Effect of methotrexate dose in graft-versus-host disease prophylaxis after single-unit cord blood transplantation in adult acute myeloid leukemia.

To investigate the association between methotrexate (MTX) dosage and engraftment, graft-versus-host disease (GVHD) incidence, and survival in umbilical cord blood transplantation (UCBT), we compared transplant outcomes after UCBT with various GVHD prophylaxis regimens, using registry data with additional data collection. Patients transplanted for acute myeloid leukemia with a calcineurin inhibitor (CNI) and either MTX or mycophenolate mofetil (MMF) combination were selected. In total, 888 single-unit UCBTs (MTX15-10-10, 415; MTX10-7-7, 294; MTX5-5-5, 71; MMF, 108) were included. In multivariate analyses with MTX15-10-10 as the reference, the likelihood of neutrophil and platelet engraftment was significantly worse in the MTX10-7-7 group, and similarly better in MMF group compared with MTX15-10-10. All variables including CyA vs Tac and 4-group GVHD prophylaxis became significant for the risk of grade II-IV acute GVHD in the final multivariate model. We observed significant additional effects of combined MTX dose in the Tac group, which were larger with lower MTX dose and MMF. No significant difference was observed in survival risk among GVHD prophylaxis groups. Despite the potential background differences in the combined CNI and conditioning regimen, we conclude that the recommended GVHD prophylaxis is a combination of CyA plus MTX15-10-10 or Tac plus MMF.

Silent NK/T cell reactions to dasatinib during sustained deep molecular response before cessation are associated with longer treatment-free remission.

This study presents the final report of the multicenter, prospective tyrosine kinase inhibitor discontinuation study, D-STOP, after a 3-year follow-up of 54 patients with chronic CML who discontinued dasatinib after a sustained deep molecular response (DMR) for ≥2 years with dasatinib treatment. Estimated treatment-free remission (TFR) rates at 12 and 36 months were 63.0% [95% confidence interval (CI): 48.7-74.3] and 59.3% (95% CI: 45.0-71.0), respectively. CD3- CD56+ NK, CD16+ CD56+ NK, and CD57+ CD56+ NK large granular lymphocyte (NK-LGL), CD8+ CD4- cytotoxic T cell, and CD57+ CD3+ T-LGL cell numbers were relatively elevated throughout the 24-month consolidation only in failed patients who molecularly relapsed within 12 months. In successful patients, these subsets elevated transiently after 12 months, but returned to basal levels after 24-month consolidation. Therefore, smaller changes in NK/T, particularly the NK subset throughout consolidation, reflected higher TFR rates. TFR rates of those patients exhibiting elevation in CD3- CD56+ NK >376 cells/µL, CD16+ CD56+ NK > 241 cells/µL, or CD57+ CD56+ NK-LGL >242 cells/µL during consolidation compared with others were 26.7% (8.3%-49.6%) vs 78.3% (55.4%-90.3%), HR 0.032 (0.0027-0.38; P = .0064), 31.2% (11.4%-53.6%) vs 85.0% (60.4%-94.9%), HR 0.039 (0.0031-0.48; P = .011), or 36.8% (16.5%-57.5%) vs 77.3% (53.7%-89.8%), HR 0.21 (0.065-0.69; P = .010), respectively. Therefore, silent responses of T/NK subsets to dasatinib throughout consolidation were significant for longer TFR. Elevated NK/T, particularly NK lymphocytes responsive to dasatinib, may be immunologically insufficient to maintain TFR. Their decline, subsequently replaced by altered lymphocyte population with less response to dasatinib during sustained DMR, might be immunologically significant. (D-STOP, NCT01627132).

Regulatory T cell inhibition by dasatinib is associated with natural killer cell differentiation and a favorable molecular response-The final results of the D-first study.

