- Email: [email protected]
Reduced-intensity versus myeloablative allogeneic transplantation
HEMONC 176 19 June 2017 Hematol Oncol Stem Cell Ther (2017) xxx, xxx– xxx
No. of Pages 6, Model 6+
1
Available at www.sciencedirect.com
ScienceDirect
5 6
journal homepage: www.elsevier.com/locate/hemonc
4
Reduced-intensity versus myeloablative allogeneic transplantation
7
Daniel J. Weisdorf
3
8 9
10
University of Minnesota, Department of Medicine, Division of Hematology, Oncology and Transplantation, 420 Delaware Street SE, MMC 480, Minneapolis, MN 55455, United Sates Received 6 February 2017; accepted 28 February 2017
11
19 20 13 21 14 22 15 23 16 24 17 25 18 26
KEYWORDS Conditioning intensity; Graft versus leukemia; Myeloablative; Reduced intensity; Stem cell transplantation
27 28 29 30 35 32 31 33 34
36
37 38 39 40 41 42 43 44
Abstract Allotransplantation cures patients by cytoreduction and the graft-versus-tumor (leukemia; graft-versus-leukemia [GVL]) alloresponse; both eliminate residual disease. The spectrum of conditioning intensity influences toxicities and non-relapse mortality. The spectrum of tumor sensitivity to the GVL response influences relapse. Balancing tolerable toxicities (influenced by patients’ performance status and comorbidities) is also influenced by the graft. Intense immunosuppression (for engraftment and graft-versus-host disease prevention) may constrain the immunologic potency of the graft and limit the antineoplastic capacity of the transplant, thus requiring more intense or more effective conditioning regimens to limit the risks of relapse and permit satisfactory disease-free survival. Ó 2017 King Faisal Specialist Hospital & Research Centre. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-ncnd/4.0/).
Introduction Allotransplantation cures patients by cytoreduction of their residual tumor and by allowing the antineoplastic effects of the graft-versus-tumor (leukemia; graft-versus-leukemia [GVL]) alloresponse to eliminate residual disease. While conditioning intensity has a spectrum which influences transplant toxicities and non-relapse mortality (NRM), there is also a spectrum of tumor sensitivity to the GVL response. Some diseases (chronic myelogenous leukemia, follicular E-mail address: [email protected]
lymphoma, chronic lymphocytic leukemia) are highly GVL responsive and in those situations, a lesser intensity, better tolerated conditioning regimen may suffice. However, other more resistant diseases (advanced acute leukemia, high-risk cytogenetic or molecular phenotype leukemia or even remission leukemias with detectable minimal residual disease) may escape control with even more intense regimens. They may be particularly vulnerable to relapse following reduced-intensity conditioning (RIC) transplantation. This clinical dilemma balancing tolerable toxicities (influenced by patients’ performance status and associated comorbidities) and influenced by the graft source may
http://dx.doi.org/10.1016/j.hemonc.2017.05.002 1658-3876/Ó 2017 King Faisal Specialist Hospital & Research Centre. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Please cite this article in press as: Weisdorf DJ, Reduced-intensity versus myeloablative allogeneic transplantation ..., Hematol Oncol Stem Cell Ther (2017), http://dx.doi.org/10.1016/j.hemonc.2017.05.002
45 46 47 48 49 50 51 52 53 54 55 56
HEMONC 176 19 June 2017
No. of Pages 6, Model 6+
2 57 58 59 60 61 62 63 64 65 66 67 68
69 70
71 72 73
D.J. Weisdorf
require lesser intensity regimens to ensure safety. However, intensive immunosuppression may be required to facilitate engraftment, particularly using umbilical cord blood or mismatched donor grafts. More intense immunosuppression for graft-versus-host disease (GVHD) prophylaxis, including graft T-cell depletion, use of anti-thymocyte globulin or alemtuzumab, may constrain the immunologic potency of the graft, thereby limiting the antineoplastic capacity of the transplant procedure. Particularly in these circumstances, more intense or more effective conditioning regimens must be employed to limit the risks of relapse and yield satisfactory disease-free survival [1].
Myeloablative versus reduced-intensity versus non-myeloablative regimens Consensus discussions reported from the Center for International Blood and Marrow Transplant Research (CIBMTR) have defined myeloablative or high-dose regimens, most often
including single or multiple alkylators and sometimes including total body irradiation (TBI) [2]. These high-dose regimens are called myeloablative because they preclude hematologic recovery in the setting of graft rejection. Additionally, they are profoundly myelosuppressive and thus, induce pancytopenia promptly after transplantation. Nonmyeloablative regimens are less myelosuppressive, although potently immunosuppressive, to facilitate engraftment of matched donor cell infusions, but offer little in antineoplastic potency [3]. Majority of transplants, particularly in older people, are now performed using intermediate intensity or RIC, which generally use lower dose alkylator or even intermediate to low dose TBI. They occasionally are called reduced-toxicity regimens.
