Australian Doctor 10th May issue 2024

26 HOW TO TREAT : CELLULAR THERAPIES IN HAEMATOLOGY

10 MAY 2024 ausdoc . com . au myeloid leukaemia ( see figure 9 ). Further cytogenetic and molecular testing demonstrate high-risk disease ( chromosome 17p deletion with loss of the tumour suppressor gene TP53 ).

Mark is started on 7:3 induction chemotherapy ( cytarabine continuously for seven days , with short infusions of an anthracycline on each of the first three days ) and achieves remission . In view of the high-risk genetic abnormality , allogeneic transplantation in first remission is recommended . Although no suitable family donor is identified , a donor registry search identifies a fully matched unrelated donor in Germany who subsequently undergoes stem cell mobilisation and collection with the cryopreserved cells sent to Australia .

Mark is then admitted to hospital for myeloablative chemotherapy with fludarabine and busulfan , the stem cells are reinfused , and he receives post-infusion prophylaxis for GVHD ( methotrexate and cyclosporin ). Two days post-transplant , Mark develops severe mucositis with dysphagia and odynophagia requiring total parenteral nutrition . By day 12 , his cell counts start to recover . Mark then develops a maculopapular rash over his trunk , which on skin biopsy is consistent with acute GVHD , this resolves promptly with high-dose corticosteroids .

Mark is discharged home . On a bone marrow biopsy on day 30 post-transplant , he is found to be in remission . He continues with full dose cyclosporin until day 100 , and then is gradually weaned . At nine months he develops a further skin rash and xerostomia , consistent with chronic

GVHD . Cyclosporine is again prescribed , together with prednisolone . Two months later the cyclosporine is once again weaned .

Apart from a mild rash , Mark remains well and in remission and resumes his university studies .

Case study three

Alex , a 62-year-old male , presents to his GP with a one-month history of subjective fevers , drenching night sweats and 4kg of weight loss .

On examination , he is found to have a large left inguinal lymph node , and a biopsy identifies a diffuse large

How to Treat Quiz .

B-cell lymphoma . A PET scan demonstrates lymph nodes above and below the diaphragm with uptake in the bone marrow , indicating stage IV disease .

Alex is treated with six cycles of R-CHOP ( rituximab , cyclophosphamide , doxorubicin hydrochloride [ hydroxydaunomycin ], vincristine sulfate [ Oncovin ], prednisone ) chemotherapy . While an interim PET scan after three cycles demonstrates a partial response , a post-treatment scan reveals significant persistent disease . He subsequently receives three cycles of R-DHAC ( rituximab , dexamethasone , cytarabine , cisplatin )

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1 . Which THREE are roles of cellular therapies ? a Direct cytotoxicity to malignant cells . b Replenish the bone marrow with healthy cells . c Activate the immune system to fight disease or infection . d Act as a vehicle for the replacement of a deficient or dysfunctional gene .

2 . Which THREE are indications for autologous stem cell transplant ? a Multiple myeloma . b Breast cancer . c Relapsed / refractory lymphoma . d Rapidly progressive autoimmune diseases .

3 . Which ONE is an uncommon complication of conditioning chemotherapy ? a Mucositis . b Pancytopenia . c Failure to engraft . d Gastrointestinal toxicity .

4 . Which THREE are advantages of allogeneic stem cell transplant ? a The potential to cure an otherwise incurable disease . b An anti-tumour effect on residual malignant cells , resulting in ongoing disease control . c A lower procedure-related morbidity and mortality . d Tumour-free graft source .

5 . Which TWO statements regarding allogeneic stem cell transplant are correct ? a An identical twin is the first choice . b It is important to consider the ethical implications when gaining consent from a donor . c Stem cells may be collected from bone marrow , peripheral blood or umbilical cord blood . d Haploidentical transplant is associated with lower risk of GVHD , graft rejection or both .

6 . Which THREE are major indications for allogeneic transplantation ? a Acute leukaemia . b Relapsed / refractory lymphoma . c Bone marrow failure syndromes . d Low-risk myelodysplastic syndrome .

7 . Which THREE may be complications of allogeneic transplantation ? a Infection . b CRS . c GVHD . d Gastrointestinal toxicity .

8 . Which TWO statements regarding CAR T-cells are correct ? a CAR T-cell preparations target the common true tumour antigens on the malignant cell . b A CAR is a synthetic receptor on the cell membrane of immune effector cells that contains an immunoglobulin fragment specific to a target antigen .

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CELLULAR THERAPIES IN HAEMATOLOGY

salvage chemotherapy , and , on reassessment , a new disease site is found in his mesenteric lymph nodes . Development of progressive disease in this context indicates that a standard autologous transplant is unlikely to be successful and he is referred for consideration for CAR T-cell therapy . After a successful evaluation , Alex ’ s T-cells are collected and sent for processing . He receives conditioning therapy with fludarabine / cyclophosphamide and his CAR T-cells are infused . Two days after infusion Alex has persistent fevers above 38 ° C . On two occasions he becomes hypoxic

c Most CAR T-cell products used in Australia are allogenic . d Autologous CAR T-cells are produced from the patient ’ s own T-cells .

9 . Which THREE statements regarding the CAR process are correct ? a This is an option in those where conventional treatment has failed . b Those aged over 65 are deemed unsuitable for this treatment . c Genetic material for the CAR is integrated into the T-cells using retroviruses , lentiviruses or genome editing . d Before CAR T-cell conditioning , lymphodepleting chemotherapy is used to reduce the number of T-cells , B-cells and NK cells in the recipient .

10 . Which THREE are immune complications of CAR T-cell infusion ? a Cytopenias . b CRS . c ICANS . d Haemophagocytic lymphohistiocytosis . with oxygen saturations of 92 % on room air . He is given two doses of tocilizumab and his fevers resolve . He develops a moderate neutropenia with neutrophils of 0.8x10 9 / L ( normal is 2.0-7.5x10 9 ), and thrombocytopenia with platelets of 34x10 9 / L ( normal is 150-400x10 9 / L ); these complications subsequently resolve . Alex is discharged two weeks after CAR T-cell infusion , and a repeat PET at one month demonstrates complete resolution of his sites of active disease .

CONCLUSION

HAEMATOPOIETIC stem cell transplants , CAR T-cell therapy and other cellular therapies are increasingly used to treat haematological and other conditions . While these therapies are potentially life-saving , they are associated with significant toxicity , including long-term impacts on patients ’ overall health . The GP plays a central role in the long-term care of patients who have received cellular therapies ; key aspects of this care include primary and secondary prevention of cardiovascular , malignant , hormonal , bone and psychological complications .

Australian Doctor 10th May issue 2024 | Page 26

26 HOW TO TREAT : CELLULAR THERAPIES IN HAEMATOLOGY

26 HOW TO TREAT : CELLULAR THERAPIES IN HAEMATOLOGY

How to Treat Quiz .