Practice-Changing Study in HIV-Related LymphomaSAN FRANCISCO ― Patients with HIV-related lymphoma should now be considered candidates for stem cell transplantation if need be, and the treatment does not need to be limited to certain centers, according experts commenting on the results of a new study.Autologous hematopoietic stem cell transplantation (AHCT) has been offered to patients with relapsed or treatment-resistant HIV-related lymphoma since the late 1990s, observed lead study author Joseph Alvarnas, MD, of City of Hope Medical Center, in Monrovia, California.But transplantation has been limited to centers with HIV-specific expertise, Dr Alvarnas explained to reporters at a press conference here at the American Society of Hematology (ASH) 56th Annual Meeting.In addition, most clinical trials of AHCT have excluded patients with HIV, he added.In an effort to open up these two closed worlds, a clinical trial of AHCT was undertaken in patients with HIV-related lymphoma that had relapsed or was refractory.Among 40 patients who participated, the overall 1-year survival rate was 86.6%, and the progression-free survival rate was 82.3%, both of which compared well with 151 matched control patients with lymphoma who did not have HIV.In fact, there was no statistically significant difference between the HIV-related lymphoma patients and the control patients for rates of survival, treatment failure, disease progression, and treatment-related mortality.Dr Alvarnas summarized that patients with HIV-related lymphoma that is responsive to antiviral treatment "should be considered candidates for autologous HCT if they meet standard transplant criteria."The implication was that these patients can be treated in a much wider range of facilities and not just centers with HIV specialization.Another expert agreed.I think the data you saw today will change the standard of practice. Dr Brad Kahl "I think the data you saw today will change the standard of practice," said Brad Kahl, MD, of the University of Wisconsin Carbone Cancer Center, in Madison. "The impact is large," he added.The exclusion of these patients in clinical trials "on the basis of HIV infection alone" is "no longer justified," added Dr Alvarnas.And thus another barrier in HIV disease should be dropped, suggested both clinicians.Prognosis Used to Be Less Than 2 Months The limited opportunities for patients with HIV-related lymphoma are a legacy of their dismal prognosis before the advent of combination antiviral therapy (cART), suggested Dr Alvarnas."When I started in San Francisco at UCSF back in 1985, the median survival for someone [with HIV] diagnosed with one of these lymphomas was less than 2 months," he told an audience of reporters at a meeting press conference.Dr Alvarnas explained that the effectiveness of cART for HIV enabled this new study.He said that the hallmarks of cART ― such as viral suppression, recovery of T-cell immunity, and decreased infections ― allowed oncologists to offer standard antilymphoma therapies to HIV- infected patients.In the new study, researchers from the National Cancer Institute Bone Marrow Transplant Clinical Trials Network worked in collaboration with the AIDS Malignancy Consortium.All 40 patients had received fewer than 2 salvage regimens. Prior to transplant, 30 patients (75%) were in complete remission (CR), eight (20%) were in partial remission (PR), and two (5%) had relapsed/progressive disease (RPD).Patients underwent AHCT using the BEAM regimen (carmustine 300 mg/m2 [day -6], etoposide 100 mg/m2 twice daily [days -5 to -2], cytarabine 100 mg/m2 [days -5 to -2], and melphalan 140 mg/m2 [day -1]).Patients received AHCT on day 0 and standard supportive care through discharge. Antiviral therapy was withheld during the preparative regimen and until any therapy-related GI toxicity (nausea and vomiting) had resolved.At 100 days posttransplant, 36 patients (92.3%) had achieved complete response, one (2.6%) had reached partial remission, and two (5.1%) had relapsed.<iframe style="BORDER-BOTTOM: 0px; BORDER-LEFT: 0px; VERTICAL-ALIGN: bottom; BORDER-TOP: 0px; BORDER-RIGHT: 0px" id="google_ads_iframe_/4312434/profpromo/medscpnewsdesktop_1" height="3" marginheight="0" src="javascript:""" frameborder="0" width="240" allowtransparency="" name="google_ads_iframe_/4312434/profpromo/medscpnewsdesktop_1" marginwidth="0" scrolling="no">Within a year after transplant, 17 patients (42.5%) developed a total of 42 unique infections. Nine of 17 patients developed severe infection.By 1 year posttransplant, five patients had died (three from recurrent/persistent disease, one from cardiac arrest, and one from invasive fungal infection). The cumulative incidence of treatment-related mortality was 5.2%. This was a secondary outcome and was also not statistically significantly different from the outcomes seen in control patients.The study was funded by the National Institutes of Health and the AIDS Malignancy Consortium. The authors have indicated no relevant financial relationships. Dr Kahl reports being a consultant for Celgene Corporation, Cell Therapeutics, Genentech, Gilead Sciences, Inc, Infinity Pharmaceuticals, Millenium Pharmaceuticals, Inc, Seattle Genetics, and Roche and has received research funding AbbVie, Allos, Gilead Sciences, Inc, Infinity Pharmaceuticals, and Pharmacyclics. American Society of Hematology (ASH) 56th Annual Meeting: Abstract 674. To be presented December 8, 2014
First-Time Finding in Posttransplant Hodgkin LymphomaSAN FRANCISCO ― Maintenance therapy with brentuximab vedotin (Adcetris, Seattle Genetics, Inc) can extend progression-free survival in high-risk patients with Hodgkin lymphoma following transplantation, according to new data.This is the first time a study has demonstrated that adding a maintenance therapy after transplant can improve outcomes.At a median follow-up of 2 years, progression-free survival was 65% for patients who received brentuximab, compared with 45% in the placebo arm ― a 20% absolute improvement."This was sustained across all subgroups," said lead author Craig H. Moskowitz, MD, clinical director of the Division of Hematologic Oncology at Memorial Sloan Kettering Cancer Center in New York City.Speaking at a press briefing held here during the American Society of Hematology (ASH) 56th Annual Meeting, Dr Moskovitz noted that "once this study is published, and among patients who met the eligibility criteria to be on the study, in my opinion, this treatment could be standard of care."High-dose chemotherapy plus autologous stem cell transplant (ASCT) has been the standard of care for patients with chemosensitive relapsed/refractory Hodgkin lymphoma for the past 2 decades. For about half of patients, this regimen is curative. But despite optimization of salvage chemotherapy, supportive care, and patient selection, the authors note that improvements in post-ASCT outcomes have plateaued. This phenomenon is most likely due to disease progression in patients with high-risk factors, and the majority of this group will progress following transplantation. Thus, they note, new therapies are needed for this group."We've been transplanting patients with Hodgkin lymphoma for almost 30 years, and unfortunately, progression-free survival has been fairly stable at 40% to 55%,” explained Dr Moskowitz. Brad Kahl, MD, moderator of the session, agreed that this is the first study to show a significant benefit in this population. "The big question is about the long-term use of brentuximab vedotin as maintenance therapy," he pointed out.It is unknown at this time whether the patients who responded to the drug will eventually relapse or will be cured, said Dr Kahl, director of the University of Wisconsin Lymphoma Service and clinical research director for hematologic malignancies for the University of Wisconsin Carbone Cancer Center.Patient Aspects Important Brentuximab vedotin is an antibody-drug conjugate (ADC) composed of a CD30 monoclonal antibody conjugated by a protease-cleavable linker to a microtubule-disrupting agent, monomethyl auristatin E (MMAE).The AETHERA trial was initiated to evaluate whether early treatment with brentuximab vedotin after ASCT can prevent progression in high-risk Hodgkin lymphoma patients.This phase 3, randomized, multicenter study compared brentuximab vedotin with placebo in 327 patients at risk for posttransplant disease progression. All trial participants either had achieved remission or had stable, nonprogressing disease at time of transplant.They were enrolled in one of three high-risk categories: refractory to frontline therapy (196 patients, 60%); relapse less than 12 months after frontline therapy (107 patients, 33%); and relapse 12 months or longer after frontline therapy with extranodal disease (26 patients, 8%).All patients were required to have obtained a complete remission, partial remission, or to have stable disease after salvage therapy prior to ASCT.After undergoing ASCT, the cohort received brentuximab vedotin 1.8 mg/kg q3wk and best supportive care or placebo and best supportive care for up to 16 cycles (approximately 12 months). Those with progressive disease discontinued study therapy and could request unblinding.There were two aspects with regard to patient characteristics that were important, Dr Moskowitz pointed out."One is that almost of half of patients needed more than one salvage therapy to become chemosensitive disease to even be eligible for a transplant. In itself, patients who need more than one salvage regimen have about a 20% to 30% chance of actually being a long-term survivor.”"Second," Dr Moskowitz continued, "probably the most important factor is patients who have primary refractory disease. About 60% of the patients did not achieve a remission with up-front chemotherapy."The median age of patients was 32 years, and they were evenly divided with respect to sex. The median number of prior systemic therapies (frontline and salvage) was two (range, two to eight), and overall, 78% of the group had multiple risk factors for progression.At the current time, overall survival is 88%.<iframe style="BORDER-BOTTOM: 0px; BORDER-LEFT: 0px; VERTICAL-ALIGN: bottom; BORDER-TOP: 0px; BORDER-RIGHT: 0px" id="google_ads_iframe_/4312434/profpromo/medscpnewsdesktop_1" height="3" marginheight="0" src="javascript:""" frameborder="0" width="240" allowtransparency="" name="google_ads_iframe_/4312434/profpromo/medscpnewsdesktop_1" marginwidth="0" scrolling="no">Interim analysis of overall survival did not show a significant difference between treatment arms (P = .62). But that was not surprising, explained Dr Moskowitz. "Patients were allowed to cross over, so the likelihood of having an overall survival difference was not expected."The main reasons for treatment discontinuation were disease progression (n = 93, 28%), adverse events (n = 61, 19%), patient decision (n = 15, 5%), and investigator decision (n = 1,<1%).< p="">Of the 50 deaths, eight occurred prior to disease progression.Adverse events of any grade that occurred in more than 15% of patients included peripheral sensory neuropathy (36%), upper respiratory tract infection (25%), neutropenia (24%), fatigue (21%), cough (19%), and pyrexia (17%).Adverse events of grade 3 or higher that were observed in 10 or more patients were neutropenia (20%), peripheral sensory neuropathy (6%), thrombocytopenia (3%), and peripheral motor neuropathy (3%). In addition, 144 patients (44%) experienced treatment-emergent peripheral neuropathy.Dr Moskowitz and several coauthors have reported financial relationships with industry. American Society of Hematology (ASH) 56th Annual Meeting: Abstract 673. Presented December 8, 2014.
