Secondary Poor Graft Function Research Articles

The effect of glucose-6-phosphate dehydrogenase deficiency on allogeneic hematopoietic stem cell transplantation in patients with hematological disorders

Objectives: To determine the effect of glucose-6-phosphate-dehydrogenase (G6PD) deficiency on patients' complications and prognosis following allogeneic stem cell hematopoietic transplantation (allo-HSCT) . Methods: 7 patients with G6PD deficiency (study group) who underwent allo-HSCT at Peking University People's Hospital from March 2015 to January 2021 were selected as the study group, and thirty-five patients who underwent allo-HSCT during the same period but did not have G6PD deficiency were randomly selected as the control group in a 1∶5 ratio. Gender, age, underlying diseases, and donors were balanced between the two groups. Collect clinical data from two patient groups and perform a retrospective nested case-control study. Results: The study group consisted of six male patients and one female patient, with a median age of 37 (range, 2-45) years old. The underlying hematologic diseases included acute myeloid leukemia (n=3), acute lymphocytic leukemia (n=2), and severe aplastic anemia (n=2). All 7 G6PD deficiency patients achieved engraftment of neutrophils within 28 days of allo-HSCT, while the engraftment rate of neutrophils was 94.5% in the control group. The median days of platelet engraftment were 21 (6-64) d and 14 (7-70) d (P=0.113). The incidence rates of secondary poor graft function in the study group and control group were 42.9% (3/7) and 8.6% (3/35), respectively (P=0.036). The CMV infection rates were 71.4% (5/7) and 31.4% (11/35), respectively (P=0.049). The incidence rates of hemorrhagic cystitis were 57.1% (4/7) and 8.6% (3/35), respectively (P=0.005), while the bacterial infection rates were 100% (7/7) and 77.1% (27/35), respectively (P=0.070). The infection rates of EBV were 14.3% (1/7) and 14.3% (5/35), respectively (P=1.000), while the incidence of fungal infection was 14.3% (1/7) and 25.7% (9/35), respectively (P=0.497). The rates of post-transplant lymphoproliferative disease (PTLD) were 0% and 5.7%, respectively (P=0.387) . Conclusions: The findings of this study indicate that blood disease patients with G6PD deficiency can tolerate conventional allo-HSCT pretreatment regimens, and granulocytes and platelets can be implanted successfully. However, after transplantation, patients should exercise caution to avoid viral infection, complications of hemorrhagic cystitis, and secondary poor graft function.

Eltrombopag for the Treatment of Allogeneic Hematopoietic Stem Cell Transplantation-Related Poor Graft Function.

Allogeneic stem cell transplantation (ASCT) is a crucial therapeutic strategy for hematological and non-hematological disorders. Poor graft function (PGF) after ASCT presents a critical challenge that does not have a standardized treatment approach. A thrombopoietin-mimetic oral drug eltrombopag shows promise in some bone failure syndromes. This study aimed to analyze the efficacy of eltrombopag in treating PGF after ASCT. Patients receiving eltrombopag for PGF after ASCT between 2017 and 2020 were retrospectively evaluated. Patients' characteristics, details for ASCT, timing, treatment, and possible contributors for PGF, response to eltrombopag treatment, and overall response rate (ORR) were analyzed. Results: Eighteen patients were assessed. Eltrombopag treatment yielded a favorable response in 11 patients, resulting in an ORR of 61%. The ORR in secondary PGF was better than that in primary PGF (83% and 17% respectively). There was a marked enhancement in platelet and hemoglobin levels following eltrombopag treatment (p=0.001 and p=0.030, respectively), while neutrophil values exhibited no significant change (p=0.8). Among the responding patients, four individuals (22%) underwent a tapering and discontinuation of eltrombopag. No toxicity was observed above grade one, and no patient discontinued eltrombopag because of intolerability or adverse events. Our findings affirm that eltrombopag can treat poor graft function after allogeneic stem cell transplantation without significant toxicities. These results contribute to the growing body of evidence supporting the use of eltrombopag in poor graft function after allogeneic stem cell transplantation, providing insights into its potential benefits and limitations.

Post-engraftment Bloodstream Infections After Allogeneic Hematopoietic Cell Transplantation: Risk Factors and Association with Mortality.

Bloodstream infections (BSIs) are major cause of morbidity and mortality after allogeneic hematopoietic cell transplantation (allo-HCT). This study aimed to analyze the incidence, etiology, risk factors and outcomes of post-engraftment BSI in allo-HCT recipients. The retrospective study included 261 patients with documented engraftment after first allo-HCT performed from January 2018 till September 2021. Of 261 patients 29 (11.1%) developed at least one post-engraftment BSIs episode with a median time to post-engraftment BSI of 49 days (range, 1 - 158 days from the engraftment). A total of 45 pathogens were isolated from blood - 64.4% (n = 29) were represented by Gram-negative bacteria, and 35.6% (n = 16) - by Gram-positive bacteria. Secondary graft failure (hazard ratio [HR]: 39.93; 95% confidence interval [CI]: 7.64-208.74; P <0.001), secondary poor graft function (HR: 18.07; 95% CI: 3.53 - 92.44; P <0.001), and acute gut graft-versus-host-disease (GvHD) grade II-IV (HR: 29.86; 95% CI: 10.53 - 84.68; P <0.001) were associated with the higher risk of Gram-negative post-engraftment BSIs. Overall 30-day survival after post-engraftment BSIs was 71.4%. By multivariate analysis post-engraftment BSIs (HR: 3.09; 95% CI: 1.29 - 7.38; P = 0.011), and acute gut GvHD grade II-IV (HR: 6.60; 95% CI: 2.78 - 15.68; P <0.001) were associated with the higher 180-day non-relapse mortality risk. Gram-negative bacteria prevailed in the etiology of post-engraftment BSIs with secondary graft failure. secondary poor graft function. and acute gut GvHD being the main predisposing factors for their development. Post-engraftment BSIs were associated with the higher risk of non-relapse mortality after allo-HCT.

