Active infection at the time of CD34+ selected stem cell boost is associated with treatment failure and poor survival.

BACKGROUND: The use of CD34+ selected stem cell boost (SCB) post allogeneic hematopoietic cell transplant (alloHCT) has been increasing. Predictors of treatment failure following SCB, both in the context of poor graft function (PGF) or other settings, are not well-characterized. We report among the largest single center retrospective experiences of the use of SCB and evaluate potential predictors of response and outcomes. METHODS: 58 patients who underwent HCT between 2015 and 2022 and who received SCB were identified. The indication for SCB was predominantly PGF, defined as the presence of 2 or more cytopenias for at least two consecutive weeks beyond day +14 after alloHCT in the presence of ≤ 30% bone marrow cellularity and ≥ 90% donor myeloid chimerism in the absence of morphological disease. RESULTS: The median dose of infused CD34+ selected SCB products was 3.88 x 106 CD34+ cells/kg (range: 0.99-9.92). The median 2-year OS and NRM following SCB was 47% and 38%, respectively. The cumulative incidences of 6-month grade III-IV acute and 2-year moderate-severe chronic GVHD following SCB were 3.4% and 12%, respectively. Overall response (CR + PR) was attained in 36/58 (62%) patients, and in 69% with PGF. On multivariable analysis, an active infection at the time of SCB was the greatest predictor of poor response and survival (p=0.013) following SCB. CONCLUSION: SCB can restore hematopoiesis in the majority of patients, particularly for those with poor graft function in whom there is no active infection at infusion.

Comparison of Older Related versus Younger Unrelated Donors for Older Recipients of Allogeneic Hematopoietic Cell Transplantation with Acute Myeloid Leukemia or Myelodysplastic Syndrome: A Large Single-Center Analysis.

For patients undergoing allogeneic hematopoietic cell transplantation (alloHCT), HLA-matched related donors (MRDs) have traditionally been the preferred donor source. However, as the age of recipients increases, their sibling donors are aging as well. In this study, we investigated whether younger matched unrelated donors (MUDs) might be a better donor source than similarly aged sibling donors for patients age >60 years with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). A total of 499 patients age 60 to 70 years with AML or MDS who underwent alloHCT from an older MRD (donor age ≥50 years) or a younger MUD (donor age ≤35 years) between 2010 and 2022 were evaluated. Of these, 360 patients (72%) received an MUD graft and 139 (28%) received an MRD graft. The median recipient age was 64 years in the MRD group and 66 years in the MUD group. With a median follow-up among survivors of 53 months (range, 9 to 147 months ), the 4-year progression-free survival was 40% in the MRD group and 41% in the MUD group (P = .79) and the 4-year overall survival was 50% and 44%, respectively (P = .15), with no between-group differences in nonrelapse mortality, relapse, and acute or chronic graft-versus-host disease. In the MUD group, we also compared the effect of donor age 18 to 24 years and donor age 25 to 35 years and found no differences in outcomes between the groups. We conclude that outcomes are comparable between the use of older MRDs and use of younger MUDs for elderly patients with AML or MDS, that there is no donor age effect among younger MUDs, and that the use of either donor type is reasonable.

Innovations in conditioning and post-transplant maintenance in AML: genomically informed revelations on the graft-versus-leukemia effect.

