Accepted Manuscript Title: Autologous Stem Cell Transplantation for Follicular Lymphoma. Favourable Long-Term Survival, Irrespective of Pre-Transplant Rituximab Exposure. Author: Ana Jiménez-Ubieto, Carlos Grande, Dolores Caballero, Lucrecia Yáñez, Silvana Novelli, Miguel Teodoro Hernández-Garcia, María Manzanares, Reyes Arranz, José Javier Ferreiro, Sabella Bobillo, Santiago Mercadal, Andrea Galeo, Javier López Jiménez, José María Moraleda, Carlos Vallejo, Carmen Albo, Elena Pérez, Carmen Marrero, Laura Magnano, Luis Palomera, Isidro Jarque, Pilar Martínez-Sánchez, Alejandro Martín, Erika Coria, Armando López-Guillermo, Antonio Salar, Juan José Lahuerta, GELTAMO (Grupo Español de Linfomas y Trasplantes de Médula Ósea) Cooperative Study Group PII: DOI: Reference:
S1083-8791(17)30468-8 http://dx.doi.org/doi: 10.1016/j.bbmt.2017.05.021 YBBMT 54682
To appear in:
Biology of Blood and Marrow Transplantation
Received date: Accepted date:
30-3-2017 17-5-2017
Please cite this article as: Ana Jiménez-Ubieto, Carlos Grande, Dolores Caballero, Lucrecia Yáñez, Silvana Novelli, Miguel Teodoro Hernández-Garcia, María Manzanares, Reyes Arranz, José Javier Ferreiro, Sabella Bobillo, Santiago Mercadal, Andrea Galeo, Javier López Jiménez, José María Moraleda, Carlos Vallejo, Carmen Albo, Elena Pérez, Carmen Marrero, Laura Magnano, Luis Palomera, Isidro Jarque, Pilar Martínez-Sánchez, Alejandro Martín, Erika Coria, Armando López-Guillermo, Antonio Salar, Juan José Lahuerta, GELTAMO (Grupo Español de Linfomas y Trasplantes de Médula Ósea) Cooperative Study Group, Autologous Stem Cell Transplantation for Follicular Lymphoma. Favourable Long-Term Survival, Irrespective of PreTransplant Rituximab Exposure., Biology of Blood and Marrow Transplantation (2017), http://dx.doi.org/doi: 10.1016/j.bbmt.2017.05.021. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Autologous stem cell transplantation for follicular lymphoma. Favourable long-term survival,
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irrespective of pre-transplant rituximab exposure.
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Authors: Ana Jiménez-Ubieto1*, Carlos Grande1*, Dolores Caballero2, Lucrecia Yáñez3, Silvana
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Novelli4, Miguel Teodoro Hernández-Garcia5, María Manzanares6, Reyes Arranz7, José Javier
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Ferreiro8, Sabella Bobillo9, Santiago Mercadal10, Andrea Galeo11, Javier López Jiménez12, José
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María Moraleda13, Carlos Vallejo14, Carmen Albo15, Elena Pérez16, Carmen Marrero17, Laura
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Magnano18, Luis Palomera19, Isidro Jarque20, Pilar Martínez-Sánchez1, Alejandro Martín2,Erika
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Coria21, Armando López-Guillermo18, Antonio Salar22, and Juan José Lahuerta1, on behalf of the
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GELTAMO (Grupo Español de Linfomas y Trasplantes de Médula Ósea) Cooperative Study
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Group.
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Author Affiliations: (1) Hospital Universitario 12 de Octubre, Madrid; (2) Hospital Universitario
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de Salamanca-IBSAL, Salamanca; (3) Hospital Universitario Marqués de Valdecilla, Santander;
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(4) Hospital Universitario Sant Pau, Barcelona; (5) Hospital Universitario de Canarias, Tenerife;
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(6) Hospital Universitario de Jerez, Jerez; (7) Hospital Universitario La Princesa, Madrid; (8)
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Hospital Universitario Donostia-Aránzazu, San Sebastián; (9) Hospital Universitario Vall de
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Hebrón, Barcelona; (10) Hospital Universitario de Bellvitge, l'Hospitalet de Llobregat; (11)
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Hospital Universitario A Coruña, A Coruña; (12) Hospital Universitario Ramón y Cajal, Madrid;
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(13) Hospital Universitario Virgen de la Arriaxaca, Murcia; (14) Hospital Central de Asturias,
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Asturias; (15) Hospital Universitario de Vigo, Vigo; (16) Hospital Universitario Morales de
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Messeguer, Murcia; (17) Hospital Universitario Nuestra Señora de La Candelaria, Tenerife; (18)
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Hospital Clinic de Barcelona, Barcelona; (19) Hospital Clínico Universitario Lozano Blesa,
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Zaragoza; (20) Hospital Universitario la Fe, Valencia; (21) Hospital Clínico San Carlos, Madrid;
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(22) Hospital del Mar, Barcelona.
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*Ana Jiménez-Ubieto and Carlos Grande contributed equally to this work.
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Corresponding author:
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Ana Jiménez Ubieto M.D., Ph.D.
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Hospital Universitario 12 de Octubre, Avda de Córdoba s/n, 28041, Madrid, Spain
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E-mail:
[email protected]
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Page 1 of 31
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Previous presentation: This study has been presented as oral communications in part at the
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57th ASH Annual Meeting & Exposition, 5 - 8 December 2015, Orlando; at the 56th ASH Annual
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Meeting & Exposition 6-9 December 2014, San Francisco and at the 20th Congress of European
38
Hematology Association (EHA), 11 - 14 June 2015, Austria, Vienna and at the 21th Congress of
39
European Hematology Association (EHA), 9 - 12 June 2016, Denmark, Copenhagen.
