Delayed-onset Neutropenia Research Articles

In patients with follicular lymphoma, delayed-onset neutropenia induced by anti-CD20 monoclonal antibodies frequently occurs during maintenance therapy and is preferentially associated with obinutuzumab.

The prevalence of anti-CD20 monoclonal antibody (MoAb)-associated delayed-onset neutropenia (DON) varies between 8 and 27%. Despite the wide use of MoAbs as maintenance in follicular lymphoma (FL), data regarding DON occurrence and clinical consequences are limited. This study assessed DON prevalence, severity and risk factors in FL patients during maintenance. Data were retrieved from electronic medical records of FL patients treated at Rambam between 2006 and 2021. The maintenance cohort included 155 patients receiving 165 treatment courses; the non-maintenance cohort included 58 patients receiving 67 courses. Median time on maintenance was 1.81 ± 0.28 years. During maintenance, 23.2% of patients developed DON, with 13.8% experiencing at least one recurrent event. In the non-maintenance cohort, 29.3% developed DON, with 38.8% recurrence. Median time from maintenance initiation to the first neutropenic episode was 5 (1.25-12) months, whereas in the non-maintenance cohort, DON occurred earlier [1.9 (0.97-3.71) months; p = 0.06]. The only DON risk factors in patients on maintenance were induction with the obinutuzumab/bendamustine combination [odds ratio (OR): 4.546 (95%CI = 1.419-14.563); p = 0.011] or obinutuzumab maintenance [OR: 3.138 (95%CI = 1.23-7.94); p = 0.016]. In the non-maintenance cohort, such factors included ≥ 1 line of therapy [OR: 3.93 (95%CI = 1.00-15.38); p = 0.04] and a lower absolute neutrophil count at induction completion. Differences in the likelihood of DON development between patients receiving maintenance with obinutuzumab or rituximab possibly reflect mechanistic dissimilarities between type I and type II MoAbs. Regardless, prolonged MoAb use bears a mitigatory effect, reducing recurrence of DON. The findings obtained could assist in predicting the risk of DON in individual FL patients, optimizing informed treatment choices.

A Phase 2, Randomized, Multicenter, Placebo-Controlled, Proof-of-Concept Trial of Oral Fexinidazole in Adults With Chronic Indeterminate Chagas Disease.

Chagas disease (CD) has significant global health impact, but safe, effective treatments remain elusive. The nitroimidazole fexinidazole is a potential treatment. This double-blind, randomized, placebo-controlled, dose-finding, proof-of-concept study was conducted in Bolivia. Adults with serologically confirmed chronic indeterminate CD and positive PCR were randomly assigned to 1 of 6 fexinidazole regimens (1200 or 1800 mg/day for 2, 4, or 8 weeks) or placebo. Target recruitment was 20 patients/arm. The primary endpoint was sustained parasitological clearance by serial negative qPCR from end of treatment (EOT) until 6 months follow-up in the intention-to-treat (ITT) population. Follow-up was extended to 12 months. Enrollment was interrupted after 4/47 patients presented with transient asymptomatic grade 3 and 4 neutropenia. Treatment of ongoing patients was stopped in all patients administered >2 weeks. A total of 40 patients received treatment with fexinidazole from 3 days to 8 weeks. Delayed-onset neutropenia (n = 8) and increased liver enzymes (n = 8) were found in fexinidazole patients vs none in the placebo arm. In the ITT analysis, sustained parasitological clearance from EOT to 12 months follow-up varied between 66.7% (1200 mg-2 week) and 100.0% (1800 mg-2 week). Rapid, sustained clearance of parasitemia was observed in all treated patients with available data, but not in any patients in the placebo group, at 12 months (P = .0056). Further exploratory exposure-response analysis suggested low dosages of fexinidazole may be safe and effective. Further evaluation is needed to establish fexinidazole's minimum effective dosage and risk-benefit relationship. Results suggest potential for effective treatment regimens <10 days. NCT02498782.

A Rodent Model of Sulfur Mustard Hematologic Toxicity for the Efficacy Evaluation of Candidate Medical Countermeasures.

