[Wednesday reading literature] Big coffee commented on Chen Suning/Xue Song: AML with t(8;21) and KIT mutations relapsed after allo-HSCT and treated with avatinib for rapid remission

Acute myeloid leukemia (AML) with t(8;21) is a heterogeneous disease, and patients with intermediate and high-risk t(8;21) AML may benefit from allogeneic hematopoietic stem cell transplantation (allo-HSCT)
.

KIT mutation is currently the only recognized indicator of poor prognosis in AML with t(8;21), and patients with KIT-mutated t(8;21) AML have a poor prognosis and a high recurrence rate
.

Recently, "Leukemia & Lymphoma" reported the first case of relapse of AML allo-HSCT with t(8;21) and KIT mutations successfully treated with avatinib1
.

On this occasion, Dr.
Xue Song was specially invited to interpret this case in detail, and Professor Chen Suning of the First Affiliated Hospital of Soochow University made comments and sharing
.

Xue Song, Attending Physician, Youth Member, Hematology Translational Medicine Committee, China Anti-Cancer Association Member, Lymphoma and Hematology Committee, Beijing Anti-Cancer Association Background Acute myeloid leukemia (AML) is a highly heterogeneous hematological malignancy.
In recent years, great progress has been made in treatment, including molecular targeted therapy and allogeneic hematopoietic stem cell transplantation (allo-HSCT), but the long-term survival rate of AML patients is still only about 25%
.

AML with different cellular/molecular biological backgrounds differs significantly in terms of prognosis, and AML with the t(8;21)/AML1-ETO fusion gene generally has a favorable prognosis
.

However, AML patients with KIT-mutated AML1-ETO have a significantly worse prognosis, and relapse after transplantation is not uncommon even after allo-HSCT
.

Treatment options for relapsed AML after transplantation are limited, but novel targeted agents offer potentially effective treatment options
.

Avatinib is a multi-targeted tyrosine kinase inhibitor (TKI) that inhibits PDGFRA exon18 and KIT exon11/17 mutations
.

Avatinib inhibits the activity of the KIT D816V mutation at very low concentrations and has been approved for the treatment of systemic mastocytosis (ASM)
.

Dr.
Xue Song, Department of Hematology, Aerospace Center Hospital (now working in the Second Department of Transplantation, Lu Daopei Hospital) reported for the first time the use of avatinib to treat a case of AML1-ETO+ AML with KIT mutation who relapsed after transplantation.
The patient's extramedullary lesions and bone marrow AML1-ETO Gene quantification showed cases of rapid regression
.

Case profile The patient, female, was 8 years old
.

Chief complaint: intermittent fever for 2 weeks
.

Auxiliary examination Blood routine: white blood cells (WBC) 29×109/L, hemoglobin (Hb) 80g/L, platelets (PLT) 87×109/L Bone marrow morphology: AML flow cytometry (FCM): abnormal myeloid blasts Occupying 50.
4% of nuclear cells, abnormal cells are positive for CD117, CD34, HLA-DR, CD13, CD38, CD123 and cMPO, weakly positive for CD56 and CD33, CD11b, CD15, CD10, CD20, CD3, CD4, CD36, CD14, CD22 , CD14, CD22, CD8, CD2, CD5, CD16, CD19, CD25, CD11c, CD64c, CD79a and cCD3 were all negative
.

Genetic examination: AML1-ETO fusion gene and KIT gene mutation Chromosomal karyotype: 46,XX,t(8;21)(q22;q22) diagnosed with t(8;21)/AML1-ETO and KIT mutation AML after diagnosis and treatment On June 21, 2017, he started to receive the IA regimen (daunorubicin and cytarabine) induction therapy, and the bone marrow morphology showed no remission on July 11, 2017, and he switched to the HAG regimen (Takata chinensis).
Ester base, aclarithromycin, and G-CSF) were not relieved, but after switching to D-CAG regimen (decitabine, aclarithromycin, cytarabine, and G-CSF), complete remission (CR), Patients discontinued treatment after receiving one cycle of D-CAG consolidation therapy
.