P823: THE INCIDENCE, OUTCOMES, AND RISK FACTORS OF SECONDARY POOR GRAFT FUNCTION IN HAPLOIDENTICAL HEMATOPOIETIC STEM CELL TRANSPLANTATION FOR ACQUIRED APLASTIC ANEMIA

Background: Secondary poor graft function (sPGF) increases the risk of life-threatening complications after transplantation and is an obstacle to achieving better outcomes after hematopoietic stem cell transplantation (HSCT). Aims: We aimed to determine the incidence, clinical outcomes, and risk factors of sPGF in haploidentical HSCT (haplo-HSCT) for acquired aplastic anemia (AA) patients. Methods: We retrospectively reviewed 430 consecutive AA patients receiving haplo-HSCT in Peking University People’s Hospital between January 2006 and December 2020. Results: We reported the estimated 3-year cumulative incidence of sPGF was 4.64%, while no primary PGF occurred. The median time to sPGF was 121 days (range 30-626 days) after transplantation. To clarify the risk factors for sPGF, 17 sPGF cases and 382 without PGF were further analyzed. Compared to patients without PGF, the 2-year overall survival was significantly poorer for sPGF patients (67.7% vs 90.8%, p =.002). Twelve sPGF patients were alive until the last follow-up, and 7 achieved transfusion independency. The multivariable analyses revealed that a history of refractory cytomegalovirus viremia (CMViremia) (OR=7.038, p=.002) post-transplantation independently increased the risk of sPGF. There was weak evidence that a history of grade 3-4 acute graft-versus-host disease (aGvHD) increased the risk of sPGF (p=.092). Summary/Conclusion: In conclusion, sPGF can develop in 4.64% of AA patients after haplo-HSCT and significantly decreases survival. The independent hazard elements for sPGF were a history of refractory CMViremia and grade 3-4 aGvHD. We advocated better post-transplantation strategies to balance the risk of immunosuppression and viral reactivation for haplo-HSCT in AA patients.

The Incidence, Outcomes, and Risk Factors of Secondary Poor Graft Function in Haploidentical Hematopoietic Stem Cell Transplantation for Acquired Aplastic Anemia.

Secondary poor graft function (sPGF) increases the risk of life-threatening complications after hematopoietic stem cell transplantation (HSCT). The incidence, clinical outcomes, and risk factors of sPGF have not been elucidated in haploidentical (haplo-) HSCT for acquired aplastic anemia (AA) patients. We retrospectively reviewed 423 consecutive AA patients who underwent haplo-HSCT between January 2006 and December 2020 and report a 3-year cumulative incidence of 4.62% (95% confidence interval [CI]: 3.92%-10.23%) of sPGF. While no primary PGF occurred. The median time to sPGF was 121 days (range 30-626 days) after transplantation. To clarify the risk factors for sPGF, 17 sPGF cases and 382 without PGF were further analyzed. Compared to patients without PGF, the 2-year overall survival was significantly poorer for sPGF patients (67.7% vs 90.8%, p =.002). Twelve sPGF patients were alive until the last follow-up, and 7 achieved transfusion independency. The multivariable analyses revealed that later neutrophil engraftment (OR 2.819, p=.049) and a history of refractory cytomegalovirus viremia (OR=7.038, p=.002) post-transplantation were associated with sPGF. There was weak evidence that a history of grade 3-4 acute graft-versus-host disease increased the risk of sPGF (p=.063). We advocated better post-transplantation strategies to balance the risk of immunosuppression and viral reactivation for haplo-HSCT in AA patients.

Bloodstream infections in different stage of reconstitution after first allogeneic hematopoietic stem cell transplantation

Background. Bloodstream infections (BSI) are common after allogeneic hematopoietic stem cell transplantation (allo-HSCT). The objective of study was to analyze pre- and post-engraftment BSI.Materials and methods. From January 2018 till May 2021242 patients after first allo-HSCT were enrolled in the study. Median age was 35 (17–65) years. The majority of transplants were done for acute leukemias (71.9 %) in remission (91.7 %) with reduced-intensity conditioning regimens (71.5 %) and peripheral blood stem cells (74.4 %) as a graft source.Results. Of 242 patients 95 (39.2 %) developed BSI: 79 (83.2 %) developed 1 BSI episode, 16 (16.8 %) – 2 or more. Overall 113 BSI episodes were registered: 94 (82.7 %) were caused by single microorganism, 19 (17.3 %) were polymicrobial. Probability of pre-engraftment BSI was 31.0 %, post-engraftment – 11.8 %. In total 134 microorganisms were identified: 61.2 % – gram-negative and 38.8 % – gram-positive bacteria. Gram-negative BSI rate was significantly higher during post-engraftment compared to pre-engraftment phase (57.7 % vs. 70.3 %; р = 0.008). Major risk factor for pre-engraftment BSI was mismatched unrelated allo-HSCTs (hazard ratio (HR) 2.55; 95 % confidence interval (CI) 1.32–4.91; р = 0.03), for post-engraftment BSI – secondary poor graft function (HR 21.70; 95 % CI 7.95–59.24; р &lt;0.0001) and graft failure (HR 21.55; 95 % CI 6.27–74.08; р &lt;0.0001), and gut graft-versus-host disease (HR 12.90; 95 % CI 5.77–28.80; р &lt;0.0001). Thirty-day survival after each BSI episode was 90.3 % and was significantly lower in patients with post-engraftment BSI compared to pre-engraftment (71.9 % vs. 97.5 %; р &lt;0.0001).Conclusion. Gram-negative bacteria prevailed in the etiology of BSI. The main risk factors for pre-engraftment BSI was allo-HSCT from mismatched unrelated donors, for post-engraftment BSI – secondary poor graft function and graft failure. Post-engraftment BSI is associated with worse prognosis.

