Up-Regulation of the Vitamin D Pathway in Acute Myeloid Leukemia: A Novel Cause of Hypercalcemia

Special Article - Acute and Chronic Myeloid Leukemia

Ann Hematol Oncol. 2017; 4(3): 1141.

Up-Regulation of the Vitamin D Pathway in Acute Myeloid Leukemia: A Novel Cause of Hypercalcemia

Casan JML¹*, Ghotb S², Morgan S¹, Wei AH1,2 and Ting SB2,3

¹Department of Haematology, The Alfred Hospital, Australia

²Australian Centre for Blood Diseases, Monash University, Australia

³Department of Haematology, Eastern Health, Australia

*Corresponding author: Casan JML, Department of Haematology, The Alfred Hospital, Commercial Rd, Prahran 3181, Victoria, Australia

Received: February 06, 2017; Accepted: February 28, 2017; Published: March 13, 2017


We report the first documented occurrence of hypercalcemia due to excessive production of calcitriol in acute myeloid leukemia (AML). The patient presented with severe hypercalcemia and renal failure accompanying a new diagnosis of AML. This extremely rare AML complication proved refractory to conventional hypercalcemia treatments but responded promptly to chemotherapy. Subsequent PCR studies performed on the leukemia blasts for vitamin D-related genes revealed dramatic up-regulation compared to healthy CD34+ cells and other primary AML cells. Recent data highlight a role for vitamin D in hematopoietic cell proliferation. Accordingly, this case may highlight another aspect of molecular heterogeneity in AML.

Keywords: Acute leukemia; AML; Hypercalcemia; Pathology; Leukemia clinical

Case Presentation

Hypercalcemia frequently occurs as a paraneoplastic phenomenon, commonly accompanying solid organ cancers as well as lymphoid hematologic malignancies. However, hypercalcemia is a rare complication of myeloid cancer, and documentation in acute myeloid leukemia (AML) is limited to an exiguous collection of case reports [1-3]. The most commonly identified mechanisms of hypercalcemia in cancer include the secretion of parathyroid-related peptide (PTHrp), bony metastatic disease and tumour production of active vitamin D (calcitriol). The few published instances of hypercalcemia in AML have shown it to be secondary to either ectopic parathyroid hormone secretion, leukemic bony invasion or the release of bone resorptive mediators. We describe a case of newly diagnosed AML presenting with severe hypercalcemia causing acute kidney injury (AKI), subsequently demonstrated to be secondary to leukemic blast production of active vitamin D with gross overexpression of vitamin D-related genes, which resolved promptly following commencement of chemotherapy. Hypervitaminosis D is a well-documented cause of hypercalcemia and is known to occur in granulomatous diseases such as Sarcoidosis [4], as well as both Hodgkin and non-Hodgkin lymphomas [5]. However, to the best of our knowledge, there is no previous evidence of this phenomenon occurring in a myeloid malignancy. Accordingly, this case represents a novel pathogenic mechanism causing hypercalcemia in AML.

AA, a 68-year-old male presenting with fatigue and dyspnea was found to have circulating blasts on a full blood examination. The patient was referred to our institution and subsequently diagnosed with acute myelomonocytic leukemia (78% blasts on bone marrow biopsy). Cytogenetic and fluorescence in-situ hybridisation demonstrated a normal karyotype, and flow cytometry revealed a myelomonocytic immunophenoytope with no aberrant lymphoid markers. Mutations in IDH2 (c.419G>A p.R140Q) and NPM1 (c.1165G>T) were detected by multiplexed mass spectrometry (MassARRAY System, Sequenom, San Diego, CA, USA). Accompanying the diagnosis of AML, AA had marked hypercalcemia (corrected calcium 3.3 mmol/L, normal range 2.1-2.6 mmol/L) and AKI with serum creatinine measuring 263 umol/L (normal range 60-110 umol/L). Given the rarity of AMLassociated hypercalcemia, we were reluctant to attribute this initially to his leukemia; therefore, extensive investigations were undertaken to elucidate the cause. In search of a second concurrent malignancy, the patient underwent computed tomography and positron emission tomography scanning, which revealed FDG avid vocal cord nodules. Direct laryngoscopy and multiple biopsies of these nodules revealed no malignant pathology. Parathyroid hormone (PTH) levels were appropriately suppressed (0.9 pmol/L, normal range 1.6-6.9 pmol/L) and levels of PTHrp (<2 pmol/L) and serum ACE (37 units/L, normal range 20-70 units/L) were within normal limits. Inactive vitamin D, (calcidiol or 25(OH)D3) levels were also normal (88 nmol/L, normal range >50 nmol/L). However, the active vitamin D (calcitriol or 1,25(OH)2D3) level was grossly elevated beyond the upper limit of the assay (>500 pmol/L, upper limit of normal: 190 pmol/L).

Both the hypercalcemia and kidney injury proved refractory to several initial therapeutic strategies including aggressive crystalloid hydration as well as an intravenous dose of 60 mg of pamidronate. Such treatments would be expected to yield significant improvement in other conditions causing hypercalcemia. However, despite the failure of these first-line hypercalcemia therapies, there was a precipitous fall in calcium level following the initiation of chemotherapy with idarubicin and cytarabine, 7+3 regimen (Figure 1). Within several days, AA’s serum calcium levels returned to normal levels, and his kidney function followed a similar pattern of improvement, returning to his baseline level (90 umol/L) shortly thereafter. The rapid normalisation of serum calcium levels also mirrored peripheral blast clearance, and repeat testing of calcitriol levels over time has demonstrated progressive improvement towards a normal concentration. The patient achieved complete morphological remission with no detectable minimal residual disease (MRD) (10-colour flow cytometric method, sensitivity to 0.1%) following induction chemotherapy. AA remains in complete remission with MRD negativity after consolidation chemotherapy and is currently on maintenance azacitidine therapy. His hypercalcemia has not recurred and his renal function remains within normal limits and comparable to his baseline results.

Citation:Casan JML, Ghotb S, Morgan S, Wei AH and Ting SB. Up-Regulation of the Vitamin D Pathway in Acute Myeloid Leukemia: A Novel Cause of Hypercalcemia. Ann Hematol Oncol. 2017; 4(3): 1141. ISSN:2375-7965