In February 2020, the patient was admitted to hospital due to epistaxis.
Bone marrow aspirate showed AML recurrence.
The patient was negative for AML1-ETO after 4 cycles of chemotherapy, and was subsequently given dasatinib 50 mg/d maintenance therapy
.

In December 2020, the patient developed facial paralysis and cervical lymph node enlargement.
The bone marrow morphology showed that blast cells accounted for 75%, and 72.
12% of abnormal myeloid blast cells were seen in the residual bone marrow immune system.
The AML1-ETO quantification was: 797.
1%, all exons Sequencing detected a missense mutation in the c-KIT gene: D816l
.

Received D-CAG regimen plus dasatinib in turn, HA regimen (homharringtonine and cytarabine) + veneclase, D-HA regimen (decitabine, homoharringtonine and arabinoside) Cytidine) + veneclax and dasatinib, CLAG regimen (cladribine, cytarabine and G-CSF) + veneclax for one cycle each
.

Despite multiple episodes of sepsis, her condition did not go into remission
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In June 2021, the patient had left proptosis, MRI showed intraorbital space-occupying lesions, and PET-CT showed elevated FDG metabolism (Fig.
1A,B)
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The bone marrow morphology showed that blasts accounted for 66%, and 43.
59% of abnormal myeloid blasts were found in the residual bone marrow immunity.
The AML1-ETO quantification was 483.
8%
.

Figure 1.
Imaging examinations at different time points.
The patient underwent salvage allo-HSCT due to ineffectiveness of salvage chemotherapy
.

The patient started pretreatment with TBI/IDA/CLAG/ATG regimen on June 30, 2021, and the patient was given a donor as his father on July 9, 2021, allo-HSCT with HLA matching 5/10, +11 days The neutrophils were implanted, the platelets were implanted on +14 days, the bone marrow morphology was in remission on +27 days, and no abnormal blast cells were found in the bone marrow immune residue.
No lesions with increased FDG uptake were found on PET-CT (Fig.
1C, D), all of which indicated that the patients achieved good disease remission after transplantation
.

On the 50th day after transplantation, the patient developed fever and erythematous rash (the rash area was greater than 50% of the body surface area), and was clinically diagnosed as acute graft-versus-host disease (aGVHD), which improved after treatment with methylprednisolone and ruxolitinib
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On the 67th day after transplantation, the patient's bone marrow morphology was in remission, no abnormal blast cells were found in the bone marrow immune residues, AML1-ETO quantification was 8.
7%, and cyclosporine and ruxolitinib were discontinued
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On the 80th day after transplantation, the patient developed left proptosis again
.

PET-CT scans showed extramedullary recurrence (Fig.
1E,F)
.

Bone marrow morphological blasts accounted for 4.
5%, and 0.
47% abnormal myeloid blasts were seen in bone marrow immune residues.
AML1-ETO quantification: 109.
4% On the 81st day after transplantation, the patient started taking avatinib (200 mg/d, for off-label use).
) treatment, the patient's exophthalmos subsided in about 1 week, the bone marrow morphology on the 105th day after transplantation was in remission, no abnormal blast cells were found in the bone marrow immune residue, and the AML1-ETO quantification was 0.
13%
.

PET-CT scans showed significant shrinkage of intraorbital lesions without hypermetabolic foci (Fig.
1G,H)
.

The patient achieved AML1-ETO-negative status on day 124 post-transplant
.

Treatment and outcomes throughout the transplantation process are summarized in Figure 2
.

Figure 2 Summary of Treatment and Outcomes Throughout Transplantation Case Summary and Experience AML with t(8;21)/AML1-ETO is a heterogeneous disease with markedly variable prognosis
.

Although patients with high-risk factors can benefit from allo-HSCT, many patients relapse after transplantation
.

Previous studies have shown that the KIT gene mutation, especially the D816 mutation located on Exon17, is the main adverse prognostic factor in t(8;21) AML, with a short median remission period and a high cumulative recurrence rate
.

