemia-free survival (HR = 0.77, 95% CI: 0.63-0.95, p = 0.015) compared with FBiv. These results suggest that Flu + Mel has a more intense disease control potential and Flu + ivBu is less toxic than the other. Both RIC regimens provide similar survival outcomes and are effective and useful regimens for patients with AML who received allo-HCT.

Progress in Allogeneic Hematopoietic Cell Transplantation in Adult T-Cell Leukemia-Lymphoma.

The prognosis of aggressive adult T-cell leukemia-lymphoma (ATL) remains poor because of frequent infections and drug resistance. Dose-intensified chemotherapy followed by autologous stem cell transplantation failed to improve the prognosis of patients with ATL; however, we first revealed that allogeneic hematopoietic cell transplantation (allo-HCT) might improve their prognosis. We showed that reduced-intensity stem cell transplantation using peripheral blood was feasible for elderly patients. Further, the prognosis of patients in remission, who receive cord blood transplantation, has been recently improved and is equivalent to that of patients who receive transplants from other stem cell sources. As for the timing of HCT, the patients who underwent transplantation early showed better outcomes than those who underwent transplantation late. Based on the analysis of patients with aggressive ATL, including those who received transplants, we identified five prognostic factors for poor outcomes: acute-type ATL, poor performance status, high soluble interleukin-2 receptor levels, hypercalcemia, and high C-reactive protein level. Next, we developed a new prognostic index: the modified ATL-PI. The overall survival (OS) rates were significantly higher in patients who underwent allo-HCT than those who did not in the intermediate and high-risk groups stratified using the modified ATL-PI. Two new anti-cancer agents, mogamulizumab and lenalidomide, were recently approved for ATL patients in Japan. They are expected to induce longer survival in ATL patients when administered along with transplantation. However, a retrospective analysis that the risk of severe, acute, and corticosteroid-refractory graft-versus-host disease was higher in patients who received mogamulizumab before allo-HCT, and that mogamulizumab might increase the transplant-related mortality (TRM) rates and decrease the OS rates compared to those of patients who did not receive mogamulizumab. However, our recent study showed that administration of mogamulizumab before allo-HCT tended to improve the survival of patients with ATL. In conclusion, allo-HCT procedures for patients with aggressive ATL have considerably progressed and have helped improve the prognosis of these patients; however, many concerns still remain to be resolved. Further development of allo-HCT by using new molecular targeting agents is required for the improvement of cure rates in patients with ATL.

Very early lineage-specific chimerism after reduced intensity stem cell transplantation is highly predictive of clinical outcome for patients with myeloid disease

BackgroundThe importance of chimerism status in the very early period after hematopoietic stem cell transplantation is unclear. We determined PBMC and T-cell donor chimerism 50 days after transplantation and related this to disease relapse and overall survival. Methods144 sequential patients underwent transplantation of which 90 had AML/MDS and 54 had lymphoma. ‘Full donor chimerism’ was defined as ≥99% donor cells and three patient groups were defined: 40% with full donor chimerism (FC) in both PBMC and T-cells; 25% with mixed chimerism (MC) within both compartments and 35% with ‘split’ chimerism (SC) characterised by full donor chimerism within PBMC and mixed chimerism within T-cells. ResultsIn patients with myeloid disease a pattern of mixed chimerism (MC) was associated with a one year relapse rate of 45% and a five year overall survival of 40% compared to values of 8% and 75%, and 17% and 60%, for those with SC or FC respectively. The pattern of chimerism had no impact on clinical outcome for lymphoma. ConclusionThe pattern of lineage-specific chimerism at 50 days after transplantation is highly predictive of clinical outcome for patients with myeloid malignancy and may help to guide subsequent clinical management.

National survey on total-body irradiation prior to reduced-intensity stem cell transplantation in Japan: The Japanese Radiation Oncology Study Group.

