High-dose Cyclophosphamide Therapy Research Articles

Magnetic resonance imaging-negative myeloneuropathy and bilateral facial paresis unfurling systemic lupus erythematosus.

Systemic lupus erythematosus is a chronic autoimmune connective tissue disorder that can affect all the neuroaxes in the central and peripheral nervous systems. Myelopathy in systemic lupus erythematosus is one of the least common neuropsychiatric syndromes accounting for 1%–2% of cases. Myelopathy has long been diagnosed based on clinical findings, laboratory tests, and gold-standard gadolinium-enhanced magnetic resonance imaging (MRI). MRI-negative myelopathy is a recently described subset of myelopathies. Here, we report the case of a young woman from rural West Bengal, India, who presented with overlapping features of white-matter and gray-matter myelopathy associated with peripheral neuropathy and bilateral asymmetric lower motor neuron-type facial paresis. The historical analysis yielded clues toward an etiological diagnosis of systemic lupus erythematosus, further substantiated by seropositivity of lupus-specific autoantibodies. Her neurological disabilities responded poorly to oral administration of hydroxychloroquine, bolus intravenous administration of methylprednisolone, and high-dose cyclophosphamide therapy but eventually responded remarkably well to cyclical rituximab therapy. This case adds to the tally of cases of MRI-negative lupus myelopathy. MRI-negative myelopathy in systemic lupus erythematosus can be easily missed if not meticulous attention is paid during clinical history taking and examinations.

Addition of bortezomib to high-dose cyclophosphamide therapy as a conditioning regimen for autologous peripheral blood stem cell harvest leads to an increased yield of hematopoietic stem cells.

Peripheral blood stem cell harvest (PBSCH) is a crucial procedure for autologous stem cell transplantation in patients with multiple myeloma. We herein report a retrospective study to verify the usefulness of bortezomib and high-dose cyclophosphamide therapy (Bor-HDCY) as a conditioning regimen for PBSCH. Thirty-three patients were evaluated. The median age at the first apheresis was 61 (interquartile range, 53-64) years old, and 18 (54.5%) patients were male. Bor-HDCY was performed in 15 patients, and HDCY was performed in 18. In the patients who underwent Bor-HDCY, the CD34+ cell count at the first apheresis was significantly higher than in the others (P<0.01), and the total CD34+ cell count also tended to be high (P=0.0933). In terms of apheresis days, two-thirds of the patients who underwent HDCY had two-day apheresis, whereas most who underwent Bor-HDCY had one-day apheresis. According to univariate analysis, Bor-HDCY (P<0.01), VRd (Bor, lenalidomide, and dexamethasone) as induction therapy (P=0.0529), and ≥VGPR before PBSCH (P=0.0767) were factors associated with a higher CD34+ cell count at first apheresis. Although multivariate analysis showed that there were no independently significant factors influencing the CD34+ cell count at the first apheresis, the stepwise selection method revealed that only the Bor-HDCY regimen remained in the final model (P<0.005). Bor-HDCY may be a useful conditioning regimen for increasing the CD34+ cell yield.

The Value of High-Resolution Vessel Wall Magnetic Resonance Imaging in the Diagnosis and Management of Primary Angiitis of the Central Nervous System in Children

Purpose: High-resolution vessel wall-magnetic resonance imaging (VW-MRI) has been used to detect regional vessel wall pathology, significantly contributing to the diagnosis of primary angiitis of the central nervous system (PACNS) from other arteriopathies. In this study, we aimed to describe three cases of PACNS initially presenting as acute ischemic stroke, diagnosed and followed up with VW-MRI. Methods: The medical records of three patients diagnosed with PACNS were retrospectively reviewed. We also reviewed the clinical application of VW-MRI in published articles for the pediatric cases since 2016. Results: The initial presenting symptoms were headache, diplopia, confused mentality, hemiplegia, dysarthria, and dizziness. All patients had acute infarction on brain MRI, with suspicion of vasculopathy on magnetic resonance angiography. VW-MRI revealed narrowing of vessels with concentric wall thickening and diffuse enhancement in the anterior cerebral artery (n=1), middle cerebral artery (n=1), posterior cerebral artery (n=2), lenticulostriate artery (n=1), anterior inferior cerebellar artery (n=1), and vertebral artery (n=1), suggestive of vascular wall pathology. After excluding the possible etiologies of vasculitis, the clinical diagnosis of PACNS was established. Three patients received high-dose steroid and cyclophosphamide therapy. Two patients were treated with long-term azathioprine based upon the findings of persistent vessel enhancement on VW-MRI. All patients were regularly followed up with VW-MRI for more than 1 year. We summarized the clinical and radiological features of the published pediatric cases using VW-MRI to date. Conclusion: High-resolution VW-MRI plays an important role in diagnosing childhood PACNS, as results correlate with disease activity.

