Author: Dr. Gule Lala, Internist, Pakistan Institute of Medical Sciences, Islamabad.
Today's journal discussion was about Asciminib that targets the gatekeeper mutation. It is being studied in patients with chronic myeloid leukemia that does not respond to the tyrosine kinase inhibitors (TKIs), including ponatinib. The study will be discussed after a brief discussion on chronic myeloid leukemia.Case Scenario:
A 50 years of age woman is investigated for weight loss and anemia. She got no medical history of note. General physical examination reveals pale conjunctivae and per abdominal examination splenomegaly is present. On laboratory investigation, her Hemoglobin is 10 gms/dl, WBCs of 69000/ul, platelet counts of 700000/ul. The peripheral smear showed leukocytosis and all stages of granulocyte maturation. Cytogenetic analysis showed the presence of translocation t( 9;22) ( q34;q11).Which hematological malignancy is most strongly associated with this translocation?
CML (Chronic Myeloid Leukemia):
- CML is a clonal disorder caused by a malignant transformation of pluripotent stem cells, characterized by the dysregulated production and uncontrolled proliferation of mature and maturing granulocytes with fairly normal differentiation.
What are the Myeloproliferative disorders?
These include:- Chronic myeloid leukemia (CML),
- BCR-ABL1+ Chronic neutrophilic leukemia (CNL)
- Polycythemia vera (PV)
- Primary myelofibrosis (PMF) (including pre-fibrotic/ early-stage PMF and overt fibrotic stage)
- Essential thrombocythemia (ET)
- Chronic eosinophilic leukemia not otherwise specified (NOS)
Translocation of t(9;22)(q34;q11.2). The fusion of Abelson oncogene from 9q34 with breakage cluster region on 22q11.2. This rearrangement is known as the Philadelphia chromosome.[/caption]
Clinical Findings in a patient with CML:
- 50 percent of the patients are asymptomatic.
- Fatigue
- Night sweats
- Low-grade fever
- Abdominal fullness
- Bone pain
- Leukostasis
- Involvement of extramedullary tissues such as the lymph nodes, skin, and soft tissues is generally limited to patients with blast crisis.
Lab investigations in a patient with CML (Chronic myeloid leukemia)
The Median WBC count is 150,000/ul. There is absolute eosinophilia and basophilia. Peripheral smear:- Myeloid series is left shifted with mature forms dominating.
- Blast cells may be seen. Their percentage depends on the stage of CML
- Anemia ( with normal RBC morphology)
- Platelet counts are normal or elevated
- The LAP (Leukocyte alkaline phosphatase) score is low.
Leukostasis:
Leukostasis is a pathologic diagnosis in which white cell plugs are seen in the microvasculature. Clinically, leukostasis is typically diagnosed empirically when a patient with leukemia and hyperleukocytosis presents with respiratory or neurological distress. Prompt treatment is indicated since, if left untreated, the one-week mortality rate is approximately 20 to 40 percent.Hyperleukocytosis:
Hyperleukocytosis refers to a laboratory abnormality that has been variably defined as a total leukemia blood cell count greater than 50 x 10 ∧ 9/L (50,000/microL) or 100 x 10 ∧ 9/L (100,000/microL). In contrast, leukostasis (also called symptomatic hyperleukocytosis) is a medical emergency most commonly seen in patients with acute myeloid leukemia or chronic myeloid leukemia in blast crisis. It is characterized by an extremely elevated blast cell count and symptoms of decreased tissue perfusion.Cytoreduction
Cytoreduction can be achieved through the use of chemotherapy. This should be accompanied by tumor lysis syndrome prophylaxis with aggressive hydration and allopurinol. [caption id="attachment_10776" align="aligncenter" width="566"]
Marrow cellularity is increased with increase myeloid to erythroid ratio.Marrow blast is normal or slightly elevated[/caption]
Phases of CML (Chronic myeloid leukemia):
The three phases of CML are:- Chronic stable phase,
- Accelerated phase,
- Blast crisis
Chronic Phase:
- Peripheral blood has elevated WBC counts ranging from 12000/ul to 10,00,000/ul (median counts of 100,000/ul)
- Neutrophils may be seen in all phases of their maturation
- The LAP score is low
- There is absolute eosinophilia and monocytosis.
- The platelet counts are normal or elevated (a low platelet count should prompt one to consider alternate diagnosis like myelodysplastic syndrome)
- < 10% blasts are present in the peripheral blood and bone marrow biopsy.
Accelerated phase:
- 10 to 19 percent blasts in the peripheral blood or bone marrow
- Peripheral blood basophils ≥20 percent
- Platelets >1,000,000/microL, unresponsive to therapy
- Progressive splenomegaly and increasing white cell count, unresponsive to therapy
- Cytogenetic evolution.
Blast phase:
- ≥20 percent peripheral blood or bone marrow blasts
- Large foci or clusters of blasts on the bone marrow biopsy.
- Presence of extramedullary blastic infiltrates.