Reduced-intensity stem cell transplantation (RIST) minimizes the adverse effects of traditional hematopoietic stem cell transplantation, and low-dose total-body irradiation (TBI) is administered over a short period prior to RIST (TBI–RIST). Different institutes adopt different approaches for the administration of TBI–RIST, and since no study had previously investigated this issue, a survey of the TBI schedules in Japan was conducted. In October 2015, the Japanese Radiation Oncology Study Group initiated a national survey of TBI–RIST procedures conducted between 2010 and 2014. Of 186 institutions performing TBI, 90 (48%) responded to the survey, 78 of which performed TBI–RIST. Of 2488 patients who underwent TBI for malignant disease at these institutions, 1412 (56.8%) patients were treated for leukemia, 477 (19.2%) for malignant lymphoma, 453 (18.2) for myelodysplastic syndrome, 44 (1.8%) for multiple myeloma, and 102 (4.1%) for other malignant diseases. Further, 206 (52.0%) of 396 patients (a high proportion of patients) who underwent TBI for benign disease had aplastic anemia. The TBI–RIST equipment and treatment methods were similar to those used for myeloablative regimens. Routinely shielded organs included the lungs (43.6%), eyes (50.0%) and kidneys (10.2%). The ovaries (14.1%), thyroid (6.4%) and testicles (16.7%) were also frequently shielded, possibly reflecting an emphasis on shielding reproductive organs in children. TBI–RIST was performed more frequently than myeloablative conditioning in patients with benign disease. Genital and thyroid shielding were applied more frequently in patients treated with TBI–RIST than in patients treated with myeloablative conditioning. In conclusion, this study indicates the status of TBI–RIST in Japan and can assist future efforts to standardize TBI–RIST treatment methods and to design a future multicenter collaborative research study.

Busulfan-Containing Conditioning Regimens in Allogeneic Hematopoietic Stem-Cell Transplantation for Acute Lymphoblastic Leukemia: Single Tertiary Center Experience in Taiwan

The allogeneic hematopoietic stem-cell transplantation (allo-HSCT) is viewed as the ultimate cure for acute lymphoblastic leukemia (ALL). An essential component of allo-HSCT is the conditioning regimen administered before the hematopoietic stem-cell infusion. This study is aimed to compare outcomes of ALL patients receiving either a busulfan with cyclophosphamide (BuCy) or a total body irradiation(TBI)-based regimen. We retrospectively analyzed data from National Taiwan University Hospital institute registry. We enrolled 224 adult patients with ALL who received allo-HSCT between 1997 and 2016 and compared outcomes of patients receiving either a BuCy-based or a TBI-based regimen. There were more B-cell ALL than T-cell ALL (67.8% vs 32.2%). A total of 41 patients (22.5%) carried the Philadelphia chromosome (Ph) while 38 patients (20.9%) carried complex karyotype. Before the allo-HSCT, 164 (73.2%) patients achieved first or late complete remission (CR). The main source of stem-cell was from peripheral blood (71%), followed by bone marrow (22.3%). Siblings comprised 54.9% of the donors. A total of 141 patients (63%) received BuCy-based conditioning, either myeloablative (MA) or reduced intensity stem cell transplantation (RIST) and 83 patients (37%) received TBI-based regimen. The mean dose of stem cell was 4.96 ± 2.42 × 106/Kg CD34+ cells. We use cyclosporine and mycophenolate mofetil for prophylaxis of graft-versus-host disease (GvHD). In results, patients received BuCy-based regimen performed as well as TBI-based group in terms of 5-year overall survival (47.5% vs 37.3%, p=0.115). As to 5-year relapse-free survival (RFS), BuCy group had slightly better result, especially the group received myeloablative conditioning (MA, Bu-based vs. MA, TBI-based, p=0.059), albeit the p value didni¦t reach significance, the curves went on departing ways. In this study, all regimen groups yielded similar treatment-related mortality (TRM), (MA, Bu-based vs RIST, Bu-based vs MA, TBI-based: 17% vs 10.9% vs 21.7%, p=0.308) and incidences of grade 3-4 acute GvHD at day+100, (p=0.445). Further, in patients with extramedullary disease, there was no difference among groups; and interestingly, BuCy group with MA conditioning seemed to yield better result than TBI group (p=0.072). By multi-variate analysis, disease status before allo-HSCT is the only risk factor impacting OS and RFS. In conclusion, patients received BuCy-based regimen or TBI-based regimen as conditioning had similar results in terms of OS, RFS, TRM, and GvHD.