SUN-697 Importance of Immunosuppressive Therapy for Managing Insulin Resistance Type B

Background: Autoimmune Antibodies against insulin receptors leading to refractory hyperglycemia is known as Type B insulin resistance. In addition to insulin management, immunosuppressive therapy appears to be an essential part for successful management. Clinical Case: A 20 year old African American woman with no significant past medical history presented to the Emergency Department with worsening nausea and vomiting for 5 days and shortness of breath. She admitted to polyuria, unintentional weight loss of 15 pounds in the last six months, decreased appetite, and hyper-pigmented rashes mostly on her back. The patient was not on any medications at home. No known drug allergies, no past surgical history. Family history was significant for Grandmother with Type 2 Diabetes Mellitus and Lupus on father’s side of family. The patient denied use of alcohol, tobacco, illicit and IV drug use. T: 37.2 °C, HR: 124, RR: 25, BP: 105/74, SpO2: 100%. Weight 45kg. Physical exam significant for Tachycardia but normal rhythm. Initial work up revealed new onset diabetes HbA1c 9.6% and massive pericardial effusion on echocardiogram s/p pericardiocentesis. Due to developing complaints of intermittent cyanosis of fingertips and intermittent joint pain of fingers, Rheumatology work up was ordered and positive for mixed connective tissue disease. Patient was treated with Cellcept 1500 mg BID, Plaquenil Sulfate 300 mg daily, and prednisone 12.5 mg BID. Hospital course was complicated due to hyperglycemia in 300s-400mg/dL requiring high amounts of insulin. Diabetes work up was negative for GAd-65 and islet cell antibodies. C-peptide was elevated at 16.1 ng/mL (0.8-3.1 ng/mL) and anti-Insulin an antibodies was 20uU/mL. Patient was euthyroid. Hyperglycemia persisted despite increasing doses of long and short acting insulin subcutaneously. The patient eventually required Insulin intravenously at 50 units/hour plus 50 units of short acting Insulin every 4 hours subcutaneously. The patient was transferred to a facility to begin Combined Immunosuppressive Therapy plus insulin to manage hyperglycemia due to insulin resistance. After six months of rituximab, high-dose pulsed steroids, cyclophosphamide, plus insulin therapy, glycemic index improved with HbA1c reduced to 5.6%. Conclusion: Combined Immunosuppressive Therapy in addition to insulin management of refractory hyperglycemia due to type B insulin resistance has been shown to not only be effective in controlling refractory hyperglycemia but preventing against recurrences as well. Reference: 1) Klubo-Gwiezdzinska J, Lange M, Cochran E, Semple RK, Gewert C, Brown RJ, Gorden P. Combined Immunosuppressive Therapy Induces Remission in Patients With Severe Type B Insulin Resistance: A Prospective Cohort Study. Diabetes Care. 2018 Nov;41(11):2353-2360.

Clinical features and treatment outcomes in patients with T-cell large granular lymphocytic leukemia: A single-institution experience

AimLarge granular lymphocyte leukemia (LGLL) is a rare lymphoproliferative disorder associated with failure of hematopoiesis and autoimmune diseases. This study describes the clinical features and treatment responses of 108 patients with T-cell large granular lymphocyte leukemia (T-LGLL). MethodsClinical data were collected from T-LGLL patients treated at an anemia treatment center within the hematology and blood diseases unit of a single hospital from January 2009 to April 2019. ResultsThe majority of patients (78 %) were symptomatic at the time of presentation. Splenomegaly was observed in 41 % of cases, while hepatomegaly and lymphadenopathy were rare (6 % and 7 %, respectively). Cyclosporine (CsA) monotherapy was used as first-line therapy for 16 patients, with an overall response rate (ORR) of 56 %. CsA in combination with steroids was administered in 83 patients, with an ORR of 48 %. Among patients experiencing relapse or resistance to first-line therapy, 10 received antithymocyte globulin (ATG) therapy, with an ORR of 50 %; an additional 9 patients received a modified regimen of high-dose cyclophosphamide (CTX) therapy, yielding an ORR of 78 %. ConclusionsThis study provides new information regarding the clinical features and therapeutic strategies for T-LGLL, which can be used to improve clinical decision making for T-LGLL patients. The data presented here indicate the CsA is an effective option for the treatment of T-LGLL, while modified regimens of high-dose CTX or ATG are safe and effective choices for patients with CsA refractory disease.

