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Key Points Dasatinib-based 2-step induction resulted in a 100% CR rate with minimal toxicities and 53% MRD negativity.This protocol treatment increased the number of HSCTs in CR1, thereby improving 3-year EFS., Visual Abstract, The standard treatment for adults with Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia (ALL) in Japan is imatinib-based chemotherapy followed by allogeneic hematopoietic stem cell transplantation (HSCT). However, ∼40% of patients cannot undergo HSCT in their first complete remission (CR1) because of chemotherapy-related toxicities or relapse before HSCT or older age. In this study, we evaluated dasatinib-based 2-step induction with the primary end point of 3-year event-free survival (EFS). The first induction (IND1) was dasatinib plus prednisolone to achieve CR, and IND2 was dasatinib plus intensive chemotherapy to achieve minimal residual disease (MRD) negativity. For patients who achieved CR and had an appropriate donor, HSCT during a consolidation phase later than the first consolidation, which included high-dose methotrexate, was recommended. Patients with pretransplantation MRD positivity were assigned to receive prophylactic dasatinib after HSCT. All 78 eligible patients achieved CR or incomplete CR after IND1, and 52.6% achieved MRD negativity after IND2. Nonrelapse mortality (NRM) was not reported. T315I mutation was detected in all 4 hematological relapses before HSCT. Fifty-eight patients (74.4%) underwent HSCT in CR1, and 44 (75.9%) had negative pretransplantation MRD. At a median follow-up of 4.0 years, 3-year EFS and overall survival were 66.2% (95% confidence interval [CI], 54.4-75.5) and 80.5% (95% CI, 69.7-87.7), respectively. The cumulative incidence of relapse and NRM at 3 years from enrollment were 26.1% and 7.8%, respectively. Dasatinib-based 2-step induction was demonstrated to improve 3-year EFS in Ph+ ALL. This study was registered in the UMIN Clinical Trial Registry as #UMIN000012173.

Allogeneic hematopoietic stem cell transplantation (allo-SCT) is the sole curative therapy for myelodysplastic syndromes (MDS). However, whether bridging therapy (BRT) including azacitidine (AZA) and combination chemotherapy (CCT) prior to allo-SCT should be performed is unclear. We analyzed BRT and the outcomes of patients with myelodysplastic syndrome with excess blasts (MDS-EB) who were registered in a prospective observational study in order to clarify the optimal allo-SCT strategy for high-risk MDS. A total of 371 patients were included in this study. Among 188 patients (50.7%) who were considered for allo-SCT, 141 actually underwent allo-SCT. Among the patients who underwent allo-SCT, 64 received AZA, 29 received CCT and 26 underwent allo-SCT without BRT as an initial treatment. The multivariate analysis identified BRT as independent factors influencing overall survival (AZA vs. without BRT, hazard ratio [HR] 3.33, 95% confidence interval [95%CI] 1.44–7.70, P = 0.005; CCT vs. without BRT, HR 3.82, 95%CI 1.60–9.14, P = 0.003). In a multivariate analysis, BRT showed an independent association with progression-free survival (AZA vs. without BRT, HR 2.23, 95%CI 1.03–4.83, P = 0.041; CCT vs. without BRT, HR 2.94, 95%CI 1.29–6.69, P = 0.010). Transplant-eligible patients with MDS-EB should undergo upfront allo-SCT without BRT.

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.

The Vulnerable Elders Survey-13 (VES-13) is a well-studied simplified frailty screening tool for elderly patients in the oncology setting. We conducted a prospective clinical trial to evaluate the efficacy and safety of dose-adjusted treatment based on the VES-13 in transplant-ineligible patients with newly diagnosed multiple myeloma (MM). In the Fit group (VES-13

Pretransplant measurable residual disease (MRD) has been shown to be associated with relapse incidence following allogeneic hematopoietic cell transplantation (HCT) for acute myeloid leukemia (AML). However, it remains less clear whether pretransplant MRD status affects transplant outcomes in core binding factor AML (CBF-AML). We retrospectively evaluated the effect of pretransplant MRD, which was measured by a polymerase chain reaction of RUNX1-RUNX1T1 or CBFB-MYH11 fusion transcripts, on transplant outcomes for a cohort of 959 adult patients with t(8;21) or inv(16) AML treated by allogeneic HCT during complete remission (CR), between 2000 and 2018. Multivariate analysis showed the absence of pretransplant MRD was significantly associated with lower relapse (hazard ratio [HR], 0.46; P

This study reports two cases of dasatinib-associated lymphadenopathy (DAL). Case 1 involved a 58-year-old man diagnosed with chronic myelogenous leukemia (CML). After 13 months of starting on dasatinib treatment, a molecular response (MR) 4.5 was achieved. Due to the loss of MMR, dasatinib was discontinued at 39 months but restarted at 42 months. Right cervical lymphadenopathy appeared 51 months after starting the treatment. DAL was diagnosed based on the findings of a cervical lymph node biopsy. After dasatinib was switched to ponatinib, the lymphadenopathy disappeared without recurrence. In case 2, a 54-year-old man was diagnosed with CML. He was started on dasatinib and MR 4.5 was achieved after 6 months. Left cervical lymph node adenopathy appeared 21 months later, and a diagnosis of DAL was made based on the findings of a cervical lymph node biopsy. After discontinuation of dasatinib, cervical lymph node adenopathy disappeared without recurrence. The possibility of DAL should be considered if lymphadenopathy is observed during dasatinib treatment.

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.

We analyzed clinical cutoffs for defining computed tomography (CT) methods for sarcopenia and examined the prognostic value of CT for allogeneic hematopoietic stem cell transplantation (allo-HCST) outcomes of patients with myeloid malignancy. One hundred twenty-five adult patients with acute myeloid leukemia and myelodysplastic syndrome who underwent first allo-HSCT between 2000 and 2017 were included. Sarcopenia was assessed using CT-based skeletal muscle index (SMI) and mean muscle attenuation at L3. A statistical difference in SMI was confirmed between sarcopenia (n = 52) and nonsarcopenia (n = 73) patients. There were no significant correlations of muscularity with age, performance status, or other characteristics of HSCT. After 2 years, overall survival (OS) was 43.5% and 70.1%, disease-free survival was 52.9% and 68.6%, nonrelapse mortality (NRM) was 20.8% and 8.4%, incidence of acute GVHD (≥ grade 2) was 38.8% and 39.1%, that of chronic GVHD was 53.2% and 37.3%, and median duration of hospitalization was 88 days and 74 days (P = 0.026), respectively, in the sarcopenia and nonsarcopenia groups. Multivariate analysis showed that presence of sarcopenia is a novel adverse factor for high NRM and poor OS. Pretransplant CT-defined sarcopenia is correlated with decreased OS, increased NRM, and prolonged hospitalization.

