Extramedullary Relapse Of Acute Myeloid Leukemia Research Articles

Isolated cerebrospinal fluid relapse of acute myeloid leukemia status post stem cell transplant: A neuroleukemiosis manifesting as polyneuropathy.

The patient was a 19 year-old male who was diagnosed with acute myeloid leukemia (AML) with Homozygous CEBPA mutation (C-terminal in-frame duplication) in addition to a pathogenic NRAS mutation and three associated GATA2 mutations. He received chemotherapy followed by matched related hematopoietic stem cell transplant (HSCT). The post-transplant course was complicated with acute graft vs host disease, which was treated with tacrolimus and prednisone (10 mg daily). Although demonstrating initial engraftment, bone marrow biopsy 76 days after the transplant showed early relapse. He was then treated with azacitidine/venetoclax followed by a donor lymphocyte infusion, and eventually underwent remission with a complete engraftment of donor cells 193 days after the transplant. Approximately 14 months after the transplant, the patient complained of back pain and general weakness. The patient developed progressive numbness and tingling in his bilateral upper extremities and his left lower extremity. This was followed by an involvement of the right lower extremity and right side facial droop. He also reported a difficulty in urination and defecation with associated numbness of his testicles and buttocks. Magnetic resonance imaging (MRI) of brain and spine showed multiple enlarged and enhancing cervical (Figure 1A), thoracic (Figure 1B), lumbar, and sacral nerve roots including the cauda equina (Figure 1C), as well as abnormal enhancement of the right facial nerve. Neurologic evaluation suggested a diagnosis of polyneuropathy, including a possibility of Guillain-Barre syndrome. Lumbar puncture was performed and examination of cerebrospinal fluid (CSF) showed markedly increased mononucleated cells (1323/μL; reference: 0-5). Microscopic evaluation revealed many blasts with cytological features suggestive of myeloid blasts (Figure 1D). Flow cytometric analysis demonstrated 88% blasts that were positive for CD34 and myeloid antigens CD117, CD13 and CD33 with aberrant CD7, the immunophenotypic profile similar to that detected in the diagnostic analysis. The bone marrow examination exhibited trilineage hematopoiesis with complete engraftment of donor cells and no increase in blasts, suggesting an isolated CSF relapse with neuroleukemiosis. The patient started intrathecal methotrexate and hydrocortisone, and re-instituted azacitidine/venetoclax. Sixteen days after intrathecal (three doses) and systemic chemotherapy (two cycles), his neurologic symptoms improved with relieved pain, tingling and urinary retention. Lumbar puncture examination showed no morphologic or flow cytometric evidence of leukemic blasts in CSF fluid. Cranial radiation was considered at the time when this manuscript was prepared. Extramedullary relapse of AML occurs in approximately 3% of the cases after HSCT, and a significant fraction demonstrates isolated CSF relapse.1, 2 The underlying mechanism is unclear, but may be explained by a sanctuary site of CSF with insufficient patrol by anti-leukemic T-cells of the donor origin.1 Although extramedullary relapse of AML overall shows better survival than bone marrow relapse, the prognosis of isolated CSF relapse as a special extramedullary presentation is unknown largely due to rarity of the reported cases. As seen in extramedullary relapse in general, isolated CSF relapse of AML typically predicts subsequent systemic relapse, portending a dismal clinical outcome.1 Because a standard therapy with efficacy has not been established, the better approach for the management of CSF relapse after HSCT may focus on antecedent recognition of the risk factors and early diagnosis by increased surveillance. Interestingly, leukemic involvement in central nervous system often presents with parenchyma lesion or dural/meningeal enhancement.3 However, spinal nerve root involvement with clinical manifestations and radiological findings resembling polyneuropathy or lumbosacral plexopathy as seen in this case is extremely rare.4 Given the nonspecific radiological features and unusual clinical presentation, we advocate a diagnostic vigilance and emphasize examination of CSF in patients with history of AML status post HSCT and neurologic symptoms suggestive of spinal neuropathy, in order to avoid a delay in diagnosis. Acknowledgement of the authorsʼ contribution to the manuscript: Y.Z. prepared the images, and wrote the manuscript; B.M. interpreted the images and edited the manuscript; E.W. organized the study, and wrote the manuscript. The authors declare no potential conflicts of interest.

