Multidisciplinary Management of Endocrinopathies and Treatment-Related Toxicities in Patients with Bloom Syndrome and Cancer

Abstract

The treatment of malignancy in cancer predisposition syndromes that also confer exquisite sensitivity to standard chemotherapy and radiation regimens remains a challenge. Bloom syndrome is one such disorder that is caused by a defect in DNA repair, predisposing to the development of early-onset age-related medical conditions and malignancies. We report on two patients with Bloom syndrome who responded well to chemotherapy despite significant alterations to standard protocols necessitated by hypersensitivity. Both patients experienced severe toxicities and exacerbation of endocrine comorbidities during chemotherapy. A multidisciplinary team of oncologists and endocrinologists is best suited to care for this patient population.

INTRODUCTION

The current overall survival rate of over 80% for childhood cancer¹ has resulted from adherence to evidence-based, risk-stratified, standardized treatment protocols and a detailed understanding of the management of chemotherapy-induced toxicity. However, the treatment of cancer in patients with rare cancer predisposition syndromes such as Bloom syndrome (BS) that also confer exquisite sensitivity to the standard chemotherapy and radiation remains a challenge². BS is a rare autosomal recessive disorder that is caused by a loss of function mutation of the BLM gene encoding a RecQ helicase involved in DNA repair and maintenance of chromosomal stability. Defective BLM protein results in errors in replication with high levels of chromosomal rearrangement and breakage^3-5, giving rise to premature aging, early-onset age-related medical conditions, and a wide variety of malignancies early in life^6,7. In patients with BS, significant sensitivity to both DNA-damaging chemotherapy and ionizing radiation complicates the management of these neoplasms by exacerbating comorbidities and predisposing to toxicities and poor outcomes^2,6,8. Reported here is our multidisciplinary experience in managing metabolic derangements and treatment-induced toxicities in two patients with BS and cancer.

CASE 1

A 23-year-old male was diagnosed with BS during his first year of life by sister chromatid exchange (SCE) due to presentation with severe intrauterine growth retardation, characteristic facies and frequent infections. Despite his thin body habitus and young age, he developed type 2 diabetes mellitus (T2DM) at age 14 which was treated with metformin. Saxagliptin was added at age 22 for further optimization of blood glucose control. Other comorbidities included hypertriglyceridemia, severe vitamin D deficiency, hypertension, and hypogammaglobulinemia treated with fenofibrate, weekly high dose ergocalciferol, enalapril, and monthly intravenous immunoglobulin (IVIG), respectively. Body mass index (BMI) during his adult life ranged from 18-21 kg/m² and he had minimal subcutaneous fat.

At age 19, he had a transient episode of severe aplastic anemia of unknown etiology which was complicated by multisystem organ failure requiring dialysis and intubation. He recovered spontaneously with only supportive care, his blood counts including mean corpuscular volume (MCV) normalized within a period of 6 months and remained normal for 4 years.

At age 23, he presented with malaise, lymphadenopathy, and pancytopenia and was diagnosed with acute myeloid leukemia (AML) with myelodysplastic features. Due to BS chemosensitivity, anthracyclines and topoisomerases were avoided and he received a modified Capizzi induction regimen consisting of four doses of cytarabine (ARA-C) reduced by 80%, followed by full-dose asparaginase. Induction was complicated by prolonged febrile neutropenia, severe mucositis, pulmonary edema, and a severe, diffuse desquamating drug rash secondary to ARA-C requiring a prolonged steroid taper. His pre-existing T2DM was exacerbated by steroid-induced hyperglycemia, requiring addition of basal insulin glargine and pre-meal insulin lispro adjusted based on self-monitored blood glucose (SMBG) readings for target levels of 80-140 mg/dl. After prolonged steroid therapy, he developed secondary adrenal insufficiency (AI) necessitating daily physiologic replacement with hydrocortisone for the remainder of his life. He developed severe exacerbation of hypertriglyceridemia (2600 mg/dl, reference range 0-150 mg/dl) likely secondary to asparaginase toxicity, necessitating discontinuation of saxagliptin due to risk of pancreatitis, escalation of fenofibrate dose, and initiation of omega-3 ethyl ester, atorvastatin, and enoxaparin thromboprophylaxis. Triglycerides remained acutely elevated above 500 mg/dl for several months.

Despite significantly reduced-dose AML induction chemotherapy, he achieved complete remission by morphology, cytogenetics, and fluorescence in-situ hybridization. Given severe toxicity to ARA-C, a five-day course of low dose clofarabine was initiated as second induction. He developed rapid onset of fever, severe drug rash, pancytopenia, and pulmonary edema within hours of the first dose, so the decision was made to discontinue all therapy and forego bone marrow transplantation due to the overwhelming risk of morbidity and mortality. After seven months in remission, he developed isolated bone marrow relapse and was treated with palliative chemotherapy at metronomic dosing to limit toxicity and prolong his life. Ultimately, thirteen months after relapse, he died from pneumonia complicated by septic shock and acute respiratory distress syndrome (Figure 1A).

FIGURE 1.

