IgM peak independently predicts treatment-free survival in chronic lymphocytic leukemia and correlates with accumulation of adverse oncogenetic events.

We examined the significance of IgM peaks in chronic lymphocytic leukemia (CLL), including its association with newly reported MYD88, BIRC3, NOTCH1 and SF3B1 mutations. A total of 27, 25, 41 and 57 patients with monoclonal IgM or IgG peaks (IgM and IgG groups), hypogammaglobulinemia (Hypo-γ group) and normal immunoglobulin serum levels (normal-γ group) were, respectively, included. IgM peaks were mainly associated with Binet stage C and the del(17p). Biased usage of IGHV3-48 was shared by both IgM and IgG groups. IGHV3-74 and IGHV4-39 gene rearrangements were specific for IgM and IgG peaks, respectively. SF3B1, NOTCH1, MYD88 and BIRC3 mutation frequencies were 12%, 4%, 2% and 2%, respectively, being over-represented in IgM, IgG and Hypo-γ groups for SF3B1, and being equal between normal-γ and IgM groups for MYD88. Overall, 76%, 87%, 49% and 42% of cases from IgM, IgG, Hypo-γ and normal-γ groups had at least one intermediate or poor prognosis genetic marker, respectively. By multivariate analysis, IgM peaks were associated with shorter treatment-free survival independently from any other univariate poor prognosis biological parameters, including IgG peaks, Hypo-γ, IGHV status, SF3B1 mutations, cytogenetics and lymphocytosis. Therefore, as with IgG peaks, IgM peaks aggravated the natural course of CLL, with increased accumulation of adverse genetic events.

Multicenter, randomized comparative trial of fludarabine and the combination of cyclophosphamide-doxorubicin-prednisone in 92 patients with Waldenström macroglobulinemia in first relapse or with primary refractory disease.

Few reports are available on the treatment of patients with Waldenström macroglobulinemia (WM) and primary or secondary resistance to alkylating-agent-based regimens. From December 1993 through December 1997, 92 patients with WM resistant to first-line therapy (42) or with first relapse (50) after alkylating-agent therapy were randomly assigned to receive fludarabine (25 mg/m(2) of body-surface area on days 1-5) or cyclophosphamide, doxorubicin (Adriamycin), and prednisone (CAP; 750 mg/m(2) cyclophosphamide and 25 mg/m(2) doxorubicin on day 1 and 40 mg/m(2) prednisone on days 1-5). The first end point evaluated was the response rate after 6 treatment courses. Forty-five patients received CAP and 45 received fludarabine. Two patients died before the first course of chemotherapy. No statistical differences were observed between the 2 treatment arms with respect to hematologic toxicity or infections. Mucositis and alopecia occurred significantly more often in patients treated with CAP. Partial responses were obtained in 14 patients (30%) treated with fludarabine and 5 patients (11%) treated with CAP (P =.019). Responses were more durable in patients treated with fludarabine (19 months versus 3 months), and the event-free survival rate was significantly higher in this group (P <.01). Forty-four patients died, 22 in the fludarabine group and 22 in the CAP group. There was no statistical difference in the median overall survival time in the 2 study arms. Fludarabine was thus more active than CAP in salvage therapy of WM and should be tested as first-line therapy in a randomized comparison with alkylating agents.

Evaluating treatment strategies in advanced Waldenström macroglobulinemia: use of quality-adjusted survival analysis.

A randomized phase II multicenter clinical trial comparing the efficacy of fludarabine (FAMP) to that of the association of cyclophosphamide, doxorubicin and prednisone (CAP) in 92 patients with Waldenstrom's macroglobulinemia in first relapse or with primarily resistant disease, was conducted on the behalf of the 'Groupe Coopératif Macroglobulinémie'. The main analysis of this study failed to demonstrate a clear cut benefit of FAMP in terms of overall survival (OS), although a significant benefit in terms of time to disease progression and event-free survival (EFS) was noted. In this rare disorder, where few randomized trials have been conducted, we took advantage of this trial to assess treatment differences while integrating quality of life considerations. We thus performed a quality-adjusted survival analysis, using the quality-adjusted time without symptoms or toxicity (Q-TWiST) approach. Four health states differing in terms of quality of life (QoL) were defined, namely treatment-related toxicity, treatment free of toxicity, no treatment or symptoms, and relapse. The average time spent in these health states (TOX, CT, TWiST and REL, respectively) were then weighted by utility coefficients reflecting relative QoL value according to that of TWiST and summed up giving the so-called Q-TWiST. No difference was found between randomized groups in terms of mean CT. Mean TOX in the two groups were similarly close except when considering alopecia as a relevant toxic event. By contrast, mean TWiST was 5.9 months longer in the FAMP group than in the CAP group (P = 0.006). Unsurprisingly, given the absence of difference in OS but the difference in EFS in favor of the FAMP group, mean REL was increased by 6.8 months in the CAP group (P = 0.047). As a result, benefit of FAMP in terms of average Q-TWiST only relied on the value of the utility coefficient attributed to REL (U(REL)), with a significant benefit when UREL ranged from 0 to 0.28, ie in patients undergoing poor QoL after relapse, which is likely.

