Abstract
Allogeneic hematopoietic stem cell transplantation (Allo-HCT) remains the only curative treatment for myelofibrosis (MF). Transplantation in patients with MF is mostly done using a reduced intensity conditioning regimen with calcineurin inhibitors for graft versus host disease (GVHD) prophylaxis. Here we sought to evaluate outcomes of patients who underwent an ex vivo CD34+-selected allo-HCT using myeloablative conditioning (MAC). Twenty-seven patients were included in this retrospective analysis. All patients were conditioned with busulfan, melphalan and fludarabine and antithymocyte globulin to prevent graft rejection. G-CSF mobilized peripheral blood stem cell grafts were depleted of T-cells using immunomagnetic CD34+ selection by CliniMACS device. Median follow-up among survivors was 50.6 months. The estimated 3-year overall survival, relapse free survival and the combined endpoint of GVHD/relapse free survival were 88% (95% CI, 75–100%), 80% (95% CI, 66 to 98%) and 74% (95% CI, 59 to 93%), respectively. The cumulative incidence of grade II-IV acute GVHD at day 100 was 33.3% (95% CI 16.4–51.3%), and two patients suffered chronic GVHD. There were no cases of primary graft failure. However, delayed graft failure occurred in two patients.
We conclude that CD34+ selected allo-HCT with a MAC resulted in high survival rates in this cohort of patients with MF.
INTRODUCTION
Despite the advent of small molecule inhibitors for myelofibrosis (MF) capable of reducing symptom burden and improving quality of life as well improving survival with the use of ruxolitinib, a selective inhibitor of Janus kinase (JAK) 1 and 2 (1), (2), (3), allogeneic hematopoietic stem cell transplantation (allo-HCT) remains the only treatment strategy with curative potential. In the absence of allo-HCT, median survival from diagnosis ranges from 1.3 to 6.67 years in patients with intermediate or high risk disease based on Dynamic International Prognostic Scoring (DIPSS)-Plus (4). However, only a minority of patients with MF are referred for allo-HCT due to concerns for morbidity and non-relapse mortality (NRM).
Reduced intensity conditioning (RIC) has abrogated the negative impact of older age on poor outcomes in patients with MF undergoing allo-HCT in some retrospective studies (5) (6), but high rates of transplant-related toxicity and acute and chronic graft versus host disease (GVHD) persist. Early NRM in particular stands as a major barrier to successful transplant. In a recent Center for International Blood and Marrow Transplant Research (CIBMTR) analysis of 551 patients with MF who underwent allo-HCT including 41% who received RIC, patients with DIPSS-Intermediate-1 or higher disease only experienced a survival advantage over non-HCT strategies after the first year due to high rates of early NRM. GVHD was determined to be the leading cause of death within the first year post-HCT (7), highlighting the need for transplant approaches in MF that reduce post-HCT complications.
Ex-vivo CD34+ positive graft selection has been shown to effectively reduce the rates of GVHD by minimizing infusion of alloreactive T-cells (8) (9). We previously published our experience of patients with acute leukemia (10) (11) and myelodysplastic syndrome (MDS) (12) (13) who underwent ex-vivo CD34+-selected allo-HCT without planned post-transplant immunosuppression. Analyses in these diseases demonstrate comparable survival outcomes to patients who underwent unmodified allo-HCT but with much lower incidence of acute and chronic GVHD. Herein we report outcomes of patients with primary MF or MF evolving from preceding polycythemia vera or essential thrombocythemia (post-PV/ET) who underwent ex-vivo CD34+-selected allo-HCT at a single institution.
MATERIALS AND METHODS
Patients
Adult patients (age ≥18 years) with primary or post-PV/ET MF who underwent ex-vivo CD34+-selected allo-HCT at Memorial Sloan Kettering Cancer Center (MSKCC) between October 2010 and July 2019 were included in this retrospective analysis. Patients were excluded if disease had transformed to acute leukemia at any point. Baseline patient and disease characteristics, prior treatments and clinical outcome data were retrieved from the institutional database. All patients and donors provided written informed consent for treatment. Donor-recipient HLA matching was established using high-resolution DNA sequence-specific oligonucleotide typing for HLA-A, -B, -C, -DQB1 and -DRB1 loci. All patients provided written informed consent for transplantation according to the principles of the Declaration of Helsinki, and transplantation outcome analysis was approved by the MSKCC Institutional Review and Privacy Board.
