2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

Addition of Monoclonal Antibodies to RIC SCT
GVHD remains the major concern after RIC SCT and
attempts have been made to utilize monoclonal antibodies to
reduce the incidence of GVHD without increasing the subsequent
risk of relapse. Excellent results have been obtained
at MDACC using RIC based on a combination of fludarabine
and cyclophosphamide with the addition of rituximab, an
approach designed to maximize GVL by early tapering of
immune suppression with use of rituximab and DLI. Among
39 patients treated, median age 57 (range, 34 to 70), median
time from diagnosis to transplantation was 4.5 years. 33 All
patients had recurrent advanced disease, were heavily pretreated
with a median of three (range, 2 to 8) chemotherapy
regimens, and had been previously treated with fludarabine/
rituximab-based regimens. At transplant, 34 patients (87%)
had active disease, including nine (23%) with evidence of
Richter’s transformation. In this series, only four of the
donors were unrelated. Fourteen patients required immunomodulation
with rituximab and DLI for persistent disease
after SCT. Only one patient died early, and among the 38
evaluable patients, 27 (71%) achieved CR with a 48% estimated
OS at 4 years and current PFS of 44%. Acute grade 2
through 4 GVHD was observed in 45%, but chronic extensive
GVHD was reduced without concomitant increased risk of
relapse.
GVHD can be decreased using alemtuzumab in the conditioning
regimen to reduce donor lymphocytes, but this is
associated with delayed immune reconstitution, increases
the risk of infective complications, and appears to impair
GVL. In 41 consecutive patients with CLL (24 HLA-matched
sibling donors and 17 unrelated volunteer donors, including
4 mismatched) treated with the conditioning regimen alemtuzumab
with fludarabine and melphalan had impressive
antitumor effects with 100% of patients with chemotherapysensitive
disease and 86% with chemotherapy-refractory
disease responding. 32 The TRM rate was 26%, OS was 51%,
and relapse risk was 29% at 2 years. GVHD rates were
relatively low with acute GVHD occurring in 17 (41%) and
chronic GVHD in 13 (33%). The unexpectedly high TRM
rate was because of a high incidence of fungal and viral
infections.
How to Select Who and When to Offer
Allogeneic SCT
All studies of SCT have enrolled younger patients with
“high-risk” disease. This term is very loosely defined and it is
difficult to determine precisely the risk factors used in each
of the reported studies. EBMT guidelines have been established
outlining indications for SCT in CLL, which conclude
that there is a evidence base for the efficacy of allogeneic
SCT in CLL and that this procedure is indicated in patients
with high-risk CLL. 38 Patients at high risk are defined in
Table 3 and include those requiring treatment who have
TP53 abnormalities (who merit allogeneic SCT in first
response), patients who fail to achieve CR, who progress
within 12 months after fludarabine, who relapse within 24
months after having achieved a response with combination
therapy, those who have relapsed after prior autologous
SCT, or those patients who are fludarabine refractory. It
should be noted that the only category that requires assessment
of biologic risk is detection of TP53 abnormalities.
Ongoing prospective clinical studies will determine the ef-
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JOHN G. GRIBBEN
Table 3. EBMT Guidelines for Transplantation in CLL 38
Allo-SCT is a reasonable treatment option in poor-risk CLL including:
● Fludarabine resistance—nonresponse or early relapse (� 12 months) after
purine analogue-based therapy
● Relapse � 24 months after purine analogue combinations or auto-SCT (plus
high-risk genetics)
● p53 mutation with treatment indication
Auto-SCT indicated in clinical trial only
Abbreviation: EBMT, European Blood and Marrow Transplantation; Allo-SCT,
allogeneic stem cell transplantation; CLL, chronic lymphocytic leukemia; auto-
SCT, autologous SCT.
fect of biomarkers including IgV H mutational status and
other cytogenetic abnormalities in identification of patients
at sufficiently high risk to merit use of allogeneic SCT in first
CR.
The definition of “refractory” CLL is of particular importance
and the terms “refractory” CLL and “fludarabinerefractory”
CLL are often used interchangeably. But with
the large number of treatment options, the consideration of
treatment context is important. The type of therapy to which
patients fail to respond and previous therapies received are
of major importance. The clinical importance of refractory
CLL is based on the fact that these patients have very poor
prognosis (median 1–2 years OS in most studies) despite
various and intense salvage therapy strategies. 2,39-40 Most
trials of investigational agents use this definition as an
entry point for early drug development. The most recent
CLL guidelines define refractory CLL as treatment failure
(less than partial remission [PR]) or disease progression
within 6 months of the last antileukemic therapy. 3 These
still correspond to the definition coined when CLL treatment
was based on chlorambucil or fludarabine monotherapy. In
current standard practice, patients eligible to consider allogeneic
SCT are most likely to have received combination
chemoimmunotherapy. There is accumulating evidence that
patients who are formally not refractory based on the current
definition but relapse within 3 years after chemoimmunotherapy
also have very poor outcome and are unlikely to
have durable responses to subsequent chemotherapy. 2
The guidelines suggest three groups of patients who may
be offered therapy. The first group is those with TP53 loss,
and these are the patients who have the poorest response
and shortest duration of remission. Allogeneic SCT is considered
appropriate in first response after initial therapy for
these patients. Those patients who failed to achieve CR to
FCR and/or have very short (� 24 months) response to prior
FCR can be added to this very high-risk group. These
patients are prime candidates for drugs with proven activity
in TP53 deleted/mutant cells, investigational agents in clinical
trials, and then for allogeneic SCT if they respond.
A second scenario of “high-risk” CLL is identification of
subgroups destined to relapse relatively early after standard
treatment and it is in this group that biomarker analysis
will prove useful. Candidates within this group include
patients with high beta-2-microglobulin or thymidine kinase,
unmutated immunoglobulin heavy chain variable region
(IgVH) or 11q deletion. 9,41 These patients are the ones
who gained most by the addition of rituximab to FC. 9
Biomarker analysis will also be useful to identify those
patients in whom allogeneic SCT should not be offered (no
11q deletion, no TP53 deletion/mutation, mutated IGHV,
low beta-2-MG, no prior therapy) who have very favorable
outcome despite progressing to indication for treatment.