A multicenter retrospective study was performed to evaluate the prognostic factors in 104 patients with relapsed or refractory acute lymphoblastic leukemia (ALL), who underwent allogeneic hematopoietic cell transplantation (HCT) between 2005 and 2015. The median age was 38 (range, 17 to 68), and the median blast fraction in peripheral blood and bone marrow was 1% (range, 0 to 99%) and 52% (range, 0 to 100%), respectively. With a median follow-up of 47 months (range, 8.3 to 105 months), overall survival (OS), nonrelapse mortality, and relapse mortality at 1 year were 25%, 44%, and 31%, respectively. Multivariate analysis demonstrated independent predictors for poor OS, including nuclear cell count in the bone marrow ≥10 × 104/μL (hazard ratio [HR], 2.14; 95% confidence interval [CI], 1.33 to 3.43; P = .002), elevated lactate dehydrogenase level (HR, 1.66; 95% CI, 1.05 to 2.62; P = .031), and no primary induction failure (HR, 2.05; 95% CI, 1.11 to 3.78; P = .022). A prognostic scoring index was designed based on these survival predictors. At 2 years, OS was 28%, 14%, and 0% for good (score 0 or 1; n = 47), intermediate (score 2; n = 40), and poor (score 3; n = 17), respectively (P

A soluble form of suppression of tumorigenicity 2 (sST2) has emerged as a biomarker for acute graft-versus-host disease (GVHD) and non-relapse mortality (NRM). We prospectively monitored sST2 levels during the early phase of hematopoietic stem cell transplantation (HSCT) and evaluated the clinical association with transplant-related complications including acute GVHD.Thirty-two adult Japanese patients who received a first allogeneic HSCT were enrolled in this study. Levels of sST2 were measured at fixed time points (pre-conditioning, day 0, day 14, day 21, and day 28).The median age was 50.5 years (range=16-66). With a median follow-up of 21.5 months (range=0.9-35.4), 9 patients developed grade II-IV acute GVHD. Median sST2 levels on the day of HSCT were higher than baseline and reached the maximum value (92.7 ng/mL; range=0-419.7) on day 21 after HSCT. The optimal cut-off value of sST2 on day 14 for predicting grade II-IV acute GVHD was determined as 100 ng/mL by ROC analysis. The cumulative incidence of acute GVHD was 56.7% and 16.5% in the high- and low-sST2 groups, respectively (p0.01). Multivariate analyses showed that high sST2 levels at day 14 were associated with a higher incidence of acute GVHD (hazard ratio=9.35, 95% confidence interval=2.92-30.0, p0.01). The cumulative incidence of NRM was increased in the highs-ST2 group (33% vs 0%, p0.01), but all the patients died of non-GVHD complications. Among 6 patients in the high-sST2 group without grade II-IV GVHD, 5 patients developed veno-occlusive disease (VOD) and one also had thrombotic microangiopathy (TMA).The early assessment of sST2 after HSCT yielded predictive values for the onset of acute GVHD and other transplant-related complications including VOD and TMA.Akut graft-konakçı hastalığı (GVHD) ve relaps dışı mortalite (NRM) için bir biyobelirteç olarak, tümör oluşumu 2’nin baskılanmasının (sST2) çözünür bir formu ortaya konulmuştur. Hematopoietik kök hücre transplantasyonunun (HSCT) erken safhasında sST2 düzeylerini prospektif olarak izledik ve akut GVHD dahil transplantla ilişkili komplikasyonlarla klinik ilişkisini değerlendirdik.Bu çalışmaya ilk allojenik HSCT’si olan 32 yetişkin Japon hasta alındı. sST2 seviyeleri sabit zaman noktalarında (hazırlık rejimi öncesi, 0. gün, 14. gün, 21. gün ve 28. gün) ölçüldü.Ortanca yaş 50,5 idi (aralık=16-66). Ortalama 21,5 aylık takip süresi (aralık= 0,9-35,4) ile 9 hastada Grade II-IV akut GVHD gelişti. Nakil gününde ortanca sST2 seviyeleri bazal değerlerden daha yüksekti ve HSCT’den sonraki 21. günde maksimum değere (92,7 ng/mL; aralık=0-419,7) ulaştı. Grade II-IV akut GVHD’yi tahmin etmek için 14. günde sST2’nin optimal eşik değeri, ROC analizi ile 100 ng/mL olarak belirlenmiştir. Akut GVHD’nin kümülatif insidansı yüksek ve düşük sST2 gruplarında sırasıyla %56,7 ve %16,5 idi (p0,01). Çok değişkenli analizler 14. günde yüksek sST2 düzeylerinin daha yüksek akut GVHD insidansı ile ilişkili olduğunu göstermiştir (tehlike oranı=9, 35, %95 güven aralığı=2,92-30,0, p0,01). NRM’nin kümülatif insidansı yüksek sST2 grubunda artmıştır (%33’e karşı %0, p0,01), ancak tüm hastalar GVHD dışı komplikasyonlardan öldü. Yüksek sST2 grubunda grade II-IV GVHD olmayan 6 hastadan 5’inde veno-oklüzif hastalık (VOD) gelişti ve birinde trombotik mikroanjiyopati (TMA) vardı.HSCT sonrası sST2’nin erken değerlendirmesi, akut GVHD’nin başlangıcı ve VOD ve TMA dahil transplantla ilişkili diğer komplikasyonlar için prediktif değerler vermiştir.

To prospectively validate the incidence, manifestations, and outcomes of graft-versus-host disease (GVHD) by National Institutes of Health criteria, we recruited 406 hematopoietic stem cell transplantation recipients at 16 transplant centers in Japan from May 2012 to June 2014. The 2-year cumulative incidence of late acute and chronic GVHD was 3.2% (n = 13) and 35.4% (n = 145), with a median onset of 3.6 and 4.7 months after transplant, respectively. The global severity at onset was mild in 30.3%, moderate in 43.5%, and severe in 26.2%. Eighty-two patients were followed up for 2 years, with 79.3% still manifesting GVHD symptoms, and 80.6% (n = 117) of the patients received systemic immunosuppressive treatment (IST), with a 2-year cumulative incidence of IST termination of 33.1%. Severe patients showed a significantly lower rate of IST termination than those with mild and moderate severities (mild, 38.5%; moderate, 40.9%; and severe, 17.2%). The 2-year incidence of nonrelapse mortality (NRM) and relapse was not significantly different according to the severity at onset (NRM: mild [16.6%] versus moderate [8.7%] versus severe [16.1%]; relapse: mild [14.9%] versus moderate [14.7%] versus severe [5.3%]). As a result, 2-year overall survival (OS) and GVHD-specific survival (GSS) were equivalent according to the severity at onset (mild: OS = 81.0%, GSS = 85.7%; moderate: OS = 84.2%, GSS = 92.5%; severe: OS = 83.9%, GSS = 89.2%). Our study helped identify the characteristics of late acute and chronic GVHD in Japanese patients. Further investigation is needed to identify an optimal endpoint for survival prediction.

Bosutinib has been evaluated for treatment of chronic-phase chronic myeloid leukemia (CP-CML) in several clinical studies, including in Japan. This open-label, single-arm, phase 2 study evaluated the efficacy and safety of bosutinib at a starting dose of 400 mg once daily in Japanese patients (n = 60) with newly diagnosed CP-CML. The minimum follow-up period was 3 years and median duration of treatment was 35.9 months. At study completion, 60% of patients were still on treatment. Cumulative rates of major molecular response (MMR), molecular response4 (MR4), and MR4.5 at any time were 70.0%, 53.3%, and 48.3%, respectively. No patient who achieved MMR or MR4 had a confirmed loss of response. No patient experienced on-treatment transformation to accelerated/blast phase or died within 28 days of the last bosutinib dose. Any-grade treatment-emergent adverse events (TEAEs) occurred in 100% (grade ≥ 3: 81.7%) of patients. The most common TEAEs were diarrhea (86.7%), increased alanine aminotransferase (55.0%), and increased aspartate aminotransferase (46.7%). No new safety signals emerged during the follow-up period. Bosutinib continues to demonstrate a favorable benefit/risk profile and is an important treatment option for Japanese patients with newly diagnosed CP-CML. Optimal management of TEAEs during initial treatment with bosutinib should be prioritized.Trial Registration: ClinicalTrials.gov ID: NCT03128411.

