Outcomes Post-Allogeneic Hematopoietic Cell Transplantation Relapse in Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia

Background Allogeneic hematopoietic cell transplantation (HCT) is a potentially curative treatment for Philadelphia-chromosome positive acute lymphoblastic leukemia (Ph+ ALL), but historically ~30% eventually relapse and outcomes in this setting have been poor. Recent advancements in transplantation techniques, the increasing use of tyrosine kinase inhibitor (TKI) maintenance therapy, and novel therapeutics, such as blinatumomab (B), inotuzumab ozogamicin (InO), and chimeric antigen receptor (CAR) T-cell therapy, have improved outcomes. These novel agents in managing Ph+ ALL post-HCT relapse have not been well described. Herein, we report our experience managing Ph+ ALL post-HCT relapse.

Methods We retrospectively analyzed Ph+ ALL patients (pts) between July 1, 2003-January 17, 2019 who underwent HCT at City of Hope, with a focus on pts who relapsed morphologically or by flow and their response to subsequent therapy. The primary endpoint was complete remission (CR) rate. Secondary endpoints include overall survival (OS) and molecular response. Complete molecular response (CMR) was defined as undetectable BCR-ABL1 with a sensitivity assay of 0.01%, while MMR was defined as a BCR-ABL1 ≤0.1% or a 3-log reduction in BCR-ABL1 on the International Scale. Time-to-event analyses were done via Kaplan-Meier and were compared by a log-rank test. Alive pts were censored at their last follow-up date.

Results 166 Ph+ ALL pts underwent HCT at our institution, of whom, 26 (16%) had evidence of relapsed disease either morphologically or by flow after a median follow-up of 97 months. Pt, disease, transplant, relapse site, and post relapse therapies used are described in Table 1. Of 17 pts with systemic relapse, 9 (53%) achieved CR after 1 salvage line: 6 (35%) with chemotherapy + TKI, 1 (6%) with B + TKI, 1 (6%) with CAR T-cells + TKI, and 1 (6%) with chemotherapy alone. Among the 8 of 9 (89%) evaluated for molecular response, 7 (87.5%) achieved CMR and 1 (13%) achieved MMR. Among the 8 (47%) refractory to first-line salvage, 3 (38%) achieved CR after a median of 2 (range, 1-3) additional therapies. 5 (29.4%) pts with systemic relapse underwent second HCT, 4 (80%) in CR2 and 1 (20%) in CR3. All 5 of these patients died: 4 (80%) by ALL progression, and 1 (20%) by infection while in CR. The 2-year OS for pts with systemic relapse was 44% (95% CI, 20.2-66.1) (Figure 1). One pt underwent two donor lymphocyte infusions (DLI) and achieved CMR both times but eventually died of ALL progression. A second pt underwent DLI but was refractory and died with active ALL. The median number of therapies post-HCT for those with systemic relapse was 4 (range, 1-12).

Of 7 isolated CNS relapses, 6 (86%) achieved CMR, and their 2-year OS was 71% (95% CI, 25.8-92.0). 1 pt (14%) was refractory to therapy. Of 2 isolated lymph node relapses, one was successfully salvaged with chemotherapy followed by DLI and remains alive after >10 years of follow-up while the second pt was successfully salvaged but progressed even after a second HCT in CR2 and died at 1.4 years from an unknown cause. The median number of therapies post-HCT for those with isolated CNS relapse and lymph node relapse were 2 (range, 1-4) and 2 (range, 1-3), respectively.

As for novel therapies used any time post-HCT, 5 (19%) received B, 2 (8%) received InO, and 2 (8%) received CAR T-cells. 3 (60%) achieved CMR with B and 2 (40%) were refractory, of whom, 1 (50%) was successfully salvaged with CAR T-cells but ultimately died of ALL. The other was not salvaged and died with active ALL. Of the 2 (8%) who received InO, 1 (50%) achieved CMR with concurrent ponatinib while the other was refractory but was successfully salvaged with subsequent chemotherapy plus ponatinib. Of the 2 (8%) who received CAR T-cells, 1 (50%) achieved CMR as previously mentioned but relapsed and did not respond to 2 additional CAR T infusions and died of ALL, while the other achieved MMR but had molecular progression and subsequently achieved CMR with ponatinib and remained alive after 7.1 months of follow-up.

There were 20 (77%) deaths. Causes of death include ALL (n=10, 50%), infection with ALL in remission (n=4, 20%), and infection with active ALL (n=2, 10%). 4 (20%) had an unknown cause of death.

Conclusion Although utilization of novel agents in our cohort was limited, systemic Ph+ ALL relapse post-HCT in the current era remains challenging to manage. Isolated CNS relapses post-HCT may be associated with a more favorable prognosis than systemic relapses.

Aldoss:Amgen: Consultancy; Kite: Consultancy; AbbVie: Consultancy, Research Funding; Agios: Consultancy, Honoraria; Jazz Pharmaceuticals: Honoraria, Speakers Bureau; Autolus Limited: Consultancy. Al Malki:NexImmune: Consultancy, Research Funding; Hasna Biopharma: Membership on an entity's Board of Directors or advisory committees; Miltenyi Biotec: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; CareDx: Consultancy, Research Funding; Gilead: Consultancy, Research Funding. Salhotra:Orca Bio: Research Funding; BMS: Research Funding; Kadmon: Other: Advisory board meeting . Ali:Incyte Corporation: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Aribi:SeaGen: Consultancy. Ball:Oncovalent: Membership on an entity's Board of Directors or advisory committees. Artz:Abbvie: Honoraria; Magenta: Honoraria. Marcucci:Abbvie: Other: Speaker and advisory scientific board meetings; Agios: Other: Speaker and advisory scientific board meetings; Novartis: Other: Speaker and advisory scientific board meetings. Stein:Amgen: Speakers Bureau. Nakamura:Magenta Therapeutics: Consultancy; Kadmon: Consultancy; Helocyte Inc: Research Funding; BluebirdBio: Consultancy; Omeros: Consultancy; Sanofi: Consultancy. Pullarkat:Amgen, Dova, and Novartis: Consultancy, Other: Advisory Board Member; AbbVie, Amgen, Genentech, Jazz Pharmaceuticals, Novartis, Pfizer, and Servier: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Mei:Celgene: Research Funding; Incyte: Research Funding; Beigene: Research Funding; Novartis: Consultancy; EUSA: Honoraria; CTI: Honoraria; Morphosys: Research Funding, Speakers Bureau. Koller:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Speakers Bureau; Treadwell Therapeutics: Other: Safety Review Committee.

Bosutinib and nilotinib are off-label uses in Ph+ ALL. The CAR T products described are investigational.