While exposure to sulfur mustard (SM) is commonly associated with the production of vesicating dermal, ocular, and respiratory injuries, systemic damage to bone marrow and lymphatic tissue can decrease critical immune cell populations leading to higher susceptibility to life-threatening infection and septicemia. There are currently no approved medical countermeasures for SM-induced myelosuppression. An intravenous SM challenge model was developed in adult rats as a preliminary proof-of-principle platform to evaluate the efficacy of candidate immunostimulants. Adult male and female Sprague Dawley rats were exposed to SM through tail vein injection. Toxicity progression was monitored through clinical observations, body weights, body temperatures, hematology, serum clinical chemistry, and flow cytometry of blood and bone marrow samples. Following SM exposure, overt toxicity progression was characterized by weight loss, changes in body temperature, and manifestation of toxic clinical signs (diarrhea, lethargy, hunched posture, rough hair coat, respiratory distress, and death). Drastic alterations in complete blood cell profiles included an early-onset lymphopenia followed by a delayed-onset neutropenia and thrombocytopenia. Only transient changes in serum clinical chemistry parameters were observed. Flow cytometry analysis of circulating blood revealed that B-cells were more predominantly affected by SM exposure than T-cells. Challenge with SM resulted in loss of hematopoietic and mesenchymal stem cell populations in the bone marrow. The small animal model developed in this study replicates many key aspects of human SM exposures and should serve as a relevant, rapid, and cost-effective platform to screen candidate medical countermeasures for SM-induced hematologic toxicity.

Acute Cellular Rejection in ABO-Incompatible Renal Transplant Recipients Receiving Rituximab Is Associated with Delayed-Onset Neutropenia.

BACKGROUND Rituximab induces long-lasting B cell depletion in the peripheral blood and increases the levels of proinflammatory cytokines associated with regulatory B cell depletion. Previous reports showed that B cell-related cytokine release after administration of rituximab may induce acute cellular rejection (ACR) and delayed-onset neutropenia. The present study was conducted to investigate the correlation between acute rejection and delayed-onset neutropenia in ABO-incompatible renal transplant recipients who underwent administration of rituximab for 1 year after transplantation. MATERIAL AND METHODS From June 2006 to July 2015, 47 patients with chronic renal failure received ABO-incompatible renal transplant with rituximab induction at Osaka City University Hospital. All 47 patients underwent plasmapheresis due to removal of anti-A/B antibodies and administration of rituximab, and their transplants were carried out successfully. We investigated the correlation between ACR and delayed-onset neutropenia in ABO-incompatible renal transplant recipients who underwent administration of rituximab for 1 year after transplantation. RESULTS Fourteen patients (29.8%) experienced ACR (group A), and 33 recipients did not develop ACR (group B). The frequency of delayed-onset neutropenia was higher in group A than in group B (p=0.0503). Multivariate logistic regression analysis revealed that the frequency of ACR correlated significantly with the prevalence of delayed-onset neutropenia. CONCLUSIONS Our results indicated that ACR in ABO-incompatible renal transplant recipients receiving rituximab was associated with delayed-onset neutropenia.

Late-onset neutropenia due to clozapine.

Sir, Clozapine is an antipsychotic drug effective against treatment-resistant schizophrenia. Compared with the classic neuroleptic drugs, clozapine carries a lower risk of extrapyramidal side effects.[1] Despite these advantages, clozapine-induced neutropenia and agranulocytosis can occur with a cumulative incidence of 2.7% and 0.73%, respectively.[2] Although the risk of blood dyscrasias is the highest during the first 6–18 weeks;[3] hence, this side effect can occur even after ≥5 years of treatment with clozapine.[4] Here, we report the case of a 46-year-old woman who developed neutropenia due to clozapine after 8 years of treatment. A 46-year-old woman with a history of schizophrenia since 2004 was treated with therapeutic doses of risperidone for the first 6 months after diagnosis. Because of the lack of improvement in her clinical status, risperidone was replaced by clozapine at an initial dose of 25 mg/day in December 2004; this dose was slowly titrated up to 300 mg/day. Because of her alterations in electroencephalography patterns, valproate 500 mg/day was added in May 2005. Sertraline 100 mg/day was initiated in September 2007 to treat depressive symptoms, and was discontinued in June 2008 because of the clinical improvement. Between 2004 and 2011, the results of hematological monthly monitoring were normal. Although the white blood cell (WBC) count was 6500/mm3 with an absolute neutrophil count (ANC) of 5100/mm3 in December 2011, it declined to 4100/mm3 and 3800/mm3, respectively, over 2 months (ANC was 3170/mm3 and 2660/mm3, respectively). In March 2012, her WBC count had dropped to 2100/mm3 with an ANC of 1280/mm3; however, there were no signs of infection. Laboratory tests and hematological consultations ruled out infectious diseases that could cause neutropenia. The results of her physical examination were unremarkable. After the diagnosis of neutropenia was made, all medications were discontinued, and blood counts were measured weekly. The WBC count reached the normal limit (WBC: 6300/mm3) within 3 weeks after the discontinuation of her medications. Since then, the patient's mental status has been stable with pharmacotherapy, including sertindole 16 mg/day and amisulpride 800 mg/day. Her clinical status remains good, without any recurrence of adverse hematological events. Neutropenia, in this case, could have been due to either clozapine or valproate or a combination of both. A case report described a patient who developed late-onset neutropenia because of sodium valproate; however, the drop in WBC counts emerged after dose escalation in this case.[5] To the best of our knowledge, delayed-onset neutropenia due to a stable dose of valproate has not yet been reported, although it has been observed in the association with a stable dose of clozapine, even after several years.[4] We cannot be certain drugs that caused by the side effect, because of both the drugs were discontinued at the same time, we believe that the neutropenia was most likely to be caused by clozapine. Our case report underscores the importance of regular blood monitoring in patients treated with clozapine. Clinicians should also be aware of other psychotropic medications that can impose the risk of blood dyscrasias. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.

