Lower Transplant-related Mortality Research Articles

Allogeneic stem cell transplantation for mantle cell lymphoma\u2014update of the prospective trials of the East German Study Group Hematology/Oncology (OSHO#60 and #74)

Mantle cell lymphoma (MCL) is a non-Hodgkin’s lymphoma with an often aggressive course, incurable by chemotherapy. Consolidation with high-dose therapy and autologous stem cell transplantation (autoSCT) has a low transplant-related mortality but does not lead to a survival plateau. Allogeneic stem cell transplantation (alloSCT) is associated with a higher early mortality, but can cure MCL. To investigate alloSCT for therapy of MCL, we conducted two prospective trials for de novo MCL (OSHO#74) and for relapsed or refractory MCL (OSHO#60). Fifteen and 24 patients were recruited, respectively. Induction was mainly R-DHAP alternating with R-CHOP. Conditioning was either Busulfan/Cyclophosphamide or Treosulfan/Fludarabin. Either HLA-identical siblings or matched-unrelated donors with not more than one mismatch were allowed. ATG was mandatory in mismatched or unrelated transplantation. Progression-free survival (PFS) was 62% and overall survival (OS) was 68% after 16.5-year follow-up. Significant differences in PFS and OS between both trials were not observed. Patients below 56 years and patients after myeloablative conditioning had a better outcome compared to patients of the corresponding groups. Nine patients have died between day +8 and 5.9 years after SCT. Data from 7 long-term surviving patients showed an excellent Quality-of-life (QoL) after alloSCT. AlloSCT for MCL delivers excellent long-term survival data. The early mortality is higher than after autoSCT; however, the survival curves after alloSCT indicate the curative potential of this therapy. AlloSCT is a standard of care for all feasible patients with refractory or relapsed MCL and should offer to selected patients with de novo MCL and a poor risk profile. For defining the position of alloSCT in the therapeutic algorithm of MCL therapy, a randomized comparison of autoSCT and alloSCT is mandatory.

Role of Stem Cell Transplantation in Multiple Myeloma.

Simple SummaryThe aim of this review is to provide an overview of the current scientific evidence concerning the role of stem cell transplantation in multiple myeloma. During the past decade, several new treatment options have become available, thereby questioning the role of stem cell transplantation for the management of multiple myeloma. This review focuses on these studies, demonstrating a benefit for autologous stem cell transplantation (auto-SCT). We also reviewed maintenance post auto-SCT and utility of allogeneic stem cell transplant.Autologous stem cell transplantation (auto-SCT) has been the standard of care in eligible newly diagnosed multiple myeloma (MM) patients. Outcomes of patients with MM have improved significantly due to the advent of several novel drugs. Upfront use of these drugs in induction therapy has significantly increased the rate and depth of responses that have translated into longer remission and survival. This has now raised a debate regarding the role and relevance of auto-SCT in the management of myeloma. However, clinical trials have confirmed the utility of auto-SCT even in the era of novel drugs. Tandem auto-SCT followed by maintenance has shown a progression-free survival (PFS) benefit in high-risk MM, and hence can be considered in young and fit patients with high-risk disease. Auto-SCT has the advantages of resetting the bone marrow microenvironment, short-lived toxicity compared to the long-term physical and financial toxicities of continued chemotherapy in the absence of SCT, very low transplant-related mortality (TRM) in high volume centers, and providing longer disease-free survival when followed by maintenance therapy. Allogeneic SCT is one potentially curative option for MM, albeit with an increased risk of death due to high TRM. Strategies to modulate the graft-versus-host disease (GVHD) while maintaining or improving the graft-versus-myeloma (GVM) effect could place allogeneic SCT back in the treatment armamentarium of MM.

Outcome of Children with Different Non-Malignant Disorders Given Alphabeta T and B-Cell Depleted HLA-Haploidentical Hematopoietic Stem Cell Transplantation (TBdepl-haploHSCT)

