ABSTRACT
Primary mediastinal large B-cell lymphoma (PMBCL) is a rare hematologic
malignancy with distinct clinical and immunopathological features. We
report a case of a young male with disease refractory to multiple lines
of therapy, including CAR-T cells, who achieved his first complete
remission after haploidentical BMT, following donor leukocyte infusions
(DLI) given concurrently with blinatumomab. While DLI has been used
after T-replete haplo-BMT with PT-CY, there are no reports on its use
for PMBCL. Similarly, blinatumomab is active against B-cell lymphomas,
but literature is lacking in patients with PMBCL. Our experience
illustrates that blinatumomab can be used concurrently with DLI in a
haploidentical setting to achieve disease response in PMBCL. Despite our
encouraging experience with this case, we would not recommend this
approach outside of a clinical trial as blinatumomab may exacerbate the
GvHD risks of DLI especially in a haploidentical setting.
Primary mediastinal large B-cell lymphoma (PMBCL) is a rare hematologic
malignancy representing only 2-3% of non-Hodgkin lymphomas
(NHLs)1. It has distinct clinical and
immunopathological features intermediate to diffuse large B-cell (DLBCL)
and Hodgkin lymphomas. It is characterized by bulky, locally invasive
disease that can infiltrate the lungs, pleura, chest wall and
pericardium, often compromising the airway and venous blood flow. While
prognosis is generally favorable, especially for younger individuals,
those who relapse have a dramatically lower chance of survival.
A 21-year-old male presented with left cervical swelling and pain over
his clavicle. A CT of his chest and abdomen was obtained, showing a
large anterior mediastinal mass. Pathologic and immunohistochemical
examination showed fibrotic tissue with nests of large CD10- CD30- BCL6+
MUM1+ PAX5+ B-cells with loss of surface immunoglobulin expression and
expression of CD19, CD20, CD23 and PD-L1 and a Ki-67 proliferative index
of 90%, confirming the diagnosis of PMBCL, non-germinal center type.
The cells were negative for rearrangement of cMYC, BCL2 and BCL6
translocation by fluorescence in situ hybridization.
Upon diagnosis, he received six cycles of dose adjusted etoposide,
prednisone, vincristine, cyclophosphamide, doxorubicin and rituximab
(DA-EPOCH-R)2. An end of treatment PET-CT scan
demonstrated refractory disease, necessitating involved field
irradiation. A follow-up PET-CT scan revealed extension of disease below
the diaphragm (Figure 1A) . The patient then received salvage
chemotherapy of ifosfamide, carboplatin, etoposide and rituximab
(ICE-R), but his disease progressed. A cycle of rituximab, gemcitabine,
navelbine and doxorubicin (R-GND) was given for debulking and
pembrolizumab was initiated with an early response (Figure 1B).However, his disease again demonstrated progression following eight
cycles of pembrolizumab (Figure 1C) . A repeat biopsy
demonstrated that the tumor developed expression of CD30 in a diffuse
and strong membranous fashion, leading to treatment with brentuximab
vedotin resulting in a partial response (PR) (Figure 1D) . He
then received an infusion of CAR-T cells (Tisagenlecleucel), but his
disease progressed (Figure 1E) . Subsequent treatments included
bendamustine and brentuximab followed by gemcitabine, cisplatin and
dexamethasone, again yielding a very good PR (Figure 1F) .
Having completed nine failed radiochemoimmunotherapy regimens, he
consented to a T-replete haploidentical bone marrow transplantation
(haplo-BMT) with his brother as the donor. He was conditioned with a
myeloablative regimen of busulfan, fludarabine and melphalan with
post-transplant cyclophosphamide (PT-CY)3-5. He showed
no clinical signs of acute graft-versus-host disease (aGvHD) despite
maintaining low tacrolimus levels (4-6 ng/ml) during the first month
post-BMT. Early tacrolimus taper was started on day +33 with
discontinuation on day +40. On day +44, a suprasternal chest wall mass
emerged and a repeat biopsy on day +47 confirmed PMBCL. A PET-CT scan on
day +49 demonstrated interval progression of disease (Figure
2a) .
