Prognostic Impact of Serum ß2-Microglobulin Levels in Hodgkin Lymphoma Treated with ABVD or Equivalent Regimens: A Comprehensive Analysis of 915 Patients.

The significance of serum beta-2 microglobulin (sß2m) in Hodgkin lymphoma (HL) is controversial. We analyzed 915 patients with HL, who were treated with ABVD or equivalent regimens with or without radiotherapy. Sß2m levels were measured by a radioimmunoassay (upper normal limit 2.4 mg/L). Sequential cutoffs (1.8-3.0 by 0.1 mg/L increments, 3.5 and 4.0 mg/L) were tested along with ROC analysis. The median sß2m levels were 2.20 mg/L and were elevated (>2.4 mg/L) in 383/915 patients (41.9%). Higher sß2m was associated with inferior freedom from progression (FFP) at all tested cutoffs. The best cutoff was 2.0 mg/L (10-year FFP 83% vs. 70%, p = 0.001), which performed better than the 2.4 mg/L cutoff ("normal versus high"). In multivariate analysis, sß2m > 2.0 mg/L was an independent adverse prognostic factor in the whole patient population. In multivariate overall survival analysis, sß2m levels were predictive at 2.0 mg/L cutoff in the whole patient population and in advanced stages. Similarly, sß2m > 2.0 mg/L independently predicted inferior HL-specific survival in the whole patient population. Our data suggest that higher sß2m is an independent predictor of outcome in HL but the optimal cutoff lies within the normal limits (i.e., at 2.0 mg/L) in this predominantly young patient population, performing much better than a "normal versus high" cutoff set at 2.4 mg/L.

Symptomatic ovarian involvement as the initial presentation of primary mediastinal large b-cell lymphoma.

Primary mediastinal large B- cell lymphoma (PMLBCL) is a mature aggressive B-cell lymphoma which affects mainly young and middle-aged women. The majority of patients present with bulky mediastinal lymphadenopathy. Extranodal involvement is a rare phenomenon at disease presentation. Herein, we describe a case of a young female with PMLBCL presenting with symptomatic, bulky ovarian involvement. The 23-year old patient presented at the Emergency Department with abdominal pain. The chest X-ray film revealed a mediastinal mass and CT scan revealed a large pelvic mass, possibly involving the ovaries. Due to the development of signs of acute abdomen, she was urgently transferred to the operation room where surgical resection of the right ovary and the adjacent mass was performed. The histological examination of the resected material revealed proliferation of PMLBCL cells. This is the first report in the scientific literature describing symptomatic ovarian mass as the initial mode of presentation of PMLBCL.

Serum ferritin levels in previously untreated classical Hodgkin lymphoma: correlations and prognostic significance.

Serum ferritin (SF) is frequently elevated in classical Hodgkin lymphoma (cHL). We report on its prognostic significance in an unselected series of 529 cHL patients treated with state-of-the-art therapy. Higher baseline levels correlated with markers of advanced/aggressive disease. SF levels were significantly higher in male and older patients, those with high body mass index and mixed cellularity histology. The strongest correlation was recorded between SF and complement reactive protein (CRP) levels. Gender-specific SF cutoffs which provided the best discrimination in terms of freedom from progression (FFP) were identified. In multivariate analysis elevated SF levels, advanced stage and high lactate dehydrogenase (LDH) were independent prognostic factors of inferior FFP. SF also appears to retain independent prognostic significance for progression-free survival (PFS) but not for overall survival (OS). In conclusion, SF levels in cHL reflect disease activity and are associated with adverse patient outcomes.

Very Early Onset of Therapy-Related Acute Myeloid Leukemia with 11q23 Rearrangement Presenting with Unusual PET Findings after R-DA-EPOCH for Primary Mediastinal Large B-Cell Lymphoma.

BACKGROUND: R-DA-EPOCH is an effective regimen for PMLBCL, which permits the omission of consolidative radiotherapy in the majority of patients. PATIENT: We describe a 27-year-old female patient, who achieved a complete remission after treatment with six cycles of R-DA-EPOCH (up to the final level). At 6 months after the end of treatment, PET/CT revealed an unexpected, diffusely increased 18FDG uptake by the bone marrow. Simultaneously, pancytopenia with monocytosis was observed. RESULT: The patient was diagnosed with therapy-related myelodysplastic syndrome, which rapidly evolved into acute myeloid leukemia (t-MDS/AML) with MLL rearrangements. She achieved a complete remission after induction therapy, received an allogenic transplant and remains disease-free 2 years later. CONCLUSIONS: The extremely early onset of t-MDS/AML, together with the unexpected PET/CT findings make this case unique and highlights the need for the accurate estimation of the possible dose-dependent risk of t-MDS/AML after R-DA-EPOCH in the real-life setting in patients with PMLBCL.

