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Waldenström macroglobulinemia (WM) is a distinct B-cell lymphoproliferative disorder for which clearly defined criteria for the diagnosis, initiation of therapy, and treatment strategy have been proposed as part of the consensus panels of the International Workshop on Waldenström's Macroglobulinemia (IWWM). At IWWM-8, a task force for treatment recommendations was impanelled to review recently published and ongoing clinical trial data as well as the impact of new mutations (MYD88 and CXCR4) on treatment decisions, indications for B-cell receptor and proteasome inhibitors, and future clinical trial initiatives for WM patients. The panel concluded that therapeutic strategies in WM should be based on individual patient and disease characteristics. Chemoimmunotherapy combinations with rituximab and cyclophosphamide-dexamethasone, bendamustine, or bortezomib-dexamethasone provide durable responses and are still indicated in most patients. Approval of the BTK inhibitor ibrutinib in the United States and Europe represents a novel and effective treatment option for both treatment-naive and relapsing patients. Other B-cell receptor inhibitors, second-generation proteasome inhibitors (eg, carfilzomib), and mammalian target of rapamycin inhibitors are promising and may increase future treatment options. Active enrollment in clinical trials whenever possible was endorsed by the panel for most patients with WM., (© 2016 by The American Society of Hematology.)

Allogeneic hematopoietic stem cell transplantation (SCT) is the only curative option for patients with primary myelofibrosis (PMF), but information on its net advantage over conventional therapies is lacking. Using ad hoc statistical analysis, we determined outcomes in 438 patients <65 years old at diagnosis who received allogenic SCT (n = 190) or conventional therapies (n = 248). Among patients at low risk per the Dynamic International Prognostic Scoring System (DIPSS) model, the relative risk of death after allogenic SCT vs those treated with nontransplant modalities was 5.6 (95% CI, 1.7-19; P = .0051); for intermediate-1 risk it was 1.6 (95% CI, 0.79-3.2; P = .19), for intermediate-2 risk, 0.55 (95% CI, 0.36-0.83; P = .005), and for high risk, 0.37 (95% CI, 0.21-0.66; P = .0007). Thus, patients with intermediate-2 or high-risk PMF clearly benefit from allogenic SCT. Patients at low risk should receive nontransplant therapy, whereas individual counseling is indicated for patients at intermediate-1 risk., (© 2015 by The American Society of Hematology.)

Chronic infection with hepatitis C virus (HCV) may lead to B cell activation and transformation into non-Hodgkin lymphoma (NHL). Molecular mechanisms of B cell transformation by HCV are poorly understood. One of the most common lymphoproliferative disorders in HCV-infected patients is splenic marginal zone lymphoma (SMZL). A case of a 42-years old man, affected by HCV-related SMZL, effectively treated with an IFN-free, NS3-NS4A inhibitor-based regimen, is hereby described. The patient was treated for 16 weeks with faldaprevir, deleobuvir, and ribavirin, achieving a very rapid viral eradication without relevant toxicities. A rapid haematologic response was noted as well, with a statistically significant correlation between viral decay and lymphocyte improvement (coefficient r = 0.55, p = 0.042). The viral clearance led to SMZL cure, even without the use of IFN. Thus, the causative role, played by HCV in SMZL development, is once again reinforced, whereby the antiviral, rather than the anti-proliferative activity of IFN is indirectly proven. A regimen including DAAs should be considered when treating a HCV-related extra-hepatic disease., (Copyright © 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Waldenström macroglobulinemia (WM) is a distinct B-cell lymphoproliferative disorder for which clearly defined criteria for the diagnosis, initiation of therapy, and treatment strategy have been proposed as part of the consensus panels of International Workshops on WM (IWWM). As part of the IWWM-7 and based on recently published and ongoing clinical trials, the panels updated treatment recommendations. Therapeutic strategy in WM should be based on individual patient and disease characteristics (age, comorbidities, need for rapid disease control, candidacy for autologous transplantation, cytopenias, IgM-related complications, hyperviscosity, and neuropathy). Mature data show that rituximab combinations with cyclophosphamide/dexamethasone, bendamustine, or bortezomib/dexamethasone provided durable responses and are indicated for most patients. New monoclonal antibodies (ofatumumab), second-generation proteasome inhibitors (carfilzomib), mammalian target of rapamycin inhibitors, and Bruton's tyrosine kinase inhibitors are promising and may expand future treatment options. A different regimen is typically recommended for relapsed or refractory disease. In selected patients with relapsed disease after long-lasting remission, reuse of a prior effective regimen may be appropriate. Autologous stem cell transplantation may be considered in young patients with chemosensitive disease and in newly diagnosed patients with very-high-risk features. Active enrollment of patients with WM in clinical trials is encouraged.