Clinical impact and predisposing factors of delayed-onset neutropenia after autologous hematopoietic stem-cell transplantation for B-cell non-Hodgkin lymphoma: association with an incremental risk of infectious events

BackgroundClinical significance of delayed-onset neutropenia (DON) after autologous hematopoietic stem-cell transplantation (ASCT) has not been well described. We conducted a retrospective cohort study to examine risk factors and clinical impact of DON.Design and methods: Subjects were consecutive 108 patients with B-cell lymphoma receiving ASCT. We defined DON as absolute neutrophil counts <1.0 × 109/l at any point from 30 days onward after ASCT without apparent causes of neutropenia. Documented infectious events were reviewed from 1 to 18 months after ASCT. ResultsFifty-two percent of patients received rituximab. Cumulative incidence of DON was 50% at 1 year. Rituximab usage was identified as an independent risk factor of DON. A total of 117 infectious events were documented, of which 24 events occurred during DON period. Cumulative incidence of total infectious events was 75% and 42% in the groups with and without DON, respectively (P = 0.001). Varicella–zoster virus (P = 0.033) and upper respiratory infection (P = 0.016) were frequent in the patients experiencing DON. In a multivariable analysis, DON remained a significant factor for total infectious events and upper respiratory infection. ConclusionsRituximab usage is an independent risk factor of DON. DON correlates with increased occurrence of infectious events. Careful follow-up would be needed after the onset of DON.

Rituximab And Sargramostim Immunotherapy Following Autologous Stem Cell Transplant For Aggressive Non-Hodgkin's Lymphoma

High dose chemotherapy with autologous stem cell transplant (ASCT) improves survival in patients with aggressive non-Hodgkin's lymphoma (NHL), but relapse occurs in 40-50% of patients. Rituximab exerts its anti-tumor effect through complement and antibody-dependent cell cytotoxicity (ADCC). Sargramostim is involved in the activation and differentiation of macrophages and dendritic cells and increases monocyte-mediated ADCC. The addition of sargramostim to rituximab may potentiate the anti-tumor effect of rituximab by enhancing recruitment and activation of effector cells that mediate ADCC. We evaluated the safety and efficacy of rituximab and sargramostim given as “adjuvant immunotherapy” to patients following ASCT for aggressive NHL. 8 patients (5 male, 3 female; median age 53, range 34-69) with CD20+ diffuse large B cell (6) or mantle cell (2) NHL relapsed, primary refractory or in first complete remission (intermediate-high or high risk IPI) underwent stem cell mobilization using rituximab and cyclophosphamide followed by high dose chemotherapy with rituximab, carmustine, etoposide, cytarabine and melphalan. Adjuvant immunotherapy consisted of rituximab 375 mg/M2 IV weekly and sargramostim 250 ug s.c. TIW during weeks 5 to 8 and 24 to 27 post transplant. Seven patients had successful mobilization (mean CD34/kg collected 12.5E6 and infused 9E6) and underwent transplant. Median time to neutrophil and platelet engraftment was 9 and 10 days respectively. Six patients are alive with no evidence of disease from 3 to 18 months post transplant. One patient relapsed at 11 months. 4/4 patients receiving at least once cycle of adjuvant immunotherapy developed grade 1 to 4 neutropenia from 3 to 34 weeks post adjuvant rituximab. Neutrophil counts recovered following treatment with G-CSF, but recurred in all 4 patients without additional exposure to rituximab. One patient who had engrafted platelets developed grade 2 thrombocytopenia on day 33 post transplant. Platelets spontaneously recovered. Delayed-onset neutropenia is a known complication of rituximab. The incidence may be higher when rituximab is used following ASCT. It is not clear if the timing of rituximab administration post transplant or the concomitant use of sargramostim contributed to the high incidence of delayed neutropenia in this study. Larger studies and longer followup will be needed to determine if adjuvant immunotherapy decreases relapse.