Experimental Antibodies Target Multiple MyelomaSAN FRANCISCO — Adding a new type of agent — an anti-CD38 monoclonal antibody — to standard therapy for multiple myeloma could be a viable and effective strategy, research indicates.The agents bind to a CD38 antigen, which is expressed on a myeloma cell, and then signals the patient's immune cells to attack myeloma cells."The antibodies bind to the surface of the cell and hold up a flag...saying 'immune system, come get me'," according to Thomas Martin, MD, from the University of California, San Francisco.He spoke during a press conference here at the American Society of Hematology 56th Annual Meeting.He presented early data on the use of the experimental monoclonal antibody SAR650984 (Sanofi Oncology), in combination with lenalidomide and dexamethasone, to treat relapsed/refractory multiple myeloma. The combination had an overall response rate of 58% in the phase1b dose-escalation trial. Dr Martin called it a "fairly dramatic response," given that the 31 patients had received an average of 4 previous lines of therapy.Progression-free survival was 6.2 months. Overall, 15 (48.4%) patients had progression-free survival events (1 death unrelated to treatment and 14 cases of progression). Median follow-up was 6 months.Notably, the overall response rate with the combination was 62.5% in patients who relapsed or were refractory to their last lenalidomide-containing regimen.Dr Martin believes that anti-CD38 monoclonal antibodies — there are 2 other agents in development at other companies — will be great additions to the treatment of this cancer."I think the CD38 drugs are blockbuster drugs," he said.Another clinician is not so sure. It is "too early to plant the victory flag in the ground," said Brad Kahl, MD, from the University of Wisconsin in Madison.Dr Martin said that there is an "unmet medical need in myeloma," by which he means treatments that "have significant activity in the relapsed/refractory setting."The therapies for immune-mediated inflammatory diseases (thalidomide, lenalidomide, pomalidomide) and proteasome inhibitors (bortezomib and carfilzomib) are blockbuster classes of drug that have collectively extended survival from 3 years to 7 to 10 years, Dr Martin reported.However, in a more heavily pretreated refractory/relapsed population, average survival is about 9 months, he said.In this study, patients with relapsed or refractory myeloma were treated with SAR650984 at one of three dose levels (3, 5, and 10mg/kg) every 2 weeks, in combination with lenalidomide and dexamethasone.<iframe style="BORDER-BOTTOM: 0px; BORDER-LEFT: 0px; VERTICAL-ALIGN: bottom; BORDER-TOP: 0px; BORDER-RIGHT: 0px" id="google_ads_iframe_/4312434/profpromo/medscpnewsdesktop_1" height="3" marginheight="0" src="javascript:""" frameborder="0" width="240" allowtransparency="" name="google_ads_iframe_/4312434/profpromo/medscpnewsdesktop_1" marginwidth="0" scrolling="no">SAR650984 was administered intravenously on days1 and 15 of a 28-day cycle, with dose escalation. Lenalidomide 25mg was administered on days1 to 21, and was adjusted to 10mg if baseline creatinine clearance was 60mL/min or less, and dexamethasone 40mg was administered on days1, 8, 15, and 22.An expansion cohort of 18 patients was treated at the maximum tolerated dose of SAR650984 (10mg/kg).About one-third of the patients (38%) had an infusion reaction during the first cycle, Dr Martin reported, but only 3% discontinued therapy as a result.The most common treatment-emergent adverse events (of any grade) were fatigue (41.9%), nausea (38.7%), upper respiratory tract infection (38.7%), and diarrhea (35.5%)."This combination was well tolerated," summarized Dr Martin.Dr Martin Reports financial ties to industry, including Sanofi Oncology, the maker of SAR650984. Dr Kahl reports ties with multiple pharmaceutical companies. American Society of Hematology (ASH) 56th Annual Meeting: Abstract83. To be presented December8, 2014.
Treat Young Adults With ALL as Children for Better OutcomesSAN FRANCISCO — Adolescents and young adults with acute lymphocytic leukemia (ALL) who are treated with pediatric regimens have significantly better in event-free and overall survival, new research shows.Outcomes are often better in children with ALL than in older patients, in part because of differences in the biology of the disease, but also because of the higher-intensity protocols used to treat children. Therapeutic protocols geared toward adults with leukemia tend to be less intense and be less toxic.In this large prospective study of ALL patients 16 to 39 years of age, 2-year event-free survival was 66% with an intensive pediatric treatment regimen, and overall survival was 79%.In historic control subjects treated with regimens geared toward adult patients, event-free survival is 34%, according to lead author Wendy Stock, MD, professor of medicine and director of the leukemia program at the University of Chicago Comprehensive Cancer Center."These outcomes are similar to those in other prospective international studies of pediatric regimens in adolescents and young adults," said Dr Stock, who presented the study findings during a press briefing here at the American Society of Hematology (ASH) 56th Annual Meeting."These data started 14 years ago at the ASH meeting, when we presented data showing that young adults 16 to 20 years of age who were treated in adult NCI Cooperative group studies in the United States fared much worse than patients in the same age group who were treated in pediatric studies," Dr Stock noted.Other groups around the world were finding the same results. Over the next few years, Dr Stock and her team developed a protocol derived from pediatric group studies and applied it to the young adult population, which comprised patients 16 to 40 years of age."We asked if adult hematologists/oncologists in the cooperative groups could achieve the same results in a slightly larger age range using a pediatric protocol," she said.High-Risk Patients Identified The C10403 trial involved 296 evaluable patients. Median age at diagnosis was 24 years (range, 17 to 39 years), 61% of the cohort was male, and 76% had B-cell ALL.Approximately 25% of the cohort was nonwhite, 15% was Hispanic or Latino, and 32% was obese (a body mass index above 30kg/m).Dr Stock's team notes that their regimen was identical to that used in the Capizzi methotrexate group of Children's Oncology Group (COG) AALL0232 (J Clin Oncol. 2011;29[18Suppl]:3). It consisted of remission induction, remission consolidation, interim maintenance, delayed intensification, and prolonged maintenance therapy.To date, 70 deaths have been reported and 87 patients remain on the protocol. At a median follow-up of 28 months, there have been 105 events in the surviving patients.Median event-free survival is 59.4 months, and 2-year event-free survival rate is 66%. Event-free survival is similar for patients with B-cell ALL and T-cell ALL (65% and 68%, respectively).The 2-year overall survival rate is 78% (78% for B-cell ALL and 80% for T-cell ALL); median overall survival has not yet been reached.Being older than 20 years and having a white blood cell count above 30,000cells/L were associated with worse event-free and overall survival.Philadelphia chromosome-like ALL, which is characterized by a gene-expression profile similar to that of BCR–ABL1-positive ALL, was detected in 28% of patients. Two-year event-free survival was markedly worse in patients with Philadelphia chromosome-like ALL than in those without (52% vs 81%).After the initiation of induction therapy, the presence of minimal residual disease (MRD) on day28 and a BCR–ABL1-like signature (and CRLF2 overexpression) were also associated with significantly worse survival.The absence of MRD after induction therapy was associated with excellent disease-free survival, Dr Stock reported.For five patients, death during therapy was related to treatment."This study will serve as a foundation for future studies where new targeted antibodies and kinase inhibitors may be incorporated to eradicate MRD and result in further improvements in survival," she concluded.Already the Standard? This study helps confirm what has been seen in other studies, said KarenK. Ballen, MD, director of the leukemia program at the Massachusetts General Hospital in Boston.<iframe style="BORDER-BOTTOM: 0px; BORDER-LEFT: 0px; VERTICAL-ALIGN: bottom; BORDER-TOP: 0px; BORDER-RIGHT: 0px" id="google_ads_iframe_/4312434/profpromo/medscpnewsdesktop_1" height="3" marginheight="0" src="javascript:""" frameborder="0" width="240" allowtransparency="" name="google_ads_iframe_/4312434/profpromo/medscpnewsdesktop_1" marginwidth="0" scrolling="no">"I think this is already becoming the standard of care," she told Medscape Medical News. "We use what we refer to as a 'pediatric inspired' regimen for this age group."The cutoff age in this study was 39 years, but Dr Ballen, who was not involved in the study, pointed out that it is "hard to know what the actual cutoff age is" that separates adult from young adult."Our own study went up to age 50, but as patients get older, it gets harder to tolerate the regimen," she said. "Chronological age, performance status, and comorbidity status might be important to determine the cutoff point for a very aggressive approach like this one."Physiologic age is only one factor; it also depends on how fit the individual is, Dr Ballen explained. "Basically, we need to look at the individual patient and determine which protocol might be best."Dr Stock reports being a member of the board of directors and advisory committees for Sigma-Tau Pharmaceuticals, and receiving research funding from the company. Several of her coauthors report financial relationships with industry. American Society of Hematology (ASH) 56th Annual Meeting: Abstract796. To be presented December9, 2014.
Tangle in AML: Is VALOR 'Crummy' or the 'New Standard'?SAN FRANCISCO — Press conferences at major medical meetings are usually carefully scripted affairs, with moderators acting as diplomats or cheerleaders for investigators who present their hard-earned study data.But this week, there was some improvisation here at the American Society of Hematology (ASH) 56th Annual Meeting.The drama ensued when results from a phase3 randomized controlled trial of relapsed or refractory acute myeloid leukemia (AML) were presented to reporters during a press briefing.The 711-patient trial, known as VALOR, is one the biggest trials ever in AML, said lead study author Farhad Ravandi, MD, from the University of Texas M.D. Anderson Cancer Center in Houston.Final analysis showed that patients treated with the quinolone derivative vosaroxin (Qinprezo, Sunesis) plus the chemotherapy cytarabine had better overall survival than those treated with placebo plus cytarabine (7.5 vs 6.1 months).However, the 6-week difference was not statistically significant (P= .06).Nevertheless, the result is important, said Dr Ravandi."In solid tumors, we are excited about a 1- or 2-month survival improvement [in metastatic disease]," he explained. "I don't see why we shouldn't be excited in AML as well."Dr Ravandi said he believes that relapsed/refractory AML is "the equivalent of metastatic cancer; patients with AML present with disease all over their body, right from day1."He also pointed out that there is a great treatment need in the setting of relapsed/refractory disease.Lacking the same enthusiasm about the results was press briefing moderator David Steensma, MD, from the Dana-Farber Cancer Institute in Boston."The magnitude of the benefit was not great. I would have loved to have seen a 5-month or an 8-month improvement in overall survival. We didn't see that," he noted."Relapsed/refractory AML is a really, really difficult population — no question about it," Dr Steensma conceded. And he acknowledged that treatment advances can come in small increments.But the overall survival benefit in VALOR was "pretty crummy," said Dr Steensma. "We need to do better than that."Dr Ravandi, in contrast, struck a very different note when he reviewed the data on overall survival (the primary efficacy end point) stratified by age groups.In patients 60 years and older, who made up about two-thirds of the study population, median survival was better in the vosaroxin group than in the placebo group (7.1 vs 5.0 months; P= .006).There was a "clear advantage" for patients in this age group who were treated with vosaroxin, he noted."In my opinion, these data support the use of this combination as a new standard for salvage therapy in older patients with AML," said Dr Ravandi.Dr Steensma acknowledged that the benefit was more pronounced in older patients, but did not comment on its status as a treatment option.Small Steps? Although new agents have led to impressive advances in many hematologic cancers in recent years, AML has not been so lucky, Dr Ravandi pointed out; the last new AML drug was approved in 2000.The VALOR trial was an effort to pair a new agent with a chemotherapy that has been used in AML since the 1960s, according to ASH press materials.Dr Ravandi and colleagues enrolled adult AML patients from 124 sites around the world with relapsed disease or disease unresponsive to other therapies.All patients received intravenous (IV) cytarabine 1g/m over 2 hours on days1 to 5. In addition, they were randomized, in a 1:1 ratio, to receive either IV vosaroxin 90mg/m over 10 minutes on days1 and 4, and 70mg/m in subsequent cycles, or placebo. Up to two induction and two consolidation cycles were administered.The eligibility criteria for the trial were "important," said Dr Ravandi.Patients had refractory disease — defined as persistent disease after induction, or first complete remission (CR) in less than 90 days — or were in first relapse (an early relapse was defined as a first CR in 90 days to 12 months; a late relapse was defined as a first CR in 12 to 24 months). Patients had received 1 or 2 cycles of induction chemotherapy, including at least 1 cycle of anthracycline (or anthracenedione) and cytarabine.Overall, 29.5% of patients underwent allogeneic stem cell transplantation (ASCT). Transplant rates were comparable in the vosaroxin and placebo groups (30.1% vs 29.0%).In a predefined analysis censoring for subsequent ASCT, median overall survival was better with vosaroxin than with placebo (6.7 vs 5.3 months; P= .02).In addition to age, patients were stratified by disease status (refractory, early relapse, late relapse).The difference in overall survival between the vosaroxin and placebo groups was only significant in the early-relapse group (6.7 vs 5.2 months; P= .05).A CR was achieved by more patients in the vosaroxin group than in the placebo group placebo (30.1% vs 16.3%).The primary safety end point was early mortality (defined as 30- and 60-day death), which was similar in the two groups. The most common serious adverse events were, for the vosaroxin and placebo groups, febrile neutropenia (11.3% vs 7.4%), sepsis (8.7% vs 4.3%), pneumonia (7.6% vs 4.9%), bacteremia (8.5% vs 2.9%), and stomatitis (3.4% vs 1.4%).Dr Ravandi believes the VALOR trial is an advance in the treatment of relapsed/refractory AML. "We should not discount small steps forward," he said.Dr Ravandi and many of the study authors report financial ties with Sunesis. Dr Steensma reports financial ties with many pharmaceutical companies, including Amgen, Astex, Boehringer Ingelheim, Celgene, Genoptix, Incyte, and MEI Pharma. American Society of Hematology (ASH) 56th Annual Meeting: AbstractLBA-6. Presented December9, 2014.