The international prognostic scoring system (IPSS) provides reliable risk assessment in patients with primary myelofibrosis (PMF). Recent clinical trials in PMF patients with intermediate-2 or high IPSS risk have shown a survival advantage of ruxolitinib over placebo (COMFORT-1) or best available therapy (COMFORT-2). Because crossover was allowed in these studies, we analyzed the cohort of ruxolitinib-naive patients used for developing the dynamic IPSS (DIPSS). By adopting ad hoc statistical analyses, we compared survival from diagnosis of 100 PMF patients receiving ruxolitinib within COMFORT-2 with that of 350 patients of the DIPSS study. Subjects were properly matched, and both left-truncation and right-censoring were accounted in order to compare higher IPSS risks exclusively. Patients receiving ruxolitinib had longer survival (5 years, 95% confidence interval [CI]: 2.9-7.8 vs 3.5 years, 95% CI: 3.0-3.9) with a hazard ratio of 0.61 (95% CI: 0.41-0.91; P = .0148). This observation suggests that ruxolitinib may modify the natural history of PMF.

Background: Several population-based and cohort studies have reported an increased risk of second cancers in lymphoproliferative disorders (LPDs). The cause of second cancers in LPDs is probably multifactorial, and the relative contribution of treatments, genetic predisposition, and immune dysfunction typical of LPDs is still unclear., Patients and Methods: We retrospectively studied 230 patients with Waldenström macroglobulinemia (WM) to assess the frequency, characteristics, and predictive factors of second cancers and to evaluate whether patients with WM are at higher risk of second cancers compared with an age- and sex-matched control population., Results: In a competing-risk model, the cumulative incidence of solid cancers was 6% at 5 years, 11% at 10 years, and 17% at 15 years, whereas the incidence of hematologic malignancies was 4% at 5 years, 7% at 10 years, and 8% at 15 years. Compared with an age- and sex-matched population, the overall risk of second cancers was 1.7-fold higher than expected (95% confidence interval [CI], 1.22-2.38; P = .002). Patients with WM were at increased risk for diffuse large B-cell lymphoma (DLBCL) (standardized incidence ratio [SIR], 8.64; 95% CI, 3.88-19.22; P < .0001), myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) (SIR 9.5; 95% CI, 3.6-25.3; P < .0001), and brain cancer (SIR, 7.59; 95% CI, 1.9-30.4; P < .0001). The risk of a second hematologic malignancy was 5-fold higher in treated than in untreated patients (P = .08)., Conclusion: Patients with WM are at increased risk of DLBCL, MDS/AML, and brain cancers compared with the general population. Further studies are needed to clarify whether the increased incidence of second cancers is related to treatments, to the immunologic impairment associated with the disease, or to genetic predisposition., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: The clinical course of patients with B-cell CLL is often complicated by autoimmune phenomena. The DAT might be positive at some time during the course of the disease in up to 35% of cases. The aim of this retrospective study was to investigate the relationship between the occurrence of a positive DAT and biological features of CLL patients., Patients and Methods: In our institution, 146 untreated patients with CLL were studied using the DAT., Results: According to the statistical analysis, a high level of β2-microglobulin and unmutated IgHV emerged as factors significantly related to the presence of DAT positivity. Time to first TFS was significantly shorter in DAT-positive patients. The adverse effect of a DAT positive result was maintained in terms of TFS when patients with mutated IgHV status were excluded from statistical analysis., Conclusion: These results suggest that the DAT might provide additional prognostic information regarding patients with IgHV unmutated status., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Waldenström macroglobulinemia (WM) (symptomatic and indolent) and immunoglobulin M (IgM) monoclonal gammopathy of undetermined significance (IgMMGUS) can be identified based on the bone marrow (BM) infiltration and the existence of symptoms. The purpose of this study was to investigate the biological and genetic characteristics of both disorders comparing the molecular signature of WM versus IgMMGUS using microarray analysis. We investigated BM CD19(+) cells isolated from 21 WM patients and 10 IgMMGUS cases, and CD138(+) BM cells isolated from all of the WM patients and 4 of the IgMMGUS cases. Gene expression profiling of WM versus IgMMGUS CD19(+) cells highlighted 151 differently expressed genes and the comparison with CD138(+) cells demonstrated 43 differently expressed genes in WM versus IgMMGUS. Regulation of transcription, Janus kinase/signal transducer and activator of transcription, PI3K/Akt/mammalian target of rapamycin, mitogen-activated protein kinase signaling pathways are the relevant gene ontology biological processes occurring in CD19(+) cells, and immune response, cell activation, and signaling processes developing in CD138(+) cells mainly distinguish WM and IgMMGUS., (Copyright © 2013 Elsevier Inc. All rights reserved.)