Acute Myeloid Leukemia (AML) is the prototype of cancer genomics as it was the first published cancer genome. Large-scale next generation/massively parallel sequencing efforts have identified recurrent alterations that inform prognosis and have guided the development of targeted therapies. Despite changes in the frontline and relapsed standard of care stemming from the success of small molecules targeting FLT3, IDH1/2, and apoptotic pathways, allogeneic stem cell transplantation (alloHSCT) and the resulting graft-versus-leukemia (GVL) effect remains the only curative path for most patients. Advances in conditioning regimens, graft-vs-host disease prophylaxis, anti-infective agents, and supportive care have made this modality feasible, reducing transplant related mortality even among patients with advanced age or medical comorbidities. As such, relapse has emerged now as the most common cause of transplant failure. Relapse may occur after alloHSCT because residual disease clones persist after transplant, and develop immune escape from GVL, or such clones may proliferate rapidly early after alloHSCT, and outpace donor immune reconstitution, leading to relapse before any GVL effect could set in. To address this issue, genomically informed therapies are increasingly being incorporated into pre-transplant conditioning, or as post-transplant maintenance or pre-emptive therapy in the setting of mixed/falling donor chimerism or persistent detectable measurable residual disease (MRD). There is an urgent need to better understand how these emerging therapies modulate the two sides of the GVHD vs. GVL coin: 1) how molecularly or immunologically targeted therapies affect engraftment, GVHD potential, and function of the donor graft and 2) how these therapies affect the immunogenicity and sensitivity of leukemic clones to the GVL effect. By maximizing the synergistic action of molecularly targeted agents, immunomodulating agents, conventional chemotherapy, and the GVL effect, there is hope for improving outcomes for patients with this often-devastating disease.

Prophylactic maintenance with venetoclax/azacitidine after reduced-intensity conditioning allogeneic transplant for high-risk MDS and AML.

ABSTRACT: We conducted a phase 1 trial assessing safety and efficacy of prophylactic maintenance therapy with venetoclax and azacitidine (Ven/Aza) for patients with high-risk myelodysplastic syndromes (MDS)/acute myeloid leukemia (AML) undergoing reduced intensity allogeneic stem cell transplantation (allo-SCT) after Ven and fludarabine/busulfan conditioning (Ven/FluBu2 allo-SCT) with tacrolimus and methotrexate as graft-versus-host disease (GVHD) prophylaxis. Among 27 patients who underwent Ven/FluBu2 allo-SCT (55.6% with prior Ven exposure, and 96% with positive molecular measurable residual disease), 22 received maintenance therapy with Aza 36 mg/m2 intravenously on days 1 to 5, and Ven 400 mg by mouth on days 1 to 14 per assigned dose schedule/level (42-day cycles × 8, or 28-day cycles × 12). During maintenance, the most common grade 3-4 adverse events were leukopenia, neutropenia, and thrombocytopenia, which were transient and manageable. Infections were uncommon (n = 4, all grade 1-2). The 1-year and 2-year moderate/severe chronic GVHD rates were 4% (95% confidence interval [CI], 0.3%-18%) and 22% (95% CI, 9%-40%), respectively. After a median follow-up of 25 months among survivors, the median overall survival (OS) was not reached. Among the 22 patients who received Ven/Aza maintenance, the 2-year OS, progression-free survival, nonrelapse mortality, and cumulative incidence of relapse rates were 67% (95% CI, 43%-83%), 59% (95% CI, 36%-76%), 0%, and 41% (95% CI, 20%-61%), respectively. Immune monitoring demonstrated no significant impact on T-cell expansion but identified reduced B-cell expansion compared with controls. This study demonstrates prophylactic Ven/Aza maintenance can be safely administered for patients with high-risk MDS/AML, but a randomized study is required to properly assess any potential benefit. This trial was registered at www.clinicaltrials.gov as #NCT03613532.

Opportunistic Infections in Patients Receiving Post-Transplantation Cyclophosphamide: Impact of Haploidentical versus Unrelated Donor Allograft.

