Acute myeloid leukemia post cytotoxic therapy following medulloblastoma in a child successfully treated with a single cycle of CPX-351 followed by stem cell transplantation – a case report

doi:10.21203/rs.3.rs-8330941/v1

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Case Report

Acute myeloid leukemia post cytotoxic therapy following medulloblastoma in a child successfully treated with a single cycle of CPX-351 followed by stem cell transplantation – a case report

https://doi.org/10.21203/rs.3.rs-8330941/v1

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Secondary malignancies are significant complications of childhood cancer treatment. In the pediatric population, their incidence ranges from 3% to 12%, varying based on the primary cancer type and treatment modalities used. Long-term monitoring of childhood cancer survivors facilitates early detection of secondary cancer. The most common secondary malignancy in childhood is acute myeloid leukemia post cytotoxic therapy (AML-pCT). The treatment of AML-pCT is challenging, as the cumulative cytostatic dose (especially anthracyclines) used in the previous therapy and the often already impaired regenerative capacity of the bone marrow and other organ dysfunction should be taken into account. The prognosis of AML-pCT is poorer than AML de novo with the worst outcome in patients with AML following brain tumors as the primary malignancy. Here we present a patient who developed secondary acute myeloid leukemia after completing therapy for medulloblastoma and was successfully treated with a single cycle of liposomal daunorubicin/cytarabine (CPX-351, Vyxeos) followed by hematopoietic stem cell transplantation.

acute myeloid leukemia post cytotoxic therapy

secondary malignancy

medulloblastoma

children

liposomal daunorubicin/cytarabine (CPX-351/Vyxeos)

hematopoietic cell transplantation

Cancer treatment carries the risk of serious long-term toxicities. One of them is therapy-related secondary malignancy, with the most common in childhood being acute myeloid leukemia post cytotoxic therapy (AML-pCT), previously referred to as therapy-related acute myeloid leukemia (t-AML). Exposure to alkylating agents, epipodophyllotoxins, stem cell transplantation, radiation therapy, and genetic predispositions can contribute to the development of myelodysplastic syndrome post cytotoxic therapy and AML-pCT [1, 2], which are included in the category of myeloid neoplasms post cytotoxic therapy (MN-pCT) in the recent World Health Organization (WHO) classification 2022 [3].

In pediatric cases, AML-pCT is most frequently associated with prior treatment for acute lymphoblastic leukemia, osteosarcoma, Ewing sarcoma, Hodgkin and non-Hodgkin lymphomas, neuroblastoma, rhabdomyosarcoma, and brain tumors [1, 4].

Treatment for AML-pCT is a great challenge considering complications from prior therapy and cumulative doses of chemotherapeutic agents (anthracyclines in particular), and prognosis is worse compared to de novo AML [1, 4].

Most treatment protocols for AML-pCT currently recommend double induction chemotherapy followed by allogeneic stem cell transplantation [5]. Recent studies revealed that a liposomal formulation containing daunorubicin and cytarabine in a 1:5 molar ratio (CPX-351/Vyxeos) may be successfully used in secondary AML treatment in adults [6, 7, 8]. There is limited data on CPX-351 usage on children with secondary AML [9], however, its safety and effectiveness were shown in relapsed pediatric AML [10].

Here, we present a case report of a child who developed AML-pCT following treatment of medulloblastoma and was successfully treated with a single cycle of CPX-351 followed by hematopoietic stem cell transplantation (HSCT).

A 3-year-old male was diagnosed with anaplastic medulloblastoma, large cell WHO IV, non-WNT/non-SHH with metastases to the pontocerebellar angle and to the spinal cord. After the partial tumor resection of the cerebellum, the patient underwent two cycles of chemotherapy with vincristine + etoposide + carboplatin and etoposide + ifosfamide + cisplatin, followed by salvage radiotherapy (total dose: 5400 cGy) of the brain and spinal cord. This led to an improvement of the patient’s neurological condition. Follow-up imaging after radiotherapy showed regression of metastases in the spinal cord, a residual neoplastic lesion in the posterior cranial fossa, and a stable status of the pontocerebellar angle. The patient underwent eight cycles of chemotherapy after radiotherapy utilizing vincristine, lomustine, and cisplatin. Cumulative doses of chemotherapy used in the treatment of medulloblastoma are presented in Table 1.

Table 1

Cumulative doses of chemotherapy used in the treatment of medulloblastoma
Chemotherapy	Cumulative dose mg/m²
Vincristine	37.5
Etoposide	600
Carboplatin	1000
Ifosfamide	4500
Lomustine	525
Cisplatin	700

The treatment was completed 16 months from diagnosis. There was no tumor recurrence or progression in a follow-up MRI. The patient was monitored to early recognize long-term toxicities and was diagnosed with secondary hypothyroidism. About 6 months after the treatment completion, the patient achieved a complete hematopoietic recovery.