We evaluated the effects of regulatory T cell (Treg) inhibition during dasatinib treatment on the anticancer immune response, particularly on natural killer (NK) cells and cytotoxic T lymphocytes (CTLs). Fifty-two newly diagnosed Japanese patients with chronic myeloid leukemia (CML) in the chronic phase were enrolled in the D-first study; all received 100 mg of dasatinib once daily and were followed for at least 36 months. The cumulative deep molecular response (DMR, MR4) rate was 65% by 36 months; the 3-year overall survival was 96%. CD4+ T cell counts were stable, whereas the proportion of CD4+CD25+CD127low (Treg) cells decreased in a time-dependent manner. The DMR rate by18 months was significantly better in low Treg patients (<5.7% at 12 months) compared to the remaining patients (odds ratio 4.07). NK cell and CTL counts at several time points were inversely correlated with Treg counts. Furthermore, the degree of NK cell differentiation (CD3-CD57+/CD3-CD56+) was closely and inversely correlated with the proportion of Treg cells throughout the observation period, and showed a gradually increasing trend. In conclusion, our results demonstrate that Treg inhibition by dasatinib contributes to better treatment response through enhancement of the immune system, particularly via NK cell differentiation.

Dasatinib cessation after deep molecular response exceeding 2 years and natural killer cell transition during dasatinib consolidation.

Tyrosine kinase inhibitors (TKI) improve the prognosis of patients with chronic myelogenous leukemia (CML) by inducing substantial deep molecular responses (DMR); some patients have successfully discontinued TKI therapy after maintaining DMR for ≥1 year. In this cessation study, we investigated the optimal conditions for dasatinib discontinuation in patients who maintained DMR for ≥2 years. This study included 54 patients with CML who were enrolled in a D-STOP multicenter prospective trial, had achieved DMR, and had discontinued dasatinib after 2-year consolidation. Peripheral lymphocyte profiles were analyzed by flow cytometry. The estimated 12-month treatment-free survival (TFS) was 62.9% (95% confidence interval: 48.5%-74.2%). During dasatinib consolidation, the percentage of total lymphocytes and numbers of CD3- CD56+ natural killer (NK) cells, CD16+ CD56+ NK cells and CD56+ CD57+ NK-large granular lymphocytes (LGL) were significantly higher in patients with molecular relapse after discontinuation but remained unchanged in patients without molecular relapse for >7 months. At the end of consolidation, patients whose total lymphocytes comprised <41% CD3- CD56+ NK cells, <35% CD16+ CD56+ NK cells, or <27% CD56+ CD57+ NK-LGL cells had higher TFS relative to other patients (77% vs 18%; P < .0008; 76% vs 10%; P < .0001; 84% vs 46%; P = .0059, respectively). The increase in the number of these NK cells occurred only during dasatinib consolidation. In patients with DMR, dasatinib discontinuation after 2-year consolidation can lead to high TFS. This outcome depends significantly on a smaller increase in NK cells during dasatinib consolidation.

Dasatinib rapidly induces deep molecular response in chronic-phase chronic myeloid leukemia patients who achieved major molecular response with detectable levels of BCR-ABL1 transcripts by imatinib therapy.

BACKGROUND: With the introduction of imatinib, a first-generation tyrosine kinase inhibitor (TKI) to inhibit BCR-ABL1 kinase, the outcome of chronic-phase chronic myeloid leukemia (CP-CML) has improved dramatically. However, only a small proportion of CP-CML patients subsequently achieve a deep molecular response (DMR) with imatinib. Dasatinib, a second-generation TKI, is more potent than imatinib in the inhibition of BCR-ABL1 tyrosine kinase in vitro and more effective in CP-CML patients who do not achieve an optimal response with imatinib treatment. METHODS: In the present study, we attempted to investigate whether switching the treatment from imatinib to dasatinib can induce DMR in 16 CP-CML patients treated with imatinib for at least two years who achieved a major molecular response (MMR) with detectable levels of BCR-ABL1 transcripts. RESULTS: The rates of achievement of DMR at 1, 3, 6 and 12 months after switching to dasatinib treatment in the 16 patients were 44% (7/16), 56% (9/16), 63% (10/16) and 75% (12/16), respectively. The cumulative rate of achieving DMR at 12 months from initiation of dasatinib therapy was 93.8% (15/16). The proportion of natural killer cells and cytotoxic T cells in peripheral lymphocytes increased after switching to dasatinib. In contrast, the proportion of regulatory T cells decreased during treatment. The safety profile of dasatinib was consistent with previous studies. CONCLUSION: Switching to dasatinib would be a therapeutic option for CP-CML patients who achieved MMR but not DMR by imatinib, especially for patients who wish to discontinue TKI therapy.

