Historically, allogeneic hematopoietic stem cell transplantation (HSCT) has been considered the only curative option for patients with high-risk acute lymphoblastic leukemia (ALL). Over the years, access to allogeneic HSCT has increased as donor classifications have broadened to include mismatched unrelated donors, haploidentical donors, and umbilical cord blood (UCB). Despite the increasing access to transplantation for these patients, questions remain regarding optimal transplant and post-transplant strategies to target long-term disease-free survival (DFS) with limited toxicities.
This article discusses who is best suited for allogeneic transplant and challenges that remain for optimizing pre- and post-transplant best practices.
Philadelphia chromosome (Ph)-positive B-cell ALL can be treated with frontline hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone or ponatinib. In addition, combination blinatumomab and dasatinib may become a potential frontline option for these patients. Identifying relapse predictors, such as Ph-like kinase activating translocations and mutations, is important to recognize patients who would benefit from transplant earlier in the course of therapy. For other patients with intermediate-risk genotypes, it is increasingly becoming standard of care to use minimal residual disease (MRD) status after induction, or after two to three cycles of chemotherapy, to determine whether to proceed to allogeneic transplant.
Although questions remain on when to transition to transplant in patients with MRD negativity, for patients who are MRD-positive and at high risk of relapse, allogeneic HSCT after intervention can induce a deeper remission.
Bridging Therapy Options
The article assesses data on three potential bridging therapies for patients with ALL: blinatumomab, inotuzumab ozogamicin, and chimeric antigen receptor (CAR) T-cell therapy.
Blinatumomab may be effective for patients with persistent MRD positivity after two to three cycles of chemotherapy, as it is associated with an 80% likelihood of converting to MRD negativity. The article notes that this is “an excellent approach” for bridging patients to allogeneic HSCT. In long-term follow-up from the BLAST trial, in which blinatumomab was given to patients with MRD-positive B-cell ALL, relapse was less common in the 72% of patients who subsequently received allogeneic transplant after blinatumomab therapy. In addition, 45.9% of patients were alive and had not relapsed after receiving blinatumomab followed by allogeneic HSCT compared with 30.4% of patients who received blinatumomab alone (among MRD responders), “demonstrating that blinatumomab should, in most cases, not be used as solitary therapy for MRD-positive B-cell ALL and patients should proceed to allogeneic HSCT whenever possible,” according to the article.
Inotuzumab ozogamicin in the relapsed setting is associated with high rates of complete remission (CR; 80.7%). Although inotuzumab has not been formally assessed for MRD-positive B-cell ALL, the article notes that it may be considered in patients who remain MRD-positive after blinatumomab who have not yet received allogeneic HSCT. Of note, inotuzumab is associated with a risk of veno-occlusive disease, occurring in 14% of patients in the phase III INO-VATE study. Limiting the cumulative dose of inotuzumab to no more than two cycles and using a reduced dose in combination with chemotherapy may mitigate this adverse event in patients awaiting allogeneic transplant.
CAR T-cell therapy as bridging therapy is “controversial,” according to the article, as single-center data have shown disparate results in patients undergoing allogeneic HSCT after CAR-T therapy. In studies, just a small percentage of patients have proceeded from CAR-T therapy to allogeneic HSCT. “It appears likely that some patients may benefit from consolidative allogeneic HSCT after achieving remission with CAR-T therapy, but it is presently difficult to identify which patients merit the additional risk of allogeneic HSCT,” the article notes.
As blinatumomab and inotuzumab potentially move to the frontline setting for ALL, it will become difficult to determine who should undergo allogeneic HSCT in first remission, which agents to use, and when to maximize cure rates, according to the review.
Optimal donor type for adults with ALL has not yet been identified, but progress has been made in identifying alternative donors. Between 2008 and 2018, the number of allogeneic transplants occurring in patients with ALL in first CR doubled to roughly 900 per year, according to data reported to the Center for International Blood and Marrow Transplantation Research. The number of haploidentical donors used in these transplants more than tripled during that time to over 300 per year, “indicating this graft source is indeed enabling allogeneic HSCT for more patients with ALL,” according to the article.
UCB grafts are less commonly used in this patient population but may be an option for some patients. A study of 582 patients undergoing allogeneic HSCT for acute leukemia or myelodysplastic syndromes (including about a third with ALL) found that those with MRD prior to transplant had significantly higher risk of relapse with matched unrelated donor grafts compared with UCB grafts (hazard ratio=3.01; 95% CI, 1.22-7.38; P=.02).
Following transplant, high-sensitivity MRD quantification via next-generation sequencing (NGS) can identify patients at risk of relapse and allow time for further intervention. Peripheral blood monitoring using NGS may allow for more frequent monitoring of molecular status, which can provide more lead time before relapse to deploy new treatment strategies.
Additional studies on optimal treatment options and timing for intervention post-transplant are needed. Post-transplant tyrosine kinase inhibitor maintenance therapy has been associated with high rates of DFS in Ph+ ALL. A very small study (n=9 treated patients) showed that ponatinib post-
allogeneic HSCT resulted in a 100% relapse-free survival (RFS) and overall survival.
Preemptive withdrawal of immune suppression post-transplant is another option frequently utilized, but the effectiveness of this approach has not been widely studied, thus additional studies are needed. A study of patients who did not undergo preemptive withdrawal of immune suppression observed that the presence of leukemia MRD prior to transplant had a significant impact on five-year RFS (40%) compared with those who were MRD-negative prior to HSCT (64%; P=.005). Comparatively, preemptive withdrawal of immune suppression resulted in more similar RFS outcomes between the two groups (68% vs 69%, respectively). Preemptive immune suppression withdrawal did not result in increased graft-versus-host disease (GVHD) in the study.
Donor lymphocyte infusions (DLIs) may be useful for patients who withdraw from immune suppression but remain mixed donor chimeras or have evidence of MRD or relapsed leukemia. Interferon-alpha is an alternative to DLI to stimulate graft-versus-leukemia effects. However, in a study, interferon-alpha was significantly associated with GVHD risk (90.9%) compared with DLI (62.9%; P<.001), although the risk of relapse did not significantly differ between the two groups (27.3% vs 35.6%, respectively).
Studies are also exploring the use of checkpoint inhibitors to increase the efficacy of blinatumomab in this patient population.