Haploidentical donor transplant is associated with secondary poor graft function after allogeneic stem cell transplantation: A single-center retrospective study.

BackgroundSecondary poor graft function (sPGF) is a serious complication after allogeneic hematopoietic stem cell transplantation (allo‐HSCT) related to poor outcome. We aimed to retrospectively evaluate the morbidity and hazard elements of sPGF after allo‐HSCT.MethodsEight hundred and sixty‐three patients who achieved initial engraftment of both neutrophils and platelets were retrospectively reviewed in this study.ResultsFifty‐two patients developed sPGF within 180 days post‐transplants, with the median onset time was 62 days (range, 34–121 days) post‐transplants. The overall cumulative incidence of sPGF within 180 days post‐transplantation was 6.0%, with 3.4%, 3.4%, and 10.1%, respectively, in matched sibling donor (MSD), matched unrelated donor (MUD), and haploidentical donor (HID) transplant (p < 0.0001). Multivariable analysis showed that HID (HID vs. MSD: hazard ratio [HR] 2.525, p = 0.004; HID vs. MUD: [HR] 3.531, p = 0.017), acute graft versus host disease (aGVHD) within +30 days ([HR] 2.323, p = 0.003), and cytomegalovirus (CMV) reactivation ([HR] 8.915, p < 0.0001) within +30 days post‐transplants were hazard elements of sPGF. The patients with sPGF had poorer survival than good graft function (51.7±8.1% vs. 62.9±1.9%, p < 0.0001). Our results also showed that only CMV reactivation was the hazard element for the development of PGF in HID transplant ([HR] 12.521 p < 0.0001).ConclusionHID transplant is also an independent hazard element of sPGF except for aGVHD and CMV reactivation.

Addition of Plerixafor Overcomes Poor Mobilization in Autologous and Allogeneic Stem Cell Grafts and Leads to Efficient and Sustained Engraftment

▪Poor hematopoietic stem cell (HSC) mobilization upon granulocyte-colony stimulating factor (G-CSF) remains a significant problem for autologous and allogeneic hematopoietic cell transplantation (HCT). In up to 20% of patients, no sufficient autografts can be collected. The chemokine receptor CXCR4 plays a pivotal role in the homing of HSCs to the bone marrow. CXCR4 inhibition by the bicyclam derivative plerixafor can lead to improved HSC yields. We here evaluated the effects of plerixafor supported HSC apheresis in order to enable otherwise impossible HCT and with regard to graft quality and transplantation outcomes in both the autologous and allogeneic setting.Data retrospectively obtained from all 2,257 leukaphereses between 2014 and 2017 (588 for autologous and 1,669 for allogeneic transplantation) were analyzed. 48 individuals (31 male and 17 female, median age 52 years, range 31-72 years) were identified who received plerixafor due to insufficient HSC mobilization upon G-CSF stimulation. 44 patients (non-hodgkin lymphoma n=19, multiple myeloma n=19, systemic sclerosis n=3, Ewing sarcoma n=2, germinal cell cancer n=1) collected HSC for autologous, 4 HLA-identical siblings for allogeneic transplantation representing a low rate of poor mobilizers of 7% (44/588) and 0.2% (4/1669) autologous and allogeneic donors, respectively.A median of 1 dose plerixafor (range, 1-3 doses) was applied. Aphereses after addition of plerixafor were performed at a median of 2 days (range, 1-651 days) after insufficient attempts (median CD34+ cells 13/µl; range, 0-46/µl). 4 patients received a second mobilization chemotherapy before plerixafor application. 2 donors received plerixafor despite collection of >3.0x106 HSC per kilogram recipient body weight (kg BW) to enable in vitro graft manipulation or more than one HCT.Patients collecting HSC for autologous HCT received a median of 7 therapy cycles (range, 3-25 cycles) before HSC mobilization. Allogeneic donors tended to be older (median age of 54 years; range, 49-69 years).HSC mobilization was improved in 38/44 patients and 4/4 allogeneic donors. Before and after plerixafor application, median CD34+ cell counts were 0.6x106 (0.1-4.1 x106) cells/kg BW in 51 aphereses (range, 1-3 per patient) and 2.0x106 (range, 0.1-23.3 x106) cells/kg BW in 94 aphereses (range, 1-4 per patient), respectively (p<0.0001).Autologous HCT was performed in 32/44 patients. In the remaining, no HCT was performed due to further insufficient HSC mobilization despite plerixafor application (n=6), death due to progressive disease (n=3) or due to infection (n=1) before HCT. Two recent patients did not undergo autologous HCT, yet. All patients received G-CSF during autologous HCT. Median neutrophil (>500/µl) and platelet (>20,000/µl) engraftment was reached on day 12 (range, days 9-21) and 14 (range, days 10-23), respectively. No primary or secondary graft failure or poor graft function (PGF) was observed.The collected allogeneic grafts were applied to the patients in all 4 cases. Allogeneic HCT patients did not receive G-CSF. Median neutrophil and platelet engraftment was noted on days 13 (range, days 11-20) and 15 (range, days 11-23), respectively. Again, neither primary or secondary graft failure nor PGF was noted.Median overall survival after HCT for patients receiving autologous and allogeneic grafts was 31 (range, 1-72) and 7 (range, 5-53) months, respectively.For both autologous and allogeneic grafts, addition of plerixafor improved HSC yields in most poor mobilizers and therefore enabled for an otherwise impossible HCT including in vitro manipulation of allogeneic grafts and repetitive HCT. Of note, using G-CSF and plerixafor mobilization resulted in insufficient cell counts in only 0.3% of donors (6/2,257; for patients 6/588: 1%; for allogeneic donors 0/1,669: 0%) allowing HCT for almost every patient. Of note, poor mobilizers overall appeared to be seldom. Since plerixafor application was successful in most patients, these data might also help to reduce G-CSF application especially to patients who should not suffer from additional pulmonal toxicity (e.g. in systemic sclerosis). Hematopoietic engraftment after HCT of plerixafor mobilized grafts was rapid and sustained without observation of graft failure or PGF. The time to engraftment was comparable to G-CSF mobilized grafts showing that the quality of plerixafor mobilized grafts is to be estimated equal. DisclosuresBethge:Miltenyi Biotech GmbH: Consultancy, Honoraria, Research Funding; Neovii GmbH: Honoraria, Research Funding.

