Treosulfan + Fludarabine +/− Thymoglobulin - An Effective Low Toxicity Conditioning Regimen for Allogeneic Hematopoietic Stem Cell Transplantation in Chronic Myeloid Leukemia.

Abstract Allogeneic hematopoietic stem cell transplantation (alloHSCT) is the only treatment of proved long-term efficacy in chronic myeloid leukemia (CML). However, high procedure-related toxicity observed after oral busulfan- or TBI-based conditioning limits its applicability and deteriorates outcome. Between 2003–2005 a phase II study was conducted to evaluate the feasibility of a new preparetive regimen consisting of Treosulfan (a soluble alkylyting agent) 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. Results were compared to those from the historical control group of CML patients treated with oral Busulfan (16 mg/kg) + Cyclophosphamide (120 mg/kg) (BuCy) in the same institution between 2000–2003. 35 patients (age 35, range 16–52 years) with CML in the 1st chronic phase (n=33) or in 2nd chronic phase (n=2) were included in the study. Median interval from diagnosis to alloHSCT equaled 10 (6–144) months. 22 (63%) patients were given transplant from an unrelated donor, 13 (37%) - from an HLA identical sibling. Bone marrow was used a source of stem cells in 29 patients, peripheral blood - in 6 cases. 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 (10–42) days, and to PLT >50 G/L - 21 (13–38) days. 1/35 patient experienced grade 3 mucositis; no severe (grade 3–4) neutropenic infection nor VOD was observed. The incidence of grade II acute GVHD was 17%, grade III–IV - 3%. The cumulative incidence of non-relapse mortality (NRM) at 2 years equaled 14% (4/35). Causes of death were: EBV-LPD, late neuroinfection, late fungal infection, acute GVHD. At 2 years the probability of the overall survival and hematological relapse-free survival equaled 86% (+/−7%) and 83% (+/−7%). Respective rates for the control BuCy group (n=78) were significantly lower: 55% (+/−6%), p=0.02, and 54% (+/−6%), p=0.03. Seven patients in the Treosulfan+Fludarabine group required immunosuppression taper and additional interferone or imatinib treatment because of incomplete donor chimerism or molecular/cytogenetic relapse after initial response. We conclude that Treosulfan+Fludarabine+/−Thymoglobulin myeloablative conditioning is associated with low organ toxicity, low incidence of acute GVHD and NRM. The regimen is feasible for CML patients and appears superior in comparison with BuCy.

Download Full-text

Treosulfan, Fludarabine, and Antithymocyte Globulin - A Low Toxicity Conditioning Regimen for Unrelated Donor - Hematopoietic Stem Cell Transplantation in Chronic Myeloid Leukemia.

Blood ◽

10.1182/blood.v108.11.2948.2948 ◽

2006 ◽

Vol 108 (11) ◽

pp. 2948-2948

Author(s):

Jerzy Holowiecki ◽

Sebastian Giebel ◽

Jerzy Wojnar ◽

Miroslaw Markiewicz ◽

Aleksandra Holowiecka-Goral ◽

...

Keyword(s):

