Role of Ketamine and Opioid Rotation in the Management of Opioid Induced Hyperalgesia in a Patient With Acute Promyelocytic Leukemia.

INTRODUCTION: Opioid analgesics are commonly used to manage moderate to severe cancer related pain. However long-term use of opioids has been known to lead to several unintended side effects, including opioid induced hyperalgesia (OIH) which is defined as the paradoxical increase in pain sensitization to pain stimulus following opioid exposure. Currently there are limited reports on the association between patients with cancer and OIH, and this phenomenon is rarely described in patients with leukemia or lymphoma. Here we report a patient with acute promyelocytic leukemia who developed opioid induced hyperalgesia following rapid escalation of opioids. CASE REPORT: A 36-year-old female being treated for acute promyelocytic leukemia presented with rapidly worsening acute on chronic hip pain requiring increasing opioid requriements. Given the rapid escalation of opioid dose with minimal response and physical exam findings consistent with allodynia/hyperalgesia a diagnosis of opioid induced hyperalgesia was made. MANAGEMENT AND OUTCOME: Following recognition of opioid induced hyperalgesia, the patient was managed with opioid rotation and ketamine, which resulted in prompt alleviation of pain. DISCUSSION: Opioid induced hyperalgesia is likely an underrecognized phenomenon in patients with cancer-related pain. A high index of clinical suspicion are necessary for diagnosis and proper management of this disease entity.

Clinical and preclinical characterization of CD99 isoforms in acute myeloid leukemia.

In an effort to identify target genes in acute myeloid leukemia (AML), we compared gene expression profiles between normal and AML cells from various publicly available datasets. We identified CD99, a gene that is up-regulated in AML patients. In 186 patients from The Cancer Genome Atlas AML dataset, CD99 was over-expressed in patients with FLT3-ITD and was down-regulated in patients with TP53 mutations. CD99 is a trans-membrane protein expressed on leukocytes and plays a role in cell adhesion, trans-endothelial migration, and T-cell differentiation. The CD99 gene encodes two isoforms with distinct expression and functional profiles in both normal and malignant tissues. Here we report that, although the CD99 long isoform initially induces an increase in cell proliferation, it also induces higher levels of reactive oxygen species, DNA damage, apoptosis and a subsequent decrease in cell viability. In several leukemia murine models, the CD99 long isoform delayed disease progression and resulted in lower leukemia engraftment in the bone marrow. Furthermore, the CD99 monoclonal antibody reduced cell viability, colony formation, and cell migration, and induced cell differentiation and apoptosis in leukemia cell lines and primary blasts. Mechanistically, CD99 long isoform resulted in transient induction followed by a dramatic decrease in both ERK and SRC phosphorylation. Altogether, our study provides new insights into the role of CD99 isoforms in AML that could potentially be relevant for the preclinical development of CD99 targeted therapy.

Gelatinous bone marrow transformation and emergence of clonal Philadelphia-negative cytogenetic abnormalities with excess blasts in a patient with chronic myeloid leukemia treated with dasatinib.

Gelatinous bone marrow transformation (GBMT) is a rare pathologic entity of unclear etiology characterized by adipose cell atrophy, focal hematopoietic tissue hypoplasia, and a distinct eosinophilic substance that stains with Alcian blue at pH 2.5. It is traditionally described in the context of malnutrition and cachexia from generalized disease and is important to identify because of its potential reversibility. Several recent case reports have described GBMT in patients with chronic myeloid leukemia (CML) on the first-generation tyrosine-kinase inhibitor (TKI) imatinib. Here, we describe a case of gelatinous transformation in a patient with CML receiving the second-generation TKI dasatinib who subsequently developed clonal cytogenetic abnormalities in Philadelphia chromosome negative cells with excess peripheral blasts consistent with advanced secondary myelodysplastic syndrome. While the development of clonal cytogenetic abnormalities in Philadelphia-negative cells has been frequently described in the setting of TKI, most abnormalities are transient and generally do not effect disease progression and/or transformation like in this case. Remarkably, after TKI discontinuation, repeat bone marrow biopsies had markedly diminished amounts of gelatinous transformation - supporting reversible GBMT with TKI removal. We review the relevant pathophysiology underlying our patient's possible therapeutic-mediated complications during CML therapy in an attempt to better understand the role of TKIs in the pathogenesis of these conditions.

Cardiac birth defects in a twin infant born to a woman with chronic myeloid leukemia on dasatinib.