Background: allogeneic HSCT is the only potentially curative treatment for many non-malignant diseases (NMD), either inherited or acquired. However, many patients lack an HLA-matched donor (familiar (MFD) or unrelated (MUD)) and the outcome of children transplanted from an HLA-haploidentical relative (haplo) was historically inferior to that of transplants from a MFD or a MUD. We previously published promising results in a cohort of 23 children with NMD given this type of allograft (Bertaina et al., Blood 2014), demonstrating a low transplant-related mortality (TRM) and high cure rates. Here, we report the outcome of a large cohort of children affected by NMD who received a TBdepl-haploHSCT at our Center (NCT01810120). Patients and methods: Between February 2011 and June 2020, 80 consecutive patients affected by NMD received TBdepl-haploHSCT from an HLA-partially matched relative at Ospedale Pediatrico Bambino Gesù in Rome, Italy. Patients had many different disorders (see Table for details on patient- and transplant-related characteristics). Median time from diagnosis to transplant for the whole cohort was 12 months (range 1-177), while it was 2.5 months (range 1.3-11.2) for SCID patients. All patients, including children with SCID, received a conditioning regimen, which varied according to the original disease. Pre-transplant anti-thymocyte globulins (from day -4 to day -2) were given to modulate bi-directional donor/recipient alloreactivity, while rituximab (on day -1) was administered to prevent PTLD. Moreover, no post-transplant pharmacological GvHD prophylaxis was given. Results: fifty-eight patients (72.5%) achieved primary donor cell engraftment, while 3 patients experienced secondary graft failure (GF); the cumulative incidence of either primary or secondary GF was 27.8% (95% CI 17.2-37.0). Median time to neutrophil and platelet recovery was 13.5 (range 9-33) and 10 days (range 7-51), respectively. As expected, GF occurred more frequently in children with disorders known to be associated with an increased GF risk (i.e., HLH, thalassemia, SAA or osteopetrosis) (see also Figure 1A). Three children (4%) experiencing GF died because of infectious complications before retransplant. Sixteen of the 22 patients with either primary or secondary GF were successfully retransplanted (2 with a mismatched unrelated cord blood unit, the other having received a second TBdepl-haploHSCT from either the same donor or the other parent). Since 3 other patients died [all because of infectious complications, 2 due to disseminated adenovirus infection and 1 to CMV pneumonia)], TRM is 7.8% (95% CI 1.6-13.7). Eighteen patients experienced acute GVHD of any grade, the cumulative incidence of this complication being 22% (95% CI 13.5-31.8); 10/18 patients developed grade II acute GVHD (no patient developed grade III or IV aGVHD), this resulting into a cumulative incidence of 12.9% (95% CI 6.6-21.4). Only one patient at risk developed mild chronic GVHD. Twenty-two and 7 patients developed clinically-relevant (i.e., with a viral load > 1000 copies/ml and/or requiring specific antiviral-treatment) CMV and adenovirus infection, respectively, at a median time of 4 (range 0-16) and 1 (range 1-4) weeks from HSCT. Time averaged area under the curve (i.e., viral burden under the curve/weeks at risk for infection) for CMV and ADV are reported in Figure 1B. With a median follow-up of 36 months (range 2 - 110), the 5-year probability of overall survival and event-free survival for the entire cohort of patients is 92.1% (95% CI 83.3-96.4) (Figure 1C) and 68.1% (95% CI 56.4-77.2), respectively. Considering the 16/22 given a successful 2nd allograft, the 5-year disease-free survival is 88.4% (95% CI 78.9-93.8). Details on reconstitution of CD3+, CD4+ and CD8+ lymphocytes are reported in Figure 1D. Conclusions: TBdepl-haploHSCT is an effective option for children with different NMD. GF (either primary or secondary) is a challenging problem in a sub-group of patients at risk (i.e., those with HLH, thalassemia, SAA or osteopetrosis): thus, new strategies to overcome this problem are desirable. However, a second transplant is able to rescue most of these patients. Prompt availability of this type of transplant, limiting infectious risk, low incidence of both acute and chronic GvHD preserving a good quality of life in patients makes this strategy an attractive choice in patients with NMD. Figure 1 Disclosures Merli: Bellicum Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; SOBI: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Honoraria; Sanofi-Genzyme: Honoraria; Atara Therapeutics: Honoraria. Algeri:BlueBird Bio: Membership on an entity's Board of Directors or advisory committees; Atara Therapeutics: Membership on an entity's Board of Directors or advisory committees. Locatelli:Jazz Pharmaceeutical: Speakers Bureau; Medac: Speakers Bureau; Miltenyi: Speakers Bureau; Bellicum Pharmaceutical: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Comparison of FLU-BU12 Conditioning with the Standard BU-CY Myeloablative Regimen in High-Risk Pediatric ACUTE Myeloid Leukemia Patients Undergoing Allogeneic STEM Cell Transplantation

INTRODUCTION: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative therapy for high-risk acute myeloid leukemia (AML).The preparative regimen consisting of busulfan and cyclophosphamide (BuCy) is considered as one of the classical myeloablative conditioning regimens (MAC); however, it is associated with significant early and long-term toxicities, leading to a high rate of transplant-related mortality (TRM). P urpose: To compare toxicities and outcomes of BuCy and FluBu12 conditioning in the pediatric population. Methods: We retrospectively analyzed 71 pediatric high-risk AML patients in CR1/2 (n=51, 71,8%) and R/R disease (n=20, 28,2%) received allo-HSCT from MSD (n=16, 22,5%), MUD (n=43, 60,6%) and Haplo donor (n=12, 16,9%). BuCy and FluBu conditioning regimens were used in 47 (66,2%) and 24 (33,8%) patients respectively. Median age was 6 years (0-17). GVHD prophylaxis was PTCy±CNI±m-TOR inhibitor in 32 (45%) or ATG±CNI in 39 (55%) patients. The primary end points were TRM, relapse-free survival (RFS), graft-versus-host disease (GVHD) free, relapse free survival (GRFS) and overall survival (OS). Secondary end points included neutrophil engraftment, sinusoidal obstruction syndrome (SOS), acute and chronic GVHD. Patient were censored at the time of death or last follow-up. Probabilities of OS, RFS and GRFS were estimated using Kaplan-Meier curves. TRM was defined as any death that occurred in the absence of disease relapse; relapse was a competing risk for this event. Results: Engraftment rate was 91% and 87,5% in patients received BuCy and FluBu, respectively (p=0,4). There was a trend to lower day 100 TRM after FluBu (4,1% vs 14,9% after BuCy, p=0,07). Overall survival at 2 years did not differ as well (BuCy 48,9%, FluBu 56%, p=0,5). BuCy showed borderline higher RFS at 2 years (70,2% vs 52%, p=0,06). The composite endpoint GRFS did not differ between two study cohorts being 31,8% and 29,2% at 2 years for BuCy and FluBu (p=0,7). We observed a tendency towards a higher incidence of III0-IV0 aGVHD and cGVHD following BuCy when compared with FluBu: 57,1% vs 41% (p=0,06) and 46,5% vs 28,5% respectively (p=0,2). No significant differences were found between the BuCy and FluBu groups in risk of SOS (6% and 8%, respectively). Conclusions: The optimal conditioning regimen for children with AML is still a matter of debate. Our results suggest that FluBu represents a valid myeloablative regimen, able to provide lower TRM, aGVHD and cGVHD. This conditioning might become an alternative approach in patients with a high risk of severe post-transplant complications. Disclosures No relevant conflicts of interest to declare.

