The Equipoise Between the Treatment of Glioblastoma and the Risk of Secondary Acute Myelogenous Leukemia: An Illustrative Case Report

Abstract

We present a case report of a 56-year-old woman who was diagnosed with biopsy-proven left thalamic glioblastoma multiforme (GBM). She was treated with standard concurrent chemotherapy and radiation, as well as a 2-year period of adjuvant temozolomide. She relapsed 2 ½ years after starting her initial therapy and was treated with bevacizumab and lomustine, but she relapsed. She was then placed on a phase 1/2 clinical trial that included KHK2455 and mogamulizumab-kpkc individually and in combination for almost 4 years. She had a rapid demise due to the development of a neutropenic pneumonia and treatment-induced acute myeloid leukemia (AML) and elected for hospice care.

Introduction

Glioblastoma multiforme is the most common primary malignant brain tumor. The inclusion of the alkylating temozolomide (TMZ) chemotherapy was established by a randomized study examining postoperative radiotherapy (RT) versus postoperative RT plus TMZ chemotherapy. ¹ In this study, the addition of TMZ improved the median overall survival (OS) from 12.1 to 14.6 months. Further work from this study demonstrated that the majority of this benefit was obtained by patients with O⁶-methylguanine-deoxyribonucleic acid (DNA) methyl-transferase (MGMT) promoter methylation, establishing MGMT methylation as a strong predictor of benefit from alkylating chemotherapy. ² Since this trial’s publication in 2005, progress in GBM has been elusive. A single trial has shown a modest improvement in OS by the introduction of tumor-treating fields (TTFields, an antimitotic treatment) into the upfront management of GBM. ³ The median OS in the experimental arm was 20.5 versus 15.6 months in the standard arm. Numerous attempts at improving outcomes have failed to show benefit, including attempts at targeting epidermal growth factor receptor vIII (EGFRvIII) ⁴ and vascular endothelial growth factor inhibitors.^5,6

Standard therapy for relapsed glioblastoma multiforme (rGBM) patients includes focal therapies that include laser interstitial thermal therapy (LITT), RT, radiosurgery, surgery, and brachytherapy. Systemic treatment includes bevacizumab and lomustine, sometimes in combination, which may result in temporary control with a modest OS of approximately 10 months. In a retrospective analysis of 299 patients with rGBM, the median OS for all patients was 6.5 months, and median progression-free survival (excluding patients receiving best supportive care [BSC]) was 5.5 months. ⁷ Older age, tumor extent to multiple lobes, and steroid use were significantly associated with a shorter survival. In addition, 104 patients with rGBM undergoing systemic treatments had a significantly longer survival compared with patients receiving BSC (11 vs 3.1 months). In the REGOMA trial, 54 patients with rGBM received regorafenib 160 mg once daily for the first 3 weeks of a 4-week cycle. ⁸ The median OS was 10.2 months. Grade 3 drug-related adverse events occurred in 10 patients (18%); 1 patient (2%) reported a grade 4 adverse event.

A multicenter randomized phase 3 clinical trial which tested the safety and efficacy of treatment with nivolumab compared with bevacizumab following rGBM after RT and TMZ therapy revealed no significant difference in patient OS between these groups. ⁹ The median OS was 9.8 months for the nivolumab arm and 10 months in the bevacizumab group.

