Current challenges of hematologic complications due to immune checkpoint blockade: a comprehensive review.

Immune checkpoint blockade has demonstrated durable clinical benefits in a variety of malignancies. These immune checkpoint inhibitors (ICIs) produce unwanted autoimmune reactions due to an impaired self-tolerance. Hematologic immune-related adverse events (heme-irAEs) have been increasingly reported in the literature with a reported fatality rate of 12%. In this review, we illustrate 3 cases treated at Johns Hopkins Hospital for ICI-induced agranulocytosis, aplastic anemia, and thrombocytopenia. We then summarize the available evidence regarding the incidence and prevalence of heme-irAEs. We identified immune thrombocytopenia and hemolytic anemia as the most commonly reported heme-irAEs which are more commonly observed with nivolumab therapy. Median time to onset of heme-irAEs varies between patients but occurs earlier with CTLA-4 inhibitors than with anti-PD-L1/PD-1 agents. We also describe the current challenges regarding the recurrence of heme-irAEs despite immune checkpoint blockade termination. We provide the available evidence supporting a mixed T-cell and B-cell immune-mediated response. Finally, we review the treatment algorithm of these complications and provide treatment alternatives to steroid-refractory cases.

An infant with concurrent serotype 6C invasive pneumococcal disease and infectious mononucleosis.

Streptococcus pneumoniae is a main causative agent of serious invasive bacterial infections. However, concurrent infection with invasive pneumococcal disease (IPD) and viral infectious mononucleosis (IM) is rare. We report an infant with serotype 6C infection causing IPD occurring simultaneously with IM. A previously healthy 11-month-old girl referred to our hospital because of fever, leukopenia, and elevated C-reactive protein presented to us with disturbance of consciousness, tachycardia, tachypnea and agranulocytosis. Other findings included tonsillitis with purulent exudates and white spots, bilateral cervical adenopathy, and hepatosplenomegaly. We diagnosed her illness as sepsis and administered a broad-spectrum antibiotic, an antiviral agent, and granulocyte transfusions. After treatment was initiated, fever gradually decreased and general condition improved. IPD was diagnosed based upon isolation of S. pneumoniae of serotype 6C from blood cultures obtained on admission. Concurrently the girl had IM, based upon quantitation of Epstein-Barr viral DNA copies in blood and fluctuating serum antibody titers. Although simultaneous IPD and IM is a rare occurrence, this possibility is important to keep in mind.

Agranulocytosis occurrence following recent acute infectious mononucleosis.

Infectious mononucleosis secondary to Epstein-Barr virus typically follows a relatively benign and self-limited course. A small subset of individuals may develop further progression of disease including hematologic, neurologic, and cardiac abnormalities. A mild transient neutropenia occurring during the first weeks of acute infection is a common finding however in rare cases a more profound neutropenia and agranulocytosis may occur up to 6weeks following the onset of initial symptoms. We describe the case of an 18-year-old woman who presented 26days following an acute infectious mononucleosis diagnosis with agranulocytosis and fever. No source of infection was identified and the patient had rapid improvement in her symptoms and resolution of her neutropenia. The presence of fever recurrence and other non-specific symptoms in individuals 2-6weeks following acute infectious mononucleosis symptom onset may warrant further assessment for this uncommon event.

Nonchemotherapy drug-induced agranulocytosis in children detected by a prospective pharmacovigilance program.

OBJECTIVES: A prospective evaluation of nonchemotherapy drug-induced agranulocytosis (DIA) cases, which are infrequent in the pediatric population. We characterize agranulocytosis cases and assess lab test differences between drug- and nondrug-induced agranulocytosis. METHODS: Through our Prospective Pharmacovigilance Program from Laboratory Signals at Hospital we detected pediatric agranulocytosis cases from July 2007 to December 2010. This program estimates the incidence, drug causality, clinical features, outcomes of DIA pediatric cases, and assesses laboratory differences with respect to non-DIA. RESULTS: We detected 662 agranulocytosis in 308 pediatric patients, of which 14 were caused by nonchemotherapy drugs. The incidence rate of DIA for 10,000 pediatric patients was 3.92 (Poisson 95% confidence interval 1.09-8.77); 78.6% of DIA cases occurred in patients younger than 3 years. The final outcome was recovery without sequela in all cases. The pharmacologic group most frequently implicated was antimicrobial drugs (11 drugs), 7 of which were beta-lactams. The drugs most frequently suspected were cefotaxime and vancomycin (3 cases each). We found 3 drugs (cloperastine, codeine, and enoxaparin) not previously described to induce DIA. Automatic linear modeling (n = 56, R2 = 45.2%) showed a significant inverse association with platelets (R2 = 17.5%), hemoglobin, and alanine transaminase, and a direct association with red cell distribution (R2 = 16.2%). A generalized linear model (Type III, n = 1188; DIA, n = 86; likelihood ratio chi-squared = 156.16) retained eosinophils (p <.001), platelets (p <.001), total serum proteins (p <.001), and hemoglobin (p =.039). CONCLUSIONS: We found a higher incidence of DIA in children than previously described. Our findings also suggest an immune-mediated destruction or myeloid toxicity, possibly facilitated by an increase in drug exposure.

