Blinatumomab consolidation improves OS in ALL


Though adults with newly diagnosed acute lymphoblastic leukemia (ALL) can achieve a high rate of complete remission (CR) with conventional chemotherapy, they frequently relapse and have suboptimal survival rates even if their measurable residual disease (MRD) status is negative after induction.

Mark Litzow, MD, Mayo Clinic, Rochester, MN, presented the results of a Phase III trial randomizing patients to conventional chemotherapy with or without blinatumomab to determine if patients who become MRD- (<0.01%) after induction have improved outcomes with the addition of blinatumomab.

In the ECOG-ACRIN E1910A trial (NCT02003222), 488 were enrolled on step one induction therapy, a total of 224 MRD- patients were randomized; 112 patients to each arm, with 22 MRD- patients in each arm proceeding to allogeneic bone marrow transplant (BMT).

The addition of blinatumomab to consolidation chemotherapy resulted in a significantly better overall survival in patients with newly diagnosed B-lineage ALL who were MRD- after intensification chemotherapy. The complete response (CR)/complete response with incomplete hematologic recovery (CRi) rate after induction chemotherapy was 81%. At the third interim efficacy analysis, 56 of the MRD- patients, had died, 17 in the blinatumomab arm and 39 in the control chemotherapy arm. Blinatumomab also demonstrated a significant improvement in overall survival (OS; median OS: not reached versus. 71.4 months, respectively; Hazard ratio 0.42, 95% CI: 0.24 – 0.75; two-sided p=0.003). Median follow-up was 43 months.


No significant safety concerns were noted and thus the addition of blinatumomab to consolidation chemotherapy in adults aged 30-70 years represents a new standard of care for BCR:ABL1-negative patients with ALL.1

Iptacopan superior to SOC in patients with PNH and residual anemia


Up to 20% of patients with hemolytic paroxysmal nocturnal hemoglobinuria (PNH) have clinically meaningful residual anemia with standard of care (SOC) intravenous (IV) anti-C5 monoclonal antibodies. In his presentation, Regis Peffault De Latour, of the French Référence Center for Aplastic Anemia and Paroxysmal Nocturnal Hemoglobinuria, Paris, France, reported the primary efficacy and safety data from the 24-week randomized treatment period of the pivotal, multicenter, Phase III APPLY-PNH trial (NCT04558918) of iptacopan, a first-in-class, oral, selective complement factor B inhibitor.

The two primary endpoints were the proportion of patients with a ≥2 g/dL mean hemoglobin (Hb) increase from baseline and the proportion of patients with Hb ≥12 g/dL, each in the absence of red blood cell transfusions (RBCTs). Both of these endpoints were achieved with iptacopan monotherapy, showing superiority over SOC; 51/60 iptacopan-treated versus 0/35 SOC-treated patients with evaluable/non-missing data had a ≥2 g/dL Hb increase from baseline, and 42/60 versus 0/35, respectively, achieved Hb ≥12 g/dL (both P<0.0001).


Iptacopan monotherapy also showed superiority in several of the secondary endpoints: transfusion avoidance, changes from baseline in Hb level, Functional Assessment of Chronic Illness Therapy – Fatigue (FACIT-F) score and absolute reticulocyte count , and rate of clinical breakthrough hemolysis. At 24 weeks, nearly all patients (60/62) in the iptacopan arm remained RBCT free versus 14/35 in the SOC arm.

There were no deaths and no serious encapsulated bacteria infections. One iptacopan-treated patient had a major adverse vascular event. Two SOC-treated patients had serious adverse events of hemolysis. No patients discontinued iptacopan or SOC because of adverse events (AEs).

This led the investigators to suggest that single agent iptacopan may represent a practice-changing, treatment for patients with PNH who have an inadequate response to IIV anti-C5 SOC therapy, and could potential become a preferred treatment option for patients with hemolytic PNH.2

Non-myeloablative chemoimmunotherapy versus HDC-autoHCT in primary CNS lymphoma


Gerald Illerhaus, MD, Klinikum Stuttgart, Stuttgart, Germany, discussed the primary endpoint results of the Phase III MATRix/IELSG43 trial (NCT02531841) in patients with newly diagnosed primary central nervous system lymphoma (PCNSL).

The trial found that after high-dose methotrexate (HD-MTX) based induction immunochemotherapy, consolidative high-dose chemotherapy and autologous hematopoietic cell transplantation (HDC-autoHCT) had a significantly better outcome than non-myeloablative chemoimmunotherapy (R-DeVIC regimen).

In total 346 patients started treatment, of which 260 (75%) completed the induction therapy with 239 (69%) responding (27% achieved a complete remission [CR] and 52% a partial remission [PR]). 115 patients went on to be randomly assigned to arm A (R-DeVIC regimen) and 114 to arm B (HDC-autoHCT). Both consolidation strategies were well tolerated: R-DeVIC and HDC-autoHCT were completed in 100 (87%) and 111 (97%) patients, respectively.


