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

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.

Imatinib mesylate (STI571) in the treatment of relapse of chronic myeloid leukemia after allogeneic stem cell transplantation

Blood ◽  
2002 ◽  
Vol 99 (10) ◽  
pp. 3861-3862 ◽  
Author(s):  
Eduardo Olavarria ◽  
Charles Craddock ◽  
Francesco Dazzi ◽  
David Marin ◽  
Sarah Marktel ◽  
...  
Keyword(s):  
Stem Cell ◽  
Chronic Myeloid Leukemia ◽  
Stem Cell Transplantation ◽  
Imatinib Mesylate ◽  
Cell Transplantation ◽  
Allogeneic Stem Cell Transplantation ◽  
Myeloid Leukemia ◽  
Specific Inhibitor ◽  
Chronic Phase ◽  
Donor Lymphocyte Infusion

Donor lymphocyte infusion (DLI) can restore durable molecular remission in a high percentage of patients with chronic myeloid leukemia (CML) who have relapses after allogeneic stem cell transplantation, but for patients who do not respond survival is poor. Imatinib mesylate (STI571) is a specific inhibitor of BCR-ABL tyrosine kinase that can induce hematologic and cytogenetic remissions in patients with CML. We report here a male patient who had a relapse to chronic phase after stem cell transplantation for CML, did not benefit from treatment with DLI, and then was administered STI571 at a dose of 400 mg daily. There was a rapid, complete hematologic response, and complete restoration of donor-type hematopoiesis (100% 46, XX marrow metaphases) was achieved after 6 months of therapy, though RT-PCR studies still detected BCR-ABL transcripts in the blood at low level. This case demonstrates that imatinib mesylate can be highly effective in the management of patients who have relapses after allograft for CML.

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

Blood ◽  
2003 ◽  
Vol 101 (2) ◽  
pp. 441-445 ◽  
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.

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

Blood ◽  
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

Allogeneic Stem Cell Transplantation for Patients with Chronic Myeloid Leukemia After Prior Treatment with Nilotinib or Dasatinib

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2348-2348
Author(s):  
Michael Schleuning ◽  
Marijke Scholten ◽  
Anja van Biezen ◽  
Arnon Nagler ◽  
Jane F. Apperley ◽  
...  
Keyword(s):  
Stem Cell ◽  
Chronic Myeloid Leukemia ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Allogeneic Stem Cell Transplantation ◽  
Myeloid Leukemia ◽  
Second Generation ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
The Impact

Abstract Abstract 2348 Stem cell transplantation (SCT) will continue to be a treatment option for patients with chronic myeloid leukemia, despite the introduction of tyrosine kinase inhibitors (TKI). However, many patients will have received prior therapy with TKI, including Nilotinib or Dasatinib at the time of allogeneic SCT. While the use of Imatinib prior to SCT seems to have no adverse impact on the outcome of allogeneic SCT little is known on the impact of prior use of second generation TKI. Therefore we conducted a retrospective registry study and identified 56 patients with CML who received an allotransplant after having been treated with Nilotinib and/or Dasatinib. Best responses to second generation TKI were major molecular response in 11%, complete cytogenetic response in 7%, partial cytogenetic response in 18%, complete hematologic remission in 25% and no response in 34%, respectively. At SCT, 37% of the patients were in accelerated or in blast phase, 36% in CP2 or higher and 27% in first chronic phase. Graft failure occurred in two patients. The median follow-up for surviving patients is 19 months. At 24 months the estimated non-relapse mortality was 33% and the relapse incidence 15%. Probability of survival is more than 85% at 2 years in patients transplanted in CP1. In univariate analysis there was a non significant trend in favor for pretreatment with Nilotinib as compared to the other groups. However, in multivariate analysis only stage of the disease was a predictor for survival. With respect to overall survival no significant differences could be identified for the following variables: patient age, donor type, stem cell source, intensity of the conditioning, time diagnosis to transplant, in or ex vivo T-cell depletion, response to treatment with second generation TKI. Patients transplanted in blast crisis had a significant higher risk of non relapse mortality. In summary, despite the shortcomings of a retrospective study, the data reported clearly show the feasibility and efficacy of allo SCT in patients pretreated with second generation TKI and it should be emphasized that the timing of allogeneic stem cell transplantation remains crucial to avoid unacceptable high treatment related mortality. Disclosures: Ekblom: Bristol-Myers Squibb: Honoraria.