The combination FCR (fludarabine, cyclophosphamide, and rituximab) proved to be active in Waldenström's macroglobulinemia in a mixed population of untreated and previously treated patients. Prolonged myelosuppression and concerns about purine analogue treatment led to the conclusion that this regimen should be avoided in younger patients in first-line treatment. In this retrospective study on 40 patients we observed a response rate of 80% (32) after FCR salvage treatment with 32.5% (13) of patients reaching at least a very good partial remission. None of the prognostic variables had a significant effect on response or good quality of response achievement. Median event-free survival was reached at 77 months; median progression-free survival was not reached after a median follow-up of 51 months with any difference when categorizing patients according to quality of response. The results of this study suggest that the FCR regimen might overcome poor prognostic features and should be taken into account as salvage treatment. Tardive immunosuppression and myelosuppression warrant accurate patient follow-up., (Copyright © 2013 Elsevier Inc. All rights reserved.)

By whole-genome and/or Sanger sequencing, we recently identified a somatic mutation (MYD88 L265P) that stimulates nuclear factor κB activity and is present in >90% of Waldenström macroglobulinemia (WM) patients. MYD88 L265P was absent in 90% of immunoglobulin M (IgM) monoclonal gammopathy of undetermined significance (MGUS) patients. We therefore developed conventional and real-time allele-specific polymerase chain reaction (AS-PCR) assays for more sensitive detection and quantification of MYD88 L265P. Using either assay, MYD88 L265P was detected in 97 of 104 (93%) WM and 13 of 24 (54%) IgM MGUS patients and was either absent or rarely expressed in samples from splenic marginal zone lymphoma (2/20; 10%), CLL (1/26; 4%), multiple myeloma (including IgM cases, 0/14), and immunoglobulin G MGUS (0/9) patients as well as healthy donors (0/40; P < 1.5 × 10(-5) for WM vs other cohorts). Real-time AS-PCR identified IgM MGUS patients progressing to WM and showed a high rate of concordance between MYD88 L265P ΔCT and BM disease involvement (r = 0.89, P = .008) in WM patients undergoing treatment. These studies identify MYD88 L265P as a widely present mutation in WM and IgM MGUS patients using highly sensitive and specific AS-PCR assays with potential use in diagnostic discrimination and/or response assessment. The finding of this mutation in many IgM MGUS patients suggests that MYD88 L265P may be an early oncogenic event in WM pathogenesis.

Acute myeloid leukemia (AML) is a genetically heterogeneous clonal disorder characterized by two molecularly distinct self-renewing leukemic stem cell (LSC) populations most closely related to normal progenitors and organized as a hierarchy. A requirement for WNT/β-catenin signaling in the pathogenesis of AML has recently been suggested by a mouse model. However, its relationship to a specific molecular function promoting retention of self-renewing leukemia-initiating cells (LICs) in human remains elusive. To identify transcriptional programs involved in the maintenance of a self-renewing state in LICs, we performed the expression profiling in normal (n = 10) and leukemic (n = 33) human long-term reconstituting AC133(+) cells, which represent an expanded cell population in most AML patients. This study reveals the ligand-dependent WNT pathway activation in AC133(bright) AML cells and shows a diffuse expression and release of WNT10B, a hematopoietic stem cell regenerative-associated molecule. The establishment of a primary AC133(+) AML cell culture (A46) demonstrated that leukemia cells synthesize and secrete WNT ligands, increasing the levels of dephosphorylated β-catenin in vivo. We tested the LSC functional activity in AC133(+) cells and found significant levels of engraftment upon transplantation of A46 cells into irradiated Rag2(-/-)γc(-/-) mice. Owing to the link between hematopoietic regeneration and developmental signaling, we transplanted A46 cells into developing zebrafish. This system revealed the formation of ectopic structures by activating dorsal organizer markers that act downstream of the WNT pathway. In conclusion, our findings suggest that AC133(bright) LSCs are promoted by misappropriating homeostatic WNT programs that control hematopoietic regeneration.