Stem Cell ◽

Chronic Myeloid Leukemia ◽

Hematopoietic Stem Cell Transplantation ◽

Myeloid Leukemia ◽

Acute Gvhd ◽

Kinase Inhibitors ◽

Chronic Phase ◽

Unrelated Donor ◽

Hematopoietic Stem ◽

Grade 3

Abstract Unrelated donor - hematopoietic stem cell transplantation (URD-HSCT) is the treatment of proved long-term efficacy for chronic myeloid leukemia (CML) patients not having an HLA-identical sibling. However, high procedure-related toxicity observed after oral busulfan- or TBI-based conditioning limits its applicability and deteriorates outcome [Radich, Blood2003, 102, 31–5]. This is of increasing importance in the presence of challanging options offered by tyrosine kinase inhibitors. Between 2003–2006 we introduced a new preparetive regimen consisting of Treosulfan (a soluble alkylyting agent) 14 g/m2/d on days -6, -5, -4, Fludarabine 30 mg/m2/d on days -6, -5, -4, -3, -2, and, anti-thymocyte globulin (ATG) at a total dose of 6 mg/kg. Thirty patients (age 32, range 16–48 years) with CML in the 1st chronic phase (n=29) or in 2nd chronic phase (n=1) were included in the study. Median interval from diagnosis to alloHSCT equaled 1.0 (0.5–12.0) years. 63% of patients had previously been treated with Imatinib. The donors were selected based on high resolution typing for both HLA class I and II. 43% of donors were mismatched for a single HLA-C (n=9), HLA-DQB1 (n=3) or HLA-B locus (n=1). Bone marrow was used a source of stem cells in 19 patients, peripheral blood - in 11 cases. GVHD prophylaxis consisted of Cyclosporin A and short-course Methotrexate. All patients engrafted with the median time to neutrophil recovery >0.5 G/L and PLT >50 G/L of 19 (10–30) days and 18 (12–29) days, respectively. Complete donor chimerism was achieved until day +100 in all but one patient. Grade 3–4 neutropenic infections occurred in 13% of patients. Grade 3–4 mucositis as well as hepatic toxicity including VOD were not observed. The incidence of grade II acute GVHD was 23%, whereas grade III-IV acute GVHD was not observed. The incidence of extensive chronic GVHD was 10%. At 3 years the probability of the overall survival and hematological relapse-free survival equaled 82% (+/−7%). The cumulative incidence of non-relapse moratlity was 18% (+/−7%) (fungal infection n=3, bacterial infection n=1, EBV-LPD n=1). Four patients required donor lymphocyte infusion or additional interferon or imatinib treatment because of incomplete donor chimerism or molecular/cytogenetic relapse after initial response. We conclude that treosulfan + fludarabine + ATG conditioning is associated with low organ toxicity, low incidence of severe GVHD and NRM. The regimen is feasible option for CML patients referred for URD-HSCT in tyrosine kinase inhibitors era.

Download Full-text

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

Blood ◽

10.1182/blood.v104.11.1022.1022 ◽

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.

Download Full-text

Imatinib Mesylate Versus Allogeneic Hematopoietic Stem Cell Transplantation For Patients With Chronic Myeloid Leukemia In Chronic Phase

Blood ◽

10.1182/blood.v122.21.5518.5518 ◽

2013 ◽

Vol 122 (21) ◽

pp. 5518-5518

Author(s):

Liu Xiaoli ◽

Guanlun Gao ◽

Xuan Zhou ◽

Na Xu ◽

Yajuan Xiao ◽

...

Keyword(s):

