CASE DESCRIPTION
Our patient is an African American female diagnosed at 6-weeks of age
who presented for evaluation of persistent vomiting, lethargy and an
unusual skin rash after several weeks of concern for failure to thrive.
Initial white blood cell (WBC) count was 834x109/L
with 98% circulating lymphoblasts. Flow cytometry performed on
peripheral blood revealed ALL with 98% of total cells expressing CD19.
Cytogenetic analysis revealed a t(11;19)(q23.3;p13.3) translocation and
flouresent in situ hybridization analysis confirmed a KMT2A-r
ALL. Cerebrospinal fluid (CSF) analysis revealed central nervous system
(CNS) involvement. The patient underwent leukoreduction and subsequently
initiated treatment as per the Interfant-06 standard protocol
(clinigaltrials.gov: NCT00550992).
End of induction assessment demonstrated clearance of the
extra-medullary disease and a bone marrow morphologic remission but flow
cytometric evidence of minimal residual disease of 0.36%. Three months
after diagnosis she relapsed with confirmed ALL detected in the bone
marrow and CSF with chloromatous skin lesions following a period of
delayed blood cell count recovery from consolidation therapy. She
received high-dose methotrexate (HD-MTX) (3.3gm/m2)
with 6-mercaptopurine (6MP) and intrathecal methotrexate/hydrocortisone
(IT MTX/HC) that resulted in clearance of peripheral blood and CSF
lymphoblasts and resolution of chloromas.
She underwent autologous CD3 lymphocyte apheresis using the CMNC program
in the Spectra Optia automatic apheresis system for CAR-T generation
over a course of 3 collection days at the age of 5-months and weighing
6.8kg. The device was primed with whole blood which was reinfused to her
at the completion of the procedures. Absolute lymphocyte count (ALC) at
the start of collection was 0.88x109/L. On day 1 the
product output was poor with a total nuclear cell count (TNC) of
0.14x109/L and a CD3 count of
0.02x109/L cells.
Adjustments were made for collection on days 2 and 3. On day 2, the TNC
obtained was 1.4x109 and the CD3 count was
0.42x109 cells. Day 3 yielded
2.64x109 TNC and 0.31x109 CD3
lymphocytes. The procedure totaled 4.18x109 TNC and
0.76x109 CD3 cells over 3 days. Despite her small
size, the cellular goals for apheresis were the same as for an adult and
were appropriately met without any complications.
CNS and peripheral blood lymphoblasts re-emerged following chemotherapy
with high dose cytarabine and pegaspargase but cleared following HD-MTX
(3.75gm/m2), 6MP, dexamethasone, vincristine and IT
MTX/HC. Lymphodepleting therapy with a 2-day course of cyclophosphamide
and fludarabine was administered 7 days prior to tisagenlecleucel
infusion. The total cell viability in the final CAR-T product was 85.4%
with 2.7% CAR positive viable cells, below the 3% threshold required
by the Food and Drug Administration (FDA) for product release. However,
the overall number of chimeric antigen receptor (CAR) viable transduced
T-cells was 2.3x106 cells/kg, meeting the clinical
specifications required for commercial use.[23] As the final product
did not meet all the required specifications, she received the
manufactured cells on compassionate use exemption at 7-months of age.
Figure-1 summarizes her WBC count, lymphoblast count, C-reactive
protein, ferritin, fibrinogen, maximum daily temperature and clinical
course following CAR-T infusion. Her course was complicated by grade 2
cytokine release syndrome (CRS) in conjunction with the emergence of
confirmed CD19 lymphoblasts detected in peripheral blood on day 7. CRS
was manifested by persistent high fevers, tachycardia, tachypnea and
grunting. She received two doses of tocilizumab on days 7 and 10. She
developed tumor lysis syndrome (TLS) and subsequent acute kidney injury
manifested by an increase in creatinine from 0.32mg/dL to 0.61mg/dL. She
subsequently developed Klebsiella pneumoniae bacteremia,
disseminated intravascular coagulation and unexplained hypoglycemia.
Full recovery from TLS and CRS occurred following the clearance of
peripheral lymphoblasts by day 13. She was discharged home on day 26 in
remission confirmed by morphologic and flow cytometric assessment of
bone marrow.
At 9-months old she proceeded with a planned myeloablative
(busulfan/cyclophosphamide) haploidentical allogeneic HSCT from her
14-year old sister. Tacrolimus and mycophenolate mofetil were used for
graft-vs-host-disease prophylaxis. She developed reversible
hyperbilirubinemia, transaminitis and hepatomegaly. Complications
included Klebsiella pneumoniae bacteremia, mucositis,
hypertension and pericardial effusion. She was discharged on day 34 in
remission confirmed by CSF evaluation and morphologic and flow
cytometric analysis of her bone marrow. She is now 12-months post-HSCT
and remains in a remission.