[Selected donor CD34(+) cell boosts for salvage treatment of poor graft function following allogeneic hematopoietic stem cell transplantation in primary myelofibrosis: 3 cases report].

A retrospective analysis was conducted on three patients with primary myelofibrosis who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) at Shanghai Zhaxin Traditional Chinese and Western Medicine Hospital from 2020 to 2023. They subsequently developed poor graft function. The patients received selected donor CD34(+) cell boosts as salvage therapy. There were two male patients and one female patient, with a median age of 68 (39-69) years. The median time from allo-HSCT to the selected donor CD34(+) cell boost was 83 (56-154) days. The median infusion of selected donor CD34(+) cells was 7.67 (7.61-9.06) ×10(6)/kg, with a CD34(+) cell purity of 97.76% (96.50%-97.91%) and a recovery rate of 70% (42%-75%) . Hematological recovery was achieved in two cases. No acute GVHD was observed in any of the three patients. One case of moderate oral chronic GVHD was noted. Selected donor CD34(+) cell boosts for the treatment of poor graft function after allo-HSCT in primary myelofibrosis was effective and no severe acute or chronic GVHD was observed.

Prognostic and Predictive Models in Myelofibrosis.

PURPOSE OF REVIEW: Myelofibrosis (MF) includes prefibrotic primary MF (pre-PMF), overt-PMF and secondary MF (SMF). Median overall survival (OS) of pre-PMF, overt-PMF and SMF patients is around 14 years, seven and nine years, respectively. Main causes of mortality are non-clonal progression and transformation into blast phase. RECENT FINDINGS: Discoveries on the impact of the biological architecture on OS have led to the design of integrated scores to predict survival in PMF. For SMF, OS estimates should be calculated by the specific MYSEC-PM (MYelofibrosis SECondary-prognostic model). Information on the prognostic role of the molecular landscape in SMF is accumulating. Crucial treatment decisions for MF patients could be now supported by multivariable predictive algorithms. OS should become a relevant endpoint of clinical trials. Prognostic models guide prediction of OS and treatment planning in MF, therefore, their timely application is critical in the personalized approach of MF patients.

Allogeneic Hematopoietic Cell Transplantation for Myelofibrosis Aged 70 Years or Older: A Study from the German Registry for Stem Cell Transplantation.

Current consensus recommends hematopoietic cell transplantation (HCT) for patients with myelofibrosis with intermediate or high-risk disease and age of less than 70 years. However, a higher chronological age should not be prohibitive for the eligibility decision in general, acknowledging that current life expectancy for the general population aged 70 years is ∼15 years, and current numbers of patients transplanted at 70 years or older is steadily increasing. The following study aimed to evaluate characteristics and outcomes of HCT in 115 myelofibrosis patients aged 70 years or older. This is a retrospective multicenter study, using the German Registry for Stem Cell Transplantation and Cellular Therapy (DRST). Adult myelofibrosis patients were included who received HCT up until 2021. Patients with secondary leukemia were excluded. Main endpoints were HCT demographics over time and outcomes after HCT (including overall survival, relapse incidence, non-relapse mortality, and graft-versus-host disease/relapse-free survival). Numbers of HCT increased over the past decade, with a significant spike since 2019. Comorbidity status of transplanted patients improved over time, while reduced-intensity conditioning was the preferred HCT platform, especially in most recent years. The 3-year overall survival was 55% (95% confidence interval [CI], 44%-65%). The 1-year cumulative incidence of relapse was 7% (95% CI, 3%-13%) and the 1-year cumulative incidence of non-relapse mortality was 22% (95% CI, 14%-31%). The 3-year graft-versus-host disease and relapse-free survival was 37% (95% CI, 27%-47%). Driver mutation genotype (in particular, non-CALR/MPL genotype) appeared to be the only variable that was significantly and independently associated with better survival in multivariable analysis, whereas neither comorbidity index nor dose intensity of pre-transplant conditioning appeared to influence outcome. This study demonstrated feasibility of curative treatment with HCT for myelofibrosis aged 70 or older, with significant increases in HCT numbers and improved fitness of older adults over recent years.

