scholarly journals Philadelphia Chromosome-Positive Leukemia in the Lymphoid Lineage—Similarities and Differences with the Myeloid Lineage and Specific Vulnerabilities

2020 ◽  
Vol 21 (16) ◽  
pp. 5776 ◽  
Author(s):  
Lukasz Komorowski ◽  
Klaudyna Fidyt ◽  
Elżbieta Patkowska ◽  
Malgorzata Firczuk
Keyword(s):  
Tyrosine Kinase ◽  
Kinase Inhibitors ◽  
Fusion Gene ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Great Majority ◽  
Metabolic Reprogramming ◽  
Chromosome 9 ◽  
Treatment Protocols ◽  
Resistant Disease

Philadelphia chromosome (Ph) results from a translocation between the breakpoint cluster region (BCR) gene on chromosome 9 and ABL proto-oncogene 1 (ABL1) gene on chromosome 22. The fusion gene, BCR-ABL1, is a constitutively active tyrosine kinase which promotes development of leukemia. Depending on the breakpoint site within the BCR gene, different isoforms of BCR-ABL1 exist, with p210 and p190 being the most prevalent. P210 isoform is the hallmark of chronic myeloid leukemia (CML), while p190 isoform is expressed in majority of Ph-positive B cell acute lymphoblastic leukemia (Ph+ B-ALL) cases. The crucial component of treatment protocols of CML and Ph+ B-ALL patients are tyrosine kinase inhibitors (TKIs), drugs which target both BCR-ABL1 isoforms. While TKIs therapy is successful in great majority of CML patients, Ph+ B-ALL often relapses as a drug-resistant disease. Recently, the high-throughput genomic and proteomic analyses revealed significant differences between CML and Ph+ B-ALL. In this review we summarize recent discoveries related to differential signaling pathways mediated by different BCR-ABL1 isoforms, lineage-specific genetic lesions, and metabolic reprogramming. In particular, we emphasize the features distinguishing Ph+ B-ALL from CML and focus on potential therapeutic approaches exploiting those characteristics, which could improve the treatment of Ph+ B-ALL.

Treatment Selection for Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia in the Era of Tyrosine Kinase Inhibitors

Chemotherapy ◽  
2019 ◽  
Vol 64 (2) ◽  
pp. 81-93 ◽  
Author(s):  
Yingying Ma ◽  
Quanchao Zhang ◽  
Peiyan Kong ◽  
Jingkang Xiong ◽  
Xi Zhang ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Molecular Response ◽  
Term Survival ◽  
Hematopoietic Stem ◽  
Philadelphia Chromosome Positive

With the advent of tyrosine kinase inhibitors (TKIs), the treatment of Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) has entered a new era. The efficacy of TKIs compared with other ALL treatment options is emphasized by a rapid increase in the number of TKI clinical trials. Subsequently, the use of traditional approaches, such as combined chemotherapy and even allogeneic hematopoietic stem cell transplantation (allo-HSCT), for the treatment of ALL is being challenged in the clinic. In light of the increased use of TKIs in the clinic, several questions have been raised. First, is it necessary to use intensive chemotherapy during the induction course of therapy to achieve a minimal residual disease (MRD)-negative status? Must a patient reach a complete molecular response/major molecular response before receiving allo-HSCT? Does MRD status affect long-term survival after allo-HSCT? Is auto-HSCT an appropriate alternative for allo-HSCT in those Ph+ ALL patients who lack suitable donors? Here, we review the recent literature in an attempt to summarize the current status of TKI usage in the clinic, including several new therapeutic approaches, provide answers for the above questions, and speculate on the future direction of TKI utilization for the treatment of Ph+ ALL patients.

scholarly journals Genetics and prognosis of ALL in children vs adults

Hematology ◽  
2018 ◽  
Vol 2018 (1) ◽  
pp. 137-145 ◽  
Author(s):  
Kathryn G. Roberts
Keyword(s):  
Tyrosine Kinase ◽  
Kinase Inhibitors ◽  
Lymphoblastic Leukemia ◽  
Diagnostic Testing ◽  
Survival Rates ◽  
Philadelphia Chromosome ◽  
Genetic Alterations ◽  
Tyrosine Kinase Signaling ◽  
Disease Biology ◽  
Long Term Prognosis

Abstract Acute lymphoblastic leukemia (ALL) is characterized by genetic alterations that block differentiation, promote proliferation of lymphoid precursor cells, and are important for risk stratification. Although ALL is less common in adolescents and young adults (AYAs) and adults than children, survival rates are inferior, and long-term prognosis for adults is poor. Thus, ALL remains a challenging disease to treat in the AYA and adult populations. A major contributing factor that influences prognosis in this population is the reduced prevalence of genetic subtypes associated with favorable outcome and a concomitant increase in subtypes associated with poor outcome. Recent advances in genomic profiling across the age spectrum continue to enhance our knowledge of the differences in disease biology between children and adults and are providing important insights into novel therapeutic targets. Philadelphia chromosome-like (Ph-like) ALL is one such subtype characterized by alterations that deregulate cytokine receptor or tyrosine kinase signaling and are amenable to inhibition with approved tyrosine kinase inhibitors. One of the greatest challenges now remaining is determining how to implement this breadth of genomic information into rapid and accurate diagnostic testing to facilitate the development of novel clinical trials that improve the outcome of AYAs and adults with ALL.

scholarly journals Tyrosine Kinase Inhibitors and Reduced-Dose Chemotherapy for Adult Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia

2021 ◽  
Author(s):  
chunping wu ◽  
mengting zeng ◽  
yuanzhong chen ◽  
yong wu
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Lymphoblastic Leukemia ◽  
Survival Rates ◽  
Philadelphia Chromosome ◽  
Standard Chemotherapy ◽  
Chemotherapy Group ◽  
Reduced Dose

