Allogeneic HSCT for classical BCR::ABL1-negative myeloproliferative neoplasms in children: the retrospective study of the EBMT Pediatric Diseases WP

doi:10.21203/rs.3.rs-3609706/v1

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Allogeneic HSCT for classical BCR::ABL1-negative myeloproliferative neoplasms in children: the retrospective study of the EBMT Pediatric Diseases WP

https://doi.org/10.21203/rs.3.rs-3609706/v1

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published 16 Apr, 2024

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This retrospective EBMT registry-based study evaluated 42 children (0.4–18 years, median 6.1) with BCR::ABL1-neg MPN (PMF, n = 33; ET, n = 3; PV, n = 1, sAML, 3; post-ET/PV-MF, n = 2) transplanted from MSD (n = 21) or non-MSD (n = 21) between 2000–2022. Conditioning was usually chemotherapy-based (n = 40; 95.2%) and myeloablative (n = 38; 92.7%). Twenty one patients received HSC from BM, 15 (36%) from PB, and 6 (14%) from CB. Day + 60 CI of neutrophil and platelet recovery was 85.7% and 78.4%. Day + 100 CI of aGvHD II-IV was 35.9% and was lower in transplanted from MSD (20% vs 52.6%, p = 0.03). Six-year CI of cGvHD was 16.6%. Six-year RI was 17.8%, PFS 64.9%, GRFS 49.1%, and OS 68.6%. Six-year RI between 2008–2022 was lower than between 2000–2007 (4.5% vs 30%, p = 0.046). In obtaining BM compared with those transplanted with HSC from BM or CB the 6-year PFS and OS was significantly higher (83.5% vs 51.4%, p = 0.04 and 80.1% vs 48.4%, p = 0.02, respectively), whereas NRM was lower (0% vs 35.3%, p = 0.004). So far, this is the largest and first one multicenter study on transplant-specific characteristics and outcomes of allo-HSCT in children with BCR::ABL1-neg MPN, which indicates need of prospective studies to establish indications for allo-HSCT and optimal transplant procedure in them.

classical BCR::ABL1-neg MPN

allo-HSCT

children

The classical BCR::ABL1-negative myeloproliferative neoplasms (BCR::ABL1-neg MPN) include polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF) [1]. The discovery of three driver mutated genes, i.e. JAK2, MPL and CALR, became the major landmark in the understanding of BCR::ABL1-neg MPN [2]. These three mutations are detected in more than 80% of adult patients and correlate with clinical characteristics, disease-related complications as well as with prognosis and therefore are helpful in treatment stratification [3, 4].

In contrast to adult population, the BCR::ABL1-neg MPN are very rare in pediatric population with an incidence approximately 100 x lower than in adults [5], which severely limits the possibility to perform prospective clinical studies concerning these malignancies in children and adolescents.

Apart from that, JAK2, MPL, and CALR mutations occur in less than 50% of children, posing a significant diagnostic challenge given the lack of an objective clonal marker [6, 7]. In addition, in the pediatric population much more frequently than in adults the thrombocytosis and erythrocytosis not related to clonal myeloproliferation are observed. What’s more, in the pediatric population the normal range of hemoglobin level, hematocrit value and erythrocytes number depend on the child’s age. Thus, in children and adolescents the utility of the WHO diagnostic criteria of ET, PV, and PMF is limited [1]. Therefore, in the majority of pediatric patients the diagnosis of Ph-neg MPN is still difficult [8, 9].

In addition, in contrast to adult population, there is a lack of established prognostic criteria and clear treatment recommendations based on these criteria, including specific recommendations for allogeneic hematopoietic stem cell transplantation (allo-HSCT) in pediatric patients suffering from BCR::ABL1-neg MPN [7, 9].

So far there was no study analyzing outcomes of allo-HSCT in a larger group of pediatric patients with BCR::ABL1-neg MPN, and therefore the data on allo-HSCT outcomes in them remain casuistic and scanty [10, 11, 12, 13, 14, 15].

