Investigation of biomarkers to predict outcomes in allogeneic hematopoietic stem cell transplantation.

BACKGROUND: Various biomarkers have been developed and evaluated to predict the prognosis and complications of allogeneic hematopoietic cell transplantation (HCT). Most previous studies conducted on different biomarkers evaluated single effects such as those associated with inflammation, immunology, iron metabolism, and nutrition, and only a few studies have comprehensively analyzed markers. OBJECTIVE: The study aimed to survey comprehensive multiple markers prior to HCT and extract those that significantly predict the outcomes. STUDY DESIGN: A prospective multicenter observational study was performed. (UMIN000013506) Patients undergoing HCT for hematologic diseases were consecutively enrolled. Besides the usual clinical biomarkers, serum samples for extra-clinical biomarkers were collected and cryopreserved before starting the conditioning regimen. A total of 32 candidate biomarkers were selected, 23 from hematology, biochemistry, immunology, nutrition, and iron metabolism, and 9 from composite markers. Based on the area under the curve (AUC) values for survival, promising biomarkers was extracted. Internal validation for these markers was applied based on bootstrap methods. Setting the cut-off values for them, log-rank test was applied and outcomes including overall survival (OS), relapse, and non-relapse mortality (NRM) were evaluated using multivariate analyses. Furthermore, detailed analysis including transplant-related complications and external validation were conducted focusing on C-reactive protein (CRP) to platelet (Plt) ratio. RESULTS: A total of 152 patients with hematologic malignancies were enrolled from April 2014 to March 2017. CRP, soluble interleukin-2 receptor (IL2R), CRP to albumin (Alb) ratio, CRP to Plt ratio, Plt to IL2R ratio, and IL2R to Alb ratio were identified as promising markers. Internal validation successfully confirmed their reliability of AUC and multivariate analysis demonstrated the statistical significance between the higher and the lower markers. Above all, a higher CRP to Plt ratio was significantly associated with a lower OS (hazard ratio [HR] 2.77; 95% confidence interval [CI] 1.30-5.91; P = 0.008) and higher non-relapse mortality rates (HR 2.79; 95%CI 1.14-6.80; P = 0.024) at 180 days. Furthermore, univariate analysis showed that a higher CRP to Plt ratio was significantly associated with a higher incidence of sinusoidal obstructive syndrome (P < 0.001) and bloodstream infection (P = 0.027). An external validation test confirmed the significance of the CRP to Plt ratio for these outcomes. CONCLUSION: The multicenter prospective observational study successfully identified significant biomarkers in patients with hematologic malignancies who received HCT. In particular, CRP to Plt ratio was identified as a novel and useful biomarker for predicting transplant outcomes. Further investigations are needed to validate the novel markers, analysis of the pathophysiology, and application to treatment settings other than HCT.

Pretransplantation Inflammatory and Nutritional Status in Elderly Allogeneic Hematopoietic Stem Cell Transplantation: Prognostic Value of C-Reactive Protein-to-Albumin Ratio.

There are no clear criteria for selecting elderly patients with hematologic malignancies eligible for allogeneic hematopoietic stem cell transplantation (HSCT). This study aimed to evaluate inflammatory and nutritional status biomarkers as prognostic indicators of allogeneic HSCT in elderly patients. We compared the prognostic effects of 4 representative pretransplantation biomarkers: C-reactive protein-to-albumin ratio (CAR), Glasgow Prognostic Score (GPS), prognostic nutritional index (PNI), and albumin-to-globulin ratio (AGR). A total of 143 patients age ≥60 years who underwent their first allogeneic HSCT for a hematologic malignancy were enrolled between 2010 and 2020 in our single-center cohort. The median patient age was 65 years (range, 60 to 72 years). Pretransplantation high CAR, high GPS, and low PNI scores were associated with poor overall survival (OS), but the AGR was not associated with OS. Among the 4 biomarkers, CAR stratified OS most significantly (P < .001). Multivariate analyses identified only high CAR as an independent prognostic factor associated with OS (hazard ratio [HR], 1.98; P = .031) and showed that a Hematopoietic Cell Transplantation-Specific Comorbidity Index (HCT-CI) score ≥3 also was associated with OS (HR, 2.04; P = .012). High CAR was correlated with poor performance status, male sex, and high Disease Risk Index, but not with high HCT-CI score. When the patients were stratified into 3 groups according to a composite risk assessment using CAR and HCT-CI, the 3-year OS decreased significantly with increasing scores (82.8%, 50.3%, and 27.0%, respectively; P < .0001). In conclusion, CAR is the most useful prognostic indicator among the inflammatory and nutritional status biomarkers for allogeneic HSCT in elderly patients. Inflammatory and nutritional status in the elderly may be important prognostic factors for allogeneic HSCT independent of HCT-CI score.

