Does autologous transplantation directly increase the risk of secondary leukemia in lymphoma patients?

Patients who undergo autologous stem cell transplantation (ASCT) for lymphoma have a significant risk of therapy-related acute myeloid leukemia and myelodysplasia (t-AML/MDS). Compared to that seen in other indications such as breast cancer, multiple myeloma or germ cell tumors, there is a substantially increased risk for t-AML/MDS following ASCT for lymphoma. This risk has largely been attributed to the extent of pre-transplant chemotherapy and radiation therapy. In many of the larger series to date, it has not been possible to directly implicate autologous transplantation itself as a risk factor for t-AML/MDS. Although pre-transplant therapy is certainly an important factor in the development of t-AML/MDS, specific components of the autologous transplantation procedure itself may also contribute to the risk of t-AML/MDS. Specifically, priming chemotherapy, total body irradiation, and the extensive cellular proliferation which occurs during engraftment may all play a role in the development of t-AML/MDS. Furthermore, there is an increasing body of evidence that certain inherited polymorphisms in genes governing drug metabolism, DNA repair and leukemogenesis may influence susceptibility to t-AML/MDS. In this paper, we review the evidence implicating the above risk factors for t-AML/MDS, present a potential mechanism for t-AML/MDS and propose interventions to reduce the rate of t-AML/MDS in lymphoma patients.

DAS181 Treatment of Severe Parainfluenza Virus 3 Pneumonia in Allogeneic Hematopoietic Stem Cell Transplant Recipients Requiring Mechanical Ventilation.

Parainfluenza virus (PIV) may cause life-threatening pneumonia in allogeneic hematopoietic stem cell transplant (HSCT) recipients. Currently, there are no proven effective therapies. We report the use of inhaled DAS181, a novel sialidase fusion protein, for treatment of PIV type 3 pneumonia in two allogeneic hematopoietic SCT recipients with respiratory failure.

A p74 common gamma receptor chain isoform facilitates IL-2 and IL-15 responses by the myelomonocytic cell line Tf-1beta2.

Functional forms of the IL-2, IL-4, IL-7, IL-9, and IL-15 receptors require the gamma c receptor component. We have described previously a myeloid cell line called Tf-1beta, which binds IL-2 with intermediate-affinity and proliferates in response to IL-2. In this study, we characterize gamma c expression on Tf-1beta2 cells, a derivative of Tf-1beta cells stimulated exclusively with IL-2. Although Tf-1beta2 cells bind IL-2 with intermediate-affinity and proliferate in response to IL-2, this cell line does not express the p64 gamma c chain at the protein level. This result was surprising because prior studies suggest these cells should not be expected to proliferate in response to IL-2 or IL-15 in the absence of the p64 gamma c chain. A p74 protein was detected by western blot following immunoprecipitation with an anti-gamma c polyclonal antibody, and a p74 protein was identified consistently in complex with IL-2 and IL-15 on these cells. However, the gamma c gene in these Tf-1beta2 cells shows no evidence of mutation by sequence analysis. Furthermore, inhibition of glycosylation of these Tf-1beta2 cells by tunicamycin treatment yields a standard 39-kDa molecule recognized on western blot with anti-gamma c antibody, as seen for the standard 64-kDa isoform of gamma c. These results demonstrate that a 74-kDa gamma c receptor isoform was involved in the response of the Tf-1beta2 cells to cytokines which normally interact with the 64-kDa gamma c chain.

Post-autologous transplant maintenance therapies in lymphoid malignancies: are we there yet?

