July 2015 Edition Vol.11, Issue 7

European Hematology Association: Remains of the Day

European Hematology Association:
Remains of the Day (cont.)

In the reported trial, a phase 3 investigation that enrolled patients with relapsed/refractory ALL who had undergone at least one salvage treatment (N=326), INO was compared with physician’s choice of one of three SOC regimens: FLAG (fludarabine, cytarabine; high dose Ara-C, and GCSF); Ara-C plus mitoxantrone; or high-dose Ara-C.
All patients tested positive for the CD22 target.
Results for this investigation showed a significant improvement in outcome with INO treatment, with complete response (CR) rates of 35.8% for INO vs. 19.8% for the SOC arm (p=0.006), and a CR/CRi rate of 80.7% vs. 33.3% for SOC (p<0.0001; CRi=complete response with an incomplete hematologic recovery).
Of those responders, minimal residual disease was achieved in 78.4% for INO vs. 28.1% in standard chemotherapy arm. 
“It should be noted that two-thirds of patients in the INO arm who had a prior transplant were still able to achieve a complete remission,” said Dr. DeAngelo. 

INO was well tolerated – the only the measure that was greater with INO treatment was an elevated AST, a liver enzyme. All other side effects were greater in the SOC arm.

The study is ongoing, and data regarding overall survival will not mature until Q1 2016.

Venetoclax in CLL

Venetoclax is an oral drug that targets the BCL-2 protein, a key component of the molecular pathway involved in programmed cell death, or apoptosis, a naturally occurring process that occurs in cells that are damaged or stressed. In the setting of chronic lymphoid leukemia (CLL), cells overexpress BCL-2 in an effort to avoid the apoptosis signal; ventoclax blocks the survivalist activity of BCL-2, and thereby restores the apoptotic pathway. 

“What is does is tells a CLL cell that is happy under any stress, because it has a lot of this BCL-2 protein to, well, drop dead,” said study investigator Andrew Roberts PhD, Royal Melbourne Hospital, Melbourne Australia. 
CLL is the most common leukemia in Europe and North America and while there are many patients with a good prognosis, those who relapse early after SOC, or who don’t respond at all to initial treatments have a very poor prognosis. “This is why new treatments are very much needed,” explained Dr. Roberts.  
In this phase 1b, open-label study, venetoclax was combined with the hematologic warhorse, rituximab, in a cohort of patients with relapsed/refractory CLL (N=49).  
After a median time on study of 13 months, the venetoclax/rituximab combination produced a CR rate of 41%, with an overall response rate of 84%.
Of note, 6 patients were deemed healthy enough to go off treatment after achieving a deep CR. “That’s pretty exciting. Only one of these patients has had a recurrence, and that’s two years after stopping treatment.”  
Adverse events of greater that 25% incidence for the cohort were neutropenia (53%) and diarrhea and nausea (both 47%).
There was one treatment-related death reported, this due to tumor lysis syndrome. 
“All drugs have side effects, and the most dramatic side effect observed is when this drug works too well when you first give it,” said Dr. Roberts. As a result, initial doses of the drug have been lowered for further investigations.  

Results to date for venetoclax have led the FDA to grant breakthrough designation in May of this year, and the combination is currently being compared with standard chemotherapy (bendamustine) in an international randomized phase 3 trial. 

Sorafenib in AML

This is not a new drug by any means. Sorafenib, a small molecule inhibitor of several kinases, was initially approved for renal cell carcinoma in 2005. Despite observed in vitro activity in hematologic malignancies, the drug has currently no indications this setting. 

The SORAML trial, a phase 2 investigation, looked at the use of sorafenib in a cohort of younger (<65) patients with newly diagnosed acute myeloid leukemia (AML; N=267).   

All of the study patients first received two cycles of induction with DA (daunorubicin and cytarabine) or HAM (cytarabine, mitoxantrone) followed by cytarabine consolidation (SOC). Following SOC induction steps, and consolidation, patients were randomized to receive either sorafenib or placebo. 

After three years of follow-up, the reported progression-free survival for the sorafenib arm was 20.5 months vs. 9.2 months for SOC; overall survival at three years was 63% for sorafenib vs. 56% for placebo. 

Median overall survival has not been reached in either treatment arm. 

As expected, there were more adverse events with the addition of sorafenib, and in particular, patients with uncontrolled hypertension were excluded due to sorafenib’s tendency to elevate blood pressure. 

“This is the first randomized trial showing the efficacy of kinase inhibitors in AML,” said study investigator, Gerhard Ehninger, MD, University Hospital Technical University Dresden, “And this, after more than 20 years of attempts to improve event- and relapse-free survival in this disease setting.”

So this is good news, right? Well, yes, sort of… “Since the patent for sorafenib is running out the drug company is not interested in expanding the label for this use, despite this demonstrated benefit,” said Dr. Ehninger, adding that, in his opinion this sorafenib combination could easily become the new standard of care, “but the company is just not interested because it’s such a small market.” 

That said, Dr. Ehninger is not deterred. He is conducting an even larger trial with sorafenib in the hopes that, with even more significant data in hand, sorafenib’s manufacturer will be supportive of this niche indication. 

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