Chronic myeloid leukemia: reminiscences and dreams

Mughal, Tariq I.; Radich, Jerald P.; Deininger, Michael W.; Apperley, Jane F.; Hughes, Timothy P.; Harrison, Christine J.; Gambacorti‐Passerini, Carlo; Saglio, Giuseppe; Cortés, Jorge E.; Daley, George Q.

doi:10.3324/haematol.2015.139337

Cited by 97 publications

(85 citation statements)

References 184 publications

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“…[1][2][3][4] Yet, drug resistance or inadequate tolerability affecting up to one third of patients led to the development of new generations of TKI with a greater potency against the oncogenic BCR-ABL1 kinase and different safety profiles. 5 Two of these agents, the second-generation (2G)-TKI dasatinib and nilotinib, are efficient rescue therapies for patients with imatinib resistance or intolerance. 6,7 Since 2010, they also became treatment options for newly diagnosed CP-CML, on the basis of higher rates of optimal responses and a lower risk of progression in comparison with imatinib.…”

Section: Introductionmentioning

confidence: 99%

Discontinuation of dasatinib or nilotinib in chronic myeloid leukemia: interim analysis of the STOP 2G-TKI study

Réa

Nicolini

Tulliez

et al. 2017

Blood

283

249

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Key Points• First-line or subsequent dasatinib or nilotinib can be safely stopped in CML patients with deep and longlasting molecular responses. • A suboptimal response or resistance prior to dasatinib or nilotinib is associated with significantly worse treatmentfree remission.STOP second generation (2G)-tyrosine kinase inhibitor (TKI) is a multicenter observational study designed to evaluate 2G-TKI discontinuation in chronic myeloid leukemia (CML). Patients receiving first-line or subsequent dasatinib or nilotinib who stopped therapy after at least 3 years of TKI treatment and in molecular response 4.5 (MR4.5) with undetectable BCR-ABL1 transcripts for the 2 preceding years at least were eligible for inclusion. This interim analysis reports outcomes of 60 patients with a minimum follow-up of 12 months (median 47, range: 12-65). Twenty-six patients (43.3%) experienced a molecular relapse defined as the loss of a major molecular response (MMR). Relapses occurred after a median time of 4 months (range: 1-38). Cumulative incidences of molecular relapse by 12 and 48 months were 35% (95% confidence interval [CI], 24.79% to 49.41%) and 44.76% (95% CI, 33.35% to 59.91%), respectively. Treatment-free remission (TFR) rates at 12 and 48 months were 63.33% (95% CI, 51.14% to 75.53%) and 53.57% (95% CI, 40.49% to 66.65%), respectively. In univariate analysis, prior suboptimal response or TKI resistance was the only baseline factor associated with significantly worse outcome. A landmark analysis demonstrated that loss of MR4.5 3 months after stopping TKI was predictive of failure to maintain MMR later on. During the treatment-free phase, no progression toward advanced phase CML occurred, and all relapsing patients regained MMR and MR4.5 after restarting therapy. In conclusion, discontinuation of first-line or subsequent 2G-TKI yields promising TFR rates without safety concerns. Further research is encouraged to better define conditions that will offer patients the highest chance to remain free from 2G-TKI therapy. (Blood. 2017;129(7):846-854)

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Section: Introductionmentioning

confidence: 99%

Discontinuation of dasatinib or nilotinib in chronic myeloid leukemia: interim analysis of the STOP 2G-TKI study

Réa

Nicolini

Tulliez

et al. 2017

Blood

283

249

View full text Add to dashboard Cite

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“…Just under half a century ago, a seminal work conducted by Janet Rowley in Chicago, led to the discovery of chromosomal translocations associated with CML and other hematological malignancies . This work supported the notion of cytogenetic changes being pivotal drivers of hematological neoplasms.…”

