Abstract

A marrow reaction associated with acute-graft-versus-host disease (a-GVHD) has been demonstrated in experimental models; its existence in human transplantation is controversial. The present study aimed to investigate whether clonogenic marrow precursors would be an early marker for a-GVHD and transplant-related mortality (TRM). We prospectively studied 133 patients for colony-forming unit-granulocyte monocyte (CFU-GM) at day +18/+19 post-transplantation. CFU-GM frequency below the 25(th) percentile predicted for acute GVHD score I°-IV° when evaluated in multivariate logistic regression analysis (OR 13.551, CI 1.583-116.031; p=0.01). In the group showing a clonogenic frequency below the 25(th) percentile, the cumulative incidence of GVHD grade II°-IV° was significantly more frequent in respect to the group showing a frequency over the 25(th) percentile, 86% versus 54% (Gray test: p=0.02). In multivariate Cox proportional analysis, a CFU-GM frequency below the 25(th) percentile at day +18, was associated with a reduced overall survival (OS), (HR 1.778, CI 1.022-3.093; p?=?0.04). Patients showing a frequency of CFU-GM <25° percentile had increased TRM in respect to patients showing a clonogenic cell frequency > 25° percentile, (33.5% versus 13.0%, p= 0.01). Patients were divided based on median content of viable CD34+ cells and measurement of viable CD34+ cells was predictive for OS (p=0.005) and TRM (p=0.003). A weak correlation was found between CFU-GM frequency in marrow at day +18 and plasmatic levels of IL2 rec in plasma (r= -0.226, p=0.03). We conclude that marrow progenitor cell counts, on day +18, maybe a useful marker for identifying patients at risk for severe a-GVHD, TRM and inferior Survival.

Abstract

With the exception of high-dose methotrexate (HD-MTX), there is currently no defined standard treatment for newly diagnosed primary central nervous system lymphoma (PCNSL). This review focused on first-line induction and consolidation treatment of PCNSL and aimed to determine the optimal combination of HD-MTX and the long-term beneficial consolidation methods. A comprehensive literature search of MEDLINE identified 1407 studies, among which 31 studies met the inclusion criteria. The meta-analysis was performed by using Stata SE version 15. Forest plots were generated to report combined outcomes like the complete response rate (CRR), overall survival, and progression-free survival. We also conducted univariate regression analyses of the baseline characteristics to identify the source of heterogeneity. Pooled analysis showed a CRR of 41% across all HD-MTX-based regimens, and three- and four-drug regimens had better CRRs than HD-MTX monotherapy. In all combinations based on HD-MTX, the HD-MTX?+?procarbazine?+?vincristine (MPV) regimen showed pooled CRRs of 63% and 58% with and without rituximab, respectively, followed by the rituximab?+?HD-MTX?+?temozolomide regimen, which showed a pooled CRR of 60%. Pooled PFS and OS showed that post-remission consolidation with autologous stem cell transplantation (ASCT) was associated with the best survival outcome, with a pooled 2-year OS of 80%, a 2-year PFS of 74%, a 5-year OS of 77%, and a 5-year PFS of 63%. Next, whole-brain radiation therapy (WBRT)?+?chemotherapy showed a pooled 2-year OS of 72%, 2-year PFS of 56%, 5-year OS of 55%, and 5-year PFS of 41%, with no detectable CR heterogeneity throughout the entire treatment process. In HD-MTX-based therapy of newly diagnosed PCNSL, MPV with or without rituximab can be chosen as the inductive regimen, and the rituximab?+?HD-MTX?+?temozolomide regimen is also a practical choice. Based on our study, high-dose chemotherapy supported by ASCT is an efficacious approach for consolidation. Consolidation with WBRT?+?chemotherapy can be another feasible approach.

