Highlights from the 50th Annual Meeting of the American Society of Hematology.
The American Society of Hematology held its 50th Annual Meeting in San Francisco in December, hosting more than 21,000 hematologists, clinicians, and scientists from around the world. This grand forum presented a superb educational program, cutting-edge scientific sessions, and peer-reviewed oral and poster presentations about the latest and most exciting developments in scientific research. The following represents just a few of the meeting’s highlights. For more, visit http://abstracts.hematologylibrary.org/content/vol112/issue11.
Romidepsin Shows Encouraging Activity in Heavily Pretreated Refractory Cutaneous T-cell Lymphoma
The novel histone deacetylase inhibitor (HDAC) romidepsin showed encouraging activity in treatment-refractory cutaneous T-cell lymphoma in an international, multicenter, open-label, Phase IIb registration trial, according to Youn Kim, MD, Stanford Comprehensive Cancer Center, Stanford, CA. The noteworthy activity of romidepsin, as well as the favorable safety profile for the drug, suggest that it will be further evaluated as a potential treatment for advanced, refractory cutaneous T-cell lymphoma. Vorinostat was the first HDAC inhibitor to be approved for cutaneous T-cell lymphoma. Romidepsin, a potent pan-HDAC inhibitor, is active against multiple HDAC isoforms. The drug has exhibited activity in both cutaneous T-cell lymphoma and peripheral T-cell lymphoma.
In 72 evaluable patients, overall disease control rate was 78% (overall response rate [ORR] 42%, complete response [CR] 8%, partial response [PR] 33%, stable disease [SD] 36%). An intent-to-treat (ITT) analysis of 96 patients who entered the study (regardless of whether they received treatment) showed an overall disease control rate of 63% (ORR 34%, CR 6%, PR 28%, SD 29%). Romidepsin achieved responses in advanced stage cutaneous T-cell lymphoma; ORR was 48% in patients with stage > IIB disease, and four of eight patients with Sezary syndrome achieved PR. Duration of response was noteworthy in these heavily pre-treated patients who received a median of three prior systemic therapies, according to Kim. The median time to disease progression was 8.3 months in the ITT analysis and 17.7 months in 72 evaluable patients.
Pruritus, as assessed by a decrease in visual analogue scale (VAS) of at least 30mm, was evaluated as a secondary outcome in this trial. The majority of patients experienced relief of moderate or severe pruritus, despite not being given concomitant steroids or antihistamines. Romidepsin improved pruritus in 33 of 52 patients (63%) with moderate to severe pruritus at baseline: 17 patients who achieved CR or PR and 16 patients who did not achieve overall response. Thus, although a proportion of patients don’t achieve CR or PR on romidepsin, they may achieve symptomatic relief of pruritus.
Romidepsin was well tolerated by this difficult-to-treat population. Grade 3 or 4 adverse events occurred as single occurrences in 15% of patients. The most common grade 3 or 4 events included fatigue (6%), nausea (2%), diarrhea (1%), and vomiting (1%). The most frequently reported treatment-related events of all grades were nausea (56%), fatigue (30%), vomiting (26%), anorexia (20%), diarrhea (14%), headache (14%), loss of taste (13%), persistent abnormal taste (11%), and thrombocytopenia (10%). The study allayed concern about cardiac toxicity with an HDAC inhibitor, since minimal or no effect on the QTc interval was observed.
FCR New Standard of Care for Untreated and Treatment-refractory CLL
Rituximab added to fludarabine and cyclophosphamide (FCR) represents a new standard of care for previously untreated patients with chronic lymphocytic leukemia (CLL), as well as those with relapsed/refractory CLL, according to two large randomized controlled clinical trials comparing FCR to standard chemotherapy with FC.
The first study (CLL 8) evaluated 817 previously untreated patients with advanced CLL. About three-quarters were male, about two-thirds were Binet Stage B, and median age was 61 years. First-line treatment with FCR was superior to FC for response rate and progression-free survival. Patients in the FCR arm had a 44.5% complete response (CR) rate compared with 22.9% in the FC arm (P=.01). The partial response (PR) rate was lower in the FCR arm (3.3% versus 8.8% for FC), which was attributed to the higher CR rate with FCR.
