Prognostic factors in haploidentical transplantation with post-transplant cyclophosphamide for acute myeloid leukemia.

BACKGROUND AIMS: Haploidentical hematopoietic stem cell transplantation (haplo-HCT) is an appropriate option when an HLA-matched related or unrelated donor is not available. Haplo-HCT using post-transplant cyclophosphamide (PTCy) is being increasingly performed worldwide due to its effective suppression of GVHD and its safety. METHODS: We conducted a large nationwide cohort study to retrospectively analyze 366 patients with acute myeloid leukemia undergoing haplo-HCT with PTCy between 2010 and 2019 and to identify prognostic factors. RESULTS: A multivariate Cox analysis revealed that an older recipient age (≥60 years), a male donor to a male recipient, a cytomegalovirus IgG-negative donor to a cytomegalovirus IgG-positive recipient, a poor cytogenetic risk, a noncomplete remission status at the time of transplantation, and a history of HCT were independently associated with worse overall survival (OS). Based on each hazard ratio, these factors were scored (1-2 points) and stratified by their total score into three groups: favorable (0-1 points), intermediate (2-3 points), and poor (4 points or more) groups, and 2-year OS rates were 79.9%, 49.2%, and 25.1%, respectively (P < 0.001). CONCLUSIONS: The present study revealed significant prognostic factors in haplo-HCT with PTCy, and a scoring system based on these factors may be used to predict outcomes.

Real-world clinical characteristics of post-essential thrombocythemia and post-polycythemia vera myelofibrosis.

There are few prospective studies on patients with post-essential thrombocythemia myelofibrosis (PET-MF) and post-polycythemia vera myelofibrosis (PPV-MF). Therefore, we conducted a nationwide longitudinal prospective survey to clarify the clinical characteristics of these diseases. A total of 197 PET-MF and 117 PPV-MF patients diagnosed between 2012 and 2021 were analyzed. The median age at diagnosis was 70.0 years for both diseases. The time from diagnosis of ET or PV to that of MF was 9.6 and 10.4 years, respectively, with no significant difference. Patients with PPV-MF had higher hemoglobin levels and white blood cell counts than those with PET-MF, whereas those with PET-MF had higher platelet counts than those with PPV-MF. Although splenomegaly was more frequent in patients with PPV-MF at diagnosis, there was no difference in the frequency of constitutional symptoms. Ruxolitinib was the most common treatment administered to 74.6% and 83.8% of patients with PET-MF and PPV-MF, respectively. Patients with PET-MF and PPV-MF had similar prognoses, with 3-year overall survival (OS) of 0.742 in PET-MF and 0.768 in PPV-MF patients. In both diseases, leukemic transformation was the leading cause of death, followed by infection. The 3-year OS for patients with PET/PPV-MF and primary MF diagnosed during the same period was 0.754 and 0.626, respectively, with no significant difference. This survey provides real-world clinical features and prognostic data on secondary myelofibrosis in the ruxolitinib era.

Changing trends in the risk factors for second primary malignancies after autologous stem cell transplantation for multiple myeloma before and after the introduction of proteasome inhibitors and immunomodulatory drugs.

The incidence of second primary malignancies (SPM) in long-term survivors of multiple myeloma (MM) is increasing because of increased life expectancy. We retrospectively analyzed the risk factors for SPM in patients with MM after autologous stem cell transplantation (ASCT) before and after the introduction of proteasome inhibitors and immunomodulatory drugs (IMiDs). In total, 2,340 patients newly diagnosed with MM who underwent ASCT between 1995 and 2016 were enrolled in this study. Forty-three patients developed SPM (29 solid, 12 hematological, and 2 unknown tumors), with cumulative incidence rates of 0.8% and 2.5% at 24 and 60 months, respectively. The cumulative incidence rates of hematological and solid SPM at 60 months were 0.8% and 1.8%, respectively. The overall survival (OS) rate at 60 months after ASCT was 62.9% and the OS rates after the diagnosis of SPM at 24 months were 72.2% for hematological SPM and 70.9% for solid SPM. Multivariate analysis revealed that the use of IMiDs (P=0.024) and radiation (P=0.002) were significant independent risk factors for SPM. The probabilities of developing SPM and death due to other causes (mainly MM) at 60 months were 2.5% and 36.5%, respectively, indicating that the risk of SPM was lower than that of death from MM. Furthermore, SPM between the pre-novel and novel agent eras (ASCT between 2007 and 2016) groups significantly increased (1.9% vs. 4.3% at 60 months; P=0.022). The early occurrence of SPM after ASCT should be monitored cautiously.

