Outcome Improvement Over Time in Reduced Intensity Conditioning Hematopoietic Transplantation: A 20 Years Experience

doi:10.21203/rs.3.rs-2588033/v1

Download PDF

Article

Outcome Improvement Over Time in Reduced Intensity Conditioning Hematopoietic Transplantation: A 20 Years Experience

https://doi.org/10.21203/rs.3.rs-2588033/v1

This work is licensed under a CC BY 4.0 License

Version 1

posted

You are reading this latest preprint version

Background: RIC-alloHSCT had been our standard of care for patients more than 50, with comorbidities or previously transplanted.

Methods: 484 consecutive RIC-alloHSCT were included. GVHD prophylaxis consisted of CsA-MTX(147), CsA-MMF(124), tacro-siro(145) and PTCy-tacro(68).

Results: The median time of overall follow-up in survivors was 8-years (with at least 3-years in all four GVHD prophylaxis groups).Neutrophil and platelet engraftment was longer for PTCy-tacro (p0.0001). CumInc of grade III-IV aGVHD was 17% at 200 days and of moderate-severe cGvHD was 36% at 8-years. GVHD prophylaxis was the only prognostic factor in the MVA(p0.0001). NRM and relapse were 29% and 30%; OS and PFS were 43% and 39% at 8-years. At 3-years, OS was highest in the PTCy-tacro (68%) than in the tacro-siro (61%) and CsA+MTX/MMF (49%) cohorts (P<0.01). In the three groups respectively, the 200-days incidence of grade III-IV aGvHD (6%vs.12%vs.23%) and 3-year moderate-severe cGVHD (8%vs.40%vs.38%) were lower in the PTCY cohort.

Conclusion: This large single institution experience shows the improvement of RIC-alloHSCT over time, mainly due to a better prevention of acute and chronic GVHD. Based on our recent results we strongly support PTCy as the current standard of care since in our hands associates to the best 3-year survival.

Health sciences/Medical research/Stem-cell research

Health sciences/Medical research/Translational research

long-term follow-up

reduced intensity conditioning

post-transplant cyclophosphamide

Allogeneic hematopoietic stem cell transplantation (alloHSCT) is the only curative strategy in patients with various hematologic malignancies [1]. Since the mid-1990s the concept of reduced-intensity conditioning regimen (RIC) [2] was introduced allowing less toxic preparative regimens and a higher expectation of leukemia/lymphoma control through graft versus tumor [3] effects. This effect is based on the alloreactivity of donor immune cells against tumor cells. RIC platforms must provide sufficient immunosuppression to achieve donor T-cell and hematopoietic engraftment with decreased conditioning-related toxicity. This approach however does not necessarily reduce the incidence of GVHD. Of note, RIC protocols extend the use of alloHSCT to older patients as well as younger with comorbidities and/or previously transplanted [4]

During the early 21^st century a plethora of RIC protocols were introduced [5-8]. Among the most common, those based on the combination of fludarabine with melphalan or busulfan [9-12], using various GVHD prophylaxis [13-30]. A detailed review of all the published RIC platforms is outside the scope of this manuscript. In our center, however, we chose fludarabine-busulfan or melphalan for patients with myeloid and lymphoid malignancies, respectively.

Patients treated at our institution constituted prospective sequential cohorts in which conditioning was maintained and, in contrast, the GVHD prophylaxis consisted of four different approaches with the intention to achieve the best prevention of this complication and decrease transplant related mortality.

In the current study we analyze the main outcomes in these consecutive cohorts treated at a single institution. This reflects a real-life experience of the evolution of clinical practice over more than 20-years. We show that there has been a significant progress in this setting and that it is possible to identify the prognostic factors that define good and poor candidates for the procedure. Finally, we analyzed the long-term outcomes in patients alive and progression-free 1-year after RIC-alloHSCT through a landmark-analysis.

Patients

The study is a retrospective analysis of 484 adult patients who received a RIC-alloHSCT from an HLA identical sibling or a 10/10 or 9/10 matched unrelated donor (UD) at our institution from 1999 to 2020. Transplants were performed according to the approved institutional protocols, and all patients signed the informed consent. Exclusion criteria were very poor performance status, severe cardiac and/or respiratory dysfunction, and active infection. Patients with aplasia or non-hematological malignancies were excluded from this report.

Conditioning regimens and Graft versus host disease prophylaxis

All patients received the standard conditioning regimen based on fludarabine (30 mg/m2 (IV), from -8 to -4) and melphalan (70 mg/m2 on day -2 and -1) or oral busulfan (1 mg/kg, 10 doses orally or the equivalent IV, from -6 to -4) [35]. When PTCy was included as GVHD prophylaxis, low-dose thiotepa (3 mg/kg) was added on the first day of standard conditioning to avoid graft failure (36).

