Intrathecal alemtuzumab: a potential treatment of refractory leptomeningeal T-cell prolymphocytic leukemia

Alsawah, Fares; Benitez, Lydia; Choi, Sarah M.; Marini, Bernard L.; Skyles, Amy J.; Burke, Patrick W.; Pettit, Kristen; Crouch, A. D.; Fox, Heather; Bixby, Dale

doi:10.1182/bloodadvances.2019000289

Cited by 9 publications

(6 citation statements)

References 12 publications

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“…More studies, however, are needed to determine whether prolonged CNS CD5-IL15/IL15sushi CAR T cells could be beneficial as a mechanism to prevent relapse or would instead be detrimental due to increased risk of uncontrolled growth. If the need to eradicate the CNS CD5-IL15/IL15sushi CAR T cells emerges, intrathecal CAMPATH and/or rituximab may be safe in limited doses [ 30 , 31 ], although the efficiency of these antibodies in depleting CAR T cells in the CNS is unknown.…”

Section: Discussionmentioning

confidence: 99%

Treatment of Aggressive T Cell Lymphoblastic Lymphoma/leukemia Using Anti-CD5 CAR T Cells

Feng

Cinquina³

et al. 2021

Stem Cell Rev and Rep

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While treatment for B-cell malignancies has been revolutionized through the advent of CAR immunotherapy, similar strategies for T-cell malignancies have been limited. Additionally, T-cell leukemias and lymphomas can commonly metastasize to the CNS, where outcomes are poor and treatment options are associated with severe side effects. Consequently, the development of safer and more effective alternatives for targeting malignant T cells that have invaded the CNS remains clinically important. CD5 CAR has previously been shown to effectively target various T-cell cancers in preclinical studies. As IL-15 strengthens the anti-tumor response, we have modified CD5 CAR to secrete an IL-15/IL-15sushi complex. In a Phase I clinical trial, these CD5-IL15/IL15sushi CAR T cells were tested for safety and efficacy in a patient with refractory T-LBL with CNS infiltration. CD5-IL15/IL15sushi CAR T cells were able to rapidly ablate the CNS lymphoblasts within a few weeks, resulting in the remission of the patient’s lymphoma. Despite the presence of CD5 on normal T cells, the patient only experienced a brief, transient T-cell aplasia. These results suggest that CD5-IL15/IL15sushi CAR T cells may be a safe and useful treatment of T-cell malignancies and may be particularly beneficial for patients with CNS involvement.Graphical Abstract

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Section: Discussionmentioning

confidence: 99%

Treatment of Aggressive T Cell Lymphoblastic Lymphoma/leukemia Using Anti-CD5 CAR T Cells

Feng

Cinquina³

et al. 2021

Stem Cell Rev and Rep

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“…To the best of our knowledge, this is the first report of a case in which the efficacy and tolerance to intrathecal alemtuzumab injections were evaluated. In a previous report by Alsawah et al, the authors claimed successful treatment with 3 mg of intrathecal alemtuzumab for CNS involvement that was refractory to prior treatment with intrathecal cytarabine and methotrexate and whole brain irradiation [ 7 ]. However, when intrathecal alemtuzumab administration was initiated in their case, the patient's CSF leukemic cell count was 1 μ L, limiting the evaluation of the treatment efficacy.…”

Section: Discussionmentioning

confidence: 99%

Treatment of T-Cell Prolymphocytic Leukemia with Central Nervous System Involvement Using Intrathecal Alemtuzumab Administration

Mori

Oshima

Kimura

et al. 2020

Case Reports in Hematology

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T-cell prolymphocytic leukemia (T-PLL) is a rare hematologic cancer with a dismal prognosis. Although a small number of patients have central nervous system (CNS) involvement, a standard treatment approach for these patients has not been established. Herein, we present a case of T-PLL with CNS involvement that was treated with a higher dose of intrathecal alemtuzumab than that previously reported. A 66-year-old man who had T-PLL with CNS involvement was admitted to our hospital. Intravenously administered alemtuzumab, a monoclonal antibody against the CD52 antigen, successfully reduced leukemia cells in peripheral blood; however, intrathecal treatment with methotrexate, cytarabine, and prednisone had a limited effect on the CNS involvement. Therefore, we intrathecally injected alemtuzumab as an experimental treatment. Although we escalated the dose of intrathecal alemtuzumab up to 5 mg, no adverse reaction was noted; however, this treatment did not completely clear the leukemia cells from the patient’s cerebrospinal fluid (CSF). We performed whole brain and whole spinal irradiation therapies and subsequently performed allogeneic transplantation from a human leukocyte antigen-matched sibling donor with a conditioning regimen containing total body irradiation. At 21 days after transplantation, leukemia cells remained in his CSF. Although intrathecal alemtuzumab did not eliminate the CNS-invading leukemia cells, it was well-tolerated in our case. Further accumulation of similar cases is needed to determine the benefits and safety of intrathecal alemtuzumab administration.

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“…With all other options exhausted, we attempted elimination of CSF circulating CAR T cells by intrathecal administration of alemtuzumab. 13 The symptoms markedly improved, and CSF CAR T DNA became undetectable (Figure 1C). Intrathecal alemtuzumab was stopped after 4 applications (cumulative dose, 10 mg).…”

Section: Case Presentationmentioning

confidence: 99%

Fatal late-onset CAR T-cell–mediated encephalitis after axicabtagene-ciloleucel in a patient with large B-cell lymphoma

et al. 2021

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Treatment with CD19-directed CAR T cells has evolved as a standard of care for multiply relapsed or refractory large B-cell lymphoma (r/r LBCL). A common side effect of this treatment is the immune-effector cell-associated neurotoxicity syndrome (ICANS). Severe ICANS can occur in up to 30-40% of patients treated with axicabtagene ciloleucel (axi-cel), usually within the first 4 weeks post dosing, and usually responding well to steroids. Here, we describe a case of progressive central neurotoxicity occurring 9 months post axi-cel in a patient with r/r LBCL having undergone a prior alloHCT. Despite extensive systemic and intrathecal immunosuppression neurological deterioration was inexorable and eventually fatal within 5 months. High CAR T cell DNA copy numbers and higly elevated levels of IL-1 and IL-6 were found in the CSF as clinical symptoms emerged, and CAR T cell brain infiltration was observed on autopsy, suggesting that CAR T cells played a major pathogenetic role. This case of unexpected devastating late neurotoxicity warrants intensified investigation of neurological off-target effects of CD19-directed CAR T cells and highlights the need for continuous monitoring for late toxicities in this vulnerable patient population.

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Intrathecal alemtuzumab: a potential treatment of refractory leptomeningeal T-cell prolymphocytic leukemia

Abstract: Key Points This is the first report of successful treatment of therapy-resistant leptomeningeal T-PLL with intrathecal alemtuzumab. Intrathecal alemtuzumab is a potentially safe and efficacious therapeutic alternative for treatment of leptomeningeal T-PLL.

Cited by 9 publications

References 12 publications

Treatment of Aggressive T Cell Lymphoblastic Lymphoma/leukemia Using Anti-CD5 CAR T Cells

Treatment of Aggressive T Cell Lymphoblastic Lymphoma/leukemia Using Anti-CD5 CAR T Cells

Treatment of T-Cell Prolymphocytic Leukemia with Central Nervous System Involvement Using Intrathecal Alemtuzumab Administration

Fatal late-onset CAR T-cell–mediated encephalitis after axicabtagene-ciloleucel in a patient with large B-cell lymphoma

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