Long Term Results of Fludarabine/Melphalan as Reduced Intensity Conditioning Regimen (RIC) for Transplantation in Mantle Cell Lymphoma (MCL): Age Matters

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4388-4388
Author(s):  
Jorge Gayoso ◽  
Rodrigo Martino ◽  
Pascual Balsalobre ◽  
Javier De la Serna ◽  
José Francisco Tomás ◽  
...  
Keyword(s):  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Disease Free Survival ◽  
Long Term Results ◽  
Mixed Chimerism ◽  
Reduced Intensity Conditioning ◽  
Who Grade ◽  
Reduced Intensity

Abstract Introduction: Myeloablative allogeneic stem cell transplantation in patients (pts) with MCL has been traditionally used only in young pts without co-morbidities due to its high toxicity. During the last 10 years, many different reduced intensity conditioning (RIC) regimens have been introduced into clinical practice trying to reduce this toxicity, preserving the establishment of a meaningful graft-tumor effect (GVT). However, few homogeneus pts series have been reported focused on MCL, with encouraging results in some studies. Thus, we report herein the outcome of 18 consecutive MCL pts who received an allo-PBSC-RIC from an HLA-identical sibling donor with a long follow-up. Patients and methods: The RIC consisted in iv fludarabine 125–150 mg/m2 from day-8 to -4 and iv melphalan 80 or 140 mg/m2 on day-3 to -2. Rituximab 375 mg/m2 was added to RIC in 8 pts on days-9, +1, +8 and +15. GVHD prophylaxis consisted in standard cyclosporine and methotrexathe. Gradual cyclosporine tappering from day +50 was initiated if mixed chimerism or persistent disease were present. We focus on engraftment kinetics, early toxicities, non-relapse mortality (NRM), chimerism kinetics, GVHD as well as estimated anti-tumoral efficacy, progression-free and overall survival (PFS and OS). Results: 18 MCL pts were included from 2000 to 2008, with a median follow-up of 50 months. Median age was 56 years (range: 43–68), 13 were males, with a median pre-RIC treatment lines of 2 (1–4) including 2 autoHSCT. Before alloRIC, 13 pts (72%) were in 1st or later CR, while 5 pts (28%) were in chemo-sensitive PR. Median CD34+/kg infused cells were 5,8 ×106 (4,3–10,8) and 2,0 ×108 (0,7–4,1) CD3+ lymphocytes/kg. All pts engrafted, reaching ANC>500 on day +16 (13–20) and platelets>20.000 on day +12 (8–32), with no graft failures. Early toxicity (<day +100) included WHO grade 3–4 mucositis in 8 (44%), febrile neutropenia in 6 (33%) and bacterial infections in 4 (22%) with 2 deaths (1 varicella-zoster encephalitis and 1 refractory acute GVHD). There were 2 other deaths during the 1st year, both due to infections in the setting of extensive chronic GVHD, for a 1-year NRM of 22%. Complete donor T-cell chimerism (CC) was present at day +30 in 71% of evaluated pts and in 100% pts at day +90. Acute grade II–IV GVHD ocurred in 39% of pts at risk, with 17% of grade III–IV. Chronic GVHD affected 12/16 pts (75%), wich was extensive in 6 (38%). Only 1 patient (trasplanted in PR after 2 treatment lines) relapsed (6%). The 5-year estimated PFS and OS were both 77% (CI95%=58–97%) and 14 pts remain alive in CR. The only apparent prognostic factor in our study is age: 8 pts aged 60 or older have an OS of 33,3% vs 100% for the 10 pts younger than 60 years (p<0.001). Conclusions: AlloRIC with fludarabine and melphalan in MCL pts offers a good toxicity profile, with high engraftment rate and good long term disease-free survival, especially in pts younger than 60. The very low long-term relapse rate seen in the context of a high incidence of chronic GVHD supports the continued sensitivity of MCL to a GVT effect. Figure Figure

Long Term Outcome After Low Dose TBI Based Conditioning Hematopoietic Stem Cell Transplantation (HSCT) From Related and Unrelated Donors for Older Patients with AML

