Discussion
Although there is no consensus on optimal treatment approaches for Ph+
MPAL, TKIs are often used based on their efficacy in CML. In CML,
decision-making related to specific TKIs to be used and their doses
relies on patient age and comorbidities. Low-dose imatinib may control
Ph+ MPAL in cases where second-generation TKIs cannot be used due to
complications and comorbidities in elderly patients and can be
considered as a safe alternative therapy.
Our review of the literature of relevant cases identified only four
reports of elderly patients who were diagnosed with Ph+ MPAL according
to the 2016 WHO classification (Table).7-9 These cases
were treated with second-generation TKIs; however, none of the studies
involved patients treated with only imatinib. The first of the reported
four cases was a 71-year-old female with hypertension who was initially
treated with imatinib (400 mg/day) and later developed edema and
fatigue; therefore, the imatinib dose was reduced to 300 mg/day. She
maintained cytogenetic CR without serious complications for
approximately 20 months; however, reverse transcription-polymerase chain
reaction detected the presence of BCR-ABL1 fusion gene. Her
treatment was replaced with nilotinib after the first hematological
relapse, and she achieved second cytogenetic CR for seven months. After
the second hematological relapse, she was treated with dasatinib and
achieved cytogenetic CR for approximately two years.7The second case was an 85-year-old male with prostate cancer who was
treated with radiation and combination chemotherapy with dasatinib. He
was successfully treated with dasatinib which controlled the disease
without fatal complications.8 The third case was a
69-year-old female with a 15-year history of type 2 DM, whereas the
fourth case was a 69-year-old female who was diagnosed with breast
cancer 17 years earlier and was treated with surgery, systemic
chemotherapy, and hormonal therapy. The last two patients were treated
with dasatinib (140 mg/day) and prednisolone and maintained molecular CR
for 16 and 7 months, respectively.9
The present case (case 5) highlights two important clinical
implications. First, low-dose imatinib might provide safe disease
control in elderly patients with Ph+ MPAL. Second, imatinib can be
safely continued without fatal complications by monitoring drug
concentrations in blood.
Patients with Ph+ MPAL have recently been treated with 600 mg/day
imatinib, similar to that used in patients with Ph+ B-cell precursor
acute lymphoblastic leukemia, which has led to improved 5-year OS and
disease-free survival rates that are comparable with those of Ph+ B-cell
precursor acute lymphoblastic leukemia.5 However, we
should consider the risk of adverse events that can arise in elderly
patients with Ph+ MPAL who might develop complications such as that
occurred in the present case. Therefore, in the present case we
monitored the blood concentrations of imatinib, which allowed the
delivery of optimal doses without adverse events. Blood imatinib
concentrations above 1,000 ng/mL is considered to be effective in
CML10-12; therefore, we targeted the same cutoff value
for controlling the imatinib dose with drug concentration monitoring. As
a result, Ph+ MPAL could be controlled with imatinib at a low-dose
ranging from 150 to 200 mg/day, indicating that low-dose imatinib could
control Ph+ MPAL if effective blood concentration is maintained.
The initial treatment with dasatinib had to be discontinued due to
interstitial pneumonitis in the present patient, who could safely
continue treatment after switching to imatinib. Interstitial
pneumonitis, which can develop in 2.9% of patients treated with
dasatinib, is grade 3 or higher in half of the affected cases.
Conversely, interstitial pneumonitis reportedly occurs in only 1.3% of
patients under treatment with imatinib and the symptoms are expected to
improve by steroids and other treatments.13 In
contrast, 1.4% of patients treated with nilotinib develop interstitial
pneumonitis, which has a mortality rate of 22.2% in these
patients.14 Therefore, switching to imatinib might be
considered as an option in patients who develop interstitial pneumonitis
during treatment with second-generation TKIs.
Patients treated with TKIs rarely experience cardiac complications,
including congestive heart failure (1.7%) and QT prolongation (QT
interval > 480 ms, 0.7%; QT interval > 500
ms, 0.4%), due to imatinib.15,16 Therefore, imatinib
was considered in the present patient with QT prolongation. Conversely,
the reported rates of QT prolongation are 10.2%, 1.1%, and 0.5% in
nilotinib-treated patients with QT intervals of >450,
>480, and >500 ms, respectively, whereas the
reported rate of QT interval above 500 ms is 1% in dasatinib-treated
patients, which is higher than that reported in nilotinib-treated
patients.
The present patient was initially treated with dasatinib instead of
nilotinib due to the cardiovascular complications and the preexisting
history of DM. However, he was switched to imatinib because of
interstitial pneumonitis and QT prolongation. In agreement with previous
reports, there were no major complications after the switch and the
patient could continue treatment. Therefore,
imatinib should be considered as a
good option for continued treatment in elderly patients with Ph+ MPAL
and cardiovascular complications.
Low-dose imatinib was safe and
could control disease in an elderly patient with Ph+ MPAL. Reports of
elderly patients with Ph+ MPAL are limited, and accumulation of clinical
cases is necessary to elucidate appropriate treatment approaches for
elderly individuals with Ph+ MPAL.
Author Contribution
Yusuke Okayama wrote the manuscript with support from Teruhito Takakuwa.
All authors discussed the case and contributed to the final manuscript.
Conflict of Interest
None declared.
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Figure 1. Blast cells in bone marrow.
(A) Bone marrow examination showed hypocellularity with 41.4% medium-
or large-sized blasts (May-Giemsa stain, ×1,000 magnification). (B)
Blast cells were negative for myeloperoxidase according to histochemical
analysis (Myeloperoxidase stain, ×400 magnification).
Figure 2. Flow cytometric analysis of bone marrow cells.
Blast cells were strongly positive for CD10, CD19, CD33, CD34, HLA-DR,
cytoplasmic CD79a, TdT, and KORSA, and weakly positive for MPO.
Figure 3. A computed tomography (CT) scan ten days after the initiation
of dasatinib.
The CT scan showed interstitial pneumonitis.
Figure 4. Drug concentration monitoring of imatinib.
It showed the distribution of imatinib blood concentration (Imatinib
Cmin) and imatinib dose for one year. Imatinib at
150–200 mg/day could maintain Imatinib
Cmin>1,000 ng/mL.
Figure 5. Clinical course.
PSL prednisolone, Cr creatinine