Myeloablative regimens Cyclophosphamide and TBI or busulfan plus cyclophosphamide have been the long standing and most commonly
Fig. 1 Increasing utilization of RIC transplantation (CIBMTR); adapted from CIBMTR Summary slides (2015). (A) Allogeneic transplants registered with the CIBMTR. (B) Increasing allogeneic transplant recipients >60 years-of-age. ALL = acute lymphoblastic leukemia; AML = acute myeloid leukemia; CIBMTR = Center for International Blood and Marrow Transplant Research; NHL = nonHodgkin lymphoma; RIC = reduced-intensity conditioning. Please cite this article in press as: Weisdorf DJ, Reduced-intensity versus myeloablative allogeneic transplantation ..., Hematol Oncol Stem Cell Ther (2017), http://dx.doi.org/10.1016/j.hemonc.2017.05.002
74 75 76 77 78 79 80 81 82 83 84 85 86 87
88
89 90
HEMONC 176 19 June 2017
No. of Pages 6, Model 6+
Reduced-intensity versus myeloablative allogeneic transplantation 91 92 93 94 95 96 97 98 99 100 101 102 103
used myeloablative conditioning regimens. Both combine the immunosuppressive, marrow ablative, and hopefully tumor ablative capabilities of each regimen component to yield effective engraftment with tolerable toxicity and disease control. In the last decade, fludarabine plus high-dose alkylators (melphalan or busulfan) have been widely applied as reduced-toxicity myeloablative regimens [4]. While no formal comparative data has defined either a dose or tumor specificity of which alkylator is preferred, their potency in both lymphoid and myeloid neoplastic transplants is well recognized. High-dose cytarabine or etoposide have been added, generally in ablative transplants for myeloid disease, and other agents including fludarabine or cladribine have
Table 1
3
sometimes been substituted for fludarabine in ablative, but usually in reduced-intensity regimens.
RIC regimens
104 105
106
Fludarabine, coupled with low-dose (200 cGy) TBI was the original, widely used non-myeloablative regimen [4]. While extensively tested, it has been recognized that in more resistant disease, relapse rates are excessive. Intermediate-dose alkylators (often busulfan or melphalan) are added to supplement the anti-tumor potency of these RIC regimens. While initial engraftment is also often incomplete and mixed donor chimerism evolves over time to full
Outcomes of myeloablative and RIC transplantation.
Reference
Cohort
N
Relapse
NRM
OS (DFS)
Scott [8]
AML/MDS Randomized
272
48% 14%
4.4% 15.8%
RIC 68% (47% at 18 mo) MAC 77% (68%)
Abdul Wahid [9]
Acute leukemia Meta-analysis 23 reports
15,258
MAC better
RIC better
OS OR 1.00 (.85–1.17) CR superior for RIC Concern re publication bias PFS modestly superior for MAC
Bornhauser [10]
AML CRI 2004–2009
197
=
RIC better > 2 y
Luger [11]
AML/MDS 1997–2004
4772
MAC better
=
=
Marks [12]
ALL CR1, 2, Ph-
1521
=
=
=
Mohty [13]
ALL CR1, 2
576
MAC better
RIC better
=
Ringden [14]
AML 1999–2005
1555
MAC better
=
=
Shimoni [15]
AML
1423
MAC better
RIC better
(31%) @ 10 y (32%)
Flynn [16]
AML/MDS 1990–2003
219
MAC better
=
=
Scott [17]
AML/MDS 1998–2003
150
=
=
=
Lim [18]
AML/MDS 1998–2006
1333
MAC better
RIC better
=
Terwey [19]
AML 1999–2008
202
=
=
=
Bachanova [22]
ALL Ph+ 2000–2009
197
MAC better; for MRD+
RIC better
=
Sibai [20]
Myeloid
248
RIC 26% MAC 14%
=
=
Baron [5]
AML UCB
894
MAC better
RIC better
=
Savani [21]
AML Age > 50 y
1924
=
RIC better
RIC OS (LFS) better
Warlick [6]
AML SIB/URD/UCB
414
= across donor types
MAC better all donors
Note: = indicates no significant difference reported between RIC and MAC. ALL = acute lymphoblastic leukemia; AML = acute myeloid leukemia; CR = complete remission; DFS = disease-free survival; LFS = leukemia-free survival; MAC = myeloablative conditioning; MDS = myelodysplastic syndrome; mo = month; NRM = non-relapse mortality; OS = overall survival; Ph+ = Philadelphia chromosome-positive; RIC = reduced-intensity conditioning; SIB = matched sibling; UCB = umbilical cord blood; URD = unrelated donor; y = year. Note: From ‘‘Comparison of reduced-intensity and myeloablative conditioning regimens for allogeneic hematopoietic stem cell transplantation in patients with acute myeloid leukemia and acute lymphoblastic leukemia: a meta-analysis,” by Wahid et al. [9]. Adapted in part with permission. Please cite this article in press as: Weisdorf DJ, Reduced-intensity versus myeloablative allogeneic transplantation ..., Hematol Oncol Stem Cell Ther (2017), http://dx.doi.org/10.1016/j.hemonc.2017.05.002
107 108 109 110 111 112 113 114
HEMONC 176 19 June 2017
4 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132
133 134
135 136 137 138 139
No. of Pages 6, Model 6+
D.J. Weisdorf
donor chimerism, these regimens have not substantially truncated the risks of GVHD and the accompanying immunologically-based anti-tumor effects. However, RIC regimens have been used more often for older patients and those with comorbidities, thereby making formal comparisons of NRM and relapse confounded by the populations chosen for each treatment. These regimens might be more suited for the highly GVL-sensitive tumors mentioned earlier or the lower risk phenotypes of acute leukemia. Additionally, more recent experience has popularized the use of supplemental therapies to augment the anti-tumor potencies of RIC transplantation. These have included rituximab, or related compounds for CD20+ lymphoid malignancies, CD33 immunotoxins for myeloid disease, tyrosine-kinase inhibitors for chronic myeloid leukemia or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL), and FLT-3 inhibitors for acute leukemia with that mutation.
Adoption of reduced-intensity regimens for transplantation In the last decade, the increases in transplantation for older patients and the widespread application of reduced-inten sity/reduced-toxicity regimens has been remarkable. Particularly for acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), a yearly increase in the number
of transplants has occurred using all available donor types (Fig. 1). Since older patients may often have siblings with medical conditions precluding their suitability as a donor, these have often included alternative donors, either adult volunteer unrelated donors, an increasing of umbilical cord blood transplants [5,6], in the last 5 years in particular, haploidentical transplantation from partially-matched related donors (most often siblings or children of adults) using post-transplant cyclophosphamide as GVHD prophylaxis [7].
