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In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 1800-1800

Abstract: Fractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone (hyper-CVAD) alternating with high-dose methotrexate and cytarabine (MA) therapy is a widely used combination chemotherapy for lymphoid malignancies. Its use in combination with Ribuximab (R) has been shown to be safe and effective for Burkitt's lymphoma (BL) and mantle cell lymphoma (MCL). Acute toxicities of the treatment are mostly hematologic, leading to cases with neutropenic fever and infection. However, long-term toxicities in terms of patients' immune function have not been fully elucidated. Purpose To evaluate the long-term immune function after R-hyper-CVAD/MA therapy, and to compared it with those after R-CHOP therapy. Method Patients who have received R-hyper-CVAD/MA therapy or R-CHOP therapy for more than 6 cycles for B-cell lymphomas (diffuse large B cell lymphoma (DLBCL), BL and MCL) between January 2007 and December 2012 were identified. The patients' immune functions were assessed in regards to white blood cell (WBC) count, lymphocyte count, lymphocyte surface marker analysis and immunoglobulin (Ig) measurement. Result Altogether, 21 patients underwent evaluation. 11 patients received R-CHOP therapy, and 10 patients received R-hyper-CVAD/MA therapy. The mean age of the patients was 57 and 53.3 years-old, respectively. All patients in the R-CHOP group had DLBCL, whereas patients who received R-hyper-CVAD/MA were either treated for BL in 4, MCL in 1 and DLBCL in 5 patients. The median time from the initiation of treatment to the assessment of immune function was 1060 (range 434 – 2475) and 947.5 (range 448 – 1966) days, respectively. In terms of immune function, IgG level, the proportion of CD4, CD8 positive (+) cells, CD4/8 ratio were significantly different between those who received R-CHOP therapy and R-hyper-CVAD/MA therapy. The median IgG level was 910 mg/dL in those who received R-CHOP therapy as opposed to 484 mg/dL in those who received R-hyper-CVAD/MA therapy. 4 patients in the R-CHOP group presented with IgG level below normal range, whereas 9 patients in the R-hyper-CVAD/MA group had an IgG level below normal range (p = 0.011). The median proportion of CD4 and CD8 (+) cells were 32.7%, 24.8% in the R-CHOP group and 23.35%, 41.35% in the R-hyper-CVAD/MA group, leading to the median CD4/8 ratio of 1.22 and 0.5, respectively. The total WBC count, lymphocyte count, proportion of CD19 (+) cells, IgM or IgA levels were within normal limit, and did not significantly differ between groups. Of the patients in the R-hyper-CVAD/MA group, 3 patients required regular immunoglobulin replacement, and 1 patient had 2 episodes of hospitalization within 2 years of last treatment, one due to viral meningitis and another due to pneumonia. None of the patients in the R-CHOP group presented with infection episodes that required hospitalization. Conclusion Our results suggest that patients with aggressive B-cell lymphoma treated with R-hyper-CVAD/MA therapy remain at higher risk of developing hypo-gammaglobulinemia, even after 5 years out of treatment. Despite the recovery of B-lymphocytes, the proportion of CD4 (+) cells remained low in those who received R-hyper-CVAD/MA therapy, leading to an increased proportion of CD8 (+) cells and decreased CD4/8 ratio. Patients who have received R-hyper-CVAD/MA therapy should be closely monitored for their immune function for a longer period due to prolonged hypogammaglobulinemia. Disclosures: Okamoto: Novartis, BMS, GSK, Kirin, Chugai, Alexion: Honoraria, Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V122.21.1800.1800

