HLA-mismatched Related Donors Research Articles

Late cytomegalovirus disease after hematopoietic cell transplantation: significance of novel transplantation techniques

AbstractPreemptive therapy (PET) and letermovir prophylaxis are effective in preventing cytomegalovirus (CMV) disease within the first 100 days after allogeneic hematopoietic cell transplantation (HCT) but are associated with late-onset CMV disease. We retrospectively examined the clinical manifestations, risk factors, prevention algorithm, and outcome of late CMV disease in CMV seropositive day 100 survivors transplanted between 2001-2017 (PET cohort) and 2018-2021 (letermovir cohort). There were 203 episodes of late CMV disease among 2469 day 100 survivors, and the estimated cumulative incidence of first late CMV disease was 7.2% (95% confidence interval [CI], 6.2-8.3) with no difference between the PET (7.4%; 95% CI, 6.4-8.6) and the letermovir group (5.4%; 95% CI, 3.2-8.3). Thirty-seven patients (1.5%) had a second episode of CMV disease. In multivariable Cox regression models, posttransplant cyclophosphamide was associated with an increased risk of gastrointestinal CMV disease. CMV viremia or disease detected before day 100, corticosteroid treatment after day 100 at dose ≥1 mg/kg, acute and chronic graft-versus-host disease, lymphopenia, HLA-mismatched related donor status, were also associated with late CMV disease. HLA-mismatched donor status and late use of corticosteroids (≥1 mg/kg) were risk factors for late CMV disease recurrence. Late CMV disease occurred most frequently in a setting of prolonged low-level untreated viremia and was independently associated with death by 2 years after HCT. In summary, late CMV disease continues to occur in the present era. Improved prevention strategies for late CMV disease are needed.

Geriatric Nutritional Risk Index Is an Important Predictor of Survival in Allogeneic Hematopoietic Stem Cell Transplant Recipients

Introduction:The body mass index (BMI) and geriatric nutritional risk index (GNRI) are nutrition-related risk assessment tool and has been used in various clinical settings. The relationship between BMI and the associated risk of hematopoietic stem cell transplantation (HSCT), such as relapse and non-relapse mortality (NRM), have been reported (Fuji S et al. BMT. 2014;49:1505). However, the relationship between GNRI and HSCT outcome remains inconclusive. We aimed to evaluate the association between GNRI and overall survival (OS), relapse, and NRM of patients who received allogenic HSCT for hematological malignancies. Methods:We retrospectively analyzed aged 16 years or older patients who underwent first allogeneic HSCT from January 2010 to December 2022 at the Jikei university hospital. The primary endpoints of this study was OS at 5 years. Secondary endpoints were NRM, the incidences of relapse, all-grade acute GVHD and chronic GVHD. Nutritional risk was evaluated both BMI and GNRI. Patients were classified into three groups based on pre-transplant BMI (underweight; BMI <18.5, overweight; BMI ≥25, and others as standard), and also classified into three groups based on pre-transplant GNRI (low-risk; GNRI>98, intermediate-risk; 92≤GNR≤98, and high-risk; GNR<92). GNRI was calculated as follows: (1.519 x serum albumin) + (41.7 x current body weight/ ideal body weight). Data on serum albumin level and body weight were collected at the beginning of conditioning regimen. Results:Two hundred and three patients who received allogeneic HSCT for hematological malignancies (acute myeloid leukemia; n=98, acute lymphoblastic leukemia; n=51, myelodysplastic syndrome; n=27, myeloproliferative neoplasms; n=8, chronic myeloid leukemia; n=18, and other leukemias; n=2) were evaluated. The median age was 52 years old (range 16-69). The median follow-up period of survivors was 1394 days (range 51-4420) after allogeneic HSCT. The donor sources consisted of 39 (19.2%) HLA-matched related donor, 50(24.6%) HLA-mismatched related donor, 26(12.8%) HLA-matched unrelated donor and 88(43.4%) HLA-mismatched unrelated donor. One hundred and nine patients (53.7%) received myeloablative conditioning regimens. Based on the BMI, underweight, standard, overweight were included 33 (16.3%), 139 (68.4%), and 31 (15.3%) patients, respectively. While, based on the GNRI, the low-risk, intermediate-risk and high-risk were divided into 105 (51.7%), 46 (22.8%), and 51 (25.2%) patients, respectively . The 5-year OS rates of standard, underweight, and overweight were 52.6%, 39.5%, and 62.1%, respectively (p=0.07). On the other hand, the 5-year OS of low-risk, intermediate-risk, and high-risk were 62.6%, 50.4%, and 33.2%, respectively (p=0.01). In addition, multivariate analysis showed high-risk group showed significantly lower OS (p=0.03). Five-year cumulative incidences (CI) of relapse in the standard, underweight, and overweight, were 46.4%, 45.4%, and 25.0%, respectively (p=0.11). However, multivariate analysis showed that CI of relapse ratio was significantly lower in overweight group (p=0.02). While, 5-year CI of relapse rates in the low-risk, intermediate-risk, and high-risk were 36.5%, 47.2%, and 52.5%, respectively (p=0.03). However, multivariate analysis showed that there were no significant differences in relapse among three risk groups (p=0.06). There were no significant differences in CI of NRM, acute GVHD and chronic GVHD either BMI or GNRI. Subgroup analysis in the patients who underwent HSCT in complete remission revealed that there was no significant difference in OS among the three BMI groups (p=0.11), as well as the three GNRI groups (p=0.06). For the patients in non-remission at the time of allogeneic HSCT, there was no significant difference in OS between the three groups in BMI; however, OS was shorter in the high-risk group in GNRI (p=0.01). Conclusions:In our study, OS of high-risk group defined by GNRI showed significantly poor , especially in non-remission patients. Although overweight defined by BMI did predict low CI of relapse, overweight did not predict OS. These results suggest that nutrition-related risk assessed by GNRI could be prognostic marker for survival in patients who received allogeneic HSCT.

