Anaplastic Large Cell Lymphoma (ALCL) is a subtype of NON-HODGKIN'S LYMPHOMA (NHL) characterized by a cohesive proliferation of large pleomorphic cells that express the CD30 (Ki-1) antigen [1]. Among those ALCL, systemic ALCL is estimated to be 1-2% of NHL cases in the adult population and reaches 10-15% in the pediatric population [2-5]. Due to their aggressivity, the majority of patients are presented in the advantage stage and only 40-60% of cases involve extranodal tissue, including skin tissue (26%), bone (14%), soft tissue (15%), lung (12%) and liver (8%) [2,6]. Systemic ALCL has two types: Those with Anaplastic Lymphoma Kinase (ALK)+ and those with ALK- [1,2]. Until now, there is no standardized therapeutic regimen for systemic ALCL therapy. Even though BV+CHP (Brentuximab Vedotin plus Cyclophosphamide, Doxorubicin, Prednisone) is usually preferred to the CHOP (CHP+Vincristine) due to its superior survival without added toxicity [9], Brentuximab Vedotin (BV) had not readily available in developing countries. BV chemotherapy needs to be ordered first before it can be used. Therefore, we report a case of refractory systemic ALCL with ALK+ and bone tissue involvement in a developing country, which was successfully treated using Brentuximab Vedotin Plus Cyclophosphamide, Vincristine and Prednisone (BV+CVP).

KW, a 16-year-old male, Balinese ethnicity, came with a complaint of an initially painless lump on his left thigh which had been getting bigger since ± 6 months. In the last 3 days before hospital admission, there was pain in his left hip and it was felt getting worse, the pain did not radiate, the pain made it difficult for the patient to walk. History of collisions and falls, tingling and numbness in the lower extremities were denied. The patient has also complained of intermittent fever that had been felt in the last 6 months. Fever improved with the administration of antipyretic. Cough, shortness of breath, nausea and vomiting were denied. The patient also complained of general weakness and weight loss due to the decrease of appetite. Urination and defecation were in normal limit.

On physical examination, the patient was found to be moderately ill, shortness of breath, alert, normal blood pressure, slight tachycardia, tachypnea, normal temperature and oxygen saturation. Enlarged lymph nodes in the left axilla and left inguinal were palpable. On physical examination of the heart and lungs, no abnormalities were found. Physical examination of the abdomen did not reveal any tenderness, the liver span was 10 cm and the spleen was not palpable, the traube space was tympanic, there were no signs of ascites, bowel sounds were within normal limits. On examination of the extremities, it was found that there was a single unilateral mass on the left thigh, ±8 cm in diameter, supple and fixed on palpation, not warm and painless on palpation. The complete blood count examination showed a leukocytosis with mild hypochromic microcytic anemia. In addition, there was also a decrease in albumin levels and a slight increase in procalcitonin which indicated the presence of an inflammatory condition in the patient's body. The result of the chest X-ray showed that pneumonia was suspected from pulmonary metastases, which was characterized by consolidation in the upper zone of the right lung, without an increase in broncho vascular markings, while the size and shape of the heart were within normal limits (Figure 1).

Figure 1(a-d): Radiology Examination; (a) Chest X-Ray, (b) Pelvic X-Ray, (c) Left Femur X-Ray and (d) Left Cruris X-Ray

The X-ray examination of the left femur revealed a complete fracture of the left subtrochanteric bone, displacement of the fracture fragment (+) which suggested a pathological fracture of the left subtrochanteric femur. In addition, there was a lytic lesion on the metadiaphysis of the 1/3 proximal of the left femur which destroyed the cortex suggesting bone metastases. In addition, there was large wounds on the patient’s body. On pelvic X-ray examination, there were lytic lesions accompanied by cortical destruction of the left ilium, left acetabulum and left femoral head suggesting bone metastases. In addition, there was soft tissue swelling in the left hip region. An X-ray examination of the left crural revealed a lytic lesion on the proximal left tibial bone metadiaphysis which suggested bone metastases. It also had shown the left tibia bone traction (Figure 1). The histomorphology and immunohistochemical (IHK) examination results of the biopsy from left acetabulum has shown Anaplastic Large Cell Lymphoma (ALCL) ALK+ accompanied with CD30 (+), CD 45 (+) ALK (+).

