The Doctor's Channel - Hematology-Oncology

Interruptions in anti-HIV therapy carry high risk of thrombocytopenia

2010-01-11T15:21:51+00:00

NEW YORK (Reuters Health) - In HIV-infected patients, risk factors for thrombocytopenia include interruptions in antiretroviral therapy, high HIV RNA levels, hepatitis C virus (HCV) infection, and cirrhosis, according to two papers in the Journal of Acquired Immune Deficiency Syndromes for December 15.

In the first paper, Dr. Marie-Anne Bouldouyre, from Hopital Saint Louis, Paris, and colleagues report that one in four patients who interrupted their highly active antiretroviral therapy (HAART) developed thrombocytopenia (<150,000 platelets/microliter) over the 96-week study period.

In the second study, Dr. Kristen M. Marks and colleagues at Weill Cornell Medical College, New York, and associates showed that the odds of thrombocytopenia (here defined as <100,000 platelets/microliter for >3 months) were increased by 5.3-fold with an HIV RNA level >400 copies/mL, by 6.1-fold with HCV infection, and by 24.0-fold with cirrhosis.

A number of studies have examined antiretroviral treatment interruptions as a way of making therapy more manageable, Dr. Bouldouyre and colleagues note. Even though the results indicate that such an approach yields "unacceptable" increases in morbidity and mortality, some patients still stop their medications for periods of time.

To examine the impact of interrupted antiretroviral therapy on platelet counts, the authors analyzed data from 391 "well-suppressed" patients who had been randomized to receive HAART either intermittently (8 weeks off, 8 weeks on) or continuously for 96 weeks as part of an earlier trial.

At 96 weeks, the thrombocytopenia rate was much higher in the intermittent therapy group than in the continuous treatment group: 25.4% vs. 9.8% (p < 0.001). Moreover, the median time to thrombocytopenia in the former group was just 9 weeks compared with 40 weeks in the latter.

On multivariate analysis, intermittent therapy upped the odds of thrombocytopenia by 4.1-fold (p < 0.0001). Other risk factors included a history of thrombocytopenia (OR, 11.9) and a low baseline platelet count (OR, 3.4). Moreover, the authors found that as platelet counts fell, so did CD4+ cell counts, while HIV RNA levels rose.

In the paper from the New York-based group, the authors note that thrombocytopenia was a common finding in HIV patients during the 1980s and early 1990s, but little has been reported since the introduction of potent antiretroviral therapy in the mid 1990s.

Their case-control study included 146 HIV-infected patients with and without thrombocytopenia who were seen at two HIV clinics at New York Presbyterian Hospital-Weill Cornell Center in the last few years. Cases and controls were matched by age, gender, and first clinic visit.

Fifty-eight percent of case patients had platelet counts of 50,000/microliter or lower and 38% had levels of 30,000/microliter or lower. As noted, uncontrolled HIV replication, HCV infection, and cirrhosis were all risk factors for thrombocytopenia.

Major bleeding events (gastrointestinal, intracranial, or requiring hospitalization) were 6.5-times more common in case patients than in controls (p = 0.014).

Reference:
J Acquir Immune Defic Syndr 2009;52:531-537,595-599.

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Elevated INR in liver disease not protective against clots

2010-01-08T16:05:13+00:00

NEW YORK (Reuters Health) - Although patients with liver disease often have an increased international normalized ratio (INR), their coagulopathy does not protect against venous thromboembolism (VTE), new research suggests.

The findings stem from a study of 190 hospitalized patients with chronic liver disease. Twelve patients developed VTE, resulting in a rate of 6.3%. Most importantly, the rate did not vary significantly by INR quartile.

"An elevated INR in the setting of chronic liver disease does not appear to protect against the development of hospital-acquired VTE," conclude Dr. Ousama Dabbagh and colleagues from the University of Missouri, Columbia. "The notion that 'auto-anticoagulation' protects against venous thromboembolism is unfounded."

In the study, which was reported in the December 29th online issue of Chest, patients were divided into quartiles based on admission INR cutoffs of 1.4, 1.7, and 2.2. In all four groups, the most common cause of liver disease was alcohol, followed by hepatitis B or C. Roughly 25% of patients received either mechanical or drug prophylaxis of thrombosis; the rate was comparable in each INR group.