GVHD prophylaxis changed over time as follows: a) from 1999 to 2004 cyclosporine A (CsA) plus short course methotrexate (MTX) was used (14-18) with ATG in recipients of a single HLA allele mismatched UD; b) CsA plus mycophenolate mofetil (MMF) (19-22) between 2005 and 2008 (CsA-MTX and MMF were analyzed as the same group); c) from 2009 to 2016 tacrolimus plus sirolimus (tacro-siro) was administered (23-30), first in UD transplants and later regardless of donor type (23) ; d) finally, during 2016 our standard-of-care was changed to post-transplant cyclophosphamide (PTCy,50 mg/kg on +3 and+4), as previously explored in the haploSCT setting (31-32) plus tacrolimus (PTCY-tacro), adding low-dose thiotepa to FB or FM to avoid graft failure (36-37).

Supportive care and definitions

Details of the supportive care and definitions can be found in the supplemental materials.

Statistical methods

Clinical information was obtained through the medical history. SPSS version 26 (IBM, Armonk, NY) and R studio programs (R studio, Boston, MA) were used for statistical analyses. The median time to follow-up and engraftment according to GVHD prophylaxis were compared with the Anova test. Overall survival (OS) was defined as the time from day 0 to death from any cause, and progression-free survival (PFS) was the time from day 0 to progression or death. The KM method was used to calculate the actuarial OS and PFS. The long-rang test was used to evaluate the impact of any variables in OS and PFS, and the Cox-regression was the multivariate analyses method (MVA). Cumulative incidence (CumInc) estimate with competing risk was used to calculate the incidences of acute and chronic GVHD (aGVHD and cGVHD), non-relapse mortality (NRM), and relapse. Competing risks for aGHVD and cGVHD were death for any cause or progression up to 200 days for aGVHD and until the last follow-up for cGvHD. The competing risk for NRM was relapse and for relapse was NRM. The Fine-Gray test was used to evaluate the impact of any variable on NRM or relapse. The variables included in the univariate analysis (UVA) were HCT-CI-age (39), EBMT-risk-score (40), DRI (41), female donor to male patient, lymphoid or myeloid underlying disease, type of donor, GVHD prophylaxis, donor and patient cytomegalovirus IgG serostatus, conditioning regimen and disease status at transplantation. Variables with p<0.2 in the UVA were included in the MVA (variables which had an impact on outcomes in UVA are shown in the supplemental material). However, disease status and patient age are part of the EBMT-score, the DRI and/or the HCT-CI-age and were thus not included separately in the MVA. OS, PFS, NRM, and relapse were calculated at 100 days, 3-years, and 8-years of follow-up. aGVHD was determined at two different times (100 and 200 days), and cGVHD was calculated at the end of follow-up. For late complications and secondary malignancies, a landmark-analysis was done selecting survivors with at least 1-year of follow-up.

Patient and donors

The median follow-up in survivors was eight years (range 1-22 years). However, as expected, the median follow-up differed in the consecutive GVHD prophylaxis cohorts; CsA-MTX/MMF groups (N 271, 13-years (range 6-22), tacro-siro (N 145, 6-years (range 1-12), and PTCy-tacro (N 68, 3-years (range 1-6) [p 0.001]. Since analyzing the impact of the introduction of PTCy as GVHD prophylaxis was a major study objective, outcomes were compared at 3-years post-transplant since this the shortest median survival of the GVHD prophylaxis strategies used over time. Patient and donor characteristics are shown in table 1.

Engraftment and early mortality

The overall CumInc of neutrophil (>0.5x10⁹/L) and platelet recoveries (>20x10⁹/L) were 97% and 90% at 30 days. The median time to neutrophil recovery was 17 days (range 10-76) and platelet recovery 14 days (range 6-104), with 54 patients (11%) never reaching a platelet count below 20x10e/L. Primary graft failure occurred in six patients (N 4 in the PTCy-tacro, and one each in CsA-MTX/MMF and tacro-siro cohorts). Five patients died without engraftment recovery (three due to infection, one of veno-occlusive disease, and one relapsed at +29 days).

Patients who received PTCY-tacro as GVHD prophylaxis had much longer times to engraftment; the median time to neutrophil and platelets engraftment was +22 days (range 16-42) and +26 days (range 12-104) while non-PTCY recipients recovered neutrophils at +17 (range 10-76) and platelets at + 15 days (range 6-73) [p 0.0001] (Figure 1). G-CSF was started in those who had < 0.1 x 10⁹/L neutrophils on day +21.

Acute and chronic graft versus host disease

CumInc of grade II-IV and III-IV aGVHD were 25% and 15% at 100 days and 30% and 17% at 200 days, with a median day of onset of 41 days (range 5-200) and 38 days (range 7-200), respectively.