Fractionated Gemtuzumab Ozogamicin Followed By Non-Engraftment Donor Leukocyte Infusions for Relapsed/Refractory Acute Myeloid Leukemia

Background: Previous studies have shown durable AML patient responses following donor lymphocyte infusions (DLI) in the absence of engraftment in both the frontline and relapsed setting (Dey et al, BJH 2005, Colvin et al, BBMT 2009, Ai et al, Blood 2010). Herein we report results from the completed dose-escalation phase from our trial of fractionated dosing of gemtuzumab ozogamicin (GO) followed by non-engraftment mismatched allogeneic donor cells infusion in patients with relapsed/refractory (R/R) AML. In this trial, instead of engraftment, it is postulated that donor cells serve as a potent immune stimulator. Study Design and Methods: In this phase I/II study, GO 6-9mg/m 2 total dose was administered as a fractionated 2-3mg/m 2 dose (capped at 4.5mg) on days 1, 4, and 7, followed by infusion of HLA-mismatched (0-3/6 antigens) related donor cells on day 8 [NCT03374332]. The dose-escalation phase 1 cohort used a 3+3 design combining GO with donor leucocyte infusion (DLI) at dose 1-2x10 7 CD3+ cells/kg (Dose Level 1) or 1-2x10 8 CD3+ cells/kg (Dose Level 2). Patients enrolled in the phase II portion were treated at the maximum tolerated dose (MTD) level. Lab correlative studies were drawn pre and post DLI to assess immune effector cells and leukemic blast surface expression as well as cytokine release profiles. Patients 18 years of age and older with histologically confirmed R/R AML who had recurrence or progression after at least 1 prior standard treatment were eligible. Enrollees must have had no active systemic infections and adequate lung, liver, cardiac, and renal function with an ECOG PS 0-1. Patients in CR or CRi after initial treatment could receive up to 2 additional treatments with GO+DLI. Results: Eleven patients (7 men and 4 women) were enrolled into the study. The median age was 72 years (54-81 years) and patients had received 1-4 previous lines of treatment. All patients were refractory to hypomethylating agents and venetoclax. No patient was a candidate for allogeneic stem cell transplant at the time of study enrollment. Ten patients received 3/6 and one patient received 1/6 HLA mismatched donor cells from a first- or second-degree relative. The MTD was determined to be 2x10 8 CD3+ cells/kg. Three patients were enrolled on dose level 1 and eight patients were enrolled on dose level 2. Treatment was well tolerated with minimal Grade 3 or 4 non-hematologic adverse events attributable to the study ( Table 1). One patient at dose level 2 developed septic shock and died prior to DLI while another patient at dose level 2 developed cryptococcal fungemia and died within one week of DLI. No donor experienced a Grade 3 or 4 adverse event. All patients had fever post DLI that fit criteria for Grade 1 or 2 CRS while one patient developed Grade 3 CR. Two patients with Grade 2 CRS and one patient with Grade 3 CRS received tociluzimab. One patient attained a CR after one cycle of GO+DLI. All other patients had progressive disease. Ultimately the study was stopped early due to futility. Median IL-6 and IL-8 levels were higher in the first 3 patients at dose level 2 (605.5pg/mL and 218.5 pg/mL) compared to the three patients in dose level 1 (79pg/mL and 57.8 pg/mL) but the difference was not statistically significant. IL-10 levels were significantly higher in dose level 2 than dose level 1(125 vs 14.8 pg/mL, p=0.05) Conclusions: The MTD of DLI in combination with GO for relapsed/refractory AML patients is 2x10 8 CD3+ cells/kg. Treatment in an older relapsed/refractory population was well tolerated. Patients reliably developed fevers post DLI with Grade1 or 2 CRS. However, there was no evidence that fever development corresponded to a clinical benefit or that the addition of non-engraftment DLI augmented the effect of single agent gemtuzumab. Additional analysis of cytokine release profiles for the remaining patients as well as immune checkpoint inhibition on leukemic blasts for all patients will be presented at the meeting.

Incidence of Sinusoidal Obstruction Syndrome/Veno-Occlusive Disease and Treatment with Defibrotide in Allogeneic Transplantation: A Multicenter Australasian Registry Study

Sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD) is an established complication in patients undergoing allogeneic hemopoietic stem cell transplantation (HSCT). Defibrotide is an effective and safe pharmacologic option for treating diagnosed SOS/VOD. By exploring data provided to the Australasian Bone Marrow Transplant Recipient Registry (ABMTRR) by centers in Australia and New Zealand, this study aimed to describe the incidence of SOS/VOD and patterns of defibrotide use from 2016 to 2020. Patients who underwent allogeneic hemopoietic stem cell transplantation between 2016 and 2020 were identified from the ABMTRR. Data were extracted for a total of 3346 patients, 2692 from adult centers and 654 from pediatric centers, with a median follow-up of 21.5 months and 33.3 months, respectively. Descriptive statistics were used to describe the patient population, including the incidence of SOS/VOD and defibrotide use. Comparisons were made between patients without SOS/VOD and those with SOS/VOD, divided into defibrotide and no defibrotide cohorts. Associations with overall survival (OS) and day 100 survival with such variables as sex, age, disease at transplantation, stem cell source, conditioning agents, SOS/VOD diagnosis, and use of defibrotide, were determined. The reported incidence of SOS/VOD was 4.1% in adult centers and 11.5% in pediatric centers. Defibrotide was administered to 74.8% of adult patients and 97.3% of pediatric patients with SOS/VOD. Significant variability in the use, dosage, and duration of defibrotide was seen across the adult centers. The day 100 survival rate and median OS for patients managed with defibrotide was 51.8% and 103 days, respectively, for adult patients and 90.4% and not reached, respectively, for pediatric patients. In adults, older age at transplantation, an HLA-matched nonsibling relative donor, and a diagnosis of SOS/VOD treated with defibrotide were associated with reduced OS. In pediatric patients, the patient and transplantation characteristics associated with reduced OS were a diagnosis of SOS/VOD and a ≥2 HLA-mismatched related donor. A collaborative approach across Australasia to diagnosing and managing SOS/VOD, particularly with respect to consistent defibrotide use, is recommended.

