Clinical News
Written in Blood
with CML, in whom a BCR-ABL1/
ABL ratio of <10 percent at three
months post-initiation of imatinib
was associated with improved overall survival.
Based on the results of this
phase IV study, “an alternative
treatment, such as a switch for a
second-generation tyrosine kinase
inhibitor, could be proposed in
cases of insufficient decrease in the
BCR-ABL1 transcript level,” Dr.
Millot told ASH Clinical News.
To address this gap in clinical
knowledge, Dr. Millot and investigators enrolled 44 consecutive
patients aged ≤18 years with newly
diagnosed CML into their study.
From March 2004 to December
2008, patients received imatinib 260
mg/m2 daily. Four children were
not included in the analysis because
they had missing molecular assessment at three months.
Investigators analyzed the BCRABL1/ABL ratio at three months
following imatinib initiation of the
remaining 40 patients:
• 37 percent of the patients had a
ratio of >10 percent
• 45 percent had a ratio of 1 to 10
percent
• 18 percent had a ratio of <1
percent
A higher ratio was associated with
a larger spleen size and a higher
white blood cell count compared
with patients with a ratio of ≤10
percent. The dose of imatinib administered was similar between the
two groups during the first three
months of treatment, “suggesting
that treatment exposure was not an
independent influencing factor,” Dr.
Millot noted.
At one year, compared to patients who had a ratio >10 percent
at three months post–imatinib
initiation, those who had a ratio
≤10 percent had higher rates of
both complete cytogenetic response
(76% vs. 47%) and major molecular
response (48% vs. 7%).
Furthermore, with a median
follow-up of 71 months, a transcript
level ≤10 percent correlated with
better progression-free survival:
• ≤10% at three months: 100% vs.
92% at 36 months follow-up
• >10% at three months: 100% vs.
61% at 48 months follow-up
Although the results are encouraging, Dr. Millot and colleagues noted
that the reliability of this 10 percent
cut-off at three months after starting
imatinib as a surrogate for one-year
response needs to be confirmed in
larger cohorts of children.
Reference
• Millot F, Guilhot J, Baruchel A, et al. Impact of early
molecular response in children with chronic myeloid
leukemia treated in the French Glivec phase 4 study.
Blood. 2014 August 28. [Epub ahead of print]
Once-Weekly Bortezomib Produced Durable Responses,
Survival in Relapsed AL Amyloidosis
Results from a phase I/II study of single-agent bortezomib suggest that
a once-weekly dosing regimen produced similar efficacy results to a
twice-weekly regimen — with the added benefit of improved tolerability.
Bortezomib produced a durable hematologic response and promising
long-term overall survival in patients with relapsed systemic light chain
(AL) amyloidosis.
According to Donna E. Reece, MD, of Princess Margaret Cancer
Center, Toronto, Canada, and lead author of the study published in
Blood, the current study was not designed to compare a once-weekly
and twice-weekly regimen, but
“the findings are in accordance
with prior studies of once- versus twice-weekly bortezomib
administration in patients with
multiple myeloma or lymphoma,
in which less intensive, onceweekly dosing in the context of
combination therapy improved
treatment tolerability without
compromising efficacy.”
AL amyloidosis is treated with
many of the same approaches
used in the treatment of multiple
myeloma, such as high-dose
—Donna Reece, MD
melphalan followed by stem cell
transplantation. However, not all
patients are eligible for transplant. In those patients, several early studies
have begun to explore the use of bortezomib, a proteasome inhibitor.
Dr. Reece and colleagues enrolled 70 patients with relapsed primary
systemic AL amyloidosis into the CAN2007 trial. Patients were treated
with increasing doses of bortezomib given once- and twice-weekly.
Prespecified maximum planned dose levels were 1.6 mg/m2 onceweekly and 1.3 mg/m2 twice-weekly, and treatment was planned for a
maximum of eight cycles. Notably, 18 patients in the once-weekly and 34
patients in the twice-weekly groups received the maximum planned dose.
Hematologic responses were similar for patients in the maximum dose
once-weekly group and the twice-weekly group. About two-thirds of
patients responded to bortezomib at higher doses (68.8% in the onceweekly and 66.7% in the twice-weekly group), while only 38.9 percent
had a confirmed response. This includes complete response rates of 37.5,
24.2, and 11.1 percent with lower doses.
“n the future,
I
bortezomib
might prove
useful as part
of initial AL
treatment.”
22
ASH Clinical News
These responses were durable and rapid, the authors noted: 78.8
percent and 75.5 percent of responders in the once- and twice-weekly
maximum-dose groups remaining in remission for at least one year.
Time to first response was 2.1 months and 0.7 months, and time to best
response was 3.2 months and 1.2 months, in the once- and twice-weekly
maximum dose groups. While the twice-weekly regimen appeared to
result in more rapid response, toxicity appeared generally lower with the
higher, once-weekly dose — with higher rates of grade ≥3 adverse events
(79% vs. 50%) and discontinuations (38% vs. 28%) and dose reductions
(53% vs. 22%) related to adverse events.
At the time of data cutoff, 19 percent of patients had experienced
hematologic disease progression, while the overall one-year progressionfree rate was 77.4 percent.
For all 70 patients, the overall one-year survival rate reached 89.6
percent, which included:
• 93.8 percent in the 1.6 mg/m2 once-weekly group
• 84.0 percent in the 1.3 mg/m2 t wice-weekly group
• 94.1 percent in the lower-dose group
At a median follow-up of 51.8 months, the median overall survival
was 62.1 months in the maximum dose once-weekly group but was not
reached in the maximum dose twice-weekly group.
Most patients (57%) went on to receive subsequent AL therapy (most
commonly dexamethasone, bortezomib, lenalidomide, cyclophosphamide, melphalan, or thalidomide), leading researchers to believe that the
notable overall survival reported in this study may be due, in part, to the
greater availability in recent years of additional AL therapies based on
novel agents.
“In the future, bortezomib might prove useful as part of initial AL
treatment,” Dr. Reece and co-authors concluded, “and possibly as part
of extended therapy after HDM-SCT or alternative non-transplantation
therapies.” ●
Reference
• Reece DE, Hegenbart U, Sanchorawala V, et al. Long-term follow-up from a phase 1/2 study of single-agent bortezomib in
relapsed systemic AL amyloidosis. Blood. 2014 September 8. [Epub ahead of print]
October 2014