Language: English

Publisher: American Society of Hematology

Publication Date: 2013

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 1887-1887

Abstract: Background: Tyrosine kinase inhibitor (TKI) remains to be the mainstay of treatment for patients with chronic myelogenous leukemia (CML). Second generation TKIs have been shown to successfully treat patients who are resistant or intolerant to imatinib, as well as induce faster and deeper molecular response when used as first line therapy. Since the initial report of the French STIM study (Mahon FX, et al. Lancet Oncol 2010; 11: 1029-35) that showed successful discontinuation of imatinib therapy in approximately 50% of patients who have sustained complete molecular response (CMR), several groups have confirmed that a subset of patients can discontinue TKI for a long period. While factors associated with successful discontinuation are not yet well defined, it also remains an open question whether patients who have failed the initial attempt of discontinuation will have to remain on life-long treatment with TKIs. Patients and Methods: Patients who have been treated at Keio University Hospital for CML, who had been in confirmed stable CMR for over 2 years at the time of study enrollment, and who had no history of accelerated phase/ blastic phase while on treatment with TKI, were eligible to enroll in the study. Patients were monitored monthly for the first 6 months after discontinuation, every 2 months until 12 months, and every 2 to 3 months thereafter. Treatment with a TKI was initiated if the peripheral blood quantitative PCR (TMA method) value exceeded 100 copies. Once the patient was restarted on TKI therapy, and regained sustained CMR for over 2 years, they were allowed to reenter the study and discontinue treatment, upon patients' choice. Results: Sixty-seven patients have been enrolled in the study, of which 53 patients who have been observed for over 2 years since first TKI (imatinib 48; dasatinib 1; nilotinib 4) discontinuation were analyzed. The median age of the patients was 54 (range 28-83) years. Thirty-seven (69.8%) patients were male. In terms of baseline characteristics, 18 (34.0%) had been treated with interferon prior to TKI use, and 41 (77.4%) were CMV positive. The Sokal risk score was low in 34 (64.2%), intermediate in 11 (20.8%) and high in 4 (7.5%) patients. Among the 53 patients, 45 (84.9%) were checked for the existence of BIM deletion, among which 7 (13.2%) patients were positive. The median time on TKI treatment was 98 (range 32-147) months and the median duration of CMR was 38 (range 24-106) months. The median follow-up of the patients at the time of this analysis since study enrollment was 61 (range 26-66) months. Treatment was restarted in 28 (45%) patients (imatinib 7; dasatinib 20; nilotinib 1). While this occurred within the first 6 months of treatment discontinuation in most patients, 6 patients were started on treatment beyond 12 months of drug-free survival (DFS) (at month 14, 20, 23, 36, 36, and 52, respectively). Five patients presented with a fluctuating copy number early after TKI discontinuation, whereas 1 patient only became positive for bcr-abl after 30 months of treatment discontinuation. The estimated 24-months DFS was 52.8% (95% confidence interval (CI) 39.5-65.8%) (Fig 1). All patients have restored CMR at least at one occasion after recommencing TKIs. No single factor was significantly associated with success of discontinuation. Among the patients who had sustained CMR for over 24 months after re-initiation of TKI, 10 patients elected to challenge discontinuation of TKI for the second time. All patients were on dasatinib at the time of discontinuation. The median age of these patients was 58.5 (range 31-75) years. The median time on TKI prior to second discontinuation was 33 (range 26-45) months and the median duration of CMR after treatment re-initiation was 26.5 (range 25-44) months. All but one patient were restarted on treatment at the time of the analysis (median observation 26 (range 13-35) months), leading to a DFS of 20% (95% CI 5.0-54.1%) at 12 and 24 months (Fig 1). Conclusion: Long-term observation of the outcome of TKI discontinuation in CML patients who had sustained CMR for over 2 years showed cases of late relapses as well as small chance of success on the second attempt of TKI discontinuation even with the use of second generation TKIs. While the result of first discontinuation was similar to previous reports, attempt of second discontinuation was less successful compared to the French group, despite changing the drug of use from imatinib to dasatinib. Figure 1 Figure 1. Disclosures Matsuki: Nippon Shinyaku: Honoraria; Celgene: Honoraria; Bristol-Myers Squibb: Honoraria. Sakurai:Celgene: Honoraria. Karigane:Celgene: Honoraria. Kikuchi:Celgene: Honoraria; Takeda Pharmaceutical Company: Honoraria; Kyowa Hakko Kirin: Honoraria. Yokoyama:BMS: Research Funding. Okamoto:Eisai Co., Ltd.: Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding; Nippon Shinyaku Co., Ltd.: Research Funding; Alexion Pharmaceuticals, Inc.: Research Funding; Astellas Pharma Inc.: Research Funding; Toyama Chemical Co., Ltd.: Research Funding; Otsuka Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Kyowa Hakko Kirin Co., Ltd.: Research Funding; Shionogi & Co., Ltd.: Research Funding; Bristol-Myers Squibb K.K.: Honoraria, Research Funding; Asahi Kasei Pharma Corp.: Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; Teijin Pharma Limited: Research Funding; Pfizer Inc.: Honoraria, Research Funding; JCR Pharmaceuticals Co., Ltd.: Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V128.22.1887.1887