Abstract

BACKGROUND Pleraxifor for peripheral blood stem cell (PBSC) mobilization in children with malignancies is often given following failure of standard mobilization (SM) rather than as a primary mobilizing agent. STUDY DESIGN AND METHODS In this retrospective multicenter study, we report the safety of plerixafor-based PBSC mobilization in children with malignancies and compare outcomes between patients who received plerixafor upfront with SM (Group A) with those who received plerixafor following failure of SM (Group B). In the latter pleraxifor was given either following a low peripheral blood (PB) CD34 (<20 cells/cu.mm) (Group B1) or as a second collection process due to an unsuccessful yield (CD34?+? RESULTS The study cohort (n = 47) with a median age of 8 (range 0.6-21) year, comprised 19 (40%) Group A and 28 (60%) Group B patients (B1 = 12 and B2 = 16). Pleraxifor mobilization was successful in 87.2% of patients, similar between Groups A and B (84.2% vs 89.2%) and resulted in a median 4-fold increase in PB CD34. Median number of apheresis attempts was 2 in Groups A and B1 but 4 in Group B2. In Group B2, median total CD34+ yield post-plerixafor was 9-fold higher than after SM (P = .0013). Mild to moderate transient adverse events affected 8.5% of patients. Among patients who proceeded to autologous transplant (n = 39), all but one engrafted. CONCLUSION Plerixafor-based PBSC collection was safe and effective in our cohort and supports consideration as a primary mobilizing agent in children with malignancies.

Abstract

Adverse reactions may still occur in some patients after receiving haematopoietic stem cell transplantation (HSCT), even when choosing a human leukocyte antigen (HLA)-matched donor. The adverse reactions of transplantation include disease relapse, graft-versus-host disease (GVHD), mortality and CMV infection. However, only the relapse was discussed in our previous study. Therefore, in this study, we investigated the correlation between the gene polymorphisms within the HLA region and the adverse reactions of post-HSCT in patients with acute leukaemia (n?=?176), where 72 patients were diagnosed with acute lymphocytic leukaemia (ALL) and 104 were acute myeloid leukaemia (AML). The candidate single nucleotide polymorphisms were divided into three models: donor, recipient, and donor-recipient pairs and the data of ALL and AML were analysed individually. Based on the results, we found 16 SNPs associated with the survival rates, the risk of CMV infection, or the grade of GVHD in either donor, recipient, or donor-recipient matching models. In the ALL group, the rs209132 of TRIM27 in the donor group was related to CMV infection (p?=?0.021), the rs213210 of RING1 in the recipient group was associated with serious GVHD (p?=?0.003), and the rs2227956 of HSPA1L in the recipient group correlated with CMV infection (p?=?0.001). In the AML group, the rs3130048 of BAG6 in the donor-recipient pairs group was associated with serious GVHD (p?=?0.048). Moreover, these SNPs were further associated with the duration time of survival after transplantation. These results could be applied to select the best donor in HSCT.

Abstract

Clofarabine is active in refractory/relapsed acute myeloid leukemia (AML). In this phase 2 study, we treated 18- to 65-year-old AML patients refractory to first-line 3 + 7 daunorubicin/cytarabine induction or relapsing after 3 + 7 induction and high-dose cytarabine consolidation, with clofarabine (30 mg/m(2) /d, Days 1-5), cytarabine (750 mg/m(2) /d, Days 1-5), and mitoxantrone (12 mg/m(2) /d, Days 3-5) (CLAM). Patients achieving remission received up to two consolidation cycles of 50% CLAM, with eligible cases bridged to allogeneic hematopoietic stem cell transplantation (allo-HSCT). The mutational profile of a 69-gene panel was evaluated. Twenty-six men and 26 women at a median age of 46 (22-65) years were treated. The overall response rate after the first cycle of CLAM was 90.4% (complete remission, CR: 69.2%; CR with incomplete hematologic recovery, CRi: 21.2%). Twenty-two CR/CRi patients underwent allo-HSCT. The 2-year overall survival (OS), relapse-free survival (RFS), and event-free survival (EFS) were 65.8%, 45.7%, and 40.2%, respectively. Multivariate analyses showed that superior OS was associated with CR after CLAM (P = .005) and allo-HSCT (P = .005), and superior RFS and EFS were associated with allo-HSCT (P < .001). Remarkably, CR after CLAM and allo-HSCT resulted in 2-year OS of 84.3% and 90%, respectively. Karyotypic aberrations and genetic mutations did not influence responses or survivals. Grade 3/4 neutropenia/thrombocytopenia and grade 3 febrile neutropenia occurred in all cases. Other nonhematologic toxicities were mild and uncommon. There was no treatment-related mortality and the performance of allo-HSCT was not compromised. Clofarabine, cytarabine, and mitoxantrone was highly effective and safe in refractory/relapsed AML. This study was registered at ClinicalTrials.gov (NCT02686593).