Augmented immunosuppression and PTCY-based haploidentical hematopoietic stem cell transplantation for thalassemia major.

Alternate donor HSCT for thalassemia major from a matched unrelated donor or haploidentical family donor is a feasible therapeutic option in children with no matched family donor. Aggressive pretransplant immunosuppression, reduced toxicity conditioning, and PTCY result in excellent thalassemia-free survival. We describe here our experience in this cohort. We performed a retrospective analysis of the data on children who underwent a haploidentical HSCT for thalassemia major with PTCY at our center from August 2017 to August 2019. All children received pretransplant immune suppression for 6weeks with fludarabine and dexamethasone, hypertransfusion and chelation with intravenous desferrioxamine. Conditioning included thiotepa, fludarabine, rabbit ATG, and cyclophosphamide, and GvHD prophylaxis included PTCY with tacrolimus. Twenty children were included and nineteen children engrafted. Acute hypertension occurred in five children, bacterial infection in eight children and viral respiratory infection in three children. Three children suffered from graft rejection. Reactivation of viruses namely CMV, adenovirus, and BK virus was seen in 60% of children. Grades 1-2 acute GvHD of the skin in four children (20%) and limited chronic GvHD of the skin in four children (20%). Immune cytopenia was documented in three children (15%). Haploidentical HSCT offers a therapeutic option for children with thalassemia major with no suitably matched family or unrelated donors. Our reduced toxicity regimen with PTCY offers a DFS of 75% and OS of 95% with low transplant-related mortality of 5%.

Treosulfan-Based Conditioning Regimen for Second Allograft in Patients with Myelofibrosis.

Simple SummaryCurrently, the only curative therapy in myelofibrosis is allogeneic hematopoietic stem cell transplantation. Donor lymphocyte infusion and second stem cell transplantation are the two main treatment options for myelofibrosis patients who relapse after the first transplantation. The optimal conditioning regimen for the second transplantation in myelofibrosis patients is not well defined. Our study aimed to address this question and showed that treosulfan-based conditioning for second allograft in relapsed myelofibrosis patients resulted in longtime freedom from disease in about 50% of the patients. This data supports the second allogeneic hematopoietic stem cell transplantation with a less toxic treosulfan-based conditioning regimen that is effective in relapsed, donor lymphocyte infusion resistant myelofibrosis patients with long term low transplant-related mortality and relapse rates.Relapse after allogeneic hematopoietic stem cell transplantation (AHSCT) in myelofibrosis (MF) patients remains as a significant issue despite advances in transplantation procedures and significant prolongation in survival. Second AHSCT is a potential treatment option but associated with high treatment-related mortality and novel less toxic conditioning regimens are needed. In 33 MF patients with relapse after AHSCT and failure to donor lymphocyte infusion (DLI) we investigated treosulfan (36–42 g/m2) in combination with fludarabine and anti-thymocyte globulin (ATG) as conditioning regimen for a second AHSCT with matched related (n = 2), unrelated (n = 23), or mismatched unrelated (n = 8) donors. All patients achieved leukocyte engraftment after a median of 11 days, and 56 ± 13% experienced acute GVHD grade II–IV at day 100. The therapy-related mortality at day 100 and at 3 years was 16% and 31%, respectively. The cumulative incidence of relapse at 5 years was 16%, resulting in a 5-year disease-free and overall survival of 45% and 47%, respectively. Treosulfan-based conditioning for second allograft in relapsed MF patients resulted in about 50% of the patients in long-term freedom from disease.

Secondary skin neoplasms in patients after autologous and allogeneic hematopoietic stem cell transplantation procedures.

The increasing number of hematopoietic stem cell transplantation (HSCT) procedures and lower transplant-related mortality has led to a growing population of survivors facing long-term increased risk of secondary malignancy, including cutaneous neoplasms. In this review, we aim to discuss the incidence, risk factors and preventive strategies for secondary skin neoplasms after autologous and allogeneic HSCT. Cutaneous neoplasms, such as basal cell carcinoma, squamous cell carcinoma and melanoma, are among the most common solid cancers arising in patients after HSCT. Besides risk factors established in the general population, primary disease, chronic graft-versus-host disease (CGvHD), prolonged immunosuppression, especially with the use of cyclosporine and azathioprine, radiation exposure, light skin color, male sex, and young age at transplantation play a role in the development of cutaneous neoplasms in HSCT recipients. Skin cancer development after HSCT may be explained by cumulative effects of chemotherapy and radiotherapy-induced DNA damage, prolonged immunosuppressive conditions and chronic mucosal inflammation, particularly after allogeneic HSCT. Delayed immune recovery and persistent immunodeficiency in patients with graft-versus-host disease (GvHD) may also contribute to carcinogenesis. Regular dermatological surveillance and prompt recognition of precancerous and cancerous lesions is crucial for patient's prognosis and management.