Adverse impact of delay of platelet recovery after autologous hematopoietic cell transplantation for aggressive non-Hodgkin lymphoma and multiple myeloma.

BACKGROUND AIMS: The prognostic impact of platelet recovery after autologous hematopoietic cell transplantation (AHCT) on clinical outcomes remains to be elucidated. We aimed to clarify the impact of platelet recovery on clinical outcomes, risk factors of delayed platelet recovery and the necessary dose of CD34+ cells for prompt platelet recovery in each patient. METHODS: Using a nationwide Japanese registry database, we retrospectively analyzed clinical outcomes of 5222 patients with aggressive non-Hodgkin lymphoma (NHL) or multiple myeloma (MM). RESULTS: At a landmark of 28 days after AHCT, a delay of platelet recovery was observed in 1102 patients (21.1%). Prompt platelet recovery was significantly associated with superior overall survival (hazard ratio [HR] 0.32, P < 0.001), progression-free survival (HR 0.48, P < 0.001) and decreased risks of disease progression (HR 0.66, P < 0.001) and non-relapse/non-progression mortality (HR 0.19, P < 0.001). The adverse impacts of a delay of platelet recovery seemed to be more apparent in NHL. In addition to the dose of CD34+ cells/kg, disease status, performance status and the hematopoietic cell transplant-specific comorbidity index in both diseases were associated with platelet recovery. We then stratified the patients into three risk groups according to these factors. For the purpose of achieving 70% platelet recovery by 28 days in NHL, the low-, intermediate- and high-risk groups needed more than 2.0, 3.0 and 4.0 × 106 CD34+ cells/kg, respectively. In MM, the low-risk group needed approximately 1.5 × 106 CD34+ cells/kg, whereas the intermediate- and high-risk groups required 2.0 and 2.5 × 106 CD34+ cells/kg to achieve about 80% platelet recovery by 28 days. CONCLUSIONS: A delay of platelet recovery after AHCT was associated with inferior survival outcomes.

Fludarabine plus reduced-intensity busulfan versus fludarabine plus myeloablative busulfan in patients with non-Hodgkin lymphoma undergoing allogeneic hematopoietic cell transplantation.

Allogeneic hematopoietic cell transplantation (HCT) offers a possible cure for patients with relapsed and refractory non-Hodgkin lymphoma (NHL) through potentially beneficial graft versus lymphoma effects. However, allogeneic HCT is associated with high nonrelapse mortality (NRM). Fludarabine with reduced-intensity busulfan (Flu/Bu2) and myeloablative busulfan (Flu/Bu4) are commonly used in conditioning regimens for allogeneic HCT; however, data on their use in patients with NHL is limited. We investigated the effect of busulfan dose on outcomes by comparing Flu/Bu2 and Flu/Bu4 in patients with NHL who underwent allogeneic HCT. Our study included 415 adult patients with NHL who received Flu/Bu2 (315 patients) or Flu/Bu4 (100 patients) between January 2008 and December 2019. All patients were enrolled in the Transplant Registry Unified Management Program 2 of the Japanese Data Center for Hematopoietic Cell Transplantation. The primary endpoint was the 5-year overall survival (OS). To minimize potential confounding factors that may influence outcomes, we performed propensity score matching. The 5-year OS was 50.6% (95% confidence interval (CI), 39.4%-60.8%) and 32.2% (95% CI, 22.4-42.4%) in the Flu/Bu2 and Flu/Bu4 groups, respectively (p = 0.006). The hazard ratio comparing the two groups was 2.13 (95% CI, 1.30-3.50; p = 0.003). Both groups had a similar 5-year cumulative incidence of relapse (38.2% vs 41.3%; p = 0.581), and the Flu/Bu4 group had a higher cumulative incidence of 5-year NRM (15.7% vs 31.9%; p = 0.043). In this study, Flu/Bu4 was associated with worse OS compared with Flu/Bu2 because of high NRM in patients with NHL.

Efficacy and safety of allogeneic hematopoietic cell transplantation in acute myeloid leukemia patients aged > 65 years with unfavorable cytogenetics.

