Donor CD34+ Cell Chimerism at Day 28 and Chronic Graft-Versus-Host Disease (GvHD) but Not High-Risk Cytogenetics Influence Outcome of Allogeneic Hematopoetic Cell Transplantation (HCT) Following Reduced Intensity Conditioning (RIC) in Patients with AML and MDS.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 547-547 ◽  
Author(s):  
Haifa K. Al-Ali ◽  
Claudia Nehring ◽  
Rainer Krahl ◽  
Cornelia Becker ◽  
Sabine Leiblein ◽  
...  
Keyword(s):  
Risk Factors ◽  
T Cell ◽  
High Risk ◽  
Chronic Gvhd ◽  
Disease Free Survival ◽  
Group I ◽  
Cd34 Cells ◽  
Patients At Risk ◽  
Group Ii

Abstract HCT after RIC is used increasingly to treat older or infirm patients with AML or MDS. In the current analysis we looked for risk factors influencing outcome including cytogenetics, kinetics of donor CD34+ and T-cell chimerism (CC). Patients and methods: From July 1998 - December 2005, 119 consecutive patients [66 m/53 f; median age 60 (range 21–74) years] with AML (n=99; 83%) and high-risk MDS (n=20; 17%) were treated within the OSHO AML studies before HCT. Seventy (59%) of the patients had intermediate-risk cytogenetics and 44 (37%) high-risk cytogenetics. Patients were either in CR1 (n= 66; 55%), CR2 (n=18; 15%), >CR2 (n=28; 24%), or were untreated (n=7; 6%) at transplant. HCT was performed from matched related (n= 33; 28%) and matched unrelated (n= 86; 72%) donors after RIC (200cGy TBI + fludarabine 30 mg/m2/day on 3 consecutive days) and followed by immunosuppression with cyclosporine and mycophenolate mofetil. Marrow donor chimerism was determined in T-, and CD34+−cells at days (d) 28, 56, 84, and thereafter at 3 month intervals using either XY chromosome FISH in gender mismatched, or PCR based analysis of polymorphic micro satellite regions in gender matched HCT. Results: Engraftment was documented in 112 (94%) of the 119 patients. Survival (OS), disease free survival (DFS), relapse incidence (RI), and non-relapse mortality (NRM) of engrafted patients was 40%, 38%, 46%, and 30% at 3 years respectively. In multivariate analysis, only >90% donor CD34+ CC at d 28, chronic GvHD, and CR1, but not cytogenetic risk factors were associated with an improved OS and DFS. Patients with >90% donor CD34+ CC at d 28 (group I) had an OS of 50% compared to 9% in patients with donor CD34+ CC <90% (group II) (p=0.002). Accordingly, RI in group I was 35% compared to 85% in group II (p<0.0001). Again, donor CD34+ CC at d 28 but neither donor T-cell chimerism nor high-risk cytogenetics correlated with relapse. Relapse occurred in 41/109 (38%) patients at a median of 121 d. All patients (n=19) with haematological relapse within 100 days post transplant died despite reduction/withdrawal of immunosuppression. Of the 22 patients with later relapse, six went into permanent complete remission by reduction/withdrawal of immunosuppression. A decrease of CD34+ chimerism was detected in a further six patients and all responded to a decrease in immunosuppression. The incidence of acute (grades ≥ I) and chronic (limited and extensive) GvHD was 50%, and 55% respectively. OS was 10%, 46%, and 62% for patients with no GvHD (A), acute GvHD only (B), and chronic GvHD (C) (p=0.0001). DFS for A, B, C was 20%, 38%, and 55% respectively ((p=0.0001). RI was highest for A (72%) compared to B (49%) and C (25%) (p<0.0001). Conclusions: HCT after RIC offers long-term OS and DFS in AML/MDS even in patients with high-risk cytogenetics. CR1, donor CD34+ CC >90% at d 28 and chronic GvHD correlate with an improved outcome and decreased relapse incidence. Careful monitoring of donor CD34+ CC can identify patients at risk for relapse, thereby allowing early immunmodulation.