Language: English

Publisher: American Society of Hematology

Publication Date: 2016

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 1888-1888

Abstract: Background: Among tyrosine kinase inhibitors (TKIs), imatinib mesylate was the first TKI successfully used for the treatment of chronic myelogenous leukemia (CML) in chronic phase (CP), and a majority of patients still remains on its long-term treatment. Although imatinib has been well tolerated in clinical practice, and the side effect profile has usually been mild to moderate, there are limited data available regarding the long-term TKIs treatment on kidney function and associated complications such as anemia. This study aimed to evaluate the effect of long-term imatinib treatment on estimated glomerular filtration rate (eGFR) and hemoglobin (Hb) level in patients with CML in CP. Patients and methods: By using the institutional database, patients with CML in CP who had been on imatinib as the first and the only TKI for over 5 years at Keio University Hospital (Tokyo, Japan) were selected and retrospectively analyzed. Estimated GFR was calculated by the Modification of Diet in Renal Disease equation for Japanese defined by the Japanese Society of Nephrology. All statistical analyses were performed with EZR, which is a graphical user interface for R. Results: Eighty-two patients were evaluable. The median age at initiating imatinib was 49.5 years (range, 19-76). The median duration of imatinib treatment was 105 months (range, 60-170). During this study period, imatinib was given at a dose of 400mg/day. The dose reduction was indicted in 8 patients but not because of progressing renal impairment. The mean eGFR was 77 ml/min/1.73m2 (range, 38-120), and the value was below 60 ml/min/1.73m2 in 12 patients before initiating imatinib. The mean value significantly decreased to 62 ml/min/1.73m2 (range, 34-98) over the 5 years after imatinib treatment (P 〈 0.001), and the values reached 〈 60 ml/min/1.73m2 in 43 of 82 patients (P 〈 0.001). In an univariate analysis of patients excluding 12 patients with below 60 ml/min/1.73m2, older age and lower eGFR value at the initiation of imatinib were associated with later development of chronic kidney disease ( 〈 60 ml/min/1.73m2) (P 〈 0.001 and 0.002, respectively). Mean Hb level at 5 years after starting imatinib was significantly lower as compared with that before (12.9+1.7 g/dl vs. 12.4+1.3 g/dl, P 〈 0.01). The declining rate of eGFR was negatively correlated with those of Hb levels (correlation coefficient -0.249, P 〈 0.05). In 20 patients with low Hb level (9.7+1.2 g/dl) and renal dysfunction, median serum erythropoietin (EPO) level was 31.9 mIU/ml (range, 9.1-119). Furthermore, 11 patients with eGFR 〈 60 ml/min/1.73m2 achieving a durable molecular remission took part in an institutional TKI discontinuation trial. At 1 year after discontinuing imatinib, their mean eGFR values significantly improved (50.0 + 6.5 to 56.0 + 10.2 ml/min/1.73m2, P 〈 0.05) as well as Hb level (12.0 + 1.7 to 14.0 + 1.6 g/dl, P 〈 0.01). Conclusion: Our findings indicated that long-term use of imatinib is frequently associated with reversible but continuous decline in eGFR level, which could lead to anemia partly due to inadequate production of EPO. Although the degree of nephrotoxicity is usually mild, close monitoring of renal function is recommended particularly in older patients with pre-existing renal dysfunction. Disclosures Sakurai: Celgene: Honoraria. Karigane:Celgene: Honoraria. Matsuki:Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Nippon Shinyaku: Honoraria. Kikuchi:Celgene: Honoraria; Takeda Pharmaceutical Company: Honoraria; Kyowa Hakko Kirin: Honoraria. Okamoto:Nippon Shinyaku Co., Ltd.: Research Funding; Alexion Pharmaceuticals, Inc.: Research Funding; Otsuka Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Asahi Kasei Pharma Corp.: Research Funding; Teijin Pharma Limited: Research Funding; Kyowa Hakko Kirin Co., Ltd.: Research Funding; Shionogi & Co., Ltd.: Research Funding; Astellas Pharma Inc.: Research Funding; Toyama Chemical Co., Ltd.: Research Funding; Eisai Co., Ltd.: Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding; Bristol-Myers Squibb K.K.: Honoraria, Research Funding; Pfizer Inc.: Honoraria, Research Funding; JCR Pharmaceuticals Co., Ltd.: Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V128.22.1888.1888

