scholarly journals Myeloablative conditioning with fludarabine and busulfan for allogeneic PBSCT in chronic phase CML

2005 ◽  
Vol 11 (2) ◽  
pp. 22
Author(s):  
M. Iravani ◽  
M. Tavakoli ◽  
A.R. Shamshiri ◽  
A. Mousavi ◽  
B. Bahar ◽  
...  
Keyword(s):  
Chronic Phase ◽  
Myeloablative Conditioning ◽  
Allogeneic Pbsct

Non-Myeloablative Allografting from HLA-Identical Sibling Donors for Treatment of CML.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2316-2316
Author(s):  
Fabio R. Kerbauy ◽  
Thoralf Lange ◽  
Ted Gooley ◽  
Judith Shizuru ◽  
Jerald Radich ◽  
...  
Keyword(s):  
T Cell ◽  
Hematopoietic Cell Transplantation ◽  
Chronic Phase ◽  
Median Number ◽  
Phase Iii ◽  
Myeloablative Conditioning ◽  
Phase Iii Clinical Trials ◽  
Hematopoietic Reconstitution ◽  
Conditioning Regimens ◽  
Total Body

Abstract We retrospectively analyzed data from 24 patients with chronic myeloid leukemia (CML) treated with HLA-matched related donor hematopoietic cell transplantation (HCT) after non-myeloablative conditioning with 2 Gy total body irradiation (TBI), given either alone (n=8) or in combination with 3 days of fludarabine, 30mg/m2/day (n=16). Postgrafting immunosuppression consisted of cyclosporine and mycophenolate mofetil. CML patients in first chronic phase (CP1) (n=14), second chronic phase (n=4) or accelerated phase (n=6) who were not candidates for conventional HCT, were enrolled in a median of 28.5 (range, 11–271) months after diagnosis. The median age at HCT was 58 (range, 27–71) years. Unmodified G-CSF mobilized peripheral blood stem cell grafts containing medians of 7.9 (range, 2–18.1) x106 CD34+ cells/kg and 3.4 (range 1.7–2.4) x 108 CD3+ cells/kg, respectively, were infused. The median number of days in which ANC was less than 0.5 x 109/L was 5 (range, 0–8) days and 12 patients maintained ANCs greater than 0.5 x 109/L after HCT. Only 2 patients developed platelet counts less than 20 x 109/L. All patients had initial donor engraftment (>5% donor T-cell chimerism) at day 28 after transplant, and 17 (71%) achieved sustained full donor chimerism (>95% donor T-cell chimerism). There were 4 rejections followed by autologous hematopoietic reconstitution among 8 patients not given fludarabine, and donor lymphocyte infusions (DLI) were ineffective to reverse rejections. Fifteen (60%) patients achieved CR and 13 (54%) had complete molecular remissions, (defined as RT-PCR negativity for bcr-abl). Thirteen of 24 patients (54%) were alive and in CR at a median of 36 (range, 4–49) months after HCT. There were 5 (21%) deaths from non-relapse causes, one of them (4%) during the first 100 days. The incidences of grade II, III and IV acute GVHD were 38%, 4%, and 8%, respectively. The 2-year incidence of chronic extensive GVHD was 32%. The 2-year estimated overall survivals for patients in CP1 (n=14) and beyond CP1 (n=10) were 70% and 56%, respectively. Ten patients in CP1 received conditioning with fludarabine in addition to 2 Gy TBI; all ten achieved CR and 9 complete molecular remissions. Seven of 10 patients are alive in molecular remissions with a median follow-up of 36 (range, 6–49) months. In summary, non-myeloablative HCT were well tolerated in a group of patients who were older and/or medically infirm and therefore ineligible for myeloablative HCT. This approach should be considered for patients who fail to respond to initial conventional therapy and are not eligible for myeloablative conditioning regimens. The effectiveness of non-myeloablative compared to conventional myeloablative HCT will need to be definitively assessed in Phase III clinical trials.