Almost 5 years after the medulloblastoma diagnosis, the gradual deterioration in the patient’s complete blood count was observed (Fig. 1). The patient was admitted to the hospital with pancytopenia – hemoglobin: 79 g/l, leukocytes: 1340/µL, neutrophils: 300/µL and platelets: 51000/µL. A bone marrow biopsy was performed and revealed a population of myeloblasts (approximately 7%) with an abnormal immunophenotype, features of dysgranulopoiesis, and dyserythropoiesis, which led to MDS-pCT diagnosis. HLA typing of the patient, parents, and siblings was conducted, identifying an HLA-matched sibling donor.

Two weeks later, a trephine biopsy and bone marrow biopsy were performed. Myelogram revealed 28% leukemic blasts. The histological findings strongly suggested a neoplastic bone marrow disorder with pronounced features of myelodysplasia and evolving acute marrow myeloid leukemia of monocytic lineage. Molecular diagnostics revealed mutations in the NPM1 gene. No other genetic abnormalities were found in cytogenetic and molecular genetic analysis. AML-pCT was diagnosed.

The cerebrospinal fluid analysis and magnetic resonance of the brain did not show central nervous system involvement. Intrathecal cytarabine and methotrexate were given as a prophylaxis of central nervous system involvement. The patient received 3 doses of CPX-351 (liposomal cytarabine 120 mg/m² plus daunorubicine 53 mg/m²) on days 1, 3, and 5 of the cycle. It was complicated by an erythematous-hemorrhagic rash, prolonged pancytopenia, inflammation of the mastoid processes, and oral mucositis.

A follow-up bone marrow aspirate 4 weeks after CPX-351 administration revealed hypocellular bone marrow with a blast count of 0.5% and MRD-FC < 0.1%. Complete remission with partial hematological recovery was recognized.

The patient proceeded to HSCT. Conditioning with treosulfan, fludarabine, and thiotepa (TreoFluTT) was used. A stem cell product derived from bone marrow of an HLA-matched sibling donor (brother) was transfused, delivering 4.5 × 10^6 CD34 + cells/kg of body weight. During the early post-transplant period, grade III gastrointestinal mucositis (WHO) and acute cutaneous GvHD grade IIc occurred. Engraftment, defined as ANC > 500/µL and WBC > 1000/µL, was achieved on day + 20 following G-CSF administration. The platelet count remained above 20,000/µL from day + 24. The patient was discharged in good general condition on day + 28 after transplantation, with recovery of hematopoiesis.

After two years of follow-up from AML-CT diagnosis, the patient remained in remission without any signs of disease recurrence and with complete hematopoietic recovery. Chronic post-transplant toxicities persisted, including stable mild renal impairment and hypertension controlled with one hypotensive drug.

As the number of pediatric cancer survivors continues to rise due to improvements in pediatric malignancies outcomes, there is a growing concern about long-term toxicities, including AML-pCT among children and adolescents. The probability of secondary malignancy occurrence is influenced by several factors, such as the specific cytostatic agents administered and their dosages, the patient's genetic predisposition, and other existing risk factors [11].

The interval between the initial diagnosis requiring chemotherapy and/or radiotherapy and the onset of AML-pCT varies widely, ranging from several months to many years. Notably, approximately 50% of childhood AML-pCT occurs within two to five years following their initial diagnosis [12]. In the described case, the time span between the diagnosis of medulloblastoma and AML-pCT was 5 years.

The prognosis for AML-pCT is notably poorer than that of de novo AML [1, 4, 12]. Brown et al. reported a 5-year overall survival rate of 31% for AML-pCT patients, compared to the 77% for all childhood acute myeloid leukemia cases in Australia [12]. It is caused mainly by the detrimental effects of previous cytotoxic treatments on bone marrow and other organ functions. Furthermore, chronic immunosuppression heightens vulnerability to infections, complicating the therapeutic approach [4]. Many authors agree that poorer outcomes in AML-pCT compared to de novo AML may be the result of the higher rate of deaths from toxicities [4, 13]. The report from Polish Pediatric Leukemia and Lymphoma Study Group (PPLLSG) revealed that the rate of early deaths and deaths in remission was significantly higher in patients with AML-pCT compared to de novo AML (12.5% and 7.5% vs 6% and 1.5%) [4]. AML secondary to brain tumors exhibits the most unfavorable prognosis (5-year OS 6–25%) compared to cases following systemic malignancies (5-year OS 37–59%) and other solid tumors (5-year OS 28–58%), primarily due to long-term toxicities of the first malignancy treatment observed commonly in that group of patients [1, 4]. Taking into account the risk of life-threatening toxicities in the described patient, it was decided to use CPX-351 considered as more tolerable and effective.