Stem Cell ◽

Chronic Myeloid Leukemia ◽

Hematopoietic Stem Cell Transplantation ◽

Stem Cell Transplantation ◽

Imatinib Mesylate ◽

Hematopoietic Stem Cell ◽

Myeloid Leukemia ◽

Chronic Phase ◽

Hematopoietic Stem ◽

Risk Patients

Abstract Background and Objective Following the introduction of the tyrosine kinase inhibitor (TKI) imatinib in treatment of chronic myeloid leukemia (CML) patients, the allogeneic hematopoietic stem cell transplantation (allo-HSCT) scene in CML has changed dramatically. This retrospective cohort study was designed to compare medical outcomes of Imatinib mesylate and allo-HSCT for patients with CML in chronic phase. Patients and Methods From February 2002 to February 2012, 198 patients treated consecutively at the Nanfang Hospital,Southern Medical University were assigned to two groups according to treatment with imatinib or allo-HSCT. One hundred fifteen cases of imatinib group were given imatinib at an initial dose of 400mg daily and the dose was then adjusted according to the patient´s blood and therapy response. All the patients were evaluated for hematologic, cytogenetic and molecular response every 1-3months. Eighty-three cases of allo-HSCT group received myeloablative preconditioning regimen, and methotrexate (MTX) and cyclosporine A (CsA) were used for graft-versus-host disease(GVHD), parts combined with mycophenolate mofetil (MMF) and antihuman thymocyte globulin(ATG). The primary end points of the study were complete cytogenetic response (CCyR), relapse rate, overall survival (OS) and progression-free survival (PFS) after therapy. Results In total, 59 (68.9%) patients treated over 12 months achieved a CCyR after 12 months in imatinib group, while 67 (95.7%) patients in allo-HSCT group. The relapse rates were 14.8% (n=17) in imatinib group and 10.8% (n=9) in allo-HSCT group (P=0.456). Ten-year cumulative OS rates were 93.9% in imatinib group and 77.1% in allo-HSCT group(P=0.015) and ten- year cumulative PFS rates of two groups were 86.1% vs.88.0%(P=0.508). For Sokal rating stratified analysis, the ten-year OS rates of two groups were 96.4% vs.68.0% (P = 0.049) for high-risk patients,92.6% vs. 57.1% (P = 0.019) for intermediate-risk patients , while the ten-year PFS rates of two groups were 89.3% vs. 88.0% for high-risk patients (P = 0.942), 70.4% vs. 85.7% for intermediate-risk patients (P = 0.405).The ten-year OS rates and PFS rates were not significant difference for low-risk patients. The cumulative OS rates of two groups were 94.7% vs. 73.5%(P=0.019)for the patients who were not less than 30 years old,and the cumulative PFS rates of two groups were 84.2% vs. 94.1% respectively (P=0.147). Conclusion Imatinib mesylate treatment is superior to allogeneic hematopoietic stem cell transplantation for patients with chronic myeloid leukemia in chronic phase. Disclosures: No relevant conflicts of interest to declare.

Download Full-text

Allogeneic Hematopoietic Stem Cell Transplantation for Patients with Chronic Myeloid Leukemia in Second Chronic Phase Attained by Imatinib after Onset of Blast Crisis.

Blood ◽

10.1182/blood.v110.11.4566.4566 ◽

2007 ◽

Vol 110 (11) ◽

pp. 4566-4566

Author(s):

Ying Wang ◽

De Pei Wu ◽

Aing-Ning Sun ◽

Zheng-ming Jin ◽

Miao Miao

Keyword(s):

Stem Cell ◽

Chronic Myeloid Leukemia ◽

Hematopoietic Stem Cell Transplantation ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Myeloid Leukemia ◽

Blast Crisis ◽

Chronic Phase ◽

Hematopoietic Stem ◽

Allogeneic Hsct

Abstract The prognosis for patients with chronic myeloid leukemia (CML) in blast crisis (BC) remains dismal even with the availability of the BCR-ABL tyrosine kinase inhibitor imatinib, since it only offers short-term benefit in most cases. Allogeneic hematopoietic stem cell transplantation (HSCT) seems to be a viable option for BC-CML patients who attained remission. We treated 10 patients (9 males, 1 female) with ablative allogeneic HSCT, who achieved second chronic phase (CP) by the use of imatinib after onset of BC between October 2003 and August 2006. Median patient age was 32 years (range, 17–46). Imatinib was given orally at daily doses ranging from 600 to 800mg according to patients tolerance for at least 2 months (range, 2–5) prior to HSCT Among them, 4 patients received HSCT from human leukocyte antigen mismatched haplo-identical family donors, the others underwent a transplant from HLA matched related (n=5) or unrelated (n=1) donors. At the time of transplantation, 5 patients were in complete hematologic response with 3 patients achieved a cytogenetic response, 5 patients were in partial hematologic response. After a median follow-up of 26 months (range, 10–44), 6 (60%) out of the 10 patients were alive with mean Karnofsky score reaching 80. Among them, 5 patients achieved a molecular remission. 1 patient died in relapse 4 months after transplantation, the others died of severe acute graft-versus-host disease and associated infections. No unusual organ toxicities and engraftment difficulties were observed. Extensive chronic GVHD developed in 3 of 6 patients who could be evaluated. Patients transplanted with haplo-identical donors had a high treatment-related modality, 3 out of 4 patients died. These results suggest that allogeneic HSCT may represent a feasible treatment for patients with CML in second CP attained by imatinib after onset of BC especially when a suitable donor is available.

Download Full-text