Randomized Comparison of Primary Allogeneic Stem Cell Transplantation and Best Available Drug Treatment in Chronic Myeloid Leukemia.

Abstract Early allogeneic hematopoietic stem cell transplantation (HSCT) has been proposed as primary treatment modality for patients (pts) with chronic myeloid leukemia (CML). This concept has been challenged by persisting transplantation mortality and improved drug therapy. In order to verify retrospective and observational results and to counsel pts and doctors about survival prospects with each treatment strategy, a randomized controlled trial was designed to compare primary HSCT and best available drug treatment in a cohort of 621 newly diagnosed CML pts in chronic phase. Assignment to treatment strategy was by eligibility for HSCT and genetic randomization according to availability of a matched related donor. Evaluation followed the intention to treat principle. 354 pts (62% male; median age 40 years, range 11–59) were eligible and randomized. 135 pts (38 %) had a matched related donor of which 123 (91%) received a transplant within a median of 10 months (range 2–106) from diagnosis. 4 pts died before scheduled transplantation, 8 pts withdrew consent. 219 pts (62%) had no related donor and received best available drug treatment. Of these, 97 pts (44%) received a matched unrelated donor (MUD) transplant in 1st chronic phase and were censored at the time of transplantation. As 1st line treatment after randomization pts received interferon alpha based therapy. In the course of the study a total of 197 pts were switched to imatinib after failure of interferon alpha. Currently 31 (57%) of 54 living pts of the drug treatment group receive imatinib or 2nd generation tyrosine kinase inhibitors (dasatinib n=2, nilotinib n=1). With a median observation time of 8.9 years (range 4.2–11.2) median survival of all 621 pts was 8.1 years. During the first 8 years after diagnosis survival curves of drug treated patients were superior to those of transplanted patients reflecting transplant-related mortality. Beyond 8 years survival curves were no longer distinct. 5 (10) year survival was 62% (53%) for transplanted and 73% (52%) for drug treated pts, in the low risk group 68% (59%) for transplanted and 85% (62%) for drug treated pts, respectively. Survival was superior for drug treated pts up to the cutpoint of survival curves at year 8 (p=0.041) and during the study period up to 11 years from diagnosis (p=0.049), particularly so in low risk pts (p=0.027 to cutpoint, p=0.032 overall). Significantly higher proportions of complete cytogenetic remissions (91% vs 61%, p=0.002) and of major molecular responses (ratio BCR-ABL/ABL <0.1%; 81% vs 45%, p=0.001) were found in the transplant group indicating higher levels of residual disease in the group receiving drug treatment. In summary, the general recommendation of HSCT as 1st line treatment option in chronic phase CML can no longer be maintained. It should be replaced by a trial with modern drug treatment first and a risk adapted strategy according to the individual disease and transplantation risks thereafter. HSCT remains an important treatment option in a risk adapted strategy on the basis of higher cytogenetic and molecular long term remission rates.

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Nonmyeloablative allogeneic stem cell transplantation for the treatment of chronic myeloid leukemia in first chronic phase

Blood ◽

10.1182/blood-2002-02-0535 ◽

2003 ◽

Vol 101 (2) ◽

pp. 441-445 ◽

Cited By ~ 152

Author(s):

Reuven Or ◽

Michael Y. Shapira ◽

Igor Resnick ◽

Avraham Amar ◽

Aliza Ackerstein ◽

...

Keyword(s):

Stem Cell ◽

Chronic Myeloid Leukemia ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Myeloid Leukemia ◽