AML-123: Targeted Conditioning with Anti-CD45 Iodine (131I) Apamistamab [Iomab-B] Leads to High Rates of Transplantation and Engraftment in Older Patients with Active, Relapsed, or Refractory (rel/ref) AML: Preliminary Midpoint Results from the Prospective, Randomized Phase 3 SIERRA Trial

Context Despite new therapies for AML, older patients with rel/ref AML do not have durable responses and are ineligible for potentially curative HCT. The SIERRA trial addresses this unmet need. Objective Midpoint analysis, with safety, engraftment data, and transplant rates. Design Phase 3, randomized patients in the CC arm who do not attain remission may then receive Iomab-B followed by HCT. Setting USA and Canada. Patients or other participants Aged ≥55 years with active rel/ref AML. Interventions Iomab-B plus RIC (FLU/TBI) and HCT, or CC. Main outcome measures Primary endpoint - durable CR (dCR) ≥ 180 days. However, this analysis is on safety and transplant rates. Results First 50% of patients (n=75) had a median age of 64, with 85% failing ≥2 induction therapies and 33% failing targeted therapies. Median baseline marrow blasts Iomab-B (30%) and CC (26%). All patients transplanted after Iomab-B engrafted (median days 15 for ANC, 18 for platelets). After randomization, 82% (31/38) patients in the CC arm failed salvage therapy, despite 32% (12/38) receiving targeted therapy. Majority (73%, 8/11) of patients receiving venetoclax with HMA or LDAC did not achieve remission. Of the 31 patients not achieving remission on CC, 20 (65%) crossed over to receive Iomab-B/HCT. The most common reason preventing crossover was disease progression. CC showed increased incidence of Grade ≥3 febrile neutropenia vs Iomab-B (46% vs 23%). Iomab-B administration was generally well tolerated with 1 Grade 3 and no Grade 4 infusion reactions. There were no Iomab-B-related deaths and 100-day non-relapse mortality was 6% on the Iomab-B arm. Conclusions Despite advanced age, active disease and many prior therapies, 84% (31/37) of all patients in the Iomab-B arm were able to undergo HCT and all successfully engrafted. In comparison, only 18% (7/38) of the patients on the CC arm achieved remission and underwent conventional HCT despite a high percentage receiving recently approved agents and targeted therapies. Iomab-B has a favorable safety profile with no graft failures and low transplant-related mortality. These preliminary results represent significant improvements over the current rates of transplantation in this patient population. SIERRA trial is currently enrolling ( www.sierratrial.com or clinicaltrials.gov NCT02665065 ).

Outcomes with autologous stem cell transplant vs. non-transplant therapy in patients 70 years and older with multiple myeloma.

We evaluated 79 patients with multiple myeloma (MM) ≥70 years referred to our blood and marrow transplant clinic, within 1 year of diagnosis from 2010 to 2019, for consideration of autologous stem cell transplant (ASCT). Thirty-eight (48%) of 79 patients underwent ASCT. ASCT was not pursued in 41 (52%) patients due to: patient or physician preference in 80% (n = 33) or ineligibility in 20% (n = 8). Baseline characteristics of patients in the two groups were similar. Median PFS from treatment start amongst patients undergoing ASCT (n = 38) vs. not (n = 41) was 41 months vs. 33 months, p = 0.03. There was no difference in OS, with estimated 5-year OS of 73% vs. 83%, respectively (p = 0.86). Day +100 transplant-related mortality(TRM) was 0%. ASCT was an independent favorable prognostic factor for PFS in multivariate analysis, after accounting for HCT-CI score, performance status, hematologic response, and maintenance. Finally, patients ≥70 years undergoing ASCT had similar PFS compared to a contemporaneous institutional cohort of patients <70 years (n = 631) (median PFS from transplant: 36 vs. 47 months, p = 0.25). In this retrospective analysis, ASCT was associated with low TRM and better PFS in fit older adults with MM compared to non-transplant therapy, with comparable benefits as seen in younger patients.

Immune Modulation Properties of Zoledronic Acid on TcRγδ T-Lymphocytes After TcRαβ/CD19-Depleted Haploidentical Stem Cell Transplantation: An analysis on 46 Pediatric Patients Affected by Acute Leukemia.

TcRαβ/CD19-cell depleted HLA-haploidentical hematopoietic stem cell transplantation (haplo-HSCT) represents a promising new platform for children affected by acute leukemia in need of an allograft and lacking a matched donor, disease recurrence being the main cause of treatment failure. The use of zoledronic acid to enhance TcRγδ+ lymphocyte function after TcRαβ/CD19-cell depleted haplo-HSCT was tested in an open-label, feasibility, proof-of-principle study. Forty-six children affected by high-risk acute leukemia underwent haplo-HSCT after removal of TcRαβ+ and CD19+ B lymphocytes. No post-transplant pharmacological graft-versus-host disease (GvHD) prophylaxis was given. Zoledronic acid was administered monthly at a dose of 0.05 mg/kg/dose (maximum dose 4 mg), starting from day +20 after transplantation. A total of 139 infusions were administered, with a mean of 3 infusions per patient. No severe adverse event was observed. Common side effects were represented by asymptomatic hypocalcemia and acute phase reactions (including fever, chills, malaise, and/or arthralgia) within 24–48 h from zoledronic acid infusion. The cumulative incidence of acute and chronic GvHD was 17.3% (all grade I-II) and 4.8% (all limited), respectively. Patients given 3 or more infusions of zoledronic acid had a lower incidence of both acute GvHD (8.8 vs. 41.6%, p = 0.015) and chronic GvHD (0 vs. 22.2%, p = 0.006). Transplant-related mortality (TRM) and relapse incidence at 3 years were 4.3 and 30.4%, respectively. Patients receiving repeated infusions of zoledronic acid had a lower TRM as compared to those receiving 1 or 2 administration of the drug (0 vs. 16.7%, p = 0.01). Five-year overall survival (OS) and disease-free survival (DFS) for the whole cohort were 67.2 and 65.2%, respectively, with a trend toward a better OS for patients receiving 3 or more infusions (73.1 vs. 50.0%, p = 0.05). The probability of GvHD/relapse-free survival was significantly worse in patients receiving 1–2 infusions of zoledonic acid than in those given ≥3 infusions (33.3 vs. 70.6%, respectively, p = 0.006). Multivariable analysis showed an independent positive effect on outcome given by repeated infusions of zoledronic acid (HR 0.27, p = 0.03). These data indicate that the use of zoledronic acid after TcRαβ/CD19-cell depleted haploHSCT is safe and may result in a lower incidence of acute GvHD, chronic GvHD, and TRM.