For this reason the retrospective, multicenter study on transplant-specific characteristics and outcomes of allo-HSCT performed between 2000 and 2022 in pediatric patients with BCR::ABL1-neg MPN and reported to the EBMT Registry was carried out within the EBMT Pediatric Diseases Working Party.

This was a retrospective EBMT Registry-based analysis approved by the EBMT Pediatric Diseases Working Party and performed in the cohort of pediatric patients fulfilling the following criteria: children and adolescents (< 18 years) receiving first allogeneic hematopoietic stem cell transplantation (allo-HSCT) for the classical BCR::ABL1-neg MPN (polycythemia vera, PV; essential thrombocythemia, ET; primary myelofibrosis, PMF; post-PV MF; post-ET MF; BCR::ABL1-neg MPN transformed to secondary acute myeloblastic leukemia, sAML), and transplanted between January 1st 2000 and December 31st 2022.

In the studied cohort of pediatric patients following outcome measures were analysed: cumulative incidence of neutrophiles recovery defined as ANC ≥ 0,5x10⁹/L for 3 consecutive days unsupported by granulocyte colony stimulating factor; platelets recovery defined as ≥ 20x10⁹/L for 3 consecutive days (with no platelet transfusions 7 days prior) [16, 17]; acute GvHD (aGvHD) and chronic GvHD (cGvHD) occurence and grading according to standard criteria [18, 19]; non-relapse mortality (NRM) defined as death without evidence of relapse; relapse incidence (RI) defined as time from transplantation to first occurrence of relapse; progression-free survival (PFS) defined as time from transplantation to relapse or death due to neoplasm; GvHD-free, relapse-free survival (GRFS) defined as time from transplantation to first event of aGvHD grade III-IV, extensive cGvHD, relapse or death, and overall survival (OS) defined as time from transplantation to death from any cause.

Statistical methods

Quantitative variables were described as median, quartile 1 and 3, minimum and maximum. Differences between two groups and quantitative variables were tested using the Wilcoxon test. Qualitative variables were described as number and percentage. Differences between groups and qualitative variables were tested using Chi2 test or fisher test when Chi2 test validation was not respected.

OS, PFS and GRFS were estimated using the Kaplan-Meier method. All outcomes with competing events were estimated using the cumulative incidence function. NRM and RI were mutually competing events. Death and relapse were competing events for GVHD outcomes. Death was a competing event for ANC and platelet recovery, and secondary HSCT. Second HSCT was a competing event for ANC and platelet recovery. All outcomes were censored at last follow-up. The median follow-up was estimated using the reverse Kaplan-Meier method. Univariable tests of covariate impact on outcomes were done using log Rank test for OS, PFS and GRFS, and Gray test for cumulative incidence outcomes. All tests were at 0.05 level and two-sides. Analyses were performed using the R software version 4.0.2.

Ethical aspects

The study was conducted in accordance with the EBMT Guidelines for Retrospective Studies and the principles of the Declaration of Helsinki. EBMT Centers commit to obtain informed consent according to the local regulations applicable at the time of transplantation in order to report pseudoanonymised data to the EBMT.

Patient descriptive analysis

A total of 42 children and adolescents who underwent allo-HSCT for BCR::ABL1-neg MPN between 2000 and 2022 were analysed based on data reported to the EBMT Registry (Table 1). PMF was diagnosed in 33 (78.6%) patients, ET in 3 (7.1%), sAML in 3 (7.1%), post-ET/PV MF in 2 (4.8%), and PV in one (2.4%). There were 25 male (59.5%) and 17 female patients, respectively (40.5%). Median age at diagnosis was 4.5 years (range: 0.1–17.7), at allo-HSCT 6.1 years (range 0.4–18), and the median time from diagnosis to transplantation was 8.4 months (range: 1.2-136.4). At transplantation Lansky’s score below 90 points was found in 9 (23.7%) patients.

Before the start of conditioning regimen 13 (46.4%) had palpable splenomegaly, hemoglobin level 9.0 g/dL (range: 5.9–11.8), leukocytes count 6.3 x 10⁹/L (range: 1.1–25.6), and platelets count 110.5 x 10⁹/L (range: 1-1505).