Low Dose ◽

Chronic Phase ◽

Mixed Chimerism ◽

High Dose ◽

Disease Free

Reduced-intensity or nonmyeloablative stem cell transplantation (NST) is designed to induce host-versus-graft tolerance by engraftment of donor stem cells. The rationale behind NST is to induce optimal graft-versus-leukemia (GVL) effects for elimination of all malignant cells by donor alloreactive immunocompetent cells as an alternative to standard high-dose myeloablative chemoradiotherapy. NST based on the use of fludarabine, low-dose busulfan, and anti–T-lymphocyte globulin (ATG) was employed in 24 patients aged 3 to 63 years with chronic myeloid leukemia (CML) in first chronic phase (CP). Graft-versus-host disease (GVHD) prophylaxis consisted of low-dose cyclosporine (CSP), in some cases with low-dose methotrexate. Early discontinuation of CSP was attempted in cases of mixed chimerism in an attempt to amplify GVL effects. All 24 patients showed rapid 3-lineage engraftment, mostly without complete aplasia; 6 patients did not require transfusion of any blood products. NST was associated with minimal procedure-related toxicity. The incidence of acute GVHD (grade I or higher) was 54%; however, this incidence increased following CSP withdrawal. After a follow-up of up to 70 months (median, 42 months), 21 of 24 patients remained alive and disease free. The GVL effects induced by donor immunocompetent lymphocytes eradicated all host hematopoietic cells, as evidenced by molecular testing. The Kaplan-Meier probability of survival and disease-free survival at 5 years is 85% ± 8% (95% confidence interval, 70%-100%). NST may successfully replace myeloablative stem cell transplantation, providing a safer, well-tolerated therapeutic option for all patients with CML in first CP with a matched donor. However, this conclusion must be tested in a prospective randomized clinical trial.

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HLA-Haploidentical Related Hematopoietic Stem Cell Transplantation and Mesenchymal Stem Cell Transplantation in Patients with Hematologic Malignancies.

Blood ◽

10.1182/blood.v108.11.5408.5408 ◽

2006 ◽

Vol 108 (11) ◽

pp. 5408-5408

Author(s):

Xiaoyan Zhang ◽

Jianyong Li ◽

Kejiang Cao ◽

Hanxin Wu ◽

Hua Lu ◽

...

Keyword(s):

Bone Marrow ◽

Stem Cell ◽

Chronic Myeloid Leukemia ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Clinical Features ◽

Myeloid Leukemia ◽

Chronic Phase ◽

Hematologic Malignancies ◽

Hematopoietic Stem

Abstract Background: Allogeneic hematopoietic stem cell transplantation (HSCT) is the only way to cure many hematologic malignancies. HLA-haploidentical related HSCT was performed in case of lack of HLA-matched donors. From the results of in-vitro and animal studies, Mesenchymal stem cells (MSCs) transplanted simultaneously with hematopoietic stem cells (HSCs) may support hematopoietic regeneration and have the immunomodulatory effect. MSCs together with HSCs transplantation from the same HLA-haploidentical donor were used in patients with hematologic malignancies. Patients and Methods: Three patients were chronic myeloid leukemia (blast crisis), chronic myeloid leukemia (chronic phase) and refractory T-cell lymphoblastic lymphoma (leukemia phase) respectively. Complete demographic and clinical details of these 3 patients are shown in Table 1. Bone marrow mononuclear cells obtained from their HLA-haploidentical related donors were cultured and expanded in vitro about 2 months before transplantation. Immunophenotype of the harvested cells were detected in order to identify them. After conditioned by cytosine arabinoside/cyclophosphamide/total body irradiation regimen, patients were co-transplanted with HSCs and ex-vivo expanded MSCs. Cyclosporine, methotrexate, antithymocyte globulin, mycophenolate mofetil and anti-CD25 monoclonal antibody were used together for prophylaxis of GVHD. Clinical features after transplantation in these patients were observed. Results: About 2×106 MSCs per kilogram of recipients’ weight were successfully expanded from bone marrow samples. These cells were CD73, CD90, CD105 positive and CD34, CD45, CD38, CD10, CD20, CD33, HLA-DR negative by flow cytometric analysis. No adverse response was observed during and after infusion of MSCs. Hematopoietic reconstruction was successful in all the patients. And they had full donor-type chimerism 1 month after transplantation. N1 received donor lymphocyte infusion (DLI) to prevent the relapse. N2 relapsed and received the therapy of STI571 combined with DLI. She had a complete remission at last. No graft-versus-host disease (GVHD) was observed in N1 and N2 until they received DLI. N1 died of infection 11 months after transplantation. N2 and N3 now have been followed up for 41 and 31 months respectively. Clinical features of patients after transplantation are shown in Table 2. Conclusions: Bone marrow derived MSCs can be tolerant well in HLA-haploidentical HSCT. Its exact effect in human HLA-haploidentical allogeneic HSCT needs to be studied further. Tab.1 Patient Demographic and Clinical Data Patient Diagnosis Age Sex Course of disease before transplantation Donor Mismatched HLA loci Abbr: LPL - lymphoblastic lymphoma; CML - chronic myeloid leukemia; BC - blast crisis; CP - chronic phase; yr - year; mo - month N1 T-LPL 22 F 7 yr mother 3 N2 CML-BC 32 F 6mo sibling brother 3 N3 CML-CP 22 M 5mo father 3 Tab.2 Clinical features of patients after transplantation Patient Hematopoietic reconstruction Donor-type chimerism Time of relapse time of DLI acute GVHD chronic GVHD survival Abbr: DLI - donor lymphocyte infusion; d - day; mo - month N1 15 d 100% no 5 mo IV (after DLI) extensive die in 11 mo N2 16 d 100% 6mo 6 mo IV (after DLI) no >41 mo N3 15 d 100% no no I limited >31 mo

