Recent Reports on Treatment for Leukemias, Sinusoidal Obstruction Syndrome, and Graft-vs-Host Disease

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Syed A. Abutalib, MD

Syed A. Abutalib, MD

In this installment of Hematology Expert Review, I will summarize five studies from the recent literature addressing important questions about leukemias and their treatment, anticoagulant therapy with the new agent defibrotide (Defitelio), and the use of antilymphocyte globulin to prevent chronic graft-vs-host disease.

BCR-ABL Transcripts in CML

Study: Impact of BCR-ABL transcript type on response and survival in patients (n = 481) with chronic-phase chronic myeloid leukemia (CML) treated with tyrosine kinase inhibitors1

Study group/institution: The University of Texas MD Anderson Cancer Center

Question being asked: Which treatment-related outcomes are influenced by specific BCL/ABL transcript types in chronic-phase CML?

Findings and conclusions: In multivariate analysis, the e14a2 transcript type predicted better responses at 3, 6, and 12 months compared with the e13a2 transcript type. The type of transcript predicted for improved probability of event-free survival (P = .043 for e14a2) and transformation-free survival (P = .04 for both) but not overall survival. 

Patients with e14a2 and coexpressed transcripts demonstrated a significantly higher incidence of sustained molecular response compared with e13a2 (8-year probability, 43% vs 24%; P = .0021). The investigators also reported a suggestion that treatment with imatinib at 400 mg daily was associated with a lower probability of response among patients with e13a2.

Limitations and future prospects: This study was a retrospective analysis. If these data are confirmed in a prospective trial, it might suggest that specific transcript type could be a useful tool to help select optimal tyrosine kinase inhibitors for patients with newly diagnosed, chronic-phase CML.

Targeted Therapy for APL

Study: Nonchemotherapy approach for patients with acute promyelocytic leukemia (APL) in the non–high-risk disease category2

Study group/institution: Gruppo Italiano Malattie Ematologiche dell’Adulto (GIMEMA) Foundation, Rome; German-Austrian Acute Myeloid Leukemia Study Group, and Study Alliance Leukemia

Question being asked: What is the best induction therapy for patients with low- and intermediate-risk APL? Patients were randomly assigned to receive either all-trans retinoic acid (ATRA) plus arsenic trioxide (Trisenox) for induction and consolidation therapy or standard ATRA/idarubicin induction therapy followed by three cycles of consolidation therapy with ATRA plus chemotherapy and maintenance therapy with low-dose chemotherapy and ATRA.

Findings and conclusions: With a median follow-up of 53 months, the event-free survival rate (primary endpoint) at 50 months among the 156 patients in the intention-to-treat analysis was 96% (95% confidence interval [CI] = 92%–100%) in the ATRA/arsenic trioxide group and 81% (95% CI = 73%–91%) in the ATRA/chemotherapy group (P = .003). The overall survival rates were 99% (95% CI = 96%–100%) and 88% (95% CI = 81%–96%) in the respective groups (P = .006). 

Postremission events in the ATRA/chemotherapy group included six relapses and five deaths in remission (one of which was due to secondary leukemia). In the ATRA/arsenic trioxide group, there were two relapses and one death in remission, with no further events being recorded in this treatment group after the original publication in 2013.3

Strengths and practice implications: This study was a randomized phase III multicenter trial with long-term data. Together with data from the United Kingdom National Cancer Research Institute,4 these data strongly suggest that patients with non–high-risk APL (ie, patients presenting with a white blood cell count ≤ 10 × 109/L) have better outcomes with ATRA/arsenic trioxide than with the standard induction regimen of ATRA/chemotherapy.

Minimal Residual Disease in AML

Study: Assessment of minimal residual disease in standard-risk AML5

Study group/institution: UK National Cancer Research Institute Acute Myeloid Leukemia Working Group

Question being asked: What are the implications of NPM1-mutated transcripts monitored in blood during active therapy for AML?

