Lorlatinib for the Treatment of Inflammatory Myofibroblastic Tumor after Allogeneic Hematopoietic Stem Cell Transplantation

Abstract

Inflammatory myofibroblastic tumors (IMTs) are rare sarcomas composed of myofibroblastic and fibroblastic cells, accompanied by inflammatory cell infiltration. Many IMTs exhibit clonal rearrangement of anaplastic lymphoma kinase (ALK). We herein report a 56-year-old woman with uterine IMT harboring a thrombospondin-1::ALK fusion that developed after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Laboratory data before systemic therapy indicated increased interleukin-6 and severe leukocytosis. The patient was treated with lorlatinib; however, the response duration was approximately two months. Similar case reports need to be compiled and evaluated to elucidate the efficacy of lorlatinib in post-allo-HSCT IMT with ALK rearrangement.

Introduction

Inflammatory myofibroblastic tumors (IMTs) are distinctive, rarely metastasizing neoplasms comprising myofibroblastic and fibroblastic cells accompanied by the infiltration of inflammatory cells. They mainly affect children and young adults, with a slight preponderance in women (1). Approximately 50-70% of IMTs, particularly those occurring in children and young adults, exhibit clonal rearrangement of anaplastic lymphoma kinase (ALK) at 2p23. ALK has various fusion partners, including EML4, TPM3, TPM4, CLTC, CARS, HNRNPA1, ATIC, SEC31 L1, RANBP2, DES, FN1, thrombospondin-1 (THBS1), and IGFBP5 (2).

We herein report a rare case of IMT that occurred after allogeneic hematopoietic stem cell transplantation (allo-HSCT). The IMT had a THBS1::ALK fusion, and was treated with the third-generation ALK inhibitor lorlatinib.

Case Report

A 56-year-old woman with a mass in the uterine body and multiple lung and lymph node metastases was referred to our hospital for a diagnosis and treatment. She had a history of chronic lymphocytic leukemia and right breast cancer and had undergone total mastectomy for breast cancer at 49 years old at a nearby hospital. She had been diagnosed with chronic lymphocytic leukemia at 36 years old and treated with rituximab. However, the disease became refractory, and ibrutinib was administered 28 months prior to referral to our hospital. Ibrutinib caused fulminant hepatitis and hepatitis-associated severe aplastic anemia. The patient had been transferred to another hospital and undergone allogeneic peripheral blood stem cell transplantation from a sibling donor. The conditioning regimen consisted of fludarabine, melphalan, and total-body irradiation (4 Gy). Graft-versus-host disease (GVHD) prophylaxis comprised cyclosporine A and mycophenolate mofetil. All immunosuppressants were discontinued nine months after transplantation. Ten months after transplantation, prednisolone (25 mg/day) was initiated for stomatitis due to chronic GVHD, but the dose was gradually tapered to 10 mg/day on the first visit to our hospital.

Twenty-two months after transplantation, she was diagnosed with a tumor in the uterine corpus (Fig. 1) with multiple lung and lymph node (abdominal para-aortic, bilateral common iliac, and right supraclavicular lymph node) metastases and was transferred to the gynecology department of our hospital 23 months after transplantation.

Figure 1.

Sagittal view of T2-weighted images on magnetic resonance imaging before the operation. The walls of the uterine body are highly thickened (white arrows).

During the first visit to our hospital (day 1), the patient complained of severe lower abdominal pain, atypical genital bleeding, and mild stomatitis secondary to chronic GVHD. Laboratory tests yielded the following results (Table): white blood cells (WBC)=16.92×10⁹/L [normal range (NR): 3.3-8.6×10⁹/L; neutrophils=68.2%, lymphocytes=11.3%, monocytes=4.7%, eosinophils=14.1%, basophils=0.5%, and large unstained cells=1.1%], hemoglobin=11.2 g/dL, platelet count=522×10⁹/L (NR: 158-348×10⁹/L), total protein=7.5 g/dL, total bilirubin=0.4 mg/dL, aspartate aminotransferase=19 U/L, alanine aminotransferase=8 U/L, lactate dehydrogenase=172 U/L, blood urea nitrogen=13 mg/dL, creatinine=0.47 mg/dL, C-reactive protein (CRP)=8.82 mg/dL (NR: ＜0.14 mg/dL), prothrombin time-international normalized ratio=1.1, activated partial thromboplastin time=47.8 s (NR: 24.0-39.0 s), fibrinogen=552 mg/dL (NR: 200-400 mg/dL), and D-dimer=0.9 μg/mL.