In UVA variables which had a statistically significant impact on the occurrence of grade II-IV and III-IV aGVHD include for the former female donor to male recipient, lymphoid underlying disease, disease status at SCT and the GVHD prophylaxis used (table2); of note the lower 200-day incidence of grade III-IV aGVHD in the PTCY-tacro group (6% vs.12% vs.23%) (table2 and figure2a).

In the MVA variables which impacted on grade II-IV aGVHD were female-to-male (p 0.03, HR:1.5; CI95%: 1.04-2.18), lymphoid vs myeloid underlying disease (p 0.03, HR:1.4; CI95%: 1.04-2), while GVHD prophylaxis with PTCY-tacro reduced the risk (p 0.03, HR:0.7; CI95%: 0.6-0.9). In addition, PTCY-tacro as GVHD prophylaxis was the only variable protective for grade III-IV aGVHD in MVA (p 0.0001; HR:0.5; CI95%: 0.3-0.7).

The CumInc of overall and moderate-severe cGVHD were 48% and 36%, respectively (the median month of onset of cGvHD was 6 months (range 2-135). In UVA variables which impacted moderate-severe cGVHD (table2) were female-to-male, myeloid underlying disease and GVHD prophylaxis other than PTCy-tacro. In MVA variables which protected against moderate-severe cGVHD were lymphoid vs myeloid underlying disease (p 0.007; HR:0.6; CI 95%: 0.4-0.8) and GVHD prophylaxis with PTCy-tacro (p 0.001; HR:0.7; CI 95%: 0.6-0.8); of note the lower 3-year incidence of moderate-severe cGVHD in the PTCY-tacro group (8% vs.40% vs.38%) (table2 and figure2b).

Non-relapse mortality and relapse

The CumInc of NRM was 10% (95%CI; 2-18%) at 100 days, 23% at 3-years (95%CI; 19-27%), and 29% (95%CI; 25-33%) at 8-years (figure 3a). In the UVA (table3), the variables with an impact on NRM were HCT-CI-age (<2), the EBMT-score (<3) (figure 3b), female-to-male, patient CMV serology, disease status at transplant and type of GVHD prophylaxis (table3). In MVA variables with an impact on NRM included HCT-CI-age >3 (p 0.002; HR:1.9; CI95% 1.25 to 2.8), EBMT score >4 (p 0.005; HR:1.7; CI95% 1.2-2.4), donor female to male recipient (p 0.007; HR:1.64; CI95% 1.15-2.4) and positive patient CMV serology (p 0.03; HR:1.7; CI95%, 1.1-2.8).

The causes of NRM according to GVHD prophylaxis are shown in figure4a, although this variable did not show an impact on NRM as of 3-years of follow-up.

The overall CumInc of relapse was 9% (95%CI; 5-11%) at 100 days, 28% (95%CI; 24-32%) at 3-years and 30% (95%CI; 26-34%) at 8 years (figure3c). In the UVA the DRI and response at SCT had an impact on relapse (table3), while only the DRI high-very high (p 0.0001; HR:3; CI95%: 2.1-4.26) was shown as an independent factor in the MVA (figure3d).

Overall survival and progression free survival

OS was 87% (95%CI; 85-89%) at 100 days, 56% (95%CI; 52-57%) at 3-years and 43% (95%CI; 45-49%) at 8-years. The variables with an impact on the 3-year survival in UVA were HCT-CI-age (<2), DRI (low-intermediate), female to male, type of GvHD prophylaxis, first and second CR at SCT, while the EBMT-score showed a trend (<3 vs >4 p 0.09) (table 3). In MVA HCT-CI-age <2 (p 0.021, HR:0.7, CI95%: 0.6-0.9), low-intermediate DRI (p 0.0001, HR:0.6, CI95%: 0.5-0.7), female donor to male recipient (p 0.23, HR:1.4, CI95%: 1.1-1.7) and type of GVHD prophylaxis (negative impact if CsA-MTX/MMF were used; p 0.014, HR:1.7, CI95% 1.1-2.7, with no differences between tacro-siro and PTCy-tacro in the risk of 3-year OS).

The causes of mortality distribution over time are shown in figure4b. Secondary malignancies (SM) were the cause of 13 deaths (4%), nine patients in the CsA-MMF/MTX and four patients in the tacro-siro group.

The PFS was 81% (95%CI; 79-83%) at 100 days, 47% (95%CI; 45-49%) at 3-years and 39% (95%CI; 40-44%) at 8-years. The variables that had an impact on the 3-year PFS in UVA were HCT-CI-age (<2), DRI, female to male recipient, type of GVHD prophylaxis and disease status at SCT (table3), while EBMT-score showed only a trend. In MVA variables with an impact on the 3-year PFS included low-intermediate DRI (p 0.0001, HR:0.5, CI95%: 0.44-0.7) and type of GVHD prophylaxis (with a negative impact of CsA-MTX/MMF vs. other; p 0.005, HR:1.7; CI95%: 1.2-2.7; with no differences between tacro-siro and PTCy-tacro in the risk of 3-year PFS).