Post-transplantation cyclophosphamide (PTCy) is an effective strategy for graft-versus-host disease (GVHD) prophylaxis and is the standard of care for haploidentical hematopoietic cell transplantation (HCT). It is increasingly used for matched and mismatched unrelated donor (MUD/MMUD) HCT, but infections remain a concern. The objective of this study was to evaluate the characteristics and risk factors for infections in haploidentical and unrelated donor HCT recipients treated with PTCy-based GVHD prophylaxis. This single-center retrospective study examined 354 consecutive adults undergoing HCT with PTCy-based GVHD prophylaxis (161 MUD/MMUD; 193 haploidentical) between 2015 and 2022. Opportunistic infections (OIs), including cytomegalovirus (CMV), adenovirus (AdV), Epstein-Barr virus (EBV), and invasive fungal disease (IFD), were assessed from day 0 through day +365. The 1-year cumulative incidence functions of OIs and nonrelapse mortality (NRM) were calculated using dates of relapse and repeat HCT as competing risks. Secondary analysis evaluated risk factors for OIs and NRM using univariate and multivariable Cox regression models. Haploidentical HCT recipients had an increased risk of OIs compared to unrelated donor allograft recipients (39% for haploidentical versus 25% for MUD/MMUD; hazard ratio [HR], 1.70; 95% confidence interval [CI], 1.16 to 2.49; P = .006). On multivariable analysis, haploidentical donor (HR, 1.50; 95% CI, 1.01 to 2.23; P = .046), prior HCT (HR, 1.99; 95% CI, 1.29 to 3.09; P = .002), and diagnosis of aGVHD (HR, 1.47; 95% CI, 1.02 to 2.14; P = .041) were associated with increased risk of OIs. NRM within the first year was not significantly different between the 2 cohorts (HR, 1.11; 95% CI, .64 to 1.93; P = .70). Overall, haploidentical donor was a significant risk factor for OIs in patients receiving PTCy, although 1-year NRM was not different between haploidentical HCT and MUD/MMUD HCT recipients. CMV and AdV infections were significantly increased among haploidentical HCT recipients, whereas the incidences of EBV infection and IFD were similar in the 2 cohorts. Our findings may have implications for infection monitoring and prophylaxis in the setting of PTCy, particularly in haploidentical HCT recipients.

Heightened TLR7 signaling primes BCR-activated B cells in chronic graft-versus-host disease for effector functions.

ABSTRACT: Chronic graft-versus-host disease (cGVHD) is a debilitating, autoimmune-like syndrome that can occur after allogeneic hematopoietic stem cell transplantation. Constitutively activated B cells contribute to ongoing alloreactivity and autoreactivity in patients with cGVHD. Excessive tissue damage that occurs after transplantation exposes B cells to nucleic acids in the extracellular environment. Recognition of endogenous nucleic acids within B cells can promote pathogenic B-cell activation. Therefore, we hypothesized that cGVHD B cells aberrantly signal through RNA and DNA sensors such as Toll-like receptor 7 (TLR7) and TLR9. We found that B cells from patients and mice with cGVHD had higher expression of TLR7 than non-cGVHD B cells. Using ex vivo assays, we found that B cells from patients with cGVHD also demonstrated increased interleukin-6 production after TLR7 stimulation with R848. Low-dose B-cell receptor (BCR) stimulation augmented B-cell responses to TLR7 activation. TLR7 hyperresponsiveness in cGVHD B cells correlated with increased expression and activation of the downstream transcription factor interferon regulatory factor 5. Because RNA-containing immune complexes can activate B cells through TLR7, we used a protein microarray to identify RNA-containing antigen targets of potential pathological relevance in cGVHD. We found that many of the unique targets of active cGVHD immunoglobulin G (IgG) were nucleic acid-binding proteins. This unbiased assay identified the autoantigen and known cGVHD target Ro-52, and we found that RNA was required for IgG binding to Ro-52. Herein, we find that BCR-activated B cells have aberrant TLR7 signaling responses that promote potential effector responses in cGVHD.

Cell Therapy Informatics: Updates on the Integration of HCT/IEC Functionalities into an Electronic Medical Record System in the US to Promote Efficiency, Patient Safety, Research, and Data Interoperability.

The use of electronic health/medical record (EMR) systems has streamlined medical practice and improved efficiency of clinical care in recent years. However, EMR systems are not generally well designed to support research and tracking of longitudinal outcomes across populations, which are particularly important in hematopoietic stem cell transplantation (HCT) and immune effector cell therapy (IEC), where data reporting to registries and regulatory agencies are often required. Since its formation in 2014, the HCT EMR user group has worked with a large EMR vendor (Epic) to develop many functionalities within the EMR to improve the care of HCT/IEC patients and facilitate the capture of HCT/IEC data in an easily interoperable format. Awareness and the widespread adoption of these new tools among transplant centers remains a challenge, however. In this report, we aim to increase awareness and adoption of these new features in the Epic EMR across the transplantation community, advocate for the use of data standards, and promote future collaboration with other commercial EMRs to develop standardized HCT/IEC content to improve patient care and facilitate interoperable data exchange.