“A higher CR translates to longer time to progression,” explained Michael Hallek, MD, of the University of Cologne in Cologne, Germany, who led this trial on behalf of the German CLL Study Group.
At a median observation time of 25.5 months, median progression-free survival was 42.8 months for FCR versus 32.3 months for FC, a highly statistically significant difference favoring the addition of rituximab (P=.000007).
FCR was deemed safe. Although a higher rate of neutropenia occurred in the rituximab-containing arm, no increase in the number of infections or other serious side effects were seen in the FCR arm. FCR was well tolerated in physically fit patients who were older than ages 65 or 70 years, Hallek said. Final results of the REACH trail showed that the addition of rituximab to FC extended event-free survival by 10 months, compared with standard FC for patients with r elapsed/refractory CLL.
“We consider this a major advance,” said lead investigator Tadeusz Robak, MD, PhD, Medical University in Lodz, Poland. “There is now enough evidence to support use of FCR in untreated and difficult-to-treat patients with CLL,” said lead investigator Tadeusz Robak, MD, PhD, Medical University in Lodz, Poland.
REACH was the largest study in relapsed/refractory CLL, enrolling 552 patients from 17 countries in Europe, North America, Australia, and New Zealand. Patients were randomized to three cycles of FCR or FC, then restaged and treated for three more cycles; those with progressive disease at restaging were dropped from the study.
FCR doubled the CR rate: 24.3% versus 13% for FC (P=.0007). Median progression-free survival was 30.6 months with FCR and 20.6 months with FC (P=.0002).
The study did not raise any new or unexpected safety concerns related to rituximab. The safety was in line wit hprevious studies of rituximab, Robak said. A slight increase in adverse events was observed with the addition of rituximab, including febrile neutropenia, infusion-related reactions, benign and malignant neoplasms, and Hepatitis B. Infections were manageable and similar in both arms.
Four-Drug Combination as Initial Therapy in Previously Untreated Multiple Myeloma
Noting that various combination regimens of bortezomib, lenalidomide, dexamethasone, and cyclophosphamide have demonstrated substantial activity in previously untreated multiple myeloma, researchers began a randomized, multicenter, three-arm, phase I/ II study to determine whether combining all four agents would show even greater activity. Shaji Kumar, MD, and colleagues presented safety and efficacy data from the phase-I arm of their study, which focused on identifying the maximum-tolerated dose of this combination.
Twenty-five treated patients (median age, 61 years) received bortezomib 1.3mg/m2, dexamethasone 40mg PO, lenalidomide 15mg PO, and cyclophosphamide 100, 200, 300, 400, or 500mg/m2 PO for up to eight 21-day cycles, followed by bortezomib 1.3mg/m2 for four 42-day maintenance cycles. When required, patients received prophylactic antibiotics, acyclovir, transfusion support, and concomitant anticoagulants. The primary end-point, maximum tolerated does, was the highest dose of cyclophosphamide in combination with bortezomib —dexamethasone– lenalidomide resulting in ≤1 dose-limiting toxicity in six patients.
Adverse events notwith standing (constipation [64%], fatigue [60%], and nausea [52%]), hematologic toxicities were acceptable (grade-3 neutropenia [16%], grade-4 [4%], and grade-4 thrombocytopenia [4%]). The researchers reported their preliminary response rates as follows: 100% ≥ partial response, 68% ≥ very good partial response, 32% complete response (CR)/near CR, 28% CR/stringent CR, and 20% stringent CR.
Overall, concluded Kumar, the four-drug combination was well tolerated, hematologic toxicities were manageable, and the regimen proved feasible and highly active in patients newly diagnosed with multiple myeloma. Accordingly, enrollment to the phase-II section of the study will proceed.
