Isaac Ben-Bassat

Immune-Mediated Complications during Interferon Therapy in Hematological Patients

Interferon (IFN), a leukocyte-derived cytokine, has been used to treat several hematological malignancies. The most common adverse effects of IFN are flu-like symptoms. Autoimmune side effects are infrequent but may be hazardous and irreversible. These may occur in several ways: autoantibodies may either appear during the treatment or existing titers may rise, subclinical autoimmune phenomena may become clinically manifest or autoimmune diseases may appear de novo. The main categories of IFN immune-mediated side effects are: thyroid, hematological, connective tissue, renal and miscellaneous disorders. The most common ones are thyroid disorders, which manifest either as hypo- or hyperthyroidism. Patients with pre-existing autoantibodies are more susceptible to the exacerbation of thyroid autoimmunity, probably since IFN enhances the levels of autoimmunity. Hematological disorders include autoimmune anemia and thrombocytopenia and thrombotic thrombocytopenic purpura. The immunological derangement of autoimmune hemolytic anemia manifests as enhanced destruction of antibody-coated red blood cells and induction of autoreactive B cells secreting these antibodies. Although autoimmune thrombocytopenia is rare, a sharp reduction in the platelet counts, beyond that expected from the antiproliferative effects of IFN, should raise this possibility. Thrombotic thrombocytopenic purpura has recently been included among the autoimmune disorders. Sporadic cases have been reported in association with IFN treatment. The clinical spectrum of IFN-induced connective tissue disorders ranges from typical systemic lupus erythematosus to seropositive or seronegative rheumatoid arthritis. Some authors also reported on the development of Behçet’s disease in chronic myeloid leukemia patients treated with IFN. The underlying reason for the skin hyperreactivity in Behçet’s disease and the effect of IFN treatment in these patients may be altered neutrophil activity in both disorders. Several series evaluated the incidence of Raynaud’s phenomenon in patients treated with IFN for hematological disorders. Some of them reported on a rather high incidence of nailfold capillary microscopy abnormalities with or without Raynaud’s phenomenon. Whether IFN-induced Raynaud’s phenomenon is immune-mediated or directly caused vasospasm, is still unknown although the occurrence of several autoantibodies suggests an immune mechanism. Adverse effects of IFN therapy on the kidney include proteinuria and rarely nephrotic syndrome or acute and chronic renal failure. The mechanism of renal injury is unclear although an immune mechanism is suggested. Sporadic cases of other immune-mediated side effects have been published. These include dermatological adverse effects manifesting as psoriasis, pemphigus and vitiligo, and also rare cases of sarcoidosis, hepatitis, colitis or cryoglobulinemia. In conclusion, patients treated with IFN should be monitored for symptoms of autoimmunity. Patients with previous autoimmune phenomena should be treated, if possible, with alternative drugs since there is risk of exacerbation of these manifestations in these patients.

Hybrid acute leukemia

Editorial consacre aux leucemies biphenotypiques et biclonales: definition, donnees biochimiques, revue des 68 cas trouves dans la litterature

The late adverse events of rituximab therapy--rare but there!

Rituximab, an anti CD20 monoclonal antibody, has now become a cornerstone in the treatment of many CD20 positive hematological malignancies and a variety of autoimmune disorders. In contrast to the acute allergic and cytokine associated reactions, late adverse events of rituximab are indeed uncommon but at the same time probably under-reported. In this review, we detail late adverse events reported since its use in hemato-oncological neoplasias and other disorders. These adverse events include the development of late-onset neutropenia, defects of immune reconstitution with associated immune compromise, infections, progressive multifocal leukoencephalopathy, reactivation of hepatitis, intestinal perforation and interstitial pneumonitis. Possible mechanisms involved in rituximab-associated complications and the pathogenesis of these adverse effects are reviewed and discussed. Evidence based graded recommendations for the management of these adverse effects are proposed.