A Phase II Prospective Feasibility Study of Clofarabine Cytoreduction Prior to Allogeneic Hematopoietic Cell Transplantation (HCT) for Patients with Relapsed or Refractory Acute Leukemias and Advanced Myelodysplastic Syndromes

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 496-496
Author(s):  
Rajiv Agarwal ◽  
Frederick L Locke ◽  
Rangesh Kunnavakkam ◽  
Koen van Besien ◽  
Richard A. Larson ◽  
...  
Keyword(s):  
T Cell ◽  
High Risk ◽  
Myelodysplastic Syndromes ◽  
Research Funding ◽  
Chronic Gvhd ◽  
Acute Leukemias ◽  
T Cell Depletion ◽  
Kaplan Meier ◽  
One Year

Abstract Abstract 496 HCT may provide long-term disease control for patients (pts) with relapsed and/or refractory acute leukemias (AL) and advanced myelodysplastic syndromes (MDS). Active disease burden at HCT is associated with high relapse rates and poor long-term outcomes. We hypothesized tolerable intensification would be achieved safely by clofarabine cytoreduction followed by HCT conditioning at the nadir and would result in improved outcomes. We performed a prospective study (3/08 – 9/10) to examine the feasibility and efficacy of clofarabine (Clo) cytoreduction prior to HCT for relapsed or refractory AL and MDS with > 5% marrow blasts. Clo was administered at 30mg/m2/day IV over 2 hours for 5 consecutive days. On Day 12 post Clo initiation, a bone marrow (BM) biopsy determined cytoreduction, followed by HCT conditioning by day 21 post-Clo. Our primary endpoint was to assess the proportion of pts who achieved effective cytoreduction, defined as BM cellularity <20% and BM blasts<10% on Day 12 post Clo initiation. Our secondary endpoints included (a) the proportion of pts able to proceed to HCT within 21 days of initiating Clo bridge, (b) Clo-related toxicities, and (c) disease free (DFS) and overall survival (OS) on Day 100 post HCT. 29 pts were enrolled and evaluable; 11 AML, 7 MDS, 3 t-MN, 4 secondary AML, 2 CML, 2 ALL; median age was 51 years (range 23–69); sex: 16 M, 13 F. 16 pts had high risk and 13 had intermediate risk cytogenetic profiles. 3 of 12 pts evaluated showed a FLT3 ITD mutation. 18 of 23 evaluable pts had high C-reactive protein levels at study entry (>5mg/L). All pts had ECOG performance status of 0 to 1. The median Charlson co-morbidity index was 1 (range 0–8). Effective cytoreduction was achieved in 15/29 pts (52%). Clo bridge therapy was well tolerated with mild toxicities (CTCAE v.3) prior to HCT as follows: 7% with grade (gr.) 1 creatinine elevation; 46% gr.1–2 and 7% gr.3 bilirubin elevation; 50% gr.1–2 and 25% gr.3 SGOT elevation, which were reversible. There were no hand-foot syndrome, cardiac, or CNS toxicities. All 29 pts (100%) successfully proceeded to HCT conditioning after clofarabine bridge – one pt with refractory AML, who achieved cytoreduction and conditioning, died one day before HCT due to sepsis. Median time from Clo initiation to HCT was 21 days (range 18–77). Two pts were delayed due to infection and/or failure to cytoreduce; both received second bridge with HiDAC mitoxantrone and achieved cytoreduction followed by HCT. 25 of 29 underwent reduced intensity conditioning (flu-mel-campath-17, clo-mel-campath 3, flu-mel-atg 5) and 26 of 28 received T-cell depletion (campath 22, ATG 5). Among the 28 transplanted pts, graft sources included: 23 PBSC (11 matched related, 12 matched unrelated), and 5 haploidentical PBSC plus a cord blood unit. With a median follow up 343 days after HCT, the median PFS = 353 days (95% CI 229–573) and the median OS = 381 days (95% CI 229–649). One year PFS is 65% by Kaplan-Meier estimate for cytoreduced pts compared to 33% in non-cytoreduced pts. Of the 28 pts who received transplant, 3 pts died before Day 100 – one due to sepsis before Day 28 post HCT, and two due to disease progression. At Day 28 post HCT, 26/27 pts (96%) had BM biopsies showing no evidence of residual disease – one pt had residual AML. The cumulative incidence of gr.2–3 acute GVHD by Day 100 was 9/27 pts, and 2/25 pts developed mild or moderate chronic GVHD within the first year. The Kaplan Meier estimate for one year survival is 65% (95% CI 35–84%) for the cytoreduced pt group and 41% (95% CI 16–65%) for the non-cytoreduced pt group. In summary, clofarabine bridge achieved cytoreduction in 52% of very high risk pts with advanced hematologic malignancies with low toxicity. Cytoreduction was associated with prolonged PFS, but late relapse remains problematic. Despite RIC and T-cell depletion, most pts achieved remission post-HCT with low rates of acute and chronic GVHD. This bridging approach provides a platform for testing novel post-transplant interventions. Disclosures: Off Label Use: Clofarabine is being used for treatment of advanced leukemia for cytoreduction prior to HCT. Locke:Genzyme: Honoraria. van Besien:Genzyme: Research Funding. Odenike:Genzyme: Membership on an entity's Board of Directors or advisory committees, Research Funding. Stock:Genzyme: Research Funding.