Prognostic significance of the CFA ratio for newly diagnosed acute myeloid leukemia: A multicenter retrospective study.

The CFA ratio, calculated using pretreatment C-reactive protein (CRP), fibrinogen, and albumin levels (CRP × fibrinogen/albumin), was previously reported to be a significant prognostic factor for acute myeloid leukemia (AML). This multicenter retrospective study evaluated the prognostic value of the CFA ratio in 328 adult patients with newly diagnosed AML from April 2000 to March 2018. The median age was 49.5 years (range, 15-75 years), and 60.7% of the population were males. According to the European LeukemiaNet (ELN) risk classification, 67 patients (20.4%) were in the favorable-risk group, 197 patients (60.1%) in the intermediate-risk group, and 58 patients (17.7%) in the adverse-risk group. The median CFA ratio was 1.07 (0-67.69). Based on the calculated cutoff CFA ratio of 1.44, the cohort included 176 and 152 patients with low and high CFA ratios, respectively. At a median follow-up of 91.2 months, the 7-year overall survival (OS) and disease-free survival (DFS) rates were 51.2% and 48.6%, respectively, in the overall cohort. The 7-year OS rates were 61.7% and 39.0% in the low and high CFA ratio groups, respectively (p < 0.001). The 7-year DFS rates were 58.1% and 37.0% in the low and high CFA ratio groups, respectively (p = 0.004). In univariate analysis, age ≥50 years, male sex, ELN risk class, and comorbidities were associated with poor OS. Age, ELN risk class, comorbidities, and high CFA ratio were associated with poor OS in multivariate analysis. Subgroup analysis revealed that the CFA ratio was significant in the intermediate and adverse ELN risk classes. These findings indicate the prognostic significance of the CFA ratio in AML.

Clinical significance of total nucleated cell count in bone marrow of patients with acute lymphoblastic leukemia who underwent allogeneic hematopoietic stem cell transplantation.

The clinical implications of recipient bone marrow nucleated cell count (NCC) prior to allogeneic hematopoietic stem cell transplantation (allo-HSCT) remain unknown. We conducted a multicenter retrospective study to evaluate the clinical significance of bone marrow NCC prior to allo-HSCT in patients with acute lymphoblastic leukemia. Patients who were in remission and underwent the initial allo-HSCT were included and stratified into high- and low-NCC groups using an NCC of 10 × 104/µL as the cut-off. The 3-year overall survival (OS), non-relapse mortality (NRM), and relapse rates for the high- and low-NCC groups were 51.2 vs. 84.5% (p < 0.001), 27.5 vs. 6.5% (p < 0.001), and 31.1 vs. 24.4% (p = 0.322), respectively. The high-NCC group had significantly poorer OS and higher NRM when compared with the low-NCC group. In summary, high recipient bone marrow NCC is associated with higher NRM and lower OS following allo-HSCT.

Treatment strategy at the decision for allogeneic transplantation in patients with myelodysplastic syndrome in the era of azacitidine: A KSGCT prospective study.

The optimal bridge strategy at the decision for allogeneic hematopoietic stem cell transplantation (HSCT) in patients with myelodysplastic syndrome (MDS) is unclear. We performed a prospective observational study in which 110 patients with MDS who were decided to undergo HSCT were enrolled. Among these 110 patients, 77 patients were enrolled in this study within 1 month from the decision for HSCT. Among these 77 patients, 13 patients had a human leukocyte antigen (HLA)-matched sibling, 54 patients started an unrelated donor search, and the other 10 patients directly selected cord blood (CB) at the decision for HSCT, and 13 (100%), 38 (70.4%), and 9 (90%) patients actually underwent HSCT within 1 year, respectively. The overall survival (OS) at 1 year from their enrollment was 70.9%, and the selection of azacitidine use at the decision for HSCT was not associated with OS. Among 60 of the 77 patients who actually underwent HSCT within a year from their enrollment, a lower relapse rate after HSCT was observed in those who selected CB at the decision to undergo HSCT. However, this preferable effect of CB selection disappeared when patients who were enrolled in this study in > 1 month from the decision for HSCT were additionally included in the analyses. In conclusion, the selection of bridge strategy at the decision for HSCT did not affect outcomes in patients with MDS. The immediate performance of HSCT may be associated with better outcomes.

