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 Table of Contents  
EDITORIAL
Year : 2017  |  Volume : 130  |  Issue : 2  |  Page : 127-129

Tyrosine Kinase Inhibitor for Treatment of Adult Allogeneic Hematopoietic Stem Cell Transplantation Candidate with Philadelphia-Positive Acute Lymphoblastic Leukemia


Department of Hematology, Chinese People's Liberation Army General Hospital, Beijing 100082, China

Date of Submission28-Oct-2016
Date of Web Publication10-Jan-2017

Correspondence Address:
Dai-Hong Liu
Department of Hematology, Chinese People's Liberation Army General Hospital, Beijing 100082
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0366-6999.197976

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Keywords: Acute Lymphoblastic Leukemia; Allogeneic; Transplantation; Tyrosine Kinase Inhibitor


How to cite this article:
Wang L, Liu DH. Tyrosine Kinase Inhibitor for Treatment of Adult Allogeneic Hematopoietic Stem Cell Transplantation Candidate with Philadelphia-Positive Acute Lymphoblastic Leukemia. Chin Med J 2017;130:127-9

How to cite this URL:
Wang L, Liu DH. Tyrosine Kinase Inhibitor for Treatment of Adult Allogeneic Hematopoietic Stem Cell Transplantation Candidate with Philadelphia-Positive Acute Lymphoblastic Leukemia. Chin Med J [serial online] 2017 [cited 2017 Feb 20];130:127-9. Available from: http://www.cmj.org/text.asp?2017/130/2/127/197976

Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL) accounts for approximately 25-33% of all adult ALL cases. Its prognosis was dismal until the introduction of tyrosine kinase inhibitors (TKIs) in clinical applications. TKIs combined with chemotherapy resulted in higher rates of complete remission (CR) and complete molecular remission (CMR) compared with chemotherapy alone. However, allogeneic stem cell transplantation (allo-SCT) has been considered the only potentially curative option once the patient achieves CR. There are still questions that remain unanswered regarding the use of TKIs prior to or after allo-SCT. Imatinib was the first TKI used for induction and maintenance therapy in combination with chemotherapy. What is its optimal dosage and how long should it be maintained? Does the second generation of TKIs result in a better outcome in terms of induction and maintenance? Is there a cured fraction of patients who might achieve long-term survival without allo-SCT, and if yes, how could these patients be identified? What is the role of TKIs use after allo-SCT? Herein, evidence regarding the use of TKIs prior to and after allo-SCT is discussed.


  Use of Tyrosine Kinase Inhibitors Prior to Allogeneic Stem Cell Transplantation Top


Efficacy of induction and maintenance

Before the era of TKIs, 60-90% of Ph+ ALL patients achieved CR after induction chemotherapy, and <20% of patients achieved long-term leukemia-free survival (LFS).[1] The long-term LFS after allo-SCT was 30-50%.[2],[3] The international ALL trial MRC UKALL XII/ECOG2993 enrolled 267 Ph+ ALL patients (<55 years old) who received allo-HSCT with sibling or matched unrelated donors from 1993 to 2004. The 5-year overall survival (OS) was 44% after sibling allo-SCT, 36% after matched unrelated allo-SCT, and 19% after chemotherapy.[3]

The introduction of TKIs in clinical applications induced dramatic changes in the patient outcomes of Ph+ leukemia. Thomas et al.[4] showed that the rate of CR was 96% in newly diagnosed Ph+ ALL patients treated with imatinib combined with chemotherapy. Sixty percent of the patients achieved CMR. The 2-year LFS was 85%, and there was no unexpected toxicity related to the use of imatinib. This study was the first large study on the treatment of adult Ph+ ALL with TKI combined chemotherapy. The results suggested that this combination strategy resulted in a higher CR rate, a deeper molecular remission, and a similar tolerance, compared with chemotherapy alone. The improved CR and CMR rates provide efficient time for patients to find a suitable donor and to complete the preparation procedures for allo-SCT. The doses of imatinib varied substantially, and the effect of its dose intensity on outcomes has not been well explored in the setting of Ph+ ALL. Lim et al.[5] showed that a dose intensity of 600 mg imatinib daily during the initial 7-8 weeks was strongly correlated with longer CR duration and superior OS. The intensity of the combined chemotherapy, either for induction or consolidation after CR, has been recommended as the same as that for Ph-negative ALL without L-asparaginase, such as vindesine, daunorubicin, cyclophosphamide, and prednisone.[6] This strategy is aimed at the achievement of rapid and deep CR. Reduced-intensity chemotherapies, such as vindesine and prednisone, should be avoided except in the cases of unfit, elder patients.