A 21-year-old woman was diagnosed with chronic myeloid leukemia in March 2014. The patient and her family did not wish to freeze eggs before dasatinib initiation. After 66 months of oral dasatinib administration and 40 months of MR4.5 maintenance, the patient requested to discontinue dasatinib due to a desire to conceive. MR4.5 maintenance was continued, and she achieved spontaneous pregnancy 6 months after dasatinib discontinuation. The patient gave birth to a normal baby 13 months later and was on MR4.5 maintenance 21 months after dasatinib discontinuation.

Coronavirus disease 2019 (COVID-19) has emerged as a global pandemic until today, but treatment options remain limited. COVID-19 vaccination is expected to decrease the number of patients with COVID-19 worldwide. In Japan, two types of mRNA COVID-19 vaccine, BNT162b2 (Pfizer/BioNTech) and mRNA-1273 (Moderna), have been approved and administered. However, their side effects remain poorly elucidated. This paper presents two cases of immune thrombocytopenia (ITP) after BNT162b2 mRNA COVID-19 vaccination. Whether or not ITP is triggered by the vaccination or not is difficult to identify. Further investigation with a large number of cases is warranted to clarify the side effects of BNT162b2 mRNA COVID-19 vaccination.

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.

A multicenter retrospective study was performed to explore a prognostic scoring index in order to identify a population who are least likely to benefit from allogeneic hematopoietic cell transplantation (HCT) in patients with relapsed or refractory acute myeloid leukemia (AML). The cohort included 519 patients with AML, who received HCT between 2005 and 2015 at a status of relapse or primary induction failure. Multivariate analysis demonstrated five independent predictors for OS, including C-reactive protein ≥ 1 mg/dL, peripheral blood blast fraction ≥ 20%, poor-risk karyotype, performance status ≥ 2, and bone marrow unrelated donor as a stem cell source. A prognostic scoring index was explored based on these predictors, and successfully separated the cohort into four groups. At 2 years, OS was 47%, 24%, 8%, and 0% for Good (Score 0, 1: n = 118), Intermediate-1 (Score 2: n = 75), Intermediate-2 (Score 3: n = 39), and Poor (Score 4: n = 24), respectively (P

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.

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.

Minimal residual disease (MRD) monitoring by quantitative real-time reverse transcription PCR (qRT-PCR) is the standard of care in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-positive ALL). We evaluated the impact of MRD status at hematopoietic cell transplantation (HCT) on relapse, as measured by a unified protocol at a central laboratory. Only patients with Ph-positive ALL who had minor transcripts (e1a2) and who underwent allogeneic HCT in first complete remission between 2008 and 2017 were included. First, patients with negative-MRD (n = 196) and positive-MRD (n = 61) at HCT were analyzed. As expected, MRD positivity at HCT was significantly associated with an increased risk of hematological relapse (hazard ratio [HR], 2.91; 95% CI 1.67–5.08; P

Background Treatment-free remission (TFR), the ability to maintain a molecular response (MR), occurs in approximately 50% of patients with chronic myelogenous leukemia (CML) treated with tyrosine kinase inhibitors (TKIs). Methods A multicenter phase 2 trial (Delightedly Overcome CML Expert Stop TKI Trial: DOMEST Trial) was conducted to test the safety and efficacy of discontinuing imatinib. Patients with CML with a sustained MR of 4.0 or MR4.0-equivalent for at least 2 years and confirmed MR4.0 at the beginning of the study were enrolled. In the TFR phase, the international scale (IS) was regularly monitored by IS-PCR testing. Molecular recurrence was defined as the loss of MR4.0. Recurrent patients were immediately treated with dasatinib or other TKIs including imatinib. Results Of 110 enrolled patients, 99 were evaluable. The median time from diagnosis to discontinuation of imatinib was 103 months, and the median duration of imatinib therapy was 100 months. Molecular recurrence-free survival rates were 69.6%, 68.6% and 64.3% at 6, 12, and 24 months, respectively. After discontinuation of imatinib therapy, 26 patients showed molecular recurrence, and 25 re-achieved deep MR after dasatinib treatment. Molecular response MR4.0 was achieved in 23 patients within 6 months and 25 patients within 12 months. Multivariate analysis revealed that a longer time from diagnosis to discontinuation of imatinib therapy (p = 0.0002) and long duration of imatinib therapy (p = 0.0029) predicted a favorable prognosis. Conclusions This DOMEST Trial showed the feasibility of TKI discontinuation in a Japanese clinical setting.

Aim Primary malignant lymphomas arising from the female genital tract are very rare, with an incidence rate of 0.5%. Because of its rarity, its clinical characteristics, prognosis and optimal treatment are still unclear. Here, we retrospectively evaluated female patients with uterine lymphoma. Methods Between January 2000 and October 2016, 4362 patients were newly diagnosed with malignant lymphoma by the participating institutions of YACHT. Among these 4362 patients, we retrospectively evaluated 14 adult patients with primary uterine lymphoma. Results The median follow up time was 41 months. The median age at diagnosis was 68 years. Of 14 patients, 10 (72%) were diagnosed with diffuse large B-cell lymphoma. Seven patients presented with vaginal bleeding and three with abdominal pain. Eleven patients (79%) had advanced stages at diagnosis. Three patients (21%) had ovarian involvement and 2 (14%) had vaginal involvement. Induction chemotherapy regimens were R-CHOP in seven patients (50%), CHOP in three (21%) and other regimens in four (29%). Among 14 patients, 12 patients (86%) achieved a complete response and 2 (14%) experienced disease progression. Three patients (21%) showed relapse. Five patients (36%) died because of malignant lymphoma. The 3-year overall survival rate was 57.9%. Soluble interleukin-2 receptor levels > 5000 U/mL, anemia, a bulky mass and the presence of > 1 extranodal sites, B symptom at diagnosis were associated with a poor prognosis. Conclusion Female genital lymphoma is very rare, and further study of more cases is warranted.