Abstract Purpose: To compare the outcomes of tyrosine kinase inhibitors in combination with reduced-dose chemotherapy with those of standard induction chemotherapy and to compare the outcomes between TKIs with chemotherapy regimen and transplantation in adults with Philadelphia chromosome-positive acute lymphoblastic leukemia Methods: We retrospectively reviewed all patients treated with tyrosine kinase inhibitors in combination with chemotherapy. These patients were divided into the TKIs with reduced-dose chemotherapy group (62 patients) and the TKIs with standard chemotherapy group (143 patients). In further treatment, patients were divided into the transplant group (55 patients) and the non-transplant group (143 patients).Results: The complete remission rate (88.7% vs 83.9%, P=0.372) and early mortality rate (3.2% vs 3.5%, P=0.922) were similar between the TKIs with reduced-dose chemotherapy group and the TKIs with standard chemotherapy group. The proportions of lung infection (P=0.047) and bloodstream infection (P=0.024) and the proportion of patients with >21 days of hospitalization (P<0.001), on >4 types of antibiotics (P=0.003), and on restrictive tigecycline and/or polymyxin (P=0.031) were higher in the standard chemotherapy group than in the TKIs with reduced-dose chemotherapy group. For cost analysis, the total costs and antimicrobial costs were higher in the standard chemotherapy group than in the TKIs with reduced-dose chemotherapy group. The 3-year overall survival rates and 3-year disease-free survival rates were significantly better in the transplant group than in the non-transplant group. Conclusion: An induction regimen combining TKIs with reduced-dose chemotherapy and transplantation in first CR remains a good option for patients with Ph+ALL.

scholarly journals The Paradigm of Targeting an Oncogenic Tyrosine Kinase: Lesson from BCR-ABL

2021 ◽  
Author(s):  
Enrico Bracco ◽  
M. Shahzad Ali ◽  
Stefano Magnati ◽  
Giuseppe Saglio
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinases ◽  
Molecular Mechanisms ◽  
Kinase Activity ◽  
Fusion Gene ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Protein Tyrosine Phosphatases ◽  
Selective Inhibition ◽  
Tyrosine Kinase Activity

The aberrant tyrosine phosphorylation, either due to constitutive tyrosine kinases (TKs) or to inactivation of protein tyrosine phosphatases (PTPs), is a widespread feature of many cancerous cells. The BCR-ABL fusion protein, which arises from the Philadelphia chromosome, is a molecular distinct and peculiar trait of some kind of leukemia, namely Chronic Myeloid and Acute Lymphoblastic Leukemia, and displays constitutive tyrosine kinase activity. In the chapter, we will highlight the milestones that had led to the identification of the BCR-ABL fusion gene and its role as the only molecular pathogenic event sufficient to elicit and sustain chronic myeloid leukemia. We will also discuss the effort made to unveil the molecular mechanisms of action of the chimeric tyrosine kinase that eventually lead to aberrant cell proliferation and impaired cell-death. Furthermore, we will also review the lesson learned from the selective inhibition of BCR-ABL which currently represent a breakthrough in the treatment of several tumors characterized by defective tyrosine kinase activity.

Discontinuation of Maintenance Tyrosine Kinase Inhibitors in Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia outside of Transplant

2020 ◽  
pp. 1-8
Author(s):  
Bachar Samra ◽  
Hagop M. Kantarjian ◽  
Koji Sasaki ◽  
Ahmad S. Alotaibi ◽  
Marina Konopleva ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Median Duration ◽  
Kinase Inhibitors ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Cell Transplant ◽  
Tki Discontinuation

<b><i>Background:</i></b> The addition of tyrosine kinase inhibitors (TKIs) to chemotherapy has dramatically improved outcomes of patients with Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL). When allogeneic hematopoietic stem cell transplant (HSCT) is performed, maintenance TKI is generally given for a fixed duration. However, the optimal duration of TKI outside of HSCT remains unknown, and the common practice is to continue indefinitely. Here, we report characteristics and outcomes of 9 patients treated with chemotherapy + TKI without HSCT and later discontinued TKI. <b><i>Methods:</i></b> Among 188 patients with Ph-positive ALL who did not undergo HSCT, 9 of them discontinued maintenance TKI mainly due to side effects. Patients were closely monitored with serial PCR testing for the BCR-ABL1 transcript. Major molecular response (MMR) was defined as BCR-ABL1 transcript ≤0.1% on the international scale for p210 transcripts and a 3-log reduction from baseline for p190 transcripts. Deep molecular remission (DMR) was defined as the absence of quantifiable BCR-ABL1 transcripts with a sensitivity of 0.01%. Molecular relapse was defined as loss of MMR. Treatment-free remission (TFR) was defined from time of TKI discontinuation to molecular relapse, last follow-up, or death from any cause. <b><i>Results:</i></b> At the time of TKI discontinuation, transcript level was undetected in 6 patients, &#x3c;0.01% in 2 patients, and 0.01% in another patient. Prior to discontinuation, the median duration of TKI therapy and of DMR was 70 and 47 months, respectively. No morphological relapse occurred. Three patients (33%) had molecular relapse at a median of 6 months. All 3 resumed TKI therapy, and 2 of them regained DMR after a median of 13 months. After a median follow-up of 49 months, the median TFR was not reached, and the 4-year TFR rate was 65%. The median duration of DMR in patients with and without molecular relapse was 22 and 58 months, respectively (<i>p</i> = 0.096). <b><i>Conclusion:</i></b> TKI discontinuation outside of HSCT in Ph-positive ALL in the setting of compelling toxicity may be safe only among a highly selected group of patients with deep and prolonged DMR undergoing close and frequent monitoring. Validation of these findings in prospective clinical trials is highly needed.

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