Annals of Case Reports

Introduction

B-cell acute lymphoblastic leukemia (ALL) remains a formidable disease with a low overall survival rate, particularly when accompanied by extramedullary involvement [1, 2]. The infiltration of leukemic cells into extramedullary sites serves as a predictor of poor chemotherapy response and an inferior prognosis [3, 4]. Notably, cutaneous involvement in B-cell ALL is a rarely observed manifestation that often signifies an aggressive disease state [5].  Chimeric antigen receptor-modified T cell (CART) therapy targeting CD19 has demonstrated therapeutic benefits for patients with relapsed and refractory B-cell ALL, even in the presence of extramedullary disease. However, comprehensive data elucidating the underlying mechanisms of CART cell migration to extramedullary sites in relation to clinical and laboratory dynamics is limited. In this report, we present a case study of a patient with refractory B-cell ALL experiencing extramedullary relapse, who received CART therapy. The patient initially exhibited progression of leukemia cutis, followed by near complete resolution of the extramedullary disease.

Case Presentation

An 18-year-old male with a one-month history of fatigue, intermittent blurry vision, and dyspnea initially presented to the UT Southwestern Medical Center in August 2022. His initial lab work revealed a WBC count of 138.7k, H/H of 6.0/18.7, and PLT of 11k. A bone marrow biopsy (BMB) with the flow cytometric analysis showed 90% blasts supporting a diagnosis of acute B-cell ALL was established: CD79a (+), CD38 (partial dim +), CD34 (+), CD22 (+ 100%), CD25 (partial +), CD20 (few +/positive in 100.00% of the total blast population), CD19 (variably +), CD10 (bright +), HLA-DR (+), TdT (+), CD123 (-), CD45 (-), CD5 (-), surface immunoglobulin light chain (-), myeloperoxidase (-). Nextgeneration sequencing revealed JAK2 R867Q and IGH-CRLF2 rearrangements consistent with a diagnosis of Philadelphia-like ALL while cytogenetic analysis showed a normal male karyotype. The patient was started on induction chemotherapy with the CALGB 10403 protocol (intrathecal cytarabine, prednisone, vincristine, daunorubicin, pegaspargase, intrathecal metothrexate). Post-induction bone marrow biopsy on C1D37 revealed residual ALL with 10% blasts. For reinduction the patient was switched to hyperCVAD (cyclophosphamide, vincristine sulfate, doxorubicin hydrochloride, and dexamethasone) with rituximab and intrathecal (IT) cytarabine and methotrexate. Repeat BMB (C1D18) showed persistent disease with 5% blasts, and the patient was started on Blinatumomab salvage therapy. On the C1D26 of therapy with Blinatumomab BMB was negative for the minimal residual disease (MRD). Patient was started on the second cycle of the Blinatumomab with the plan for stem cell transplantation (SCT) due to refractory nature of his disease. During the second cycle of blinatumomab on the C2D8 the patient developed bilateral neck and ear pain as well as asymptomatic slightly raised reticular lesions with no surrounding erythema (Figure 1, provided by family) and was started on amoxicillin due to concern for the infection. On the C2D13 his condition has not improved, and he presented to the hospital with cervical and mandibular lymphadenopathy. PET/CT showed extramedullary ALL relapse involving the scalp, salivary glands, cervical lymph nodes, mediastinum, and retroperitoneum. The patient was therefore started on mini-hyperCVD (lower doses of cyclophosphamide, vincristine, dexamethasone) and Inotuzumab salvage therapy. After the first cycle of the minihyperCV and Inotuzumab, he presented to the MD Anderson Cancer Center (MDACC) for the second opinion in January 2023. The plan was to continue with miniCVD with Inotuzumab and adding dexamethazone and Blinatumomab in preparation for potential CART therapy. On the C2D11 of the therapy, the patient has developed neutropenic fever along with bilateral parotid glands swelling. He was admitted and started on broad spectrum antibiotics. A biopsy of the parotid gland was performed which confirmed extramedullary relapse with leukemic involvement. Due to disease progression, CART therapy was deemed necessary and after the discharge from the hospital, on C2D26 in February patient underwent T-cell collection for the CART therapy. On C2D33 a planned PET/CT confirmed active leukemic involvement of the scalp, parotid gland, spleen, and right lower lung lobe (Figure 2 A, B, C).  A skin biopsy also performed at that time confirmed leukemia cutis with immunohistochemistry (ICH) showing diffusely CD19-positive cells with 2-3% of CD3 positive cells (Figure 3 A, B, C). The patient was hospitalized on March 8, 2023, for salvage chemotherapy with cladribine, idarubicin, cytarabine, and pegasparaginase which led to improvement in the rash after the completion of chemotherapy by the time he was discharged. 

Figure 1: Patient’s developing rash on the scalp with slightly raised reticular lesions and no surrounding erythema four month prior to CART therapy.