Bridging to transplant and post-transplant maintenance therapy with FLT3 inhibitors in patients with relapsed or refractory FLT3 mutated acute myeloid leukemia.

OBJECTIVES AND METHODS: This single-center retrospective study was performed to evaluate the safety and efficacy of FMS-like tyrosine kinase 3 (FLT3) inhibitors before and after allogeneic hematopoietic cell transplantation (HCT) in relapsed/refractory patients with FLT3-mutation positive acute myeloid leukemia (AML). RESULTS: Ten patients who met the eligibility criteria were included. Eight of them achieved hematological remission at HCT, within a median span of 79 days (range: 43-197). In post-HCT, patients started maintenance therapy (MT; median time-to-start 79 days, range: 43-197), and the median duration of MT was 390 days (range: 67-815). Grade 3 hematological adverse events (AEs) were found in two patients, and non-hematological AEs were found in five patients. Nine patients underwent either dose reduction, discontinuation of therapy, or a switch to another FLT3 inhibitor due to AEs. Disease relapse occurred in one patient during MT. At the time of the last follow-up, seven patients are alive and disease-free, while three have died due to infection or transplant complications. CONCLUSION: In relapsed/refractory FLT3 mutation-positive AML, the use of FLT3 inhibitors can lead to high response rates and provide a safe bridge from HCT to MT. If sufficient attention is paid to safety, this therapy is expected to prevent disease relapse even with reduced dosages.

Prognostic factors for the development of lower respiratory tract infection after influenza virus infection in allogeneic hematopoietic stem cell transplantation recipients: A Kanto Study Group for Cell Therapy multicenter analysis.

OBJECTIVES: Influenza virus infection (IVI) occasionally causes lower respiratory tract infection (LRTI) in allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients. Although the progression to LRTI entails a high mortality, the role of early antiviral therapy for its prevention has not been fully elucidated. METHODS: This was a multicenter retrospective study using an additional questionnaire. Allo-HSCT recipients who developed IVI between 2012 and 2020 were included. RESULTS: A total of 278 cases of IVI after allo-HSCT were identified from 15 institutions. The median patient age was 49 years, and the median time from allo-HSCT to IVI was 918 days. Neuraminidase inhibitors were administered within 48 hours of symptom onset (early neuraminidase inhibitor [NAI]) in 199 (76.9%) patients. Subsequently, 36 (12.3%) patients developed LRTI. On the multivariate analysis, age ≥50 years (hazard ratio [HR], 2.16; 95% confidence interval [CI], 1.02-4.58) and moderate to severe chronic graft-versus-host disease (HR, 2.28; 95% CI, 1.14-4.58) were significantly associated with progression to LRTI, whereas early NAI suppressed the progression (HR, 0.17; 95% CI, 0.06-0.46). The IVI-related mortality rate was 2.2%. CONCLUSION: To reduce the risk of LRTI development after IVI, early NAI therapy should be considered in allo-HSCT recipients, especially with older patients and those with chronic graft-versus-host disease.

Dose-finding trial of azacitidine as post-transplant maintenance for high-risk MDS: a KSGCT prospective study.

This 3+3 dose-escalation phase I multicenter study investigated the optimal dose of azacitidine (AZA) for post-hematopoietic stem cell transplantation (HSCT) maintenance, which remains unknown in Japan. Recipients of a first HSCT for high-risk myelodysplastic syndromes (MDS, n = 12) or acute myeloid leukemia (AML) with antecedent MDS (n = 3) received post-HSCT AZA maintenance in 2015-2019. The optimal AZA dose was defined as the dose at which 50-70% of patients can complete four cycles without dose-limiting toxicity (DLT). The initial dose level 1 was set as 30 mg/m2 for 5 days per 28-day cycle, and dose levels 0, 2, and 3 were set as 20, 40, and 50 mg/m2. DLT was defined as any grade 3 non-hematological or grade 4 hematological toxicity. The 15 evaluable patients were 55 (37-64) years old. The median observation of the post-HSCT survivors was 935 (493-1915) days. The median number of days post-HSCT to the start of AZA was 101 (59-176). In the first, second, and third cohorts, five of nine patients completed four cycles at dose level 1. In the final cohort, five of six additional patients completed at the same dose. In total, 10 (67%) patients tolerated AZA 30 mg/m2, which was determined as optimal. DLT occurred in five cases: grade 3 hepatotoxicity, pneumonia, enterocolitis, and grade 4 thrombocytopenia and neutropenia. The 2-year overall survival and disease-free survival rates post-HSCT were 77.0% and 73.3%. Post-HSCT AZA maintenance was well-tolerated and merits further evaluation for patients with MDS or AML with antecedent MDS. Trial registration: UMIN000018791.