Blinatumomab Eradicates Minimal Residual Disease in ALLSAN FRANCISCO ― More than three quarters of patients with acute lymphocytic leukemia (ALL) who had residual disease after chemotherapy and were subsequently treated with the novel immunotherapy blinatumomab (Blincyto, Amgen Inc) experienced a complete eradication of minimal residual disease (MRD).The phase 2 study met its primary objective, with 78% of patients achieving a complete MRD response, a measure of eradication of residual disease at the molecular level, after only one treatment cycle.In addition, almost all complete responses (98%) occurred within the first treatment cycle.In patients with high MRD ALL, following intensive therapy, a rapid MRD response induced by blinatumomab has the potential to improve patient outcomes, explained lead author Nicola Gkbuget, MD, of Goethe University in Frankfurt, Germany."Reponses occurred in all subgroups, including older patients and patients with high MRD levels, and no predictive factor for MRD response was identified," said Dr Gokbuget during a press briefing.Persistent MRD that occurs after standard induction therapy or that reappears after a patient achieves a negative MRD status is a strong prognostic factor for relapse and overall survival, she explained. Nearly all patients with persistent or recurrent MRD relapse despite continued chemotherapy."This is basically a group of patients who are resistant to conventional chemotherapy drugs," said Dr Gokbuget.Persistent MRD is considered to be an indication for an allogeneic transplant, but patients with high MRD have a greater risk for relapse even after undergoing transplantation. "We urgently need new treatments for them, and the treatments, of course, have to be non-chemotherapy," Dr Gokbuget emphasized.Blinatumomab is the first of a novel class of drugs known as bispecific T-cell engagers (BiTE) and is designed to direct cytotoxic T-cells to CD19-expressing cancer cells. CD19 is a protein expressed on the surface of B-cell-derived ALLs and non-Hodgkin's lymphomas.The US Food and Drug Administration (FDA) approved blinatumomab earlier this month for use in the treatment of patients with Philadelphia chromosomenegative precursor B-cell acute ALL who experience relapse or whose disease is refractory to previous treatment.To evaluate the efficacy and safety of blinatumomab in patients with detectable MRD, Dr Gokbuget and colleagues enrolled 116 adults with ALL in a phase 2 trial, with the primary endpoint being the proportion of patients achieving a complete MRD response after one cycle of blinatumomab. All patients had achieved a complete hematologic response, and none had undergone transplantation.In this trial, Dr Gokbuget pointed out, patients were treated with blinatumomab before they went into a full relapse.The study also had a number of secondary endpoints, including overall survival, relapse-free survival, duration of complete MRD response, and incidence and severity of adverse events. However, she added that data for most of these are not available at this time.Blinatumomab 15 g/m/day was given by continuous IV infusion for 4 weeks, followed by a 2-week treatment-free period (1 cycle). Patients who responded could receive up to 4 cycles of treatment or undergo hematopoietic stem cell transplantation after one or more cycles. Those who experienced a hematologic relapse discontinued treatment.Nearly all patients (n = 115, 99%) completed treatment and the 30-day safety follow-up. Of this cohort, 72 (63%) patients are alive and continue to be followed. Participation by 43 patients (37%) ended because of death.The most frequently reported adverse event was pyrexia (90%), followed by tremor (29%), chills (28%), fatigue (24%), nausea (22%), vomiting (22%), and diarrhea (20%). Severe adverse events that occurred in 3% or more of patients included pyrexia (16%), tremor (7%), aphasia (5%), encephalopathy (5%), overdose (5%), neutropenia (4%), and C-reactive protein increase (3%)."This is an important study, and ultimately, I think our goal is to overcome the use of chemotherapy and radiation, which can destroy healthy cells along with malignant ones," commented Catherine Bollard, MD, MBChB, a bone and marrow transplant specialist at George Washington University/Children's National Medical Health System, Washington, DC. "This strategy, along with others, is harnessing our immune system to target cancer cells. The caveat is that when you rev up the immune response, there is some toxicity associated with that, so we will have to balance that."Dr Bollard, who moderated the session, added that she believes that new therapies such as this one will revolutionize treatment of hematologic cancers.The study was funded by Amgen. Dr Gokbuget has reported consultancy, honoraria, and research funding from Amgen; several coauthors report relationships with Amgen and other companies, as noted in the abstract. Dr Bollard has received honoraria from Cellmedica. American Society of Hematology (ASH) 56th Annual Meeting: Abstract 379. Presented December 7, 2014.
New Guidelines on Chemotherapy-Induced Peripheral NeuropathyDawn L. Hershman, MD, Mary E. Anderson, PhDMay13,2014 Optimum Approaches to Managing CIPNEditor's Note: The American Society of Clinical Oncology (ASCO) issued new guidelines on the prevention and management of chemotherapy-induced peripheral neuropathy (CIPN) on April 14, 2014,[1] as reported previously on Medscape. The incidence of CIPN varies by the type of chemotherapeutic agent(s), the total dose, and such patient-related factors as race.[2-6] CIPN is a particularly important adverse effect because it may compromise a patient's ability to tolerate chemotherapy and become a serious, long-lasting, and even permanent debility. To provide guidance to clinicians and patients who are making decisions about CIPN, ASCO convened a multidisciplinary expert panel charged with providing evidence-based answers to the question, "What are the optimum approaches in the prevention and management of CIPNs in adult cancer survivors?" Unfortunately, the expert consensus was that no approach exists that can be recommended for prevention. Only one agent is recommended for treatment, and that is only a moderate recommendation. However, the experts did issue moderate-to-strong recommendations against using certain agents, which has important clinical implications. Dawn L. Hershman, MD, MS, co-chair of the guideline expert panel, spoke to Medscape about the ASCO guideline and how it affects the clinical prevention and management of CIPN. Dr. Hershman is Associate Professor of Medicine and Epidemiology, Division of Medical Oncology, Columbia University College of Physicians and Surgeons, New York, New York. Medscape: What was it about the clinical landscape at this time that prompted ASCO to develop clinical guidelines for preventing and treating CIPN? Dr. Hershman: ASCO has set a priority of looking into a variety of issues that affect cancer survivors, including CIPN, fatigue, and depression. CIPN is one of the most common adverse effects and is associated with many different types of cancer therapies. Although it has a significant impact on patients' quality of life, to date few treatments are available for either treating or preventing CIPN.Medscape: The purpose of the clinical practice guidelines expert panel was to "develop evidence-based guidance" for the optimum prevention and management of CIPN. How did the committee accomplish that? Dr. Hershman: We performed a comprehensive literature review of all the trials that have been completed looking at either the treatment or prevention of CIPN. Then we looked at the quality of the studies, and trials that were deemed to be of sufficient quality were included. Only randomized controlled trials were included. We reviewed many studies that either were nonrandomized or were observational and as such didn't meet our strict criteria for inclusion. We wanted to be able to comprehensively evaluate each study's benefits and limitations to make reasonable judgments in terms of what we should or should not be giving to patients.Unfortunately, many of the studies are very different from each other in terms of design. Because we don't have a good understanding of the mechanism of CIPN for a variety of drugs, some of the prevention and treatment strategies that we use come from the neurologic literature, from animal studies, or from observation. Many of those studies, when rigorously tested, have not found any single agent to be of particular benefit, and many different drugs or supplements have been tested.Prevention: What Not to TakeMedscape: What were the recommendations for prevention? Dr. Hershman: Some supplements that people take, thinking that these products should make them feel better, could actually cause harm. One such supplement is acetyl-L-carnitine (ALC). A phase 3 study showed that patients who took that supplement actually had more peripheral neuropathy than patients in the placebo group.[7] The panel made a strong recommendation against using ALC and nimodipine on the basis of strong evidence. There was a strong recommendation against the use of diethyldithio-carbamate as well, but the evidence was weaker.Moderate recommendations were made against the use of amifostine, amitriptyline, calcium and magnesium infusions for patients receiving oxaplatin-based chemotherapy, glutathione for paclitaxel/carboplatin chemotherapy, Org 2766, retinoic acid, recombinant human leukemia inhibitory factor, and vitamin E.Some drugs showed some evidence of utility, but the clinical trials were small and had methodologic issues that may have resulted in false-negative findings. Venlafaxine is one of those agents; the data[8] weren't strong enough to recommend its use, but they were also not strong enough to recommend that it should not be used. The panel could not reach conclusions about acetylcysteine, carbamazepine/oxycarbazepine, glutamate/glutamine, glutathione for cisplatin or oxaliplatin, Goshajinkigan Kampo medicine, or omega-3 fatty acids.Little to Offer for TreatmentMedscape: What were the recommendations for the treatment of CIPN? Dr. Hershman: The drug with the strongest support for use in the treatment of CIPN is duloxetine. A randomized, placebo-controlled trial showed benefit of duloxetine in reducing pain from neuropathy.[9] Only one study has been done to look at duloxetine, and it was underpowered to examine differences according to the chemotherapy agent (eg, oxaliplatin vs a taxane), so there are still some unanswered questions about duloxetine. One of those questions is its long-term tolerability, because this was a short-term study and the medication was associated with some side effects. The recommendation to use duloxetine was moderate.Several other drugs have had conflicting results or have shown significant benefits in the neurologic literature. Some of the clinical trials that have been done were quite small and the outcome measures may not have been perfect. Nevertheless, these agents deserve continued study. Given the fact that CIPN can be a life-altering side effect of chemotherapy, our suggestion is that it is not unreasonable to at least try these agents to see whether there is some improvement on a patient-by-patient basis. These agents include: (1) a tricyclic antidepressant such as nortriptyline[10]; (2) gabapentin[11] and drugs with a similar mechanism of action; and (3) compounded topical gel[12] containing baclofen, amitriptyline HCl, and ketamine. There is a moderate recommendation against using lamotrigine.[13] Medscape: The guidelines include a section on communicating with patients. What are some of the most important subjects to discuss? Dr. Hershman: It's important for patients to be aware that they should let their physicians know as soon as they start to experience numbness, tingling, or pain. There may be other cancer treatment options that are equally efficacious, and the clinician may choose to change treatment. If not, there can be a discussion about the potential risks and benefits of the treatment that the patient is receiving. It's also important to discuss risks and benefits of medications or supplements that patients can obtain without a prescription. ALC is a case in point; it is available over the counter, so many patients may be unaware that it can be harmful.Medscape: What is the next step in finding effective preventive or treatment approaches for CIPN? Dr. Hershman: It would be better if our guidelines showed that many more agents were useful in the treatment and prevention of CIPN. The most important result of our work is that it really opens our eyes to the fact that although a considerable amount of research has been done, we still don't have good options for CIPN. To get to the next stage, we need a better understanding of the causative mechanism of CIPN and the reasons why some patients are more susceptible to CIPN than others. This may allow physicians to better personalize treatments based on risks of toxicity. If we have a better understanding of the mechanism, we may also figure out factors that might make it worse and that are important to avoid. These guidelines bring to the forefront the evidence that is available. Many physicians use agents that have no efficacy, so it's important that we communicate what people should be avoiding in terms of treating CIPN.Medscape: In view of the paucity of high-quality data, should clinicians talk to their patients about possible participation in clinical trials? Dr. Hershman: Absolutely. The only way that we will move this field forward is with more research. Some of the studies have been fairly surprising. ALC is an example; preclinical data and phase 2 data suggested a benefit, but when you do the more definitive, larger, placebo-controlled study, you see that it actually might make things worse. Without that evidence, we could be doing harm. It's very important that we think about new options for patients, but we must study them in a rigorous way so that we know that what we offer our patients isn't actually hurting them. That is the message to get across: that we have a lot more work to do, and we should be careful about giving drugs or supplements without studying them.