Hyponatremia induced by high-dose cyclophosphamide therapy: a retrospective cohort study Cyclophosphamide and Hyponatremia

To determine the incidence of hyponatremia in patients under high-dose cyclophosphamide therapy. Retrospective cohort of adult patients who received high-dose cyclophosphamide therapy between 2010 and 2014 at the Hospital Italiano de Buenos Aires. The primary end-point was hyponatremia (defined as plasma sodium levels < 135 mEq/L), and secondary end-points were symptomatic hyponatremia, severe hyponatremia (plasma sodium levels < 120 mEq/L). A total of 96 patients received high-dose cyclophosphamide therapy during the study period. 27 patients met exclusion criteria and accounted for 28.1% , so that 69 patients were included in the primary analysis. Study population mean age was 56.5 years (SD 12.8) and 37.6% were female. The cumulative incidence were as follows: 52% (CI 95% 39¬–64) for hiponatremia, 5.8% (CI 95 % 0 –12) for severe hyponatremia, and 8.7% (CI 95% 1.3–16) for symptomatic hyponatremia. The only independent variable associated with the development of hyponatremia was female gender (OR 3.89, CI 95% 1.02–8.55, p=0.04). Cumulative incidence found in this study appears higher than in previous reports, probably because only patients under high-dose cyclophosphamide therapy were included. Cumulative incidence of severe and symptomatic hyponatremia were lower

Bronchial Varices in a Patient with Behçet&amp;apos;s diasese: A Case Report

We report a case of a 65-year-old man with Behcet's disease who presented with massive hemoptysis caused by bronchial varices. A computed tomography (CT) scan and bronchoscopy were performed to identify the bleeding site. The CT scan revealed pneumonia and a combined hemorrhage in the right-middle and lower lobes. Massive bleeding was detected during the bronchoscopy and emergency embolization was attempted but angiographic findings were normal. An anteriojugulo-right femoral bypass operation was performed to relieve the tortuous and hypertrophied jugular venous obstruction. However, thrombectomy and thrombolysis followed because of graft thrombosis six days post-surgery. The patient was treated with steroid and high-dose cyclophosphamide therapy for his Behçet's disease, which caused the venous obstructions; the saccular bronchial varices in the right-middle and right lower lobes on bronchoscopy regressed slightly after four cycles of cyclophosphamide therapy

Acute exacerbation of IPF has systemic consequences with multiple organ injury, with SRA+ and TNF-α+ cells in the systemic circulation playing central roles in multiple organ injury

BackgroundThe pathophysiologic mechanisms underlying acute exacerbation of idiopathic pulmonary fibrosis (IPF) are not fully understood. Few studies have examined autopsy findings in patients who have died from an acute exacerbation of IPF. The pathologic findings in systemic organs have not been described.MethodsWe retrospectively reviewed the autopsy findings in 12 patients who had died from an acute exacerbation of IPF and two of connective tissue disease- associated interstitial lung disease between 2005 and 2015. We recorded demographic and clinical characteristics, autopsy findings and cytologic findings in peripheral blood.ResultsThe median age at autopsy was 68 years (range 45–87 years); 11 subjects (78.5 %) were men. High-dose corticosteroid, cyclophosphamide and oxygen therapy had been administered to all patients. Underlying lesions had the usual interstitial pneumonia pattern; diffuse alveolar damage and contraction band necrosis were observed in all cases. Large cells expressing scavenger receptor A (SRA+) had been observed in the systemic circulation of 11 of the 14 cases (78.6 %) before acute exacerbation, and cells expressing tumor necrosis factor-α (TNF-α+) were detected after its diagnosis in nine (64.3 %). Both were detected in all cases at autopsy. There was neutrophil and platelet accumulation predominantly in capillaries, and extensive capillary endothelial cells injury.ConclusionsOur findings suggest that acute exacerbation of IPF has systemic consequences with multiple organ injury, with SRA+ and TNF-α+ cells in the systemic circulation playing central roles in multiple organ injury.