There were very little data regarding using second-generation TKIs for Ph+ ALL. Dasatinib was approved to be effective in imatinib-resistant Ph+ ALL.[7] Oral administration of dasatinib achieves a therapeutic concentration in the cerebrospinal fluid, showing that it is advantageous for the treatment of acute leukemia in comparison with imatinib. Ottmann et al.[8] reported that 42% of 36 imatinib-resistant Ph+ ALL patients achieved hematological remission with dasatinib treatment combined with chemotherapy. Ravandi et al.[1] conducted a phase II study combining the hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone regimen with dasatinib in newly diagnosed patients (median age of 53 years, range: 21-79). With a median follow-up of 14 (range: 4-37) months, 94% of the patients achieved CR, and the 2-year survival rate was 64%. More recent data suggest that dasatinib treatment resulted in deeper complete hematologic remission and cytogenetic remission compared with imatinib regimen. In the GIMEMA LAL 1205 protocol from multiple centers in Italy, patients with newly diagnosed Ph+ ALL, older than 18 years of age, received dasatinib induction therapy for 84 days combined with steroids for the first 32 days and intrathecal chemotherapy for the remaining days. Totally 53 patients (median age of 54 years) achieved CR. At 20 months, the OS was 69.2% and the LFS was 51.1%. The LFS was significantly higher in patients who showed a decrease in the breakpoint cluster region and the Abelson leukemia virus (BCR-ABL) levels to <10−3 at day 85 compared with patients who did not reach these levels.[9] A report from the European Working Group on Adult ALL group showed the outcomes of elder patients (n = 71, all >55 years, median age: 69 years) with dasatinib (140 mg/d, 100 mg/d over 70 years) with low-intensity chemotherapy. The CR rate was 96%, the CMR rate was 65% during consolidation, and the 5-year OS was 36%.[10]

Is there a subgroup that might achieve long-term survival without allogeneic stem cell transplantation?

TKIs combined with chemotherapy results in CMR in some adult Ph+ ALL patients. This fact has raised the question of whether some of these patients with CMR could be cured without allo-SCT. There were a few small cohort studies showing that the prognosis of patients treated with imatinib-combined chemotherapy was similar to those who received allo-SCT in CR1. In the report by Thomas et al.,[4] six of the ten patients who did not receive allo-SCT were still alive without recurrence of disease after a median follow-up of 20 months. Kuang et al.[11] reported the clinical results of sustaining integrating imatinib and interferon (IFN)-α in maintenance therapy in patients ineligible for allo-SCT. Maintenance therapy lasted for 5 years with an imatinib dose of 400 mg daily, an IFN-α dose of 3 million units at 2-3 doses/week, and chemotherapy that included vindesine and dexamethasone. For 41 patients without allo-SCT with a median follow-up of 32 months, the 3-year LFS and OS were 42.7% and 57.9%, respectively. BCR/ABL persistent negativity at 6 and 9 months might be beneficial in choosing suitable patients for the imatinib/IFN-α maintenance strategy.

Ravandi et al.[12] demonstrated the predictive value of minimal residual disease (MRD) assessment by real-time quantitative polymerase chain reaction (RQ-PCR) and multiparameter flow cytometry (MFC) in Ph+ ALL patients at CR1. With a median follow-up of 383 (range: 232-501) weeks for patients using imatinib (n = 54) and 123 (range: 1-235) weeks for dasatinib (n = 68), the 3-year OS of patients who were negative for MRD by MFC at 3 months and 12 months after CR1 was 65-70% and over 80%, respectively. For patients with an MRD <0.1% by RQ-PCR after 3 or 9 months of CR1, the 3-year OS was over 60%. A long-term follow-up of the Group for Research on Adult Acute Lymphoblastic Leukemia Philadelphia- positive-2003 trial described the outcomes of 45 patients whose postremission therapy was partly decided by MRD results.[13] Imatinib doses of 600-800 mg daily were given with consolidation chemotherapy. The OS was 50% after allo-SCT (n = 24), 33% for patients without allo-SCT (n = 9), and 80% after autologous SCT (n = 10). Seven of the ten patients achieved CMR (MRD <10−4). Short et al.[14] showed that patients with Ph+ ALL who achieved CMR at 3 months had superior survival compared with those with less significant molecular responses (median OS: 127 vs. 38 months, P = 0.009; relapse-free survival: 126 vs. 18 months, P = 0.007), even without allo-SCT. A prospective controlled study is needed to determine whether autologous SCT with CMR should be performed instead of allo-SCT.