CKD-5D Patients3.4.3: For adult CKD 5D patients, we suggest that ESA therapy be used to avoid having the Hb concentration fall below 9.0 g/dL (90 g/L) by starting ESA therapy when the Hb is between 9.0–10.0 g/dL (90–100 g/L). (2B)3.4.4: Individualization of therapy is reasonable as some patients may have improvements in quality of life at higher Hb concentration and ESA therapy may be started above 10.0 g/dL (100 g/L). (Not Graded)According to the available evidence for the haemodialysis population, we have information about Hb target ranges between 9.5–11.5 g/dL and 13.5–14.5 g/dL.[3,44,55]Conversely, the Hb range of 11.5–13.5 is still a grey area.ESA Maintenance Therapy3.5.1: In general, we suggest that ESAs not be used to maintain Hb concentration above 11.5 g/dL (115 g/L) in adult patients with CKD. (2C)3.5.2: Individualization of therapy will be necessary as some patients may have improvements in quality of life at Hb concentration above 11.5 g/dL (115 g/L) and will be prepared to accept the risks. (Not Graded)3.6: In all adult patients, we recommend that ESAs not be used to intentionally increase the Hb concentration above 13 g/dL (130 g/L). (1A)There is a high degree of evidence showing that Hb normalization using ESA therapy has no benefit or can even be harmful in CKD patients compared with partial anaemia correction or placebo. Recommendation 3.6 is thus accepted in full.Conversely, as demonstrated by the low grade of evidence of recommendation 3.5.1 and 3.5.2, the upper limit of Hb levels that should not be exceeded intentionally with ESA therapy in CKD patients is still a grey area. In 2007 following the publication of the Cardiovascular Reduction Early Anaemia Treatment Epoetin beta (CREATE)[56]and Correction of Haemoglobin and Outcomes in Renal Insufficiency (CHOIR)[57]studies, KDOQI guidelines set a lower Hb limit (11.0 g/dL) and suggested an upper limit around 12 g/dL without intentionally exceeding 13 g/dL. This was accepted in full by the first position paper of the ERBP on the topic.[2]In the same period, a panel of experts of the KDIGO group concluded that levels of 9.5–11.5 g/dL were considered associated with better outcomes than those of >13 g/dL, but that there was no evidence either way for intermediate levels (11.5–13 g/dL).[58]The TREAT trial further increased the degree of evidence that complete anaemia correction has no benefit (the study showed a neutral effect on the risk of death or of reaching a cardiovascular composite end point compared with the placebo arm).[5]The increased risk of stroke and death for malignancies in those with a previous history of cancer, which was found in the experimental harm of the TREAT trial, has already been discussed in the section about ESA initiation.Unfortunately, the trial design does not help us to fill in the gap in knowledge about intermediate Hb values given that many patients of the control group remained at intermediate Hb levels (from a median value of 10.4 g/dL at baseline to 11.2 g/dL at the end of the study, with a median value of 10.6 g/dL during the trial follow-up). These achieved values are very close to the upper limit of Hb level suggested by the current KDIGO guidelines.[7]As already discussed, the fact that in the control group of the TREAT study, Hb levels had a positive trend during follow-up despite minimal or no ESA therapy may indicate that these findings are not necessarily applicable to the overall CKD populations.Another point deserving a comment is the possibility of a different risk of increased death or cardiovascular events following ESA therapy according to the CKD stage. In 2007 the KDOQI group performed a meta-analysis of available trials in the dialysis and non-dialysis populations and found a trend towards increased cardiovascular risk only in patients not on dialysis assigned to higher Hb targets.[3]The reason for this discrepancy is not clearly understandable, considering that dialysis patients have in general a higher burden of co-morbidities, are exposed to high Hb values following the dialysis session and are more likely to receive higher ESA doses and intravenous iron, possibly exposing patients to enhanced oxidative stress. The impact of marked haemoconcentration at the end of the dialysis session, especially in those patients with high interdialytic body increases, has not taken into account by KDIGO recommendations when suggesting a lower Hb target for ND-CKD patients.Following the publication of the TREAT trial,[5]Palmeret al.[59]performed a meta-analysis of 27 randomized trials of ESAs in CKD patients with anaemia and found no statistically significant difference in the risk for all-cause mortality, serious cardiovascular events, or fatal and nonfatal myocardial infarction between a higher and lower Hb target. Unfortunately, the separate analysis of the 10 studies including only ND-CKD patients was done only on the risk of reaching ESRD. Moreover, the study by Parfreyet al.[44]was excluded by the sub-analysis about the risk of stroke.Recently, Coyne[60]reanalysed the data of the Normal Haematocrit Trial[55]using the clinical trial report filed by the FDA in 1996. Summarizing, he found that randomization to the higher target increased significantly the risk for the primary end point (in the 1998 publication the P value was not given), the risk of death (risk ratio 1.27, 95% CI 1.04–1.54), non-access thrombotic events (P = 0.041), and hospitalization rate (P = 0.04). While according to the 1998 publication achieved Hb values were related with improvement in 'physical function', no improvement was found at the intention-to-treat analysis (randomization to the higher Hb target). The authors of the Normal Haematocrit Trial[61]strongly disagreed with this data.Altogether, these findings are in line with the KDIGO recommendation (Grade 1A) that 'ESAs should not be used to intentionally increase the Hb concentration above 13 g/dL'.Conversely, no data suggest clear harm at the Hb range values suggested by previous guidelines (11–12 g/dL). This is especially true for CKD stage 5D patients in whom no further clinical trials have been published since 2007.In this light, we feel that caution should be used in the specific patient populations with some particular risk factors especially among diabetic patients (symptomatic limb arteriopathy, stroke or asymptomatic ischaemic heart disease, cancer) or in those who are hyporesponsive to ESA treatment and considering that in the control groups of trials testing partial versus complete anaemia correction Hb values ranged between 9 and 12 g/dL, in the opinion of the group it is reasonable to use ESA therapy to generally maintain CKD patients with Hb values ranging between 10 and 12 g/dL.This suggestion is consistent with the previous one given by the Anaemia Group of ERBP following the publication of the TREAT trial,[5]advising to aim to Hb values between 11 and 12 g/dL in general in CKD patients treated with ESA but aim at a lower Hb target in high-risk patients.[6]In the opinion of the group, this Hb range is deliberately and helpfully reasonably wide which we feel is better to be used in everyday clinical practice avoiding excessive Hb variability and leaving room for physicians to set their patients to the lower or higher edge of the range according to patient characteristics or 'informed' preferences. In this regard, it is important to consider that from an epidemiological prospective if we shift the Gaussian curve too much to the left of Hb distribution in CKD patients treated with ESA, we inevitably increase the number of transfusions. This aspect has to be taken into account also in light of the fact that there is a worldwide shortage looming in the supply and availability of blood and blood products.This trend is already on-going, as testified by recent epidemiological data in the USA following the publication of the FDA warning about ESA therapy in 2010 and changes in reimbursement policies of ESAs. According to the US Renal Data System, in each of the first 9 months of 2011, the share of dialysis patients covered by Medicare who received blood transfusions increased by 9–22% over the corresponding months in 2010.[62]This was paralleled by an 18% decrease in ESA dose from 2010 to 2011. Similar findings were shown by an analysis of the DOPPS study in the same time period.[24]Chapter 4: Red Cell Transfusion to Treat Anaemia in CKD4.1.1: When managing chronic anaemia, we recommend avoiding, when possible, red cell transfusions to minimize the general risks related to their use. (1B)4.1.2: In patients eligible for organ transplantation, we specifically recommend avoiding, when possible, red cell transfusions to minimize the risk of allosensitization. (1C)4.2.1: When managing chronic anaemia, we suggest that the benefits of red cell transfusions may outweigh the risks in patients in whom (2C):-ESA therapy is ineffective (e.g. haemoglobinopathies, bone marrow failure, ESA resistance)-The risks of ESA therapy may outweigh its benefits (e.g. previous or current malignancy, previous stroke)In the opinion of the group, these recommendations together with their rationale are wise and acceptable. According to our comment in the section about ESA initiation, the risk of stroke in those with a previous history is not significantly increased by darbepoetin alfa use and complete anaemia correction.[45]Consequently, it is questionable that the benefits of red cell transfusions may outweigh the risks in patients with a previous stroke.4.2.2: We suggest that the decision to transfuse a CKD patient with non-acute anaemia should not be based on any arbitrary Hb threshold, but should be determined by the occurrence of symptoms caused by anaemia. (2C)This recommendation is based on previous guidelines[63,64]emphasizing that blood transfusion should be driven mainly by patient symptoms and not on a given Hb level threshold. In the opinion of the group, this point is critical and deserves a number of comments.First, it is true that the exact Hb threshold at which a haemodynamically stable medical patient with anaemia could benefit of a blood transfusion in terms of outcome is still a grey area. This is particularly true for CKD patients in whom evidence regarding this aspect is lacking (except the frustrating experience with blood transfusions when ESA therapy was still not available). It is also clear that the more restrictive the transfusion strategy, the lower the risk of infectious and non-infectious complications related to blood transfusions and the lower the blood use. The fact that at very low Hb levels platelet function may be compromised should also be taken into account. In the future, the supply of blood products will become more difficult as blood donors become rarer due to the demographic aging of the general population with fewer potential donors and more patients with medical conditions in need of a blood transfusion.Anaemia-related symptoms may be vague and their occurrence is not tightly associated with anaemia severity. Considering that, as already pointed out by the KDIGO group, at Hb levels below 10 g/dL transfusion needs markedly increase, based mainly on symptoms, the decision of whether or not to transfuse a given patient implies the risk of submitting CKD patients to unnecessary blood transfusion and conflating this therapeutic strategy as an equal alternative to ESA therapy, especially in cases in whom the risk of ESA therapy may be vague. As already pointed out in the section about ESA maintenance therapy, the number of haemodialysis patients receiving blood transfusions is already increasing in the USA.