Compared efficacy of myeloablative and reduced-intensity transplantation Almost no prospective randomized data has been reported directly comparing ablative and reduced-intensity regimens [8]. Retrospective analysis from the CIBMTR and the EBMT as well as individual or multicenter analyses have described modestly lower NRM for the reduced-intensity regimens, but countered with generally higher relapse rates [9–21] (Table 1). These comparisons are, of course, confounded by the selection habits of applying reduced-intensity regimens to older patients, those with comorbidities or those who are frailer, leaving them more vulnerable to transplant toxicity and mortality. Conversely, good clinical judgment may have selected more patients for reduced-intensity regimens who had more GVL-sensitive phenotypes, less heavilytreated patients, and those with diseases more likely to be
Fig. 2 MA versus RIC transplantation for AML. AML = acute myeloid leukemia; CI = confidence interval; MA = myeloablative; MAC = myeloablative conditioning; mo = month; OS = overall survival; RIC = reduced-intensity conditioning. Note: From ‘‘Results of a phase iii randomized, multi-center study of allogeneic stem cell transplantation after high versus reduced intensity conditioning in patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML): Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 0901,” by Scott et al. [8]. Adapted with permission. Please cite this article in press as: Weisdorf DJ, Reduced-intensity versus myeloablative allogeneic transplantation ..., Hematol Oncol Stem Cell Ther (2017), http://dx.doi.org/10.1016/j.hemonc.2017.05.002
140 141 142 143 144 145 146 147 148
149 150
151 152 153 154 155 156 157 158 159 160 161 162 163 164
HEMONC 176 19 June 2017
No. of Pages 6, Model 6+
Reduced-intensity versus myeloablative allogeneic transplantation 165 166 167 168 169 170 171 172 173 174 175 176 177 178 179 180 181 182 183 184 185 186 187 188 189 190 191 192 193 194 195 196 197 198 199 200 201 202 203 204 205 206 207 208 209 210 211 212 213
214 215 216 217 218 219 220 221 222 223
controlled by the GVL effect of the allograft. As shown in the table, it is difficult to generalize about the comparative benefit of myeloablative versus reduced-intensity transplants for the major diseases where it has been explored, namely AML, MDS and ALL. Most patients with nonHodgkin’s lymphoma or chronic lymphocytic leukemia have been treated with reduced-intensity regimens because of their advanced age and for many, because of a proceeding autologous transplant leaving only those unsuited for autografting or relapsed patients as candidates for allogeneic transplantation (see Fig. 2). A recent prospective randomized trial from the Blood and Marrow Transplant Clinical Trials Network suggests strongly, though not definitively, that myeloablative regimens are preferred for patients with AML [8]. A substantially lower relapse rate was seen in those randomized to the ablative regimens, yielding a survival advantage for those randomized to this cohort. Somewhat surprisingly, no such advantage was seen in patients with MDS who were similarly between myeloablative and reduced-intensity regimens [8]. Relapse rates in those with MDS were identical in the two conditioning intensity cohorts. This confounds any generalization that myeloid disease with favorable features is better treated with pretransplant myeloablative conditioning. Confirmatory data from similar prospective trials is still required before reduced-intensity regimens are deemed inadequate for patients with AML. Subset selection of those with minimal residual disease-negative AML or with favorable cytogenic molecular phenotypes may yield promising outcomes with either regimens, but may be suitable for the somewhat lesser toxicity associated with RIC. Thus, the comparisons of reduced-intensity and myeloablative transplantation remain the subject of continuing intense study. Reduced-intensity transplantation has broadened the applicability of allografting to the older population most commonly affected by the hemologic malignancies treated with allotransplantation and to those whose performance status is also compromised by the comorbidities common in late middle age. Suitable patient selection, aggressive supportive care, and possibly posttransplant therapies including maintenance or consolidation-type therapy may be beneficial to broaden the success and applicability of RIC transplantation. The wisest approach may require tailoring the conditioning regimen to the patient and their disease rather than declaring one regimen intensity as superior. Careful and critical interpretation of future prospective data will refine approaches and improve patient outcomes.
References [1] Gyurkocza B, Sandmaier BM. Conditioning regimens for hematopoietic cell transplantation: one size does not fit all. Blood 2014;124:344–53. [2] Giralt S, Ballen K, Rizzo D, Bacigalupo A, Horowitz M, Pasquini M, et al. Reduced-intensity conditioning regimen workshop: defining the dose spectrum. Report of a workshop convened by the center for international blood and marrow transplant research. Biol Blood Marrow Transplant 2009;15:367–9.