Autologous versus unrelated donor stem cell transplantation for adults with primary acute myeloid leukemia in first remission

目的分析自体造血干细胞移植（auto-HSCT）与无关供者造血干细胞移植（URD-HSCT）治疗首次完全缓解期（CR1）成人原发性急性髓系白血病（AML）的疗效，比较并探讨两种移植方式的差异及适应人群。方法对2008年3月至2018年11月在中国医学科学院血液病医院接受auto-HSCT及URD-HSCT的成人原发性AML患者进行回顾性分析。结果共纳入147例患者，其中auto-HSCT组87例，URD-HSCT组60例，两组病例基线特征基本一致。auto-HSCT组、URD-HSCT组+30 d粒细胞植活率差异无统计学意义［92.6%（95% CI 86.9%～98.3%）对98.3%（95% CI 95.0%～100.0%），P＝0.270］，auto-HSCT组+60 d血小板累积植活率低于URD-HSCT组［83.6%（95% CI 75.8%～91.4%）对93.3%（95% CI 87.0%～99.6%），P<0.001］。URD-HSCT组急性GVHD累积发生率为56.7%（95% CI 43.0%～68.2%），Ⅱ～Ⅳ度急性GVHD累积发生率为16.7%（95% CI 8.5%～27.2%），慢性GVHD累积发生率为33.3%（95% CI 21.7%～45.4%），广泛型慢性GVHD累积发生率为15.0%（95% CI 7.3%～25.2%）。中位随访53.8（0.8～127.8）个月，auto-HSCT组、URD-HSCT组5年总生存（OS）率分别为71.7%（95% CI 61.7%～81.7%）、67.8%（95% CI 55.8%～79.8%）（P＝0.556），无白血病生存（LFS）率分别为64.6%（95% CI 54.4%～74.8%）、68.1%（95% CI 56.3%～79.9%）（P＝0.642）。auto-HSCT组5年累积复发率高于URD-HSCT组［31.9%（95% CI 22.2%～42.1%）对15.1%（95% CI 7.4%～25.6%），P＝0.015］，移植相关死亡率（TRM）低于URD-HSCT组［3.4%（95% CI 0.9%～8.9%）对16.7%（95% CI 8.5%～27.2%），P＝0.006］。HLA相合及不全相合的无关供者移植在造血重建、GVHD、OS、LFS、复发及TRM方面差异均无统计学意义。遗传学低、中危患者auto-HSCT、URD-HSCT组移植后OS率、LFS率差异均无统计学意义，高危患者auto-HSCT后累积复发率高于URD-HSCT，LFS率低于URD-HSCT。结论对于成人原发性AML-CR1患者，auto-HSCT与URD-HSCT具有相似的OS率和LFS率，auto-HSCT组复发率较高而TRM较低。缺乏同胞供者的遗传学高危组患者应选择URD-HSCT以减少移植后复发，提高生存率。

Analysis of treatment response and prognostic factors of T-LBL patients treated with pediatric-like ALL therapy following HSCT

目的探讨经急性淋巴细胞白血病（ALL）儿童方案治疗达到完全缓解（CR）和部分缓解（PR）的T淋巴母细胞淋巴瘤（T-LBL）患者应用造血干细胞移植巩固治疗的疗效及预后因素。方法收集2013年1月至2017年1月于唐都医院血液病中心接受治疗的T-LBL患者的临床资料，将达到CR或PR的患者纳入研究，进行回顾性分析。结果①48例患者接受了ALL儿童方案治疗，经2个疗程的诱导化疗后39例达CR，9例达PR。其中接受自体造血干细胞移植（auto-HSCT）者14例，接受异基因造血干细胞移植（allo-HSCT）者7例，21例患者移植后造血功能均顺利重建。②中位随访时间31（9～16）个月。3年总生存（OS）率为61.0%（95% CI 53.7%～68.3%），3年无进展生存（PFS）率为54.8%（95% CI 47.1%～62.2%）。③移植组和未移植组3年OS率分别为84.7%和42.8%（P＝0.006），两组3年PFS率分别为75.4%和38.9%（P＝0.004）。④auto-HSCT组与allo-HSCT组患者的OS率、PFS率差异均无统计学意义（P值分别为0.320、0.597）。⑤骨髓侵犯、未接受造血干细胞移植是影响患者长期预后的独立危险因素［ HR＝5.804（95% CI 1.140～29.549），P＝0.034；HR＝5.871（95% CI 1.711～20.140），P＝0.005］。结论ALL儿童方案化疗序贯造血干细胞移植治疗T-LBL疗效确切，安全性好。auto-HSCT与allo-HSCT患者的OS率及PFS率差异均无统计学意义。骨髓侵犯、未接受造血干细胞移植是影响T-LBL患者长期预后的独立危险因素。

HLA-Haploidentical Hematopoietic Cell Transplantation for Treatment of Nonmalignant Diseases Using Nonmyeloablative Conditioning and Post-Transplant Cyclophosphamide.