Successful reversal of severe liver function impairment with Brentuximab vedotin in multiply relapsed/refractory classical Hodgkin lymphoma.

PURPOSE: To present our experience on the use of Brentuximab Vedotin (BV) in patients with relapsed/refractory classical Hodgkin Lymphoma (cHL) and severe liver function impairment with marked jaundice. METHODS: Two patients with relapsed/refractory cHL were evaluated. BV was administered in the presence of liver dysfunction and severe jaundice due to liver infiltration by cHL, as confirmed by PET-CT. Complete blood counts, biochemical profile, physical and imaging findings were reviewed to assess BV efficacy and tolerance. RESULTS: Case 1 had stage IVB, mixed cellularity cHL. Following ABVD chemotherapy, the patient experienced a relapse and responded to IGEV (ifosfamide, gemcitabine, vinorelbine, steroids) chemotherapy followed by autologous stem cell transplantation (ASCT). Thereafter, he experienced a second relapse with constitutional symptoms, severe jaundice and pancytopenia. Liver involvement was confirmed by PET-CT. Case 2 was admitted with a very late relapse of cHL. After a single cycle of gemcitabine-vinorelbine chemotherapy, which was not tolerated, the patient developed fever, anemia and jaundice, with laboratory findings indicating bone marrow and liver infiltration. The latter was confirmed by PET-CT. Both patients received BV monotherapy according to its formal indication at the reduced dose of 1.2 mg/kg due to severe liver impairment and experienced a rapid clinical and laboratory improvement. BV was well tolerated and offered a clinical benefit for approximately 4 months. CONCLUSIONS: BV was safely administered to patients with relapsed/refractory cHL and severe liver function impairment with marked jaundice due to liver involvement, offering significant clinical improvement and reversal of liver abnormalities. BV may serve as a bridge to further salvage combination chemotherapy or a transplant procedure.

Potential role of AKT/mTOR signalling proteins in hairy cell leukaemia: association with BRAF/ERK activation and clinical outcome.

The potential role of AKT/mTOR signalling proteins and its association with the Raf-MEK-ERK pathway was investigated in hairy cell leukaemia (HCL). BRAFV600E expression and activated forms of AKT, mTOR, ERK1/2, p70S6k and 4E-BP1 were immunohistochemically assessed in 77 BM biopsies of HCL patients and correlated with clinicopathological and BM microvascular characteristics, as well as with c-Caspase-3 levels in hairy cells. Additionally, we tested rapamycin treatment response of BONNA-12 wild-type cells or transfected with BRAFV600E. Most HCL cases expressed p-p70S6K and p-4E-BP1 but not p-mTOR, being accompanied by p-ERK1/2 and p-AKT. AKT/mTOR activation was evident in BONNA-12 cells irrespective of the presence of BRAFV600E mutation and was implicated in cell proliferation enhancement. In multivariate analysis p-AKT/p-mTOR/p-4E-BP1 overexpression was an adverse prognostic factor for time to next treatment conferring earlier relapse. When p-AKT, p-mTOR and p-4E-BP1 were examined separately only p-4E-BP1 remained significant. Our findings indicate that in HCL, critical proteins up- and downstream of mTOR are activated. Moreover, the strong associations with Raf-MEK-ERK signalling imply a possible biologic interaction between these pathways. Most importantly, expression of p-4E-BP1 alone or combined with p-AKT and p-mTOR is of prognostic value in patients with HCL.

Prognostic Implication of the Absolute Lymphocyte to Absolute Monocyte Count Ratio in Patients With Classical Hodgkin Lymphoma Treated With Doxorubicin, Bleomycin, Vinblastine, and Dacarbazine or Equivalent Regimens.

