Meeting Highlights

American Society of Hematology 55th Annual Meeting and Exposition Walter Alexander

The American Society of Hematology hosted 22,495 investigators, hematologists, other health professionals, and exhibitors from 113 countries in New Orleans from December 7 to 11, 2013. This report reviews key sessions on pharmacological treatments for sickle-cell disease, myelofibrosis, multiple myeloma, chronic myeloid leukemia, and β-Thalassemia.

Reduction in Time to Resolution of Vaso-Occlusive Crisis and Decreased Opioid Use in a Prospective, Randomized, Multi-Center, Double-Blind, Adaptive Phase 2 Study in Sickle-Cell Disease • Marilyn J. Telen, MD, Duke University Medical Center, Durham, North Carolina Use of investigational GMI-1070 (GlycoMimetics, Gaithersburg, Maryland), a pan-selectin inhibitor, led to improvements in clinically meaningful outcomes in patients with sickle-cell disease recently hospitalized for a vaso-occlusive crisis (VOC), according to Dr. Telen. GMI-1070 led to faster resolution of VOC, shorter hospital stays, and reduced parenteral opioid analgesia. Sickle-cell disease, the most common genetic disease in the U.S., affects 90,000 to 100,000 individuals in the U.S. and millions worldwide, Dr. Telen said. The most common clinical manifestation of sickle-cell disease, painful vaso-occlusive crises, accounts for between 75,000 and 90,000 hospital admissions annually. Symptom relief with narcotics as supportive therapy is generally all that can be offered to sickle-cell patients for VOC. Dr. Telen and colleagues explored the safety and efficacy of GMI-1070 in a prospective, randomized, multicenter, doubleblind, adaptive phase 2 study, subsequent to animal studies showing restoration of blood flow with GMI-1070 and early phase human studies showing no significant safety concerns. The phase 2 study enrolled 76 individuals (ages 12–51 years; 43 GMI-1070 and 33 placebo). The primary endpoint was time to resolution of VOC. The median time to resolution of VOC was reduced by 63 hours with GMI-1070 (P = 0.187), and the mean time to resolution was reduced by 41 hours (P = 0.192). “While these were not statistically significant, the differences are actually quite large,” Dr. Telen commented. Also, the mean hourly opioid analgesic administered during hospitalization was reduced (48-hour reduction, P = 0.067), and the cumulative opioid dose was reduced by 83% (P = 0.010) with GMI-1070. Trends favoring GMI-1070 were also observed for median time to discharge from hospital (reduced by 84 hours, The author is a freelance medical writer living in New York City.

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P = 0.092) and for the mean time to discharge (reduced by 55 hours, P = 0.096). Dr. Telen noted that GMI-1070 had an apparently benign safety profile in this population. “These results provide strong rationale for a phase 3 trial for GMI-1070 for sickle cell patients with vaso-occlusive crisis.” GlycoMimetics is collaborating with Pfizer on the development of the phase 3 study.

A Pooled Overall Survival Analysis of the COMFORT Studies: 2 Randomized Phase 3 Trials of Ruxolitinib for the Treatment of Myelofibrosis

• Alessandro M. Vannucchi, MD, University of Florence, Florence, Italy Ruxolitinib is a potent Janus kinase (JAK1/JAK2) inhibitor that has shown superiority over conventional therapies for treatment of myelofibrosis. In the phase 3 COMFORT I and II studies, patients with intermediate-2 or high-risk primary myelofibrosis, post-polycythemia myelofibrosis, or post-essential thrombocythemia myelofibrosis initially received ruxolitinib 15 or 20 mg b.i.d. based on their platelet counts at baseline (100– 200 and greater than 200 x 109/L, respectively) and were individually titrated to maximize safety and efficacy. COMFORT I was a double-blind study; COMFORT II was open-label. Overall, 301 patients were randomized to ruxolitinib (COMFORT I, n = 155; COMFORT II, n = 146), and 227 patients were randomized to placebo (n = 154) or best available therapy (n = 73). In the combined ruxolitinib group, 162 patients (54%) had high-risk myelofibrosis and 138 (46%) had intermediate-2 risk at baseline compared with 135 (59%) and 91 (40%) patients in the combined control group, respectively. Patients had been allowed to cross over from the control arm of each study in the event of protocol-defined progressive splenomegaly, defined as an increase of at least 25% in spleen volume from baseline or on-study nadir. Dr. Vannucchi noted that at the time of the analysis, all ongoing control patients had crossed over to ruxolitinib. Such crossovers, he commented, may have led to underestimation of survival benefit. Dr. Vannucchi’s team of investigators conducted a pooled analysis of overall survival in the COMFORT I and II studies using a method (rank-preserving structural failure time, or RPSFT) designed to account for patients crossing over to ruxolitinib in the control arm. Survival was consistent across both studies at this three-year update. In the pooled ruxolitinib group, 24% of patients (71 of 301) had died compared with 33% of patients (76 of 227) in the control group, a 35% reduction in the risk of death by intentionto-treat analysis (hazard ratio, 0.65; 95% CI, 0.46–0.90; P = 0.01). The RPSFT analysis correcting for crossover, however, placed the hazard ratio at 0.29 (95% CI, 0.13–0.63; P = 0.01), indicat-