Impaired Hematopoiesis after Allogeneic Hematopoietic Stem Cell Transplantation: Its Pathogenesis and Potential Treatments

Impaired hematopoiesis is a serious complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Bone marrow aplasia and peripheral cytopenias arise from primary and secondary graft failure or primary and secondary poor graft function. Chimerism analysis is useful to discriminate these conditions. By determining the pathogenesis of impaired hematopoiesis, a timely and appropriate treatment can be performed. Hematopoietic system principally consists of hematopoietic stem cells and bone marrow microenvironment termed niches. Abnormality in hematopoietic stem and progenitor cells and/or abnormality in the relevant niches give rise to hematological diseases. Allo-HSCT is intended to cure each hematological disease, replacing abnormal hematopoietic stem cells and bone marrow niches with hematopoietic stem cells and bone marrow niches derived from normal donors. Therefore, treatment for graft failure and poor graft function after allo-HSCT is required to proceed based on determining the pathogenesis of impaired hematopoiesis. Recent progress in this area suggests promising treatment manipulations for graft failure and poor graft function.

Risk factors for secondary poor graft function after bone marrow transplantation in children with acquired aplastic anemia.

In patients with acquired AA, PGF is a major cause of cytopenia after hematopoietic stem cell transplantation. An increased incidence of PGF, especially sPGF, has been noted after the introduction of the FLU/CY regimen in children with acquired AA. To clarify the risk factors for sPGF, the clinical data of 49 patients (median age, 11years; range, 1-19years) with AA who received allogeneic BMT at Nagoya University Hospital from 1997 to 2016 were analyzed. Out of the 49 patients, 7 developed sPGF, and the 5-year CI was 0.15 (95% CI, 0.04-0.25). Five received the FLU/CY regimen, and the 5-year CI of sPGF was significantly higher in patients who received the regimen (0.36; 95% CI, 0.12-0.62) than in those who were conditioned with the non-FLU/CY regimen (0.06; 95% CI, 0.01-0.17; P=.01). The multivariate analysis confirmed that the FLU/CY regimen (hazard ratio, 6.12; 95% CI, 1.16-32.4; P=.03) was a significant risk factor for sPGF. sPGF improved spontaneously without stem cell boost infusions in 5 patients, ranging from 460 to 3539days after BMT. The 10-year CI of the spontaneous trilineage recovery was 0.83 (95% CI, 0.00-0.97), and all 7 patients are alive. The FLU/CY regimen was identified as a risk factor for the sPGF development in patients with AA. The establishment of the optimal conditioning regimens for children with AA is warranted.

Comparative Study of Mizoribine and Mycophenolate Mofetil Combined with a Calcineurin Inhibitor-Based Immunosuppressive Regimen in Patients with Alternative Donor Hematopoietic Cell Transplantation.

Cytomegalovirus (CMV) infection and graft-versus-host disease (GVHD) remain the major causes of nonrelapse mortality (NRM) in patients following alternative donor hematopoietic stem cell transplantation (HCT). Mizoribine (MZR) showed an anti-CMV effect in addition to its immunosuppressive effect in patients with renal transplantation. In this study, we aimed to evaluate the efficacy and safety of MZR combined with a calcineurin inhibitor (CNI) as a method of prophylactic immunosuppression in recipients following alternative donor HCT. Eighty patients were enrolled in the study and randomized to the MZR (n=40) or MMF (n=40) cohort before transplantation conditioning. Analyses involved a comparison of the outcomes between the 2 cohorts, as well as risk analyses of early nonrelapse mortality (NRM) and severe CMV infection. In contrast to MMF, MZR was associated with a lower but statistically nonsignificant median CMV DNA peak load (P=.075), significantly fewer episodes of persistent/refractory infection (odds ratio [OR], .12), and a lower failure rate of CMV treatment (OR, .82), but a significantly higher rate of hyperuricemia (OR, 2.75). Transplantation efficacy was comparable in the 2 cohorts regarding engraftment, the development of secondary poor graft function and GVHD, and the estimated OS and PFS. The 1-year NRM of the MZR cohort did not differ from that of the MMF cohort, whereas the rate of 1-year NRM caused by viral infections was reduced in the MZR cohort and was of borderline statistical significance (P=.05). In the multivariate analysis, lower doses of CD34+ cells in grafts (hazard ratio [HR], 3.65) and persistent/refractory CMV infections (versus no CMV infection: HR, 7.31; versus CMV infection that was not persistent/refractory: HR, 4.46) were predictors of increased 1-year NRM. The use of MMF (versus MZR cohort: OR, 11.54) and grade II-IV acute GVHD (OR, 15.32) were independent risk factors for developing persistent/refractory CMV infection. When combined with CNIs, MZR functioned well in terms of both immunosuppression and reduced severity of CMV infection; however, further studies are warranted to verify its use as a potential immunosuppressant for alternative donor HCT.