Acute Fibrinous and Organizing Pneumonia with Myelodysplastic Syndrome: Corticosteroid Monotherapy Led to Successful Ventilator Weaning.

A 62-year-old man with myelodysplastic syndrome (MDS) presented to our hospital with a high fever. Although treatment with broad-spectrum antibiotics was initiated, his respiratory status worsened to the point that he required mechanical ventilation. However, he was successfully treated with a corticosteroid without immunosuppression. Sequential transbronchial lung biopsies revealed abundant fibrin exudate in the alveolar spaces, which was subsequently replaced by fibroblasts, showing that acute fibrinous and organizing pneumonia (AFOP) gradually changes into organizing pneumonia. Our case demonstrated both the efficacy of corticosteroid-monotherapy and the histological course of AFOP.

Association of pleural effusion with an early molecular response in patients with newly diagnosed chronic-phase chronic myeloid leukemia receiving dasatinib: Results of a D-First study.

Despite the efficacy and safety of dasatinib treatment for chronic-phase chronic myeloid leukemia (CML-CP), adverse effects such as pleural effusion (PE) are still a serious concern. We determined the clinical significance of PE incidence using patient data derived from the D-First clinical study. In the present study, chest radiography and quantification of specific lymphocyte subsets were performed routinely after initiation of dasatinib treatment. Among 52 patients with newly diagnosed CML-CP, 17 (33%) developed PE within 18 months after initial dasatinib administration, but all cases were moderate (Grade 1, 10 patients; Grade 2, 7 patients). CD56+ lymphocyte counts at 1 month correlated significantly with the incidence of PE, whereas lymphocytosis did not. The major molecular response (MMR) rate at 3 months (although not at later times) was significantly higher in PE-positive patients than PE-negative patients (59% versus 24%, respectively; P=0.013). Deep molecular response rates did not differ significantly between the PE groups at any time point during the observation period. Our results suggest that an immune-mediated mechanism involving natural killer cells underlies the development of PE in patients receiving dasatinib for 18 months. This mechanism likely promotes transient tumor regression in patients newly diagnosed with CML-CP.

[Peripheral neuropathy occurring soon after cord blood transplantation].

We experienced two cases of peripheral neuropathy in the early phase following cord blood transplantation. Case 1 was a 66-year-old man with recurrent T-ALL. On day 8, he experienced a sharp pain originating in both the palms and the soles, which worsened spreading to the knees, and was accompanied by muscle weakness. The neurological symptom progressed to the point of being unable to walk. A nerve conduction velocity test showed demyelination and axonopathy. In the CSF analysis, albuminocytologic dissociation and a rise in myelin basic protein were detected. These findings met the diagnostic criteria for chronic inflammatory demyelinating polyneuropathy (CIDP). The symptoms improved with intravenous immunoglobulin (IVIG). He is now able to walk and continues to visit our department. Case 2 was a 42-year-old man with primary mediastinal large B-cell lymphoma. As the disease was refractory, he underwent reduced intensity cord blood transplantation (RICBT). Flare and numbness started in the palms and soles on day 26, with the symptoms progressing thereafter. A nerve conduction velocity test showed demyelination and axonopathy. The symptoms improved after IVIG administration. The diagnosis of peripheral neuropathy after transplantation is often difficult, but when an immunologic disorder is suspected to be the cause, early administration of IVIG may be effective.

Early cytotoxic lymphocyte expansion contributes to a deep molecular response to dasatinib in patients with newly diagnosed chronic myeloid leukemia in the chronic phase: results of the D-first study.