Posttransplant cyclophosphamide vs tacrolimus-based GVHD prophylaxis: lower incidence of relapse and chronic GVHD.

The ability of posttransplant cyclophosphamide (PTCY) to facilitate haploidentical transplantation has spurred interest in whether PTCY can improve clinical outcomes in patients with HLA-matched unrelated donors undergoing peripheral blood stem cell transplantation (PBSCT). We investigated our institutional experience using PTCY-based graft-versus-host disease (GVHD) prophylaxis compared with conventional tacrolimus-based regimens. We compared overall survival, progression-free survival (PFS), relapse, nonrelapse mortality, and acute and chronic GVHD in 107 adult patients receiving a PTCY-based regimen vs 463 patients receiving tacrolimus-based regimens for GVHD prophylaxis. The 2 cohorts were well balanced for baseline characteristics except that more patients in the PTCY cohort having received 7-of-8-matched PBSCT. There was no difference in acute GVHD. All-grade chronic GVHD and moderate-to-severe chronic GVHD were substantially reduced in patients receiving PTCY compared with in those receiving tacrolimus-based regimens (2-year moderate-to-severe chronic GVHD: 12% vs 36%; P < .0001). Recipients of PTCY-based regimens also had a lower incidence of relapse compared with recipients of tacrolimus-based regimens (25% vs 34% at 2-years; P = .027), primarily in patients who received reduced intensity conditioning. This led to improved PFS in the PTCY cohort (64% vs 54% at 2 years; P = .02). In multivariable analysis, the hazard ratio was 0.59 (P = .015) for PFS and the subdistribution hazard ratio was 0.27 (P < .0001) for moderate-to-severe chronic GVHD and 0.59 (P = .015) for relapse. Our results suggest that PTCY prophylaxis is associated with lower rates of relapse and chronic GVHD in patients who receive HLA-matched unrelated donor PBSCT.

Single-cell landscape analysis unravels molecular programming of the human B cell compartment in chronic GVHD.

Alloreactivity can drive autoimmune syndromes. After allogeneic hematopoietic stem cell transplantation (allo-HCT), chronic graft-versus-host disease (cGVHD), a B cell-associated autoimmune-like syndrome, commonly occurs. Because donor-derived B cells continually develop under selective pressure from host alloantigens, aberrant B cell receptor (BCR) activation and IgG production can emerge and contribute to cGVHD pathobiology. To better understand molecular programing of B cells in allo-HCT, we performed scRNA-Seq analysis on high numbers of purified B cells from patients. An unsupervised analysis revealed 10 clusters, distinguishable by signature genes for maturation, activation, and memory. Within the memory B cell compartment, we found striking transcriptional differences in allo-HCT patients compared with healthy or infected individuals, including potentially pathogenic atypical B cells (ABCs) that were expanded in active cGVHD. To identify intrinsic alterations in potentially pathological B cells, we interrogated all clusters for differentially expressed genes (DEGs) in active cGVHD versus patients who never had signs of immune tolerance loss (no cGVHD). Active cGVHD DEGs occurred in both naive and BCR-activated B cell clusters. Remarkably, some DEGs occurred across most clusters, suggesting common molecular programs that may promote B cell plasticity. Our study of human allo-HCT and cGVHD provides understanding of altered B cell memory during chronic alloantigen stimulation.

Cytokine release syndrome in haploidentical stem cell transplant may impact T-cell recovery and relapse.