Background: Although introduction of pediatric-type Berlin-Frankfurt-Munster (BFM) chemotherapy has markedly improved the prognosis of adolescent and young adult (AYA) patients with Philadelphia chromosome-negative acute lymphoblastic leukemia (Ph-negative ALL), their higher toxicity has become an emerging issue with an increased post-remission mortality in AYA patients than pediatric patients. Allogeneic stem cell transplantation (allo-SCT) with myeloablative conditioning (MAC) regimens containing total body irradiation (TBI) is recognized as an important treatment option for patients with higher risk diseases. However, safety and efficacy of allo-SCT with TBI-MAC have not been fully investigated among AYA patients who received pediatric-type chemotherapy. Patients and methods: AYA was defined as 16 to 39 years old. Of the 143 AYA patients with Ph-negative ALL who underwent the first allo-SCT in the first remission between 2007 and 2016 at the 20 institutions, 106 patients who were treated with one BFM chemotherapy regimen before transplant and were conditioned with MAC regimens containing more than or equal to 8 Gy of TBI dose. The reasons for the transplant were surveyed with a multi-answer questionnaire. Overall survival (OS) was defined as the interval from the date of transplant to the date of death. Fisher's exact test was used to compare binary variables. The cumulative incidence (CI) of non-relapse mortality (NRM) and relapse were evaluated with Gray's test, considering relapse and NRM as a competing risk, respectively. OS was estimated with the Kaplan-Meier method and compared using the log-rank test. Factors associated with at least borderline significance (p < 0.20) in univariate analyses were subjected to multivariate analysis. The Fine-Gray and Cox proportional hazard model were used for multivariate analysis of risk factors and prognostic factors, respectively. Values of p < 0.05 were considered to indicate statistical significance. Results: Of the 106 patients included in this study, 61 were male, and 45 were female. The median age at transplant was 29 years (range, 16-39 years). Donor types were related, unrelated, and cord blood in 47 (44%), 47 (44%), and 12 (12%) patients, respectively. The difficulty of continuing chemotherapy due to side effects as the reason for transplant was included in 13 patients (12%). As chemotherapy before transplant, pediatric-type and adult-type regimens were used in 56 (53%) and 50 patients (47%), respectively. There was no significant difference in baseline characteristics and transplant procedures between the pediatric-type group and the adult-type group, except for proportion of patients over 30 years (14% vs. 64%, respectively; p < 0.01), those with more than or equal to 2 of hematopoietic cell transplant comorbidity index (13% vs. 36%, respectively; p < 0.01), and transplant between 2007 and 2011 (36% vs. 64%, respectively; p < 0.01). The CI of NRM, the OS rates, and the CI of relapse were not significantly different between two groups (NRM: 4% vs. 12% at three years after transplant, respectively; p = 0.26), (OS: 86% vs. 70%, respectively; p = 0.14), and (relapse: 16% vs. 24%, respectively; p = 0.32), respectively. Multivariate analysis for NRM revealed that more than or equal to 1 of performance status at transplant (hazard ratio [HR] = 4.8; p < 0.01) and transplant due to side effects of chemotherapy (HR = 3.5; p = 0.04) were identified as independent risk factors, but not pediatric-type chemotherapy (HR = 0.48; p = 0.23). The proportions of transplant due to side effects of chemotherapy were similar between two groups (13% vs. 12%, respectively; p = 1). No independent prognostic factor for OS was found, while transplant between 2007 and 2011 (HR = 2.5; p = 0.04) was extracted as an independent risk factor of relapse. Regarding transplant complications, significant differences were not shown in CI of grade II to IV acute graft-versus-host disease (GVHD), chronic GVHD, bacteremia, cytomegalovirus reactivation, hemorrhagic cystitis, and avascular necrosis between two groups. No characteristic cause of NRM was found in the pediatric-type group. Conclusion: These findings suggested that conventional allo-SCT with TBI-MAC can be performed without increasing NRM in AYA patients with Ph-negative ALL even after pediatric-type chemotherapy. Disclosures Kimura: MSD: Honoraria; Sumitomo Dainippon Pharma: Honoraria; Astellas: Honoraria; Pfizer: Honoraria; Kyowa Kirin: Honoraria; Chugai Pharmaceutical: Honoraria; Bristol-Myers Squibb: Honoraria; Ono Pharmaceutical: Honoraria; Eisai: Honoraria; Nippon Kayaku: Honoraria; Takeda Pharmaceutical: Honoraria; SymBio Pharmaceutical: Honoraria. Usuki: MSD: Speakers Bureau; Alexion: Speakers Bureau; Pfizer: Research Funding; Kyowa Kirin: Research Funding, Speakers Bureau; Eisai: Speakers Bureau; Nippon shinyaku: Research Funding, Speakers Bureau; Astellas-Amgen-Biopharma: Research Funding; Nippon Boehringer Ingelheim: Research Funding; Takeda: Research Funding, Speakers Bureau; Celgene: Research Funding, Speakers Bureau; Janssen: Research Funding; Ono: Research Funding, Speakers Bureau; Brisol-Myers Squibb: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau; Otsuka: Research Funding, Speakers Bureau; Sumitomo Dainippon: Research Funding; Daiichi Sankyo: Research Funding, Speakers Bureau; Symbio: Research Funding, Speakers Bureau; Gilead: Research Funding; Abbvie: Research Funding; Astellas: Research Funding, Speakers Bureau; Mundipharma: Research Funding; Yakult: Speakers Bureau; PharmaEssentia: Speakers Bureau. Sakaida: Bristol Myers Squibb: Research Funding; Chugai: Research Funding; Ono: Research Funding; Kyowa Kirin: Research Funding. Fujisawa: Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Otsuka: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding. Handa: Abbvie: Honoraria; MSD: Research Funding; Shionogi: Research Funding; Sanofi: Honoraria, Research Funding; Ono: Honoraria; BMS: Honoraria; Janssen: Honoraria; Daiichi Sankyo: Research Funding; Celgene: Honoraria, Research Funding; Chugai: Research Funding; Kyowa Kirin: Research Funding; Takeda: Honoraria, Research Funding. Hatta: Bristol-Myers Squibb: Honoraria; Novartis KK: Honoraria; Pfizer Japan Inc.: Honoraria; Otsuka Pharmaceutical.: Honoraria. Kanda: Otsuka Pharmaceutical: Honoraria, Research Funding; Sanofi: Research Funding; MSD: Honoraria.

