Acute Myeloid Leukemia: The Race to Diagnosis and Treatment!

Introduction: Acute myeloid leukemia (AML) is one of the hematologic emergencies that require prompt treatment. Advanced changes in the molecular pathogenesis has been emerging with major impact on prognosis and treatment. FLT3 mutation is associated poor prognosis and early relapse in AML. Midostaurin is a multi-kinase inhibitor, when combined with induction 7+3 chemotherapy, improves the response rate and disease-free survival. Purpose: To evaluate our institution efficiency obtaining the appropriate molecular studies in AML cases at the time of diagnosis. Time is very sensitive in the management of acute myeloid leukemia. Induction chemotherapy should be administered once morphologic diagnosis is made. It requires high collaboration between the hematologist, pathologist and laboratory staff. Once molecular studies are available, the need for targeted therapy will be determined. next generation sequencing (NGS) is fast and comprehensive method in molecular analysis Methods: The electronic medical records were reviewed for all AML cases diagnosed between January 2016 and December 2018. Quality measures were defined by: Average duration between bone marrow biopsy and the morphology results, average duration between bone marrow biopsy and date of molecular order, the type of molecular study ordered, average duration between molecular order and available results. We investigated the delay in administering midostaurin in cases with FLT3 mutation. Results: Between January 2016 and December 2018, there was 86 AML cases diagnosed and treated in our hospital. All patients were admitted to the hospital. The average duration between bone marrow biopsy and morphology results is 3 days. Molecular studies were obtained in 65 cases (75.5%). In 2018, molecular studies were ordered in 91% of new AML cases. Molecular studies were ordered as: (NGS)-54 gene in 18 cases; the rest were ordered as custom panel. The average duration between the molecular order and result dates is 9.3 days. The Average duration between induction date and molecular results is 8.8 days. FLT 3 mutation analysis was included in 51 cases (59%) and was detected in 18 cases (21%). Midostaurin is administered in 13 cases. The average delay in administering midostaurin is 2.75 days. Discussion: Our institution experience has improved in the past 3 years increasing the rate of ordering molecular studies. However, there is an average 2.7-day delay in administering targeted therapy due to the delay ordering and getting the results in appropriate time manner. We suggested the following changes: 1. Standardize the order by obtaining NGS-54 gene panel on all Leukemia cases. 2. Discuss all new leukemia cases in multidisciplinary conference to ensure better communication. 3. Address the efficacy of these measures in new AML cases diagnosed in 2019.https://scholarlycommons.henryford.com/merf2019qi/1007/thumbnail.jp

Outcomes of Patients with Thrombocytopenia Evaluated at Hematology Subspecialty Clinics

BACKGROUND: Thrombocytopenia is a frequently encountered laboratory abnormality and a common reason for hematology referrals. Workup for thrombocytopenia is not standardized and frequently does not follow an evidence-based algorithm. We conducted a systematic analysis to evaluate the laboratory testing and outcomes of patients evaluated for thrombocytopenia at hematology clinics in a tertiary referral center between 2013 and 2016. PATIENT AND METHODS: We performed a comprehensive chart review for patients evaluated for thrombocytopenia during the study period. Patients were followed for 1 year from the initial hematology evaluation and assessed for the development of a hematologic malignancy, rheumatologic, or infectious diseases among other clinical outcomes. RESULTS: We evaluated 472 patients with a median (range) age of 61 (17-94) years. The majority (63.8%) had mild thrombocytopenia. Within 1 year of follow-up, 14 patients (3.0%) were diagnosed with a hematologic malignancy. A higher likelihood of developing a hematologic malignancy was noted in patients with concurrent leukopenia (hazard ratio [HR] 9.97, 95% confidence interval [CI] 3.28-30.32, p \u3c .01) and increasing age (HR per 10-year deciles 1.52, 95% CI 1.03-2.25, p = .03). In patients with asymptomatic isolated mild thrombocytopenia, laboratory testing did not reveal any significant positive findings and patients did not receive any new major diagnosis during the follow-up period. CONCLUSION: Our findings provide basis and call for development of an evidence-based algorithmic approach for evaluation of patients with thrombocytopenia, testing, and referrals. It also supports a conservative approach mainly driven by physical exam signs, symptoms, and other laboratory findings for patients with isolated mild thrombocytopenia

Outcomes of patients with thrombocytopenia evaluated at hematology subspecialty clinics