Consolidation treatment with R-DEVIC or HDC-autoHCT resulted in a substantial increase of patients with CR (65% in arm A and 68% in arm B, respectively; p= 0.71). Three-year progression-free survival (PFS), the primary endpoint, differed significantly between the two arms: 79% (95% CI 71-86) after HDC-autoHCT and 53% (95% CI 43-62%) after R-DeVIC (HR 0.42; p=0.0003). The three-year OS was 86% (95% CI 78-91) for HDC-autoHCT arm and 71% (95% CI 61-78) for R-DeVIC arm (HR 0.47; p=0.01).

During the trial, 13 (3.8%) patients died of treatment-related complications during induction treatment, 11 due to neutropenic infectious complications, while six patients died of toxicity during consolidation treatment (two arm A and four arm B). A further six patients died of unrelated causes while relapse-free (five arm A and one arm B). The evaluation of neurocognitive functions showed no difference between arms.3

Cyclophosphamide, tacrolimus, and mycophenolate mofetil as GvHD prophylaxis


Controlling both graft-versus-host disease (GvHD) and disease relapse is essential for allogeneic hematopoietic cell transplantation (alloHCT) success. Shernan Holtan, MD, of the University of Minnesota, Minneapolis, MN, presented results of a randomized Phase III study comparing outcomes of alloHCT in those randomized to receive a three-drug combination of post-transplant cyclophosphamide (PTCy), tacrolimus, and mycophenolate mofetil (PTCy/Tac/MMF) versus SOC calcineurin inhibitor such as tacrolimus (Tac) plus methotrexate (MTX; Tac/MTX).

In the BMT CTN 1703 trial (NCT03959241), eligible adults with hematologic malignancies undergoing reduced intensity conditioning (RIC) alloHCT were randomized 1:1 to receive PTCy/Tac/MMF (n=214) or Tac/MTX (n=217).


In the multivariate Cox regression model of the primary endpoint, the PTCy treatment group had a significantly lower hazard of GvHD/relapse or progression-free survival (GRFS) than Tac/MTX (hazard ratio 0.641, 95% confidence interval [CI] 0.492 to 0.835, p=0.001). The adjusted one-year GRFS rate was 52.7% (95% CI: 45.8%, 59.2%) for the PTCy arm and 34.9% (95% CI: 28.6%, 41.3%) for the control arm). The lower proportion of GRFS events in the PTCy arm was due to a reduction in both acute and chronic GvHD.

The Day 100 grade III-IV acute GvHD rate was 6.3% versus 14.7% (p=0.001), and chronic GvHD rate at one year was 21.9% versus 35.1% (p=0.005) for PTCy versus Tac/MTX, respectively. There was no significant difference in the relapse/progression rate at one year (20.8% versus 20.2%, p=0.9), or OS rate at one year post-transplant (76.8% versus 72.6% , p=0.3), in PTCy versus Tac/MTX.

Grade 3 infection rates were similar between the arms (12.2% for PTCy versus 13.3%, p=0.8) but grade 2 infections were greater for PTCy (33.7% versus 23.5%, p=0.002). There was no significant difference in cytomegalovirus (CMV) reactivation between the treatment arms (p=0.8), nor in proportion of chimerism at day +100 (p=0.2), nor secondary graft failure between the arms (p=0.2).

As a result of the higher one-year GRFS and significant improvements in GvHD risk without increased risk of relapse or death, the investigators suggest PTCy/Tac/MMF, which is already SOC for mismatched transplants, should also become SOC for GvHD prophylaxis from closely-matched donors receiving reduced-intensity conditioning.4

Anticoagulant therapy in women with recurrent miscarriage and inherited thrombophilia


Studies have shown an association between recurrent miscarriage and inherited thrombophilia. In her presentation, Saskia Middeldorp, MD, PhD, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, Netherlands, and Radboud University Medical Center, Nijmegen, Netherlands, discussed the results of a Phase III randomized trial (EudraCT 2015-002357-35) evaluating whether anticoagulant therapy with low-molecular-weight heparin (LMWH) can increase live birth rate in these women.

Women (18-42 years) who had two or more pregnancy losses and confirmed inherited thrombophilia who were actively trying to conceive or less than seven weeks pregnant were eligible for inclusion. The primary outcome measure was live birth rate. Secondary outcomes included adverse pregnancy outcomes, such as miscarriage, obstetric complications, and congenital malformations. Safety outcomes included bleeding episodes, thrombocytopenia, and skin reactions to the prescribed study medication.

A total of 326 women conceived and were randomized; 164 were assigned to the LMWH group and 162 were assigned to the standard surveillance group. Observed live birth rates were 116/162 (71.6%) in the LMWH group and 112/158 (70.9%) in the standard surveillance group (adjusted OR 1.08 [95% CI 0.65 to 1.78]; absolute difference 0.7% [95% CI -9.2% to 10.6%]). AEs were reported for 39 women (23.8%) in the LMWH group and 37 (22.8%) women in the standard surveillance group.


