Editor's Pick: Allogeneic Haematopoietic Stem Cell Transplantation for Chronic Myeloid Leukaemia in the Era of Tyrosine Kinase Inhibitors - European Medical Journal

Continue

Editor’s Pick: Allogeneic Haematopoietic Stem Cell Transplantation for Chronic Myeloid Leukaemia in the Era of Tyrosine Kinase Inhibitors

9 Mins
Hematology
Download PDF

Allogeneic haematopoietic stem cell transplant (alloSCT) is an effective therapeutic choice for chronic myeloid leukaemia and remained the only curative option for many years. However, the introduction of targeted drugs against the BCR-ABL1 tyrosine kinase has changed the therapeutic approach for this disease. In this article, the authors describe the current indications for alloSCT during the tyrosine kinase inhibitor era and explore the role of these drugs in multiple situations, including before and after transplant.

Dr David Gómez-Almaguer   Hospital Universitario Dr. Jose E. González UANL, México

Authors:
*Ahmet Emre Eskazan,1 Mario Tiribelli2

1. Division of Hematology, Department of Internal Medicine, Cerrahpasa Faculty of Medicine, Istanbul University, Istanbul, Turkey
2. Division of Hematology and BMT, Department of Medical Area, University of Udine, Udine, Italy
*Correspondence to [email protected]

Disclosure:

Dr Eskazan has received advisory board honorarium from Novartis and speaker’s bureau honoraria from Novartis and Bristol-Myers Squibb, outside the present study. Dr Tiribelli has received speaker’s bureau and advisory board honoraria from Novartis, Bristol-Myers Squibb, Pfizer, and Incyte, outside the present study. Both authors contributed equally to this work.

Acknowledgements:

Dr Eskazan would like to thank his beloved wife Dr Tugce Eskazan for being in his life and for her continuous support, and their sweet daughter Defne for bringing sunshine to their lives. Dr Tiribelli would like to thank his loved wife Dr Marta Medeot and adored daughter Teresa for their precious and steady day-to-day support.

Received:
20.04.18
Citation:
EMJ Hematol. ;6[1]:63-70. DOI/10.33590/emjhematol/10312853. https://doi.org/10.33590/emjhematol/10312853.
Keywords:
Allogeneic haematopoietic stem cell transplantation (alloSCT), chronic myeloid leukaemia (CML), tyrosine kinase inhibitor (TKI)

Each article is made available under the terms of the Creative Commons Attribution-Non Commercial 4.0 License.

Abstract

The introduction of tyrosine kinase inhibitors (TKI) has dramatically improved the prognosis of chronic myeloid leukaemia (CML) patients and, therefore, changed the therapeutic scenario of this disease. Before the advent of the first TKI imatinib, allogeneic haematopoietic stem cell transplantation (alloSCT) was the only curative approach for CML, and all patients deemed eligible for transplant were referred to a centre for transplant where possible. Nowadays, with the wide availability of five different TKI, indications to alloSCT have been reduced to only include patients in the advanced phase of CML and those with multiple TKI treatment failures. Nonetheless, even in the TKI era, alloSCT retains its curative potential. Herein, the authors give an overview of the indications to allogeneic transplant for CML and the management of TKI in the pre and post-transplant settings.

INTRODUCTION

BCR-ABL1 tyrosine kinase inhibitor (TKI) therapy is the current standard of care for patients with chronic myeloid leukaemia (CML) in the chronic phase (CML-CP). Nowadays, these patients usually have near-normal life spans and survival has reached approximately 80–90%.1,2 The percentage of patients progressing to advanced-phase disease (particularly to blast crisis [BC]) is smaller when compared to the pre-TKI era. In CML-CP patients receiving upfront second-generation TKI (2G-TKI), this rate is even lower when compared to imatinib, a first-generation TKI.3,4 Prior to the era of targeted therapy with TKI, early treatment modalities for patients with CML-CP included arsenic, busulfan, hydroxyurea, and IFN-α with or without cytosine arabinoside, but, in general, none of these treatments can induce a long-term survival benefit. During the 1980s, allogeneic haematopoietic stem cell transplantation (alloSCT) became the only curative therapy for CML.5 However, not all patients could undergo alloSCT because there were (and still are) some challenges, including age and donor availability problems that physicians and patients face during and after alloSCT, and this procedure can be associated with significant early and late transplant-related morbidities and even mortality. After the year 2000, with the introduction of imatinib, the number of transplants performed for CML-CP substantially decreased and, although it remains an important therapeutic option for eligible patients, the place of alloSCT in the management of CML has become limited.

