High-dose methotrexate (Hd-MTX) therapy has recently been applied to the treatment of adult acute lymphoblastic leukemia (ALL) based on pediatric protocols; however, its effectiveness for adult ALL ...has not yet been confirmed in a rigorous manner. We herein conducted a randomized phase III trial comparing Hd-MTX therapy with intermediate-dose (Id)-MTX therapy. This study was registered at UMIN-CTR (ID: C000000063). Philadelphia chromosome (Ph)-negative ALL patients aged between 25 and 64 years of age were enrolled. Patients who achieved complete remission (CR) were randomly assigned to receive therapy containing Hd-MTX (3 g/m
) or Id-MTX (0.5 g/m
). A total of 360 patients were enrolled. The CR rate was 86%. A total of 115 and 114 patients were assigned to the Hd-MTX and Id-MTX groups, respectively. The estimated 5-year disease-free survival rate of the Hd-MTX group was 58%, which was significantly better than that of the Id-MTX group at 32% (P=0.0218). The frequencies of severe adverse events were not significantly different. We herein demonstrated the effectiveness and safety of Hd-MTX therapy for adult Ph-negative ALL. Our results provide a strong rationale for protocols containing Hd-MTX therapy being applied to the treatment of adult ALL.
To assess the impact of minimal residual disease (MRD) and tyrosine kinase inhibitor (TKI) administration on allogeneic hematopoietic cell transplantation (allo-HCT) for Ph-positive ALL (Ph+ALL), we ...retrospectively analyzed data from a registry database for 432 adult Ph+ALL patients in first CR (CR1) who received pre-transplant TKI administration. Negative MRD (MRD(-)) at allo-HCT was achieved in 277 patients. OS in patients transplanted in MRD(-) was significantly better than that in patients transplanted in MRD(+) (MRD(-): 67% vs MRD(+): 55% at 4 years; P=0.001). MRD(-) at allo-HCT was a significant risk factor for survival along with age at allo-HCT in multivariate analyses. Incidence of relapse in patients transplanted in MRD(-) was significantly lower than that in patients transplanted in MRD(+) (MRD(-): 19% vs MRD(+): 29% at 4 years; P=0.006). In multivariate analyses, MRD(+) at allo-HCT was a significant risk factor for relapse. A post-transplant TKI was administered to 103 patients. In subanalyses regarding the effect of post-transplant TKI administration, post-transplant TKI administration was a significant risk factor for relapse in multivariate analyses (P<0.0001). MRD status at allo-HCT is one of the most important predictive factors for Ph+ALL patients transplanted in CR1.
To differentiate between infectious and non-infectious diseases occurring in immunocompromised patients without acquired immunodeficiency syndrome (AIDS) using high-resolution computed tomography ...(HRCT).
HRCT images of 555 patients with chest complications were reviewed retrospectively. Infectious diseases (n=341) included bacterial pneumonia (n=123), fungal infection (n=80), septic emboli (n=11), tuberculosis (n=15), pneumocystis pneumonia (n=101), and cytomegalovirus pneumonia (n=11), while non-infectious diseases (n=214) included drug toxicity (n=84), infiltration of underlying diseases (n=83), idiopathic pneumonia syndrome (n=34), diffuse alveolar haemorrhage (n=8), and pulmonary oedema (n=5). Lung parenchymal abnormalities were compared between the two groups using the χ2 test and multiple logistic regression analysis.
The χ2 test results showed significant differences in many HRCT findings between the two groups. Multiple logistic regression analysis results indicated the presence of nodules with a halo and the absence of interlobular septal (ILS) thickening were the significant indicators that could differentiate infectious from non-infectious diseases. ILS thickening was generally less frequent among most infectious diseases and more frequent among most non-infectious diseases, with a good odds ratio (7.887, p<0.001). The sensitivity and accuracy for infectious diseases in the absence of ILS thickening were better (70% and 73%, respectively) than those of nodules with a halo (19% and 48%, respectively), while the specificity in the nodules with a halo was better (93%) than that of ILS thickening (78%).
The presence of nodules with a halo or the absence of ILS thickening tends to suggest infectious disease. Specifically, ILS thickening seems to be a more reliable indicator.
•HRCT findings of chest diseases in non-AIDS immunocompromised hosts were assessed.•Discrimination between infectious and noninfectious diseases in 555 cases was done.•Nodules with a halo and ILS thickening were the key indicators for differentiation.•ILS thickening seems to be a more reliable indicator for differentiation.
