Decision analysis for transplant candidates with primary myelofibrosis in the ruxolitinib era [decision analysis study]

Highlights:

Regarding quality-adjusted life years (QALY), delayed hematopoietic stem cell transplantation after ruxolitinib failure may be a reasonable option compared to immediate transplant in patients with primary myelofibrosis.

Primary myelofibrosis (PMF) is one of the "Philadelphia negative" myeloproliferative neoplasms with the worst overall survival (OS). Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a cure for a substantial number of patients but is still not applicable universally due to toxicity. Recent data suggests better outcomes after allo-HSCT if patients received a transplant after responding to ruxolitinib rather than postponing the transplant until after ruxolitinib failure. Using a decision analysis model (Markov model), the authors of this study evaluated the optimal strategy between immediate allo-HSCT after diagnosis and delayed allo-HSCT after ruxolitinib failure. The probabilities of the main event were referred from two studies: a retrospective study including 2,916 patients to estimate the clinical course of immediate allo-HSCT and fro delayed HSCT, the long-term comparison in the Controlled Myelofibrosis Study with Oral JAK Inhibitor Treatment (CONFORT-II) trial including 219 patients. The authors constructed a decision tree to compare quality-adjusted life years (QALY) of two strategies: immediate HSCT and delayed HSCT after ruxolitinib failure. Failure was defined as the lack of reduction in spleen volume of >35% from baseline or an increase in spleen volume after a >35% reduction had been achieved. In the subgroup analyses, the authors analyzed patients aged <60 years and ≥60 years separately. The 5-year overall survival probability calculated in this model was 47.1% for patients in the "immediate HSCT" group and 60.1% for the "delayed HSCT after ruxolitinib failure" group. QALY were 2.19 and 2.26 after the decisions for immediate HSCT and delayed HSCT after ruxolitinib failure, respectively. In patients <60 years, immediate HSCT was equivalent to delayed HSCT after ruxolitinib failure, with QALY of 2.31 and 2.31, respectively. In patients aged ≥60 years, immediate HSCT was inferior to delayed HSCT after ruxolitinib failure, with QALY of 1.98 and 2.21, respectively. According to these results, because chronic graft-versus-host disease strongly affects the quality of life after HSCT, it is probable that the decision of delayed HSCT after ruxolitinib failure is preferable to immediate transplant in older patients. Both strategies seem to be worth considering in younger patients.

Biomarker-derived fast-and-frugal decision tree for preemption of veno-occlusive disease/sinusoidal obstructive syndrome  [Letter to the editor].

Highlights:

The veno-occlusive disease/sinusoidal obstructive syndrome (VOD/SOS) biomarker-based fast-and-frugal decision tree (FFT) model offers a method to guide risk-adapted preemptive therapy for VOD/SOS.

