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The use of CD19-specific chimeric antigen receptor (CD19-CAR) T-cell
therapies has improved outcomes in patients with relapsed or refractory
Acute Lymphoblastic Leukemia (ALL) (1). Their use is associated with a
unique toxicity profile, including cytokine-release syndrome (CRS) and
immune effector cell–associated neurotoxicity syndrome (ICANS). These
are treatment specific, immune-related adverse events and detailed and
tailored management protocols have been established (2). However,
real-world clinical experience has shown that hematological toxicity
(hematotoxicity) is the most common long-term adverse event (3). The
underlying pathophysiologic mechanism of hematotoxicity and its optimal
management remain unclear.
Here we present the case of a 21-year-old man with B-ALL who developed
hematotoxicity and severe life-threatening infections following CD19-CAR
T-cell therapy and required a CD34+ hematopoietic stem cell boost
(HSCB). He was initially diagnosed with B-cell ALL with IGH
rearrangement and received remission induction therapy with CALGB10403.
He had persistent disease at day 29 bone marrow (BM) evaluation and due
to his high-risk disease status, proceeded to a myeloablative
haplo-identical hematopoietic stem cell transplant (HSCT) utilizing a
sibling donor. He relapsed nine months following HSCT with
>90% CD19+ leukemic blasts by flow cytometry and received
salvage chemotherapy with minimal response. Due to persistent refractory
disease, he was referred for consideration of CD19-CAR T-cell therapy.
He underwent autologous collection and successful manufacture of a
CD19-CAR product, Tisagenlecleucel. Following bridging therapy with a
modified hyper-CVAD regimen and Venetolcax, he developed pancytopenia
and did not have hematological recovery prior to admission for CAR
T-cell therapy.
He received lymphodepleting (LD) chemotherapy with fludarabine and
cyclophosphamide prior to CD19-CAR T-cell infusion. On day +7 post
CD19-CAR T-cell infusion, he developed grade 2 CRS requiring one dose of
tocilizumab. At time of discharge, on day +13 he remained pancytopenic
and transfusion dependent. On day +19, he presented with fever and
hypotension in the setting of typhlitis and was admitted to the
intensive care unit (ICU). He continued to have severe hypotension and
developed a cardiac arrest requiring cardiopulmonary resuscitation with
compressions and epinephrine, intubation, and pressor support. Blood
cultures were positive for Clostridium septicum , and he improved
after initiation of antibiotic therapy with meropenem. However, on day
+30, he developed another episode of culture negative septic shock again
requiring transfer to ICU for pressor support and intubation for tenuous
hemodynamic status. CT scan of the abdomen demonstrated an extensive
inflammatory process consistent with typhlitis and colitis, with edema
of the right rectus muscle and subcutaneous abdominal wall edema. He
recovered from this event after re-initiation of broad-spectrum
antibacterial therapy but on day +47 again developed septic shock,
requiring a third admission to ICU for pressor support. Blood cultures
grew Enterobacter faecium and Staphylococcus epidermidis .
An abdominal MRI demonstrated worsening of intrabdominal process, now
with a fluid collection tracking in the right para colic gutter
extending from the tip of the liver to the level of the cecum, with no
discrete wall to suggest abscess, likely due to ongoing pancytopenia.
Given ongoing intrabdominal signs and symptoms, multiple episodes of
septic shock and pancytopenia, he required continued empiric broad
spectrum antibacterial therapy. To evaluate etiology of pancytopenia, he
underwent BM evaluations (on day +22 and day +43 post CD19-CAR T-cell
infusion) that showed a markedly hypocellular marrow with severely
decreased trilineage hematopoiesis, without evidence of recurrent
leukemia.
Due to persistent pancytopenia and recurrent life-threatening
infections, he received a CD34+ HSCB (5.1 x106 CD34+
cells/kg) from his sibling HSCT donor on day +69. Neutrophil recovery
occurred on day +13 and platelet engraftment occurred on day + 16
following the CD34+ HSCB. He had no further episodes of septic shock or
bacteremia following the CD34+ HSCB. Complete radiological resolution of
ongoing intrabdominal process was documented on day + 65 after CD34+
HSCB and empiric antibacterial therapy was discontinued. He did not
develop graft-versus- host-disease (GVHD). Importantly, he had continued
and ongoing B-cell aplasia (BCA) at 9 months post CD19-CAR T-cell
therapy and 6 months following the CD34+ HSCB and remains in complete
remission (CR; no detectable disease by flow cytometry or next
generation sequence testing) suggesting no interference from the infused
donor CD34+ HSCB.
Hematotoxicity is a known side effect of CAR T-cell therapy and can have
devastating consequences including risk of hemorrhage and
life-threatening infections compounded by concurrent B-cell aplasia,
leading to high rates of morbidity and mortality (3). The ELIANA
CD19-CAR T-cell trials found 37% of patients had cytopenia that did not
resolve by day 28 (1). Juluri et al., highlighted prolonged and
persistent cytopenias amongst adult patients with ALL of whom only 85%
had neutrophil and 82% platelet recovery at a median follow up of 3
years (4). While LD chemotherapy can play a role, the etiology is likely
multifactorial since hematotoxicty has also been observed in patients
who did not receive it (5). High grade CRS has been shown to be
associated with delayed hematopoietic recovery (3, 4). Other studies
show that baseline cytopenias (6) and patients who received prior
allogeneic transplants, particularly those who received CAR T-cells less
than one year following transplant, were at increased risk (7). Our
patient received CD19-CAR T-cell therapy within one year of transplant
and had severe baseline cytopenia suggesting he was at higher risk for
hematotoxicity, despite the absence of high-grade CRS. The CAR-HEMATOTOX
score helps predict hematotoxicity in adult patients with lymphoma who
receive CD19 CAR T cell therapy and has been shown to be a useful tool
that has been validated in multiple cohorts (6). However, a similar
model needs to be validated for patients with ALL.
While eventual recovery from hematotoxicity may be possible, patients
are at high risk of succumbing to infections (8). CD34+ HSCB can be a
useful therapeutic intervention to shorten the duration of pancytopenia.
It can be either autologous (auto) or derived, from the recent
transplant donor (allogeneic; allo). The successful use of autoCD34+
HSCB following CAR T-cell therapy induced hematotoxicity has been
reported in case reports and recently in a larger retrospective study of
31 patients (9). The majority (84%) of patients responded and time to
response corelated with duration of preceding neutropenia. However, 4/5
patients with active infection did not respond and all non-responders
died. For patients with ALL, autoCD34+HSCB is not an option due to BM
involvement. While alloCD34+ HSCB is commonly used in the
post-transplant setting to rescue hematopoiesis (10), there is limited
data regarding its use following CAR T-cell therapy. Recently, two small
case series have highlighted the successful use of alloCD34+HSCB (11,
12). Rapid hematopoietic recovery was noted following alloCD34+ HSCB
without evidence of GVHD and one patient developed CRS following the
boost, presumably due to CD19+ B cells in the product.
In conclusion, we highlight the safety and efficacy of an alloCD34+ HSCB
in our patient with severe hematotoxicity and life-threatening
infections following CD19-CAR T-cell therapy. The alloCD34+ HSCB had no
apparent effect on the activity of CD19-CAR T cells since the patient
continued to have B-cell aplasia and remains in CR. Thus, patients with
ALL who receive CD19-CAR T-cell therapy after HSCT and develop
hematotoxicity might benefit from earlier use of alloCD34+ HSCB to
reduce the risk of hemorrhage and life-threatening infections. Larger
studies are needed to that assess its safety, efficacy, and optimal
timing post CAR T-cell therapy.