A high complete remission (CR) rate has been reported in newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) following imatinib-based therapy. However, the overall ...effect of imatinib on the outcomes of allogeneic hematopoietic stem cell transplantation (allo-HSCT) is undetermined. Between 2002 and 2005, 100 newly diagnosed adult patients with Ph+ALL were registered to a phase II study of imatinib-combined chemotherapy (Japan Adult Leukemia Study Group Ph+ALL202 study) and 97 patients achieved CR. We compared clinical outcomes of 51 patients who received allo-HSCT in their first CR (imatinib cohort) with those of 122 historical control patients in the pre-imatinib era (pre-imatinib cohort). The probability of overall survival at 3 years after allo-HSCT was 65% (95% confidence interval (CI), 49-78%) for the imatinib cohort and 44% (95% CI, 35-52%) for the pre-imatinib cohort. Multivariate analysis confirmed that this difference was statistically significant (adjusted hazard ratio, 0.44, P=0.005). Favorable outcomes of the imatinib cohort were also observed for disease-free survival (P=0.007) and relapse (P=0.002), but not for non-relapse mortality (P=0.265). Imatinib-based therapy is a potentially useful strategy for newly diagnosed patients with Ph+ALL, not only providing them more chance to receive allo-HSCT, but also improving the outcome of allo-HSCT.
Essentials
Acquired Glanzmann thrombasthenia (aGT) is generally caused by function‐blocking antibodies (Abs).
We demonstrated a unique aGT case due to marked reduction of αIIbβ3 with anti‐αIIbβ3 Abs.
...The anti‐αIIbβ3 Abs of the patient did not inhibit platelet function but reduced surface αIIbβ3.
Internalization of αIIbβ3 induced by the Abs binding may be responsible for the phenotype.
Summary
Background
Acquired Glanzmann thrombasthenia (aGT) is a bleeding disorder generally caused by function‐blocking anti‐αIIbβ3 autoantibodies.
Aim
We characterize an unusual case of aGT caused by marked reduction of surface αIIbβ3 with non‐function‐blocking anti‐αIIbβ3 antibodies (Abs).
Methods
A 72‐year‐old male suffering from immune thrombocytopenia since his 50s showed exacerbation of bleeding symptom despite mild thrombocytopenia. Platelet aggregation was absent with all agonists but ristocetin. Analysis of αIIbβ3 expression and genetic analysis were performed. We also analyzed effects of anti‐αIIbβ3 Abs of the patient on platelet function and αIIbβ3 expression.
Results
Surface αIIbβ3 expression was markedly reduced to around 5% of normal, whereas his platelets contained αIIbβ3 to the amount of 40–50% of normal. A substantial amount of fibrinogen was also detected in his platelets. There were no abnormalities in ITGA2B and ITGB3 cDNA. These results indicated that reduced surface αIIbβ3 expression caused a GT phenotype, and active internalization of αIIbβ3 was suggested. Anti‐αIIbβ3 IgG Abs were detected in platelet eluate and plasma. These Abs did not inhibit PAC‐1 binding, indicating that the Abs were non‐function‐blocking. Surface αIIbβ3 expression of a megakaryocytic cell line and cultured megakaryocytes tended to be impaired by incubation with the patient's Abs. After 2 years of aGT diagnosis, his bleeding symptom improved and surface αIIbβ3 expression was recovered to 20% of normal with reduction of anti‐αIIbβ3 Abs.
Conclusion
We demonstrated a unique aGT phenotype due to marked reduction of surface αIIbβ3. Internalization induced by anti‐αIIbβ3 Abs may be responsible in part for the phenotype.
Allogeneic hematopoietic cell transplant (HCT) is a curative procedure for myeloid malignant neoplasms, but relapse after HCT remains critical. A conditioning regimen involving granulocyte ...colony-stimulating factor-combined high-dose cytarabine, cyclophosphamide, and total body irradiation (G-CSF–combined high-dose cytarabine/cyclophosphamide/total-body irradiation HDCA/CY/TBI) was reported to improve outcomes after cord blood transplant (CBT) for myeloid malignant neoplasms, but this regimen was not previously evaluated among patients undergoing bone marrow transplant (BMT) or peripheral blood stem cell transplant (PBSCT).
We retrospectively analyzed 28 patients who underwent allogeneic HCT including BMT from a related (1 patient) or unrelated donor (9 patients), PBSCT from a related donor (7 patients), or single-unit CBT from an unrelated donor (11 patients) after a G-CSF–combined HDCA/CY/TBI regimen.
