Non-malignant Disease Group Research Articles

Umbilical Cord Blood Transplantation after Graft Failure from a Previous Hematopoietic Stem Cell Transplantation

Graft failure (GF) is a life-threatening complication after allogeneic hematopoietic stem cell transplantation (HCT). In the absence of autologous recovery, a second HCT is necessary to attempt to prevent death due to prolonged pancytopenia. Previous studies describing outcomes of second HCT performed after GF with different types of donor sources report wide ranges of overall survival (OS) and transplantation-related mortality (TRM); however, studies including a large number of patients undergoing a second HCT with umbilical cord blood (UCB) as the graft source are scarce. This retrospective registry-based study examined data extracted from Eurocord and the European Society for Blood and Marrow Transplantation (EBMT) databases to evaluate outcomes of 247 UCBTs performed in EBMT transplant centers after GF following a previous HCT. Data were analyzed separately for patients with malignant diseases (n=141) and those with nonmalignant diseases (n=106). The most frequent HCT that resulted in GF was also UCBT (65.0% for patients with malignant diseases and 68.9% for those with nonmalignant diseases), and most GFs occurred within 100 days after transplantation (92.3% and 85.9%, respectively). The median follow-up was 47 months for surviving patients with malignant diseases and 38 months for those with nonmalignant diseases. We observed a similar cumulative incidence of neutrophil engraftment of 59.1% (95% confidence interval [CI], 51.4% to 67.9%) and 60.4% (95% CI, 51.7%-70.6%), respectively, at a median time of 23 days and 24 days, correspondingly. The 3-year OS was 28.9% (95% CI, 21.8% to 37.3%) in the malignant disease group and 49.1% (95% CI, 39.5%-58.8%) in the nonmalignant disease group. In patients with malignancies, TRM was 39.9% (95% CI, 32.5% to 49.1%) at 100 days and 57.5% (95% CI, 49.4%-66.8%) at 3 years. In multivariate analyses, none of the characteristics studied was statistically significantly associated with engraftment or OS. Although survival is not optimal in patients requiring a second HCT, UCBT remains a valid life-saving option for patients with GF.

Eltrombopag for thrombocytopenia in 24 children after hematopoietic stem cell transplantation

Objective: To evaluate the efficacy and safety of eltrombopag for children with thrombocytopenia after hematopoietic stem cell transplantation (HSCT). Methods: Clinical data of 24 patients with thrombocytopenia after HSCT,who were treated with eltrombopag in the Department of Pediatrics, Sun Yat-sen Memorial Hospital, Sun Yat-sen University from August 1, 2018 to April 1, 2019 were analyzed retrospectively. The response rate and adverse reactions of eltrombopag were evaluated. Patients were divided into groups by source of hematopoietic stem cells (umbilical cord blood group and peripheral stem cell group) and type of disease (malignant and non-malignant disease group) and the clinical outcomes between groups were compared. Rank Sum test was used for comparisons between groups. Results: Among 24 cases, 15 were males and 9 females, the age of starting eltrombopag was 7.7 (2.6-13.7) years, the time of eltrombopag treatment after HSCT was 27.5 (8.0-125.0) days, the time from treatment to complete response (CR) was 23.5 (6.0-83.0) days, with the treatment course 36.5 (8.0-90.0) days. The total dose of eltrombopag was 1 400(200-5 900) mg. Complete response rate was 92% (22/24),without eltrombopag related adverse reactions. Comparing with peripheral stem cell group (n=8), the course and total dose of eltrombopag in umbilical cord blood group (n=16) were significantly reduced(24.5 (8.0-81.0) vs. 65.5 (35.0-90.0) d, Z=-3.004, P=0.002; 900.0 (200.0-3 850.0) vs. 2 862.5 (1 175.0-5 900.0) mg, Z=-2.604, P=0.007), but no significant differences were found in the time from treatment to complete response, platelet count after 2 weeks of eltrombopag withdrawal or platelet count at the end point of follow-up (all P>0.05). Comparing malignant patients (n=12) and non-malignant patients (n=12), no significant differences were found in the time from treatment to complete response, course, total dose, platelet count after 2 weeks of eltrombopag withdrawal, and platelet count at the end point of follow-up in non-malignant patients (all P>0.05). Conclusion: Eltrombopag is safe and maybe effective for thrombocytopenia after HSCT, especially for umbilical cord blood transplantation.

