Title: A case of chronic myelogenous leukemia with the T315I mutation
who progressed to myeloid blast phase and was successfully treated with
asciminib
Sarah Tomassetti1, 2, Jennifer Lee1,
2, Xin Qing 2,3
1Division of Hematology and Oncology, Harbor-UCLA
Medical Center and The David Geffen School of Medicine at UCLA, Los
Angeles, CA, USA
2The Lundquist Research Institute, Torrance, CA, USA
3Department of Pathology, Harbor-UCLA Medical Center
and The David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
Running Title: Blast phase chronic myelogenous leukemia, T315I mutation,
asciminib
Corresponding author:
Sarah Tomassetti M.D
Division of Hematology and Oncology
Harbor-UCLA Medical Center/The Lundquist Institute
1000 West Carson Street N18, Torrance, CA 90502
Phone: (310) 745-2882 Fax: (310) 787-0967
E-mail: sarah.tomassetti@gmail.com
Number of Tables: 0
Number of Figures: 3
Word count (Please indicate the word count including Abstract and body
text. This is not to include the title page, reference list or figure
legends): 2,447
Keywords: Blast phase, chronic myelogenous leukemia, T315I mutation,
asciminib
ABSTRACT:
Patients with chronic myelogenous leukemia (CML) harboring the T315I
mutation who progress to blast phase CML while on ponatinib may be
successfully treated with asciminib monotherapy following induction
therapy with cytotoxic chemotherapy.
INTRODUCTION:
CML is a myeloproliferative neoplasm that represents approximately
15-20% of adult leukemias [1]. CML was the first leukemia to be
characterized by a consistent chromosomal aberration, the 22q- or
Philadelphia (Ph) chromosome. The Ph chromosome is formed by a fusion
that results in creation of a balanced genetic translocation,
t(9;22)(q34;q11.2).
Initial therapies used to treat CML consisted of radiotherapy and
systemic agents such as busulfan, hydroxyurea, and interferon-alfa
(INF-a) [11]. This approach controlled the signs and symptoms of
chronic phase (CP) CML to some extent, but it did not prevent the
inevitable progression to a rapidly fatal blast phase CML. Later,
allogeneic stem cell transplant became the first treatment to eradicate
the Ph-positive clone within the bone marrow and offer a potential cure.
In fact, in the 1990s, CML became one of the most common indications for
allogeneic transplant worldwide [2, 12].
The treatment and prognosis of CML took a dramatic turn with the advent
of the first small molecule tyrosine kinase inhibitor (TKI), imatinib.
Imatinib was the first drug to specifically target and inhibit the
BCR-ABL fusion protein and was approved by the Food and Drug
Administration for the treatment of CP CML in 2001. This targeted
approach drastically altered the clinical course of CML, improving the
overall survival from 4-5 years to that near age matched controls [13,
14].
Since the approval of imatinib, there are now 4 tyrosine kinase
inhibitors approved by the US FDA for the first-line treatment of CP
CML: imatinib, nilotinib, dasatinib, and bosutinib. Similar to imatinib,
these TKIs all target the ATP-binding pocket of the ABL1 domain.
Clinical trials with second generation TKIs have shown faster and deeper
responses and decreased progression to BP CML, but have failed to show
improvements in overall survival [15-18]. Patients who progress on
first-line TKI are usually given a second generation TKI.
Resistance to TKIs is thought to be due to point mutations in the
ATP-binding domain. In particular, the ABL1 T315I mutation, known as the
“gatekeeper” mutation, confers resistance to all TKIs with the
exception of ponatinib [17, 19]. This T315I mutation comprises about
10-27% of mutations found in those who fail imatinib and 3-15% of
patients overall [20]. Until recently, for patients with the ABL1
T315I mutation who fail ponatinib, there were few options outside of
allogeneic transplant [21]. However, with the development of
asciminib, patients with the T315I mutation now have an alternative
option.