Table.

Summary of the Laboratory Data.

		Normal range	1st visit day	2nd admission
Complete blood count
White blood cells	×109/L	3.3-8.6	16.92	79.59
Neutrophils	%	30.0-70.0	68.2	95.7
Lymphocytes	%	18.0-55.0	11.3	1.3
Monocytes	%	≤12.0	4.7	1.4
Eosinophils	%	≤8.0	14.1	1.2
Basophils	%	≤2.0	0.5	0.1
Large unstained cells	%	1.0-4.0	1.1	0.4
Hemoglobin	g/dL	11.6-14.8	11.2	8.5
Platelets	×109/L	158-348	522	609
Biochemistry
Aspartate aminotransferase	U/L	13-30	19	29
Alanine aminotransferase	U/L	7-23	8	15
Lactate dehydrogenase	U/L	124-222	172	269
Total bilirubin	mg/dL	0.4-1.5	0.4	0.3
Blood urea nitrogen	mg/dL	8.0-20.0	13	32
Creatinine	mg/dL	0.47-0.79	0.47	1.89
Total protein	g/dL	6.6-8.1	7.5	5.6
C-reactive protein	mg/dL	<0.14	8.82	22.29
Coagulation
PT-INR		0.85-1.20	1.1	1.05
APTT	s	24.0-39.0	47.8	37.6
Fibrinogen	mg/dL	200-400	552	597
D-dimer	µg/mL	<1.0	0.9	16.6
Cytokine
Interleukin-6	pg/mL	<7.0	No data	153
G-CSF	pg/mL	10.5-57.5	No data	136

PT-INR: prothrombin time-international normalized ratio, APTT: activated partial thromboplastin time, G-CSF: granulocyte colony-stimulating factor

A biopsy of the uterine corpus suggested a malignant mesenchymal tumor. The tumor was metastatic; however, her abdominal pain was so severe that she was admitted for total hysterectomy, bilateral salpingo-oophorectomy, and para-aortic lymphadenectomy on day 30. The walls of the uterine corpus are highly thickened. A pathological examination revealed an IMT in which spindle-to-epithelioid tumor cells proliferated diffusely with an infiltrate of lymphocytes, plasma cells, eosinophils, and neutrophils. Epithelioid tumor cells had large vesicular nuclei with nucleoli and amphophilic or eosinophilic cytoplasm (Fig. 2A, B). Immunohistochemistry revealed diffuse cytoplasmic ALK staining (Fig. 2C). The tumors were extensively exposed in the serosa and cut margins of the uterus. Metastases with extranodal extensions were observed in the dissected bilateral abdominal para-aortic and sacral lymph nodes. A commercial DNA panel analysis could not identify any targetable mutations, but an RNA panel analysis (TruSight RNA Pan-Cancer Panel; Illumina, San Diego, USA) performed by our laboratory detected a THBS1::ALK fusion.

Figure 2.

Histopathological findings. (A) Low-power view showing the diffuse proliferation of tumor cells and inflammatory infiltrate (magnification, ×40). (B) High-power view of the resected IMT. Proliferation of epithelioid tumor cells with infiltrate of lymphocytes and neutrophils (magnification, ×400). (C) ALK immunohistochemical staining. Diffuse cytoplasmic staining is observed (magnification, ×100). ALK: anaplastic lymphoma kinase, IMT: inflammatory myofibroblastic tumor

The patient was discharged on day 48. However, she complained of severe pain in her perineum and buttocks on day 78, and imaging examinations revealed local pelvic recurrence of IMT, enlargement of the abdominal para-aortic lymph nodes, and lung metastases. Laboratory test results revealed severe leukocytosis and an elevated CRP level. She was transferred to the Department of Musculoskeletal Oncology of our hospital for systemic therapy and was hospitalized for the second time on day 93.

