Analysis of internal tandem duplications of FLT3 (FLT3/ITD) was performed on bone marrow samples obtained at diagnosis and relapse from 108 adult patients with de novo acute myeloid leukemia (AML) to determine the role of this mutation in leukemic relapse. Eighty-three patients had wild-type FLT3 at both diagnosis and relapse, 16 had FLT3/ITD at both stages, whereas 8 had acquired the mutation and 1 had lost it at relapse. Using Genescan analysis, we found that FLT3/ ITD levels at first relapse were significantly higher than those at diagnosis (mean ؎ SE, 40.5% ؎ 4.8% versus 17.9% ؎ 3.6%, P < .001). The increase in mutation levels at relapse as compared with diagnosis did not correlate with the difference in blast cell percentages at both stages (P ‫؍‬ .777). A hemizygous deletion of wild-type FLT3 was found in 4 patients at relapse compared to none at diagnosis. Nine of the 11 patients carrying a single mutation at diagnosis relapsed with an identical mutation. All 6 patients with more than one FLT3/ ITD mutation at diagnosis showed changes in mutation patterns and levels at first relapse; however, each patient retained at least one mutation in the relapse sample. The changes of mutation patterns had implications for the monitoring of minimal residual disease. Our results suggest that FLT3/ITD may contribute as the initial transforming event in AML, and relapse can reflect the selection and outgrowth of a mutant clone or evolution of a new clone harboring this mutation. (Blood.

Background Maintenance therapy following autologous stem cell transplantation can delay disease progression and prolong survival in multiple myeloma (MM). Ixazomib is ideally suited for maintenance therapy given its efficacy, convenient once-weekly oral dosing, and low toxicity profile. Methods The phase 3, double-blind, placebo-controlled, TOURMALINE-MM3 study randomised 656 patients with newly diagnosed MM from 227 clinical/hospital sites in 30 countries in Europe, the Middle East, Africa,

BACKGROUNDThe clinical relevance of mutations of the FMS‐like tyrosine kinase 3 (FLT3) gene in specific cytogenetic subgroups is not clear. The authors examined internal tandem duplication (ITD) and Asp835 mutations of FLT3 in patients with acute promyelocytic leukemia (APL) to determine the incidence of these mutations and to analyze the results for correlations with clinicohematologic features and outcome.METHODSBone marrow samples from 107 patients with APL were analyzed. Isoforms of PML‐RARα were identified using a reverse transcription–polymerase chain reaction assay. A standard polymerase chain reaction (PCR) assay was used to detect FLT3/ITD mutations. Asp835 mutations were analyzed by PCR amplification of exon 20 followed by EcoRV digestion. All aberrant PCR products subsequently were sequenced.RESULTSTwenty‐two patients had FLT3/ITD mutations: 9 of 63 patients with L‐type PML/RARα, 13 of 34 patients with S‐type PML/RARα, and 0 of 10 patients with V‐type PML/RARα (P = 0.005). The incidence of FLT3/ITD mutations was significantly higher in patients with S‐type PML/RARα than in patients with L‐type PML/RARα or V‐type PML/RARα. Twenty patients had Asp835 mutations (L‐type PML/RARα: n = 11; S‐type PML/RARα: n = 8; V‐type PML/RARα: n = 1). The frequency of Asp835 mutations was not significantly different among patients with different PML/RARα isoforms (P = 0.582). Three patients had both ITD and Asp835 mutations. The microgranular variant (M3v) form of leukemia was found to be associated with a higher frequency of ITD (P = 0.002) but not with a higher frequency of Asp835 mutations (P = 1.000); analysis of clinicohematologic variables revealed no significant differences in FLT3 mutation incidence among other patient subgroups. There was no significant difference in complete remission rate, overall survival, or event‐free survival between patients with ITDs and those without ITDs or between patients with Asp835 mutations and those without Asp835 mutations.CONCLUSIONSThe current study found that ITD or Asp835 mutations of the FLT3 gene were present in 36.4% of patients with APL; however, these mutations had no prognostic impact. FLT3/ITD frequently was associated with S‐type PML/RARα and with the M3v form of leukemia. Cancer 2003;98:1206–16. © 2003 American Cancer Society.DOI 10.1002/cncr.11636