Ruxolitinib is JAK1/JAK2 inhibitor with established clinical benefit in myelofibrosis (MF). We analyzed long-term outcomes of 107 patients with intermediate-2 or high-risk MF receiving ruxolitinib at MD Anderson Cancer Center (MDACC) on phase 1/2 trial. After a median of 32 months of follow-up, 58 patients (54%) were still receiving ruxolitinib, with overall survival (OS) of 69%. The splenomegaly and symptom reductions achieved with ruxolitinib were sustained with long-term therapy. Therapy was well tolerated; discontinuation rates at 1, 2, and 3 years were 24%, 36%, and 46%, respectively. OS of 107 MDACC patients was significantly better (P = .005) than that of 310 matched (based on trial enrollment criteria) historical control patients, primarily because of highly significant difference in OS in the high-risk subgroup (P = .006). Furthermore, among MDACC patients, those with high-risk MF experienced the same OS as those with intermediate-2 risk. Patients with ≥ 50% reduction in splenomegaly had significantly prolonged survival versus those with < 25% reduction (P < .0001). Comparison of discontinuation rates and reasons for stopping the therapy to those reported for other 51 patients in the phase 1/2 trial, and 155 ruxolitinib-treated patients in phase 3 COMFORT-I study, suggest that continued therapy with ruxolitinib at optimal doses contributes to the benefits seen, including OS benefit.

Although combination regimens have improved outcomes over monotherapy in chronic lymphocytic leukemia (CLL), patients eventually relapse. Combined fludarabine, cyclophosphamide, and monoclonal anti-CD52 antibody alemtuzumab (FCC) provided synergistic cytotoxicity with effective clearing of minimal residual disease. This phase 2 study determined FCC efficacy and safety in relapsed/refractory CD52(+) B-CLL after ≥ 1 line of treatment. From January 2005 through June 2008, up to 6 courses of oral fludarabine 40 mg/m² per day, oral cyclophosphamide 250 mg/m² per day, and subcutaneous alemtuzumab (Mab-Campath) 10 mg (increased to 20 mg after first 10-patient cohort) were administered days 1 to 3 every 28 days. The primary objective was overall response rate (ORR); secondary objectives included response duration, time to disease progression, and safety and tolerability. ORR was 67% in 43 patients; 30% achieved complete response. ORR significantly improved with 1 versus ≥ 2 prior therapies (P = .018), and without versus with previous monoclonal antibody treatment (P = .003). Median progression-free survival was 24.4 months, not reached in patients achieving complete response. Median overall survival was 33.6 months. Myelosuppression was the most common adverse event, with a low percentage of cytomegalovirus reactivations and manageable infections. However, close vigilance of opportunistic infections is warranted. FCC provides effective immunotherapy in relapsed/refractory CLL, including in patients with poor-risk prognostic factors.

We evaluated the risk of transformation of asymptomatic immunoglobulin (Ig) M monoclonal gammopathy (aIgM MG) into symptomatic lymphoproliferative disease in 287 patients all analyzed for bone marrow histopathology and immunophenotyping. This series included 201 patients with IgM MG of undetermined significance (IgM MGUS) and 86 with smoldering Waldenström's macroglobulinemia (sWM). After a median of 50 months (range, 12-322 months), 32 cases of aIgM-MG (11.1%) evolved into symptomatic malignant lymphoproliferative disease, as follows: symptomatic WM (n=26), non-Hodgkin lymphoma (n=6). The cumulative transformation percentage at 5 and 10 years was 8% and 19.5%, respectively. The parameters significantly correlated with evolution were, at univariate analysis, BM lymphoplasmacytic infiltration, high erythrocyte sedimentation rate, serum MC, serum IgM size, and serum IgA size. Among patients with aIgM-MG, those at high risk of evolution were patients with sWM, a distinct entity with serum IgM monoclonal protein≥3 g/dL and/or ≥10% bone marrow lymphoplasmacytic infiltration.