Treatment of chronic myeloid leukemia:
Goals of therapy:
- To achieve clinical remission
- Maintain long-term disease control
- Avoid disease progression to accelerated phase or blast
Tyrosine kinase inhibitors:
First-generation TKIs (Tyrosine kinase inhibitors):
Imatinib.Important side effects of imatinib are bone marrow suppression, fluid retention/edema, gastrointestinal effects, heart failure, and hepatotoxicity.
Second-generation TKIs:
- Dasatinib
- Nilotinib
- Bosutinib
Third generation TKIs:
Ponatinib Important side effects of Ponatinib are bone marrow suppression, atherosclerosis-related events, electrolyte imbalance, and hepatotoxicity. Black Box Warnings: QT prolongation.Response to treatment:
Complete Hematologic response:
- White blood cell count of <10,000/microL with no immature granulocytes
- Less than 5 percent basophils
- Platelet count of less than 450,000/microL
- The spleen is not palpable.
Cytogenetic response:
- It is assessed by chromosome analysis of marrow cells (at least 20 metaphases should be analyzed)
- No cytogenetic response (>95 percent of Philadelphia chromosome positivity),
- Minimal (66 to 95 percent),
- Minor (36 to 65 percent),
- major (1 to 35 percent), and
- complete (Absence of Philadelphia chromosome-positive cells) or <1 percent BCR-ABL1-positive nuclei of at least 200 nuclei measured by FISH of blood interphase cell nuclei (in a patient with an inadequate number of metaphasis).
Molecular response:
It is assessed by Quantitative PCR of the peripheral blood and defined according to the level of detection of the assay. The term complete molecular response should be abandoned because of the increased sensitivity of the PCR assays.
- MR2 – Detectable disease at a level of ≤ 1 percent on the IS (≥2 log reduction from the standardized baseline), also termed "complete cytogenetic response."
- MR3 – Detectable disease at a level of ≤ 0.1 percent on the IS (≥3 log reduction from the standardized baseline), also termed a "major molecular response."
- MR4 –
- Either detectable disease at a level of ≤0.01 percent on the IS (≥4 log reduction) or
- undetectable disease in cDNA with ≥10,000 ABL1 transcripts.
- MR4.5 – Either detectable disease at a level of ≤0.0032 percent on the IS (≥4.4 log reduction) or undetectable disease in cDNA with ≥32,000 ABL1 transcripts.
The gatekeeper mutation:
T3151 mutation in abl is specifically resistant to the first and second-generation TKIs but sensitive to ponatinib.What's new:
Asciminib in Chronic Myeloid Leukemia after ABL Kinase Inhibitor Failure
(Dec 2019 ) Phase 1, a dose-escalation study published in NEJM
Introduction:
- This is a Phase 1 study that was conducted to determine the safety, maximum tolerated dose or recommended dose, pharmacokinetics, and antileukemic activity of asciminib in patients with Ph-positive leukemia after failure of multiple approved TKIs.
Asciminib MOA (Mechanism of action):
- Asciminib is an allosteric inhibitor that binds a myristoyl site of the BCR-ABL1 protein, locking BCR-ABL1 into an inactive conformation through a mechanism distinct from those for all other ABL kinase inhibitors.
- Asciminib targets both Native and mutated BCR-ABL1, including the gatekeeper T315I mutant.
Study design:
-
Primary objective
- To determine the maximum tolerated dose or the recommended dose(or both) of asciminib administered twice daily in patients with chronic-phase or accelerated phase CML.
- Secondary objectives
- Safety, pharmacokinetics, and efficacy.
The study included a dose-escalation phase and an expansion phase for patients treated at either the maximum tolerated dose or the recommended dose.
Eligibility criteria:
- 18 years of age or older
- Ph-positive chronic-phase or accelerated-phase CML
- A hematologic, cytogenetic, or molecular disease that was relapsed or refractory to at least two different TKIs before study entry or had unacceptable side effects from the TKIs.
- 17 Patients with a BCR-ABL1 T315I mutation were eligible after they had received at least one.
*Asciminib was administered once or twice daily (at doses of 10 to 200 mg). The median follow-up was 14 months.
Results of the study:
- Patients were heavily pretreated.
- 70% (105 of 150 patients) had received at least three TKIs.
- The maximum tolerated dose of asciminib was not reached.
- Among patients with chronic-phase CML, 34 (92%) with a hematologic relapse had a complete hematologic response
- 31 (54%) had a complete cytogenetic response who previously did not have a complete cytogenetic response at baseline
- A major molecular response was achieved by 12 months in 48% of patients, including (57%) that had resistance/side effects from ponatinib, a major molecular response was achieved/maintained by 12 months in 5 patients.
- Clinical responses were durable; a major molecular response was maintained in 40 of 44 patients.
- Asciminib was active in heavily pretreated patients with CML who had resistance to or unacceptable side effects from TKIs, including patients in whom ponatinib had failed and those with a T315I mutation.