Allogeneic hematopoietic cell transplant (HCT) is often the only curative therapy for patients with nonmalignant diseases; however, many patients do not have an HLA-matched donor. Historically, poor survival has been seen after HLA-haploidentical HCT because of poor immune reconstitution, increased infections, graft-versus-host disease (GVHD), and graft failure. Encouraging results have been reported using a nonmyeloablative T cell-replete HLA-haploidentical transplant approach in patients with hematologic malignancies. Here we report the outcomes of 23 patients with various nonmalignant diseases using a similar approach. Patients received HLA-haploidentical bone marrow (n=17) or granulocyte colony-stimulating factor-mobilized peripheral blood stem cell (n=6) grafts after conditioning with cyclophosphamide 50 mg/kg, fludarabine 150 mg/m2, and 2 or 4 Gy total body irradiation. Postgrafting immunosuppression consisted of cyclophosphamide, mycophenolate mofetil, tacrolimus, ± sirolimus. Median patient age at HCT was 10.8 years. Day 100 transplant-related mortality (TRM) was 0%. Two patients died at later time points, 1 from intracranial hemorrhage/disseminated fungal infection in the setting of graft failure and 1 from infection/GVHD. The estimated probabilities of grades II to IV and III to IV acute GVHD at day 100 and 2-year National Institutes of Health consensus chronic GVHD were 78%, 26%, and 42%, respectively. With a median follow-up of 2.5 years, the 2-year overall and event-free rates of survival were 91% and 78%, respectively. These results are encouraging and demonstrate favorable disease-specific lineage engraftment with low TRM in patients with nonmalignant diseases using nonmyeloablative conditioning followed by T cell-replete HLA-haploidentical grafts. However, additional strategies are needed for GVHD prevention to make this a viable treatment approach for patients with nonmalignant diseases.

The CD34+ Cell Dose Matters in Hematopoietic Stem Cell Transplantation with Peripheral Blood Stem Cells from Sibling Donors

The effect of CD34+ cell dose in allogeneic hematopoietic stem cell transplantation (HSCT) on overall survival (OS) and incidence of acute and chronic graft-versus-host disease (GvHD) has not been established and few studies have been performed. Our single center analysis included 189 patients with hematological malignancies who received peripheral blood stem cell (PBSC) grafts from sibling donors. Myeloablative conditioning was used in 88 cases and 101 received reduced intensity conditioning. The median CD34+ cell dose was 5.6 × 106/kg (0.6–17.0). In the multivariate analysis, a CD34 cell dose of 6–7 × 106/kg was associated with better OS and lower transplant-related mortality (TRM), while a dose of <5 × 106/kg led to increased relapse and reduced chronic GVHD (cGVHD). A high CD34 cell-dose (>6.5 × 106/kg) correlated with less acute GVHD (aGVHD) II–IV. We conclude that the CD34 cell dose has an impact on the outcome of HSCT from sibling donor PBSCs.

Improving Post-Transplant Outcomes Following Allogeneic Hematopoietic Stem Cell Transplant for Sickle Cell Disease in a Low Resource Setting: Experience from a Dedicated Post-Transplant Clinic in Nigeria

<h3>Background</h3> Allogeneic hematopoietic stem cell transplantation (Allo-HCT) is potentially curative in eligible patients with sickle cell disease (SCD). Improved transplant technology coupled with low transplant-related mortality has resulted in the development of a cottage industry in most of Africa, where 85% of all SCD births world-wide occurs. Families are seeking curative options primarily outside their country of residence, only to return back to a low-resource setting like Nigeria where long-term programs for the management of patient's post-transplant are lacking. <h3>Methods</h3> To address this perceived care gap, a dedicated post-transplant care clinic was developed. Patients were seen at various time points post-transplant (Days+112- 415). Most patients, (7/8), received haploidentical peripheral blood stem cell transplant from parental donors, while one patient received matched related bone marrow transplant. Three patients received myeloablative conditioning and five received non-myeloablative conditioning as well as preconditioning with hydroxyurea, azathioprine and chronic blood transfusion therapy. All patients who underwent haploidentical HCT received post-transplant Cytoxan as part of their GVHD prophylaxis. <h3>Result</h3> All patients had sickle cell anemia (HbSS), ages ranged from 2-18 years, all were considered asymptomatic (Figure 1). Main life-threatening health complications encountered include EBV reactivation in 38% (3/8), chronic GVHD 63% (5/8), others included febrile illnesses, pseudomembranous colitis, renal tubular acidosis, malnutrition and mixed chimerism (Figure 2). About 50% of the patients self-discontinued immunosuppression therapy without adequate guidance and most had delayed health maintenance measures such as routine immunizations and appropriate antimicrobial prophylaxis (Figure 3). Other logistical challenges encountered include delayed timely reporting of diagnostic tests (Chimerism: 14 to 21 days turnaround time; viral studies: 14 to 21 days turnaround time; drug trough levels: 14 to 21 days turnaround time), unavailability of irradiated blood products and lack of cost-effective medications. <h3>Conclusion</h3> A dedicated comprehensive, long-term care program for children with SCD residing in a low income setting who have undergone Allo-HCT, can improve their post-transplant outcomes. Locally adapted supportive care strategies can address the unique challenges encountered by these patients.