Ex-vivo T-cell Depletion and Transplantation Procedure
Granulocyte colony-stimulated factor (G-CSF)-mobilized peripheral blood stem cell (PBSC) grafts were depleted of T-cells by positive selection of CD34+ stem cells using the CliniMACS CD34+ Reagent System (Miltenyi Biotech, Gladbach, Germany). All patients received myeloablative conditioning (MAC) using busulfan, melphalan and fludarabine as follows: busulfan 0.8mg/kg/dose q 6hr on days -9 to -7; melphalan 70mg/m2/day on days -6 to -5 and fludarabine 25mg/m2/day on days -6 to -2. Rabbit anti-thymocyte globulin (ATG) was given on days -3 and -2 to prevent graft rejection. No patients received planned post-transplant GVHD prophylaxis. All patients received prophylaxis for sinusoidal obstruction syndrome and opportunistic antimicrobial prophylaxis according to institutional guidelines. All patients received G-CSF beginning on day +7 at a dose of 5 mcg/kg/day subcutaneously until the absolute neutrophil count (ANC) was ≥ 1,000/μL on 3 consecutive days.
Study Definitions
Comorbidities were scored using the Hematopoietic Cell Transplantation Comorbidity Index (HCT-CI) (14). DIPSS-Plus calculated at the time of transplantation was used for disease specific risk stratification (4). Neutrophil engraftment was defined as the first of three consecutive days of an absolute neutrophil count (ANC) ≥500/ul. Platelet engraftment was defined as platelet count ≥ 20,000/ul without transfusion support in the preceding seven days. Primary graft failure was defined as the absence of neutrophil recovery (≥500/ul) by day 28 and delayed graft failure as drop in ANC to <500/ul after primary engraftment occurred. International Working Group for Myelofibrosis Research and Treatment (IWG-MRT) criteria were used to define relapsed disease (15). GVHD was diagnosed clinically and confirmed pathologically whenever possible. The International Bone Marrow Transplant Registry classification guided the acute GVHD grading, except grades A-D were labeled grades I-IV (16). Chronic GVHD was defined according to National Institutes of Health consensus criteria (17), and followed the institutional guidelines for review and adjudication of GVHD (18). Cause of death (COD) was defined according to the CIBMTR/NMDP’s hierarchy (19). GVHD-free/relapse-free survival (GFRS) is a composite endpoint defined as time from transplantation until grade 3–4 acute GVHD, chronic GVHD requiring systemic treatment, relapse, or death by any cause.
Statistical analysis
Overall survival (OS), relapse free survival (RFS) and the composite endpoint of GRFS were estimated using Kaplan-Meier methodology, whereas relapse, NRM and grade II-IV acute GvHD were estimated using cumulative incidence method to account for competing risks. Relapse, death in the absence of relapse, and death in the absence of acute GVHD were considered a competing risk for NRM, relapse, and acute GVHD, respectively. All time to event outcomes were estimated from the date of transplantation. Statistical analyses were completed using R statistical software, version 3.6.0.
RESULTS
Patient and disease characteristics
Twenty-seven consecutive patients were included in this analysis. Baseline patient, donor and disease characteristics are summarized Table 1. The median age at the time of transplant was 61 years (range, 29–70). Twelve patients (44.4%) had primary MF and 23 (85.2%) had intermediate-2 or high-risk MF according to DIPSS-plus scoring system. All but one patient had splenomegaly, including 15 patients with splenomegaly at the time of transplant (55.6%) and 10 patients had underwent previous splenectomy (37.0%). JAK2V617F mutational analysis data was available in all patients and was positive in 19 (70.3%). In 16 patients, results of high-throughput sequencing with a targeted deep sequencing assay (HemePACT) as described previously were available (20); in these patients, Mutation-Enhanced International Prognostic Scoring System 70-plus version 2.0 (MIPSS70-plus v 2.0) was low risk in four patients, intermediate risk in two patients, high risk in eight patients and very high risk in two patients. It should be noted that MIPSS70-plus was not validated in patients with post-PV/ET MF, despite being commonly applied in this population (21) (22). Fifteen patients (55.6%) were treated with a JAK2 inhibitor prior to transplantation. Eighteen patients (66.7%) received an unrelated graft including three mismatched grafts based on high resolution typing (level of mismatch 9/10 [n=1] and 8/10 [n=2]). The median time from diagnosis of MF to HCT was 24 months (range, 2–90) and shorter in post-PV/ET MF (13 months, range 2–82) than in patients with PMF (32 months, range, 7–90).