Unrelated donor bone marrow transplantation (UR-BMT), unrelated donor cord blood stem cell transplantation (UR-CBT), and haploidentical peripheral blood stem cell transplantation (Haplo-PBSCT) are the main alternative stem cell sources for allogeneic hematopoietic cell transplantation (HCT) in Japan. The present study aimed to identify factors associated with the outcomes of UR-BMT, UR-CBT, and Haplo-PBSCT in older patients with acute myeloid leukemia (AML) and intermediate- or poor-risk cytogenetics to improve the clinical efficacy and safety of allogeneic HCT. We retrospectively analyzed data for 448 AML patients aged > 65 years who received UR-BMT (n = 102), UR-CBT (n = 250), or Haplo-PBSCT (n = 96) between 2014 and 2020. Overall survival (OS) in the UR-BMT group was superior (P = 0.033) to that in the other groups. However, all patients without complete remission (non-CR) who had Karnofsky performance status (KPS) < 80 at HCT and poor-risk cytogenetics died within 1 year after HCT. Multivariate Cox regression analysis identified KPS <80 at HCT and poor-risk cytogenetics as independent predictors of worse OS in non-CR patients. KPS < 80 may be an alternative indicator for non-CR AML patients with poor-risk cytogenetics during the selection of HCT, alternative treatments, or best supportive therapy, and the optimal KPS is important for the success of HCT.

Tandem autologous stem cell transplantation in elderly patients with myeloma: A multicenter retrospective analysis.

Tandem autologous stem cell transplantation (ASCT) has been reconsidered for high-risk patients with myeloma, and the eligibility criteria for up-front ASCT have been updated to include more elderly patients. This study aimed to evaluate the efficacy and tolerability of tandem ASCT in elderly patients with myeloma compared to tandem ASCT in young patients and single ASCT in elderly patients. A retrospective study using the Transplant Registry Unified Management Program database of the Japanese Society for Transplantation and Cellular Therapy, which included 64 elderly and 613 young patients who received tandem ASCT, and 891 elderly patients who received single ASCT, was conducted. The median overall survival (OS) over 38.5 months in the elderly and young patients who received tandem ASCT, and elderly patients who received single ASCT was 78.9, 92.5, and 77.1 months, respectively; no significant difference in the median OS was observed. The cumulative incidence of transplantation-related mortality was similar in the elderly and young patients receiving tandem ASCT. High-risk cytogenetic abnormality was not identified as a poor prognostic factor for OS in elderly patients who received tandem ASCT but in those who received single ASCT. Thus, tandem ASCT was effective and tolerable in elderly patients with myeloma.

Advantages of peripheral blood stem cells from unrelated donors versus bone marrow transplants in outcomes of adult acute myeloid leukemia patients.

BACKGROUND AIMS: In allogeneic stem cell transplantation, unrelated donors are chosen in cases where appropriate related donors are not available. Peripheral blood stem cells (PBSCs) are more often selected as a graft source than bone marrow (BM). However, the prognostic benefits of PBSCs versus BM transplants from unrelated donors have not been carefully examined in patients with acute myeloid leukemia (AML). This study compared outcomes of adult AML patients who underwent unrelated PBSC and BM transplantation, evaluating post-transplant complications, including engraftment, graft-versus-host disease (GVHD) and infections, and determined subgroups of patients who are most likely to benefit from unrelated PBSCs compared with BM transplants. METHODS: The authors analyzed 2962 adult AML patients who underwent unrelated PBSC or BM transplants between 2011 and 2018 (221 PBSC and 2741 BM) using the Japanese nationwide registry database, in which graft source selection is not skewed toward PBSCs. RESULTS: In 49.7% of patients, disease status at transplantation was first complete remission (CR1). In 57.1% of cases, HLA-matched donors were selected. Myeloablative conditioning was performed in 75.1% of cases, and anti-thymocyte globulin (ATG) was added to conditioning in 10.5%. Multivariate analyses showed a trend toward favorable non-relapse mortality (NRM) in PBSC recipients compared with BM recipients (hazard ratio [HR], 0.731, P = 0.096), whereas overall survival (OS) (HR, 0.959, P = 0.230) and disease-free survival (DFS) (HR, 0.868, P = 0.221) were comparable between PBSC and BM recipients. Although the rate of chronic GVHD (cGVHD) was significantly higher in PBSC patients (HR, 1.367, P = 0.016), NRM was not increased, mainly as a result of significantly reduced risk of bacterial infections (HR, 0.618, P = 0.010), reflecting more prompt engraftments in PBSC recipients. Subgroup analyses revealed that PBSC transplantation was advantageous in patients transplanted at CR1 and in those without ATG use. PBSC recipients experienced significantly better OS and/or DFS compared with BM recipients in this patient group. CONCLUSIONS: The authors' results confirmed the overall safety of unrelated PBSC transplantation for adult AML patients and suggested an advantage of PBSCs, especially for those in CR1. Further optimization of the prophylactic strategy for cGVHD is required to improve the overall outcome in transplantation from unrelated PBSC donors.