Twenty one (50%) children were transplanted from matched sibling donors (MSD), and the remaining 21 (50%) from non-MSD (Table 2). Among 21 patients transplanted from MSD, 17 (81%) underwent HSCT for PMF, 3 (14.3%) for sAML and one (4.8%) patient for ET, while out of 21 patients transplanted from non-MSD, 16 (76.2%) underwent transplantation for PMF, 2 (9.5%) for ET, 2 (9.5%) for post-ET/PV MF and one (4.8%) for PV, respectively. The median age of children transplanted from MSD was 4.6 years (range: 0.1–17.7) at diagnosis and 6.8 years (range: 0.4–18) at transplantation. Among children transplanted from non-MSD the median age at diagnosis was 4.4 years (range: 0.3–16.9), while the median age at transplantation was 5.7 years (range: 0.9–17.7). The Lansky score below 90 points was found in 5 (25%) recipients transplanted from MSD, and in 4 (22%) transplanted from non-MSD.

Twenty (47.6%) patients were transplanted between 2000–2007, and the remaining 22 (52.4%) between 2008–2022 (Table 1). Out of 22 patients who received HSCT between 2008–2022 nineteen (86.3%) underwent transplantation for myelofibrosis [17 (77.3%) for PMF and 2 (9%) for post-ET/PV MF], 2 (9.1%) for ET, and one (4.5%) patient for PV (Table 1). The median age at diagnosis and at HSCT in children transplanted between 2000–2007 was 5.6 years (range: 0.1–17.4) and 8.9 years (range: 0.4–17.6), and those who underwent transplantation between 2008–2022 it was 4.5 years (0.4–17.7) and 5.7 years (range: 0.9–18), respectively. In terms of indications for HSCT between 2000–2007 sixteen (80%) patients were transplanted for PMF, 3 (15%) for sAML, and one (5%) patient for ET, whereas between 2008–2022 seventeen (77.3%) patients underwent transplantation for PMF, 2 (9.1%) for ET, and two (9.1%) for sMF. Pre-transplant Lansky performance status below 90 was found in 9 out of 38 (23.7%) patients with available data, including 5 (27.8%) patients transplanted between 2000–2007, and in 4 (20%) patients transplanted between 2008–2022 (Table 1).

Transplant descriptive analysis

Donor and source of hematopoietic stem cell and conditioning regimen

Twenty one (50%) children were transplanted from matched sibling donor (MSD), 3 from matched non sibling donor (7%), 4 from haploidentical donor (9.5%) including 1 Haplo-CB, and 14 (33.3%) from unrelated donor (UD) including 4 cord blood and 1 double cord blood (Table 2).

Fifteen (71.4%) patients transplanted from MSD and 6 (28.6%) transplanted from non-MSD (p = 0.004) received hematopoietic stem cells (HSC) from bone marrow (BM), whilst peripheral blood (PB) was the source of HSC in 6 (28.6%) recipients undergoing MSD-HSCT and in 9 (42.9%) recipients undergoing transplantation from non-MSD (p = 0.004) (Table 2). Apart from that 6 (28.6%) patients transplanted from non-MSD obtained HSC from cord blood (CB), but no one transplanted from MSD.

Thirty-eight (92.7%) patients received myeloablative conditioning (MAC), and only 3 (7.3%) obtained non-myeloablative, reduced intensity conditioning (RIC) (2 transplanted from MSD, and 1 from non-MSD) (Table 2). Conditioning regimen was chemotherapy-based in 40 (95.2%) patients, whilst FTBIbased was used only in 2 (4.8%) transplanted from non-MSD, including one obtaining FTBI along with busulfan, cyclophosphamide and fludarabine and one obtaining FTBI alone. Busulfan-based regimen was utilized in 29 (69%) patients, including 19 (90.5%) receiving HSC from MSD and 11 (52.4%) transplanted from non-MSD. Treosulfan-based regimen was given exclusively to 8 (19.1%) recipients who underwent non-MSD HSCT.