The stratification of high-risk patients for VOD/SOS in allogeneic hematopoietic stem cell transplant (allo-HSCT) patients could improve the care and guide the early administration of defibrotide. A model based on three biomarkers [L-ficolin, hyaluronic acid (HA), and stimulation 2 (ST2)] measured as early as 3 days after allo-HSCT improved risk stratification for SOS occurrence and survival and may guide risk-adapted preemptive therapy. Using data prospectively accrued from 80 pediatric patients across four US centers, the authors developed an FFT-driven generalized decision curve analysis (gDCA) (reformulated from previously published Cox-based models. The privilege of this model is that it allows decision-making through ordered cues (tests) and binary (yes/no) decisions formulated via a series of if-then statements. The cues consisted of 3 biomarker laboratory values. The Youden index determined the optimal cutoff point for each biomarker. The sequence in the original study was interrogated, L-ficolin first, advancing to HA second, and ST2 last, where low levels of L-ficolin (<1100 ng/mL) and high levels of HA (>200 ng/mL) and ST2 (>45 ng/mL) were associated with the greater cumulative incidence of SOS (Han et al.2023. See Link 2 to  full article). The authors created two biomarker groups: a 3-biomarker positive score and a 3-biomarker negative score, formed according to a score >0 and equal to 0, respectively. The clinical utility of this model was evaluated through a three-strategy model that was compared in terms of calculated net benefit (NB): (1) do not provide treatment to any patient, (2) administer prophylaxis to all patients, and (3) use the FFT-driven VOD/SOS model to guide defibrotide preemptive treatment. The strategy with the highest NB was the best management strategy, regardless of statistical significance. The final model was an extension of the threshold model, where defibrotide treatment is initiated when the model-predicted probability exceeds the treatment threshold. A treatment threshold was defined as T = AE/RRR, where AE refers to harm (expressed as absolute adverse events between 2 treatments) and RRR defines relative risk reduction in patients receiving defibrotide compared with placebo. According to previous data, the best threshold was T = 2.5%/40% = 6.25%. The analysis of NB in the function of RRR showed that for a very large RRR (>65%), offering prophylaxis to all patients is the best management strategy, and for RRR <2.5%, no prophylaxis should be offered. Between 2.5% and  65%, the VOD/ SOS model is the best strategy for preemptive defibrotide. According to the calculated treatment threshold, preemptive treatment should be initiated when the estimated probability of VOD/SOS by the model is >6.25%. This novel and complex study shows the utility of a sequential use of 3 biomarkers to guide prophylaxis with defibrotide compared to prophylaxis for all or no defibrotide at all in patients with high risk of VOD/SOS.

Clinical and Immune Effects of Peri-Transplantation JAK Inhibition for Myelofibrosis [Retrospective observational study].

Highlights: 

Peri-transplant JAK inhibition with ruxolitinib and fedratinib showed promising results in engraftment and acute graft-versus-host disease (GvHD) rates in patients with myelofibrosis

The European LeukemiaNet and the European Society for Blood and Marrow Transplantation recommend using ruxolitinib at least 2 months before hematopoietic stem cell transplantation (HSCT) and careful weaning before conditioning to avoid the rebound phenomenon. However, incorporating JAK inhibition into the transplant algorithm leads to improved outcomes, which is still unclear. In a retrospective cohort,  a total of 109 patients with primary myelofibrosis, post-polycythemia vera, and post-essential thrombocythemia myelofibrosis who underwent a first allogeneic HSCT (allo-HSCT) were compared in terms of immune reconstitution (primary outcome) and clinical secondary endpoints [hemoglobin levels on the day of transplant, number of packed red blood cells transfused between day 0 and day 30 post-transplant, acute GvHD, donor chimerism, neutrophil and platelet engraftment, relapse incidence, and overall survival]: A first group with 33 patients continuing ruxolitinib/fedratinib at start of conditioning until stable engraftment (PERI-group); a second group with 38 patients receiving ruxolitinib/fedratinib before transplant until start of conditioning (PRE-group), and a third group with 38 patients that had never received ruxolitinib/fedratinib (NON-group). JAK inhibitor treatment in the PERI-group was stopped in a planned fashion on day 28 post-transplant. No differences were seen in hematotoxicity and safety. The PERI-group was associated with significantly increased early B-cell recovery at days 14, 21, and 30 and a higher proportion of gamma-delta T cells and natural killer (NK) cells at days 100 and 180. Concerning engraftment, all patients (100%) in the PERI-group achieved neutrophil engraftment vs. 95% (95% confidence interval [CI],  88%–100%) in the PRE-group vs. 90% (95% CI, 80%–99%) in the NON-group. Cumulative incidence of acute GvHD grade II-IV at day 100 after transplant was 15% in the PERI-group (95% CI, 3%–27%) vs. 29% in the PRE-group (95% CI, 15%–43%) vs. 34% in the NON-group (95% CI, 19%–49%). The cumulative incidence of relapse at 1 year after transplant was 9% in the PERI-group compared with 16% in the PRE-group and 18% in the NON-group. These data suggest a favorable impact of peri-transplant JAK inhibition regarding immune cell function, safety, GvHD, and relapse.

