Funding for this publication for Joshua A Levine is from Northwestern University, Department of Medicine, Physician Scientist Training Program Grant

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1 AACE Clinical Case Reports Rapid Electronic Articles in Press Rapid Electronic Articles in Press are preprinted manuscripts that have been reviewed and accepted for publication, but have yet to be edited, typeset and finalized. This version of the manuscript will be replaced with the final, published version after it has been published in the print edition of the journal. The final, published version may differ from this proof. Case Report ACCR A CASE OF ACUTE MYELOID LEUKEMIA ASSOCIATED LEUKOCYTIC HYPOPHYSITIS PRESENTING WITH CENTRAL DIABETES INSIPIDUS Joshua A. Levine MD PhD 1 ; Ashley Pariser MD 2 ; Eve Bloomgarden MD 1 From: 1 Northwestern University Feinberg School of Medicine, Division of Endocrinology, Metabolism, and Molecular Medicine; 2 Yale University School of Medicine, Yale Cancer Center Running Title: AML associated central diabetes insipidus Corresponding address: Eve Bloomgarden Northwestern University Feinberg School of Medicine Division of Endocrinology, Metabolism, and Molecular Medicine 645 N Michigan Ave Suite 530 Chicago, IL, eve.bloomgarden@nm.org Conflict of Interest: The authors have no conflicts of interest. Funding for this publication for Joshua A Levine is from Northwestern University, Department of Medicine, Physician Scientist Training Program Grant Joshua A Levine and Ashely Pariser contributed equally to this publication

2 Abstract Objective Central diabetes insipidus is a rare complication of acute myeloid leukemia and myelodysplastic syndrome. There are fewer than 100 cases report in the literature. To date there are no published case reports in the endocrinology literature. We report a case of myelodysplastic syndrome transformed to secondary acute myeloid leukemia that was complicated by central diabetes insipidus. Methods We detail the course of a 65-year-old female who presented with central diabetes insipidus in the setting of acute myeloid leukemia. Results The patient s central diabetes insipidus was successfully controlled with desmopressin. As her disease was treated, her central diabetes insipidus resolved. Conclusion This case highlights an important association between acute myeloid leukemia, myelodysplastic syndrome, and central diabetes insipidus. To our knowledge, this is the first published case in the endocrinology literature of central diabetes insipidus secondary to acute myeloid leukemia. Abbreviations: CDI = central diabetes insipidus; AML = acute myeloid leukemia; MDS = yelodysplastic syndrome; NPO = nothing by mouth; MRI = magnetic resonance imaging; ddavp = desmopressin; ASP2215 = gilteritinib. Introduction Central diabetes insipidus (CDI) is a rare complication of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) with less than 100 cases reported in the hematologic/oncologic literature (1). CDI can precede the diagnosis of AML/MDS or can

3 manifest during treatment and is thought to confer a poorer prognosis (1). The pathogenesis of CDI in AML/MDS may be secondary to leukemic infiltration of the infundibulum, hemorrhage, thrombosis, infection, or autoimmunity (2-4). CDI does not always develop when there is leukemic infiltration in or around the infundibulum or neurohypophysis and it may develop in the absence of infiltration (5). The most common cytogenetic abnormality seen in AML with CDI occurring in 80% of reported cases is monosomy 7, followed by abnormalities of chromosome 3 such as inv(3)(q21;q26) and t(3;3)(q21;q26). Many of the cases reported had both cytogenetic findings (2, 6). It remains unknown why these chromosomal abnormalities are associated with CDI. We present a case of MDS transformed to secondary AML with CDI in a patient with normal cytogenetics. Case Presentation A 65-year-old woman with a known diagnosis of MDS presented to our institution after a bone marrow biopsy demonstrated conversion to AML with 100% cellularity and 80% blasts. She reported fevers, worsening fatigue, dyspnea, a dry cough, and a 25 pound weight loss. The patient was admitted for induction chemotherapy. During her admission, she developed fevers and dyspnea and a bronchoscopy was scheduled for evaluation which required her to not to drink or eat (NPO). Morning lab values were notable for new hypernatremia to 154 meq/l. On further questioning, she noted profound thirst but had not asked for water because she was NPO for her upcoming procedure. Endocrinology was consulted for evaluation of hypernatremia. Laboratory values were as follow: serum osmolarity 182 meq/l; urine osmoloarity 182 meq/l; urine specific gravity 1.01; cortisol 16.7 g/dl; urine output cc/hr, consistent with a diagnosis of diabetes insipidus. Prior to her NPO status she was eunatremic. Magnetic resonance imaging (MRI) of the brain showed a thickened pituitary stalk with absence of the posterior bright spot (Figure 1a). She had no evidence of anterior pituitary dysfunction with a morning cortisol level of 16.7 g/dl, a thyroid stimulating hormone level of 2.54 IU/mL and a free thyroxine level of 0.7 ng/dl. The patient was started on intranasal desmopressin (ddavp) with immediate improvement in symptoms and