Mechanisms of Fatal Cardiotoxicity following High-Dose Cyclophosphamide Therapy and a Method for Its Prevention

Observed only after administration of high doses, cardiotoxicity is the dose-limiting effect of cyclophosphamide (CY). We investigated the poorly understood cardiotoxic mechanisms of high-dose CY. A rat cardiac myocardial cell line, H9c2, was exposed to CY metabolized by S9 fraction of rat liver homogenate mixed with co-factors (CYS9). Cytotoxicity was then evaluated by 3-(4,5-dimethyl-2-thiazolyl)¬2,5-diphenyl¬2H-tetrazolium bromide (MTT) assay, lactate dehydrogenase release, production of reactive oxygen species (ROS), and incidence of apoptosis. We also investigated how the myocardial cellular effects of CYS9 were modified by acrolein scavenger N-acetylcysteine (NAC), antioxidant isorhamnetin (ISO), and CYP inhibitor β-ionone (BIO). Quantifying CY and CY metabolites by means of liquid chromatography coupled with electrospray tandem mass spectrometry, we assayed culture supernatants of CYS9 with and without candidate cardioprotectant agents. Assay results for MTT showed that treatment with CY (125–500 μM) did not induce cytotoxicity. CYS9, however, exhibited myocardial cytotoxicity when CY concentration was 250 μM or more. After 250 μM of CY was metabolized in S9 mix for 2 h, the concentration of CY was 73.6 ± 8.0 μM, 4-hydroxy-cyclophosphamide (HCY) 17.6 ± 4.3, o-carboxyethyl-phosphoramide (CEPM) 26.6 ± 5.3 μM, and acrolein 26.7 ± 2.5 μM. Inhibition of CYS9-induced cytotoxicity occurred with NAC, ISO, and BIO. When treated with ISO or BIO, metabolism of CY was significantly inhibited. Pre-treatment with NAC, however, did not inhibit the metabolism of CY: compared to control samples, we observed no difference in HCY, a significant increase of CEPM, and a significant decrease of acrolein. Furthermore, NAC pre-treatment did not affect intracellular amounts of ROS produced by CYS9. Since acrolein seems to be heavily implicated in the onset of cardiotoxicity, any competitive metabolic processing of CY that reduces its transformation to acrolein is likely to be an important mechanism for preventing cardiotoxicity.

Autoinduction of Voriconazole Metabolism in a Child with Invasive Pulmonary Aspergillosis

Inter- and intra-patient variability in voriconazole pharmacokinetics has been described in children as the result of age-specific differences in hepatic metabolism, saturable nonlinear pharmacokinetics, CYP450 2C19 polymorphisms, decreased bioavailability compared with adults, and drug-drug interactions. We introduce dose-dependent autoinduction of metabolism as another cause for altered voriconazole pharmacokinetics in children and summarize previously published literature on this phenomenon. A 10-year-old girl with severe aplastic anemia developed invasive pulmonary aspergillosis after high-dose cyclophosphamide therapy and required high doses of voriconazole for longer than 2months. She initially achieved a therapeutic trough of 1.4μg/ml on voriconazole 11mg/kg/dose orally every 12hours but required dose escalations to 9.3mg/kg/dose orally every 8hours to maintain a trough above 1μg/ml. Because there were no changes in concomitant medications, route of administration, adherence, or oral intake, we conclude that the only plausible explanation for the precipitous drop in voriconazole troughs was autoinduction of metabolism, a phenomenon previously reported in adults receiving higher than usual doses or prolonged courses (longer than 2months). These data highlight the need for continued therapeutic drug monitoring of voriconazole after initial therapeutic troughs are achieved because autoinduction of metabolism can lead to significant declines in subsequent voriconazole troughs, potentially leading to treatment failure.

Improved outcome of adult Burkitt lymphoma/leukemia with rituximab and chemotherapy: report of a large prospective multicenter trial

AbstractThis largest prospective multicenter trial for adult patients with Burkitt lymphoma/leukemia aimed to prove the efficacy and feasibility of short-intensive chemotherapy combined with the anti-CD20 antibody rituximab. From 2002 to 2011, 363 patients 16 to 85 years old were recruited in 98 centers. Treatment consisted of 6 5-day chemotherapy cycles with high-dose methotrexate, high-dose cytosine arabinoside, cyclophosphamide, etoposide, ifosphamide, corticosteroids, and triple intrathecal therapy. Patients >55 years old received a reduced regimen. Rituximab was given before each cycle and twice as maintenance, for a total of 8 doses. The rate of complete remission was 88% (319/363); overall survival (OS) at 5 years, 80%; and progression-free survival, 71%; with significant difference between adolescents, adults, and elderly patients (OS rate of 90%, 84%, and 62%, respectively). Full treatment could be applied in 86% of the patients. The most important prognostic factors were International Prognostic Index (IPI) score (0-2 vs 3-5; P = .0005), age-adjusted IPI score (0-1 vs 2-3; P = .0001), and gender (male vs female; P = .004). The high cure rate in this prospective trial with a substantial number of participating hospitals demonstrates the efficacy and feasibility of chemoimmunotherapy, even in elderly patients. This trial was registered at www.clinicaltrials.gov as #NCT00199082.