Successful Reduced Intensity Stem Cell Transplant in a Patient with Myeloproliferative Neoplasm/Myelodysplastic (MPN/MDS) Overlap Syndrome Diagnosed with West Nile Virus Encephalitis.

West Nile Virus (WNV) infections are associated with high morbidity and mortality rates in transplant recipients. Limited information exists regarding the management of WNV in the peri-transplant period. The optimal duration of time for delaying transplantation remains unclear. We describe the first successful case of a patient diagnosed with WNV encephalitis in the pre-transplant period who subsequently underwent successful reduced intensity conditioning (RIC) HSCT. Our patient initially presented with low grade fevers, malaise, cough and fatigue a fortnight before planned HSCT for myelodysplastic syndrome (see Figure). Chest X-ray and respiratory tract PCR were negative. As Colorado is endemic for WNV, a WNV nucleic acid amplification test (NAAT) was sent and returned positive. WNV IgM in blood was positive (6.22), WNV IgG was negative (0.70), WNV serum reverse transcriptase polymerase chain reaction (RT-PCR) was negative. A week later he was admitted with high-grade fevers, rigors, retro-orbital headaches and confusion. Exam was unrevealing. Magnetic Resonance Imaging of brain did not show encephalitis. Cerebrospinal fluid IgG was negative (0.7), CSF WNV RNA PCR was negative. One week following discharge both WNV serum IgM (7.45) and WNV IgG (2.21) were positive. Given concerns for possible WNV encephalitis, decision was made to delay HSCT and monitor for neuroinvasive disease. He improved with resolution of fever and neurological symptoms and 1.5 months after initial presentation underwent RIC Matched Unrelated Donor (MUD) Allogeneic peripheral blood HSCT. Conditioning regimen involved fludarabine and melphalan. Post-transplant, he was on methotrexate and tacrolimus for graft versus host disease prophylaxis. On Transplant Day + 10, WNV serum IgM was positive at 4.31, WNV IgG positive at 4.12; however, serum WNV RNA PCR were reported negative. He engrafted on Transplant Day +18, bone marrow biopsy from day +28 revealed 100% donor cells. At day +100, there was no evidence of relapse of WNV infection.

Clinical significance of low-dose total body irradiation in HLA-mismatched reduced-intensity stem cell transplantation

The significance of low-dose total body irradiation (TBI) in HLA-mismatched reduced-intensity conditioning stem cell transplantation (RICT) remains unknown. We, retrospectively, evaluated the impact of low-dose TBI in patients with hematological malignancies who received first RICT from ≥1 antigen-mismatched donors between 2004 and 2014. Of the 575 patients, 361 patients received low-dose TBI (2 or 4 Gy). There were no significant differences in neutrophil engraftment or platelet recovery between TBI and non-TBI groups. The benefit of low-dose TBI on neutrophil engraftment was not observed in any subgroups. Low-dose TBI was not associated with decreased secondary graft failure. Suppressed mixed chimerism and autologous hematopoiesis by low-dose TBI was observed. There were no significant differences in cumulative incidences of acute GVHD or nonrelapse mortality rates in either group; however, low-dose TBI improved overall survival (OS), especially in patients with high-risk disease, multi-HLA mismatch, and fludarabine/busulfan conditioning. Multivariate analysis demonstrated that low-dose TBI was an independent prognostic factor for OS. Compared with the non-TBI group, 4 Gy TBI, but not 2 Gy TBI, was associated with increased acute GVHD and reduced relapse. These findings suggest that low-dose TBI may be beneficial for patients at high risk for relapse in HLA-mismatched RICT.

Outcome of reduced-intensity allogeneic stem cell transplantation in Egyptian patients with myelodysplastic syndromes

Outcome of reduced-intensity allogeneic stem cell transplantation in Egyptian patients with myelodysplastic syndromes

Reduced-intensity conditioning haematopoietic stem cell transplantation in genetic diseases: Experience of the Spanish Working Group for Bone Marrow Transplantation in Children

Reduced-intensity conditioning haematopoietic stem cell transplantation in genetic diseases: Experience of the Spanish Working Group for Bone Marrow Transplantation in Children

Treatment of Older Patients with Acute Lymphoblastic Leukaemia.