5
[3] Bacigalupo A, Ballen K, Rizzo D, Giralt S, Lazarus H, Ho V, et al. Defining the intensity of conditioning regimens: working definitions. Biol Blood Marrow Transplant 2009;15:1628–33. [4] Storb R, Gyurkocza B, Storer BE, Sorror ML, Blume K, Niederwieser D, et al. Graft-versus-host disease and graftversus-tumor effects after allogeneic hematopoietic cell transplantation. J Clin Oncol 2013;31:1530–8. [5] Baron F, Ruggeri A, Beohou E, Labopin M, Sanz G, Milpied N, et al. RIC versus MAC UCBT in adults with AML: A report from Eurocord, the ALWP and the CTIWP of the EBMT. Oncotarget 2016;7:43027–38. [6] Warlick ED, de Latour RP, Shanley R, Robin M, Bejanyan N, Xhaard A, et al. Allogeneic hematopoietic cell transplant outcomes in acute myeloid leukemia: similar outcomes regardless of donor type. Biol Blood Marrow Transplant 2015;21:357–63. [7] Kasamon YL, Bolan ˜os-Meade J, Prince GT, Tsai HL, McCurdy SR, Kanakry JA, et al. Outcomes of nonmyeloablative HLA-haploidentical blood or marrow transplantation with high-dose post-transplantation cyclophosphamide in older adults. J Clin Oncol 2015;33:3152–61. [8] Pasquini MC, Logan B, Wu J, Devine S, Porter DL, Maziarz RT, et al. Results of a phase III randomized, multi-center study of allogeneic stem cell transplantation after high versus reduced intensity conditioning in patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). Blood 2015;126, LBA–8. [9] Abdul Wahid SF, Ismail NA, Mohd-Idris MR, Jamaluddin FW, Tumian N, Sze-Wei EY, et al. Comparison of reduced-intensity and myeloablative conditioning regimens for allogeneic hematopoietic stem cell transplantation in patients with acute myeloid leukemia and acute lymphoblastic leukemia: a metaanalysis. Stem Cells Dev 2014;23:2535–52. [10] Bornha ¨user M, Kienast J, Trenschel R, Burchert A, Hegenbart U, Stadler M, et al. Reduced-intensity conditioning versus standard conditioning before allogeneic haemopoietic cell transplantation in patients with acute myeloid leukaemia in first complete remission: a prospective, open-label randomised phase 3 trial. Lancet Oncol 2012;13:1035–44. [11] Luger SM, Ringde ´n O, Zhang MJ, Pe ´rez WS, Bishop MR, Bornhauser M, et al. Similar outcomes using myeloablative vs reduced-intensity allogeneic transplant preparative regimens for AML or MDS. Bone Marrow Transplant 2015;47:203–11. [12] Marks DI, Wang T, Pe ´rez WS, Antin JH, Copelan E, Gale RP, et al. The outcome of full-intensity and reduced-intensity conditioning matched sibling or unrelated donor transplantation in adults with Philadelphia chromosome-negative acute lymphoblastic leukemia in first and second complete remission. Blood 2010;116:366–74. [13] Mohty M, Labopin M, Volin L, Gratwohl A, Socie ´ G, Esteve J, et al. Reduced-intensity versus conventional myeloablative conditioning allogeneic stem cell transplantation for patients with acute lymphoblastic leukemia: a retrospective study from the European Group for Blood and Marrow Transplantation. Blood 2010;116:4439–43. [14] Ringde ´n O, Labopin M, Ehninger G, Niederwieser D, Olsson R, Basara N, et al. Reduced intensity conditioning compared with myeloablative conditioning using unrelated donor transplants in patients with acute myeloid leukemia. J Clin Oncol 2009;27:4570–7. [15] 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 reducedintensity conditioning: a report on behalf of the acute leukemia working party of European group for blood and marrow transplantation. J Hematol Oncol 2016;9:118.
Please cite this article in press as: Weisdorf DJ, Reduced-intensity versus myeloablative allogeneic transplantation ..., Hematol Oncol Stem Cell Ther (2017), http://dx.doi.org/10.1016/j.hemonc.2017.05.002
224 225 226 227 228 229 230 231 232 233 234 235 236 237 238 239 240 241 242 243 244 245 246 247 248 249 250 251 252 253 254 255 256 257 258 259 260 261 262 263 264 265 266 267 268 269 270 271 272 273 274 275 276 277 278 279 280 281 282 283 284 285 286 287 288 289 290
HEMONC 176 19 June 2017
6 291 292 293 294 295 296 297 298 299 300 301 302 303 304 305 306 307 308 309
No. of Pages 6, Model 6+
D.J. Weisdorf
[16] Flynn CM, Hirsch B, DeFor T, Barker JN, Miller JS, Wagner JE, et al. Reduced intensity compared with high dose conditioning for allotransplantation in acute myeloid leukemia and myelodysplastic syndrome: a comparative clinical analysis. Am J Hematol 2007;82:867–72. [17] Scott BL, Sandmaier BM, Storer B, Maris MB, Sorror ML, Maloney DG, et al. Myeloablative vs nonmyeloablative allogeneic transplantation for patients with myelodysplastic syndrome or acute myelogenous leukemia with multilineage dysplasia: a retrospective analysis. Leukemia 2006;20:128–35. [18] Lim Z, Brand R, Martino R, van Biezen A, Finke J, Bacigalupo A, et al. Allogeneic hematopoietic stem-cell transplantation for patients 50 years or older with myelodysplastic syndromes or secondary acute myeloid leukemia. J Clin Oncol 2010;28:405–11. [19] Terwey TH, Vega-Ruiz A, Hemmati PG, Martus P, Dietz E, Le Coutre P, et al. NIH-defined graft-versus-host disease after reduced intensity or myeloablative conditioning in patients with acute myeloid leukemia. Leukemia 2012;26:536–42.
[20] Sibai H, Falcone U, Deotare U, Michelis FV, Uhm J, Gupta V, et al. Myeloablative versus reduced-intensity conditioning in patients with myeloid malignancies: a propensity scorematched analysis. Biol Blood Marrow Transplant 2016;22:2270–5. [21] Savani BN, Labopin M, Kro ¨ger N, Finke J, Ehninger G, Niederwieser D, et al. Expanding transplant options to patients over 50 years. Improved outcome after reduced intensity conditioning mismatched-unrelated donor transplantation for patients with acute myeloid leukemia: a report from the Acute Leukemia Working Party of the EBMT. Haematologica 2016;101:773–80. [22] Bachanova V, Marks DI, Zhang MJ, Wang H, de Lima M, Aljurf MD, et al. Ph+ ALL patients in first complete remission have similar survival after reduced intensity and myeloablative allogeneic transplantation: Impact of tyrosine kinase inhibitor and minimal residual disease. Leukemia 2013;28:658–65.
