[Show abstract][Hide abstract] ABSTRACT: Outcome of systemic peripheral T-cell lymphomas (PTCL) is unsatisfactory and no controlled clinical study guides the therapy. Phase II studies suggest to consolidate response achieved after front-line treatment with stem cell transplant (SCT). We retrospectively evaluate the impact of front-line SCT consolidation in a single Center cohort of 209 patients treated during the last two decades. Median age was 49 years (range 15-85) with a prevalence of male sex (61%), advanced stage (68%) while IPI was >2 in 44%. Primary treatment was MACOP-B (39%) CHO(E)P (39%), intensive regimens (18%) or others (4%). Complete response to primary treatment (i.e. before SCT) was 60% (5% partial remission). Forty-four patients further proceeded to SCT while 92 did not receive consolidation. Outcome of primary responders was good, with a 3-year overall survival of 74% (82% in ALCL ALK+ and 69% for the other histologies). By multivariate analysis a better overall survival was significantly associated with IPI<2 (P=0.001), primary response (P=0.000), and ALCL ALK+ (P=0.012). The multivariate analysis performed on responders, showed that only IPI was predictive of a better survival while ALCL ALK+ and undergoing SCT were not. Response to primary treatment rather than post-remission programs is the crucial determinant of PTCL outcome.
[Show abstract][Hide abstract] ABSTRACT: Background:
Primary refractory disease is a main challenge in the management of non-Hodgkin's Lymphoma (NHL). This survey was performed to define the rate of refractory disease to first-line therapy in B and T-cell NHL subtypes and the long-term survival of primary refractory compared to primary responsive patients.
Medical records were reviewed of 3,106 patients who had undergone primary treatment for NHL between 1982 and 2012, at the Hematology Centers of Torino and Bergamo, Italy. Primary treatment included CHOP or CHOP-like regimens (63.2%), intensive therapy with autograft (16.9%), or other therapies (19.9%). Among B-cell NHL, 1,356 (47.8%) received first-line chemotherapy with rituximab. Refractory disease was defined as stable/progressive disease, or transient response with disease progression within six months.
Overall, 690 (22.2%) patients showed primary refractory disease, with a higher incidence amongst T-cell compared to B-cell NHL (41.9% vs. 20.5%, respectively, p<0.001). Several other clinico-pathological factors at presentation were variably associated with refractory disease, including histological aggressive disease, unfavorable clinical presentation, Bone Marrow involvement, low lymphocyte/monocyte ration and male gender. Amongst B-cell NHL, the addition of rituximab was associated with a marked reduction of refractory disease (13.6% vs. 26.7% for non-supplemented chemotherapy, p<0.001). Overall, primary responsive patients had a median survival of 19.8 years, compared to 1.3 yr. for refractory patients. A prolonged survival was consistently observed in all primary responsive patients regardless of the histology. The long life expectancy of primary responsive patients was documented in both series managed before and after 2.000. Response to first line therapy resulted by far the most predictive factor for long-term outcome (HR for primary refractory disease: 16.52, p<0.001).
Chemosensitivity to primary treatment is crucial for the long-term survival in NHL. This supports the necessity of studies aimed to early identify refractory disease and to develop different treatment strategies for responsive and refractory patients.
[Show abstract][Hide abstract] ABSTRACT: The peripheral blood lymphocyte to monocyte ratio (LMR) at diagnosis can be clinically relevant in patients with diffuse large B-cell lymphoma (DLBCL). We reviewed the outcome of 1,057 DLBCL patients followed from 1984 to 2012 at four centers. LMR was analyzed as a clinical biomarker by ROC analysis and Harrell's C-statistics. Patients were characterized by a median age of 61 years, IPI >2 in 39% and they were treated with a rituximab-containing chemotherapy in 66%. LMR proved strongly predictive for survival in patients treated with rituximab-based programs, but not in those receiving chemotherapy alone. Additionally, a LMR value ≤ 2.6 (as determined by ROC analysis) was associated with a worst performance status, a higher LDH, an advanced clinical stage and a higher IPI score (p= 0.000). In patients treated with rituximab containing programs, a LMR value < 2.6 was found in most of the primary refractory patients (75%) and proved as the best cut off to predict both response and survival (p=0.018). Finally, multivariate analysis and Harrell's C-statistic confirmed the IPI-independent role of LMR on survival (p= 0.0000). In conclusion, LMR is a potent predictor of clinical response and survival in DLBCL treated with rituximab-containing chemotherapy.