Three-Year Outcomes in Recipients of Mismatched Unrelated Bone Marrow Donor Transplants Using Post-Transplantation Cyclophosphamide: Follow-Up from a National Marrow Donor Program-Sponsored Prospective Clinical Trial

The use of post-transplantation cyclophosphamide (PTCy) as graft-versus-host disease (GVHD) prophylaxis has resulted in reductions in GVHD and improved outcomes in allogeneic hematopoietic cell transplantation (HCT) using HLA-mismatched related donors. We report the 3-year outcomes of the first multicenter prospective clinical trial using PTCy in the setting of mismatched unrelated donor (MMUD) bone marrow HCT. The study enrolled 80 patients, treated with either myeloablative conditioning (MAC; n=40) or reduced-intensity conditioning (RIC; n=40), with the primary endpoint of 1-year overall survival (OS). The median follow-up for this study was 34 months (range, 12 to 46 months) in the RIC group and 36 months (range, 18 to 49 months) in the MAC group. Three-year OS and nonrelapse mortality were 70% and 15%, respectively, in the RIC group and 62% and 10% in the MAC group. No GVHD was reported after 1 year. The incidence of relapse was 29% in the RIC group and 51% in the MAC group. OS did not differ based on HLA match grade (63% in the 7/8 strata and 71% in the 4 to 6/8 strata). These encouraging outcomes, which were sustained for 3 years post-HCT, support the continued exploration of MMUD HCT using a PTCy platform. Important future areas to address include relapse reduction and furthering our understanding of optimal donor selection based on HLA and non-HLA factors.

Risk and Predictive Factors for Candidemia After Allogeneic Hematopoietic Cell Transplantation: JSTCT Transplant Complications Working Group

Although antifungal prophylaxis that covers Candida species is a standard of care in allogeneic hematopoietic cell transplantation (HCT), candidemia mainly caused by non-albicans Candida species still occurs and is associated with a high mortality rate. This study aimed to evaluate the risk factors for candidemia after allogeneic HCT. Particularly, we evaluated the impact of patient factors such as hematopoietic cell transplantation–specific comorbidity index (HCT-CI) and performance status (PS) in addition to well-recognized risk factors including donor type, delayed engraftment, and graft-versus-host disease (GVHD). By using data from a Japanese transplant registry database, we analyzed 26,236 pediatric and adult patients with hematological malignancies who underwent their first allogeneic HCT. The posttransplant period was divided into early (days 0-40), late (days 41-100) and very late (days 101-365) phases. The 1-year cumulative incidence of candidemia was 1.8%. When we analyzed pretransplantation factors, age ≥40 years (hazard ratio [HR] 1.85), male (HR 1.34), HCT-CI (HCT-CI 1-2, HR 1.56; HCT-CI ≥ 3, HR 2.21), PS ≥ 2 (HR 2.01), high-risk disease (HR 1.78) and donor type including HLA-mismatched related donor (MMRD) (HR 1.96), HLA-mismatched unrelated donor (HR 2.05), and cord blood (CB) (HR 2.85) were significantly associated with an increased incidence of candidemia. Focusing on the early phase (days 0-40), HCT-CI, PS, high-risk disease and CB transplantation together with engraftment and severe acute GVHD significantly affected the development of candidemia. In the late phase (days 41-100), higher HCT-CI, male, and donor type including MMRD, and CB were associated with the occurrence of candidemia together with acute GVHD and disease relapse. In the very late phase (days 101-365), HCT-CI ≥ 3 and high-risk disease significantly affected the occurrence of candidemia together with acute and chronic GVHD, and disease relapse. In addition to well-recognized risk factors including donor type, engraftment and GVHD, patient factors such as HCT-CI and PS were associated with the development of candidemia, which suggests that severely ill patients with transplantation-associated complications are more likely to develop candidemia.

Successful mismatched hematopoietic stem cell transplantation for pediatric hemoglobinopathy by using ATG and post-transplant cyclophosphamide.

The use of HLA-mismatched (un)related donors is historically associated with a higher incidence of transplant-related complications and mortality. However, the use of such donors may overcome the limited availability of HLA-matched donors for patients with β-thalassemia major (TM) and sickle cell disease (SCD). We investigated hematopoietic stem cell transplantation (HSCT) outcomes of pediatric TM and SCD patients treated with a mismatched donor using a treosulfan-based conditioning in combination with ATG and post-transplant cyclophosphamide (PT-CY) and compared these results to the clinical outcome of patients treated by matched donor HSCT without PT-CY. Thirty-eight children (n = 24 HLA-identical or 10/10-matched donors; n = 14 HLA-mismatched donors), who received a non-depleted bone marrow graft were included. Event-free survival (EFS) and GvHD were not higher in the mismatched PT-Cy group as compared to the matched group. Moreover, despite delayed neutrophil engraftment (day +22 vs. +26, p = 0.002) and immune recovery in the mismatched PT-Cy group, this did not result in more infectious complications. Therefore, we conclude that in the absence of an HLA-identical or a matched unrelated donor, HSCT with a mismatched unrelated or haploidentical donor in combination with ATG plus PT-CY can be considered a safe and effective treatment option for pediatric hemoglobinopathy patients.