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Meeting Highlights: American Society of Hematology ing that the observed treatment effect in the intention-to-treat analysis is very likely an underestimate, Dr. Vannucchi said. A survival benefit with ruxolitinib was observed for both intermediate-2 and high-risk patients. The risk of death in high-risk patients treated with ruxolitinib was similar to that of intermediate-2 control patients. Larger spleen volume at baseline was prognostic for shortened survival; the risk of death increased by 9% for each additional 5 dL in spleen volume at baseline (HR, 1.09; 95% CI, 1.03–1.15; P = 0.003). An assessment of correlation between spleen volume reduction by week 24 and overall survival in ruxolitinib-treated patients demonstrated that with a reduction of 10% to less than 25% (n = 62), the hazard ratio was 0.36 (0.18–0.72). With a 25% to less than 35% reduction (n = 49) the hazard ratio was 0.25 (0.18–0.61), and with a 35% to less than 50% reduction (n = 64) it was 0.24 (0.11–0.56). For those with 50% or greater reductions (n = 47) the hazard ratio was 0.18 (0.07–0.47). Spleen volume reductions were uncommon in the control group. Dr. Vannucchi commented that the fact that they did not correlate with overall survival precludes use of spleen volume reductions independent of treatment as surrogate markers for survival. Dr. Vannucchi concluded, “The COMFORT studies provide evidence that we’ve been able to extend the lives of patients with myelofibrosis with ruxolitinib. … It’s promising to start seeing the long-term effects of this therapy, which has changed the treatment paradigm for most patients with this life-threatening disease.”

Comparative Effectiveness on Survival of Zoledronic Acid Versus Pamidronate in Multiple Myeloma

• Kristen Sanfilippo, MD, MPHS, Washington University School of Medicine, St. Louis, Missouri Disease-related bone destruction, which occurs in 80% of multiple myeloma patients, places them at risk for skeletalrelated events, bone lesions requiring surgery or radiation, spinal cord compression, pathologic fracture, and hypercalcemia. Prophylactic therapy, however, can decrease skeletalrelated events and has potential to improve overall survival, Dr. Sanfilippo said in an interview at her poster. Bisphosphonates are the treatment of choice for preventing bone destruction. Between the two approved bisphosphonates in the U.S., zoledronic acid and pamidronate, only pamidronate was available in generic formulation until March 2013, when generic zoledronic acid also became available. Prior multiple myeloma research by Morgan et al., she pointed out, has shown increased overall survival with zoledronic acid versus clodronate (from a different class of bisphosphonates). Zoledronic acid and pamidronate inhibit protein prenylation, which interferes with tumor cell adhesion, migration, and proliferation. Given that zoledronic acid is tenfold more potent than pamidronate with respect to protein prenylation inhibition, it seemed likely that benefits might accrue to those preferentially receiving it. “We wanted to see if one was better than the other,” Dr. Sanfilippo said. In data from 1,343 patients treated within

the Veterans Health Administration system from 2002 to 2009 who received zoledronic acid, pamidronate, or both, investigators used propensity scores to balance covariates and tested for associations between bisphosphonate use and skeletal-related events. After a median follow-up of 26.9 months in 383 patients receiving only zoledronic acid and 635 receiving only pamidronate, overall survival was significantly improved among those receiving zoledronic acid (median 32.4 months vs. 23.4 months). Higher comorbidity index, creatinine of 2 mg/dL or more, and BMI of less than 18.5 (P < 0.05) were also identified with decreased overall survival. After controlling for confounding factors, overall survival was still significantly improved with zoledronic acid (16% reduced mortality risk vs. pamidronate [HR, 0.84; 95% CI, 0.72–0.98; P = 0.023]). Zoledronic acid, as compared with pamidronate, also reduced skeletal-related event risk by 21% (HR, 0.79; 95% CI, 0.68–0.99). The shorter infusion time with zoledronic acid (15 minutes compared with 120 minutes for pamidronate) is another advantage. The biggest concern with zoledronic acid, Dr. Sanfilippo said, is the risk for osteonecrosis of the jaw (ONJ). “Recent small studies, however, have shown that if you do preventive care and have patients work with a dentist, you can bring the ONJ rate down. So that concern is fading,” she said.