Figure 2: A – FDG-active extramedullary disease in the scalp (arrow); B - FDG-active extramedullary disease in the bilateral parotid glands (arrow); C - FDG-active extramedullary disease in the right upper lung lobe (arrow); D, E, F – no signs of FDG-active extramedullary disease.

Figure 3: A – Initial skin biopsy prior to CART therapy initiation; hematoxylin and eosin (H&E) showing leukemic cell infiltration of the skin consistent with a diagnosis of leukemia cutis; B - Initial skin biopsy prior to CART therapy initiation; CD19 immunohistochemistry (ICH) staining showing cells diffusely positive for CD19; C - Initial skin biopsy prior to CART therapy initiation, CD3 ICH staining showing 2-3% cells positive for CD3; D – First skin biopsy after the initiation of the CART therapy on the day +10; H&E showing leukemic cell infiltration of the skin; E – First skin biopsy after the initiation of the CART therapy on the day +10; CD19 ICH staining showing cells diffusely positive for CD19; F - First skin biopsy after the initiation of the CART therapy on the day +10; CD3 ICH staining showing 1% cells positive for CD3; G - Second skin biopsy after the initiation of the CART therapy on the day +13; CD3 ICH staining showing 1% cells positive for CD3; H – Second skin biopsy after the initiation of the CART therapy on the day +13; H&E showing leukemic cell infiltration of the skin; H - Third skin biopsy, CD19 ICH staining showing 50% cells positive for CD19; I - Second skin biopsy after the initiation of the CART therapy on the day +13; CD3 ICH staining showing 50% cells positive for CD3

In late March, he presented with neutropenic fever, was admitted, and was started on broad spectrum antibiotics. On presentation, his WBC was 0.2, Hb 9.1, platelet count 29k. His infectious workup remained negative, and one week after admission, he exhibited no signs of infection and was started on a lymphodepletion regimen with fludarabine and cyclophosphamide. Of note, his scalp rash has resolved completely by that time. Four days later, on March 27, 2023, the patient received brexucabtagene autoleucel (Tecartus) infusion at a dose of 1 x 106 CAR-positive viable T cells per kg. On the day of infusion, he developed hypotension with a blood pressure of 87/53, which resolved with intravenous fluids administration. He had no events between day +1, and day +8, excluding an hour long, spontaneously resolving, and episode of depressed mood without suicidal ideations on day +5. On day +9, he developed an asymptomatic light pink slightly raised maculopapular rash on the scalp (Figure 4). By the next day (+10), the rash progressed to become more raised, had increased in size and spread to his upper back and now had bright pink coloration with a purple tinge (Figure 4). The dermatology service was consulted, and a punch biopsy of the lesion on the back was performed. Later that day, the patient developed a fever with a T max of 39.2 C and hypotension with a blood pressure of 92/60. Along with broad-spectrum antibiotics, he received tocilizumab 8 mg/kg intravenously due to concern for Grade 2 cytokine release syndrome (CRS). He remained febrile and hypotensive overnight with a blood pressure in the 80-90s over 50-60s, despite intravenous fluids, and therefore received an additional dose of tocilizumab 8 mg/kg due to ongoing concern for CRS. On day +11, he remained afebrile, and his rash progressed in size, now becoming even more raised, erythematous, non-blanching, tender, and itchy (Figure 4, C, H). His infectious workup remained negative. The skin biopsy revealed leukemia cutis with ICH showing diffusely CD19-positive cells with only 1% of CD3 positive cells (Figure 3, D, E, F). On day +12, the patient developed a fever to 38.7o C, however his rash became less raised, but more itchy and painful (Figure 4). His infectious workup remained negative, and the fever was attributed to Grade 1 CRS. On day +13, he remained afebrile and normotensive and the area of involvement by the rash was decreased in size, and the lesions were less raised, less painful, and now non-itchy (Figure 4). The dermatology team performed a second skin biopsy on that day, which again showed leukemia cutis, but now the ICH showed CD19 positivity in 50% of cells (Figure 3, G, H, I). Through the course of days +14 to day +18, the patient remained afebrile, and his rash continued to decrease in size, becoming asymptomatic (Figure 4). The patient was successfully discharged to follow up in the outpatient setting. The summary of the clinical and laboratory parameters in relation to the timing of CART therapy is reflected in the Figure 5. Repeat PET/CT on the day +27 of CART therapy showed near complete resolution of previously noted FDG-avid lesions involving the scalp, bilateral salivary glands, nasolacrimal region, right upper lobe, gastric fundus, and bone marrow (Figure 2 D, E, F). On the day +26 BMB revealed 20-30% cellularity with 1% blasts and trilineage maturation. Flow cytometry was negative for residual B-lymphoblastic leukemia. Yet, on the day +27 CART cell level in the peripheral blood was 1 cell per uL. During the follow-up appointment in the outpatient on day +38 clinical examination did not reveal any signs of skin rash. He experienced marrow relapse after 5 months in remission.