Severe neutropenia following a prolonged course of vancomycin that progressed to agranulocytosis with drug reexposure.

OBJECTIVE: To report a case of severe neutropenia after discontinuing prolonged treatment with vancomycin that progressed to agranulocytosis with vancomycin reexposure. CASE SUMMARY: A 78-year-old woman presented with severe neutropenia (absolute neutrophil count [ANC] 37 cells/µL) and hypocellular bone marrow with absence of myeloid elements 8 weeks after discontinuing a 3-week treatment course of vancomycin 750 mg every 12 hours. Filgrastim 300 µg daily was started for neutropenia and vancomycin 750 mg every 12 hours and aztreonam 1 g every 8 hours were initiated for catheter-related acute thrombophlebitis of the upper extremity. The patient's ANC decreased to 10 cells/µL within 3 days of starting vancomycin. We suspected an autoimmune process, potentially related to vancomycin exposure, and began treatment with methylprednisolone 1 mg/kg daily. The ANC precipitously dropped to 0 cells/µL despite treatment with steroids and an increased filgrastim dose of 480 µg/day. All antibiotics were discontinued on the fifth day of hospitalization. Within 48 hours, her neutrophil count showed recovery (white blood cell count 500 cells/µL; 10% neutrophils). DISCUSSION: Idiosyncratic drug-induced agranulocytosis is an uncommon phenomenon but is often associated with serious consequences such as sepsis. We believe this case is unique because of the unusually late neutropenia discovered several weeks after finishing a prolonged course of vancomycin. Furthermore, agranulocytosis developed after unintentional rechallenge with vancomycin. According to the Naranjo probability scale, this case illustrates a probable adverse event caused by vancomycin. CONCLUSIONS: This case demonstrates a serious adverse event potentially associated with vancomycin use, and calls attention to the safety of rechallenging with vancomycin during a possible drug-induced neutropenia.

Hairy cell leukemia with CCND1/IGH fusion gene and BRAF V600E mutation.

A 75-year-old male evaluated for pancytopenia. Abnormal lymphocytes with hairy projections noted on peripheral blood. Bone marrow examination showed diffuse proliferation of CD20+ B-lymphocytes. Flowcytometry revealed monoclonal lambda-restricted B-cells expressing CD19, CD20, CD11c, CD103, CD25 and CD123, negative for CD5 and CD10. Additional staining showed positivity for cyclin-D1, Annexin-A1 and TRAP. FISH identified t(11;14). PCR was positive for BRAF V600E. Given the above findings, nonspecificity of t(11;14) and the presence of BRAF V600E; the diagnosis of HCL was favored. Patient achieved CR with infusional cladribine. Herein, we report the co-occurrence of CCND1/IGH and BRAF V600E in HCL, a rare scenario that could characterize a new subtype of HCL.

DTPACE: an effective, novel combination chemotherapy with thalidomide for previously treated patients with myeloma.

PURPOSE: To improve outcome in previously treated patients (at least two cycles of standard therapy) with multiple myeloma, thalidomide was combined with cytotoxic chemotherapy as induction therapy. PATIENTS AND METHODS: The regimen consisted of 4-days of oral dexamethasone, daily thalidomide, and 4 days of continuous-infusion cisplatin, doxorubicin, cyclophosphamide, and etoposide (DTPACE). Response to two cycles of DTPACE for induction was evaluated in 236 patients. Before being treated with DTPACE, 148 patients (63%) had shown progressive disease while receiving standard chemotherapy, and 55 patients (23%) had chromosome 13 abnormalities. RESULTS: The partial remission rate (PR) after two cycles of DTPACE was 32%, with 16% attaining a complete remission (CR) or near-CR (nCR; defined as only immunofixation electrophoresis-positive). Patients with high lactate dehydrogenase (LDH; n = 98) showed a better response than those with normal LDH (n = 138): PR or better, 43% v 27% (P =.01); CR + nCR, 25% v 11% (P =.01). Patients with chromosome 13 abnormalities (n = 55) responded equally well as the other patients (n = 181): PR or better, 35% v 33% (P =.84); CR + nCR, 17% v 15% (P =.73). Patients who received 100% dose of DTPACE for two cycles (n = 115) achieved higher response rates than those with less than 100% dose (n = 121): PR or better, 49% v 17% (P <.0001); CR + nCR, 27% v 6% (P <.0001). CONCLUSION: Combination therapy of oral dexamethasone and thalidomide with infusional chemotherapy is effective as induction therapy before autotransplantation, especially in patients with high-risk features.