Dasatinib is one of the key treatment options for chronic myeloid leukemia (CML) patients. Increase in lymphocyte counts has been known to be predictive of a good treatment response under dasatinib treatment as a second line therapy. However, clinical significance of lymphocyte dynamics in the upfront setting has yet to be clarified. To investigate the significance of lymphocyte dynamics in newly diagnosed chronic phase (CP)-CML, patient data of D-First study (ClinicalTrials.gov NCT01464411) were analyzed. Fifty-two CML-CP patients enrolled to this study were treated with dasatinib (100 mg day(-1) ) and all were followed-up for 18 months. The incidence of lymphocyosis was observed in 14 (27%), but it was not associated with deep molecular response achievement. However, natural killer (NK) cell or cytotoxic T lymphocyte (CTL) counts at 1 month were significantly higher in patients with deep molecular response (DMR) by 18 months compared to those without DMR. When the patients were divided into two groups according to those calculated thresholds by receiver operating characteristic curve (407/µL for NK cells and 347/µL for CTLs), the cumulative DMR rates by 18 months were significantly better in higher value group compared to lower value group. In contrast, regulatory T cell counts were significantly lower at 12 and 15 months in patients achieved DMR. These results suggest the presence of dual effects of dasatinib on immune system through the cytotoxic lymphocytes activation and Treg deregulation in different periods in newly diagnosed CML-CP.

Efficiency of high-dose cytarabine added to CY/TBI in cord blood transplantation for myeloid malignancy.

Cord blood transplantation (CBT) is an effective therapeutic option for adults with acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) after the conventional cyclophosphamide and total body irradiation (CY/TBI) regimen, but posttransplant relapse is still of high importance. High-dose cytarabine (HDCA) can be added to CY/TBI for an intensified regimen; however, its additional effects have not yet been completely elucidated. Therefore, we conducted a cohort study to compare the prognosis of HDCA/CY/TBI (n = 617) and CY/TBI (n = 312) in CBT for AML/MDS, using a Japanese transplant registry database. The median age was 40 years, and 86.2% of the patients had AML; high-risk disease was observed in 56.2% of the patients. The median follow-up period after CBT was approximately 3.5 years. Overall survival was significantly superior in the HDCA/CY/TBI group (adjusted hazard ratio [HR], 0.56; 95% confidence interval [CI], 0.45-0.69; P < .01), and tumor-related mortality was lower (HR, 0.50; P < .01). The incidence of grade II to IV acute graft-vs-host disease (aGVHD) and chronic GVHD was significantly higher in the HDCA/CY/TBI group (HR, 1.33 and 2.30, respectively), but not grade III to IV aGVHD. Incidence of infectious episodes showed no significant difference. Nonrelapse mortality was not increased by the addition of HDCA. Higher-dose CA (12 rather than 8 g/m(2)) was more effective, particularly in patients at high-risk for disease. This study is the first to show the superiority of HDCA/CY/TBI to CY/TBI in CBT for AML/MDS. A large-scale prospective study is warranted to establish new conditioning regimens including HDCA administration.

Cord Blood Transplantation for Multiple Myeloma: A Study from the Multiple Myeloma Working Group of the Japan Society for Hematopoietic Cell Transplantation.

Cord blood has been investigated as an alternative source for hematopoietic stem cell transplantation, but information about its use for multiple myeloma is limited. The purpose of this study was to evaluate the feasibility of cord blood transplantation (CBT) for patients with multiple myeloma. Eighty-six patients with multiple myeloma who underwent a first CBT between 2001 and 2011 were included in this retrospective study. Sixty-two of them had received other types of stem cell transplantation before CBT. The cumulative incidences of neutrophil engraftment at day 50, grade II to IV acute graft-versus-host disease (GVHD), and chronic GVHD were 81.4%, 39.0%, and 19.5%, respectively. The incidence of nonrelapse mortality at 2 years was 39.0%, but it was only 6.2% in patients who underwent planned tandem autologous/reduced-intensity conditioning CBT (auto/RIC-CBT). Progression-free survival (PFS) and overall survival (OS) at 6 years were 13.0% and 15.2%, respectively. Less than a partial response before CBT and lack of prior transplantation were independent significant adverse factors for PFS, whereas the presence of prior transplantation and planned tandem transplantation were associated with better OS. OS at 6 years in patients who underwent auto/RIC-CBT was 45.9%. In addition, the development of chronic GVHD was associated with superior PFS. In conclusion, we demonstrated that cord blood is feasible as an alternative graft source for myeloma patients. Although CBT provided long-term survival for a fraction of patients, optimal use of this graft requires further clinical studies.