BACKGROUND: Thrombocytopenia is a frequently encountered laboratory abnormality and a common reason for hematology referrals. Workup for thrombocytopenia is not standardized and frequently does not follow an evidence-based algorithm. We conducted a systematic analysis to evaluate the laboratory testing and outcomes of patients evaluated for thrombocytopenia at hematology clinics in a tertiary referral center between 2013 and 2016. PATIENT AND METHODS: We performed a comprehensive chart review for patients evaluated for thrombocytopenia during the study period. Patients were followed for 1 year from the initial hematology evaluation and assessed for the development of a hematologic malignancy, rheumatologic, or infectious diseases among other clinical outcomes. RESULTS: We evaluated 472 patients with a median (range) age of 61 (17-94) years. The majority (63.8%) had mild thrombocytopenia. Within 1 year of follow-up, 14 patients (3.0%) were diagnosed with a hematologic malignancy. A higher likelihood of developing a hematologic malignancy was noted in patients with concurrent leukopenia (hazard ratio [HR] 9.97, 95% confidence interval [CI] 3.28-30.32, p \u3c .01) and increasing age (HR per 10-year deciles 1.52, 95% CI 1.03-2.25, p = .03). In patients with asymptomatic isolated mild thrombocytopenia, laboratory testing did not reveal any significant positive findings and patients did not receive any new major diagnosis during the follow-up period. CONCLUSION: Our findings provide basis and call for development of an evidence-based algorithmic approach for evaluation of patients with thrombocytopenia, testing, and referrals. It also supports a conservative approach mainly driven by physical exam signs, symptoms, and other laboratory findings for patients with isolated mild thrombocytopenia

Isolated Ocular Manifestation of Relapsed Chronic Myelogenous Leukemia Presenting as Myeloid Blast Crisis in a Patient on Imatinib Therapy: A Case Report and Review of the Literature

Blast phase in chronic myelogenous leukemia (CML) has rarely been reported to involve extramedullary sites like skin, lymph nodes, and central nervous system. Clinical history, characteristic hematologic findings (elevated leukocyte counts, myelocytic predominance, and basophilia), and Philadelphia chromosome are of high diagnostic significance especially in isolated extramedullary presentations. We describe a unique case of CML relapse with blast phase involving the eye. A 66-year-old man with a known diagnosis of CML on imatinib and in molecular remission for 3 years presented with a painful blind eye. Histologic examination revealed diffuse involvement of choroid, iris, vitreous humor, and the optic nerve by blast cells. The blasts expressed CD34, aberrant TdT, and a myeloid phenotype (CD13, CD33, and CD117). Fluorescence in situ hybridization (FISH) of vitreous fluid detected BCR-ABL1 gene rearrangement. Additionally, trisomy 8 and gains of 9 and 22 were seen which were not present in the initial diagnostic marrow study 3 years ago. At relapse, the bone marrow, peripheral blood, and the cerebrospinal fluid were not involved by CML. Patient received induction chemotherapy and single dose prophylactic intrathecal methotrexate and was maintained on antityrosine kinase therapy and eventually underwent allogenic stem cell transplantation

Hematology/Oncology Fellowship Emergency Restructuring in Response to the COVID-19 Pandemic—Henry Ford Hospital, Michigan

The COVID-19 pandemic has wreaked havoc and created challenges in various subspecialty training programs, including hematology/oncology fellowship programs. The challenge of social distancing, providing care for those infected by COVID-19, continuing appropriate treatment of time-sensitive diseases, and the looming threat of health care worker infections required swift planning and restructuring of training programs. The Accreditation Council for Graduate Medical Education provided leeway to tackle the challenges faced by institutions and training programs in the setting of the COVID-19 pandemic. Currently, there is no established guideline specific to hematology and oncology fellowship programs. While understanding that there is no one-size-fits-all, shared experiences can assist training programs to incorporate best practices and customize their programs to provide an active educational environment that balances patient care needs, didactics, scholarly activities, and wellbeing during the process of rapid changes and adaptation. We share our hematology/oncology fellowship program\u27s restructuring approach in response to the COVID-19 pandemic

Paraneoplastic Syndrome in Splenic Marginal Zone Lymphoma: A Rare Phenomenon of Paraplegia as an Atypical Presenting Manifestation

We describe a case presenting complaint of complete lower body paraparesis, which was discovered to have splenic marginal zone lymphoma (SMZL). While paraneoplastic syndromes are more common in tumors, such as small cell lung cancer, very few reports exist on this condition with SMZL. We describe such a rare entity with a clinical course spanning twenty-four months after diagnosis

