Treatment of Adults With Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia-From Intensive Chemotherapy Combinations to Chemotherapy-Free Regimens: A Review.

Abstract

Importance:

With the advent of potent BCR::ABL1 tyrosine kinase inhibitors (TKIs), Philadelphia chromosome-positive (Ph-positive) acute lymphoblastic leukemia (ALL) is now a relatively favorable-risk acute leukemia. In this review, we discuss the current evidence for frontline therapies of Ph-positive ALL, the major principles that guide therapy, and the progress with chemotherapy-free regimens.

Observations:

Incorporating TKIs into the chemotherapy regimens of patients with newly diagnosed Ph-positive ALL has led to improved remission rates, higher probability of reaching allogeneic stem cell transplantation (SCT), and longer survival compared with chemotherapy alone. Early achievement of a complete molecular remission (CMR) is an important end point in Ph-positive ALL and identifies patients who have excellent long-term survival and may not need allogeneic SCT. Second-generation TKIs combined with intensive or low-intensity chemotherapy resulted in higher CMR rates compared with imatinib-based regimens. This translated into better outcomes, with less reliance on allogeneic SCT. To further improve the outcomes, the potent third-generation TKI ponatinib was added to chemotherapy. The combination of hyper-CVAD and ponatinib resulted in an overall CMR rate of 84% and a 5-year survival rate of 73% and 86% among patients who did and did not undergo allogeneic SCT, respectively, suggesting that allogeneic SCT may not be needed with this regimen. The recent chemotherapy-free combination of dasatinib and blinatumomab was safe and effective in patients with newly diagnosed Ph-positive ALL and resulted in an estimated 3-year OS rate of 80%; 50% of patients underwent allogeneic SCT. The chemotherapy-free regimen of ponatinib and blinatumomab resulted in a CMR rate of 86% and a 2-year survival rate of 93%, with no relapses or leukemia-related deaths, and with only 1 patient proceeding to allogeneic SCT.

Conclusions and Relevance:

The promising results obtained with the chemotherapy-free regimens of blinatumomab plus TKIs question the role of allogeneic SCT in first remission. Patients with Ph-positive ALL who achieve early and deep molecular responses have excellent long-term outcomes and may not benefit from allogeneic SCT.

• Authors: Elias Jabbour, Fadi G Haddad, Nicholas J Short, Hagop Kantarjian
• Journal: JAMA oncology (JAMA Oncol) Vol. 8 Issue 9 Pg. 1340-1348 (09 01 2022) ISSN: 2374-2445 [Electronic] United States
• PMID: 35834222 (Publication Type: Journal Article, Review)

Chemical References

• Protein Kinase Inhibitors
• Imatinib Mesylate
• Dasatinib

Topics

• Adult
• Antineoplastic Combined Chemotherapy Protocols (adverse effects)
• Dasatinib (therapeutic use)
• Hematopoietic Stem Cell Transplantation
• Humans
• Imatinib Mesylate (therapeutic use)
• Philadelphia Chromosome
• Precursor Cell Lymphoblastic Leukemia-Lymphoma (drug therapy, genetics)
• Protein Kinase Inhibitors (adverse effects)