Allogeneic hematopoietic stem-cell transplantation for patients with Richter transformation: a retrospective study on behalf of the Chronic Malignancies Working Party of the EBMT [Retrospective study].

Highlights:

Although the outcomes of transplant in patients with Richter transformation (RT) have improved, a high incidence of non-transplant related mortality and chronic graft-versus-host disease (GvHD) are unmet needs in this transplant scenario.

Regardless of pathway inhibitor exposure, transplant-eligible patients with a history of RT have an indication for allogeneic hematopoietic stem cell transplantation (allo-HSCT). A significant proportion of patients with chronic lymphocytic leukemia /small lymphocytic lymphoma develop RT (between 2 and 10%). A retrospective, multicenter, registry-based analysis of the Chronic Malignancies Working Party of the European Society for Blood and Marrow Transplantation reported the outcomes of 66 RT patients undergoing allo-HSCT between 2008 and 2018. At the time of transplant, 28 (42.4%) patients were in complete remission (CR), 29 (43.9%) were in p = 0.032). The authors suggest that an optimal bridging therapy to gain complete remission before allo-HSCT could lead to better outcomes. High rates of NRM and chronic GvHD remain a significant unmet need in this field.

Ruxolitinib for pediatric patients with treatment-naïve and steroid-refractory acute graft-versus-host disease: the REACH4 study [Clinical Trial].

Highlights: 

The REACH4 study confirmed that the efficacy and security profile of ruxolitinib for the treatment of pediatric acute graft-versus-host disease (aGvHD) is consistent with what is already known in adults.

One-third of pediatric patients with aGvHD show no response to the first-line treatment for this condition with glucocorticoids and calcineurin inhibitors. Moreover, long-term use of corticosteroid therapy in children can lead to serious adverse events. The evidence of ruxolitinib (a Janus kinase 1/2 inhibitor) in pediatric patients with aGvHD is limited. The phase 1 (dose-finding and safety) and 2 (safety and efficacy), open-label, multicenter study of ruxolitinib in patients aged ≥28 days and <18 years (REACH4) reported the main findings of this treatment added to the immunosuppressive regimen with methylprednisolone (or equivalent prednisolone) with/without cyclosporine or tacrolimus. The trial included 45 patients with treatment-naïve or steroid-refractory grade 2 to 4 aGVHD. The phase 2 primary objective was the activity of ruxolitinib as assessed by the overall response rate (ORR) at day 28. The dose of ruxolitinib was given for up to 24 weeks or until early discontinuation and modified according to age: ≥12 to <18 years: 10 mg twice daily; ≥6 to <12 years: 5 mg twice daily; <6 years: 4 mg/m2 twice daily. Survival, progression, and safety data were evaluated at months 12, 18, and 24. Pharmacokinetic parameters were similar across the age groups (no patients were enrolled between ≥28 days and <6 years. The ORR at day 28 was 84.4% (90% confidence interval  [CI], 72.8-92.5), and the durable ORR at day 56 was 66.7% (90% CI, 53.4-78.2). The most common adverse events (AEs) were anemia (20.0%), decreased neutrophil count (17.8%) and decreased white blood cell count (15.6%). Serious AEs were seen in 15.6% of patients without fatal AEs. These encouraging data confirm the efficacy and security of ruxolitinib in the pediatric population, but more in-depth investigation involving a larger population is needed.

Novel machine learning technique further clarifies unrelated donor selection to optimize transplantation outcomes [Retrospective Study].

Highlights:

●      Donors aged 18 – 30 years had similar overall survival (OS) after matched unrelated donor (MUD) allogeneic hematopoietic stem cell transplant (Allo-HCT). Male sex was associated with improved event free survival (EFS) but not with improved OS.

●      Cytomegalovirus status (CMV), parity, HLA-DQB1, and HLA-DPB1 T-cell epitope status were associated with an impact on EFS/OS of <1% and were considered indifferent for the outcome.