Preclinical animal studies have demonstrated an association between maternal use of tyrosine kinase inhibitors and embryofetal toxicity; yet, multiple clinical case series have reported normal pregnancy outcomes and healthy infants in women on these medications during the course of their pregnancy. We describe a case of a woman with chronic myeloid leukemia who had taken the second-generation tyrosine kinase inhibitor dasatinib during the first 12 weeks of her dichorionic diamniotic twin pregnancy and subsequently delivered two low-birth weight infants, one with severe cardiac malformations and the other without apparent birth abnormalities. To our knowledge, this is the first reported case of fetal cardiovascular defects in an infant born to a woman on dasatinib during a twin pregnancy and supports current recommendations to avoid this medication during pregnancy. We also review relevant preclinical and clinical studies of tyrosine kinase inhibitor use during pregnancy and explore alternative therapeutic options for patients with chronic myeloid leukemia during pregnancy to aid clinicians in the appropriate management of these patients so as to minimize both maternal and fetal risks.

Allogeneic stem cell transplantation for Philadelphia chromosome-positive acute myeloid leukemia.

Philadelphia chromosome-positive acute myeloid leukemia (Ph(+)-AML) has a poor response to anthracycline- and cytarabine-containing regimens, high relapse rate, and dismal prognosis. Although therapy with imatinib and allogeneic stem cell transplantation (allo-SCT) is promising, relatively short follow-up limits understanding of long-term results of these therapies. This report describes the outcomes of 3 cases of Ph(+)-AML diagnosed and transplanted at the University of Nebraska Medical Center between 2004 and 2011. These patients, young and without major comorbidities, received induction therapy with 7 days of cytarabine and 3 days of idarubicin along with imatinib and consolidation therapy with high-dose cytarabine (with or without imatinib). All patients underwent 10/10 HLA-matched peripheral blood allo-SCT (sibling donor for first and third patients and unrelated donor for the second patient; all had acute graft-versus-host disease (GVHD), and the first and third patients had chronic GVHD. All patients are currently alive and experiencing complete remission at 116, 113, and 28 months after diagnosis, respectively. This report shows that the use of allo-SCT with resultant graft-versus-leukemia effect and the addition of imatinib can result in long-term remission and possible cure in some patients with Ph(+)-AML.

Chronic myelogenous leukemia, version 1.2015.

Chronic myelogenous leukemia (CML) is usually diagnosed in the chronic phase. Untreated chronic phase CML will eventually progress to advanced phase (accelerated or blast phase) CML. Tyrosine kinase inhibitors (TKIs) have been shown to induce favorable response rates in patients with accelerated and blast phase CML. The addition of TKIs to chemotherapy has also been associated with improved outcomes in patients with blast phase CML. Allogeneic hematopoietic stem cell transplant remains a potentially curative option for patients with advanced phase CML, although treatment with a course of TKIs will be beneficial as a bridge to transplant. This manuscript discusses the recommendations outlined in the NCCN Guidelines for the diagnosis and management of patients with advanced phase CML.

Reversible bone marrow aplasia induced by pegylated interferon-α-2a therapy in a patient with primary myelofibrosis.

Interferon has been widely used in the management of patients with hematological malignancies such as polycythemia vera, myelofibrosis, chronic myeloid leukemia and viral infections such as chronic hepatitis C. Hematological adverse effects such as cytopenias have been observed, particularly in patients who receive a combination of interferon-α-2a and ribavirin for hepatitis C. Mild myelosuppression can be seen with pegylated interferon; however, bone marrow aplasia in patients with myelofibrosis has not been reported. It is important to be aware of such a serious complication since persistent bone marrow aplasia can be fatal. We describe a case of pegylated interferon-induced reversible bone marrow aplasia in a patient with primary myelofibrosis.

Meta-analysis of the efficacy and adverse effects of acalabrutinib in the management of relapsed/refractory chronic lymphocytic leukemia.

