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Optimizing ALL Treatment
Expert Guidance on Optimizing Treatment Strategies for Acute Lymphoblastic Leukemia

Released: April 16, 2020

Expiration: April 15, 2021

Amir Fathi
Amir Fathi, MD
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Generation of TAA-Targeted CAR T-Cells for Treatment of Cancer

CAR T‑cell therapy is increasingly studied in B-cell ALL with 1 CAR T-cell therapy currently approved. This modality is emerging as a promising treatment option for patients with relapsed/refractory disease.

The process of generating CAR T-cells begins by performing leukapheresis to collect T-cells from the patient and sent for manufacturing of the CAR T-cells. There is construction of a CAR gene, which is a modified T‑cell receptor targeting CD19. This CAR gene, with the use of a retrovirus vector, is transduced into the patient’s T‑cells that are then expanded ex vivo. These modified CAR T‑cells are then sent back to the treating center and infused into the patient with relapsed/refractory B‑cell ALL.44-46 As one can imagine, this approach is quite complicated and requires multiple steps. Additionally, a typical CAR T-cell therapy is not an off‑the‑shelf treatment as is the case with blinatumomab or InO. CAR T-cell therapy requires time to prepare and logistics to administer and therefore can be quite an involved procedure. 

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CAR T-Cell Manufacturing, Treatment, Assessment

The various steps involved in CAR T‑cell manufacturing and treatment are illustrated in this figure.46 There is an initial leukapheresis step to collect T‑cells from the patient, followed by CAR T‑cell production. During that time, the patient may require salvage chemotherapy to slow disease progression followed by disease assessment. Conditioning chemotherapy is given before the infusion of the CAR T‑cells to prepare for the T‑cells to do their job in terms of eliminating residual leukemic cells. Infusion of the CAR T‑cells follows, and can be given as 1 or 2 doses, depending on the product. Then there is another disease assessment several weeks later to see if there is a therapeutic response.

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CAR T-Cell–Associated Toxicities

There are a variety of toxicities associated with CAR T‑cell therapy.47 These include more common adverse events such as neurologic toxicity and CRS, which have also been seen, although less frequently, with blinatumomab. Less common toxicities include B‑cell aplasia, infusion anaphylactic reactions, and hemophagocytic lymphohistiocytosis.

Phase II ELIANA Trial of Tisagenlecleucel in Pediatric and Young Patients With B-Cell ALL: Study Design

ELIANA was a multicenter, open-label, single-arm phase II trial that examined a CAR T‑cell product, tisagenlecleucel, in 92 pediatric and young patients with relapsed/refractory B‑cell ALL.47 Patients were aged between 3 and 21 years, with ≥ 5% bone marrow lymphoblasts, and no isolated extramedullary disease relapse, previous CD19-directed therapy, or previous gene therapy. The conditioning regimen for this CAR T‑cell product was fludarabine and cyclophosphamide, with 1 single dose of tisagenlecleucel (0.2-5.0 x 106/kg IV if ≤ 50 kg, or 0.1-2.5 x 108 IV if > 50 kg) administered following conditioning. The primary endpoint was ORR within 3 months. Secondary endpoints included MRD status, duration of response, OS, and safety.

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ELIANA: Remission and Survival

Efficacy outcomes in this relatively small population of patients treated with tisagenlecleucel were very promising.47 Among 61 patients who achieved remission, the median duration of response was not reached at the time of publication. The median OS was also quite promising at 19.1 months, with 90% of patients alive at 6 months.

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ELIANA: Adverse Events

CRS was observed in 77% of patients and neurologic events in 40%. The median time to onset for CRS was 3 days with a median duration of 8 days. Overall, 21% of patients experienced grade 3 CRS, and grade 4 events were seen in 25%. Grade 3 neurologic events were seen in 13% of patients but no grade 4 events were observed. Other AEs seen on study included cytopenias, infections, febrile neutropenia, and tumor lysis syndrome.