Matched sibling Allo-HCT yields the best outcomes, but it is only available for ~30% of patients. An MUD considerably expands access to a transplant, with best results seen when an 8/8 high resolution human leukocyte antigen (HLA)-A, B, C, and DRB1 matched donor is used. In the case of more than one 8/8 matched donor being available, other factors, such as CMV status, parity, sex, and other HLA-match types have been considered, with donor age having potentially the largest contribution to OS, while the effect of other variables remains unclear.

The authors used as a training cohort, the Center for International Blood and Marrow Transplant Research (CIBMTR) registry of 11,181patients with first Allo-HCT and who were HLA-A, B, C, and DRB1 high-resolution matched (8/8) MUD from 2016 to 2019, using 10,016 (85%) as a training cohort and 1,802 as a validation cohort. The impact of donor variables (age, sex, parity, CMV status, HLA-DQB1 matching, and HLA-DPB1 T-cell epitope permissive mismatch) on EFS and OS was assessed using a flexible machine learning method (NFT BART- Nonparametric Failure Time Bayesian Additive Regression Trees) and patient-specific factors such as performance status, patient age, HCT-comorbidity index, amongst others, were included.

The only significant donor factor that was associated with OS was age, where, compared with 18-year-old donors, those aged ≥31 years were associated with lower OS. Both donor age (≤32 years), and use of a male donor, regardless of recipient sex, improved EFS. Donor CMV, parity, HLA-DQB1, and HLA-DPB1 T-cell epitope matching fell within the zone of indifference (<1% impact on EFS/OS).

The authors conclude that these results support the importance of donor age on outcomes after 8/8 MUD Allo-HCT, and given the impact of donor age, recommend selecting the earliest available donor within the 18 to 30 age range for HCT to optimize OS. If several donors in this age range are available, a male donor may be chosen to optimize EFS.

A systematic review and meta-analysis of  HHV-6 and mortality after hematopoietic cell transplant  

Highlights:

In a meta-analysis of 28 studies, human herpesvirus 6B (HHV-6B+ reactivation is associated with increased non-relapse mortality (NRM, odds ratio [OR] 1.84 (95% confidence interval [CI]: 1.29-2.62, p<0.01). The model did not exhibit significant heterogeneity, with 0% of the observed effects attributed to variation between studies ( I² 0%, p=0.55).

For overall mortality (OM), the OR was 1.37 (95% CI: 1.07–1.76, p<0.05), indicating that patients with HHV-6B detection had significantly increased odds of death due to any cause. There was considerable heterogeneity in the model (I² =36.7%, p < 0.05) after HCT, suggesting that the observed effect may be due to variation between studies rather than a true pooled effect.

HHV-6B infection is common, and reactivation following HCT is seen in 30-70% of cases. It has been associated with increased immunosuppression, allogeneic vs. autologous, conditioning regimen, and other variables. In some studies, HHV-6B reactivation has been linked to worse outcomes. The authors performed a systematic review and meta-analysis on the impact of HHV-6B reactivation following HCT.

The authors identified 28 studies that fulfilled their selection criteria. NRM was defined as mortality not attributed to relapse, whereas OM was defined as any cause of mortality following HCT. Eight studies were pooled for the NRM using a random effects model and demonstrated the association of HHV-6B reactivation with NRM; 25 studies provided OM data. Due to the limited number of studies, a Bayesian aggregation analysis was performed with similar results. HHV-6B reactivation was also associated with OM but not relapse-related mortality.

The authors conclude that these results strongly support the association of HHV-6B reactivation with NRM and a weaker association with OM, with the caveat that the current analysis has limitations given the heterogeneity in HHV-6B reactivation criteria, assay, and population across studies.

High activity of the new myeloablative regimen of gemcitabine/clofarabine/busulfan for allogeneic transplant for aggressive lymphomas [Clinical Trial].

