Post-transplant cyclophosphamide (PTCy) is becoming the standard prophylaxis for graft-versus-host disease (GVHD) in HLA-haploidentical allogeneic hematopoietic cell transplantation (allo-HCT) and in ...HLA-matched allo-HCT. Immune reconstitution in the post-transplant setting may influence the graft-versus-tumor (GVT) effect because PTCy has a profound effect on T cell and natural killer cell functions and their reconstitution after allo-HCT. However, many recent studies have shown that the incidence of relapse after allo-HCT with PTCy is comparable to that after conventional allo-HCT. To further improve the outcomes, it is critical to establish a strategy to maintain or effectively induce the GVT effect when using PTCy as a platform for GVHD prophylaxis. However, there is a paucity of studies focusing on the GVT effect in allo-HCT with PTCy. Therefore, focusing on this issue may lead to the establishment of more appropriate strategies to improve transplantation outcomes without exacerbating GVHD, including novel therapies involving cell modification.Post-transplant cyclophosphamide (PTCy) is becoming the standard prophylaxis for graft-versus-host disease (GVHD) in HLA-haploidentical allogeneic hematopoietic cell transplantation (allo-HCT) and in HLA-matched allo-HCT. Immune reconstitution in the post-transplant setting may influence the graft-versus-tumor (GVT) effect because PTCy has a profound effect on T cell and natural killer cell functions and their reconstitution after allo-HCT. However, many recent studies have shown that the incidence of relapse after allo-HCT with PTCy is comparable to that after conventional allo-HCT. To further improve the outcomes, it is critical to establish a strategy to maintain or effectively induce the GVT effect when using PTCy as a platform for GVHD prophylaxis. However, there is a paucity of studies focusing on the GVT effect in allo-HCT with PTCy. Therefore, focusing on this issue may lead to the establishment of more appropriate strategies to improve transplantation outcomes without exacerbating GVHD, including novel therapies involving cell modification.
The successful application of post-transplantation cyclophosphamide (PTCy) as graft-versus-host disease (GVHD) prophylaxis in HLA-haploidentical allogeneic hematopoietic cell transplantation ...(allo-HCT) led to the expansion of its application to HLA-matched related and unrelated allo-HCT. Notably, single-agent PTCy was found to be feasible for GVHD prevention in HLA-matched bone marrow transplantation. Single-agent PTCy prophylaxis was later attempted to control GVHD in HLA-matched peripheral blood stem cell transplantation (PBSCT), but this approach was inadequate to alleviate GVHD as evidenced by the high incidence of severe GVHD and/or non-relapse mortality. Therefore, various combinations of immunosuppressants with PTCy have been explored to identify the optimal drug combination that would efficiently prevent GVHD in HLA-matched PBSCT. A recent murine study helped clarify the putative mechanism underlying the activity of PTCy, demonstrating that PTCy impairs the proliferation and function of alloreactive T cells from the donor, but does not eliminate alloreactive T cells altogether. In addition, imbalanced reconstitution of NK cell as well as T cells has been observed in HLA-haploidentical allo-HCT. Therefore, it remains unclear whether or not PTCy-containing GVHD prophylaxis should replace the classical GVHD prophylaxis regimen in the HLA-matched setting, and convincing evidence supporting the benefits of PTCy is needed.
A combination of three post-transplant drugs, cyclophosphamide (PTCy), a calcineurin inhibitor, and mycophenolate mofetil, has long been used for prophylaxis of graft-versus-host-disease (GVHD) after ...HLA-haploidentical allogeneic hematopoietic cell transplantation (allo-HCT). Recently, this combination has been used following HLA-matched allo-HCT as well, but the optimal combination of drugs for GVHD prophylaxis in an HLA-matched setting remains unclear. This prospective phase II study evaluated the safety and efficacy of PTCy plus tacrolimus (TAC) for GVHD prophylaxis after allo-HCT from HLA-matched related donors (MRD) or HLA-matched unrelated donors (MUD). The cumulative incidences of grades II–IV and III–IV acute GVHD at 100 days post-transplantation were 18% and 5.9%, respectively, in the MRD group, and 18% and 9.1%, respectively, in the MUD group. The cumulative incidences of moderate to severe chronic GVHD at 1 year were 12% and 9.1% in the MRD and MUD groups, respectively. The 1-year overall survival rates in the MRD and MUD groups were 88% and 64%, respectively, and the 1-year GVHD-free, relapse free survival rates were 59% and 50%, respectively. These results suggest that GVHD prophylaxis with a less intensive double drug combination (PT/Cy and TAC) might be feasible after HLA-matched allo-HCT.