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Journal: Biology Bone Marrow Trasplantation
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Manuscript type: Research Article
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Scientific category: Stem Cell Transplantation
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Abstract: 310
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Text word count: 4126
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Tables and Figures: 3 tables and 4 figures.
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References: 49
48
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Page 2 of 31
49
Highlights
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A considerable number of sensitive FL patients who received an HDT/ASCT can reach durable
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remissions and might be considered cured after a long-term follow-up, irrespective of
53
rituximab exposure. Results obtained in patients transplanted in second or subsequent
54
responses in the rituximab era, -a scenery without randomized studies available- are excellent.
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As this strategy has an acceptable and well-known security profile we suggest that this “old
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tool” continues to be very useful, also in the era of new drugs.
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Abstract
59 60
High-dose chemotherapy supported by autologous stem cell transplantation (HDT/ASCT) has
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contributed to modify the natural history of follicular lymphoma (FL). However, an overall
62
survival (OS) benefit has only been demonstrated at relapse after a rituximab free
63
chemotherapy regimen. A total of 655 FL patients were reported to the Spanish GELTAMO
64
registry and received their first ASCT between 1989 and 2007. 203 patients received ASCT in
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first complete response (CR1), 174 in CR2, 28 in third CR3, 140 in first partial response (PR1),
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81 in subsequent PR, and 29 with resistant/refractory disease; 184 patients received rituximab
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prior to ASCT. With a median follow-up of 12 years from ASCT median PFS and OS were 9.7
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and 21.3 years, respectively. Actuarial 12-year PFS and OS were 63% % (95% CI 58%–68%) and
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73% (95% CI 68%–78%) for patients in CR, -with a plateau in the curves beyond 15.9 year-, 25%
70
(95% CI 19%–28%) and 49% (95% CI 42%–56%) for patients in PR, 23% (95% CI 8%–48%) and
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28% (95% CI 9%–45%) for patients with resistant/refractory disease, (p46
317/649 (49%)
145/346 (42%)
171/303 (57%)
Male
330 (50%)
166 (47%)
164 (54%)
Female
325 (50%)
184 (53%)
141 (46%)
Grade 1
240/556 (43%)
106/264 (40%)
134/292 (46%)
Grade 2
227/556 (40%)
121/264 (46%)
106/292 (36%)
Grade 3
89/556 (16%)
31/264 (12%)
50/292 (17%)
Follicular small cleaved cell
244/613 (40%)
123/333 (37%)
121/280 (43%)
Follicular mixed small cleaved and large cell
273/613 (45%)
153/333 (46%)
120/280 (43%)
Follicular large cell
96/613 (16%)
57/333 (17%)
39/280 (14%)
0–1
509/592 (86%)
273/317 (86%)
236/275 (86%)
1≥2
83/592 (14%)
44/317 (14%)
39/275 (14%)
I–II
65/653 (10%)
29/348 (8%)
36/305 (12%)
III–IV
588/653 (90%)
319/348 (92%)
269/305 (86%)
Absent
453/639 (71%)
244/346 (71%)
209/293 (71%)
Present
186/639 (29%)
102/346 (29%)
84/293 (29%)
≤4
213/360 (59%)
96/179 (54%)
117/181 (65%)
>4
147/360 (41%)
83/179 (56%)
64/181 (35%)
Yes
388/608 (64%)
212/331 (64%)
176/277 (64%)
No
220/608 (36%)
119/331 (36%)
101/277 (36%)
High
150/559 (27%)
71/293 (24%)
79/266 (30%)
Normal
409/559 (73%)
222/293 (76%)
187/266 (70%)
Characteristics
pa
Age at diagnosis, years Median (range)
Sex 0.2
FL histological grade 0.7
Working Formulation classification 0.6
ECOG performance status b 1
Ann Arbor Stage 0.6
B symptoms 1
Number of nodal sites 0.01
Bone marrow involvement 1
Lactate dehydrogenase 0.4
Tumour mass
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Page 26 of 31
1
462/638 (72%)
241/346 (70%)
221/292 (76%)
CR1
203 (31%)
97 (28%)
105 (34%)
CR2
174 (27%)
79 (23%)
94 (31%)
CR3
28 (4%)
10 (3%)
18 (6%)
PR1
140 (21%)
95 (27%)
45 (15%)
PR≥2
81 (12%)
45 (13%)
35 (11%)
Resistant/refractory disease
29 (4%)
19 (5%)
8 (3%)
Yes
184/620 (30%)
5/338 (1%)
179/282 (65%)
No
436/620 (70%)
333/338 (99%)
103/282 (35%)
Yes
108/654 (17%)
93/350 (27%)
15/304 (5%)
No
546/654 (83%)
257/350 (73%)
289/304 (95%)
Yes
517/604 (86%)
245/322 (76%)
272/282 (96%)
No
87/604 (14%)
77/322 (24%)
10/282 (4%)
No
492/639 (77%)
258/339 (76%)
234/300 (78%)
Positive selection
100/639 (16%)
43/339 (13%)
4/300 (1%)
Negative selection
47/639 (7%)
38/339 (11%)
62/300 (21%)
Hemoglobin level (g/dL) ≥12