Donor lymphocyte infusion after haploidentical hematopoietic stem cell transplantation for acute myeloid leukemia.

Although haploidentical donor lymphocyte infusion (DLI) is a valid treatment option for relapsed acute myeloid leukemia (AML), the incidence and risk factors for graft-versus-host disease (GVHD) and the efficacy of haploidentical DLI have not been fully evaluated. We retrospectively analyzed the outcomes after haploidentical DLI for 84 patients with AML using a nationwide database and additional questionnaires. The median number of DLI cycles and infused CD3+ cell dose was 1 and 1.0 × 106/kg, respectively. The infused CD3+ cell count of 5.0 × 105/kg or higher was associated with acute GVHD (grade II-IV, 32.1% vs. 10.5%, p = 0.03; grade III-IV, 21.4% vs. 5.3%, p = 0.10). Patients who developed grade III-IV acute GVHD more frequently succumbed to treatment-related mortality (46.7% vs. 15.8% at 1 year, p = 0.002), although the relapse-related mortality was significantly low (40.0% vs. 72.2% at 1 year, p = 0.025). The overall response to DLI was significantly higher in the preemptive DLI group (47.4%) than in the therapeutic group (13.9%, p = 0.002). In the multivariate analysis, preemptive DLI was the predictive factor for overall response (odds ratio, 5.58; p = 0.003). Our results indicated the substantial risk of acute GVHD after haploidentical DLI with CD3+ cell count of 5.0×105/kg or higher and the favorable outcomes after preemptive DLI.

Donor UNC-93 Homolog B1 genetic polymorphism predicts survival outcomes after unrelated bone marrow transplantation.

UNC-93 homolog B1 (UNC93B1) is a key regulator of toll-like receptors (TLRs), pattern recognition receptors that sense invading pathogens and manage the innate immune response and deliver them from the endoplasmic reticulum to their respective endosomal signaling compartments. Several types of TLRs are known to contribute to the inflammatory process after allogeneic hematopoietic stem cell transplantation (SCT), so UNC93B1 might play integral roles there. We investigated the influence of the UNC93B1 single-nucleotide polymorphism (SNP) rs308328 (T>C) on transplant outcomes in a cohort of 237 patients undergoing unrelated HLA-matched bone marrow transplantation (BMT) for hematologic malignancies through the Japan Marrow Donor Program. The donor UNC93B1 C/C genotype was associated with a better 3-year overall survival than the donor UNC93B1 C/T or T/T genotype. An analysis of the UNC93B1 rs308328 genotype may therefore be useful for selecting the donor, estimating the prognosis, and creating therapeutic strategies after allogeneic SCT.

Improved survival of multiple myeloma patients treated with autologous transplantation in the modern era of new medicine.

