An Introduction to New Technology in the Treatment of Leukemia and Lymphoma
From Janice P. Dutcher, M.D. and Peter H. Wiernik, M.D.
Professor of Medicine at New York Medical College, Associate Director for Clinical Affairs at Our lady of Mercy Comprehensive Cancer Center, Bronx New York
Chairman of “Team Leukemia”
Our Lady of Mercy Cancer Center, New York Medical College, Bronx, New York, USA
During the past several years, the focus of new agents for leukemias has been directed at leukemia-specific targets such as mutations, translocations, and pro-survival proteins (molecular therapeutics), as well as immunotherapies targeting the leukemia cells. Early on, this was successfully employed through the use of monoclonal antibodies directed at B- cells such as rituximab, and radioimmunoconjugates. Additionally, gemtuzumabozogamicin is a monoclonal antibody directed toward CD33 on myeloid leukemia cells complexed with a toxin to kill those cells. Next generationtargeted therapies directed at the Philadelphia chromosome in chronic myeloid leukemia have been effective in the treatment Philadelphia chromosome positive acute lymphocytic leukemia (ALL), including in the pediatric population.
Acute Lymphocytic Leukemia (ALL)
- Blinatumomab is a bispecific monoclonal antibody that binds to anti-CD19 on leukemia cells and CD3BITE to engage T-cells to kill leukemia cells. This has been approved for use in patients with B-cell precursor ALL of any age, who demonstrate minimal residual disease (MRD+) at the time of clinical and hematologic remission. It is also approved for treatment of children whose B-cell precursor ALL has returned or did not respond to initial therapy.
- Recent reports describe blinatumomab in combination with dasatinib for Philadelphia chromosome positive ALL in adults (Foa, et al. NEJM 2020; 383:1613-23) , and as consolidation therapy prior to allogeneic hematopoietic stem cell transplant for children with high-risk B-cell precursor ALL (Locatelli F, et al. 2020; Proc ESBMT).
- Inotuzumabozogamicin is a CD22 antibody-drug conjugate approved for treatment of adult and pediatric CD22-positive B-ALL, which was shown to be highly effective in previously treated children and young adults with recurrent or refractory CD22-positive B- ALL in a Children’s Oncology Group study with 65% achieving MRD <0.01%. (O’Brien MM, et al. Blood 2019; 134 (suppl 1):741. This agent is undergoing study in newly diagnosed pediatric patients with high risk B-ALL.
- Tisagenlecleucel is the anti-CD19 chimeric antigen receptor (CAR) T-cell therapy initially developed for treatment of relapsed or refractory B-cell ALL in children and young adults. In a global study, “a single infusion provided durable remission” (Maude SL, et al. NEJM 2018; 378:439-448).
- Additionally, a recent study adding sequential Rituximab for MRD to intensive chemotherapy to adolescents and young adults with B-cell ALL has shown great promise. (Eldadah S, et al. Soc Hem Oncol 2020; abst ALL-312)
- Additional efforts in the treatment of Philadelphia chromosome positive ALL have led to the following study: Dasatinib, a second generation Abl-tyrosine kinase inhibitor, has recently been compared with imatinib in pediatric patients with Philadelphia chromosome positive ALL, both in combination with intensive chemotherapy. The Dasatinib regimen“ yielded superior results and provided excellent control of central nervous system leukemia without the use of prophylactic cranial irradiation” (Shen S, et al. JAMA Oncol 2020; 6:358-366).
- For children with T-ALL, an entity comprising about 10-15% of childhood ALL, Nalarabine is now approved. This agent, when added to chemotherapy, has increased 5-year disease-free survival from 60% to 90% of subjects treated (Dunsmore KP, et al. J Clin Oncol 2020; 38:3282-3293).