UM171 Expansion Overcomes Shortcomings of Cord Blood Transplantation While Maintaining Benefits

Background Benefits of cord blood (CB) transplantation include low rates of relapse and chronic graft-versus-host disease (GVHD). However, CB use has rapidly declined because of the high rates of infections, severe acute GVHD, and transplant-related mortality (TRM) as well as prolonged hospitalization. We therefore initiated a clinical trial with UM171, a potent agonist of hematopoietic stem cell (HSC) self-renewal, to attempt to solve these limitations and permit transplantation of smaller, better HLA-matched CBs. Methods Expansion culture lasted 7 days and patients received a myeloablative conditioning regimen followed by a single CB transplant including both the expanded CD34+ cells and the lymphocyte-containing CD34- fraction. Results Between 9/16-11/18, 22 adults with mostly high- to very high-risk hematologic malignancies were transplanted. Median transplant co-morbidity index was 2 (0-5). Five patients had already failed an allogeneic transplant, 3 patients had acute leukemia not in remission, and 2 patients had relapsed/refractory aggressive lymphoma. UM171 treatment profoundly changed the cellular composition of the graft, including a 600 and 8000-fold increase in dendritic and mast cell progenitors, respectively. Neutrophil engraftment was prompt with median time to 100 and 500 neutrophils/μL of 9.5 and 18 days, respectively. Patients seemed to derive clinical benefit from achieving 100 neutrophils rapidly translating into early resolution of febrile neutropenia (median day 7) contributing to shorter hospitalization when compared to conventional CB transplants at same institution with larger cell doses and similar time to 500 neutrophil engraftment. Median CD4 counts at 3 and 12 months were 218 and 413/μL, respectively. Incidence of grade 3-4 acute GVHD was low (9%) and there was no steroid refractory GVHD or moderate-severe chronic GVHD. More than 90% of patients were off immunosuppressive therapy by 12 months. One patient died of TRM ( Conclusions A 7-day UM171 expansion CB protocol is feasible and provides clinical benefits beyond engraftment, such as very low TRM. If confirmed, UM171 expansion may overcome the shortcomings of CB transplants while maintaining its benefits of low risk of chronic GVHD and relapse. We have now embarked on a phase 2 trial to confirm if a UM171 modified graft, enriched in dendritic cells, will have a potent antileukemia effect in extremely high-risk patients such as refractory leukemias and high risk mutations (e.g.: p53, EVI-1).

Comparison of Survival Between Autologous and Allogeneic Stem Cell Transplantation in Patients with Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma: A Meta-Analysis

This study aimed to compare the efficacy of allogeneic stem cell transplantation (allo-SCT) versus autologous SCT (auto-SCT) in patients with relapsed or refractory B-cell non-Hodgkin lymphoma (B-NHL). Medline, CENTRAL, and EMBASE databases through December 31, 2019 were searched. The primary endpoints were overall survival (OS) and progression-free survival (PFS) rates. The secondary outcomes include transplant-related mortality (TRM), event-free survival, relapse/or progression, and nonrelapse mortality (NRM). The 18 retrospective studies enrolled 8,058 B-NHL patients (allo-SCT = 1,204; auto-SCT = 6,854). The OS was significantly higher in patients receiving auto-SCT than allo-SCT (pooled odds ratio [OR]: 1.69, 95% confidence interval [CI]: 1.29 to 2.22, P < 0.001), but no significant difference was found in PFS (pooled OR: 0.98, 95% CI: 0.69 to 1.38, P = 0.891). Auto-SCT patients also had lower TRM and NRM (TRM: OR = 0.23, P < 0.001; NRM: OR = 0.16, P < 0.001), but higher relapse or progression rate (OR = 2.37, P < 0.001) than allo-SCT patients. Subgroup analysis performed for different grades and subtypes of B-NHL showed higher OS in auto-SCT patients with high-grade B-NHL and diffused large B-cell lymphoma (DLBCL). There was, nevertheless, higher PFS in allo-SCT patients with low-grade B-NHL and follicular lymphoma (FL), and lower PFS in allo-SCT patients with DLBCL than their auto-SCT counterparts. In conclusion, the meta-analysis demonstrated that relapsed or refractory B-NHL patients who received auto-SCT have improved OS than those treated with allo-SCT, especially among those with DLBCL, but lower PFS among those with FL. However, the study is limited by a lack of randomized trials, patients’ heterogeneity, and possible selection bias.

Survival analysis of multiple myeloma patients after autologous stem cell transplantation.