Abstract

Emergence of clones carrying point mutations in the BCR-ABL1 kinase domain (KD) is a common mechanism of resistance to tyrosine kinase inhibitor (TKI)-based therapies in Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). Sanger sequencing (SS) is the most frequently used method for diagnostic BCR-ABL1 KD mutation screening, but it has some limitations-it is poorly sensitive and cannot robustly identify compound mutations. Next-generation sequencing (NGS) may overcome these problems. NSG is increasingly available and has the potential to become the method of choice for diagnostic BCR-ABL1 KD mutation screening. A group discussion within an ad hoc constituted Panel of Experts has produced a series of consensus-based statements on the potential value of NGS testing before and during first-line TKI-based treatment, in relapsed/refractory cases, before and after allo-stem cell transplantation, and on how NGS results may impact on therapeutic decisions. A set of minimal technical and methodological requirements for the analysis and the reporting of results has also been defined. The proposals herein reported may be used to guide the practical use of NGS for BCR-ABL1 KD mutation testing in Ph+ ALL.

Abstract

BACKGROUND Cross-matched platelet (cross-matched PLT) transfusion is effective for immune-mediated platelet transfusion refractoriness (PTR), but is more costly and time-consuming for physical cross-match than using standard PLT units. Recent studies have reported the utility of human leucocyte antigens (HLA) virtual cross-matched PLT (HLA-matched PLT) that is defined as HLA-A/B matched or no antibody against donor-specific antigen. Here, we evaluated the effect of HLA-matched PLTs for PTR in post hematopoietic stem cell transplant (HSCT) recipients. STUDY DESIGN AND METHODS Our study included a total of 241 PLTs in 16 patients who underwent HSCT at Okayama University Hospital between 2010 and 2017, receiving either HLA-matched or cross-matched PLTs. We calculated the 24-hour corrected count increments (CCI-24) to evaluate the effect of PLTs. A CCI-24 ≥ 4500 was considered to be a successful transfusion. RESULTS We analyzed 139 cross-matched PLTs and 102 HLA-matched PLTs. In the immune-mediated PTR, the rate of successful transfusion was 60.5% for cross-matched PLT and 63.4% for HLA-matched PLT (p = 0.825). On the other hand, the median CCI-24 for cross-matched PLT transfusions and HLA-matched PLT transfusions were 1856 and 5824 (p < 0.001), with a success rate of 28.1 and 54.1% in cases with non-immune-mediated PTR, respectively (p = 0.001). CONCLUSION The effectiveness of HLA-matched PLT is not inferior to cross-matched PLT. This result indicates that physical cross-match can be omitted in post HSCT PTR.