Acute Myeloid Leukemia (AML)
New agents and regimens for myeloid leukemias are targeting specific mutations identified in subgroups of AML patients, as well as developing treatments for specific patient populations, including those who may not be candidates for more intensive chemotherapy. Although many of these subgroups are more common among older adults, somatic mutations in genes such as WT1 and FLT3 and or c-KIT/CD117 are observed in a small minority of pediatric AML, and specifically directed therapy may impact positively on outcome (Niktoreh N, et al. J Oncol 2019; doi.org/10.1155/2019/1609128).Additionally, some of the less toxic regimens for older adults are being evaluated as second and third line regimens in pediatric and young adult patients.
- Among approximately 30% of adult patients with AML, the leukemic cells carry somatic mutations called FMS-like tyrosine kinase 3 (FLT3) mutations. Agents have been developed to address these mutations.
- Midostaurin is the first FLT3 mutation inhibitor to be approved for newly diagnosed that is FLT3 mutation positive AML, documented by an FDA-approved test. This agent is currently in clinical use.
- Gilteritinib is a second generation FLT3 inhibitor that is currently in use and also undergoing studies in combination with other regimens, including with chemotherapy. This agent is approved for patients with relapsed and refractory AML bearing this mutation. (Perl AE, et al NEJM 2019; 381:1728-40)
- Quizartinib is another potent FLT3 inhibitor being studied in combination with non-cytotoxic therapy in older patients with FLT3 mutated AML.
- Myelodysplastic syndrome (MDS) is rarely a pediatric disease, but drugs evaluated in this setting may move into the setting of AML, and Downs related AML. Recently approved was the combination of decitabine and cedazuridine for adults with MDS or chronic myelomonocytic leukemia (CMML) (clinicaltrialsgov – reference numbers: NCT02103478, NCT03306264).
- Another target shown to be proleukemic when mutated is Isocitrate dehydrogenase (IDH), a key enzyme in metabolic enzyme cycles. Mutations in this enzyme, noted as IDH1 and IDH2 can lead to de novo, or post-myeloproliferative AML. Two agents have been developed, ivosidenib (IDH1) and enasidenib (IDH2) which are both oral and are combined with standard induction therapy, and which stimulate differentiation and are then utilized as maintenance. This has led to much higher rates of complete remission and duration of remission in patients with these mutations. (Liu X, et al. Biomarker Res 2019; 7:22; Chifotides HT, et al. DOI 10.1192/bloodadvances2020001528)
- Over many years, there has been great interest in developing less toxic and less myelosuppressive regimens, particularly for older patients with AML (>70 years). The evaluation of these agents and regimens in pediatric patients is ongoing.
- The combination of Azacitadine and Venetoclax has been approved for treatment of previously treated acute myeloid leukemia (AML).Venetoclax is also approved in combination with azacitidine, decitabine or low dose cytarabine in previously untreated patients > 75 years old or for those unable to receive intensive chemotherapy. The addition of Venetoclax to Azacitadine improved the rate of remission and overall survival compared to azacitadine alone (clinicaltrials.gov – reference number: NCT029993523; DiNardo CD, et al.NEJM 2020:383:617-29).
- Venetoclax in addition to induction chemotherapy in pediatric AML is being studied, and the use of Azacitadine as a bridge to stem cell transplant is also undergoing evaluation.
- Azacitidine has now also been formulated as an oral medication, after years of usage as intravenous and subcutaneous administration. The oral formulation has been studied as a maintenance agent after intensive induction chemotherapy with or without consolidation therapy. A major survival benefit was observed in those receiving maintenance azacytidine (clinicaltrials.gov reference number – NCT01757535)
- Glasdegibis in development, and is a hedgehog pathway inhibitor. It is undergoing evaluation in combination with cytarabinein AML patients aged >75 years who cannot receive intensive chemotherapy.
- A new agent for high risk MDS is undergoing study, pevonedistat, in combination with azacitidine, and shows prolongation of time to progression. This agent is a small molecule inhibitor of NEDD8-activating enzyme, and disrupts protease degradation of select proteins (Watts J, et al. Proc Soc Hematol Oncol 2020, Abstract MDS-336).
- VYXEOS is a newly constructed combination of daunorubicin plus cytarabine in a pharmacologically guided dose combination. It is approved for treatment of adults with newly-diagnosed therapy-related AML or AML with myelodysplastic related changes.