Disease relapse after autologous hematopoietic transplant (auto-HCT) remains the number one cause of post-transplant therapy failure and mortality. The last decade has seen a proliferation of clinical studies looking at the prevention of post-auto-HCT therapy failure with various maintenance strategies. The benefit of such therapies is in turn dependent on disease histology and timing of transplantation. Although high dose therapy (HDT) provides durable responses in chemosensitive relapsed diffuse large B-cell lymphoma (DLBCL), a sizable subset experiences disease relapse. Unfortunately, the addition of rituximab as a post-auto-HCT maintenance strategy did not improve survival outcomes. The preliminary results with programmed death -1 (PD-1) Ab as post-auto maintenance in DLBCL is promising but requires randomized validation. In follicular lymphoma, the 5- and 10-year PFS rates are ~60% and 31%, respectively. Although the addition of rituximab improved PFS, there is no survival benefit, to date. Disease relapse after auto-HCT in mantle cell lymphoma (MCL) is not uncommon. Rituximab maintenance in this setting provides a PFS benefit. Given the poor prognosis of post-auto-HCT failures in MCL, maintenance can be considered on a case-by-case basis. In chemosensitive relapsed Hodgkin lymphoma, addition of brentuximab vedotin after auto-HCT improved 2-year PFS (65 vs 45%) and can be considered as an option for maintenance therapy post auto-HCT, in select higher risk patients. Ongoing trials evaluating the efficacy of post-auto-HCT maintenance with novel agents (for example, immunomodulators, proteasome inhibitors, PD-1 inhibitors, Bruton's tyrosine kinase inhibitors and so on) will likely change the practice landscape for lymphoma patients following HDT and auto-HCT.

Safety of outpatient autologous hematopoietic cell transplantation for multiple myeloma and lymphoma.

Autologous hematopoietic cell transplantation (Auto-HCT) is commonly an in-patient procedure. However, Auto-HCT is increasingly being offered on an outpatient basis. To better characterize the safety of outpatient Auto-HCT, we compared the outcome of 230 patients who underwent Auto-HCT on an in-patient vs outpatient basis for myeloma or lymphoma within a single transplant program. All outpatient transplants occurred in a cancer center day hospital. Hematopoietic recovery occurred earlier in the outpatient cohort, with median time to neutrophil recovery of 10 vs 11 days (P<0.001) and median time to platelet recovery of 19 vs 20 days (P=0.053). Fifty-one percent of the outpatient cohort never required admission, with this percentage increasing in later years. Grade 3-4 non-hematologic toxicities occurred in 29% of both cohorts. Non-relapse mortality at 1 year was 0% in the outpatient cohort and 1.5% in the in-patient cohort (P=0.327). Two-year PFS was 62% for outpatient vs 54% for in-patient (P=0.155). One- and two-year OS was 97% and 83% for outpatient vs 91% and 80% for in-patient, respectively (P=0.271). We conclude that, with daily outpatient evaluation and aggressive supportive care, outpatient Auto-HCT can result in excellent outcomes for myeloma and lymphoma patients.

Bortezomib-based induction for transplant ineligible AL amyloidosis and feasibility of later transplantation.

Recent studies support the use of bortezomib-based therapies in light chain amyloidosis (AL). We performed a retrospective analysis of the safety, efficacy and long-term survival (median follow-up 3 years) after bortezomib-based treatment in 28 consecutive patients with de novo AL deemed ineligible at initial presentation. The first 14 patients received bortezomib and dexamethasone (VD), and the second 14 patients received cyclophosphamide, bortezomib and dexamethasone (CVD; CyBorD). Both regimens were well tolerated with no treatment-related mortality. The overall hematological response (HR) rate was 93% in both the groups. Median time to response was shorter in the CVD group (39 days vs 96 days in the VD group; P=0.002). Hematological and organ responses induced with bortezomib-based therapy enabled 8 (33%) of initially transplant ineligible patients to undergo autologous hematopoietic stem cell transplantation (AHCT), including 4 patients with cardiac stage III or IV. Seven of the eight patients (88%) who underwent subsequent AHCT achieved sustained HR at a median of 33 months posttransplant. These data suggest that bortezomib-based induction followed by AHCT is a viable therapeutic strategy for transplant-ineligible AL. Larger, multicenter prospective trials are necessary to confirm our findings.

A prognostic model predicting autologous transplantation outcomes in children, adolescents and young adults with Hodgkin lymphoma.