Preview · Article · Dec 2013 · American Journal of Hematology
[Show abstract][Hide abstract] ABSTRACT: We evaluate the long-term results of a prospective clinical study enrolling more than 100 adult patients with Burkitt lymphoma/leukemia. Depending on extent of disease, treatment consisted of six-eight rituximab infusions and four-six intensive chemotherapy courses (attenuated in patients aged >55 years) with high-dose methotrexate, fractionated ifosfamide/cyclophosphamide, other drugs in rotation, and intrathecal chemoprophylaxis. One-hundred five patients were treated (median age 47 years, range 17-78 years); 48% had Burkitt leukemia, 25% were older than 60 years, 37% exhibited an Eastern Cooperative Oncology Group performance score >1, and 14% were HIV-positive. Complete response rate and 3-year overall and disease-free survival were 79%, 67% and 75%, respectively, ranging from 100% to 45% for survival (P=0.000) and from 100% to 60% for disease-free survival (P=0.01) in patients with low, intermediate and high adapted international prognostic index. In multivariate analysis, only age (< vs >60 years) and performance status (0-1 vs >1) retained prognostic significance, identifying three risk groups with overall and disease-free survival probabilities of 88% and 87.5%, 57% (P=0.0000) and 70.5%, 20% and 28.5% (P=0.0001), respectively. Relapse rate was only 7% in patients treated with an intercycle interval <25 days. This regimen achieved 100% curability in patients with low adapted international prognostic index (21% of total), and very close to 90% in patients aged ≤60 years with performance score 0-1 (48% of total). Rapid Burkitt lymphoma/leukemia diagnosis with prompt patient referral to prevent clinical deterioration, and careful supervision of treatment without chemotherapy delay can achieve outstanding therapeutic results. ClinicalTrial.gov ID, NCT01290120.
[Show abstract][Hide abstract] ABSTRACT: A definition of response by cytoreductive therapy in essential thrombocythemia was recently provided by the European LeukemiaNet (ELN). Complete, partial, or no clinicohematologic responses were defined on the bases of platelet count, disease-related symptoms, spleen size, and white blood cell count. To provide estimates and clinical correlation of responses according to these criteria, we retrospectively examined 416 essential thrombocythemia patients treated with hydroxyurea for at least 12 months. Complete response, partial response, and no response were 25%, 58%, and 17%, respectively. Age more than 60 years and JAK2V617F mutation were significant predictors of response. After a median follow-up of 3.9 years, we registered 23 deaths, 16 hematologic transformations, and 27 thrombotic events (rate, 1.66% patients/year). Age, previous thrombosis, leukocytosis (white blood cell count > 10 x 10(9)/L), but not ELN responses, were independently associated with higher risk of thrombosis. The actuarial probability of thrombosis was significantly influenced by leukocytosis (P = .017) and not by platelet count, indicating that platelet number does not seem of prime relevance in the definition of ELN response.
[Show abstract][Hide abstract] ABSTRACT: Conflicting results about the effects of hydroxyurea on the burden of mutant allele in patients with myeloproliferative neoplasms (MPN) harboring the JAK2V617F mutation have been produced recently. Owing to these conflicting results, the aim of our study was to analyze changes of JAK2V617F allele burden occurring during long-term follow-up in 172 patients with PV or ET and the relationships with hydroxyurea treatment. We conclude that in untreated patients with ET and PV changes in V617F allele burden occur very smoothly over years and we failed to confirm previous reports supporting the effectiveness of hydroxyurea in reducing the burden of JAK2V617F allele.
[Show abstract][Hide abstract] ABSTRACT: Although imatinib may be effective in hypereosinophilic syndromes, the exact response kinetics are not known. Imatinib was administered at 100-400 mg/d each week in a 12-week response-oriented schedule, targeting a complete clinical and haematological remission (CR). CR was achieved in 11/23 patients (6/6 with FIP1L1-PDGRFA rearrangement and 5/17 without, P = 0.006), most after 2 weeks of 100 mg/d imatinib. The maximum imatinib dose had no effect in early unresponsive patients. Low-dose, short-course imatinib may represent a rational choice for identifying responsive cases, both within and outside the pre-defined FIP1L1 rearrangement subset.
Full-text · Article · Oct 2009 · British Journal of Haematology
[Show abstract][Hide abstract] ABSTRACT: A direct comparison of the incidence and risk factors of major thrombosis in essential thrombocythemia (ET) and polycythemia vera (PV) according to their respective JAK2V617F allele burden is the object of this study.
We compared the rate (%/patients/year) of major thrombosis in 867 ET patients (57% JAK2V617F) with that of 415 PV patients (all JAK2V617F) and examined risk factors.
Patients with ET wild-type, ET V617F, and PV showed a rate of thrombosis of 1.4%, 2.1%, and 2.7%/patients/year, respectively. The latter was found to progressively increase according to time of diagnosis. Actuarial probability of arterial and venous thrombosis in the first 5 years of diagnosis was roughly similar in the three groups. While in the subsequent periods, the curves of mutated ET patients diverged from wild-type, and after 10 to 15 years the ET-mutated arm approached PV.