Core-binding factor leukemia (CBFL) is a subgroup of acute myeloid leukemia (AML) characterized by genetic mutations involving the subunits of the core-binding factor (CBF). The leukemogenesis model for CBFL posits that one, or more, gene mutations inducing increased cell proliferation and/or inhibition of apoptosis cooperate with CBF mutations for leukemia development. One of the most common mutations associated with CBF mutations involves the KIT receptor. A high expression of KIT is a hallmark of a high proportion of CBFL. Previous studies indicate that microRNA (MIR) 222/221 targets the 3' untranslated region of the KIT messenger RNA and our observation that AML1 can bind the MIR-222/221 promoter, we hypothesized that MIR-222/221 represents the link between CBF and KIT. Here, we show that MIR-222/221 expression is upregulated after myeloid differentiation of normal bone marrow AC133(+) stem progenitor cells. CBFL blasts with either t(8;21) or inv(16) CBF rearrangements with high expression levels of KIT (CD117) display a significantly lower level of MIR-222/221 expression than non-CBFL blasts. Consistently, we found that the t(8;21) AML1-MTG8 fusion protein binds the MIR-222/221 promoter and induces transcriptional repression of a MIR-222/221-LUC reporter. Because of the highly conserved sequence homology, we demonstrated concomitant MIR-222/221 down-regulation and KIT up-regulation in the 32D/WT1 mouse cell model carrying the AML1-MTG16 fusion protein. This study provides the first hint that CBFL-associated fusion proteins may lead to up-regulation of the KIT receptor by down-regulating MIR-222/221, thus explaining the concomitant occurrence of CBF genetic rearrangements and overexpression of wild type or mutant KIT in AML.

Age older than 65 years, hemoglobin level lower than 100 g/L (10 g/dL), white blood cell count greater than 25 x 10(9)/L, peripheral blood blasts 1% or higher, and constitutional symptoms have been shown to predict poor survival in primary myelofibrosis (PMF) at diagnosis. To investigate whether the acquisition of these factors during follow-up predicts survival, we studied 525 PMF patients regularly followed. All 5 variables had a significant impact on survival when analyzed as time-dependent covariates in a multivariate Cox proportional hazard model and were included in 2 separate models, 1 for all patients (Dynamic International Prognostic Scoring System [DIPSS]) and 1 for patients younger than 65 years (age-adjusted DIPSS). Risk factors were assigned score values based on hazard ratios (HRs). Risk categories were low, intermediate-1, intermediate-2, and high in both models. Survival was estimated by the HR. When shifting to the next risk category, the HR was 4.13 for low risk, 4.61 for intermediate-1, and 2.54 for intermediate-2 according to DIPSS; 3.97 for low risk, 2.84 for intermediate-1, and 1.81 for intermediate-2 according to the age-adjusted DIPSS. The novelty of these models is the prognostic assessment of patients with PMF anytime during their clinical course, which may be useful for treatment decision-making.

Therapeutic decision-making in primary myelofibrosis (PMF) is becoming more challenging because of the increasing use of allogeneic stem cell transplantation and new investigational drugs. To enhance this process by developing a highly discriminative prognostic system, 1054 patients consecutively diagnosed with PMF at 7 centers were studied. Overall median survival was 69 months (95% confidence interval [CI]: 61-76). Multivariate analysis of parameters obtained at disease diagnosis identified age greater than 65 years, presence of constitutional symptoms, hemoglobin level less than 10 g/dL, leukocyte count greater than 25 x 10(9)/L, and circulating blast cells 1% or greater as predictors of shortened survival. Based on the presence of 0 (low risk), 1 (intermediate risk-1), 2 (intermediate risk-2) or greater than or equal to 3 (high risk) of these variables, 4 risk groups with no overlapping in their survival curves were delineated; respective median survivals were 135, 95, 48, and 27 months (P< .001). Compared with prior prognostic models, the new risk stratification system displayed higher predictive accuracy, replicability, and discriminating power. In 409 patients with assessable metaphases, cytogenetic abnormalities were associated with shorter survival, but their independent contribution to prognosis was restricted to patients in the intermediate-risk groups. JAK2V617F did not cluster with a specific risk group or affect survival.

