High rate of spontaneous inhibitor clearance during the long term observation study of a single cohort of 524 haemophilia A patients not undergoing immunotolerance

BACKGROUND: The natural history of inhibitors in patients with haemophilia A not undergoing immune tolerance induction (ITI) is largely unknown. A recent randomized controlled trial suggests that the higher the FVIII dose used for ITI, the faster the clearance and the lower the rate of bleeding, without any difference in the rate of tolerance. We aimed at assessing the rate of spontaneous inhibitor clearance in a large cohort of patients not undergoing ITI. METHODS: A retrospective analysis of anti-FVIII inhibitors of long-term registry data in a single centre cohort of 524 haemophilia A patients considered for synovectomy was performed. Patients were tested for inhibitors before and 15 days after any and each surgical episode and thereafter did not undergo immune tolerance at any time. RESULTS: The cumulative incidence of inhibitors overall was 34% (180 out of 524) with the highest percentage of 39% (168 out of 434) in severe patients which represented 83% of the cohort. Among the 180 inhibitor patients: 63 had permanent inhibitors; 70 fulfilled current criteria for transient inhibitors but a third category of 47 additional patients cleared the alloantibody spontaneously in >6 months. At logistic regression, both the inhibitor titre and the gene mutation were shown to predict time to clearance. CONCLUSIONS: Spontaneous clearance of inhibitors over variable time in the absence of ITI treatment was found in up to 2/3 of the cases

Peripheral Blood Lymphocytic Profile in Patients with Diffuse Large B Cell Lymphoma and Follicular Lymphoma.

Abstract Diffuse Large B Cell Lymphoma (DLBCL) and Follicular Lymphoma (FL) are the most common adult low-grade non Hodgkin’s lymphomas. The influence of these diseases in peripheral blood lymphocytes is not well defined. Indeed the lymphocytic arrangement can be altered on account of the leukaemic form (although it slightly ever occurs); on the other hand the cause of occasional anomalies can be the involvement of the immune system against neoplasm. In order to contribute to the knowledge of these conditions we have analysed, at diagnosis, the lymphocytic immunophenotype in peripheral blood of 61 subjects: 27 were affected by DLBCL, average age 68, and 34 by FL, average age 61 years. Therefore we quantified the number of lymphocytes and evaluated essential markers, using flow cytometry, to define T, B, NK subsets by: CD3, CD4, CD8, CD19, SIgk, Sigl, CD56, and expression of CD11a molecule on T CD8. The absolute peripheral blood lymphocytes count presented a reduction in 51% and in 32% of the cases with an increase in 4% and in 3% of the subjects respectively considering DLBCL and FL. On the contrary T cells (CD3) had similar decrease, 33% and 32%, and different augmentation 15% and 3%. T cells ratio CD4/CD8 was under normal in 23% and in 12% of the patients but over normal in 12% and 29% always in DLBCL and FL. B cells (CD19) were reduced in 35% and in 12% of the subjects but increased in 8% and in 14%, whereas clonal restriction was present in 8% and in 20% of the components of the two groups. Natural Killer lymphocytes (CD56) were under normal in 12% and in 6% of bthe cases but over in 40% and 20%. Finally CD11a was over-expressed in 87% and in 68% of the patients of the respective pathologies. After selecting patients aged over 60 years, following four parameters that showed a significant variability was obtained: 1) lymphopenia in 50% of the cases in both groups; 2) similar results 11% and 15% about clonal restriction; 3) increase of the NK population 42% and 30% in DLBCL and FL; 4) very high over-expression of CD11a on T CD8 of 90% and 80%. Therefore DLBCL and FL are lymphoproliferative diseases where there is an important subtraction of lymphocytes, particularly in elderly people, from peripheral blood (perhaps because of accumulation in lymphnodes). These lesions present clonal restriction of B cells only in few cases (confirming the low known leukaemic form) while Natural Killer population are well represented especially in DLBCL. The over-expression of CD11a is the most altered parameter and seems almost a typical marker of these diseases above all in over 60 years subjects. Consequently if rarely happens that a leukaemic form of DLBCL and FL are found by flow cytometry however immunological defined alterations are very frequent in most of the cases of old patients.</jats:p

The Italian database of haemophilia B mutations

San Diego (USA)