[62]Compared with CKD-5D, the ND-CKD population is even more likely to experience a marked increase in blood transfusion in the near future following the publication of KDIGO guidelines. Indeed, for this patient population, a lower Hb value at which one can recommend in general the start of ESA therapy cannot be foreseen. Many of these patients may be future candidates for kidney transplantation; so, the possible risk of allosensitization following blood transfusion should be considered when taking the decision to start ESA therapy or setting the optimal Hb value during treatment.In addition to these considerations, after the closure of the process of development of KDIGO guidelines,[7]the American Association of Blood Bank published a new set of clinical practice guidelines on red blood cell transfusion.[65]These guidelines clearly remark that a liberal transfusion strategy would be acceptable over a restrictive one only if reliable evidence demonstrates its superiority. According to the panel, a liberal transfusion strategy is unlikely to result in clinically important reduction in mortality or on other secondary end-points but exposes patients to a much higher number of blood transfusions.[56]In hospitalized, haemodynamically, stable patients transfusion decision should be influenced both by symptoms and Hb values. In particular, they suggest considering transfusion at Hb values ≤7 g/dL or at Hb values ≤8 g/dL in postoperative surgical patients.[56]In hospitalized patients with pre-existing cardiovascular disease, transfusion should be considered at Hb values ≤8 g/dL or in the presence of symptoms (chest pain, orthostatic hypotension, tachycardia unresponsive to fluid resuscitation or congestive heart failure).[56]Altogether, in the opinion of the group, at present there is no evidence that in CKD patients a liberal transfusion strategy mainly driven by symptoms improves patient outcome or that it is not harmful. Moreover, the group feels that it is important to remark that blood transfusions should be used wisely in the CKD population. In the individual haemodynamically stable patient, a blood transfusion should be considered in the presence of stringent indications (i.e. very low Hb levels, clear symptoms related to anaemia, ESA resistance and considerable risk in using ESA therapy).Another aspect to be commented on is the role of blood transfusion therapy in the management of CKD patients with chronic anaemia in whom physicians have decided that risks of ESA therapy outweigh the benefits. According to the experience driven from hereditary or acquired transfusion-dependent anaemia, transfusions provide effective treatment and prevention of many complications, but iron overload is an inevitably serious complication of chronic blood transfusions and can lead to significant morbidity and mortality if left untreated. Moreover, despite the efficiency of red cell transfusions in increasing Hb levels acutely, patients requiring chronic transfusion experience long periods of suboptimal Hb levels. According to the experience gathered from patients with myelodysplastic syndrome, those who are transfusion dependent have a significantly higher percentage of hypertrophic cardiac remodelling than those who are not.[66]In the opinion of the group, these aspects should also be considered when balancing the risk/benefit of blood transfusion compared with ESA therapy in the single patient.The investigation of the burden of iron overload following an increase in the number of transfusions in the CKD population (especially in those periodically receiving blood transfusions) should be an objective of future research.Sidebar 1We suggest using for the European population with CKD the following:The diagnosis of anaemia should be made and further evaluation should be undertaken when Hb concentrations are <13.5 g/dL in adult males (13.2 g/dL in men >70 years) and <12.0 g/dL in adult females of all ages.We suggest using for the European population with CKD the following:For adult CKD patients with anaemia not on iron or ESA therapy we suggest a trial with iron therapy (either IV or, when tolerated, orally as a first step in ND-CKD patients, especially in CKD II to III, or in PD patients) if:there is an absolute iron deficiency (TSAT <20% and serum ferritin <100 ng/mL)ORan increase in Hb concentration without starting ESA treatment is desiredand TSAT is <25% and ferritin is <200 ng/mL in ND-CKD patients and <25% and ferritin is <300 ng/mL in dialysis patients. Following iron treatment, the limit of TSAT of 30% and serum ferritin of 500 ng/mL should not be intentionally exceeded in both ND-CKD and dialysis patientsWe suggest using for the European population the following:For adult CKD patients on ESA therapy who are not receiving iron supplementation, we suggest a trial of IV iron (in ND-CKD patients oral iron therapy should be started as a first step if tolerated) if an increase in Hb concentration or a decrease in ESA dose is desired and TSAT is <30% and ferritin is <300 ng/mL.In haemodialysis patients, a course of IV iron therapy can be considered in those having higher serum ferritin levels in the presence of hyporesponsiveness to ESA or a risk/benefit ratio going against ESA use.Caution is suggested in exceeding a ferritin value of 500 ng/mL during combined iron and ESA treatment in dialysis patients, especially in those patients with adequate TSAT percentage (>30%).We suggest using for the European population with CKD the following:Risk factors for stroke (including a past history of stroke) and the presence of active malignancy or a past history of malignancy should be taken into account when weighing the risk/benefit ratio of prescribing ESA therapy. However, these are not absolute contraindications to ESA treatment and the nephrologist should discuss them together with the single patient, balancing with him/her the risk benefit ratio.We suggest using for the European population the following:The decision on whether and when to start ESA therapy in CKD-ND patients should be individualized taking into account the rate of fall of Hb concentration, prior response to iron therapy, the risk of needing a transfusion, the risks related to ESA therapy and the presence of symptoms attributable to anaemia.Hb values should not routinely be allowed to fall below 10 g/dL in ND-CKD patientsESA therapy should not be started if there is a temporary and obvious cause of anaemia potentially reversible (inflammation, infections, bleeding, iron deficiency, surgical procedures etc).In low-risk patients (i.e. in younger patients with very few comorbidities) or in those in whom a clear benefit on quality of life can be foreseen, the start of ESA therapy could be considered at higher Hb values (no >12 g/dL).In high risk patients, including those with asymptomatic ischaemic heart disease, treatment initiation with ESA should be started at Hb values between 9 and 10 g/dL in order to maintain a Hb value ~10 g/dL during maintenance therapy.In the patients with ischaemic heart disease with worsening ischaemic symptoms associated with anaemia, ESA treatment initiation could be considered at higher Hb levels (>10 g/dL).We suggest using for the European population with CKD the following:The decision of whether and when to start ESA therapy in CKD-5D patients should be individualized taking into account the risks related to ESA therapy, the presence of symptoms attributable to anaemia and the risk of needing a transfusion.Hb values should not be allowed to routinely fall below 10 g/dL in CKD 5D patients. In low-risk patients (i.e. in younger patients with very few comorbidities), in those with ischaemic heart disease with worsening ischaemic symptoms associated with anaemia, or in those in whom a clear benefit on quality of life can be foreseen, the start of ESA therapy could be considered at higher Hb values but not exceeding 12 g/dL.In high-risk patients, including those with asymptomatic ischaemic heart disease, treatment initiation with ESA should be started at Hb values between 9 and 10 g/dL in order to maintain a Hb value ~10 g/dL during maintenance therapy.We suggest using for the European population the following:Hb values >13 g/dL should not be intentionally aimed for during ESA therapy.It is reasonable to use ESA therapy to generally maintain CKD patients with Hb values ranging between 10 and 12 g/dL individualizing the value in this target range according to the possible comorbidities of the patients.Caution should be used in patients with specific risk factors especially among diabetics (symptomatic limb arteriopathy, stroke or non-symptomatic ischaemic heart disease, cancer) or in those who are hyporesponsive to ESA treatment). In these patients, if ESA therapy is used, it seems wise to aim towards the lower Hb levels of the suggested target range (10–12 g/dL).We suggest using for the European population with CKD the following:A restrictive blood transfusion strategy is recommended in the CKD population.In the individual haemodinamically stable patient, a blood transfusion should be considered in the presence of stringent indications (i.e. very low Hb levels (Hb values ≤7 g/dL or at Hb values ≤8 g/dL in postoperative surgical patients and in patients with pre-existing cardiovascular disease), clear symptoms related to anaemia, ESA resistance, considerable risk using ESA therapy).
