Outcome of ALL in Adult Patient with Down Syndrome, Single Center Experience

Background: Individuals with down syndrome (DS) have an approximately 20-fold increased risk of developing acute lymphoblastic leukemia (ALL) and significantly worse outcomes due to a higher relapse rate and treatment related-toxicities including severe mucositis and prolonged hospitalization. Previous studies showed that, among the pediatric age group, the transplant-related mortality (TRM) of allogenic HSCT in DS-ALL is 39%, though subsequent studies attributed treatment failure to leukemia relapse. Chimeric antigen receptor therapy is a newly emergent therapy, used on a limited number of children. Currently, there is insufficient data regarding the outcome and optimal treatment strategy for adult patients with DS-ALL at time of diagnosis or relapse.

Method: We retrospectively reviewed the outcome of adult patients who were initially treated or continued their treatments after being transferred from pediatric institutes to Princess Margaret Cancer Centre over the last 20 years.

Adult patients with DS and de-novo ALL (diagnosed after the age of 18 years) and those with late relapsed DS-ALL who had not previously received intensive asparaginase therapy were treated according to a modified Dana Farber Cancer Institute (DFCI) ALL protocol. This protocol includes an at least four-fold higher total dose of E. coli-derived asparaginase compared to other adult regimens. Reduced doses of methotrexate were used due to the increased risk of mucositis reported in children. After 2018, relapsed patients received either CAR-T or Blinatumomab.

Results: Thirteen adult patients with DS-ALL were treated at our center. Nine of them were diagnosed with de novo adult DS-ALL and four with late relapsed disease as adults after previous treatment for childhood DS-ALL. There was no CNS involvement in all patients at diagnosis or relapse.

The median age of de-novo adult DS-ALL was 30 years (range 21-46 years). Seven patients (77.7%) achieved complete remission (CR) after initial induction with DFCI; two patients (22.3%) died within 60 days of induction due to sepsis. Meanwhile, the median age of patients with late relapses was 12.5 years (range 7-15 years) at initial diagnosis, and 23.5 years (15-36 years) at relapse.

Four of the seven (57%) de-novo adult DS-ALL patients relapsed after CR1 of 11, 35, 36, 48 months. Two of them received palliative therapy, one received re-induction with HyperCVAD, and one with Blinatumomab, achieving CR2 of 3 and 8.5 months, respectively. Unfortunately, all relapsed de-novo DS-ALL patients have died. The remaining three of the seven (43%) patients are alive and in continuous CR1 at 129, 36 and 33 months.

Two of the four patients with late relapse DS-ALL received re-induction with DFCI, achieving CR2 of 8 and 15 months, followed by a second refractory relapse. The third patient died during re-induction by HyperCVAD due to septic shock. The last patient received CART-Cell therapy and achieved CR2 for 27 months. He is currently in remission after one cycle of Blinatumomab.

The overall and relapse-free survival of adult patients with DS-ALL at 3 years was 77% and 69.2% respectively, and thus shows inferior results when compared to a similarly treated population of adults (aged 18-35 years) without DS (3-year OS 83%, 3-year RFS 77%) at our center. De-novo DS-ALL overall and relapse-free survival was 66.6% and 55.5%, respectively.

Conclusion:To our knowledge, we are describing the largest single-centre retrospective study involving DS in adult ALL patients. We found that the observed barriers to successful treatment were similar to those in pediatric cases. Pediatric chemotherapeutic regimens can be used for adult DS-ALL but are associated with more toxicities and higher relapse rates when compared to adult without DS. CAR-T therapy should be considered a first-line treatment at the time of relapse. Blinatumomab and Inotuzumab can be used as third-line treatments for second relapse. Ultimately, patients who are fit for allogenic bone marrow transplant, should consider it as a curative option during second remission. Future studies involving patients with DS-ALL should explore the use of Blinatumomab and Inotuzumab in combination with first-line chemotherapies.

Perusini:Pfizer: Consultancy. Gupta:AbbVie: Consultancy, Other: Participation on a Data Safety or Advisory board; Pfizer: Consultancy, Other: Participation on a Data Safety or Advisory board; Sierra Oncology: Consultancy; Roche: Other: Participation on a Data Safety or Advisory board; Constellation Pharmaceuticals, Inc., a MorphoSys Company: Consultancy, Honoraria; BMS Celgene: Consultancy, Honoraria, Other: Participation on a Data Safety or Advisory board; Novartis: Consultancy, Honoraria. Schimmer:Jazz: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Otsuka Pharmaceuticals: Consultancy, Honoraria; UHN: Patents & Royalties: the use of DNT cells to treat AML; BMS: Consultancy, Honoraria, Research Funding; Astra Zeneca: Consultancy, Honoraria; Medivir AB: Research Funding; Takeda Pharmaceuticals: Consultancy, Honoraria, Research Funding. Schuh:Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Teva Pharmaceutical Industries: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; GlycoMimetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Phebra: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Yee:TaiHo: Consultancy; Gilead: Research Funding; Geron: Research Funding; F. Hoffmann La Roche: Consultancy, Research Funding; Shattuck Labs: Consultancy; Takeda: Consultancy; Novartis: Consultancy, Honoraria, Research Funding; Abbvie: Honoraria; Janssen: Research Funding; Pfizer: Consultancy; Jazz: Consultancy, Research Funding; GlaxoSmithKline: Consultancy; Astex: Research Funding; Forma Therapeutics: Research Funding; Karyopharm: Research Funding; Treadwell: Research Funding; Bristol-Myers Squibb/Celgene: Consultancy; Astellas: Consultancy. Richard-Carpentier:Astellas: Consultancy, Honoraria, Other: Advisory Board Participation; AbbVie: Consultancy, Honoraria, Other: Advisory Board Participation; Pfizer: Consultancy, Other: Advisory Board Participation; BMS: Other: Advisory Board Participation; Taiho: Other: Advisory Board Participation.