The advent of Bruton tyrosine kinase inhibitor (BTKi) therapy with ibrutinib introduced a highly effective targeted therapy in the management of chronic lymphocytic leukemia (CLL). However, due to the adverse effect profile some patients cannot tolerate this novel therapy. Newer, more potent and targeted BTK inhibitors such as acalabrutinib have been developed. Acalabrutinib is an irreversible and second generation BTKi that covalently inhibits BTK with greater selectivity than ibrutinib. As novel BTKis are developed, a greater understanding of their efficacy and adverse effect rates can assist clinicians and patients in the shared clinical decision-making process. A search was conducted using the PICOS model and PRISMA guidelines. PubMeb, Embase, and Cochrane Library databases were searched using the keywords: Acalabrutinib, Acalabrutinib Monotherapy, Tyrosine Kinase Inhibitor, and Relapsed/Refractory (R/R) CLL. After initial literature review 12 studies were chosen for evaluation in this meta-analysis. Meta-analysis and follow up meta-regression models were completed. The results were as follows: ORR 82% (95% CI 74%-90%, I2 = 84.14%, p < 0.01), CR 4% (95% CI 2%-6%, I2 = 0.00%, p = 0.99), mortality rate 12% (95% CI 6%-19%, I2 = 87.23%, p < 0.01), mortality rate due to adverse effect 7% (95% CI 3%-10%, I2 = 67.67%, p = 0.01), mortality due to pneumonia 2% (95% CI 1%-3%, I2 = 0.00%, p = 0.43), mortality due to CLL progression 4% (95% CI 2%-6%, I2 = 61.03%, p = 0.04), neutropenia (≥ grade 3) 18% (95% CI 15%-20%, I2 = 0.00%, p = 0.70), thrombocytopenia (≥ grade 3) 7% (95% CI 4%-11%, I2 = 54%, p = 0.09), anemia (≥ grade 3) 9% (95% CI 6%-12%, I2 = 36.93%, p = 0.18), pneumonia (≥ grade 3) 10% (95% CI 6%-14%, I2 = 66.37%, p = 0.02) and atrial fibrillation 7% (95% CI 3%-11%, I2 = 80.13%, p = 0.00). The results demonstrate that acalabrutinib shows efficacy in the treatment of R/R CLL with tolerable adverse reaction rates.

Marginal Zone Lymphoma Manifesting as Macrophage Activation Syndrome: A Case Report.

Macrophage activation syndrome (MAS) is a form of secondary hemophagocytic lymphohistiocytosis (HLH) when it occurs in the context of rheumatologic disorders. HLH is a rare and potentially life-threatening syndrome characterized by excessive immune system activation. It is mainly seen in children and can be genetic based or related to infections, malignancies, rheumatologic disorders, or immunodeficiency syndromes. MAS can present with nonspecific symptoms, leading to a delay in diagnosis. This report describes a case of a 64-year-old female with marginal zone lymphoma and systemic lupus erythematosus who presented with a purpuric rash and acute kidney injury. She underwent a kidney biopsy and was diagnosed with MAS. This case highlights the importance of promptly recognizing MAS's symptoms and signs, allowing timely diagnosis and early therapeutic intervention. This potentially fatal condition tends to respond well to rapid treatment initiation with corticosteroids and to address the underlying condition.

Mobilization of hematopoietic progenitors from normal donors using the combination of granulocyte-macrophage colony-stimulating factor and granulocyte colony-stimulating factor results in fewer plasmacytoid dendritic cells in the graft and enhanced donor T cell engraftment with Th1 polarization: results from a randomized clinical trial.

Granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) both mobilize CD34(+) stem cells into the blood when administered before apheresis but have distinct effects on dendritic cell (DC) differentiation. We previously demonstrated that the combination of GM+G-CSF results in fewer plasmacytoid DCs (pDCs) when used to mobilize peripheral blood stem cells for autologous transplantation. To test the hypothesis that the content of pDCs in an allograft can be modulated with the cytokines used for mobilization, we randomized the human leukocyte antigen-matched sibling donors of 50 patients with hematological malignancies to a mobilization regimen of either GM+G-CSF (n = 25) or G-CSF alone (n = 25). Primary and secondary endpoints included the cellular constituents of the mobilized grafts, the kinetics of posttransplantation immune reconstitution, and clinical outcomes of the transplantation recipients. Grafts from donors receiving GM+G-CSF contained equivalent numbers of CD34(+) cells with fewer pDCs and T cells, with a higher fraction of Th1-polarized donor T cells than G-CSF mobilized grafts. Immune recovery was enhanced among recipients of GM+G-CSF. Survival was not significantly different between transplantation recipients in the two arms. The use of GM+G-CSF modulates immune function and recovery after allogeneic transplantation and should be explored in larger studies powered to evaluate clinical outcomes.

Chronic Myelogenous Leukemia, Version 1.2014.

The 2014 NCCN Clinical Practice Guidelines in Oncology for Chronic Myelogenous Leukemia recommend quantitative reverse-transcription polymerase chain reaction (QPCR) standardized to International Scale (IS) as the preferred method for monitoring molecular response to tyrosine kinase inhibitor (TKI) therapy. A BCR-ABL1 transcript level of 10% or less (IS) is now included as the response milestone at 3 and 6 months. Change of therapy to an alternate TKI is recommended for patients with BCR-ABL1 transcript levels greater than 10% (IS) at 3 months after primary treatment with imatinib. Continuing the same dose of TKI or switching to an alternate TKI are options for patients with BCR-ABL1 transcript levels greater than 10% (IS) at 3 months after primary treatment with dasatinib or nilotinib. The guidelines recommend 6-month evaluation with QPCR (IS) for patients with BCR-ABL1 transcript levels greater than 10% at 3 months. Monitoring with QPCR (IS) every 3 months is recommended for all patients, including those who meet response milestones at 3, 6, 12, and 18 months (BCR-ABL1 transcript level ≤10% [IS] at 3 and 6 months, complete cytogenetic response at 12 and 18 months).

