Page 1781 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 102 Immune Checkpoint Blockade in Hematologic Malignancies 1585

results suggest that PD-1 blockade is generally tolerable for patients HM and for targeting of other immune checkpoints. Initial studies
with HM. in solid malignancies suggested that tumors with demonstrable
PD-L1 expression on the tumor cell surface had higher response rates
30,31
CHECKPOINT BLOCKADE THERAPIES AFTER to PD-1 blockade ; at first look, this pattern seems to also hold in
HMs, as response rates have been highest in HL where PD-L1 expres-
HEMATOPOIETIC STEM CELL TRANSPLANTATION sion is very frequent. However, in solid tumors, patients whose
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tumors did not demonstrate PD-L1 expression have also had mean-
HSCT, using autologous or allogeneic grafts, is an important part of ingful responses, suggesting that PD-L1 expression should not yet be
the treatment of many HMs, and may provide a fruitful setting for used to exclude patients from clinical trials.
CBT. In the case of autologous HSCT, the minimal disease burden Indeed, variation in tumor cell surface expression of PD-L1 is
and presence of a remodeled immune system with a relative prepon- unlikely to entirely explain the apparent differences in clinical
derance in the early post-HSCT period of immune cells that are response to PD-1 blockade among HL, various NHLs, and MM.
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targets of CBT, like natural killer (NK) cells and T-effector cells, PD-L1 expression is a highly dynamic process that varies with time
may allow the effective leveraging of CBT. PD-1 blockade has already and environment and is likely poorly captured by isolated in vitro
been studied after autologous transplant in DLBCL. In an inter- tumor biopsy analyses. Tumor-cell ligand expression also ignores the
national phase 2 study, 72 patients with DLBCL received three doses important role of immune cells in the tumor microenvironment
of pidilizumab beginning 1–3 months after autologous stem cell whose expression of PD-1 and its ligands may affect response to
transplant. Progression-free survival at 18 months after HSCT was therapy. While its role is less clearly delineated, PD-L2 may also be
72%, higher than the 52% rate observed in a similar historic control an important predictive marker for response to PD-1 blockade.
cohort. Notably, the rate of progression-free survival among the PD-L2 amplification is uncommon in solid malignancies, but it is
higher risk group of patients with positron emission tomography overexpressed in HL, primary mediastinal large B-cell lymphoma
(PET)-positive disease before transplant was 70%. In addition, (PMBL), and some T-cell lymphomas. 12,23 Lastly, the impressive
among the 35 patients with measurable disease after transplant, the response rates in HL also suggest that the mechanism of PD-L1
overall response rate after pidilizumab was 51% (CR, 34%). Impor- overexpression may be important; in the case of HL, constitutive
27
tantly, pidilizumab was well tolerated without significant irAEs. overexpression of PD-L1/2 driven by EBV infection or genetic
Together, these findings suggest that PD-1 blockade may have direct amplification events may result in a unique dependence on the PD-1
antitumor activity and important clinical activity in the postautolo- signaling pathway for survival, which could underlie HL’s high vul-
gous transplant setting, warranting additional studies. Based on these nerability to PD-1 blockade. This phenomenon occurs in a few other
promising early results, there are now several ongoing trials of HMs: there are virally-driven DLBCL and T-cell NHL subtypes,
PD-1 blockade after autologous transplant in HL, DLBCL, and which appear to also show very frequent PD-L1 surface expression;
MM (NCT02362997, NCT02181738, NCT02038933, and and a specific NHL subtype, PMBL, which also harbors frequent
NCT02331368). 9p24.1 amplification and concomitant PD-L1 and PD-L2 expres-
Allogeneic HSCT also represents an attractive, if challenging, field sion. 12,32 Those tumor subtypes are very attractive targets for PD-1
in which to deploy CBT. This form of transplantation is an important blockade, as is being explored in ongoing trials.
part of treatment for many HMs, as the attendant GVT effect may
be salutary in patients who are not curable with conventional che-
motherapy or autologous HSCT. Yet failure to develop an effective Treatment Setting
GVT occurs frequently, manifesting as postallogeneic HSCT relapse,
and the outcomes for those patients are usually dismal. The postal- Clinical experience with CBT in HMs thus far has been limited to
logeneic transplant setting is attractive for CBT because the treatment the R/R setting; however, treatment will likely move to earlier stages
strategy is already based on immune manipulation. CBT was studied of diseases in the coming years, at least in HL. This transition has
in this context in a phase 1 study of ipilimumab in patients with several important implications. Published trials have used CBT to
recurrent or progressive disease after allogeneic transplant. Remark- augment the immune response of patients who have received numer-
ably, ipilimumab did not induce significant graft-versus-host disease ous rounds of cytotoxic therapy. In newly diagnosed patients who
(GVHD) and the rate of irAEs did not differ greatly from that seen have relatively normal immune function, responses may be signifi-
outside of the transplant setting. In addition, objective responses were cantly different. For this reason, earlier treatment with CBT may
seen in three patients including two sustained CRs in patients with result in a more robust antitumor immune response. At the same
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HL. In a follow-up study investigating repeated dosing of ipilim- time, it may also increase the incidence and severity of irAEs. Con-
umab in the posttransplant relapse setting, 6 of 27 patients have tinued investigation is critical to determine how the setting of treat-
achieved formal responses including 4 CRs in acute myeloid leukemia ment will alter its efficacy and tolerability.
and 2 PRs in patients with MM and HL. These responses are notable At this time, there is limited but exciting experience with CBT
given that these patients had been highly pretreated including some after HSCT. Yet if continued investigations confirm the early results,
who had received prior donor lymphocyte infusion after posttrans- post-HSCT CBT may become an important part of transplantation,
plant relapse. They suggest an important potential role for CBT after and may affect both the efficacy of HSCT and its place in the
allogeneic transplant. With repeated dosing, ipilimumab did result in treatment course of patients with HMs.
increased irAEs, including two patients with grade 4 pneumonitis,
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three cases of GVHD, and one treatment-related death. In most
cases, however, AEs were manageable and did not prevent continued Endpoint Definition
treatment with ipilimumab; however, safety of CBT in this setting
will need to be carefully monitored. Early trials in CBT in solid malignancies showed that patients
occasionally had evidence of progression before a response, longer
times to CR than with traditional treatments, and long-term disease
LESSONS FROM CTLA-4 AND PD-1 BLOCKADE stability despite meeting traditional criteria for progressive disease.
30
As a result, new response criteria, the immune-related response cri-
Selection of Tumors and Patients teria, were proposed for solid malignancies to account for different
radiographic responses to therapy and to prevent early withdrawal of
33
Unlike CTLA-4, the expression of PD-1 and its ligands varies widely treatment from patients who might eventually show a response.
across tumor types and patients. Differences in expression have been Hints of a similar pattern of delayed radiographic responses and
helpful in predicting the responses to PD-1 blockade in solid tumors, disease stability have been seen in HMs. For example, 21% of patients
and those lessons may be instructive for the development of CBT in had a delayed response (4 months or more after initiation of therapy)