Persistent pancytopenia and a hypocellular bone marrow after induction chemotherapy in a young adult with acute myelogenous leukemia; What is missing here?

Manuscript type : Case Report | Article Date : 2015/01/19

  • Autors

    1. Van Doren Layla
    2. Sapkin Joshua
    3. Akhtari Mojtaba
  • Abstract

    Congenital bone marrow failure syndromes (CBMFS) are generally diagnosed in infancy and early childhood, but may go unrecognized until adulthood. These syndromes are increasingly being diagnosed into adulthood, possibly due to the availability of genetic testing. We describe a young gentleman diagnosed with acute myelogenous leukemia (AML) who underwent induction chemotherapy with resulting persistent pancytopenia and hypocellular bone marrow without any signs of recovery which is usually seen about 4 weeks after induction. He was incidentally found to have near complete fatty replacement of the pancreas on imaging. The constellation of findings was consistent with a CBMFS. The patient was subsequently diagnosed with Shwachman Diamond syndrome.
  • Description


    Congenital bone marrow failure syndromes are a group of genetic disorders with decreased production of one or more cell lineage and are characterized by a predisposition for malignancy, particularly hemato-logic malignancies.1 Shwachman Diamond syndrome most often presents in infancy with bone marrow failure and exocrine pancreatic dysfunction. The management of these syndromes was once thought to be a field limited solely to pediatric subspecialties; however, there is increasing recognition of these syn-dromes being diagnosed in adulthood. It is imperative to recognize these syndromes when they do present in adulthood for appropriate management, as treatment related toxicities can be life threatening. This case highlights a patient with Shwachman Diamond syn-drome initially presenting with acute myelogenous leukemia and subsequent bone marrow failure after induction chemotherapy.


    A 39-year-old male with a past medical history of acute myelogenous leukemia (AML) status post in-duction chemotherapy presented to our institution to establish care for further management and surveil-lance of his AML. 18 months prior to presentation, the patient was diagnosed with AML (Fig. 1) and received induction chemotherapy with cytarabine and daunorubicin. Following induction chemotherapy, he was deemed not a candidate for post-induction consolidation due to complications of pulmonary as-pergillosis, acalculous cholecystitis requiring lapras-copic cholecystectomy, chemotherapy related hepatic failure, and persistent pancytopenia and hypocellular bone marrow on subsequent bone marrow biopsies. On the initial clinic visit, the patient was noted to be febrile to Fo 102.7; thus, he was admitted for further management. Upon admission, the patient was not-ed to have non-productive cough, fevers, and chills with associated pleuritic chest pain several days prior to admission. Clinical exam was revealing for faint left lung crackles, short stature, and temperature was Fo102.4. Initial set of laboratory investigations was notable for an Absolute neutrophil count (ANC) 0.6 K/cumm, platelet (Plt) 34 K/cumm, and hemoglobin (Hgb) 12 g/dL. Therefore, he was started on cefepime for neutropenic fever treatment. A Chest CT was obtained to assess for pulmonary in-fection and the patient was incidentally found to have near complete fatty replacement of the pancreas (Fig. 2). This finding prompted further testing of pancreatic function. Pancreatic enzyme concentrations were all decreased; elastase 37 mcg/g (normal >200 mcg/g), amylase 14U/L (21 -101 U/L), isoenzyme 4 U/L (16 -46 U/L), and serum trypsinogen C mutation, which is a common mutation in Swachman-Diamond syndrome because it is present in a nearby SBDS pseudogene which is an inactive gene with many mu-tations. Sections of the pseudogene are transferred to the SBDS gene, causing Swachman-Diamond syn-drome. The other mutation found was c.693delA, a frameshift mutation, causing loss of normal protein function. The presence of these two mutations was consistent with the diagnosis of Swachman-Diamond syndrome. Pancreatic enzyme replacement was not warranted, as he was pancreatic sufficient. Upon discharge, he continued to be followed in Hematology clinic every two to three weeks. He continued to receive granu-locyte colony-stimulating factor (G-CSF) for neutro-penia and remained on prophylactic anti-microbials (levofloxacin, fluconazole, and acyclovir) until two months after his initial presentation, at which time repeat bone marrow biopsy revealed recurrence of AML with 60% blasts. He was then initiated on dose reduced chemotherapy with fludarabine and cytarabine as bridging to an allogeneic hematopoietic stem cell transplant. The patient’s brother was a match for transplant and found to be heterozygous for Shwach-man Bodian-Diamond gene; thus, the patient is cur-rently undergoing hematopoietic stem cell transplant.


