Hematopoietic Progenitor Cell Transplantation in Children, Adolescents, and Young Adults With Relapsed Mature B-Cell NHL

Although children, adolescents, and young adults with newly diagnosed B-cell non-Hodgkin\u27s lymphoma enjoy excellent overall survival with current chemoimmunotherapy, those with relapsed and/or refractory disease have a dismal prognosis. Although most clinicians would agree that hematopoietic progenitor cell transplantation after reinduction therapy is frontline therapy for these patients, there is no consensus as to what type of hematopoietic progenitor cell transplantation promises the best event-free and overall survival. This review outlines the disparate types of stem cell therapy that have been used in this difficult-to-treat population as well as the role of maintenance and CAR T-cell therapy in conjunction with stem cell therapy

Cellular and Humoral Immunotherapy in Children, Adolescents and Young Adults With Non-Hodgkin Lymphoma

The prognosis is dismal (2-year overall survival less than 25%) for childhood, adolescent, and young adult (CAYA) with relapsed and/or refractory (R/R) non-Hodgkin lymphoma (NHL). Novel targeted therapies are desperately needed for this poor-risk population. CD19, CD20, CD22, CD79a, CD38, CD30, LMP1 and LMP2 are attractive targets for immunotherapy in CAYA patients with R/R NHL. Novel anti-CD20 monoclonal antibodies, anti-CD38 monoclonal antibody, antibody drug conjugates and T and natural killer (NK)-cell bispecific and trispecific engagers are being investigated in the R/R setting and are changing the landscape of NHL therapy. A variety of cellular immunotherapies such as viral activated cytotoxic T-lymphocyte, chimeric antigen receptor (CAR) T-cells, NK and CAR NK-cells have been investigated and provide alternative options for CAYA patients with R/R NHL. Here, we provide an update and clinical practice guidance of utilizing these cellular and humoral immunotherapies in CAYA patients with R/R NHL

Protein phosphatase 1 regulatory subunit 1A regulates cell cycle progression in Ewing sarcoma

Introduction: We recently identified protein phosphatase 1 regulatory subunit 1A (PPP1R1A) as oneof the EWS/FLI core targets that promotes tumor growth and metastasis in Ewing sarcoma (ES), an aggressive pediatric bone and soft tissue tumor. In the current study, we seek to further define the role of PPP1R1A in ES and identify rational combinatorial therapy with improved and specific efficacy in treating primary and metastatic ES. Experimental design: We evaluated ES cell proliferation and cell cycle progression in control and PPP1R1A depleted ES cells. PPP1R1A regulation of cell cycle modulators was analyzed to characterize the underlying mechanism of PPP1R1A mediated cell cycle control. The effects of combination of PPP1R1A and IGF-1R inhibition on ES cell viability and migration in vitro as well as tumor growth and metastasis in an orthotopic xenograft mouse model were investigated. Results: PPP1R1A regulates ES cell cycle in G1/S phase by down-regulating cell cycle inhibitors p21Cip1 and p27Kip1 which results in Rb protein hyperphosphorylation and by promoting normal transcription of replication-dependent histone genes. Furthermore, the combination of PPP1R1A and IGF-1R inhibition induced a synergistic/additive effect on decreasing cell proliferation and migration in vitro and xenograft tumor growth and metastasis in vivo. Conclusions: Taken together, our findings suggest a role of PPP1R1A as an ES specific cell cycle modulator and that simultaneous targeting of PPP1R1A and IGF-1R pathways is a promising specific and effective strategy to treat both primary and metastatic ES

Final Results of Phase I/II Trial of Mitoxantrone in Combination with Clofarabine (MITCL) in Children with Relapsed/Refractory Acute Leukemia

BACKGROUND: Despite excellent outcomes in pediatric leukemias, multiply relapsed or refractory patients have lower response rates to reinduction therapy and low overall long-term survival. (Hunger/Raetz, Blood 2020; Kaspers, Br J Haematol 2014) Clofarabine and Mitoxantrone have proven efficacy in children with leukemia and may display synergy together. (Jeha et al, J Clin Oncol 2009; Parker et al, Lancet 2010) Our previously reported Phase I results demonstrated the maximal tolerated dose of this combination to be Clofarabine 35mg/m2 x 5 days and Mitoxantrone 12mg/m2 x 4 days. Here, we present our final results utilizing this novel combination for high risk pediatric leukemias to achieve MRD negativity as a bridge to hematopoietic allogeneic stem cell transplantation (HSCT). OBJECTIVE: We sought to determine the safety, overall response rate and long term EFS/OS in a Phase I/II trial of clofarabine in combination with mitoxantrone as reinduction therapy for relapsed or refractory pediatric acute leukemia. METHODS: We conducted a prospective, Phase I/II, dose escalation, safety and efficacy study (NCT01842672). Eligible patients were 0-30.99yr old with acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML) either with relapse, induction failure or persistent post consolidation MRD. Patients were given 1 to 3 cycles of clofarabine (Phase I escalating doses 20, 30, 35 and 40mg/m2/day; RP2D 35mg/m2/day) Day 1-5, in combination with mitoxantrone 12mg/m2/day on Day 3-6. Figure 1. CNS prophylaxis was accomplished initially with intrathecal liposomal cytarabine and subsequently with standard cytarabine. MRD was defined by multidimensional flow cytometry as previously reported. (Loken et al, Blood 2012; Borowitz et al, Blood 2015) RESULTS: A total of 39 patients enrolled (18 patients in Phase I, 21 patients in Phase II). Median Age was 13yrs (8months-23yrs). Demographics included 23 ALL (9 = IF/MRD, 11 = Relapse 1, 3 = Relapse 2), 16 AML (8 = IF/MRD, 6 = Relapse 1, 2 = Relapse 2). During the Phase I portion, there were 2 Grade III/IV toxicities at Dose Level 4 (1 hepatic toxicity, 1 prolonged myelosuppression) requiring de-escalation to Dose Level 3. Median time to neutrophil recovery was 24 days in both phases. The Phase I MTD (RP2D) of this combination was established at 35mg/m2/dose Clofarabine. In Phase II, one additional patient developed Grade IV prolonged myelosuppression. There were no other dose limiting toxicities. Thirty three of 39 (85%) leukemia patients achieved a CR after 1 cycle of therapy. This included 21 of 23 (91%) ALL patients and 12 of 16 (75%) AML patients. Of these, 88% achieved MRD negativity based on flow cytometry. Thirty one of 33 patients achieving CR went on to receive HSCT. One patient died prior to HSCT. Seven patients died of non-relapse HSCT complications. One patient died of recurrent disease post-HSCT. The remaining 24 patients continue to demonstrate complete remission with MRD negativity. The overall and event free survival at 1 year and 3 years for the cohort of patients who responded to therapy is 85% (CI95 0.84-0.97) and 77% (CI95 0.64-0.98), respectively at a median follow up time of 53 months (range 10-101). (Figure 2) CONCLUSION: The combination of clofarabine and mitoxantrone reinduction therapy for relapsed or refractory acute pediatric leukemia has been demonstrated to be safe and well tolerated at a RP2D of 35mg/m2 Clofarabine in children with poor risk relapsed or refractory acute leukemias. Our response data is encouraging with 85% CR rate with high MRD negativity in leukemic patients allowing patients to safely proceed to allogeneic stem cell transplant with a 3yr EFS and OS of 77%. A larger cohort and longer term follow-up is needed to assess late toxicities, particularly cardiac, as well as EFS/OS more definitively at later endpoints and to better define subgroups. A successor trial is planned and ongoing