Compared with standard surveillance, the use of LMWH did not result in higher live birth rates in women who had two or more pregnancy losses and confirmed inherited thrombophilia. Thus the researchers advised against the routine use of LMWH in these women, and against routine testing for inherited thrombophilia in women with recurrent pregnancy loss.5

Superior PFS with zanubrutinib in R/R CLL/SLL


Jennifer Brown, of the Dana-Farber Cancer Institute, Boston, MA, presented the results of the randomized Phase III ALPINE study (NCT03734016) in which zanubrutinib demonstrated superior overall response rate (ORR) and PFS over ibrutinib in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia and small lymphocytic lymphoma (R/R CLL/SLL).

A total of 652 patients were randomized to receive zanubrutinib, a next-generation Bruton tyrosine kinase Inhibitor (BTKi; n=327) or ibrutinib (n=325). Demographic and disease characteristics were balanced between the arms with median age 67 and 68 years, respectively, and median prior lines of therapy being one in both arms.


At a median follow-up of 29.6 months zanubrutinib PFS, assessed by independent review committee, was superior to ibrutinib; not reached versus 35.0 months, respectively (HR: 0.65 [95% CI, 0.49-0.86]; two-sided P=.0024). PFS, regardless of IRC or investigator assessment, consistently favored zanubrutinib across major predefined subgroups, including del(17p)/TP53 mutation and IGHV status. Compared with ibrutinib, zanubrutinib also had a higher ORRIRC (86.2 versus 75.7%, nominal two-sided P=.0007), with a rate of partial response with lymphocytosis (PR-L) or better of 91.7% versus 83.1% (nominal two-sided P=.001).

Treatment discontinuation rate was lower with zanubrutinib (26.3%) versus ibrutinib (41.2%). Rates of grade ≥ three AEs (67.3 versus 70.4%), SAEs (42.0% versus 50.0%), dose interruption (50.0% versus 56.8%), and dose reduction (12.3 versus 17.0%) were also lower with zanubrutinib. Rate of atrial fibrillation/flutter was also lower with zanubrutinib (5.2% versus 13.3%).

There were no grade five AEs due to cardiac disorders with zanubrutinib versus six (1.9%) with ibrutinib. Overall, 48 (14.7%) patients treated with zanubrutinib and 60 (18.5%) treated with ibrutinib had died (OS HR: 0.76 [95% CI, 0.51-1.11]).

Investigators concluded that, with the ALPINE results, zanubrutinib has proven superiority to ibrutinib in both efficacy and safety with R/R CLL/SLL.6


  1. Litzow MR, Sun Z, Paietta E, et al. Consolidation Therapy with Blinatumomab Improves Overall Survival in Newly Diagnosed Adult Patients with B-Lineage Acute Lymphoblastic Leukemia in Measurable Residual Disease Negative Remission: Results from the ECOG-ACRIN E1910 Randomized Phase III National Cooperative Clinical Trials Network Trial. Blood. 2022 Dec 6;140(Supplement 2):LBA-1.
  2. Peffault de Latour R, Roeth A, Kulasekararaj A, et al. Oral Monotherapy with Iptacopan, a Proximal Complement Inhibitor of Factor B, Has Superior Efficacy to Intravenous Terminal Complement Inhibition with Standard of Care Eculizumab or Ravulizumab and Favorable Safety in Patients with Paroxysmal Nocturnal Hemoglobinuria and Residual Anemia: Results from the Randomized, Active-Comparator-Controlled, Open-Label, Multicenter, Phase III Apply-PNH Study. Blood. 2022 Dec 6;140(Supplement 2):LBA-2.
  3. Illerhaus G, Ferreri AJM, Binder M, et al. Effects on Survival of Non-Myeloablative Chemoimmunotherapy Compared to High-Dose Chemotherapy Followed By Autologous Stem Cell Transplantation (HDC-ASCT) As Consolidation Therapy in Patients with Primary CNS Lymphoma – Results of an International Randomized Phase III Trial (MATRix/IELSG43). Blood. 2022 Dec 6;140(Supplement 2):LBA-3.
  4. Holtan SG, Hamadani M, Wu J, et al. Post-Transplant Cyclophosphamide, Tacrolimus, and Mycophenolate Mofetil As the New Standard for Graft-Versus-Host Disease (GVHD) Prophylaxis in Reduced Intensity Conditioning: Results from Phase III BMT CTN 1703. Blood. 2022 Dec 6;140(Supplement 2):LBA-4.
  5. Quenby S, Booth K, Hiller L, et al. Low-Molecular-Weight Heparin Versus Standard Pregnancy Care for Women with Recurrent Miscarriage and Inherited Thrombophilia (ALIFE2): An Open-Label, Phase III Randomized Controlled Trial. Blood. 2022 Dec 6;140(Supplement 2):LBA-5.
  6. Brown JR, Eichhorst B, Hillmen P, et al. Zanubrutinib Demonstrates Superior Progression-Free Survival (PFS) Compared with Ibrutinib for Treatment of Relapsed/Refractory Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma (R/R CLL/SLL): Results from Final Analysis of ALPINE Randomized Phase 3 Study. Blood. 2022 Dec 6;140(Supplement 2):LBA-6.
Written by Hannah Balfour
Edited by Thomas Southgate & Elitsa Kamberska

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