Autologous hematopoietic cell transplantation (AutoHCT) is a potentially curative treatment modality for relapsed/refractory Hodgkin lymphoma (HL). However, no large studies have evaluated pretransplant factors predictive of outcomes of AutoHCT in children, adolescents and young adults (CAYA, age <30 years). In a retrospective study, we analyzed 606 CAYA patients (median age 23 years) with relapsed/refractory HL who underwent AutoHCT between 1995 and 2010. The probabilities of PFS at 1, 5 and 10 years were 66% (95% confidence interval (CI): 62-70), 52% (95% CI: 48-57) and 47% (95% CI: 42-51), respectively. Multivariate analysis for PFS demonstrated that at the time of AutoHCT patients with Karnofsky/Lansky score ⩾90, no extranodal involvement and chemosensitive disease had significantly improved PFS. Patients with time from diagnosis to first relapse of <1 year had a significantly inferior PFS. A prognostic model for PFS was developed that stratified patients into low-, intermediate- and high-risk groups, predicting for 5-year PFS probabilities of 72% (95% CI: 64-80), 53% (95% CI: 47-59) and 23% (95% CI: 9-36), respectively. This large study identifies a group of CAYA patients with relapsed/refractory HL who are at high risk of progression after AutoHCT. Such patients should be targeted for novel therapeutic and/or maintenance approaches post-AutoHCT.

Characterization of a novel DQB1 allele associated with HLA-DQw3: implications for oligotyping.

During HLA-DQ oligotyping, the presence of a novel HLA-DQB1 allele was suggested by a pattern of probe hybridization that was inconsistent with the presence of any possible combination of two known alleles. The nucleotide sequence of the second exon of the HLA-DQB1 gene was determined, revealing a novel HLA-DQB1 sequence differing from the DQB1*0301 allele by a single nucleotide substitution at codon 57. All published HLA-DQ oligotyping systems could assign inaccurate oligotypes when this allele is present. An additional amplification primer was utilized to achieve discrimination of all possible combinations of known HLA-DQB1 alleles.

Human adjuvant disease revisited: a review of eleven post-augmentation mammoplasty patients.

OBJECTIVES: We have reviewed 11 women post-augmentation mammoplasty who were referred to our clinic with diffuse rheumatic complaints. All patients had undergone mammoplasty with silicone gel-filled implants prior to the onset of their locomotor symptoms (mean latency time 7.8 years). One physician interviewed and examined each of these patients following a standardized format for clinical retrieval. RESULTS: Of the patients reviewed, 6 patients had clinical fibromyalgia based on the ACR criteria, and the remaining 5 patients had symptoms consistent with the "chronic fatigue syndrome." None of our patients were found to have evidence of a defined connective tissue disease. Antinuclear antibodies were detected in 4 (36%) patients and low level titres of extractable nuclear antigens in only 2 (18%). CONCLUSIONS: Previously a causal relationship between the use of silicone gel-filled breast implants and the subsequent development of symptoms referred to as human adjuvant disease (HAD) has been proposed. On the basis of currently accepted criteria we have preferred to diagnose our post-mammoplasty patients without specific connective tissue disease, as having chronic fatigue syndrome (CFS), or when tender points are present, as having fibromyalgia (FMS), rather than implying that such cases represent a separate and unique rheumatological disease entity. In the light of our current understanding of CFS and FMS, a relationship between them and the previous silicone mammoplasty seems possible.

Remote cardiac rehabilitation.

The implementation of a remote cardiac rehabilitation service to educate people about heart disease is currently under way in northern Alberta. Twenty per cent of patients in the catchment area live in remote areas outside the regional centre and are faced with the usual difficulties of attending urban health-care programmes. The availability of the remote cardiac rehabilitation service enables patients to receive the same rehabilitation benefits as their urban counterparts.

Allogeneic hematopoietic cell transplantation for diffuse large B cell lymphoma: who, when and how?