Prognostic factors in allogeneic transplantation for patients with high-risk multiple myeloma after reduced intensity conditioning.

OBJECTIVES: The aim of this study was to identify prognostic factors for outcome of high-risk patients with multiple myeloma after allogeneic transplantation prepared by reduced intensity conditioning (RIC). MATERIALS AND METHODS: Data from 45 consecutive patients (median age 52 years, range 38-68), who received grafts from a sibling (n = 34) or unrelated donor (n = 11) were analyzed. Fourteen patients received an RIC allotransplant while chemosensitive (>/=partial remission [PR]), whereas 31 chemoresistant patients (

Myeloma of the central nervous system: strong association with unfavorable chromosomal abnormalities and other high-risk disease features.

Involvement of the central nervous system (CNS) by multiple myeloma, defined by the detection of malignant plasma cells in the cerebrospinal fluid in the presence of suggestive symptoms, is considered extremely rare. We present the characteristics of 25 such patients (18 previously reported) intended to receive high-dose treatment at the University of Arkansas over the last 12 years; an extensive review of the published literature since 1968, including 71 patients, is also presented. In both patient groups, high tumor burden was overwhelmingly present while circulating plasma cells were detected in a significant proportion of cases. We also observed a strong association of CNS involvement with unfavorable cytogenetic abnormalities (especially translocations and deletion of the chromosome 13), plasmablastic morphology and additional extramedullary myeloma manifestations. The presence of these features should alert clinicians to the possibility of CNS involvement. The prognosis of such patients is poor despite aggressive systemic and local treatment and reflects the underlying disease biology. Application of allogeneic transplantation and administration of prophylactic CNS treatment are also discussed. Further elucidation of the factors predisposing patients with high-risk disease features to CNS myeloma involvement is needed.

Both hypodiploidy and deletion of chromosome 13 independently confer poor prognosis in multiple myeloma.

Complete or partial deletion of chromosome 13 or translocations involving 13q (delta13) by conventional cytogenetic analysis confers a poor prognosis in multiple myeloma (MM) patients, even with timely application of tandem autologous transplants. It was recently suggested that the prognostic significance of delta13 is related to its frequent association with hypodiploidy but by itself does not have a poor prognostic significance. We therefore analysed our experience in 1475 consecutive MM patients in whom we intended treatment with tandem transplants after a melphalan-based conditioning regimen. Patients with abnormal cytogenetic analysis were grouped into hypodiploid/hypotetraploid, pseudodiploid and hyperdiploid groups, according to their modal chromosome number. Their event-free and overall survival were compared with those of patients with a normalkaryotype. Both hypodiploidy and delta13 were found to independently confer poor prognosis in MM patients. Furthermore, these parameters in combination with easily obtained pretransplant levels of beta-2 microglobulin and albumin define three groups of MM patients with clearly distinct outcomes.

Prognostic impact of cytogenetic and interphase fluorescence in situ hybridization-defined chromosome 13 deletion in multiple myeloma: early results of total therapy II.

Cytogenetic abnormalities of chromosome 13 (CA 13) and those detected by fluorescence in situ hybridization (FISH 13) have both been associated with poor prognosis in multiple myeloma (MM) patients. The prognostic implications of CA, FISH 13 and other standard laboratory parameters were examined in the first 231 patients enrolled in Total Therapy II, an intensive cytotoxic chemotherapy programme with tandem autotransplants. Three-year projections of event-free survival (EFS) and overall survival (OS) were 71% and 77% respectively. CA 13 was detected in 14% and significantly correlated with FISH 13 (present in 51%), tumour burden, proliferative activity and lactic dehydrogenase (LDH). Both EFS and OS were significantly shorter in patients with CA 13, FISH 13, LDH >or= 190 U/l, beta2 microglobulin >or= 4 mg/l and C reactive protein >or= 4.0 mg/l; other CA was an additional risk factor for OS. Two-thirds of CA 13 patients were identified by FISH 13 and plasma-cell-labelling index (PCLI) >or= 0.4%; however, PCLI failed to identify additional risk groups in FISH subsets. Although present in considerably fewer patients, CA 13 imparted more rapid relapse (61% at 3 years) and death (43% at 3 years) than FISH 13 (38% and 35%; P = 0.02 and 0.1 respectively) and should be part of the initial work-up of patients with MM.