Timeline of endocrine and oncologic events. (A) Case 1; (B) Case 2. T2DM, type 2 diabetes mellitus; secondary AI, secondary adrenal insufficiency; AML, acute myeloid leukemia; HPA axis, hypothalamic-pituitary-adrenal axis; HR-ALL, high risk acute lymphoblastic leukemia; 6-MP, 6-mercaptopurine; ARA-C, cytarabine; DI, delayed intensification; NAFLD, non-alcoholic fatty liver disease

CASE 2

A 24-year-old female was diagnosed with BS by SCE in early childhood due to failure-to-thrive, characteristic facies, and frequent infections. Her comorbidities included T2DM, hyperlipidemia, hypertriglyceridemia, hypothyroidism, hypogammaglobulinemia, non-alcoholic fatty liver disease (NAFLD), severe vitamin D deficiency, vitamin B12 deficiency, recurrent sinusitis, recurrent urinary tract infections, and asthma. During monthly IVIG, she was premedicated with hydrocortisone which significantly exacerbated her hyperglycemia (SMBG > 500 mg/dl). Her T2DM was managed with metformin and glimepiride with sliding scale insulin lispro as needed for steroid induced hyperglycemia. Other medications included omega-3 ethyl ester, levothyroxine, weekly high dose ergocalciferol, montelukast and albuterol. Her BMI during her adult life ranged from 23-26 kg/m².

She presented with pancytopenia at age 13 and was diagnosed with high-risk pre-B cell acute lymphoblastic leukemia (ALL). She was treated with modified standard risk therapy despite her high-risk disease in order to avoid anthracyclines and alkylating agents, with significant dose reductions of most other chemotherapeutic agents except for steroids and asparaginase. Attempts to dose-escalate vincristine beyond 40% were limited due to development of severe neuropathic pain, diffuse numbness, tinnitus and temporary hearing loss. At the end of a modified standard-risk induction, she was in complete minimal residual disease (MRD) negative remission. She developed adrenal insufficiency secondary to steroid withdrawal after induction requiring physiologic steroid replacement throughout therapy and long-term stress dosing upon partial recovery of her hypothalamic-pituitary-adrenal (HPA) axis. Consolidation, which included reduced dose ARA-C, 6-mercaptopurine and full-dose asparaginase, was complicated by early pancytopenia, febrile neutropenia and pneumonia necessitating frequent dose interruptions as well as severe hypertriglyceridemia (>6000 mg/dl) treated with fenofibrate and enoxaparin thromboprophylaxis. The second half of consolidation and delayed intensification were withheld. Maintenance cycles were modified due to prolonged neutropenia, and maintenance therapy was ultimately discontinued after 2.3 years of total therapy due to significant toxicity. Despite these significant alterations to her chemotherapy, she remains in remission 11 years from diagnosis (Figure 1B).

DISCUSSION

BS is a rare genetic disorder caused by a mutation in BLM, the gene encoding the BLM helicase^9-11. It is characterized by growth retardation, immunodeficiency, early development of age-related comorbidities, predisposition to early and varied cancers, and increased sensitivity to drug toxicity^6,7,11,12. Like BS, trisomy 21 is a chromosomal disorder that predisposes individuals to malignancy and chemosensitivity. However, due to the persistence of the mutation in the cancer cells, patients with Down syndrome are known to have improved outcomes and increased disease-free survival with reduced doses of chemotherapeutic agents¹³. Similarly, we hypothesize that just as the mutated BLM helicase predisposes patients with BS to developing malignancies and treatment-related toxicities, the cancer cells also contain the mutated BLM helicase which augments susceptibility to treatment and likely underlies the robust response that we observed in our patients with significantly reduced chemotherapy dosing.

Many patients with BS who were treated with standard chemotherapy suffered significant or fatal toxicities^14-17. Others received various dose modifications and reductions which in most cases reduced toxicity, and in some successfully induced remission^18-22. We report on two patients with BS who were treated for leukemia with markedly reduced-intensity regimens and achieved remission, one of whom with a disease-free survival of currently greater than 11 years. Based on our experience with these patients, we propose several principles to consider when designing a treatment regimen. As was done successfully with our patients, we recommend avoidance of the use of alkylating agents, topoisomerases and anthracyclines due to the risks of secondary malignancy and cardiotoxicity. Additionally, significant dose reductions ranging from 20-60% of typical dosing of many of the other chemotherapeutic agents allowed for tolerable toxicities in our patients throughout treatment with remission induction in our patient with AML and long-term remission in our patient with ALL. We recommend starting at lower doses and escalating as tolerated, with close monitoring for toxicity as further dose modifications may be required in order to complete therapy.