Asciminib is a first-in-class STAMP (Specifically Targeting the ABL
Myristoyl Pocket) inhibitor. It is an allosteric inhibitor that binds to
the myristoyl pocket of the BCR-ABL1 protein to induce a conformational
change and lock the BCR-ABL protein in an inactive confirmation
[22]. This mechanism is distinct from the previously approved TKIs
that all target the ATP-binding site of BCR-ABL1. Asciminib targets both
native and mutated BCR-ABL1, including the T315 mutant [17].
Asciminib was shown to be effective in the phase 1, CABL001X2101
(NCT02081378), dose escalation study of 141 patients with CP CML and 9
patients with AP CML who were previously intolerant to or resistant to
greater than or equal to 2 prior TKIs who were treated with asciminib
monotherapy [17]. Overall, 48% of all patients had a major
molecular response (MMR) by 12 months, including 57% who were
previously resistant to or intolerant to ponatinib [17]. Asciminib
was well tolerated with the most common side effects (occurring in 25%
or more) being fatigue, headache, and increased lipase.[17].
These promising results prompted the ASCEMBL trial (NCT03106779), a
phase 3, randomized, open-label trial of 233 CP CML patients previously
treated with at least 2 TKIs who were given asciminib 40mg orally twice
daily or bosutinib 500mg orally daily [23]. In this trial, 25% of
those treated with asciminib and 13% of those treated with bosutinib
achieved MMR at 24 weeks[23]. Based on the results of these two
trials, in 2021 the US FDA granted accelerated approval of asciminib for
the treatment of Ph positive CP CML in adults previously treated with 2
or more TKIs or with the T315I mutation.
Since the introduction of imatinib and other small molecule TKIs, the
rate of progression to blast phase has decreased from 20% to around
1-1.5% per year [24, 25]. Treatment options for BP CML remain
limited and most recommend TKI with or without cytotoxic chemotherapy to
achieve a second chronic phase CML followed by allogeneic transplant
[26]. Prognosis is poor with an overall survival of about 8 months
without allogeneic transplant [27].
For patients who are found to have the T315I mutation upon progression
to blast phase, ponatinib with or without cytotoxic chemotherapy is a
viable option [28]. However, at this time, there is no FDA approved
therapy outside of cytotoxic chemotherapy for patients with the T315I
mutation who progress to blast phase CML while already on ponatinib.
Given its demonstrated efficacy in CP CML patients with the T315I
mutation, asciminib with or without cytotoxic chemotherapy may be an
effective treatment in this patient population. Here, we present a
unique case of a patient with AP CML and the T315I mutation who
progressed to myeloid BP CML while on ponatinib and was treated with
asciminib.
CASE PRESENTATION:
In July of 2018, a 62-year old woman with no prior medical history
presented to an outside hospital for gout where she was told her white
blood cell count (WBC) was “very high” and her red blood cells (RBC)
and platelets (plt) were “low.” She received a bone marrow biopsy, but
never followed up afterwards. Six months later, she presented again to
the outside hospital for shortness of breath and was found to have a
pleural effusion. At that time, she had a WBC count of 354 K/cumm, plt
count of 933 K/cumm, and was reportedly anemic. The differential and
blast count at that time is unknown. She received several thoracenteses
over the hospital course and was started on hydroxyurea. She was
diagnosed with AP CML and was started on imatinib. Upon discharge at the
outside institution, she had a WBC count of 144 k/cumm with 6% blasts,
hemoglobin of 7.5 g/dL, and plt count of 1,184 K/cumm.
After taking imatinib for about 1 week, she presented to our institution
at which time her WBC count had decreased to 79.4 K/cumm, hemoglobin of
6.6 g/dL, and plt count of 895 K/cumm. Peripheral blood polymerase chain
reaction (PCR) for BCR-ABL1/ABL1 was 57.940% and detected the P210
BCR-ABL1 fusion transcript. She was continued on imatinib 600 mg per day
for AP CML. After 1 month, her WBC count normalized at 5.1 K/cumm, but
she remained anemic (hemoglobin 7.8 g/dL) and with thrombocytosis (plt
846 K/cumm). After 6 months of imatinib therapy, her PCR BCR-ABL1/ABL1
remained persistently elevated at 38.728%. ABL mutational testing was
negative and she was switched to dasatinib 100 mg daily.