Cytokine release syndrome (CRS) following haploidentical hematopoietic cell transplantation (HCT) resembles CRS after chimeric antigen receptor-T therapy. We conducted this single-center retrospective study to evaluate the association of posthaploidentical HCT CRS with clinical outcomes and immune reconstitution. One hundred sixty-nine patients who underwent haploidentical HCT between 2011 and 2020 were identified. Of these, 98 patients (58%) developed CRS after HCT. CRS was diagnosed based on the presence of fever within the first 5 days after HCT without evidence of infection or infusion reaction and was graded according to established criteria. The development of posthaploidentical HCT CRS was associated with a lower incidence of disease relapse (P = .024) but with an increased risk of chronic graft-versus-host disease GVHD (P = .01). The association of CRS with a lower incidence of relapse was not confounded by graft source or disease diagnosis. Neither CD34 nor total nucleated cell dose was associated with CRS independently of graft type. In patients developing CRS, CD4+ Treg (P < .0005), CD4+ Tcon (P < .005), and CD8+ T cells (P < .005) increased 1 month after HCT compared with those who did not develop CRS, but not at later time points. The increase in CD4+ regulatory T cells 1 month after HCT was most notable among patients with CRS who received a bone marrow graft (P < .005). The development of posthaploidentical HCT CRS is associated with a reduced incidence of disease relapse and a transient effect on post-HCT immune reconstitution of T cells and their subsets. Therefore, the validation of these observations in a multicenter cohort is required.

Multicenter Phase I Trial of Ivosidenib as Maintenance Treatment Following Allogeneic Hematopoietic Cell Transplantation for IDH1-Mutated Acute Myeloid Leukemia.

PURPOSE: Isocitrate dehydrogenase 1 (IDH1) mutations occur in 5% to 10% of patients with acute myeloid leukemia (AML). Ivosidenib is an IDH1 inhibitor, approved for use in patients with IDH1-mutated AML. PATIENTS AND METHODS: We conducted a multicenter, phase I trial of maintenance ivosidenib following allogeneic hematopoietic cell transplantation (HCT) in patients with IDH1-mutated AML. Ivosidenib was initiated between days 30 and 90 following HCT and continued for up to 12 28-day cycles. The first dose level was 500 mg daily, with level reduction to 250 mg daily, if needed, in a 3 × 3 de-escalation design. Ten additional patients would then receive the MTD or recommended phase 2 dose (RP2D). The primary endpoint was establishing the MTD or RP2D of ivosidenib. RESULTS: Eighteen patients were enrolled, of whom 16 initiated post-HCT ivosidenib. One dose-limiting toxicity, grade(g) 3 QTc prolongation, was observed. The RP2D was established at 500 mg daily. Attributable g≥3 adverse events were uncommon, with the most common being QTc prolongation in 2 patients. Eight patients discontinued maintenance, with only one due to adverse event. Six-month cumulative incidence (CI) of gII-IV aGVHD was 6.3%, and 2-year CI of all cGVHD was 63%. Two-year CI of relapse and nonrelapse mortality (NRM) were 19% and 0%, respectively. Two-year progression-free (PFS) was 81%, and 2-year overall survival (OS) was 88%. CONCLUSIONS: Ivosidenib is safe and well-tolerated as maintenance therapy following HCT. Cumulative incidence of relapse and NRM, as well as estimations of PFS and OS, were promising in this phase I study.

Clinical Features of Acute Kidney Injury in the Early Post-Transplantation Period Following Reduced-Intensity Conditioning Allogeneic Hematopoietic Stem Cell Transplantation.