Can Planned CD34+ Stem Cell Boost Prevent Poor Graft Function after Peripheral Blood Haploidentical Hematopoietic Transplantation?

<h3>Introduction</h3> Traditional outcome measurements for hematopoietic recovery after Haploidentical HCT (haplo-HCT) with post-transplant cyclophosphamide (PTCy) may not capture a subset of patients who meet engraftment milestones, and have full donor chimerism, but subsequently suffer poor graft function (PGF) resulting in prolonged cytopenias and requiring transfusion support. This is termed secondary PGF, occurs in 5-26% of patients, and is associated with significant morbidity and mortality. CD34+ selected donor cell infusions have been employed in this setting without causing graft versus host disease (GVHD). <h3>Objectives</h3> We hypothesized that planned CD34+ stem cell boost (SCB) after PTCy could be used to prevent PGF after haplo-HCT. <h3>Methods</h3> Full donor chimerism was defined as ≥ 95% donor chimerism from bone marrow on day +30. Poor graft function was defined as transfusion dependence with ≥ two cytopenic lines (ANC < 1500 cells/mm3, platelets < 30 000/mm3 and Hgb < 8.5 g/dL) in the presence of full donor chimerism and in the absence of severe GVHD, CMV infection, and relapse. Patients underwent haplo-HCT per institutional protocol. Part of the donor product underwent CD34+ selection and cells were cryopreserved. On day 5-6, CD34+ selected donor product was infused. <h3>Results</h3> Between February 1, 2018 and August 30, 2018, nine patients underwent planned SCB after haplo-HCT. All patients received GVHD prophylaxis with PtCY, tacrolimus, and mycophenolate per institutional guidelines. The comparison cohort consisted of all patients who have undergone haplo-HCT at our institution between July 7^th, 2009 and October 8^th, 2018. All nine SCB patients had neutrophil engraftment (NE) with a median time of 16 days (13 – 25) compared with 17 days (12 – 78) in the comparison cohort (p = 0.40). Six of eight evaluable SCB patients had platelet engraftment (PE) with a median time of 22.5 days (12 – 55) compared with 26 days (9 – 134) in the comparison cohort (p = 0.675). One patient was censored due to death prior to PE on day +19. None of the 8 surviving patients developed secondary PGF. Two patients in the planned SCB group developed grade III acute GVHD involving the GI tract. The remaining seven had no GVHD. <h3>Conclusion</h3> These patients were selected on the basis of being high risk for graft failure or poor graft function. Two patients had active disease at the time of transplant and five of the nine patients were undergoing their second HCT. Time to NE and PE in the SCB group were 1 and 3.5 days faster than in the comparison group. This equivalency is notable given that the SCB patients were specifically selected for being high risk or graft failure. None of the SCB patients had secondary graft failure, compared with published rates between 5.6% and 26%. This approach appears to be safe with acceptable incidence of severe acute GVHD.

Predictors of recovery following allogeneic CD34+-selected cell infusion without conditioning to correct poor graft function.

Poor graft function is a serious complication following allogeneic hematopoietic stem cell transplantation. Infusion of CD34+-selected stem cells without pre-conditioning has been used to correct poor graft function, but predictors of recovery are unclear. We report the outcome of 62 consecutive patients who had primary or secondary poor graft function who underwent a CD34+-selected stem cell infusion from the same donor without further conditioning. Forty-seven of 62 patients showed hematologic improvement and became permanently transfusion- and growth factorindependent. In multivariate analysis, parameters significantly associated with recovery were shared cytomegalovisur seronegative status of both the recipient and donor, the absence of active infection and matched recipientdonor sex. Recovery was similar in patients with mixed and full donor chimerism. Five-year overall survival rates were 74.4% (95% confidence interval [95% CI: 59-89]) in patients demonstrating complete recovery, 16.7% (95% CI: 3-46) in patients with partial recovery and 22.2% (CI 95% 5-47) in those who had no response. In patients with blood count recovery, those with poor graft function in one or two lineages had a better 5-year overall survival (93.8%, 95% CI: 82-99) than those with trilineage failure (53%, 95% CI: 34-88). New strategies including cytokine or agonist support, or a second transplant need to be investigated in patients whose blood counts do not recover.