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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.

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Three decades of transplantation for chronic myeloid leukemia: what have we learned?

Blood ◽

10.1182/blood-2010-08-301341 ◽

2011 ◽

Vol 117 (3) ◽

pp. 755-763 ◽

Cited By ~ 57

Author(s):

Jiří Pavlů ◽

Richard M. Szydlo ◽

John M. Goldman ◽

Jane F. Apperley

Keyword(s):

Stem Cell ◽

Chronic Myeloid Leukemia ◽

Stem Cell Transplantation ◽

Tyrosine Kinase ◽

Tyrosine Kinase Inhibitors ◽

Cell Transplantation ◽

Myeloid Leukemia ◽

Kinase Inhibitors ◽

Chronic Phase ◽

Hematopoietic Stem

Abstract Last year marked 30 years of hematopoietic stem cell transplantation as a curative treatment of chronic myeloid leukemia (CML). Initially studies used stem cells from identical twins but techniques rapidly developed to use cells first from HLA-identical siblings and later unrelated donors. During the 1990s CML became the most frequent indication for allogeneic transplantation worldwide. This, together with the relative biologic homogeneity of CML in chronic phase, its responsiveness to graft-versus-leukemia effect and the ability to monitor low level residual disease placed CML at the forefront of research into different strategies of stem cell transplantation. The introduction of BCR-ABL1 tyrosine kinase inhibitors during the last decade resulted in long-term disease control in the majority of patients with CML. In those who fail to respond and/or develop intolerance to these agents, transplantation remains an effective therapeutic solution. The combination of tyrosine kinase inhibitors with transplantation is an exciting new strategy and it provides inspiration for similar approaches in other malignancies.

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Durability of responses following donor lymphocyte infusions for patients who relapse after allogeneic stem cell transplantation for chronic myeloid leukemia

Blood ◽

10.1182/blood.v96.8.2712 ◽

2000 ◽

Vol 96 (8) ◽

pp. 2712-2716 ◽

Cited By ~ 177

Author(s):

Francesco Dazzi ◽

Richard M. Szydlo ◽

Nicholas C. P. Cross ◽

Charles Craddock ◽

Jaspal Kaeda ◽

...

Keyword(s):

Stem Cell ◽

Chronic Myeloid Leukemia ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Allogeneic Stem Cell Transplantation ◽