Language: English

Publisher: American Society of Hematology

Publication Date: 2016

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 3061-3061

Abstract: Introduction: Tyrosine kinase inhibitors (TKIs) have dramatically improved the prognosis of chronic myelogenous leukemia (CML). The treatment with TKIs continues to improve the depth of response and overall survival of CML patients, but the life-long use of TKI is known to be associated with late complications such as cardiovascular events as well as heavy financial burden, and thus impairs the quality of life. To overcome these issues, many studies evaluating the possibility of TKI discontinuation have been ongoing worldwide. In order to achieve durable treatment-free remission, it is crucial to understand the dynamics of CML-leukemia initiating cells (LICs). We previously reported that CD25 was highly expressed in murine and human CML-LICs (Kobayashi CI et al., Blood, 2014). The aim of this study was to assess whether the proportion of CD25 positive cells in hematopoietic stem/progenitor cell fraction of bone marrow cells in CML patients treated with TKIs is associated with their molecular response and could serve as a novel surrogate marker to stop TKI therapy. Methods: Bone marrow samples were obtained from patients with CML in chronic phase who were diagnosed and have been treated solely with TKIs at Keio University Hospital (Tokyo, Japan). This study was approved by the institutional ethical committee and informed consent was obtained from each patient. Both quantitative and qualitative PCR of BCR-ABL was performed using bone marrow mononuclear cells (BMMNCs). The proportion of CD25 positive cells in bone marrow hematopoietic stem/progenitor cell (HSPC; CD34+CD38-) fraction was evaluated by flow cytometry using FITC-labeled anti-CD34, PE- labeled anti-CD38 and APC-labeled anti-CD25 antibodies. The response to TKIs at the time of evaluation was determined according to the previous report (Yoshida C et al., Int J Clin Oncol, 2012): complete cytogenetic remission (CCyR) defined as Philadelphia chromosome undetectable and quantitative PCR copy numbers 〉 731 among BMMNCs; major molecular remission (MMR) as quantitative PCR copy numbers ≤731, and complete molecular remission (CMR) as undetectable BCR-ABL by quantitative and qualitative PCR. Results: Bone marrow samples obtained from 95 patients were evaluated (median age 53 years old; male/female, 67/28). Analysis was performed prior to TKI exposure in nine patients and under TKI therapy including 2nd generation TKI in 64 patients (imatinib, 22; dasatinib, 33; nilotinib, 9). Remaining 22 patients were treatment free because they enrolled in a clinical trial of TKI discontinuation. The proportion of CD25 positive cells in HSPC fraction significantly decreased in patients with prior TKI exposure relative to patients at diagnosis (n=86; Mean 4.2%, SD 7.0% vs n=9; Mean 22.4%, SD 11.3%, P 〈 0.01). In addition, the proportion of CD25 positive cells in HSPC fraction significantly correlated the level of quantitative PCR (Figure, P 〈 0.0001), and MMR was also dividable from CMR by the proportion of CD25 positive cells (MMR; n=29, Mean 4.6%, SD 4.8% vs CMR; n=49, Mean 2.6%, SD 2.5%, P 〈 0.05). The expression of CD25 was still detected in the majority of patients who achieved CMR, including those who sustained CMR after the discontinuation of TKIs. Conclusion: We confirmed that the expression of CD25 in HSPC fraction of CML patients was significantly correlated with the response to TKI therapy, and may serve as an asset to select patients who are likely to achieve durable treatment-free survival. Figure Figure. Disclosures Karigane: Celgene: Honoraria. Sakurai:Celgene: Honoraria. Matsuki:Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Nippon Shinyaku: Honoraria. Kikuchi:Celgene: Honoraria; Takeda Pharmaceutical Company: Honoraria; Kyowa Hakko Kirin: Honoraria. Mitsuhashi:LSI Medience: Consultancy. Okamoto:Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; Asahi Kasei Pharma Corp.: Research Funding; Astellas Pharma Inc.: Research Funding; Shionogi & Co., Ltd.: Research Funding; Nippon Shinyaku Co., Ltd.: Research Funding; Alexion Pharmaceuticals, Inc.: Research Funding; Toyama Chemical Co., Ltd.: Research Funding; Otsuka Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Teijin Pharma Limited: Research Funding; Bristol-Myers Squibb K.K.: Honoraria, Research Funding; Kyowa Hakko Kirin Co., Ltd.: Research Funding; Eisai Co., Ltd.: Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding; Pfizer Inc.: Honoraria, Research Funding; JCR Pharmaceuticals Co., Ltd.: Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V128.22.3061.3061