High-risk patients who were risk stratified according to KIT mutation status and AML1-ETO quantitative level had a 3-year cumulative recurrence rate of 38.
4% after allo-HSCT
.

Donor lymphocyte infusion (DLI) is the main immunotherapy method for relapse after HSCT.
About 60% of relapsed AML patients can achieve CR after chemotherapy combined with DLI, but only about 33% of patients can achieve long-term leukemia-free survival
.

The clinical outcome of patients who relapsed within 6 months after allo-HSCT was extremely poor.
Because the patients relapsed early after transplantation, experienced acute GVHD just before relapse, and had poor response to chemotherapy, dasatinib and veneclax before transplantation, In addition, extramedullary recurrence usually does not respond well to the GVL effect, so chemotherapy + donor cell infusion therapy is not administered to the patient
.

KIT mutations are present in approximately 40% of AML1-ETO AML cases, and TKIs targeting KIT are feasible
.

Dasatinib is a TKI with anti-KIT mutation activity, but the patient received dasatinib in combination with chemotherapy and other targeted therapies with no apparent effect
.

Avatinib is a multi-targeted TKI that inhibits the tyrosine kinase activity of the KIT D816 mutant at very low concentrations (Figure 3)
.

The PATHFINDER study showed that avatinib 200mg/d significantly reduced the allele ratio of KIT D816V in ASM patients with a favorable safety profile
.

The patient's bone marrow and extramedullary lesions were rapidly and significantly relieved after treatment with 200 mg/d avatinib, and the adverse reactions were controllable
.

Figure 3 Biochemical data on the activity of avatinib in 19 KIT and PDGFRA mutant proteins We previously reported that patients with leukemia with BRCA1/2 mutations or other "BRCAness" phenotypes who relapsed after allo-HSCT could aggregate from poly ADP-ribose Enzyme (PARP) inhibitor therapy
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AML1-ETO-positive leukemia cells lack BRCA1/2 function and are therefore sensitive to PARP inhibitors such as olaparib
.

KIT mutations have been shown to modulate the sensitivity of AML with AML1-ETO to PARP inhibitors and are associated with PARP inhibitor resistance, and inhibition of mutated KIT kinases restores sensitivity to PARP inhibitors
.

Therefore, in R/R AML patients with AML1-ETO and KIT mutations after allo-HSCT, avatinib combined with PARP inhibitors may have therapeutic potential
.

Professor Chen Suning Chief Physician of the First Affiliated Hospital of Soochow University Deputy Director of Jiangsu Hematology Institute Member of the Chinese Medical Association Hematology Branch Member of the Standing Committee of the Chinese Pathophysiology Society Experimental Hematology Branch There are t(8;21)(q22;q22);RUNX1/RUNX1T1 AML, usually classified as good prognosis group AML, with a high complete remission rate, and some patients with high-dose cytarabine in multiple courses can be clinically cured
.

However, clinically, such patients have a high recurrence rate
.

The recurrence rate of this type of AML patients with KIT mutation was higher than that of KIT wild-type patients
.

Avatinib, a potent KIT kinase inhibitor, was approved by the FDA in 2020 for the treatment of gastrointestinal stromal tumors and in June 2021 for advanced systemic mastocytosis
.

Currently, there is no report of avatinib in patients with RUNX1/RUNX1T1 and KIT-mutated AML who have relapsed after transplantation
.

This patient is a relapsed/refractory RUNX1/RUNX1T1 AML patient with extramedullary lesions and KIT gene mutation.
After salvage haplotype transplantation, intramedullary and extramedullary recurrence occurred, and the disease was ideally controlled after avatinib
.

It is suggested that further clinical trials should be designed to confirm the safety and efficacy of avatinib in patients with RUNX1/RUNX1T1 and KIT mutation AML patients who relapse after transplantation
.

References: 1.
Xue S, Huang W, Liu F, et al.
Rapid response to avapritinib of acute myeloid leukemia with t(8;21) and KIT mutation relapse post allo-HSCT.
Leuk Lymphoma.
2022 Apr 19:1- 4.
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