Severe thrombocytopenia and fibrinolysis mimicking disseminated intravascular coagulation after rituximab infusion

American Journal of HematologyVolume 85, Issue 2 p. 146-146 CorrespondenceFree Access Severe thrombocytopenia and fibrinolysis mimicking disseminated intravascular coagulation after rituximab infusion† Ioannis Kotsianidis, Ioannis Kotsianidis Department of Hematology, Democritus University of Thrace Medical School, Alexandroupolis, GreeceSearch for more papers by this authorAggelos Goutzouvelidis, Aggelos Goutzouvelidis Department of Hematology, Democritus University of Thrace Medical School, Alexandroupolis, GreeceSearch for more papers by this authorAthanasios Anastasiades, Athanasios Anastasiades Department of Hematology, Democritus University of Thrace Medical School, Alexandroupolis, GreeceSearch for more papers by this authorIrene Bouchliou, Irene Bouchliou Department of Hematology, Democritus University of Thrace Medical School, Alexandroupolis, GreeceSearch for more papers by this authorEvangelia Nakou, Evangelia Nakou Department of Hematology, Democritus University of Thrace Medical School, Alexandroupolis, GreeceSearch for more papers by this authorEmmanouil Spanoudakis, Emmanouil Spanoudakis Department of Hematology, Democritus University of Thrace Medical School, Alexandroupolis, GreeceSearch for more papers by this authorAnna V. Christophoridou, Anna V. Christophoridou Department of Hematology, Democritus University of Thrace Medical School, Alexandroupolis, GreeceSearch for more papers by this authorDimitrios Margaritis, Dimitrios Margaritis Department of Hematology, Democritus University of Thrace Medical School, Alexandroupolis, GreeceSearch for more papers by this authorGeorge Bourikas, George Bourikas Department of Hematology, Democritus University of Thrace Medical School, Alexandroupolis, GreeceSearch for more papers by this authorCostas Tsatalas, Costas Tsatalas Department of Hematology, Democritus University of Thrace Medical School, Alexandroupolis, GreeceSearch for more papers by this author Ioannis Kotsianidis, Ioannis Kotsianidis Department of Hematology, Democritus University of Thrace Medical School, Alexandroupolis, GreeceSearch for more papers by this authorAggelos Goutzouvelidis, Aggelos Goutzouvelidis Department of Hematology, Democritus University of Thrace Medical School, Alexandroupolis, GreeceSearch for more papers by this authorAthanasios Anastasiades, Athanasios Anastasiades Department of Hematology, Democritus University of Thrace Medical School, Alexandroupolis, GreeceSearch for more papers by this authorIrene Bouchliou, Irene Bouchliou Department of Hematology, Democritus University of Thrace Medical School, Alexandroupolis, GreeceSearch for more papers by this authorEvangelia Nakou, Evangelia Nakou Department of Hematology, Democritus University of Thrace Medical School, Alexandroupolis, GreeceSearch for more papers by this authorEmmanouil Spanoudakis, Emmanouil Spanoudakis Department of Hematology, Democritus University of Thrace Medical School, Alexandroupolis, GreeceSearch for more papers by this authorAnna V. Christophoridou, Anna V. Christophoridou Department of Hematology, Democritus University of Thrace Medical School, Alexandroupolis, GreeceSearch for more papers by this authorDimitrios Margaritis, Dimitrios Margaritis Department of Hematology, Democritus University of Thrace Medical School, Alexandroupolis, GreeceSearch for more papers by this authorGeorge Bourikas, George Bourikas Department of Hematology, Democritus University of Thrace Medical School, Alexandroupolis, GreeceSearch for more papers by this authorCostas Tsatalas, Costas Tsatalas Department of Hematology, Democritus University of Thrace Medical School, Alexandroupolis, GreeceSearch for more papers by this author First published: 18 November 2009 https://doi.org/10.1002/ajh.21597Citations: 5 † Conflict of interest: Nothing to report. AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat References 1 Byrd JC,Waselenko JK,Maneatis TJ, et al. Rituximab therapy in hematologic malignancy patients with circulating blood tumor cells: Association with increased infusion-related side effects and rapid blood tumor clearance. J Clin Oncol 1999; 17: 791– 795. 2 O'Brien SM,Kantarjian H,Thomas DA, et al. Rituximab dose-escalation trial in chronic lymphocytic leukemia. J Clin Oncol 2001; 19: 2165– 2170. 3 Cattaneo C,Spedini P,Casari S, et al. Delayed-onset peripheral blood cytopenia after rituximab: Frequency and risk factor assessment in a consecutive series of 77 treatments. Leuk Lymphoma 2006; 47: 1013– 1017. 4 Chaiwatanatorn K,Lee N,Grigg A, et al. Delayed-onset neutropenia associated with rituximab therapy. Br J Haematol 2003; 121: 913– 918. 5 Ram R,Bonstein L,Gafter-Gvili A, et al. Rituximab-associated acute thrombocytopenia: An under-diagnosed phenomenon. Am J Hematol 2009; 84: 247– 250. 6 Dhand S,Bahrain H. Rituximab-induced severe acute thrombocytopenia: A case report and review of literature. Cancer Invest 2008; 26: 913– 915. 7 Thachil J,Mukherje K,Woodcock B. Rituximab-induced haemorrhagic thrombocytopenia in a patient with hairy cell leukaemia. Br J Haematol 2006; 135: 273– 274. 8 Viero P,Cortelazzo S,Barbui T,Semeraro N. Generation of procoagulant activity by hairy cells in response to endotoxin and phorbol esters. Eur J Cancer Clin Oncol 1986; 22: 857– 862. Citing Literature Volume85, Issue2February 2010Pages 146-146 ReferencesRelatedInformation