These findings support the concept of a continuum between ET JAK2 mutated and PV, not only in reference to the hematological phenotype, but also in terms of vascular events.
[Show abstract][Hide abstract] ABSTRACT: A total of 186 patients with primary myelofibrosis (PMF) were genotyped for JAK2V617F at diagnosis aimed at analyzing the correlation of mutational status and mutated allele burden with outcome variables, including time to anemia, leukocytosis, leukopenia, thrombocytopenia, massive splenomegaly, leukemia, and with overall survival. A total of 127 JAK2V617F-mutated patients (68% of whole series) were divided in quartiles of V617F allele burden. After a median follow-up of 17.2 months, 23 patients died, 15 because of leukemia. A JAK2V617F mutated status did not impact on the rate of leukemia transformation or overall survival. Patients in the lower quartile had shorter time to anemia and leukopenia and did not progress to large splenomegaly. Furthermore, survival was significantly reduced in the lower quartile compared with upper quartiles and JAK2 wild-type patients. In multivariate analysis, factors associated with reduced survival were age, a blast count more than 1%, and a JAK2V617F burden within first quartile. Causes of death in the lower quartile were represented mainly by systemic infections. We conclude that a low JAK2V617F allele burden at diagnosis is preferentially associated with a myelodepletive rather than myeloproliferative phenotype and represents an independent factor associated with shortened survival in patients with PMF.
[Show abstract][Hide abstract] ABSTRACT: Among 994 patients with essential thrombocythemia (ET) who were genotyped for the MPLW515L/K mutation, 30 patients carrying the mutation were identified (3.0%), 8 of whom also displayed the JAK2V671F mutation. MPLW515L/K patients presented lower hemoglobin levels and higher platelet counts than did wild type (wt) MPL; these differences were highly significant compared with MPLwt/JAK2V617F-positive patients. Reduced hemoglobin and increased platelet levels were preferentially associated with the W515L and W515K alleles, respectively. MPL mutation was a significant risk factor for microvessel disturbances, suggesting platelet hyperreactivity associated with constitutively active MPL; arterial thromboses were increased only in comparison to MPLwt/JAK2wt patients. MPLW515L/K patients presented reduced total and erythroid bone marrow cellularity, whereas the numbers of megakaryocytes, megakaryocytic clusters, and small-sized megakaryocytes were all significantly increased. These data indicate that MPLW515L/K mutations do not define a distinct phenotype in ET, although some differences depended on the JAK2V617F mutational status of the counterpart.
[Show abstract][Hide abstract] ABSTRACT: Established risk factors for thrombosis in essential thrombocythemia (ET) include age and previous vascular events. We aimed to refine this risk stratification by adding baseline leukocytosis.
We enrolled 657 patients with ET followed for a median of 4.5 years who developed 72 major thrombosis. Cox proportional hazard model was performed to analyze the thrombotic risk and to discriminate ET patients with or without thrombosis, multivariable C statistic index was used. We searched for leukocytes cutoff with the best sensitivity and specificity by a receiver operating characteristic curve.
Results confirmed that age and prior events are independent risk factors for thrombosis and showed a gradient between baseline leukocytosis and thrombosis. On the contrary, no significant association was found either for JAK2(V617F) allele burden and for other laboratory parameters, including platelet number. In the model with conventional risk factors alone, C statistic ratio for total thrombosis was 0.63 and when leukocytosis was added, the change was small (C = 0.67). In contrast, in younger and asymptomatic patients (low-risk category), C statistic value indicated an high risk for thrombosis in patients with leukocytosis, similar to that calculated in conventionally defined high-risk group (C = 0.65). The best leukocyte cutoff values for predicting the events was found to be 9.4 (x 10(9)/L).
We suggest to include baseline leukocytosis in the risk stratification of ET patients enrolled in clinical trials.
[Show abstract][Hide abstract] ABSTRACT: To elucidate the role of thrombocytosis, alone or in combination with standard (age, previous cardiovascular events) and novel (leukocytosis, JAK2(V617F) mutational status) risk factors, in the cardiovascular events of essential thrombocythemia (ET), we analyzed a cohort of 1063 patients. We found that a platelet count at diagnosis greater than 1000 x 10(9)/L was associated with significantly lower rate of thrombosis in multivariable analysis and, if combined with leukocytes less than 11 x 10(9)/L, pointed to a "low-risk" category with a rate of thrombosis of 1.59% of patients/year. On the contrary, the highest risk category (thrombosis rate, 2.95% of patients/year) was constituted of patients with leukocytosis, lower platelet count, and a JAK2(V617F) mutated genotype in most cases (77% vs 26% in the low-risk group), independently from standard risk factors. These data challenge the theory that elevated platelet count increases thrombosis risk in ET and suggest prospective clinical trials to support this hypothesis.