Findings and conclusions: Data from patients treated on the National Cancer Research Institute AML17 trial were analyzed. Persistence of NPM1-mutated transcripts in blood was present in 15% of the patients after the second chemotherapy cycle and was associated with a greater risk of relapse after 3 years of follow-up than was an absence of such transcripts (82% vs 30%, hazard ratio [HR] = 4.80, 95% CI = 2.95–7.80, P < .001) and a lower rate of survival (24% vs 75%, HR for death = 4.38, 95% CI = 2.57–7.47, P < .001). In a multivariate analysis, the presence of minimal residual disease was the only independent prognostic factor for death (HR = 4.84, 95% CI = 2.57–9.15, P < .001). 

These results were validated in an independent cohort. On sequential monitoring of minimal residual disease, relapse was reliably predicted by a rising level of NPM1-mutated transcripts. 

Limitations and future prospects: This study was a retrospective analysis. Knowing that the presence of NPM1-mutated transcripts in the blood does not portend a worse outcome in all patients, what should be the optimal preemptive intervention? The minimal residual disease results should be interpreted in the context of specific “induction and consolidation” therapies. A prospective randomized trial using a validated technique to detect minimal residual disease in a homogeneously treated population is needed. 

Defibrotide Therapy

Study: Phase III trial of defibrotide for the treatment of severe veno-occlusive disease/sinusoidal obstruction syndrome and multiorgan failure after hematopoietic cell transplant6

Study group/institution: multicenter study

Question being asked: What are the safety and efficacy of defibrotide in patients (n = 102; children and adults) with established hepatic veno-occlusive disease/sinusoidal obstruction syndrome and advanced multiorgan failure (ie, by day +28 post–hematopoietic cell transplant)? 

Findings and conclusions: Outcomes of patients were compared with 32 historical controls identified from 6,867 medical charts of hematopoietic cell transplant recipients by blinded independent reviewers. The primary endpoint was survival at day +100 post-transplant. 

Observed survival rates were 38.2% in the defibrotide group and 25% in the control group (23% estimated difference; 95.1% CI = 5.2%–40.8%, P = .0109, using a propensity-adjusted analysis). Observed day +100 complete response rates were 25.5% for defibrotide recipients and 12.5% for controls (19% difference using similar methodology; 95.1% CI = 3.5%–34.6%, P = .0160). 

Defibrotide-related adverse events included hemorrhage or hypotension. The incidence of common hemorrhagic adverse events (including pulmonary alveolar bleeding [11.8% and 15.6%] and gastrointestinal bleeding [7.8% and 9.4%]) was similar between the defibrotide and control groups, respectively. 

Limitations and practice implications: This was a historically controlled, multicenter, open-label, phase III study. Given the highly consistent and promising results for defibrotide treatment of hepatic veno-occlusive disease/sinusoidal obstruction syndrome with multiorgan failure7,8 and the lack of any other effective therapy for this life-threatening disease, it was the unanimous view of the investigators, as well as the determination of their respective institutional review boards, that a placebo-controlled study was incompatible with clinical equipoise. 

Defibrotide sodium was approved by the U.S. Food and Drug Administration on March 30, 2016.9 Defibrotide therapy is now the preferred approach for a diagnosis of veno-occlusive disease/sinusoidal obstruction syndrome with renal or pulmonary dysfunction, in both the adult and pediatric populations. 

Use of the drug is contraindicated in patients being treated concurrently with anticoagulants or fibrinolytic therapies. The recommended dose and schedule for defibrotide sodium is 6.25 mg/kg intravenously every 6 hours given as a 2-hour infusion for at least 21 days and continued until resolution of veno-occlusive disease or up to 60 days of treatment. 

Preventing Graft-vs-Host Disease

Study: Antilymphocyte globulin for prevention of chronic graft-vs-host disease, assessed in a prospective, multicenter, open-label, randomized phase III study10

Question being asked: What is the impact of antilymphocyte globulin (10 mg/kg × 3 doses [days 3, 2, and 1 before transplantation]) on cumulative incidence of chronic graft-vs-host disease at 2 years in a myeloablative setting among patients (aged 18–65 years) in complete remission from acute leukemias who received peripheral-blood hematopoietic cells from HLA-matched sibling donors?