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2030-2030
Author(s):  
Dietger Niederwieser ◽  
Leo F Verdonck ◽  
Jan J Cornelissen ◽  
Michael Cross ◽  
Rainer Krahl ◽  
...  
Keyword(s):  
De Novo ◽  
Chronic Gvhd ◽  
Disease Free Survival ◽  
Study Groups ◽  
Long Term Results ◽  
Term Outcome ◽  
Hematopoietic Stem ◽  
Long Term Outcome

Abstract Abstract 2030 HSCT after reduced or minimal intensity conditioning is increasingly used to treat AML patients not eligible for conventional HSCT. Short term outcome has been reported frequently and risk factors have been identified; long term results still await in depth evaluation. We report here 5 years follow up results from a prospective phase II study conducted by two AML study groups in Europe. Patients were recruited from AML protocols HOVON/SAKK AML 43 and the OSHO AML 1997 study. The regimen consisted of fludarabine (FLU), 30 mg/m2/d on days −4, −3, and −2, 2 Gy TBI on day 0 (the day of HSCT) with mycophenolate mofetil, [15 mg/kg p.o. b.i.d. from 5 hours after HSCT to day +40], and cyclosporine, [CSP; 6.25 mg/kg p.o. bid from day –3 to day +180] after HSCT. Cyclosporine was adjusted to trough levels and reduced according to a predetermined tapering schedule and donor type. A total of 96 patients were recruited between 5/2002 and 8/2005 in the study. Age was median 62 (range 40 – 74) years, 54 patients were male (56%) and 73 patients (76%) had de novo AML. The remission status on entry was CR1 in 83 (86%) patients and CR2 in 13 (14%). Of the 96 patients, 20% had high risk cytogenetics and SCT was performed a median of 75 days after chemotherapy. There were no statistical differences in the above described characteristics except for more secondary AML (p=0.04) and more CR2 patients (p=0.07) among the 59 unrelated SCT (61%) as compared to the 37 related SCT (39%). Graft rejection at two years was observed in 6% of the patients. Absence of chronic GvHD was diagnosed in 40% and limited chronic GvHD in 29% of the patients, with no difference between related and unrelated SCT. Probability of overall survival (OS) at 6 years with a median follow up of 64 (49–92) months reaches a plateau after 5 years at 0.33±0.05 and was not significantly better in CR1 than in CR2. However, there was a trend towards better OS at 6 years for unrelated 0.41±0.11 as compared to related 0.29±0.07 SCT (p=0.08) in CR1 only. This difference was significant for disease free survival (DFS) (0.48±0.09 unrelated vs 0.27±0.06 related; p=0.04), the major reason being a higher relapse rate in related as compared to unrelated SCT (0.62±0.08 vs 0.40±0.09). The overall non-relapse mortality at 6 years was 0.21±0.05. We conclude that OS and DFS reach a stable plateau from 5 years after SCT to more than 8 years after SCT. In CR1 patients, DFS is superior after unrelated as compared to related SCT. Accordingly, strategies designed to decrease relapse, especially after related SCT, have already been implemented in the ongoing protocols. The preferential use of unrelated rather than related donors may be beneficial and should be considered in future protocols. Disclosures: Off Label Use: Transplantation in elderly patients.

Excellent Disease-Free Survival after Double Cord Blood Transplantation Using a Reduced Intensity Chemotherapy Only Conditioning Regimen in a Diverse Adult Population.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2048-2048 ◽  
Author(s):  
Karen K. Ballen ◽  
Thomas R. Spitzer ◽  
Beow Yeap ◽  
McAfee Steve ◽  
Bimalanghsu R. Dey ◽  
...  
Keyword(s):  
Cord Blood ◽  
Aplastic Anemia ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Disease Free Survival ◽  
Free Survival ◽  
Cord Blood Unit ◽  
Disease Free ◽  
Reduced Intensity