Table 1.
Patient characteristics
| Characteristics | N. | % | |
|---|---|---|---|
| Male/female | 19/8 | 70.4/29.6 | |
| Age, years, median (range) | ≥60 | 61 (29 – 70) | |
| 15 | 55.6 | ||
| Diagnosis | PMF | 12 | 44.4 |
| Post-PV MF | 3 | 11.1 | |
| Post-ET MF | 12 | 44.4 | |
| DIPSS-Plus at transplant | Intermediate 1 | 4 | 14.8 |
| Intermediate 2 | 20 | 74.1 | |
| High | 3 | 11.1 | |
| JAK2 V617F status | Positive | 19 | 66.7 |
| Negative | 7* | 28.5 | |
| unknown | 1 | 4.8 | |
| Splenomegaly at the time of transplant | Yes | 15 | 55.6 |
| Prior splenectomy | 10 | 37.0 | |
| No | 2 | 7.4 | |
| Fibrosis grade | MF-2 | 4 | 14.8 |
| MF-3 | 23 | 85.2 | |
| Pre-transplant therapy | Any | 22 | 81.5 |
| JAK2 INH | 15 | 55.6 | |
| HCT-CI score | 0 | 11 | 40.7 |
| 1–2 | 10 | 37.0 | |
| ≥3 | 6 | 22.2 | |
| Donor | MRD | 9 | 33.3 |
| MUD | 15 | 55.6 | |
| MMUD | 3 | 11.1 | |
| Stem cell source | PBSC | 27 | 100 |
| CMV status: patient/donor | −/− | 11 | 40.7 |
| −/+ | 3 | 11.1 | |
| +/− | 3 | 11.1 | |
| +/+ | 10 | 37.0 | |
Abbreviations: PMF, primary myelofibrosis; PV, polycythemia vera; ET, essential thrombocythemia; HCT-CI, hematopoietic cell transplantation-comorbidity index; DIPSS, dynamic international prognostic scoring; MRD, matched related donor; MUD, matched unrelated donor; MMUD, mismatched unrelated donor; PBSC, peripheral blood stem cell; CMV, cytomegalovirus
Of the JAK2 nonmutated patients, three had a CALR (calreticulin) mutation and one had a MPL (myeloproliferative leukemia) mutation.
Engraftment
The median CD34+ cell dose was 8.08 × 106/kg (range, 2.68–20.17) and the median CD3+ cells dose was 2.22 × 103/kg (range, 1.01–7.29). Neutrophil engraftment occurred at a median of 11 days (range, 8–14) and platelet engraftment at a median of 24 days (range, 14–81) excluding one patient who failed to engraft platelets. This patient died on post-transplant day 97 from hypoxemic respiratory failure due to diffuse alveolar hemorrhage, alongside multiple other complications. Another patient experienced refractory thrombocytopenia post-HCT complicated by subdural hematoma and achieved platelet engraftment only after splenectomy was performed on day 54.
Two patients experienced delayed graft failure and received stem cell boosts in response. One patient received an unmodified boost administered with ATG on day 593 with subsequent engraftment. The second patient received an ex-vivo CD34+-selected stem cell boost on day 424 for pancytopenia without subsequent improvement in peripheral blood counts. This patient continues to meet criteria for delayed graft failure which is felt to be attributable to persistent splenomegaly and extensive post-transplant, donor-derived clonal hematopoiesis. One patient received an ex-vivo CD34+-selected stem cell boost on day 77 due to persistent thrombocytopenia despite pre-transplant splenectomy. Platelet counts subsequently recovered.
Survival and Non-relapse mortality
With a median follow-up among survivors of 50.6 months, the estimated 3-year OS (Fig I), RFS (Fig II) and GRFS (Fig III) were 88% (95% CI, 75–100%), 80% (95% CI, 66 to 98%) and 74% (95% CI, 59 to 93%), respectively. 3-year NRM was 12.4% (95% CI, 2.9% to 29.3%) (Fig VI). Three patients died during the follow-up period; acute GVHD was the primary cause of death in two patients, and one patient who succumbed to hypoxemic respiratory failure related to diffuse alveolar hemorrhage had ongoing stage IV skin GVHD at the time of death. While a high incidence of infectious complications was noted in this cohort, as detailed in table 2, no patients died of infectious complications, or from relapse.