Among 20 patients transplanted between 2000–2007 busulfan-based regimen was administered in 17 (85%) patients, FluMel for 2 (10%) and TBI for 1 (5%), while in 22 patients transplanted between 2008–2022 busulfan-based regimen was given in 12 (54.5%), treosulfan-based in 8 (36.5%), TBI + BuCyFlu in 1 (4.5%), and CyFlu in 1 (4.5%) (Table 2).

GvHD prophylaxis and grading

Data on GvHD prevention were available in 40 children out of 42 (Table 2). In 37 (92.5%) patients GvHD prevention was based on cyclosporin A (CsA). CsA along with short-course methotrexate (MTX) was administered in 24 (60%) recipients, including 16 (80%) after MSD-HSCT and in 8 (40%) after non-MSD-HSCT. CsA alone was given in 7 (17.5%) patients, among them in 1 (5%) transplanted from MSD and in 6 (30%) transplanted from non-MSD. In 5 (12.5%) recipients CsA was combined with mycophenolate mofetil (MMF), including 1 (5%) undergoing MSD-HSCT and in 4 (20%) who underwent non-MSD HSCT. In vivo T-cell depletion (TCD) was performed in 27 (67.5%) patients, among them in 9 (45%) before transplantation from MSD and in 18 (90%) before transplantation from non-MSD. Complete and detailed data on GvHD prophylaxis for the whole study cohort and according to donor type are presented in Table 2.

Among 18 children with available data on in vivo TCD, who were transplanted between 2000–2007, the anti-thymocyte globulin (ATG) was given in 9 (50%), while out of 22 children transplanted between 2008–2022 ATG was given in 18 (81.8%) (Table 2).

Transplant specific outcomes

Neutrophil and platelet engraftment

The day + 30 and day + 60 cumulative incidence of neutrophil recovery was 76.2% (59.7–86.6) and 85.7% (69.7–93.6), respectively (Table 3). The 60 days incidence of platelet recovery was 78.4% (60.5–88.9), and after 180 days it was 83.8% (66-92.7).

Acute and chronic GvHD

The day + 100 CI of aGvHD II-IV was 35.9% (21.1–50.9), and was lower after MSD-HSCT (20%; 6-39.9) compared to non-MSD-HSCT (52.6%; 27.7–72.6) (p = 0.03). The day + 100 CI of aGvHD III-IV was 10.3% (3.2–22.2) and there was no significant difference between MSD-HSCT (5%; 0.3–21.1) and non-MSD-HSCT (15.8%; 3.7–35.5) (p = 0.27) (Table 4).

The 6-year CI of cGvHD was 16.6% (6.5–30.6), including extensive cGvHD 12.4% (3.6–26.8), which at 6 years from transplantation did not significantly differ in children transplanted from MSD (5.6%; 0.3–23.4) and from non-MSD (19.1%; 4-42.6) (p = 0.32) (Table 4).

With respect to stem cell source, i.e. bone marrow versus other sources, there was no significant difference in terms of the day + 100 incidence of aGvHD II-IV (36.8%; 15.9–58.1 vs 35%; 15.1–55.9) and III-IV (10.5%; 1.7–29 vs 10%; 1.6–27.8) as well as with regard to the 2-year incidence of cGvHD (21.5%; 6.3–42.5 vs 11.7%; 1.7–32.3) and extensive cGvHD (11.1%;1.7–30.4 vs 12.7%; 1.8–34.8) was similar (Table 4).

Non-relapse mortality (NRM)

Seven patients died without evidence of relapse, including 4 patients due to graft failure (13, 32, 74, and 644 days after HSCT) and 3 due to GVHD (62, 102, and 109 days after HSCT) (Table 5).

In the whole study cohort the 6-year CI of NRM was 17.2% (7.4–30.5), while in children transplanted from MSD it was 10.1% (1.6–28.3) and it did not differ significantly from that one in those transplanted from non-MSD (23.8%; 8.3–43.6) (p = 0.22), but it was significantly lower in children obtaining bone marrow (0%) than in those transplanted with hematopoietic stem cell from other sources (35.3%; 14.9–56.5) (p = 0.004) (Table 6, Fig. 1). The 6-year NRM between 2000–2007 (20%; 5.9–40) and between 2008–2022 (13.6%; 3.3–31.3) was not significantly different (Table 6, Fig. 1).