Abstract Umbilical cord blood is a useful stem cell source for patients without matched related or unrelated donors. However, single cord blood unit transplantation in adults is associated with high transplant related mortality, mostly due to infection. In this study, we used a reduced intensity conditioning regimen followed by infusion of two partially matched cord blood units. The conditioning regimen was fludarabine 30mg/m2/day x 6 days, melphalan 100mg/m2/day x 1 day, and rabbit antithymocyte globulin 1.5 mg/kg/day x 4 days. Cord blood units were a 4/6 or better HLA match or better with each other and with the patient, and contained a minimum combined pre-freeze cell dose of 3.7 x 107NC/kg. GVHD prophylaxis was cyclosporine and mycophenolate mofetil. Twenty-one patients, 15 males (71%) and 6 females (29%), median age 49 years (range 24–63 years) participated in a Phase I study. The diagnoses were AML (n=8), ALL (n=1), NHL (n=5), CLL (n=2), MDS (n=2), Hodgkins Disease (n=2), and aplastic anemia (n=1). Fifteen percent of patients were non Caucasian. The cell doses infused were a median of 4.0 x107 NC/kg (range 3.0–5.3 x107) and 2.0 X105 CD34+ cells/kg (range 0.6–10.0 x105). Two patients (both with MDS complicating aplastic anemia) experienced primary graft failure, and received successful second cord blood transplants using a different conditioning regimen. Among the remaining 19 patients, the median time to an absolute neutrophil count >500 was 20 days (range 15–34 days). The median time to a platelet count >20,000 unsupported were 41 days (range 21–125 days). One patient experienced a secondary graft failure, and is well following infusion of previously stored autologous cells. 4 patients (21%) experienced Grades II-IV acute GVHD, and only one patient (5%) experienced Grade III GVHD. There were no patients with Grade IV GVHD and no deaths from acute GVHD. Twelve patients were evaluable for chronic GVHD, and 3 patients (25%) had chronic GVHD of which one case was extensive disease. The 100 day transplant related mortality was 14%. The deaths were due to a CNS bleed, Epstein Barr virus lymphoproliferative disorder, and staphylococcal sepsis. Chimerism analysis showed predominance of one cord by Day +100 in 79% of patients evaluable for 100-day follow-up. In 85% of these patients the first cord blood unit infused predominated. One patient has had progressive disease. With a median follow-up of 7 months (range 2–16 months), the overall survival is 79% and the disease-free survival is 64%. The projected one year disease-free survival is 64%. In conclusion, 1) engraftment of adult patients appears to be acceptable using double cord blood products and reduced intensity, non TBI conditioning regimen; 2) the risk of serious acute and chronic GVHD is low, 3) patients with aplastic anemia/MDS may require more intensive immunosuppression to allow engraftment, 4) GVL appears to be preserved despite the low T cell dose.

Outcome of Sibling Reduced-Intensity Conditioning Allogeneic Stem Cell Transplantations in Low-Grade B Cell Lymphoproliferative Disorders. A Single Centre Experience.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 5059-5059
Author(s):  
Ronan Desmond ◽  
Marianna David ◽  
Eibhlin Conneally ◽  
Paul Browne ◽  
Mairead Ni Conghaile ◽  
...  
Keyword(s):  
Stem Cell ◽  
B Cell ◽  
Chronic Gvhd ◽  
Autologous Transplantation ◽  
Conditioning Regimen ◽  
Lymphoproliferative Disorders ◽  
Mixed Chimerism ◽  
Low Grade ◽  
Reduced Intensity Conditioning ◽  
Reduced Intensity

Abstract Reduced intensity conditioning allogeneic stem cell transplantations (allo-SCT) have been developed to exploit graft-versus-malignancy effect while reducing the toxicity of allo-SCT. We report the outcome of 21 patients with low-grade B cell lymphoproliferative disorders transplanted in a single center. The mean age of the patients was 54 years (range 32–66) with 11 males, 10 females. Follicular lymphoma was the diagnosis in 10 patients, CLL in 5, mantle cell lymphoma in 4, MALT lymphoma in 1 and lymphoplasmocytoid lymphoma in 1 patient. The median number of prior treatment lines was 2. All patients received peripheral blood stem cell transplants from sibling donors and no patients had undergone a prior autologous SCT. 12/21 patients (57%) received a ATG based conditioning regimen while the remainder, 9/21 (42%) received a Campath containing conditioning regimen. Full donor chimerism was confirmed in 17/19 (89%) patients. Acute graft versus host disease (GVHD) developed in 5/21 (23%) of the patients. Chronic GVHD occurred in 7/21 (33%) with 5/21 occuring post donor lymphocyte infusion (DLI). DLI has been administered in 11/21 patients (52%), 2 for progressive disease and 9 for re-emerging mixed chimerism. Non-relapse mortality (NRM) at 100 days and 1 year were 5% and 12.5% respectively. With a median follow up of 21 months (range 3–54) the overall survival rates (OS) at 1 year and 2 years were 72% and 58% respectively. Progression free survival (PFS) at 1 year and 2 years were 66% and 50%. We have shown that reduced intensity conditioning allogeneic stem cell transplantation is associated with a low TRM comparible to that of autologous transplantation and allows long term control of low grade B-cell lymphoproliferative disorders.