All patients achieved neutrophil and platelet engraftment, which were significantly more rapid in the BMT/PBSCT group than in the CBT group. Eighteen patients were alive at a median follow-up of 54.3 months. The 3-year relapse and nonrelapse mortality rates were 28.6% and 7.1%, respectively, which were similar between the BMT/PBSCT and CBT groups. Overall survival and disease-free survival at 5 years after HCT were 62.6% and 64.3%, respectively, which were also similar between the BMT/PBSCT and CBT groups. Only disease status at HCT had a significant impact on overall survival and disease-free survival (86.7% with standard risk vs 38.5% with high risk and 86.7% with standard risk vs 38.5% with high risk, respectively).
A G-CSF–combined HDCA/CY/TBI regimen is a promising conditioning in patients with myeloid malignant neoplasms who undergo not only CBT but also BMT or PBSCT.
•We assessed G-CSF-combined HDCA/CY/TBI conditioning in myeloid malignancies.•The conditioning regimen is promising in myeloid malignancies.•It provides favorable survival with low NRM after allogeneic HCT.•This conditioning regimen provides favorable outcomes regardless of donor sources.
CD5-positive (CD5+) diffuse large B-cell lymphoma (DLBCL) shows poor prognosis and frequent central nervous system (CNS) relapses under anthracycline-containing chemotherapy. The aim of this study ...was to determine the prognosis and CNS relapse incidence of CD5+ DLBCL in the rituximab era.
We analyzed 337 patients with CD5+ DLBCL who received chemotherapy with (R-chemotherapy group; n = 184) or without (chemotherapy group; n = 153) rituximab.
No significant difference was found in clinical background comparisons between the two groups. In the R-chemotherapy group, 60% of the patients were older than 65 years at diagnosis. Both the complete response rate and overall survival (OS) were significantly better in the R-chemotherapy group (P = 0.0003 and P = 0.002, respectively). Multivariate analysis confirmed that chemotherapy without rituximab was associated with unfavorable OS. However, the probability of CNS relapse did not differ between the two groups (P = 0.89). The CNS relapse was strongly associated with short OS (P < 0.0001). In the R-chemotherapy group, 83% of patients who experienced CNS relapse had parenchymal disease.
Our results indicate that rituximab improves the OS of patients with CD5+ DLBCL but does not decrease the CNS relapse rate. More effective treatments with CNS prophylaxis are needed for CD5+ DLBCL patients.
Idiopathic pneumonia syndrome (IPS) is an acute lung dysfunction of non-infectious aetiology and a severe complication following haematopoietic stem cell transplantation (HSCT). Recently, the ...American Thoracic Society (ATS) updated the concept of IPS and extended the concept to a wider range; it defined IPS as “an idiopathic syndrome of pneumopathy after HSCT, with evidence of widespread alveolar injury and in which infectious aetiologies and cardiac dysfunction, acute renal failure, or iatrogenic fluid overload have been excluded.” The ATS also categorised the presumed site of primary tissue injury into three patterns (pulmonary parenchyma, vascular endothelium, and airway epithelium), each of which has several entities. Since the therapeutic strategies for IPS are clearly different from those of infectious diseases, and therapeutic delay causes a poor prognosis, radiologists should be aware of some characteristic HRCT findings of IPS, which includes a wide spectrum of entities. In this article, the characteristic HRCT findings of these entities, including acute interstitial pneumonia/acute respiratory distress syndrome, eosinophilic pneumonia, non-cardiogenic capillary leak syndrome, diffuse alveolar haemorrhage, transfusion-related acute lung injury, organising pneumonia, and bronchiolitis obliterans syndrome, are shown.
The superiority of the pediatric protocol for adolescents with acute lymphoblastic leukemia (ALL) has already been demonstrated, however, its efficacy in young adults remains unclear. The ALL202-U ...protocol was conducted to examine the efficacy and feasibility of a pediatric protocol in adolescents and young adults (AYAs) with BCR-ABL-negative ALL. Patients aged 15-24 years (n=139) were treated with the same protocol used for pediatric B-ALL. The primary objective of this study was to assess the disease-free survival (DFS) rate and its secondary aims were to assess toxicity, the complete remission (CR) rate and the overall survival (OS) rate. The CR rate was 94%. The 5-year DFS and OS rates were 67% (95% confidence interval (CI) 58-75%) and 73% (95% CI 64-80%), respectively. Severe adverse events were observed at a frequency that was similar to or lower than that in children treated with the same protocol. Only insufficient maintenance therapy significantly worsened the DFS (hazard ratio 5.60, P<0.001). These results indicate that this protocol may be a feasible and highly effective treatment for AYA with BCR-ABL-negative ALL.
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