Case Report/Case Presentation

A 56-year-old woman presented with right face, arm, and leg weakness along with dysarthria. The magnetic resonance imaging (MRI) of the brain revealed a left thalamic mass, with subsequent biopsy demonstrating a GBM. The GBM was MGMT promoter hypermethylated, but negative for isocitrate dehydrogenase 1 or 2 mutations. She had no co-morbidities and was started on concurrent radiation and TMZ, followed by maintenance TMZ for 2 years. An MRI at that time showed 2 small enhancing lesions, and a repeat MRI 2 months later revealed 3 lesions. The patient was then started on bevacizumab 10 mg/kg every 2 weeks, but a repeat MRI 4 months later revealed progression of disease. Lomustine was added to the bevacizumab, but again there was evidence of disease progression 4 months later, so both drugs were discontinued. Five months later, the patient was entered into a phase 1/2 study with oral daily KHK2455 and intravenous mogamulizumab (initially weekly for cycle 1 and then every 2 weeks in subsequent cycles) (NCT02867007). This was a multicenter study, in which 36 patients with various types of metastatic cancers were given a stable dose of IV mogamulizumab (1 mg/kg) and an increasing dose of the KHK2455 (phase 1 part of the study: final dose was 10 mg daily by mouth). The data were presented as an abstract in 2018. ¹⁰ Serious KHK2455-related treatment-emergent adverse events (TEAEs) included gastrointestinal necrosis (KHK2455 monotherapy), and nausea and drug eruption (combination therapy). In addition, 5 drug-related TEAEs in combination therapy led to discontinuation of the study. Six of 36 evaluable patients from all dosing groups achieved durable disease stabilization (at 6 months), while our patient demonstrated a confirmed partial response (43.5% tumor reduction more than a 2-year observation period). ¹¹ Our patient was on the study for approximately 2 years and was doing well, so she was then placed on a single patient Investigational New Drug (IND) protocol (NCT04321694) with the same combination when the study closed. She continued on the protocol for approximately 2 more years. This timeline of events is displayed in Figure 1. Representative images of her brain MRIs are noted in Figure 2, where (1) demonstrates the mass at diagnosis, (2) is post concurrent TMZ and radiation, and (3) is her last brain MRI.

Figure 1.

Timeline of events and treatments.

Figure 2.

(A) Initial MRI (T2 FLAIR sequence) showing left thalamic lesion consistent with MGMT hypermethylated, IDH1/2 WT. (B) MRI was obtained after completion of concurrent chemoradiation with TMX, followed by maintenance TMZ. (C) Nodular foci of T2 hyperintensity that remained unchanged.

As treatment continued, the patient had increasingly frequent episodes of treatment being held, dropping down the doses, and Neupogen support for worsening neutropenia. Her functional status declined as well. She was then admitted to the hospital with pneumonia and neutropenic fever. Her white blood count was 5.5 × 10⁹/L; her hemoglobin was 10.7 gm/dL; and her platelet count was 67 × 10⁹/L. Her absolute neutrophil count was 0.3× 10⁹/L, and she was noted to have 4.7× 10⁹/L variant lymphocytes (61%) in the peripheral smear. Flow cytometry (Figure 3) of the peripheral blood demonstrated blasts comprising 67% of total events expressed (cluster differentiation, CD34, CD13, CD33, CD117, and Human Leukocyte Antigen-DR (HLA-DR), with CD64 dim and CD45 dim). A monocytic population comprised 26% of total events and expressed CD36, CD64, CD33, and CDHLA-DR, with major loss of CD14 (comprising 36% of total monocytes). The patient was diagnosed with AML with monocytic differentiation (Figure 3). The patient and her spouse declined therapy for the AML and she was discharged to hospice where she died shortly thereafter. She died at the age of 64 years, 8 years after being diagnosed with GBM.

Figure 3.

(A) Representative image of a monoblast (left) and immature monocyte (right), with fine chromatin, prominent nucleoli, and a small nuclear indentation. (Credit: Cho J. and Venkataraman, G. “Monoblast and immature monocytic cell in peripheral blood” ASH Image Bank, 7/5/2018). (B) Myeloid blasts (CD45 dim, red) are confirmed on flow cytometry and make up 67% of total events. (C) Monocytes (blue/purple) at all stages of maturation express high levels of CD36 and CD64. (D) As monocytes mature, they acquire increasing levels of CD14. This plot demonstrates a major immature population of monocytes (purple) that are lacking CD14.