ALLOGENEIC HAEMATOPOIETIC STEM CELL TRANSPLANTATION FOR CHRONIC MYELOID LEUKAEMIA PRIOR TO THE TYROSINE KINASE INHIBITOR ERA

The first documented disappearance of a Philadelphia chromosome-positive (Ph+) clone following alloSCT was performed in syngeneic twins,6 which was then followed by transplantation using human leukocyte antigen (HLA)-matched sibling donors and later unrelated donors.7 Eventually, in the 1990s, CML was the most frequent indication for alloSCT. CML was a testing ground for the use of alloSCT,8 and this disease provided the first example for risk assessment with the European Group for Blood and Marrow Transplantation (EBMT) risk score,9 showing that disease stage was more important than the bulk of the disease; this score is still the most powerful predictor of transplant outcome for haematological malignancies. Patients with the lowest risk score have been shown to have a transplant-related mortality of 20% and a 5‑year overall survival (OS) of 72%, whereas those with the highest score have been shown to have a transplant- related mortality of 72% with a 5-year OS of 22%.10 CML was also the first disease for which a consistent graft-versus-leukaemia (GvL) effect was demonstrated.11 Relapse risk was very high after T cell depletion and, conversely, donor lymphocyte infusion (DLI) was proven to be very effective in CML, especially with the additional role of pre-emptive DLI use in patients receiving reduced-intensity conditioning regimens. Although myeloablative conditioning remains the preferred approach for the majority of transplant-eligible CML patients, the understanding of transplant immunology resulted in the development of reduced-intensity conditioning regimens to extend access to alloSCT to those who are unfit for the myeloablative conditioning regimens.

THE PLACE OF ALLOGENEIC HAEMATOPOIETIC STEM CELL TRANSPLANTATION IN THE ERA OF TYROSINE KINASE INHIBITORS

Indications for Allogeneic Haematopoietic Stem Cell Transplantation

The data derived from the Strengths, Weaknesses, Opportunities, Threats (SWOT) analysis of the Worldwide Network for Blood and Marrow Transplantation (WBMT) policy clearly showed that the number of patients with CML undergoing alloSCT was extensively reduced, with only 1,059 allotransplants (only 3.3% of the total number of transplants) performed globally in 2012.12 In a study by Özen et al.,13 prior to the introduction of imatinib in Turkey, the percentage of patients receiving alloSCT for CML was 40%, whereas this percentage was 11% and 5% between 2002 and 2006 and after 2007, respectively. Supporting this finding, at the EBMT 2018 meeting, there were only five abstracts regarding SCT in CML out of a total of 1,083.

Most patients presenting with CML-CP receive upfront treatment with imatinib and approximately 70% achieve complete cytogenetic response (CCyR) after 12 months of therapy; however, during long-term follow-up, about 40% of these patients switched to a second-line TKI therapy due to resistance and/or intolerance.14 Nearly half of patients who fail frontline imatinib may achieve durable responses with 2G-TKI (dasatinib, nilotinib, and bosutinib).15-17 Although it can be beneficial, after failing two lines of TKI treatment the chance of achieving optimal responses with third-line 2G-TKI is relatively low.18 In patients with CML-CP receiving upfront dasatinib or nilotinib, by 24 months of TKI therapy, only 77% and 76% of the cases were still on 2G-TKI treatment, respectively.19,20 Also, in CML-CP patients who harbour a Thr315Ile mutation, the third-generation TKI ponatinib can be a reasonable option,21 and can be used in patients with CML-CP who fail two lines of TKI treatment. A paper reporting data within the era of TKI showed that when alloSCT was performed among cases in first CP with a low EBMT risk score (0–2), using standard myeloablative conditioning with standard graft-versus-host disease (GvHD) prophylaxis and an optimal stem cell source (e.g., HLA-identical sibling), the low transplant-related mortality results were remarkable.22

In the most recent European LeukemiaNet (ELN) recommendations, CML-CP patients and siblings should undergo HLA typing at diagnosis only in cases of baseline warning signs.23 In cases of first-line imatinib failure, it is also recommended to search for a sibling donor. In addition, in patients with CML-CP who failed upfront 2G-TKI (nilotinib and dasatinib), searching for an unrelated stem cell donor is recommended in case an HLA-identical sibling donor is unavailable.23 In patients harbouring a Thr315Ile mutation, the search for a sibling or unrelated stem cell donor is highly advised at any line of TKI therapy.