Durable Engraftment and Long-Term Survival Following Fludarabine-Based Nonmyeloablative Hematopoietic Cell Transplantation (HCT) in Patients with ATG-Refractory Severe Aplastic Anemia (SAA) and Other Nonmalignant Hematological Disorders.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 252-252 ◽  
Author(s):  
Sakti Chakrabarti ◽  
Y. Takahashi ◽  
R. Srinivasan ◽  
I. Espinoza ◽  
T. Igarashi ◽  
...  
Keyword(s):  
T Cell ◽  
Hematopoietic Cell Transplantation ◽  
Bone Marrow Failure ◽  
Chronic Gvhd ◽  
Disease Free Survival ◽  
Term Survival ◽  
Long Term Survival ◽  
Hematological Disorders ◽  
Post Transplant

Abstract We evaluated the toxicity-profile, engraftment potential, and efficacy of fludarabine-based nonmyeloablative allogeneic HCT in patients with a variety of nonmalignant hematological disorders. Twenty three patients (median age 29 years; range 11–52) with nonmalignant hematological disorders including ATG refractory SAA (n=13), severe paroxysmal nocturnal hemoglobinuria (PNH: n=9), and pure red cell aplasia (PRCA; n=1) were transplanted from 5/99 – 8/2004 at the NHLBI. The majority of patients had an extensive transfusion history including 11/23 who had HLA allo-antibodies and 4/23 with allo-antibodies to RBCs. Conditioning with fludarabine (25 mg/m2 x 5 days), ATG (40mg/kg x 4 days) and cyclophosphamide (60mg/kg x 2 days) was followed by infusion of an un-manipulated G-CSF mobilized allograft from an HLA matched sibling (n=18), parent (n=2), or single antigen mismatched sibling (n=3). GVHD prophylaxis consisted of cyclosporine (CSA) either alone (n=2) or combined with mycophenolate mofetil (n=10) or mini-dose methotrexate (n=11). Despite a high prevalence of pre-transplant allo-immunization, all patients achieved sustained donor engraftment in both myeloid and T-cell lineages. Myeloid recovery (neutrophils >500cells/uL) occurred at a median 14 days post transplant (range 8–18 days). Conversion from mixed to full donor myeloid and T-cell chimerism occurred in all patients by 110 days post-transplant. CMV reactivation occurred in 11/21 patients at risk (KM probability 52%) without any cases of CMV disease. Grade II–IV and III–IV acute GVHD was the major transplant complication occurring in 13/23 (KM probability 60%) and 8/23 (KM probability 38%) patients respectively. Fourteen of 21 evaluable patients developed chronic GVHD (limited in 11 cases), which resolved completely with low-dose alternate day steroids and/or CSA in all but 1 case. One patient who received an allograft from his HLA matched father died 16 months post-transplant from complications related to chronic GVHD. With a median follow up of 25 months (range 1–64 months), 20/21 patients evaluable more than 100 days post-transplant survive in complete remission with full donor chimerism in all lymphohematopoietic lineages (KM probability of long-term survival 92.8 %-see figure ). Conclusion: Fludarabine-based nonmyeloablative transplantation achieves excellent donor engraftment and long-term disease free survival in heavily transfused and allo-immunized patients with ATG refractory SAA and other nonmalignant hematological disorders associated with bone marrow failure.