Achievement and Maintenance of Deeper Molecular Response by Switching to Nilotinib in Patients With Chronic Myeloid Leukemia in Chronic Phase (CML-CP) With Residual Disease on Long-Term Imatinib: ENESTcmr 36-Month Follow-Up

• Brian Leber, MD, McMaster University, Hamilton, Ontario, Canada

ENESTnd Update: Nilotinib Versus Imatinib in Patients With Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase (CML-CP) and the Impact of Early Molecular Response and Sokal Risk at Diagnosis on Long-Term Outcome

• Giuseppe Saglio, MD, San Luigi Gonzaga Hospital, University of Turin, Orbassano, Italy Two presentations about chronic phase chronic myeloid leukemia (CML-CP) based on long-term ENEST (Nilotinib Efficacy and Safety in Clinical Trials) data (one on newly diagnosed patients and the other on those with complete molecular responses) confirm nilotinib 300 mg as a standard of care. They demonstrate that switching to nilotinib from imatinib can effect the deeper molecular responses that may ultimately allow cessation of drug treatment. Dr. Saglio reported on adults from 217 centers and 35 countries with newly diagnosed Philadelphia positive CML-CP (n = 846) who had been randomized to nilotinib 300 mg twice daily (b.i.d.; n = 282), nilotinib 400 mg b.i.d. (n = 281), or imatinib 400 mg once daily (q.d.; n = 283). Efficacy in the nilotinib arms was evaluated based on achievement of early molecular response (EMR) (BCR-ABLIS less than or equal to 10% at

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Meeting Highlights: American Society of Hematology three months). Follow-up, set originally at five years, has been extended to 10 years. “By five years, more than half of nilotinib-treated patients had achieved MR4.5,” Dr. Saglio said. “That is a key eligibility criterion for many treatment-free remission studies.” The cumulative incidence of major molecular response (BCR-ABLIS less than or equal to 0.1%) at five years was 77% for both nilotinib 400 mg b.i.d. and for nilotinib 300 mg b.i.d. compared to 60% for imatinib (P < 0.0001). Attainment of the more stringent standard of MR4.5 (molecular response less than or equal to 4.5 logs [BCR-ABLIS less than or equal to 0.0032]) was reported in 54% and 52% of patients receiving nilotinib 300 mg b.i.d. and 400 mg b.i.d., respectively, versus 31% for imatinib 400 mg q.d. (both nilotinib doses vs. imatinib, P < 0.0001). Event-free survival (freedom from all-cause death, progression, loss of partial cytogenetic response, complete cytogenetic response, or complete hematologic response) rates at five years were 92.6% in the imatinib arm, 95.0% in the nilotinib 300-mg arm, and 97.4% in the nilotinib 400-mg arm. Rates of progression-free survival (freedom from all-cause death and progression to accelerated phase or blastic phase) were 94.7% for imatinib, 96.5% for nilotinib 300 mg, and 98.3% for nilotinib 400 mg. Progression to accelerated phase or blast crisis on core treatment was significantly less common for nilotinib doses (nilotinib 300 mg b.i.d., 0.7%; nilotinib 400 mg b.i.d., 1.1%; imatinib 400 mg q.d., 4.2%, P = 0.0059 and P = 0.0185, respectively, compared to imatinib). With the nilotinib regimens, especially at the 400-mg b.i.d. dose, cardiovascular events (ischemic heart disease, ischemic cerebrovascular events, peripheral arterial disease) were numerically more frequent. About 85% of patients with a cardiovascular event had at least one risk factor and were not optimally managed for hyperglycemia and hypercholesterolemia, Dr. Saglio noted. He concluded, “These long-term data confirm nilotinib 300 mg b.i.d. as a standard of care in patients with newly diagnosed CML-CP.” Dr. Leber noted that molecular responses became significantly deeper when 207 imatinib-treated patients with residual disease were switched to nilotinib. All were Philadelphia chromosome positive CML-CP patients who had achieved complete cytogenetic response (CCyR) but had detectable BCR-ABL after two years or more on imatinib. Dr. Leber identified two critical unanswered questions addressed since the 24-month update: • “How many patients randomized to imatinib can achieve deep molecular responses after crossover to nilotinib?” • “How many patients on imatinib who didn’t cross over achieved undetectable BCR-ABL (sensitivity of at least 4.5 logs by RQ-PCR [real-time quantitative reverse-transcription polymerase chain reaction] (MR4.5)?” The analysis looked at 104 patients who crossed over at 24 months from imatinib to nilotinib 400 mg b.i.d., comparing them at 36 months to 103 patients remaining on their same dose of imatinib. No cases of progression to accelerated phase or blast crisis