Not surprisingly, in the overall cohort, patients with higher INRs were generally sicker. Of the 12 patients with VTE, 1 was Child-Pugh stage A, 3 were B, and 8 were C.

While hospital length of stay was similar among INR groups, hospital mortality rates rose with higher INRs (32% in highest INR group vs. 4% in lowest INR group, p < 0.001).

"In this study, half of cases of VTE occurred in patients with INR greater than 1.6, and there was still a risk of VTE with INR greater than 2.2," the authors warn.

They conclude, "Our study shows that elevated INR in chronic liver disease should not give clinicians a sense of security."

Reference:
Chest 2009.

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Leukemia relapse risk drops with 2-unit umbilical cord blood transfusion

2009-11-24T13:58:00+00:00

NEW YORK (Reuters Health) – Transfusion of two rather than one unit of partially HLA-matched umbilical cord blood (UCB) appears to reduce the risk of relapse in leukemia patients in first or second complete remission, new research shows.

“Our analysis showed that patients in first or second remission from the leukemia had a significantly lower likelihood of leukemia recurrence if they were transplanted with two UCB units than if they were transplanted with one (19% vs. 34%),” lead author Dr. Michael Verneris, from the University of Minnesota Medical School, Minneapolis, said in a statement.

The findings, reported in the November 5th issue of Blood, stem from a study of 88 patients with acute lymphoblastic leukemia (ALL) and 89 with acute myeloid leukemia (AML) who were treated at a single center.

Fifty-three percent of the subjects received two units of UCB and 47% received one unit. Cyclophosphamide and total body irradiation with or without fludarabine were used for conditioning.

The median time to relapse was 209 days, and the relapse rate was 26% at 5 years, the report indicates. The relapse rates for patients with ALL and AML were comparable, hovering around 26%.

Patients with advanced disease (three or more complete remissions in the past) were 3.6-times more likely to experience a relapse than were those with less advanced disease (one or two complete remissions). Use of 2 units of UCB rather than 1 unit reduced the risk of relapse in patients with advanced disease by 40%, but this was not statistically significant.

In subjects with less advanced disease, use of 2 UCB units rather than 1 cut the risk of relapse by 50% (p < 0.03).

No significant difference in leukemia-free survival at 5 years was noted between subjects given 1 UCB unit and those given 2 units: 40% vs. 51%.

“We believe our finding provides evidence that using two units of UCB for transplantation may be more effective in preventing leukemia relapse and gives hope to patients with hematological malignancies so that they may live cancer-free,” Dr. Verneris concluded.

Reference:
Blood 2009;114:4293-4299.

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Erythropoiesis-stimulating agents: concern over patterns of use and risks

2009-11-16T13:28:30+00:00

NEW YORK (Reuters Health) - Use of erythropoiesis-stimulating agents in US cancer patients undergoing chemotherapy has increased 10-fold since their introduction, yet there's been no associated decline in the rate of blood transfusions, according to a study published today.

"It is also clear that when erythropoiesis-stimulating agents are given to cancer patients undergoing chemotherapy outside of the controlled setting of a clinical trial, there is (about) a twofold increased risk of venous thromboembolism," Dr. Dawn L. Hershman, of Columbia University Medical Center, New York City, noted in an email to Reuters Health.

"There was concern from the beginning that thromboembolism may be a complication associated with these drugs," she noted.

Using the Surveillance, Epidemiology and End-Results-Medicare database, Dr. Hershman and colleagues identified 56,210 patients aged 65 and older who received chemotherapy between 1991 and 2002. Of these, 15,346 (27%) received an erythropoiesis-stimulating agent.

According to a report in the November 10th online issue of the Journal of the National Cancer Institute, the proportion of patients treated with erythropoietin or darbepoetin increased from 4.8% in 1991 to 45.9% in 2002 (p < 0.001).

Despite this increase, the annual rate of blood transfusions was a constant 22% during the same time period, the report states. "Many of the patients in the study received both erythropoiesis-stimulating agents and blood transfusions over the course of their treatment," Dr. Hershman told Reuters Health.

In addition, the records showed that venous thromboembolism developed in 14.3% of patients who received an erythropoiesis-stimulating agent compared to 9.8% of those who did not (hazard ratio, 1.93). Overall survival was no different in those who did and did not receive these drugs.