Autoimmune cytopenias in chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) is frequently complicated by secondary autoimmune cytopenias (AIC) represented by autoimmune hemolytic anemia (AIHA), immune thrombocytopenia (ITP), pure red cell aplasia, and autoimmune granulocytopenia. The distinction of immune cytopenias from cytopenias due to bone marrow infiltration, usually associated with a worse outcome and often requiring a different treatment, is mandatory. AIHA and ITP are more frequently found in patients with unfavorable biological risk factors for CLL. AIC secondary to CLL respond less favorably to standard treatments than their primary forms, and treating the underlying CLL with chemotherapy or monoclonal antibodies may ultimately be necessary.

Successful preoperative treatment of a Graves' disease patient with agranulocytosis and hemophagocytosis using double filtration plasmapheresis.

Agranulocytosis is an uncommon but serious complication of Graves' disease under thionamide therapy. In some patients removal of circulating thyroid hormones and thyroid antibodies by plasmapheresis is an effective adjunctive therapeutic option. In perioperative settings, however, plasmapheresis may cause excess bleeding intraoperatively due to coagulation factor depletion unless fresh frozen plasma (FFP) products are used in the replacement fluid mix. Double filtration plasmapheresis (DFPP) in which only a small amount of albumin supplementation is used may be a potential alternative to conventional apheresis interventions where clotting factor depletion is problematic. We report a case of a patient with Graves' disease complicated with intravenous immunoglobulin responsive methimazole-induced agranulocytosis/hemophagocytosis who underwent successful preoperative DFPP treatment in preparation for thyriodectomy. In addition to conventional apheresis using FFP replacement, DFPP may offer an effective adjunct option in the management of hyperthyroid patients needing emergent surgical interventions.

Randomized comparison of safety and pharmacokinetics of caspofungin, liposomal amphotericin B, and the combination of both in allogeneic hematopoietic stem cell recipients.

The combination of liposomal amphotericin B (LAMB) and caspofungin (CAS) holds promise to improve the outcome of opportunistic invasive mycoses with poor prognosis. Little is known, however, about the safety and pharmacokinetics of the combination in patients at high risk for these infections. The safety and pharmacokinetics of the combination of LAMB and CAS were investigated in a risk-stratified, randomized, multicenter phase II clinical trial in 55 adult allogeneic hematopoietic stem cell recipients (aHSCT) with granulocytopenia and refractory fever. The patients received either CAS (50 mg/day; day 1, 70 mg), LAMB (3 mg/kg of body weight/day), or the combination of both (CASLAMB) until defervescence and granulocyte recovery. Safety, development of invasive fungal infections, and survival were assessed through day 14 after the end of therapy. Pharmacokinetic sampling and analysis were performed on days 1 and 4. All three regimens were well tolerated. Premature study drug discontinuations due to grade III/IV adverse events occurred in 1/18, 2/20, and 0/17 patients randomized to CAS, LAMB, and CASLAMB, respectively. Adverse events not leading to study drug discontinuation were frequent but similar across cohorts, except for a higher frequency of hypokalemia with CASLAMB (P < 0.05). Drug exposures were similar for patients receiving combination therapy and those randomized to monotherapy. There was no apparent difference in the occurrence of proven/probable invasive fungal infections and survival through day 14 after the end of therapy. CASLAMB combination therapy in immunocompromised aHSCT patients was as safe as monotherapy with CAS or LAMB and had similar plasma pharmacokinetics, lending support to further investigations of the combination in the management of patients with invasive opportunistic mycoses.

Agranulocytosis in dengue hemorrhagic fever: a neglected condition.