LONG TERM COMPLICATIONS

To study late complications, we performed a landmark analysis of patients who were alive and progression-free 1-year post-RIC alloHSCT, considering day 0 as day +365, and the results refer to follow-up which equals days post-transplant -365 days. Three hundred thirty-five patients were included in the 1-year landmark analysis. Late complications which occurred in these patients were identified by review of each patient’s electronic medical records. Only new-onset complications which met the following criteria were included: (i) required surgery; (ii) required long-term medication; (iii) required any hospitalization; (iv) led to any physical disability; and (v) any secondary neoplasm(s). Infectious complications, relapse-related complications and chronic GVHD were not analyzed.

The 7-year landmark probability or CumInc of OS, PFS, NRM, and relapse were 60% (95% CI 57-63%), 56% (95% CI 53-59%), 15% (95% CI 11-19%) and 27% (95% CI 23-31%), respectively. One hundred ninety-seven patients (58%) developed at least one late complication (range 0-7), which occurred at a median of 37 months (range 4-237) beyond 1-year post-HSCT.

The most common complications, and their numbers and frequencies were as follows. Ophthalmological complications occurred in 20% of the patients (n=66), of which 91% consisted of cataracts. Skeletal events were diagnosed in 54 cases (16%), the most common being osteoporosis-related fractures, which represented 74% of these events, followed by 20% of avascular necrosis. Cardiac complications (ischemic heart disease, congestive heart failure or atrial fibrillation) occurred in 45 patients (15%), while new onset metabolic disorders (diabetes, arterial hypertension or hypercholesterolemia) occurred in 38 cases (11%). Liver or gastrointestinal disorders were diagnosed in 25 cases (7.5%), while non-infectious pulmonary complications occurred in 7% (n=22). Other complications included deep vein thrombosis (n=17, 5%), chronic renal failure (n=12, 4%), severe psychosis ((n=9, 3%), and non-GVHD-defining autoimmune disease (n=6, 2%).

A secondary malignancy (SM) developed in 44 patients (13%), of whom seven developed two SMs. The most common SM were solid tumors (n=46, 88%), followed by a hematologic malignancy in 5 cases (12%). The most common solid tumors were skin cancers (n=16), head and neck (n=6), prostate (n=5), colon or stomach (n=5), lung (n=3), gynecologic (n=3), breast (n=2), liver (n=2), pancreatic (n=1) and urinary bladder cancer (n=1).

The current study analyses the outcomes after alloRIC recipients from related or unrelated HLA matched or 1-allele mismatched donors in a single center over a period of more than 20 years. Fludarabine plus alkylating-based conditioning (busulfan or melphalan) was unchanged whereas four approaches for GVHD prophylaxis were used, from the CsA+MTX or MMF to the current PTCy-based strategy. The rates and kinetics of engraftment of neutrophils and platelets were similar to prior studies, with a significant delay with the recent introduction of PTCy [31]. In addition, primary graft failure was more common with PTCY (6%), as reported by the ALWP-EBMT group in the reduced intensity haploSCT setting [42]. As previously reported, we added low dose thiotepa in an effort of reducing the risk of graft failure with PTCy (36).

The results in the overall series of patients with a median follow-up of 8-years among survivors showed an OS of 43% and a PFS of 39%. Although comparisons with registry studies is questionable since our study included all types of underlying diseases and disease status, the survival is similar to that reported with a median follow-up of 8.5-years in patients with AML by the EBMT-ALWP (35% and 32% for OS and PFS) [43] and by the EBMT-CMWP in patient allografted for MDS (27% OS and 21% PFS at 13-years for recipients of HLA-identical sibling donor transplants) [44-45].

The most significant change in the incidences of acute and chronic GVHD during these two decades was seen after the introduction of PTCy-tacro as GVHD prophylaxis. The incidence of grade III-IV aGVHD was only 6% with PTCy-tacro, as opposed to 12% with tacro-siro and 23% with CsA plus either MTX or MMF. In addition, a dramatic reduction of the incidence of moderate-severe cGVHD has occurred, with an incidence of only 6% with PTCy-tacro group as opposed to the historical 40% incidence with all the other GVHD prophylaxes used. In fact, in MVA GVHD prophylaxis was the only independent factor for grade III-IV aGVHD and moderate-severe cGVHD, the use of PTCY-tacro as GVHD prophylaxis. Results from the recently reported BMT CTN 1703 trial in the ASH 2021 meeting (46)) confirm the lower risk of GVHD with PTCy. In this alloRIC trial the day 100 grade III-IV acute GVHD was 6.3% vs 14.7% p=0.001), and chronic GVHD rate at 1-year was 21.9% vs 35.1% (p=0.005) for PTCy vs tacrolimus+MTX, respectively [47].