were reported, and no patients lost their responses. Among nilotinib patients at 24 months, 43% achieved MR4.5 as compared to 21% of those on imatinib (P = 0.0006). After 36 months, 47% of nilotinib patients achieved MR4.5, as compared to 24% of the original imatinib cohort, with an added 9% of nilotinib crossover patients (P = 0.0453). Dr. Leber pointed out that while 78 imatinib patients had detectable BCR-ABL at 24 months (43 crossed over to nilotinib and 35 continued on imatinib), at 36 months, 26 of those crossing over achieved MR4.5, as compared to none among those remaining on imatinib. Among the 52 patients in the original nilotinib group with detectable BCR-ABL at 24 months, an additional four had achieved MR4.5 at 36 months. Median time to MR4.5 was more than a year shorter in the nilotinib group than in the imatinib group. Rates of grade 3 or 4 adverse events (29% with nilotinib and 28% with imatinib) and rates of adverse events leading to discontinuation (9% and 15%, respectively) were similar between groups. Cardiovascular events (ischemic heart disease, cerebrovascular events, peripheral arterial disease) occurred in 12 of 101 nilotinib-receiving patients (including two of 46 crossover patients), as compared to two of 103 imatinib patients. Analysis of the additional year of follow-up, Dr. Leber concluded, “supports the strategy of switching to nilotinib in patients seeking to attain deep molecular responses.”

Initial Phase 3 Results of the FIRST Trial (MM-020/ IFM 07 01) in Newly Diagnosed Multiple Myeloma Patients Ineligible for Stem Cell Transplantation • Thierry Facon, MD, Service des Maladies du Sang, Hopital Claude Huriez, CHRU Lille, Lille, France

Melphalan-prednisone-thalidomide (MPT), based on demonstrated superior overall survival (OS) and progression-free survival (PFS) as compared with melphalan and prednisone, has been the standard treatment for multiple myeloma, according to Dr. Facon. The FIRST (Frontline Investigation of Lenalidomide Plus Dexamethasone Versus Standard Thalidomide) trial compared standard MPT to continuous lenalidomide with low-dose dexamethasone in transplant-ineligible newly diagnosed multiple myeloma patients. Investigators enrolled 1,623 patients (median age 73 years, about 53% male) from 246 centers in 18 countries. Patients included in FIRST were either at least 65 years of age or other­ wise not candidates for stem cell transplantation. They were randomized to one of three arms: low-dose dexamethasone (40 mg on days 1, 8, 15, 22, 28) plus either continuous lenalidomide (25 mg on days 1–21) in 28-day cycles until disease progression (Arm A) or lenalidomide (25 mg on days 1–21) in 28-day cycles for 72 weeks (18 cycles, Arm B), or MPT in 42-day cycles for 72 weeks (12 cycles, Arm C). While patients with renal impairment were enrolled, dialysis patients were excluded. Starting doses of lenalidomide and dexamethasone were adjusted based on renal function and age, respectively. The melphalan starting dose was adjusted based on age, absolute neutrophil count, platelet count, and renal function; thalidomide was adjusted for age. Analysis showed the primary endpoint of PFS to be sig-