Mechanisms and Prevention of Fatal Cardiotoxicity Following High-Dose Cyclophosphamide Therapy

Background: High-dose Cyclophosphamide (CY) is a mainstay in most conditioning regimens for hematopoietic stem cell transplantation. Recently, high-dose, posttransplantation CY, a novel effective strategy for preventing graft-versus-host disease, has been attracting a lot of attention. CY is activated by the hepatic cytochrome P-450 (CYP) enzyme system to form 4-hydroxy-cyclophosphamide (HCY), which is in equilibrium with aldocyclophosphamide (AldoCY). Depending on the type of the cell, AldoCY decomposes to form cytotoxic phosphoramide mustard and the byproduct acrolein. Alternatively, aldoCY is oxidized to the inactive metabolite o-carboxyethylphosphoramide mustard (CEPM) by aldehyde dehydrogenase1 (ALDH1). The dose-limiting toxic effect of CY, observed only after administration of high-doses, is cardiotoxicity. Since the mechanism underlying this phenomenon has not yet been elucidated, we investigated the cardiotoxic mechanisms of high-dose CY. To determine preliminary mechanisms that may prevent the occurrence of CY-induced cytotoxicity in H9C2 cells, we also evaluated the protective effects of potential cardioprotectant agents (PCA).Methods: A rat cardiac myocardial cell line, H9C2, was exposed to CY metabolized by S9 fraction of rat liver homogenate mixed with co-factors (CYS9). The concentration of CY in this experiment was determined based on values measured in blood samples from patients receiving CY in high doses. The degree of cytotoxicity was then evaluated by MTT assay, LDH release, production of reactive oxygen species (ROS), and incidence of apoptosis. We also investigated how the myocardial cellular effects of CYS9 were modified by acrolein scavenger N-acetylcysteine (NAC), antioxidant isorhamnetin (ISO), and ƒÀ-ionone (BIO) a CYP inhibitor. Quantifying CY and CY metabolites, using liquid chromatography coupled with electrospray tandem mass spectrometry (LC/MS/MS), we assayed culture supernatants of CYS9 with or without PCA and also tested with HCY, CEPM and acrolein. In addition, we observed the cytotoxicity of CYS9 and the protective effects of PCA using a live-cell imaging system. Finally, using leukemia cell lines, we confirmed whether each of the above PCAs inhibits the antileukemic effects of CYS9.Results: The peak average concentration of CY in three patients receiving high-dose CY therapy was 257 ± 46 ƒÊM. After 250 ƒÊM of CY was metabolized in S9 mix for 2 h, the concentration of HCY was 17.6 ± 4.3, CEPM 26.6 ± 5.3 ƒÊM, and acrolein 30.8 ± 1.3 ƒÊM. Assay results for MTT and LDH release showed that treatment with CY (500 ƒÊM) did not cause cytotoxicity. However, CYS9 (CY 250 ƒÊM) exhibited myocardial cytotoxicity. NAC, ISO, and BIO all inhibited CYS9-induced cytotoxicity (Fig.1). When treated with ISO or BIO, metabolism of CY was significantly inhibited. Pre-treatment with NAC, however, did not inhibit the metabolism of CY. Compared to control samples, we observed no difference in HCY, a significant increase of CEPM, and a significant decrease of acrolein (Fig.2). Furthermore, NAC pre-treatment did not affect intracellular ROS levels produced by CYS9. Live-cell imaging also confirmed that CYS9 induced acute cytotoxicity, which was inhibited by NAC. Finally, NAC did not inhibit the CYS9-induced antileukemic effect.Discussion: According to results from LC/MS/MS, we ascertained that, when metabolized in vitro by S9, CY would produce similar levels of metabolic substance concentrations as in vivo. When H9C2 was pre-treated with NAC, ISO, and BIO, each inhibited cell damage by CYS9. When treated with ISO and BIO, we observed that CY metabolism itself was inhibited. This result suggests that cardiac cell damage may depend on individual differences in CY metabolic capacity. As preventative drugs, however, both BIO and ISO seem likely to interfere with antitumor effects and are thought to be unsuitable.NAC pre-treatment did not inhibit CY metabolism: compared to control samples, there was no difference in HCY concentration, but there was a significant increase in CEPM concentration. Less acrolein, however, was present after exposure to NAC. The increase in CEPM suggests that scavenging of acrolein by NAC prevents inhibition of ALDH1; in the absence of acrolein, AldoCY is metabolized to CEPM. NAC attenuates high-dose CY induced cardiotoxicity through a mechanism related to its ability to decrease of acrolein. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Lupus mesenteric vasculitis: Clinical features and associated factors for the recurrence and prognosis of disease