Erythropoiesis-stimulating agents, the authors note in their report, are of particular interest from a public policy standpoint because they're so costly. "The total US sales of erythropoiesis-stimulating agents increased from $6.4 billion in 2002 to $10 billion in 2006, accounting for a greater Medicare Part B expenditure than any other drug," they said.

"We speculate that this use was fueled by aggressive marketing to patients and physicians that focused on a promise of increased energy during chemotherapy treatment," the researchers write.

This study, Dr. Hershman said, "stresses the need to continue to monitor new drugs for long-term safety. It is also important to make sure the benefits outweigh the risks."

Reference:
J Natl Cancer Inst 2009.

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Low-dose dexamethasone superior to high-dose for myeloma; trial stopped early

2009-10-27T10:15:32+00:00

NEW YORK (Reuters Health) - In patients with newly diagnosed multiple myeloma, combining the thalidomide analog lenalidomide with low-dose dexamethasone led to better short-term survival than lenalidomide plus high-dose dexamethasone, along with fewer serious side effects.

In fact, the randomized trial was stopped early, at a median follow-up of 12.5 months, because overall survival was significantly higher with low-dose than with high-dose dexamethasone (96% vs 87%, p = 0.0002).

As Dr. S. Vincent Rajkumar, from the Mayo Clinic in Rochester, Minnesota, and associates report in an online publication October 22 in The Lancet Oncology, all of the 445 patients with untreated, symptomatic myeloma took lenalidomide, 25 mg daily, on days 1-21 of a 28-day cycle. The high-dose dexamethasone group took 40 mg by mouth on days 1-4, 9-12, and 17-20 of the 28-day cycle. The low-dose group took 40 mg on days 1, 8, 15, and 22.

After 4 cycles, patients could discontinue therapy to undergo stem cell transplantation or continue until disease progression. The median duration of therapy was 4 months in the high-dose group and 6 months in the low-dose group.

After 4 cycles, the overall response rate was higher with the high-dose regimen (79% vs 68.3%, p = 0.008).

During the first 4 months, the high-dose group had significantly more grade 3 or higher adverse effects (52% vs 35%, p = 0.0001) and early mortality (5% vs 0.4%, p = 0.003).

At 12.5 months, when the study was stopped, patients in the high-dose group were crossed over to low-dose. Two-year overall survival rates were 87% and 75% in the high-dose and low-dose groups, respectively.

The investigators note that "almost all current phase 3 trials" are now using low-dose dexamethasone for combination regimens.

They point out, however, that "high-dose dexamethasone might still have a role in the treatment of patients with acute renal failure caused by myeloma cast nephropathy, cord compression from myeloma, or aggressive refractory disease."

Reference:
Lancet Oncol 2009.

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Suicidal ideation seen in adult survivors of childhood cancer

2009-10-23T14:35:29+01:00

NEW YORK (Reuters Health) - Adult survivors of childhood cancer, particularly those in poor physical health, are at increased risk for suicidal thoughts, according to an October 19 online report in the Journal of Clinical Oncology.

This study is "one more reminder that there are long term consequences of the treatment of childhood cancer," Dr. Christopher J. Recklitis from the Dana-Farber Cancer Institute, Boston, said in a phone call to Reuters Health.

"Fortunately, most childhood cancer survivors do well in terms of their adjustment but there is a small proportion that are more likely to have some psychological adjustment problems," he added.

Dr. Recklitis and colleagues analyzed physical and psychological function in 9126 adult survivors of childhood cancer and 2968 cancer-free siblings. The cancer survivors were younger than age 21 at diagnosis and were greater than 5 years from diagnosis. Most of the cancer survivors were more than 11 years from diagnosis.

Leukemia was the most common diagnosis (n = 2681), followed by Hodgkin's disease (n = 1645), CNS cancer (n = 1136), bone cancer (n = 997), sarcoma (n = 881), non-Hodgkin's lymphoma (n = 842), Wilms tumor (n = 584) and neuroblastoma (n = 360).

According to the authors, a significantly greater number of cancer survivors than siblings reported suicide ideation (7.8% vs 4.5%; OR, 1.79). Survivors of CNS cancers had the highest prevalence of suicidal thoughts (10.6%) and were significantly more likely to report suicidal thoughts than the leukemia survivors (OR, 1.5).

Suicide ideation was not associated with age at diagnosis, time since diagnosis, type of cancer therapy, recurrence or second malignancy.