Long Term Results of Non-Myeloablative Stem Cell Transplantation in Non-Hodgkin’s Lymphomas: FLU150/MEL80 (Madrid Protocol).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 5047-5047
Author(s):  
Jorge Gayoso ◽  
Pascual Balsalobre ◽  
Jose F. Tomás ◽  
Javier de la Serna ◽  
David Serrano ◽  
...  
Keyword(s):  
Stem Cell ◽  
Chronic Gvhd ◽  
Long Term Results ◽  
Mixed Chimerism ◽  
Cell Transplant ◽  
Mantle Cell ◽  
Heavily Pretreated ◽  
Hodgkin's Lymphomas

Abstract Introduction: Myeloablative allogeneic stem cell transplant has been reserved for long time to young well-fitted patients (pts) due to its high toxicity. Lately, different non-myeloablative (NMA) conditioning regimens have been employed to reduce this toxicity preserving the graft-vs-tumor effect (GVT). Here we present our experience in advanced lymphoma pts. Patients & methods: Since year 2000, we used iv fludarabine 150 mg/m2 days −7 to −4 and iv melphalan 80 mg/m2 day −2 as NMA conditioning for heavily pretreated lymphoma pts, aged >55y or with comorbidities. GVHD prophylaxis consisted in cyclosporine and short course MTX. Stem cells were obtained from peripheral blood of an HLA-identical sibling donor. Gradual cyclosporine tappering from day +50 was initiated if mixed chimerism or persistent disease were present. We evaluated: engraftment rate, toxicities, transplant related mortality (TRM), chimerism kinetics, GVHD incidence and disease free and overall survival (DFS and OS). Results: 18 lymphoma pts (8 follicular, 4 mantle cell, 4 peripheral T and 2 DLBCL) were transplanted since 5/2000 to 1/2007 due to co-morbidities in 4, age>55y in 6 and heavily pretreated pts in 10. Median age was 52y (31–61), 10 were males, median treatment lines were 3 (1–5) including 4 auto-transplanted(22%). After the last treatment, 10 pts were in CR(56%), 4 pts had chemo-sensitive PR(22%) and 4 chemo-resistant disease(22%). Median CD34+/kg infused cells were 5,0 x106(3,7–10,8) and 2,0 x108(0,4–4,4) CD3+ lymphocytes/kg. All pts engrafted, reaching ANC>500 on day +14 (10–20) and platelets>20.000 on day +12 (9–33), except 1 early death. There weren’t any early or late engrafment failures. Early toxicity until day +100 included febrile neutropenia in 6, severe mucositis in 2, hepatic toxicity in 2, VOD in 1, hemorragic cystitis and arrythmia in 1. There were 2 deaths before day +100: 1 refractory congestive heart failure and 1 Pseudomonas’ sepsis(TRM 11,1%) and 2 late deaths beyond +1y due to infections during chronic GVHD treatment. Viral infections were the most prevalent(72%), mainly CMV reactivations (44%) that were relapsing in 17%. There were 7 bacterial infections (4 bacteriemias, 1 meningitis, 1 pneumonia and 1 urinary sepsis). Complete chimerism (CC) was present on day +30 in 38% pts and in 93% pts on day +90. Only 1 pt persisted on mixed chimera until day +180 and 10/10 evaluated pts were on CC after 1 year. Acute grade II-IV GVHD ocurred in 37%, with 25% grade III-IV. Chronic GVHD affected 10/15 pts (67%), limited in 27% and extensive in 40%. Only 1/10 CR pts at transplant relapsed after 95 days and 4/4 pts with chemo-sensitive PR reached CR that persisted after achieving CC on day +90. All chemo-refractory pts died (4/4): 2 early toxic deaths and 2 progressions. Median follow-up was 55 months(28–83) with DFS of 61% and 66,7% OS at 5y. Twelve pts persisted alive in CR with chronic GVHD in 4(33%). Predictors for DFS and/or OS were follicular and mantle cell histology vs others (p<.01), CR or PR at transplant vs refractory (p<.01) and <3 pretreatment lines vs >2 lines (p<.06). Conclusions: After long term follow-up, NMA conditioning with fludarabine and low melphalan dose in advanced lymphoma pts offers good toxicity profile, with high engraftment rate and good disease control if pts were in chemo-sensitive disease pretransplant.