Hematopoietic stem cell transplantation has been applied to treat the hematologic malignancies since the 1980s. However, allogenic transplantation has inherent complications such as graft-versus-host disease and graft failure. Autologous transplantation has become more and more popular because of its lower transplant-related mortality. This study was performed to analyze the possible prognostic factors for myeloma patients post stem cell transplantation. Patients' information was collected by history review and follow-up through the phone call. Kaplan-Meier was used to exhibit overall survival (OS) and progression-free survival (PFS). Univariate and multivariate analyses were performed using Cox proportional hazards model. A P<0.05 is considered statistically significant. Thirty patients with multiple myeloma were included in this study, 7 of them died because of myeloma relapse and myeloma-associated complications. The average survival time was 29.8 months and the median follow-up was 25.1 months. The 1-year OS and PFS were 93.3% and 90.0%, respectively. Both the 3-year OS and PFS were 76.7%. In a variety of factors, improved renal function showed a good effect on the outcome of transplantation. To prevent cancer relapse after autologous transplantation, it is of great significance to achieve a complete remission prior to the transplantation.

Allogeneic CD34-Selected HSCT Following CAR T-Cells Is Associated with Low TRM and Favorable OS in Pediatric/Young Adult Patients with Relapsed/Refractory B-ALL

Background: Chimeric antigen receptor (CAR) T-cells have transformed the therapeutic options for patients with relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL). The tolerability and outcome of allo-HSCT following CAR T-cell therapy is yet to be defined. Methods: We retrospectively reviewed pediatric and young adult patients with R/R B-ALL who received allo-HSCT following CAR T-cells. Outcomes of interest were overall survival (OS), cumulative incidence of relapse, and transplant-related mortality (TRM). These were estimated using log-rank analysis. Variables of interest were disease status at time of allo-HSCT, time from CAR T-cell therapy to start of allo-HSCT, conditioning regimen, graft source and manipulation, GVHD prophylaxis, donor HLA matching, neutrophil/platelet engraftment, relapse and cause of death. Results: Sixteen patients, with a median age of 13 (range 1-20), at time of allo-HSCT were included. All patients achieved MRD-negative complete remission (CR) following CAR T-cells and proceeded to allo-HSCT as definitive therapy. CR status included CR1 (n=6), CR2 (n=5), CR3 (n=4), and CR4 (n=1). The median time from CAR T-cells to the start of allo-HSCT conditioning was 46.5 days (range 20 -126). Conditioning was TBI-based (n=13) or chemotherapy only (n=3). Graft source included PBSC (n=8) or BM (n=8). Graft manipulation included CD34-selected T-cell depleted (TCD) (Miltenyi) (n=9) or an un-modified HSCT (n=7). Donors were HLA-matched related (n=8), HLA-matched unrelated (n=3), or HLA-mismatched unrelated (n=5). GVHD prophylaxis in the non-manipulated grafts included a calcineurin inhibitor (CNI) plus MTX (n=5), CNI plus MMF (n=1) or post-transplant cyclophosphamide (n=1). Available data included: 15/15 patients achieved neutrophil engraftment (median 12 days; range 9-29) and 13/15 patients achieved platelet engraftment (median 30 days; range 16-265). The 12-month cumulative incidence of relapse was 0% in patients receiving CD34-selected transplant, versus 25% [95% CI: 0 to 67%] in patients receiving un-modified transplant (log-rank p=0.80) and the 24-month cumulative incidence of relapse for the whole cohort was 25% [0-47%]. Late relapse (&gt;12 months from allo-HSCT) occurred in three (n=3) patients in the CD34-selected TCD cohort with a median time to relapse from allo-HSCT of 24.2 months (range 16.3 - 24.7 months). Two (n=2) patients achieved subsequent MRD-neg/CR following additional CD19-specific CAR T-cell infusions (CRs ongoing at 12.4 and 1.4 months). The other patient (n=1) experienced a CD19-negative relapse and is awaiting infusion of CD22-specific CAR T-cells. Early relapse occurred in one (n=1) patient (4.7 months from allo-HSCT) following un-modified allo-HSCT with subsequent MRD-neg/CR following treatment with CD19-specific CAR T-cells (CR ongoing at 5.2 month). Three (n=3) patients in the un-modified cohort died due to TRM (24-month TRM = 46% [7-86%]), including veno-occlusive disease (multi-organ failure/infection) (n=2) and GVHD (n=1), while no TRM was noted in the CD34-selected TCD cohort (p=0.03). The TRM for the entire cohort was 19% at 24 months [0-39%]. The 24-month OS for the entire cohort was 81% [61 -100%], with 100% OS in CD34-selected TCD recipients and 54% in the un-modified recipients (p=0.03). Conclusion: CAR T-cells when followed by a CD34-selected TCD allo-HSCT resulted in less TRM and favorable OS when compared to un-modified allo-HSCT. Disease control is not impacted by the type of allo-HSCT and late relapse was seen following CD34-selected TCD. Successful re-treatment with CAR T-cells to induce remission is possible and analysis as to the durability of this response is ongoing. Disclosures Margossian: Novartis: Membership on an entity's Board of Directors or advisory committees. Prockop:Atara Biotherapeutics: Other: Support for industry sponsored trails ; Mesoblast: Other: Support for industry sponsored trails . Shah:Jazz pharmaceuticals: Speakers Bureau. Boelens:Takeda: Consultancy; Magenta: Consultancy; Bluerock: Consultancy; Avrobio: Consultancy. Curran:Juno Therapeutics: Consultancy, Research Funding; Novartis: Consultancy.

Safety and Efficacy of Autologous Stem Cell Transplantation in Dialysis-Dependent Myeloma Patients - the Diadem Study from the Chronic Malignancies Working Party of the EBMT

Safety and Efficacy of Autologous Stem Cell Transplantation in Dialysis-Dependent Myeloma Patients - the Diadem Study from the Chronic Malignancies Working Party of the EBMT