Immunoglobulin Prophylaxis in Hematopoietic Stem Cell Transplantation: Systematic Review and Meta-Analysis

PURPOSE Because the role of immunoglobulins (IVIG) prophylaxis in patients undergoing hematopoietic stem-cell transplantation (HSCT) has not been established in terms of survival and infection prevention, we conducted a meta-analysis evaluating these issues. METHODS Systematic review and meta-analysis of randomized-controlled trials comparing prophylaxis with polyvalent IVIG or cytomegalovirus (CMV)-IVIG and control or another preparation or dose. PUBMED, Cochrane Library, LILACS, and conference proceedings were searched. Two reviewers appraised the quality of trials and extracted data. Relative risks (RRs) with 95% CIs were estimated and pooled. RESULTS Thirty trials including 4,223 patients undergoing bone marrow transplantation (BMT) were included. There was no difference in all-cause mortality when polyvalent IVIG or CMV-IVIG was compared to control (RR, 0.99; 95% CI, 0.88 to 1.12; and RR, 0.86; 95% CI, 0.63 to 1.16, respectively). There was no difference in clinically documented infections when polyvalent IVIG was compared with control (RR, 1.00; 95% CI, 0.90 to 1.10; five trials). CMV infections were not significantly reduced with either polyvalent IVIG or CMV-IVIG. Interstitial pneumonitis was reduced with polyvalent IVIG in older studies but not in the more recent ones, nor in studies assessing CMV-IVIG. Polyvalent IVIG increased the risk for veno-occlusive disease (RR, 2.73; (95% CI, 1.11 to 6.71). Graft-versus-host disease was not affected. CONCLUSION Because there is no advantage in terms of survival or infection prevention, IVIG does not have a role in HSCT.

Two cycles of escalated BEACOPP followed by four cycles of ABVD utilizing early-interim PET/CT scan is an effective regimen for advanced high-risk Hodgkin's lymphoma

BACKGROUND Escalated combination therapy with bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine and prednisone (escBEACOPP) regimen is superior to cyclophosphamide, vincristine, procarbazine and prednisone alternating with doxorubicin, bleomycin, vinblastine and dacarbazine (COPP-ABVD) for advanced-stage Hodgkins lymphoma (HL) patients. However, the original schedule of eight cycles of escBEACOPP was associated with significant toxicity. This study was conducted in an attempt to reduce the toxicity of the original schedule, while attempting to preserve improved initial tumor control. PATIENTS AND METHODS Forty-five newly diagnosed patients with advanced-stage HL and International Prognostic Score > or = 3 received two initial cycles of escBEACOPP and then were evaluated by positron emission tomography (PET)/computed tomography scan. If a good imaging response was obtained, they were treated by four cycles of ABVD. RESULTS Following the first two cycles of escBEACOPP, the overall response was 100% and at the end of all therapy, 40 (89%) patients were in complete response (disappearance of all clinical evidence of disease and PET negativity), three (7%) in partial response (PET-positive residual lesions and a size reduction of the majority of large masses by >50%), while two (4%) had progressive disease. After a median follow-up of 48 months, progression-free survival (PFS) and overall survival at 4 years were 78% and 95%, respectively. The 4-year PFS for early PET-negative patients (n = 31) and early PET-positive patients (n = 13) were 87% and 53%, respectively (P = 0.01). CONCLUSIONS These data indicate that combined escBEACOPP-ABVD may improve the outcome in patients with high-risk advanced HL. The potential benefit of early-interim PET activity as a guide to continuing therapy in these patients merits further study in the future.

Rituximab reduces relapse risk after allogeneic and autologous stem cell transplantation in patients with high‐risk aggressive non‐Hodgkin's lymphoma

Summary. High‐dose chemotherapy and autologous stem cell transplantation (SCT) have limited success in patients with refractory aggressive lymphoma. Allogeneic SCT may offer some advantage in this setting by providing graft‐versus‐lymphoma effect, but the relapse risk remains substantial. In this study, we evaluated the safety and efficacy of rituximab administration after SCT in patients at high‐risk for post‐transplant relapse, in order to reduce relapse risk. Twenty‐eight patients were included with the intent to treat them with rituximab after autologous (n = 16) or allogeneic (n = 12) SCT. Twenty‐four were given rituximab starting a median of 47 d post SCT. Three died of SCT complications prior to therapy. Nine patients not achieving a complete remission (CR) post SCT converted to CR with rituximab and with the onset of graft‐versus‐host disease (GVHD) in three. With a median follow‐up of 12 months (range, 3–33 months) the estimated 2‐year overall survival and disease‐free survival was 85 ± 7% and 55 ± 13% respectively. When only those patients who were actually treated are analysed, these rates were 95 ± 7% and 64 ± 13% respectively. The relapse risk was 35 ± 14%. Seven patients had recurrent neutropenia episodes associated with severe hypogammaglobulinaemia, which were further prevented with intravenous immunoglobulin. None of the 10 allogeneic SCT recipients treated with rituximab had severe GVHD. Rituximab may be an effective adjuvant therapy after SCT to reduce the relapse rate and improve the outcome in high‐risk aggressive lymphoma. Larger scale comparative trials are necessary to better define its role in SCT.