Allogeneic hematopoietic stem cell transplantation (HCT) is a potentially curative therapy for patients with hematologic malignancies but is associated with acute kidney injury (AKI). To date, few studies have examined risk factors for AKI at engraftment, or the relationship between AKI and clinical outcomes. This study examined the incidence and risk factors for periengraftment AKI, as well as the association between AKI and overall survival (OS) and nonrelapse mortality (NRM). We conducted a retrospective analysis of adult patients undergoing reduced-intensity conditioning (RIC) allogeneic HCT at the Dana-Farber Cancer Institute between 2012 and 2019. Periengraftment (day 0 to day 30) AKI incidence and severity were defined using modified KDIGO (Kidney Disease: Improving Global Outcomes) criteria. Factors associated with periengraftment AKI risk were examined using Cox regression analysis. The impact of periengraftment AKI on OS and NRM (defined as death without recurrent disease after HCT), was evaluated using Cox regression and the Fine and Gray competing risks model, respectively. Kidney recovery, defined as a return of serum creatinine (SCr) to within 25% of baseline or liberation from kidney replacement therapy (KRT), was examined at day 90 post-HCT. Periengraftment AKI occurred in 330 of 987 patients (33.4%) at a median of 13 days (interquartile range, 4 to 30 days) post-transplantation. Factors associated with a higher multivariable-adjusted risk of AKI were supratherapeutic rapamycin (hazard ratio [HR], 1.56; 95% confidence interval [CI], 1.20 to 2.03; P < .001), fludarabine/melphalan conditioning (HR, 1.35, 95% CI, 1.01 to 1.81; P = .05, compared to fludarabine/busulfan and fludarabine, cyclophosphamide, and total body irradiation), HCT Comorbidity Index ≥4 (HR, 1.43; 95% CI, 1.14 to 1.79; P = .002), albumin <3.4 g/dL (HR, 2.04; 95% CI, 1.33 to 3.12; P = .001), hemoglobin ≤12 (HR, 1.96; 95% CI, 1.38 to 2.78; P < .001), supratherapeutic tacrolimus (HR, 1.45; 95% CI, 1.07 to 1.95; P = .02), and baseline SCr >1.1 mg/dL (HR, 1.87; 95% CI, 1.48 to 2.35; P < .001). Periengraftment AKI was associated with worse OS (HR, 1.40; 95% CI, 1.16 to 1.71; P < .001) and NRM (subdistribution HR, 2.10; 95% CI, 1.52 to 2.89; P < .001). Kidney recovery occurred in 18%, 15%, and 30% of patients with stage 1, stage 2, and stage 3 AKI without KRT, respectively, and 4 of 16 patients (25%) were liberated from KRT. Periengraftment AKI is common among RIC allogeneic HCT recipients. We identified several important risk factors for periengraftment AKI. Its association with worse OS and NRM underscores the importance of timely recognition and management.

Phase 2 clinical trial evaluating abatacept in patients with steroid-refractory chronic graft-versus-host disease.

Steroid-refractory chronic graft-versus-host disease (cGVHD) after allogeneic transplant remains a significant cause of morbidity and mortality. Abatacept is a selective costimulation modulator, used for the treatment of rheumatologic diseases, and was recently the first drug to be approved by the US Food and Drug Administration for the prophylaxis of acute graft-versus-host disease. We conducted a phase 2 study to evaluate the efficacy of abatacept in steroid-refractory cGVHD. The overall response rate was 58%, seen in 21 out of 36 patients, with all responders achieving a partial response. Abatacept was well tolerated with few serious infectious complications. Immune correlative studies showed a decrease in interleukin -1α (IL-1α), IL-21, and tumor necrosis factor α as well as decreased programmed cell death protein 1 expression by CD4+ T cells in all patients after treatment with abatacept, demonstrating the effect of this drug on the immune microenvironment. The results demonstrate that abatacept is a promising therapeutic strategy for the treatment of cGVHD. This trial was registered at www.clinicaltrials.gov as #NCT01954979.

Prognostic Biomarkers for Hepatic Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome in Myeloablative Allogeneic Hematopoietic Cell Transplantation: Results from the Blood and Marrow Transplant Clinical Trials Network 1202 Study.

Hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a potentially life-threatening complication of hematopoietic cell transplantation (HCT). This study aimed to determine a blood biomarker signature early post-HCT that identifies patients at high risk for VOD/SOS. A set of 23 plasma biomarkers, selected from the VOD/SOS literature, was measured on days 0, 7, and 14 after myeloablative HCT using blood samples from patients enrolled in the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) Protocol 1202. Eligible cases were diagnosed with VOD/SOS in BMT CTN 1202 using the Baltimore criteria. Controls (without VOD/SOS) were matched to cases for conditioning regimen and age. Significant biomarkers were identified using the Bonferroni-adjusted Wilcoxon rank-sum test (P ≤ .002). Thirty-three patients with mild or severe VOD/SOS were identified (cases) and matched to 107 controls. Two, 8, and 5 biomarkers measured from the plasma of these patients were significantly associated with the development of VOD/SOS at days 0, 7, and 14, respectively, with the strongest associations on days 7 and 14. Biomarker associations were stronger for severe VOD/SOS risk and were stronger prognostic markers for VOD/SOS cases occurring within 28 days of HCT. Hyaluronan was most strongly associated with VOD/SOS risk, with an area under the receiver operating characteristic curve (AUC) of .81 on day 7 and .79 on day 14. Multivariate models of up to 5 biomarkers generated AUCs ranging from .82 to .85. All associations with VOD/SOS risk were independent of clinical risk factors. This study confirms previously identified biomarkers of VOD/SOS risk and identified novel prognostic biomarker signatures that identify patients at risk for VOD/SOS shortly after HCT. Multivariate analysis suggests that a combination of up to 5 of these protein biomarkers may provide a prognostic tool for identifying patients at risk for VOD/SOS.

Intensity of induction regimen and outcomes among adults with Ph+ALL undergoing allogeneic hematopoietic stem cell transplantation.

Tyrosine kinase inhibitors (TKIs) are essential for the treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) and have allowed for effective, low intensity induction regimens including no or minimal chemotherapy. Whether the use of low intensity induction regimens impacts outcomes after allogeneic hematopoietic stem cell transplant (alloHCT) is less understood. We identified consecutive adult patients with Ph+ ALL undergoing alloHCT in first complete remission (CR1) at our center from 2010 to 2021 and examined the impact of pre-transplant induction intensity on outcomes. Among the 87 identified patients, 44 (51%) received low intensity induction and 43 (49%) received induction with high intensity chemotherapy. Patients receiving low intensity induction were older (median age 60 vs. 47 years, p < 0.01). Following induction, measurable residual disease (MRD) negativity by BCR::ABL1 RT-PCR was similar in the low and high intensity induction cohorts (54% and 52% respectively). Receipt of reduced intensity transplant conditioning was not associated with intensity of induction regimen (39% vs. 19% in low vs. high, respectively, p = 0.06). At a median follow-up of 21 months from transplant, there was no difference between low and high intensity induction with respect to 2-year disease-free survival (58% vs. 56%), 2-year overall survival (62% vs. 63%), 2-year cumulative incidence of relapse (9% vs. 17%), and 2-year non-relapse mortality (33% vs. 29%). We also found no difference in outcomes when patients were segmented by both induction and conditioning regimen intensities. Our retrospective analysis suggests that induction intensity does not impact post-transplant outcomes among patients with Ph+ ALL transplanted in CR1.

Favorable outcomes following allogeneic transplantation in adults with hemophagocytic lymphohistiocytosis.

Hemophagocytic lymphohistiocytosis (HLH) is a syndrome marked by a severe hyperinflammatory state characterized by aberrant T- and natural killer-cell activity leading to prolonged hypercytokinemia and can be rapidly fatal if not diagnosed and treated early. While upfront therapy is aimed at reducing hyperinflammation and controlling possible triggers, allogeneic hematopoietic stem cell transplantation (HSCT) is indicated for primary and relapsed/refractory cases to attain sustained remission. While this has been explored extensively in the pediatric population, there are limited data on adults undergoing HSCT for HLH. We analyzed transplant outcomes in an adult HLH population in the modern era who were transplanted at Dana-Farber Cancer Institute from 2010 onwards. Patients were uniformly transplanted on a reduced intensity platform incorporating early administration of alemtuzumab with standard infectious and graft-versus-host disease (GVHD) prophylaxis. Engraftment was documented for all patients. At 3 years after transplantation, overall survival (OS) was 75% (95% confidence interval [CI], 51-89) while 3-year progression-free survival (PFS) was 71% (95% CI, 46-86). The 3-year cumulative incidence of relapse was 15% (95% CI, 3.4-33). There were no isolated HLH relapses without relapse of malignancy. The cumulative incidence of nonrelapse mortality at 3 years was 15% (95% CI, 3.5-34). Infectious complications and GVHD outcomes were comparable to standard reduced-intensity conditioning (RIC) transplantation at our institute. Mixed chimerism was common but did not correlate with transplant outcomes. Our data suggest that the immune defect in HLH can be abrogated with allogeneic transplantation using a reduced intensity regimen with early administration of alemtuzumab as preconditioning, providing a potentially curative option for this difficult disease.