PB1990 THE CHANGE OF BONE MARROW MICROENVIRONMENT OF SECONDARY POOR GRAFT FUNCTION AFTER ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION AND ITS EFFECT ON PROGNOSIS

Background:Secondary poor graft functionis a serious life‐threatening complication after allogeneic hematopoietic stem cell transplantation, which pathogenesis, evolution and prognosis are still unclear.Aims:To explore the role of adhesion related indicators in secondary poor graft functionafter allogeneic hematopoietic stem cell transplantationMethods:In this study, clinical data and post‐transplantation status of 106 patients with hematological tumour who were enrolled in our center and underwent allo‐HSCT from Jan. 1, 2016 to Jan. 31, 2017 was counted.The patients were divided into good graft function (GGF) group and secondary poor graft function (sPGF) group according to the implantation status after transplantation. The differences of age, primary disease, stem cell source, HLA matching, sex matching, ABO blood group matching, degree of bone marrow hyperplasia before transplantation, recurrence rate and mortality between the two groups were compared.29 patients with sPGF after transplantation were selected as the experimental group while 29 patients with GGF were selected as the control group.Results:The changes of adhesion related indicators in the two groups were detected.There were no significant differences in age, primary disease, stem cell origin, HLA matching, sex matching, ABO blood group matching and the degree of bone marrow proliferation before transplantation between the two groups (P &gt; 0.05). The infection rate of CMV in sPGF group was significantly higher than that in GGF group, and the remission rate before transplantation in sPGF group was significantly lower than that in GGF group (P &lt; 0.05).Cox regression analysis showed that the survival rate of patients with sPGF after allo‐HSCT was significantly lower than that of patients without sPGF (P &lt; 0.05, HR = 3.598).The expression of CD44, CD29, ICAM‐1 and VCAM‐1 in sPGF group was not significantly different from that in control group (P &gt; 0.05), but the expression of CD105 was higher than that in control group, and the expression of Cx43 was lower than that in control group (P &lt; 0.05).Summary/Conclusion:We believe that the survival rate of patients with sPGF after allo‐HSCT will decrease significantly, and the occurrence of sPGF after transplantation may be related to the increase of CD105 expression and the decrease of Cx43 expression in bone marrow stromal cells before transplantation.

Virus reactivation and low dose of CD34+ cell, rather than haploidentical transplantation, were associated with secondary poor graft function within the first 100days after allogeneic stem cell transplantation.

Secondary poor graft function (sPGF) is defined as secondary cytopenia after initial engraftment of allogeneic stem cell transplantation (allo-SCT). It has been shown to be associated with poor prognosis; however, there are very few reports on the incidence, risk factors, and outcomes of sPGF. Between January 2015 and December 2015, 564 patients, who received transplantation at Peking University People's Hospital, were retrospectively reviewed. Among the 490 patients who achieved initial engraftment of both neutrophils and platelets, 28 patients developed sPGF. The cumulative incidence of sPGF on day 100 was 5.7%. The median time of sPGF was 54.5 (34-91) days after transplantation. Low (< median) CD34+ cell dose (p = 0.019, HR 3.07 (95% CI, 1.207-7.813)), Epstein-Barr Virus (EBV) reactivation (p = 0.009, HR 3.648 (95%CI, 1.382-9.629)), and cytomegalovirus (CMV) reactivation (p = 0.003, HR 7.827 (95%CI, 2.002-30.602)) were identified as independent risk factors for sPGF. There was no significant difference in PGF incidence between the matched sibling donor (MSD) group and haploidentical donor (HID) group (p = 0.44). The overall survival of patients with sPGF at 1year after transplantation was significantly poorer than that of patients with good graft function (GGF) (50.5% versus 87.2%, p < 0.001). In conclusion, sPGF developed in 5.7% patients after allo-SCT, especially in patients with CMV, EBV reactivation, or infusion with a low dose of CD34+ cells. The prognosis of sPGF is still poor owing to a lack of standard treatment.

High Cure Rate By Allogeneic Stem Cell Transplantation for Myelofibrosis Patients Aged 65 or Older