New drugs for multiple myeloma (MM) have dramatically improved patients' overall survival (OS). Autologous stem cell transplantation (ASCT) remains the mainstay for transplant-eligible MM patients. To investigate whether the post-ASCT prognosis of MM patients has been improved by new drugs, we undertook a retrospective observational analysis using the Transplant Registry Unified Management Program database in Japan. We analyzed 7323 patients (4135 men and 3188 women; median age, 59 years; range 16-77 years) who underwent upfront ASCT between January 2007 and December 2018. We categorized them by when they underwent ASCT according to the drugs' introduction in Japan: group 1 (2007-2010), group 2 (2011-2016), and group 3 (2017-2018). We compared the groups' post-ASCT OS. The 2-year OS rates (95% confidence interval [CI]) of groups 1, 2, and 3 were 85.8% (84.1%-87.4%), 89.1% (88.0%-90.1%), and 92.3% (90.0%-94.2%) (P < .0001) and the 5-year OS (95% CI) rates were 64.9% (62.4%-67.3%), 71.6% (69.7%-73.3%), and not applicable, respectively (P < .0001). A multivariate analysis showed that the post-ASCT OS was superior with these factors: age less than 65 years, performance status 0/1, low International Staging System (ISS) stage, receiving SCT for 180 days or less post-diagnosis, better treatment response pre-ASCT, later year of ASCT, and receiving SCT twice. A subgroup analysis showed poor prognoses for the patients with unfavorable karyotype and poor treatment response post-ASCT. The post-ASCT OS has thus improved over time (group 1 < 2 < 3) with the introduction of new drugs for MM. As the prognosis of high-risk-karyotype patients with ISS stage III remains poor, their treatment requires improvement.

The differential effect of disease status at allogeneic hematopoietic cell transplantation on outcomes in acute myeloid and lymphoblastic leukemia.

This study aimed to compare the effect of disease status at the time of allogeneic hematopoietic cell transplantation (HCT) on post-transplant outcomes between acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). Japanese nationwide registry data for 6901 patients with AML and 2469 patients with ALL were analyzed. In this study, 2850 (41%), 937 (14%), 62 (1%), and 3052 (44%) AML patients and 1751 (71%), 265 (11%), 23 (1%), and 430 (17%) ALL patients underwent transplantation in first complete remission (CR1), second CR (CR2), third or subsequent CR (CR3 +), and non-CR, respectively. The probabilities of overall survival at 5 years for patients transplanted in CR1, CR2, CR3 + , and non-CR were 58%, 61%, 41%, and 26% for AML patients and 67%, 45%, 20%, and 21% for ALL patients, respectively. Multivariate analyses revealed that the risks of relapse and overall mortality were similar for AML patients transplanted in CR1 and CR2 (P = 0.672 and P = 0.703), whereas they were higher for ALL patients transplanted in CR2 than for those transplanted in CR1 (P < 0.001 for both). The risks of relapse and overall mortality for those transplanted in CR3 + and non-CR increased in a stepwise manner for both diseases, with the relevance being stronger for ALL than for AML patients. These results suggest a significant difference in the effect of disease status at HCT on post-transplant outcomes in AML and ALL. Further investigation to incorporate measurable residual disease data is warranted.

Pretreatment Immature Platelet Fraction as a Surrogate of Reticulated Platelets Predicts the Response to Corticosteroids in Adults with Immune Thrombocytopenia.

OBJECTIVES: Reticulated platelets circulating in the blood reflect megakaryopoietic activity and platelet turnover and can be automatically and low-invasively measured as the immature platelet fraction (IPF) using a Sysmex XN hematocytometer. The present study retrospectively investigated whether or not the IPF can predict the treatment response to corticosteroids in adult patients with primary immune thrombocytopenia (ITP). METHODS: Forty-six patients who had been newly diagnosed with primary treatment-naïve ITP and started treatment with corticosteroids were analyzed. RESULTS: Among the 46 primary ITP patients, 33 (72%) responded to the treatment and 13 (28%) did not. The percentage of IPF (IPF%) among the nonresponders was significantly lower than that of the responders (6.6 vs. 16.0%; p < 0.001). In the receiver operating characteristics analysis, the optimum IPF% cut-off value for predicting the treatment response was 12%, with a specificity of 85% and a sensitivity of 76%. CONCLUSIONS: Our findings thus suggest that measuring the IPF% as a surrogate of reticulated platelets is useful to identify patients likely to respond to corticosteroids.

Biallelic loss of FAM46C triggers tumor growth with concomitant activation of Akt signaling in multiple myeloma cells.