Shorter halving time of BCR-ABL1 transcripts is a novel predictor for achievement of molecular responses in newly diagnosed chronic-phase chronic myeloid leukemia treated with dasatinib: Results of the D-first study of Kanto CML study group.

To investigate the factors that affect molecular responses on dasatinib treatment in patients with chronic-phase chronic myeloid leukemia (CML-CP), we performed a clinical trial named the "D-First study." Fifty-two patients with newly diagnosed CML-CP were enrolled in this study and received 100 mg dasatinib once daily. A deep molecular response (DMR) was defined as <50 copies/µg RNA of BCR-ABL1 transcript value corrected by GAPDH, which ensures <0.01% of BCR-ABL1 transcript value according to International Scale (BCR-ABL1(IS)). The halving time for BCR-ABL1 transcripts was calculated using transcript levels before dasatinib treatment, transcript levels after 3 months of treatment, and the treatment time between these two points. In terms of molecular response, 38 of 51 (75%) patients reached major molecular response (MMR) by 12 months, and the rate of DMR by 18 months was 59% (30/51). While both BCR-ABL1 transcript levels before treatment and a shorter halving time of BCR-ABL1 transcripts (≤14 days) were significant factors affecting achievement of MMR by 12 months, the Sokal score at diagnosis was not associated with MMR. Importantly, the halving time was the only factor that predicted achievement of DMR by 18 months. We showed that patients with CML-CP treated with dasatinib can be stratified according to the early treatment response as determined by the halving time of BCR-ABL1 transcripts. These data emphasize the significance of the early response from dasatinib treatment in achieving a DMR. (ClinicalTrials.gov; NCT01464411).

Clinical efficacy and safety of biapenem for febrile neutropenia in patients with underlying hematopoietic diseases: a multi-institutional study.

A multi-institutional study was conducted to assess efficacy and safety of biapenem (BIPM), a carbapenem antibiotic, as an initial-stage therapeutic agent for febrile neutropenia (FN) in patients with hematopoietic diseases. A total of 216 patients from 25 medical institutions were enrolled in this study; of these, 204 were included in the safety analysis and 178 in the efficacy analysis. The combined (excellent and good) response rate was 67.9%, and antipyretic effect (subsidence + tendency to subsidence) was achieved within 3 and 5 days of treatment in 67.3 and 75.9% of patients, respectively. Thus, the clinical responses were gratifying. A response rate of 61.7% (37/60) was observed even in high-risk FN patients in whom neutrophil counts prior to and at 72 h after the start of BIPM were ≤100/µl. BIPM is considered to be a highly promising drug, with prompt onset of clinical benefit, as an initial-stage therapeutic agent for the treatment of FN in patients with hematopoietic diseases.

Incidence and risk factors of early bacterial infections after unrelated cord blood transplantation.

Incidence and characteristics of early bacterial infection within 100 days after unrelated cord blood transplantation (UCBT) were assessed for 664 pediatric and 1208 adult recipients in Japan. Cumulative incidence of early bacterial infection at day 100 post-UCBT was 11% (95% confidence interval [CI], 8%-13%) for children and 21% (CI, 19%-24%) for adults (P < .0001). Early bacterial infection in adults had a significant impact on mortality (hazard ratio [HR] = 2.1, CI, 1.7-2.6; P < .0001), although no significant risk factors were identified. Multivariate analysis identified older age group (6-10, and 11-15 years versus 0-5 years of age) at transplant (HR = 2.0 and 2.7, CI, 1.1-3.5 and 1.4-4.9; P = .020 and .002, respectively) as an independent risk factor of early bacterial infection for children. Early bacterial infection in children did not have a significant impact on mortality when adjusted. Of 315 bacteremia, 74% were caused by Gram-positive microorganisms. Pneumonia occurred in 39 patients including 13 cases of Stenotrophomonas maltophilia pneumonia. Early bacterial infection had a negative effect on survival for adults and the median day of development was 10 days after transplant, suggesting that the prevention of bacterial infection in the very early post-UCBT phase is important.