An update on recent developments in non-Hodgkin's lymphoma

The management of non-Hodgkin's lymphoma (NHL) has changed considerably over the last 15 years with the recognition of independent prognostic factors leading to the development of a predictive model of outcome, the International Non-Hodgkin's Lymphoma Prognostic Factors Index (IPI) and more recently gene array studies. Since then, the therapeutic approaches have tried to improve the outcome of patients with adverse prognostic factors with the building of intensified regimens rather than the classical CHOP regimen. The introduction of monoclonal antibodies (MoAb) into the management of NHL has dramatically improved the response rates and rituximab is now approved for the treatment of diffuse large B-cell lymphoma and follicular lymphoma. Subsequently, MoAb have been conjugated to radioisotopes to target radiotherapy to tumor sites and improve overall survival. The advantages of these radiolabeled antibodies are not only to enhance the therapeutic potency of MoAb by targetting specifically CD20+ tumour cells but also to protect the neighbouring normal organs from cytotoxicity. Finally, the initial staging as well as the evaluation of the response after treatment has been better defined with the introduction of positron emission tomography (PET) into the assessment of NHL. The accuracy of PET imaging in the detection of residual disease and extranodal localizations appears to be the most helpful non-ivasive modality in NHL. The aim of this review is to focus on recent and most significant improvements in the management of lymphomas.     

Chronic myeloid leukemia in first chronic phase not responding to alpha-interferon: outcome and prognostic factors after autologous transplantation. EBMT Working Party on Chronic Leukemias.

We report the data obtained from the European Bone Marrow Transplant Registry for patients with CML who received autologous transplantation (AT) in chronic phase (CP) because alpha-IFN was ineffective. Forty-one CML patients (median age: 40.5 years; median Sokal index: 0.78) were included in this study. Bone marrow (16 cases) or blood (25 cases) progenitor cells were collected at diagnosis in 19 patients, during stable chronic phase or while the patient had cytogenetic (Cy) or complete hematologic response (CHR) in the other 22, and were manipulated ex vivo in 10 cases. The conditioning regimen consisted of busulfan associated with other chemotherapeutic regimens in 36 cases. Two patients died from interstitial pneumonitis (one case) and hemorrhage (one case). From the date of AT, the estimated probability of survival for the 41 patients was 84 +/- 13% and 51 +/- 29% at 2 and 4 years, respectively. Considering the 39 evaluable patients, the actuarial probability of achieving CHR, major and complete CyR 2 years after AT was 92 +/- 9%, 46 +/- 17%, and 30 +/- 15%, respectively. The Sokal score at diagnosis and the achievement of hematologic response after transplant were of prognostic importance. We suggest that a significant proportion of CML patients not responding to alpha-IFN may benefit from AT.     

Une maladie de Waldenström révélée par une macroglobulinemia cutis

Waldenström macroglobulinemia is defined by a bone marrow lymphoplasmacytic infiltration associated with serum IgM monoclonal gammopathy. Specific properties of the IgM gammopathy induce the main clinical manifestations revealing the disease: hyperviscosity syndrome, autoimmune peripheral neuropathy, cryoglobulinemia or hemolysis, and exceptional skin deposit such as macroglobulinosis cutis that we here report. Physicians should be aware of these clinical manifestations to avoid diagnostic delay.     

Severe cutaneous drug reactions to celecoxib (Celebrex)

INTRODUCTION: Celecoxib (Celebrex) is a Cox 2 selective non steroidal anti-inflammatory agent. Adverse reactions reported are usually benign, such as maculopapular exanthema. However, recently severe toxiderma have started to appear. We report two patients who developed a sever celecoxib drug skin reaction. OBSERVATIONS: Case no 1. In a 73 year-old woman, treated with celecoxib for cervical arthralgia, a maculopapular exanthema five days after treatment was started. The exanthema, initially edematous and purpural became bullous with multi-visceral failure (disseminated intravascular coagulation, renal failure, hepatitis and pancreatic). The disease slowly regressed. Case no 2. A 72 year-old man, treated for cervicalgia with celecoxib, presented a pustular exanthema of the face and the trunk, ten days after introduction of the treatment, associated with an inflammatory syndrome and hepatic cytolysis. Within 8 days the disease had regressed. In both these patients, the celecoxib patch tests were positive. DISCUSSION: Until now, the side effects reported with celecoxib have been generally benign exanthemas. We report two cases of severe celecoxib-induced toxiderma: a hypersensitivity syndrome with multi-organ failure and an acute generalized atypical exanthematous pustulosis. These severe toxidermas have rarely been reported in the literature, but we now need to reassess the risks with these new molecules.     

Clinical relevance of direct quantification of pp65 antigenemia using flow cytometry in solid organ and stem cell transplant recipients

A total of 1,305 blood samples from 85 solid organ transplant (SOT) recipients and 25 stem cell transplant (SCT) recipients at risk for cytomegalovirus (CMV) infection were prospectively collected and tested using the shell vial assay (SVA) and a leukocytic qualitative PCR (q-PCR). Of these, 462 specimens were further tested by direct quantification of CMV antigenemia by flow cytometry (FC-Ag), 125 were tested with a quantitative competitive PCR, and 200 were tested for pp65 antigenemia using the slide method (S-Ag). Laboratory data were statistically analyzed according to the presence of CMV-related symptoms. In SOT and SCT recipients, active CMV infection occurred in 63.5 and 36%, respectively, and CMV disease occurred in 53 and 24%, respectively. FC-Ag results correlated better with q-PCR and S-Ag than with SVA. The first test found to be positive during follow-up was FC-Ag in 73% of cases. In SOT recipients, FC-Ag showed the highest sensitivity and negative predictive value for the diagnosis of any grade of CMV disease. For FC-Ag, the threshold beyond which CMV disease was highly probable seemed to lie at 0.20% positive polymorphonuclear leukocytes. FC-Ag appears to be a useful test for the early detection of CMV infection and the prediction of CMV disease.     