Introduction : Bosutinib is approved in Japan for patients with newly diagnosed Philadelphia chromosome-positive (Ph+) chronic phase (CP) chronic myeloid leukemia (CML) and Ph+ CML resistant/intolerant to prior therapy. In the primary report of a phase 2 study of first-line bosutinib in Japanese patients with CP CML (NCT03128411), the major molecular response (MMR) rate at 12 months was 55.0% and adverse events (AEs) were manageable and consistent with the known safety profile of bosutinib. Here we report the final 3-year efficacy and safety results of this phase 2 study. Methods : Japanese patients with newly diagnosed CP CML received bosutinib 400 mg once daily (QD). Dose escalation to a maximum of bosutinib 600 mg QD was permitted for unsatisfactory response. The bosutinib dose could be reduced to 300 mg QD for toxicity; following sponsor approval, dose reduction to bosutinib 200 mg QD was permitted for 4 weeks maximum. Long-term secondary endpoints of the study included duration of response, event-free survival, and overall survival (OS). This final analysis was based on ≥3 years of follow-up. Results: A total of 60 patients were treated with bosutinib. Median age was 55 years (range 20-83), 60.0% of patients were male, and 46.7%, 41.7%, and 11.7% had low-, intermediate-, and high-risk Sokal scores, respectively. Median duration of follow-up was 39.2 months (range 13.2-45.1), and median duration of treatment was 35.9 months (range 0.3-44.2). At study completion, 36 (60.0%) patients were still on treatment. The most common reason for treatment discontinuation was AEs (35.0%). Median dose intensity was 357.4 mg/day (range 95.3-548.1), with 400 mg QD being the most commonly utilized dose (>50% of ongoing patients across the treatment period). Dose reductions or interruptions due to AEs occurred in 36 (60.0%) and 50 (83.3%) patients, respectively; dose escalations due to insufficient response occurred in 10 (16.7%) patients. Cumulative rates of MMR, MR 4, and MR 4.5 at any time were 70.0%, 53.3%, and 48.3%, respectively (Table 1). Among patients who achieved MMR or MR 4, none had a confirmed loss of response. Cumulative rates of MMR at any time in patients with low-, intermediate-, and high-risk Sokal scores were 57.1%, 88.0%, and 57.1%, respectively. In patients with dose reductions to 300 (n=36) and 200 (n=9) mg QD, 63.9% (n=23) and 33.3% (n=3) newly achieved MMR or maintained a previously attained MMR after dose reduction. No patient progressed to accelerated/blast phase while on treatment. The cumulative incidence of progression or death adjusting for competing risk of treatment discontinuation at 3 years (90% CI) was 1.7% (0.2-6.4). Two (3.3%) patients died on study, 1 due to disease progression and 1 due to an AE considered unrelated to treatment. The 3-year Kaplan-Meier OS estimate (90% CI) was 96.7% (89.7-98.9). No evaluable patient had an emergent mutation while on treatment or at treatment completion. Any grade treatment-emergent AEs (TEAEs) occurred in 100% of patients and grade ≥3 TEAEs in 81.7% of patients. The most common TEAEs are shown in Table 2. There were no deaths on treatment. The most common (≥10%) TEAEs leading to dose reduction were alanine aminotransferase (ALT) increased (21.7%) and aspartate aminotransferase (AST) increased (13.3%), and the most common (≥10%) TEAEs leading to dose interruption were ALT increased (28.3%), AST increased (16.7%), diarrhea (11.7%), and liver disorder (10.0%). TEAEs leading to treatment discontinuation in ≥2% of patients were ALT increased (10.0%), AST increased (8.3%), lipase increased (3.3%), drug eruption (3.3%), and erythema multiforme (3.3%). Conclusions: After ≥3 years of follow-up, bosutinib continued to show clinical benefit, with approximately half of patients achieving deep molecular responses. The overall efficacy results were consistent with the global BFORE trial of first-line bosutinib. No new safety signals emerged with this longer follow-up. Bosutinib continues to demonstrate a favorable risk/benefit profile and is an important treatment option in Japanese patients with newly diagnosed CP CML. Figure 1 Figure 1. Disclosures Ono: Celgene: Honoraria, Research Funding; Kyowa Kirin Co., Ltd.: Honoraria, Research Funding; Chugai Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Novartis Pharma KK: Honoraria; Bristol-Myers Squibb Company: Honoraria; Pfizer Japan Inc.: Honoraria; Otsuka Pharmaceutical Co., Ltd.: Honoraria; ONO PHARMACEUTICAL CO., LTD.: Honoraria, Research Funding; Takeda Pharmaceutical Company Limited.: Honoraria; Astellas Pharma Inc.: Honoraria; Eisai Co., Ltd.: Honoraria; Janssen Pharmaceutical K.K: Honoraria; DAIICHI SANKYO COMPANY, LIMITED.: Honoraria; Mundipharma K.K.: Honoraria; TAIHO PHARMACEUTICAL CO., LTD.: Research Funding; Merck Sharp & Dohme: Honoraria, Research Funding. Hino: TEIJIN PHARMA LIMITED.: Research Funding; SEKISUI MEDICAL CO., LTD.: Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; Abbott: Research Funding; Asahi Kasei Corporation:: Research Funding; ARKRAY: Research Funding; JCR Pharmaceuticals Co., Ltd.: Research Funding; Janssen Pharmaceutical: Honoraria; Bristol-Myers Squibb Comapany: Honoraria; Pfizer Japan Inc.: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; NIPPON SHINYAKU CO.,LTD.: Honoraria; Japan Blood Products Organization: Honoraria, Research Funding; Chugai Pharmaceutical Co., Ltd.: Honoraria; Takeda Pharmaceutical Company Limited.: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding; Sanofi: Honoraria; Kyowa Kirin Co., Ltd: Honoraria, Research Funding; ONO PHARMACEUTICAL CO., LTD.: Honoraria, Research Funding; Otsuka Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Eisai Co., Ltd: Honoraria, Research Funding; AstraZeneca: Honoraria; Astellas Pharma Inc.: Honoraria; MSD: Honoraria, Research Funding; Meiji Seika Pharma Co., Ltd.: Honoraria; CSL Behring: Honoraria; TAIHO PHARMACEUTICAL CO., LTD.: Research Funding; DAIICHI SANKYO COMPANY, LIMITED.: Research Funding; TOSOH CORPORATION: Research Funding. Matsumura: MSD: Research Funding; Nippon Shinyaku: Research Funding; Novartis: Research Funding, Speakers Bureau; Ono: Research Funding; Otsuka: Consultancy, Research Funding, Speakers Bureau; Pfizer: Research Funding, Speakers Bureau; Shionogi: Research Funding; Taiho: Research Funding; Takeda: Research Funding; Sumitomo Dainippon: Research Funding; Nihon Pharmaceutical: Research Funding; Daiichi Sankyo: Research Funding, Speakers Bureau; Japan Blood Products Organization: Research Funding; Mundipharma: Research Funding; AYUMI Pharmaceutical: Research Funding; Mitsubishi Tanabe: Research Funding; Kyowa Kirin: Research Funding; Eisai: Research Funding; Chugai: Research Funding; Addvie: Research Funding; Eli Lilly Japan: Research Funding; Amgen: Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; Janssen: Speakers Bureau; Astellas: Speakers Bureau; Asahi Kasei: Research Funding. Fujisawa: Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Otsuka: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding. Ishizawa: Otsuka: Research Funding; Novartis: Honoraria, Research Funding, Speakers Bureau; Sanofi: Research Funding; SymBio: Honoraria, Research Funding; Kyowa Kirin: Consultancy; Pfizer: Research Funding; Bristol Myers Squibb: Speakers Bureau; IQVIA: Research Funding; Eisai: Honoraria; Chugai: Honoraria; Ono: Honoraria; Celgene: Honoraria; Takeda: Honoraria; Bayer: Research Funding; AbbVie: Research Funding. Sakaida: Kyowa Kirin: Research Funding; Ono: Research Funding; Chugai: Research Funding; Bristol Myers Squibb: Research Funding. Sekiguchi: Ono: Research Funding; A2 Healthcare: Research Funding; Astellas: Research Funding; Janssen: Research Funding; Merck Sharp & Dohme: Research Funding; Otsuka: Research Funding; Pfizer: Research Funding; PPD-SNBL: Research Funding; Sumitomo Dainippon: Research Funding; Daiichi Sankyo: Research Funding; Bristol Myers Squibb: Research Funding. Ono: Pfizer: Current Employment, Current equity holder in publicly-traded company. Aizawa: Pfizer: Current Employment. Tanetsugu: Pfizer: Current Employment. Koide: Pfizer: Current Employment. Takahashi: Chugai: Research Funding; Eizai: Research Funding; Asahikasei: Research Funding; Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Otsuka Pharmaceutical: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Ono: Research Funding; Kyowahakko-Kirin: Research Funding; Toyamakagaku: Research Funding.