T-cell depletion of bone marrow transplants for leukemia from donors other than HLA-identical siblings: advantage of T-cell antibodies with narrow specificities

AbstractT-cell depletion of donor marrow decreases graft–versus–host disease resulting from transplants from unrelated and human leukocyte antigen (HLA)-mismatched related donors. However, there are diverse strategies for T-cell–depleted transplantation, and it is uncertain whether any improve leukemia-free survival (LFS). To compare strategies for T-cell–depleted alternative donor transplants and to compare T-cell depleted with non-T-cell–depleted transplants, we studied 870 patients with leukemia who received T-cell–depleted transplants from unrelated or HLA-mismatched related donors from 1982 to 1994. Outcomes were compared with those of 998 non-T-cell–depleted transplants. We compared LFS using different strategies for T-cell–depleted transplantation considering T-cell depletion technique, intensity of pretransplant conditioning, and posttransplant immune suppression using proportional hazards regression to adjust for other prognostic variables. Five categories of T-cell depletion techniques were considered: narrow-specificity antibodies, broad-specificity antibodies, Campath antibodies, elutriation, and lectins. Strategies resulting in similar LFS were pooled to compare T-cell–depleted with non-T-cell–depleted transplants. Recipients of transplants T-cell depleted by narrow-specificity antibodies had lower treatment failure risk (higher LFS) than recipients of transplants T-cell depleted by other techniques. Compared with non-T-cell–depleted transplants (5-year probability ± 95% confidence interval [CI] of LFS, 31% ± 4%), 5-year LFS was 29% ± 5% (P = NS) after transplants T-cell depleted by narrow-specificity antibodies and 16% ± 4% (P < .0001) after transplants T-cell depleted by other techniques. After alternative donor transplantation, T-cell depletion of donor marrow by narrow-specificity antibodies resulted in LFS rates that were higher than those for transplants T-cell depleted using other techniques but similar to those for non-T-cell–depleted transplants.

Partially mismatched pediatric transplants with allogeneic CD34^+ blood cells from a related donor

This was a phase I, multi-center study of 13 pediatric patients (median age, 11 years) to evaluate toxicity, hematopoietic recovery, and graft-versus-host disease (GVHD) after allogeneic transplantation of enriched blood CD34(+) cells obtained from genotypically haploidentical but partially HLA-mismatched related donors (8 parents and 5 siblings). With regard to rejection, donor HLA disparity was 1 (5), 2 (6), or 3 loci (2). With regard to GVHD, recipient HLA disparity was 0 (1), 1 (3), 2 (8), or 3 (1). The patients suffered from acute myelogenous leukemia (6), chronic myelogenous leukemia (4), acute lymphoblastic leukemia (2), or hemolytic anemia plus immunodeficiency disorder (1). To reduce the risk of graft failure through the infusion of a large amount of stem cells, peripheral blood cells (PBC) were mobilized by recombinant granulocyte colony-stimulating factor (G-CSF; lenograstim, 10 microgram/kg/d for 5 days) and collected by 2 to 5 aphereses. To both enhance engraftment and reduce GVHD, CD34(+) cells were enriched using immunomagnetic procedures with the Baxter ISOLEX 300 system (Baxter Healthcare Corp, Irvine, CA) and cryopreserved. After variable cytoreductive regimens, a median of 7.7 (range, 2.2 to 14) x 10(6)/kg of CD34(+) cells and 1.03 (0.05 to 2.09) x 10(5)/kg CD3(+) cells were infused. Using Center-specific posttransplant supportive care and immunosuppressive GVHD prophylaxis, two patients experienced early death; one from veno-occlusive disease at day 17 and one from sepsis at day 18. Nine of 11 patients showed signs of engraftment; however, subsequent rejection was seen in 4 patients, 2 of whom had autologous recovery. Eight patients were evaluated in the early phase of marrow recovery. The median number of days to achieve an absolute granulocyte count of 0.5 x 10(9)/L was 14 (range, 9 to 20) and that to achieve a platelet count of 20 x 10(9)/L was 17.5 (range, 12 to 23). Donor chimerism persisted in five patients until death or current survival. All of the surviving patients with functioning-donor-type hematopoiesis were given total body irradiation. De novo acute GVHD (grades II and IV) was observed in two of the eight evaluated patients. Scheduled donor lymphocyte infusion (DLI), using the CD34(-) fraction, was administered to four patients, free of de novo acute GVHD, beginning between 28 to 43 days after transplant. Three of these patients developed acute GVHD (grades I, II, and IV). Cytomegalovirus infection was a major infectious complication but was successfully managed with gamma-globulin and gancyclovir treatment with or without additional DLI. Five patients are currently surviving, free of disease, with a follow-up ranging from 476 to 937 days. Each survivor has functioning hematopoiesis, three of donor origin and two of autologous origin. In conclusion, our results show that enriched blood CD34(+) cells from a mismatched haploidentical donor are a feasible alternative source of stem cells, but do not appear to ensure engraftment. Because none of the patients who were administered DLI survived, the therapeutic efficacy and safety of periodic DLI, as an integrated part of such transplants, needs to be clarified in further studies.