Highlights

●      Conditioning with gemcitabine/clofarabine/busulfan (Gem/Clo/Bu) was active (overall response rate [ORR], complete response [CR] rates in B-non-Hodgkin lymphoma [B-NHL] 78%/71%, T-NHL 93%/93%, and HL 67%/67%), allowing for complete chimerism, and with manageable toxicity in a cohort of aggressive lymphomas undergoing allogeneic hematopoietic stem cell transplantation (Allo-HCT)

●      When compared to a historical cohort of 112 control patients with aggressive lymphomas treated with fludarabine and melphalan (Flu/Mel) conditioning for Allo-HCT with a matched unrelated or sibling donor, Gem/Clo/Bu patients had better median event-free survival (EFS: 12 vs. 3.3 months, p = 0.001) and overall survival (OS: 25 vs. 7 months, p = 0.003) based on propensity score matching.

Allo-HCT represents an effective therapeutic option for lymphomas due to its graft-versus-lymphoma effect. Myeloablative conditioning (MAC) regimens have significant toxicity and are associated with increased non-relapse mortality (NRM) in lymphoma, whereas non-MAC regimens have improved NRM but can be associated with early progression of disease given limited cytoreductive activity. Based on previous experience, a MAC regimen combining Gem/Clo/Bu was created to allow for effective cytoreduction and allow engraftment while minimizing the toxicity.

This Phase I/II enrolled patients with aggressive lymphoma (B-NHL, T-NHL, or HL) aged 12-65 years with adequate organ reserve and performance status (Eastern Cooperative Oncology Group – 0 or 1) received Gem on days (d) −6 and −4 (475–975 mg/m2/day), followed by Clo (40 mg/m2/day x 4, days -6 to -3) and Bu (target area under the curve (AUC) of 4000 μMol min x 4, (d −6 to −3) as conditioning for 8/8 human leukocyte antigen-matched donor Allo-HCT. Patients with CD20⁺ disease also received rituximab, and all patients received graft-vs-host disease prophylaxis with tacrolimus, mycophenolate mofetil, and anti-thymocyte globulin for those with unrelated donor grafts. For additional information on inclusion criteria, schedule, and supportive care, please refer to the manuscript.

Sixty-four patients were enrolled and treated, comprising 31 with B-NHL, 22 with T-NHL and 11 with HL. Of 37 patients treated at the maximum tolerated dose 23 (62%) experienced grade 3 mucositis, and 9 patients (24%) had grade 2 mucositis. Mucositis started early on median day +1 (−1 to +9) and lasted a median of 3 days (range, 1–14) at peak severity. Other less common toxicities included diarrhea four grade 3, six grade 2), skin rash (four grade 2) and hand-foot syndrome (three grade 2). There was complete marrow ablation in all patients, and full donor chimerism was seen early (median 100% on day +28) and persisted up to day +180. The regimen was considered active based on the response, EFS, and OS mentioned above.

The authors conclude that the Gem/Clo/Bu regimen had manageable toxicities, provided adequate marrow ablation, and was effective in Allo-HCT for aggressive lymphomas, based on the ORR, CR, EFS, and OS seen within the cohort and compared to a matched cohort of 113 patients treated with Mel/Flu conditioning.

Emapalumab therapy for hemophagocytic lymphohistiocytosis before reduced-intensity transplantation improves chimerism [Retrospective Study].

Highlights:

●      The use of emapalumab before reduced intensity conditioning (RIC) allogeneic hematopoietic cell transplant (Allo-HCT) was associated with lower rates of mixed chimerism (48% vs. 77%; p = 0.03) and severe mixed chimerism (5% vs. 38%; p < 0.01). Intervention-free survival (IFS) was also higher in patients receiving emapalumab (73% vs. 43%; p = 0.03).

Hemophagocytic lymphohistiocytosis (HLH) is characterized by pathologic immune activation resulting in excessive inflammatory cytokine production. Interferon gamma (IFN-γ) is a key in this syndrome. Emapalumab is an anti-IFN-γ antibody and blocks IFN-γ, and is approved for recurrent or refractory HLH. RIC Allo-HCT is commonly used given the improved transplant-related mortality when compared to myeloablative regimens; however, it lowers IFS given the higher incidence of secondary graft failure and mixed chimerism.