Post-polycythemia vera myelofibrosis (post-PV MF) is a late evolution of PV. In 647 patients with PV, we found that leukocytosis leukocyte count>(15x10(9)/L) at diagnosis is a risk factor for the evolution of post-PV MF. In a series of 68 patients who developed post-PV MF, median survival was 5.7 years. Hemoglobin level less than 100 g/L (10 g/dL) at diagnosis of post-PV MF was an independent risk factor for survival. The course of post-PV MF, however, is a dynamic process that implies a progressive worsening of clinical parameters. Using a multivariate Cox proportional hazard regression with time-dependent covariates, we found that a dynamic score based on hemoglobin level less than 100 g/L (10 g/dL), platelet count less than 100x10(9)/L, and leukocyte count more than 30x10(9)/L is useful to predict survival at any time from diagnosis of post-PV MF. The resulting hazard ratio of the score was 4.2 (95% CI: 2.4-7.7; P<.001), meaning a 4.2-fold worsening of survival for each risk factor acquired during follow up. In conclusion, leukocytosis at diagnosis of PV is a risk factor for evolution in post-PV MF. A dynamic score based on hemoglobin level, and platelet and leukocyte count predicts survival at any time from diagnosis of post-PV MF.

Essential thrombocythemia (ET) may occur in women of childbearing age. To investigate the risk of pregnancy complications, we studied 103 pregnancies that occurred in 62 women with ET. The 2-tailed Fisher exact test showed that pregnancy outcome was independent from that of a previous pregnancy. The rate of live birth was 64%, and 51% of pregnancies were uneventful. Maternal complications occurred in 9%, while fetal complications occurred in 40% of pregnancies. The Mantel-Haenszel method showed that fetal loss in women with ET was 3.4-fold higher (95% confidence interval [CI]: 3-3.9; P < .001) than in the general population. Half of the women studied carried the JAK2 (617V>F) mutation, and a multivariate logistic regression model identified this mutation as an independent predictor of pregnancy complications (P = .01). Neither the platelet count nor the leukocyte count was a risk factor. JAK2 (617V>F)-positive patients had an odds ratio of 2.02 (95% CI: 1.1 - 3.8) of developing complications in comparison with JAK2 (617V>F)-negative patients. Aspirin did not prevent complication in JAK2 (617V>F)-positive patients and appeared to worsen outcome in JAK2 (617V>F)-negative patients. A relationship was found between JAK2 (617V>F) and fetal loss (P = .05). This study indicates that patients carrying the JAK2 (617V>F) mutation have higher risk of developing pregnancy complications.

Cryoglobulinemia refers to the presence in serum of immunoglobulins that precipitate at a cold temperature. Type I cryoglobulins are single monoclonal immunoglobulins usually associated with haematological disorders. Types II and III are mixed cryoglobulins, composed of monoclonal or polyclonal IgM respectively, having rheumatoid factor activity that bind to polyclonal immunoglobulins. Mixed cryoglobulinemia (MC) syndrome is a consequence of immune-complex mediated vasculitis and is characterized by a typical clinical triad: purpura, weakness, arthralgias; many organs particularly kidney and peripheral nervous system may be involved. MC may be associated with infectious and systemic disorders and since 1990 studies have demonstrated that hepatitis C virus (HCV) may be considered the principal trigger of the disease. The relation between MC and HCV infection shows new insights in the interpretation of the link between viral infection, autoimmune phenomena and lymphoproliferative disorders evolution. In fact, the virus chronically stimulates B-cell polyclonal proliferation from which a monoclonal population may emerge. In symptomatic patients with HCV related MC therapeutic strategy should include an attempt at viral eradication. Antiviral therapy may also be effective in determining the regression of B-cell lymphoproliferative disorder. Rituximab could represent a safe and effective alternative to standard immunosuppression and exerts selective B-cell control.