A Prospective Haploidentical Peripheral Blood Stem Cell Transplant Study Using a Pre-Defined Conditioning Regimen Intensity Based on Age and the Hematopoietic Cell Transplantation Comorbidity Index- Anzhit 1: Encouraging Preliminary Survival Outcomes at One Year Follow up

Background HLA-matched sibling and unrelated donors are not always available for patients that are in need of an allogeneic haematopoietic stem cell transplant. Partially HLA-mismatched related (haploidentical) donors can be identified for the vast majority of patients but these transplants were historically complicated by excessive graft versus host disease (GVHD), nonrelapse mortality (NRM), and poor overall survival (OS). Haploidentical haematopoietic stem cell transplantation (Haplo HSCT) has become increasingly common over the last ten years, predominately due to the successful use of post-transplant cyclophosphamide (PTCy) in mitigating graft versus host disease (GVHD). Most studies using PTCy have been retrospective with various conditioning regimens and stem cell sources making interpretation of results difficult. ANZHIT-1 is a prospective Australian multi-centre phase II study of Haplo HSCT with defined conditioning and GVHD prophylaxis regimens. Methods: This is an ethics approved Phase II study (ACTRN: 12617000151336) conducted between 2015-2020 at six Australian allogeneic HSCT centres. All patients received peripheral blood Haplo HSCT from haploidentical family members. The reduced intensity regimen (RIC) was fludarabine, cyclophosphamide and 200cGy TBI and the myeloablative regimen (MAC) was fludarabine with IV busulfan 3.2mg/kg x 4. PTCy 50mg/kg D+3, D+4 was used with MMF (to D35) and a calcineurin inhibitor (CNI) as GVHD prophylaxis. CNIs were weaned and ceased by D+120 in patients who did not have evidence of GVHD. Choice of conditioning regimen was based on age and hematopoietic cell transplantation comorbidity index (HCT-CI) scores. Patients who had an HCTCI &amp;gt;3 or age &amp;gt;50yrs received RIC. Data collection was through the Australian Bone Marrow Transplant Recipient Registry. Survival was analysed using the Kaplan-Meier method. Results: Seventy eight patients were included in the study with a median follow up of 402.5 days (28-1259). There was a male predominance (66%). The median age was 53 years (range 18-69) and the median HCT-CI score was 1 (range 0-5). Thirty nine patients had acute myeloid leukaemia, 12 acute lymphoblastic Leukaemia, 14 Non Hodgkin lymphoma or Hodgkin lymphoma, 4 myelodysplastic syndrome and 9 other diagnoses. The majority received RIC (59%). Median neutrophil and platelet engraftment times were 18 days (range: 12-92) and 28 days (range: 13-262) respectively. Acute GVHD grade III-IV occurred in 14.1% of patients whilst chronic GVHD occurred in 20.5%. Moderate to severe cGVHD according to NIH consensus criteria occurred in 10.3% of patients. Overall survival probability at one year was 74.1% (95% CI: 52.9-86.8) for MAC recipients and 77.8% (95% CI: 61.6-87.8) for RIC recipients (Figure 1). Non relapse mortality (NRM) at D100 and 1 year were 2.2% and 8.7% respectively in the RIC group compared to 6.3% and 18.8% respectively in the MAC group. Causes of NRM included infection (n=5), GVHD (n=3) and VOD, respiratory failure and multi-organ failure in one patient each. Haemorrhagic cystitis and poor graft function were relatively common post-transplant morbidities but rarely contributed to NRM. Despite the use of peripheral blood stem cells and early weaning of CNIs, only 3/11 NRM deaths were due to GVHD. Relapse was the most common cause of death in the RIC group with 17.4% of patients relapsing at a median of 114 days (range 36-564) compared to only 6.3% at a median of 90.5 days (range 64-154) in the MAC group. Conclusion: This prospective Haplo HSCT trial utilising PTCY demonstrates encouraging overall survival rates. The RIC regimen had a promising toxicity profile but early relapse remains a concern despite early weaning of CNIs. In contrast, the MAC regimen is associated with a low relapse rate but NRM at one year remains significant. Further refinement of the conditioning and GVHD prophylaxis regimens will be incorporated in the follow-on study, ANZHIT-2, which will begin accrual in late 2020. Disclosures Bajel: Pfizer: Honoraria; Amgen: Honoraria, Speakers Bureau; Novartis: Honoraria; Astellas: Honoraria; Abbvie: Honoraria. Greenwood:Servier: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Hamad:Novartis: Honoraria; Abbvie: Honoraria.

Reduced-intensity conditioning is effective for hematopoietic stem cell transplantation in young pediatric patients with Diamond-Blackfan anemia.

Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative therapy for the hematologic manifestations of Diamond-Blackfan anemia (DBA). However, data regarding the optimal conditioning regimen for DBA patients are limited. We retrospectively compared the outcomes of DBA patients who underwent HSCT using either myeloablative conditioning (MAC) or reduced-intensity conditioning (RIC) regimens. The patients belonged to a cohort treated at our hospitals between 2000 and 2018. HSCT was performed in 27 of 165 patients (16.4%). The median age at the time of HSCT was 3.6 years. Stem cell sources included bone marrow for 25 patients (HLA-matched sibling donors, n = 5; HLA-mismatched related donors, n = 2; HLA-matched/mismatched unrelated donors, n = 18) or cord blood for 2 patients. MAC or RIC regimens were used in 12 and 15 patients, respectively. Engraftment was successful in all 27 patients who underwent HSCT. Three patients who underwent HSCT using MAC regimens developed sinusoidal obstruction syndrome. The 3-year overall survival (OS) and failure-free survival rates (FFS) post-transplantations were 95.2% and 88.4%, respectively, with no significant differences between MAC and RIC regimens. Our data suggest that HSCTs using RIC regimens are effective and obtain engraftment with excellent OS and FFS for young DBA patients.

Prospective Study of Allogeneic Hematopoietic Stem Cell Transplantation with Post-Transplantation Cyclophosphamide and Antithymocyte Globulin from HLA-Mismatched Related Donors for Nonmalignant Diseases

Allogeneic hematopoietic stem cell transplantation (HSCT) is performed as a curative treatment for children with nonmalignant diseases, such as bone marrow failure syndromes and primary immunodeficiencies. Because graft-versus-host-disease (GVHD) is a major factor affecting survival probability and quality of life after HSCT, the availability of HLA-matched donors restricts the application of HSCT. Recently, HSCT with post-transplantation cyclophosphamide (PTCy) has emerged as a potent method to prevent GVHD after HSCT from HLA-haploidentical donors, and some studies have suggested the safety of PTCy-HSCT for nonmalignant diseases. We conducted a prospective clinical trial aiming to help confirm the safety of HSCT and further reduction of GVHD using a combination of PTCy and low-dose antithymocyte globulin (ATG) from HLA-mismatched related donors for children with nonmalignant diseases. Six patients underwent HSCT and achieved engraftment at a median of 14.5 days, and no patient developed severe acute GVHD. All patients had sustained donor chimerism without developing chronic GVHD at the last follow-up. In conclusion, HSCT with PTCy and low-dose ATG from an HLA-mismatched related donor were feasible to control GVHD for nonmalignant diseases in the children involved in our study. © 2020 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.