Language: English

Publisher: American Society of Hematology

Publication Date: 2016

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 3765-3765

Abstract: Abstract 3765 Background: The introduction of imatinib mesylate in the treatment of chronic myeloid leukemia (CML) has dramatically changed its treatment outcome. The drug alone can induce durable hematologic, cytogenetic and molecular response, leading to a marked improvement of progression free survival (PFS). One of the next directions of treatment is to explore the possibility of long-term discontinuation of tyrosine kinase inhibitors (TKIs), and to identify the factors associated with sustained complete molecular response (CMR) after discontinuation. The French STIM study is the first large prospective trial to show that imatinib can be safely discontinued in a subset of patients who have maintained CMR for at least 2 years. We have performed a similar prospective study to confirm this result in the Japanese population. Purpose: To evaluate whether CMR will be sustained after stopping imatinib therapy, and to identify the clinical characteristics that could be associated with persistent CMR after drug discontinuation in the Japanese population. Method: Adult patients with CML, treated at Keio University Hospital, with sustained CMR (defined as negative quantitative and qualitative PCR of bcr-abl in the bone marrow) for over 2 years were enrolled in the study. After the discontinuation, patients were monitored monthly for the first 6 months and every 2 months thereafter, by peripheral blood quantitative PCR (TMA method; Amp-CML). Treatment with imatinib or one of the other TKIs was initiated if the Amp-CML value exceeded 100 copies. Patients: 30 patients have been enrolled in the study at the time of the analysis. 20 patients (66.6%) were male. The median age of the patients was 54 (range 28 –77) years old. 11 patients (36.7%) had a previous history of interferon treatment. 20% of the patients were negative for CMV serology. The Sokal risk score was low in 19 (63.3%), intermediate in 7 (23.3%) and high in 2 (6.7%) patients. The median time on imatinib treatment was 92 (range 32–114) months and the median duration of CMR was 55.5 months, ranging from 24 to 94 months. The median daily dose of imatinib taken at the time of discontinuation was 400 mg (range 200–400). Results: The median follow-up of the patients at the time of this analysis was 5 months (range 1–6). Imatinib or one of the second generation TKIs were restarted in 11 patients (36.7%) (4 at month 2, 6 at month 3 and 1 at month 5; 3 were on imatinib, and 8 on dasatinib), leading to an estimated 6 months drug-free survival rate of 55.8%. All patients responded to either TKI. 5 patients have at least one positive PCR but the value have not exceeded 100 copies over time and have not been retreated by TKIs, leading to an estimated 6 months PCR-negative survival of 37.8%. According to the criteria of the French STIM study (positive and rising PCR value in two consecutive observation), an estimated 6 months relapse-free survival in our patient population was 46.8%. In comparing patients with sustained drug-free, relapse-free, or PCR-negative survival with those who did not, univariate or multivariate analysis did not show any significant difference for age, previous interferon treatment, duration of imatinib treatment, duration of CMR, sex, cytomegalovirus serology, peripheral blood NK or T cell subpopulation, or Sokal risk score. Although clinical side effects such as facial puffiness or muscle cramping markedly decreased with the discontinuation of imatinib, QOL analysis using SF-36 before and 2 months after the discontinuation did not show any significant improvement. Conclusion: Sustained CMR was achieved in a substantial proportion of patients who had been in CMR for over 2 years after the discontinuation of imatinib. All patients restarted on TKI treatment remained sensitive to treatment. There was no significant factor identified as a predisposing condition for sustained CMR in our patient population. However, our results are comparable to that of the previous French STIM study in terms of relapse-free survival, suggesting that there is no ethnic difference in the effect of stopping imatinib. This study is the first to evaluate the effect of imatinib discontinuation in the Asian population, and thus provides an important insight into the effect of imatinib and drug-free survival of CML patients in sustained CMR. Longer observation period and increased number of patients is necessary to draw a concrete conclusion, and to identify the factors relative to persistence of CMR. Disclosures: Okamoto: Bristol Myers Squibb: Honoraria, Research Funding; Novartis Pharma: Honoraria, Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V118.21.3765.3765

