EHA 2016: Stopping TKIs in CML and Improving Overall Survival in ALL

By Kathy Boltz, PhD

According to findings from the large European Stop TKI (EURO-SKI) Study, stopping tyrosine kinase inhibitor (TKI) therapy in patients with chronic myeloid leukemia (CML) can be safe. Findings were presented at the recently held 2016 European Hematology Association (EHA) 21st Annual Congress and reported here.  

The EURO-SKI trial sought to determine what fraction of patients can be sustained in molecular relapse-free remission after stopping TKI treatment and what clinical and biological factors predict a successful TKI-stop.  A total of 750 patients with CML were evaluated for molecular relapse-free survival in this large trial.

Since TKI therapy has high cost and a diminished quality of life over time, patients with CML with durable complete molecular responses often ask if they can safely stop kinase inhibitor treatment without relapse.1

At 6 months after stopping TKI therapy, EURO-SKI found that 62% of the patients still maintained treatment response. Treatment response was defined as major molecular response (MMR). 

Duration of TKI therapy and a very good therapy response (ie, MR4) prior to stopping were found to be good predictors of a successful stop. However, the other prognostic indicators of gender, age, and risk score were not linked to likelihood of successful stopping of TKI therapy.

After 12 months after stopping TKI therapy, 56% of the patients maintained molecular relapse-free survival, meaning they did not relapse. 

“Stopping TKI therapy in a very large cohort of CML patients appears feasible and safe,” said lead author Johan Richter, MD, PhD, Skåne University Hospital, Lund, Sweden. 

Among the 750 patients evaluated for molecular relapse after stopping TKI treatment, 347 events of molecular relapse occurred. 

Prognostic modeling for patients who received imatinib found that treatment duration and duration of deep molecular relapse significantly correlated with MMR status at 6 months after stopping TKI. Each additional year of imatinib treatment increased the odds of maintaining MMR by 16%. 

“We have identified a cutoff suitable for stopping imatinib therapy, which is around 6 years,” said Richter. At 6 months, molecular relapse-free survival was 65.5% for imatinib treatment of longer than 5.8 years and 42.6% for treatment of 5.8 years or less, based on the minimal p-value approach.

The enrolled patients had a median duration of TKI therapy of 7.6 years (range, 3.0-14.2 years), and a median duration of deep molecular remission before stopping TKI therapy of 4.7 years (range, 1.0-13.3 years). 

The majority of patients (n=710) received imatinib first line, while some patients (n=35) received nilotinib, and others (n=14) dasatinib. Because of intolerance, 115 patients had been switched to second-line TKIs, with most receiving either nilotinib or dasatinib.

Molecular relapse-free survival slightly declined over time. At 6 months, the molecular relapse-free survival rate was 62%; at 12 months, 56%; at 24 months, 52%; and at 36 months, 49%. For patients who resumed treatment, the median time to restart was 4.1 months.

Richter noted that some of the patients who withdrew from TKI therapy experienced musculoskeletal pain, which was considered newly emergent and mostly transient; 1.2% (n=9) experienced Grade 3 pain, and 235 patients (30.9%) experienced musculoskeletal symptoms.

EHA 2016: Stopping TKIs in CML and Improving Overall Survival in ALL (continued)

Blinatumomab improved overall survival in R/R acute lymphoblastic leukemia (ALL)

This confirmatory study supported the accelerated FDA approval of blinatumomab (BLINCYTO; Amgen) for relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL). Blinatumomab was FDA approved in December 2014 as a breakthrough therapy for Philadelphia chromosome-negative (Ph-) B-cell precursor ALL and was granted conditional marketing approval in the EU in November 2015 for adults with R/R Ph- B-cell precursor ALL.

Overall survival (OS) was prolonged almost 2-fold with blinatumomab vs standard of care (SOC) chemotherapy in R/R ALL (7.7 months vs 4.0 months, respectively). The open-label TOWER phase 3 study randomized patients 2:1 to receive blinatumomab (n=271) or SOC (n=134). Patients had R/R Ph- B-cell precursor ALL. 

The trial was ended early for efficacy based on the recommendation of an independent data monitoring committee. This was the first study to show improved survival with immunotherapy vs SOC in R/R ALL.

"Acute lymphoblastic leukemia is the most aggressive type of B-cell malignancy," said Max S. Topp, MD, professor and head of hematology, University Hospital of Würzburg, Germany. "The data presented today not only reinforce the potential of immunotherapy delivered by T cell engaging bispecific antibody constructs, but also validate the efficacy of BLINCYTO in these heavily pretreated patients."

Blinatumomab is a bispecific CD19-directed CD3 T cell engager (BiTE) antibody construct. It binds specifically to CD19 on B-precursor ALL cells and to CD3 on normal T cells. This type of modified antibody juxtaposes T cells to cancer cells. 

Currently, no broadly accepted standard regimen exists for adult patients with ALL beyond chemotherapy. The prognosis for adults with R/R ALL is typically very poor, as their median OS is 3 to 5 months.