Immunoglobulin prophylaxis in chronic lymphocytic leukemia and multiple myeloma: systematic review and meta-analysis

The role of intravenous immunoglobulins (IVIG) prophylaxis in hypogammaglobulinemic patients with lymphoproliferative disorders (LPD) and plasma cell dyscrasias (PCD) has not been established. We performed a systematic review and meta-analysis of randomized-controlled trials comparing prophylaxis with polyvalent IVIG versus control. The primary outcomes were all-cause mortality and major infections. Nine trials, assessing patients with chronic lymphocytic leukemia (CLL) and multiple myeloma (MM), were included. No survival benefit could be demonstrated, RR 1.36 (95% CI 0.58–3.19, two trials), but there was a significant decrease in the occurrence of major infections, RR 0.45 (95% CI 0.27–0.75, three trials) and a significant reduction in clinically documented infections, RR 0.49 (95% CI 0.39–0.61, three trials). Adverse events, usually not requiring discontinuation of IVIG, occurred significantly more with IVIG. On the basis of the available data, IVIG cannot be recommended routinely for patients with CLL or MM with hypogammaglobulinemia and/or recurrent infections and should be considered on individual basis.

Management of adult patients with acute lymphoblastic leukemia in first complete remission: systematic review and meta-analysis

The optimal postremission therapy in adults with acute lymphoblastic leukemia (ALL) is still a matter of debate. The objective of this study was to compare the various potential therapeutic options for patients who achieved first complete remission.

Extramedullary progression despite a good response in the bone marrow in patients treated with thalidomide for multiple myeloma

We report two patients who were treated with thalidomide for resistant multiple myeloma (MM) and developed extramedullary plasmacytomas despite a good response in the bone marrow. The first patient had progressive disease 18 months post autologous peripheral stem cell transplant. Two and a half months after the initiation of thalidomide therapy extensive new plasmacytomas of the skin and nasal mucosa appeared while the medullary response continued. The second patient was treated with thalidomide for resistant MM. Despite a medullary response he developed neurological signs compatible with cranial nerve involvement and an MRI study was suggestive of a plasmacytoma involving the sellar region. We assume that a change in the expression of some adhesion molecules on the myeloma and/or the stromal cells is responsible for this phenomenon. Treating Physicians should be aware of this phenomenon in MM patients receiving thalidomide.

Rheumatic Manifestations Preceding Adult Acute Leukemia: Characteristics and Implication in Course and Prognosis

The manifestations and outcome of adult patients with acute leukemia (AL) were examined to study the characteristics of the rheumatological prodrome of AL and to find whether it is a marker of a distinct clinical and laboratory course and whether it has any prognostic implication. During a 10-year period, 8/139 (5.8%) of AL patients presented with rheumatic manifestations. The average duration of the arthritis syndrome preceding the diagnosis of AL was 3.25 months. The most common pattern of presentation was a reactive arthritis-like syndrome involving the large joints asymmetrically and associated with low back pain. Distinctive features suggesting a paraneoplastic arthritis were severe pain disproportionate to physical findings, a poor response to conventional antirheumatic treatment, and early significant osteopenia or lytic bone lesions. The epidemiological, clinical and laboratory characteristics of patients with or without rheumatic manifestations were comparable, except for fever on presentation, the presence of transient metabolic derangement following chemotherapy, and the initial average hemoglobin, hematocrit and serum uric acid values. Moreover, the initial outcome of the two groups was similar, as the early mortality rates were comparable (42.8% vs. 45% for patients with or without arthritis, respectively). In conclusion, rheumatic syndrome presentation of adult AL is uncommon, and apparently has no deleterious effects on initial prognosis. A timely diagnosis requires an increased awareness to distinctive features.