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