Donor types and outcomes of transplantation in myelofibrosis: a CIBMTR study.

ABSTRACT: We evaluate the impact of donor types on outcomes of hematopoietic cell transplantation (HCT) in myelofibrosis, using the Center for International Blood and Marrow Transplant Research registry data for HCTs done between 2013 and 2019. In all 1597 patients, the use of haploidentical donors increased from 3% in 2013 to 19% in 2019. In study-eligible 1032 patients who received peripheral blood grafts for chronic-phase myelofibrosis, 38% of recipients of haploidentical HCT were non-White/Caucasian. Matched sibling donor (MSD)-HCTs were associated with superior overall survival (OS) in the first 3 months (haploidentical hazard ratio [HR], 5.80 [95% confidence interval (CI), 2.52-13.35]; matched unrelated (MUD) HR, 4.50 [95% CI, 2.24-9.03]; mismatched unrelated HR, 5.13 [95% CI, 1.44-18.31]; P < .001). This difference in OS aligns with lower graft failure with MSD (haploidentical HR, 6.11 [95% CI, 2.98-12.54]; matched unrelated HR, 2.33 [95% CI, 1.20-4.51]; mismatched unrelated HR, 1.82 [95% CI, 0.58-5.72]). There was no significant difference in OS among haploidentical, MUD, and mismatched unrelated donor HCTs in the first 3 months. Donor type was not associated with differences in OS beyond 3 months after HCT, relapse, disease-free survival, or OS among patients who underwent HCT within 24 months of diagnosis. Patients who experienced graft failure had more advanced disease and commonly used nonmyeloablative conditioning. Although MSD-HCTs were superior, there is no significant difference in HCT outcomes from haploidentical and MUDs. These results establish haploidentical HCT with posttransplantation cyclophosphamide as a viable option in myelofibrosis, especially for ethnic minorities underrepresented in the donor registries.

Impact of busulfan versus treosulfan dose intensity in myelofibrosis undergoing hematopoietic cell transplantation.

One key aspect of allogeneic hematopoietic cell transplantation (HCT) is pretransplant conditioning, balancing risk for relapse versus non-relapse mortality. Conditioning regimens with different alkylators at different doses can influence outcome, but data are missing for myelofibrosis, a challenging cohort of patients usually presenting at older age and with comorbidities. We evaluated in a multicenter retrospective study the comparative efficacy and safety of busulfan versus treosulfan in combination with fludarabine for myelofibrosis patients undergoing HCT. This study included 1115 patients (busulfan, n = 902; treosulfan, n = 213) receiving first HCT between 2005 and 2021. Patients were generally balanced for key patient characteristics. Overall survival at 4 years was 62% for the busulfan group versus 58% for the treosulfan group (p = .22). Impact on outcome was dose-dependent. Overall survival was 65% (95% CI, 61%-69%) for reduced intensity busulfan versus 69% (95% CI, 54%-84%) for reduced intensity treosulfan, 53% (95% CI, 44%-63%) for higher intensity busulfan, and 55% (95% CI, 46%-63%) for higher intensity treosulfan. Incidence of relapse was similar across intensity groups. In multivariable analysis, the hazard for death (with reduced intensity busulfan as reference) was 0.88 (95% CI, 0.39-2.01) for reduced intensity treosulfan (p = .77), 1.42 (95% CI, 0.96-2.10) for higher intensity busulfan (0.08), and 1.61 (95% CI, 1.14-2.26) for higher intensity treosulfan (p = .006). In terms of non-relapse mortality, comparison was not significantly different, while the hazard ratio for higher intensity treosulfan was 1.48 (95% CI, 0.98-2.23; p = .06). Here, we showed comparable outcomes and improved survival in myelofibrosis undergoing HCT with reduced intensity busulfan or treosulfan.

Phase 1 Study of CK0801 in Treatment of Bone Marrow Failure Syndromes.