Higher doses of CD34+ peripheral blood stem cells are associated with increased mortality from chronic graft-versus-host disease after allogeneic HLA-identical sibling transplantation.

Allogeneic peripheral blood stem cell transplantation (PBSCT) has emerged as an alternative to bone marrow transplantation. PBSCT can be associated with a higher incidence of chronic graft-versus-host disease (cGVHD). In this study, we investigated whether there was a correlation between the composition of PBSC grafts (CD34+ and CD3+ cells) and hematological recovery, GVHD, relapse, and relapse-free survival (RFS) after myeloablative HLA-identical sibling PBSCT. The evolution of 100 acute or chronic leukemia patients was analyzed. Neither hematological recovery, acute or cGVHD, nor relapse, was significantly associated with CD3+ cell dose. Increasing CD34+ stem cells was associated with faster neutrophil (P=0.03) and platelet (P=0.007) recovery. Moreover, 47 of the 78 patients evaluable for cGVHD (60%; 95% CI, 49-71%) developed extensive cGVHD. The probability of extensive cGVHD at 4 years was 34% (95% CI, 21-47%) in patients receiving a 'low' CD34+ cell dose (<8.3 x 10(6)/kg), as compared to 62% (95% CI, 48-76%) in patients receiving a 'high' CD34+ cell dose (>8.3 x 10(6)/kg) (P=0.01). At a median follow-up of 59 months, this has not translated into a difference in relapse. In patients evaluable for cGVHD, RFS was significantly higher in patients receiving a 'low' CD34+ cell dose as compared to those receiving a 'high' CD34+ cell dose (P=0.04). This difference was mainly because of a significantly higher cGVHD-associated mortality (P=0.01). Efforts to accelerate engraftment by increasing CD34+ cell dose must be counterbalanced with the risk of detrimental cGVHD.     

Randomized trial of bone marrow versus lenograstim-primed blood cell allogeneic transplantation in patients with early-stage leukemia: a report from the Société Fran?aise de Greffe de Moelle.

PURPOSE: To compare hematologic recovery in patients receiving allogeneic blood cell transplantation (BCT) with those receiving allogeneic bone marrow transplantation (BMT). PATIENTS AND METHODS: One hundred eleven patients with leukemia in the early stages and with HLA-matched sibling donors were randomized in this study. One hundred one underwent transplantation. Standard procedures for collection and transplantation were used. Patients did not receive prophylactic granulocyte colony-stimulating factor after undergoing transplantation. In addition to clinical end points being established, a prospective and comparative economic evaluation of the first 6 months after transplantation was performed. RESULTS: Groups were balanced for patient, donor, and transplant characteristics. Blood cell collection led to the collection of a higher number of CD34(+) and CD3(+) cells than did bone marrow collection (P < 10(-6)) without reported side effects for the donor. Patients in the BCT group reached platelet counts of 25 and 50 x 10(9) platelets/L 8 and 11 days earlier than did the BMT group (P < 10(-4) and P < 10(-5)), respectively. This resulted in fewer platelet transfusions during the first 180 days after transplantation (P =.002) for the former group. The time to reach neutrophil counts of 0.5 and 1 x 10(9) neutrophils/L was 6 and 7 days shorter, respectively, in the BCT group than in the BMT group (P < 10(-5)). This quicker hematologic recovery was associated with a shorter length of hospitalization and a decrease in total cost of procedure during the first 6 months. CONCLUSION: This study establishes that allogeneic BCT results in quicker hematologic recovery but is associated with a higher occurrence of chronic graft-versus-host disease.     

Fluorescence in situ hybridization on peripheral-blood specimens is a reliable method to evaluate cytogenetic response in chronic myeloid leukemia.

PURPOSE: To evaluate the usefulness of fluorescence in situ hybridization (FISH) on peripheral-blood specimens to evaluate the cytogenetic response to treatment in patients with chronic myeloid leukemia (CML). PATIENTS AND METHODS: In a first attempt, we analyzed 62 bone marrow specimens using interphase FISH and compared the results with those of conventional cytogenetics. In a second step, we analyzed 60 paired sets of bone marrow and peripheral-blood specimens with interphase FISH. RESULTS: The results of interphase FISH agreed with conventional cytogenetics on bone marrow for most patients, and only minor differences were found (r =.98). The comparison of interphase FISH on bone marrow versus peripheral-blood specimens showed a strong correlation between these two specimen sources (r =.97). CONCLUSION: Our results confirmed that FISH is a sensitive technique for the evaluation of response to treatment in patients with CML. Moreover, our study suggests that follow-up of cytogenetic response to therapy can be evaluated on peripheral-blood specimens, thus enabling an easier and more frequent evaluation of patients. The next step will be to evaluate this technique in a large prospective trial to define the prognostic value of complete remissions evaluated by FISH.