A European Renal Best Practice Position Statement / Kidney Disease Improving Global Outcomes (KDIGO) Guidelines on Anaemia Management in Chronic Kidney Disease: A European Renal Best Practice (ERBP) Position StatementAbstract and IntroductionAbstractRecently, the Kidney Disease: Improving Global Outcomes (KDIGO) group has produced comprehensive clinical practice guidelines for the management of anaemia in CKD patients. These guidelines addressed all of the important points related to anaemia management in CKD patients, including therapy with erythropoieis stimulating agents (ESA), iron therapy, ESA resistance and blood transfusion use. Because most guidelines were 'soft' rather than 'strong', and because global guidelines need to be adapted and implemented into the regional context where they are used, on behalf of the European Renal Best Practice Advisory Board some of its members, and other external experts in this field, who were not participants in the KDIGO guidelines group, were invited to participate in this anaemia working group to examine and comment on the KDIGO documents in this position paper. In this article, the group concentrated only on those guidelines which we considered worth amending or adapting. All guidelines not specifically mentioned are fully endorsed.IntroductionThe European Renal Best Practice (ERBP) group was created in 2008 with the aim of issuing suggestions for clinical practice in areas in which evidence is either lacking or weak, or position statements about guidelines produced by other bodies, such as the Kidney Disease: Improving Global Outcomes (KDIGO).[1]KDIGO is a non-profit organization governed by an international board aimed at 'improving the care and outcomes of kidney disease patients worldwide by promoting coordination, collaboration and integration of initiatives to develop and implement clinical practices guidelines'. As a result of a large, international effort, KDIGO has already produced a number of evidence-based guidelines on different topics in the field of nephrology.In 2009 the ERBP Anaemia Working Group published its first position paper,[2]which focused on the 2007 update on the haemoglobin (Hb) targets by the National Kidney Foundation: Dialysis Outcome Quality Initiative[3]and on emerging issues that were not covered by the complete set of KDOQI recommendations in 2006.[4]In 2009, the Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT) study was published.[5]This large, randomized, placebo-controlled trial raised a number of safety issues about erythropoiesis-stimulating agent (ESA) use in the chronic kidney disease (CKD) population with type 2 diabetes when administered with the aim of normalizing Hb values. Promptly, the Anaemia Working Group of ERBP published a second position paper[6]giving guidance on the interpretation of these new findings together with their possible implication on Hb targets and treatment strategy when using ESAs in CKD patients.The TREAT study, which is the largest study performed so far in the field of renal anaemia, is an important part of the available evidence about anaemia management in CKD patients. Indeed, the KDIGO guidelines on anaemia management were only started after its publication.These guidelines have recently been published.[7]Under the auspices of the ERBP, some of its members and other experts in the field, who were not participants in the KDIGO guidelines group, were invited to participate in this ERBP Anaemia Working Group to examine and comment the KDIGO guidelines in the present position paper. Importantly for the nephrological community, even if the KDIGO-produced recommendations were graded according to the available evidence, many of these are clearly derived from low-grade evidence. As a result, many recommendations are largely opinion based and quite vague. Consequently, they may not fulfil one of the main aims of guidelines, i.e. aiding clinical decision-making on the part of doctors who cannot integrate all of the published data concerning new technology and knowledge in their everyday clinical practice. This is because though the TREAT study was a very important advance in knowledge, there are still many areas of clinical uncertainty. Consequently, a number of recommendations have to be given not solely on the findings by themselves but also on their interpretation.The ERBP group felt there was a need to adapt some of the recommendations of the KDIGO guidelines to the European population. Consequently, we concentrated only on those guidelines which we considered worth amending or adapting. All guidelines not specifically mentioned are fully endorsed. We also decided to focus only on the adult population with CKD.This position paper is not intended to represent a set of new guidelines, as it is not the result of a systematic review of the evidence, but is intended to be of most use to the practicing kidney specialist, and those allied to the clinical team, when dealing with anaemia management in the CKD population in everyday clinical practice. This is particularly apposite and valuable considering the marked trend towards treatment individualization, which has become an important strategy leaving the practising physician with too many treatment options and complex risk/benefit balances to make informed and sensible clinical decisions.Chapter 1: Diagnosis of Anaemia in CKDKDIGO 1.3.1Diagnose anaemia in adults and children >15 years with CKD when the Hb concentration is <13.0 g/dL (or 130 g/L) in males and <12.0 g/dL (or 120 g/L) in females. (Not Graded)Precision around the diagnosis of anaemia is relevant for two reasons. First, it is intended to alert physicians that if a patient's Hb level falls below a certain value then physicians and those concerned with the diagnosis and treatment of renal anaemia should consider whether an anaemia workup should be started to identify possible causation. The earlier this is done, the greater is the possibility to correct any underlying disease and avoid further decline in Hb values. Conversely, if this workup is done too early, patients may undergo unnecessary testing. This can be a complex judgement. Second, the definition of anaemia influences the prevalence of this disease/complication across epidemiological studies. Indeed, the prevalence of anaemia between phase III and IV of the National Health and Nutrition Examination Survey (NHANES) slightly differs partially because a different definition is used.[8,9]According to the chosen definition the prevalence of anaemia across populations may also influence the role of this condition as a poor outcome predictor in several diseases including CKD.The definition of anaemia in CKD patients has been changing across guidelines over the last few years. In 2004 the Revised European Best Practice Guidelines on Anaemia indicated as a definition for anaemia in CKD the following: 'In patients living below 1500 m, Hb values were considered below normal if they were <11.5 g/dL in women and <13.5 g/dL in men (<12 g/dL in those aged >70 years)'.[10]This definition had the advantage of differentiating the definition of anaemia between older or younger males but did not differentiate between post-menopausal and younger women. It had perhaps the disadvantage of missing anaemia diagnosis in male patients >70 years, given a relatively low threshold in this category.In 2006 the KDOQI guidelines on anaemia suggested that the diagnosis of anaemia should be made, and further evaluation should be undertaken, when Hb concentrations were <13.5 g/dL in adult males and <12.0 g/dL in adult females.[4]This definition was obtained from the mean Hb of the lowest fifth percentile of the sex-specific general adult population and assumes a lack of adjustment downward for age in males and an adjustment upward for iron deficiency in females.[4]This definition is simple and easy to remember, increasing the likelihood that physicians may apply it in everyday clinical practice.The new KDIGO suggestion[7]is based on the World Health Organisation (WHO) definition of anaemia.[11]It is true that this definition has been applied across populations, but it also true that it has been derived from very few data using older methodologies by a WHO expert committee.[12]Its primary aim was to screen for malnutrition and it is therefore perhaps inappropriately applied to the general population of developed countries, and especially so for a population of patients affected by a chronic disease. Given that the majority of the European population is of Caucasian ethnicity, it should also be taken into account that Caucasian men have an Hb set point that is 1–2 g/dL higher than African Americans.[13]Similar differences have been described between Caucasian, African American and Asian women. According to the Scripp-Kaiser database, the lower limit of normality of Hb values should be of 13.7 g/dL for Caucasian men aged between 20 and 60 years and 13.2 g/dL for older men. For women of all ages the set point should be 12.2 g/dL.[14]Similarly, higher Hb values were found in the Caucasian population of NHANES III.In the opinion of the ERBP Working Group, the WHO definition of anaemia is useful for epidemiological purposes but it may be too blunt a tool and thus has the potential to miss a number of anaemia diagnoses in everyday clinical practice.Independently from these reference Hb values, a diagnosis of anaemia should be considered in the presence of a falling level of Hb in patients on whom baseline Hb levels are normal.Chapter 2: Use of Iron to Treat Anaemia in CKDKDIGO 2.1.2For adult CKD patients with anaemia not on iron or ESA therapy, we suggest a trial of IV iron (or in CKD ND patients alternatively a 1–3 month trial of oral iron therapy) if (2C):-an increase in Hb concentration without starting ESA treatment is desired-and TSATis ≤30% and ferritin is ≤500 ng/mL (≤500 μg/L)It is well known that iron therapy is an important step in the treatment of anaemia in CKD patients, as both absolute and functional iron deficiencies are common. In the TREAT study,[5]the patients in the control group maintained a relatively high mean Hb level during the follow-up despite the fact that they received minimal darbepoetin alfa doses [median 0, interquartile range (IQR) 0–5 μg/month] as a rescue therapy. This was partially influenced by the fact that many of these patients were not fully iron-replete [median transferrin saturation (TSAT) 23%, IQR 18–29%] and thus received a course of oral or IV iron. These results have certainly contributed to re-evaluate the role of iron therapy not only in patients who are iron deficient but also in those with apparently adequate iron stores (as defined by serum biomarkers).[15,16]Thus, we agree with this recommendation about the possibility first to perform a trial of IV iron (or oral iron therapy in the ND-CKD population when tolerated) in anaemic CKD patients if an increase in Hb levels is desired. This would also be helpful in reducing the need for blood transfusions.[17]In ND-CKD patients with mild to moderate anaemia, oral iron should be used as first-line therapy for a minimum of 3 months in the absence of known gastrointestinal intolerance to preserve the veins of the arm for possible future dialysis access (AV fistula). Conversely, IV iron is the first choice in this population in the presence of severe anaemia or when oral iron is ineffective.We also agree with the statement that 'For any individual patient the optimal balance of Hb level, ESA dose, and iron dose at which clinical benefit is maximized and potential risk is minimized is not known'.[7,18]Indeed, peripheral-iron blood indices of iron storage transport and handling have limited utility in identifying depletion of bone marrow iron stores.However, in our opinion, the proposed limits of serum ferritin and TSAT, which the new KDIGO guidelines suggest should help drive the decision on whether or not administer iron therapy in patients not receiving ESA, are too wide and are not adoptable for a number of reasons.First, no clear distinction is made between absolute and functional iron deficiency when giving the strength of the recommendation whether to start iron therapy. For patients with absolute iron deficiency (serum ferritin <100 ng/mL and TSAT <20%), the indication for iron therapy should be stronger since the likelihood of obtaining an increase in Hb level following iron therapy is much higher. Conversely, it is true that even in patients with adequate bone marrow iron stores, sometimes, it is possible to obtain an increase in Hb levels following iron therapy. However, this quantitative effect is lower in patients who are not iron deficient. Stancuet al.[15]showed that, following the administration of 1000 mg of IV iron to 100 patients with ND-CKD, an erythropoietic response was obtained in 63% of those who had iron-deplete bone marrow but only in 30% in those who were iron-replete. The chances of a positive response increased by 7% for each 1% decrease in TSAT.[15]In this European, mostly Caucasian population, the median serum ferritin and TSAT values were much lower (176 ng/mL and 23%, respectively) than the upper threshold up to which iron therapy could be prescribed according to KDIGO recommendations (i.e. serum ferritin ≤500 ng/mL and TSAT ≤30%). Of note, ferritin values in the Stancu's paper were much <500 ng/mL despite the fact that two-thirds of the patients were chronically inflamed (C-reactive protein level >10 mg/L).Spinowitzet al.