Relapse incidence (RI), progression-free survival (PFS), GvHD-free, relapse-free survival (GRFS), and overall survival (OS)

For the whole study group the 6-year RI was 17.8% (7.7–31.4), the 6-year PFS was 64.9% (47.9–77.6), the 6-year GRFS 49.1% (31.5–64.6), and OS 68.6% (51.1–80.9) (Table 6, Fig. 2) with the median follow-up of 6.8 years (3.2–11.2).

In univariate analysis, the 6-year RI, PFS, GRFS, and OS in children transplanted from MSD in comparison with those transplanted from non-MSD were not significantly different (Table 6; Figs. 3, 4, 5, 6).

In relation to the source of hematopoietic stem cells the 6-year PFS in children obtaining bone marrow (80.1%; 55.2–92.1) was significantly higher than in those obtaining hematopoietic stem cells from other sources (48.4%; 25-68.5) (p = 0.04) (Table 6; Fig. 4), and also the 6-year OS in children receiving bone marrow (83.5%; 56.7–94.5) was significantly higher than in children transplanted with hematopoietic stem cell from their other sources (51.4%; 26.7–71.5) (P = 0.02) (Table 6; Fig. 6).

With regard to the time period between 2000–2007, the 6-year RI was significantly higher (30%; 11.7–50.8) compared to that one between 2008–2022 (4.5%; 0.3–19.5) (p = 0.046) (Table 6; Fig. 3), however, there was no significant difference between these two time periods in terms of the 6-year PFS, the 6-year GRFS, and the 6-year OS (Table 6; Figs. 4, 5, 6).

Comparing the pediatric population with the population of adults the BCR::ABL1-neg MPN are not only much rarer, but also in more than 50% of pediatric patients these neoplasms are triple-negative, i.e. without JAK2 or CALR or MPL mutation, which drive BCR::ABL1-neg MPN in absolute majority of adult patiens [5, 6, 7],

Rarity of BCR::ABL1-neg MPN in children and adolescents severely limits the possibilities to perform clinical studies on these malignancies in pediatric population, and in the consequence, in contrast to adult population, still there are still no established specific diagnostic and prognostic criteria and clear treatment recommendations based on these criteria, including indications for allo-HSCT in pediatric patients suffering from BCR::ABL1-neg MPN [1, 7, 8].

For these reasons there have been no prospective or even retrospective studies on long-term outcomes of allo-HSCT in a representative group of pediatric patients with BCR::ABL1-neg MPN, and the reports published so far on results of allo-HSCT in these patients remain scanty and casuistic [10, 11, 12, 13, 14, 15].

However, this retrospective study on allo-HSCT outcomes in a larger group of children and adolescents transplanted for BCR::ABL1-neg MPN became possible in the EBMT Registry.

To date the study group is the largest cohort of children and adolescents with BCR::ABL1-neg MPN receiving allo-HSCT ever collected and analysed.

Previously, the largest group of children with primary myelofibrosis treated and cured with allo-HSCT was published by Hussain et al. [14]. This cohort consisted of 8 patients less than 2 years of age diagnosed during infancy. However five of these patients have parents with close consanguinity, two of them had a strong family history of infant myelofibrosis with recurrent early childhood deaths, which might suggest a congenital predisposition. Apart from this report there have been several other reports of familial cases of infant myelofibrosis primarily in regions of the world with high degree of consanguinity [12, 20]. All of the familial cases presented at a very young age and had poor outcomes without HSCT. Thus, the cohort described by Hussein et al. [14] seems to be a very specific one not necessarily reflecting the biology and clinics of BCR::ABL1-neg MPN in the whole pediatric population.