A Fludarabine-Based Non-Myeloablative Conditioning Regimen in Allogeneic Stem Cell Transplantation from Related and Unrelated Donors in Chronic Myeloid Leukemia.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 5372-5372
Author(s):  
Yi Luo ◽  
He Huang ◽  
Zhen Cai ◽  
Yamin Tan ◽  
Xiaoyan Han
Keyword(s):  
Stem Cell ◽  
Chronic Myeloid Leukemia ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Allogeneic Stem Cell Transplantation ◽  
Myeloid Leukemia ◽  
Conditioning Regimen ◽  
Chronic Phase ◽  
Myeloablative Conditioning ◽  
Unrelated Donors

Abstract Objective: To evaluate the efficacy and safety of a fludarabine-based non-myeloablative conditioning regimen in allogeneic stem cell transplantation (SCT)from related and unrelated donor for chronic myeloid leukemia in chronic phase(CML-CP). Methods: Fifteen consecutive patients with CML-CP between May, 2005 and July, 2006 were treated with a single non-myeloablative conditioning regimen in this study. They were 10 males and 5 females with a median age of 41 years (range, 18–49). Donors were HLA-A, B and high resolution DR fully matched siblings (n=8), matched unrelated donors (n=6), and 1-locus mismatched unrelated donors (n=1). The stem cells were collected from either peripheral blood (n=9) or bone marrow (n=6). The conditioning regimen included fludarabine 30 mg/m2/day (days -10 to -5), oral busulfan 4 mg/kg/day (n=4 patients), or intravenous busulfan 3.2 mg/kg/day (n=11 patients) (days -6 to -5) and anti-thymocyte globulin (Fresenius, Germany) (5mg/kg/day) (days -4 to-1). Mycophenolate mofetil combined with cyclosporin A and methotrexate was used for prevention of acute graft-versus-host disease(GVHD) after transplantation. Lipoprostagandin E1 was used in prophylactic regimen for hepatic veno-occlusive disease(VOD). To assess engraftment, degree of chimerism, minimal residual disease and relapse, all patients were monitored by cytogenetic analysis and donor vs host-specific DNA markers using short tandem repeats (STR) assay. The average cell number of MNC transfused was 4.83 (3.14~11.5)×108/kg; CD34+ cells were 3.47(2.38~6.24)×106/kg, CFU-GM was 2.15 (1.85~3.06) ×105/kg. Results: Engraftment of neutrophils and platelets was achieved in 14 out of 15 (93.3%) patients within a median of 13 days (range, 8–21) and 18 days (range, 10–35), respectively. Fourteen patients achieved complete donor chimerism in the peripheral blood before day +35 and one developed graft failure. No patients developed acute GVHD and VOD, but one died from interstitial pneumonia while she was in continuous complete remission 2 months following transplantation. With a median follow-up of 5 months (range 1.5 to 15), 13 of them were still in CCR. The overall non-relapse mortality in this group was 6.67% (1/15 patients). Overall survival, and disease-free survival rates were 93.3% and 86.7%, respectively. Conclusion: A fludarabine-based non-myeloablative conditioning regimen in allogeneic stem cell transplantation from related and unrelated donors is an effective and safe choice for patients with chronic myeloid leukemia in chronic phase.

scholarly journals Reduced-Intensity Allogeneic HSCT for Children and Adolescents/Young Adults with CML: A Study from the Adult and Pediatric CML Working Group of the Japan Society for Hematopoietic Cell Transplantation

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3008-3008
Author(s):  
Hiroyuki Shimada ◽  
Akihiko Tanizawa ◽  
Takeshi Kondo ◽  
Hideki Muramatsu ◽  
Masahiro Yasui ◽  
...  
Keyword(s):  
Stem Cell ◽  
Research Funding ◽  
Hematopoietic Cell Transplantation ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Japan Society ◽  
Myeloablative Conditioning ◽  
Significant Difference ◽  
Reduced Intensity