328
Please cite this article in press as: Weisdorf DJ, Reduced-intensity versus myeloablative allogeneic transplantation ..., Hematol Oncol Stem Cell Ther (2017), http://dx.doi.org/10.1016/j.hemonc.2017.05.002
310 311 312 313 314 315 316 317 318 319 320 321 322 323 324 325 326 327
No. of Pages 6, Model 6+
1
Available at www.sciencedirect.com
ScienceDirect
5 6
journal homepage: www.elsevier.com/locate/hemonc
4
Reduced-intensity versus myeloablative allogeneic transplantation
7
Daniel J. Weisdorf
3
8 9
10
University of Minnesota, Department of Medicine, Division of Hematology, Oncology and Transplantation, 420 Delaware Street SE, MMC 480, Minneapolis, MN 55455, United Sates Received 6 February 2017; accepted 28 February 2017
11
19 20 13 21 14 22 15 23 16 24 17 25 18 26
KEYWORDS Conditioning intensity; Graft versus leukemia; Myeloablative; Reduced intensity; Stem cell transplantation
27 28 29 30 35 32 31 33 34
36
37 38 39 40 41 42 43 44
Abstract Allotransplantation cures patients by cytoreduction and the graft-versus-tumor (leukemia; graft-versus-leukemia [GVL]) alloresponse; both eliminate residual disease. The spectrum of conditioning intensity influences toxicities and non-relapse mortality. The spectrum of tumor sensitivity to the GVL response influences relapse. Balancing tolerable toxicities (influenced by patients’ performance status and comorbidities) is also influenced by the graft. Intense immunosuppression (for engraftment and graft-versus-host disease prevention) may constrain the immunologic potency of the graft and limit the antineoplastic capacity of the transplant, thus requiring more intense or more effective conditioning regimens to limit the risks of relapse and permit satisfactory disease-free survival. Ó 2017 King Faisal Specialist Hospital & Research Centre. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-ncnd/4.0/).
Introduction Allotransplantation cures patients by cytoreduction of their residual tumor and by allowing the antineoplastic effects of the graft-versus-tumor (leukemia; graft-versus-leukemia [GVL]) alloresponse to eliminate residual disease. While conditioning intensity has a spectrum which influences transplant toxicities and non-relapse mortality (NRM), there is also a spectrum of tumor sensitivity to the GVL response. Some diseases (chronic myelogenous leukemia, follicular E-mail address: [email protected]
lymphoma, chronic lymphocytic leukemia) are highly GVL responsive and in those situations, a lesser intensity, better tolerated conditioning regimen may suffice. However, other more resistant diseases (advanced acute leukemia, high-risk cytogenetic or molecular phenotype leukemia or even remission leukemias with detectable minimal residual disease) may escape control with even more intense regimens. They may be particularly vulnerable to relapse following reduced-intensity conditioning (RIC) transplantation. This clinical dilemma balancing tolerable toxicities (influenced by patients’ performance status and associated comorbidities) and influenced by the graft source may
http://dx.doi.org/10.1016/j.hemonc.2017.05.002 1658-3876/Ó 2017 King Faisal Specialist Hospital & Research Centre. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Please cite this article in press as: Weisdorf DJ, Reduced-intensity versus myeloablative allogeneic transplantation ..., Hematol Oncol Stem Cell Ther (2017), http://dx.doi.org/10.1016/j.hemonc.2017.05.002
45 46 47 48 49 50 51 52 53 54 55 56
HEMONC 176 19 June 2017
No. of Pages 6, Model 6+
2 57 58 59 60 61 62 63 64 65 66 67 68
69 70
71 72 73
D.J. Weisdorf
require lesser intensity regimens to ensure safety. However, intensive immunosuppression may be required to facilitate engraftment, particularly using umbilical cord blood or mismatched donor grafts. More intense immunosuppression for graft-versus-host disease (GVHD) prophylaxis, including graft T-cell depletion, use of anti-thymocyte globulin or alemtuzumab, may constrain the immunologic potency of the graft, thereby limiting the antineoplastic capacity of the transplant procedure. Particularly in these circumstances, more intense or more effective conditioning regimens must be employed to limit the risks of relapse and yield satisfactory disease-free survival [1].
Myeloablative versus reduced-intensity versus non-myeloablative regimens Consensus discussions reported from the Center for International Blood and Marrow Transplant Research (CIBMTR) have defined myeloablative or high-dose regimens, most often
including single or multiple alkylators and sometimes including total body irradiation (TBI) [2]. These high-dose regimens are called myeloablative because they preclude hematologic recovery in the setting of graft rejection. Additionally, they are profoundly myelosuppressive and thus, induce pancytopenia promptly after transplantation. Nonmyeloablative regimens are less myelosuppressive, although potently immunosuppressive, to facilitate engraftment of matched donor cell infusions, but offer little in antineoplastic potency [3]. Majority of transplants, particularly in older people, are now performed using intermediate intensity or RIC, which generally use lower dose alkylator or even intermediate to low dose TBI. They occasionally are called reduced-toxicity regimens.
Myeloablative regimens Cyclophosphamide and TBI or busulfan plus cyclophosphamide have been the long standing and most commonly
Fig. 1 Increasing utilization of RIC transplantation (CIBMTR); adapted from CIBMTR Summary slides (2015). (A) Allogeneic transplants registered with the CIBMTR. (B) Increasing allogeneic transplant recipients >60 years-of-age. ALL = acute lymphoblastic leukemia; AML = acute myeloid leukemia; CIBMTR = Center for International Blood and Marrow Transplant Research; NHL = nonHodgkin lymphoma; RIC = reduced-intensity conditioning. Please cite this article in press as: Weisdorf DJ, Reduced-intensity versus myeloablative allogeneic transplantation ..., Hematol Oncol Stem Cell Ther (2017), http://dx.doi.org/10.1016/j.hemonc.2017.05.002
74 75 76 77 78 79 80 81 82 83 84 85 86 87
88
89 90
HEMONC 176 19 June 2017
No. of Pages 6, Model 6+
Reduced-intensity versus myeloablative allogeneic transplantation 91 92 93 94 95 96 97 98 99 100 101 102 103
used myeloablative conditioning regimens. Both combine the immunosuppressive, marrow ablative, and hopefully tumor ablative capabilities of each regimen component to yield effective engraftment with tolerable toxicity and disease control. In the last decade, fludarabine plus high-dose alkylators (melphalan or busulfan) have been widely applied as reduced-toxicity myeloablative regimens [4]. While no formal comparative data has defined either a dose or tumor specificity of which alkylator is preferred, their potency in both lymphoid and myeloid neoplastic transplants is well recognized. High-dose cytarabine or etoposide have been added, generally in ablative transplants for myeloid disease, and other agents including fludarabine or cladribine have
Table 1
3
sometimes been substituted for fludarabine in ablative, but usually in reduced-intensity regimens.