Loss of heterozygosity or mutation of the family with sequence similarity 46, member C (FAM46C) gene on chromosome band 1p12 is associated with shorter overall survival of patients with multiple myeloma (MM). In this study, using human MM cell lines (KMS-11, OCI-My5, and ANBL-6), we generated FAM46C-/- cell clones and examined the effect of disruption of FAM46C on cell survival and cellular signaling. Cell proliferation assays showed increased clonogenicity of FAM46C-/- KMS-11 cells compared to WT cells. Xenograft experiments showed significantly shorter overall survival of mice harboring the FAM46C-/- cell-derived tumors than mice with the FAM46CWT cell-derived tumors. Notably, levels of phosphorylated Akt and its substrates increased both in vitro and in vivo in the FAM46C-/- cells compared to WT cells. In addition, caspase activities decreased in the FAM46C-/- cells. Results of gene set enrichment analysis showed that loss of FAM46C significantly activated serum-responsive genes while inactivating phosphatase and tensin homolog (PTEN)-related genes. Mechanistically, loss of FAM46C decreased the PTEN activity, number of apoptotic cells, and caspase activities. PF-04691502, a selective PI3K inhibitor, suppressed the augmented phosphorylation of Akt and its substrate FoxO3a. Treatment with afuresertib (a specific Akt inhibitor) in combination with bortezomib additively decreased FAM46C-/- MM cell survival. Collectively, this study is the first to report that loss of FAM46C triggers the concomitant activation of the PI3K-Akt signaling pathway, which might be a therapeutic target for MM with abnormalities in the FAM46C gene.

Conditioning Intensity for Allogeneic Hematopoietic Cell Transplantation in Acute Myeloid Leukemia Patients with Poor-Prognosis Cytogenetics in First Complete Remission.

The optimal intensity of conditioning regimen may be dependent on not only age and comorbidities but also disease characteristics and risk of relapse after allogeneic hematopoietic cell transplantation (HCT). We, therefore, analyzed the transplant outcomes of 840 adult patients with cytogenetically poor-risk acute myeloid leukemia (AML) in first complete remission (CR1) who received first allogeneic HCT with either myeloablative conditioning (MAC; n = 652) or reduced-intensity conditioning (RIC; n = 188) between 2006 and 2017. The median age at HCT was 50.5 years (range: 16 to 77 years). The multivariate analysis showed that patients receiving MAC had a significantly higher overall survival and lower leukemia-related mortality than those receiving RIC (P = .011 and P = .025, respectively). In the subgroup analysis, these results applied to patients aged 16 to 59 years, with HCT-comorbidity index scores ≥3, and with cytogenetic remission. Among MAC regimens, there was a trend for worse survival and nonrelapse mortality with the busulfan/fludarabine-based regimen compared with the total body irradiation (TBI) ≥8 Gy-based regimen (P = .082 and P = .062, respectively), whereas the busulfan/cyclophosphamide-based regimen and the fludarabine/melphalan-based regimen had similar outcomes with the TBI-based regimen. These data suggest that MAC is preferable to RIC for patients with cytogenetically poor-risk AML undergoing allogeneic HCT in CR1.

[Emergence of Howell-Jolly bodies in a patient with splenic hypoplasia complicated by fulminant pneumococcal infection].

We report the case of a patient with fulminant pneumococcal infection along with the presence of Howell-Jolly bodies (HJBs) and splenic hypoplasia at the onset. A 71-year-old man developed fever during outpatient chemotherapy for IgG-κ multiple myeloma and was diagnosed with septic shock due to invasive pneumococcal infection. HJBs were observed on peripheral blood smears at this visit. Computed tomography revealed marked hypoplasia of spleen, suggesting the presence of hyposplenic function. Antibacterial therapy was initiated and the pneumococcal infection was cured; however, there was no notable change in his splenic hypoplasia. Splenic hypoplasia can be associated with fatal infections; hence, care should be taken when it is found in the elderly and in patients with cancer and those receiving immunosuppressive treatment. Even today, when automated hematology analyzers have become common, not all patients with hematological diseases have peripheral blood smears checked with a normal optical microscope. This study suggests that HJBs may be useful for simple and rapid screening of splenic hypofunction. The importance of detecting HJBs in peripheral blood smears with a normal optical microscope should be re-recognized.

Upfront allogeneic hematopoietic cell transplantation (HCT) versus remission induction chemotherapy followed by allogeneic HCT for acute myeloid leukemia with multilineage dysplasia: A propensity score matched analysis.