4 normalization of serum sodium and concomitant rise in urine concentration suggesting a diagnosis of CDI. She remained eunatremic on ddavp. She was readmitted to our institution 2 months later with neutropenic fever and new onset Sweet s Syndrome. During the admission she developed hyponatremia, with a sodium of 131 meq/l and her ddavp was discontinued with resulting resolution of her hyponatremia. MRI was notable for resolution of the pituitary stalk thickening (Figure 1b). While not taking ddavp, labs were notable for a sodium of 140 meq/l, a urine specific gravity of and 1850 cc of urine over 24 hours. Her CDI has yet to recur over a ten month period. Discussion CDI remains a known but uncommon manifestation of both MDS and AML. Several case series and reports have demonstrated that symptoms of CDI often precede the diagnosis of AML(1, 2, 5, 7) and similar to our patient can be seen after transformation of MDS to AML 1. Our patient was only diagnosed with central DI as her free water access was restricted in anticipation of a procedure during her hospitalization. Fortunately, the hypernatremia was quickly recognized as CDI and treatment was initiated. She also presented with absence of a pituitary bright spot and thickening of the pituitary stalk. Interestingly, there is variable changes on MR and CT brain amongst patients with AML and CDI (1, 2, 5). Castagnola et al demonstrated no changes on CT brain amongst their 5 patient series (5), while Muller et al found only two patients without a bright spot and one patient with enhancement of the pituitary stalk out of 14 patients for whom imaging studies were available (2). The majority of patients evaluated in these series had chromosome 3 and 7 abnormalities. Less literature is available on patients presenting with AML, CDI and normal cytogenetics; however, two case studies on patients with AML, CDI and normal cytogenetics showed enhancement of the pituitary stalk similar to our patient (8, 9).

5 Given that many patients with chromosomal abnormalities and CDI do not have evidence of imaging abnormalities, other theories have been developed as to the relationship between these gene abnormalities and development of CDI. One proposed mechanism includes decreased neutrophil migration and chemotaxis due to reduction of GP130 due to monosomy 7 (10). For patients with 3q21q26 abnormalities, dysregulation of platelets particularly thrombocytosis and dysmegakaryopoiesis has been proposed as a possible mechanism for the development of CDI as many patients with AML, CDI and 3q21q26 abnormalities are also found have thrombocytosis at the time of presentation. Given that our patient had both normal cytogenetics and thrombocytopenia on presentation, it is unlikely that either of these mechanisms explains her development of CDI. Among other proposed mechanisms includes leukemic infiltration, hemorrhage, leukostasis of secondary vessels, autoimmune hypophysitis, and secondary infections and it is possible that one or a combination of these mechanisms has led to the development of CDI in her case (11). Our patient similar to the two other patients with normal cytogenetics reported in the literature, had a robust response to ddavp administration which allowed for improvement of her CDI symptoms. Most patients in the literature respond well to ddavp irrespective of their underlying cytogenetics. In some instances, patients CDI improved and they no longer require ddavp. However, in other case studies and series, patients CDI persists despite aggressive treatment of their underlying leukemia (5). Given our patient s resolution of pituitary stalk thickening with treatment with azacytidine and gilteritinib (ASP2215), it is possible that improvement in her underlying leukemia lead to her ability to maintain near normal sodium levels without administration of ddavp. However, other patients in the literature have shown improvement of CDI with hydration and chemotherapy treatment despite persistence of their underlying leukemia (2). More research is needed in order to determine etiology and pathophysiology of DI among AML patients. Although monosomy 7, 3q21q26 and normal cytogenetics are