Clinical risk factors for patients with myelodysplastic syndromes undergoing allogeneic hematopoietic stem cell transplantation.

Objectives: Allogeneic hematopoietic stem cell transplantation (allo-HCT) is the only curative treatment for myelodysplastic syndromes (MDS), although predicting post-transplant outcomes remains inconclusive. This study evaluated patients who underwent allo-HCT for MDS to identify prognostic factors and develop a clinical risk model.Methods: We evaluated 55 patients between June 2000 and March 2015 to identify prognostic factors and develop a model for three-year overall survival (OS) and event-free survival (EFS). Cox regression analysis was performed on four factors: age ≥55 years; Hematopoietic Cell Transplant-Comorbidity Index >2; intermediate or worse cytogenetic status based on revised International Prognostic Scoring System; and unrelated donor status associated with poor OS in the univariate analysis. A clinical risk model was constructed using the sum of the regression coefficients and evaluated using receiver operating characteristic analysis and five-fold cross-validation.Results: Patient median age was 51 (range: 30-67) years. Median follow-up was 45.8 (range: 1.27-193) months; the three-year OS and EFS rates were 61.8% and 56.4%, respectively. The areas under the curves (AUCs) for OS and EFS were 0.738 and 0.778, respectively, and the average AUC for 50 times five-fold cross-validation were 0.711 and 0.723 for three-year OS and EFS, respectively.Conclusion: A four-clinical-risk-factor model that could effectively predict post-transplantation outcomes and help decision-making in MDS treatment was developed.

Outcomes in patients with acute lymphoblastic leukemia who underwent second allogeneic hematopoietic cell transplantation for relapse after first transplantation.

Outcomes in patients with acute lymphoblastic leukemia (ALL) who experience relapse after allogeneic hematopoietic cell transplantation (HCT) are unsatisfactory. This study aimed to evaluate the outcomes of patients with ALL who underwent second HCT (HCT2) for relapse after first HCT. It was a single-center retrospective study including adult patients with ALL who underwent HCT2 between 1991 and 2020. The cohort was stratified according to the transplant year, and included 39 patients with a median age of 29 years. A more recent transplant year was associated with achievement of complete remission (CR) and use of reduced-intensity conditioning (RIC), compared with an earlier transplant year. The overall survival (OS) rate and 2-year cumulative incidence of non-relapse mortality (recent vs. earlier) were 55% vs. 8% (P < 0.001) and 26% vs. 75% (P < 0.001), respectively. In multivariate analysis, non-CR (vs. CR; HR 3.6, 95% CI 1.2-11.3, P = 0.025) and myeloablative conditioning (vs. RIC; HR 3.5, 95% CI 1.3-9.4, P = 0.011) were negative prognostic factors for OS. Outcomes of the recent cohort from real-world data are promising, and achieving CR and using the RIC regimen at HCT2 may be an important therapeutic strategy.

Clinical impact of cigarette smoking on the outcomes of allogeneic hematopoietic stem cell transplantation: a multicenter retrospective study.

Smoking is associated with a high risk for different diseases including respiratory tract infections in immunocompetent patients. However, data about the effects of cigarette smoking on the outcomes of allogeneic hematopoietic stem cell transplantation (allo-HSCT) are limited. Therefore, we retrospectively investigated 608 patients aged ≥20 years with hematological disorders who received their first allo-HSCT at our group of hospitals between 2000 and 2015, and evaluated the impact of cigarette smoking before allo-HSCT on clinical outcomes by dividing patients into two groups according to the Brinkman index (BI) (nonsmokers or light smokers [BI: 0-500] and heavy smokers [BI: ≥ 500]). Multivariate analyses showed that heavy smoking was associated with a high 5-year cumulative incidence of chronic graft-versus-host disease (cGVHD) (hazard ratio [HR]: 1.73, 95% confidence interval [CI]: 1.15-2.61, p < 0.01). The 5-year overall survival (HR: 1.16, 95% CI: 0.86-1.58, p = 0.33) and disease-free survival (HR: 1.12, 95% CI: 0.83-1.52, p = 0.45) were similar between the two groups. Hence, cigarette smoking is correlated with cGVHD, although prospective studies must be conducted to further verify this result.