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

Blood ◽  
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.

In search of the original leukemic clone in chronic myeloid leukemia patients in complete molecular remission after stem cell transplantation or imatinib

Blood ◽  
2010 ◽  
Vol 116 (8) ◽  
pp. 1329-1335 ◽  
Author(s):  
Manuel Sobrinho-Simões ◽  
Vicki Wilczek ◽  
Joannah Score ◽  
Nicholas C. P. Cross ◽  
Jane F. Apperley ◽  
...  
Keyword(s):  
Stem Cell ◽  
Chronic Myeloid Leukemia ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Quantitative Polymerase Chain Reaction ◽  
Patient Specific ◽  
Molecular Response ◽  
Leukemic Clone

Abstract It is not clear if absence of BCR-ABL transcripts—complete molecular response (CMR)—is synonymous with, or required for, cure of chronic myeloid leukemia (CML). Some patients achieve CMR with imatinib (IM), but most relapse shortly after treatment discontinuation. Furthermore, most patients in long-term remission (LTR) post–stem cell transplantation (SCT) are considered functionally cured, although some remain occasionally positive for low-level BCR-ABL mRNA. Interpretation of the latter is complicated because it has been observed in healthy subjects. We designed a patient-specific, highly sensitive, DNA quantitative polymerase chain reaction to test follow-up samples for the original leukemic clone, identified by its unique genomic BCR-ABL fusion (gBCR-ABL). In 5 IM-treated patients in CMR, gBCR-ABL was detected in transcript-negative samples; 4 patients became gBCR-ABL-negative with continuing IM therapy. In contrast, of 9 patients in LTR (13-27 years) post-SCT, gBCR-ABL was detected in only 1, despite occasional transcript-positive samples in 8 of them. In conclusion, in IM-treated patients, absence of transcripts should not be interpreted as absence of the leukemic clone, although continuing IM after achievement of CMR may lead to further reduction of residual disease. Post-SCT, we found little evidence that the transcripts occasionally detected originate from the leukemic clone.

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

Blood ◽  
2011 ◽  
Vol 117 (3) ◽  
pp. 755-763 ◽  
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.

Treatment of Pediatric Chronic Myeloid Leukemia in the Year 2010: Use of Tyrosine Kinase Inhibitors and Stem-Cell Transplantation

Hematology ◽  
2010 ◽  
Vol 2010 (1) ◽  
pp. 368-376 ◽  
Author(s):  
Meinolf Suttorp ◽  
Frédéric Millot
Keyword(s):  
Stem Cell ◽  
Chronic Myeloid Leukemia ◽  
Stem Cell Transplantation ◽  
Tyrosine Kinase ◽  
Cell Transplantation ◽  
Myeloid Leukemia ◽  
Second Generation ◽  
Young Patients ◽  
Hematopoietic Stem ◽  
First Choice

AbstractAllogeneic hematopoietic stem cell transplantation (allo-SCT) remains the only proven cure for chronic myeloid leukemia (CML), a rare malignancy in childhood. With the excellent results induced by the tyrosine kinase inhibitor (TKI) imatinib in adults in the last decade, the appropriate management of children with CML has also changed radically, and only a minority are now transplanted as a front-line treatment. Data on pediatric experiences with imatinib in CML from controlled trials remain very limited, but this review of available data describes the role of imatinib in children with CML, addressing: 1) the starting dose; 2) pharmacokinetics in childhood; 3) possible adverse effects, with a focus on the still-growing skeleton; 4) early monitoring of treatment efficacy in an attempt to avoid failure; 5) the timing of allo-SCT in children; and 6) treatment of CML relapse after allo-SCT. Because the characteristics of CML in children seem to overlap extensively with what is described in adult internal medicine, most answers and pediatric algorithms are adapted from the treatment of CML in adults. Today in 2010, allo-SCT in children should be postponed until CML becomes refractory to imatinib. The approach for young patients with suboptimal responses is unclear because data on the efficacy and safety of second-generation TKIs in childhood are almost entirely missing. Other than being included in a formal trial on second-generation TKIs, allo-SCT for patients failing imatinib remains the first choice.

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

Blood ◽  
2000 ◽  
Vol 96 (8) ◽  
pp. 2712-2716 ◽  
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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