Majority of patients from analysed cohort, altogether 38 (90.5%), underwent allo-HSCT for PMF (n = 33; 78.3%) or for sAML (n = 3; 7.1%) or for post-ET/PV MF (n = 2; 4.8%), i.e. for those BCR::ABL1-neg MPN subtypes, which according to experience in adults are related to worst survival and can only be cured with allo-HSCT, which can induce molecular remission and resolution of bone marrow fibrosis [21]. According to retrospective analysis performed on behalf of the CMWP of EBMT among adult patients transplanted for myelofibrosis between 1995–2018 78.2% underwent allo-HSCT for PMF and remaining 21.8% for post-ET/PV MF [22].

Indeed, allo-HSCT can cure a substantial proportion (55%) of adult patients with MPN, post-ET/PV MF and sAML, but is still not universally applicable due to risk of severe toxic, immunological and infectious complications, which leads to therapy-related morbidity and mortality [21, 22].

Therefore, to determine the prognosis and indications for allo-HSCT in adult patients with PMF or post-ET/PV-MF the risk scores taking into account patient-specific risk factors including molecular markers have been developed currently [23, 24, 25]. In contrast, to the date in children and adolescents with PMF or post-ET/PV-MF, the specific prognostic factors were not investigated and in consequence so far there are no the specific pediatric risk-scores allowing establishing indication for allo-HSCT.

The whole study group was characterized by young median age at diagnosis (5.5 years) and at transplantation (6.1 years), by a short median time between diagnosis and transplantation (8.4 months), and by marked predominance of male over female (59.5% vs 40.5%). For comparison, the median age of adults who underwent allo-HSCT for myelofibrosis between 1995–2018 was 57.2 years, 62.8% were male, and the median interval diagnosis-allo-HSCT was 31.1 months [22].. The rate of performance status below 90 in studied children was somewhat lower (23.7%) than in adults (32.5%) in whom it was identified as one of factors associated with worse NRM and OS [22].

Half of the patients from the studied cohort were transplanted from MSD and the second half from non-MSD. Apart from that almost half (47.6%) of patients underwent allo-HSCT between 2000–2007, and only somewhat more than half (52.4%) between 2008–2022. Thus, there was a unique opportunity to compare allo-HSCT outcomes in pediatric patients transplanted for BCR::ABL1-neg MPN from MSD and from non-MSD as well as in those transplanted between 2000–2007 and between 2008–2022.

In terms of donor type, in children transplanted from MSD the diagnosis profile, median age at diagnosis and at transplantation were similar to those observed in children transplanted from non-MSD.

Among differences between these two subpopulations, the Lansky score below 80 points was more commonly found before MSD-HSCT (25%), than before non-MSD-HSCT (5.3%), the median time-period between diagnosis and transplantation was significantly shorter in case of MSD-HSCT (4.9 months) than in case of non-MSD-HSCT (11 months) (p = 0.008), and bone marrow was significantly more frequent source of HSC for MSD-HSCT (71.4%) than for non-MSD-HSCT (28.6%) (p = 0.008). In case of adults transplanted for myelofibrosis the peripheral blood was the predominant source of HSC (in total 88.9%) irrespectively from the donor type [22].

Myeloablative, chemotherapy-based conditioning regimen was given to 92.7% of patients. Between 2000–2007 it was usually busulfan-based regimen (85%) and no one patient obtained treosulfan-based regimen, whereas between 2008–2022 more than one third of patients (36.4%) received treosulfan-based regimen. Only 7.3% of patients were given non-myeloablative regimen. In contrast, as many as 63.1% of adult recipients with myelofibrosis received the reduced intensity conditioning [22].

GvHD prophylaxis was almost exclusively CsA-based. The T-cell depletion in vivo was used in 90% of patients from non-MSD-HSCT group and it was twice as often as in MSD-HSCT group (p = 0.002).

On day + 60 after transplantation the cumulative incidence of neutrophil and platelet recovery was 85.7% and 78.4%, respectively.

Day + 100 incidence of aGvHD grade II-IV was (36%) and was comparable with that one observed in adults transplanted for myelofibrosis (28–35%) [22].