A granulocytosis in dengue hemorrhagic fever has not been mentioned, it mayprobably be included under the term of leucopenia. Here is the case of a 14-year Thai boy presenting with fever and diarrhea for 3 days. He was diagnosed as dengue hemorrhagic fever, grade I because he had hemoconcentration, thrombocytopenia without bleeding and positive IgM dengue antibody On the 5th day, he developed agranulocytosis and was treated with G-CSF and empirical antibiotics. His leucocyte count was successfully normalized within 1 day and persistently sustained until discharge.

Transplantation of allogenic bone marrow in canine cyclic neutropenia.

Transplantation of normal bone marrow cells to a gray collie dog with cyclic neutropenia resulted in normal granulocytopoiesis. The finding suggests that cyclic neutropenia occurs because the hematopoietic stem cells are defective. Because of the similarity of human and canine cyclic neutropenia, it also suggests that the human disease may be curable by marrow transplantation.

Idiosyncratic drug-induced agranulocytosis: possible mechanisms and management.

The incidence of drug-induced neutropenia has not changed in the western hemisphere over the last 30 years. Yet, the drug panorama has changed considerably. This implies that host factors may play an intriguing role for this idiosyncratic reaction. The knowledge as to mechanisms for the reaction has advanced with emerging understanding of neutropoiesis and immune regulation. Nonetheless, it is still remarkably difficult to pinpoint why and how a drug causes this unexpected, severe adverse event in a patient. Patient characteristics, e.g. genetics, appear to be keys for better understanding, predictions and prevention. Am. J. Hematol. 2009. (c) 2009 Wiley-Liss, Inc.

Preoperative therapeutic plasma exchange in patients with thyrotoxicosis.

The purpose of this report was to determine the effectiveness of therapeutic plasma exchange (TPE) in preoperative preparation of patients with thyrotoxicosis scheduled for either thyroid or nonthyroid surgery. We retrospectively reviewed 11 patients with thyrotoxicosis and those who prepared surgery with plasmapheresis between 1999 and 2008 at our institution. Ten patients underwent thyroid surgery and one patient was operated for femur fracture during antithyroid drug treatment. The indications for plasmapheresis in all patients with severe thyrotoxicosis were poor response to medical treatment (seven patients), agronulocytosis due to antithyroid drugs (three patients), iodine-induced thyrotoxicosis (Jodd Basedow effect in one patient), and rapid preparation for urgent orthopedic operation (one patient). After TPE, we observed a marked decrease in free thyroxin (FT3) and free triiodothyronin (FT4) levels; however, the decline in the biochemical values were not statically significant (P > 0.62, P > 0.15). Although both FT3 and FT4 levels remained above the normal limits in two of 11 patients, the signs and symptoms of thyrotoxicosis improved in all patients and no thyroid storm observed during the perioperative period. TPE can be considered a safe and effective alternative to prepare patients with thyrotoxicosis for surgery when drug treatment fails or is contraindicated and when emergency surgery is required.

Fatal toxic epidermal necrolysis and severe granulocytopenia following therapy with cefuroxime.

Toxic epidermal necrolysis (TEN) is one of the most threatening adverse reactions to various drugs. No case of concomitant occurrence TEN and severe granulocytopenia following the treatment with cefuroxime has been reported to date. Herein we present a case of TEN that developed eighteen days of the initiation of cefuroxime axetil therapy for urinary tract infection in a 73-year-old woman with chronic renal failure and no previous history of allergic diathesis. The condition was associated with severe granulocytopenia and followed by gastrointestinal hemorrhage, severe sepsis and multiple organ failure syndrome development. Despite intensive medical treatment the patient died. The present report underlines the potential of cefuroxime to simultaneously induce life threatening adverse effects such as TEN and severe granulocytopenia. Further on, because the patient was also taking furosemide for chronic renal failure, the possible unfavorable interactions between the two drugs could be hypothesized. Therefore, awareness of the possible drug interaction is necessary, especially when given in conditions of their altered pharmacokinetics as in case of chronic renal failure.

[Case of agranulocytosis associated with thymoma].

A 75-year-old-woman had undergone extended thymectomy, right upper and middle lobe resection, and radiation therapy (40 Gy) for thymoma at the age of 63. She visited our hospital complaining of low grade fever, cough, anorexia and a sore throat. Peripheral blood count revealed agranulocytosis. Agranulocytosis associated with thymoma was diagnosed, because there were no other possible causes of agranulocytosis such as drugs, infection, recent radiation therapy, or bone marrow invasion. In spite of giving G-CSF, steroid therapy and immunosuppressants, she died of pneumonia caused by agranulocytosis. We consider that agranulocytosis is a very rare complication of thymoma.