[Show abstract][Hide abstract] ABSTRACT: A multicenter retrospective analysis was performed to estimate the frequency of thrombosis and hemorrhage after surgical procedures in patients with polycythemia vera (PV) and patients with essential thrombocythemia (ET). Data from 105 patients with PV and 150 patients with ET were analyzed, for a total of 311 surgical interventions. An emergency procedure was performed in 25 (8.1%) patients; 194 surgeries were done under general anesthesia, and 21 (23%) of 91 abdominal interventions were done under laparoscopy; 155 (50.1%) were major surgeries. Subcutaneous heparin was administered in 169 (54.3%) of 311 cases and antiplatelet therapy in 48 (15.4%) of 311 case interventions. One hundred eighty-eight (74%) of 255 patients were on cytoreductive therapy before surgery. No events were observed in 259 (83.2%) of 311 procedures during 3 months of follow-up; there were 12 arterial and 12 venous thrombotic events, 23 major and 7 minor hemorrhages, and 5 deaths. Arterial thromboses were more frequent in ET (5.3% vs 1.5%; P=.08), venous events were more frequent in PV (7.7% vs 1.1%; P=.002). There was not a correlation between bleeding episodes and the type of diagnosis, use of antithrombotic prophylaxis, or type of surgery. A high proportion of PV and ET surgeries was complicated by vascular occlusion (7.7%) or by a major hemorrhage (7.3%). Prospective investigations analyzing the optimal prophylaxis in these patients are suggested.
[Show abstract][Hide abstract] ABSTRACT: Leukocytes contribute to the pathogenesis of thrombosis in essential thrombocythemia (ET) through recently discovered mechanisms of activation and interaction with platelets and endothelial cells. To evaluate whether an increased leukocyte count was associated with thrombosis and whether this effect can be modulated by therapy, we analyzed the clinical course of 439 patients with ET followed at the Ospedali Riuniti di Bergamo. The strength of the association was measured at diagnosis or before thrombotic events by multivariable analyses carried out using data at baseline as well as time-varying covariates. The results showed that (1) an increased leukocyte count at diagnosis was associated with thrombosis during follow-up ("baseline analysis," relative risk [RR] 2.3, 95% confidence interval [CI] 1.4-3.9, P = .001); (2) hydroxyurea (HU) lowered leukocytosis and reduced the strength of the association between leukocytosis and thrombosis ("time-dependent analysis," RR 1.6, 95% CI 0.9-2.0, not significant [NS]); (3) the association of leukocytosis and thrombosis was more evident in untreated low-risk patients (RR 2.7, 95% CI 1.2-6.4, P = .01) compared with HU-treated high-risk patients (RR 1.6, 95% CI 0.8-3.2, NS); and (4) the presence of JAK2 V617F was not identified as a risk factor for thrombosis during follow-up despite a significant association between the mutation and leukocytosis. We suggest validation of these findings in prospective clinical studies.
[Show abstract][Hide abstract] ABSTRACT: Clinical trials have shown that high dose chemotherapy (HDT) with peripheral stem cell autotransplantation is presently the best treatment for patients with symptomatic multiple myeloma (MM). In the context of an outcomes research project, we analyzed the feasibility of this strategy in clinical practice in a large cohort of consecutive, unselected patients with newly diagnosed MM and looked at the major determinants of response of patients enrolled in a HDT with tandem autotransplantation (Total Therapy I, TTI) program.
Two hundred and fourteen patients were treated outside of a clinical trial and regularly followed-up at our Center for symptomatic MM. Ninety-seven patients (45%) received conventional chemo-radiotherapy regimens, 110 (51%) entered the TTI program and the remaining 7 patients (3.3%) were enrolled in other programs involving HDT with autotransplantation.
Patients enrolled in HDT with tandem autotransplantation programs were 14 years younger and less likely to have co-morbidities than patients treated with conventional therapy. Median overall survivals of the two groups were 60 and 33 months, respectively. Thirteen percent of the patients enrolled in the TTI program did not receive the first HDT with autotransplantation, mostly because of disease progression, and another 16% did not proceed to the second HDT with autotransplantation mainly because of infections or drug-related complications. Most patients achieved complete remission after the second autotransplantation, with acceptable toxicity. However, only patients with a major reduction of the myeloma burden at the end of induction therapy enjoyed significantly prolonged event-free and overall survivals.
Approximately one third of patients with newly diagnosed symptomatic MM completed the TTI program. These data suggest the need to improve the induction therapy in order to increase both the number of patients able to proceed to autotransplantation programs and to enhance the rate of early response.