The authors compared outcomes of 50 pediatric patients treated with (n=22) or without (n=28) emapalumab at a single institution. All patients received a first Allo-HCT for primary HLH or Epstein-Barr virus-related disorders. Patients who received emapalumab within 21 days of the Allo-HCT preparative regimen were considered as emapalumab exposed. Mixed chimerism and severe mixed chimerism was defined as <95% whole blood chimerism at two points and <25% at any point, respectively.  IFS was the primary outcome and was defined as the time to administration of any cellular product for mixed chimerism (donor lymphocyte infusion, CD34-selected cell boost, or second Allo-HCT, or death within 5 years post HCT).

Patients treated with emapalumab had significantly lower rates of mixed and severe mixed chimerism when compared to the controls. Similarly, IFS was higher in those receiving emapalumab. There was a higher 5-year overall survival for those treated with emapalumab that was not statistically significant 82% vs. 71%, p = 0.39).

The authors conclude that although there are limitations to these results due to the single institution and retrospective nature of the study, the data support the use of emapalumab to decrease mixed chimerism following RIC Allo-HCT in pediatric patients with HLH.

Autologous stem cell transplantation in T-cell/histiocyte-rich large B-cell lymphoma: EBMT Lymphoma Working Party study [Retrospective study].

Highlights:

●      Patients with relapsed/refractory (R/R) T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL) with chemo-sensitive disease had favorable outcomes after autologous hematopoietic stem cell transplant (auto-HCT) salvage when compared to diffuse large B-cell lymphoma (DLBCL).

Despite the widespread use of auto-HCT as consolidation to salvage in relapsed DLBCL, its use in THRLBCL, a rare subtype of DLBCL, has not been formally reported. The authors report the outcomes of 201 THRLBCL patients treated with auto-HCT consolidation after chemotherapy salvage and compared them to the outcomes of 5543 DLBCL patients from the European Society for Blood and Marrow Transplantation registry. Only patients with chemo-sensitive disease were included, defined as those achieving at least a partial response after the last course of chemotherapy salvage.

Patients with THRLBCL were more frequently male (80% vs. 60%, p < 0.001), of younger age (median 49.3 vs. 58.5 years, p  < 0.001), and had a Karnofsky score ≥90 (81% vs. 71%, p = 0.004) when compared to DLBCL patients. Compared with the latter, THRLBCL was associated with significantly better 2-year progression-free survival (PFS, 78% vs. 59%; p < .001) and overall survival (OS, 81% vs. 74%; p = 0.02) because of a significantly lower 2-year relapse incidence (16% vs. 35%; p < 0.001). On multivariate analysis, favorable relapse risk (hazard ratio [HR], 0.46; 95% confidence interval [CI], 0.31-0.7) and PFS (HR, 0.58; 95% CI, 0.41-0.82) of patients with THRLBCL remained significant, whereas OS benefits (HR, 0.78; 95% CI, 0.54-1.12) did not. These results were validated in a propensity score-matched analysis.

The authors conclude these findings support the use of auto-HCT as consolidation for chemo-sensitive R/R THRLBCL.

Role of molecular alterations in transplantation decisions for patients with primary myelofibrosis [Retrospective Study].

Highlights: 

●      Patients with primary myelofibrosis (PMF) and high Mutation-Enhanced International Prognostic Score System (MIPSS)70 and MIPSS70+V2 who received allogeneic hematopoietic transplantation (allo-HCT) had improved 6-year overall survival (OS) when compared to a propensity-matched cohort without allo-HCT.

●      The benefit of allo-HCT in intermediate MIPSS70 was restricted to patients with a low or intermediate myelofibrosis transplant scoring system (MTSS) score.

Allo-HCT represents the only curative approach for PMF. However, non-relapse mortality limits the benefit of allo-HCT and is affected by performance status, comorbidities, and underlying disease-related factors such as the burden of symptoms and disease biology. It has been previously reported that patients with intermediate-2 or high Dynamic International Prognostic Scoring System (DIPSS) benefit from allo-HCT. However, this score only incorporates cytogenetic data and does not account for other essential driver mutations in PMF.