In a recently published paper, it was shown that patients with newly diagnosed high-risk CML and non-responders to first-line TKI can benefit from an early low-risk alloSCT with improved long-term survival, shorter time of treatment, a higher rate of molecular remissions, and lower healthcare costs,24 which were consistent with another previous study performed in the imatinib era.25 In that study, patients undergoing early low-risk alloSCT had no early additional mortality but a significantly higher rate of molecular remissions compared to those with imatinib.25

While proceeding to alloSCT, one should balance the potential risks of the transplant against the risk of disease progression. The indications for alloSCT in patients with CML-CP include failing to achieve durable responses with two lines of TKI therapy and cases with a Thr315Ile mutation. Even eligible patients with a low transplant score who fail initial TKI therapy might be considered for an early alloSCT rather than salvage TKI therapy. In patients with CML-CP who have a Thr315Ile mutation, alloSCT can be curative; however, in cases with advanced disease phases (accelerated phase [AP] or BC), transplantation should be preserved for patients who return to second CP after anti-CML therapy.26

In cases with AP or BC, eligible patients should undergo alloSCT,27-29 and among patients with BC harbouring a Thr315Ile mutation, the outcomes are better with alloSCT than those with ponatinib.21 The current evidence suggests that alloSCT may be the best chance of cure in BC patients. In these patients, alloSCT should be performed following a treatment with a suitable TKI selected according to mutation profile in combination with chemotherapy in order to achieve a second CP.30 Nowadays, more CML patients are transplanted in second CP or advanced phases than in first CP.

Although long-term TKI treatment effectively controls the disease in most patients, this has resulted in a significant economic impact for patients and healthcare systems worldwide, especially for those in low-income countries.31 In the developing world, early alloSCT can be considered in the management of selected cases before disease transformation, and this treatment modality may be, sometimes unavoidably, due to economic issues, chosen over 2G-TKI.24 As generic imatinib becomes available, this would decrease the therapy-related expenses, thus increasing the accessibility of TKI therapy, which might further minimise the rate of CML progression and the need for alloSCT.32,33

The Impact of Prior Tyrosine Kinase Inhibitor Use on Allogeneic Hematopoietic Stem Cell Transplantation Outcomes

Several previous studies have demonstrated that the use of TKI prior to transplant does not seem to have a negative impact on the outcome of alloSCT in CML.34-40 In a more recent study by Kondo et al.,41 the authors included patients receiving one, two, or three TKI before alloSCT (153, 49, and 35 patients, respectively). They clearly showed that, in addition to conventional risk factors, using three TKI prior to transplantation was associated with an adverse outcome. Non-relapse mortality rate was higher in patients with three TKI than those in patients treated with one or two TKI, and the authors concluded that alloSCT could be considered for young patients with CML-CP who had resistance to second-line TKI therapy and who had an appropriate donor.41

The Type of Transplant: Myeloablative Versus Reduced-Intensity Conditioning

Transplantation should be performed with an HLA-identical sibling or HLA-matched unrelated donor; if unavailable, a haploidentical donor can be used, bearing in mind that haploidentical transplants in CML are rare.42 Although the number of patients undergoing haploidentical alloSCT continues to increase, in a recent activity survey report of EBMT, it was demonstrated that 398 transplants were performed for CML and, of these, only 26 were haploidentical.43 For years, myeloablative conditioning regimens were used in CML and are still in use among fit patients. It remains the standard of care for those who tolerate the regimen and includes total body irradiation and cyclophosphamide or busulfan and cyclophosphamide.27 For GvHD prevention, the combination of cyclosporine and short-term methotrexate is commonly used. Since long-term remission is usually dependent on the GvL effect, reducing the intensity of the condition­ing and reinforcing the GvL effect with pre-emptive DLI enables transplantation of elderly patients and those with comorbidities.44-47 Although T cell depletion is associated with reduced severity and frequency of GvHD, the risks of relapse48 and infection49 are both increased.

Source of Haematopoietic Stem Cells

Generally, over the last decades there has been a shift from bone marrow to peripheral blood as a source for stem cells. However, the use of peripheral blood stem cells for CML-CP has been associated with an increased risk of non-relapse mortality and chronic GvHD.50,51 The issue of increased GvHD risk is of particular interest in CML due to the frequent need for DLI to treat molecular relapse after transplant. If the eventual goal is to limit the risks on GvHD, as may be the case in CML-CP, a prudent approach would favour the use of bone marrow-derived haematopoietic stem cells.

Prevention of Relapse after Allogeneic Haematopoietic Stem Cell Transplantation

Relapse after alloSCT still represents an important cause of failure of transplant procedures, mainly in high-risk disease cases which make up the majority of CML patients undergoing alloSCT. Though the real value of the use of TKI after a successful alloSCT is still unknown, mainly because most CML patients receive transplant after failure of multiple TKI, the possible role of prophylactic TKI therapy to prevent disease relapse remains attractive.