Delayed-Onset Neutropenia Associated with Divalproex Sodium; Acute Psychosis Induced by Clarithromycin; Acute Phase Reaction with Ibandronate; Duloxetine-Associated Tachycardia; Hepatotoxicity with Valerian; Serotonin Syndrome with a Single Dose of Buprenorphine/Naloxone

The purpose of this feature is to heighten awareness of specific adverse drug reactions (ADRs), discuss methods of prevention, and promote reporting of ADRs to the US Food and Drug Administration's (FDA's) MedWatch program (800-FDA-1088). If you have reported an interesting, preventable ADR to MedWatch, please consider sharing the account with our readers.

Delayed-Onset Neutropenia with Divalproex Sodium

To report the development of neutropenia in a patient after almost 8 years of being stabilized on delayed-release divalproex sodium (DVPX). A 45-year-old man had been maintained on DVPX for nearly 8 years, with serum valproic acid concentrations of 85-128 mg/L and normal white blood cell (WBC) counts and absolute neutrophil counts (ANCs). Five months prior to the development of neutropenia (defined as ANC <1800 cells/microL), the patient's DVPX dosage was decreased by 250 mg to 1250 mg every morning and 1500 mg every evening. After 2 months of that regimen, the DVPX dosage was increased back to 1500 mg twice daily. Three months after that increase, the patient's WBC count dropped to 3.7 x 10(3)/microL and ANC was 1199 cells/microL. Although the ANC was below 1800 cells/microL, he showed no physical manifestations consistent with neutropenia. DVPX was discontinued, and 2 weeks later the patient's WBC count was 7.2 x 10(3)/microL and ANC was 2290 cells/microL. Although a complete blood cell count with differential is a commonly accepted form of therapeutic drug monitoring with DVPX, the monitoring is considered most necessary to identify dose-related thrombocytopenia. However, neutropenia has been rarely associated with the use of DVPX and could contribute to the development of different types of infection, including those of a bacterial, viral, or fungal origin. Although neutropenia is generally mild in severity, potentially severe DVPX-associated neutropenia can occur any time during the course of therapy, although it is most common within the first few months of treatment. In this case, DVPX was the probable cause of the neutropenia, according to the Naranjo probability scale. However, this case of neutropenia is atypical with respect to the timeframe in which it developed and was identified. Although the documented laboratory findings suggest neutropenia, the patient did not experience any clinical complications as a result. The late onset of the patient's neutropenia is unlike other cases that have been documented in the literature. Hematologic therapeutic drug monitoring continues to be clinically important regardless of whether the patient is early in therapy or even years later in the course. In this patient, continued regular therapeutic drug monitoring identified a suspected drug-related complication and the medication was able to be discontinued without the development of clinical complications.

Clinical Significance and Risk Factors of Delayed-Onset Neutropenia (DON) after Autologous Stem Cell Transplantation (ASCT) for B-Cell Non-Hodgkin Lymphoma: A Single-Institute Analysis.