Long-Term Follow-Up of Treatment for Acute Myeloid Leukemia with Allogeneic Hematopoetic Cell Transplantation Using BuCy2 as Preparation.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3370-3370
Author(s):  
Shubham Pant ◽  
Pamela Ann Crilley ◽  
Anthony J. Dodds ◽  
Jeffrey Szer ◽  
Brian J. Bolwell ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Chronic Gvhd ◽  
Group Iii ◽  
Late Failure ◽  
Group I ◽  
First Remission ◽  
Group Ii ◽  
Acute Myeloid

Abstract In 1991, we reported the results of 127 patients with Acute Myeloid Leukemia (AML) who underwent conditioning for allogeneic transplant with busulfan, 4 mg/kg on each of 4 days and cyclophosphamide 60 mg/kg on each of 2 days. In the current abstract, we report data on 295 patients, including the initial cohort, who underwent allogenic transplantation for AML from 1984 to 1995 at 7 participating institutions. Median age of patients is 33. One hundred forty nine men and 126 women underwent transplant. All patients received marrow from related HLA-identical donors. One hundred seven patients (36%) remain alive. One hundred forty one patients were transplanted in first remission (group I), 43 in second remission (group II) and 111 patients were in > 2nd remission or had refractory disease (group III). The median follow-up of patients in the initial study was 3 years and is 12 years in the current study. Seventy-five percent of patients surviving 3 years after transplantation are estimated survivors 12 years after transplant. Relapse (20), chronic GVHD (5) and infection (3) were the major causes of death in patients who died more than 3 years after transplantation. The estimated relapse rate for group I at 3 and 12 years is 18%(95% CI: 2–32%) and 29% (95% CI 11–47%) for group II is 40% (95% CI: 8–72%) and 52% (95% CI: 16–84%), and group III is 59% (95% CI: 37–81%) and 69% (95% CI: 45–93%) respectively. The estimated leukemia-free survival (LFS) for group I at 3 and 12 years is 60% (95% CI: 44–76%) and 47% (95% CI: 29–65%), for group II is 47% (95% CI: 17–77%) and 34% (95% CI: 4– 64%)and group III is 22% (95% CI: 6–38%) and 15% (95% CI: 1–29%) respectively. Remission stage was predictive of long-term LFS (P<0.001), with patients transplanted in first remission doing better than the rest. Older age was a risk factor for late failure (death or relapse beyond 3 years, P=0.05). Remission stage at transplant (p=0.44), chronic GVHD (P=0.08) and acute GVHD (P=0.12) were not significantly predictive of late failure. In conclusion a vast majority of patients alive and well at 3 years post transplant seem destined to be cured. A proportion of patients do fail beyond 3 years, but the remission stage of disease at transplant is not predictive of late failure.

Allogeneic Stem Cell Transplantation (ASCT) in CML with Partial T-Cell Depletion, No Prophylaxis for Graft-Versus-Host Disease (GvHD) and Preemptive DLI for Patients with Post-Transplant Minimal Residual Disease (MRD): An Alternative Approach in CML Transplantation with Low Morbidity and Long Term Disease Free Survival.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 318-318 ◽  
Author(s):  
Tsila Zuckerman ◽  
Tamar Katz ◽  
Nuhad Haddad ◽  
Riva Fineman ◽  
Irit Avivi ◽  
...  
Keyword(s):  
T Cell ◽  
Acute Gvhd ◽  
Disease Free Survival ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Free Survival ◽  
Post Transplant ◽  
Gvhd Prophylaxis ◽  
Cd34 Cells