There was, however, "a strong relationship with indicators of poor physical health," Dr. Recklitis noted, with 28.8% of cancer survivors who rated their physical health as poor having suicidal thoughts compared to only 3.3% of survivors who rated their health as excellent.

Poor current physical health remained significantly associated with suicide ideation "even after adjusting for cancer diagnosis and depression," the authors note in their report.

"A greater number of chronic conditions and pain were also closely tied to suicidal thoughts," Dr. Recklitis said.

"The association of suicidal symptoms with physical health problems is important," the researchers say, "because these may be treatable conditions for which survivors seek follow-up care and underscores the need for a multidisciplinary approach to survivor care."

"Physicians treating childhood cancer survivors who have a lot of medical late-effects should probably be asking about psychological late-effects as well," Dr. Recklitis said.

Reference:
J Clin Oncol 2009.

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Dexamethasone-based protocol improves ALL survival without cranial radiation

2009-09-14T15:06:33+01:00

NEW YORK (Reuters Health) – A dexamethasone-based protocol can cut the risk of relapse and improve survival in high-risk children with acute lymphoblastic leukemia (ALL), with fewer side effects, new research shows.

The regimen, designated the Dutch Childhood Oncology Group (DCOG) ALL-9 protocol, achieved 5-year event-free survival rates of 84% for non-high risk patients and 72% for high-risk patients, according to a report in the September 10th online issue of The Lancet Oncology.

High-risk patients were those with white blood cell counts of 50,000/microliter or more, T-cell phenotype, mediastinal mass, CNS or testicular involvement, and Philadelphia chromosome or MLL rearrangement.

By comparison, the ALL-6 protocol against which ALL-9 was tested achieved a similar 5-year event free survival of 83% in its non-high-risk group in the late 1980s, but this rate was only 53% among high-risk patients. Lead author Dr. Anjo J. Veerman from VU University Medical Center, Amsterdam, The Netherlands, and colleagues explain that while ALL-9 is identical to ALL-6 for non-high risk patients, changes were made for high-risk patients, in the hopes of improving outcomes.

They emphasize that the improvement in the high-risk group was achieved without cranial irradiation and without the use of such toxic drugs as anthracyclines, cyclophosphamide, or epipodophyllotoxins.

The ALL-9 trial involved 859 children, ages 1 to 18 years, with de novo disease who were recruited between January 1997 and November 2004. Median follow up was 72.2 months.

In the non-high risk group, 601 children received induction with dexamethasone, vincristine, and L-asparaginase for 6 weeks, then medium-dose methotrexate for 3 weeks, and then maintenance therapy. The 258 high-risk patients received the same three drugs plus daunorubicin for induction for 6 weeks, then high-dose methotrexate for 8 weeks, and two intensification courses before maintenance therapy.

Triple intrathecal medication was given 13, 15, and 17 times in non-high risk, high risk, and central nervous system-affected patients, respectively.

In all patients, maintenance therapy – consisting of mercaptopurine and methotrexate alternating with dexamethasone and vincristine -- was continued until 109 weeks.

The complete remission rates in the non-high risk and high risk groups were 98.5% and 96.9%, respectively. Five deaths in the non-high risk group and four in the high risk group occurred during induction therapy. Isolated central nervous system relapses were noted in 2.6% of patients.

On multivariate analysis, the strongest predictor of outcomes was the DNA index, followed by age, and then the white blood cell count, the authors note.

“The most radical feature of (the ALL-9) protocol is the omission of prophylactic cranial irradiation in all patients,” Dr. Ching-Hon Pui, from St Jude Children’s Research Hospital in Memphis, Tennessee writes in a related editorial. “Not surprisingly, (the researchers) have reported only a few cases of osteonecrosis and only two cases of second malignancy.”

“The vast majority of their patients are expected to survive with an excellent quality of life,” Dr. Pui added.

Reference:
Lancet Oncology 2009.

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Key role for bisphosphonates in reducing myeloma bone damage

2009-08-25T15:56:01+01:00

NEW YORK (Reuters Health) – Because of their ability to prevent, reduce, and delay skeletal complications with multiple myeloma, bisphosphonates are an essential component of treatment for this malignancy, an expert panel for the European Myeloma Network states.

This conclusion is based on a review of data from randomized clinical trials, clinical practice guidelines, and other literature. Seven major placebo-controlled trials and two major pamidronate-controlled trials were included in the analysis. The findings are reported in the August issue of the Annals of Oncology.