Figure I. Overall survival post CD34+-selected allo-HCT.
Median follow-up among survivors was 50.63 months. The estimated 1- and 3-year overall survival were 93% (95% CI, 85–100%) and 88% (95% CI, 75–100%), respectively
Figure II. Relapse-free survival post CD34+-selected allo-HCT.
The estimated 1- and 3-year relapse-free survival were 85% (95% CI, 73–100%) and 80% (95% CI, 66–98%), respectively.
Figure III. GVHD/relapse-free survival post CD34+-selected allo-HCT.
The estimated 1- and 3-year GVHD/relapse-free survival were both 74% (95% CI, 59–93%).
Figure VI. Non-relapse mortality post CD34+-selected allo-HCT.
The estimated 1- and 3-year non-relapse mortality was 7.4% (95% CI, 1.2–21.4%) and 12.4% (95% CI, 2.9–29.3%), respectively.
Table 2.
Infectious complications in the first year
| Pathogen | N |
|---|---|
|
| |
| Virus | |
| CMV antigenemia | 9 (42.8) |
| with CMV disease | 0 |
| EBV reactivation | 6 (28.5) |
| with PTLD | 4 (19.0) |
| BK virus reactivation (viuria or viremia) | 11 (52.3) |
| with hemorrhagic cystitis or nephritis | 2 (9.5) |
| HHV-6 viremia without disease | 7 (33.3) |
| RSV pneumonia | 1 (4.7) |
| Adenovirus infection | 2 (9.5) |
| Norovirus infection | 1 (4.7) |
| Bacteria | 5 (23.8) |
| Gram-positive organism | 1 |
| Gram-negative organism | 4 |
| Fungus | 0 |
| CNS toxoplasmosis | 1 (4.7) |
Relapse and salvage treatments
The 3-year cumulative incidence rate of relapse was 7.4% (95% CI, 1.2 to 21.4%) (Fig IV). Three patients relapsed during the follow-up period, including two patients with cytogenetic and/or molecular relapse at three months and nearly five years post-HCT, and a third patient with morphologic relapse six months post-HCT. The two patients who suffered cytogenetic and/or molecular relapse were treated with a hypomethylating agent plus donor lymphocyte infusion (DLI); cytogenetic/molecular disease was successfully cleared in one patient, while minimal molecular disease persists in the second. The patient who suffered morphological relapse is alive without evidence of disease recurrence over five years after second unmodified allo-HCT from the original donor, which was preceded by a failed DLI trial.
Figure IV. Cumulative incidence of relapse post CD34+-selected allo-HCT.
The 1- and 3-year cumulative incidence of relapse post CD34+-selected allo-HCT were both 7.4% (95% CI, 1.2–22.4%).
Six patients were treated with DLIs including three patients who received multiple treatments. The median time to first DLI from transplant was 14.3 months (range, 7.6–26.3). Indications for initial DLI were relapse (n=2), mixed chimerism (n=3), and mixed chimerism with poor immune reconstitution (n=1). Subsequent DLIs were given for relapse in two patients, and for mixed chimerism with poor immune reconstitution in one patient.
Graft-versus-host disease (GVHD)
Acute GVHD, including classic and late onset, developed in 9 patients at a median onset of 50 days (range, 24 to 109). One patient had grade I GVHD, five patients had grade II GVHD, two patients had grade III GVHD and one patient had grade IV GVHD. The cumulative incidence of grade II-IV acute GVHD at day 100 was 33.3% (95% CI 16.4–51.3%, N=9) (Fig V). The organ most frequently affected by acute GVHD was skin (n = 8) followed by the upper gastrointestinal tract (n = 5). Of the 26 patients who survived >100 days, two patients developed late onset acute GVHD and three patients suffered persistent or recurrent acute GVHD.
Figure V. Cumulative incidence of grade II-IV acute GVHD at day 100 post CD34+-selected allo-HCT.
The estimated 100-day incidence of grade II-IV acute GVHD was 33.3% (95% CI, 16.4–51.3%).
In most cases, acute GVHD resolved after topical steroids and oral budesonide; four patients required systemic steroids, mycophenolate mofetil or initiation of calcineurin inhibitor, among other treatment strategies. Acute GVHD therapy and responses are summarized in Table 3. The patient who developed grade IV GVHD had stage IV skin involvement that did not respond to systemic steroids; this patient eventually succumbed to hypoxemic respiratory failure on day +97 with significant contribution from GVHD as noted above. Of note, this patient had received three doses of CMV-specific cytotoxic T-lymphocytes (CTLs) prior to the development of GVHD, though the risk of GVHD from third party donor-derived CTLs in recipients of allo-HCT is felt to be nearly negligible (23). Two additional patients died of GVHD complications.