Discussion

Mogamulizumab-kpkc (Poteligeo) is a humanized IgG1 kappa monoclonal antibody that binds to C-C chemokine receptor type 4 (CCR4), a G protein-coupled receptor for Cysteine-Cysteine (CC) chemokines that is involved in the trafficking of lymphocytes. CCR4 is expressed on the surface of some T-cell malignancies and is expressed on regulatory T cells (Treg) and a subset of Th2 T cells. It is Food and Drug administration (FDA) approved for the treatment of adult patients with relapsed or refractory mycosis fungoides or Sézary syndrome after at least 1 prior systemic therapy. ¹²

KHK2455 is an orally available inhibitor of indoleamine 2, 3-dioxygenase 1 (IDO1). Indoleamine 2, 3-dioxygenase 1 is an enzyme responsible for the oxidation of tryptophan into kynurenine. By inhibiting IDO1 and decreasing kynurenine in tumor cells, KHK2455 increases and restores the proliferation and activation of various immune cells, including dendritic cells (DCs), natural killer (NK) cells, and T-lymphocytes. KHK2455 also induces increased interferon (IFN) production and causes a reduction in tumor-associated regulatory T cells (Tregs). ¹³ There are preclinical data suggesting synergy between the 2 drugs. ¹¹

Treatment-related AML is relatively uncommon, due to the short OS of GBM patients and due to being exposed to TMZ or lomustine for 6 months to a year. In an old study of 28 patients with therapy-related leukemia in adult and pediatric brain tumor patients, there were 12 patients with malignant glioma; median interval from treatment to diagnosis of AML was 31 months. Nine adult malignant glioma patients all received nitrosoureas, some as the sole form of chemotherapy. No definite cases occurred after RT alone. ¹⁴

A more recent study in Japan estimated the rate of myelodysplasia and leukemia associated with TMZ-containing chemotherapy compared with nimustine (ACNU)-based therapy in 359 glioma patients between 1990 and 2009. ¹⁵ It should be noted that patients received 2 years of TMZ. The incidence rates of hematological malignancies per 1000 person-years were 2.9 cases in the ACNU-based group, 13.0 cases in the ACNU-TMZ group, and 9.9 cases in the TMZ-based group.

In a case report of 3 patients with high-grade gliomas, all patients were started on TMZ after having progressed following standard primary treatment. ¹⁶ These patients continued TMZ for 5, 7, and 8 years, respectively. As of publication, they had no serious side effects. The authors discussed the benefit these patients had and noted that none of them developed of secondary AML. Although the treatment was not “standard of care,” this small cohort of patients derived benefit in prolongation of length of life with prolonged TMZ use.

Our patient lived for almost 8 years after being diagnosed with GBM. As noted above, the average survival for patients with GBM is 14 to 20 months. The reason for her longevity is ultimately unknown, but we can consider the long time on TMZ, her MGMT promoter hypermethylation status, and her participation in the clinical trial as possibilities. Her quality of life was reasonable, although her performance status was less so, with dysarthria and weakness in her right arm and leg. During this time, she was exposed to 2 years of TMZ and 4 months of lomustine, both of which are alkylators. Mogamulizumab is reported to cause myelosuppression. Notably, this patient received this medication for approximately 4 years. The medication could have contributed to the development of the AML, or may have contributed to her living long enough to get AML, or both.

The clinical tension between OS and quality of life can be complimentary, indifferent, or in opposition to each other in patients receiving treatment for incurable cancers. This patient demonstrates a ~6-year prolongation of OS compared with historical controls and was on treatment for most of that time. When she was diagnosed with AML, it was a simple decision to pursue hospice care due to the futility of treating her leukemia. We propose that despite developing a secondary AML, she benefited from the aggressive therapy she received, as she had a relatively long length of life, and a good quality of life for most of the ~8 years. It should be noted that multiple randomized trials have shown minimal benefit of 6 versus 12 months of TMZ.^17-19 However, there are a number of institutions that treat their patient with 12 months of adjuvant TMZ.

The focus of treatment for GBM moving forward seems to be on vaccines and tumor immune environmental changing treatments and less on chemotherapy.

Conclusion

This case report is noteworthy for the patient’s extended survival despite her diagnosis of GBM. Patient was able to tolerate treatment that not only increased her survival but also impacted her quality of life.