At the second hospitalization, the laboratory tests revealed the following results (Table): WBC=79.59×10⁹/L (neutrophils=95.7%, lymphocytes=1.3%, monocytes=1.4%, eosinophils=1.2%, basophils=0.1%, and large unstained cells=0.4%), hemoglobin=8.5 g/dL, platelet count=609×10⁹/L, CRP=22.29 mg/dL, and creatinine=1.89 mg/dL (NR: 0.46-0.79 mg/dL). Interleukin-6 (IL-6) and granulocyte colony-stimulating factor (G-CSF) levels were elevated at 153 pg/mL (NR: ≤7.0 pg/mL) and 136 pg/mL (NR: 10.5-57.5 pg/mL), respectively.

The patient had bilateral hydronephrosis caused by a recurrent pelvic mass, and bilateral double-J stents were implanted on the first day of the second hospitalization. Lorlatinib (50 mg/day) was administered on day 94. The starting lorlatinib dose was reduced to half of the standard dose because of renal dysfunction and a low body weight (36.9 kg). The effect of lorlatinib was remarkably rapid: her perineal and buttock pain reduced within a day, and the WBC, CRP, and IL-6 values began to decrease (Fig. 3). The patient was discharged on day 103 of hospitalization. Lorlatinib was continued for 43 days but was discontinued from day 137 due to dizziness, speech disturbance, and peripheral sensory neuropathy, which might have been side effects of lorlatinib. The taper-and-off method for lorlatinib was not adopted because the dosage was minimal. However, her neurological symptoms worsened, and she was hospitalized for the third time on day 144.

Figure 3.

Clinical course of the patient. CRP: C-reactive protein, IL-6: interleukin-6, OP: operation, RT: radiation therapy for cerebral metastases, WBC: white blood cell

At the third admission, magnetic resonance imaging revealed multiple metastatic lesions in the left cerebral hemisphere (Fig. 4A, B). The cerebral metastases were successfully treated with stereotactic radiation therapy (total: 42 Gy/10 fractions), and lorlatinib (50 mg/day) was resumed on day 150 because it has good transferability through the blood-brain barrier. Her WBC count decreased temporarily but eventually increased again. In contrast, her CRP level continuously increased. Increasing the lorlatinib dose to 100 mg/day did not prevent the increase in the values of these markers. The patient complained of worsening dizziness and abdominal distension and refused lorlatinib treatment. The final imaging evaluation showed no remarkable change in the size of the local relapsed lesion in the pelvis and only a minimal reduction in the size of the para-aortic lymph nodes (Fig. 5A, B). Lorlatinib was replaced by brigatinib on day 191. One week after initiation of brigatinib treatment, the patient developed colonic obstruction. She eventually died of disease progression on day 212.

Figure 4.

Axial view of T1-weighted gadolinium contrast-enhanced magnetic resonance imaging scans showing well-enhanced masses in the (A) left parietal lobe and (B) frontal lobe.

Figure 5.

Axial view of T2-weighted magnetic resonance imaging scans. Metastatic para-aortic lymph nodes (A) before and (B) after administration of lorlatinib are indicated by white arrows.

Discussion

In addition to local symptoms, some patients with IMTs have systemic symptoms, such as a fever, malaise, weight loss, and hematologic abnormalities, including anemia, thrombocytosis, and leukocytosis, as well as increased CRP levels, which may be caused by cytokine release (1). Few studies have described the relationship between IMTs and the IL-6 level (3,4). Our patient exhibited severe leukocytosis, an increased CRP level, and moderate thrombocytosis before lorlatinib initiation. During this period, IL-6 and G-CSF levels were elevated, suggesting that these systemic inflammatory symptoms might have been caused by the increased levels of both cytokines. Although G-CSF levels were not monitored continuously, IL-6 levels, similar to the WBC count and CRP levels, initially decreased during treatment and then increased. We could not ascertain whether IL-6 was produced in the tumor cells or secreted from other cells, such as infiltrating inflammatory cells. However, IL-6 may be a tumor marker that reflects the disease condition.

