Tyrosine Kinase Inhibitors and Allogeneic HCT for CML
Tyrosine Kinase Inhibitors and Allogeneic HCT for CML
Background: Due to its curative potential, allogenic hematopoietic transplantation (HCT) was a mainstay of treatment for chronic myeloid leukemia (CML), but the advent of tyrosine kinase inhibitors (TKIs) has markedly altered the use of allogeneic HCT.
Methods: The authors reviewed their experiences as well as the published data regarding the impact of TKIs on the natural history of CML and thus on the application and timing of TKIs in the management of CML.
Results: Most patients with CML respond well to TKIs given as up-front therapy. Available retrospective data suggest that allogenic HCT is safe after TKI therapy. Work is ongoing regarding salvage of postallogeneic HCT failures using TKIs with and without donor lymphocyte infusion.
Conclusions: While allogeneic HCT therapy remains useful, the timing of its application in CML has changed, and it is now considered as second- or third-line therapy.
Allogeneic hematopoietic cell transplant (HCT) remains the only established curative approach in the treatment of chronic myeloid leukemia (CML). Prior to 2001, CML was among the most common indications for this procedure. With the introduction of targeted therapy to the BCR/ABL transcript, namely tyrosine kinase inhibitors (TKIs), the use of allogeneic HCT has been altered significantly. Moreover, the proportion of patients receiving transplant as first-line therapy for chronic-phase CML has decreased. In May 2001, imatinib mesylate (Gleevec®, Novartis Pharmaceutical Corp, East Hanover, New Jersey) became the first of these agents to be approved by the US Food and Drug Administration. The drug has shown clinical efficacy in interferon-resistant disease and subsequently proved superior to interferon plus cytarabine, the prior standard of care for initial therapy of CML. As the International Randomized Study of Interferon and STI571 (IRIS) trial has demonstrated, the excellent response and the prolonged benefit of this approach have made imatinib the new standard bearer in this disease. Since the approval of imatinib, two drugs — dasatinib (Sprycel®, Bristol-Myers Squibb Co, Princeton, New Jersey) and nilotinib (Tasigna®, Novartis Pharmaceutical Corp) — have been introduced as treatment for imatinibresistant or -intolerant patients, with 38% to 40% of patients achieving a complete cytogenetic response (CCyR). Most of these responses are durable. These newer therapies have placed allogeneic HCT into a third-line status against CML.
Approximately 15% to 25% of patients with CML are intolerant of the TKIs, develop resistance due to BCR/ABL domain mutations, develop other gene mutations, Pgp expression and gene amplification, or attain new cytogenetic abnormalities and progress to the accelerated or blastic phase of this disease. This manuscript reviews the timing and indications of allogeneic HCT in the treatment of CML and the outcomes of transplanted patients who have received prior therapy with the TKIs. The use of TKIs following allogeneic HCT for relapsed disease or as an adjunct to allogeneic HCT is also discussed.
Abstract and Introduction
Abstract
Background: Due to its curative potential, allogenic hematopoietic transplantation (HCT) was a mainstay of treatment for chronic myeloid leukemia (CML), but the advent of tyrosine kinase inhibitors (TKIs) has markedly altered the use of allogeneic HCT.
Methods: The authors reviewed their experiences as well as the published data regarding the impact of TKIs on the natural history of CML and thus on the application and timing of TKIs in the management of CML.
Results: Most patients with CML respond well to TKIs given as up-front therapy. Available retrospective data suggest that allogenic HCT is safe after TKI therapy. Work is ongoing regarding salvage of postallogeneic HCT failures using TKIs with and without donor lymphocyte infusion.
Conclusions: While allogeneic HCT therapy remains useful, the timing of its application in CML has changed, and it is now considered as second- or third-line therapy.
Introduction
Allogeneic hematopoietic cell transplant (HCT) remains the only established curative approach in the treatment of chronic myeloid leukemia (CML). Prior to 2001, CML was among the most common indications for this procedure. With the introduction of targeted therapy to the BCR/ABL transcript, namely tyrosine kinase inhibitors (TKIs), the use of allogeneic HCT has been altered significantly. Moreover, the proportion of patients receiving transplant as first-line therapy for chronic-phase CML has decreased. In May 2001, imatinib mesylate (Gleevec®, Novartis Pharmaceutical Corp, East Hanover, New Jersey) became the first of these agents to be approved by the US Food and Drug Administration. The drug has shown clinical efficacy in interferon-resistant disease and subsequently proved superior to interferon plus cytarabine, the prior standard of care for initial therapy of CML. As the International Randomized Study of Interferon and STI571 (IRIS) trial has demonstrated, the excellent response and the prolonged benefit of this approach have made imatinib the new standard bearer in this disease. Since the approval of imatinib, two drugs — dasatinib (Sprycel®, Bristol-Myers Squibb Co, Princeton, New Jersey) and nilotinib (Tasigna®, Novartis Pharmaceutical Corp) — have been introduced as treatment for imatinibresistant or -intolerant patients, with 38% to 40% of patients achieving a complete cytogenetic response (CCyR). Most of these responses are durable. These newer therapies have placed allogeneic HCT into a third-line status against CML.
Approximately 15% to 25% of patients with CML are intolerant of the TKIs, develop resistance due to BCR/ABL domain mutations, develop other gene mutations, Pgp expression and gene amplification, or attain new cytogenetic abnormalities and progress to the accelerated or blastic phase of this disease. This manuscript reviews the timing and indications of allogeneic HCT in the treatment of CML and the outcomes of transplanted patients who have received prior therapy with the TKIs. The use of TKIs following allogeneic HCT for relapsed disease or as an adjunct to allogeneic HCT is also discussed.