Portal vein thrombosis as the presenting manifestation of JAK2 positive myeloproliferative neoplasm.

Deep venous thrombosis (DVT) is a complication of myeloproliferative neoplasms (MPNs). However, DVTs in unusual sites such as portal vein thrombosis (PVT) are rare and may be the first clinical manifestation of occult MPNs. There is a need for increasing awareness of such manifestations; so, here we discuss a patient who presented with new portal vein thrombosis, underwent further studies, was ultimately diagnosed with JAK2 positive MPN, and started on appropriate treatment with improvement of thrombosis and controlled hematocrit.

Factors Influencing Physician Discretion to Administer CNS Prophylaxis in Diffuse Large B Cell Lymphoma: A Single Institution Retrospective Study.

INTRODUCTION/BACKGROUND: Central nervous system (CNS) relapse is an infrequent but serious and challenging complication of diffuse large B-cell lymphoma (DLBCL) that carries a dismal prognosis. While several risk factors have been identified to stratify the risk for CNS relapse including the 2015 CNS internal Prognostic index (CNS-IPI), controversy still remains regarding the indication, timing, and method of CNS prophylaxis. The purpose of this study was to determine whether IT-MTX reduced the risk of CNS relapse, as well as treatment related and financial toxicity of CNS prophylaxis. PATIENTS AND METHODS: In this retrospective study, we identified 194 patients with DLBCL who received care at Loma Linda University Cancer Center between January 2010- August 2022. We evaluated the efficacy, side effect profile, and financial toxicity of IT-MTX for CNS prophylaxis in patients with DLBCL. RESULTS: In patients with intermediate to high CNS relapse risk (CNS-IPI 2-5) IT-MTX did not reduce the 1 year risk of CNS relapse (RR 1.1296, 95% CI 0.1933-6.6012, P = .08924). The median time to CNS relapse was longer in patients who had received IT-MTX (13.5 months) vs. those who did not (7 months). Thirty-eight (52.8%) patients reported adverse side effects of any kind as a result of IT-MTX administration, with 23.6% of patients developing grade 2 to 3 adverse events. The average cost for CNS-prophylaxis was estimated to be approximately $8,059.04 over a patient's treatment course, but as high as $20,140. CONCLUSIONS: These findings suggest that IT-MTX has limited and potential transient effectiveness in preventing CNS relapse. Given the high rate of side effects and significant cost of IT-MTX, we recommend that clinicians carefully consider the risks and benefits of prophylaxis before prescribing IT-MTX for CNS-prophylaxis.

Leukemic infiltration of the optic nerve in chronic lymphocytic leukemia: A case report and review of literature.

Ophthalmic and neurologic involvement are rare complications of CLL, with few cases reported in the literature. We report a case of CLL with leukemic infiltration of the optic nerve and review of literature focusing on management and outcomes. A patient with heavily pretreated CLL presented to our hospital with progressive eye pain and was found to have infiltrative optic neuritis. CSF analysis confirmed involvement with CLL. After systemic treatment with R-CHOP and high-dose methotrexate, along with intrathecal cytarabine and hydrocortisone, she experienced significant improvement and was discharged home. Given the rarity of ophthalmic involvement in CLL, we reviewed all 15 previously reported cases of CLL with optic neuropathy as the first manifestation of CNS involvement and discussed the range of treatment options used and their respective outcomes.

Leukostasis With Isolated Central Nervous System Involvement in Chronic Phase of Chronic Myelogenous Leukemia.

Chronic myelogenous leukemia (CML) is a hematologic malignancy with unique significance to the field of hematology and oncology, specifically due to the development of tyrosine kinase inhibitors (TKIs). CML often presents with nonspecific symptoms, and the quality of life in patients with CML has drastically improved as a result of TKIs. However, complications of CML including the risk of transforming into life-threatening blast crises continue to exist. Further, as most patients are asymptomatic in the chronic phase, patients often present with serious complications associated with noncompliance to TKIs. For example, central nervous system (CNS) manifestations of CML have been reported, both as the initial presentation of undiagnosed CML and as known complication of uncontrolled CML. Hyperleukocytosis is a manifestation of uncontrolled CML and leukostasis is a complication, occurring in cases of acute myeloid leukemia (AML). Here we present a rare case of leukostasis in a patient with known CML presenting on computed tomography (CT) as intracranial masses in the chronic phase. Our goal is to discuss this rare case of leukostasis in adult CML and describe its management.