Background: DON is known as one of the adverse events after ASCT, for which rituximab usage has been reported to be a risk factor. One of the limitations in previous reports is that confounding by indication for rituximab treatment, and thus it is yet unclear if rituximab is an independent risk factor for DON. To examine the impact of rituximab considering such limitation as well as to explore possible other determinants and clinical significance of DON, we conducted a retrospective cohort study.Method: Subjects were consecutive 97 patients with B-cell non-Hodgkin lymphoma receiving ASCT between 1991 and 2007 in Aichi cancer center hospital. We defined DON as absolute neutrophil count < 0.1 x 109/L at any point after 30 days post ASCT without apparent cause of neutropenia. We investigated adverse events and risk factors using propensity score (PS), step-wise method and bootstrap resampling method. PS for preference of rituximab treatment was calculated based upon fourteen clinical factors; rituximab usage, age, sex, performance status, clinical stage, B symptom, bulky lesions, no. of extra nodal sites, lactate dehydrogenase level, no. of prior chemothearpy and local radiation, existence of bone marrow involvement, status at ASCT, and types of conditioning regimens (total-body-irradiation (TBI) containging regimens or not). Unconditional logistic regression models adjusted for PS and other potential risk factors were applied to estimates odds ratios (ORs) and their 95% confidence intervals (CIs) for occurrence of DON. Selection of potential risk factors in validation analysis was done by forward step-wise method (p-value for removal=0.10 and that for inclusion=0.05). Finally, we applied bootstrap resampling method for validation of our analyses (repeating 10,000 times with 97 sampling from original cohort).Results: 56.7% patients were treated with rituximab combined chemotherapy before ASCT, of which 26.3% had prior rituximab exposure. The median number of prior chemotherapy was one (range; one to five), and 47.4% patients received three or more prior regimens before ASCT. 22.7% patients received TBI regimen. With a median follow-up of 3.42 years, DON was observed in 46.7% patients. The lowest neutrophil count was 446 x 106/L (range; 9–992). Of the patients developing DON, 17.2% patients experienced febrile infectious events. Interstitial pneumonia (IP) was observed in 10% of the patients with DON and 5.5% without DON. No patients experienced Grade 4 or 5 events. By step-wise method, selected factors for final validation model were rituximab usage, TBI, female sex, B symptom, and prior radiation therapy. In the validation, usage of rituximab (OR=3.28: 1.07–10.0, p=0.037), and prior radiation before ASCT (1.81: 1.24–2.63, p=0.002) were identified as independent risk factors for DON. Other factors failed to demonstrate significant impact on DON.Conclusion: DON was associated with febrile infectious events in 17% patients and most of the cases achieved rapid clinical improvement. Our retrospective cohort analysis considering confounding by indication for rituximab confirmed significant impact of usage of rituximab on DON among B-cell lymphoma patients receiving autologous HSCT. Further evaluation of the impact of radiation therapy before HSCT on DON is also warranted.

Rituximab in the adjuvant treatment of pemphigus vulgaris: a prospective open-label pilot study in five patients

Rituximab is a monoclonal antibody directed against the CD20 antigen expressed on B lymphocytes. There are reports of its efficacy in the treatment of autoimmune diseases, including pemphigus. Prospectively to evaluate the efficacy of rituximab as adjuvant treatment for pemphigus vulgaris (PV). Patients with PV were treated with intravenous rituximab (375 mg m(-2)) weekly for 4 weeks in this prospective open-label pilot study. Other concurrent immunosuppression was continued. Of five patients, one achieved complete remission and was able to cease all medication, while two achieved clearance of clinical lesions but continued on systemic therapy. Two patients had progressive disease. Time to response was 2-8 months, with a 13- to 18-month response duration. Response was associated with reduction in serum antiepithelial antibodies. Two patients had significant infectious complications (one developed community-acquired pneumonia associated with delayed-onset neutropenia and the other developed cytomegalovirus infection). Rituximab has shown efficacy in the treatment of PV. Patients on multiple immunosuppressives should be closely monitored for infectious complications.

Parvovirus B19 reactivation presenting as neutropenia after rituximab treatment

A patient with primary biliary cirrhosis and associated refractory immune thrombocytopenic purpura was treated with 4 weekly courses of rituximab, a monoclonal antibody targeting B-cell surface antigen CD20. Her thrombocyte count and even cholestatic liver function tests improved. However, 17 weeks after rituximab treatment, she developed severe neutropenia (absolute neutrophil count 0.23 × 10 3/μl) and recurrent thrombocytopenia with abnormal bone marrow of all three lineages. Although delayed-onset neutropenia has been reported after rituximab, reactivated viral infections have also been encountered. Parvovirus B19 was suspected and confirmed as the cause of neutropenia in our patient. The patient was supported by GCSF treatment and recovered uneventfully after several weeks. Neutropenia after rituximab can also be the predominant manifestation of reactivated parvovirus B19 infection and have a favorable prognosis.