Primary cutaneous large-cell lymphoma: analysis of 49 patients included in the LNH87 prospective trial of polychemotherapy for high-grade lymphomas. Groupe d'Etude des Lymphomes de l'Adulte.

The objectives of this study were to evaluate the outcome after polychemotherapy for patients with primary cutaneous large-cell lymphomas (PCLL) and to validate the recently proposed immunohistologic classification of cutaneous lymphomas. Among 140 patients with positive skin biopsies included in the LNH87 protocol (for treatment of aggressive lymphomas), 49 patients met the criteria of PCLL. Characteristics were: sex ratio M/F, 2.3; age 18 to 83 years (median, 52), peripheral lymph nodes, n=22; diffuse disease, n=12; median tumor size, 4.5 cm; elevated lactate dehydrogenase, n=9; ECOG: 0/1, n=49. Histology was: follicular center B cell, n=23; B-lymphoblastic, n=1; anaplastic large-cell lymphoma, n=14 (T cell phenotype n=8); CD30- T cell lymphoma, n=11. All patients received polychemotherapy: under 70 years, ACVBP (three to four cycles and consolidation for 6 months) n=25; mBACOD (eight cycles) n=16; over 70 years, C(T)VP (six cycles) n=8. Radiation therapy was not included in the protocol. With a median follow-up of 5 years, 24/49 patients had relapsed, with 20 skin relapses. Event-free (EFS) and overall survival (OS) at 5 years were, respectively, 50 and 77%. Significant adverse prognostic factors were: histology (CD30- T cell lymphoma) and diffuse cutaneous disease (>10% of skin). The presence of nodal involvement was only significant for EFS. When compared to 140 non-cutaneous lymphoma patients included in the same trial and fully matched for the main clinical characteristics, OS was similar. In conclusion, PCLL behaves like other localized B or T cell extranodal lymphomas with the same prognostic factors (LDH, ECOG, age) except for CD30+ PCLL which have a very good prognosis.

[Acquired hemophilia caused by autoantibodies against factor VIII coagulation activity. Clinical, biological study and therapeutic indications. Experience based on a study of 9 cases]. / Hémophilie acquise par auto-anticorps dirigé contre l'activité coagulante du facteur VIII. Etude clinique, biologique et indications thérapeutiques. Expérience ã partir d'une étude de 9 cas.

STUDY DESIGNS: To describe retrospectively the experience of the Internal Medicine and Clinical Hematology Departments of a University Hospital on adult acquired hemophilia (AH) caused by autoantibody against factor VIII coagulant (f.VIII:C) activity. Diagnosis, clinical datas, associated diseases, treatment and final outcome are described and compared to the published literature. MATERIAL AND METHODS: All cases admitted in both departments since 1989 were enrolled in the study. Clotting analyses comprised clotting times (activated partial thromboplastin time, prothrombin and thrombine times), measurements of f.VIII:C level, antifactor VIII detection and measurement by the Bethesda method assay, Search for an etiologic factor could not be standardized. All patients were followed until cure, sustained improvement, or death. RESULTS: From 1989 to 1996, AH was diagnosed in nine adult patients. Mean age was 76 +/- 24.6 years (range : 65-89) and sex ratio male to female was 2. Eight bleeding episodes occurred in seven patients, resulting consistently in severe hemorrhagic anemia and leading to hemodynamic failure in two, while two others remained asymptomatic for prolonged periods. The initial levels of f.VIII:C ranged from less than 1% to 20%, and the titers of inhibitors ranged from 0.5 to 100 Bethesda units. An underlying disease, to which the appearance of their inhibitor could be related, either concomitantly or up to 1 year later, was found in four cases including (one case each): rheumatoid arthritis, lupus erythematosus with antiphospholipid syndrome, followed by non-Hodgkin malignant lymphoma, relapsing carcinoma and, biliary tract surgery. Six acute bleeding episodes necessitated symptomatic measures, based on activated prothrombin complex concentrates in four instances, with a good response in all cases. Preparation to minor surgical operations was achieved in two asymptomatic subjects by either highly purified factor VIII concentrations infusion or intravenous 1-desamino-8-D-arginine vasopressin, with a good control of local hemostasis in each case. Three received intravenous immunoglobulins, which resulted in success in one, failure in one and, questionable response in the latter. Immunosuppression, mainly with corticosteroids, cyclophosphamid, or both, was given to seven, resulting in disappearance of inhibitor in five (delay to cure ranged from 2 weeks to 10 months), improvement in one, and failure in one (in this latter case, cure was eventually achieved with the anti-Hodgkin disease MOPP chemotherapy). After a 27-month mean follow-up, six patients experienced a sustained complete response and one a sustained partial response to immuno-suppression, two untreated patients remained asymptomatic, two died later from malignancy (carcinoma and myelodysplastic syndrome). CONCLUSION: AH usually presents as a severe or even a life-threatening disease, necessitating prompt and thorough symptomatic measures directed at the cessation of bleedings and prevention of their relapse. In our experience, no death was attributable to AH or its treatment. Immunosuppression is useful in selected cases, but must be carefully discussed, since it can be highly toxic, especially in the elderly. Given the possibility of a delayed onset of some etiologic factors, a prolonged surveillance of each case of idiopathic AH is mandatory.