Based on these clinical and supporting data, the patient was diagnosed with stage IV ECOG I of systemic Anaplastic Large Cell Lymphoma (ALCL), accompanied by a pathological fracture of the left sub trochanter of the femur et causa suspected bone metastases. While waiting for the bone biopsy and IHK examination, patient was given analgetic and traction for the management of fracture in the left femur. After the histomorphology and IHK results came, Brentuximab Vedotin (BV) has not readily available in Indonesia yet. Therefore, the patient was given CHOP chemotherapy (cyclophosphamide, doxorubicin, vincristine, prednisone) 8 times. Unfortunately, the lesion became worsen. BV chemotherapy was then ordered for this patient. Since Doxorubicin has already reached its maximum dosage used, BV+CVP (Brentuximab Vedotin plus Cyclophosphamide, Vincristine, Prednisone) chemotherapy was given for 7 times. The patient's condition has greatly improved. The patient is now able to walk with the support of crutches (Figure 2). The patient is routinely followed up in to the medical hematology oncology polyclinic.

Figure 2(a-b): Clinical Photos of Patient; (a) Before Receiving Chemotherapy and (b) After Receiving Chemotherapy

Systemic Anaplastic Large Cell Lymphoma (ALCL) is a rare form of lymphoid malignancy originating from aggressive mature T cells. Based on the presence of ALK protein, systemic ALCL can be divide into two group: ALK+ and ALK- [1,2]. ALK protein is a protein formed due to the translocation of t(2;5). Translocation of the t(2;5) chromosome causes the fusion of the nucleophosmin gene (NPM1) with another gene known as the Anaplastic Lymphoma Kinase (ALK) gene [2,3]. ALK is detected by immunohistochemistry and is found in 75% to 85% of cases of ALCL [4].

Unlike our patient who were in the first second decades of like, ALK+ ALCL generally occurs in patients in the first three decades of life, whereas ALK- ALCL is commonly found in older patients (age 40-65 years). Male predominance is found in ALCL, especially in cases of ALCL ALK+ with a male to female ratio of 1.5:1 [5,6]. Clinically, most cases of ALCL (50-70%) are diagnosed at an advanced stage (III-IV), have B symptoms and extranodal involvement. The most common extranodal involvement is skin (8-21%), bone (12-17%), soft tissue (17-21%), lung (6-13%), liver (3-17%), spleen (8-21%) and bone marrow (0-16%). Our patient came with suspected bone metastasis.

Patient with systemic ALCL usually come with complaints of the presence of fever, night sweats or weight loss of more than 10% over 6 months and history of malignancy [7,8]. The typical complaints of systemic ALCL also shown in our patient who came with the enlargement of left inguinal and axillary lymph nodes, fever and weight loss. In addition to the expression of ALK, the expression of the CD30 molecule is one of the hallmarks that is always found in ALCL. Therefore, in addition to histopathological examination, the detection of anti-ALK and anti-CD30 antibodies using immunohistochemical examination could assist the ALCL diagnosis establishment, both in PCALCL and systemic ALCL [7].

Although histopathological examination and detection of anti-ALK and anti-CD30 are adequate to establish the diagnosis of ALCL, other examinations such as blood tests and radiological imaging still need to be done to determine the involvement of extra nodal tissues/organ and to differentiate between Primary Cutaneous Anaplastic Large Cell Lymphoma (PCALCL) and systemic anaplastic large cell lymphoma (systemic ALCL) with skin involvement. A retrospective study involving 87 patients with ALCL ALK+ showed abnormal laboratory results that were frequently found were elevated lactate dehydrogenase (LDH) (37%), anemia (27%) and thrombocytopenia (10%) [8]. The leukocytosis, anemia and thrombocytosis found in the ALCK ALK+ was also found in this patient. In this case, there were lymph node nodules in the left axillary and left inguinal accompanied by metastatic lesions on the tibia and femur. Therefore, so that our patient was diagnosed with stage IV ALCL based on the Ann-Arbor staging system.