The lower incidence of GVHD led to lower 3-year NRM and better OS in PTCy recipients with respect to recipients of GVHD prophylaxis with CsA+MTX/MMF, but not those who received tacro-siro prophylaxis. We do not have an explanation for this finding, but reducing the incidence of cGVHD without increasing the risk of relapse is the objective of every transplantation clinician. The impact of cGVHD on the patients’ quality of life is well known, and all efforts need to focus on reducing its incidence. Unfortunately, due to the retrospective nature of our study we do not have data on quality of life measures.

Other variables which have a strong impact on the risk of NRM include the HCT-CI-age scale, the classical EBMT risk score, female donor to male recipient sex combination and the patients’ CMV serostatus. Once again, the disease relapse risk and its status at transplantation were the strongest predictors of post-transplant relapse, as measured by the DRI [38].

Although we did not perform a time-dependent nor risk factor analysis for late onset complications in patients who were alive and disease-free 1 year after alloRIC, we did capture the major complications suffered by all evaluable patients up to their last follow-up. Thus, more than 50% of one-year survivors developed at least one late complication (193/335,58%). Any SM was diagnosed in 44 1-year survivors, of whom 13 had died at las follow-up. The rate of non-skin SM was 28/335 (8.3%). Which appears to be higher than the 1.8% reported in a large EBMT registry study including 220617 recipients of an HSCT, of whom 4065 patients developed a SM [48].

In conclusion, long-term outcomes in alloRIC recipients over the past 20 years in our institution have been especially favourable in patients with a well-controlled underlying disease at transplant (CR or low-intermediate DRI) and in those with few comorbidities (HCT-CI-age). The introduction of PTCy-based GVHD prophylaxis has markedly reduced grade III-IV aGVHD and moderate-severe cGVHD. Finally, long-term follow-up is essential in creating awareness on the high long-term complications these patients have, including SM.

CONFLICT OF INTEREST

The authors declare no conflict of interest.

Authorship statement: A.E. designed the study, performed research, analyzed data, and wrote the manuscript; R.M. and J.S. designed the study and approved the finals version; I.G.C, S.N, A.G, A.C.C, G.O, J.L, S.R, M.A, S.S, C.M and J.B: all authors approved the final version of the manuscript.

ACKNOWLEDGMENTS

This project was funded by "La Marató de TV3" Foundation 2019 41-30, AGAUR 2017 SGR 1395 and 2021 SGR 01139 from the Catalan Government and a grant from “Obra Social La Caixa” Barcelona Spain. PERIS SLT002/16/0043 from the Catalan Government and FIS PI17/01246, PI20/01621 and RD16/0011/0028 from the Instituto de Salud Carlos III, Ministerio de Economía y Competitividad, Spain.

Copelan EA. Hematopoietic stem-cell transplantation. N Engl J Med 2006; 354:1813–1826.

Spyridonidis A, Labopin M, Savani BN, Niittyvuopio R, Blaise D, Craddock C et al. Redefining and measuring transplant conditioning intensity in current era: a study in acute myeloid leukemia patients. Bone Marrow Transplant. 2020 Jun;55(6):1114-1125

Horowitz MM, Gale RP, Sondel PM, Goldman JM, Kersey J, Kolb HJ, et al. Graft-versus-leukemia reactions after bone marrow transplantation. Blood. 1990 Feb 1;75(3):555-62

Nakamura R, Forman SJ Reduced intensity conditioning for allogeneic hematopoietic cell transplantation: considerations for evidence-based GVHD prophylaxis. Expert Rev Hematol. 2014 Jun;7(3):407-21.

Giralt S, Thall PF, Khouri I, Wang X, Braunschweig I, Ippolitti C et al. Melphalan and purine analog-containing preparative regimens: reduced-intensity conditioning for patients with hematologic malignancies undergoing allogeneic progenitor cell transplantation. Blood 2001; 97: 631–637.

Slavin S, Nagler A, Naparstek E, Kapelushnik Y, Aker M, Cividalli G et al. Nonmyeloablative stem cell transplantation and cell therapy as an alternative to conventional bone marrow transplantation with lethal cytoreduction for the treatment of malignant and nonmalignant hematologic diseases. Blood 1998; 91: 756–763.

McSweeney PA, Niederwieser D, Shizuru JA, Sandmaier BM, Molina AJ, Maloney DG et al. Hematopoietic cell transplantation in older patients with hematologic malignancies: replacing highdose cytotoxic therapy with graft-versus-tumor effects. Blood 2001; 97: 3390–3400.

Childs R, Chernoff A, Contentin N, Bahceci E, Schrump D, Leitman S et al. Regression of metastatic renal-cell carcinoma after nonmyeloablative allogeneic peripheral-blood stem-cell transplantation. N Engl J Med 2000; 343: 750–758.

