Case Report

Temporal Dynamics and Efficacy of CAR-T Cell Therapy in B-ALL with Extramedullary Cutaneous Involvement: A Case Report and Discussion

by Iuliia Kovalenko1*, Mahesh Swamanathan2, Daniel Morse3, Ana M Ciurea3, Fiorinda F Muhaj3, Carlos Torres-Cabala4, Steven M Kornblau2

1University of Pittsburg Medical Center, Harrisburg, PA, USA

2Department of Leukemia MD Anderson Cancer Center, Houston, TX, USA

3Department of Dermatology MD Anderson Cancer Center, Houston, TX, USA

4Department of Pathology MD Anderson Cancer Center, Houston, TX, USA

*Corresponding author: Iuliia Kovalenko, University of Pittsburg Medical Center, Harrisburg, PA, USA

Received Date: 31 October 2023

Accepted Date: 06 November 2023

Published Date: 08 November 2023

Citation: Kovalenko I, Swamanathan M, Morse D, Ciurea AM, Muhaj FF, et al. (2023) Temporal Dynamics and Efficacy of CAR-T Cell Therapy in B-ALL with Extramedullary Cutaneous Involvement: A Case Report and Discussion. Ann Case Report 8: 1503. https://doi.org/10.29011/2574-7754.101503

Abstract

Introduction: Chimeric antigen receptor-modified T cell (CAR-T) therapy is emerging as a useful therapy for B-cell acute lymphoblastic leukemia (B-ALL) with remaining uncertainty regarding the timing of response. We present a patient with extramedullary cutaneous involvement, initially stimulated by CAR-T infusion, with a rapid resolution of the lesions and serial biopsies providing information on the timing of reactivity. Case presentation: An 18-year-old male with relapsed and refractory B-ALL developed extramedullary involvement, leukemia cutis. After receiving chemotherapy, the lesion resolved, and he then proceeded to CAR-T therapy. Starting 9 days post-CAR-T infusion, he experienced progression of leukemia cutis. Skin biopsy confirmed leukemia cutis with less than 1% of T-cells. Due to worsening, he underwent another biopsy on day 13 of CAR-T therapy, which showed CAR-T cells comprising ~50% of all cells while peripheral blood CAR-T counts were negligible. The leukemia cutis lesions then cleared over the next week, and he achieved remission, lasting 5 months. Discussion: These findings suggest an initial stimulation of residual leukemia cutis cells, likely in response to chemokine and cytokine release related to CAR-T cell infusion. This was followed by an expansion of CAR-T cells at the site of involvement but not in the peripheral blood, and subsequent eradication of the leukemia. The time course of events and the biopsies 5 days apart provide insight into the timing of potential responses. The latter highlight the need to give CAR-T cells time to respond and that the correlation between peripheral blood CAR-T levels and activity can be disparate.

Keywords: Acute Lymphoblastic Leukemia; CART Therapy; Leukemia Cutis; Cytokine Release Syndrome

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.