IMT can occur after allo-HSCT (5-7), solid organ transplantation (8-10), or AIDS (11). IL-6 exerts pleiotropic effects on various cell types in the tumor microenvironment (12). High IL-6 and IL-6 receptor expression are prognostic factors for soft tissue sarcomas (13). In our patient, a high immunosuppressive status and high IL-6 levels may have been involved in tumorigenesis and enhanced IMT.

Chronic GVHD, transplantation for severe aplastic anemia, and radiation-based conditioning regimens are risk factors for secondary cancer after allo-HSCT (14,15). Our patient presented with these risk factors, was in a state of high immunosuppression, and consequently was at an increased risk of secondary cancer development.

The common sites of secondary cancer occurrence after allo-HSCT are the oral cavity, breast, skin, and thyroid (15). However, IMT is rare, and no specific screening method has yet been recommended. Our case suggests that unexplained leukocytosis and elevated CRP levels may provide important clues for diagnosing IMT in severely immunosuppressed recipients.

Recently, the efficacy of ALK inhibitors in IMT with ALK rearrangements has been reported (16-20). However, the efficacy of ALK inhibitors in IMT after allo-HSCT is not well known, owing to its rarity. Only a few cases of IMT after allo-HSCT, treated with ALK inhibitors, have been reported. Shash et al. reported their experience with an eight-year-old girl with aggressive and metastatic IMT after umbilical cord blood transplantation. The patient was treated with crizotinib but later developed fatal pulmonary toxicity (7).

ALK inhibitors have not been approved for use against IMT in Japan. As we could not find any other appropriate medication for treating this rare sarcoma, we used lorlatinib and brigatinib after obtaining approval from the regional ethics committee of our hospital. However, treatment with these medications does not constitute a clinical trial. Alectinib is a first-line ALK inhibitor for ALK-fusion gene-positive non-small cell lung cancer, and its efficiency and safety have been confirmed (21). Furthermore, it is among the preferred regimens for IMT with ALK rearrangements in the National Comprehensive Cancer Network Guidelines (https://www.nccn.org/professionals/physician_gls/pdf/sarcoma.pdf), but it was not listed at the time of treatment. Therefore, we were unable to obtain approval for the use of alectinib from the regional ethics committee.

Some patients with IMT unrelated to transplantation have been treated with lorlatinib (19,20). However, to our knowledge, this is the first case report of post-allo-HSCT IMT treated with lorlatinib. Although the patient's symptoms and systemic inflammatory reactions improved rapidly, the response duration was relatively short (approximately two months).

Several limitations associated with the present study warrant mention. First, it was difficult to evaluate the effects of lorlatinib because the starting dose was reduced to half the standard dose owing to renal dysfunction and low body weight. This reduction may have caused IMT to acquire early resistance to lorlatinib. Baldi et al. reported the efficacy of cytotoxic chemotherapy (anthracycline-based chemotherapy and methotrexate with or without vinorelbine or vinblastine) for IMTs unrelated to transplantation (22). In addition, Wang et al. reported an IMT unrelated to transplantation that was treated with sequential switching of ALK inhibitors (20). Use of such treatments as second-line therapy after lorlatinib may improve the prognosis of patients with post-allo-HSCT IMT.

In summary, we report our experience with a patient with IMT after allo-HSCT harboring a THBS1::ALK fusion. The patient's clinical course suggested that lorlatinib was temporarily effective for this type of IMT. However, the response duration was relatively short (approximately two months). Similar case reports need to be compiled and analyzed to further elucidate the efficacy of lorlatinib for post-allo-HSCT IMT with ALK rearrangement. Nevertheless, our case suggests that IL-6 may be a tumor marker that reflects the disease condition.

The authors state that they have no Conflict of Interest (COI).