Mobilized Peripheral Blood Stem Cells Versus Unstimulated Bone Marrow As a Graft Source for T-Cell–Replete Haploidentical Donor Transplantation Using Post-Transplant Cyclophosphamide

Bashey, Asad; Zhang, Mei Jie; McCurdy, Shannon R.; Martin, Andrew St.; Argall, Trevor; Anasetti, Claudio; Ciurea, Stefan O.; Fasan, Omotayo; Gaballa, Sameh; Hamadani, Mehdi; Munshi, Pashna N.; Malki, Monzr M. Al; Nakamura, Ryotaro; O’Donnell, Paul V.; Perales, Miguel Angel; Raj, Kavita; Romee, Rizwan; Rowley, Scott D.; Rocha, Vanderson; Salit, Rachel B.; Solh, Melhem; Soiffer, Robert J.; Fuchs, Ephraim J.; Eapen, Mary

doi:10.1200/jco.2017.72.8428

Cited by 278 publications

(248 citation statements)

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“…The higher risks for acute and chronic GVHD and the absence of a survival advantage with peripheral blood suggest that with the PTCy approach for haplo transplantation, peripheral blood should be reserved for patients at high risk for disease relapse. 20 We observed lower chronic GVHD risks in patients aged 55 to 78 years, independent of donor age, and hypothesize that this is mitigated by higher early mortality in older patients. The rate of early mortality was higher in patients aged 55 to 78 years: it was 25% at 6 months and 40% at 1 year.…”

Section: Discussionmentioning

confidence: 62%

“…In young adults, transplantation of grafts from a parent was associated with higher graft failure rate. Although a thorough examination of immune mediated effects of shared maternal vs paternal antigens 9,19 or priming/tolerizing immune effects of pregnancy in maternal donors [20][21][22][23] is beyond the scope of our study, there were no differences in graft failure rates between maternal and paternal donors. Although siblings were older than offspring donors (44 vs 31 years; P , .0001), we did not observe an effect of donor age or donor-recipient relationship on graft failure.…”

Section: Discussionmentioning

confidence: 91%

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Effect of donor characteristics on haploidentical transplantation with posttransplantation cyclophosphamide

McCurdy

Zhang²,

Martin

et al. 2018

Blood Advances

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Key Points• The effect of donor age on survival is negated by the effect of patient age.• Survival did not differ between sibling and offspring donor transplantation.We studied the association between non-HLA donor characteristics (age, sex, donor- Two-year survival adjusted for CMV seropositivity, disease, and disease risk index was lower in patients aged 55 to 78 years after transplantation of grafts from donors younger than 30 years (53%) or aged at least 30 years (46%) compared with younger patients who received grafts from donors younger than 30 years (61%) and at least 30 years (60%; P , .0001).Similarly, 2-year survival in patients aged 55 to 78 years was lower after transplantation of grafts from siblings (45%) or offspring (48%) compared with patients aged 18 to 54 years after transplantation of grafts from siblings (62%), offspring (58%), and parents (61%; P , .0001). Graft failure was higher after transplantation of grafts from parents (14%) compared with siblings (6%) or offspring (7%; P 5 .02). Other non-HLA donor characteristics were not associated with survival or graft failure. The current analyses suggest patient and disease, rather than non-HLA donor characteristics, predominantly influence survival in adults.

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Section: Discussionmentioning

confidence: 62%

Section: Discussionmentioning

confidence: 91%

Effect of donor characteristics on haploidentical transplantation with posttransplantation cyclophosphamide

McCurdy

Zhang²,

Martin

et al. 2018

Blood Advances

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“…Therefore, platforms that decrease grades III to IV aGVHD without decreasing grade II aGVHD, such as is seen with PTCy-based immunomodulation, may enhance survival after transplant. As such, transplant studies should distinguish grade II aGVHD from grades III to IV aGVHD to avoid lumping the “good” in with the “bad.” Finally, higher graft dose goals, earlier withdrawal of immunosuppression, utilization of PBSCs in high-risk patients [68], and the addition of novel immunotherapeutic post-transplant maintenance strategies to precipitate grade II aGVHD, augment antitumor immunity, and prevent late HLA-loss relapse [69,70] should be explored in this well-tolerated transplant platform.…”

Section: Discussionmentioning

confidence: 99%

Grade II Acute Graft-versus-Host Disease and Higher Nucleated Cell Graft Dose Improve Progression-Free Survival after HLA-Haploidentical Transplant with Post-Transplant Cyclophosphamide