After 3 months of dasatinib, her BCR-ABL1/ABL1 decreased to 12.567%,
however she required several medications pauses and dose reductions due
to episodes of grade 4 neutropenia and grade 3 neutropenia. Her
BCR-ABL1/ABL1 nadired at 10.701%, but after about 15 months was again
elevated at 94.141%. ABL mutational testing done at that time showed a
944CT(T315I) mutation and she was switched to ponatinib.
Ponatinib therapy was also complicated by cytopenias requiring several
pauses and dose reductions. After about 3 months, her peripheral blood
showed a WBC count of 54.8 K/cumm with 68% basophils. No blasts were
seen. Bone marrow biopsy was subsequently confirmed AP CML. It was
thought that the progression to accelerated phase CML was likely the
result of the numerous drug holidays due to cytopenias and the patient
was continued on ponatinib 45mg daily.
Her counts initially improved, however 8 months after starting ponatinib
she was found to have a WBC of 35.9 K/cumm and 45% blasts in her
peripheral blood confirming progression to BP CML. Bone marrow biopsy
showed myeloid blasts harboring the Ph chromosome and a new t(7:17)
translocation (Figure 1). Next generation sequencing (NGS) (by Tempus)
showed persistent ABL1 T315I mutation, as well as a BCOR R1217F
frameshift mutation.
She was admitted to our hospital and induced with cytarabine and
anthracycline. She underwent a day 17 bone marrow (at which time her
peripheral blood WBC 3.9 k/cumm, Hb 6.7 g/dL, and plt 5 K/cumm), which
showed at least AP CML with 5-10% blasts and focal marked marrow
fibrosis (Figure 2). Within a few days her peripheral blood showed
increasing WBC count to 52.3 K/cumm with a blast count fluctuating
between 2-14%. On day 19, she underwent re-induction with venetoclax,
fludarabine, and cytarabine. Her course was complicated by neutropenia
and various infections including aspergillus pneumonia and COVID-19
infection. Bone marrow biopsy was not done on day 28 due to lack of
count recovery.
At 6 weeks post induction, her BCR-ABL1/ABL1 remained at 92.216 % in
the setting of persistent pancytopenia (WBC 0.9 k/cumm, Hb 8.1 g/dL, plt
11 K/cumm) without blasts. Given lack of molecular remission and the
fact that she had progressed to blast crisis while on ponatinib,
asciminib was requested and approved as part of the Managed Access
Program (MAP) by Novartis. She was subsequently started on asciminib 200
mg oral twice daily, the approved dosing for patients with ABL T315I
mutations in CP CML. Repeat bone marrow biopsy at 3 months post
induction therapy (6 weeks after starting asiminib) showed complete
response with no blasts and negative minimal residual disease by flow
cytometry (Figure 3). Unfortunately, no BCR-ABL1/ABL1 % was done at
this time due to logistical reasons. She was referred for allogeneic
stem cell transplant.
DISCUSSION:
To our knowledge, this is the first case reported of a patient with
CP/AP CML and the ABL1 T315I mutation who progressed to myeloid BP CML
while on ponatinib and achieved a CR with MRD negativity after induction
chemotherapy followed by asciminib maintenance.
It is well known that progression to blast phase is a result of
continued, constitutively active BCR-ABL activity leading to genetic
instability, consequential DNA damage, and impaired DNA repair. This is
supported by the fact that reduction in BCR-ABL by TKI inhibition has
been shown to lead to a lower incidence of progression to BP CML
[25]. Consequently, upon progression to BP, most patients show
additional chromosomal aberrations. High risk chromosomal aberrations
associated with short survival in BP CML have been well characterized
and include +8, +Ph, i(17q), +17, +19, +21, 3q26.2, 11q23, −7/7q
abnormalities, and complex cytogenetics [29].