Decitabine as Treatment for Elderly Patients with Acute Myeloid Leukemia
To determine the morphologic complete response rate in patients age 60 years or older who have newly diagnosed, untreated acute myeloid leukemia (AML)—who were not candidates for standard induction chemotherapy—researchers conducted a multicenter, open-label, phase- II trial of decitabine, a potent DNA hypomethylating agent approved for the treatment of patients with all French—American–British subtypes of myelodysplastic syndrome (MDS). Owing to these patients’ comorbidities and poor performance status, it was thought decitabine therapy would be less intense and better tolerated.
Of the 55 patients enrolled—all of whom received decitabine 20mg/m2 IV over one hour for five consecutive days every four weeks—most had intermediate (53%) or poor (42%) risk cytogenetics. With a median time to response of three months, responses were seen in all subgroups of patients (including five of 19 with previous MDS and five of 23 with poor-risk cytogenetics). With one year follow-up, Amanda F. Cashen, MD, and her colleagues determined the patients’ overall median survival to be 9.6 months.
Compared with the roughly 20% 30-day mortality rate usually associated with this population when receiving standard induction therapy, patients on this trial experienced that rate at merely 4%. In light of its efficacy and manageable toxicity profile in this small population of elderly patients with AML, an ongoing phase-III survival trial is being conducted in a similar, but larger group of patients with the disease.
Bendamustine Plus Rituximab More Tolerable than CHOP Plus Rituximab for Lymphoma
Mathias J. Rummel, MD, PhD, and colleagues sought to evaluate the effi cacy and safety of the combination bendamustine plus rituximab (B-R), compared with the combination cyclophosphamide-doxorubicin-vincristine- prednisone plus rituximab (CHOP-R) for the first-line treatment of patients with follicular, indolent, and mantle cell lymphomas. As the study’s primary endpoint was event-free survival (EFS), the investigators attempted to show a noninferior EFS for the B-R treatment, which was defined by a less-than-10% difference in EFS between the two comparative arms after three years.
Patients randomly received rituximab 375mg/m2 (day 1) plus either bendamustine 90mg/m2 (days 1+2) every 28 days or the CHOP course of therapy every 21 days for a six-cycle maximum. Of the 437 evaluable patients, the overall response rate for those receiving B-R was 94%, similar to the 93% achieved by those associated with CHOP-R. Complete response for the group receiving B-R compared similarly to those getting CHOP-R as well (41% vs. 33%, respectively). Fifty-eight cases of progressive or relapsed disease were noted in the B-R group’s follow-up period, compared with 75 in the CHOP-R group.
The B-R combination is considered noninferior to the standard CHOPR combination and has a better toxicity profile, stated the researchers. Overall, its recipients had lower rates of alopecia (B-R 0% vs. 89% CHOP-R), less infectious complications (B-R 25% vs. CHOP-R 37%), and less hematotoxic incidences (B-R 19% vs. CHOP-R 36%).
Studies Analyze Deferasirox for Treatment of Patients with Iron Overload
Several studies presented this year at ASH centered on the use of deferasirox (Exjade) in patients with transfusion-dependent anemias. Maria Domenica Cappellini, MD, and colleagues conducted an analysis of the EPIC study, a large, prospective, multicenter trial, and evaluated the efficacy and safety of fixed starting doses of deferasirox based on transfusion history, with subsequent dose titration based on serum ferritin (SF) trends.
All study participants had transfusion-dependent anemia and SF levels ≥1000 ng/mL, or <1000 ng/mL with a history of multiple transfusions, and R2 magnetic resonance imaging—confirmed liver iron concentration of >2 mg Fe/g dry weight. The starting dose was deferasirox 20 mg/kg/d for those patients receiving 2–4 blood units/ month; patients receiving more blood transfusions received 30 mg/kg/d, while those receiving less blood transfusions received 10 mg/kg/d. The primary efficacy endpoint was an SF change from baseline at one year.