241 transplanted patients were compared to 239 non-transplanted patients who received allo-HCT for PMF using a matched propensity-score and weighted Cox model to account for cohort heterogeneity. Allo-HCT was associated with a higher 6-year OS rate in intermediate-2 (60.1% versus 41.5%) and high-risk DIPSS patients (44.4% versus 6.55%), high-risk MIPSS70 (46.5 versus 23.9%), high-risk (73.2% versus 39.7%) 70 or very high-risk MIPSS70V2 (51.8% versus 24%). Intermediate MIPSS70 patients benefited from transplantation only when they also had a low or intermediate MTSS (80.8% versus 66.3%) but not a high or very high MTSS.

The authors conclude these results support using the different prognostic scores (DIPSS, MTSS, MIPSS70 and MIPSS70+V2) to select patients who will benefit from allo-HCT in PMF.

Artificial intelligence enabled interpretation of ECG images to predict hematopoietic cell transplantation toxicity. [Retrospective Study].

Highlights: 

A previously developed artificial intelligence (AI) application designed to predict the risk of developing atrial fibrillation (AF) was able to predict complications and mortality after hematopoietic cell transplantation (HCT) using pre-transplant electrocardiogram (ECG) images.

Previous AI-based tools have been developed to predict the risk of cardiac complications using the ECG waveform traces, demonstrating the reliable discriminatory capability to identify AF, ventricular arrhythmia, and amyloidosis.

The authors used a previously described AI model to identify the risk of AF and applied it to 1377 patients undergoing HCT (849 autologous and 528 allogeneic) at a single center between 2014 and 2022 using pre-transplant ECG, with a median follow-up of 2.9 years.

The pre-HCT AI-ECG estimate of AF risk correlated with the development of clinical AF (hazard ratio [HR], 7.37; 95% CI, 3.53-15.4; p < 0.001), inferior survival (HR, 2.4; 95% CI, 1.3-4.5; p = 0.004), and greater risk of non-relapse mortality (NRM: HR, 3.36; 95% CI, 1.39-8.13; p = 0.007), without increased risk of relapse, however the association with mortality was only noted in allogeneic HCT where the risk of NRM was greater.  The risk of 90 -day incidence of AF was also higher for patients who received post-transplant cyclophosphamide (13% vs. 5%; p = 0.01) when compared to those who received calcineurin inhibitor-based  graft-versus-host disease prophylaxis.

The authors concluded that this AI-ECG model design to stratify the risk of cardiovascular outcomes could help identify patients at higher risk of cardiac and non-cardiac complications after HCT, providing an opportunity for pre-transplant optimization.

Optimal infused CD34+ cell dose in multiple myeloma patients undergoing upfront autologous hematopoietic stem cell transplantation [Retrospective Study].

Highlights:

In patients with multiple myeloma (MM) undergoing autologous hematopoietic transplant (auto-HCT) a dose of CD34⁺ >2.5 x 10⁶ cells/kg was associated with faster hematological recovery.

In 2009, the International Myeloma Working Group established recommendations for the dose of CD34⁺ cells to be given as part of auto-HCT, with a minimum of ≥2 x 10⁶ cells/kg and a recommended dose of 4-6 x 10⁶ CD34⁺ cells/kg. However, previous studies assessing the impact of the CD34⁺ dose in MM have yielded conflicting results in terms of its impact on time to platelet and neutrophil engraftment and clinical outcomes.

The authors explored the impact of the CD34⁺ in a single institution cohort of 2479 patients who received auto-HCT for MM between 2005 and 2021. 95 patients were assigned to the low-dose CD34⁺ (≤2.5 x 10⁶ cells/kg) group and 2384 patients in the high-dose CD34⁺ (>2.5 x 10⁶ cells/kg) group, with patients in the low-dose group more frequently receiving plerixafor (60% vs. 35%, p=<0.001), older age (median 63.2 vs. 61.1 years, p= 0.013) and higher Revised- International Staging System III (19% vs. 9%, p=0.014. The time to engraftment (platelets and neutrophils), progression-free survival (PFS), and overall survival (OS) were compared between groups using a 2:1 nearest-neighbor matching.