Table 3.
Acute GVHD.
| Case | Grade | Onset, days* | Sites | Treatment (initial → additional) | Response to initial therapy | Alive/Death |
|---|---|---|---|---|---|---|
| 1 | 3 | 24 | Skin | Topical steroid | Yes | A |
| 2 | 2→3 | 32/101† | Skin, UGI, LGI | Topical steroid, oral budesonide → systemic steroid, tacrolimus, ruxolitinib | No, Persistent | A |
| 3 | 2/1 | 34/151† | Skin | Topical steroid | Yes, Recurrent | A |
| 4 | 2/3 | 37/109† | Skin | Topical steroid → systemic steroid, tacrolimus | Yes, Recurrent | D |
| 5 | 2 | 39 | Skin, UGI | Topical steroid, oral budesonide | Yes | A |
| 6 | 4 | 81 | Skin, UGI | Systemic steroid | No | D |
| 7 | 2 | 91 | UGI | Oral budesonide | Yes | A |
| 8 | 3 | 108† | Skin, UGI, liver | Systemic steroid, tacrolimus, MMF, ECP | No | D |
| 9 | 1 | 109† | Skin | Topical steroid | Yes | A |
Acute GVHD, including classic and late onset, developed in 9 patients at a median onset of 50 days (range, 24 to 109).
Abbreviations: A, alive; D, death; UGI, upper gastrointestinal; LGI, lower gastrointestinal; MMF, mycophenolate mofetil; ECP, extracorporeal photopheresis
days after transplant
three patients additionally suffered persistent acute GVHD (case 2) and recurrent acute GVHD (cases 3 and 4)
two patients suffered late acute GVHD (case 8 and 9)
Only two patients developed chronic GVHD. One patient developed mild ocular chronic GVHD 17 months post-HCT, five months following DLI administration, and did not require systemic treatment. Another patient developed moderate chronic GVHD involving the eyes, skin and liver 27 months post-HCT and eight months after administration of an unmodified stem cell boost with ATG, prophylactic tacrolimus and methotrexate. Treatment included systemic steroids and re-initiation of tacrolimus, which had been tapered off by the time of chronic GHVD development. This patient remains on tacrolimus eight years post-HCT.
Infectious complications
A high incidence of viral reactivation was noted in this cohort with more than 50% of the patients experienced BK infection, followed by CMV reactivation (42.8% and 69% among sero-positive patients), HHV-6 reactivation (33.3%) and EBV reactivation (28.5%) with 4 cases of EBV PTLD. Nine patients (33%) were diagnosed with more than one viral reactivation. Our group previously described the delay in immune reconstitution associated with CD34+ selected allograft, where at 6 months post-transplant the median CD4+ T cell count was 135/mm3 (range 1–1771/mm3) and at 12 months 252/mm3 (range 10–1151/mm3), both below the LLN (359/mm3) (REF: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5454777/). This led to vigilant guidelines of viral PCR monitoring in the first months post CD34+ allo-HCT including CMV, EBV. adenovirus, HHV-6 and toxoplasma in patients who are seropositive and allowed initiation of treatments early, resulting in a complete responses also in cases of EBV PTLD and no cases of mortality related to infectious complications.
DISCUSSION
In this single center retrospective analysis of patients with primary and post-PV/ET MF undergoing ex-vivo CD34+-selected allo-HCT with the use of a chemotherapy-based MAC, we demonstrate promising long-term outcomes and high overall survival with a low incidence of relapse in patients with advanced disease and with relatively low NRM. Taken together, these results suggest that CD34+-selected allo-HSCT following a chemotherapy-based MAC regimen is well-tolerated and an effective treatment for patients with myelofibrosis.