Introduction: Allogeneic hematopoietic stem cell transplantation (allo-SCT) is the sole curative therapy for myelodysplastic syndromes (MDS). Several studies have addressed the efficacy of bridging therapy before allo-SCT including hypomethylating agents, combination chemotherapy (e.g. induction chemotherapy regimen for acute myeloid leukemia [AML]), and low-dose chemotherapy. However, these studies were retrospective, so selection bias was unavoidable, and the optimal bridging therapy prior to allo-SCT remains unclear. We analyzed the bridging therapy and outcomes of patients with MDS registered in a prospective observational study, the JALSG-AML/MDS/CMML Clinical Observational Study-11 (CS-11). Methods: We studied 393 patients with MDS-refractory anemia with excess blasts (MDS-EB) ≤70 years old at registration for CS-11 between 2011 and 2016. We collected new data using an online survey software program (Survey Monkey ®) and analyzed these data following their integration into the CS-11 data. This study was approved by the ethical committee of Kanazawa University (No. 2018-227) and all participating institutions. Results: A total of 371 patients (94.4%) had additional data available and who were included in this study. The median age of the patients at registration of CS-11 was 64 (range: 16-70) years, and 279 (75.2%) were male. The patients' cytogenetic subgroups were divided into very good (n=3 [0.8%]), good (n=117 [31.5%]), intermediate (n=60 [16.2%]), poor (n=35 [9.4%]), very poor (n=148 [39.9%]), and missing data (n=8 [2.1%]), according to Revised International Prognostic Scoring System (IPSS-R). A total of 188 patients (50.7%) were considered for allo-SCT at the diagnosis of MDS-EB, and 141 patients (75.0%) underwent allo-SCT, whereas 181 (48.9%) patients were not considered for allo-SCT at their diagnosis. The overall survival (OS) of the patients considered for allo-SCT at their diagnosis was significantly higher than that of the patients who were not considered for allo-SCT (3-year OS, 33.7% vs. 13.9%, P Disclosures Usuki: MSD K.K.: Research Funding, Speakers Bureau; Eisai Co., Ltd.: Speakers Bureau; Alexion Pharmaceuticals, Inc.: Research Funding, Speakers Bureau; Pfizer Japan Inc.: Research Funding, Speakers Bureau; Kyowa-Kirin Co., Ltd.: Research Funding, Speakers Bureau; Nippon-Shinyaku Co., Ltd.: Research Funding, Speakers Bureau; Amgen-Astellas Biopharma K.K.: Research Funding; Mundipharma K.K.: Research Funding; Nippon-Boehringer-Ingelheim Co., Ltd.: Research Funding; Takeda Pharmaceutical Co., Ltd.: Research Funding, Speakers Bureau; Celgene K.K.: Research Funding, Speakers Bureau; Janssen Pharmaceutical K.K.: Research Funding; Ono Pharmaceutical Co., Ltd.: Research Funding, Speakers Bureau; Novartis Pharma K.K.: Research Funding, Speakers Bureau; Otsuka Pharmaceutical Co., Ltd.: Research Funding, Speakers Bureau; Sumitomo-Dainippon Pharma Co., Ltd.: Research Funding; Daiichi Sankyo Co., Ltd.: Research Funding, Speakers Bureau; SymBio Pharmaceuticals Ltd.: Research Funding, Speakers Bureau; Gilead Sciences, Inc.: Research Funding; AbbVie GK: Research Funding, Speakers Bureau; Astellas Pharma Inc.: Research Funding, Speakers Bureau; PharmaEssentia Japan KK: Research Funding, Speakers Bureau; Yakult Honsha Co., Ltd.: Research Funding, Speakers Bureau; Bristol-Myers-Squibb K.K.: Research Funding, Speakers Bureau; Apellis Pharmaceuticals, Inc.: Research Funding; Incyte Biosciences Japan G.K.: Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding, Speakers Bureau; Sanofi K.K.: Speakers Bureau; Amgen K.K.: Research Funding. Handa: Ono: Honoraria; BMS: Honoraria; Janssen: Honoraria; Daiichi Sankyo: Research Funding; Celgene: Honoraria, Research Funding; Chugai: Research Funding; Kyowa Kirin: Research Funding; Takeda: Honoraria, Research Funding; Shionogi: Research Funding; Sanofi: Honoraria, Research Funding; Abbvie: Honoraria; MSD: Research Funding. Fujisawa: Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Otsuka: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding. Suehiro: Amgen BioPharma: Research Funding; Bayer: Research Funding; Bristol-Myers Squibb: Honoraria; Celgene: Research Funding; Chugai Pharmaceutical: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; Incyte: Research Funding; Kyowa Kirin: Honoraria, Research Funding; Nippon Shinyaku: Honoraria; Novartis: Research Funding; Ono Pharmaceutical: Research Funding; Otsuka Pharmaceutical: Research Funding; Pfizer: Research Funding. Maeda: Bayer Yakuhin, Ltd.: Honoraria; Nippon Shinyaku Co., Ltd.: Honoraria; Novartis Pharmaceuticals: Honoraria, Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; Eisai Co., Ltd.: Research Funding; Astellas Pharma Inc.: Research Funding; Alexion Pharmaceuticals, Inc.: Research Funding. Yamamoto: Bristol-Myers Squibb Company: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria; Eisai Co., Ltd.: Honoraria; Kyowa Kirin Co., Ltd.: Honoraria; NIPPON SINYAKU CO., LTD: Honoraria; Novartis Pharma: Honoraria; ONO PHARMACEUTICAL CO.: Honoraria; Otsuka Pharmaceutical: Honoraria; Pfizer Japan Inc.: Honoraria; Takeda: Honoraria. Kiyoi: Astellas: Honoraria; celgene: Honoraria; Daiichi Sankyo: Honoraria; Dainippon Sumitomo: Honoraria; Eisai: Honoraria; Fijifilm: Honoraria; Kyowa Kirin: Honoraria; Otsuka: Honoraria; Perseus Proteomics: Honoraria; Pfizer: Honoraria; Pfizer: Honoraria; Sanofi: Honoraria; Takeda: Honoraria; Zenyaku Kogyo: Honoraria. Matsumura: Ono: Research Funding; Otsuka: Consultancy, Research Funding, Speakers Bureau; Pfizer: Research Funding, Speakers Bureau; Shionogi: Research Funding; Taiho: Research Funding; Takeda: Research Funding; Sumitomo Dainippon: Research Funding; Nihon Pharmaceutical: Research Funding; Daiichi Sankyo: Research Funding, Speakers Bureau; Japan Blood Products Organization: Research Funding; Mundipharma: Research Funding; AYUMI Pharmaceutical: Research Funding; Eli Lilly Japan: Research Funding; Novartis: Research Funding, Speakers Bureau; Nippon Shinyaku: Research Funding; MSD: Research Funding; Mitsubishi Tanabe: Research Funding; Amgen: Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; Janssen: Speakers Bureau; Kyowa Kirin: Research Funding; Eisai: Research Funding; Chugai: Research Funding; Astellas: Speakers Bureau; Asahi Kasei: Research Funding; Addvie: Research Funding. Miyazaki: Pfizer: Honoraria; Kyowa-Kirin: Honoraria; Abbvie: Honoraria; Bristol-Myers Squibb: Honoraria; Nippon-Shinyaku: Honoraria; Novartis: Honoraria; Astellas: Honoraria; Sumitomo-Dainippon: Honoraria, Research Funding; Janssen: Honoraria; Eisai: Honoraria; Daiichi-Sankyo: Honoraria; Takeda: Honoraria; Chugai: Honoraria; Sanofi: Honoraria.

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/m2) or Id-MTX (0.5 g/m2). 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.

This study investigated the efficacy of imatinib based therapy with intensified consolidation therapy in patients with Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL) to prevent early relapse. We conducted a phase II trial of imatinib-combined chemotherapy for newly diagnosed BCR-ABL-positive ALL in adults. Sixty-eight patients were included in the trial between October 2008 and December 2010. The median age was 49 years, with 28 patients55 years of age. Sixty-five patients achieved CR (95.6%). The estimated 2-year event-free survival (EFS) and overall survival (OS) were 62.3% and 67.4%, respectively. Allogeneic stem cell transplantation (allo-SCT) at initial CR was performed in 43 patients. Thirty-five of 39 patients55 years and 8 of 26 patients55 years underwent allo-SCT at first CR. The 3-year OS in patients55 years receiving allo-SCT at first CR, patients55 years receiving allo-SCT at first CR, patients55 years not receiving allo-SCT at first CR, and patients55 years not receiving allo-SCT at first CR were 80.4%, 41.1%, 32.5%, and 52.0%, respectively (P = 0.058). The three-year EFS in each group was 76.7%, 53.6%, not reached, and 26.4%, respectively (P = 0.150). A high CR rate was observed with imatinib-based chemotherapy allowing allo-SCT in a high proportion of patients, particularly those55 years. Moreover, intensified consolidation therapy reduced early relapse rates following induction therapy and resulted in improved OS and EFS rates following allo-SCT. This trial was registered with the UMIN (000001226).