  Use of Tyrosine Kinase Inhibitors after Allogeneic Stem Cell Transplantation Top


Recent data suggest that TKI maintenance after allo-SCT could markedly improve outcomes. Chen et al.[15],[16] reported the efficacy of imatinib in preventing hematological relapse and improving LFS when administered to Ph+ ALL patients after allo-SCT with haploidentical or matched unrelated donors without ex vivo T-cell depletion. The results demonstrated that the estimated 5-year relapse rate was lower in the imatinib-prophylaxis group compared with the nonimatinib-prophylaxis group (10.2% vs. 33.1%, P < 0.001). The 5-year LFS was remarkably higher in the imatinib-prophylaxis group (81.5% vs. 33.5%, P < 0.001) compared with the nonimatinib-prophylaxis group. The authors drew similar conclusions from the patients who received prophylactic use of TKIs after haploidentical (n = 101) or matched sibling (n = 38) allo-SCT. At a median follow-up of 36 months, the 5-year LFS and OS in the haploidentical and matched sibling groups were 65.8% and 74.0%, respectively.[17] Pfeifer et al.[17] performed a randomized trial of prophylactic or MRD-triggered imatinib after allo-SCT. The early occurrence of MRD positivity or positivity at higher levels identified a subset of patients who did not benefit from imatinib. Due to its advantage for the prevention of disease recurrence, the prophylactic use of TKIs after allo-SCT was recommended recently in the consensus by the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation.[18]

In summary, with the introduction of TKIs in the first-line therapy combined with chemotherapy, the outcomes of adult Ph+ ALL patients have been greatly improved compared with chemotherapy alone. Prospective trials are needed to determine the optimal dosage and length of maintenance of TKIs and the indication for the first line use of second-generation TKIs. Allo-SCT remains the only cure option for all patients who achieved CR. Whether the treatment strategy should be allo-SCT or TKIs combined with chemotherapy is controversial when the patients lack a matched sibling or unrelated donor. The right recommendation relies not only on the efficacy of TKIs combined with chemotherapy but also on the safety of allo-SCT from alternative donors. It is important to note that the safety and efficacy of allo-SCT from alternative donors have been improved in recent years, especially in China. When making decisions for individual patients, the physical condition of the patients and the transplantation experience of the medical center should be considered. A subgroup of patients who achieve early and durable CMR might have a potential opportunity for long-term survival with maintenance of TKIs combined with chemotherapy, IFN, or autologous SCT. The monitoring of MRD should be routinely performed for the assessment of relapse risk and adjustment of the therapeutic strategy.

 
  References Top

1.
Ravandi F, O′Brien S, Thomas D, Faderl S, Jones D, Garris R, et al. First report of phase 2 study of dasatinib with hyper-CVAD for the frontline treatment of patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia. Blood 2010;116:2070-7. doi: 10.1182/blood-2009-12-261586.  Back to cited text no. 1
    
2.
Laport GG, Alvarnas JC, Palmer JM, Snyder DS, Slovak ML, Cherry AM, et al. Long-term remission of Philadelphia chromosome-positive acute lymphoblastic leukemia after allogeneic hematopoietic cell transplantation from matched sibling donors: A 20-year experience with the fractionated total body irradiation-etoposide regimen. Blood 2008;112:903-9. doi: 10.1182/blood-2008-03-143115.  Back to cited text no. 2
    
3.
Fielding AK, Rowe JM, Richards SM, Buck G, Moorman AV, Durrant IJ, et al. Prospective outcome data on 267 unselected adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia confirms superiority of allogeneic transplantation over chemotherapy in the pre-imatinib era: Results from the International ALL Trial MRC UKALLXII/ECOG2993. Blood 2009;113:4489-96. doi: 10.1182/blood-2009-01-199380.  Back to cited text no. 3
    
4.
Thomas DA, Faderl S, Cortes J, O′Brien S, Giles FJ, Kornblau SM, et al. Treatment of Philadelphia chromosome-positive acute lymphocytic leukemia with hyper-CVAD and imatinib mesylate. Blood 2004;103:4396-407. doi: 10.1182/blood-2003-08-2958.  Back to cited text no. 4
    
5.
Lim SN, Joo YD, Lee KH, Kim DY, Lee JH, Lee JH, et al. Long-term follow-up of imatinib plus combination chemotherapy in patients with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia. Am J Hematol 2015;90:1013-20. doi: 10.1002/ajh.24137.6.  Back to cited text no. 5
    
6.
Hematology Oncology Committee, Chinese Anti-Cancer Association; Leukemia and Lymphoma Group, Chinese Society of Hematology, Chinese Medical Association. Chinese guidelines for diagnosis and treatment of acute lymphoblastic leukemia (2016) (in Chinese). Chin J Hematol 2016;37:837-45. doi: 10.3760/cma.j.issn.0253-2727.2016.10.002.  Back to cited text no. 6
    
