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Management of patients undergoing CAR T-cell therapy
serotherapy and radiotherapy) may adversely affect sub- sequent attempts at leukapheresis and washout periods need to be considered.
Table 4 provides recommendations on washout periods following various salvage treatments before starting leukapheresis. In addition, it should be noted that prior use of blinatumomab is not a contraindication to anti- CD19 CAR T-cell therapy.23
Bridging therapy
Bridging therapy refers to the administration of anti- cancer drugs including chemotherapy to maintain disease control during the period between lymphocyte collection and the final administration of the CAR T-cell product.16 This time window may be longer than anticipated for logistical reasons, sometimes but not always related to manufacturing, and will be specifically monitored through EBMT Registry collection of ‘real world’ data.
The goal of bridging therapy is to prevent clinically sig- nificant disease progression leading to impaired organ function or any other complications that might prevent the patient proceeding with lymphodepletion and receiv- ing the CAR T cells. It is also hoped that treatment of rap- idly proliferating disease will establish a balanced in vivo target-effector ratio to allow for effective CAR T-cell adoptive immunotherapy. In brief, the aim is not so much to achieve disease remission as to establish adequate dis- ease control prior to the CAR T-cell infusion.
The optimal bridging therapy for any individual will depend on disease- and patient-specific factors. However, clinicians should bear in mind that patients receiving chemotherapeutic agents, either alone or in combination, will subsequently receive lymphodepleting therapy and will be at risk of specific CAR T-cell-related complications such as cytokine release syndrome (CRS), encephalopathy and tumor lysis syndrome. Bridging therapy should there- fore ideally not induce major complications, such as infec- tions, bleeding or any organ dysfunction that might inter- fere with the planned lymphodepleting therapy and CAR T-cell infusion. Bridging therapy can be omitted in the presence of stable, low burden disease if the turn-around
Table 4. Wash-out period before leukapheresis (adapted from Kansagra et al.12).
time for the CAR T cells is expected to be short. Importantly, certain agents, especially immunotherapeutic drugs with a longer half-life, may interfere with the expansion or persistence of the infused CAR T cells and should be avoided. Examples include alemtuzumab, dara- tumumab, checkpoint inhibitors and brentuximab vedotin.
When choosing bridging therapy for lymphoma patients, factors to be considered include the prior response to chemotherapy and chemo-immunotherapy, the overall tumor burden and the distribution and sites of tumor involvement. Options include parenteral agents such as rituximab, gemcitabine, oxaliplatin, bendamustine or pixantrone; oral chemotherapy regimens e.g. variants of prednisolone, etoposide, procarbazine, and cyclophos- phamide (PEP-C), or oral cyclophosphamide 100 mg once daily; novel targeted therapies such as lenalidomide or ibrutinib; high-dose corticosteroids e.g. dexamethasone 40 mg for 4 days or high-dose methylprednisolone, repeated as needed; or radiotherapy to symptomatic or large masses.24,25
In ALL, the risk of CRS has been found to correlate with the leukemic blast burden at the time of the CAR T-cell infusion. Bridging chemotherapy is therefore especially important in ALL and the chosen agents are typically drawn from known B-ALL chemotherapy regimens although doses are often reduced to lower the risk of infectious complications and organ dysfunction.5,26 Novel and targeted agents, for example, tyrosine kinase inhibitors and monoclonal antibodies, may also be used although it is important to consider whether the agent is capable of inducing a rapid response and whether the therapy might interact with subsequent lymphodepleting and CAR T-cell therapy. Whatever treatment is chosen, bridging therapy should only be given after leukapheresis so that the quality of the CAR T-cell product is not affect- ed. The patient can be monitored after leukapheresis and during and following bridging chemotherapy either at the treating center or at the referring center provided that there are clear lines of communication between the cen- ters regarding the choice of any treatments and the man- agement of any complications. Frequent monitoring, including laboratory testing and imaging, is mandatory in
Type of therapy
Allo-HCT
Donor lymphocyte infusion High-dose chemotherapy
CNS-directed therapy
Short-acting cytotoxic/ anti-proliferative drugs
Systemic corticosteroids
SPC
No guidance
No guidance No guidance
No guidance No guidance
No guidance
EBMT recommendations
Patients should be off immunosuppression and GvHD-free
4 weeks
3-4 weeks depending on
the intensity of the chemotherapy
1 week 3 days
Ideally, 7 days to minimise any effect on lymphocyte collection
Comments
A minimum of 1 month is recommended
6 to 8 weeks may be safer to rule out any GvHD Recovery from cytopenias is required
Recovery from cytopenias is required
A shorter period of as few as 3 days
was considered acceptable by Kansagra et al.12 Regardless of timing, an ALC>0.2 x109/L is preferable given the likely effect of recent corticosteroids on lymphocyte quality
SPC: summary of product characteristics; EBMT: European Society for Blood and Marrow Transplantation; Allo-HCT: allogeneic hematopoietic cell transplantation; GvHD: graft-versus-host disease; CNS: central nervous system; ALC: absolute lymphocyte count.
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