Low absolute lymphocyte count (ALC) to absolute monocyte count (AMC) ratio (ALC/AMC) is an independent prognostic factor in Hodgkin lymphoma (HL), but different cutoffs (1.1, 1.5, and 2.9) have been applied. We aimed to validate the prognostic significance of ALC/AMC in 537 homogenously treated (doxorubicin, bleomycin, vinblastine, and dacarbazine or equivalents ± radiotherapy) classical HL patients at various cutoffs. The median ALC/AMC was 2.24 (0.44-20.50). The median AMC was 0.653 × 10(9)/L (0.050-2.070). Lower ALC/AMC was associated with established markers of adverse prognosis. In total, 477 (89%), 418 (78%), and 189 (35%) patients had an ALC/AMC ratio of ≥1.1, ≥1.5, and ≥2.9; respectively; 20% had monocytosis (≥0.9 × 10(9)/L). Ten-year time to progression (TTP) was 77% versus 55% for patients with ALC/AMC ≥1.1 and <1.1 (p = .0002), 76% versus 68% for ALC/AMC ≥1.5 and <1.5 (p = .049), 77% versus 73% for ALC/AMC ≥2.9 and <2.9 (p = .35), and 79% versus 70% for ALC/AMC ≥2.24 and <2.24 (p = .08), respectively. In stages ΙΑ/ΙΙΑ and in patients ≥60 years old, ALC/AMC had no significant effect on TTP. In advanced stages, ALC/AMC was significant only at the cutoff of 1.1 (10-year TTP 67% vs. 48%; p = .016). In younger, advanced-stage patients, the differences were more pronounced. In multivariate analysis of TTP, ALC/AMC < 1.1 (p = .007) and stage IV (p < .001) were independent prognostic factors; ALC/AMC was independent of International Prognostic Score in another model. ALC/AMC was more predictive of overall survival than TTP. At the cutoff of 1.1, ALC/AMC had independent prognostic value in multivariate analysis. However, the prognostically inferior group comprised only 11% of patients. Further research is needed prior to the widespread use of this promising marker.

Treatment of splenic marginal zone lymphoma with rituximab monotherapy: progress report and comparison with splenectomy.

BACKGROUND: Treatment of splenic marginal zone lymphoma (SMZL) patients is not standardized. Recent data suggest that rituximab is highly effective and could be considered as initial therapy. AIM: To assess the efficacy of rituximab monotherapy in a large series of patients with SMZL and compare these results with splenectomy results. METHODS: The studied population included 85 patients. Fifty-eight received rituximab at a dose of 375 mg/m2 per week for 6 weeks as induction followed by maintenance at the same dose every 2 months for 1-2 years, whereas 27 patients were treated using splenectomy only. RESULTS: The overall response rate to rituximab 2 months after the end of induction was 95% (complete response [CR], 45%; unconfirmed CR, 26%; partial response, 24%). The median times to hematologic and clinical response were 2 weeks and 3 weeks, respectively. Forty-three of 55 patients already completed the maintenance phase: 28 sustained their initial response, 14 improved their response, and one progressed. Eighty-five percent of splenectomized patients responded, and two were treated with rituximab as consolidation after splenectomy and achieved a CR. The 5-year overall and progression-free survival (PFS) rates for rituximab-treated and splenectomized patients were 92% and 77% (p = .09) and 73% and 58% (p = .06), respectively. Furthermore, maintenance therapy with rituximab resulted in a longer duration of response (at 5 years, PFS was 84% for patients receiving maintenance and 36% for patients without maintenance, p <.0001). CONCLUSIONS: Rituximab is a very effective and well-tolerated therapy and may be substituted for splenectomy as the first-line treatment of choice for patients with SMZL.

Deferasirox effectively decreases iron burden in patients with double heterozygous HbS/ß-thalassemia.

Iron overload is present in several cases of double heterozygous sickle-cell/beta-thalassemia (HbS/ß-thal). Deferasirox is an orally administered iron chelator which is effective on iron overloaded patients with transfusion-dependent anemia. The aim of this study was to investigate the efficacy and safety of deferasirox on HbS/ß-thal patients with iron overload. We evaluated 31 adult patients with HbS/ß-thal (14M/17F; median age 41 years) who had serum ferritin levels >1,000 ng/mL and who were sporadically transfused. Total iron burden was monitored by measuring serum ferritin levels before and monthly after starting deferasirox, while liver iron concentration and cardiac iron burden were measured by magnetic resonance imaging (MRI) T2 and T2* parameters at baseline and 12 months after deferasirox treatment. Deferasirox managed to reduce the mean serum ferritin levels after 12 months of treatment from 1,989 ± 923 to 1,008 ± 776 ng/mL (P < 0.001). This reduction was accompanied by a significant improvement on MRI T2* of the liver (from 3.9 ± 3.2 to 5.8 ± 3.1 ms; P < 0.01) and by a comparable improvement of biochemical parameters of liver function. Mild nausea and diarrhea of grade 1/2 were reported in 25% of patients within the first month of treatment, but did not re-occur. These data indicate that deferasirox provided effective control of iron levels (mainly of the liver) in minimally transfused patients with HbS/ß-thal, without significant adverse events, at similar doses to those studied widely for the treatment of patients with thalassemia syndromes.

