The Role of Low-dose Anti-thymocyte Globulin as Standard Prophylaxis in Mismatched and Matched Unrelated Hematopoietic Peripheral Stem Cell Transplantation for Hematologic Malignancies.

INTRODUCTION: Anti-thymocyte globulin (ATG)-based immunosuppressive therapy is often used in allogeneic hematopoietic cell transplantation to reduce incidence and severity of graft-versus-host disease (GVHD). PATIENTS AND METHODS: In our observational study, ATG (rabbit, Thymoglobulin; Sanofi, 5 mg/kg) was administered as a standardized part of the conditioning in 97 patients with a median age of 34 years (range, 14-58 years), allotransplanted for hematologic malignancies from matched (8/8; n = 52) and allele or antigen mismatched (7/8; n = 43 and 6/8; n = 2) unrelated donors. RESULTS: Five-year overall survival (OS) was 46.9%, disease-free survival was 46.5%, and treatment-related mortality was 20.6%, with a median follow-up of 29 months (range, 1-145 months). Acute GVHD (grade ≥ II) cumulative incidence was 26.9% in matched versus 50.5% in mismatched patients (P = .060), whereas extensive chronic GVHD was 45.6% versus 50%, respectively (P = .310). Five-year OS was 62.2% for the matched patients and 27.9% for the mismatched patients (P = .003) owing to a higher treatment-related mortality rate in mismatched patients (P = .032). In multivariate analysis including age, gender, time until transplantation, disease phase, mismatched donor, ABO mismatch, number of CD34+ infused, acute and chronic GVHD, the significant unfavorable factors for OS were HLA mismatch and advanced disease phase. CONCLUSION: A relatively low-dose ATG is effective in acute GVHD prophylaxis, leading to promising survival rates in matched transplants. Further comparative studies with adjusted ATG dose depending on Human leukocyte antigen disparity or alternative donors are warranted.

Nelarabine-associated reversible Guillain-Barré-like syndrome or myelopathy in an adult patient with primary refractory T-lymphoblastic lymphoma.

Nelarabine is a purine analogue used for the treatment of patients with relapsed or refractory T-cell acute lymphoblastic leukemia and T-cell lymphoblastic lymphoma mainly as a bridge to stem cell transplantation. The water-soluble prodrug of 9-beta-D-arabinofuranosyl guanine (Ara-G) is phosphorylated within leukemic cells to form ara-G triphosphate (ara-GTP), which terminates DNA chain elongation, resulting in cell death. The drug received accelerated approval by the US Food and Drug Administration (FDA) on October 2005 based on the induction of complete remissions in 2 phase II trials. In these trials, neurologic toxicity was mainly presented as peripheral neuropathy and, since, is a commonly reported side effect of the drug. However, cases of severe grade III, IV, or even fatal neurotoxicity as well as cases of ascending myelopathy have also been reported with most of these cases being irreversible. In this article, we report a reversible grade IV Guillain-Barré-like case of a patient with primary refractory T-cell lymphoblastic lymphoma treated with nelarabine. Guillain-Barré-like syndrome in this patient coexisted with toxic myelopathy which affected the whole spine. The pathogenetic mechanisms and genetic predisposition for nelarabine-associated neurotoxicity is still unknown. The role of the immune system and the patient's genetic background are under investigation along with considerations on the right treatment of the syndrome. Gaining a better understanding in the contributing mechanisms will help us to recognize individuals in danger for neurotoxicity and will lead to the prompt treatment of this complication. Yet, it can be concluded from the present case and literature review that high-dose cytarabine regimens and intrathecal installations should be avoided in close time proximity with nelarabine treatment, as they could enhance neurotoxicity.

An outbreak of Burkholderia cepacia bacteremia in hospitalized hematology patients selectively affecting those with acute myeloid leukemia.

BACKGROUND: Burkholderia cepacia complex (Bcc) is a group of common environmental bacteria that preferentially colonize and infect patients with cystic fibrosis but are also emerging as nosocomial pathogens, possibly due to their resistance to disinfectants and antimicrobials. METHODS: We investigated a 3-month outbreak of Bcc bacteremia among hospitalized hematology patients. Environmental investigation and infection control measures were implemented. A retrospective, cross-sectional study was conducted to identify risk factors. RESULTS: Bcc was repeatedly isolated from the blood of 9 patients without central venous catheter who did not easily respond to targeted antibiotic treatment and 3 died of the infection. A point source was not identified and horizontal spread was suspected. Strict infection control measures terminated the outbreak. Interestingly, diagnosis of acute myeloid leukemia but not neutropenia or prior chemotherapy was a risk factor for infection acquisition. Neutropenia was positively correlated with infection duration. CONCLUSIONS: Bcc is not only a serious threat among immunocompromized hematology patients, but is also transmissible in clinical settings. Acute myeloid leukemia appears to confer additional risk for infection acquisition.

Monosomal karyotype in acute myeloid leukemia defines a distinct subgroup within the adverse cytogenetic risk category.

Monosomal karyotype (MK) has recently been reported to identify a distinct subset of acute myeloid leukemia (AML) with adverse prognosis. We retrospectively evaluated the frequency of MK in a large cohort of 549 unselected AML cases diagnosed in our department over a period of 13 years and explored potential associations with clinicobiological features and outcome. MK was found in 62 of 549 cases (11.3%), with all but one assigned to the unfavorable cytogenetic risk category; 57 of these 62 MK cases had a complex karyotype. Comparison with a subgroup of AML cases, who had unfavorable karyotypic profiles yet without MK (non-MK) and who were treated uniformly with similar, "3+7"-based regimens, revealed significant (P < 0.05) associations between MK and advanced age, low white blood cell count at diagnosis, and inferior overall survival (6.5 vs. 15 months for non-MK cases). In conclusion, MK defines a sizeable subset of patients with unfavorable cytogenetics who exhibit a distinct clinical profile, even in direct comparison with other unfavorable karyotypes.