[19]studied another cohort of 304 ND-CKD patients who were given two 510-mg doses of ferumoxytol IV or 200 mg of elemental oral iron daily for 21 days in a 3:1 ratio. Among patients who were not receiving ESAs (n= 188), Hb increased by 0.62 ± 1.02 g/dL with ferumoxytol and by 0.13 ± 0.93 g/dL with oral iron. In this population, mean baseline serum ferritin and TSAT were ~145 ng/mL and 10%, respectively.We agree with the KDIGO group that the available evidence on this topic is inadequate and scanty. However, we believe that before deciding whether or not to give a course of iron therapy, the physician should know that this evidence has been obtained only in the ND-CKD population and that in the available studies, mean/median ferritin levels were well below the now proposed upper limit of 500 ng/mL. These considerations clearly suggest the need to differentiate in this recommendation between non-dialysis and dialysis patients, and not lump these together in an overarching recommendation. Given the paucity of evidence, we have no information about safety when prescribing long-term iron therapy at higher ferritin levels than those previously recommended in the ND-CKD population.The safety of administering IV iron therapy to ESA-nave haemodialysis patients with high serum ferritin levels has not been established. For instance, increased circulating ferritin levels have been found associated with an impaired immune response of monocytes, possibly increasing infection risk.[20]We feel that it is likely that the magnitude of the obtained increase in Hb level after IV iron therapy would be rather small in haemodialysis patients; so, the start of ESA treatment would be probably more effective (also considering that evidence-based concerns related to ESA use in the dialysis population seem less concerning than in the ND-CKD population). Therefore, a course of IV iron therapy despite ferritin values >300 ng/mL should be considered in those haemodialysis patients in whom ESA therapy may be contraindicated or considered risky (see KDIGO section about ESA initiation). Conversely, in ESA-nave anaemic patients who have adequate iron stores, the concomitant start of ESA and iron therapy may be appropriate to prevent iron deficiency due to increased erythropoiesis stimulation.Moreover, it is clear that an operative interval is lacking. After reading this recommendation, the physician remains confused because the upper limit for prescribing iron therapy coincides with the proposed limit not to be exceeded in treatment. This implies the risk of reaching very high serum ferritin levels when IV iron therapy is started at the upper edge of the interval (especially with single high doses given for long periods).Finally, whether or not to treat CKD patients with Hb values >12 g/dL and absolute iron deficiency remains an open issue. At present, it seems wise to suggest that we do treat these patients (in the absence of clear risks of targeting towards higher Hb values) but as we do so being careful to avoid intentionally exceeding an Hb value of 13 g/dL. If these patients are receiving ESA treatment, this additional iron therapy should be at least temporarily halted (see following sections about ESA initiation and ESA maintenance therapy).KDIGO 2.1.3For adult CKD patients on ESA therapy who are not receiving iron supplementation, we suggest a trial of IV iron (or in CKD ND patients alternatively a 1–3 month trial of oral iron therapy) if (2C) an increase in Hb concentration or a decrease in ESA dose is desired and TSAT is ≤30%and ferritin is ≤500 ng/mL (≤500μg/L).In CKD patients receiving ESA therapy, iron stores may be nearly normal, but they may be insufficient for the increased erythropoiesis which typically follows bone marrow ESA stimulation. In this context, iron therapy reduces significantly ESA doses requirements. This is of particular importance given concern related to ESA use especially at high doses (even if this association is limited by the bias that patients receiving higher ESA doses are usually those with more comorbidities). The fact that iron deficiency (absolute or relative) is a major cause of ESA hyporesponsiveness in CKD patients[21,22]suggests that there is still room to augment iron therapy in many CKD patients. Unfortunately, TSAT and ferritin have limitations and low power to diagnose functional iron deficiency and predict response to IV iron. Other markers such as hypochromic red cells or reticulocyte Hb may add some information when available.[23]According to recent findings of 120 dialysis facilities of the Dialysis Outcomes and Practice Patterns Study (DOPPS) Practice Monitor in the USA,[24]following the change in the ESA label by the Food and Drug Administration (FDA) in June 2010, from August 2010 to August 2011, the percentage of dialysis patients receiving IV iron went from 57 to 71%. This went together with a significant decline in ESA dosing and a slight decrease in median Hb levels.However, a larger use of iron therapy caused a substantial increase in ferritin levels. Indeed, in these patients the median ferritin level increased from 556 to 650 ng/mL with 34% of the patients exceeding the value of 800 ng/mL. Conversely, the percentage of patients with TSAT ≥50% remained around 10%. Interestingly, every 100 mg of IV iron raised TSAT by 0.43% in those subjects having TSAT values <30% but only by 0.10% in those having higher TSAT levels; Hb values remained unchanged.[25]This may suggest that targeting to TSAT levels ≥30% with IV iron therapy does not improve erythropoiesis and exposes patients to the risk of iron overload.In Europe, dialysis patients have lower median ferritin levels than those in the USA. According to the data of the UK Renal Registry, in 2009 in haemodialysis patients, the median ferritin value was of 417 ng/mL (IQR 270–598).[26]This value was similar in 2010 [444 ng/mL (IQR 299–635)].[27]However, no major changes in guideline recommendations about anaemia management took place in Europe in this period (thus, it is too early to observe ferritin changes in the European population).The safety of persistently very high ferritin levels is still unknown. In 453 men with non-dialysis CKD, a trend towards higher mortality was observed in patients with a serum ferritin level >250 ng/mL.[28]However, the study was not adequately powered to properly analyse survival data. In dialysis patients, high serum ferritin has been associated with increased mortality as well. In a cohort of 58 058 prevalent haemodialysis patients in the USA, both all-cause and cardiovascular mortality had increasing rates across increasing ferritin levels, whereas the opposite (inverse) association was observed for TSAT increments. Serum ferritin levels between 200 and 1200 ng/mL and iron saturation ratio between 30 and 50% were associated with the lowest all-cause and cardiovascular death risks.[29]However, association studies are biased by the fact that serum ferritin is also a marker of inflammation.[30]Indeed, in unadjusted, time-varying model, serum ferritin >800 ng/mL during each quarter was associated with increased death rate.The Dialysis Patients' Response to IV Iron with Elevated Ferritin (DRIVE) trial,[31]found that IV iron was effective in increasing Hb levels and reducing ESA doses in patients with high ferritin (500–1200 ng/mL) and low transferrin saturation levels (TSAT ≤25%). However, the sample size was quite small and the overall follow-up (6 weeks + 6 weeks in the DRIVE II extension period[32]) was adequate for testing acute iron toxicity but too short to provide information about safety and iron overload in the long term.High-dose baseline iron therapy has been found to be associated with poor outcome in haemodialysis patients.[33]However, this likely reflects an indication bias, because no statistically significant association was detected between mortality and any level of iron dosing.[32]According to an autopsy study of 36 haemodialysis patients published 30 years ago when erythropoietin was still not available,[34]serum ferritin did not always correlate with bone-marrow iron stores but correlated well with the degree of hepato-splenic siderosis, probably because hepato-splenic stores failed to be mobilized to the bone marrow. This should be taken into account when administering IV iron, which by passes the intestinal mechanism for the regulation of iron absorption, especially in inflamed patients in whom inhibitory factors, such as hepcidin, decrease iron release from reticulo-endothelial and hepatocyte stores.[35]The regulatory role of hepcidin may thus change the relationship between ferritin levels, iron stores and Hb levels.[36]This is why a number of patients with high serum ferritin may have functional iron deficiency and have an increase in Hb levels following iron therapy. Compared with those days, this mechanism is likely to be amplified at any level of serum ferritin level. Indeed, the CKD population has substantially changed compared with the first haemodialysis patients, who were much younger and with fewer comorbidities compared with nowadays. After the introduction of ESA in clinical practice, following a much lower use of blood transfusion, clinically significant iron overload has become a rare event.[37]However, it has been hypothesized that iron administration may exacerbate oxidative stress and increase the risk of infection, cardiovascular events and death well before causing signs of iron overload.[38–40]At present, evidence coming from clinical trials testing IV iron molecules has not shown a significant increase in deaths, cardiovascular events or infections following IV iron use. However, these studies were not adequately sized to test mortality or hard end points. Long-term safety studies examining these practices are urgently required and long overdue.Some years ago, a study was published which featured direct, non-invasive measurements of non-haeme hepatic iron content by magnetic resonance in 40 dialysis patients treated with IV iron. This study showed that two-third of the patients had signs of mild to severe iron overload despite the fact that only one-third of the patients had serum ferritin exceeding 500 ng/mL.[41]According to the receiver operating characteristic analysis, the best specificity/sensitivity ratio to identify iron overload was obtained for ferritin >340 ng/mL.[39]Recently, significant iron overload in the liver and spleen (assessed throughT2magnetic resonance) has been described in 19 of 21 haemodialysis patients with serum ferritin >1000 ng/mL and severe comorbidities who were treated with IV iron.[42]Similarly, Rostokeret al.[43]prospectively studied a cohort of 119 fit haemodialysis patients who were receiving iron and ESA therapy and measured their liver iron content by means ofT1andT2magnetic resonance. Mild to severe hepatic iron overload was observed in 84% of the patients, 36% of whom had severe iron overload approaching that found in haemocromatosis. Liver iron content is significantly related to the cumulative iron dose received[42,44]and can rapidly decrease following iron therapy discontinuation.[42]Despite the fact that excess iron in the liver is potentially harmful, the clinical consequences of high iron content estimated by magnetic resonance is not known.As is the case for ESA-nave patients, the indication to iron therapy should be stronger for absolute iron deficiency that increases ESA dose requirements inappropriately and perhaps also the risk of cardiovascular events.[45]It is true that we have no clear evidence indicating an upper limit for ferritin level that can be considered either safe or dangerous. However, the fact that the current KDIGO guideline on this topic indicates the possibility of administering a trial of iron therapy even in patients who already have high serum ferritin levels (~500 ng/mL) will certainly cause a significant rise in ferritin levels in the CKD population, especially in the haemodialysis setting, shifting to the right the frequency distribution curve. This will occur regardless of the presence or absence of signs of chronic inflammation. In our opinion, also considering that increasing TSAT above 30% does not substantially modify Hb levels, in the absence of clear evidence, prudence should prevail to limit over treatment, at least in European countries with no particular restriction to ESA treatment.Following these considerations, we agree with the KDIGO recommendation 2.1.3 that in adult CKD patients treated with ESA a trial of iron therapy may be useful if an increase in Hb concentration or a decrease in ESA dose is desired. However, caution is needed in patients with already high ferritin levels, because the safety of treating these patients is still unknown. Conversely, we agree with the KDIGO group that this is an important topic that needs to be investigated by future research.Chapter 3: Use of ESAS and Other Agents to Treat Anaemia in CKDESA Initiation3.2: In initiating and maintaining ESA therapy, we recommend balancing the potential benefits of reducing blood transfusions and anaemia-related symptoms against the risks of harm in individual patients (e.g. stroke, vascular access loss, hypertension). (1B)3.3: We recommend using ESA therapy with great caution, if at all, in CKD patients with active malignancy—in particular when cure is the anticipated outcome—(1B), a history of stroke (1B), or a history of malignancy (2C).Following the secondary analyses of the TREAT study, we agree with the greater part of these two recommendations. In particular, even if in the TREAT study data about malignancies were obtained from a secondary analysis with a relatively few number of events,[5]these findings are consistent with concerns raised about the use of ESA on increased tumour growth and death in the setting of oncology in some types of cancer (especially when used off-label).[46]However, this is still a grey area since a clear relationship between the expression of the EPO receptor in neoplastic cells and cancer proliferation following ESA administration has not been clearly established.