Of the 1,744 enrolled participants, many had underlying anemias, including: ß-thalassemia (N = 1,115), myelodysplastic syndromes (N = 341), sickle cell disease (N = 80), aplastic anemia (N = 116) and other conditions associated with anemia (N = 92). Eighty-nine percent (1,555) of the patients started on ≤20 mg/kg/d and 11% (187) started on >20 mg/kg/d. Twenty-four weeks (median) after treatment initiation, 39% of patients had dose increases (range 2—53). Overall, median SF was significantly decreased from baseline by 264 ng/mL after one year (P < 0.0001) at an average actual received dose of 22.2}5.9 mg/kg/d.
Despite some patients discontinuing because of adverse events (diarrhea, rash, nausea, or abdominal pain), consent with drawal, unsatisfactory therapeutic effect, or other reasons, none of these was considered treatment related and deferasirox was generally well tolerated with a safety profile consistent with previous clinical trials. According to the researchers, this study not only confirms the efficacy of deferasirox to reduce iron load in a wide range of patients who have transfusion-related iron overload, but it also supports the clinical approach to chronically transfused patients by significantly reducing toxic iron that can damage key organs.
Another analysis of the EPIC study concerning deferasirox was performed by Norbert Gattermann, MD, and fellow researchers to determine the efficacy and safety of the drug to maintain or reduce body iron and SF in patients with myelodysplastic syndrome (MDS). Noting that such patients are susceptible to iron overload from repeated blood transfusions and increased dietary iron absorption, the investigators enrolled 341 patients with MDS who had a median baseline SF of 2730 ng/mL.
Those patients had a mean transfusion duration of 3.6 years, and received a mean 116.4 mL/kg of blood in the previous year. The mean actual dose of deferasirox over one year of treatment was 19.2}5.4 mg/kg/day. Gattermann and colleagues determined at one year that there was a significant reduction in median SF from baseline (by last observation carried forward: —253.0 ng/mL; P = 0.0019). The median SF (range) ng/mL values at baseline, three, six, nine, and 12 months were 2729.5, 2358.0, 2209.5, 2076.0, and 1903.5, respectively. Like the previous analysis, this one assessed the same AEs that occurred, most of which were mild-to-moderate in severity.
Gattermann and colleagues determined similar results in their review of the EPIC study; that deferasirox significantly reduced SF levels over one year of treatment in patients who have MDS with iron overload when appropriate dose adjustments are made every three months based on SF trends and safety markers.
Nadroparin Reduces Thromboembolic Events in Patients Receiving Chemotherapy
As patients receiving chemotherapy for cancer are known to be at increased risk for thromboembolic events, Giancarlo Agnelli, MD, and colleagues conducted a placebo-controlled, double-blind, multicenter, clinical outcome—based study called PROTECHT. This study, which was designed to evaluate the efficacy of the low molecular weight heparin nadroparin for prophylaxis of such events, had a primary endpoint of the composite of clinically overt venous or arterial thromboembolic events, and a main safety outcome measure of major bleeding.
Of the 1,166 patients who were randomized, two groups were to receive either subcutaneous injections of nadroparin (3,800 anti-Xa IU once daily) or placebo, which was to start at the initiation of chemotherapy and last throughout the patient’s entire treatment or up to a maximum of four months. With a multitude of cancer types represented (lung, colon, breast, ovary, stomach, rectum, pancreas, head and neck), 1,150 patients received at lease one dose of the study treatment.
Agnelli noted that 16/769 (2.1%) of patients who received nadroparin and 15/381 (3.9%) of patients who received placebo experienced a thromboembolic event (interim-adjusted P = 0.033). Fifteen of the thromboembolic events occurred in patients with lung cancer (4.0%, nadroparin group; 8.8%, placebo group). Patients with pancreatic cancer experienced an overall rate of thromboembolic events of 7.5%. With regard to major bleeding, five patients in the nadroparin group (0.7%) and none in the placebo group experienced a major bleeding (P = 0.177). The minor bleeding events were similar in bothgroups: 77 events in 57 patients receiving nadroparin (7.4%) and 38 events in 30 patients (7.9%) receiving placebo.
In light of these results, the investigators concluded that, whereas nadroparin reduces the incidence of thromboembolic events in patients with cancer who are receiving chemotherapy, future confirmatory studies should center on patients who are at high thromboembolic risk, like those with lung and pancreatic cancer.