Abstract Background: The introduction of tyrosine kinase inhibitor (TKI) has reduced the indications for allogeneic hematopoietic stem cell transplants (HSCT) in patients with chronic myeloid leukemia (CML). In children and adolescents/young adults (AYA), however, the long-term side effects of TKI and financial burden could become a future issue. Thus, the role of HSCT with reduced intensity conditioning (RIC) as an alternative to TKI especially in the first chronic phase (CP1) should be defined for children and AYA with CML. However, less is well-known about the efficacy of RIC regimens on children and AYA with CML, in chronic phase (CP) as well as advanced phase. Aims: To describe the long-term outcomes of children and AYA with all phases of CML treated with a RIC HSCT and to define potential prognostic factors for outcome. Patients and Methods: We retrospectively analyzed 3796 patients with CML using data from the Transplant Registry Unified Management Program of the Japan Society of Hematopoietic Cell Transplantation and included children and AYA under 30 years old at HSCT who underwent allo-HSCT between 2001 and 2014 and received TKI before HSCT. The myeloablative conditioning regimen was defined as TBI ≥ 8 Gy, busulfan > 8mg/kg, or melphalan > 180 mg/m2. Result: The characteristics of patients are summarized in Table 1. RIC was selected preferentially in patients with better status. The median follow-up of survivors was 64 months (3 - 171 months). There was no significant difference in 5-year overall survival (OS) among CP (124 cases), accelerated phase (AP) (23 cases) and blastic phase (BP) (53 cases) at diagnosis, 83%, 71% and 73%, respectively. In CP at diagnosis, 5-year OS was significantly higher in CP1 (89 cases) at HSCT than in CP2≤/AP/BP (35 cases) (89% versus 66%, p = 0.0004), and in CP1 at HSCT, there was no difference in 5-year OS between myeloablative conditioning (MAC) (58 cases) and RIC (31 cases) (both 89%) (Figure 1). However, 5-year OS in RIC was significantly higher in children (0-14 years old, 23 cases) than in AYA (15-29 years old, 8 cases) (95% versus 75%, p = 0.0495). Two of eight AYA patients with CP1 died after RIC HSCT due to grade IV acute GVHD-related complications without disease relapse, suggesting that the indications for RIC in AYA with CP1 should be carefully judged. In AP/BP at diagnosis, 5-year OS was significantly higher in the second chronic phase (CP2) (48 cases) at HSCT than in the third chronic phase (CP3)≤/AP/BP (28 cases) (82% versus 56%, p = 0.0073). However, the rate of major cytogenetic response (MCyR) at HSCT was significantly higher in CP2 than in CP3≤/AP/BP, and when focusing only on MCyR at HSCT in AP/BP at diagnosis, there was no difference in 5-year OS between CP2 at HSCT (40 cases) and CP3≤/AP/BP (13 cases) (83% versus 78%). On condition of MCyR at HSCT in AP/BP at diagnosis, regardless of the phase at HSCT, there was no difference in 5-year OS between MAC (46 cases) and RIC (7 cases: 2 in children and 5 in AYA) (79% versus 100%) (Figure 2), suggesting that even in AP/BP at diagnosis, RIC could be indicated for the patients with good response to TKI. On multivariate analysis, disease phase at HSCT and time from diagnosis to HSCT were independent predictors of OS in CP at diagnosis (Table 2), and cytogenetic response at HSCT and stem cell source in AP/BP at diagnosis (Table 3). There was no significant difference of OS between MAC and RIC. Conclusion: In HSCT for CML after TKI administration, the indications for RIC in children under 15 years old with CP1 are appropriate. In RIC HSCT for AYA patients under 30 years old with CP1, caution should be exercised in transplant-related mortality rather than disease progression. Furthermore, even in AP/BP at diagnosis, RIC could be indicated for children and AYA patients with MCyR at HSCT. Disclosures Ichinohe: Astellas Pharma: Research Funding; Chugai Pharmaceutical Co.: Research Funding; CSL Behring: Research Funding; Eisai Co.: Research Funding; Kyowa Hakko Kirin Co.: Research Funding; Ono Pharmaceutical Co.: Research Funding; Pfizer: Research Funding; Nippon Shinyaku Co.: Research Funding; MSD: Research Funding; Otsuka Pharmaceutical Co.: Research Funding; Repertoire Genesis Inc.: Research Funding; Sumitomo Dainippon Pharma Co.: Research Funding; Taiho Pharmaceutical Co.: Research Funding; Takeda Pharmaceutical Co.: Research Funding; Zenyaku Kogyo Co.: Research Funding; Alexion Pharmaceuticals: Honoraria; Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; JCR Pharmaceuticals: Honoraria; Janssen Pharmaceutical K.K.: Honoraria; Mundipharma: Honoraria; Novartis.: Honoraria.

Treosulfan/Fludarabine - a Low Toxicity but Myeloablative Conditioning for Allogeneic Hematopoietic Stem Cell Transplantation in Chronic Myeloid Leukemia.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1022-1022
Author(s):  
Jerzy Holowiecki ◽  
Sebastian Giebel ◽  
Jerzy Wojnar ◽  
Malgorzata Krawczyk-Kulis ◽  
Iwona Wylezol ◽  
...  
Keyword(s):  
Stem Cell ◽  
Chronic Myeloid Leukemia ◽  
Hematopoietic Stem Cell Transplantation ◽  
Myeloid Leukemia ◽  
Acute Gvhd ◽  
Chronic Phase ◽  
Unrelated Donor ◽  
Myeloablative Conditioning ◽  
Hematopoietic Stem ◽  
Experienced Grade