Myeloid Leukemia ◽

Chronic Phase ◽

Molecular Remission ◽

Donor Lymphocyte Infusions ◽

Median Interval

Abstract An analysis was performed of the response to treatment with donor lymphocyte infusions (DLI) and the survival in 66 consecutive patients who relapsed after primary treatment by allogeneic stem cell transplantation for BCR-ABL–positive chronic myeloid leukemia. The transplant donor was an HLA-identical sibling (n = 35) or a “matched” unrelated volunteer (n = 31). Fifty-seven patients were transplanted in chronic phase, eight in accelerated phase, and one in second chronic phase. The recognition of relapse was based on precise molecular, cytogenetic, or hematologic criteria. The median interval from transplant to relapse was 12 months (range 3-85). The median interval from relapse to initiation of DLI was 9.4 months (range 1-70). Patients received DLI from their original transplant donors on a bulk-dose (n = 34) or on an escalating-dose (n = 32) regimen. Patients were monitored serially by hematologic, cytogenetic, and molecular criteria. Molecular remission was defined by the finding of negative results by nested primer reverse transcriptase polymerase chain reaction (RT-PCR) for BCR-ABL transcripts on two consecutive occasions, subject to satisfactory controls. Forty-four patients (67%) achieved molecular remission. Patients who had relapsed to advanced phase disease and patients with short intervals between transplant and relapse had significantly lower probabilities of achieving molecular remission. Of the 44 patients who achieved molecular remission, 4 reverted to a PCR-positive status at 15, 18, 37, and 87 weeks after remission. The probability of survival for patients who achieved molecular remission was significantly better than for those who failed to do so (95% versus 53% at 3 years post-DLI,P = .0001). We conclude that the majority of molecular remissions after DLI are durable, and thus the majority of responding patients may prove to have been cured.

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Chronic Myeloid Leukemia Relapsing 25 Years after Allogenic Stem Cell Transplantation

Case Reports in Hematology ◽

10.1155/2018/2045985 ◽

2018 ◽

Vol 2018 ◽

pp. 1-4

Author(s):

Håkon Reikvam ◽

Jørn Skavland ◽

Stein-Erik Gullaksen ◽

Randi Hovland ◽

Tobias Gedde-Dahl ◽

...

Keyword(s):

Stem Cell ◽

Chronic Myeloid Leukemia ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Myeloid Leukemia ◽

Kinase Inhibitors ◽

Philadelphia Chromosome ◽

Chronic Phase ◽

Allogenic Stem Cell Transplantation ◽

Relapsed Disease

Chronic myeloid leukemia (CML) is a myeloproliferative disorder in which neoplastic cells exhibit the Philadelphia chromosome and the related oncoproteinBCR-ABL1. Allogeneic stem cell transplantation (allo-SCT) was considered the first-line treatment for CML, before the introduction of tyrosine kinase inhibitors (TKIs). However, patients are at risk for relapse years after transplantation. We present a patient who relapsed 25 years after allo-SCT for chronic phase CML. Polymerase chain reaction (PCR) detected gradually evaluated levels ofBCR-ABL1transcripts, eventually leading to the diagnosis of relapsed disease. Additional mutational analyses did not reveal mutations in theBCR-ABL1gene, or other cooperating mutations. The patient was successfully treated with imatinib 400 mg daily, leading to new molecular remission. The case presentation emphasizes the need for long-term follow-up of such patients and the potential benefit of initiating TKI treatment with early signs of relapse.

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Imatinib mesylate experience of young patients with chronic myeloid leukemia in chronic phase—Care to cure

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.7072 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. 7072-7072

Author(s):

D. Biswajit ◽

R. Rejiv ◽

N. Manjunath ◽

G. Prasad ◽

S. Lakshmi ◽

...

Keyword(s):