RIC regimens
104 105
106
Fludarabine, coupled with low-dose (200 cGy) TBI was the original, widely used non-myeloablative regimen [4]. While extensively tested, it has been recognized that in more resistant disease, relapse rates are excessive. Intermediate-dose alkylators (often busulfan or melphalan) are added to supplement the anti-tumor potency of these RIC regimens. While initial engraftment is also often incomplete and mixed donor chimerism evolves over time to full
Outcomes of myeloablative and RIC transplantation.
Reference
Cohort
N
Relapse
NRM
OS (DFS)
Scott [8]
AML/MDS Randomized
272
48% 14%
4.4% 15.8%
RIC 68% (47% at 18 mo) MAC 77% (68%)
Abdul Wahid [9]
Acute leukemia Meta-analysis 23 reports
15,258
MAC better
RIC better
OS OR 1.00 (.85–1.17) CR superior for RIC Concern re publication bias PFS modestly superior for MAC
Bornhauser [10]
AML CRI 2004–2009
197
=
RIC better > 2 y
Luger [11]
AML/MDS 1997–2004
4772
MAC better
=
=
Marks [12]
ALL CR1, 2, Ph-
1521
=
=
=
Mohty [13]
ALL CR1, 2
576
MAC better
RIC better
=
Ringden [14]
AML 1999–2005
1555
MAC better
=
=
Shimoni [15]
AML
1423
MAC better
RIC better
(31%) @ 10 y (32%)
Flynn [16]
AML/MDS 1990–2003
219
MAC better
=
=
Scott [17]
AML/MDS 1998–2003
150
=
=
=
Lim [18]
AML/MDS 1998–2006
1333
MAC better
RIC better
=
Terwey [19]
AML 1999–2008
202
=
=
=
Bachanova [22]
ALL Ph+ 2000–2009
197
MAC better; for MRD+
RIC better
=
Sibai [20]
Myeloid
248
RIC 26% MAC 14%
=
=
Baron [5]
AML UCB
894
MAC better
RIC better
=
Savani [21]
AML Age > 50 y
1924
=
RIC better
RIC OS (LFS) better
Warlick [6]
AML SIB/URD/UCB
414
= across donor types
MAC better all donors
Note: = indicates no significant difference reported between RIC and MAC. ALL = acute lymphoblastic leukemia; AML = acute myeloid leukemia; CR = complete remission; DFS = disease-free survival; LFS = leukemia-free survival; MAC = myeloablative conditioning; MDS = myelodysplastic syndrome; mo = month; NRM = non-relapse mortality; OS = overall survival; Ph+ = Philadelphia chromosome-positive; RIC = reduced-intensity conditioning; SIB = matched sibling; UCB = umbilical cord blood; URD = unrelated donor; y = year. Note: From ‘‘Comparison of reduced-intensity and myeloablative conditioning regimens for allogeneic hematopoietic stem cell transplantation in patients with acute myeloid leukemia and acute lymphoblastic leukemia: a meta-analysis,” by Wahid et al. [9]. Adapted in part with permission. Please cite this article in press as: Weisdorf DJ, Reduced-intensity versus myeloablative allogeneic transplantation ..., Hematol Oncol Stem Cell Ther (2017), http://dx.doi.org/10.1016/j.hemonc.2017.05.002
107 108 109 110 111 112 113 114
HEMONC 176 19 June 2017
4 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132
133 134
135 136 137 138 139
No. of Pages 6, Model 6+
D.J. Weisdorf
donor chimerism, these regimens have not substantially truncated the risks of GVHD and the accompanying immunologically-based anti-tumor effects. However, RIC regimens have been used more often for older patients and those with comorbidities, thereby making formal comparisons of NRM and relapse confounded by the populations chosen for each treatment. These regimens might be more suited for the highly GVL-sensitive tumors mentioned earlier or the lower risk phenotypes of acute leukemia. Additionally, more recent experience has popularized the use of supplemental therapies to augment the anti-tumor potencies of RIC transplantation. These have included rituximab, or related compounds for CD20+ lymphoid malignancies, CD33 immunotoxins for myeloid disease, tyrosine-kinase inhibitors for chronic myeloid leukemia or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL), and FLT-3 inhibitors for acute leukemia with that mutation.
Adoption of reduced-intensity regimens for transplantation In the last decade, the increases in transplantation for older patients and the widespread application of reduced-inten sity/reduced-toxicity regimens has been remarkable. Particularly for acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), a yearly increase in the number
of transplants has occurred using all available donor types (Fig. 1). Since older patients may often have siblings with medical conditions precluding their suitability as a donor, these have often included alternative donors, either adult volunteer unrelated donors, an increasing of umbilical cord blood transplants [5,6], in the last 5 years in particular, haploidentical transplantation from partially-matched related donors (most often siblings or children of adults) using post-transplant cyclophosphamide as GVHD prophylaxis [7].