Section: Introductionmentioning

confidence: 76%

“…Interrogation of chronic myeloproliferative neoplasms (MPNs) at clonal stem cell level unfolded over a remarkably short period of time, with substantial efforts of pioneers, like Janet Rowley, John Goldman, and others, and provided critical insigts into the biology and treatment, particularly BCR‐ABL1 ‐positive MPNs . These resulted in the remarkable success of the ABL1‐kinase inhibitors for patents with chronic myeloid leukaemia (CML) and a qualified success for some patients with BCR‐ABL1‐negative MPNs.…”

Section: Introductionmentioning

confidence: 99%

Emerging translational science discoveries, clonal approaches, and treatment trends in chronic myeloproliferative neoplasms

Mughal

Pemmaraju

Radich

et al. 2019

Hematological Oncology

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The 60th American Society of Hematology (ASH) held in San Diego in December 2018 was followed by the 13th Post‐ASH chronic myeloproliferative neoplasms (MPNs) workshop on December 4 and 5, 2018. This closed annual workshop, first introduced in 2006 by Goldman and Mughal, was organized in collaboration with Alpine Oncology Foundation and allowed experts in preclinical and clinical research in the chronic MPNs to discuss the current scenario, including relevant presentations at ASH, and address pivotal open questions that impact translational research and clinical management. This review is based on the presentations and deliberations at this workshop, and rather than provide a resume of the proceedings, we have selected some of the important translational science and treatment issues that require clarity. We discuss the experimental and observational evidence to support the intimate interaction between aging, inflammation, and clonal evolution of MPNs, the clinical impact of the unfolding mutational landscape on the emerging targets and treatment of MPNs, new methods to detect clonal heterogeneity, the challenges in managing childhood and adolescent MPN, and reflect on the treatment of systemic mastocytosis (SM) following the licensing of midostaurin.

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“…It is notable that currently there is no survival advantage for either drug to be used for first-line therapy of a newly diagnosed patient with CML in chronic phase, despite the superior early molecular responses and the subsequent MR 4.5 responses. [70] Additionally, in contrast to the earlier reports, the longer follow-up of DASISION and ENESTnd raise significant concerns for the associated vascular occlusive events with nilotinib (10% with nilotinib 300 mg; 15.9% with nilotinib 400 mg), and pulmonary hypertension (6%) with dasatinib; of note is the notion of ‘sudden cardiac death’ reported in a few of the earlier nilotinib studies appear not to have been borne in the more recent larger studies. [71]…”

Section: Optimal Treatment Of Patients With CMLmentioning

confidence: 99%

Contemporary insights into the pathogenesis and treatment of chronic myeloproliferative neoplasms

Mughal

Abdel‐Wahab

Rampal

et al. 2016

Leukemia & Lymphoma

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This review is based on the deliberations at the 5th John Goldman Colloquium held in Estoril on 2nd October 2015 and the 9th post-ASH International Workshop on chronic myeloid leukemia (CML) and BCR-ABL1-negative myeloproliferative neoplasms (MPN) which took place on the 10th-11th December 2014, immediately following the 56th American Society of Hematology Annual Meeting. It has been updated since and summarizes the most recent advances in the biology and therapy of these diseases, in particular updates of genetics of MPN, novel insights from mouse MPN models, targeting CML stem cells and its niche; clinical advances include updates on JAK2 inhibitors and other therapeutic approaches to BCR-ABL1-negative MPNs, the use of alpha interferons, updates on tyrosine kinase inhibitors (TKI) randomized trials in CML, TKI cessation studies, and optimal monitoring strategies.

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Chronic myeloid leukemia: reminiscences and dreams

Cited by 97 publications

References 184 publications

Discontinuation of dasatinib or nilotinib in chronic myeloid leukemia: interim analysis of the STOP 2G-TKI study

Discontinuation of dasatinib or nilotinib in chronic myeloid leukemia: interim analysis of the STOP 2G-TKI study

Emerging translational science discoveries, clonal approaches, and treatment trends in chronic myeloproliferative neoplasms

Contemporary insights into the pathogenesis and treatment of chronic myeloproliferative neoplasms

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