McCurdy

Kanakry

Tsai

et al. 2018

Biology of Blood and Marrow Transplantation

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Compared with standard graft-versus-host disease (GVHD) prophylaxis platforms, post-transplantation cyclophosphamide (PTCy) after T cell-replete HLA-haploidentical (haplo) bone marrow transplantation (BMT) reduces the risk of grades III to IV acute (a) and chronic (c) GVHD, but maintains similar rates of grade II aGVHD. Given that mild GVHD has been associated with reduced treatment failure in HLA-matched BMT, we evaluated the risk factors for and effects of GVHD on survival in 340 adults with hematologic malignancies who engrafted after nonmyeloablative haplo-BMT with PTCy, mycophenolate mofetil, and tacrolimus. The cumulative incidence at 100 days of grade II and grades III to IV aGVHD were 30% (95% confidence interval [CI], 25% to 35%) and 2% (95% CI, 1% to 4%), respectively. The 1-year cumulative incidence of cGVHD was 10% (95% CI, 7% to 13%). In landmark analyses at 100 days, the 4-year probabilities of overall survival (OS) and progression-free survival (PFS) were, 48% (95% CI, 41% to 56%) and 39% (95% CI, 32% to 47%) for patients without grades II to IV aGVHD, compared with 63% (95% CI, 53% to 73%) and 59% (95% CI, 50% to 71%) for patients with grade II aGVHD (P = .05 and P = .009). In multivariable modeling, when compared with patients who never experienced GVHD, the hazard ratio (HR) for OS and PFS in patients with grade II aGVHD was .78 (95% CI, .54 to 1.13; P = .19) and .69 (95% CI, .48 to .98; P = .04). Higher nucleated cell graft dose was also associated with improved OS (HR, .88; 95% CI, .78 to 1.00; P = .05) and PFS (HR, .89; 95% CI, .79 to 1.0; P = .05) and decreased risk of grades III to IV aGVHD (subdistribution HR, .66; 95% CI, .46 to .96; P = .03). PTCy reduces grades III to IV aGVHD and cGVHD, but retains similar incidence of grade II aGVHD, the development of which improves PFS. Higher nucleated cell graft dose goals may also improve survival after nonmyeloablative haplo-BMT with PTCy.

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“…A recent retrospective comparison of bone marrow and peripheral blood BMT with PTCy showed a lower incidence of relapse with peripheral blood grafts, but this did not translate into improved OS [24]. Importantly, these transplantations used standard, long-course IS.…”

Section: Discussionmentioning

confidence: 99%

Shortened-Duration Tacrolimus after Nonmyeloablative, HLA-Haploidentical Bone Marrow Transplantation

Kasamon

Fuchs

Zahurak

et al. 2018

Biology of Blood and Marrow Transplantation

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With post-transplantation cyclophosphamide (PTCy) as graft-versus-host disease (GVHD) prophylaxis, nonmyeloablative HLA-haploidentical (NMA haplo) and HLA-matched blood or marrow transplantation (BMT) have comparable outcomes. Early discontinuation of immunosuppression may reduce the risk of relapse and improve immune reconstitution, but may increase the risk of GVHD. We conducted a prospective trial of NMA haplo BMT for patients with hematologic malignancies (median age, 61 years), evaluating the safety of early discontinuation of tacrolimus. All patients received T cell-replete bone marrow followed by high-dose PTCy, mycophenolate mofetil, and tacrolimus. Tacrolimus was prespecified to stop without taper at day +90, +60, or +120, contingent on having ≥5% donor T cells, no relapse, and no grade II-IV acute or significant chronic GVHD. Safety stopping rules were based on ≥5% graft failure, ≥10% nonrelapse mortality (NRM), or a ≥20% combined incidence of severe acute and chronic GVHD from the tacrolimus stop date through day +180. Of the 47 patients in the day +90 arm, 23 (49%) stopped tacrolimus as planned. Of the 55 patients in the day +60 arm, 38 (69%) stopped as planned. Safety stopping criteria were not met. In both arms, at day +180, the probability of grade II-IV acute GVHD was <40%, that of grade III-IV acute GVHD was <8%, and that of NRM was <5%. The 1-year probabilities of chronic GVHD and NRM were <15% and <10%, respectively, in both arms. The 1-year GVHD-free relapse-free survival was higher in the day 60 arm. Thus, stopping tacrolimus as early as day +60 is feasible and carries acceptable risks after NMA haplo BMT with PTCy. This approach may facilitate post-transplantation strategies for relapse reduction. © 2018 Published by Elsevier Inc. on behalf of the American Society for Blood and Marrow Transplantation.

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Mobilized Peripheral Blood Stem Cells Versus Unstimulated Bone Marrow As a Graft Source for T-Cell–Replete Haploidentical Donor Transplantation Using Post-Transplant Cyclophosphamide

Cited by 278 publications

References 31 publications

Effect of donor characteristics on haploidentical transplantation with posttransplantation cyclophosphamide

Effect of donor characteristics on haploidentical transplantation with posttransplantation cyclophosphamide

Grade II Acute Graft-versus-Host Disease and Higher Nucleated Cell Graft Dose Improve Progression-Free Survival after HLA-Haploidentical Transplant with Post-Transplant Cyclophosphamide

Shortened-Duration Tacrolimus after Nonmyeloablative, HLA-Haploidentical Bone Marrow Transplantation

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