In the last 10 years, various investigations have tested the safety and efficacy of imatinib and, later, 2G-TKI after alloSCT. Carpenter et al.52 reported on 22 patients with Ph+ leukaemias (15 with acute lymphoblastic leukaemia [ALL] and 7 with CML) prospectively treated with imatinib 400 mg from engraftment to Day 365, proving the overall safety of imatinib administration despite a high incidence of nausea, vomiting, and transaminase increase. A Japanese group53 compared 20 patients (18 with Ph+ ALL and 2 with CML) receiving imatinib for the prevention of disease relapse for at least 3 months after alloSCT with 76 patients (33 with Ph+ ALL and 43 with CML) who did not receive imatinib. Imatinib, started at 400 mg and administered within 100 days of alloSCT, was associated with a reduced incidence and severity of chronic GvHD in most patients, but this study failed to assess the prophylactic impact of TKI therapy on the incidences of leukaemia relapse due to a small number of patients and its retrospective nature.53 In 2015, Shimoni at al.54 reported on a Phase I/II study of nilotinib prophylactic maintenance in 16 patients with advanced CML or Ph+ ALL undergoing alloSCT, started after engraftment and continued until progression or toxicity. Nilotinib’s maximal tolerated dose was determined to be 200 mg twice a day. The median duration of therapy was 20 months and 6 patients stopped nilotinib due to toxicities (hepatic in 3, haematological in 1, allergic in 1, and late cerebrovascular in 1). Among the 11 patients who achieved a complete molecular response with alloSCT with or without nilotinib, only 1 progressed on nilotinib maintenance, with an overall 2-year survival rate of 55% and a 2-year relapse risk of 23%, lower than what is expected in such a high-risk population. The same group subsequently studied the immune function of 12 patients receiving nilotinib for at least 90 days after transplant, demonstrating a rapid reconstitution of NK cells and CD8+ T cells; moreover, T cell response was not inhibited by nilotinib administration.55 DeFilipp et al.56 published a monocentric experience of 26 patients (17 Ph+ ALL and 9 AP/BC CML) receiving maintenance post-alloSCT therapy with different TKI, including dasatinib (n=14), nilotinib (n=1), and ponatinib (n=1). The TKI was chosen according to pre-alloSCT response, tolerability, and ABL mutation; imatinib was started at 400 mg daily and other TKI at 50% of the pretransplant dose. The 9 CML patients were transplanted in second or third CP and started TKI (7 with dasatinib) while in molecular remission. The 5-year OS for CML and Ph+ ALL in second complete remission (reported together) was 79%. Recently, a multicentric study57 enrolled 40 patients who received nilotinib (n=11) or imatinib followed by nilotinib by Day 81 (n=29) after myeloablative alloSCT for Ph+ leukaemias; 17 patients who consented to enter the study before alloSCT were not eligible to start TKI prophylaxis at engraftment. Despite various causes of discontinuation of treatment that produced a failure rate of 77% (44 out of 57) of the starting intention-to-treat population, all 13 patients who completed nilotinib therapy were alive and in remission.57

In summary, there is no definitive evidence that prophylactic use of TKI after alloSCT may significantly reduce the risk of CML recurrence. On the other hand, there are no concerns of TKI safety in the post-alloSCT setting and the National Comprehensive Cancer Network (NCCN) 2018 guidelines58 recommend considering 1 year of standard TKI therapy after a successful transplant.

Treatment of Relapse

In patients relapsing after alloSCT, CML recurrence can occur quickly or many years after transplant,59 and is generally preceded, at least in patients receiving alloSCT in CP, by a molecularly detectable BCR-ABL1 transcript. As previously stated, prior to the era of TKI, treatment of CML relapse relied on DLI, exploiting the well-known GvL effect observed in CML.60 However, due to the potential complications of DLI use in terms of GvHD or myelosuppression, TKI have emerged as an alternative. The MD Anderson Cancer Center (MDACC) group reported in 2002 its experience of 28 CML patients (5 in CP and 23 in AP/BC) receiving imatinib 400–1,000 mg daily for relapse occurring at a median of 9 months after alloSCT. Though it was not reported if patients had received imatinib prior to alloSCT, responses were promising, particularly in CP or AP, with a CCyR rate of 63%.61 One year later, a larger study of 128 CML patients relapsing after alloSCT was published by the EBMT group.62 The study included patients in all phases of the disease (51 at CP, 31 at AP, and 46 at BC) and, among CP cases, there were few cytogenetic or molecular relapses; 50 patients had failed DLI before imatinib treatment. Beyond confirming the MDACC experience (CCyR was 58% for CP, 48% for AP, and 22% for BC, and 2-year survival for CP and AP patients was 100% and 86%, respectively), it was found that imatinib therapy was able to restore full donor chimerism in 57% patients.62 Other subsequent studies also confirmed the efficacy of imatinib in inducing durable cytogenetic and molecular responses and in restoring complete donor chimerism,63,64 as well as the possible synergic activity of imatinib and DLI, which, when used in combination, induced rapid and sustained molecular responses in patients relapsing in advanced-phase CML and that some patients maintained response even after imatinib was stopped.65 In all these studies, post-transplant imatinib was generally well tolerated and haematological toxicity was manageable with dose adjustments and brief discontinuations.