Consistent with this, our patient was found to harbor a new t(7;17) in
addition a mutation in BCOR on NGS. To our knowledge, the t(7;17) has
only been reported once in the literature and was in association with de
novo or therapy-related myelodysplastic syndromes or acute
non-lymphocytic leukemia [30]. BCOR is located on the X chromosome
and is involved in chromatin modification and transcription. It has been
reported in about 15% of patients upon progression to BP CML and has
been reported to be more common in TKI-naïve patients [31-33]. In
our patient, it is unknown whether the BCOR mutation was present prior
to BP CML as NGS was only sent at the time of BC diagnosis.
The response to TKI inhibition alone in BP is usually transient,
demonstrating that while most cells continue to be sensitive to BCR-ABL
inhibition, there is a component of BCR-ABL independent growth
advantage. In our case, the patient did not receive TKI therapy during
AML induction therapy due to the presence of the T315I mutation with
prior progression on ponatinib and lack of FDA-approved therapy. On
induction therapy alone, she was not able to achieve a complete
remission and her BCR-ABL1/ABL1 remained above 90%. It was not until
she started asciminib that she attained a complete response on bone
marrow examination with MRD negativity. Unfortunately, due to logistical
reasons, we were unable to also attain a BCR-ABL1/ABL1 at this time.
However, pathology did not note any chronic myeloid leukemia cells
present.
To the best of our knowledge, there are no published studies of BP CML
patients treated with asciminib. Additionally, there are only limited
studies of asciminib in CML patients with the T315I mutation. In the
phase 1, CABL001X2101 (NCT02081378) previously mentioned, 28 CP and 5 AP
CML patients with T315I mutation were included [17]. Among all
patients with the T315I mutation, 88% achieved a complete hematologic
response by 12 months. A MMR was achieved in 25% and 11% of those with
CP CML and AP CML, respectively [17]. In those with CP CML and the
T315I mutation who were deemed to have resistance to ponatinib, 20% had
a MMR at 12 weeks [17]. Unfortunately, the phase 3, ASCEMBL trial
excluded patients with the T315I mutation [23].
Since then, a real-world study of 31 heavily treated CP CML patients
also treated under the Novartis MAP program was published. In this
study, 28 patients (90%) had received 3 or more prior TKIs including 11
(35%) who had received ponatinib. Of these, 22 patients had intolerance
to and 9 patients had resistance to prior TKI [34]. Of the patients
without a baseline complete cytogenetic response (CCyR) or MMR, 48%
(8/17) and 33% (8/24) achieved CCyR and MMR, respectively. Of the
patients previously treated with ponatinib, 27% (3/11) achieved at
least MMR [34]. Only one patient in this study had a T315I mutation
and was treated with asciminib 200 mg orally twice daily. Unfortunately,
this patient lost hematological response after 3 months of asciminib
treatment and discontinued therapy. Interestingly, in this study, three
patients (9.7%) developed grade 4 thrombocytopenia with 2 of them
developing a concurrent grade 4 neutropenia. Like our patient, all of
these patients had similar toxicity with previous TKIs.
CONCLUSION:
This case report shows that asciminib, in combination with cytotoxic
chemotherapy, may be an effective treatment for CML patients with the
T315I mutation who progress to BP CML while on ponatinib. Consistent
with prior studies, it also shows that hematologic toxicity, when
present, seems to occur across multiple TKIs, in addition to, asciminib.
CONSENT:
Written informed consent was obtained from the patient to publish this
report in accordance with the journal’s patient consent policy.
CONFLICT OF INTEREST:
Sarah Tomassetti receives research funding from Novartis
Pharmaceuticals. The other authors have no conflicts of interests to
declare.
AUTHOR CONTRIBUTIONS:
S.T. drafted the manuscript. J.L. and X.Q. helped to draft the
manuscript and proofread the paper. X.Q. provided the initial diagnosis
and pathology images. S.T. and J.L. participated in the clinical
treatment. All of the authors read and approved the final version of the
manuscript.
ACKNOWLEDGEMENT
Special acknowledgment to all healthcare professionals involved in the
care of this patient.
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