Haploidentical transplantation for hematologic malignancies: where do we stand?

The fundamental obstacle to the successful application of partially HLA-mismatched related donor, or HLA-haploidentical stem cell transplantation, is the strength of the host and donor T-cell response to allogeneic HLA molecules, which results in increased incidences of graft failure, GVHD, and nonrelapse mortality. The holy grail of haplo-SCT is to mitigate host-versus-graft and graft-versus-host responses while preserving immune responses to infection and the patient's malignancy. Two strategies have been taken to achieve this goal. The first strategy is to supplement a T cell-depleted graft with pathogen-specific T cells or populations of T cells in which alloreactivity can be controlled. The second strategy is to eliminate alloreactive T cells selectively from a T cell-replete graft. Substantial progress has been made with both approaches so that the safety of haplo-SCT now approaches that of SCT using grafts of umbilical cord blood or from HLA-matched donors. In light of the rapid and near universal availability of HLA-haploidentical related donors, it should now be possible to identify and mobilize a donor for every patient referred for allogeneic SCT. Prospective comparisons between haploidentical SCT and unrelated donor SCT should be performed to identify the most efficacious approach to alternative donor transplantation.

Pentotstatin/TBI Conditioning Is Well-Tolerated and Permits Engraftment of a Second Allogeneic Stem Cell Transplant Following Primary or Secondary Rejection of an Allogeneic Hematopoietic Stem Graft

Introduction: Graft failure remains a major obstacle to the success of allo-HSCT. Rates of graft failure are reported to be 2% in recipients of HLA identical grafts, 9% in those with an unrelated donor, and up to 12.3% in those with an HLA-mismatched related donor (0-3 antigen mismatched). Graft failure is associated with high mortality due to prolonged cytopenia's leading to significant anemia, bleeding, and infection. Successful management of graft failure usually requires a second transplant to restore normal hematopoiesis. The selection of a preparative regimen presents a challenge in these patients who have recently undergone myelosuppressive therapy prior to the failed transplant maneuver. We have employed the use of a minimally myelosuppressive regimen consisting of a single dose of pentostatin with a low dose of total body irradiation (TBI) as conditioning prior to a second allogeneic transplant for patients who experienced primary graft rejection. Methods: Under an IRB-approved retrospective study, we describe 4 consecutive patients with graft failure after allogeneic stem cell transplantation, who received a re-conditioning regimen consisting of pentostatin and low-dose TBI prior to second allo-HSCT. The median age of patients was 38 years (23-51). The conditioning regimens of the first transplant were myeloablative doses of cyclophosphamide/rabbit ATG; busulfan/fludarabine rabbit ATG/; busulfan/fludarabine; and fludarabine/melphalan (Table 1). Median cell doses for the first transplant were 7.7 x 10E6 CD34+ cells/kg and 104 x 10E6 CD3+ cells/kg. Two patients had primary graft rejection and 2 patients had secondary graft rejection. Patients with secondary graft rejection had initial hematopoietic engraftment of neutrophils on a median of 21 days and platelets on a median 61 of days post-transplant with subsequent declines in peripheral blood counts and chimerism studies showing loss of donor cell engraftment. The donor for the second transplant was the same in one patient and different in three patients and included a HLA-matched sibling in 2/4 patients and HLA-matched unrelated donor (URD) in 2/4 patients. One patient had two transplants from the same donor followed by a third transplant from a different HLA matched sibling donor. Conditioning for the second transplant in these cases consisted of pentostatin 4 mg/m2 as a single dose on day -3 and two fractions of 200 cGy TBI on days -2 and -1 as shown in Table 2. Results: Patients underwent the second (or third) donor allogeneic transplant at a median of 99 days following the first transplant. The second donor allograft contained a median of 9.6 x 10E6 CD34+ cells/kg and 390 x 10E6 CD3+ cells/kg. All recipients of the pentostatin-TBI conditioning regimen engrafted following transplantation of allogeneic stem cells (Table 2). Engraftment following the second transplant (or third transplant, in patient #1) occurred at a median of 22 days for neutrophils and 54 days for platelets, and all patients achieved 100% myeloid and lymphoid chimerism. Patients did not experience VOD/SOS or have severe mucositis, enteritis, or pulmonary toxicity, and were hospitalized a median of 39 days from the second transplant. All four patients achieved normal blood counts following the second transplant. One patient died unexpectedly of an apparent infection following full donor hematopoietic reconstitution. Three of the four patients undergoing a second transplant using pentostatin/TBI conditioning are alive without evidence for disease relapse or graft rejection at a median follow-up of 3.5 years, with none of these patients experiencing severe acute or chronic GvHD. Conclusion: Single dose pentostatin combined with low-dose TBI represents an effective and well-tolerated conditioning regimen that facilitates engraftment of a second allogeneic transplant in patients who experienced primary or secondary graft rejection. The enhanced therapeutic efficacy of this reduced-intensity regimen that allowed consistent donor-derived hematopoietic engraftment after initial allo-graft rejection warrants further study. Disclosures Langston: Astellas Pharma: Other: Research Support; Incyte: Other: Research Support; Jazz Pharmaceuticals: Other: Research Support; Chimerix: Other: Research Support; Takeda: Other: Research Support; Kadmon Corporation: Other: Research Support; Novartis: Other: Research Support; Bristol Myers Squibb: Other: Research Support. Waller:Pharmacyclics: Other: Travel expenses, Research Funding; Cerus Corporation: Other: Stock, Patents &amp; Royalties; Chimerix: Other: Stock; Cambium Oncology: Patents &amp; Royalties: Patents, royalties or other intellectual property ; Amgen: Consultancy; Kalytera: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. OffLabel Disclosure: the use of pentostatin as part of a conditioning regimen

Related and unrelated donor transplantation for β-thalassemia major: results of an international survey.