6 relatively common among AML patients, CDI development remains uncommon. Multiple case series and studies have demonstrated that patients with AML and CDI have worse prognosis (1, 6). It is also likely that CDI is underreported among AML patients as many patients hypernatremia is likely controlled by increased water intake. In our patient s case, a schedule procedure that limited her ability to drink to thirst led to the development of hypernatremia and her diagnosis of CDI. Thus, a high index of suspicion for CDI is required in order to identify patients with CDI secondary to AML. Lastly, given that patients with normal cytogenetics are more likely in the literature to have characteristic imaging changes classically associated with CDI including a decreased bright spot and thickening of the pituitary stalk, the mechanism for development of CDI may differ compared to patients with chromosome abnormalities. References 1. Cull EH, Watts JM, Tallman MS, et al. Acute myeloid leukemia presenting with panhypopituitarism or diabetes insipidus: a case series with molecular genetic analysis and review of the literature. Leuk Lymphoma. 2014;55: Muller CI, Engelhardt M, Laubenberger J, Kunzmann R, Engelhardt R, Lubbert M. Myelodysplastic syndrome in transformation to acute myeloid leukemia presenting with diabetes insipidus: due to pituitary infiltration association with abnormalities of chromosomes 3 and 7. Eur J Haematol. 2002;69:

7 3. Dilek I, Uysal A, Demirer T, et al. Acute myeloblastic leukemia associated with hyperleukocytosis and diabetes insipidus. Leuk Lymphoma. 1998;30: Masse SR, Wolk RW, Conklin RH. Peripituitary gland involvement in acute leukemia in adults. Arch Pathol. 1973;96: Castagnola C, Morra E, Bernasconi P, Astori C, Santagostino A, Bernasconi C. Acute myeloid leukemia and diabetes insipidus: results in 5 patients. Acta Haematol. 1995;93: Harb A, Tan W, Wilding GE, et al. Acute myeloid leukemia and diabetes insipidus with monosomy 7. Cancer Genet Cytogenet. 2009;190: Dy P, Chua P, Kelly J, Liebman S. Central diabetes insipidus in the setting of acute myelogenous leukemia. Am J Kidney Dis. 2012;60: Harrup R, Pham M, McInerney G. Acute myeloid leukemia with diabetes insipidus and hypophyseal infiltration. Asia Pac J Clin Oncol. 2016;12:e350-e Loukidis K, Papadakis E, Anagnostou N, et al. Polyuria due to central diabetes insipidus presenting as an early manifestation of acute myeloid leukemia. Clin Adv Hematol Oncol. 2012;10: de la Chapelle A, Lahtinen R. Monosomy 7 predisposes to diabetes insipidus in leukaemia and myelodysplastic syndrome. Eur J Haematol. 1987;39: Ma H, Yang J, Xiang B, Jia Y. Acute myeloid leukemia with monosomy 7, ectopic virus integration site-1 overexpression and central diabetes insipidus: A case report. Oncol Lett. 2015;9:

8 Figure Legends Figure 1: Brain MRI before (a) and after (b) treatment with induction chemotherapy. Note the resolution of her pituitary stalk enlargement.