Body mass index (BMI), which represents the proportion of weight to height, is a controversial prognostic factor for acute myeloid leukemia (AML). We evaluated prognostic value of BMI in Japanese AML. The study included 369 adult patients with newly diagnosed AML who were administered either daunorubicin or idarubicin with cytarabine as induction chemotherapy. The patients were categorized into two groups according to their BMI: the NW group (BMI

Background: Treatment-free remission (TFR) is a new therapeutic goal for chronic myeloid leukemia in chronic phase (CML-CP). Deep molecular response (DMR) is a prerequisite condition to discontinue a tyrosine kinase inhbitor (TKI). In ENESTnd and DASISION trials, both nilotinib and dasatinib achieved DMR more effectively than imatinib. However, there is no direct comparative study to determine which TKI is better to achieve DMR for de novo CML-CP. So, we conducted a randomized phase 3 JALSG CML212 study to compare the achievement of MR4.5 (BCR-ABL IS≤0.0032%) between nilotinib and dasatinib. Methods: The JALSG CML212 study is a multicentral open-labeled prospective randomized controlled phase 3 study for de novo CML-CP. This study was reviewed and approved by the institutional review board of each institute and registered in the UMIN Clinical Trials Registry (#UMIN000007909). All patients provided written informed consent before enrollment. Diagnosis of CML was done by a cytogenetic study (G-banding or FISH) and/or detection of BCR-ABL by RT-PCR. The primary endpoint is a rate of cumulative achievement of MR4.5 by 18 mon. Major secondary endpoints were safety, continuity, progression-free survival (PFS), event-free survival (EFS), overall survival (OS), and cytogenetic and molecular responses. A total of 461 patients were registered from 82 institutes and 454 patients were randomly assigned to the nilotinib arm or dasatinib arm (both, n=227) with Sokal risk scores as a stratification factor. Treatment doses were 300 mg, bid for nilotinib and 100 mg, qd for dasatinib. Treatment responses were evaluated by ELN2009. Patients were allowed to stop study treatment if judged as failure by ELN2009 or showed intolerance (repetitive ≥Grade 3 or continuous Grade 2 side effects) to the allocated TKI. BCR-ABL mRNA levels were monitored every three months with international scales using a MolecularMD, ODK-1201, or M135R kit with ≥MR4.5 sensitivities. Adverse events were evaluated by the CTCAE ver 4.0. Results: The median age of the patients was 53 years old in both arms. The proportions of Sokal low, intermediate, and high risk groups were 44.1%, 37.0%, and 18.9% in the nilotinib arm and 44.5%, 37.0%, and 18.5% in the dasatinib arm, respectively, without a significant difference. Also, there was no significant difference in ECOG PS, EUTOS risk groups, complications, or frequencies of additional chromosomal abnormalities in both arms. In the ITT population, the cumulative achievement rates of MR4.5 by 18 mon were 33.0% (75/227) (95% CI:27.0-39.6%) in the nilotinib arm and 30.8% (70/227) (95% CI: 24.9-37.3%) in the dasatinib arm with no significant difference with a CMH test (p=0.62). This finding was also confirmed in the per-protocol (PP) population (33.5% in the nilotinib arm and 31.8% in the dasatinib arm, p=0.72). At 18 mon, 75.9% and 79.6% of the patients continued the allocated TKI in the nilotinib and dasatinib arms, respectively (p=0.36) (in the PP population).There was no significant difference in PFS, EFS, or OS between two arms by log-rank tests (the estimated rates at 36 mon: 98.8%, 67.2%, and 98.8% in the nilotinib arm; 99.0%, 65.4%, and 99.0% in the dasatinib arm). In addition, PFS, EFS and OS didn't differ between both arms regardless of Sokal and EUTOS risk groups. The cumulative CCyR rates by 12, 18, 24, and 36 mon were 77.1%, 78.0%, 78.4%, and 78.4% in the nilotinib arm and 78.4%, 78.9%, 78.9%, and 78.9% in the dasatinib arm, respectively without no significant difference. The MMR rates by 12, 18, 24, and 36 mon were 62.6%, 67.0%, 72.3%, and 73.1% in the nilotinib arm and 68.7%, 73.1%, 75.3%, and 77.1% in the dasatinib arm, respectively, without no significant difference. The MR4.5 rates by 12, 24, and 36 mon were 25.6%, 37.4%, and 40.5% in the nilotinib arm and 23.4%, 36.6%, and 44.5% in the dasatinib arm, respectively, with no significant difference. In the safety population, Grade 3/4 adverse events observed with ≥10% frequencies were lipase elevation (11.5%) in the nilotinib arm and neutropenia (12.8%) and thrombocytopenia (16.8%) in the dasatinib arm. Any new safety issue was observed in neither of the arms. Conclusions: Based on these results, we consider that nilotinib and dasatinib are equally effective for de novo CML-CP patients in achieving MR4.5 as well as in achieving CCyR and MMR in terms of both frequencies and times to achievement with similar continuity. Figure Disclosures Matsumura: Kyowa Kirin Co., Ltd.: Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; Shionogi & Co., Ltd.: Research Funding; Janssen Pharmaceutical K.K: Speakers Bureau; Amgen K.K.: Speakers Bureau; DAIICHI SANKYO COMPANY, LIMITED.: Speakers Bureau; Astellas Pharma Inc.: Speakers Bureau; Otsuka Pharmaceutical Co., Ltd.: Speakers Bureau; ONO PHARMACEUTICAL CO., LTD.: Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding; Eisai Co., Ltd.: Research Funding; Bristol-Myers Squibb Company: Speakers Bureau; Pfizer Japan Inc.: Speakers Bureau; Novartis Pharma KK: Speakers Bureau. Minami:Pfizer Japan Inc.: Honoraria; Novartis Pharma KK: Honoraria; Bristol-Myers Squibb Company: Honoraria; Takeda: Honoraria. Takahashi:Bristol-Myers Squibb Company: Honoraria; Pfizer Japan Inc.: Honoraria, Research Funding; Novartis Pharma KK: Honoraria, Research Funding. Nakaseko:Novartis Pharma KK: Speakers Bureau; Pfizer Japan Inc.: Speakers Bureau. Iriyama:Bristol-Myers Squibb Company: Speakers Bureau; Novartis Pharma KK: Speakers Bureau; Pfizer Japan Inc.: Speakers Bureau; Otsuka Pharmaceutical: Speakers Bureau. ONO:Mundipharma K.K.: Honoraria; Janssen Pharmaceutical K.K: Honoraria; Eisai Co., Ltd.: Honoraria; Astellas Pharma Inc.: Honoraria; TAIHO PHARMACEUTICAL CO., LTD.: Research Funding; Takeda Pharmaceutical Company Limited.: Honoraria; ONO PHARMACEUTICAL CO., LTD.: Honoraria, Research Funding; Otsuka Pharmaceutical Co., Ltd.: Honoraria; Pfizer Japan Inc.: Honoraria; Bristol-Myers Squibb Company: Honoraria; Novartis Pharma KK: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Kyowa Kirin Co., Ltd.: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; DAIICHI SANKYO COMPANY, LIMITED.: Honoraria. Fujisawa:Janssen Pharmaceutical K.K: Speakers Bureau; Celgene: Speakers Bureau; Novartis Pharma KK: Research Funding, Speakers Bureau; Bristol-Myers Squibb Company: Speakers Bureau; Pfizer Japan Inc.: Research Funding, Speakers Bureau; Otsuka Pharmaceutical: Speakers Bureau; Astellas Pharma Inc.: Research Funding, Speakers Bureau; Takeda Pharmaceutical Company Limited.: Speakers Bureau; NIPPON SHINYAKU CO.,LTD.: Research Funding. Kobayashi:Pfizer Japan Inc.: Research Funding, Speakers Bureau; Astellas Pharma Inc.: Speakers Bureau; SymBio Pharmaceuticals Limited.: Consultancy. Asou:Fuji Pharma Co.,Ltd.: Speakers Bureau; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; Eisai Co., Ltd.: Research Funding; NIPPON SHINYAKU CO.,LTD.: Honoraria, Speakers Bureau; Astellas Pharma Inc.: Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding; Novartis Pharma KK: Honoraria; Asahi Kasei Pharma.: Speakers Bureau. Kiyoi:Celgene Corporation: Research Funding; Bristol-Myers Squibb Company: Speakers Bureau; Astellas Pharma Inc.: Consultancy, Research Funding, Speakers Bureau; Chugai Pharmaceutical Co., Ltd.: Research Funding; Novartis Pharma KK: Research Funding, Speakers Bureau; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; Otsuka Pharmaceutical Co., Ltd.: Research Funding; NIPPON SHINYAKU CO.,LTD.: Research Funding; Amgen Astellas BioPharma K.K.: Consultancy; Kyowa Kirin Co., Ltd.: Research Funding; Zenyaku Kogyo Co., Ltd.: Research Funding; FUJIFILM Corporation: Research Funding; Daiichi Sankyo Co., Ltd.: Consultancy, Research Funding; Eisai Co., Ltd.: Research Funding; Pfizer Japan Inc.: Research Funding; Takeda Pharmaceutical Co., Ltd.: Research Funding; Sanofi K.K.: Research Funding; Perseus Proteomics Inc.: Research Funding. Miyazaki:NIPPON SHINYAKU CO.,LTD.: Honoraria; Otsuka Pharmaceutical: Honoraria; Novartis Pharma KK: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria; Kyowa Kirin Co., Ltd.: Honoraria; Astellas Pharma Inc.: Honoraria; Celgene: Honoraria; Sumitomo Dainippon Pharma Co., Ltd.: Honoraria. Naoe:Sysmex co.: Speakers Bureau; NIPPON SHINYAKU CO.,LTD.: Speakers Bureau; Eisai Co., Ltd.: Speakers Bureau; Astellas Pharma Inc.: Speakers Bureau; Bristol-Myers Squibb Company: Speakers Bureau.