ObjectiveTo evaluate the clinical characteristics of lupus mesenteric vasculitis (LMV) and identify the potential factors and appropriate treatments that are associated with disease relapse and prognosis in LMV. MethodsA retrospective cohort study was performed among patients admitted to the First Affiliated Hospital of Sun Yet-sen University between 2002 and 2011. Demographic information, clinical symptoms, laboratory findings, imaging characteristics like abdominal CT scan, ultrasonography, medications including corticosteroid, cyclophosphamide, and other immunosuppressive agents, and outcomes were documented. The endpoints of the study were defined as occurrence of severe complications that needed surgical intervention, disease recurrence, or death. ResultsOut of 3823 systemic lupus erythematosus (SLE) patients, 97 were diagnosed with mesenteric vasculitis with the overall prevalence of 2.5%. Among these 97 LMV patients, 13 died because of serious complications (13/97, 13.4%) and 2 presented intestinal perforation during the induction therapy stage. The logistic regression multivariate analysis indicated that leukopenia [peripheral WBC, odds ratio (OR) = 0.640, 95% confidence interval (CI): 0.456–0.896, P = 0.009], hypoalbuminemia (serum albumin, OR = 0.891, 95% CI: 0.798–0.994, P = 0.039) and elevated serum amylase (OR = 7.719, 95% CI: 1.795–33.185, P = 0.006) were positively associated with the occurrence of serious complications, while intravenous cyclophosphamide (CYC) therapy inhibited the occurrence of serious complications (OR = 0.220, 95% CI: 0.053–0.903, P = 0.036). A total of 79 patients who achieved remission were followed-up for 2–96 months and 18 cases experienced disease relapse (18/79, 22.8%). The statistical analysis adjusted by Cox proportional hazards models indicated that high-dose CYC therapy (≥1.0g/m2/month) was a protective factor for disease relapse and led to better outcomes [hazard ratio (HR) = 0.209, 95% CI: 0.049–0.887, P = 0.034], while the severe thickness of the bowel wall (>8mm) was a risk factor (HR = 7.308, 95% CI: 1.740–30.696, P = 0.007). LMV and lupus cystitis occurred concurrently in 22 (22/97, 22.7%) patients, and the symptoms of urinary tract resolved after treatment with corticosteroid and immunosupressants. ConclusionLMV is one of the serious complications of SLE with high mortality. The current study demonstrated that leukopenia, hypoalbuminemia, and elevated serum amylase were associated with severe adverse events, while CYC therapy led to better outcomes during remission-induction stage. Severe thickness of the bowel was a risk factor while high-dose CYC therapy was a protective factor for disease relapse in intensification therapy stage. It is necessary to evaluate the urinary tract involvement once LMV is diagnosed due to the frequent coexistence of these 2 diseases.

High-Dose Cyclophosphamide Therapy Associated with Diffuse Alveolar Hemorrhage after Allogeneic Hematopoietic Stem Cell Transplantation

Background: The occurrence of diffuse alveolar hemorrhage (DAH) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is rare but severe. There are few reports that have examined the correlation between pre-HSCT chemotherapeutic exposure and DAH. Objectives: We examine the role of pre-HSCT chemotherapeutic exposure, conditioning regimens, pre-HSCT comorbidities and transplant-related complications in the development of DAH after allo-HSCT and evaluate the effect of the high-dose corticosteroid strategy on DAH. Methods: A retrospective nested case-control study was designed. Cases with DAH and controls matched for year of allo-HSCT and length of follow-up were identified from a cohort of 597 patients who underwent allo-HSCT between 2006 and 2011 for acute leukemia. Results: Twenty-two patients suffered from DAH; the mean age at the time of presentation was 30.4 years (±12.9) and the mean time to presentation was 7.8 months (±8.1) post-HSCT. The pre-HSCT cyclophosphamide exposure and the cumulative cyclophosphamide dose were significantly higher among the DAH cases compared with the controls, and the cumulative cyclophosphamide dose of ≥5 g/m² was independently associated with DAH (OR = 3.4, p = 0.030). High-dose corticosteroid treatment did not significantly improve survival. Conclusions: From these results we can identify patients who are at a higher risk of developing DAH after allo-HSCT, and we found that high-dose corticosteroid therapy may not alter the poor outcome associated with this syndrome.