Clinical Trial Notation
This trial was a prospective single-center trial registered at the University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR; identification number: UMIN000023890) and the Japan Registry of Clinical Trials (jRCTs051180143).
Treatment with dasatinib, a highly potent BCR-ABL kinase inhibitor, has resulted in high rates of complete cytogenetic response and progression-free survival among patients with chronic myeloid ...leukemia (CML) in the chronic phase, after failure of imatinib treatment. We assessed the efficacy and safety of dasatinib, as compared with imatinib, for the first-line treatment of chronic-phase CML.
In a multinational study, 519 patients with newly diagnosed chronic-phase CML were randomly assigned to receive dasatinib at a dose of 100 mg once daily (259 patients) or imatinib at a dose of 400 mg once daily (260 patients). The primary end point was complete cytogenetic response by 12 months, confirmed on two consecutive assessments at least 28 days apart. Secondary end points, including major molecular response, were tested at a significance level of 0.0001 to adjust for multiple comparisons.
After a minimum follow-up of 12 months, the rate of confirmed complete cytogenetic response was higher with dasatinib than with imatinib (77% vs. 66%, P=0.007), as was the rate of complete cytogenetic response observed on at least one assessment (83% vs. 72%, P=0.001). The rate of major molecular response was higher with dasatinib than with imatinib (46% vs. 28%, P<0.0001), and responses were achieved in a shorter time with dasatinib (P<0.0001). Progression to the accelerated or blastic phase of CML occurred in 5 patients who were receiving dasatinib (1.9%) and in 9 patients who were receiving imatinib (3.5%). The safety profiles of the two treatments were similar.
Dasatinib, administered once daily, as compared with imatinib, administered once daily, induced significantly higher and faster rates of complete cytogenetic response and major molecular response. Since achieving complete cytogenetic response within 12 months has been associated with better long-term, progression-free survival, dasatinib may improve the long-term outcomes among patients with newly diagnosed chronic-phase CML. (ClinicalTrials.gov number, NCT00481247.)
Multiple myeloma (MM) is still extremely difficult to cure, and new therapeutic drugs are needed. We recently found that integrin β7 is constitutively activated in MM cells, and chimeric antigen ...receptor (CAR) T cells targeting activated integrin β7 have a significant anti-MM effect. In this study, we performed flow cytometry analysis of the expression of activated integrin β7 in bone marrow cells from 137 symptomatic MM patients. In 60/137 (44%) MM patients, activated integrin β7 was detected in most MM cells (> 80% of MM cells were in the positive gate). Activated integrin β7 was highly expressed in MM cells even in heavily treated patients. It also showed high expression in many CD38
lo
/
−
CD138
−
CD19
+
B cells, which reportedly include clonotypic B cells, in the bone marrow of MM patients. Taken together, these results suggest that CAR T-cell therapy targeting activated integrin β7 has the potential to benefit many patients with relapsed or refractory MM.
Allogeneic hematopoietic cell transplantation (allo-HCT) is a curative treatment option for malignant hematological disorders. Transplant clinicians estimate patient-specific prognosis empirically in ...clinical practice based on previous studies on similar patients. However, this approach does not provide objective data. The present study primarily aimed to develop a tool capable of providing accurate personalized prognosis prediction after allo-HCT in an objective manner.
We developed an interactive web application tool with a graphical user interface capable of plotting the personalized survival and cumulative incidence prediction curves after allo-HCT adjusted by 8 patient-specific factors, which are known as prognostic predictors, and assessed their predictive performances. A random survival forest model using the data of patients who underwent allo-HCT at our institution was applied to develop this application.