The outcome of adult acute lymphoblastic leukaemia (ALL) has improved significantly during the past decade, mainly due to intensive paediatric-based chemotherapy. Less improvement has been observed in older patients. A significantly lower rate of complete remissions, higher early mortality, higher relapse rate and poorer survival is observed in older compared with younger ALL patients. Most importantly, intensive chemotherapy with or without stem-cell transplantation is less well tolerated in older patients. In addition, there is an increasing incidence of poor prognostic factors with increasing age. Progress has been made with the development of age-adapted, moderately intensive chemotherapy protocols for Ph/BCR-ABL-negative ALL and combinations of tyrosine kinase inhibitors with chemotherapy in Ph/BCR-ABL-positive ALL. Future progress can be expected from new targeted therapies, particularly novel immunotherapies, moderately intensified consolidation strategies and reduced intensity stem-cell transplantation. For this purpose, prospective clinical trials for older patients are urgently needed.

National Survey on Total Body Irradiation Before Reduced-Intensity Stem Cell Transplantation in Japan

National Survey on Total Body Irradiation Before Reduced-Intensity Stem Cell Transplantation in Japan

Treatment of older patients with acute lymphoblastic leukemia.

The treatment of older patients with acute lymphoblastic leukemia (ALL) is an unmet medical need. With increasing age, ALL patients have a significantly lower clinical remission rate, higher early mortality, higher relapse rate, and poorer survival compared with younger patients. This is only partly explained by a higher incidence of poor prognostic factors in the older age group. Most importantly, intensive chemotherapy with or without stem cell transplantation (SCT) is less well tolerated in older patients. Some progress has been made with delivering age-adapted, moderately intensive chemotherapy protocols for Ph/BCR-ABL-negative ALL and combinations of tyrosine kinase inhibitors with chemotherapy in Ph/BCR-ABL-positive ALL. For the future, optimizing supportive care, introducing targeted therapies, novel immunotherapies, moderately intensified consolidation strategies, and reduced intensity SCT are promising approaches. Prospective clinical trials for older patients are urgently needed to test these approaches.

Research progress of reduced-intensity conditioning allogeneic hematopoietic stem cell transplantation in treatment of myelodysplastic syndrome

Allogeneic hematopoietic stem cell transplantation(allo-HSCT) is likely to be the optimum method to cure international prognostic scoring system (IPSS) intermediate and high-risk patients with myelodysplastic syndrome(MDS). However, patients suffered with MDS are usually too old to undergo myeloablative conditioning allogeneic stem cell transplantation(MAC-HSCT). On account of its advantages of higher efficiency and lower toxicity, reduced intensity conditioning allogeneic stem cell transplantation(RIC-HSCT) is widely applied in the treatment of MDS patients. Currently, fludarabine plus alkylating regimens are widely applied, but the clinical outcomes are different from each regimen. Although RIC-HSCT has unique advantages in treating intermediate and high-risk elder MDS compared with MAC-HSCT and non-HSCT therapy, whether the outcome is influenced by factors such as tumor burden, recipient age, IPSS risk stratification, type of allo-HSCT, and comorbidity before transplantation is still unclear. In this article, we review literatures on RIC-HSCT in treatment of MDS. Key words: Myelodysplastic syndrome; Transplantation conditioning; Hematopoietic stem cell transplantation

Host Foxp3+CD4+ Regulatory T Cells Act as a Negative Regulator of Dendritic Cells in the Peritransplantation Period.