Despite overall improvements in outcomes of patients with diffuse large B cell lymphoma (DLBCL), ∼30-40% of patients develop relapsed or refractory disease. For patients with chemo refractory disease, or recurrent disease following autologous hematopoietic SCT (auto-HCT), the prognosis is poor, with no consensus on the optimal therapy. Currently, owing to the graft vs lymphoma effect, hematopoietic allogeneic hematopoietic cell transplantation (allo-HCT) is the only potentially curative option for such patients. In addition, many patients who are considered today for auto-HCT actually have a low likelihood of benefit. For example, a patient with prior rituximab exposure who relapses within 1 year of diagnosis and has a second-line age-adjusted International Prognosis Index of 2 or 3 at relapse has a <25% chance of being cured by auto-HCT. It is possible that such patients may be better served with an allo-HCT. Unfortunately, in many cases, allo-HCT applicability is limited by patient age, comorbidities, performance status and treatment-related toxicities. Recent attempts to improve the efficacy of auto-HCT, such as incorporating radio-immunotherapy into the conditioning regimen, have not resulted in improved outcomes. However, incorporation of novel agents such as anti-programmed death-1 antibodies as maintenance therapy after auto-HCT show promise. Allo-HCT in relapsed/refractory DLBCL patients can result in a 30-40% PFS rate at 3 years, in part due to a graft vs DLBCL effect. While reduced-intensity/non-myeloablative conditioning is increasingly being used, certain patients may benefit from myeloablative conditioning. We present an algorithm intended to discriminate which relapsed and refractory DLBCL patients are most likely to benefit from auto-HCT vs allo-HCT. New approaches, using novel agents that target the molecular heterogeneity in DLBCL, will be an essential component of moving the field forward. Lastly, we propose a prospective registry-based study as the only feasible mechanism to define the optimal position of allo-HCT in the overall treatment strategy for DLBCL. It is hoped that this review will promote the development of prospective multicenter efforts to determine whether such patients do, in fact, benefit from earlier and/or more effective implementation of allo-HCT.

Rituximab for the treatment of patients with very high-titre acquired factor VIII inhibitors refractory to conventional chemotherapy.

Acquired factor VIII (FVIII) inhibitors are a rare cause of coagulopathy which are associated with a high mortality rate. Treatment of bleeding episodes is often difficult and may vary with the degree of titre elevation. Individuals with very high-titre antibodies [>100 Bethesda units mL(-1) (BU)] may have difficulty achieving a complete sustained remission and, consequently, various treatments including immunosuppression, cytotoxic chemotherapy and plasmapheresis have been reported. Rituximab is an anti-CD20 monoclonal antibody which has demonstrated efficacy in the treatment of individuals with acquired FVIII inhibitors, however there is limited data in the subgroup of patients with inhibitor titres >100 BU. In this study, we present four patients with acquired FVIII inhibitor titres >100 BU who were resistant to initial therapy with cyclophosphamide, vincristine and prednisone. The patients' inhibitor titres ranged from 249 BU mL(-1) to 725 BU mL(-1) and all received 4 weekly infusions of rituximab at 375 mg m(-2). Each patient partially responded to rituximab therapy with an improvement in inhibitor titres and FVIII activity, however, three of the four patients relapsed thereafter. The individual who did not relapse achieved a partial response for 13 months and then died of causes unrelated to her coagulopathy. We conclude that in patients with acquired FVIII inhibitors and titres >100 BU, treatment with rituximab alone is effective but not sufficient to achieve a sustained response. Rituximab in combination with other therapies may provide a better result in this high-risk population.

Lipid-lowering update 2001. Aggressive new goals.

OBJECTIVE: To review the central role of cholesterol in coronary artery disease (CAD), underscore the need for identifying patients at high risk of CAD, and discuss treatment of dyslipidemias. QUALITY OF EVIDENCE: Current literature (1995-2000) was searched via MEDLINE using the MeSH headings "cholesterol," "risk reduction," and "statins." Recommendations in this paper are based mainly on the results of large randomized controlled trials. Preference was given to more recent articles, clinically relevant articles, and landmark clinical trials. MAIN MESSAGE: Lipid lowering, and specifically low-density lipoprotein lowering, has been repeatedly shown in large clinical trials to improve survival dramatically and reduce cardiac events in both primary and secondary prevention. Identifying those at highest risk for future cardiac events is critical because these patients will benefit most from aggressive modification of risk factors. The definition of high risk has been expanded to include patients with diabetes mellitus and peripheral vascular disease, as well as those with established CAD. A full lipid profile is required for these patients to assess risk and develop a lipid-lowering strategy with proven effectiveness. CONCLUSION: With the advent of powerful, efficacious, and well tolerated cholesterol-modifying therapies, lipid normalization should be a mandate for all physicians caring for patients with established CAD and patients at risk of developing CAD.