Language: English

Publisher: American Society of Hematology

Publication Date: 2011

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 120, No. 21 ( 2012-11-16), p. 2788-2788

Abstract: Abstract 2788 Background and Purpose: Tyrosine kinase inhibitor (TKI) therapy has become the standard treatment for patients with chronic myelogenous leukemia (CML). It can induce durable hematologic, cytogenetic and molecular response, leading to a marked improvement of progression-free survival (PFS). On the other hand, long-term discontinuation of TKIs has recently been investigated by many groups. Our study was designed to confirm whether TKI could be safely discontinued in Japanese patients who have maintained complete molecular response (CMR) for at least 2 years, and to identify possible factors associated with prolonged drug-free survival (DFS), including immunologic profile. The effect of imatinib discontinuation in terms of quality of life (QOL) was also assessed. Method: Adult patients with CML who have sustained CMR (defined as negative quantitative and qualitative PCR of bcr-abl in the bone marrow) for more than 2 years were enrolled in the study. Treatment with imatinib or one of the other TKIs was initiated if the peripheral blood quantitative PCR (TMA method) value exceeded 100 copies. Lymphocyte subset analysis was performed before discontinuation of the drug, and at 6 months after discontinuation or re-induction of the drug in case of relapse. In 6 patients, WT-1 specific cytotoxic T lymphocyte (CTL) frequency was also assessed before, 3 and 6 months after drug discontinuation. QOL analysis was performed using SF-36 questionnaire before, 2 months and 1 year after discontinuation of imatinib. Patients: 41 patients were enrolled in the study, among which 40 patients were analyzed. The median age of the patients was 54 (range 28 – 83) years old. The Sokal risk score was low in 24 (60%), intermediate in 10 (25%) and high in 3 (7.5%) patients. The median time on imatinib treatment was 98 (range 24–126) months and the median duration of CMR was 49.5 months (range 24–106). Results: The median follow-up of the patients at the time of this analysis was 15.5 months (range 2–18). Treatment was restarted in 18 patients (45%), and the estimated DFS rate at 12 months was 55.4% (Fig 1). In 5 patients, imatinib was commenced again, whereas 13 patients were re-treated with dasatinib. All but one patient restored CMR after commencing TKIs. Among various factors including age, previous interferon treatment, duration of imatinib treatment, duration of CMR, time until CMR, sex, cytomegalovirus serology and Sokal risk score, duration of CMR was identified as a significant factor associated with prolonged DFS on univariate analysis (p=0.027), the difference which was also significant upon multivariate analysis (p=0.014). Regarding lymphocyte subsets in the peripheral blood, no significant changes were observed in CD4, 19, 56, ab TCR, gd TCR, CD4/CD25 positive cell population, but, there was a significant increase in the proportion of CD8 positive T cells among those who relapsed and those who did not (2.4% vs −2.4%, p=0.04). There was a trend for increased proportion of WT-1 specific CTL in patients who were restarted on TKI therapy. QOL scores of both physical and mental domains did not differ significantly with the discontinuation of imatinib or re-initiation of treatment, although symptoms such as facial puffiness or muscle cramping were markedly decreased with discontinuation. There was also no difference in the patients' QOL according to the choice of drug used for re-treatment. Altogether 6 patients had fluctuating PCR copy number during follow-up, of which 2 were restarted on treatment. Others have maintained low copy number or have returned to negative during follow-up. Due to the small number of patients, no specific clinical factors or immunophenotypes associated with sustained low count PCR were identified. Conclusion: Sustained CMR was achieved in a substantial proportion of patients who had been in CMR for over 2 years. All patients restarted on TKI treatment remained sensitive to treatment. Longer time in CMR was identified as a significant factor related to sustained CMR in our patient population. Increase in CTL may also correlate with the necessity to restart treatment. Longer observation period and increased number of patients is necessary to draw a concrete conclusion, and to identify the role of immunologic profiles relative to persistence of CMR. Disclosures: No relevant conflicts of interest to declare.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V120.21.2788.2788