Abstract The introduction of imatinib mesylate has revolutionized the treatment of CML, but despite significant cytogenetic responses primary therapy failure and emergence of resistance pose a major obstacle to successful treatment. ASCT still has a pivotal role in the treatment of CML and reduction of morbidity and mortality remains an important focus of ongoing studies in CML. We conducted a prospective study with ablative conditioning and partial T cell depleted ASCT from a matched sibling donor with no post-transplant GvHD prophylaxis. This was followed by an escalated donor lymphocyte infusion (DLI) administered if there was evidence for the presence of MRD, as determined by FISH and PCR/RQ-PCR for bcr-abl. Patients and methods: 40 consecutive patients underwent ASCT for CML between 1999–2005. The transplant regimen contained busulfan (12mg/kg), cyclophosphamide (120 mg/kg), anti-thymocyte globulin (ATG-Fresenius) (25mg/kg) and fludarabine (200mg/kg) followed by an infusion of ≥5×106/kg of G-CSF-mobilized and positively selected CD34 cells and 1×105/kg T cells. No post-transplant GvHD prophylaxis was given. The presence of MRD was determined every 3 months. DLI was administered in escalated doses starting with 3×106/kg and escalating in increments up to 1×108/kg. Results: 40 patients, median age 38 (19–63), 35 transplanted in first chronic phase (CP), 1 in second CP and 4 in accelerated phase. Patients were transplanted at a median of 4 months from diagnosis (1–66). The median of positively selected CD34+ cells was 9×106 cells/kg (5–24). 39 patients engrafted neutrophils at a median of 11 days (9–25) and platelets at a median of 15 days (9–134). Primary non-engraftment occurred in one patient and late graft failure in two, all salvageable by back-up marrow in two patients or donor stem cell boost in a single patient. The median follow-up of the entire cohort is 44 months (6–84). Overall Survival 80% Transplant Related Mortality (TRM) day 100 5% day > 100 10% Acute GvHD Post transplant (n = 38) Post DLI (n= 24) grade I-II 21% 21% grade II-III 0 8% grade IV 0 0 Chronic GvHD Post transplant (n = 38) Post DLI (n= 24) limited 2.6% 16% extensive 0 0 Need for DLI One dose 63% Two doses 31% ≥ Three doses 16% Disease-Free Survival Major cytogenetic response 6% Major molecular response 6% Complete cytogenetic and molecular response 88% Disease Progression 10% None of the patients developed significant VOD. Post transplant acute GvHD developed in only 21% of patients and was confined to grade I–II, all responding to a short course of immunosuppression. Additional 7 out of the 24 patients receiving DLI developed acute GvHD. There was no grade IV or mortality from GvHD. At the time of this analysis all apart from 1 patient were able to stop immunosuppressive treatment for GvHD. There were no significant infectious complications in this group. All late TRM were secondary to autoimmune complications, unrelated to GvHD, and occurred in 5 patients (13% of all) at 6–14 months post transplant. These complications included: ITP, AIHA, autoimmune pneumonitis, nephritic syndrome, TTP and Kaposi sarcoma. The mortality from these complications was 80% (4 out of 5 patients). 4 patients developed blast crisis post transplant; 2 patients have died; and the others are currently in CR post salvage treatment, DLI and imatinib. Twenty five percent of patients attained complete molecular remission without ever needing DLI, while 75 % responded after DLI, mostly following a single dose. Two patients are in major cytogenetic response, one of whom received back-up marrow and for the other a DLI donor is not available. The two patients in major molecular response are awaiting DLI. Conclusions: Matched ASCT for CML can be performed with significantly reduced TRM and morbidity using partial T cell depletion, no GvHD prophylaxis and preemptive DLI. This regimen offers > 80% long-term curative potential. Programmed DLI is safe and associated with a low risk of GvHD. The late immunological complications pose a major risk. This appears to be related to an imbalance between B and T cell reconstitution and the precise mechanisms of this need to be elucidated. In the imatinib era ASCT using this approach may be reserved for patients not responding or resistant to the imatinib mesylate.