Fewer data are available on the efficacy and safety of 2G-TKI for the treatment of CML relapse after alloSCT, since most of the published experiences are single cases or very small series of patients. The MDACC group reported at the 2006 American Society of Hematology (ASH) meeting on 11 patients (9 with CML and 2 with ALL) treated with dasatinib as salvage therapy after alloSCT; all patients had failed high-dose imatinib before transplant. Nine patients (82%) responded, including three with molecular remission, one with CCyR, and two with a partial cytogenetic response. Dasatinib was well-tolerated at a dose of 100 mg daily, while higher doses led invariably to drug discontinuation.66 Another study of nine patients with advanced CML receiving dasatinib 100–140 mg daily in the post-alloSCT period reported a lower response rate (four out of nine) and negligible toxicity, with only one patient interrupting dasatinib because of thrombocytopenia-related gastrointestinal bleeding.67 Overall, the data on 2G-TKI for the post-transplant relapse are too scarce to draw any firm conclusions.

A main limit to TKI use in the post-alloSCT relapse scenario is that most CML patients receiving transplant have often received multiple lines of treatment before alloSCT, experiencing either resistance or intolerance that had led to the ultimate transplant decision. Three studies compared DLI with TKI therapy (mainly imatinib) at first CML relapse after allo-SCT.68-70 Despite the small numbers (31, 46, and 40 patients, respectively), all studies found TKI to be at least not inferior to DLI in terms of efficacy and superior in terms of safety, even if outcomes were poor in advanced-phase relapse, confirming a possible role of combination therapy. However, future trials are needed to compare different TKI, with and without DLI, to determine the most effective and safe treatment modality.71

CONCLUSION

With the development of TKI, alloSCT has become a salvage therapy for a minority of CML patients, mostly those in CP. The current indication of alloSCT in CP is limited to cases failing ≥2 lines of TKI therapy. Also, for patients with advanced disease and cases harbouring a Thr315Ile mutation, alloSCT is a reasonable treatment option. Transplantation should be performed with an HLA-identical sibling or HLA-matched unrelated donor, or alternatively a haploidentical donor. Myeloablative conditioning is generally used in fit patients, while reduced-intensity conditioning and DLI enable transplantation in elderly patients and those with comorbidities. As a result, alloSCT remains the only proven curative approach in CML and, though limited, its use must be considered by physicians treating CML patients.

