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F. Monaco et al.
intensive cytotoxic conditioning regimen has been restricted to relatively young patients, without comorbidi- ties. In order to address these limitations, we designed a non-myeloablative (NMA) regimen specifically for older patients and in those with comorbidities. This regimen consists of fludarabine (FLU) and 200 cGy total body irra- diation (TBI) combined with post-grafting immunosup- pression with mycophenolate mofetil (MMF) and a cal- cineurin inhibitor that facilitates allogeneic HCT with HLA-matched related (MRD) or unrelated donors (URD). Results of prior studies with this regimen have been very encouraging in most hematologic malignancies;2-5 howev- er, in patients with chronic myelomonocytic leukemia (CMML) or previously untreated MDS/MPN, results have not been as successful. In a previous study, the cumulative incidence of HCT failure, defined as graft rejection or dis- ease progression before day 200 after HCT, was 46% for the entire study population, 58% for patients with CMML or MDS with excess blasts (MDS-EB), and 31% for patients with MDS [comprising MDS with single or mul- tilineage dysplasia (MDS-SLD or MDS-MLD), MDS with ring sideroblasts (MDS-RS), MDS, unclassifiable (MDS-U) MDS with <5% blasts], or MPN. The 200-day, 1-year and 2-year probabilities of progression-free survival (PFS) were 27%, 19%, and 11%, respectively, in patients with CMML or MDS-EB, and 46%, 40%, and 37%, respective- ly, in patients with MDS with <5% blasts or MPN.
Furthermore, it was shown that early achievement of full donor T-cell chimerism was associated with a reduced risk of relapse (HR 0.5, P=0.002) in patients with hemato- logic malignancies receiving NMA conditioning.6
Taken together, these data suggest that increasing the intensity of the non-myeloablative conditioning regimen might delay disease progression until establishment of full donor chimerism and development of graft-versus-tumor (GvT) effects, thereby improving outcomes of patients with CMML, untreated MDS, and MPN.
Methods
Study design
A phase II TBI dose escalation trial (Figure 1) was con- ducted at Fred Hutchinson Cancer Research Center, Veterans Affairs Puget-Sound Health Care System, and Intermountain LDS Hospital. The Institutional Review Boards of the participating centers approved the protocol; all patients signed informed consent. An independent Data and Safety Monitoring Board oversaw the trial. The trial was registered at ClinicalTrials.gov, a service of the United States National Institutes of Health under number NCT00397813.
Patients
myelosuppressive chemotherapy (defined as chemothera- py given with the intent of inducing a complete remission; hypomethylating agents and oral cytoreductive therapy were permitted). Patients with CMML who had pro- gressed and received myelosuppressive chemotherapy could be enrolled if they had less than 5% of marrow blasts.
Donors were either HLA-MRD or URD;unrelated donors with only a single allele disparity for HLA-A, B, or C as defined by high-resolution typing were allowed. Only granulocyte-colony stimulating factor (G-CSF) mobilized peripheral blood stem cells (PBSC) were per- mitted as a HCT source.
Conditioning regimens and immune suppression
The conditioning regimens (Figure 2) were FLU (30 mg/m2/day IV) on days -4, -3, -2 and TBI of three magni- tudes: 300 cGy (Level 1), 400 cGy (Level 2), or 450 cGy (Level 3) on day 0 at 6-7 cGy/min from linear accelerator, followed by HCT. For related recipients, graft-versus-host disease (GvHD) prophylaxis included cyclosporine (CSP) 5 mg/kg PO every 12 hours from day -3 to day +56 with subsequent taper to day +180 and mycophenolate mofetil (MMF) at 15 mg/kg PO every 12 hours from day 0 to day +27 and then discontinued. For unrelated recipients, GvHD prophylaxis included CSP 5 mg/kg PO every 12 hours from day -3 to day +100 with taper to day +180 and MMF at 15 mg/kg PO every eight hours from day 0 to day +40 and then tapering to day +96. Growth factors were not given during the first 21 days after HCT; infection pro- phylaxis and transfusion support were as per institutional guidelines. Bone marrow aspirates or biopsies and chimerism analyses were performed on days +28, +56, +84 and +180 after HCT.
Outcomes
The purpose of this study was to evaluate whether a more intense but still NMA conditioning regimen could reduce the combined rates of graft rejection and disease progression (together termed HCT-failure) in this group of MDS and CMML patients, while maintaining an accept- able rate of non-relapse mortality (NRM).
The primary objective was to decrease the incidence of day-200 HCT-failure to <20%. HCT-failure in this study was defined as either progression of the underlying malig- nancy or graft failure. Progression was defined as recur- rence of disease as detected by flow cytometry, morphol- ogy, cytogenetics, or mutation analysis. For patients with myelofibrosis, persistent fibrosis was not considered evi- dence of progression. Graft failure was defined as <5% donor CD3 chimerism in the peripheral blood. Secondary objectives included PFS, NRM, and the kinetics of donor engraftment.
Primary cause of death was adjudicated using previous- ly described criteria.7 When relapse occurred, it was con- sidered the primary cause of death regardless of other events. Additionally, acute and chronic GvHD incidences were also evaluated. Grading of acute and chronic GvHD was performed according to the established recognized standards.8 The first day of acute GvHD of a certain grade was used to calculate cumulative incidence curves for that GvHD grade.
Statistical analysis
For purposes of this study, HCT-failure was defined as
Participants were eligible if they had a World Health Organization defined diagnosis of CMML, MDS, MPN or paroxysmal nocturnal hemoglobinuria (PNH) with history of life-threatening complications.
Patients were ≥50 and <75 years of age or were <50 years of age but at high risk for therapy-related toxicity from standard high-dose regimens; factors considered high risk included pre-existing conditions such as a chron- ic disease affecting kidneys, liver, lungs or heart, or previ- ous failed HCT. Included patients were affected by MDS or MPN with less than 10% of blasts and not treated by
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haematologica | 2019; 104(6)