Patients in the low-dose CD34⁺ group had a longer median time to engraftment (platelets - ≥50 x 10⁹ cells/L: day 18 vs. 14 days, p <0.001; neutrophils: 12 vs. 11 days, p < 0.001, respectively), and higher median number of red blood cell transfusions (2 vs.  1 unit, p < 0.001), platelets (3 vs. 2 units, p < 0.001), and longer median hospital stay (17 [range 0–94] vs. 16 [0–38]  days, p = 0.007) when compared to the high-dose group. Median PFS and OS were lower in the low CD34⁺ group (31.6 vs. 43.6 months, p = 0.011 and 76.4 vs. 108.2 months, p < 0.001, respectively), and this effect persisted in the multivariable model and after propensity score matched . The authors also performed an optimal dose threshold analysis  using incremental doses from >2.5 up to >6 x 10⁶ cells/kg, however, no differences in PFS or OS were seen.

Autologous stem cell transplantation for multiple patients whose myeloma-defining event was SLiM [Retrospective study].

Highlights:

●      When compared to patients with multiple myeloma (MM) diagnosed based on CRAB (hypercalcemia, renal dysfunction, anemia or lytic bone disease) criteria, patients with SLiM-only MM who received autologous hematopoietic cell transplantation (auto-HCT) as an outpatient at a single center had a shorter time to neutrophil and platelet engraftment (15 vs. 16 days, p = 0.049 and 15 vs. 17 days, p =0.0004, respectively), with similar overall response rate (ORR, 100% vs.  98%), and longer 36-month progression-free survival (PFS; 91.61% vs. 65.95%, hazard ratio 0.704, p = 0.42) and 36-month overall survival (100% vs. 93.27%, p = 0.065) that were not statistically significant.

●      There were no differences between MM-SLiM and MM-CRAB patients and the use of plerixafor for mobilization (80% vs. 78%, p = 0.8), need for admission (47% vs. 50%, p = 0.7), neutropenic fever, bacteremia, days of admission in those hospitalized (9 vs. 10)<> or measurable residual disease (MRD)-negativity (30% vs. 30%), respectively.

The diagnosis of MM has relied on the presence of end-organ damage, as defined by the CRAB criteria. However, in 2014, patients with smoldering myeloma at high (>80%) 2-year progression were also considered for treatment, and diagnosis of MM based on the SLiM (>60% bone marrow plasma cells [BMPC], light chain ratio >100 with involved at least >10mg/dL, or >1 MRI lesion) was included as part of the 2014 International Myeloma Working Group criteria. Treatment for SLiM-only patients has been like those with MM diagnosed with CRAB criteria, but patient outcomes for auto-HCT in this patient subgroup are lacking.

The authors reviewed the baseline characteristics and outcomes of 30 patients diagnosed with MM based on SLiM criteria at a single center. 60 patients with MM diagnosed based on the presence of CRAB criteria were matched using age, gender, International Staging System, and melphalan dose. All patients had their auto-HCT performed as an outpatient. Patients had similar baseline characteristics and were balanced across the two groups with respect to melphalan dose (140 vs. 200mg/m2), time to auto-HCT, baseline BMPC, number of pre-auto-HCT regimens, and high-risk cytogenetics. SLiM-only patients had a shorter time for neutrophil and platelet engraftment, with similar rates of bacteremia and need for admission. ORR and MRD rates were similar across the two cohorts, and although the SLiM-only group had an improved 36-month PFS and OS, this was not statistically significant.

The authors conclude that auto-HCT is safe and effective in the SLiM-only population. Despite the improved fitness and lack of end-organ involvement in this population, infection rates and need for plerixafor, or admission, were similar between the two groups.