Baron F, Labopin M, Peniket A, Jindra P, Afanasyev B, Sanz MA et al. Reduced-intensity conditioning with fludarabine and busulfan versus fludarabine and melphalan for patients with acute myeloid leukemia: a report from the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation. Cancer. 2015;121:1048–1055.

Damlaj M, Alkhateeb HB, Hefazi M, Partain DK, Hashmi S, Gastineau DA et al. Fludarabine-Busulfan Reduced-Intensity Conditioning in Comparison with Fludarabine-Melphalan Is Associated with Increased Relapse Risk In Spite of Pharmacokinetic Dosing. Biol Blood Marrow Transplant. 2016 Aug;22(8):1431-1439.

Shimoni A, Hardan I, Shem-Tov N, Rand A, Herscovici C, Yerushalmi R et al. Comparison between two fludarabine-based reduced-intensity conditioning regimens before allogeneic hematopoietic stem-cell transplantation: fludarabine/melphalan is associated with higher incidence of acute graft-versus-host disease and non-relapse mortality and lower incidence of relapse than fludarabine/busulfan. Leukemia. 2007 Oct;21(10):2109-16.

Jain T, Alahdab F, Firwana B, Sonbol MB, Almader-Douglas D, Palmer J. Choosing a reduced-intensity conditioning regimen for allogeneic stem cell transplantation, fludarabine/busulfan versus fludarabine melphalan: a systematic review and meta-analysis. Biol Blood Marrow Transplant. 2019;25(4): 728-733.

Zhou Z, Nath R, Cerny J, Wang HL, Zhang MJ, Abdel-Azim H et al. Reduced intensity conditioning for acute myeloid leukemia using melphalan- vs busulfan-based regimens: a CIBMTR report. Blood Adv. 2020 Jul 14;4(13):3180-3190

Storb R, Deeg HJ, Whitehead J, Appelbaum F, Beatty P, Bensinger W et al. Methotrexate and cyclosporine compared with cyclosporine alone for prophylaxis of acute graft versus host disease after marrow transplantation for leukemia. N Engl J Med 1986;314(12):729-35

Ratanatharathorn V, Nash RA, Przepiorka D, Devine SM, Klein JL, Weisdorf D et al. Phase III study comparing methotrexate and tacrolimus (prograf, FK506) with methotrexate and cyclosporine for graft-versus-host disease prophylaxis after HLA-identical sibling bone marrow transplantation. Blood 1998;92(7): 2303-14

Nash RA, Antin JH, Karanes C, Fay JW, Avalos BR, Yeager AM et al. Phase 3 study comparing methotrexate and tacrolimus with methotrexate and cyclosporine for prophylaxis of acute graft-versus-host disease after marrow transplantation from unrelated donors. Blood 2000;96(6):2062-8

Khouri IF, Keating M, Korbling M, Przepiorka D, Anderlini P, O'Brien S et al. Transplant-lite: induction of graft-versus-malignancy using fludarabine-based nonablative chemotherapy and allogeneic blood progenitor-cell transplantation as treatment for lymphoid malignancies. J Clin Oncol 1998;16(8): 2817-24

Oran B, Giralt S, Saliba R, Hosing C, Popat U, Khouri I et al. Allogeneic hematopoietic stem cell transplantation for the treatment of high-risk acute myelogenous leukemia and myelodysplastic syndrome using reduced-intensity conditioning with fludarabine and melphalan. Biol Blood Marrow Transplant 2007;13(4):454-62

Pérez-Simón JA, Martino R, Caballero D, Valcarcel D, Rebollo N, de la Cámara R et al. Reduced-intensity conditioning allogeneic transplantation from unrelated donors: evaluation of mycophenolate mofetil plus cyclosporin A as graft-versus-host disease prophylaxis. Biol Blood Marrow Transplant. 2008 Jun;14(6):664-71.

Mielcarek M, Martin PJ, Leisenring W, Flowers ME, Maloney DG, Sandmaier BM et al. Graft-versus-host disease after nonmyeloablative versus conventional hematopoietic stem cell transplantation. Blood 2003;102(2):756-62

Neumann F, Graef T, Tapprich C, Vaupel M, Steidl U, Germing U et al. Cyclosporine A and Mycophenolate Mofetil vs Cyclosporine A and Methotrexate for graft-versus-host disease prophylaxis after stem cell transplantation from HLA-identical siblings. Bone Marrow Transplant. 2005 Jun;35(11):1089-93

Chhabra S, Liu Y, Hemmer MT, Costa L, Pidala JA, Couriel DR et al. Comparative analysis of calcineurin-inhibitor-based methotrexate and mycophenolate mofetil-containing regimens for prevention of Graft-versus-Host Disease after reduced intensity conditioning allogeneic transplantation. Biol Blood Marrow Transplant. 2019 January ; 25(1): 73–85.