Factors Influencing Relapse after Allogeneic Hematopoietic Cell Transplantation (HCT) Following Reduced Intensity Conditioning (RIC) in Patients with AML and MDS.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1654-1654
Author(s):  
Haifa K. Al-Ali ◽  
Claudia Nehring ◽  
Rainer Krahl ◽  
Cornelia Becker ◽  
Sabine Leiblein ◽  
...  
Keyword(s):  
High Risk ◽  
Hematopoietic Cell Transplantation ◽  
Bone Marrow Cells ◽  
Negative Impact ◽  
Chronic Gvhd ◽  
Therapeutic Interventions ◽  
Entire Cohort ◽  
Factors Influencing ◽  
Group I ◽  
Group Ii

Abstract Relapse (RI) after HCT especially after RIC remains the major risk factor affecting outcome. Factors influencing relapse in patients (pts) with AML/MDS undergoing HCT after RIC were analysed. Patients and methods: From July, 1998- December, 2006, 156 consecutive pts [86 m/70 f; median age 61 (range 21–75) years (y)] with AML, n=138 (88%) and high-risk MDS, n=18 (12%) treated within the OSHO studies received HCT after RIC [2Gy TBI ± fludarabine 30 mg/m2/day on 3 days] followed by immunosuppression with mycophenolate mofetil and cyclosporine. Donors were MRD in 40 (26%) and MUD in 116 (74%) pts. Stage of disease was CR1, n= 99 (63%), CR2, n=18 (12%), and &gt;CR2, n=39 (25%). Cytog. was intermediate-, and high-risk in 100 (64%), and 49 (31%) respectively. DCC in unsorted and flow-sorted T (CD3+)-, and CD34+-bone marrow cells at days (d) 28, 56, 84, and at 3 months interval thereafter was monitored by FISH for the XY chromosome in gender mismatched or PCR for polymorphic micro satellite regions in gender matched HCT. Results: 141 (90%) pts engrafted. OS, DFS, RI, and NRM at 5 y were 38%, 36%, 47%, and 30% respectively. In multivariate analysis, RI for pts in CR1 was significantly lower compared to pts transplanted beyond CR1 (p=0.005). For the entire cohort, type of donor had no influence on RI but for pts in CR1, RI with MUD and MRD was 29% and 60% respectively (p=0.008). NRM did not correlate with the type of donor. Interestingly, high-risk cytog. had no negative impact on outcome. OS, DFS, and RI for pts with high-risk cytog. transplanted in CR1 were 43%, 48%, and 38% respectively compared to 38%, 43%, and 45% for pts with intermediate-risk cytog. (p=0.65). Incidence of acute (grade I-IV) and chronic (limited and extensive) GvHD was 55%, and 58% respectively. GvHD correlated with an improved OS (p=0.0003) and DFS (p=0.003) but was not associated with a higher NRM (p=0.1) compared to pts with no GvHD. Also, RI was markedly influenced by GvHD (p=0.002). RI in pts with no GvHD (n=42), acute GvHD only (n=34), limited chronic GvHD (n=33), and extensive chronic GvHD (n=30) was 63%, 41%, 29%, and 18% respectively. In pts with chronic GvHD, RI was significantly lower compared to pts with no GvHD (p&lt;0.0001). Further, CD34+ DCC ≥90% at d 28 strongly correlated with outcome at 5 y. OS and DFS in pts with CD34+ DCC ≥90% at d 28 (group I) were 50%, and 47% respectively compared to pts with CD34+ DCC &lt;90% at d 28 (group II) (OS 20%, DFS 15%) (p&lt;0.0001). CD34+ DCC ≥90% at d 28 was highly predictive of early (≤100 d) and late (&gt;100 d) haematological relapse. Probability of RI in group I was 29% compared to 76% in group II (p&lt;0.0001). On the other hand, DCC in unsorted- and CD3+-cells at d 28 did not correlate with OS, DFS nor predict relapse. Conclusions: HCT after RIC offers long-term OS and DFS in AML/MDS pts. RI was lowest in pts transplanted from MUD in CR1. High-risk cytog. had no negative impact on RI. GvHD correlated with an improved outcome. CD34+ DCC ≥90% at d 28 was highly predictive of relapse after HCT. Careful monitoring of CD34+ DCC could identify pts at risk of relapse and might allow therapeutic interventions as tapering of immunosuppression.