Blinatumomab infusion was initiated on day +50 at a dose of 10
µg/m2/day, escalated to 15 µg/m2/day
on day +52. While on blinatumomab (day +54), the patient received a
haploidentical DLI from the same donor at a dose of
3x106 CD3+ cells/kg. His chest wall
mass continued to expand with intensifying pain, so, two weeks later, he
was given a second DLI infusion consisting of 1x 107CD3+ cells/kg (day +68). On day +78, the patient
developed a stage I aGvHD skin rash, and, upon exam, his chest wall mass
was noticeably smaller. aGvHD progressed to stage II skin on day +82 and
he started topical steroids. A repeat PET-CT scan on day +85 showed a
mixed response with decreased mediastinal and chest wall FDG avidity but
new focal subpleural avid areas, new mildly avid pulmonary nodules and a
new focal lesion in the hepatic dome (Figure 2b) . On day +89,
his aGvHD had progressed to stage III with vomiting, diarrhea and weight
loss. Therefore, prednisone 2 mg/kg and cyclosporine were started. With
progression of GvHD his chest mass and lymphadenopathy resolved. A
repeat PET-CT scan on day +113 confirmed a sustained tumor response and
revealed intense FDG uptake throughout the small and large colon
compatible with intestinal GvHD (Figure 2C) . After initial
improvement of skin and GI aGvHD symptoms cyclosporine was decreased in
order to optimize graft-versus-lymphoma (GvL) effects. Drug levels were
kept subtherapeutic (mean of 50 ng/ml) from day +110 until day +150, at
which time it was discontinued. Likewise, prednisone was progressively
tapered to 1 mg/kg by day +120 and discontinued on day +160. A repeat
PET-CT scan was performed on day +167, after 4 cycles of blinatumomab,
which demostrated, for the first time since his diagnosis, a complete
metabolic response of his PMBCL with less intestinal FDG uptake due to
aGvHD (Figure 2D) . Unfortunately, two months after completing
blinatumomab the patient noted increasing lympadenopthy and repeat
PET-CT confirmed extensive relapse of his PMBCL (Figure 2E) .
DA-EPOCH-R has been used frequently as front-line treatment of PMBCL,
but, due to the rarity of the disease, there is no consensus on optimal
consolidation or treatment for relapsed/refractory disease. Many of the
agents our patient received have been used previously for
relapsed/refractory PMBCL2, 6-9. In contrast to our
patient who failed to respond to anti-CD19 CAR-T cell therapy, there is
a single recent report of a patient with PMBCL who achieved a
CR10. It is also important to note that FDA approval
for tisagenlecleucel is for DLBCL and not PMBCL, however, it was decided
to treat our patient due to lack of other promising options.
Autologous HCT has traditionally been used as salvage therapy for NHL.
Our patient did not undergo an autologous HCT as he did not have
chemotherapy sensitive disease. A recent four-institution retrospective
analysis reviewed the outcomes of 28 patients with relapsed/refractory
PMBCL who received allogeneic HCT11. Eighty percent of
patients were sensitive to pre-transplant therapy. The 5-year
progression-free and overall survivals were 34% and 45%, respectively.
None of the patients received prior PD-1 blockade or CAR-T cells and
none received haploidentical HCT as was the case with our patient who
had received all three. Despite having been treated with a PD-1
inhibitor before his transplant, receiving myeloablative conditioning
and having his tacrolimus levels purposefully maintained in the low
therapeutic range and discontinued by day +40, the patient did not
develop aGvHD. Recent studies have documented that PT-CY lowers the risk
of GvHD in patients that have received checkpoint
inhibitors12.
DLI has been used after T-replete haplo-BMT with PT-CY against relapsed
leukemia and NHL, but there are no reports employing DLI for
PMBCL13. Blinatumomab has shown activity against other
B-cell lymphomas, but there are no published reports in patients with
PMBCL14. The most effective dose of blinatumomab for
NHL is 4-fold higher (60 µg/m2/day) than what our
patient received as his dose was restricted due to ongoing peripheral
neuropathy and persistent headaches. There is a single case report on
concomitant use of DLI with blinatumomab following a matched unrelated
donor transplant for leukemia but no reports in haploidentical
HCT15. While our experience illustrates that
blinatumomab can be used concurrently with DLI in a haploidentical
setting, the relative contribution of DLI versus blinatumomab in
achieving a metabolic CR was not clear. Our patient relapsed after
stopping blinatumomab, however his GvHD symptoms had also resolved and
therefore GvL activity had likely subsided as well. Although our
patient’s response to blinatumomab and DLI was short-lived, it was the
only therapy to induce a complete remission as his PMBCL had been
refractory to numerous lines of therapy, including to anti-CD19 CAR-T
cells. Despite our encouraging experience with this case, we would not
recommend this strategy outside a clinical trial as blinatumomab may
exacerbate the GvHD risks of DLI especially in a haploidentical setting.
Formally studying this treatment combination in high-risk patients may
be meaningful.