Specific data on AML post-medulloblastoma are limited. The studies on AML-pCT do not show treatment results separately for each type of the preceding malignancy. Waack et al. reported 5-year OS of 6 ± 6% in the group of 14 patients with AML post brain tumors, including 6 patients with medulloblastoma as a primary malignancy [1]. The data from PPLLSG showed 3-year OS of 25 ± 20% in 8 patients with AML following brain tumor, including 6 children with medulloblastoma [4]. The single-center study published by Cho et al. included only one patient with AML post brain tumor (histopathology was not specified), he was treated successfully [13]. There are a few case reports concerning medulloblastoma followed by AML. Mak LS, et al. described three cases of pediatric medulloblastoma who developed therapy-related myeloid neoplasms. The latency period between medulloblastoma diagnosis and the development of secondary cancer ranged from 17 to 65 months. All three patients eventually died from secondary malignancy, therapy-related complications, and progression of primary disease, respectively [14]. Karaki et al. reported a 13-years old patient who developed secondary AML in the course of the treatment of the third relapse of medulloblastoma. The girl achieved AML remission with FLAG-venetoclax chemotherapy; however, progression of medulloblastoma was observed [15]. The mentioned data indicates a poor prognosis of AML secondary to medulloblastoma.

In the past, there was no specific recommendation for AML-pCT, so the patients were treated according to the standard AML protocols (double induction chemotherapy followed by two consolidation cycles prior to HSCT) with poor outcomes [4]. Taking into account the high risk of both the therapy-related toxicities and relapse, currently double induction chemotherapy or individualized therapy followed by HSCT in complete remission (CR), CR with partial regeneration, or at least aplasia with no evidence of leukemia are recommended in most patients with AML-pCT [1, 5]. The patient described here received a single induction chemotherapy. Considering the favorable treatment response with negative MRD, the availability of a donor, and concerns about the potential toxicities of an additional chemotherapy cycle, it was decided to proceed with HSCT after the first induction cycle.

Cho et al. demonstrated that patients in remission prior to transplantation exhibit higher survival rates. Notably, approximately half of those with persistent disease also benefited from the procedure. These suggest that early preparation for HSCT following a diagnosis of AML-pCT improves survival in pediatric patients [13].

One of the drugs recently approved by the FDA for the treatment of pediatric patients aged ≥ 1 year with newly diagnosed, therapy-related acute myeloid leukemia or patients with AML-MRC was Vyxeos. It was first approved by the FDA in 2017 and by the EMA in 2018 for the treatment of adults with newly diagnosed AML-pCT or acute myeloid leukemia with myelodysplasia-related changes (AML-MRC) [6, 16, 17]. Currently, CPX-351 is not registered for pediatric use in Europe. The COG study (NCT02642965) carried out in 38 patients > 1 and ≤ 21 years of age with relapse/refractory AML showed efficacy and controllable toxicity of Vyxeos [10]. However, a phase 3 randomized COG trial for pediatric patients with de novo AML comparing standard therapy including gemtuzumab ozogamicin (GO) to CPX-351 with GO revealed that outcomes for high risk patients were comparable for both arms, whereas EFS was significantly lower and relapse rates higher for low-risk patients treated with CPX-351 compared to standard chemotherapy [18]. The data on treating pediatric patients with secondary myeloid malignancies with CPX-351 is limited. In the retrospective case series study of Hu et al., 7 pediatric patients (6 with newly diagnosed sMDS/AML and 1 with primary MDS/AML) were treated with CPX-351. In all patients, morphologic remission was achieved. Between 0.5 and 3.3 years following HSCT, six individuals were alive and free of leukemia (one patient died due to progression of the disease before the bone marrow transplant). There were no serious adverse effects nor death due to the treatment [9]. Among those 7 patients, 3 children received a single CPX-351 cycle before HSCT. However, one patient with Cornelia de Lange syndrome and AML-MRC received also gilteritinib, and in one with AML-MRC CPX-351 cycle was followed by venetoclax with decitabine before HSCT. The only one patient in that study (with AML post-neuroblastoma) was treated with a single CPX-351 cycle followed directly by HSCT [9], similarly as in the case presented here. There is ongoing St. Jude Children's Research Hospital trial with Vyxeos for the patients < 22 years with secondary myeloid neoplasms (NCT05656248).

AML following brain tumors as the primary malignancy is characterized by a very high risk of life-threatening toxicities and the poorest outcome among childhood AML-pCT. We presented the patient with AML secondary to medulloblastoma who was successfully treated with a single cycle of CPX-351 followed by HSCT. It seems that patients with AML-pCT with a good response (negative MRD) after a single induction cycle, high risk of toxicities, and available donor may proceed directly to HSCT.

No funding was received for conducting this study.

The authors have no relevant financial or non-financial interests to disclose.

Patient consent: Written informed for publication was obtained from the patient’s parents.

Ethics declaration: not applicable.

Author contributions: BF and MB: collected clinical data, drafted original manuscript, contributed equally to this article. WC, KG, SS, JG: managed patient treatment, collected clinical data, reviewed manuscript. MC: conceptualized the study, managed patient treatment, critically reviewed and modified the article.

All the authors critically reviewed and revised the manuscript.

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No competing interests reported.

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Acute myeloid leukemia post cytotoxic therapy following medulloblastoma in a child successfully treated with a single cycle of CPX-351 followed by stem cell transplantation – a case report

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