Findings and conclusions: A total of 168 patients were enrolled at 27 centers. Patients were randomly assigned in a 1:1 ratio to receive antilymphocyte globulin or not, with stratification according to center and risk of disease. Graft-vs-host disease prophylaxis consisted of cyclosporine and a short course of methotrexate. 

After a median follow-up of 2 years, the cumulative incidence of chronic graft-vs-host disease was 32.2% (95% CI = 22.1%–46.7%) in the antilymphocyte globulin group and 68.7% (95% CI = 58.4%–80.7%) in the non–antilymphocyte globulin group (P < .001). There were no significant differences between the two groups in the rates of relapse, infectious complications, acute graft-vs-host disease, or adverse events. 

The survival rate was similar in the two groups, but the rate of a composite endpoint of chronic graft-vs-host disease–free and relapse-free survival at 2 years was significantly higher in the antilymphocyte globulin group than in the non–antilymphocyte globulin group (36.6% vs 16.8%, P = .005). No post-transplantation lymphoproliferative disorder was observed during follow-up.

Limitations and future prospects: Unfortunately, the study was terminated at 2 years, and longer-term follow-up data for the patients who participated in this study are not available. The cumulative incidence of relapse at 2 years was 32.2% (95% CI = 23.4%–44.2%) in the antilymphocyte globulin group and 25.5% (95% CI = 16.3%–44.2%) in the non–antilymphocyte globulin group (P = .17). Patients in the antilymphocyte globulin group were aware of group assignment; the possibility of bias in the grading of chronic graft-vs-host disease cannot be excluded. ■

Hematology Expert Review is guest edited by Syed A. Abutalib, MD. Dr. Abutalib is Assistant Director, Hematology & Bone Marrow Transplantation Service, Cancer Treatment Centers of America, Zion, Illinois.

Disclosure: Dr. Abutalib reported no potential conflicts of interest.


1. Jain P, Kantarjian H, Patel KP, et al: Impact of BCR-ABL transcript type on response and survival in patients with chronic phase chronic myeloid leukemia treated with tyrosine kinase inhibitors. Blood 127:1269-1275, 2016.

2. Lo-Coco F, Di Donato L, for GIMEMA, et al: Targeted therapy alone for acute promyelocytic leukemia. N Engl J Med 374:1197-1198, 2016.

3. Lo-Coco F, Avvisati G, Vignetti M, et al: Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N Engl J Med 369:111-121, 2013.

4. Burnett AK, Russell NH, Hills RK, et al: Arsenic trioxide and all-trans retinoic acid treatment for acute promyelocytic leukaemia in all risk groups (AML17): Results of a randomised, controlled, phase 3 trial. Lancet Oncol 16:1295-1305, 2015.

5. Ivey A, Hills RK, Simpson MA, et al: Assessment of minimal residual disease in standard-risk AML. N Engl J Med 374:422-433, 2016.

6. Richardson PG, Riches ML, Kernan NA, et al: Phase 3 trial of defibrotide for the treatment of severe veno-occlusive disease and multi-organ failure. Blood 127:1656-1665, 2016.

7. Richardson PG, Elias AD, Krishnan A, et al: Treatment of severe veno-occlusive disease with defibrotide: Compassionate use results in response without significant toxicity in a high-risk population. Blood 92:737-744, 1998.

8. Corbacioglu S, Greil J, Peters C, et al: Defibrotide in the treatment of children with veno-occlusive disease (VOD): A retrospective multicentre study demonstrates therapeutic efficacy upon early intervention. Bone Marrow Transplant 33:189-195, 2004.

9. U.S. Food and Drug Administration: Defitelio (defibrotide sodium). Available at Accessed May 6, 2016.

10. Kröger N, Solano C, Wolschke C, et al: Antilymphocyte globulin for prevention of chronic graft-versus-host disease. N Engl J Med 374:43-53, 2016.