Day + 100 incidence of aGvHD grade II-IV was significantly lower after MSD-HSCT (20.0%) than after non-MSD-HSCT (52.6%), but the rates of aGvHD III-IV, cGvHD and extensive cGvHD after MSD-HSCT and non-MSD-HSCT did not differ significantly.

In the studied cohort of children the overall occurrence of 6y cGvHD (16.6%) and 6y extensive cGvHD (12.4%) was several times lower than those reported by McLornan et al. [22] in adults transplanted for myelofibrosis.

In this pediatric cohort the cumulative incidence of NRM after 6 years was 17.2%, while McLornan et al. (2021) observed 30% NRM after 3 years in adults. Graft failure and GvHD were the most common causes of NRM in children, whereas GvHD and infection in adults. It is worth noting that NRM did not occur at all in children receiving bone marrow.

In addition, in children obtaining bone marrow also the 6-year PFS and the 6-year OS were significantly higher than in children obtaining HSC from other sources, i.e. 80.1% vs 48.4% (p = 0.04) and 83.5% vs 51.4% (p = 0.02), respectively. In contrast, according to McLornan et al. (2021) there was no effect of stem cell source on survival outcomes in adults transplanted for myelofibrosis between 1995–2018.

For the whole study group after 6 years RI was 17.8%, PFS was 64.9%, GRFS 49.1%, and OS 68.6%. For comparison, in the cohort of adults transplanted between 1995–2018 for myelofibrosis studied by McLornan et al. [22] after 3 years RI was 21–24%, RFS was 47–50%, and OS was 55–60%.

Comparing outcomes of allo-HSCT in studied cohort of children in relation to the transplant period, the 6-year RI between 2000–2007 was significantly higher than between 2008–2022 (30% vs 4.5%) (p = 0.046), however, the 6-year PFS, GRFS, and OS – despite the visible trend to be improved - were not significantly different. Also McLornan et al. [22] demonstrated improvements in reductions in relapse risk and in overall survival over time in adults transplanted for myelofibrosis between 1995–2018.

Several limitations of this study can be recognized, including retrospective, registry-based nature of the analysis, small size of the studied cohort of pediatric patients, a lack of data on pretransplant treatment, a lack of data on mutational status, and a lack of comprehensive marrow status data at the time of allo-HSCT.

On the other hand, to date this is the largest and the first one multicenter study on transplant-specific characteristics and outcomes of allo-HSCT for BCR::ABL1-neg MPN in pediatric patients. The follow-up time is long (22 years) and the analysis supports the potentially curative role of allo-HSCT for myelofibrosis in children and adolescents. In addition, the study identifies problems related to as extremely rare neoplasms as the childhood BCR::ABL1-neg MPN are, especially in the context of allo-HSCT. Namely, there is a lack of comprehensive knowledge about molecular biology of pediatric BCR::ABL1-neg MPN and therefore, there is a lack of prognostic factors and prognostic-scores, and in consequence there is a lack of clear indications to assure appropriate pediatric patient selection for allo-HSCT.

Thus, this retrospective analysis indicates the need of prospective studies to establish molecular-based indications for allo-HSCT in children and adolescents suffering from BCR::ABL1-neg MPN, especially from myelofibrosis, and to develop the optimal pretransplant, transplant, and posttransplant allo-HSCT procedures as it takes place in adult patients with these neoplasms [26, 27].

Acknowledgements: The authors thank the principal investigators, the clinical staff, and the data managers from the hematopoietic stem cell transplant centers participating in the study.

Author Contributions: JW conceived and designed the study; JW, RR, HA, RFW, J-HD, RPdL, PS, AB, TS, IB, MGV, BG, R-MH, KG, KP, AS-S, PS, AU, PA, APM, FR, MA, AI, AT, MB and SC provided study patients; J-EG and AD, collected and assembled data; J-EG, AD and JW analyzed the data, interpreted the results and created tables and figures; JW and J-EG wrote the manuscript; all authors contributed to the final version of the manuscript and approved the manuscript.

Competing Interests: The authors declare no competing interests to report.

Data Availability Statement: Data are available on request to the EBMT PDWP.