“The purpose of this paper is to review the current evidence for the use of bisphosphonates in multiple myeloma and provide European Union-specific recommendations to support the clinical practice of treating myeloma bone disease,” lead author Dr. E. Terpos, from Alexandra University Hospital, Athens, Greece, and colleagues explain.

The strongest (grade A) recommendations include: --Bisphosphonates should be given to patients with osteolytic bone lesions or pathological fractures. --When oral bisphosphonates are used, precautions should be taken to prevent diarrhea, nausea, and other gastrointestinal complications.

Other recommendations include: --Bisphosphonates should be given to patients requiring chemotherapy with no evidence of bone lesions on plain radiographs (grade B). --Transient acute phase reactions are no reason for discontinuing bisphosphonate therapy and can be treated with therapeutic analgesics (grade B). --Calcium and vitamin D3 treatment should be considered to prevent electrolyte imbalance (grade B). --Bisphosphonates should be given to patients with osteopenia (grade C). --Bisphosphonates should not be used as treatment for monoclonal gammopathy of undetermined significance or asymptomatic multiple myeloma (grade C).

The report also discusses osteonecrosis of the jaw, an uncommon but serious complication of intravenous bisphosphonate therapy that occurs most often after dental surgery. The authors note, “Recent retrospective data indicate that a modified dosing regimen and preventive measures can greatly reduce the incidence of osteonecrosis of the jaw.”

Reference:
Ann Oncol 2009;20:1303-1317.

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Erythropoietin appears safe for heart failure patients

2009-08-17T15:47:23+01:00

NEW YORK (Reuters Health) – A meta-analysis of trial data suggests that erythropoietin can be safely used to treat anemia in patients with chronic heart failure and may help prevent hospitalization.

Studies of erythropoietin use in patients with kidney disease and cancer raised concerns that this therapy may not be safe in patients with chronic heart failure. In particular, erythropoietin use in patients with kidney disease has been linked to cardiovascular events, while in cancer patients, an increased risk of mortality and thromboembolism was seen.

To assess the effects of erythropoiesis-stimulating proteins (ESPs) in patients with chronic heart failure, Dr. P. van der Meer and colleagues conducted a meta-analysis of data from seven trials comparing ESP use with placebo or usual care. Of the 650 patients in the analysis, 363 received ESPs and 287 were given placebo.

Dr. van der Meer, from University Medical Centre Groningen, the Netherlands, and co-authors report their findings in the August 15th issue of Heart.

No significant differences were noted between ESP-treated patients and controls in terms of mortality or rates of hypertension and venous thrombosis, the report indicates.

Moreover, the results show that ESP-treated patients were 41% less likely to require hospitalization than were controls: 10.2% vs. 19.5% (p = 0.006).

“These outcomes,” the authors conclude, “are in contrast with studies in cancer and kidney disease, and support a large phase III morbidity and mortality trial of anemia correction in patients with chronic heart failure.”

Reference:
Heart 2009;95:1309-1314.

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Sinus disease does not cause headaches

2009-08-17T15:21:11+01:00

Michael Benninger, MD, Chairman, Head and Neck Institute, Cleveland Clinic, discusses myths surrounding sinus disease. Headaches are not caused by sinus infection, and postnasal drip is often mistaken for sinus infection when it is more often a result of GOR or nasal allergy.

Summary:
1. Sinus infections do not cause classic headaches. Migraines can, however, cause nasal congestion and rhinorrhea as part of a trigeminal nerve response.
2. Mucus in the throat is not caused by sinus disease. Gastroesophageal reflux and nasal allergies should be excluded in patients who complain of postnasal drip.

References and Resources
Gaude GS. Pulmonary manifestations of gastroesophageal reflux disease. Ann Thorac Med. 2009 Jul;4(3):115-23.
Nguyen HT, Sharma V, McIntyre RS. Teratogenesis associated with antibipolar agents. Adv Ther. 2009 Mar;26(3):281-94. Epub 2009 Mar 28.

Related videos on The Doctor’s Channel:
MRSA sinusitis on the rise
Laryngopharyngeal reflux

Dr. Benninger has disclosed the following:
Consulting Fees: GSK, Alcon, Sanofi-Aventis, Schein
Contracted Research: GSK

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