Recurrent bone marrow aplasia secondary to nilotinib in a patient with chronic myeloid leukemia: a case report.

Nilotinib is a potent tyrosine kinase inhibitor of breakpoint cluster region-abelson (BCR-ABL), which has been approved as front-line therapy for newly diagnosed chronic myeloid leukemia in chronic phase and as second-line therapy after imatinib failure in chronic or accelerated phase chronic myeloid leukemia. Tyrosine kinase inhibitors have been associated with myelosuppression and grade 3 or grade 4 cytopenias are not uncommon in chronic myeloid leukemia patients treated with these drugs. There are a few reports of imatinib-associated bone marrow aplasia, but to our knowledge only one reported case of bone marrow aplasia associated with nilotinib. Herein, we report a 49-year-old male patient with chronic phase chronic myeloid leukemia, who developed severe bone marrow aplasia due to nilotinib. Possible mechanisms for this significant adverse drug reaction are discussed along with a review of literature.

Outcomes of the Pregnancies with Chronic Myeloid Leukemia in the Tyrosine Kinase Inhibitor Era and Literature Review.

Chronic myeloid leukemia (CML) is a clonal myeloproliferative neoplasm (MPN) that accounts for 10% of pregnancy-associated leukemias. The Philadelphia chromosome balanced translocation, t (9:22) (q34; q11.2), is the classic mutation seen in CML. The BCR-ABL oncoprotein encoded by this mutation is a constitutively active tyrosine kinase. Tyrosine kinase inhibitor (TKI) therapy is considered a first-line treatment for CML. However, the literature has revealed risks of teratogenicity with TKI therapy during pregnancy. Understanding the risks and benefits of TKI therapy and alternative therapies such as interferon-alpha (IFN-α) will help clinicians and pregnant patients develop a personalized CML treatment plan. This manuscript presents a case series detailing the management of five pregnancies in two pregnant patients with CML and a literature review of CML management in pregnancy.

A Case Report on Hepatic Extramedullary Hematopoiesis as the Manifestation of Progression to Secondary Myelofibrosis in a Patient with Essential Thrombocytopenia.

Myeloproliferative neoplasms (MPN), which include primary myelofibrosis (PMF) and essential thrombocytopenia (ET), are characterized by the clonal proliferation of mature blood cells as a result of the overactivation of the JAK/STAT pathway. Extramedullary hematopoiesis (EMH), a common complication of PMF, occurs due to the dysregulation of the bone marrow microenvironment. We report an interesting case of a 73-year-old female with a working diagnosis of ET who was found to have EMH in the liver on biopsy after she had newly onset elevated liver enzymes and her ET had progressed to secondary myelofibrosis. We conclude that in patients with MPN who have rising liver enzymes, EMH in the liver should be part of the differential diagnosis. In addition, we believe that EMH is a sign of progression from MPN to secondary myelofibrosis and that it is imperative for performing bone marrow aspiration and biopsy in order to reassess hematopoiesis and to look for bone marrow fibrosis as well as evidence of progression.

Clinicopathologic Features and Treatment of CD10-Positive Mantle Cell Lymphoma: A Case Report and Review of Literature.

Mantle cell lymphoma (MCL) is a rare and aggressive non-Hodgkin's B cell lymphoma characterized by the translocation t(11;14) (q13;32) and overexpression of CCND1. MCL is immunophenotypically identified as CD20+, CD5+, CyclinD1+, CD43+, CD10-, BCL6-, and CD23-. It is often distinguished from B cell lymphomas of germinal center cell origin by the absence of CD10 expression. Here we report the unique clinicopathologic features of a patient with CD10+ MCL with gastrointestinal involvement and review current literature identifying this unique immunophenotype.

When to treat myelodysplastic syndromes.

The myelodysplastic syndromes represent a heterogeneous series of clonal hematologic neoplasms characterized by morphologic dysplasia, aberrant hematopoiesis and a variable risk of progression to acute myeloid leukemia. These syndromes have a complex pathobiology, and ineffective hematopoiesis is a well-recognized feature of all of them. Normal blood cell maturation, differentiation, function, and survival are impaired, and these abnormalities contribute to the development of peripheral blood pancytopenia. The majority of patients succumb to complications of either bone marrow failure or leukemic progression. The fact that the majority of patients are elderly and have other comorbidities complicates therapeutic decision making and necessitates the development of individualized treatment strategies.