Abstract Although allogeneic hematopoietic stem cell transplantation (alloHSCT) is the only treatment of proved long-term efficacy in chronic myeloid leukemia (CML), high procedure-related toxicity observed after oral busulfan- or TBI-based conditioning limits its applicability and deteriorates outcome. In a series of 13 CML patients (age 35, range 16–52 years) we introduced a novel myeloablative conditioning regimen consisting of Treosulfan (alkylyting agent, soluble Busulfan-derivative) 14 g/m2/d. on days −6, −5, −4, Fludarabine 30 mg/m2/d on days −5, −4, −3, −2, −1, and, in case of unrelated donor transplants (URD-HSCT), anti-thymocyte globulin (Thymoglobulin) at a total dose of 6 mg/kg. Twelve patients were in the 1st chronic phase, one - in 2nd chronic phase. Median disease prior to alloHSCT equaled 10 (6–90) months. 8 patients were given transplant from an unrelated donor, 5 - from HLA identical sibling. GVHD prophylaxis consisted of cyclosporin A and short-course Methotrexate. All patients engrafted after a period of absolute agranulocytosis. Median time to neutrophil recovery >0.5 G/L was 24 (13–42) days, and to PLT >50 G/L - 21 (13–38) days. 1/13 patient experienced grade 3 mucositis; no severe neutropenic infection nor hepatic toxicity was observed. None of the patients developed grade III–IV acute GVHD, 1/13 patient experienced grade II acute GVHD. One patient died of EBV-related lymphoproliferative disease; the cumulative incidence of transplant-related mortality at 1 year equaled 8% (1/13). 11/13 patients achieved complete molecular remission and complete donor chimerism within 100 days after alloHSCT. The remaining two patients required immunosuppression taper and additional interferone treatment. The probability of current disease-free survival at one year equaled 92%. We conclude that Treosulfan/Fludarabine +/− ATG myeloablative conditioning is characterized by reduced toxicity and low incidence of acute GVHD. This together with high anti-leukemic efficacy makes the regimen feasible in CML patients.

Donor Lymphocyte Transfusion (DLT) in the Treatment of Relapsed CML after Allogeneic PBSCT - A Retrospective Analysis of 346 Patients by the EBMT Chronic Leukemia Working Party.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 704-704
Author(s):  
Christoph Schmid ◽  
Anja v. Biezen ◽  
Kimmo Porkka ◽  
Yves Chalandon ◽  
Alvaro Urbano ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Chronic Gvhd ◽  
Chronic Phase ◽  
Working Party ◽  
Disease Stage ◽  
Published Data ◽  
Molecular Cytogenetic ◽  
Allogeneic Pbsct

Abstract DLT has become the gold standard for the treatment of reccurrent CML after allogeneic stem cell transplantation. However, so far, published data are based on DLT following bone marrow transplantation (BMT). During recent years, mobilized peripheral blood stem cell transplantation (PBSCT) have been increasingly performed. To evaluate the efficacy of DLT following PBSCT, we retrospectively analysed the results of 86 patients treated with DLT for CML relapse after PBSCT from HLA-identical family donors. Results were compared to 260 patients receiving DLT for relapse after related BMT. Reduced intensity transplants were excluded. BMT and PBSCT groups were balanced in terms of patient age (median: 40 vs 42 y), conditioning, stage at transplant (84% vs 76% in first chronic phase (CP) p=.2), and stage at relapse (molecular/cytogenetic: 59% both, CP: 28% vs 20%, advanced: 13% vs 21%, p=.2). However, BMT patients had been transplanted in earlier years (median: 1994 vs.1998, p<.001), had a longer remission after transplantation (median: 677 vs. 275 d, p<.001), and had experienced more aGvHD after transplantation (58% vs. 34%, p<.001). Complete molecular or cytogentic remission was achieved in 71% of the patients, with a trend towards better response in BMT recipients (p=.06). Overall (OS) and event free survival (EFS) at five years from DLT are shown in table 1. Outcome was significantly superior in BMT recipients, in particular if DLT was given for hematological, rather than cytogenetic or molecular relapse. In a cox regression model, four factors were associated with better OS/EFS: Transplantation in CP1 (p<.001/.002), early stage at relapse (molecular/cytogenetic vs. hematological, p<.00/<.001), a longer remission after transplantation (p=.005/.028), and BM vs. PBSC for transplantation (p= .003/.004). In contrast, age of patient and donor, acute or chronic GvHD after transplantation, the use of chemotherapy or imatinib before DLT, and the initial number of transfused CD3+ cells were not significant. The results of this retrospective study suggest a reduced efficacy of DLT in CML relapse following related allogeneic PBSCT as compared to BMT. This effect seems to be independent from established risk factors as disease stage and remission duration. However, since several adverse factors are not equally distributed among the two groups, a bias might be induced, although no statistically significant imbalance could be detected. Therefore, the observation needs to be confirmed in a larger cohort or a prospective study. Table 1. Outcome after DLT No BMT PBSCT p Total 346 260 86 OS at five years from DLT 71% 75% 66% < .001 EFS at five years from DLT 61% 64% 41% < . 001