    DISCUSSION Shwachman Diamond syndrome is a rare congenital bone marrow failure syndrome. It is an autosomal recessive disorder implicated in ribosome biogene-sis and expressed in all human cells. It was first de-scribed in 1964 and thought to affect 1/76,000 . The syndrome is a multi-system disease characterized by bone marrow failure, exocrine pancreatic dysfunc-tion, and skeletal abnormalities. It most often pres-ents in infancy with malabsorption and recurrent in-fections.3 Pancreatic insufficiency and bone marrow failure are the hallmarks of the syndrome. Exocrine pancreatic dysfunction is characterized by nutrient maldigestion, quantified by an elevated 72hr fecal fat content. Low serum trypsinogen, pancreatic iso-amylase, and fat soluble vitamins A, D, and E are seen on laboratory. Histologically there is extensive fatty replacement of the acini with preserved ductal architecture and islets of Langerhans.2 Extensive fatty replacement can be appreciated on radiologic imaging with CT or MRI. For uncertain reasons, there is often spontaneous im-provement in pancreatic function during childhood with >50% no longer require pancreatic supplemen-tation.4 Other causes of exocrine pancreatic insuffi-ciency, such as cystic fibrosis must be ruled out. Bone marrow failure is characterized by persistent neutropenia and is the most common hematologic ab-normality occurring in nearly all patients. It can be persistent or intermittent, but must be present on three different occasions over a period of three months. Anemia is also present with a low reticulocyte count, along with thrombocytopenia. Bone marrow biopsy often reveals a hypoplastic marrow with increased fat deposition.5 Skeletal abnormalities consistent of skeletal dyspla-sia, most often with metaphyseal dysostosis in the long bones, rib cage dysplasia, and low turnover os-teopenia. Short stature may be attributed to growth failure with malnutrition and recurrent infections as a child.2 Given the lack of large studies, rarity of the disease, and few database, there are no guidelines for man-agement and surveillance, making it difficult and complex to manage these patients. In a patient with exocrine pancreatic dysfunction, treatment guidelines for cystic fibrosis can be of use. For bone marrow failure, chronic transfusions with packed red blood cells and platelets may be warranted (leukoreduced and irradiated blood products). Careful consideration should be given for the use of G-CSF because there is a theoretical concern of progression to AML, as occurred in our patient. Attempts should be made to provide hematopoetic stem cell transplant on an ur-gent basis to the patient presenting with MDS. If the patient progresses to AML, chemotherapy will only help control the disease, but will be unsuccessful in obtaining a prolonged remission in the patient with SDS. Survival rates with hematopoietic stem cell transplant is around 50%, irrespective of the donor being a matched sibling.6 This case report demonstrated the adverse effect of administering high dose induction chemotherapy in a patient with a CBMFS. It is necessary for adult physicians to recognize a CBMFS for appropriate management, minimization of treatment related toxicity, and to facilitate genetic counseling.


    This case report demonstrated the adverse effect of administering high dose induction chemotherapy in a patient with Shwachman Diamond syndrome. Fur-thermore, recognizing a CBMFS allowed for appro-priate management with a dose reduced chemother-apy regiment to minimize treatment related toxicity, and facilitate genetic counseling. It is necessary for physicians to recognize CBMFS can go undiagnosed until adulthood and malignancy may be the initial presentation.

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