Compared efficacy of myeloablative and reduced-intensity transplantation Almost no prospective randomized data has been reported directly comparing ablative and reduced-intensity regimens [8]. Retrospective analysis from the CIBMTR and the EBMT as well as individual or multicenter analyses have described modestly lower NRM for the reduced-intensity regimens, but countered with generally higher relapse rates [9–21] (Table 1). These comparisons are, of course, confounded by the selection habits of applying reduced-intensity regimens to older patients, those with comorbidities or those who are frailer, leaving them more vulnerable to transplant toxicity and mortality. Conversely, good clinical judgment may have selected more patients for reduced-intensity regimens who had more GVL-sensitive phenotypes, less heavilytreated patients, and those with diseases more likely to be
Fig. 2 MA versus RIC transplantation for AML. AML = acute myeloid leukemia; CI = confidence interval; MA = myeloablative; MAC = myeloablative conditioning; mo = month; OS = overall survival; RIC = reduced-intensity conditioning. Note: From ‘‘Results of a phase iii randomized, multi-center study of allogeneic stem cell transplantation after high versus reduced intensity conditioning in patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML): Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 0901,” by Scott et al. [8]. Adapted with permission. Please cite this article in press as: Weisdorf DJ, Reduced-intensity versus myeloablative allogeneic transplantation ..., Hematol Oncol Stem Cell Ther (2017), http://dx.doi.org/10.1016/j.hemonc.2017.05.002
140 141 142 143 144 145 146 147 148
149 150
151 152 153 154 155 156 157 158 159 160 161 162 163 164
HEMONC 176 19 June 2017
No. of Pages 6, Model 6+
Reduced-intensity versus myeloablative allogeneic transplantation 165 166 167 168 169 170 171 172 173 174 175 176 177 178 179 180 181 182 183 184 185 186 187 188 189 190 191 192 193 194 195 196 197 198 199 200 201 202 203 204 205 206 207 208 209 210 211 212 213
214 215 216 217 218 219 220 221 222 223
controlled by the GVL effect of the allograft. As shown in the table, it is difficult to generalize about the comparative benefit of myeloablative versus reduced-intensity transplants for the major diseases where it has been explored, namely AML, MDS and ALL. Most patients with nonHodgkin’s lymphoma or chronic lymphocytic leukemia have been treated with reduced-intensity regimens because of their advanced age and for many, because of a proceeding autologous transplant leaving only those unsuited for autografting or relapsed patients as candidates for allogeneic transplantation (see Fig. 2). A recent prospective randomized trial from the Blood and Marrow Transplant Clinical Trials Network suggests strongly, though not definitively, that myeloablative regimens are preferred for patients with AML [8]. A substantially lower relapse rate was seen in those randomized to the ablative regimens, yielding a survival advantage for those randomized to this cohort. Somewhat surprisingly, no such advantage was seen in patients with MDS who were similarly between myeloablative and reduced-intensity regimens [8]. Relapse rates in those with MDS were identical in the two conditioning intensity cohorts. This confounds any generalization that myeloid disease with favorable features is better treated with pretransplant myeloablative conditioning. Confirmatory data from similar prospective trials is still required before reduced-intensity regimens are deemed inadequate for patients with AML. Subset selection of those with minimal residual disease-negative AML or with favorable cytogenic molecular phenotypes may yield promising outcomes with either regimens, but may be suitable for the somewhat lesser toxicity associated with RIC. Thus, the comparisons of reduced-intensity and myeloablative transplantation remain the subject of continuing intense study. Reduced-intensity transplantation has broadened the applicability of allografting to the older population most commonly affected by the hemologic malignancies treated with allotransplantation and to those whose performance status is also compromised by the comorbidities common in late middle age. Suitable patient selection, aggressive supportive care, and possibly posttransplant therapies including maintenance or consolidation-type therapy may be beneficial to broaden the success and applicability of RIC transplantation. The wisest approach may require tailoring the conditioning regimen to the patient and their disease rather than declaring one regimen intensity as superior. Careful and critical interpretation of future prospective data will refine approaches and improve patient outcomes.
References [1] Gyurkocza B, Sandmaier BM. Conditioning regimens for hematopoietic cell transplantation: one size does not fit all. Blood 2014;124:344–53. [2] Giralt S, Ballen K, Rizzo D, Bacigalupo A, Horowitz M, Pasquini M, et al. Reduced-intensity conditioning regimen workshop: defining the dose spectrum. Report of a workshop convened by the center for international blood and marrow transplant research. Biol Blood Marrow Transplant 2009;15:367–9.