Reduced-Intensity Conditioning for Allograft (RICT) after Cytoreductive Autograft (ASCT) in Relapsed/Resistant Hodgkin’s Lymphoma (HL)

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3294-3294
Author(s):  
A. M. Carella ◽  
E. Todisco ◽  
L. Castagna ◽  
A. Santoro ◽  
G. Catania ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Complete Remission ◽  
Long Term Results ◽  
High Dose ◽  
Reduced Intensity Conditioning ◽  
High Dose Therapy ◽  
Previous Therapy ◽  
Reduced Intensity

Abstract Reduced-intensity conditioning for transplant (RICT) aims to exploit graft vs lymphoma (GvLy) effects while reducing conditioning-related toxicity. Because GvLy responses might be insufficient when HL are bulky and lymphoma growth is rapid, we pionered that intensive cytoreduction prior to RICT may allow GvLy reaction to be exploited (Carella et al. JCO2000; 18:3918). Thirty-eight patients with relapsed (n=26) or refractory (n=12) HL underwent RICT from an HLA-identical sibling preceeded by ASCT. Previous therapy consisted of 2–6 lines. High-dose therapy with ASCT consisted of BEAM protocol (n=29) or melphalan 200 mg/m2 (n=9). RICT consisted of fludarabine-cyclophosphamide (n=30) or fludarabine-melphalan (n=8). The two groups had similar prognostic factors. The median time to neutrophils and platelets recovery was 10 days and 16 days, respectively. Chimerism studies indicated 100% donor-derived engraftment. Day 100 and cumulative (2 yrs) TRM were 5,3 % (2 pts) and 18% (7 pts), respectively. Seventeen patients (44%) are alive (12 in complete remission and 5 with stable disease) with a median follow-up of 41 months (7–110 months). Twenty-one patients expired (TRM n=7, disease progression n=14). In conclusion, tandem ASCT/RICT is feasible and effective salvage therapy for patients with advanced HL. The long-term results obtained appear encouraging.

Long Term Survival of Patients with Chronic Myelocytic Leukemia after Allogeneic Stem Cell Transplant Using a Reduced Intensity Regimen of Melphanlan, Lomustine and Cyclophosphamide.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 5308-5308
Author(s):  
Yongqian Jia ◽  
Ting Liu ◽  
Ting Niu ◽  
Caigang Xu ◽  
Wentong Meng ◽  
...  
Keyword(s):  
Disease Free Survival ◽  
Mixed Chimerism ◽  
Cell Transplant ◽  
Chronic Myelocytic Leukemia ◽  
Free Survival ◽  
Myelocytic Leukemia ◽  
Disease Free ◽  
Reduced Intensity