Hemolytic anemia with mutations SPTA1 c.6531-12C\u3eT and SLC4A1 Pro868Leu

Learning Objective: Novel phenotype of hemolytic anemia with simultaneous mutations of SPTA1 c.6531-12C\u3eT and SLC4A1 Pro868LeuCase: A 33-year-old male with no prior medical history presented with dizziness, diaphoresis and near syncope. On evaluation, hemoglobin was noted to be 6.1, Ultrasound of the abdomen showed splenomegaly measuring 18 cm. Anemia work up revealed a low haptoglobin \u3c30, reticulocytosis, hyperbilirubinemia and high LDH. Coombs test was negative. Peripheral smear showed elliptocytosis without fragmented red blood cells. These findings were consistent with non-immune hemolytic anemia. Pertinent negative studies include monoclonal protein, antinuclear antibody, rheumatoid factor, Epstein Barr Virus, Cytomegalovirus, human immunodeficiency virus, and Coombs antibody. The patient was transfused packed red blood cells and hemoglobin improved to 9.7 prior to discharge from the hospital. He also underwent bone marrow biopsy that showed a hypercellular marrow and erythroid predominance, but with very mild dyserythropoiesis. Continued work up included hemoglobin electrophoresis, glucose-6-phosphate dehydrogenase, pyruvate kinase, and paroxysmal nocturnal hemoglobinuria all resulted negative. With the diagnosis of elliptocytosis, he underwent splenectomy which showed reactive splenomegaly and red pulp expansion. Following splenectomy, his hemoglobin normalized. Red blood cell membrane studies were also negative. Genetic testing revealed mutations of SPTA1 c.6531-12C\u3eT and SLC4A1 Pro868Leu.Discussion: Mutation of SPTA1 c.6531-12C\u3eT encodes for the protein spectrin and can cause a worse phenotype of hemolytic anemia in patients with elliptocytosis or poikilocytosis. SLC4A1 Pro868Leu is seen in acanthocytosis and encodes for band 3, a protein on the red blood cell membrane involved in ion exchange. These mutations have not been reported together before but we cannot rule out that even though they are not pathogenic standing alone, that they could cause hemolysis when found together. Of the various types of non-immune hemolytic anemias, aberrations in spectrin has been shown to be associated with various membrane defects ranging from spherocytosis to poikilocytosis1. Mutations in the anion exchanger SLC4A1 Pro868Leu has be shown to result in disturbances that can disrupt membrane ion equilibrium leading to acanthocytosis. Like this channel, SLC4AE is involved in ion exchange and connects to other proteins that compose the cytoskeleton of red blood cells, stabilizing the structure1. A mutation of this channel would lead to disturbance in the red cell membrane leading to abnormalities such as acanthocytosis. Mutation of SPTA1 c.6531-12C\u3eT has been associated with a worse phenotype of hemolytic anemia in patient’s red cell membrane abnormalities. Many mutations in the SPTA1 gene affect the interaction sites of the alpha and beta spectrin molecules, leading to elliptocytosis2. Conversely, mutation at other sites can lead to pyropoikilocytosis and spherocytosis. The SPTA1 homozygous mutation showed signs of disruption at the cellular level whereas the heterozygous parents were absent of abnormalities clinically2. There are no cited cases of these two simultaneous mutations. Together these two heterozygous mutations in the same individual could lead an observable phenotype. This information can provide a proposed hypothesis for future research involving red cell membrane disorders. Furthermore, this information can be applied to future studies studying novel mutations and the impact on red cell membrane stability.https://scholarlycommons.henryford.com/merf2019caserpt/1054/thumbnail.jp

Comparison of high dose methotrexate treatments in CNS lymphoma patients: The Henry Ford experience.