The efficacy of induction chemotherapy before allogeneic hematopoietic cell transplantation (HCT) for patients with acute myeloid leukemia with multilineage dysplasia (AML-MLD) is unclear. Some patients with AML-MLD have received upfront HCT without prior induction chemotherapy. To compare the transplant outcomes between patients who received upfront HCT and those who received induction chemotherapy followed by allogeneic HCT for AML-MLD, we retrospectively analyzed the Japanese registration data of 1445 adult patients who had received allogeneic HCT between 2007 and 2016. Propensity score matching identified 269 patients in each cohort. There were no significant differences in overall survival between the two groups. The cumulative incidence of leukemia-related mortality was significantly lower in patients who received upfront HCT than those who received induction chemotherapy before HCT. In the subgroup analyses, upfront HCT had a significantly reduced incidence of leukemia-related mortality among patients aged between 60 and 70 years, those with a lower white blood cell count at diagnosis (<3000/µL), and poor cytogenetic risk, and those who received myeloablative conditioning and cord blood transplantation. Our results suggested that induction chemotherapy before HCT did not have any benefits of survival after HCT for AML-MLD. Upfront HCT contributed to the reduced incidence of leukemia-related mortality after HCT. Upfront HCT should be considered for patients with AML-MLD who are eligible for allogeneic HCT.

Allogeneic hematopoietic cell transplantation in adult acute myeloid leukemia with 11q23 abnormality: a retrospective study of the Adult Acute Myeloid Leukemia Working Group of the Japan Society for Hematopoietic Cell Transplantation (JSHCT).

An 11q23 abnormality presents in approximately 5% of adults with acute myeloid leukemia (AML) and is associated with adverse outcomes even after allogeneic hematopoietic cell transplantation (allo-HCT). To evaluate the outcomes and prognostic factors following allo-HCT for adult AML with 11q23 abnormality, we retrospectively analyzed the Japanese registration data of 322 adult AML patients with 11q23 abnormality who had received allo-HCT between 1990 and 2014. In total, the disease status at HCT was first complete remission (CR1) in 159 (49%) patients. The probability of overall survival and the cumulative incidence of relapse at 3 years were 44 and 44%, respectively. In the multivariate analysis, disease status beyond CR1 at the time of HCT was significantly associated with a higher overall mortality and relapse. The 11q23 fusion partner did not have a significant impact on survival. We also evaluated the prognostic value of minimal residual disease (MRD) status at HCT on transplant outcomes among hematological CR patients. MRD status at HCT was the significant prognostic indicator for hematological relapse and survival. These data suggested that allo-HCT offered a curative option for adult AML with 11q23 abnormality. Pretransplant MRD status was the significant prognostic indicator for relapse and survival in CR patients.

Comparison of Autologous and Unrelated Transplants for Cytogenetically Normal Acute Myelogenous Leukemia.

Allogeneic stem cell transplantation (SCT) from an HLA-matched sibling donor (MSD) is a postremission treatment that offers a potential cure for adults with cytogenetically normal (CN) acute myelogenous leukemia (AML) in first complete remission (CR1). The best alternative in the absence of an MSD remains unclear, however. The aim of this study was to retrospectively compare the outcomes of autologous peripheral blood stem cell transplantation (auto-PBSCT; n = 177) and allogeneic bone marrow transplantation (BMT) from an HLA-matched unrelated donor (MUD; n = 173) in adult patients with CN-AML/CR1. Both the multivariate analysis (hazard ratio [HR], 1.18; 95% confidence interval [CI], 0.71 to 1.97; P = .53) and propensity score models (HR, 1.40; 95% CI, 0.80 to 2.43; P = .24) indicated that the leukemia-free survival (LFS) rate of auto-PBSCT was not significantly different from that of MUD-BMT. These results suggest that in the absence of an available MSD, auto-PBSCT remains a viable alternative as postremission therapy in patients with CN-AML/CR1.

Importance of glutamine metabolism in leukemia cells by energy production through TCA cycle and by redox homeostasis.

Some cancer cells depend on glutamine despite of pronounced glycolysis. We examined the glutamine metabolism in leukemia cells, and found that HL-60 cells most depended on glutamine in the 4 acute myelogenous leukemia (AML) cell lines examined: growth of HL-60 cells was most suppressed by glutamine deprivation and by inhibition of glutaminolysis, which was rescued by tricarboxylic acid (TCA) cycle intermediate, oxaloacetic acid. Glutamine is also involved in antioxidant defense function by increasing glutathione. Glutamine deprivation suppressed the glutathione content and elevated reactive oxygen species most evidently in HL-60 cells. Glutamine metabolism might be a therapeutic target in some leukemia.