[47]Conversely, the risk of stroke following ESA treatment aimed at complete anaemia correction in CKD patients deserves further commentary. First, it is unclear whether CKD patients without diabetes have an increased risk of stroke following ESA treatment. In 2005 in a trial about complete anaemia correction with epoetin alfa in haemodialysis patients with asymptomatic heart disease Parfreyet al.[48]found a trend of towards an increase in cerebrovascular events in those randomized to the higher Hb group (n= 12, 4% andn= 4, 1%, respectively; P = 0.045). However, the number of events was rather small, and this imbalance was possibly due to statistical fluctuation. Moreover, differing from the TREAT study,[5]all these patients received ESA treatment. The increased risk was thus possibly related to different Hb targets (in the two treatment groups, achieved Hb levels were 13.1 and 10.8 g/dL, respectively). Second, according to a recent, secondary analysis of the TREAT study,[49]as reported by the KDIGO guidelines, 'the relative increase in risk of stroke related to darbepoetin alfa use was not statistically different in patients with and without a past history of stroke. This relationship may be possibly not significant because of an insufficient statistical power in a secondary analysis'. Indeed, the authors found a near double increase in the relative risk of stroke in those with a previous history than in the control group. However, the risk of stroke was independent of Hb level or darbepoetin treatment.[45]The fact that in the experimental group of the TREAT study, the darbepoetin dose was similar in patients with or without a stroke and Hb levels were lower in those developing a stroke (even if this was not statistically significant) and that no other factor had been significantly related to the risk of this event[45]suggest that ESA therapy and achieved Hb levels are not a major cause but that likely there are other unknown factors explaining the higher occurrence of stroke in patients receiving darbepoetin alfa in the TREAT trial. Indeed, while measured blood pressure values were similar in the two groups of the trial, it is possible that masked increases in blood pressure values during the day may have contributed to the increased risk of stroke. This was also in light of the fact that it is well known that ESA use aiming at higher Hb values usually worsens blood pressure control and/or increases the need of antihypertensive drugs.In the overall TREAT population, at multivariate analysis a lower body mass index was an independent predictor of stroke [P = 0.044; 95% confidence interval (95% CI) 1.00–1.05].[45]This may reinforce the hypothesis that a chronic inflammatory state may increase cardiovascular risk in the CKD population receiving ESA (often at high doses because of hyporesponsiveness). This concept is further reinforced by the fact that lower Hb values were another independent risk of stroke at multivariate analysis.Following these considerations, we believe that the degree of evidence of the history of stroke given by the KDIGO recommendation (1B) is overrated considering the available evidence.CKD-ND Patients3.4.1: For adult CKD ND patients with Hb concentration ≥10.0 g/dL (≥100 g/L), we suggest that ESA therapy not be initiated. (2D)3.4.2: For adult CKD ND patients with Hb concentration <10.0 g/dL (<100 g/L), we suggest that the decision whether to initiate ESA therapy be individualized based on the rate of fall of Hb concentration, prior response to iron therapy, the risk of needing a transfusion, the risks related to ESA therapy and the presence of symptoms attributable to anaemia. (2C)The ERBP group on anaemia already produced a position statement following the publication of the TREAT study.[5]As already underlined, this paper provided high-quality scientific evidence about ESA use in the CKD population with diabetes. However, the interpretation of the TREAT findings is complex, and there are a number of grey areas that still need more satisfactory answers. In particular, the decision of the KDIGO group in not giving a lower Hb threshold at which ESA treatment should be started in general is questionable for a number of reasons. First, the fact that in the control group the mean achieved Hb levels were well above the reference value of 9 g/dL (median Hb of 10.6 g/dL; IQR 9.9–11.3 g/dL) implies that the TREAT study cannot be considered good evidence to support the conclusion that CKD patients not on dialysis can be maintained long term at very low Hb levels safely without starting ESA therapy. Indeed, according to a meta-analysis, cohorts of CKD patients with severe anaemia (Hb <10 g/dL) had a left ventricular mass index (LVMI) ≥125 g/m2in a much larger percentage than those with moderate anaemia (mean baseline Hb ≥10 g/dL <12 g/dL) (89 and 43%, respectively).[50]Following partial anaemia correction, only those having severe anaemia at baseline experienced a significant reduction in LVMI. In addition to this, even if we were to consider the TREAT study as the starting point for giving the recommendation, the study protocol foresaw rescue therapy with darbepoetin alfa when Hb values fell below 9 g/dL. Despite this rescue option, achieved Hb values progressively increased during the follow-up (from a median value of 10.4 g/dL at baseline to 11.2 g/dL at the end of the study). This positive trend is against the common observation that CKD patients show a decrease in Hb values during the course of their disease (although the trial effect in improving patient care is well known). The fact that 46% of the control group received at least a dose of darbepoetin alfa but the median dose was of 0 μg suggests that many of these patients were not affected by severe chronic anaemia but that they occasionally reached an Hb value <9 g/dL because of intercurrent events (i.e. infections, bleeding, surgical procedures, inflammation etc.). After only a few doses of darbepoetin alfa and following iron therapy and/or resolution or improvement of the medical condition, they did not need chronic therapy with ESA to maintain their Hb values in a satisfactory target range. Thus, this cannot be considered good evidence that CKD patients should be maintained at low Hb levels without starting ESA therapy in the long term.Recently, a secondary analysis of the control group of the TREAT study showed that those patients who received five or more doses of darbepoetin alfa were more likely to receive IV iron therapy and blood transfusions and to progress to renal replacement treatment (but were not at higher risk of death) than those not receiving rescue darbepoetin alfa doses.[51]The strongest predictors of requiring darbepoetin alfa (≥5 doses) were lower baseline Hb level, lower estimated GFR and higher proteinuria level. This may be a further confirmation that the more advanced the CKD stage, the more likely is it that the patient needs intervention for anaemia. If an ESA is not prescribed, the likelihood of blood transfusion increases.In the experimental group of the TREAT study, the mean dose of darbepoetin alfa (~175 μg/month) was higher than that found in general in Europe in the same patient population;[5,52]it is also well known that in haemodialysis patients, ESA requirements are much lower in Europe than in the USA. This may suggest that KDIGO recommendations driven by the TREAT data may not necessarily be applicable to the European CKD population. The fact that the drug was administered once a month in the majority of the patients and some of them were not fully iron-replete may have contributed to these high-dose requirements. In this regard, a pre-specified subgroup analysis of the TREAT study comparing the different participating regions showed that in Western Europe and Australia there was a trend towards a reduced hazard ratio (HR) of reaching the primary composite end-point favouring the experimental group (36 events of 172 patients in the darbepoetin group, 57 events of 198 patients in the control group; HR 0.66, 95% CI 0.43–1.01). Conversely, in Eastern Europe the HR between the two groups was neutral (1.04, 95% CI 0.79–1.37).[5]Nevertheless, the risk of statistical fluctuations in this kind of secondary analysis is very high.Recently, Akizawaet al.[53]performed a small, controlled, randomized, clinical trial of 321 ND-CKD patients and tested the effect of correcting anaemia with ESA to intermediated Hb levels (11–13 g/dL) compared with Hb levels 9 to <11 g/dL. During the 48 week follow-up, they found a similar rate of cardiovascular events in the two groups (n= 42 in the higher-Hb group compared withn= 51 in the lower-Hb one). However, correcting anaemia towards intermediate Hb levels led to significant improvement in all quality of life and vitality scores compared with a lower Hb target. While LVMI remained stable in the lower Hb group, it significantly decreased in the higher Hb group (P < 0.001). Three-year cumulative renal survival rate was better in the higher than in the lower Hb group (39.9 versus 32.4%, respectively; log-rank test P = 0.111, HR 0.71, 95% CI 0.52–0.98).[54]Finally, it should also be considered that patients with symptomatic ischaemic heart disease might benefit from higher Hb levels, as demonstrated by a lower rate of revascularization procedures of coronary arteries in the group randomized to higher Hb values and darbepoetin therapy in the TREAT study.[5]Following these considerations, we agree with the KDIGO group that the decision of whether and when to start ESA therapy in CKD-ND patients should be individualized. However, we believe that Hb values should not let be allowed to routinely fall below 10 g/dL, at least if there is no obvious temporary reason for Hb fall and/or if the causing factor causes resistance to ESA. Repletion of iron stores should be ensured before and during ESA therapy.
Siltuximab (Sylvant, Janssen) is the first-ever drug to be approved by the US Food and Drug Administration (FDA) for the treatment of multicentric Castleman's disease (MCD), a rare blood disorder similar to lymphoma.The drug underwent FDA priority review, which provides an expedited review for drugs that demonstrate the potential to be a significant improvement in safety or effectiveness in the treatment of a serious condition.MCD is estimated to affect about 1100 to 1300 Americans.Siltuximab has been granted Orphan Drug Designation in both the United States and the European Union. It was recentlyrecommended for approvalin the European Union."There has been a serious need for treatment options for patients with MCD," said Frits vanRhee, MD, PhD, from the University of Arkansas for Medical Sciences in Little Rock, who headed the clinical trial that led to the drug's approval."MCD is a complex disease and up until this point, physicians have tried to reduce lymph node masses and put the disease in remission through a combination of treatments, but MCD often returns," Dr. vanRhee said in a statement. "Siltuximab gives physicians a long-awaited treatment option for a group of patients who has been suffering with this chronic, serious, and debilitating disease."Abnormal Overgrowth of LymphocytesMCD results from an abnormal overgrowth of lymphocytes, leading to enlarged lymph nodes, but it can also affect lymphoid tissue of internal organs, causing the liver, spleen, or other organs to enlarge. Symptoms include fever, night sweats, weight loss, and weakness or fatigue, and because of the weakening of the immune system, patients become susceptible to infection. In fact, infection is a common cause of death in patients with MCD, as are multisystem organ failure and malignancies, including malignant lymphoma.What causes the disease is not known, but it is associated with an overproduction of interleukin (IL)-6, and siltuximab acts as an IL-6 antagonist. It is administered by intravenous infusion once every 3 weeks.The clinical trial that resulted in approval, known as MCD2001, was conducted in 79 patients with symptomatic MCD who were negative for HIV and human herpes virus8. All participants received best supportive care, and they were randomized to also receive either siltuximab or placebo.Results from this study showed that 34% of patients receiving siltuximab had a durable tumor and symptomatic response, compared with none on placebo (P= .0012). A durable response was defined as tumor and symptomatic response (reduction in tumor size and disease symptoms) that persisted for a minimum of 18 weeks without treatment failure.The median time to treatment failure for patients who received placebo was 134 days, but was not reached for patients on the drug (P< .05). Among anemic patients, an increase in hemoglobin of 1.5g/dL was seen in 61% of patients in the siltuximab group versus none on placebo (P< .05).These results "highlight the potential for siltuximab to be a new and valuable treatment option for MCD patients who, unfortunately, had no previously available treatment options," commented RaymondS. Wong, MBChB, MD, from the Prince of Wales Hospital and the Chinese University of Hong Kong, after hepresented the studyat the American Society of Hematology meeting in December 2013.The most frequent adverse reactions (greater than 10% compared with placebo) during treatment with siltuximab in this trial were rash (28%), pruritus (28%), upper respiratory tract infection (26%), increased weight (19%), and hyperuricemia (11%). Warnings and precautions on the product label include concurrent active severe infections, administration of live vaccines, infusion-related reactions and hypersensitivity, and gastrointestinal perforation.