Non-Infectious Pulmonary Toxicity after Allogeneic Hematopoietic Cell Transplantation (HCT): A Center for International Blood and Marrow Transplant Research (CIBMTR) Study

Introduction Early non-infectious pulmonary toxicity (NIPT) is a significant HCT complication and comprises diffuse alveolar hemorrhage (DAH), idiopathic pneumonia syndrome (IPS), and cryptogenic organizing pneumonia (COP) with an overall incidence ranging 1-10%. Treatment options are primarily immunosuppressive therapy and supportive care with limited efficacy. Mortality in IPS, for example, approaches 60-80% (PMID: 21531955). Therefore, to better identify potentially high-risk patients (pts) we performed a registry-based analysis of the incidence, risk factors, and outcomes of early NIPT after HCT. Methods This retrospective study included adult pts undergoing allogenic HCT for hematologic malignancies and non-malignant disorders as reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) (2008-2017). Data analyses were divided into four common disease categories (AML/ALL, CML/MDS/MPN, NHL/CLL/PCD, and non-malignant diseases) to minimize statistical interactions in the multivariate model. The primary outcome was the incidence of and risk factors for individual NIPT and a composite of the three NIPT (IPS, DAH, COP); the secondary outcome was overall survival (OS). Multivariable Cox proportional hazards regression models were developed to identify the risk factors for NIPT and OS. In addition to baseline pre-transplant covariates, post-transplant neutrophil recovery (>500/mcL x 3 consecutive days), platelet recovery (>20k/mcL x 3 consecutive days, without transfusion in 7 previous days) and grade 2-4 acute GVHD were included as time-dependent covariates in the multivariable models. Results Characteristics of 21,587 adult pts are shown in Table 1. Median age at HCT was 54 years, 59% were male, and 39% had KPS <90. Median follow-up was 49 months. Per the HCT-Comorbidity Index (HCT-CI), 15% and 24% of pts had a severe (FEV1 and/or DLCO≤65%, dyspnea at rest, requiring supplemental oxygen) and moderate (FEV1 and/or DLCO 66-80%, dyspnea on slight activity) pulmonary comorbidity, respectively. Pre-transplant, 3% of pts had a history of mechanical ventilation, 5% had a history of pulmonary fungal infection, and 40% reported a smoking history. Most pts had a matched sibling or unrelated donor (68%) and received peripheral blood graft (71%). Myeloablative conditioning was used in 49% pts, and 39% received total body irradiation (TBI). Table 2 shows the cumulative incidence of early NIPT amongst pts in the four disease categories. Multivariable analysis in the AML/ALL group identified TBI-based conditioning, grade 2-4 acute GVHD, HCT-CI score of 1-3, and prior autologous HCT were associated with increased risk of NIPT, while platelet recovery decreased the risk of NIPT. In the CML/MDS/MPN group, smoking history, grade 2-4 acute GVHD and HCT-CI scores of 2-5+ were associated with increased risk of NIPT, while non-TBI and non-myeloablative TBI conditioning and platelet recovery were associated with a lower risk. In the NHL/HD/CLL/PCD group, a higher risk of NIPT was seen with severe pulmonary comorbidity pre-HCT and chronic GVHD, while platelet recovery and non-TBI regimens were associated with a lower risk. In the non-malignant disease group, both neutrophil and platelet recovery were associated with a lower risk of NIPT. Furthermore, the multivariable analysis for OS (Table 2) showed across all disease groups, NIPT increased the risk of mortality (vs. no NIPT; HR of 4.3 in AML/ALL, 4.1 in CML/MDS/MPN, 3.5 in NHL/CLL/PCD, 6.8 in non-malignant diseases; p<0.0001). Conclusions This large registry-based analysis of allogeneic HCT pts highlights several risk factors for the development of early NIPT including smoking history, severe pulmonary comorbidity, myeloablative TBI conditioning, and acute and/or chronic GVHD. Identification of these risk factors can enhance appropriate selection of pts prior to HCT. We also found that post-transplant, platelet and neutrophil recovery was associated with a reduced risk of NIPT. Furthermore, early NIPT is associated with a several-fold higher mortality risk in the current era despite significant advances in supportive care. Future studies are needed to optimize risk factors such as conditioning regimen and graft source selection to reduce the risk of early NIPT. Disclosures Ustun: Kadmon: Honoraria. Hamilton:Syndax Pharmaceuticals: Consultancy, Honoraria. Majhail:Anthem, Inc.: Consultancy; Incyte: Honoraria; Nkarta Therapeutics: Honoraria; Mallinckrodt: Honoraria. Sorror:Jazz Pharmaceutical: Other: Honorarium for Advisory role. . Stadtmauer:Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Novartis, Onyx Pharmaceuticals, an Amgen subsidiary, Takeda Oncology: Consultancy. Pasquini:Bristol Myers Squibb: Consultancy; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Other; Novartis: Research Funding; Kite: Research Funding.