We succeeded in showing the personalized prognosis prediction curves of 1-year overall survival, progression-free survival, relapse/progression, and nonrelapse mortality (NRM) interactively using our web application (https://predicted-os-after-transplantation.shinyapps.io/RSF_model/). To assess its predictive performance, the entire cohort (363 cases) was split into a training cohort (70%) and a test cohort (30%) time-sequentially based on the patients' transplant dates. The areas under the receiver-operating characteristic curves for 1-year overall survival, progression-free survival, relapse/progression, and nonrelapse mortality in test cohort were 0.70, 0.72, 0.73, and 0.77, respectively.
The new web application could allow transplant clinicians to inform a new allo-HCT candidate of the objective personalized prognosis prediction and facilitate decision-making.
Summary Background Nilotinib has shown greater efficacy than imatinib in patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukaemia (CML) in chronic phase after a ...minimum follow-up of 12 months. We present data from the Evaluating Nilotinib Efficacy and Safety in clinical Trials–newly diagnosed patients (ENESTnd) study after a minimum follow-up of 24 months. Methods ENESTnd was a phase 3, multicentre, open-label, randomised study. Adult patients were eligible if they had been diagnosed with chronic phase, Philadelphia chromosome-positive CML within the previous 6 months. Patients were randomly assigned (1:1:1) to receive nilotinib 300 mg twice a day, nilotinib 400 mg twice a day, or imatinib 400 mg once a day, all administered orally, by use of a computer-generated randomisation schedule, using permuted blocks, and stratified according to Sokal score. Efficacy results are reported for the intention-to-treat population. The primary endpoint was major molecular response at 12 months, defined as BCR–ABL transcript levels on the International Scale (BCR–ABLIS ) of 0·1% or less by real-time quantitative PCR in peripheral blood. This study is registered with ClinicalTrials.gov , number NCT00471497. Findings 282 patients were randomly assigned to receive nilotinib 300 mg twice daily, 281 to receive nilotinib 400 mg twice daily, and 283 to receive imatinib. By 24 months, significantly more patients had a major molecular response with nilotinib than with imatinib (201 71% with nilotinib 300 mg twice daily, 187 67% with nilotinib 400 mg twice daily, and 124 44% with imatinib; p<0·0001 for both comparisons). Significantly more patients in the nilotinib groups achieved a complete molecular response (defined as a reduction of BCR–ABLIS levels to ≤0·0032%) at any time than did those in the imatinib group (74 26% with nilotinib 300 mg twice daily, 59 21% with nilotinib 400 mg twice daily, and 29 10% with imatinib; p<0·0001 for nilotinib 300 mg twice daily vs imatinib, p=0·0004 for nilotinib 400 mg twice daily vs imatinib). There were fewer progressions to accelerated or blast phase on treatment, including clonal evolution, in the nilotinib groups than in the imatinib group (two with nilotinib 300 mg twice daily, five with nilotinib 400 mg twice daily, and 17 with imatinib; p=0·0003 for nilotinib 300 mg twice daily vs imatinib, p=0·0089 for nilotinib 400 mg twice daily vs imatinib). At 24 months, survival was comparable in all treatment groups, but fewer CML-related deaths had occurred in both the nilotinib groups than in the imatinib group (five with nilotinib 300 mg twice daily, three with nilotinib 400 mg twice daily, and ten with imatinib). Overall, the only grade 3 or 4 non-haematological adverse events that occurred in at least 2·5% of patients were headache (eight 3% with nilotinib 300 mg twice daily, four 1% with nilotinib 400 mg twice daily, and two <1% with imatinib) and rash (two <1%, seven 3%, and five 2%, respectively). Grade 3 or 4 neutropenia was more common with imatinib than with either dose of nilotinib (33 12% with nilotinib 300 mg twice daily, 30 11% with nilotinib 400 mg twice daily, and 59 21% with imatinib). Serious adverse events were reported in eight additional patients in the second year of the study (four with nilotinib 300 mg twice daily, three with nilotinib 400 mg twice daily, and one with imatinib). Interpretation Nilotinib continues to show better efficacy than imatinib for the treatment of patients with newly diagnosed CML in chronic phase. These results support nilotinib as a first-line treatment option for patients with newly diagnosed disease. Funding Novartis.