7.
Cortes J, Rousselot P, Kim DW, Ritchie E, Hamerschlak N, Coutre S, et al. Dasatinib induces complete hematologic and cytogenetic responses in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in blast crisis. Blood 2007;109:3207-13. doi: 10.1182/blood-2006-09-046888.  Back to cited text no. 7
    
8.
Ottmann O, Dombret H, Martinelli G, Simonsson B, Guilhot F, Larson RA, et al. Dasatinib induces rapid hematologic and cytogenetic responses in adult patients with Philadelphia chromosome positive acute lymphoblastic leukemia with resistance or intolerance to imatinib: Interim results of a phase 2 study. Blood 2007;110:2309-15. doi: 10.1182/blood-2007-02-073528.  Back to cited text no. 8
    
9.
Aricò M, Schrappe M, Hunger SP, Carroll WL, Conter V, Galimberti S, et al. Clinical outcome of children with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia treated between 1995 and 2005. J Clin Oncol 2010;28:4755-61. doi: 10.1200/JCO.2010.30.1325.  Back to cited text no. 9
    
10.
Rousselot P, Coudé MM, Gokbuget N, Gambacorti Passerini C, Hayette S, Cayuela JM, et al. Dasatinib and low-intensity chemotherapy in elderly patients with Philadelphia chromosome-positive ALL. Blood 2016;128:774-82. doi: 10.1182/blood-2016-02-700153.  Back to cited text no. 10
    
11.
Kuang P, Liu T, Pan L, Zhu H, Wu Y, Ye Y, et al. Sustaining integrating imatinib and interferon-a into maintenance therapy improves survival of patients with Philadelphia positive acute lymphoblastic leukemia ineligible for allogeneic stem cell transplantation. Leuk Lymphoma 2016;57:2321-9. doi: 10.3109/10428194.2016.1144882.  Back to cited text no. 11
    
12.
Ravandi F, Jorgensen JL, Thomas DA, O′Brien S, Garris R, Faderl S, et al. Detection of MRD may predict the outcome of patients with Philadelphia chromosome-positive ALL treated with tyrosine kinase inhibitors plus chemotherapy. Blood 2013;122:1214-21. doi: 10.1182/blood-2012-11-466482.  Back to cited text no. 12
    
13.
Tanguy-Schmidt A, Rousselot P, Chalandon Y, Cayuela JM, Hayette S, Vekemans MC, et al. Long-term follow-up of the imatinib GRAAPH-2003 study in newly diagnosed patients with de novo Philadelphia chromosome-positive acute lymphoblastic leukemia: A GRAALL study. Biol Blood Marrow Transplant 2013;19:150-5. doi: 10.1016/j.bbmt.2012.08.021.  Back to cited text no. 13
    
14.
Short NJ, Jabbour E, Sasaki K, Patel K, O′Brien SM, Cortes JE, et al. Impact of complete molecular response on survival in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia. Blood 2016;128:504-7. doi: 10.1182/blood-2016-03-707562.  Back to cited text no. 14
    
15.
Chen H, Liu KY, Xu LP, Liu DH, Chen YH, Zhao XY, et al. Administration of imatinib after allogeneic hematopoietic stem cell transplantation may improve disease-free survival for patients with Philadelphia chromosome-positive acute lymphoblastic leukemia. J Hematol Oncol 2012;5:29-37. doi: 10.1186/1756-8722-5-29.  Back to cited text no. 15
    
16.
Chen H, Liu KY, Xu LP, Chen YH, Han W, Zhang XH, et al. Haploidentical hematopoietic stem cell transplantation without in vitro T cell depletion for the treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia. Biol Blood Marrow Transplant 2015;21:1110-6. doi: 10.1016/j.bbmt.2015.02.009.  Back to cited text no. 16
    
17.
Pfeifer H, Wassmann B, Bethge W, Dengler J, Bornhäuser M, Stadler M, et al. Randomized comparison of prophylactic and minimal residual disease-triggered imatinib after allogeneic stem cell transplantation for BCR-ABL1-positive acute lymphoblastic leukemia. Leukemia 2013;27:1254-62. doi: 10.1038/leu.2012.352.  Back to cited text no. 17
    
18.
Giebel S, Czyz A, Ottmann O, Baron F, Brissot E, Ciceri F, et al. Use of tyrosine kinase inhibitors to prevent relapse after allogeneic hematopoietic stem cell transplantation for patients with Philadelphia chromosome-positive acute lymphoblastic leukemia: A position statement of the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation. Cancer 2016;122:2941-51. doi: 10.1002/cncr.30130.  Back to cited text no. 18
    




 

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