The Integruppo Italiano Linfomi (IIL) carried out a study to assess the outcomes of splenic marginal zone lymphoma and to identify prognostic factors in 309 patients. The 5-year cause-specific survival (CSS) rate was 76%. In univariate analysis, the parameters predictive of shorter CSS were hemoglobin levels below 12 g/dL (P < .001), albumin levels below 3.5 g/dL (P = .001), International Prognostic Index (IPI) scores of 2 to 3 (P < .001), lactate dehydrogenase (LDH) levels above normal (P < .001), age older than 60 years (P = .01), platelet counts below 100,000/microL (P = .04), HbsAg-positivity (P = .01), and no splenectomy at diagnosis (P = .006). Values that maintained a negative influence on CSS in multivariate analysis were hemoglobin level less than 12 g/dL, LDH level greater than normal, and albumin level less than 3.5 g/dL. Using these 3 variables, we grouped patients into 3 prognostic categories: low-risk group (41%) with no adverse factors, intermediate-risk group (34%) with one adverse factor, and high-risk group (25%) with 2 or 3 adverse factors. The 5-year CSS rate was 88% for the low-risk group, 73% for the intermediate-risk group, and 50% for the high-risk group. The cause-specific mortality rate (x 1000 person-years) was 20 for the low-risk group, 47 for the intermediate-risk group, and 174 for the high-risk group. This latter group accounted for 54% of all lymphoma-related deaths. In conclusion, with the use of readily available factors, this prognostic index may be an effective tool for evaluating the need for treatment and the intensity of therapy in an individual patient.

Distinct forms of tyrosine kinase domain (TKD), juxtamembrane domain, exon 8, and internal tandem duplication (ITD) mutations of c-KIT, were observed in about 46% of core binding factor leukemia (CBFL) patients. To evaluate their prognostic significance, 67 adult patients with CBFL were analyzed to ascertain the c-KIT mutation status. In acute myeloid leukemia (AML) with t(8;21), the presence of c-KIT TKD mutation at codon 816 (TKD(816)) was associated with a high white blood cell count at diagnosis (median, 29.60 x 10(9)/L) and a higher incidence (33%) of extramedullary leukemia (EML) during the course of the disease. Data also showed that the TKD(816) mutated patients (n = 12) had a significantly higher incidence of relapse and a lower overall survival (OS) at 24 months, compared with the 17 c-KIT unmutated (c-KIT(-)) patients (90% vs 35.3%, P = .002; 25% vs 76.5%, P = .006, respectively). No difference in relapse incidence (P = .126) and OS (P = .474) was observed between the c-KIT mutated other than TKD(816) (n = 7) and the c-KIT(-) patients. These findings indicate that c-KIT TKD(816) mutation has a negative impact on the outcome of AML with t(8;21).

By real-time quantitative polymerase chain reaction (RQ-PCR), we evaluated BCL2/IgH(+) cells in the bone marrow (BM) and peripheral blood (PB) from 86 patients with follicular lymphoma treated with the sequential administration of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) and rituximab. At diagnosis, the amount of BCL2/IgH(+) cells in the BM was low (1 BCL2/IgH(+) cell in 1000-100 000 normal cells) in 43% of patients, intermediate (1 in 100-1000) in 34%, and high (> 1 in 100) in 23%. A 2 log decrease of BCL2/IgH(+) cells was achieved after CHOP and an additional 2 log reduction following rituximab. By multivariate analysis, a low level of BCL2/IgH(+) cells in the BM at diagnosis was the best predictor for the achievement of a complete clinical and molecular response. At 5 years, the event-free survival rates of patients with a low/intermediate or high tumor infiltration in the BM were 59% and 32%, respectively. The freedom from recurrence of patients who achieved a molecular response in the BM, no matter whether after CHOP alone or CHOP and rituximab, was 64% as compared to 32% for patients who did not (P < .006). RQ-PCR performed at presentation on BM samples predicts treatment response and long-term clinical outcome in patients with follicular lymphoma.