Adult Case Series of Extramedullary Relapsing Acute Myeloid Leukemia (AML) after Allogeneic Stem Cell Transplantation in Whom a Rapid Response and a Reasonably Long Remission Could be Achieved with Gemtuzumab Ozogamycin (GO)

Gemtuzumab Ozogamycin (GO) is a drug conjugated monoclonal antibody which targets CD33 an antigen highly expressed on the surface of AML blasts. GO is approved for the treatment of both newly-diagnosed and relapsed AML. Despite growing evidence regarding its efficacy and safety among AML patients there is limited data about the use of GO in isolated extra-medullary relapsed AML. Extramedullary AML remains as an unmet clinical need regarding the poor prognosis and lack of a standard therapeutic approach. Our cases demonstrated a rapid and long lasting response with a favorable toxicity profile, in patients who were treated with GO as a single agent after an isolated extramedullary relapsing disease. Our first case was a 40-years-old woman admitted to our outpatient clinic with pain in her joints and redness in her back and stomach. She was diagnosed with CD33-positive Acute Myeloid Leukemia according to the immunophenotyping of bone marrow blasts. Idarubicin and ARA-C (7+3) combination initiated as a frontline induction therapy and morphological remission was achieved after the first cycle of induction. After the first cycle of consolidation chemotherapy with high dose ARA-C she has relapsed with skin myeloid sarcomas and diffuse bone marrow infiltration. Soon after the relapsing disease she was put on to ida-flag salvage chemotherapy and she responded well with the disappearance of skin lesions and morphological complete remission of bone marrow. After achieving response, an allogeneic stem cell transplantation (HSCT) was applied from her sibling donor with a myeloablative conditioning. Unfortunately patient had a relapsing extramedullary disease with reappearance of skin lesions even with an ongoing acute skin gvhd (Figure) soon after allogeneic HSCT. Bone marrow biopsy revealed no increase in blast count. We have decided to initiate a novel targetted therapy to control the extramedullary disease. As her blasts infiltrating the skin were universally CD 33 positive we considered to put her on GO therapy with the approval obtained from health authority. GO was applied according to the dosage approved by FDA for relapsing disease. After the first cycle of GO she had a rapid disappearance of all skin lesions just complicated with a febrile neutropenic episode and re-activation of CMV infection which was controlled with Gancyclovir. She has retained a complete remission regarding extramedullary disease throughout the repeated courses of GO for 3 times, and she is still in remission for 4 months after the first appearance of skin lesions (Figure). Our second case was a 24-years-old boy who admitted to our outpatient clinic with a worsening fatigue and shortness of breath. He was also diagnosed with CD33-positive Acute Myeloid Leukemia according to the immunophenotyping of bone marrow blasts and was able to achieve a morphological CR after frontline induction therapy with 7+3 protocol. After two cycles of high dose ARA-C consolidation he was transplanted from a matched unrelated donor because of an intermediate cytogenetic risk profile. At the 14th month of allogeneic transplantation he had relapsed with a bone marrow blast count of 90% and harboring a monosomy on the 10th chromosome. After the first salvage chemotherapy with IDA-FLAG protocol he has achieved a morphological CR and we have decided to proceed with an alternative donor transplantation. But unfortunately soon after discharge, he has admitted to the emergency clinic with a new onset headache and nausea and vomiting. A cranial CT revealed multiple foci of solid masses with peripheral edema. We have performed a lumbar puncture and CSF fluid revealed a high number of CD33 positive blastic cells (over 100 cells per HPF). At the time of central nervous system (CNS) relapse his bone marrow was free of blastic infiltration. We decided to initiate GO treatment with the diagnosis of isolated central nervous system relapse of AML, accompanying intra-thecal chemotherapy via an Omaya Reservoir. He has received two cycles of GO which was complicated with neutropenic fever and grade 4 leukopenia and thrombocytopenia, and his CNS lesions also responded well and clinically he had no CNS related signs or symptoms. The patient received additional GO with continued response but unfortunately after a severe pneumonia he passed away at intensive care unit. Our case series documented a clinically relevant therapeutic field for GO in isolated extramedullary relapse of AML. Disclosures No relevant conflicts of interest to declare.