IntroductionMyelofibrosis (MF) is predominantly a disease of the elderly with a median age of 65 years at diagnosis. Allogeneic stem cell transplantation (ASCT), which is associated with substantial treatment-related morbidity and mortality, is the only potentially curative option so far. The development of reduced intensity conditioning (RIC) regimens has enabled transplant to be performed successfully in older patients. To evaluate the outcome of transplantation among elderly patients, we conducted a retrospective analysis of results in 46 patients, aged 65 years or older, who were transplanted between 2002 and 2018 at the University Medical Center Hamburg-Eppendorf (UKE), Hamburg, Germany.Patients and methodsRetrospective data from 46 patients with primary or secondary MF, who underwent ASCT, were collected. Median age at ASCT was 67 years (r: 65-74). 76% of patients were classified as MF-3 according to the WHO criteria. DIPSS risk status was intermediate-1 in 4% of patients, intermediate-2 in 61% and high in 33%. 70% of patients had mutation in JAK2, 17% in CALR and 9% in MPL. All patients received peripheral blood stem cell (PBSC) as graft source. Stem cell donor was related in 9% of patients, unrelated in 91%; 74% of patients had a completely HLA-matched donor, whereas 26% had at least 1 allele or antigen mismatch. 85% of patients received busulfan 10 mg/kg orally (or 8 mg/kg intravenously) plus fludarabine (150 mg/m2) reduced intensity conditioning regimen, whereas 15% received myeloablative conditioning with busulfan 16 mg/kg orally (or 12.8 mg/kg intravenously) plus fludarabine (150 mg/m2). 96% of the patients received anti-T-lymphocyte globulin (Grafalon®, Neovii, Germany) at a cumulative dose of 30 mg/kg for matched related donor (MRD) transplants and 60 mg/kg for matched/mismatched unrelated donor (MUD/MMUD) transplants. Further GVHD prophylaxis consisted of cyclosporine A and mycophenolate from day +1 to +28.ResultsEngraftment rate was 94%, with a median time to neutrophil engraftment of 13 days (r: 10-19). Two patients (4%) experienced primary graft failure (PGF), one received a second ASCT with successful engraftment, while the other had further PGF after second ASCT and died of infection after third ASCT. Platelet engraftment rate was 87% and was reached in a median time of 21 days (r: 10-293). Five patients (11%) developed secondary poor graft function and four received CD34+ selected PBSC boost, two achieving complete remission (CR) and one obtaining CR with incomplete platelet recovery (CRp).52% of patients experienced acute GVHD grade I to IV, while the overall rate of chronic GVHD was 56%, which was moderate disease in 24% and severe disease in 13%.After a median follow-up of 4 years, 6-year estimated progression-free survival (PFS) and overall survival (OS) were 60% (95% CI: 42-78) and 64% (95% CI: 48-80), respectively. In the univariate analysis, male donor sex was the only significant factor for improved OS and PFS at 6 years (P=.001 and P=.003, respectively). A positive impact on OS was observed for mutation in CALR (P=.05), as previously reported. Interestingly, survival was not significantly different in patients aged 65-70 years compared with those aged 71-74 years.Cumulative incidence of non-relapse mortality (NRM) was 29% at 4 years (95% CI: 13-45). Major causes of death were infections (n=4) and GVHD (n=3). The only significant factor for lower NRM in the univariate analysis was male donor sex vs female (NRM 17% vs 58%, P=.004). No NRM occurred in CALR-mutated patients (p=0.00).Cumulative incidence of relapse at 6 years was 10% (95% CI: 0-22): one patient durably restored molecular response after early tapering of cyclosporine, one died because of GVHD without any further treatment, one achieved a long-lasting CR after donor lymphocytes infusions (DLI), while two patients underwent a second ASCT after DLI alone in one case and DLI plus azacitidine in the other, with long-term CR in the former.ConclusionOur results show that RIC regimen followed by allogeneic stem cell transplantation in older patients with myelofibrosis is a curative treatment option. These results are encouraging for older MF patients with minimal comorbidities. In addition to Hematopoietic cell transplantation-specific comorbidity index (HCT-CI), a comprehensive geriatric assessment could be a useful tool for a better selection of patients with the aim to further reduce NRM. DisclosuresNo relevant conflicts of interest to declare.

The Use of CD34+-Selected Stem Cell Boosts Following HLA-Haploidentical Hematopoietic Cell Transplantation

Background:Poor graft function (PGF) is an uncommon but significant complication of hematopoietic cell transplantation (HCT). There is growing interest in treatment with positively selected CD34+grafts as "stem cell boosts" (SCB). No data are, to our knowledge, available concerning the use of SCBs in the HLA-haploidentical setting.Methods:We retrospectively identified all patients undergoing SCB after peripheral blood haplo-HCT with post-transplant cyclophosphamide at our institution between June 2009 and January 2016. CD34+ cell selection was carried out on the CliniMACS instrument (Miltenyi Biotec, Auburn, CA). PGF was defined as ≥95% donor chimerism, and at least two of the following three cytopenias for at least 2 consecutive weeks without alternative explanation: ANC < 1500 cells/mm3, platelets < 30,000/mm3 and Hgb < 8.5 g/dL. PGF was classified as primary if it occurred immediately following day +14. Otherwise, it was considered secondary. Patients with 5-95% donor chimerism and ANC > 500 cells/mm3 who otherwise met the criteria for PGF were classified as PGF with mixed chimerism. Hematologic improvement (HI) was defined as having no cytopenias. Hematological response (HR) was defined as ANC > 2500 cells/mm3, platelets >100,000/mm3, and Hgb >10 g/dL. Both HI and HR required transfusion independence for the previous 30 days. Acute and chronic graft-versus-host disease (GVHD) were graded based on established criteria. Overall survival (OS) was defined as time from SCB until death or last clinical contact.Results:Nineteen of 141 patients (13%) undergoing haplo-HCT received SCB. Clinical characteristics are summarized in Table 1. SCB was given at a median of 120 days (range: 21 - 455) after haplo-HCT. Median time from SCB to death or last clinical contact was 158 days (range: 3 - 564). Nine donors underwent remobilization; 10 patients used cryopreserved product. The median SCB contained 2.52 x 106 CD34+ cells/kg (range: 0.33 - 10.92). SCBs from remobilized donors contained significantly more CD34+ cells/kg (median: 4.06) than those from original mobilization (median: 1.50) (p<0.01). Median TNC dose was 0.03 x 108 cells/kg (range: 0.01 - 0.73). All CD3+ cell doses were < 0.01 x 107cells/kg.At time of SCB, 63% (12/19) patients were cytopenic in at least two cell lines and 26% (5/19) were cytopenic in all three cell lines. Six patients had one cytopenia and one had no cytopenias, but was chronically transfusion dependent. The majority (74%) of patients had hypocellular bone marrows per pathology report. Patients with secondary PGF were less likely to have multiple cytopenias than the remaining cohort (36% versus 100%, p=0.01). No patients received conditioning prior to SCB. Eighteen patients were receiving immunosuppression, including steroids (79%), calcineurin inhibitors (63%) and mycophenolate mofetil (32%).At day +90 after SCB, 66% of surviving patients were in HI or HR.. ANC was significantly higher at day +90 (p=0.02). Hgb and platelets were significantly higher at all time points (p<0.05). No association between HR or HI and SCB CD34+ cell dose was observed. Median OS was 158 days. Median survival in patients with multiple cytopenias at SCB was 84 days, while it was not reached for those with ≤1 cytopenias. At day +90, 80% of patients with secondary PGF were alive, compared to 50% with primary PGF and 0% with PGF and mixed chimerism. In patients surviving to day +90, survival was significantly better at last follow-up among patients achieving HR or HI (88% vs. 0%, p=0.01). One patient developed new stage 2 aGVHD of the gut following SCB. Three patients developed mild-to-moderate cGVHD at 88, 128 and 130 days after SCB.Conclusion:Our results suggest that SCB after haplo-HCT is safe and associated with acceptable rates of acute and chronic GVHD. It may also be effective in reducing transfusions and inducing HI and HR. The treatment of these patients continues to be a challenge. Further studies are needed to delineate the factors influencing outcomes in this population, including timing of therapy and optimal CD34+ cell dose. [Display omitted] [Display omitted] DisclosuresDiPersio:Incyte Corporation: Research Funding. Vij:Celgene: Consultancy; Karyopharm: Honoraria; Novartis: Honoraria; Janssen: Honoraria; Takeda: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria. Fehniger:Celgene: Research Funding; Affimed: Consultancy; Fortress Biotech: Consultancy. Schroeder:Incyte Corporation: Honoraria, Research Funding.