Cutler C, Kim HT, Hochberg E, Ho V, Alyea E, Lee SJ, et al. Sirolimus and tacrolimus without methotrexate as graft-versus-host disease prophylaxis after matched related donor peripheral blood stem cell transplantation. Biol Blood Marrow Transplant.2004;10(5):328-36.

Cutler C, Li S, Ho VT, Koreth J, Alyea E, Soiffer RJ, Antin JH. Extended follow-up of methotrexate-free immunosuppression using sirolimus and tacrolimus in related and unrelated donor peripheral blood stem cell transplantation. Blood. 2007 Apr 1;109(7):3108-14. 6.

Kharfan-Dabaja MA, Parody R, Perkins J, Lopez-Godino O, Lopez-Corral L, Vazquez L. et al. Tacrolimus plus sirolimus with or without ATG as GVHD prophylaxis in HLA-mismatched unrelated donor allogeneic stem cell transplantation. Bone Marrow Transplant. 2017 Mar;52(3):438-444.

Rodriguez R, Nakamura R, Palmer JM, Parker P, Sayani S, Nademanee A et al. A phase II pilot study of tacrolimus/sirolimus GVHD prophylaxis for sibling donor hematopoietic stem cell transplantation using 3 conditioning regimens. Blood 2010;115(5):1098-105

Perez-Simón JA, Martino R, Parody R, Cabrero M, Lopez-Corral L, Valcarcel D. et al. The combination of sirolimus plus tacrolimus improves outcome after reduced-intensity conditioning, unrelated donor hematopoietic stem cell transplantation compared with cyclosporine plus mycofenolate. Haematologica . 2013 Apr;98(4):526-32.

Parody R, Lopez-Corral L, Godino OL, Cadenas IG, Martinez AP, Vazquez L et al. GvHD prophylaxis with tacrolimus plus sirolimus after reduced intensity conditioning allogeneic transplantation: results of a multicenter study. Bone Marrow Transplant. 2016 Nov;51(11):1524-1526.

Snyder DS, Palmer J, Gaal K, Stein AS, Pullarkat V, Sahebi F et al. Improved outcomes using tacrolimus/sirolimus for graft-versus-host disease prophylaxis with a reduced-intensity conditioning regimen for allogeneic hematopoietic cell transplant as treatment of myelofibrosis. Biol Blood Marrow Transplant 2010;16(2):281-6

Nakamura R, Palmer JM, O'Donnell MR, Stiller T, Thomas SH, Chao J et al. Reduced intensity allogeneic hematopoietic stem cell transplantation for MDS using tacrolimus/sirolimus-based GVHD prophylaxis. Leuk Res 2012;36(9): 1152-6.

O’Donnell PV, Luznik L, Jones RJ, Vogelsang GB, Leffell MS, Phelps M et al. Nonmyeloablative bone marrow transplantation from partially HLA-mismatched related donors using posttransplantation cyclophosphamide. Biol Blood Marrow Transplant 2002; 14: 377–386.

Luznik L, O'Donnell PV, Symons HJ, Chen AR, Leffell MS, Zahurak M et al. HLA-haploidentical bone marrow transplantation for hematologic malignancies using nonmyeloablative conditioning and high-dose, posttransplantation cyclophosphamide. Biol Blood Marrow Transplant 2008; 14: 641–650.

Shaw BE, Jimenez-Jimenez AM, Burns LJ, Logan BR, Khimani F, Shaffer BC et al National Marrow Donor Program-Sponsored Multicenter, Phase II Trial of HLA-Mismatched Unrelated Donor Bone Marrow Transplantation Using Post-Transplant Cyclophosphamide. J Clin Oncol. 2021 Jun 20;39(18):1971-1982.

Bolaños-Meade J, Reshef R, Fraser R, Fei M, Abhyankar S, Al-Kadhimi Z et al Three prophylaxis regimens (tacrolimus, mycophenolate mofetil, and cyclophosphamide; tacrolimus, methotrexate, and bortezomib; or tacrolimus, methotrexate, and maraviroc) versus tacrolimus and methotrexate for prevention of graft-versus-host disease with haemopoietic cell transplantation with reduced-intensity conditioning: a randomised phase 2 trial with a non-randomised contemporaneous control group (BMT CTN 1203). Lancet Haematol. 2019 Mar;6(3):e132-e143.

Martino R, Caballero MD, Canals C, Simón JA, Solano C, Urbano-Ispízua A et al. Allogeneic peripheral blood stem cell transplantation with reduced-intensity conditioning: results of a prospective multicentre study. Br J Haematol. 2001 Dec;115(3):653-9

García-Cadenas, R. Awol, A. Esquirol, S. Saavedra, A. Bosch-Vilaseca, S. Novelli et al. Incorporating posttransplant cyclophosphamide-based prophylaxis as standard-of-care outside the haploidentical setting: challenges and review of the literature. Bone Marrow Transplant. 2020 Jun;55(6):1041-1049.