Abstract Introduction: Non-ablative regimens have been shown to be effective and less toxic than traditional ablative regimens, but they usually need close monitoring and skillful manipulates e.g. donor lymphocyte infusions. In the present study, we used a novel reduced intensity regimen with melphanlan, lomustine and cyclophosphamide to treat patients with chronic myelocytic leukemia and made a long term follow-up. Methods: 14 patients with median age of 35(23~52) were treated with MCC regimen(Melphanlan 170 mg/m2/d×1, Lomustine 400 mg/m2/d×1, Cyclophosphamide 60 mg/kg/d×2) and the median follow-up time is 6 years; another 16 patients with median age of 33(16~44) were treated with BuCy regimen(Busulfan 4 mg/kg/d×4, Cyclophosphamide 60 mg/kg/d×2) and the median follow-up time is 4 years. Results: All the patients were engrafted successfully and the platelet recovery to 20×109/L was earlier at median 3 days in patients with MCC regimen. 4 of 10 patients examined in MCC group showed mixed chimerism at day 100 post transplant, whereas only 1 of 12 patients examined in BuCy group showed mixed chimerism. All the patients became complete donor sources later without any DLI. The regimen related toxicity was relatively lower in MCC group, especially the incidence and severity of mucositis and liver dysfunction were decreased significantly. The median duration of hospitalization was 39 days (25~55)for patients with MCC regimen, and 55 days (39~90) for BuCy regimen. The 5 year disease-free survival was 71.4% for MCC group and 62.5% for BuCy group, respectively. The transplant related mortality and relapse rate were 21% and 7% for MCC regimen, whereas 25% and 12% for BuCy regimen. Conclusions: MCC regimen is an effective and less toxic conditioning regimen and the long term disease-free survival is as the same as that of BuCy regimen. Considering the cost-effect efficacy, MCC regimen may have some prominent advantages over BuCy regimen. Figure Figure

Factors Predicting Long Term Survival after Reduced Intensity Allogeneic Stem Cell Transplantation in Acute Myeloid Leukemia.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 326-326
Author(s):  
Charles F. Craddock ◽  
Sudhir Tauro ◽  
Joanne E. Gregory ◽  
Laura Buckley ◽  
Janice Ward ◽  
...  
Keyword(s):  
Older Patients ◽  
Conditioning Regimen ◽  
Disease Free Survival ◽  
Term Survival ◽  
Free Survival ◽  
Long Term Follow Up ◽  
Disease Free ◽  
Reduced Intensity

Abstract Allogeneic stem cell transplantation (SCT) performed using a reduced intensity conditioning (RIC) regimen represents an important new treatment modality in older patients with high risk acute myeloid leukaemia (AML) whose outlook with conventional chemotherapy would be poor. However assessment of its role has been hampered by the absence of long term follow-up data. Furthermore factors determining survival after RIC SCT have not been rigorously defined. In order to examine the anti-leukemic activity of RIC allografts in more detail we have examined the outcome of 170 patients with AML transplanted using a uniform conditioning regimen over a ten year period. Long term follow-up data (maximum 119 months) was collected on patients transplanted using a conditioning regimen consisting of fludarabine (30 mg/m2 x 5 days), melphalan 140 mg/m2 x 1 day and alemtuzemab (10 mg x 5 days). The median age of transplanted patients was 54 years (range 18–71). 88 patients were in CR1 at the time of transplant, 63 CR2/3 and 19 had relapsed or refractory disease. Cytogenetic information was available on 149 patients and of these 33 patients had adverse risk and 116 intermediate risk cytogenetics by MRC criteria. 83 transplants were performed using an HLA identical sibling donor and 87 using a volunteer unrelated donor. The 100 day transplant related mortality was 9%. 29% of patients developed Grade II-IV acute GVHD and 22% chronic GVHD. The 3 year overall survival (OS) for the whole group was 48% and 3 year disease free survival (DFS) 45%. 20 patients remain in remission more than five years post-transplant. Survival was significantly influenced by status at transplant (p=0.01), patient age (p= 0.01) and presentation cytogenetics (p=0.05) as determined by multivariate Cox proportional hazards regression. The 3 yr OS for patients transplanted in CR1 or CR2 was 51% and 52% respectively compared to 13% for patients with relapsed/refractory disease. Three year OS for patients with intermediate risk cytogenetics was 52% compared with 34% for adverse risk patients. Three year OS for patients under 60 years was 51% compared with 36% for older patients. This study demonstrates the ability of RIC allografts to deliver encouraging long term disease free survival rates in high risk AML. Pre-transplant characteristics can be used to predict outcome after a RIC allograft and older patients with active disease at the time of transplant or adverse cytogenetics require novel strategies in order to improve long term survival.

Sign in / Sign up

Export Citation Format

Share Document