Comparison of cryoprotectants in hematopoietic cell infusion-related adverse events.

BACKGROUND: The standard cryoprotectant for human cellular products is dimethyl sulfoxide (DMSO), which is associated with hematopoietic cell infusion-related adverse events (HCI-AEs) in hematopoietic stem cell transplantation including peripheral blood stem cell (PBSC) transplantation (PBSCT). DMSO is often used with hydroxyethyl starch (HES), which reduces DMSO concentration while maintaining the postthaw cell recovery. The cryoprotectant medium CP-1 (Kyokuto Pharmaceutical Industrial) is widely used in Japan. After mixture of a product with CP-1, DMSO and HES concentrations are 5% and 6%, respectively. However, the safety profile of CP-1 in association with HCI-AEs has not been investigated. STUDY DESIGN AND METHODS: To compare CP-1 with other cryoprotectants, we conducted a subgroup analysis of PBSCT recipients in a prospective surveillance study for HCI-AEs. Moreover, we validated the toxicity of CP-1 in 90 rats following various dose administration. RESULTS: The PBSC products cryopreserved with CP-1 (CP-1 group) and those with other cryoprotectants, mainly 10% DMSO (non-CP-1 group), were infused into 418 and 58 recipients, respectively. The rate of ≥grade 2 HCI-AEs was higher in the CP-1 group, but that of overall or ≥grade 3 HCI-AEs was not significantly different, compared to the non-CP-1 group. Similarly, after propensity score matching, ≥grade 2 HCI-AEs were more frequent in the CP-1 group, but the ≥grade 3 HCI-AE rate did not differ significantly between the groups. No significant toxicity was detected regardless of the CP-1 dose in the 90 rats. CONCLUSIONS: Infusion of a CP-1-containing PBSC product is feasible with the respect of HCI-AEs.

A case series of patients treated with inotuzumab ozogamicin for acute lymphoblastic leukemia relapsed after allogeneic hematopoietic cell transplantation.

This single-center retrospective study was performed in consecutive patients with acute lymphoblastic leukemia who relapsed after allogeneic hematopoietic cell transplantation (HCT) and received salvage therapy using inotuzumab ozogamicin (InO). Ten patients (median age: 27 years) treated between June 2018 and July 2020 who met the eligibility criteria were included in this study. Nine patients received InO in one cycle and seven of these patients achieved complete hematological remission after salvage chemotherapy including InO. Negative minimal residual disease was confirmed in all four evaluable patients. Eight patients were successfully bridged to the subsequent HCT. After HCT, veno-occlusive disease (VOD) developed in three patients, and caused the death of one. No patient received maintenance therapy. At present, five patients are disease-free and alive, and the overall and progression-free survival rates at 1 year were 60% and 40%, respectively. High rates of disease remission and bridging to HCT with comprehensive treatments including InO may have contributed to favorable outcomes. However, further investigation is needed to reduce post-HCT complications including VOD.

Compromised anti-tumor-immune features of myeloid cell components in chronic myeloid leukemia patients.

Chronic myeloid leukemia (CML) is a form of myeloproliferative neoplasm caused by the oncogenic tyrosine kinase BCR-ABL. Although tyrosine kinase inhibitors have dramatically improved the prognosis of patients with CML, several problems such as resistance and recurrence still exist. Immunological control may contribute to solving these problems, and it is important to understand why CML patients fail to spontaneously develop anti-tumor immunity. Here, we show that differentiation of conventional dendritic cells (cDCs), which are vital for anti-tumor immunity, is restricted from an early stage of hematopoiesis in CML. In addition, we found that monocytes and basophils, which are increased in CML patients, express high levels of PD-L1, an immune checkpoint molecule that inhibits T cell responses. Moreover, RNA-sequencing analysis revealed that basophils express genes related to poor prognosis in CML. Our data suggest that BCR-ABL not only disrupts the "accelerator" (i.e., cDCs) but also applies the "brake" (i.e., monocytes and basophils) of anti-tumor immunity, compromising the defense against CML cells.