References
Radich J. When to consider allogeneic transplantation in CML. Clin Lymphoma Myeloma Leuk. 2016;Suppl:S93-5. Gambacorti-Passerini C et al. Multicenter independent assessment of outcomes in chronic myeloid leukemia patients treated with imatinib. J Natl Cancer Inst. 2011;103(7):553-61. Saglio G et al.; ENESTnd Investigators. Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N Engl J Med. 2010;362(24):2251-9. Kantarjian H et al. Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2010;362(24):2260-70. Innes AJ et al. Allogeneic transplantation for CML in the TKI era: Striking the right balance. Nat Rev Clin Oncol. 2016;13(2):79-91. Fefer A et al. Disappearance of Ph1-positive cells in four patients with chronic granulocytic leukemia after chemotherapy, irradiation and marrow transplantation from an identical twin. N Engl J Med. 1979;300(7):333-7. Pavlů J, Apperley JF. Allogeneic stem cell transplantation for chronic myeloid leukemia. Curr Hematol Malig Rep. 2013;8(1):43-51. Gratwohl A et al. The role of hematopoietic stem cell transplantation in chronic myeloid leukemia. Ann Hematol. 2015;94(Suppl 2):S177-86. Gratwohl A et al. Risk assessment for patients with chronic myeloid leukaemia before allogeneic blood or marrow transplantation. Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation. Lancet. 1998;352(9134):1087-92. Gratwohl A et al.; European Group for Blood and Marrow Transplantation and the European Leukemia Net. Risk score for outcome after allogeneic hematopoietic stem cell transplantation: A retrospective analysis. Cancer. 2009;115(20):4715-26. Butturini A, Gale RP. The role of T-cells in preventing relapse in chronic myelogenous leukemia. Bone Marrow Transplant. 1987;2(4):351-4. Niederwieser D et al. Hematopoietic stem cell transplantation activity worldwide in 2012 and a SWOT analysis of the Worldwide Network for Blood and Marrow Transplantation Group including the global survey. Bone Marrow Transplant. 2016;51(6):778-85. Özen M et al. Allogeneic transplantation in chronic myeloid leukemia and the effect of tyrosine kinase inhibitors on survival: A quasi-experimental study. Turk J Haematol. 2017;34(1):16-26. de Lavallade H et al. Imatinib for newly diagnosed patients with chronic myeloid leukemia: Incidence of sustained responses in an intention-to-treat analysis. J Clin Oncol. 2008;26(20):3358-63. Milojkovic D et al. Responses to second-line tyrosine kinase inhibitors are durable: An intention-to-treat analysis in chronic myeloid leukemia patients. Blood. 2012;119(8):1838-43. Tiribelli M et al. Excellent outcomes of 2G-TKI therapy after imatinib failure in chronic phase CML patients. Oncotarget. 2018;9(18):14219-27. Cortes JE et al. Safety and efficacy of bosutinib (SKI-606) in chronic phase Philadelphia chromosome-positive chronic myeloid leukemia patients with resistance or intolerance to imatinib. Blood. 2011;118(17):4567-76. Ongoren S et al. Third-line treatment with second-generation tyrosine kinase inhibitors (dasatinib or nilotinib) in patients with chronic myeloid leukemia after two prior TKIs: Real-life data on a single center experience along with the review of the literature. Hematology. 2018;23(4):212-20. Kantarjian HM et al. Nilotinib versus imatinib for the treatment of patients with newly diagnosed chronic phase, Philadelphia chromosome-positive, chronic myeloid leukaemia: 24-month minimum follow-up of the Phase 3 randomised ENESTnd trial. Lancet Oncol. 2011;12(9):841-51. Kantarjian HM et al. Dasatinib or imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: 2-year follow-up from a randomized Phase 3 trial (DASISION). Blood. 2012;119(5):1123-9. Nicolini FE et al. Overall survival with ponatinib versus allogeneic stem cell transplantation in Philadelphia chromosome-positive leukemias with the T315I mutation. Cancer. 2017;123(15):2875-80. Koenecke C et al. Outcome of patients with chronic myeloid leukemia and a low-risk score: Allogeneic hematopoietic stem cell transplantation in the era of targeted therapy. A report from the EBMT Chronic Malignancies Working Party. Bone Marrow Transplant. 2016;51(9):1259-61. Baccarani M et al. European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013. Blood. 2013;122(6):872-84. Gratwohl A et al.; SAKK; German CML Study Group. Long-term outcome of patients with newly diagnosed chronic myeloid leukemia: A randomized comparison of stem cell transplantation with drug treatment. Leukemia. 2016;30(3):562-9. Saussele S et al.; German CML Study Group. Allogeneic hematopoietic stem cell transplantation (allo SCT) for chronic myeloid leukemia in the imatinib era: Evaluation of its impact within a subgroup of the randomized German CML Study IV. Blood. 2010;115(10):1880-5. Xu LP et al. Allogeneic stem cell transplantation for patients with T315I BCR-ABL mutated chronic myeloid leukemia. Biol Blood Marrow Transplant. 