Transferrin receptor-1 and 2 expression in chronic lymphocytic leukemia.

Transferrin receptor (TfR)-1 and 2 mRNA and CD71 (TfR1) expression was analyzed in 118 CLL patients. Ninety-five out of 109 analyzed cases expressed CD71, mostly at a high level; 60% of CD71 (+) cases were IGH-mutated. All samples were TfR1 mRNA (+); TfR2-alpha/beta mRNA was detected in, respectively, 52/102 and 100/109 cases. Competitive RT-PCR showed widely divergent levels of TfR1 mRNA in cases with high CD71 expression, alluding to post-transcriptional control of TfR1 expression in CLL. The almost uniformly high CD71 expression in CLL is in keeping with the activated status of neoplastic cells, regardless of IGH mutational load.

Immunoglobulin light chain repertoire in chronic lymphocytic leukemia.

Immunoglobulin kappa (IGK) and immunoglobulin lambda (IGL) light chain repertoire was analyzed in 276 chronic lymphocytic leukemia (CLL) cases and compared with the relevant repertoires from normal, autoreactive, and neoplastic cells. Twenty-one functional IGKV genes were used in IGKV-J rearrangements of 179 kappa-CLL cases; the most frequent genes were IGKV3-20(A27), IGKV1-39/1D-39(O2/O12), IGKV1-5(L12), IGKV4-1(B3), and IGKV2-30(A17); 90 (50.3%) of 179 IGK sequences were mutated (similarity < 98%). Twenty functional IGLV genes were used in IGLV-J rearrangements of 97 lambda-CLL cases; the most frequent genes were IGLV3-21(VL2-14), IGLV2-8(VL1-2), and IGLV2-14(VL1-4); 44 of 97 IGL sequences (45.4%) were mutated. Subsets with "CLL-biased" homologous complementarity-determining region 3 (CDR3) were identified: (1) IGKV2-30-IGKJ2, 7 sequences with homologous kappa CDR3 (KCDR3), 5 of 7 associated with homologous IGHV4-34 heavy chains; (2) IGKV1-39/1D-39-IGKJ1/4, 4 unmutated sequences with homologous KCDR3, 2 of 4 associated with homologous IGHV4-39 heavy chains; (3) IGKV1-5-IGKJ1/3, 4 sequences with homologous KCDR3, 2 of 4 associated with unmutated nonhomologous IGHV4-39 heavy chains; (4) IGLV1-44-IGLJ2/3, 2 sequences with homologous lambda CDR3 (LCDR3), associated with homologous IGHV4-b heavy chains; and (5) IGLV3-21-IGLJ2/3, 9 sequences with homologous LCDR3, 3 of 9 associated with homologous IGHV3-21 heavy chains. The existence of subsets that comprise given IGKV-J/IGLV-J domains associated with IGHV-D-J domains that display homologous CDR3 provides further evidence for the role of antigen in CLL pathogenesis.

Rituximab is effective for selected patients with chronic steroid-refractory immune thrombocytopenic purpura.

We report results of Rituximab therapy in four patients with chronic immune thrombocytopenic purpura (ITP) refractory to 3-8 prior therapeutic regimens. Rituximab was administered at a dose of 375 mg/m2 once weekly for 4-6 weeks. Three out of four patients achieved a complete remission (rise to platelet count above 100,000/microl). Response duration was 4, 16+, and 11+ months. Rituximab was well tolerated but one patient (a 77 year-old male) developed two serious infections, pneumonia and a hepatic abscess, at 2 and 4 months. We conclude that Rituximab is effective in patients with refractory ITP; nevertheless, careful patient selection is mandatory.

Immunoglobulin heavy- and light-chain repertoire in splenic marginal zone lymphoma.

The considerable heterogeneity in morphology, immunophenotype, genotype, and clinical behavior of splenic marginal zone lymphoma (SMZL) hinders firm conclusions on the origin and differentiation stage of the neoplastic cells. Immunoglobulin (IG) gene usage and somatic mutation patterns were studied in a series of 43 SMZL cases. Clonal IGHV-D-J rearrangements were amplified in 42/43 cases (4 cases carried double rearrangements). Among IGHV-D-J rearrangements, IGHV3 and IGHV4 subgroup genes were used with the highest frequency. Nineteen IGHV genes were unmutated (> 98% homology to the closest germline IGHV gene), whereas 27/46 were mutated. Clonal IGKV-J and IGLV-J gene rearrangements were amplified in 36/43 cases, including 31 IGKV-J (8/31 in lambda light-chain expressing cases) and 12 IGLV-J rearrangements; 9/31 IGKV and 6/12 IGLV sequences were mutated. IGKV-J and IGLV-J rearrangements used 14 IGKV and 9 IGLV different germline genes. Significant evidence for positive selection by classical T-dependent antigen was found in only 5/27 IGHV and 6/15 IGKV+IGLV mutated genes. These results provide evidence for the diverse B-cell subpopulations residing in the SMZ, which could represent physiologic equivalents of distinct SMZL subtypes. Furthermore, they indicate that in SMZL, as in other B cell malignancies, a complementarity imprint of antigen selection might be witnessed either by IGHV, IGKV, or IGLV rearranged sequences.