Systemic ALCL therapy is generally chemotherapy. Until now, there is no standardized therapeutic regimen for systemic ALCL therapy. Even though BV+CHP (BV plus cyclophosphamide, doxorubicin, prednisone) is usually preferred to the CHOP (CHP+Vincristine) due to its superior survival without added toxicity [9], Brentuximab vedotin has not readily available in Bali. Therefore, we initially gave CHOP regiment. Despite unsatisfactory results with the cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) regimen, it remains the reference front-line therapy in Peripheral T-Cell Lymphomas [10]. The CHOP regimen was reported to provide a complete response of 70-80% and 5-year overall survival rates of 70-80% in ALCL ALK+ and 50% in ALCL ALK-. The CHOP regimen was also shown to be better in ALK+ Anaplastic Large Cell Lymphoma (ALCL) compared to other types of Peripheral T-Cell Lymphomas [11]. However, the use of CHOP regimen.

Chemotherapy regimen using Brentuximab Vedotin (BV) is the chemotherapy option for ALCL which has been widely studied. BV is expected to replace the CHOP regimen in the future as the first line of ALCL chemotherapy. BV is a chimeric anti-CD30 IgG1 antibody conjugated by a protease cleavable linker to a monomethyl auristatin E microtubule disrupting agent so that it has antitumor activity. The main mechanism of BV in ALCL is by interfering with monomethyl auristatin E on tumor cells expressing CD30 where CD30 is a typical marker of ALCL. A randomized phase III clinical trial comparing BV therapy in combination with cyclophosphamide, doxorubicin and prednisone (CHP) to CHOP therapy as first-line therapy in systemic ALCL patients showed significantly higher overall survival rates in the BV and CHP regimens (42, 1 month versus 20.8 months) [10,11].

Not only is it effective as a first-line therapy for ALCL, BV also provides satisfactory results in preventing ALCL relapse. A phase III randomized double-blind clinical trial comparing BV and placebo therapy to prevent relapse in ALCL patients who had received ASCT showed that BV provided a significantly higher rate of Progression-Free Survival (PFS) (42.9 months versus 24.1 months, for BV and placebo, respectively). In addition to preventing relapse, chemotherapy using single agent BV in relapsed ALCL patients showed an overall response rate of 62.5% (45% complete response and 17.5% partial response). BV also shows a good level of safety and tolerable side effects. In the young population, side effects include peripheral neuropathy, fatigue, neutropenia and diarrhea. Side effects of BV therapy in the elderly population are also relatively mild, namely peripheral neuropathy, fatigue and nausea. The promising therapeutic outcome and mild toxicity profile make BV a potential therapy for systemic ALCL patients. Currently, various clinical trials are still being carried out to evaluate BV as a new therapy in ALCL patients [10,12]. Since Doxorubicin has reached its maximum dosage of use, we used the combination of BV+CVP palliative chemotherapy (cyclophosphamide, vincristine, prednisone) and this new combination has shown significant clinical improvements, although the survival rate of this patient is still not known.

ALCL is a rare and progressive T lymphoid malignancy. Establishing the diagnosis of ALCL is not easy because it has an atypical clinical picture and requires histopathological and immunohistochemical examination. The use of BV+CVP (Brentuximab Vedotin plus Cyclophosphamide, Vincristine and Prednison) has shown significant improvement. Therefore, CVP+ brentuximab chemotherapy in this case report can be used for refractory anaplastic large cell lymphoma.

Acknowledgment

The author recognizes all medical and paramedics staff that provide care in this patient.

Conflict of Interest

The author has no conflicts of interest to declare.

Funding

The author did not receive any funding for this case report.

Statement of Ethics

This retrospective review of patient data did not require ethical approval in accordance with local/national guidelines. 

Written informed consent was obtained from the patient and the parents of the patient for publication of the details of their medical case and any accompanying images.

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