NcXHF

MANAGING OLDER PATIENTS WITH ALL
FIGURE 4. Preliminary Results of Reduced Intensity
Allografting from United Kingdom ALL XIV
Overall survival post-transplant.
TABLE 3. Major Demographic Characteristics and
Outcomes for 60 RIC Allografts
Registered for RIC transplant 91
Transplant data available 60
Median age 49
Sibling donor 36 (60%)
ECOG PS 1-2 24 (40%)
WBC 30 10e9/L 12 (20%)
High-risk cytogenetics 27/51*
Median time to transplant from diagnosis 5.4 months (4-9)
Acute GVHD grade 2-4 29%
Chronic GVHD 14 (23%)
Donor lymphocyte infusions 16/41**
Relapse
4 (2 survive)
Transplant-related mortality 6
Total deaths 8
Abbreviations: RIC; reduced intensity conditioning; ECOG; Eastern Cooperative Oncology
Group; PS, performance status; WBC, white blood count; GVHD, graft versus host disease.
*Nine patients did not have evaluable cytogenetics.
**Data only available on 41 patients currently (10 for mixed chimerism and six for
persistent or rising minimum residual disease).
show it to be an effective way of eradicating disease, uses
moderate doses of chemotherapy and involves a short period
of neutropenia, mild mucositis, and is generally not very debilitating.
A transplant may be seen as providing a more rapid
recovery than consolidation, intensifıcation, and longer than
2 years of maintenance chemotherapy. It is important to
avoid severe graft versus host disease (GVHD) in this older
age group, but RIC allografts do rely on a graft-versusleukemia
effect. The main evidence for a graft-versusleukemia
effect is that relapse is less common in patients with
grade 2 to grade 4 acute GVHD and/or chronic GVHD.
However, this effect is most operative in patients with low
levels of disease. Full intensity conditioning causes excessive
TRM in this age group and is seldom indicated. It should be
noted that RIC allografts are mainstream therapy in older patients
with AML with many studies showing acceptable TRM
in selected patients.
Two registry-based comparisons with full intensity conditioning
show adjusted survival and event-free survival to be
similar to full-intensity conditioning (Fig. 4). 20,21 Unsurprisingly,
relapse rates are increased and TRM only marginally
decreased. The optimum conditioning regimen and GVHD
prophylaxis strategy are yet to be defıned.
The United Kingdom ALL XIV trial is prospectively examining
the role of RIC sibling and unrelated donor allografting.
All patients older than age 40 are considered high risk
and are eligible for allografts if they are fıt, in CR, and have a
matched sibling or 8/8 molecularly matched unrelated donor.
(Patients with high-risk cytogenetics or persistent MRD
are permitted to have a 7/8 match). Sixty-two percent of the
fırst 374 patients are eligible, and we have data on the fırst 60
allografts. Survival with a median follow-up of 12 months exceeds
80%, and the current TRM of 9% shows that the procedure
can be performed safely on a multicenter basis. The
rates of acute and chronic GVHD are modest (Table 3).
Mixed chimerism is a common outcome of fludarabine, melphalan,
and alemtuzamab allografts; 10 patients received donor
lymphocyte infusions for this and six additional patients
received donor lymphocyte infusions for persistent or progressive
MRD. Fifteen of these 16 patients currently survive,
but follow-up is short.
FUTURE DEVELOPMENTS
The newer agents, blinatumomab and inotuzumab, 14,16 have
not been tested specifıcally in this age group, but there will be
some data from the ongoing phase III studies (Inovate and
Tower). Both drugs have been tested mainly in the relapsed/
refractory setting, but blinatumomab is very impressive at
converting persistent MRD positivity (after 3 months of chemotherapy)
to negativity (78% of 116 patients in the phase II
study). 22,23 As most older patients have dose reductions that
may result in higher incidences of persistent MRD positivity,
it is attractive to add in a 28-day course of blinatumomab to
deepen remission states before further consolidative or
maintenance chemotherapy. However, fırst we need data
comparing this agent with conventional chemotherapy and
to know if older patients tolerate the cytokine release syndrome
and neurotoxicity. Similarly, the effıcacy and safety of
inotuzumab will need to be compared with conventional salvage
therapy before we can assess the place of this drug in
older patients.
In the United Kingdom, we are working to establish a backbone
of chemotherapy that older patients can tolerate, with
reasonable CR rates and 1-year survival. We then plan to add
in novel agents to improve those outcomes without increasing
toxicity and NRM. The collection of diagnostic specimens
in these patients and correlation with clinical data may
improve our understanding of the biologic differences that
exist in older patients with ALL.
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