Pia Raanani

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.

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.

The rate and kinetics of molecular response to donor leucocyte transfusions in chronic myeloid leukaemia patients treated for relapse after allogeneic bone marrow transplantation

We have assessed the molecular response of 30 consecutive patients with chronic myeloid leukaemia (CML) treated for relapse after allogeneic bone marrow transplantation (BMT) by donor leucocyte transfusions (DLT). Response was evaluated by qualitative nested and quantitative competitive RT‐PCR for BCR‐ABL mRNA at various time intervals before and after DLT. The probability of attaining molecular remission at 2 years was 61% (95% CI 42–78%). Disease state at the time of DLT was significantly associated with response: molecular remission was achieved for 9/10 (90%) patients treated early (cytogenetic or molecular relapse) compared to only 8/20 (40%) patients treated late (haematological relapse; P=0.009). The Kaplan–Meier estimates of molecular remission at 2 years post DLT for patients treated in early or late relapse were 86.6% and 47.3% respectively (P=0.004). The median time interval from DLT to molecular remission was 11.0 months (range 2.5–32). Molecular remissions were durable for most (15/17) patients (median follow‐up 21.2 months; range 0–55). Two patterns of molecular response were found: a very rapid decline after an initial lag phase or a more gradual decline over a period of several months. We conclude that molecular monitoring is a sensitive indicator of response to DLT; different kinetics of molecular response may reflect disease heterogeneity or differences in the mode of action of DLT.

Adolescents and young adults with acute lymphoblastic leukemia have a better outcome when treated with pediatric-inspired regimens: systematic review and meta-analysis.

Survival of adults with acute lymphoblastic leukemia (ALL) is inferior to that of pediatric patients. Strategies to improve the outcome of adult population are warranted. This study aims to evaluate the efficacy and safety of pediatric‐inspired regimens given to adolescents and young adults (AYA), usually defined as 16–39 years, with ALL. Systematic review and meta‐analysis of comparative trials of AYA patients with ALL given induction chemotherapy with either pediatric‐inspired regimens or conventional‐adult chemotherapy was conducted. Relative risks (RR) with 95% confidence intervals (CIs) were estimated and pooled. Our search yielded 11 trials, including 2,489 patients. AYA patients given pediatric‐inspired regimens had a statistically significant lower all cause mortality rate at 3 years (RR 0.58; 95% CI 0.51–0.67). Complete remission rate after induction chemotherapy and event free survival were superior in the pediatric‐inspired regimens arm (RR 1.05; 95% CI 1.01–1.10 and RR 1.66; 95% CI 1.39–1.99, respectively). Relapse rate was also lower in patients given pediatric‐inspired regimens (RR 0.51; 95% CI 0.39–0.66) with comparable nonrelapse mortality between the two groups (RR 0.53, 95% CI 0.19–1.48). Pediatric‐inspired regimens are superior to conventional‐adult chemotherapy in AYA ALL patients. Further randomized controlled studies to investigate this approach in adult ALL patients are warranted. Am. J. Hematol. 87:472–478, 2012.

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.

5-azacitidine prolongs overall survival in patients with myelodysplastic syndrome - a systematic review and meta-analysis

Hypomethylating agents have recently been shown to improve the outcome of patients with myelodysplastic syndrome. A meta-analysis and systematic review was carried out of randomized controlled trials comparing treatment with hypomethylating agents to conventional care, i.e., best supportive care or chemotherapy, in patients with myelodysplastic syndrome. The outcomes assessed were overall survival, time to transformation or death, overall response rate and toxicity. Hazard ratios with 95% confidence intervals were estimated and pooled for time-to-event data. For dichotomous data, relative risks were estimated and pooled. Four trials including 952 patients examined the effect of 5-azacitidine and decitabine. Treatment with hypomethylating agents significantly improved overall survival (hazard ratio 0.72, 95% confidence interval 0.60–0.85, three trials) and time to transformation or death (hazard ratio 0.69, 95% confidence interval 0.58–0.82, four trials). In a subgroup analysis per type of drug, these benefits could be shown for 5-azacitidine but not for decitabine. Both agents favorably influenced response rates. A higher rate of grade 3/4 adverse events was observed with their use. Since 5-azacitidine prolongs overall survival and time to transformation or death it should be highly considered in the treatment of patients with high-risk myelodysplastic syndrome. Further studies are needed to establish the exact role of decitabine compared to 5-azacitidine in these patients.

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.

Prophylaxis regimens for GVHD: systematic review and meta-analysis.

Opinions are divided regarding the best prophylactic regimen for GVHD. The aim of this study was to evaluate potential survival benefit of different prophylactic regimens for acute GVHD (aGVHD). We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) including patients undergoing Allo-SCT. We included trials that assessed the addition of MTX, compared CsA and tacrolimus and evaluated the addition of steroids. Outcomes assessed were all-cause mortality (ACM) at the longest follow-up, aGVHD, chronic GVHD, TRM, relapse rate and regimen-specific adverse events. Relative risks (RRs) with 95% confidence intervals (CIs) were estimated and pooled. The regimen of MTX–CsA vs CsA alone (four trials) yielded no statistically significant difference in ACM (RR=0.84 (0.61–1.14)), but a significant decrease in aGVHD (RR=0.52 (0.39–0.7)). There was no difference in ACM for the comparison of MTX–CsA and MTX–tacrolimus (three trials); however, MTX–tacrolimus was superior to MTX–CsA in the reduction of aGVHD (RR=0.62 (0.52–0.75)) and severe aGVHD (RR=0.67 (0.47–0.95)). The addition of steroids did not affect the outcomes (four trials). We conclude that MTX–CsA and MTX–tacrolimus are both acceptable alternatives for GVHD prophylaxis, although MTX–tacrolimus may be superior in terms of aGVHD reduction.

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.