Delayed-Onset Neutropenia in a Patient Receiving Rituximab as Treatment for Refractory Kidney Transplantation

The use of rituximab against early refractory rejection in kidney transplantation or its preoperative administration for cross-match positive or ABO-incompatible transplants (1, 2, 3) has increased in the recent years, but caution is required regarding the occurrence of severe delayed-onset neutropenia. We describe a case of late-onset neutropenia secondary to rituximab administration. A 47-year-old woman with chronic nephritis (renal biopsy, mesangial proliferative glomerulonephritis) and a body weight of 45 kg started hemodialysis in August 2004. Blood tests for autoimmunity were negative for SLE. Then, a living-donor kidney was transplanted from her ABO-compatible sister on September 3, 2004. The preoperative cross-match and anti-HLA antibody were both negative, and FK, prednisolone, MMF, and basiliximab were used concomitantly. Early humoral rejection accompanied by decreased urine volume, edema and elevated creatinine was observed 48 hr later. Plasmapheresis was conducted in response 9 times on consecutive days, but because her condition was refractory and the risk of graft loss was imminent, rituximab at 150 mg/m2 was administered and resulted in a dramatic recovery. At her final visit on January 13, 2005, as an outpatient, her blood biochemical tests were normal with leukocyte count of 4260/μl, neutrophil count of 2340/μl, and platelet count of 27.6×104/ml, but 5 days later she was admitted into the hospital with sudden fever and diarrhea. The visceral function examination on admission was within the normal range, with leukocyte count of 1190/μl, agranulocytosis and visual determination was not possible. hypogammaglobulinemia, platelet count of 19.5×104/ml, and all viral and bacterial tests were negative. Bone mar-row biopsy revealed a condition of maturation arrest without hemophagocytosis, and the megakaryocytic series and erythrocytic series were within the normal range. With peripheral CD19 and CD20 both at 0%, the patient was placed in a clean room for supportive treatment, with consequent recovery from this neutropenia 7 days later. Six months after rituximab administration, CD19 and CD20 were both 0%, and in an examination after 8 months the values were still low with CD19 at 0.1% and CD20 at 0.5%. MMF administration was discontinued since the onset of neutropenia up till now to avoid over-immunosuppression. MMF immediately before onset was 0.5 g, and DLSTs on concomitant drugs were all negative. Since the transplant patients are not cancer patients, the absolute number of B-cells, which are the target of CD20, is much less than in the B-cell lymphoma patients, although the applied dose of rituximab for medical transplantation is 375 mg/m2 administered one to 4 times as with B-cell lymphoma. The occasional reports of severe delayed-onset neutropenia in the lymphoma patients who receive rituximab therapy (4–6) are also a cause for concern. The dose level of Rituximab to renal transplant patients was decided from the results of a phase I study on ML (7), pharmacokinetics of patients waiting for renal transplant (8). We urge the prompt establishment of methods for rituximab administration, and we also strongly warn that severe delayed-onset of neutropenia can occur even at small doses. Naoki Mitsuhata Ryuji Fujita Seiichi Ito Department of Urology Kure Kyosai Hospital Hiroshima, Japan Makoto Mannami Kojima Keimei Department of Urology Uwajima Tokushukai Hospital Uwajima, Japan

Delayed-Onset Grade 4 Neutropenia Associated with Rituximab Therapy in a Patient with Lymphoma: Case Report and Literature Review

A 53-year-old man developed delayed-onset neutropenia 6 weeks after completing first-line therapy with rituximab, cyclophosphamide, mitoxantrone, vincristine, and prednisone for high-grade B-cell lymphoma. Bone marrow biopsy demonstrated hypercellular marrow with normal maturation. He also developed interstitial pneumonitis, an adverse event associated with rituximab use. Infiltrates of T cells were found in the patient's lungs. For the next 6 months, the patient required subcutaneous granulocyte colony-stimulating factor 300 mug twice/week to maintain a granulocyte count above 1000 cells/mm3. He also received oral antibiotics for mouth sores and thrush. Based on the existing evidence, monitoring blood counts for as long as 8 weeks after rituximab therapy may be advisable, although the literature reports that neutropenia can develop up to 1 year after treatment. The development of a registry and uniform testing may help uncover the cause of this delayed-onset neutropenia.

Efficacy and Safety of Alemtuzumab in Patients with Relapsed B-Cell Chronic Lymphocytic Leukemia after Autologous Stem Cell Transplantation.

