Krishna Gundabolu, MBBS
In sunny San Diego, the 2018 American Society of Hematology (ASH) Annual Meeting & Exposition welcomed nearly 30,000 attendees who were eager to present, learn, network, and cheer the joint achievements of many researchers. The packed meeting was filled with important information from thousands of investigators presenting their data, and it looked to me like a milestone year, with advances across the spectrum of hematology.
Special events that caught many people’s attention included not only the Plenary Session on Sunday and the late-breaking abstract session on Tuesday, but also a joint symposium from ASH and the U.S. Food and Drug Administration (FDA) on new drug approvals in malignant hematology on Monday. This supplement to The ASCO Post summarizes some of the highlights at this meeting and more.
Erythroid-stimulating agents are the mainstay of treatment for lower-risk myelodysplastic syndromes (MDS) involving transfusion-dependent anemia. The MEDALIST trial presented at the ASH Plenary Session showed that luspatercept (by subcutaneous injection every 3 weeks), a first-in-class novel molecule neutralizing transforming growth factor–ß receptor ligand, improved the rates of red blood cell transfusion independence. With luspatercept, 37.9% remained transfusion-free for 8 weeks or longer, compared with 13.2% of placebo recipients (P < .0001) in patients with very low–, low-, and intermediate-risk MDS with ring sideroblasts who were refractory to or intolerant of an erythroid-stimulating agent.1 This could be a practice-changing finding, as there are no easy alternatives for this group of patients aside from hypomethylating agents or lenalidomide.
Chronic lymphocytic leukemia (CLL) and ibrutinib were also in the spotlight at the ASH meeting. The Alliance A041202 study presented during the Plenary Session showed that ibrutinib produced superior progression-free survival at 2 years—either as a single agent (87%) or combined with rituximab (88%)—compared to a combination of bendamustine and rituximab (74%) in patients aged 65 years or older with newly diagnosed CLL (P < .001).2,3 The ibrutinib-containing regimens also led to fewer severe adverse events. Though there is no evidence of an overall survival benefit based on currently available data, ibrutinib now can be considered as initial therapy for CLL in older patients.
ASH 2018: The 59th Annual Meeting and Exposition was held at the San Diego Convention Center. Photo by © ASH/Todd Buchanan 2018
In another potentially practice-changing study (E1912, an ECOG-ACRIN study) presented during the late-breaking abstract session, investigators studied first-line ibrutinib plus rituximab (I/R) vs chemotherapy plus immunotherapy with fludarabine, cyclophosphamide, and rituximab (FCR) in patients younger than age 70 with symptomatic CLL and no 17p deletion.4 At a median follow-up of 33.4 months, I/R yielded superior progression-free survival (hazard ratio [HR] = 0.35; P < .0001) and overall survival (HR = 0.168; P = .0003) compared to FCR and was associated with a lower incidence of severe adverse events.
Plasma Cell Disorders
The current first-line treatment options for transplant-ineligible patients with myeloma include lenalidomide/dexamethasone or bortezomib, lenalidomide, and dexamethasone.5 The MAIA study presented at the late-breaking abstract session offers a new choice in this setting. MAIA compared daratumumab/lenalidomide/dexamethasone to lenalidomide/dexamethasone, with a median follow-up of 28 months. It showed a significant reduction in the risk of disease progression for the 3-drug option (HR = 0.55; P < .0001), with deeper remissions but at the expense of higher rates of severe adverse events.6
ASH 2018: Poster session during the 59th Annual Meeting, where more than 20,000 hematology and oncology experts from around the world convened in San Diego. Photo by © ASH/Todd Buchanan 2018
Many important studies presented on sickle cell disease and thrombosis stole the limelight in benign hematology. Since the FDA’s 1998 approval of hydroxyurea to decrease the morbidity of sickle cell disease, it was not until 2017 that another drug, L-glutamine, was approved in this setting, based on a phase III trial.7 But at the ASH meeting, the prospective multinational REACH study reaffirmed the safety and benefit of hydroxyurea in children with sickle cell disease from sub-Saharan Africa, demonstrating increases in hemoglobin; decreased rates of transfusions, vaso-occlusive crisis, and acute chest syndrome; and, interestingly, a lower incidence of malaria.8 Next in the development pipeline, crizanlizumab, a P-selectin–inhibiting monoclonal antibody (administered intravenously at 5 mg/kg for 14 doses over 52 weeks), was shown to lower the rate of sickle cell disease–related pain crises in the SUSTAIN study.9 A post hoc analysis of this trial from an intention-to-treat population confirmed the benefit, with decreased annual rates of vaso-occlusive crisis (1.63 vs 2.98; P = .02) and an increased median time to the first vaso-occlusive crisis (4.07 months vs 1.38 months; P = .001) compared to placebo.10
Although gene therapy and allogeneic bone marrow transplantation are considered the only curative treatments for sickle cell disease, a novel gene therapy strategy of inactivating BCL11A (a repressor of gamma globin gene expression)—by using a lentiviral vector expressing shRNA for BCL11A after myeloablative conditioning autologous transplantation of efficiently transduced gene-modified cells—led to increased levels of fetal hemoglobin.11 This could become an option for treatment in patients with no available sibling donors.