Language: English

Publisher: American Society of Hematology

Publication Date: 2012

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 1723-1723

Abstract: Introduction: Tyrosine kinase inhibitors (TKIs) have dramatically improved the prognosis of chronic myelogenous leukemia (CML). The treatment with TKIs maintain the depth of response; however, the life-long use of TKI has also been associated with late complications such as cardiovascular events and huge financial burden impairing their quality of life. To overcome these issues, investigators have been attempting to discontinue TKIs after durable molecular remission. However, the optimal timing to stop TKIs remains to be elucidated. We previously demonstrated that CD25 was highly expressed in murine and human CML-leukemia initiating cells (LICs) (Kobayashi CI et al., Blood, 2014). In this study we tried to clarify whether the proportion of CD25-positive cells in hematopoietic stem/progenitor cell fraction of bone marrow cells in CML patients treated with TKIs is associated with their molecular response and could serve as a novel surrogate marker to select patients who are likely to obtain durable treatment-free remission after stopping TKIs. Methods: Bone marrow samples were obtained from the patients with CML in chronic phase who were treated solely with TKIs at Keio University Hospital (Tokyo, Japan). This study was approved by the institutional ethical committee and informed consent was obtained from each patient. Both quantitative and qualitative PCR of BCR-ABL1 was performed using bone marrow mononuclear cells (BMMNCs). The proportion of CD25-positive cells in bone marrow hematopoietic stem/progenitor cell (HSPC; CD34+CD38-) fraction (%CD25+) was evaluated by flow cytometry. The response to TKIs at the time of analysis was determined according to as follows: complete cytogenetic remission (CCyR) defined as Philadelphia chromosome undetectable and quantitative PCR copy numbers 〉 731 among BMMNCs; major molecular remission (MMR) as quantitative PCR copy numbers ≤731, and complete molecular remission (CMR) as undetectable BCR-ABL1 by quantitative and qualitative PCR. Results: Bone marrow samples obtained from 109 patients were evaluated (median age, 52 years; male/female, 76/33). Analysis was performed prior to TKI exposure in 26 patients and under TKI therapy in 64 patients (imatinib, 22; dasatinib, 33; nilotinib, 9). Remaining 19 patients were treatment free because they were enrolled into a clinical trial of TKI discontinuation. At diagnosis (n=26), %CD25+ were significantly correlated with hemoglobin level and platelet count (Table). The %CD25+ was significantly lower in patients with post TKI exposure than those at diagnosis without TKIs (p 〈 0.00001). In nine patients with available samples before and after TKI therapy, the %CD25+ at diagnosis was significantly higher than after TKI therapy (Mean 34.7%, SD 24.8% vs. Mean 4.96%, SD 4.17%, p 〈 0.01, Fig.a). In addition, %CD25+ was significantly correlated with copy number of BCR/ABL1 (P 〈 0.001, Fig.b). Conclusion: We confirmed that the expression of CD25 in HSPC fraction of CML patients was significantly correlated with the disease status, and may be useful as a LIC minimal residual disease marker. Disclosures Kasahara: Chugai: Research Funding. Sakurai:Bristol-Myers Squibb K.K.: Speakers Bureau. Kikuchi:Celgene: Speakers Bureau; Takeda: Speakers Bureau; Ono: Speakers Bureau. Shimizu:Bristol-Myers Squibb K.K: Honoraria. Mori:Astella Pharma: Honoraria; Kyowa Hakko Kirin: Honoraria; Novartis Pharma: Research Funding; MSD: Research Funding; MSD: Honoraria; Janssen: Honoraria; SHIONOGI: Honoraria; Taisho Toyama Pharmaceutical Co: Honoraria; Celgene: Honoraria; Ono: Honoraria; Eisai: Honoraria; Novartis Pharma: Honoraria; Shire Japan: Honoraria; CHUGAI: Honoraria; Asahi Kasei: Research Funding; Japan Blood Products Organization: Honoraria; Pfizer: Honoraria. Okamoto:Pfizer Inc.: Honoraria, Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding; Eisai Co.,Ltd.: Research Funding; Kyowa Hakko Kirin Co.: Research Funding; Bristol-Myers Squibb K.K.: Honoraria, Research Funding; Teijin Pharma Limited: Research Funding; Otsuka Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Toyama Chemical Co., Ltd.: Research Funding; Alexion Pharmaceuticals, Inc.:: Research Funding; Nippon Shinyaku Co., Ltd: Research Funding; Shionogi & Co., Ltd.: Research Funding; Astellas Pharma Inc.: Research Funding; Asahi Kasei Pharma Corp.:: Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; JCR Pharmaceuticals Co., Ltd.: Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2018-99-111586

Language: English

Publisher: American Society of Hematology

Publication Date: 2018

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7