Colonic Myeloid Sarcoma - A Rare Presentation of Relapsed Acute Myeloid Leukemia

A 36-year-old Caucasian female was admitted with abdominal pain and non-mucous, non-bloody diarrhea. Her medical history was significant for acute myeloid leukemia (AML) status post allogenic hematopoietic stem cell transplant 2 years ago and chronic graft versus host disease involving the skin, liver, and eyes. On admission, her hemoglobin was 7.3 g/dL and her white blood cell count was 12,400 cells/mL3 without blast cells. CT scan of abdomen and pelvis with intravenous contrast showed ascites along with increased edema and wall thickening involving the ascending colon and proximal transverse colon (Figure 1). Colonoscopy revealed an ulcerated, friable mass with contact bleeding from the cecum to mid-transverse colon (Figure 2). Biopsies of the mass showed prominent diffuse proliferation composed of large immature cells with delicate chromatin and prominent nucleoli with frequent mitotic figures (Figures 3 and 4). Immunohistochemistry stains were positive for CD34 and myeloperoxidase and negative for PAX5 and CD3, findings compatible with myeloid sarcoma. Bone marrow biopsy showed a hypocellular marrow with no morphologic evidence of acute leukemia. However, ascites fluid cytology showed presence of blast cells. Given that her extramedullary relapse of AML conferred a very poor prognosis, the patient was transitioned to hospice care and passed away 1 month later.Myeloid sarcoma (MS) is an extramedullary tumor of immature granulocytic cells with an incidence of 2-9% in patients with AML. Although the GI tract is involved approximately 10% of cases, colorectal MS is extremely rare. Clinical presentations of MS in the GI tract are varied, ranging from asymptomatic to abdominal pain, small bowel obstruction, diarrhea, or hemorrhage. The diagnosis requires a high index of suspicion, as radiographic and endoscopic findings are non-specific. Confirmation of the diagnosis is based on histology and immunohistochemistry profiling, including positive staining for Myeloperoxidase (MPO), CD43, CD68, lysozyme, and CD117. Every patient diagnosed with MS should undergo a bone marrow biopsy. Treatment options depend on tumor site and size, patient's age, performance status, and previous treatment for AML (if any). First line treatment for MS is chemotherapy. Appropriate patients should undergo evaluation for bone marrow transplantation. Local therapy, including surgery and/or radiotherapy, could also be offered to selected patients depending on clinical symptoms.1646_A Figure 1. CT scan of abdomen and pelvis with IV contrast showed increased edema and wall thickening in the ascending and proximal transverse colon (arrow) and ascites.1646_B Figure 2. Colonoscopy revealed ulcerated friable mass with contact bleeding in cecum, ascending colon and transverse colon.1646_C Figure 3. Low magnification photomicrograph demonstrates sharp contrast between unremarkable (left) and abnormal (right) mucosal fragments, H&E stain, 40x. Note how the abnormal fragment has surface erosions (arrows). 4: High magnification image reveals cytomorphologic features of malignant mucosal infiltrate to include increased nuclear to cytoplasmic ratios, delicate chromatin and prominent nucleoli. Many atypical mitotic figures are present (arrows) and numerous apoptotic bodies are identified (arrowheads), H&E, 400x.

Extramedullary Manifestations of Myeloid Neoplasms.

This session of the 2013 Society of Hematopathology/European Association for Haematopathology workshop focused on extramedullary manifestations of myeloid neoplasms. We divided the submitted cases into four subgroups: (1) isolated myeloid sarcoma (MS); (2) MS with concurrent acute myeloid leukemia (AML), with a focus on karyotypic and molecular findings; (3) extramedullary relapse of AML, including relapse in the posttransplant setting; and (4) blast phase/transformation of a myeloproliferative neoplasm or chronic myelomonocytic leukemia. Establishing a diagnosis of isolated MS requires a high index of suspicion and use of immunophenotypic methods. Recurrent cytogenetic abnormalities or gene mutations that occur in MS mirror those known to occur in AML. In the era of targeted therapy and sophisticated risk stratification, every attempt must be made to perform a complete workup on MS cases (or concurrent AML) since the diagnosis of MS, in itself, is no longer adequate for patient management. Cases of blastic plasmacytoid dendritic cell neoplasm were also included and discussed in this session.

Extramedullary Relapse of AML with t(9;11)(p22;q23) Associated with Clonal Evolution from Trisomy 8 into Tetrasomy 8

This report describes a patient with extramedullary relapse of acute myeloid leukemia (AML) without involving bone marrow. A 57-year-old man was diagnosed as having acute monoblastic leukemia with t(9;11)(p22;q23) and trisomy 8. Ten months after achieving complete response (CR) with chemotherapy, masses developed in his left forearm and in the back of his thigh, preceded by enigmatic peripheral neurological symptoms. Aspiration from the forearm showed leukemic relapse, and fluorescence in situ hybridization (FISH) revealed that the majority of the cells had 11q23 anomaly and tetrasomy 8. Bone marrow or meningeal relapse was not observed. To our knowledge, this is the first case report of clonal evolution associated with the development of myeloid sarcoma as a relapse in AML.