Rapid and complete reconstitution of autologous haemopoiesis after cord blood infusion in treatment‐naive patients with severe aplastic anemia receiving high‐dose cyclophosphamide/ATG therapy

Although high-dose cyclophosphamide seems to achieve durable complete remission, there are still concerns about its too much early toxicity. So, we designed a clinical study to investigate the effects of high-dose cyclophosphamide/ATG combined with cord blood infusion as first-line therapy for patients with severe aplastic anemia. Between January 2003 and September 2007, we treated 16 treatment-naive patients with severe aplastic anemia with cord blood infusion after high-dose cyclophosphamide (50mg/kg/d×2) and rabbit antithymocyte globulin (3mg/kg/d×5) therapy. Although only one patient had durable full donor engraftment, 14 of the enrolled 16 patients had rapid autologous hematopoietic recovery. The median recovery time for neutrophils and platelets was only 23 and 37d after infusion of cord blood. Of the 15 responding patients, all patients achieved treatment-free remission: nine patients met the criteria for a complete remission; six patients achieved a partial remission. Infusion of cord blood after high-dose cyclophosphamide/ATG resulted in a rapid autologous hematologic recovery and a high response rate in patients with treatment-naive patients with severe aplastic anemia. These promising results merit further investigation and confirmation on a larger number of patients.

Safety and feasibility of high-dose ranimustine (MCNU), carboplatin, etoposide, and cyclophosphamide (MCVC) therapy followed by autologous stem cell transplantation for malignant lymphoma

High-dose chemotherapy followed by autologous stem cell transplantation (auto-SCT) is widely used as a salvage therapy in the treatment of refractory malignant lymphoma. To investigate the safety and feasibility of a high-dose MCNU, carboplatin, etoposide and cyclophosphamide (MCVC) regimen, we conducted a prospective multicenter trial. Thirty patients with relapsed/refractory/poor-risk non-Hodgkin lymphoma (NHL n = 27) or Hodgkin lymphoma (HD n = 3) were uniformly treated with an MCVC regimen and underwent auto-SCT. The median follow-up duration of the surviving patients was 67 months (56-133 months). The major toxicities were anorexia (94 %), diarrhea (80 %), nausea (79 %), febrile neutropenia (70 %), alopecia (67 %) and mucositis (60 %). Three patients developed severe left ventricular dysfunction, and two patients developed severe sinusoidal obstructive syndrome (SOS). Of these patients, two died without disease progression. Treatment-related mortality was 6.6 %. Late-onset adverse events including two cases of cytomegalovirus pneumonia and one of interstitial pneumonia were observed. In DLBCL (n = 13) and transformed FL (n = 2) patients, OS and EFS at 3 years were 72 and 46 %, respectively. These results suggest that the MCVC regimen followed by auto-SCT is a feasible and tolerable therapy for relapsed/refractory malignant lymphoma. However, cardiac toxicity due to high-dose cyclophosphamide and development of SOS can occur and should be carefully monitored. Further follow-up is needed to evaluate the long-term efficacy and safety of this regimen.

A case of rapidly progressive IgA nephropathy in a patient with exacerbation of Crohn’s disease

BackgroundIgA nephropathy has been reported as a renal involvement in Crohn’s disease. Crescentic IgA nephropathy, which accounts for fewer than 5% of cases of IgA nephropathy, has a poorer prognosis than other forms of crescentic glomerulonephritis. We recently experienced a case of rapidly progressive IgA nephropathy concurrent with exacerbation of Crohn’s disease.Case presentationAn 18-year-old male diagnosed with Crohn’s disease underwent a hemicolectomy 2 years prior previously. He had maintained a state of Crohn’s disease remission with 5-aminosalicylic acid treatment. Four months prior to referral to the nephrology clinic, he experienced non-bloody diarrhea. He simultaneously developed proteinuria and microscopic hematuria with deterioration of renal function. Based on renal biopsy findings, the patient was diagnosed with crescentic IgA nephropathy. Immunostaining for interleukin-17 in renal tissue and previous exacerbated colonic ulcers was positive. Steroid pulse therapy was administered, followed by high-dose glucocorticoid and oral cyclophosphamide therapy. The patient’s renal function recovered and his gastrointestinal symptoms were alleviated.ConclusionsWe report a case of crescentic IgA nephropathy presenting with exacerbation of Crohn’s disease, and present a review of the literature focusing on the pathophysiologic relationship between these two conditions.