Another interesting feature of BS is the tendency to develop an unusually high number of severe endocrinopathies at a much younger age and lower BMI than in the general population^12,23,24. T2DM, dyslipidemia, and hypothyroidism¹¹ are endocrinopathies that are classic in BS and were diagnosed in our patients. Others included adrenal insufficiency, NAFLD, and vitamin D and B12 deficiency. These comorbidities contribute to increased sensitivity to drug toxicity in these patients, further complicating oncologic management. During treatment, both patients experienced adrenal insufficiency requiring physiologic steroid replacement, as well as severe exacerbation of hypertriglyceridemia with administration of asparaginase. In case 1, steroids used to treat a drug rash caused by ARA-C exacerbated the patient’s underlying hyperglycemia, necessitating adjustment of his diabetes regimen. Glycosylated hemoglobin A1c (HbA1c) was rendered unreliable in the setting of anemia and transfusions, however we were able to adjust insulin using SMBG readings with good results.

With respect to diabetes management, meta-analyses of observational and cohort studies have suggested that metformin may be associated with a reduced risk of developing cancer and improved survival rates in certain cancers through proposed anti-inflammatory and hypoglycemic effects, as well as through its inhibitory action on the mammalian target of rapamycin (mTOR) pathway. However, the data remains controversial and clinical trials have yet to validate its use as adjuvant therapy^25-28. Since both of our patients were taking metformin during chemotherapy, it may theoretically have potentiated the chemotherapeutic effects of the standard drugs that they received. Further studies on the use of metformin in BS patients and impact on cancer risk and treatment are warranted.

As these cases demonstrate, patients with BS are predisposed to develop early-onset malignancies and are highly sensitive to chemotherapy and radiation, which presents challenges during chemotherapy. Successful management of these patients requires careful modification of standard chemotherapy and supportive care regimens and good endocrine control. A multidisciplinary approach in collaboration with endocrinology is recommended in light of the unusually high number of severe endocrine complications in this young patient cohort. The favorable results in these two patients strongly support the creation of a national/international treatment protocol for patients with BS and cancer designed to capture efficacy and treatment-related side effects in a way that can improve upon the knowledge gained from these two case reports.

TABLE 1.

Patient demographic, anthropometric, and laboratory data

	Reference Range	Case 1	Case 2
Demographic Data
Gender	-	Male	Female
Ethnic Background	-	Ashkenazi Jewish	Ashkenazi Jewish
Anthropometric Data
Height (cm)	-	143.2 – 147.5	134.6 – 138.6
Weight (kg)	-	39.1 – 44.8	44.4 – 48.9
BMI (kg/m2)	18.5 – 24.9	18.5 – 21.1	23.7 – 26.5
Laboratory Data
HbA1c (%)	< 5.7	4.9 - 6.5	6.1 - 7.3
Hb (g/dL)	M: 13.0 – 17.0 F: 11.5 – 15.5	7.4 – 15.8	10.9 – 12.4
Hct (%)	M: 39.0 – 50.0 F: 34.5 – 45.0	20.0 – 43.0	33.0 – 37.0
Triglyceride (mg/dL)	10 - 149	462 – 2600	140 – 6000
Cholesterol (mg/dL)	120 – 199	124 - 270	162 - 297
HDL (mg/dL)	35 – 55	15 - 46	30 - 95
LDL (mg/dL)	70 – 100	27 - 60	83 - 157
Vitamin D 25-OH (mg/dL)	30.0 – 100.0	11.8 – 33.7	13.0 – 36.0
TSH (uIU/mL)	0.20 – 4.20	0.52 – 3.98	0.95 – 3.36
Total T4 (ug/dL)	5.10 – 13.00	5.16 – 13.75	5.15 – 9.62
Free T4 (ng/dL)	0.90 – 1.80	1.23	0.94 – 1.50
AM Cortisol* (ug/dL)	2.3 – 19.4	8.4 – 24.6	5.5 - 33.2
Vitamin B12 (pg/mL)	232 – 1245	261	237 - 593

BMI: body mass index; HBA1c: Glycosylated HbA1c; Hb: Hemoglobin; Hct: Hematocrit; HDL: high density lipoprotein; LDL: low density lipoprotein; TSH: thyroid stimulating hormone; T4: thyroxine

All endocrine values are presented as ranges (from lowest to highest) at different time-points for case 1 and case 2. Values without a range were only evaluated once.

^*The range implies cortisol values tested at various time-points. The hypothalamic-adrenal axis recovered at different time points during the disease/treatment course after prolonged steroid taper. When values persistently remained low, patient was diagnosed with secondary adrenal insufficiency dependent on physiologic steroid replacement.

Abbreviations Key:

BS

Bloom syndrome

SCE

Sister chromatid exchange

T2DM

Type 2 diabetes mellitus

IVIG

Intravenous immunoglobulin

BMI

Body mass index

MCV

Mean corpuscular volume

AML

Acute myeloid leukemia

ARA-C

Cytarabine

SMBG

Self-monitored blood glucose

AI

Adrenal insufficiency

NALFD

Non-alcoholic fatty liver disease

ALL

Acute lymphoid leukemia

MRD

Minimal residual disease

HPA

Hypothalamic-pituitary-adrenal

HbA1c

Glycosylated hemoglobin A1c

mTOR

Mammalian target of rapamycin

Data Availability:

The chemotherapeutic doses that were used in these patients are available from the corresponding author upon reasonable request.