Introduction Despite recent developments on various transplantation procedures and supportive therapy, nonrelapse mortality (NRM) after allogeneic stem cell transplantation (allo-SCT) remains an essential issue. In choosing the appropriate regimen for allo-SCT, decision-making information that considers the complexity of different risk factors is vital. The Hematopoietic Cell Transplantation-Comorbidity Index (HCT-CI), which was initially derived and validated by investigators at the Fred Hutchinson Cancer Research Center to predict NRM, has become a widely validated tool for predicting outcomes in many transplant settings (Sorror et al. Blood. 2005). It can also stratify patients for the risk of other outcomes, including overall survival and graft versus host disease. Patients with a high HCT-CI score tend to prefer allo-SCT with reduced-intensity conditioning. Conversely, for those who prefer allo-SCT with myeloablative conditioning (MAC) and has a low HCT-CI score, a prognostic indicator is unnecessary. Furthermore, the risk factors for NRM may differ among various conditioning regimens. Therefore, the current study aimed to establish a new prognostic model for patients specific to each MAC regimen before allo-SCT. Methods We performed a retrospective cohort study to develop prognostic models of NRM in patients conditioned with cyclophosphamide/total body irradiation (Cy/TBI) or busulfan/cyclophosphamide (Bu/Cy). We selected patients who had leukemia and lymphoma in remission or had untreated or stable myelodysplastic syndrome and experienced initial allo-SCT relapse between 2007 and 2017 in the Kanto Study of Group for Cell Therapy (KSGCT). The primary outcome measure was 2-year NRM. Furthermore, we evaluated variables such as patient age, albumin, liver function, renal function, respiratory function, ejection fraction (EF), C-reactive protein (CRP), stem cell source, donor type, antithymocyte globulin use, performance status, recipient/donor sexes, time interval from diagnosis to transplant, and HCT-CI score. To identify a set of variables for Cox proportional hazards, we used an Akaike Information Criterion (AIC)-based variable selection procedure. We assigned weights to individual parameters according to their prognostic significance in Cox proportional hazard models. The identified model's discriminative ability was assessed by Harrell's C-statistic calculated using the bootstrap method. Results Among the 555 patients analyzed, 338 received Cy/TBI, and 217 received Bu/Cy. In Cy/TBI and Bu/Cy, the median age was 39 (11-60) and 44 (18-62) years, the HCT-CI score ≤ 2 was observed in 82.1% and 87.6%, and 2-year NRM was found in 13.5% and 16.0% of the patients, respectively. Before transplantation, the most dominant parameters in Cy/TBI were abnormal liver function (AST/ALT or bilirubin >upper limit of normal) and albumin value < 4.5g/dL, whereas those in Bu/Cy were age >40 years, EF < 65 %, and CRP ≥ 0.2 mg/dL. Internal validation with bootstrap resampling showed good discrimination, with C-statistic values of 0.70 (95% CI: 0.69-0.71) in Cy/TBI and 0.68 (95% CI: 0.67-0.69) in Bu/Cy. Each of the abovementioned parameters, including age >40 years, was scored as 1 point. To evaluate the 2-year NRM, we divided the total scores into three risk groups. In the Cy/TBI group, the NRM was 6.9% in low (score 0-1, n = 186), 19.5% in intermediate (score 2, n = 127), and 35.3% in high (score 3, n = 25) scores. In the Bu/Cy group, the NRM was 8.3% in low (score 0-1, n = 93), 21.7% in intermediate (score 2, n = 98), and 29.8% in high (score 3, n = 26) scores (Figure). Higher scores were strongly associated with worse NRM and survival. Conclusions Our prognostic models for NRM estimation can distinguish patients with a high NRM risk. To our knowledge, these models are the first prognostic models used to estimate NRM for standard-risk patients specific to each MAC regimen. This new simple index may help predict NRM and choose an appropriate conditioning regimen before allo-SCT. Figure 1 Disclosures Nakasone: Takeda Pharmaceutical: Honoraria; Otsuka Pharmaceutical: Honoraria; Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Pfizer: Honoraria; Novartis: Honoraria; Janssen Pharmaceutical: Honoraria; Eisai: Honoraria; Chugai Pharmaceutical: Honoraria; Nippon Shinyaku: Honoraria. Fujisawa:Takeda Pharmaceutical Company Limited.: Speakers Bureau; Astellas Pharma Inc.: Research Funding, Speakers Bureau; Otsuka Pharmaceutical: Speakers Bureau; Pfizer Japan Inc.: Research Funding, Speakers Bureau; Bristol-Myers Squibb Company: Speakers Bureau; Novartis Pharma KK: Research Funding, Speakers Bureau; Celgene: Speakers Bureau; Janssen Pharmaceutical K.K: Speakers Bureau; NIPPON SHINYAKU CO.,LTD.: Research Funding. Nakaseko:Novartis Pharma KK: Speakers Bureau; Pfizer Japan Inc.: Speakers Bureau. Kanda:Novartis: Honoraria; Kyowa Kirin: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria; Takeda Pharmaceuticals: Honoraria; Alexion Pharmaceuticals: Honoraria; Shire: Honoraria; Daiichi Sankyo: Honoraria; Ono Pharmaceutical: Honoraria; Nippon Shinyaku: Honoraria, Research Funding; Mochida Pharmaceutical: Honoraria; Mundipharma: Honoraria; Sanofi: Honoraria, Research Funding; Meiji Seika Kaisha: Honoraria; Shionogi: Research Funding; Otsuka: Honoraria, Research Funding; Celgene: Honoraria; Chugai Pharma: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; Janssen: Honoraria; Astellas Pharma: Honoraria, Research Funding; Sumitomo Dainippon Pharma: Honoraria; Pfizer: Honoraria, Research Funding; Merck Sharp & Dohme: Honoraria.