A prospective, controlled study of Helicobacter pylori seroprevalence in coronary artery disease.

OBJECTIVE: Recent studies have suggested that chronic infections may be a risk factor for coronary artery disease. The aim of this study was to determine whether Helicobacter pylori (H. pylori) infection was an independent risk factor for coronary artery disease. METHODS: A total of 179 patients undergoing coronary angiography for suspected coronary artery disease were prospectively studied. Angiograms were read by experienced invasive cardiologists blinded to the results of H. pylori serology, which was determined by a validated multiwell ELISA assay. RESULTS: A total of 121 patients (68%) had evidence of coronary artery disease, whereas 58 patients (32%) had normal coronary angiograms. Of the 121 patients with coronary artery disease, 29 had single vessel disease, 39 had double vessel disease, and 53 had triple vessel disease, respectively. There was no significant difference in seroprevalence of H. pylori infection in patients with and without coronary artery disease (p = 0.63). The odds ratio (after adjustment for other known risk factors) for coronary artery disease in H. pylori-infected subjects was 0.45 (95% CI = 0.15, 1.37; p = 0.107). In patients with coronary artery disease, H. pylori infection did not increase the likelihood of severe disease (odds ratio for triple vessel disease = 0.53; 95% CI 0.18, 1.60; p = 0.201). CONCLUSION: H. pylori infection rates are similar in patients with normal and abnormal coronary arteries, and infection with H. pylori is not an independent risk factor for coronary artery disease. In patients who have coronary artery disease, H. pylori infection is not a risk factor for more severe disease. These data argue against a causal role for H. pylori in the pathogenesis of coronary artery disease.

Alteration of the CD34+ Tf-1 beta cell line profile in response to long-term exposure to IL-15.

Interleukin 15 (IL-15) is a cytokine with many functional characteristics that are similar to IL-2. Most of the functional activities that IL-2 and IL-15 support have been evaluated in short-term assays. It was our intention, then, to determine the long-term effects of IL-15 in comparison to IL-2. These studies were performed using the growth factor-dependent myelomonocytic cell line, Tf-1, which has been well characterized with regard to morphology, CD marker expression, responses to certain growth factors and cytokines (GM-CSF, IL-4, erythropoietin), and can differentiate through the myeloid and erythroid lineages. In order to study IL-2 and IL-15 responses, Tf-1 cells were retrovirally infected with the IL-2R beta chain gene as a means to confer IL-2 responsiveness to this cell type. The results of this study demonstrate that retroviral infection of Tf-1 successfully generated a stable IL-2 responsive cell line, Tf-1 beta, without interfering with the original characteristics of the Tf-1 cell. Tf-1 beta cells respond functionally to both IL-2 and IL-15. When Tf-1 beta cells are grown for 8 weeks in IL-2 (Tf-1 beta 2), rather than GM-CSF, the original morphology, CD marker expression, esterase activity and proliferative response is unaltered in comparison to that of the original Tf-1 beta line maintained in GM-CSF. However, long-term growth of Tf-1 beta in IL-15 (Tf-1 beta 15) results in morphological alterations, downregulation of CD33, CD38, and HLA-DR, and a decreased response to IL-15 in comparison to Tf-1 beta 2. These studies support the concept that retroviral infection, even when it confers new functions upon a cell, does not necessarily alter all other functions, as assessed by evaluation of its phenotypic profile. Furthermore, the production of the Tf-1 beta 2 and Tf-1 beta 15 sublines demonstrates that IL-2 and IL-15 can support long-term cell growth. However, this long-term growth in IL-15 leads to subtle alterations in the cell profile that are not seen with IL-2, suggesting that distinctions in IL-2 and IL-15 function do exist. Further study of the Tf-1 beta 15 cell line will be useful to clarify these functional distinctions between IL-2 and IL-15.