Treatment of chronic myelogenous leukemia (CML) requires management of long-term use of tyrosine kinase inhibitors (TKIs). Although cardiovascular adverse events (CAEs) caused by off-target effects ...of TKIs can be life-threatening, the optimal method of monitoring for CAEs has not been established. Here, we comprehensively evaluated the clinical utility of various cardiovascular parameters, including ankle-brachial blood pressure index (ABI), cardiac ankle vascular index (CAVI), and carotid ultrasonography and electrocardiogram measurements, for monitoring and predicting CAEs in 74 patients with CML receiving TKIs. Based on concordance statistics, the predictive value of established risk factor models was significantly improved by addition of both ABI and CAVI, as follows: model 1 (hypertension, smoking history, and dyslipidemia), 0.680 versus 0.817 (
p
= 0.041); model 2 (hypertension, dyslipidemia, and diabetes mellitus), 0.685 vs. 0.830 (
p
= 0.047); and model 3 (age, hypertension, dyslipidemia and diabetes mellitus) 0.737 versus 0.818 (
p
= 0.044). However, no single cardiovascular parameter independently improved the predictive value of established risk factor models. In conclusion, addition of combined assessment of ABI and CAVI to established risk factors can improve prediction of future CAEs and may enable better clinical management of patients with CML receiving TKIs.
Tyrosine kinase inhibitor (TKI) administration after allogeneic hematopoietic stem cell transplantation (HSCT) may carry a survival benefit in Philadelphia chromosome‐positive acute lymphoblastic ...leukemia (Ph+ ALL). Therefore, we investigated whether TKI prophylaxis for negative‐minimal residual disease (MRD) after HSCT would improve patient outcomes in this nationwide retrospective cohort study. We included patients with Ph+ ALL who underwent their first allogeneic HSCT between 2001 and 2016, received TKI before HSCT, and achieved negative‐MRD status within 180 days after HSCT. Of 850 patients for inclusion, 50 patients received TKI prophylaxis, mostly imatinib or dasatinib (median dose: 400 mg with imatinib and 40 mg with dasatinib). In a multivariate analysis, disease status at HSCT was the sole risk factor for relapse (hazard ratio, 3.58; P < .001 for positive‐MRD with complete remission CR and hazard ratio, 6.13; P < .001 for active disease). TKI prophylaxis was not associated with a decreased risk of relapse or superior overall survival in either the whole cohort or in the analysis limited to negative‐MRD or positive‐MRD with CR1 at HSCT. Meanwhile, TKI prophylaxis limited to dasatinib might be associated with a decreased risk of relapse (hazard ratio, 0.34; P = .140), unlike imatinib. Alternative strategies using new‐generation TKI for high‐risk patients are warranted to improve the outcomes after allogeneic HSCT.
Tyrosine kinase inhibitor prophylaxis was not associated with a decreased risk of relapse or superior overall survival despite MRD positivity at HSCT. Disease status at HSCT was a significant risk factor for relapse even in patients who achieved negative‐MRD early after HSCT.
Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curable treatment option for adolescent and young adult (AYA) patients with myelodysplastic syndrome (MDS). The study aim was to ...evaluate epidemiological data and identify prognostic factors for AYA patients with MDS undergoing allogeneic HSCT. Here, 645 patients were selected from patients enrolled in a multicenter prospective registry for HSCT from 2000 to 2015. The primary endpoint was 3-year overall survival (OS). Survival rates were estimated using the Kaplan-Meier method. Prognostic factors were identified using the multivariable Cox proportional hazards model. The 3-year OS was 71.2% (95% confidence interval CI: 67.4-74.6%). In multivariable analysis, active disease status (adjusted hazard ratio: 1.54, 95% CI: 1.09-2.18, p = 0.016), poor cytogenetic risk (1.62, 1.12-2.36, p = 0.011), poor performance status (2.01, 1.13-3.56, p = 0.016), human leukocyte antigen (HLA)-matched unrelated donors (2.23, 1.39-3.59, p < 0.001), HLA-mismatched unrelated donors (2.16, 1.09-4.28, p = 0.027), and cord blood transplantation (2.44, 1.43-4.17, p = 0.001) were significantly associated with poor 3-year OS. In conclusion, in AYA patients with MDS the 3-year OS following allogeneic HSCT was 71.2%. Active disease status, poor cytogenetic risk, poor performance status, and donor sources other than related donors were associated with poor 3-year OS.
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