Pre-conditioning intervention in patients with relapsed or refractory acute lymphoblastic leukemia who underwent allogeneic hematopoietic cell transplantation: a KSGCT multicenter retrospective analysis.

The efficacy and clinical significance of pre-conditioning intervention (PCI) before allogeneic hematopoietic cell transplantation (HCT) in patients with acute lymphoblastic leukemia (ALL) not in remission remain inconclusive. The purpose of this multicenter retrospective study was to clarify the clinical significance of PCI before HCT in patients with non-remission ALL. Patients with non-remission ALL who received HCT between 2005 and 2015 at 16 institutions were included. PCI was objectively defined and classified to three groups according to the intensity of PCI (no, intensive, or moderate). The study cohort consisted of 104 patients with a median age of 38 (range 17-68). A significant decrease of blast percentage in the peripheral blood (PB) was confirmed in both PCI groups, suggesting that PCIs were effective to stabilize the disease activity. The group with moderate PCI had higher nucleated cell count in the BM compared to the group with intensive PCI or the group without PCI. The overall survival (OS) rates of groups with intensive and no PCI showed comparable and significantly better compared to the group with moderate PCI (P = 0.009). Multivariate analysis demonstrated that the OS of moderate PCI group was significantly worse compared to that of intensive PCI group (HR = 2.43, 95% CI: 1.32-4.14, P = 0.004), while the OS of intensive PCI group was comparable to that of the group without PCI. These results suggest that the intensity of PCI rather than the response to PCI may contribute to improve the transplant outcome in patients with ALL not in remission.

Optimal treatment for Philadelphia-negative acute lymphoblastic leukemia in first remission in the era of high-intensity chemotherapy.

The optimal treatment for Philadelphia chromosome (Ph)-negative acute lymphoblastic leukemia (ALL) in first complete remission (CR1) has not been established in the high-intensity chemotherapy era. The outcomes of patients with Ph-negative ALL who underwent allogeneic hematopoietic stem cell transplantation (HSCT) from a human leukocyte antigen-matched related or unrelated donor in CR1 (HSCT-MRD group and HSCT-MUD group) were obtained from a Japanese registry database. Patients aged 16-24 years and 25-65 years were analyzed separately, and their outcomes were compared to those of patients who continued high-intensity chemotherapy in CR1 in studies (202U group and 202O group) by the Japan Adult Leukemia Study Group (JALSG). In the HSCT-MRD group, patients younger than 25 years had lower overall survival (OS) than the 202U group, presumably due to the higher non-relapse mortality (NRM) in the HSCT-MRD group. Patients 25 years and older had similar OS to the 202O group. The lower relapse rate was counterbalanced by higher NRM in the HSCT-MRD group. In the HSCT-MUD group, patients in both age groups had similar OS to their corresponding groups in the JALSG studies. In conclusion, high-intensity chemotherapy may change the role of HSCT for Ph-negative ALL.

Novel Indicators of Transplant Outcomes for PhALL: Current Molecular-Relapse-Free Survival.

Molecular relapse after allogeneic hematopoietic cell transplantation (allo-HCT) has been thought to predict clinical relapse in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (PhALL). Tyrosine kinase inhibitor (TKI) administration after allo-HCT may dynamically change the status from molecular relapse to molecular remission, but these state changes cannot be accurately represented by conventional survival indicators such as relapse-free survival, where events are usually considered irreversible. We aimed to develop novel indicators of transplant outcomes for allo-HCT recipients with PhALL and to visualize current molecular-relapse-free survival (CMRFS) and current on-TKI status (CTKI), treating molecular relapse or TKI administration after allo-HCT as a reversible event. We retrospectively analyzed 286 patients with PhALL who received allo-HCT between 2000 and 2016 in order to develop the indicators. CMRFS was defined as the probability of molecular remission without clinical relapse or death at any time after allo-HCT. Similarly, CTKI was defined as the probability of TKI administration without clinical relapse or death at any time after allo-HCT. The 1- and 5-year CMRFS rates were 67% and 59%, respectively, whereas the 1- and 5-year conventional molecular relapse-free survival rates were 42% and 37%. The 1- and 5-year CTKI rates were 14% and 8%, respectively. In a post hoc analysis focusing on patients who had achieved a molecular complete remission within 6 weeks (n = 201), the 5-year CMRFS rate (71%) was similar to the 5-year conventional molecular relapse-free survival (molRFS) rate (70%) in the non-TKI group. On the other hand, the 5-year CMRFS rate in the TKI group was 61%, whereas the 5-year conventional molRFS rate was only 38%. CMRFS and CTKI might become useful indicators of transplant success in terms of survival, leukemia-free status, and treatment-free status at any time point. Future extension of these survival models to other clinical situations is warranted.

