Characterization of engraftment dynamics in myelofibrosis after allogeneic hematopoietic cell transplantation including novel conditioning schemes

Abstract

Introduction: Myelofibrosis (MF) is a rare hematopoietic stem cell disorder progressing to bone marrow (BM) failure or blast phase. Allogeneic hematopoietic cell transplantation (HCT) represents a potentially curative therapy for a limited subset of patients with advanced MF, who are eligible, but engraftment in MF vs. AML is delayed which promotes complications. As determinants of engraftment in MF are incompletely characterized, we studied engraftment dynamics at our center.

Methods: A longitudinal cohort of 71 allogeneic HCT performed 2000-2019 with >50% after 2015 was evaluated.

Results: Median time to neutrophil engraftment ≥0.5x109/l was +20 days post-transplant and associated with BM fibrosis, splenomegaly and infused CD34+ cell number. Engraftment dynamics were similar in primary vs. secondary MF and were independent of MF driver mutations in JAK2, CALR and MPL. Neutrophil engraftment occurred later upon haploidentical HCT with thiotepa-busulfan-fludarabine conditioning, post-transplant cyclophosphamide and G-CSF (TBF-PTCy/G-CSF) administered to 9.9% and 15.6% of patients in 2000-2019 and after 2015, respectively. Engraftment of platelets was similarly delayed, while reconstitution of reticulocytes was not affected.

Conclusions: Since MF is a rare hematologic malignancy, this data from a large number of HCT for MF is essential to substantiate that later neutrophil and platelet engraftment in MF relates both to host and treatment-related factors. Observations from this longitudinal cohort support that novel conditioning schemes administered also to rare entities such as MF, require detailed evaluation in larger, multi-center cohorts to assess also indicators of long-term graft function and overall outcome in patients with this infrequent hematopoietic neoplasm undergoing allogeneic transplantation.

Keywords: allogeneic hematopoietic cell transplantation; engraftment; myelofibrosis; myeloproliferative neoplasms; reconstitution.

Figure 1

Characteristics of myelofibrosis patients undergoing allogeneic hematopoietic cell transplantation (HCT). (A) Subtype of myelofibrosis is indicated as primary myelofibrosis (PMF), post-essential thrombocythemia myelofibrosis (PET-MF), post-polycythemia vera myelofibrosis (PPV-MF) or other (including one patient with unclassifiable myeloproliferative neoplasm and one patient with MDS/MPN overlap syndrome) for the overall time-period 2000-2019 (main chart) and from 2015 onwards (small chart). (B) The frequencies of genetic driver mutations in JAK2, calreticulin (CALR) or the thrombopoietin receptor (MPL) as well as of triple negative cases non-mutated for JAK2, CALR and MPL are indicated for the overall time-period 2000-2019 (main chart) and from 2015 onwards (small chart). n.a. not available. (C) Proportions of the administered conditioning therapies for HCT in MF patients is indicated for the overall time-period 2000-2019 (main chart) and from 2015 onwards (small chart). MAC myeloablative conditioning, RIC reduced-intensity conditioning, TBF-PTCY thiotepa-busulfan-fludarabin conditioning followed by post-transplantation cyclophosphamide.

Figure 2

Time to engraftment in hematopoietic lineages in different time periods. (A) Time to engraftment of neutrophils after hematopoietic cell transplantation (HCT) for myelofibrosis (MF) defined as the first of 3 consecutive days with ≥0.5x10⁹/l neutrophils in peripheral blood is indicated for early (2000-2009), intermediate (2010-2014) and recent (2015-2019) time periods. (B) Time to engraftment of platelets after HCT for MF defined as the first of 3 consecutive days with ≥20x10⁹/l platelets in the absence of transfusions within the 7 preceding days is indicated for early (2000-2009), intermediate (2010-2014) and recent (2015-2019) time periods. (C) Time to red cell engraftment after HCT for MF defined as the first day with ≥30x10⁹/l reticulocytes is indicated for early (2000-2009), intermediate (2010-2014) and recent (2015-2019) time periods. The number of performed HCT in each time period is shown in brackets, patients who failed to engraft the respective lineage are not displayed.

Figure 3

Engraftment dynamics in hematopoietic lineages after first and second hematopoietic cell transplantation (HCT). (A) Proportion of neutrophil engraftment over time is shown for first as compared to second HCT for MF. (B) Time to engraftment of neutrophils in peripheral blood is similar in first and second HCT in MF. (C) Proportion of platelet engraftment over time is shown for first as compared to second HCT for MF. (D) Time to engraftment of platelets in peripheral blood is similar in first and second HCT in MF. (E) Proportion of red cell engraftment over time is shown for first as compared to second HCT for MF. (F) Time to red cell engraftment of platelets in peripheral blood is similar in first and second HCT in MF. Median and individual data points are indicated and compared by student’s t-test with p-values ≤0.05 considered statistically significant (B, D, F). Kaplan-Meier estimates were assessed by log-rank test (A, C, E). ns, non-significant.

Figure 4

Neutrophil engraftment dynamics in association with transplant-related factors in myelofibrosis. (A) Neutrophil engraftment after hematopoietic cell transplantation (HCT) for myelofibrosis (MF) defined as the first of 3 consecutive days with ≥0.5x10⁹/l neutrophils in peripheral blood associates significantly with thiotepa-busulfan-fludarabine conditioning followed by post-transplant cyclophosphamide (TBF-PTCy) as a preparatory regimen of HCT as compared to reduced-intensity (RIC) or myeloablative (MAC) conditioning therapies. (B) Bone marrow (BM) as CD34+ cell source used in a majority of TBF-PTCy haploidentical HCT associates with later neutrophil engraftment. (C) Post-transplant G-CSF, which is administered in all TBF-PTCy haploidentical HCT as well as in a minority of HLA-matched HCT associated with later neutrophil engraftment. Kaplan-Meier estimates were assessed by log-rank test with p-values ≤0.05 considered statistically significant. PBSC, peripheral blood stem cells; G-CSF, granulocyte-colony stimulating factor.

Figure 5

Platelet engraftment dynamics in association with transplant-related factors in myelofibrosis. (A) Platelet engraftment after hematopoietic cell transplantation (HCT) for myelofibrosis (MF) defined as the first of 3 consecutive days with ≥20x10⁹/l platelets in the absence of transfusions within the 7 preceding days associates significantly with thiotepa-busulfan-fludarabine conditioning followed by post-transplant cyclophosphamide (TBF-PTCy) as a preparatory regimen of HCT as compared to reduced-intensity (RIC) or myeloablative (MAC) conditioning therapies. (B) Bone marrow (BM) as CD34+ cell source used in a majority of TBF-PTCy haploidentical HCT associates with later platelet engraftment. (C) Post-transplant G-CSF, which is administered in all TBF-PTCy haploidentical HCT as well as in a minority of HLA-matched HCT associated with later platelet engraftment. Kaplan-Meier estimates were assessed by log-rank test with p-values ≤0.05 considered statistically significant. PBSC, peripheral blood stem cells; G-CSF, granulocyte-colony stimulating factor.

Figure 6

Time to full donor cell chimerism after allogeneic HCT for MF. Impact of selected factors on development of full donor cell chimerism are displayed. Time to 100% donor cell chimerism in peripheral blood did not show significant differences for CD34+ cell source (A) and cell number (B) nor for type of conditioning regimen (C). More extensive bone marrow fibrosis associated with later establishment of full donor cell chimerism (D). HCT, hematopoietic cell transplantation; MF, myelofibrosis.