This phase II study investigated the efficacy and safety of alemtuzumab (Campath-1H), as treatment to achieve a second minimal residual disease (MRD) negative complete remission, in patients with relapsed B-cell chronic lymphocytic leukemia (B-CLL) after autologous stem cell transplantation (ASCT). Only patients who had experienced a posttransplantation MRD negative status and with a low tumour burden at relapse were eligible for the study. Eleven patients were treated. Nine patients were Binet Stage A and two patients had converted to an MRD positive status. The median time from ASCT was 36 months (range, 15–66 months). Alemtuzumab was administered as a 30 mg intravenous injection three times weekly for a maximum of 12 weeks. All patients received valacyclovir and trimethoprim/sulfamethoxazole as infection prophylaxis during therapy and 6 months after. Cytomegalovirus (CMV) reactivation was monitored weekly using a blood antigen test. Patients with Binet stage A were evaluated according to National Cancer Institute (NCI) criteria. MRD assessment was performed in complete responders and the two MRD relapses in blood and bone marrow using sensitive techniques as MRD Flow (Rawstron et al, Blood 2001, 98: 35) and nonspecific allele IgH PCR. Among nine patients assessed for disease response by NCI criteria, two (22%) achieved a partial response and five (55%) a complete remission (overall response rate [ORR], 77%). The overall median response duration was 9 months (range, 4–18+ months) and 12 months (range, 6–18+ months) for complete responders. Five patients (45%) converted to a phenotypic and molecular complete remission, with a median response duration of 6 months (range, 4–18+ months). Two patients remained in MRD negative complete remission after therapy at 18+ and 12+ months, respectively. The treatment-free median survival has not been reached for complete responders, with a median follow-up of 14 months. All patients were evaluable for toxicity. WHO grade 1–2 infusion-related reactions were observed in up to 90% of patients with the initial escalating dose. A moderate hematological toxicity was reported, except for platelets. Frequency of grade 3–4 events during therapy were as follows: 27% of anemia, 18% of neutropenia and 54% of thrombocytopenia. A delayed-onset neutropenia occured in three patients, up to 2 months after completion of treatment. Grade 2 infections were observed in six patients (54%). Only one patient experienced a major infection. Two patients (18%) developed CMV reactivation, CMV disease was successfully prevented by treatment with oral ganciclovir, without discontinuing alemtuzumab therapy. Alemtuzumab has demonstrated activity and safety in relapsed B-CLL patients after ASCT with an ORR of 77% and an MRD negativity of 45%. However, the question of maintaining a durable MRD negative complete response remains posed.

Delayed-onset, grade IV neutropenia associated with rituximab therapy in a lymphoma patient: A case report and literature review

6682 Background: Several cases of delayed-onset (> 4 weeks post therapy) neutropenia associated with rituximab have been reported in lymphoma patients. The majority of patients have been heavily pre-treated with chemotherapy. This is the first report of delayed neutropenia in a patient receiving rituximab as part of first-line therapy. Methods: Delayed neutropenia and thrombocytopenia occurred in a 53-year old, male with high-grade B-cell lymphoma 6 weeks after completing 6 cycles of rituximab, cyclophosphamide, mitoxantrone, vincristine, and prednisone (CNOP). The patient remains in complete remission 12 months after diagnosis. Six weeks after completing therapy, significant neutropenia and thrombocytopenia developed; WBC 700/mm3, neutrophil granulocytes 0.320/μL, PLT 71 x 103/μL. Complications included severe mucositis, oropharyngeal infections, weakness, weight loss, and fatigue. Treatment with filgrastim 480 μg daily improved neutrophil and platelet counts and controlled infections. However, discontinuation of filgrastim resulted in an ANC < 1000 and recurrent infections. Grade IV neutropenia developed 3 times. Full recovery occurred 5 to 7 days after filgrastim onset. The anti-neutrophil antibody was negative. A bone marrow biopsies during filgrastim therapy demonstrated hypercellularity (80%) and no abnormal leukocytes. The cytogenetic analysis showed normal karotypes. Pertinent history includes diffuse inflammatory lung disease during chemotherapy, which responded to steroids. Results: The neutropenia continues 6 months after completion of rituximab, but is controlled on 2 doses of filgrastim per week. Thrombocytopenia has resolved. Conclusions: Although Genentech reports the rate of delayed-onset neutropenia to be < 0.02%, a growing body of evidence suggests it is more common. Monitoring blood counts for up 8 weeks after rituximab therapy is worthwhile, although the literature reports neutropenia development 24 weeks post rituximab therapy. No significant financial relationships to disclose.

Delayed-onset, grade IV neutropenia associated with rituximab therapy in a lymphoma patient: A case report and literature review

6682 Background: Several cases of delayed-onset (> 4 weeks post therapy) neutropenia associated with rituximab have been reported in lymphoma patients. The majority of patients have been heavily pr...