5
[3] Bacigalupo A, Ballen K, Rizzo D, Giralt S, Lazarus H, Ho V, et al. Defining the intensity of conditioning regimens: working definitions. Biol Blood Marrow Transplant 2009;15:1628–33. [4] Storb R, Gyurkocza B, Storer BE, Sorror ML, Blume K, Niederwieser D, et al. Graft-versus-host disease and graftversus-tumor effects after allogeneic hematopoietic cell transplantation. J Clin Oncol 2013;31:1530–8. [5] Baron F, Ruggeri A, Beohou E, Labopin M, Sanz G, Milpied N, et al. RIC versus MAC UCBT in adults with AML: A report from Eurocord, the ALWP and the CTIWP of the EBMT. Oncotarget 2016;7:43027–38. [6] Warlick ED, de Latour RP, Shanley R, Robin M, Bejanyan N, Xhaard A, et al. Allogeneic hematopoietic cell transplant outcomes in acute myeloid leukemia: similar outcomes regardless of donor type. Biol Blood Marrow Transplant 2015;21:357–63. [7] Kasamon YL, Bolan ˜os-Meade J, Prince GT, Tsai HL, McCurdy SR, Kanakry JA, et al. Outcomes of nonmyeloablative HLA-haploidentical blood or marrow transplantation with high-dose post-transplantation cyclophosphamide in older adults. J Clin Oncol 2015;33:3152–61. [8] Pasquini MC, Logan B, Wu J, Devine S, Porter DL, Maziarz RT, et al. Results of a phase III randomized, multi-center study of allogeneic stem cell transplantation after high versus reduced intensity conditioning in patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). Blood 2015;126, LBA–8. [9] Abdul Wahid SF, Ismail NA, Mohd-Idris MR, Jamaluddin FW, Tumian N, Sze-Wei EY, et al. Comparison of reduced-intensity and myeloablative conditioning regimens for allogeneic hematopoietic stem cell transplantation in patients with acute myeloid leukemia and acute lymphoblastic leukemia: a metaanalysis. Stem Cells Dev 2014;23:2535–52. [10] Bornha ¨user M, Kienast J, Trenschel R, Burchert A, Hegenbart U, Stadler M, et al. Reduced-intensity conditioning versus standard conditioning before allogeneic haemopoietic cell transplantation in patients with acute myeloid leukaemia in first complete remission: a prospective, open-label randomised phase 3 trial. Lancet Oncol 2012;13:1035–44. [11] Luger SM, Ringde ´n O, Zhang MJ, Pe ´rez WS, Bishop MR, Bornhauser M, et al. Similar outcomes using myeloablative vs reduced-intensity allogeneic transplant preparative regimens for AML or MDS. Bone Marrow Transplant 2015;47:203–11. [12] Marks DI, Wang T, Pe ´rez WS, Antin JH, Copelan E, Gale RP, et al. The outcome of full-intensity and reduced-intensity conditioning matched sibling or unrelated donor transplantation in adults with Philadelphia chromosome-negative acute lymphoblastic leukemia in first and second complete remission. Blood 2010;116:366–74. [13] Mohty M, Labopin M, Volin L, Gratwohl A, Socie ´ G, Esteve J, et al. Reduced-intensity versus conventional myeloablative conditioning allogeneic stem cell transplantation for patients with acute lymphoblastic leukemia: a retrospective study from the European Group for Blood and Marrow Transplantation. Blood 2010;116:4439–43. [14] Ringde ´n O, Labopin M, Ehninger G, Niederwieser D, Olsson R, Basara N, et al. Reduced intensity conditioning compared with myeloablative conditioning using unrelated donor transplants in patients with acute myeloid leukemia. J Clin Oncol 2009;27:4570–7. [15] 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 reducedintensity conditioning: a report on behalf of the acute leukemia working party of European group for blood and marrow transplantation. J Hematol Oncol 2016;9:118.
Please cite this article in press as: Weisdorf DJ, Reduced-intensity versus myeloablative allogeneic transplantation ..., Hematol Oncol Stem Cell Ther (2017), http://dx.doi.org/10.1016/j.hemonc.2017.05.002
224 225 226 227 228 229 230 231 232 233 234 235 236 237 238 239 240 241 242 243 244 245 246 247 248 249 250 251 252 253 254 255 256 257 258 259 260 261 262 263 264 265 266 267 268 269 270 271 272 273 274 275 276 277 278 279 280 281 282 283 284 285 286 287 288 289 290
HEMONC 176 19 June 2017
6 291 292 293 294 295 296 297 298 299 300 301 302 303 304 305 306 307 308 309
No. of Pages 6, Model 6+
D.J. Weisdorf
[16] Flynn CM, Hirsch B, DeFor T, Barker JN, Miller JS, Wagner JE, et al. Reduced intensity compared with high dose conditioning for allotransplantation in acute myeloid leukemia and myelodysplastic syndrome: a comparative clinical analysis. Am J Hematol 2007;82:867–72. [17] Scott BL, Sandmaier BM, Storer B, Maris MB, Sorror ML, Maloney DG, et al. Myeloablative vs nonmyeloablative allogeneic transplantation for patients with myelodysplastic syndrome or acute myelogenous leukemia with multilineage dysplasia: a retrospective analysis. Leukemia 2006;20:128–35. [18] Lim Z, Brand R, Martino R, van Biezen A, Finke J, Bacigalupo A, et al. Allogeneic hematopoietic stem-cell transplantation for patients 50 years or older with myelodysplastic syndromes or secondary acute myeloid leukemia. J Clin Oncol 2010;28:405–11. [19] Terwey TH, Vega-Ruiz A, Hemmati PG, Martus P, Dietz E, Le Coutre P, et al. NIH-defined graft-versus-host disease after reduced intensity or myeloablative conditioning in patients with acute myeloid leukemia. Leukemia 2012;26:536–42.
[20] Sibai H, Falcone U, Deotare U, Michelis FV, Uhm J, Gupta V, et al. Myeloablative versus reduced-intensity conditioning in patients with myeloid malignancies: a propensity scorematched analysis. Biol Blood Marrow Transplant 2016;22:2270–5. [21] Savani BN, Labopin M, Kro ¨ger N, Finke J, Ehninger G, Niederwieser D, et al. Expanding transplant options to patients over 50 years. Improved outcome after reduced intensity conditioning mismatched-unrelated donor transplantation for patients with acute myeloid leukemia: a report from the Acute Leukemia Working Party of the EBMT. Haematologica 2016;101:773–80. [22] Bachanova V, Marks DI, Zhang MJ, Wang H, de Lima M, Aljurf MD, et al. Ph+ ALL patients in first complete remission have similar survival after reduced intensity and myeloablative allogeneic transplantation: Impact of tyrosine kinase inhibitor and minimal residual disease. Leukemia 2013;28:658–65.
328
Please cite this article in press as: Weisdorf DJ, Reduced-intensity versus myeloablative allogeneic transplantation ..., Hematol Oncol Stem Cell Ther (2017), http://dx.doi.org/10.1016/j.hemonc.2017.05.002
310 311 312 313 314 315 316 317 318 319 320 321 322 323 324 325 326 327