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Tisagenlecleucel: CRS Management

CRS with CAR T‑cell therapy can manifest as a prodromal event with low‑grade fever, nonspecific fatigue, and anorexia that can then become much more pronounced.48 Initial steps can include exclusion of infection. Antibiotics can be administered if the patient is neutropenic, and if bacterial infection is documented. Symptomatic support can be administered as needed.

Some CRS cases may require mild intervention if the patient has high fever, hypoxia, or mild hypotension. For these patients, antipyretics, oxygen, IV fluids, and vigilant monitoring are recommended in case there is additional need for vasopressor and ICU transition.

If CRS worsens to moderate or aggressive forms, patients may require transfer to an ICU, vasopressor agents, oxygen, or, potentially, mechanical ventilation. In this scenario, tocilizumab can be effective and should be used. Tocilizumab can be repeated at intervals of 8 hours if there is no sufficient clinical improvement. If there is no clinical improvement within 12‑18 hours of tocilizumab dosing, methylprednisolone can be given until vasopressors and high-flow oxygen are no longer needed, and then tapered down.

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Tisagenlecleucel: Neurotoxicity Management

For grade 1 neurotoxicity, supportive care is recommended as needed. Steroids should be considered to manage grade 2/3 neurotoxicity. If a patient is experiencing grade 4 neurotoxicity, high-dose steroids plus ICU transition is recommended. If a patient encounters both CRS and neurotoxicity, tocilizumab should be considered to manage grade 2-4 events.49,50 Note: To view an Interactive Decision Support Tool on assessment and management of CAR T-Cell toxicities, please visit http://www.clinicaloptions.com/CARTtool or download the CCO Decision Support App.

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CAR T-Cell Therapy for ALL: Advantages and Limitations

There are both advantages and limitations to CAR T‑cell therapy.51-53 Advantages include HLA‑independent antigen recognition and, therefore, universal application; rapid generation of tumor‑specific and tumor-targeting T‑cells; minimal risk of graft‑vs‑host disease; potential for lasting immunity even after a single infusion; selective modification of specific T‑cell subtypes; and the additional modification capability of the CAR construct, meaning that CAR T‑cells can be further modified to be more efficacious and less toxic. Many of these modified T-cell constructs are under investigation.

The limitations of CAR T-cell therapy are the potential for severe toxicities including CRS, tumor lysis syndrome, and neurologic toxicity, as well as a variety of other, less common, toxic events.

Tisagenlecleucel: FDA Approval and Indication in ALL

The FDA indication for tisagenlecleucel in ALL is for the treatment of patients 25 years of age or younger with B‑cell ALL that is refractory or in the second or later relapse.48 Boxed warnings include CRS and neurologic toxicities. Tisagenlecleucel is only available at certain sites through restricted programs under risk evaluation and mitigation strategies. Only certified healthcare facilities with onsite and immediate access to tocilizumab can offer this therapy. In addition, healthcare providers need to be trained and knowledgeable in the management of CRS and various neurologic toxicities.

Conclusions

In conclusion, first‑line strategies for younger patients with B-cell ALL appear to be improving with pediatric‑inspired regimens vs conventional cytotoxic regimens that have been used for decades. The efficacy of conventional first‑line approaches for Ph-positive ALL is markedly improved with the incorporation of BCR‑ABL–targeted TKIs. For older patients, newer, less intensive regimens that incorporate InO or TKIs are increasingly being used and showing marked promise.

In the relapsed/refractory setting, blinatumomab and InO both prolong OS vs standard chemotherapy. Blinatumomab appears to be quite effective in clearing MRD in patients who achieve a CR following induction therapy. A subset of patients who develop unique toxicities to blinatumomab or InO require close and vigilant monitoring and management. Finally, CD19‑targeted CAR T‑cell therapy can induce a high rate of remission with promising and durable outcomes.

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