Study Evaluates Eltrombopag for Treatment of Idiopathic Thrombocytopenic Purpura
Idiopathic thrombocytopenic purpura (ITP) is a blood disorder that occurs fairly commonly in children and adults, with 50—150 new cases per million people each year. Researchers examined how eltrombopag, a first-in-class, oral, small molecule, non-peptide, thrombopoietin receptor agonist, may be used for treatment of ITP. With the RAISE study, investigators used a six-month, randomized, double-blind, placebo-controlled, phase-III study to analyze the efficacy and safety of eltrombopag in previously treated adults with the disease who had platelet counts <30,000/μL.
Gregory Cheng, MD, and colleagues enrolled 197 patients (eltrombopag 135); and had all patients’ doses individualized according to each person’s platelet response (75 mg once daily or 25 mg once daily or less). With the primary endpoint being the odds of responding during the treatment period for patients getting eltrombopag versus placebo, the researchers determined that those patients who received the drug were eight times more likely to achieve platelet counts of between 50,000 and 400,000/μL during the six-month trial period compared with those patients who received placebo (overall response [95% confidence interval] = 8.2 [4.32, 15.38]; P < 0.001).
In the group receiving eltrombopag, platelets rose after one week to 36,000/μL and later ranged from 52,000/μL to 91,000/μL for the remainder of the study. Not only did all patients respond to the drug, regardless of their splenectomy status, use of baseline ITP medications, or baseline platelet counts, but much fewer patients treated with eltrombopag had any clinically significant bleeding compared with those patients who received placebo. Furthermore, more patients receiving the drug stopped or reduced their dosages of their ITP medications compared with placebo (59% vs. 32%, respectively).
Overall, the RAISE study found long-term eltrombopag therapy success in significantly increasing platelet counts, decreasing bleeding symptoms, allowing for a reduction or discontinuation of baseline ITP therapies, and reducing the use of rescue ITP medications compared with placebo. As it was well-tolerated, with a similar safety profile to placebo, eltrombopag is an important new treatment option for patients with chronic ITP.
Dexamethasone vs. Dexamethasone and Rituximab for Treatment of Idiopathic Thrombocytopenic Purpura
In a two-year trial extending from July 2005 through June 2007, researchers conducted an analysis seeking to determine the activity of rituximab in patients with idiopathic thrombocytopenic purpura (ITP) relapsed or refractory to standards treatments. Their prospective, randomized, multicenter, phase-III study compared treatment of patients with previously untreated ITP and a platelet count of ≤ 20 x109/L who received dexamethasone alone (arm A) versus dexamethasone plus rituximab (arm B).
Arm-A patients received a single course of oral dexamethasone 40 mg (days 1, 2, 3, 4), and arm-B patients received the same as the first group plus IV rituximab 375 mg/m2 (days 7, 14, 21, 28). The primary endpoint of the study was to compare the sustained response (SR), that is, platelet count ≥50 x 109/L at month+ 6 of treatment. Using an intention-to-treat (ITT) and a per-protocol (PP) analysis, Francesco Zaja, MD, and colleagues evaluated 101 patients (arm A, 52; arm B, 49), and 64 patients (arm A, 38; arm B, 26), respectively. (27 pts who began on arm A failed to achieve initial response or SR, so they received salvage treatment with dexamethasone plus rituximab.)
Patients were systematically followed up on past the sixth month for a median observation period of 18 months (arm A, 12 patients; arm B, 27; salvage therapy, 19). The SR-loss rate (platelets < 50 x 109/L) for these three groups was 25% (3/12), 11% (3/27) and 10.5% (2/19), respectively, and the safety profile was good with no substantial difference between the two arms of randomization.
Zaja believes the combination of dexamethasone plus rituximab for treatment of patients with ITP improves overall outcome with out worsening the safety profile. The treatment is recommended as a presplenectomy option, especially for those patients with higher risk of complications. It prolonged SR and reduced rates of relapse to the point where it might even suggest a possible curative effect.