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Meeting Highlights: American Society of Hematology nificantly longer for continuous lenalidomide versus MPT (25.5 months as compared with 21.2 months for MPT [P = 0.0006]). PFS for 18 cycles of lenalidomide was 20.7 months (continuous vs. 18 cycles, P = 0.0001). A course of 18 cycles of lenalidomide was not superior to MPT (P = 0.70349). An interim overall survival analysis at four years revealed a significant advantage for continuous lenalidomide over MPT (59.4% vs. 51.4%; P = 0.0168), with 18 cycles of lenalidomide at 55.7% (vs. continuous lenalidomide, P = 0.307, vs. MPT, P = 0.184). Continuous lenalidomide was also shown to be significantly superior to MPT (P < 0.00001) and 18 cycles of lenalidomide for time to progression and time to need for a second antimyleoma therapy. Such superiority for continuous lenalidomide over MPT, Dr. Facon noted, was also shown across all other efficacy-related secondary endpoints. The response rate for continuous lenalidomide was 75% with a median duration of response of 35 months. Continuous lenalidomide had a manageable safety profile, with hematological and non-hematological adverse events as expected, Dr. Facon said. The incidence of secondary primary malignancies was lower with continuous lenalidomide versus 18 cycles of lenalidomide and MPT (7.0%, 8.1%, and 8.7%, respectively). Study discontinuation rates for adverse events were similar between arms (11%, 13%, and 14%, respectively, for continuous, 18-cycle, and MPT arms). Dr. Facon concluded, “In newly diagnosed multiple myeloma transplant-ineligible patients, the FIRST trial establishes continuous lenalidomide as a new standard of care.” That opinion was echoed by Professor Kanti Rai, MD, North Shore–Long Island Jewish Medical Center, who asked in the plenary session about the pattern of progression-free survival in FIRST. Dr. Facon confirmed that the curves for the three arms remained similar for the first 18 months, but then separated widely between continuous lenalidomide and the two other regimens. Dr. Rai commented, “So that will make a case for a paradigm shift in treatment!”

Deferasirox Compared With Deferoxamine for the Removal of Cardiac Iron in Patients With β-Thalassemia Major: 2-Year Data From the Cordelia Extension

amine at one year, with a trend toward superiority for deferasirox (P = 0.057). Target doses were an intensified deferoxamine of 50–60 mg/kg/d SC for eight to 12 hours, five to seven days per week, or once daily deferasirox at 40 mg/kg/d. Deferasirox is a much better tolerated drug than deferoxamine, the reference drug, Dr. Ayinok noted in an interview at her poster. While deferoxamine has to be administered subcutaneously for at least 10 to 12 hours a day for five to seven days per week, deferasirox is dissolved in water or juice and consumed once daily. “The deferoxamine regimen is very painful and burdensome for patients,” she said. Overall, 99.1% and 98.1% of the planned deferasirox and deferoxamine doses were taken, respectively, among the 74 patients receiving deferasirox and 29 receiving deferoxamine. At month 24, cardiac T2 increased from 11.6 to 15.9 ms in deferasirox patients and from 10.8 to 14.2 ms in deferoxamine patients, indicating 38% and 33% improvements, respectively. With both deferasirox and deferoxamine, cardiac iron concentration estimates revealed decreases during two years of treatment. Liver iron concentration decreased to 14.4 ± 16.6 mg Fe/g dw at month 24 in the deferasirox group (–15.7 ± 15.2 mg Fe/g dw; 95% CI –19.7, –11.8) and to 11.0 ± 12.1 mg Fe/g dw in deferoxamine patients (–26.0 ± 14.9 mg Fe/g dw; 95% CI –32.3, –19.7). Treatment with deferasirox for two years led to absolute reductions in serum ferritin of –2,163 ng/mL in deferasirox patients and –2,907 ng/mL in deferoxamine patients. Also, in deferasirox and deferoxamine patients, mean left ventricular ejection fraction was stable and remained within normal limits. Adverse events suspected by investigators to be related to study drugs were reported at rates of 6.8% for deferasirox and 6.9% for deferoxamine, with the most common being upper abdominal pain (6.8% deferasirox, 3.4% deferoxamine) and diarrhea (5.5% deferasirox, 0% deferoxamine). “We conclude,” Dr. Aydinok said, “that both deferasirox and deferoxamine at the treatment doses used in this study are effective for improvement of cardiac iron over two years in patients with a wide range of baseline liver iron concentrations and T2 values. “Second year results, similar to the previous year, are promising,” Dr. Aydinok added. n

• Yesim Aydinok, MD, Ege University Hospital, Izmir, Turkey Diminished T2, which when less than 10 ms confers high risk of heart failure, is caused when cardiac siderosis develops in transfusion-dependent β-thalassemia major patients. Natural removal of cardiac iron is slow, however, and it can take years before T2 is normalized to greater than 20 ms. In an extension of the CORDELIA trial, cardiac T2 continued to decrease substantially after a second year of treatment with either deferasirox or deferoxamine in patients with β-thalassemia major. Dr. Aydinok noted that most prospective comparisons of iron chelators have been limited to one-year duration. Oneyear analysis of CORDELIA, which compared iron removal with either deferasirox or deferoxamine in β-thalassemia major patients, found deferasirox to be non-inferior to deferox-

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American society of hematology: 55th annual meeting and exposition.

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