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Chapter 85 T-Cell Lymphomas 1357

status was not available) with superior overall survival compared In conclusion, aSCT can be offered in relapsed and refractory
with aSCT. PTCL based on the following observations: (1) in all studies survival
During the last 15 years, RIC regimens have been increasingly curves seem to reach a plateau after 24–36 months, suggesting the
used in patients with relapsed lymphomas in order to reduce NRM, potential curability of the disease; (2) delaying aSCT too long from
thus making this strategy feasible in older adults or heavily pretreated the time of diagnosis may significantly compromise the outcome,
patients. In 2004 one of the first reports of RIC aSCT in PTCL thus aSCT should be performed during a chemosensitive relapse; (3)
patients reported that 56% of patients were alive and in CR after 1.4 RIC regimens have increased the feasibility of performing aSCT by
years. The first prospective study evaluated the outcome of 17 relapsed reducing NRM, and aSCT may be used in older and heavily pre-
PTCL patients after a fludarabine-based RIC regimen: 14 of 17 treated patients. Hopefully in the future we will see if the combination
enrolled patients were alive (12 in CR) after a median follow-up of of new agents with aSCT can improve the outcomes of a significant
28 months, with an estimated 3-year NRM, OS, and PFS of 6%, proportion of patients with refractory disease.
81%, and 64%, respectively.
In this study, there were some data suggesting the existence of a
GvL effect, based on the following observations: (1) the achievement Emerging New Drugs for PTCL
of durable responses with aSCT in patients who had already failed a
prior autologous SCT; and (2) the demonstration of clinical responses There is little question that one of the most promising new areas in
to donor lymphocyte infusions. These preliminary results were sup- PTCL research is new drug development. Over the past several years,
ported by a larger Italian multicenter retrospective study with a longer four new drugs, all with relatively unique mechanisms of action, have
follow-up. In this study, the 5-year outcomes showed a NRM, OS, been approved for the treatment of patients with relapsed or refrac-
and PFS of 12%, 50%, and 40%, respectively, and a plateau in the tory disease. These drugs, which all now have substantial data dem-
survival curves after 36 months, suggesting a probable cure for these onstrating their marked single-agent activity in these diseases, have
patients. Following multivariate analysis, being older than 45 years created a unique opportunity to build non-CHOP–based platforms
and having refractory disease were independent prognostic factors, for treatment. In addition to the four drugs already approved, many
highlighting that timing of an aSCT can significantly influence the new drugs are in various stages of clinical development, with very
final outcome. Similarly, in a French retrospective study of 77 PTCL promising signals (Table 85.3). We will discuss some of these new
patients receiving aSCT with both RIC or myeloablative condition- agents and how they are beginning to change the treatment paradigms
ing regimens, those patients with chemosensitive disease or with less for PTCL.
than two prior courses of chemotherapy at the time of transplant
experienced better survival outcomes.
In both the Italian and French studies, survival was not signifi- Pralatrexate
cantly different among the histologic subtypes of T-cell lymphoma
(of note, the ALK mutational majority of the ALCL patients was Pralatrexate was the first drug approved for the treatment of patients
unknown), although patients with AITL did slightly better. In with relapsed or refractory PTCL in 2009. Pralatrexate is a novel
support of this finding, an EBMT retrospective analysis of 45 PTCL antifolate with very high affinity for the reduced folate carrier,
patients undergoing aSCT between 1998 and 2005 had a relapse risk designed to enhance its intracellular transport. The reduced folate
of 20% at 3 years, with a PFS of 53% and an OS of 64%. carrier is an oncofetal protein expressed at relatively high levels on
Several studies have reported survival outcomes of aSCT for the surface of malignant cells. The carrier is responsible for transport-
PTCL patients when employed as front-line consolidation therapy. ing into the cell natural folate required for DNA biosynthesis. Prala-
The only prospective study of this strategy showed encouraging trexate, designed to have a high affinity for the folate receptors, is
4-year PFS and OS of 69% using a RIC regimen and an HLA- rapidly internalized into the cell, where it undergoes efficient poly-
compatible donor. Other retrospective studies have confirmed these glutamylation by the folylpolyglutamate synthase, which enhances
data with a 2-year PFS and OS between 35%–65% and 40%–75%, the affinity of the drug for dihydrofolate reductase and increases its
respectively. intracellular retention.

TABLE Recent FDA-Approved and Emerging New Drugs in Peripheral T-Cell Lymphoma
85.3
Overall Response Complete Response
Drug Disease/No. of Patients Rate Rate PFS/DOR
Pralatrexate Relapsed/refractory PTCL 29% 11% Median DOR = 10.1 months
(accelerated approval 2009) N = 111
Romidepsin Relapsed/refractory PTCL 25% 15% Median DOR = 17 months
(accelerated approval 2011) N = 130
+
Brentuximab vedotin CD30 anaplastic large-cell lymphoma 86% 57% Median DOR = 12.6 months
(accelerated approval 2011) N = 58
KW-0761 HTLV-1 ATL 13 of 26 (50%) 8 of 13 (61%) PFS = 5.2 months
N = 27
Bortezomib Relapsed/refractory CTCL and PTCL 8 of 12 (67%) 2 of 12 (17%) Not reported
N = 12 (2 patients with (1 of 2 patients with
PTCL) PTCL)
Lenalidomide Relapsed/refractory PTCL
N = 10 (Zinzani) 30% 3 of 10 Not reported
N = 24 (Dueck) 30% 0 of 7 Median PFS 96 days
Alisertib Relapsed/refractory PTCL 4 of 8 (50%) 2 of 4 Not reported
N = 8
ATL, Adult T-cell leukemia/lymphoma; CTCL, cutaneous T-cell lymphoma; DOR, duration of response; FDA, Food and Drug Administration; HTLV-1, human
T-lymphotropic virus-1; PFS, progression-free survival; PTCL, peripheral T-cell lymphoma.