Enasidenib as maintenance following allogeneic hematopoietic cell transplantation for IDH2-mutated myeloid malignancies.

IDH2 (isocitrate dehydrogenase 2) mutations occur in approximately 15% of patients with acute myeloid leukemia (AML). The IDH2 inhibitor enasidenib was recently approved for IDH2-mutated relapsed or refractory AML. We conducted a multi-center, phase I trial of maintenance enasidenib following allogeneic hematopoietic cell transplantation (HCT) in patients with IDH2-mutated myeloid malignancies. Two dose levels, 50mg and 100mg daily were studied in a 3 × 3 dose-escalation design, with 10 additional patients treated at the recommended phase 2 dose (RP2D). Enasidenib was initiated between days 30 and 90 following HCT and continued for twelve 28-day cycles. Twenty-three patients were enrolled, of whom 19 initiated post-HCT maintenance. Two had myelodysplastic syndrome, and 17 had AML. All but 3 were in first complete remission. No dose limiting toxicities were observed, and the RP2D was established at 100mg daily. Attributable grade ≥3 toxicities were rare, with the most common being cytopenias. Eight patients stopped maintenance before completing 12 cycles, due to adverse events (n=3), pursuing treatment for graft-vs-host disease (GVHD) (n=2), clinician choice (n=1), relapse (n=1), and COVID infection (n=1). No cases of grade ≥3 acute GVHD were seen, and 12-month cumulative incidence of moderate/severe chronic GVHD was 42% (20-63%). Cumulative incidence of relapse was 16% (95% CI: 3.7-36%); 1 subject relapsed while receiving maintenance. Two-year progression-free and overall survival were 69% (95% CI: 39-86%) and 74% (95% CI, 44-90%), respectively. Enasidenib is safe, well-tolerated, with preliminary activity as maintenance therapy following HCT, and merits additional study. The study was registered at www.clinicaltrials.gov (#NCT03515512).

Calreticulin mutant myeloproliferative neoplasms induce MHC-I skewing, which can be overcome by an optimized peptide cancer vaccine.

The majority of JAK2V617F-negative myeloproliferative neoplasms (MPNs) have disease-initiating frameshift mutations in calreticulin (CALR), resulting in a common carboxyl-terminal mutant fragment (CALRMUT), representing an attractive source of neoantigens for cancer vaccines. However, studies have shown that CALRMUT-specific T cells are rare in patients with CALRMUT MPN for unknown reasons. We examined class I major histocompatibility complex (MHC-I) allele frequencies in patients with CALRMUT MPN from two independent cohorts. We observed that MHC-I alleles that present CALRMUT neoepitopes with high affinity are underrepresented in patients with CALRMUT MPN. We speculated that this was due to an increased chance of immune-mediated tumor rejection by individuals expressing one of these MHC-I alleles such that the disease never clinically manifested. As a consequence of this MHC-I allele restriction, we reasoned that patients with CALRMUT MPN would not efficiently respond to a CALRMUT fragment cancer vaccine but would when immunized with a modified CALRMUT heteroclitic peptide vaccine approach. We found that heteroclitic CALRMUT peptides specifically designed for the MHC-I alleles of patients with CALRMUT MPN efficiently elicited a CALRMUT cross-reactive CD8+ T cell response in human peripheral blood samples but not to the matched weakly immunogenic CALRMUT native peptides. We corroborated this effect in vivo in mice and observed that C57BL/6J mice can mount a CD8+ T cell response to the CALRMUT fragment upon immunization with a CALRMUT heteroclitic, but not native, peptide. Together, our data emphasize the therapeutic potential of heteroclitic peptide-based cancer vaccines in patients with CALRMUT MPN.