Posttransplantation lymphoproliferative disorders (PTLDs) represent a serious complication of solid organ transplantation. This study assessed the molecular histogenesis of 52 B-cell monoclonal PTLDs, including 12 polymorphic PTLDs (P-PTLDs), 36 diffuse large B-cell lymphomas (DLBCLs), and 4 Burkitt/Burkitt-like lymphomas (BL/BLLs). Somatic hypermutation (SHM) of immunoglobulin variable (IgV) genes documented that most monoclonal B-cell PTLDs (75% P-PTLDs, 91.3% DLBCLs, 100% BL/BLLs) derive from germinal center (GC)-experienced B cells. B-cell lymphoma 6 (BCL6) mutations occurred in 25% P-PTLDs, 60.6% DLBCLs, and 75.0% BL/BLLs. A first histogenetic category of PTLDs (31.2% DLBCLs) express the BCL6+/multiple myeloma oncogene-1 protein (MUM1-/+)/CD138- profile and mimic B cells experiencing the GC reaction, as also suggested by ongoing SHM in a fraction of these cases. A second subset of PTLDs (66.7% P-PTLDs and 31.2% DLBCLs) display the BCL6-/MUM1+/CD138- phenotype and mimic B cells that have concluded the GC reaction. A third histogenetic category of PTLDs (25.0% P-PTLDs and 31.2% DLBCLs) shows the BCL6-/MUM1+/CD138+ profile, consistent with preterminally differentiated post-GC B cells. Crippling mutations of IgV heavy chain (IgVH) and/or IgV light chain (IgVL) genes, leading to sterile rearrangements and normally preventing cell survival, occur in 4 DLBCLs and 1 BL/BLL that may have been rescued from apoptosis through expression of Epstein-Barr virus (EBV)-encoded latent membrane protein 1 (LMP1). Overall, the histogenetic diversity of monoclonal B-cell PTLDs may help define biologically homogeneous categories of the disease.

Blast crisis is the most advanced stage of chronic myelogenous leukemia (CML) and is highly refractory to therapy. CML is caused by expression of the chimeric BCR-ABL tyrosine kinase oncogene, the product of the t(9;22) Philadelphia translocation. Imatinib (Glivec, formerly STI571) is a rationally developed, orally administered inhibitor of the Bcr-Abl tyrosine kinase. A total of 260 patients with CML were enrolled in a phase II trial, of whom 229 had a confirmed diagnosis of CML in blast crisis. Patients were treated with imatinib in daily oral doses of 400 mg or 600 mg. Imatinib induced hematologic responses in 52% of patients and sustained hematologic responses lasting at least 4 weeks in 31% of patients, including complete hematologic responses in 8%. For patients with a sustained response, the estimated median response duration was 10 months. Imatinib induced major cytogenetic responses in 16% of patients, with 7% of the responses being complete. Median survival time was 6.9 months. Nonhematologic adverse reactions were frequent but generally mild or moderate. Episodes of severe cytopenia were also frequent and were attributable to the underlying condition and treatment with imatinib. Drug-related adverse events led to discontinuation of therapy in 5% of patients, most often because of cytopenia, skin disorders, or gastrointestinal reactions. These results demonstrate that imatinib has substantial activity and a favorable safety profile when used as a single agent in patients with CML in blast crisis. Additional clinical studies are warranted to explore the efficacy and feasibility of imatinib used in combination with other antileukemic drugs.

Minimal residual disease (MRD) following sequential administration of CHOP and rituximab was studied in previously untreated patients with follicular lymphoma. At diagnosis, the presence of Bcl-2/IgH-positive cells in the peripheral blood (PB) and/or bone marrow (BM) was demonstrated in all patients (n = 128) by polymerase chain reaction (PCR) analysis. Patients who achieved a clinical response following CHOP but remained PCR-positive were eligible for rituximab (375 mg/m(2) intravenously, weekly for 4 weeks). After CHOP, 57% achieved a complete response (CR), 37% a partial response (PR), and 6% were nonresponders (NR). At this stage, patients proving PCR-negative (n = 41) or failing to achieve a clinical response (n = 8) were excluded from rituximab treatment. Seventy-seven patients received rituximab and entered a scheduled MRD follow-up program. At the first molecular follow-up (+12 weeks), 59% had converted to PCR negativity in the BM and PB, with a further increase documented at the second control (+28 weeks) with 74% PCR negative. At the last molecular follow-up (+44 weeks), 63% of the patients remained PCR negative. At 3 years, the estimated overall survival of all patients is 95% (95% confidence interval [CI], 86-98). For patients achieving PCR-negative status following CHOP and therefore excluded from rituximab treatment, freedom from recurrence (FFR) was 52% (95% CI, 28-71). For patients treated with rituximab, a durable PCR-negative status was associated with a better clinical outcome since FFR was 57% (95% CI, 23-81) compared with 20% (95% CI, 4-46) in patients who never achieved or lost the molecular negativity (P <.001).