“The packed meeting was filled with important information from thousands of investigators presenting their data, and it looked to me like a milestone year, with advances across the spectrum of hematology.”— Krishna Gundabolu, MBBS
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Venous thromboembolism (VTE) is a major risk for patients with cancer and those undergoing cancer-directed therapies. In the CASSINI trial, such patients at increased risk had a significantly reduced risk of VTE and VTE-related deaths with rivaroxaban compared with placebo (2.62% vs 6.41%; P = .007), as well as a reduced risk of bleeding.12 In patients with atrial fibrillation on warfarin for systemic anticoagulation, the BRIDGE trial had demonstrated that the avoidance of bridging with low–molecular-weight heparin was noninferior to the discontinuation of warfarin with no bridging preoperatively (ie, with elective surgeries) for the prevention of arterial thrombosis. 13 Such data were missing for direct oral anticoagulants but are now available from the PAUSE trial, which was a very large study (N = 3,007) of direct oral anticoagulants including apixaban, rivaroxaban, and dabigatran. These drugs were held for 1 day (before and after surgery associated with a low risk of bleeding) or for 2 days (around procedures associated with a high risk of bleeding) in patients with creatinine clearance ≥ 50 mL/min.14 The rates of perioperative major bleeding and arterial thromboembolism were low (< 2% and < 1%, respectively). Of note, nearly 99% of patients had minimal or no residual direct oral anticoagulant levels at the time of surgery with a high risk of bleeding. ■
DISCLOSURE: Dr. Gundabolu has participated in scientific advisory boards of Pfizer, Novartis, and Shionogi and holds stock in Geron and Portola pharmaceuticals.
1. Fenaux P, PLatzbecker U, Mufti GJ, et al: The MEDALIST trial: Results of a phase 3, randomized, double-blind, placebo-controlled study of luspatercept to treat anemia in patients with very low-, low-, or intermediate-risk myelodysplastic syndromes with ring sideroblasts who require red blood cell transfusions. 2018 ASH Annual Meeting & Exposition. Abstract 1. Presented December 2, 2018.
2. Woyach JA, Ruppert AS, Heerema NA, et al: Ibrutinib alone or in combination with rituximab produces superior progression free survival compared with bendamustine plus rituximab in untreated older patients with chronic lymphocytic leukemia: Results of Alliance North American Intergroup Study A041202. 2018 ASH Annual Meeting & Exposition. Abstract 6. Presented December 2, 2018.
3. Woyach JA, Ruppert AS, Heerema NA, et al: Ibrutinib regimens versus chemoimmunotherapy in older patients with untreated CLL. N Engl J Med 379:2517-2528, 2018.
4. Shanafelt TD, Wang V, Kay NE, et al: A randomized phase III study of ibrutinib (PC-32765)-based therapy vs standard fludarabine, cyclophosphamide, and rituximab chemoimmunotherapy in untreated younger patients with chronic lymphocytic leukemia: A trial of the ECOG-ACRIN Cancer Research Group (E1912). 2018 ASH Annual Meeting & Exposition. Abstract LBA-4. Presented December 4, 2018.
5. Kumar SK, Callander NS, Alsina M, et al: NCCN Guidelines Insights: Multiple myeloma, version 3.2018. J Natl Compr Canc Netw 16:11-20, 2018.
6. Facon T, Kumar SK, Plesner T, et al: Phase 3 randomized study of daratumumab plus lenalidomide and dexamethasone versus lenalidomide and dexamethosone in patients with newly diagnosed multiple myeloma ineligible for transplant (MAIA). 2018 ASH Annual Meeting & Exposition. Abstract LBA-2. Presented December 4, 2018.
7. Niihara Y, Miller ST, Kanter J, et al: A phase 3 trial of L-glutamine in sickle cell disease. N Engl J Med 379:226-235, 2018.
8. Tshilolo L, Tomlinson G, Williams TN, et al: Realizing effectiveness across continents with hydroxyurea (REACH): A prospective multi-national trial of hydroxyurea for sickle cell anemia in sub-Saharan Africa. 2018 ASH Annual Meeting & Exposition. Abstract 3. Presented December 8, 2018.
9. Ataga KI, Kutlar A, Kanter J, et al: Crizanlizumab for the prevention of pain crises in sickle cell disease. N Engl J Med 376:429-439, 2017.
10. Liles DK, Cancado R, Kanter J, et al: Established prevention of vaso-occlusive crises with crizanlizumab is further improved in patients who follow the standard treatment regimen: Post hoc analysis of the phase II SUSTAIN study. 2018 ASH Annual Meeting & Exposition. Abstract 1082. Presented December 1, 2018.
11. Esrick EB, Brendel C, Manis JP, et al: Initial results of genetic targeting of the fetal to adult globin switch in sickle cell patients. 2018 ASH Annual Meeting & Exposition. Abstract 1023. Presented December 3, 2018.
12. Khorana AK, Soff GA, Kakkar AK, et al: Results of a randomized clinical trial (CASSINI). 2018 ASH Annual Meeting & Exposition. Abstract LBA-1. Presented December 4, 2018.
13. Douketis JD, Spyropoulos AC, Kaatz S, et al: Perioperative bridging anticoagulation in patients with atrial fibrillation. N Engl J Med 373:823-833, 2015.
14. Douketis J, Spyropoulos AC, Duncan JM, et al: Perioperative anticoagulant use for surgery evaluation (PAUSE) study: A perioperative management plan for patients with atrial fibrillation who are receiving a direct oral anticoagulant. 2018 ASH Annual Meeting & Exposition. Abstract LBA-5.