BACKGROUND: An inflammatory bone marrow microenvironment contributes to acquired bone marrow failure syndromes. CK0801, an allogeneic T regulatory (Treg) cell therapy product, can potentially interrupt this continuous loop of inflammation and restore hematopoiesis. METHODS: In this phase 1 dose-escalation study of CK0801 Treg cells, we enrolled patients with bone marrow failure syndromes with suboptimal response to their prior therapy to determine the safety and efficacy of this treatment for bone marrow failure syndromes. RESULTS: We enrolled nine patients with a median age of 57 years (range, 19 to 74) with an underlying diagnosis of aplastic anemia (n=4), myelofibrosis (n=4), or hypoplastic myelodysplasia (n=1). Patients had a median of three prior therapies for a bone marrow failure syndrome. Starting dose levels of CK0801 were 1 × 106 (n=3), 3 × 106 (n=3), and 10 × 106 (n=3) cells per kg of ideal body weight. No lymphodepletion was administered. CK0801 was administered in the outpatient setting with no infusion reactions, no grade 3 or 4 severe adverse reactions, and no dose-limiting toxicity. At 12 months, CK0801 induced objective responses in three of four patients with myelofibrosis (two had symptom response, one had anemia response, and one had stable disease) and three of four patients with aplastic anemia (three had partial response). Three of four transfusion-dependent patients at baseline achieved transfusion independence. Although the duration of observation was limited at 0.9 to 12 months, there were no observed increases in infections, no transformations to leukemia, and no deaths. CONCLUSIONS: In previously treated patients, CK0801 demonstrated no dose-limiting toxicity and showed evidence of efficacy, providing proof of concept for targeting inflammation as a therapy for bone marrow failure. (Funded by Cellenkos Inc.; Clinicaltrials.gov number, NCT03773393.).

Anti-T-lymphocyte globulin improves GvHD-free and relapse-free survival in myelofibrosis after matched related or unrelated donor transplantation.

Acute and chronic graft-versus-host disease (GvHD) are major complications of allogeneic hematopoietic cell transplantation (alloHCT). In vivo T-cell depletion with anti-T-lymphocyte globulin (ATLG) as part of the conditioning regimen prior to alloHCT is frequently used as GvHD prophylaxis, but data on its role in myelofibrosis is scarce. We took advantage of an international collaborative network to investigate the impact of ATLG in myelofibrosis undergoing first alloHCT. We included 707 patients (n = 469 ATLG and n = 238 non-ATLG prophylaxis). The cumulative incidence of acute GvHD grade II-IV was 30% for the ATLG group vs. 56% for the non-ATLG group (P < 0.001). Acute GvHD grade III-IV occurred in 20% vs. 25%, respectively (P = 0.01). Incidence of mild-to-severe chronic GvHD was 49% vs. 50% (P = 0.52), while ATLG showed significantly lower rates of severe chronic GvHD (7% vs. 18%; P = 0.04). GvHD-free and relapse-free survival (GRFS) at 6 years was 45% for the ATLG group vs. 37% for the non-ATLG group (P = 0.02), driven by significantly improved GRFS of ATLG in matched related and matched unrelated donors. No significant differences in risk for relapse, non-relapse mortality, and overall survival were observed. Multivariable modeling for GRFS showed a 48% reduced risk of GvHD, relapse, or death when using ATLG.

Outcomes of allogeneic haematopoietic cell transplantation for myelofibrosis in children and adolescents: the retrospective study of the EBMT Paediatric Diseases WP.