Clinical outcomes of unrelated cord blood transplantation in children with malignant and non-malignant diseases: Multicenter experience in China.

This multicenter retrospective study included 184 children with malignant and non-malignant diseases who underwent UCBT between January 1998 and August 2012. The malignant disease group included 101 children with ALL, AML, CML, JMML, and MDS, and the non-malignant disease group included 83 children with PID, β-thalassemia, IMD BMF, and HLH. The median duration to neutrophil and platelet engraftment was 16 and 35days in the malignant disease group vs 15 and 38days in the non-malignant disease group. The cumulative incidence of grade II-IV aGVHD and cGVHD was 25.6% and 13.5% in the malignant disease group vs 19.7% and 11.1% in the non-malignant disease group, respectively. The median duration and cumulative incidence of neutrophil and platelet engraftment, and the cumulative incidence of grade II-IV aGVHD and cGVHD were similar between the two groups. Of the 184 pediatric patients, 114 patients survived during a median follow-up period of 14months (range 4-138). The 5-year OS and DFS were not statistically different between the two groups (56.3% and 46.1% in malignant disease group vs 68.5% and 52.8% in non-malignant disease group). The above results indicate that UCB is a viable source for HSCT for children with malignant or non-malignant diseases, especially in urgent cases.

Leukocyte migration studies in gastric cancer detection: an approach toward improved specificity and sensitivity.

Peripheral blood leukocytes from patients with gastric cancer and various other malignant and nonmalignant diseases and peripheral blood leukocytes from apparently healthy volunteers were tested in the leukocyte migration inhibition test with the use of 4-5 different 3 M KCl extracts of gastric cancer tissue. An operational criterion for defining sensitization of patients' leukocytes was developed; i.e., evidence in an individual sample of leukocytes of either decreased or increased migration areas (migration index less than or equal to 0.79 and larger than or equal to 1.20, respectively) with 3 or more antigen extracts. With this as an indicator of sensitization, it was found that 91% of patients with gastric cancer (39/43), comparto 5% (5/94) and 3% (1/32) of patients with nonmalignant, nongastric diseases and normal controls, respectively, were reactive. Patients with various nongastric cancers were sensitized in 36% (49/135) of cases. Gastritis and gastric, as well as duodenal, ulcer did not influence the reactivity of patients' leukocytes, but considerable sensitization was found in patients with atrophic gastritis or intestinalization. When classified in the usual manner, i.e., by considering the reaction with individual tumor extracts, the specificity and the sensitivity of the test was markedly diminished: More false negative determinations were found in the group of gastric cancer patients, and the percentage of false positives in the group of nonmalignant diseases increased. The results gave evidence of tumor-associated antigens in gastric cancer patients, against which the host elicited a cellular immune response. The high incidence of positive reactivity of leukocytes from patients with gastric cancer, together with the considerable cross-reactivity of leukocytes from patients with nongastric cancer, pointed to the expression of antigens with organ-related and widespread specificities.