Background: The main backbone of therapy for CNS lymphoma involves systemic treatment with high dose methotrexate (HDMTX)-based regimens, with radiotherapy reserved only for cases that fail systemic therapy due to the significant cognitive toxicity of radiation. Over the last decade, rituximab and subsequently temozolomide were added to HDMTX chemotherapy regimens. Methods: Patients diagnosed with CNS lymphoma between 2009 and 2015 were identified. A retrospective cohort study was conducted of patients who received HDMTX alone (Cohort A), HDMTX and rituximab (Cohort B) and HDMTX, rituximab and temozolomide (Cohort C). Data collected included treatment related adverse events along with OS and PFS. Results: 31 patients were diagnosed with CNS lymphoma. 11, 10 and 6 patients were in cohorts A, B and C respectively. Median PFS and OS for the entire cohort were 14 and 25 months respectively. Cohort results were compared to the respective reference trials published in the literature. Cohort A had a PFS of 11 months and OS of 12 months compared to 12.8 months and 22.8+ months in the reference Phase II trial. Cohort B had a median PFS of 25+ months and OS of 41 months compared to 21 months and 33.5 months in the reference trial. Cohort C had a 2-year PFS of 0.50 compared to 0.57 in the reference trial. 3 (9.6%), 5 (16.1%), and 2 (6.4%) patients developed renal dysfunction in cohorts A, B and C respectively. 4 (12.9), 2 (6.4%), and 0 patients developed leukopenia in cohorts A, B and C respectively. 3 (9.6), 2 (6.4%), and 1 (3.2%) patients developed anemia in cohorts A, B and C respectively. 1 (3.2%), 1 (3.2%) and 1 (3.2%) patient developed thrombocytopenia in cohorts A, B and C respectively. Conclusions: The addition of Rituximab to HDMTX treatment for the treatment of CNS lymphoma increased the PFS and OS compared to HDMTX alone and is in concordance with the reference phase II trials reported in the literature if not better. In addition, our data at HFH shows no increased risk of adverse events with combination therapies compared to HDMTX alone. The addition of Temozolomide to Rituximab and High Dose methotrexate treatment showed a median 2 year PFS of 0.50 which is comparable to published reports of a 2-year PFS of 0.59

Desperate times, desperate measures: successful use of chemotherapy in treatment of haemophagocytic lymphohistiocytosis (HLH) due to disseminated histoplasmosis

We describe a case of haemophagocytic lymphohistiocytosis (HLH) secondary to disseminated histoplasmosis, which was treated with chemotherapy in addition to standard antifungal therapy. While HLH in the setting of infections is very well described, its treatment in this setting is controversial, with some physicians treating only the underlying infection, whereas others using immune suppression in addition to antimicrobials. To the best of our knowledge, this is the first report documenting the successful treatment of an adult patient with HLH due to disseminated histoplasmosis using etoposide chemotherapy after initial antifungal therapy failed to show improvement

Successful Treatment of Central Nervous System Post-Transplant Lymphoproliferative Disease With a Reduced Dose of High-Dose Methotrexate

Post-transplant lymphoproliferative disease (PTLD) is a complication of solid organ and hematopoietic stem cell transplantation that occurs as a result of immunosuppression. PTLD isolated to the central nervous system (CNS) is a rare disease and it presents with nonspecific signs and symptoms. Optimal therapy guidelines have not yet been established for CNS PTLD. Here, we report a case of successful treatment of CNS PTLD in an adult female following two subsequent kidney transplants. Initial management was with immunosuppression reduction and a trial of rituximab. There were concerns regarding using methotrexate (MTX) given the patient\u27s fragile transplant status. Magnetic resonance imaging of the brain following four cycles of rituximab revealed the progression of the disease. Subsequently, high-dose MTX (HD-MTX) was considered within the constraints of potential kidney toxicities given her transplant status and chronic kidney disease. Potential toxicities from other therapies, such as brain radiation, also factored into the final decision. The patient was treated with one cycle of a combination of rituximab and HD-MTX 1 g/m2. The patient tolerated HD-MTX and did not have evidence of renal toxicity in laboratory studies. Following that, she was started on a reduced dose of HD-MTX at 2 g/m2 every two weeks instead of the higher MTX dose range of 3.5 to 8 g/m2, which was a shared decision with the patient and nephrology after weighing the risk of kidney dysfunction with the possibility of a less than optimal response with regards to her lymphoma. She was followed with a magnetic resonance imaging of the brain, which demonstrated a complete response after four cycles. Further consolidation treatments with HD-MTX 2 g/m2 every four weeks were administered to complete one year of treatment. Following the completion of chemotherapy, the patient was able to achieve and maintain a complete response without affecting her kidney function. She continues to do well one year following treatment. This case highlights the significance of tailoring therapy to each individual based on their comorbidities and clinical response, as well as the possible merit in exploring the use of a reduced dose of HD-MTX in the treatment of CNS PTLD in patients at high risk for renal toxicity