This retrospective study evaluated 35 children (median age 5.2 years; range 0.4-18) with myelofibrosis (MF), including 33 with primary myelofibrosis and 2 with secondary myelofibrosis transplanted from matched sibling donor (MSD) (n = 17) or non-MSD (n = 18) between 2000 and 2022. Conditioning was usually chemotherapy-based (n = 33) and myeloablative (n = 32). Fifteen patients received bone marrow (BM), 14 haematopoietic cells (HC) from peripheral blood (PB), and 6 from cord blood (CB). Day +100 acute GvHD II-IV incidence was significantly lower after MSD-haematopoietic cell transplantation (MSD-HCT) than after non-MSD-HCT [18.8% (4.3-41.1) vs 58.8% (31-78.6); p = 0.01]. Six-year non-relapse mortality (NRM) was 18% (7.1-32.8), relapse incidence was 15.9% (5.6-30.9), progression-free survival (PFS) was 66.1% (47-79.7), GvHD-free relapse-free survival was 50% (30.6-66.7), and overall survival (OS) was 71.1% (51.4-84). Six-year PFS and OS were significantly higher after BM transplantation compared to HCT from other sources [85.1% (52.3-96.1) vs 50.8% (26.3-71), p = 0.03, and 90.9% (50.8-98.7) vs 54% (28.1-74.2), p = 0.01, respectively], whereas NRM was significantly lower [0% vs 32% (12.3-53.9); p = 0.02]. This first multicentre study on outcomes of allogeneic HCT in children with myelofibrosis proves feasibility and curative effect of transplantation in these children, suggests that bone marrow transplantation is associated with better outcomes, and indicates the need for further studies.

Bone marrow findings post allogeneic transplant for myeloproliferative neoplasms and chronic myelomonocytic leukemia with increased fibrosis.

BACKGROUND: Allogeneic hematopoietic stem cell transplant for myeloid neoplasms with increased fibrosis is uncommon; morphologic features posttransplant can be concerning for persistent disease. METHODS: In this retrospective study, we identified 22 patients transplanted for myeloproliferative neoplasms or chronic myelomonocytic leukemia with fibrosis at our institution, and reviewed slides from pretransplant and posttransplant bone marrow biopsies. Clinical features and results of molecular, chimerism, and cytogenetic studies were retrieved from the medical record. RESULTS: Pretransplant bone marrow biopsies commonly exhibited hypercellularity, atypical megakaryocytes, and reticulin fibrosis. At day 100, 36% of biopsies had reticulin grade >MF1 and 33% of those tested had positive molecular studies, with no significant associations between day 100 marrow characteristics and molecular profile or peripheral count recovery times. In the 1 year posttransplant biopsies (n = 12), 7 of 9 had negative molecular studies; of these, none had reticulin grade >MF1, 1 had trichrome 1+, 2 had atypical megakaryocytes, and 1 was hypercellular. CONCLUSIONS: Supporting recent literature, our study indicates that persistent day 100 reticulin fibrosis/collagen deposition does not show an association with day 100 molecular status. Our study additionally provides data for 12 patients with 1 year posttransplant marrow biopsies, with the majority of those lacking either increased fibrosis or molecular evidence of persistent disease.

Treosulfan compared to busulfan in allogeneic haematopoietic stem cell transplantation for myelofibrosis: a registry-based study from the Chronic Malignancies Working Party of the EBMT.

We aimed to compare outcomes following treosulfan (TREO) or busulfan (BU) conditioning in a large cohort of myelofibrosis (MF) patients from the EBMT registry. A total of 530 patients were included; 73 received TREO and 457 BU (BU ≤ 6.4 mg/kg in 134, considered RIC, BU > 6.4 mg/kg in 323 considered higher dose (HD)). Groups were compared using adjusted Cox models. Cumulative incidences of engraftment and acute GVHD were similar across the 3 groups. The TREO group had significantly better OS than BU-HD (HR:0.61, 95% CI: 0.39-0.93) and a trend towards better OS over BU-RIC (HR: 0.66, 95% CI: 0.41-1.05). Moreover, the TREO cohort had a significantly better Progression-Free-Survival (PFS) than both the BU-HD (HR: 0.57, 95% CI: 0.38-0.84) and BU-RIC (HR: 0.60, 95% CI: 0.39-0.91) cohorts, which had similar PFS estimates. Non-relapse mortality (NRM) was reduced in the TREO and BU-RIC cohorts (HR: 0.44, 95% CI: 0.24-0.80 TREO vs BU-HD; HR: 0.54, 95% CI: 0.28-1.04 TREO vs BU-RIC). Of note, relapse risk did not significantly differ across the three groups. In summary, within the limits of a registry-based study, TREO conditioning may improve PFS in MF HSCT and have lower NRM than BU-HD with a similar relapse risk to BU-RIC. Prospective studies are needed to confirm these findings.