Diffuse large cell lymphoma involving bone marrow is not uncommon, but primary, de novo, bone marrow diffuse large B cell lymphoma (DLBCL) is rare. To understand the clinical features and outcomes of this distinct entity, we collected 12 cases in 5 years from a single-center database. They accounted for 1.16% of lymphoma, or 2.65% of diffuse large B cell lymphoma. Nine cases presented with fever of unknown origin. Lactate dehydrogenase levels were elevated in all but one case. Nine cases belonged to the high-risk group according to their international prognosis indexes (score 4 or 5). Four patients received no chemotherapy, all of whom died within 1 month. Four patients received cyclophosphamide, adriamycin, vincristine, and prednisolone (CHOP)-like chemotherapy, and their median survival was 13 months. Finally, four patients received rituximab 375 mg/m(2) in addition to CHOP-like chemotherapy. All of them had complete remission and three are still alive without relapse. We concluded that primary bone marrow DLBCL is a rare but distinctive subtype of lymphoma. The prognosis for this entity is poor but rituximab-based treatment is promising for improving its outcomes.

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Twenty-three patients with primary salivary gland lymphoma were diagnosed between 1990 and 2001. The sites of involvement were the parotid gland in 13, the submandibular gland in 9 and the minor salivary gland in 1. The sites of lymphoma involvement beyond the salivary glands were the cervical lymph nodes in 7, bone marrow in 3, the axillary lymph nodes in 3, the nasopharynx in 2, the abdominal lymph nodes in 2, the palate, the subconjunctiva, and the spleen in 1 each patient. Histologically, 19 patients had lymphomas of mucosa-associated lymphoid tissue (MALT) with myoepithelial sialadenitis in 13, 3 patients had diffuse large cell lymphomas and 1 had follicular lymphoma. Six patients were in stage I, 4 in II, 1 in III and 12 in IV. Eight of 23 patients (35%) had autoimmune diseases before or after the diagnosis of NHL and all suffered from MALT lymphoma. Four patients with parotid MALT lymphoma had primary or secondary Sjögren’s syndrome. One each patient suffered from hyperthyroidism, systemic lupus erythematosus, membranoproliferative glomerulonephritis and cryoglobulinemia, respectively. All the 6 stage I patients had achieved complete remission (CR) without relapses 17–84 months (median 44 months) after treatment. Excluding a stage IV patient with follicular lymphoma who died at 3.5 months without treatment, CR was achieved in all of the remaining 16 patients. However, a high relapse rate (9/16, 56%) was noted in stage II–IV patients. These patients tended to relapse in the original sites, but achieved CR again after chemotherapy or radiotherapy. One patient with MALT lymphoma developed histologic transformation into diffuse large lymphoma during relapse and died of refractory disease. Overall, only 2 patients succumbed. The overall survival and relapse-free survival rates at 5 years were 94.7 and 51.4%, respectively. Thus, salivary gland lymphoma proved to be an indolent disease.

Background:Owing to the shortage of hematopoietic stem cells from matched sibling donors (MSD) and matched unrelated donors (MUD), the number of patients undergoing haploidentical allogeneic hematopoietic stem cell transplantation (allo-HSCT) has rapidly increased. Despite a comparable overall survival (OS) and leukemia-free survival using this approach, some evidence suggests that haploidentical allo-HSCT recipients have a higher incidence of cytomegalovirus (CMV) infection, though this has not been clearly established. Methods:This study retrospectively compared the cumulative incidence of CMV DNAemia, 2-year OS, and leukemia-free survival rates in acute leukemia patients with MSD (n = 41), MUD (n = 18), and haploidentical donor allografts (n = 21). Results:The cumulative incidences of CMV DNAemia at day 180 in the MSD, MUD, and haploidentical groups were 39.0, 55.6, and 85.7%, respectively (P < 0.000). As less than 50% of patients in the MSD group were detected to have CMV DNAemia, the median time to CMV DNAemia detection in patients allografted with MSD could not be obtained. However, it was 42 and 29 days, respectively, for the MUD and haploidentical groups. Multivariate analysis revealed that haploidentical allo-HSCT (MSD vs. haploidentical: HR: 0.26; 95% CI: 0.09-0.78; P = 0.017) and age (HR: 1.03; 95% CI: 1.01-1.06; P = 0.011) increased CMV infection. Finally, MSD, MUD, and haploidentical allo-HSCT provided comparable 2-year OS rates (52.1%, 65.5%, and 65.6%; P = 0.425) and 2-year leukemia-free survival rates (67.1%, 68.3%, and 80.7%, P = 0.837). Conclusion:The CMV incidence was higher for haploidentical allo-HSCT than for MSD and MUD allo-HSCT; this could be explained by graft-versus-host disease prophylaxis by multiple immunosuppressants. K E Y W O R D Sallo-HSCT, haploidentical, cytomegalovirus, overall survival, leukemia-free survival