Page 1378 - Hematology_ Basic Principles and Practice ( PDFDrive )

1224 Part VII Hematologic Malignancies

p = .019), although there was no significant difference in OS between In a phase II trial from the same institution, the importance of
the two groups. 20 achieving PET-negativity before ASCT was reinforced further and
the potential of this to guide ongoing treatment was suggested:
Intensification of HDCT Patients achieving a negative PET following initial salvage therapy
Although HDCT followed by ASCT has become standard practice with ICE proceeded to ASCT, whereas those remaining PET-positive
for the management of patients with relapsed or refractory HL, the (38%) went on to receive a second course of salvage therapy with
intensity of treatment that is required has not been fully determined. non−cross-resistant gemcitabine, vinorelbine, and liposomal doxoru-
Following cytoreduction with salvage chemotherapy, high-dose che- bicin (GVD). Those responding to GVD (26/33) then also proceeded
motherapy can be intensified by delivering an additional course of to HDCT and ASCT. At a median follow-up of 51 months, patients
treatment over a shorter period of time, before proceeding to a with negative PET scans before ASCT (either after one or two lines
standard myeloablative regimen and ASCT, so-called sequential of salvage therapy) had an improved EFS of >80% compared with
HDCT. Whether or not this approach improves outcome, particu- 28.6% in those who were PET-positive (p < .001). Furthermore, of
larly for those patients who achieve less than a complete response those patients undergoing a second salvage attempt with GVD, 52%
(CR) post−salvage therapy, is unclear. In a randomized control trial achieved a negative PET scan and the outcome of these patients was
performed by the GHSG, EORTC, and EBMT intergroup, the comparable to those who were PET-negative post−initial ICE. 23
impact of sequential HDCT was evaluated. Patients with relapsed In summary, these data demonstrate the benefit of achieving PET
HL who had responded to two cycles of DHAP were randomly negativity before ASCT. As such, despite still being investigational,
assigned either standard HDCT with BEAM followed by ASCT or there is mounting evidence to support a formal role for PET
sequential high-dose cyclophosphamide, methotrexate, and etoposide post−salvage chemotherapy as a predictive biomarker for directing
before BEAM and ASCT. There was no significant difference between further treatment in this relapsed/refractory population of patients:
the two arms with regards to FFTF or OS, but sequential HDCT For those with a negative PET following salvage therapy, in whom a
21
was associated with greater toxicity. Sequential HDCT has therefore complete response is confirmed, HDCT followed by ASCT remains
not replaced standard HDCT before ASCT in the treatment of standard of care. However, for those with suboptimal response or
patients with relapsed or refractory HL, although further work evalu- evidence of disease progression by PET criteria following initial
ating its role is ongoing. salvage therapy, it may be more appropriate to attempt further salvage
Another intensification approach being investigated for patients approaches first, with ASCT being reserved for those in whom a
with refractory HL or with unfavorable risk is tandem autologous successful second response is achieved. Validation of this approach,
transplantation, in which two courses of HDCT are each followed however, is required before it can be considered standard and, at
by a transplant of the patient’s own peripheral blood stem cells. In present, the use of interim PET-guided treatment should be restricted
the large multicenter H96 trial led by the GELA, patients were to clinical trials.
risk-stratified as follows: high-risk patients with primary refractory
disease or at least two risk factors (time to relapse <12 months, stage
III−IV disease at relapse or relapse in previously irradiated sites) Treatment Options for Patients Who Relapse
underwent tandem ASCT whereas intermediate-risk patients with Following ASCT
one risk factor underwent single ASCT only. Five-year OS was 85%
in the intermediate-risk group and 57% in the high-risk tandem Although durable remissions have been reported following ASCT,
transplant group, an improvement on 30% previously reported in approximately 40% of these individuals will experience further recur-
this poor-risk population. Randomized control trials are needed to rence of their disease. Patients who experience relapse after ASCT
establish the true value of tandem autologous transplant for patients often have a poor prognosis with mean survival estimated at just over
with relapsed or refractory HL. 2 years. For these individuals, the treatment options are limited, with
Despite the intensity of salvage chemotherapy before ASCT, up to focus typically on achieving palliative control of disease and keeping
40% of patients will not attain a response. 19–21 Whether subsequent treatment-related toxicity to a minimum, rather than on cure.
ASCT is of benefit to these chemoresistant individuals remains unclear Further responses can be observed with single-agent chemotherapy
because of a lack of randomized data in the literature. Second attempts including gemcitabine, vinorelbine, or bendamustine, but remissions
to achieve responses that are good enough to support subsequent are often not durable. IFRT may be of benefit for patients with
ASCT have been made using other non−cross-resistant agents, but localized relapse at previously uninvolved sites, particularly for those
this appears to be effective in only a proportion of patients and the in whom further HDCT and ASCT is not deemed appropriate. The
overall outcome of these individuals tends to be unfavorable compared aim of RT in this setting is to extend disease control to delay the need
with those who respond to salvage chemotherapy initially. for palliative chemotherapy. A more common role for RT in the
peritransplant setting, however, is as adjuvant therapy, either directly
Role of PET Post−Salvage Therapy and before or after ASCT, to consolidate the responses achieved with
HDCT and ASCT.
Before ASCT In a highly selected group of patients who relapse after first ASCT,
a second autologous transplant may also be considered. This approach
Emerging data on the role of PET imaging as a means of assessing tends to be restricted to those relapsing more than 1 year after first
response post−salvage chemotherapy have reinforced the importance ASCT, although data defining a clear role for second autograft are
of achieving a second complete response before transplantation and lacking. Another approach is to consider a reduced-intensity alloge-
may be of particular benefit for these refractory patients in guiding neic stem cell transplant.
more appropriate ongoing treatment.
The prognostic value of PET before HSCT and ASCT has been
investigated in clinical studies. In a large prospective analysis from Allogeneic Transplant
Memorial Sloan Kettering Cancer Center (MSKCC) identifying
prognostic factors for patients with relapsed or refractory HL under- Allogeneic stem cell transplantation (aSCT) may be offered as a
going transplant, 153 patients with chemosensitive disease to ICE means of salvage therapy for a specific group of patients with relapsed
salvage therapy received HDCT and ASCT. Response was assessed or progressive disease following ASCT. The benefits of aSCT over
by CT and functional imaging (gallium or FDG-PET) both before autologous include the advantage of using a disease-free graft and the
and after salvage therapy. Normalization of functional imaging (FI) ability to exploit a “graft versus lymphoma” effect as a direct result
after salvage therapy was identified as being strongly predictive of of acquisitioning a new immune system from a healthy donor.
outcome: 5-year EFS was 75% in FI-negative patients versus 31% in The challenge of aSCT is to generate sufficient immunosuppres-
FI-positive patients (p < .0001). 22 sion to permit donor engraftment, while reducing treatment-related