Transplantation for myelofibrosis patients in the ruxolitinib era: a registry study from the Société Francophone de Greffe de Moelle et de Thérapie Cellulaire.

In this SFGM-TC registry study, we report the results after stem cell transplantation (HSCT) in 305 myelofibrosis patients, in order to determine potential risk factors associated with outcomes, especially regarding previous treatment with ruxolitinib. A total of 102 patients were transplanted from an HLA-matched-sibling donor (MSD), and 143 patients received ruxolitinib. In contrast with previous studies, our results showed significantly worse outcomes for ruxolitinib patients regarding overall survival (OS) and non-relapse mortality (NRM), especially in the context of unrelated donors (URD). When exploring reasons for potential confounders regarding the ruxolitinib effect, an interaction between the type of donor and the use of ATG was found, therefore subsequent analyses were performed separately for each type of donor. Multivariable analyses did not confirm a significant negative impact of ruxolitinib in transplantation outcomes. In the setting of URD, only age and Fludarabine-Melphalan (FM) conditioning were associated with increased NRM. For MSD, only Karnoksfy <70% was associated with reduced OS. However, a propensity score analysis showed that ruxolitinib had a negative impact on OS but only in non-responding patients, consistent with previous data. To conclude, with all the precautions due to confounders and bias, ruxolitinib itself does not appear to increase mortality after HSCT.

SOHO State of the Art Updates and Next Questions | Early Intervention in Myelofibrosis: Where Are We and Does It Matter?

Historically, therapeutic clinical trials in myelofibrosis have predominantly focused on targeting patients with higher-risk disease who are at risk of increased morbidity and mortality. The endpoints have been designed to target regularly measured disease parameters that are of immediate pertinence to patient's welfare including splenic volume reduction and symptom reduction. These efforts have resulted in meaningful and measurable improvements in disease parameters in these high-risk study populations and multiple FDA approved agents. However, they have not tackled specific interventions that may be applied to patients with earlier or less advanced disease state. In this review, we summarize evidence from completed and ongoing clinical trials investigating different aspects of intervention targeted at less advanced disease and advocate for the merit of this approach.

The application of JAK inhibitors in the peri-transplantation period of hematopoietic stem cell transplantation for myelofibrosis.

Myelofibrosis (MF) is a myeloproliferative neoplasm (MPN) with a poor prognosis, and allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only treatment with curative potential. Ruxolitinib, a JAK1/2 inhibitor, has shown promising results in improving patients' symptoms, overall survival, and quality of life, and can be used as a bridging therapy to HSCT that increases the proportion of transplantable patients. However, the effect of this and similar drugs on HSCT outcomes is unknown, and the reports on their efficacy and safety in the peri-transplantation period vary widely in the published literature. This paper reviews clinical data related to the use of JAK inhibitors in the peri-implantation phase of hematopoietic stem cell transplantation for primary myelofibrosis and discusses their efficacy and safety.

Management of Patients with Early Myelofibrosis: A Discussion of Best Practices.

PURPOSE OF REVIEW: Summarize best practices for management of patients with early myelofibrosis (MF). RECENT FINDINGS: Myelofibrosis is a progressive myeloproliferative neoplasm (MPN) that generally produces burdensome symptoms and ultimately leads to worse overall survival than that observed in healthy controls or patients with other MPNs. Several Janus kinase inhibitors and various interferon formulations are now available for treatment of MF, with ruxolitinib notable for extending overall survival in addition to improving MF signs and symptoms. The chronic nature of the disease can lead some patients to avoid immediate treatment in favor of a watch-and-wait approach. This review summarizes the patient management approach taken in my practice, providing guidance and a discussion of best practices with an emphasis on the importance and clinical benefits of active treatment in early MF. In particular, a case is made to consider treatment with ruxolitinib for patients with intermediate-1 risk disease and to minimize delay between diagnosis and treatment initiation for patients with intermediate or high-risk disease.