Recurrent Levamisole-Induced Agranulocytosis Complicated by Bowel Ischemia in a Cocaine User.

BACKGROUND Levamisole is a common adulterant of cocaine and up to 69% of seized cocaine in United States contains levamisole. It is a synthetic imidazothiazole derivative which was previously used as an immunomodulating agent for treatment of various connective tissue disorders and colorectal carcinoma. However, it was withdrawn later from the market due to significant toxicity associated with it. CASE REPORT We present the case of a 59-year-old male patient with a history of active cocaine use who presented to the hospital with febrile neutropenia and agranulocytosis. He underwent extensive work-up for neutropenia and was suspected to have it secondary to levamisole-adulterated cocaine. He was treated with antibiotics and granulocyte-stimulating factor. His white cell count improved and he was discharged home. He continued to use cocaine after discharge from the hospital. He returned to the hospital 3 weeks later with recurrent neutropenia and agranulocytosis complicated by septic shock and bowel necrosis which required prolonged antibiotics and a bowel resection. CONCLUSIONS Levamisole-induced agranulocytosis should be considered in patients who present with neutropenia and a history of cocaine use. Physicians should have high clinical suspicion and consider it a potential etiology of agranulocytosis when other causes have been excluded.

Agranulocytosis Induced by Vancomycin. Case Report and Literature Review.

BACKGROUND Vancomycin has been used for decades to treat infections by Gram-positive bacteria, particularly those caused by methicillin-resistant staphylococci. Agranulocytosis is an infrequent complication of this antibiotic, postulated in its genesis a mechanism immune-mediated by antineutrophil antibodies and antineutrophil cytoplasm antibodies (ANCA). Treatment includes discontinuing vancomycin, and granulocyte colony-stimulating factor administration. CASE REPORT We present the case of a patient who developed agranulocytosis secondary to vancomycin during the treatment of an infectious endocarditis, which was reversed when the antibiotic was stopped. Concomitantly to neutropenia, he had ANCA positivity, which subsequently became negative. CONCLUSIONS Agranulocytosis induced by vancomycin is infrequent and generally occurs after day 12 of treatment. In most cases, like in our case, it is caused by an immune-mediated mechanism. More studies are needed to determine the pathogenic mechanism and the ANCA role in this adverse effect.

Recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) shortens the period of neutropenia after autologous bone marrow transplantation in a primate model.

The effect of granulocyte-macrophage colony-stimulating factor (GM-CSF) on hematopoietic reconstitution after autologous bone marrow transplantation was evaluated in a primate model. Animals were given a continuous intravenous infusion of recombinant human GM-CSF for several days both before and after transplantation or only after the transplant procedure. Marrow ablation was accomplished by total body irradiation. In both groups of animals, the neutrophil count reached 1,000/mm3 by 8-9 d posttransplant compared with an interval of 17 and 24 d for two concurrent controls. After withdrawal of GM-CSF, neutrophil counts fell to values comparable to those observed in untreated controls. Accelerated recovery of platelet production was also observed in four of the five animals. Two additional animals were initially given GM-CSF several weeks posttransplantation because of inadequate engraftment. Prompt and sustained increases in neutrophil and platelet counts were observed. We conclude that GM-CSF may be useful in accelerating bone marrow reconstitution.

Canine cyclic neutropenia. A stem cell defect.

Two normal collie dogs were given 1,200 R total body irradiation followed by successful marrow grafts from their grey collie littermates with cyclic hematopoiesis. During observation periods of 97 and 41 days after grafting, both previously normal recipients showed regular cyclic fluctuations of their granulocyte and reticulocyte counts similar to those observed in their donors. These findings suggest that canine cyclic neutropenia is due to a defect in the marrow stem cell.

Diagnosis and management of autoimmune complications of chronic lymphocytic leukemia/ small lymphocytic lymphoma.

Autoimmune cytopenia is an important but poorly understood clinical complication of chronic lymphocytic leukemia/ small lymphocytic lymphoma. We review the pathogenesis, clinical presentation, and management of autoimmune hemolytic anemia, immune thrombocytopenia, and pure red blood cell aplasia in patients with chronic lymphocytic leukemia/ small lymphocytic lymphoma.