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Tables are available in the Supplementary Files section.

The authors have declared there is NO conflict of interest to disclose.

Table1.Patientscharacteristics.xlsx
Table 1. Patient characteristics – total and according to donor type (MSD vs non-MSD) and across analysed era (2000-2007 vs 2008-2022). (HSCT, hematopoietic stem cell transplantation; PMF, primary myelofibrosis; ET, essential thrombocythaemia; PV, polycythemia vera; sAML, secondary AML; sMF, secondary myelofibrosis; MSD, matched sibling donor)
Table2.Transplantcharacteristics.xlsx
Table 2. Transplant characteristics – total and according to donor type (MSD vs non-MSD) and across analysed era (2000-2007 vs 2008-2022) (MSD, matched sibling donor; non-MSD, non-matched sibling donor; UD, unrelated dor; CB, cord blood; UCB, unrelated cord blood; BM, bone marrow; PB, peripheral blood; Bu, busulfan; Cy, cyclophosphamide; Flu, fludarabine; Thio, thiothepa; Mel, melphalan; Treo, treosulfan; TBI, total body irradiation; ATG, anti-thymocyte globuline; CSA, cyclosporine A; MFF, mycophenolate mofetil; TACRO, tacrolimus; MTX, methotrexate; PT, post-transplantation; TCD, T-cell depletion; CMV, cytomegalovirus)
Table3.Neutrophilandplateletengraftment.xlsx
Table 3. Neutrophil and platelet engraftment (ANC, absolute neutrophil count)
Table4.UnivariateanalysisofacuteandchronicGvHD.xlsx
Table 4. Univariate analysis of acute and chronic GvHD occurence (HSCT, hematopoietic stem cell transplantation; MPN, myeloproliferative neoplasm; HSC, hematopoietic stem cell; PMF, primary myelofibrosis; MSD, matched sibling donor; non-MSD,, non-matched sibling donor; BM, bone marrow; aGvHD, acute graft versus host disease; cGvHD, chronić graft versus host disease)
Table5.Nonrelapsemortality.xlsx
Table 5. Non-relapse mortality – patient characteristics and causes (PMF, primary myelofibrosis; PV, polycythemia vera; MSD, matched sibling donor; UCB, unrelated cord blood; UD, unrelated donor; PB, peripheral plood; Cy, cyclophosphamide; Flu, fludarabine; Treo, treosulfan; Thio, thiothepa; Bu, busulfan; TBI, total body irradiation; TCD, T-cell depletion; ATG, anti-thymocyte globuline; CSA, cyclosporine A; MTX, methotrexate; MFF, mycophenolate mofetil; TACRO, tacrolimus; aGvHD, acute graft versu host disease)
Table.6.NRMRIPFSGRFSandOS.xlsx
Table 6. Non-relapse mortality (NRM) cumulative incidence, relapse incidence (RI), progression-free survival (PFS), GvHD-free, relapse-free survival (GRFS) and overall survival.(OS). (HSCT, hematopoietic stem cell transplantation; MPN, myeloproliferative neoplasm; PMF, primary myelofibrosis; MSD, matched sibling donor; BM, bone marrow; NRM, non-relapse mortality; RI, relapse incidence; PFS, progression-free survival; GRFS, GvHD-free, relapse-free survival; OS, overall survival)

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Allogeneic HSCT for classical BCR::ABL1-negative myeloproliferative neoplasms in children: the retrospective study of the EBMT Pediatric Diseases WP

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Abstract

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Introduction

Methods

Statistical methods

Ethical aspects

Results

Patient descriptive analysis

Transplant descriptive analysis

Donor and source of hematopoietic stem cell and conditioning regimen

GvHD prophylaxis and grading

Transplant specific outcomes

Neutrophil and platelet engraftment

Acute and chronic GvHD

Non-relapse mortality (NRM)

Relapse incidence (RI), progression-free survival (PFS), GvHD-free, relapse-free survival (GRFS), and overall survival (OS)

Discussion

Declarations

References

Tables

Additional Declarations

Supplementary Files

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Journal Publication

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