Impact of myelofibrosis on patients with myelodysplastic syndromes following allogeneic hematopoietic stem cell transplantation.

BACKGROUND: The prognostic significance of myelofibrosis (MF) grade in patients with myelodysplastic syndrome (MDS) following an allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains elusive. METHODS: We retrospectively analyzed data from 153 patients with MDS who underwent allo-HSCT and divided the patients into the MF-0/1 (N = 119) and MF-2/3 (N = 34) cohorts to explore the impact of MF on outcomes of allo-HSCT. RESULTS: The 2-year rates of relapse, non-relapse mortality (NRM), overall survival (OS), and progression-free survival (PFS) were 10.9% (95% confidence interval [CI] 5.9%-17.7%), 16.3% (95% CI 10.2%-23.6%), 76.6% (95% CI 69.0%-85.1%), and 72.8% (95% CI 65.0%-81.5%) in the MF-0/1 cohort, and 16.9% (95% CI 5.8%-32.9%), 14.7% (95% CI 5.3%-28.7%), 71.8% (95% CI 57.6%-89.6%), and 68.4% (95% CI 53.6%-87.2%) in the MF-2/3 cohort, respectively. No significant difference in the outcomes of allo-HSCT was observed between the two cohorts. Both univariate and multivariate analyses confirmed that MF-2/3 in patients with MDS had no effect on the prognosis of transplantation. In addition, major/bidirectional ABO blood type between donors and recipients was an independent risk factor for OS (hazard ratio [HR], 2.55; 95% CI 1.25-5.21; P = 0.010) and PFS (HR, 2.21; 95% CI 1.10-4.42; P = 0.025) in the multivariate analysis. In the subgroup of patients diagnosed with MDS with increased blasts (MDS-IB), it was consistently demonstrated that the clinical outcomes of the MF-2/3 cohort were comparable with those of the MF-0/1 cohort. The risk factors for OS and PFS in patients with MDS-IB were non-complete remission at transplantation and major/bidirectional ABO blood type. CONCLUSIONS: In conclusion, MF grade had no significant effect on prognosis of allo-HSCT in patients diagnosed with MDS. Major/bidirectional ABO blood type should be carefully considered in the context of more than one available donor.

Clinical Features and Long-Term Outcomes of a Pan-Canadian Cohort of Adolescents and Young Adults with Myeloproliferative Neoplasms: A Canadian MPN Group Study.

Myeloproliferative neoplasms (MPNs) are a group of chronic hematologic malignancies that lead to morbidity and early mortality due to thrombotic complications and progression to acute leukemia. Clinical and mutational risk factors have been demonstrated to predict outcomes in patients with MPNs and are used commonly to guide therapeutic decisions, including allogenic stem cell transplant, in myelofibrosis. Adolescents and young adults (AYA, age ≤45 years) comprise less than 10% of all MPN patients and have unique clinical and therapeutic considerations. The prevalence and clinical impact of somatic mutations implicated in myeloid disease has not been extensively examined in this population. We conducted a retrospective review of patients evaluated at eight Canadian centers for MPN patients diagnosed at ≤45 years of age. In total, 609 patients were included in the study, with median overall survival of 36.8 years. Diagnosis of prefibrotic or overt PMF is associated with the lowest OS and highest risk of AP/BP transformation. Thrombotic complications (24%), including splanchnic circulation thrombosis (9%), were frequent in the cohort. Mutations in addition to those in JAK2/MPL/CALR are uncommon in the initial disease phase in our AYA population (12%); but our data indicate they may be predictive of transformation to post-ET/PV myelofibrosis.