Improvement in Poor Graft Function after Allogeneic Hematopoietic Stem Cell Transplantation upon Administration of Mesenchymal Stem Cells from Third-Party Donors: A Pilot Prospective Study

Poor graft function (PGF) is a refractory complication that occurs after allogeneic hematopoietic stem cell transplantation (allo-HSCT). In the present study, we prospectively evaluated the efficacy and safety of mesenchymal stem cells (MSCs) expanded from the bone marrow of a third-party donor to patients with PGF after allo-HSCT. Twenty patients with PGF (7 with primary and 13 with secondary PGF) received MSCs (1 × 10(6)/kg) one to three times at 28-day intervals. Seventeen patients were responsive to MSCs, whereas three were not. Within the first 100 days after MSC treatment, 13 patients developed 20 episodes of infection. Moreover, five patients experienced cytomegalovirus-DNA viremia, and seven experienced Epstein-Barr virus (EBV)-DNA viremia within the first 100 days after MSC treatment; three of the latter developed EBV-associated posttransplant lymphoproliferative disorders (PTLD) within the follow-up period. Grade II acute graft-versus-host disease (GVHD) occurred in one patient, and local chronic GVHD occurred in two patients after receiving MSC treatment, including one acute GVHD and one chronic GVHD, respectively, after accepting donor lymphocyte infusions due to PTLD. After a follow-up period of an average of 508 days (range 166-904 days) posttransplantation, 11 patients died. No short-term toxic side effects were observed after MSC treatment. Two patients experienced leukemic relapse. With the exception of three patients with PTLD, no secondary tumors occurred. These results indicate that MSCs derived from the bone marrow of a third-party donor are beneficial in the treatment of both primary and secondary PGF that develops after allo-HSCT. However, additional studies will be needed to determine whether such treatment might increase the risk of EBV infection and reactivation or the development of EBV-associated PTLD.

Analysis of risk factors for secondary cytopenia after allogeneic hematopoietic stem cell transplantation

To investigate the incidence and risk factors for secondary cytopenia after allogeneic hematopoietic stem cell transplantation (allo-HSCT). The clinical data of a total of 260 patients received allo-HSCT between Jan 1, 2006 to Jan 1, 2008 were retrospectively analyzed for the incidence and risk factors of secondary cytopenia. According to the hematopoietic reconstitution after transplantation, the patients were divided into (1) secondary neutropenia group; (2) secondary thrombocytopenia group and (3)secondary poor graft function group. During the 100 days after allo-HSCT, the secondary neutropenia (38.8% vs 18.0%, P=0.0005) or secondary thrombocytopenia (25% vs 12%, P=0.01) occurred in haploidentical HSCT (haplo-HSCT) patients were more often than that in HLA-matched group. Poor graft function showed no significant difference between the above two groups (5.6% vs 2.0%, P=0.21). Multivariate analyses revealed that cytomegalovirus (CMV) infection significantly increased the risk of secondary neutropenia. GVHD and CMV infection were independent risk factors for secondary thrombocytopenia. Meanwhile, CMV infection was an independent risk factor for secondary poor graft function. Secondary cytopenia remains a serious complication following allo-HSCT, especially in haplo-HSCT. Higher occurrence of GVHD and CMV infection may lead to higher incidence of secondary cytopenia in haplo-HSCT.

Efficacy of donor's purified CD34(+) cells for treatment of poor graft function following allogeneic hematopoietic stem cell transplantation

This study was aimed to evaluate the efficacy and safety of donor's purified CD34(+) cells for treatment of secondary poor graft function (PGF) following allogeneic hematopoietic stem cell transplantation (allo-HSCT) . Ten patients suffering from secondary PGF after allo-HSCT in our hospital from January 2009 to December 2011 were treated with the donor's purified and G-CSF mobilized CD34(+) cells. All the patients were observed for infusion-related complication and survival status. CliniMACS system was used to separate cells, the results of sorting purified and recovery rate were calculated and statistically analysed. The results showed that the purified of CD34(+) cells reached to (89.31 ± 1.73)%, and the recovery rate reached to (93.27 ± 8.14)%; 10 patients in the process of infusion did not suffer from seriously adverse complications, all of them obtained hematopoietic recovery, neither GVHD nor infection occurred after infusion of donor's purified CD34(+) cells. It is concluded that using CliniMACS system for donor's peripheral CD34(+) separation, both the purified and recovery of CD34(+) cells are satisfied, and the infusion of donor's purified CD34(+) cell is a safe and effective method to treat secondary PGF after allo-HSCT.