We studied 1110 patients with β-thalassemia major aged ≤25 years who received transplants with grafts from HLA-matched related (n = 677; 61%), HLA-mismatched related (n = 78; 7%), HLA-matched unrelated (n = 252; 23%), and HLA-mismatched unrelated (n = 103; 9%) donors between 2000 and 2016. Ninety percent of transplants were performed in the last decade. Eight-five percent of patients received ≥20 transfusions and 88% were inadequately chelated. All patients received myeloablative-conditioning regimen. Overall and event-free survival were highest for patients aged ≤6 years and after HLA-matched related and HLA-matched unrelated donor transplantation. The 5-year probabilities of overall survival for patients aged ≤6 years, 7 to 15 years, and 16 to 25 years, adjusted for donor type and conditioning regimen were 90%, 84%, and 63%, respectively (P < .001). The corresponding probabilities for event-free survival were 86%, 80%, and 63% (P < .001). Overall and event-free survival did not differ between HLA-matched related and HLA-matched unrelated donor transplantation (89% vs 87% and 86% vs 82%, respectively). Corresponding probabilities after mismatched related and mismatched unrelated donor transplantation were 73% vs 83% and 70% vs 78%. In conclusion, if transplantation is considered as a treatment option it should be offered early (age ≤6 years). An HLA-matched unrelated donor is a suitable alternative if an HLA-matched relative is not available.

A Pilot Prospective Single-Arm Clinical Study on Decitabine Plus CAG or IA Followed with HLA-Mismatched Nonmyeloablative Transplantation (micro transplantation) on De Novo Elderly Acute Myeloid Leukemia and Int-2/High Risk Myelodysplastic Syndrome Patients

Objective: To observe the efficacy and safety of Decitabine plus CAG or IA followed with HLA-mismatched nonmyeloablative transplantation (micro transplantation) on de novo elderly Acute Myeloid Leukemia and Int-2/high risk Myelodysplastic Syndrome patientsMethods: Till submission of this article, 10 patients were enrolled in this prospective clinical study. Patients were admitted from January 2017 to June 2018 to our centre. 6 of whom were elderly AML (≥60 years) and 4 were Int-2/high risk MDS according to IPSS-R scoring system. Induction chemotherapy were decitabine (15 mg/m2) for 5 days followed with CAG (cytarabine 10 mg/m2 q12h; aclarubicin 10 mg/day and G-CSF at 300 μg/day x 6 days for AML and 4 days for MDS), then followed with a transfusion of HLA-mismatched (≤7/10 matched HLA loci) related donor peripheral stem cells (micro transplantation) 24 hours after chemotherapy. Consolidation therapy was another 3 courses of chemotherapies which were decitabine (15 mg/m2) for 5 days with IA (3+7) for AML or CAG (6 days) for MDS, followed by micro transplantation 24 hours after each course. Till now, the total observable treatment courses were 21.Results: The average age of the patients was 63.5 years (range from 55 to 71 years). The average number of transfusion mononuclear cells (MNC) at per course was 3.26 (1.87-5.25) x 108/kg, the average CD34+ cells was 1.12 (0.34-3.16) x 106/kg, and the average of CD3+ T cells was 3.93 (1.87-7.17) x 107/kg. Among them, 5 cases (50%) obtained CR (CR+CRi), 3 cases obtained PR (30%). The ORR was 83.3% for elderly AML patients, 75% for MDS patients and 80% for all patients. The median recovery time of neutrophil (from the end of chemo to neutrophil ≥0.5 x 109) was 9 days and was 8.5 days for platelets (from the end of chemo to platelets ≥20 x 109). 1 patient developed severe aGVHD and died, 1 patient died of heart failure, no other serious adverse events were observed in rest patients. 7 of 10 cases developed peripheral T cell increase after stem cell transfusion, including the total CD3+ T cells, CD4+ and CD8+ T cells, with an average peak at day7. The increased T cells were verified as host origin by short tandem repeat (STR) detection performed on 1 patient. 8 of 10 cases occurred cytokine related fever (CRF) after stem cell transfusion. The fever was usually happened within 24 hours after stem cell transfusion, with an average duration of 5 days and a mean peak temperature at 39.7 ℃. With CRF there was an increase of cytokines with different patterns in different patients but majorly on IL-6, IL-2, IFN-r and TNF-a. Also there was an increase of C-Reactive Protein (CRP) which reached an average peak level as 116.9 mg/L. Patients with CRF had a CR+CRi rate at 62.5%.Conclusion: Our preliminary results of this study indicate that Decitabine plus CAG or IA followed with micro transplantation have an ORR at 80% in de novo elderly Acute Myeloid Leukemia and Int-2/high risk Myelodysplastic Syndrome patients with controllable recover time of neutrophils and platelets. Although the incidence of acute graft versus host disease (aGVHD) in micro transplantation was as low as 1-2% according to reports, it is still possible. How to predict and avoid severe aGVHD is still under investigate. The presence of cytokine related fever may associate with the increase of hosts' T cells, which may relate to the improvement of therapeutic response. Larger cohorts and more investigates need to be done to clarify above findings. DisclosuresNo relevant conflicts of interest to declare.