Esquirol A, Pascual MJ, Ortiz M, Piñana JL, Ferra C, Garcia Cadenas I et al. Single-agent GvHD prophylaxis with tacrolimus after post-transplant high-dose cyclophosphamide is a valid option for haploidentical transplantation in adults with hematological malignancies. Bone Marrow Transplant. 2017 Sep;52(9):1273-1279.

Esquirol A, Pascual MJ, Garcia-Cadenas I, Herruzo B, Ferrà C, Pérez A et al. Combining Three Different Pretransplantation Scores Improves Predictive Value in Patients after Haploidentical Stem Cell Transplantation with Thiotepa, Busulfan, and Fludarabine Conditioning and Post-Transplantation Cyclophosphamide. Transplant Cell Ther. 2021 Jul;27(7):614.e1-614e8.

Sorror ML, Storb RF, Sandmaier BM, Maziarz RT, Pulsipher MA, Maris MB et al. Comorbidity-age index: a clinical measure of biologic age before allogeneic hematopoietic cell transplantation. J Clin Oncol. 2014;32:3249–3256.

Gratwohl A. The EBMT risk score. BoneMarrow Transplant. 2012;47:749–756.

Armand P, Kim HT, Logan BR, Wang Z, Alyea EP, Kalaycio ME et al. Validation and refinement of the Disease Risk Index for allogeneic stem cell transplantation. Blood. 2014;123:3664–3671.

Ruggeri A, Labopin M, Angelucci E, Blaise D, Ciceri F, Koc Y et al. Prognostic factors for neutrophil engraftment after haploidentical cell transplantation with PT-Cy in patients with acute myeloid leukemia in complete remission, on behalf of the ALWP-EBMT. Bone Marrow Transplant. 2021 Aug;56(8):1842-1849

Shimoni A, Labopin M, Savani B, Volin L, Ehninger G, Kuball J et al. Long-term survival and late events after allogeneic stem cell transplantation from HLA-matched siblings for acute myeloid leukemia with myeloablative compared to reduced-intensity conditioning: a report on behalf of the acute leukemia working party of European group for blood and marrow transplantation. J Hematol Oncol. 2016 Nov 8;9(1):118.

Martino R, Henseler A, Van Lint M, Schaap N, Finke J, Beelen D et al. Long-term follow-up of a retrospective comparison of reduced-intensity conditioning and conventional high-dose conditioning for allogeneic transplantation from matched related donors in myelodysplastic syndromes. Bone Marrow Transplant. 2017 Aug;52(8):1107-1112.

Scott BL, Pasquini MC, Fei M, Fraser, Wu J, Devine SM et al. Myeloablative versus Reduced-Intensity Conditioning for Hematopoietic Cell Transplantation in Acute Myelogenous Leukemia and Myelodysplastic Syndromes—Long-Term Follow-Up of the BMT CTN 0901 Clinical Trial. Transplant Cell Ther. 2021 Jun;27(6):483.e1-483.e6

Holtan SG, Hamadani M, Wu J, AL Malki MM, Runaas L, Elmariah H et al. Post-Transplant Cyclophosphamide, Tacrolimus, and Mycophenolate Mofetil As the New Standard for Graft-Versus-Host Disease (GVHD) Prophylaxis in Reduced Intensity Conditioning: Results from Phase III BMT CTN 1703. Late breaking abstracts, December 2022. Blood (2022) 140 (Supplement 2): LBA-4.

Wachsmuth LP, Patterson MT, Eckhaus MA, Venzon DJ, Gress RE, and Kanakry CG. Posttransplantation cyclophosphamide prevents graft-versus host disease by inducing alloreactive T cell dysfunction and suppression. J Clin Invest. 2019;129(6):2357-2373

Tichelli A, Beohou E, Labopin M, Socié G, Rovó A, Badoglio M et al Evaluation of Second Solid Cancers After Hematopoietic Stem Cell Transplantation in European Patients. JAMA Oncol. 2019;5(2): 229–235.

Tables 1-3 is available in the Supplementary Files section.

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

table1.xls
Table 1
table2.xls
Table 2
table3.xls
Table 3
onlinesupplementalmaterial.docx
Supplemental materials

Download PDF

Version 1

posted

You are reading this latest preprint version

Outcome Improvement Over Time in Reduced Intensity Conditioning Hematopoietic Transplantation: A 20 Years Experience

Status:

Version 1

Abstract

Figures

Introduction

Patients And Methods

Results

Discussion

Declarations

References

Tables

Additional Declarations

Supplementary Files

Status:

Version 1