Benjamin Tomlinson

Enhancing acute myeloid leukemia therapy - monitoring response using residual disease testing as a guide to therapeutic decision-making

ABSTRACT Introduction: Current standards for monitoring the response of acute myeloid leukemia (AML) are based on morphologic assessments of the bone marrow and recovery of peripheral blood counts. A growing experience is being developed to enhance the detection of small amounts of AML, or minimal residual disease (MRD). Areas covered: Available techniques include multi-color flow cytometry (MFC) of leukemia associated immunophenotypes (LAIP), quantitative reverse transcriptase polymerase chain reaction (QRT-PCR) for detecting fusion and mutated genes (RUNX1-RUNX1T1, CBFB-MYH11, and NPM1), overexpression of genes such as WT1, and next generation sequencing (NGS) for MRD. Expert commentary: While MRD monitoring is standard of care in some leukemia subsets such as acute promyelocytic leukemia, this approach for the broader AML population does not universally predict outcomes as some patients may experience relapse in the setting of undetectable leukemia while others show no obvious disease progression despite MRD positivity. However, there are instances where MRD can identify patients at increased risk for relapse that may change recommended therapy. Currently, prospective investigations to define clinically relevant MRD thresholds are ongoing. Risk-adapted trials are needed to best define the use of MRD in the follow up of AML patients after initial induction therapy.

Concurrent blinatumomab and donor lymphocyte infusions for treatment of relapsed pre-B-cell ALL after allogeneic hematopoietic cell transplant.

Concurrent blinatumomab and donor lymphocyte infusions for treatment of relapsed pre-B-cell ALL after allogeneic hematopoietic cell transplant

Co-occurrence of type I CALR and two MPL mutations in patient with primary myelofibrosis

Dear Editor, Primary myelofibrosis (PMF) is a myeloproliferative neoplasm (MPN) characterized by recurrent somatic mutations in JAK2, CALR, and MPL genes. Although these mutations were initially reported to be mutually exclusive in MPN, several studies have reported the coexistence of JAK2 and CALR [1–5] as well as JAK2 and MPL mutations [6, 7]. Here, we report for the first time, to the best of our knowledge, a case of PMF with coexistence of CALR and two MPL mutations. A 52-year-old woman being evaluated for a knee replacement was found to have thrombocytosis and underwent a bone marrow biopsy at an outside institution in 2013 which demonstrated features of prefibrotic PMF (Fig. 1a–c). She was given a diagnosis of essential thrombocytosis (ET) based on her clinical presentation. By report, molecular studies for JAK2 and MPL mutations were negative by Sanger sequencing.CALRmutation analysis was not performed at that time as the association between CALR mutations and MPNs was not yet well-established [8, 9]. She was initially treated with hydroxyurea but this was stopped due to intolerable side effects and no further therapy was initiated. Over the course of the next 3 years, she gradually developed anemia, splenomegaly, and increasing night sweats, accompanied by a normalization of her platelet count. She was referred to our institution for second opinion. A second bone marrow biopsy performed in 2016 showed marked increase in reticulin fibrosis with clusters of atypical megakaryocytes (Fig. 1d–f). Mutational analysis by next-generation sequencing performed on this second bone marrow specimen revealed type I CALR mutation (p.L367Tfs*46) at an allele frequency of 47% and two MPL mutations: p.S505C and p.W515 L at a lower variant allele frequency of 4%. The identical variant allele frequency and location in cis of the paired MPL alterations suggest occurrence of MPL mutations on the same chromosome. Cytogenetics and FISH did not identify chromosomal abnormalities, and the patient’s diagnosis was changed to overt PMF based on the original biopsy findings and subsequent clinical course. The discordance between theMPL results in the initial and subsequent bone marrow could be due to a difference in the testing methodology in that the MPL mutations were present in the initial sample at a frequency that is below the level of detection for Sanger sequencing. The status of the CALR mutation in the initial sample is unknown and the original sample is not available for testing. Recent studies suggest that CALR mutations appear to be an early and initiating event in MPN [2, 8, 9] making it conceivable that our patient’s disease acceleration may be associated with a potential subclonal expansion of MPL-mutated clones, even though mutation rate during the course of a MPN is reported to be low [2, 9]. The coexistence of these two in cis MPL mutations has been reported previously in a patient of ET [10]. Interestingly, CALR mutations, as compared with JAK2 orMPLmutations, may be associated with a slower rate of progression in PMF [11]. However, the pathogenetic mechanisms of these coexisting mutations and their biological significance require further investigation. This case demonstrates that CALR and MPL mutations are not mutually exclusive in MPN. The stepwise single-gene * Navid Sadri navid.sadri@uhhospitals.org

Timing Embryo Preservation for a Patient with High-Risk Newly Diagnosed Acute Myeloid Leukemia

Great strides have been made in the treatment of acute myeloid leukemia (AML) resulting in increased number of survivors over all age groups, but especially in patients of reproductive age. Given the gonadotoxicity of high-dose induction chemotherapy and subsequent allogeneic stem cell transplant, it is paramount that fertility preservation options are discussed and explored at the time of diagnosis as fertility preservation has been associated with greater quality of life in survivors. Starting the conversation early is especially important for female patients given the time needed for all currently available fertility preservation techniques. Furthermore, due to a lack of current guidelines for the optimal timing of treatment, patients often encounter difficulties trying to balance life-saving treatment and fertility preservation. We present a case of female patient of reproductive age diagnosed with AML who opted for ovarian stimulation, oocyte retrieval, and subsequent IVF following a cycle of induction chemotherapy with satisfactory results for both embryo generation and disease treatment.