Though a direct comparison cannot be drawn, these results appear to compare favorably to outcomes seen with conventional grafts. CIBMTR registry data of patients undergoing allo-HCT with RIC for myelofibrosis between 2011 and 2017 demonstrate a 3-year OS of 54% ± 2% (24). The rate of NRM in our series also compares favorably with historical controls; a recent European Society for Blood and Marrow Transplantation retrospective analysis of patients with MF undergoing allo-HCT between 2000 – 2016 showed a risk of NRM of 26% at 1 year. In comparison, the estimated 3-year NRM in our series 12.4% (95% CI, 2.9% to 29.3%). Of note, our MAC was chemotherapy-based and did not include total body irradiation, which may partially explain the better outcomes compared with those historically reported with MAC regimens in patients with MF (25) (26). In fact, a recent multicenter analysis of patients with MF transplanted using a RIC or MAC regimen, which included many of the patients in this series, showed better OS in patients conditioned with MAC (27), which stands in contrast to historical data.
We note a higher incidence of acute GVHD compared to our center’s reported outcomes of CD34+ selected allo-HSCT following a MAC regimen in patients with acute leukemia and myelodysplasia (12). Further, GVHD was the primary or major contributing cause in all three patients who suffered NRM in our series. This finding is not unique to our study; in two recent large registry analyses, the leading cause of NRM in patients undergoing allo-HCT for MF was GVHD, followed by infection and organ failure/toxicity (7) (28). This may suggest differences in the biology of the diseases and a more inflammatory milieu in patients with MF. In the current era, most patients undergoing transplantation for MF have been exposed to pre-HCT JAK inhibition; studies of the optimal administration of JAK inhibition peri-transplantation are ongoing and may be one upcoming strategy to mitigate this higher risk of GVHD(29) (30) (31). Despite this higher incidence of acute GVHD, rates of chronic GVHD were quite low with this transplantation strategy as has been seen in other diseases, with only two patients developing chronic GVHD, neither of whom suffered severe disease.
A particular challenge of transplantation of myelofibrosis is poor graft function due to a fibrotic bone marrow and splenomegaly. In our series, no patient suffered primary graft failure and patients overall experienced timely neutrophil engraftment, although one patient failed to engraft platelets and eventually died of transplant complications. Two patients experienced delayed graft failure, one of whom successfully engrafted after receiving a stem cell boost, and two additional patients suffered delayed platelet recovery which improved after post-transplant splenectomy.
Finally, the incidence of relapse was notably low: three patients relapsed during the follow-up period including patients with cytogenetic and molecular relapse only. All three patients were salvaged with further cellular therapy (i.e. DLI or second allo-HCT), suggesting the potential of a strong graft-versus-leukemia effect in this disease.
This study has several limitations; this is a single center, retrospective analysis and patients undergoing this transplantation platform were subject to selection bias based on performance status and comorbidities. MF is a disease characterized by significant clinical heterogeneity, and our sample size is too limited to analyze the impact of disease risk on post-transplantation outcomes. In the recently reported prospective, multicenter study of calcineurin inhibitor-free GVHD prophylaxis (BMT CTN Protocol 1301), patients with acute leukemia or myelodysplasia randomized to receive a CD34+-selected grafts suffered worse overall survival compared to patients receiving tacrolimus/methotrexate or post-transplant cyclophosphamide (PTCy) following bone marrow grafts(9). The lower survival in the CD34+-selected arm was driven by NRM and in particular, infection: 28.6% of deaths that occurred in the CD34+-selected arm were driven by infection, as compared to 3.7% of deaths in the PTCy arm and 13.3% of deaths in the tacrolimus/methotrexate arm. Important differences exist between these findings and our present study. The findings from BMT CTN 1301 trial do not necessarily extend to patients with MF, who were not included in the study. Given the high rates of GVHD-driven mortality historically seen after allo-HCT for MF, GVHD mitigation with CD34+-selection may be particularly helpful in this disease. Further, though infectious complications were seen in our series as outlined in Table 2, none of our patients succumbed to infectious complications. As a representative example, 43% of patients in the present series experienced CMV reactivation, but none suffered from CMV disease. In addition, most of the patients on our study were transplanted prior to the routine use of letermovir prophylaxis, which would be expected to further reduce CMV reactivation. Finally, recent efforts to optimize and personalize dosing strategies of the conditioning agents used in our CD34+-selected platform are expected to further improve transplant outcomes and reduce toxicity(32) (33).
In conclusion, CD34+-selection represents a promising strategy for well selected patients with MF. As increasing numbers of patients with MF are being referred for consideration of allo-HCT, further improving on transplantation outcomes remains a high priority.
Financial disclosures:
This research was supported in part by National Institutes of Health award numbers P01 CA23766 and NIH/NCI Cancer Center Support Grant P30 CA008748. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Footnotes
COI statement: None of the authors has a conflict of interest associated with this publication
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