Stopping tyrosine kinase inhibitors started after allogeneic HCT in patients with Philadelphia chromosome-positive leukemia.

For patients with Philadelphia chromosome (Ph)-positive leukemia, there is no consensus regarding how long tyrosine kinase inhibitors (TKI) should be given or whether TKI could be stopped if TKI is administrated after allogeneic hematopoietic cell transplantation (allo-HCT). We analyzed relapse-free survival (RFS) in 92 allo-HCT patients who received TKI for >3 months after allo-HCT, and aimed to develop a novel indicator, called as current TKI- & relapse-free (cTRFree) achievement. TKI after allo-HCT was started as planned in 39 patients, based on measurable residual disease (MRD) in 53 at a median of 152 days after allo-HCT. There was no difference in post-TKI RFS between the planned and MRD-based starting groups (P = 0.69). Second-generation TKIs were associated with superior RFS in Ph-positive acute leukemia (HR 2.71, P = 0.031). TKI was stopped before relapse in 48 patients. Stopping TKI as a time-dependent covariate was not associated with subsequent hematological relapse (HR 1.18, P = 0.72). In the TKI-stop group, TKI administration for >6 months tended to be associated with superior RFS (HR = 0.30, P = 0.08). As an indicator of transplant success, cTRFree was 35% 5 years after starting TKI. TKI could be stopped for recipients with sustained undetectable MRD. However, further prospective studies will be required to establish clinical recommendations.

Successful treatment with lenalidomide for relapsed adult T-cell leukemia/lymphoma after cord blood cell transplantation.

The prognosis for relapsed adult T-cell leukemia/lymphoma (ATL) after allogeneic hematopoietic stem cell transplantation is poor. Here, we report the case of a 67-year-old man who survived for 26 months after treatment with lenalidomide for post-transplant relapsed ATL. He underwent induction therapy with two cycles of modified VCAP-AMP-VECP and achieved complete remission. He received cord blood cell transplantation following a reduced-intensity conditioning regimen. Seven months after transplantation, swelling of the systemic lymph nodes appeared, and relapsed ATL was diagnosed based on a biopsy of the cervical lymph node. Treatment with 10 mg of lenalidomide induced partial remission. At 18 months after transplantation, skin tumors were successfully treated by increasing the dose of lenalidomide to 15 mg with the emergence of skin graft-versus-host disease. Although he died from ATL at 34 months after transplantation, systemic relapsed lesions were controlled by treatment with lenalidomide for 26 months. Our case suggests that lenalidomide is well tolerated and is an effective option for the treatment of post-transplant relapsed ATL.

Clinical Benefits of Preconditioning Intervention in Patients with Relapsed or Refractory Acute Myelogenous Leukemia Who Underwent Allogeneic Hematopoietic Cell Transplantation: A Kanto Study of Group for Cell Therapy Multicenter Analysis.

A multicenter retrospective study was conducted to evaluate the clinical significance of preconditioning intervention (PCI) before allogeneic hematopoietic cell transplantation (HCT) in patients with acute myelogenous leukemia (AML) not in remission. The study cohort consisted of 519 patients classified according to the intensity (intensive/moderate) of PCI and their response to PCI. The group treated with PCI had higher blast counts in the peripheral blood (PB) and had a lower overall survival (OS) rate (P < .001) and higher nonrelapse mortality (NRM) rate (P = .035) compared with those without PCI (no PCI group). Approximately 40% of the patients (68 of 236) achieved a good response to PCI (good PCI group), and those patients had lower blast counts in the PB compared with the group with poor response to PCI (poor PCI group). OS in the good PCI group was comparable to that in the no PCI group and significantly better than that in the poor PCI group (hazard ratio, .54; 95% confidence interval, .39 to .77; P < .001). However, OS was significantly lower in patients with intensive/moderate PCI compared with the no PCI group. These results suggest that PCI increases NRM without decreasing the post-transplantation relapse rate, but may be beneficial for patients with lower blast counts in PB irrespective of its intensity.