Host Foxp3+CD4+ regulatory T cells (Tregs) have been shown to suppress graft-versus-host disease (GVHD) in experimental bone marrow transplantation (BMT) models; however, the detailed mechanism is unknown. To address this issue, we established a murine MHC-haploidentical BMT model (BDF1 (H-2b/d) → B6C3F1 (H-2b/k)), in which transplantation following conditioning with high-dose (13 Gy) or low-dose (5 Gy) total body irradiation corresponds to myeloablative stem cell transplantation (MAST) or reduced-intensity stem cell transplantation (RIST) BMT. All MAST recipients died of GVHD within 70 d, whereas RIST recipients developed almost no GVHD and survived for at least 3 mo. In this BMT model, we investigated the kinetics of immune cells in the mesenteric lymph nodes because GVHD was most prominent in the intestines. Host Tregs that survived after total body irradiation could proliferate transiently by day 4. Comparing the kinetics of immune cells among MAST, RIST, and anti-CD25 mAb-treated RIST, we found that the transiently surviving host Tregs were fully functional, closely contacted with host dendritic cells (DCs), and significantly restrained the maturation (CD80 and CD86 expression) of DCs in a dose-dependent manner. There was a positive correlation between the ratio of DCs to host Tregs and the extent of maturation of DCs. Host Tregs suppressed alloresponse mainly by contact inhibition. Host Tregs are already active in lymph nodes before transplantation and restrain the maturation of host DCs, thereby dampening the ability of DCs to activate allogeneic donor T cells and consequently reducing the magnitude of graft-versus-host reaction. Thus, host Tregs are negative regulators of host DCs that act in the peritransplantation period.

Outcomes of Allogeneic Stem Cell Transplantation in Elderly Patients with Acute Myeloid Leukemia: A Systematic Review and Meta-analysis

A large number of elderly patients with acute myeloid leukemia (AML) are not offered treatments with curative intent, such as allogeneic stem cell transplantation (SCT), because of fears of toxicity and perceived futility of intensive treatment. Therefore, the outcomes of SCT in elderly AML patients remain poorly defined. We performed a meta-analysis of all previous articles up until September 22, 2015 of SCT in AML patients >60 years. The primary endpoints were relapse-free survival (RFS) and overall survival (OS) at 6 months and at 1, 2, and 3 years. A total of 13 studies (749 patients) were included. The pooled estimates and 95% confidence intervals (CI) for RFS at 6 months, 1 year, 2 years, and 3 years were 62% (95% CI, 54% to 69%), 47% (95% CI, 42% to 53%), 44% (95% CI, 33% to 55%), and 35% (95% CI, 26% to 45%), respectively. The corresponding numbers for OS were 73% (95% CI, 66% to 79%), 58% (95% CI, 50% to 65%), 45% (95% CI, 35% to 54%), and 38% (95% CI, 29% to 48%), respectively. We found no evidence of publication bias in our primary endpoints, with the exception of relapse, where there appeared to be a relative lack of small studies with high relapse rates. Sensitivity analysis did not identify an overtly influential study for our primary endpoints, with 1 exception in 2-year RFS analysis. The present analysis argues against significant publication bias and demonstrates consistency among reports despite differences in patient-, disease-, center-, and transplantation-related characteristics. Our results suggest that reduced-intensity SCT is a viable treatment option for elderly AML patients with a 3-year RFS of 35% for those over the age of 60. These results argue against using age per se as the sole criterion against SCT and would help remove some of the barriers that often preclude curative intent treatment. Correct identification of patients who would benefit from SCT can improve outcomes in this frequently undertreated population.

Azacitidine Pre-Treatment Followed by Reduced-Intensity Stem Cell Transplantation in Patients with Higher-Risk Myelodysplastic Syndrome

Azacitidine (AZA) is commonly used in patients with myelodysplastic syndrome (MDS). To determine the role of AZA before allogeneic stem cell transplantation (allo-SCT), we conducted a prospective study of AZA pre-treatment followed by allo-SCT in patients with higher-risk MDS. Twenty-one patients who were scheduled for their third to sixth cycle of AZA pre-treatment followed by allo-SCT were enrolled. AZA pre-treatment was interrupted early in 3 patients (14.3%) because of leukaemic transformation or death. The overall response rate to AZA pre-treatment was 57.1%. There were 2 cases of complete remission, 1 case of partial remission, and 9 cases of haematologic improvement. Fourteen patients (66.7%) received the planned allo-SCT and 5 patients were alive at the last follow-up. Three-year progression-free survival (PFS) and 3-year overall survival (OS) in the 14 patients who received allo-SCT were 30.0% (95% CI 3.3-56.7) and 42.9% (95% CI 17.1-68.7), respectively. PFS and OS were not influenced by response to AZA pre-treatment (p > 0.05). In this study, AZA had a role as a bridge therapy to prevent leukaemic transformation prior to selection of a donor for allo-SCT and showed low toxicity. It may be considered in patients with higher-risk MDS.