2016;22(6):1080-6. Nair AP et al. Allogeneic hematopoietic stem cell transplantation is an effective salvage therapy for patients with chronic myeloid leukemia presenting with advanced disease or failing treatment with tyrosine kinase inhibitors. Biol Blood Marrow Transplant. 2015;21(8):1437-44. Mukherjee S, Kalaycio M. Accelerated phase CML: Outcomes in newly diagnosed vs. progression from chronic phase. Curr Hematol Malig Rep. 2016;11(2):86-93. Hehlmann R et al. Management of CML-blast crisis. Best Pract Res Clin Haematol. 2016;29(3):295-307. Jain P et al. Prognostic factors and survival outcomes in patients with chronic myeloid leukemia in blast phase in the tyrosine kinase inhibitor era: Cohort study of 477 patients. Cancer. 2017;123(22):4391-402. Gómez-Almaguer D et al. The treatment of CML at an environment with limited resources. Hematology. 2016;21(10):576-82. Soysal T et al. Generics in chronic myeloid leukemia: Current arguments for and against and the established evidence. Expert Rev Hematol. 2014;7(6):697-9. Eskazan AE. The issue of financial toxicity in the management of chronic myeloid leukemia with blast crisis. J Med Econ. 2018;21(7):709-11. Deininger M et al. The effect of prior exposure to imatinib on transplant-related mortality. Haematologica. 2006;91(4):452-9. Oehler VG et al. The effects of imatinib mesylate treatment before allogeneic transplantation for chronic myeloid leukemia. Blood. 2007;109(4):1782-9. Jabbour E et al. Novel tyrosine kinase inhibitor therapy before allogeneic stem cell transplantation in patients with chronic myeloid leukemia: No evidence for increased transplant-related toxicity. Cancer. 2007;110(2):340-4. Lee SJ et al. Impact of prior imatinib mesylate on the outcome of hematopoietic cell transplantation for chronic myeloid leukemia. Blood. 2008;112(8):3500-7. Shimoni A et al. Prior treatment with the tyrosine kinase inhibitors dasatinib and nilotinib allows stem cell transplantation (SCT) in a less advanced disease phase and does not increase SCT toxicity in patients with chronic myelogenous leukemia and Philadelphia positive acute lymphoblastic leukemia. Leukemia. 2009;23(1):190-4. Breccia M et al. Second-generation tyrosine kinase inhibitors before allogeneic stem cell transplantation in patients with chronic myeloid leukemia resistant to imatinib. Leuk Res. 2010;34(2):143-7. Piekarska A et al. Pretransplantation use of the second-generation tyrosine kinase inhibitors has no negative impact on the HCT outcome. Ann Hematol. 2015;94(11):1891-7. Kondo T et al. Clinical impact of pretransplant use of multiple tyrosine kinase inhibitors on the outcome of allogeneic hematopoietic stem cell transplantation for chronic myelogenous leukemia. Am J Hematol. 2017;92(9):902-8. Ma YR et al. Transplantation from haploidentical donor is not inferior to that from identical sibling donor for patients with chronic myeloid leukemia in blast crisis or chronic phase from blast crisis. Clin Transplant. 2016;30(9):994-1001. Passweg JR et al. Use of haploidentical stem cell transplantation continues to increase: The 2015 European Society for Blood and Marrow Transplant activity survey report. Bone Marrow Transplant. 2017;52(6):811-7. Or R et al. Nonmyeloablative allogeneic stem cell transplantation for the treatment of chronic myeloid leukemia in first chronic phase. Blood. 2003;101(2):441-5. Crawley C et al.; Chronic Leukemia Working Party of the EBMT. Outcomes of reduced-intensity transplantation for chronic myeloid leukemia: An analysis of prognostic factors from the Chronic Leukemia Working Party of the EBMT. Blood. 2005;106(9):2969-76. Kebriaei P et al. Long-term follow-up of allogeneic hematopoietic stem-cell transplantation with reduced-intensity conditioning for patients with chronic myeloid leukemia. Blood. 2007;110(9):3456-62. Warlick E et al. Reduced intensity conditioning is superior to nonmyeloablative conditioning for older chronic myelogenous leukemia patients undergoing hematopoietic cell transplant during the tyrosine kinase inhibitor era. Blood. 2012;119(17):4083-90. Martin PJ et al. Effects of in vitro depletion of T cells in HLA-identical allogeneic marrow grafts. Blood. 1985;66(3):664-72. Soiffer RJ, Martin P, “T-cell depletion of allogenetic hematopoietic stem cell grafts,” Atkinson K et al. (eds.), Clinical bone marrow and blood stem cell transplantation (2004), Cambridge, UK: Cambridge University Press, pp. 416-25. Eapen M et al. Long-term survival after transplantation of unrelated donor peripheral blood or bone marrow hematopoietic cells for hematologic malignancy. Biol Blood Marrow Transplant. 2015;21(1):55-9. Anasetti C et al.; Blood and Marrow Transplant Clinical Trials Network. Peripheral-blood stem cells versus bone marrow from unrelated donors. N Engl J Med. 2012;367(16):1487-96. Carpenter PA et al. Prophylactic administration of imatinib after hematopoietic cell transplantation for high-risk Philadelphia chromosome-positive leukemia. Blood. 