The effect of prolonged administration of hydroxyurea on morbidity and mortality in adult patients with sickle cell syndromes: results of a 17-year, single-center trial (LaSHS).

The aim of this prospective study was to evaluate the long-term efficacy and safety of hydroxyurea (HU) in patients with sickle cell disease (SCD). Thirty-four patients with sickle cell anemia (hemoglobin S [HbS]/HbS), 131 with HbS/beta(0)-thal, and 165 with HbS/beta(+)-thal participated in this trial. HU was administered to 131 patients, whereas 199 patients were conventionally treated. The median follow-up period was 8 years for HU patients and 5 years for non-HU patients. HU produced a dramatic reduction in the frequency of severe painful crises, transfusion requirements, hospital admissions, and incidence of acute chest syndrome. The probability of 10-year survival was 86% and 65% for HU and non-HU patients, respectively (P = .001), although HU patients had more severe forms of SCD. The 10-year probability of survival for HbS/HbS, HbS/beta (0)-thal, and HbS/IVSI-110 patients was 100%, 87%, and 82%, respectively, for HU patients and 10%, 54%, and 66%, for non-HU patients. The multivariate analysis showed that fetal hemoglobin values at baseline and percentage change of lactate dehydrogenase between baseline and 6 months were independently predicted for survival in the HU group. These results highlight the beneficial effect of HU, which seems to modify the natural history of SCD and raise the issue of expanding its use in all SCD patients.

Carrier screening and prenatal diagnosis of hemoglobinopathies. A study of indigenous and immigrant couples in northern Greece, over the last 5 years.

Hemoglobinopathies constitute the most frequent monogenic disorders worldwide and thalassemias are the most frequent genetic disorders in Greece. Over a 5-year period (2002-2006), 1,375 couples were screened for hemoglobinopathies and counseled at our Thalassaemia Prevention Unit, Hippokration Hospital, Thessaloniki, Greece. In 148 cases (10.7%), both partners carried an abnormal hemoglobin (Hb) gene and genetic counseling was offered. One hundred out of 116 pregnancies were at-risk of giving birth to an offspring carrying either the homozygous or double heterozygous forms of the mutations under discussion. The remaining 16 pregnancies involved couples who were heterozygous for mutations that did not cause severe clinical disease, and were exempted from prenatal diagnosis. Twenty-six fetuses were found to be homozygotes or double heterozygotes for clinically significant mutations. These couples were informed of the danger of having an affected child but the termination or continuation of the pregnancy was left to the couples to decide. Nevertheless, all the couples preferred to terminate the pregnancies. The National Thalassaemia Prevention Programme has effectively decreased the incidence of thalassemia major and sickle cell syndromes in Greece.

The molecular heterogeneity of beta-thalassemia in Greece.

Beta-thalassemia is the most predominant genetic defect in Greece. In this study, we investigated the heterogeneity and the frequency of beta-thalassemia mutations among 3796 heterozygotes detected in the course of DNA based diagnoses. The diagnostic strategy included Denaturing Gradient Gel Electrophoresis (DGGE), Allele Specific Oligonucleotide Hybridization (ASO), GAP PCR, Restriction Enzyme (RE) analysis and direct sequencing and led to 100% identification of the underlying molecular lesion. Six out of 33 different beta-globin defects identified accounted for more than 91.4% of the total beta-thalassemia chromosomes in Greece. The beta-globin gene mutations cd29 C-->T, IVS-I-2 T-->C, IVS-I-5 G-->T, cd37 G-->A and poly A Kurdish AATAAA-->AATAAG are for the first time reported in Greece, whereas cd7 GAG-->TAG is a new beta(0)-thalassemia mutation detected in an adult man from Albania residing in Greece. Three DNA single nucleotide polymorphisms (IVS-I-85 T-->C, IVS-I-91 C-->T and IVS-I-108 T-->C) were also revealed; among these, IVS-I-85 T-->C and IVS-I-91 C-->T are new and described for the first time worldwide.