Risk Factors Affecting Cardiac Left Ventricular Systolic and Diastolic Function and Hypertrophy in the Chronic Phase Post-Allogeneic Hematopietic Cell Transplantation

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2000-2000
Author(s):  
Mitsutaka Nishimoto ◽  
Hirohisa Nakamae ◽  
Takahiko Nakane ◽  
Hideo Koh ◽  
Yoshiki Hayashi ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Ventricular Hypertrophy ◽  
Peak Flow ◽  
Surrogate Marker ◽  
Chronic Phase ◽  
Left Ventricular ◽  
High Dose ◽  
Myeloablative Conditioning ◽  
History Of

Abstract Abstract 2000 The long-term survival rate after allogeneic hematopoietic cell transplantation (HCT) has been significantly improved over recent decades due to improvements in the HCT procedure. However, chronic complications such as cardiovascular disease have become increasingly evident and constitute a serious problem among long-term survivors after HCT. It is well-known that high-dose cyclophosphamide (CY) used for conditioning is one of the major causes of acute cardiotoxicity after HCT; however, it is still unclear which factors contribute to chronic cardiotoxicity. Although there is a possibility that chronic GVHD (cGVHD) causes cardiac tissue damage via cytokines such as IL-2, or TNF-alpha, it is unclear whether or not cGVHD influences cardiac function. In the present retrospective cohort study, we investigated which factors affected cardiac function and left ventricular hypertrophy (LVH) in the chronic phase after HCT. We examined left ventricular systolic and diastolic functions and LVH in patients who received HCT between April 2000 and March 2011 and survived for more than one year post-HCT. Only the patients who had undergone an echocardiographic examination before HCT were eligible for the study. We assessed left ventricular ejection fraction (LVEF) as a surrogate marker of LV systolic function and the early peak flow velocity/atrial peak flow velocity (E/A) as a surrogate marker of LV diastolic function using echocardiography. LVH after HCT was identified when the interventricular septal wall (IVS) and/or the posterior wall (PW) became more than 12 mm thick after HCT. We examined the factors that could have had some influence on cardiac function after HCT including age, sex, cumulative dose of anthracycline, use of high-dose CY in the conditioning, total body irradiation (TBI), intensity of conditioning regimen (myeloablative vs. reduced intensity conditioning), a history of hypertension, hemoglobin and serum ferritin levels. A total of 58 patients (25 males and 33 females) were eligible for participation in the study. The median age of enrolled patients was 46 years (range: 21–73). The median cumulative dose of anthracycline was 90 mg/m2 (0–431mg/m2). Forty-nine patients received myeloablative conditioning and 20 of these patients received myeloabative conditioning with TBI 12 Gy. Twenty-four patients were treated for cGVHD and 7 had a history of hypertension and 2 had an LVEF of less than 55% before HCT. Six had an LVEF of less than 55% at more than 1 year after HCT. In the multiple regression analysis that assessed the relationship between LVEF or E/A and the factors, myeloablative conditioning with TBI 12Gy was significantly associated with a decrease in LVEF after HCT (coefficient= −7.57, P=.001). However, in a comparison of Ara-C/CY/TBI and CY/TBI conditioning, the degree of change in the LVEF before and after HCT was similar between the two groups (repeated measures of ANOVA analysis. P=.0972). Patients who had received myeloablative conditioning had a significant decrease in E/A after HCT(coefficient= -.31, P=.02). Furthermore, a history of hypertension was also slightly associated with a decrease in E/A after HCT(coefficient= -.30, P=.05). In addition, only age was identified as a significant risk factor of left ventricular hypertrophy after HCT in the multivariate logistic analysis. However, in the present study, we could not identify a significant impact of cGVHD on cardiac function and LVH post HCT. We concluded, based on our results, that the presence of cGVHD did not significantly contribute to a decrease in cardiac function in the chronic phase after HCT. Our results also suggest that the intensity of conditioning for HCT had a significant effect on chronic cardiac function after HCT. Disclosures: No relevant conflicts of interest to declare.

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