Abstract

BACKGROUND AND OBJECTIVES D-negative patients are at risk of developing an alloantibody to D (anti-D) if exposed to D during transfusion. The presence of anti-D can lead to haemolytic transfusion reactions and haemolytic disease of the newborn. Anti-D alloimmunization can also complicate allogeneic haematopoietic stem cell transplantation (HSCT) with haemolysis and increased transfusion requirements. The goal of this study was to determine whether cancer centres have transfusion practices intended to prevent anti-D alloimmunization with special attention in patients considered for HSCT. METHODS AND MATERIALS To understand transfusion practices regarding D-positive platelets in D-negative patients with large transfusion needs, we surveyed the 28 cancer centres that are members of the National Comprehensive Cancer Network((R)) (NCCN((R)) ). RESULTS Nineteen centres responded (68%). Most centres (79%) avoid transfusing D-positive platelets to RhD-negative patients when possible. Four centres (21%) avoid D-positive platelets only in D-negative women of childbearing age. If a D-negative patient receives a D-positive platelet transfusion, 53% of centres would consider treating with Rh immune globulin (RhIg) to prevent alloimmunization in women of childbearing age. Only one centre also gives RhIg to all D-negative patients who are HSCT candidates including adult men and women of no childbearing age. CONCLUSION There is wide variation in platelet transfusion practices for supporting D-negative patients. The majority of centres do not have D-positive platelet transfusion policies focused on preventing anti-D alloimmunization specifically in patients undergoing HSCT. Multicentre, longitudinal studies are needed to understand the clinical implications of anti-D alloimmunization in HSCT patients.

Abstract

Graft-versus-host disease (GVHD) is one of the major causes of morbidity and mortality in 25-70% of patients. The gold standard (GS) test to confirm the diagnosis of GVHD has some limitations. The current study was conducted to evaluate the accuracy of three serum markers in diagnosing GVHD without a GS. 94 patients who were hospitalized for allogeneic transplantation were studied. Mean levels from day of haematopoietic stem cell transplantation (HSCT) to discharge of serum uric acid (UA), lactate dehydrogenase (LDH), and creatinine (Cr) were measured for all participants. We adapted a Bayesian latent class analysis to modelling the results of each marker and combination of markers. The Sensitivity, Specificity, and area under receiver operating characteristic curve (AUC) for LDH were as 51%, 81%, and 0.70, respectively. For UA, the Sensitivity, Specificity, and AUC were 54%, 75%, and 0.71, respectively. The estimated Sensitivity, Specificity, and AUC of Cr were 72%, 94%, and 0.86, respectively. Adjusting for covariates, the combined Sensitivity, Specificity, and AUC of the optimal marker combination were 76%, 83%, and 0.94, respectively. To conclude, our findings suggested that Cr had the strongest diagnosis power for GVHD. Moreover, the classification accuracy of the three-marker combination outperforms the other combinations.

Abstract

In addition to T cells, NK cells can also participate in the outcome of hematopoietic stem cell transplantation (HSCT) mainly through the interaction between donor killer cell immunoglobulin-like receptors (KIRs) and recipient human leukocyte antigen (HLA) class I molecules. There is a risk of GVHD other than leukemia relapse after allogeneic HSCT that activation of donor NK cells in the absence of appropriate inhibitory ligands will be one of the reasons. To investigate the impact of donor KIRs and recipient KIR/HLA class I combinations on GVHD and leukemia relapse in patients with acute leukemia after HSCT, 100 patients with acute leukemia who received HSCT from their HLA-matched siblings were included in this study. Genotypes of 16 KIR genes and two 2DS4 variants (full length and deleted alleles), along with HLA-A/B genotypes, were determined by PCR-SSP. HLA-C genotyping was done with the SSO-Luminex method. Chimerism analysis was done using 16 short tandem repeats (STRs) to detect early leukemia relapse. Acute (a)GVHD occurred in 38 patients, and 16 of them died during the study. None of the recipients showed any sign of leukemia relapse after HSCT. Full donor chimerism was observed in all tested patients during the first year after HSCT. Our results also indicated an increased risk of aGVHD in AA recipients with the C2/Cx, Bw4(+) (or A-Bw4(+)) or HLA-A3(-)/A11(-) genotypes who received HSCT from Bx donors. Our results showed that donor selection based on donor-recipient KIR genotypes and recipient HLA class I status can improve the outcome of HSCT.