Results of the randomized Phase III UKALL 2011 study


Standard treatment for acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LBL) involves chemotherapy at each stage, which causes both short- and long-term adverse effects. At ASH, Ajay Vora, MD, Great Ormond Street Hospital, London, UK, presented the results of the randomized Phase III study UKALL 2011 (EudraCT 2010-020924-22), which aimed to reduce induction toxicity, relapse risk and maintenance morbidity in children and young adults with ALL or LBL by making changes to the current standard therapy.

Dr Vora reported on two of the primary endpoints: methotrexate randomization (R2IM), establishing whether the use of high-dose methotrexate can reduce central nervous system relapse rate (CNSR), and pulses randomization (R2pulses) analyzing whether monthly pulses of vincristine and dexamethasone can be omitted without increasing the risk of relapse.



There was no difference in CNSR with high-dose methotrexate versus standard interim maintenance (HR: 0.99 (0.65-1.51), p=0.97, 5-year rates: 5.6% and 5.6%) or any other endpoints for R2IM. However, in those treated with standard dexamethasone there was a significant reduction in bone marrow relapse rate (BMR) with high-dose methotrexate (HR 0.62 (95% CI: 0.40 – 0.95) p = 0.029) and a trend for improvements in event-free (EFS) and overall survival (OS; HRs: 0.75 [95%CI: 0.53 – 1.04], p=0.087 and 0.61 [0.37 – 1.03], p=0.067). For R2pulses, in patients treated with standard dexamethasone, standard interim maintenance without vincristine/dexamethasone pulses had a lower EFS, but there was no appreciable benefit of pulses in high-dose methotrexate treated patients; 5-year EFS difference: -2.8% (95% CI: -7.4% to 4.4%) and BMR (ALL): +0.4% (-6.7% to 4.3%).1


Results from the randomized Phase III ASAP trial


In his presentation, Johannes Schetelig, MD, MSc, University Hospital TU Dresden, Germany, shared results from the Phase III ASAP trial (NCT02461537), the first randomized controlled trial to question the benefit of intensive remission induction chemotherapy prior to allogeneic hematopoietic cell transplantation (alloHCT) in relapsed or refractory (R/R) acute myeloid leukemia (AML).


It is known that patients achieving complete remission ahead of transplant have favorable outcomes, but the benefit of inducing this with intensive chemotherapy is thus far undetermined. In the trial patients were randomized 1:1 to the intensive chemotherapy remission induction strategy (RIST)-arm or to disease control (DISC-arm) with watchful waiting recommended but low-dose cytarabine and single doses of mitoxantrone permitted for disease-control.

Dr Schetelig reports that chemotherapy with high-dose cytarabine and mitoxantrone before alloHCT did not result in a higher overall success rate, and did not confer a survival advantage. The primary endpoint, complete response (CR) at 56 days after alloHCT, was reached by 84.1% of patients in the DISC-arm and 81.3% of pts in the RIST-arm (test for non-inferiority, p=0.047). One-year leukemia-free survival (LFS) from CR at day 56 was 71.5% in the DISC-arm and 69.9% in the RIST-arm (z test, p=0.8). OS at one year and three years from randomization was 69.1% (95%-CI, 60.6-76.1%) versus 71.9% (95%-CI, 63.3-78.9%) and 51.0% (95%-CI, 41.8-59.6%) versus 54.2% (95%-CI, 44.4-62.9%) in the DISC- and RIST-arm, respectively (log-rank p=0.47).

Overall investigators suggest that, because watchful waiting followed by sequential conditioning and alloHCT resulted in comparable CR rates and OS, this should be the approach taken without prior remission induction intensive chemotherapy whenever a stem cell donor is readily available.2


Final analysis of the Neutrodiet trial


The use of low-microbial protective diet (PD) has been widely adopted as a standard of care (SOC) to prevent infections in patients with neutropenia after hematopoietic stem cell transplantation (HSCT), despite a lack of standardization and the fact that its efficacy has never been tested prospectively. Federico Stella, MD, Università degli Studi di Milano, Milan, Italy, will present the final analysis of the Neutrodiet multicenter, randomized trial, which found no significant difference in terms of infection rates, feeding outcomes and acute graft-versus-host disease (aGvHD) incidence between protective diet (PD) and non-restrictive diet (NRD).

Grade >2 infections occurred in 38 (34%) and 44 patients (39%), assigned to PD and NRD respectively (RR = 0.86; 95% Confidence Interval [CI] = 0.6-1.2, p=0.5). The incidence of fever of unknown origin and sepsis was similar, respectively 43% in PD versus 39% in NRD (RR=1.3; 95% CI = 0.9-1.7, p=0.2) and 11% in PD versus 14% in NRD (RR=0.7; 95% CI = 0.4-1.5, p=0.5).

No differences were found between arms in terms of body weight variations, incidence of nausea and mucositis, hospitalization length, parenteral nutrition (PN) use and PN duration. In addition, there was no difference in terms of any grade aGvHD and intestinal aGvHD, respectively 30% in PD versus 33% in NRD (RR=0.9; 95% CI = 0.4-2.1, p>0.99) and 13% in PD versus 8% in NRD (RR=1.6; 95% CI = 0.3-7.4, p=0.6).



Analysing patients’ daily diaries reveals that the NRD was associated with higher satisfaction, leading the investigators to suggest the use of a restrictive diet is an unnecessary burden for patients.3

Results from European MCL Network’s randomized TRIANGLE trial


High-dose cytarabine-containing immunochemotherapy followed by autologous hematopoietic cell transplantation (autoHCT) and rituximab maintenance is the current SOC for younger patients with mantle cell lymphoma (MCL). However, with the BTK inhibitor ibrutinib showing promise, the European MCL Network’s randomized, open-label, three-arm TRIANGLE trial (EudraCT 2014-001363-12) compared the failure-free survival (FFS) of SOC (arm A), SOC plus ibrutinib (A+I) and ibrutinib containing treatment without autoHCT (arm I).



Martin Dreyling, MD, LMU University Hospital Munich, Munich, Germany, shared how the addition of ibrutinib during induction and as maintenance with or without autoHCT showed strong efficacy with acceptable toxicity. Overall response (OR) and CR rates were 94% and 36% of 272 evaluable patients in arm A (R-CHOP/R-DHAP) versus 98% and 45% of 559 evaluable patients in the combined A+I/I arms (ibrutinib-R-CHOP/R-DHAP). After a median follow-up of 31 months, A failed to show superiority over I with three-year FFS 72% for A versus 86% for I (p=0.9979, hazard ratio: 1.77. A+I was superior to A in terms of FFS with 3-year FFS 88% (A+I) versus 72%, respectively (p=0.0008, hazard ratio: 0.52).

Three-year OS was 86% in A, 91% in A+I, and 92% in I. There were no substantial differences in the occurrence of grade 3-5 AEs during induction with the three regimens, and the two autoHCT-containing arms did not substantially differ in grade 3-5 AEs. In contrast, during maintenance, there were substantially more grade 3-5 AEs in A+I as compared to A and I (A+I/A/I: neutropenia: 44%/17%/23%, leukopenia: 4%/2%/2%, febrile neutropenia: 6%/3%/3%, infections and infestations: 25%/13%/19%, cardiac disorders: 3%/1%/4%).

The results led investigators to conclude that the current standard high-dose regimen is not superior to the ibrutinib-containing regimen without autoHCT, and that therefore ibrutinib could be used in the first-line treatment of younger patients with MCL. They noted however that more follow-up is required to establish the role of autoHCT in the context of ibrutinib-containing treatment.4


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