Natural history of paroxysmal nocturnal hemoglobinuria clones in patients presenting as aplastic anemia

To investigate the natural history of paroxysmal nocturnal hemoglobinuria (PNH) clones in patients with acquired aplastic anemia (AA). Twenty-seven patients with AA and a detectable PNH clone were monitored for a median of 5.7 years (range 1.5-11.5 years). Twenty-two patients received high-dose cyclophosphamide (HiCy) therapy. The erythrocyte and granulocyte PNH clone sizes were measured using flow cytometry and analyzed via CellQuest software. PE-conjugated anti-glycophorin A, anti-CD15, FITC-conjugated anti-CD59, and FLAER staining were used to define glycosylphosphatidylinositol-AP-deficient cells. We found a linear relationship between PNH clone size and the development of intravascular hemolysis, assessed by lactate dehydrogenase (LDH) values (Pearson correlation coefficient = 0.80, P < 0.001 for erythrocyte PNH clones; and Pearson correlation coefficient = 0.73, P < 0.0001 for granulocyte PNH clones). An erythrocyte PNH size of 3-5% and granulocyte PNH size of 23% were the thresholds to predict hemolysis as measured by an elevated LDH (receiver operating characteristic analyses with AUC = 0.96 for erythrocyte PNH clone sizes and AUC = 0.88 for granulocyte PNH clone sizes). Patients with small (≤15%) initial PNH clone sizes were less likely to develop an elevated LDH (mean ± SD: 236.9 ± 109.9 vs. 423.1 ± 248.8; P = 0.02). Over time, the PNH clone sizes remained stable in 25.9% of patients; 48.1% experienced a rise in the PNH clone size; and 25.9% experienced a decrease. The risk of developing clinically significant PNH after HiCy therapy appears to be low in AA patients with PNH clones, especially for those with small initial PNH clones and for those who respond to HiCy therapy.

High-Dose Cyclophosphamide Without Stem Cell Rescue in 207 Patients With Aplastic Anemia and Other Autoimmune Diseases

High-dose cyclophosphamide has long been used as an anticancer agent, a conditioning regimen for hematopoietic stem cell transplantation, and a potent immunosuppressive agent in autoimmune diseases including aplastic anemia. High-dose cyclophosphamide is highly toxic to lymphocytes but spares hematopoietic stem cells because of their abundant levels of aldehyde dehydrogenase, the major mechanism of cyclophosphamide inactivation. High-dose cyclophosphamide therapy induces durable remissions in most patients with acquired aplastic anemia. Moreover, high-dose cyclophosphamide without hematopoietic stem cell rescue has shown activity in a variety of other severe autoimmune diseases. Here we review the history of cyclophosphamide as it applies to aplastic anemia and other autoimmune diseases. We include historical data from early patients treated for aplastic anemia as well as data from 140 patients from an observational retrospective study in a single tertiary care hospital. This latter component was designed to assess the safety and efficacy of high-dose cyclophosphamide therapy without stem cell rescue in patients with refractory autoimmune diseases. We analyzed the 140 patients with severe, progressive autoimmune diseases treated. All patients discussed here received cyclophosphamide, 50 mg/kg per day for 4 consecutive days. Response, relapse, and overall survival were measured. Response was defined as a decrease in disease activity in conjunction with a decrease or elimination of immune-modulating drugs. Relapse was defined as worsening disease activity and/or a requirement for an increase in dose of, or administration of new, immunosuppressive medications. Hematologic recovery occurred in all patients. The overall response rate was 94%, and 44% of those patients remained progression free with a median follow-up of 36 months (range, 1-120 mo) for the 140 patients analyzed together. The overall actuarial and event-free survival across all diseases at 60 months was 90.7% and 20.6%, respectively. High-dose cyclophosphamide without stem cell rescue is well tolerated and induces a high rate of remission in severe autoimmune diseases.

High-Dose Cyclophosphamide Without Stem Cell Rescue for the Treatment of Refractory Behcet's Disease

Behcet's disease (BD) is a systemic inflammatory disorder characterized by recurrent mucocutaneous ulcerations, ocular inflammation, and numerous severe systemic inflammatory manifestations. While most patients respond to standard immunosuppressive therapies, a subset will develop refractory disease. In this report, the use of a novel therapy for the treatment of BD is described. Two patients with severe refractory BD who were treated with nonmyeloablative high-dose cyclophosphamide therapy without stem cell rescue. After treatment, both patients were completely weaned off immunosuppressive therapy and entered disease-free remissions of 18 and 24 months, respectively. These data suggest high-dose cyclophosphamide therapy without stem cell rescue as an alternative for the treatment of refractory BD.