Stem Cell ◽

Chronic Myeloid Leukemia ◽

Adverse Effects ◽

Stem Cell Transplantation ◽

Imatinib Mesylate ◽

Cell Transplantation ◽

Myeloid Leukemia ◽

Young Patients ◽

Chronic Phase ◽

Molecular Response

7072 Background: Chronic myeloid leukemia (CML) with introduction of imatinib has been transformed into a chronic illness. The options of treatment in a patient less than 35 years include imatinib or allogenic stem cell transplantation. Hence we studied this unique subset to look at the response rates, adverse effects, progression free survival, and overall survival with imatinib mesylate. Methods: 477 patients with Philadelphia positive CML in chronic phase were retrospectively analyzed from January 2002 to December 2007 at Cancer Institute (WIA), Chennai, India. Standard criteria were used for response evaluation and adverse effects. Results: A total of 248 young CML patients with age less than 35 years (51.9%) were diagnosed in chronic phase. The median age of study population was 27 years (4–35). The male to female ratio was 1.9: 1. Risk stratification was done using Sokal index and were classified into low (32.3%), intermediate (50.4%), and high (17.3%). All patients received imatinib 400 mg as the initial dose. Complete hematological remission (CHR) was seen in 96.7%.Cytogenetic (FISH) and molecular (RTPCR) monitoring was possible in 53.2% and 17.3%, respectively. 72% of the patients had major cytogenetic response. Major molecular response was seen in 34.8% while complete molecular response occurred in 23.2% of the patients. Primary and secondary imatinib failure was seen in 3.1% and 16.9%, respectively. 6.7% had grade 3 and grade 4 hematological toxicities. The other common non hematological toxicities included pedal edema (13.7%), hypo or hyper pigmentation (60.0%), hyalgia (14.5%), diarrhea (1.6%), and liver dysfunction (1.6%). None of the patients discontinued imatinib due to toxicities. The 3-year DFS and OS was 86.2% and 89.5%, respectively. Patients with male sex (p = 0.04), spleen > 8 cm (p = 0.02), high sokal index (p = 0.02), and loss of CHR (p < 0.001) were associated with poor outcome. Conclusions: Imatinib in young patients have an excellent tolerance and response. A small subset does not respond to therapy or develop resistance during treatment. Hence it is essential to identify these poor responders and to offer stem cell transplantation at the earliest. No significant financial relationships to disclose.

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

Blood ◽

10.1182/blood.v106.11.5309.5309 ◽

2005 ◽

Vol 106 (11) ◽

pp. 5309-5309

Author(s):

Jerzy Holowiecki ◽

Sebastian Giebel ◽

Jerzy Wojnar ◽

Malgorzata Krawczyk-Kulis ◽

Iwona Wylezol ◽

...

Keyword(s):

Stem Cell ◽

Chronic Myeloid Leukemia ◽

Hematopoietic Stem Cell Transplantation ◽

Stem Cell Transplantation ◽

Myeloid Leukemia ◽

Acute Gvhd ◽

Chronic Phase ◽

Unrelated Donor ◽

Hematopoietic Stem ◽

Grade 3

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.

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

Blood ◽

10.1182/blood.v108.11.5372.5372 ◽

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.

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Stem cell transplantation for chronic myeloid leukemia in children

Blood ◽

10.1182/blood-2002-12-3637 ◽

2003 ◽

Vol 102 (4) ◽

pp. 1224-1231 ◽

Cited By ~ 72

Author(s):

Kate Cwynarski ◽

Irene A. G. Roberts ◽

Simona Iacobelli ◽

Anja van Biezen ◽

Ronald Brand ◽

...

Keyword(s):

Stem Cell ◽

Chronic Myeloid Leukemia ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Myeloid Leukemia ◽

Philadelphia Chromosome ◽

Chronic Phase ◽

Disease Stage ◽

Hematopoietic Stem ◽

Advanced Phase

Abstract Hematopoietic stem cell transplantation (SCT) is the only proven cure for chronic myeloid leukemia (CML), a rare disease in childhood. We report outcomes of 314 children with Philadelphia-chromosome–positive (Ph+) CML undergoing SCT from HLA-matched siblings (n = 182) or volunteer-unrelated donors (VUD; n = 132). Three-year overall survival (OS) and leukemia-free survival (LFS) rates were 66% and 55% (n = 314). For 156 children in first chronic phase (CP1) who underwent transplantation from HLA-identical siblings, OS and LFS rates were 75% and 63%. For 97 children who underwent SCT in CP1 from VUD, 3-year OS and LFS rates were 65% and 56%, reflecting higher transplantation-related mortality (TRM) after VUD SCT (35% vs 20%; multivariate hazard ratio [HR], 1.9; 95% confidence interval [CI], 1.0-3.5; P = .05). In a multivariate model for OS and LFS, outcomes were superior in CP1 than in advanced phase (AP/CP1) (OS HR, 2.0; 95% CI, 1.3-3; P = .001; LFS HR, 1.8; 95% CI, 1.2-2.6; P = .003). For relapse, donor source (VUD/sibling) (HR, 0.38; 95% CI, 0.19-0.76; P = .006) and disease stage (AP/CP1) (HR, 2.4; 95% CI, 1.36-4.3; P = .003) were significant. This is the first large series to show that SCT confers long-term LFS in most children with CML and helps assess alternative therapy, including tyrosine kinase inhibitors.

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