The OS benefit from blinatumomab vs SOC for intent-to-treat patients (stratified log-rank p=.012; HR=0.71 [95% CI, 0.55-0.93]) held across subgroup analyses. 

When the OS data were censored for allogeneic hematopoietic stem cell transplantation (allo-HSCT), the median OS was 6.9 months for blinatumomab treatment (95% CI, 5.3-8.8 months) vs 3.9 months for SOC (95% CI, 2.8-4.9 months; stratified log-rank p=.004; HR=0.66 [95% CI, 0.50-0.88]). 

Further, blinatumomab improved OS regardless of age, for 0 or 1 prior salvage therapy, for  +/- prior allo-HSCT, and for baseline bone marrow blasts above or below 50%.

Overall response rate was 45% in the blinatumomab group vs 30% in the SOC group (p=.007). Complete remissions occurred in 34% of patients treated with blinatumomab and 16% of patients treated with SOC (p<.001). 

Among patients who responded, molecular remission (<10-4 blasts in the first 12 weeks) occurred in 76% of patients treated with blinatumomab and 48% of patients treated with SOC. 

Adverse events in patients treated with blinatumomab were consistent with prior studies. Blinatumomab was associated with less frequent Grade 3 or higher neutropenia and infection than SOC, while both treatment regimens had similar rates of neurologic events of Grade 3 or higher (9% vs 8%).

EHA 2016: Stopping TKIs in CML and Improving Overall Survival in ALL (continued)

Inotuzumab Ozogamicin in R/R ALL

In the phase 3 INO-VATE study of relapsed or refractory ALL (n=326), 2-year survival rates increased to 23% with inotuzumab ozogamicin (Pfizer) compared with 10% with SOC. The FDA granted breakthrough therapy designation for inotuzumab ozogamicin in October 2015. This designation was based on an interim analysis from the INO-VATE trial, and the final results of that trial were presented at EHA 2016. 

“Relapsed or refractory ALL is an aggressive leukemia in urgent need of new treatment options as about half of adult patients will not respond to chemotherapy or will see their disease return,” said Hagop M. Kantarjian, MD, lead study investigator and professor, The University of Texas MD Anderson Cancer Center, Houston, Texas. 

Only 20% to 40% of newly diagnosed adults with ALL are cured with current treatment regimens. Further, for adults with ALL who relapse after first-line therapy or are refractory to it, only 10% will survive 5 years or more with current treatment options.

Inotuzumab ozogamicin is an antibody-drug conjugate that targets CD22, which is found on cancer cells in almost every B-ALL patient. The antibody is linked to a cytotoxic agent, calicheamicin, which induces apoptosis.

“The efficacy results seen in patients treated with inotuzumab ozogamicin in this study are impressive, particularly median progression-free survival, high rates of hematological remission, and absence of minimal residual disease,” stated Kantarjian. 

Patients treated with inotuzumab ozogamicin had a median progression-free survival of 5.0 months vs 1.8 months with SOC (hazard ratio=0.45; p<.001). 

Complete responses were 80.7% with inotuzumab ozogamicin vs 29.4% with SOC. Minimal residual disease (MRD) was negative for 78.4% of the patients treated with inotuzumab ozogamicin vs 28.1% of patients treated with chemotherapy.

“About 3 to 5 times more patients on inotuzumab were ultimately able to access allogeneic stem cell transplantation. In my opinion, inotuzumab is well tolerated with appropriate prevention measures,” said Kantarjian. “These results suggest inotuzumab ozogamicin, if approved, could be a valuable new addition to currently available treatment options for ALL patients, including as a bridge to stem cell transplantation, which is the best chance for a cure at this stage of the disease.”

Inotuzumab ozogamicin treatment allowed 41% of patients to proceed to stem-cell transplant vs 11% of patients treated with SOC (p<.001).2

Cytopenias were the most common treatment-emergent adverse events in both arms. Inotuzumab led to a higher incidence of liver function abnormalities (all Grade, 23% vs 11%). 

Veno-occlusive liver disease (VOD) was more common in the inotuzumab arm than in the SOC arm (11% vs 1%, respectively), though only 3% of the patients receiving inotuzumab developed VOD prior to SCT.

“My hope is that in the near future, inotuzumab will be used not as a single agent, but in combination with chemotherapy or with other monoclonal antibodies that target CD19 both in salvage and frontline settings. This will hopefully improve the outcome of patients with ALL significantly compared to what we know today,” concluded Kantarjian.


  1. Sweet K and Oehler V. Discontinuation of tyrosine kinase inhibitors in chronic myeloid leukemia: when is this a safe option to consider? Hematology Am Soc Hematol Educ Program. 2013;2013:184-188. doi: 10.1182/asheducation-2013.1.184.
  2. Kantarjian HM et al. Inotuzumab ozogamicin versus standard therapy for acute lymphoblastic leukemia. New Engl J Med. 2016;375(8):740-753.
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