Poor outcomes associated with +der(22)t(9;22) and −9/9p in patients with Philadelphia chromosome‐positive acute lymphoblastic leukemia receiving chemotherapy plus a tyrosine kinase inhibitor

Short, Nicholas J.; Kantarjian, Hagop M.; Sasaki, Koji; Ravandi, Farhad; Ko, Heidi Chwan; Yin, C. Cameron; Cortes, Jorge; Garris, Rebecca; O’Brien, Susan; Patel, Keyur P.; Khouri, Maria; Thomas, Deborah A.; Jain, Nitin; Kadia, Tapan M.; Benton, Christopher B.; Issa, Ghayas C.; Konopleva, Marina

doi:10.1002/ajh.24625

Cited by 46 publications

(31 citation statements)

References 17 publications

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“…22,23 The prognostic relevance of IKZF1, CDKN2A/2B, PAX5 and other recurrent genomic aberrations in the setting of allogeneic SCT for adult patients with Ph+ ALL has hardly been examined. To this end, in adult Ph+ ALL, the presence of additional cytogenetic lesions in adult Ph+ ALL patients was shown to negatively influence prognosis in the therapeutic setting of TKI combined with chemotherapy 24 or even beyond aSCT. 25 Furthermore, TKI resistance in this patient group has been linked to ABL1 kinase mutations and/or the presence of genomic deletions such as IKZF1 or CDKN2A/2B.…”

Section: Introductionmentioning

confidence: 99%

Genomic CDKN2A/2B deletions in adult Ph+ ALL are adverse despite allogeneic stem cell transplantation

Pfeifer

Raum

Marković

et al. 2018

Blood

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We investigated the role of copy number alterations to refine risk stratification in adult Philadelphia chromosome positive (Ph) acute lymphoblastic leukemia (ALL) treated with tyrosine kinase inhibitors (TKIs) and allogeneic stem cell transplantation (aSCT). Ninety-seven Ph ALL patients (median age 41 years; range 18-64 years) within the prospective multicenter German Multicenter ALL Study Group studies 06/99 (n = 8) and 07/2003 (n = 89) were analyzed. All patients received TKI and aSCT in first complete remission (CR1). Copy number analysis was performed with single nucleotide polymorphism arrays and validated by multiplex ligation-dependent probe amplification. The frequencies of recurrently deleted genes were: IKZF1, 76%; CDKN2A/2B, 45%; PAX5, 43%; BTG1, 18%; EBF1, 13%; ETV6, 5%; RB, 14%. In univariate analyses, the presence of CDKN2A/2B deletions had a negative impact on all endpoints: overall survival ( = .023), disease-free survival ( = .012), and remission duration ( = .036). The negative predictive value of CDKN2A/2B deletions was retained in multivariable analysis along with other factors such as timing of TKI therapy, intensity of conditioning, achieving remission after induction phase 1 and BTG1 deletions. We therefore conclude that acquired genomic CDKN2A/2B deletions identify a subgroup of Ph ALL patients, who have an inferior prognosis despite aSCT in CR1. Their poor outcome was attributable primarily to a high relapse rate after aSCT.

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Section: Introductionmentioning

confidence: 99%

Genomic CDKN2A/2B deletions in adult Ph+ ALL are adverse despite allogeneic stem cell transplantation

Pfeifer

Raum

Marković

et al. 2018

Blood

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“…[27][28][29] These genomic aberrations, as well as other reported prognostic factors such as high presentation WBC or presence of additional cytogenetic abnormalities, are not yet routinely considered when deciding on allo-HCT. 15,30 Reported pediatric studies have raised questions about the necessity of allo-HCT in first CR. However, the applicability of these data to the adult population remains unproven.…”

Section: Patientmentioning

confidence: 99%

How I treat Philadelphia chromosome–positive acute lymphoblastic leukemia

Ravandi

2019

Blood

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The introduction of agents targeted at specific molecular events is changing the treatment paradigms in a number of malignancies. Historically, we have relied entirely on DNA-interactive, cytotoxic drugs for treating patients with leukemia. Increased understanding of the leukemic cell biology and pathogenesis, and the ways they evade the immune surveillance mechanisms, will likely lead to the development of more effective agents, and regimens less reliant on chemotherapy, able to achieve deep levels of disease eradication. In Philadelphia chromosome–positive acute lymphoblastic leukemia, the introduction of increasingly potent tyrosine kinas inhibitors (TKIs) has revolutionized therapy. These drugs have been established as the cornerstone of any therapeutic strategy in this disease, and a number of trials have better defined the best ways to incorporate them into the established paradigms. Despite using TKIs, we have continued to remain reliant on cytotoxic chemotherapy regimens and allogeneic hematopoietic cell transplant to achieve the best long-term outcomes. However, with the introduction of more potent TKIs and other novel agents, as well as better methods for monitoring minimal/measurable residual disease, we are entering an era where we hope to diminish our reliance on transplantation and cytotoxic chemotherapy in this disease.

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“…In another study, 152 patients with Ph+ ALL receiving first‐line intensive chemotherapy plus TKIs were evaluated . ACAs were recognized in 118 patients (78%).…”

Section: Significance Of Additional Chromosomal Abnormalities In Ph+ Allmentioning

confidence: 99%

“…However, these small numbers do not permit any generalization regarding the type of TK. Therefore, TKI efficacy should be further evaluated in poor‐risk ACAs group before a firm recommendation could be made regarding the precise impact in Ph+ALL …”

Section: Significance Of Additional Chromosomal Abnormalities In Ph+ Allmentioning

confidence: 99%

Advances in BCR/ABL positive ALL

Horowitz

Rowe

2019

Adv Cell Gene Ther

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The advent of tyrosine kinase inhibitors (TKIs) has ushered in a new era in the management of patients with Philadelphia chromosome‐positive acute lymphoblastic leukemia (Ph+ ALL). Although, as a group, these inhibitors have led to one of the most successful targeted therapies in leukemia, Ph+ ALL still remains a formidable disease. Unlike chronic myeloid leukemia (CML) where TKIs lead to dramatic long‐lasting responses as single agents, the biology of Ph+ ALL is far more complex and adjunctive therapies are mandatory. These may include corticosteroids, chemotherapy, antibody‐based therapies or, even, allogeneic hematopoietic cell transplantation. Clearly, other genes or mutations are in place that affect the outcome of Ph+ ALL. Additional chromosomal abnormalities are common in Ph+ ALL and have a varying impact on prognosis; some adverse, others less so. Genomic alterations have come into their own in the last decade and have increased our understanding of the mechanisms of resistance and differing responses to therapy. In this review, these genetic aberrations will be considered in some detail. In addition, innovations in current practice – including the use of immunological therapies – will be carefully reviewed. For the first time in decades, the long‐held imperative requiring an allogeneic transplant for a curative approach in adult Ph+ ALL is now being questioned and clinical trials are underway to resolve this issue. However, despite much progress in the past two decades, both in the biology and therapy of Ph+ ALL, this disease still presents a compelling challenge and much remains to be overcome.

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Poor outcomes associated with +der(22)t(9;22) and −9/9p in patients with Philadelphia chromosome‐positive acute lymphoblastic leukemia receiving chemotherapy plus a tyrosine kinase inhibitor

Cited by 46 publications

References 17 publications

Genomic CDKN2A/2B deletions in adult Ph+ ALL are adverse despite allogeneic stem cell transplantation

Genomic CDKN2A/2B deletions in adult Ph+ ALL are adverse despite allogeneic stem cell transplantation

How I treat Philadelphia chromosome–positive acute lymphoblastic leukemia

Advances in BCR/ABL positive ALL

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