Prognostic Impact of Donor Source on Allogeneic Hematopoietic Stem Cell Transplantation Outcomes in Adults with Chronic Myelomonocytic Leukemia: A Nationwide Retrospective Analysis in Japan

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative therapeutic option for patients with chronic myelomonocytic leukemia (CMML). We retrospectively compared the post-transplantation outcomes of 159 patients with CMML who underwent allo-HSCT using 4 types of donor sources: HLA-matched related donor graft, unrelated bone marrow (U-BM), unrelated cord blood (U-CB), and HLA-mismatched related donor graft. The median patient age at allo-HSCT was 54 years (range, 16 to 75 years). In multivariate analyses, the use of HLA-matched related donor grafts correlated with better overall survival than U-BM (hazard ratio [HR], 2.05; 95% confidence interval [CI], 1.21 to 3.48; P = .008), U-CB (HR, 3.80; 95% CI, 2.07 to 6.95; P < .001), or HLA-mismatched related donor grafts (HR, 6.18; 95% CI, 2.70 to 14.15; P < .001). Mortality after the relapse or progression of CMML did not significantly differ among the 4 types of donor source. Transplantation-related mortality was highest in recipients of U-CB (HR, 3.32; 95% CI, 1.33 to 8.26; P = .010). In patients with CMML, allo-HSCT using an alternative donor may contribute to durable remission; however, further improvements in transplantation-related mortality are required for this type of transplantation.

Reduced-Intensity Haploidentical Bone Marrow Transplantation with Post-Transplant Cyclophosphamide for Solid Tumors in Pediatric and Young Adult Patients

High-risk, recurrent, or refractory solid tumors in pediatric, adolescent, and young adult (AYA) patients have an extremely poor prognosis despite current intensive treatment regimens. We piloted an allogeneic bone marrow transplant platform using reduced-intensity conditioning (RIC) and partially HLA-mismatched (haploidentical) related donors for this population of pediatric and AYA solid tumor patients. Sixteen patients received fludarabine, cyclophosphamide, melphalan, and low-dose total body irradiation RIC haploidentical BMT (haploBMT) followed by post-transplantation cyclophosphamide (PTCy), mycophenolate mofetil, and sirolimus. All assessable patients were full donor chimeras on day 30 with a median neutrophil recovery of 19 days and platelet recovery of 21 days. One patient (7%) exhibited secondary graft failure associated with concomitant infection. The median follow-up time was 15 months. Overall survival was 88%, 56%, and 21% at 6, 12, and 24 months, respectively. Median survival from transplant date was 14 months with a median progression-free survival 7 months. We observed limited graft-versus-host disease in 3 patients and nonrelapse mortality in 1 patient. We demonstrated that RIC haploBMT with PTCy is feasible and has acceptable toxicities in patients with incurable pediatric and AYA solid tumors; thus, this approach serves as a platform for post-transplant strategies to prevent relapse and optimize progression-free survival.

Long-Term Outcome of Adenosine Deaminase-Deficient Patients-a Single-Center Experience.

Inherited defects in the adenosine deaminase (ADA) enzyme can cause severe combined immune deficiency (SCID) and systemic abnormalities. Management options for ADA-deficient patients include enzyme replacement therapy (ERT), hematopoietic stem cell transplantation (HSCT), and gene therapy (GT). Here, we describe the long-term benefits of these treatments. Survival, infections, systemic sequelae, and laboratory assessments were recorded for all ADA-deficient SCID patients, managed at a single center since 1985, who survived 5 or more years following treatment. Of 20 ADA-deficient patients, the 8 (40%) who survived 5 or more years (range 6-29.5years, median 14years) were included in the study. Among the long-term survivors, two patients were treated exclusively with ERT, five underwent HSCT (three from HLA-matched sibling donors, two from HLA-mismatched related donors), and one received GT. The long-term survivors often suffered from recurrent respiratory infections; however, opportunistic infections occurred in only one patient. Systemic sequelae included lung disease such as bronchiectasis and asthma (four patients), neurologic abnormalities (six patients), metabolic disturbances (two patients), allergy and autoimmunity (six patients), and neoplasms (three patients). Normal CD4+ T cell numbers and function, as well as antibody production, were usually observed after HSCT and GT, but not after ERT. Late deaths occurred in two patients at 15 and 25years after HSCT, respectively, and were attributed to respiratory failure. ADA-deficient patients commonly suffer from long-term complications, emphasizing the need for improved management and for multi-disciplinary follow-up.

Positive Cytotoxic Crossmatch Predicts Delayed Neutrophil Engraftment in Allogeneic Hematopoietic Cell Transplantation from HLA-Mismatched Related Donors

Although a positive cytotoxic crossmatch (XM) has been reported to predict graft failure, mainly in solid organ transplantations, its significance in allogeneic hematopoietic cell transplantation (HCT) remains to be elucidated. We retrospectively assessed the impact of positive XM on neutrophil engraftment in 41 patients who underwent HCT with an HLA-mismatched related donor. XM was positive in 22 patients. Six of these 22 patients were also positive for anti-HLA antibody, whereas only 1 was positive for donor-specific anti-HLA antibody. The cumulative incidence of engraftment at day +28 was 89.5% in patients with negative XM versus 59.1% in those with positive XM (P = .08). In particular, positive B cell warm XM was significantly associated with a lower probability of engraftment at day +28 (46.7% versus 88.5%; P = .04). In a multivariate analysis, both positive XM and positive B cell warm XM were significantly associated with delayed engraftment (hazard ratio [HR], .46; P = .02 and HR, .41; P = .01, respectively). There was no significant difference in the achievement of engraftment between those with and without detection of anti-HLA antibodies. In conclusion, positive XM might be associated with a delayed neutrophil engraftment after HCT from HLA-mismatched related donors.