Survival after relapse following tandem autotransplants in multiple myeloma patients: the University of Arkansas total therapy I experience.

Despite the superiority of high-dose (compared with standard) treatment in multiple myeloma, relapses still occur. We evaluated relapse patterns, salvage treatments employed and outcome in patients given tandem transplants on our total therapy I protocol. We focused on 146 patients (of 231 enrolled) who received tandem autotransplants < or =12 months apart and survived > or =2 months after the second transplant. With a median follow-up of 9 years after enrollment, 31 (21%) patients remain in complete or stable partial remission. Ninety-five (65%) patients received therapy for relapsing myeloma. The median time from the first transplant to relapse was 2.9 years. The median overall survival from relapse was 2.4 years. In one-quarter (23/95) of cases, the postrelapse interval exceeded the interval from the first transplant to relapse. On multivariate analysis, the presence of any cytogenetic abnormalities [P<0.001, Hazard Ratio (HR): 3.84] and beta-2 microglobulin levels >4 mg/l at relapse (P<0.001, HR: 2.87) were significant for poor survival after relapse. The median survival after relapse was 5.1, 1.3 and 0.7 years in patients with none (44%), one (46%) and two (10%) poor-risk factors, respectively. In conclusion, a sizeable fraction of myeloma patients relapsing after tandem autotransplants without poor-risk features enjoyed meaningful survival prolongation when appropriately treated.

Global gene expression profiling of multiple myeloma, monoclonal gammopathy of undetermined significance, and normal bone marrow plasma cells.

Bone marrow plasma cells (PCs) from 74 patients with newly diagnosed multiple myeloma (MM), 5 with monoclonal gammopathy of undetermined significance (MGUS), and 31 healthy volunteers (normal PCs) were purified by CD138(+) selection. Gene expression of purified PCs and 7 MM cell lines were profiled using high-density oligonucleotide microarrays interrogating about 6800 genes. On hierarchical clustering analysis, normal and MM PCs were differentiated and 4 distinct subgroups of MM (MM1, MM2, MM3, and MM4) were identified. The expression pattern of MM1 was similar to normal PCs and MGUS, whereas MM4 was similar to MM cell lines. Clinical parameters linked to poor prognosis, abnormal karyotype (P =.002) and high serum beta(2)-microglobulin levels (P =.0005), were most prevalent in MM4. Also, genes involved in DNA metabolism and cell cycle control were overexpressed in a comparison of MM1 and MM4. In addition, using chi(2) and Wilcoxon rank sum tests, 120 novel candidate disease genes were identified that discriminate normal and malignant PCs (P <.0001); many are involved in adhesion, apoptosis, cell cycle, drug resistance, growth arrest, oncogenesis, signaling, and transcription. A total of 156 genes, including FGFR3 and CCND1, exhibited highly elevated ("spiked") expression in at least 4 of the 74 MM cases (range, 4-25 spikes). Elevated expression of these 2 genes was caused by the translocation t(4;14)(p16;q32) or t(11;14)(q13;q32). Thus, novel candidate MM disease genes have been identified using gene expression profiling and this profiling has led to the development of a gene-based classification system for MM.

Myeloma of the central nervous system: association with high-risk chromosomal abnormalities, plasmablastic morphology and extramedullary manifestations.

Involvement of the central nervous system (CNS) by multiple myeloma, as defined by the detection of malignant plasma cells in the cerebrospinal fluid in the presence of suggestive symptoms, is considered extremely rare. We report on the characteristics of 18 such patients diagnosed and treated at the University of Arkansas over the last 10 years for an overall incidence of approximately 1%. Their evaluation revealed association of CNS involvement with unfavourable cytogenetic abnormalities (especially translocations and deletion of the chromosome 13), high tumour mass, plasmablastic morphology, additional extramedullary myeloma manifestations and circulating plasma cells. The presence of these features should alert clinicians to the possibility of CNS involvement. The outcome of these patients was extremely poor despite the use of aggressive local and systemic treatment including autologous stem cell transplants. Given this universally poor prognosis, the application of allogeneic transplants should be studied in this clinical setting.