With proven single-agent activity and favorable toxicity profile of MEK-1/2 inhibition in advanced leukemia, investigation into combination strategies to overcome proposed resistance pathways is warranted. Resistance to MEK inhibition is secondary to upstream hyperactivation of RAS/RAF or activation of the PI3K/PTEN/AKT/mTOR pathway.

BackgroundThe optimal strategy for vaccination to induce CD8+ T cell responses against WT1 is not known.MethodsA pilot randomized study in HLA-A02+ patients to receive vaccination with WT1 in Montanide or in poly ICLC, a TLR3 agonist, to explore the novel immune adjuvant was conducted. Seven patients were randomized. Four patients received WT1 in Montanide, and three with WT1 in poly ICLC. Five patients were in morphologic remission and two had residual morphologic disease at the study entry.ResultsAll patients finished the induction phase without any major toxicity except mild transient local injection reaction. One patient on the Montanide arm developed aseptic ulceration at two vaccine sites which healed without antibiotics. Three of 4 patients on the Montanide arm had a decreased expression of WT1 after WT1 vaccination, and two of them demonstrated generation of WT1-specific cytotoxic CD8+ T cell responses with biased TCR beta chain enrichment. In contrast, no obvious WT1-specific immune responses were detected in two patients on the poly ICLC arm, nor was there clonal enrichment by TCR alpha/beta sequencing; however, these patients did also have decreased WT1 expression and remained in remission several years after the initiation of treatment.ConclusionsWT1 peptide vaccine with Montanide as an adjuvant induces detectable WT1-specific CD8+ T cell responses with clonal TCR enrichment, which may be capable of controlling leukemia recurrence in the setting of minimal residual disease. Poly ICLC may induce anti-leukemic activity in the absence of detectable WT1 specific CD8+ T cell responses.Trial registration NCT01842139, 7/3/2012 retrospectively registered; https://clinicaltrials.gov/ct2/show/NCT01842139.

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Delayed engraftment and cord graft failure (CGF) are serious complications after unrelated cord blood (UCB) hematopoietic stem cell transplantation (HSCT), particularly when using low-cell-dose UCB units. The haplo-cord HSCT approach allows the use of a lower dose single UCB unit by co-infusion of a CD34+ selected haploidentical graft, which provides early transient engraftment while awaiting durable UCB engraftment. We describe the frequency, complications, and risk factors of CGF after reduced-intensity conditioning haplo-cord HSCT. Among 107 patients who underwent haplo-cord HSCT, 94 were assessable for CGF, defined as <5% cord blood chimerism at day 60 in the myeloid and CD3 compartments, irrespective of neutrophil and platelet counts. CGF occurred in 14 of 94 assessable patients (15%). Median survival after CGF was 12.7 months with haploidentical or mixed haploidentical–autologous hematopoiesis persisting in the 7 surviving. Median progression-free survival after CGF was 7.7 months and was not statistically different from those without CGF (10.47 months; P = .18). In univariate analyses, no UCB factors were associated with CGF, including cell dose, cell viability, recipient major ABO mismatch against the UCB unit, or degree of HLA match. We also found no association of CGF with recipient cytomegalovirus serostatus, haploidentical donor age, or day 30 haploidentical chimerism. However, higher haploidentical total nucleated and CD34+ cell doses and day 30 UCB chimerism < 5% in either the myeloid or CD3 compartments were associated with greater risk of CGF. We conclude that assessing chimerism at day 30 may foretell impending CGF, and avoidance of high haploidentical cell doses may reduce risk of CGF after haplo-cord HSCT. However, long-term survival is possible after CGF because of predominant haploidentical or mixed chimerism and hematopoietic function.

Prior invasive fungal infection (IFI) has historically limited the use of allogeneic stem cell transplantation for patients with hematologic malignancies. Transplantation of such patients frequently resulted in recurrent infection and high mortality rates. Several new antifungal agents have been introduced over the past 5 years with broader spectra of activity against molds such as Aspergillus and a favorable toxicity profile. In this study, we present a series of 16 consecutive patients with hematologic malignancy and prior invasive fungal infection who underwent allogeneic transplantation. Of these patients, the majority of whom were treated with voriconazole and/or caspofungin, only four experienced recurrent fungal infection and recurrent fungal infection was the primary cause of death in only one patient. The estimated 45% 2-year survival in this series is similar to that for other patients with high risk hematologic malignancy undergoing stem cell transplantation. We conclude that suspected prior invasive fungal infection should not preclude the use of allogeneic stem cell transplantation.