2007;109(7):2791-3. Nakasone H et al.; Kanto Study Group for Cell Therapy. Prophylactic impact of imatinib administration after allogeneic stem cell transplantation on the incidence and severity of chronic graft versus host disease in patients with Philadelphia chromosome-positive leukemia. Leukemia. 2010;24(6):1236-9. Shimoni A et al. Phase 1/2 study of nilotinib prophylaxis after allogeneic stem cell transplantation in patients with advanced chronic myeloid leukemia or Philadelphia chromosome-positive acute lymphoblastic leukemia. Cancer. 2015;121(6):863-71. Varda-Bloom N et al. Immunological effects of nilotinib prophylaxis after allogeneic stem cell transplantation in patients with advanced chronic myeloid leukemia or Philadelphia chromosome-positive acute lymphoblastic leukemia. Oncotarget. 2017;8(1):418-29. DeFilipp Z et al. Does post-transplant maintenance therapy with tyrosine kinase inhibitors improve outcomes of patients with high-risk Philadelphia chromosome-positive leukemia? Clin Lymphoma Myeloma Leuk. 2016;16(8):466-71. Carpenter PA et al. Posttransplant feasibility study of nilotinib prophylaxis for high-risk Philadelphia chromosome positive leukemia. Blood. 2017;130(9):1170-2. National Comprehensive Cancer Network. NCCN guidelines for patients. Chronic myeloid leukemia. 2018. Available at: https://www.nccn.org/patients/guidelines/cml/files/assets/common/downloads/files/cml.pdf. Last accessed: 21 March 2018. Goldman JM et al. Relapse and late mortality in 5-year survivors of myeloablative allogeneic hematopoietic cell transplantation for chronic myeloid leukemia in first chronic phase. J Clin Oncol. 2010;28(11):1888-95. Dazzi F et al. Donor lymphocyte infusions for relapse of chronic myeloid leukemia after allogeneic stem cell transplant: Where we now stand. Exp Hematol. 1999; 27(10):1477-86. Kantarjian HM et al. Imatinib mesylate therapy for relapse after allogeneic stem cell transplantation for chronic myelogenous leukemia. Blood. 2002;100(5):1590-5. Olavarria E et al.; Chronic Leukaemia Working Party of the European Group of Bone and Marrow Transplantation (EBMT). Response to imatinib in patients who relapse after allogeneic stem cell transplantation for chronic myeloid leukemia. Leukemia. 2003;17(9):1707-12. DeAngelo DJ et al. Extended follow-up of patients treated with imatinib mesylate (gleevec) for chronic myelogenous leukemia relapse after allogeneic transplantation: Durable cytogenetic remission and conversion to complete donor chimerism without graft-versus-host disease. Clin Cancer Res. 2004;10(15):5065-71. Hess G et al. Sustained complete molecular remissions after treatment with imatinib-mesylate in patients with failure after allogeneic stem cell transplantation for chronic myelogenous leukemia: Results of a prospective Phase II open-label multicenter study. J Clin Oncol. 2005;23(30):7583-93. Savani BN et al. Imatinib synergizes with donor lymphocyte infusions to achieve rapid molecular remission of CML relapsing after allogeneic stem cell transplantation. Bone Marrow Transplant. 2005;36(11):1009-15. Atallah E et al. The role of dasatinib in patients with Philadelphia (Ph) positive acute lymphocytic leukemia (ALL) and chronic myeloid leukemia (CML) relapsing after stem cell transplantation (SCT). Blood. 2006;108:4520. Klyuchnikov E et al. Second-generation tyrosine kinase inhibitors in the post-transplant period in patients with chronic myeloid leukemia or Philadelphia-positive acute lymphoblastic leukemia. Acta Haematol. 2009;122(1):6-10. Weisser M et al. A comparison of donor lymphocyte infusions or imatinib mesylate for patients with chronic myelogenous leukemia who have relapsed after allogeneic stem cell transplantation. Haematologica. 2006;91(5):663-6. Shanavas M et al. A comparison of long-term outcomes of donor lymphocyte infusions and tyrosine kinase inhibitors in patients with relapsed CML after allogeneic hematopoietic cell transplantation. Clin Lymphoma Myeloma Leuk. 2014;14(1):87-92. Zeidner JF et al. The evolution of treatment strategies for patients with chronic myeloid leukemia relapsing after allogeneic bone marrow transplant: Can tyrosine kinase inhibitors replace donor lymphocyte infusions? Leuk Lymphoma. 2015;56(1):128-34. Eskazan AE et al. Relapse after allogeneic hematopoietic stem cell transplant in patients with chronic myeloid leukemia: Tyrosine kinase inhibitors, donor lymphocyte infusions or both? Leuk Lymphoma. 2015;56(10):2995-6.

Rate this content's potential impact on patient outcomes

Average rating / 5. Vote count:

No votes so far! Be the first to rate this content.

Thank you!

Please share some more information on the rating you have given