scholarly journals Alternating-day cyclosporine and prednisone for treatment of high-risk chronic graft-v-host disease

Blood ◽  
1988 ◽  
Vol 72 (2) ◽  
pp. 555-561 ◽  
Author(s):  
KM Sullivan ◽  
RP Witherspoon ◽  
R Storb ◽  
HJ Deeg ◽  
S Dahlberg ◽  
...  
Keyword(s):  
High Risk ◽  
Chronic Gvhd ◽  
Renal Dialysis ◽  
Marrow Transplant ◽  
Primary Treatment ◽  
Aseptic Necrosis ◽  
Actuarial Survival ◽  
Host Disease ◽  
Group I ◽  
Group Ii

Abstract Therapy of chronic graft-v-host disease (GVHD) has been unsatisfactory in patients with platelet counts less than 100,000/microL. Survival at 5 years after marrow transplant is only 26% in such patients treated with trimethoprim-sulfamethoxazole (TMP-SMX) and every other day with prednisone. Since October 1982, 61 patients with high-risk extensive chronic GVHD were treated with a new alternating-day regimen of prednisone (1 mg/kg every other day) and oral cyclosporine (6 mg/kg every 12 hours every other day) with one double-strength TMP-SMX tablet twice daily. Forty patients (group I) received primary treatment of thrombocytopenic chronic GVHD (median platelet count 35 [range 7 to 87] x 10(3)/microL). Twenty-one patients (group II) received salvage treatment after failing initial prednisone +/- azathioprine. Twenty-one patients in group I and 15 in group II survive with a minimum of 2 years and a median of 3.7 years follow-up. At 4 years after transplant, actuarial survival is 51% (group I) and 67% (group II). Causes of death included interstitial pneumonia (six), relapse (five), GVHD without infection (five), infection (four), organ failure (three), and hemorrhage (two). Mortality increased with the progressive type onset of chronic GVHD and treatment failure. Toxicity included hypertension (13), nephrotoxicity (nine), nausea (seven), aseptic necrosis (five), neurologic abnormalities (four), and diabetes (three). Median cyclosporine levels at four and 36 hours were 296 and 64 ng/mL, respectively. Four patients required permanent discontinuation of cyclosporine, but none required renal dialysis. Karnofsky performance scores for 25 survivors are 90% to 100%, scores for six survivors are 70% to 89%, and scores for five survivors are less than 70%. Alternating-day cyclosporine and prednisone has acceptable toxicity and appears to improve survival in patients with high-risk chronic GVHD.

scholarly journals Alternating-day cyclosporine and prednisone for treatment of high-risk chronic graft-v-host disease

Blood ◽  
1988 ◽  
Vol 72 (2) ◽  
pp. 555-561
Author(s):  
KM Sullivan ◽  
RP Witherspoon ◽  
R Storb ◽  
HJ Deeg ◽  
S Dahlberg ◽  
...  
Keyword(s):  
High Risk ◽  
Chronic Gvhd ◽  
Renal Dialysis ◽  
Marrow Transplant ◽  
Primary Treatment ◽  
Aseptic Necrosis ◽  
Actuarial Survival ◽  
Host Disease ◽  
Group I ◽  
Group Ii

Therapy of chronic graft-v-host disease (GVHD) has been unsatisfactory in patients with platelet counts less than 100,000/microL. Survival at 5 years after marrow transplant is only 26% in such patients treated with trimethoprim-sulfamethoxazole (TMP-SMX) and every other day with prednisone. Since October 1982, 61 patients with high-risk extensive chronic GVHD were treated with a new alternating-day regimen of prednisone (1 mg/kg every other day) and oral cyclosporine (6 mg/kg every 12 hours every other day) with one double-strength TMP-SMX tablet twice daily. Forty patients (group I) received primary treatment of thrombocytopenic chronic GVHD (median platelet count 35 [range 7 to 87] x 10(3)/microL). Twenty-one patients (group II) received salvage treatment after failing initial prednisone +/- azathioprine. Twenty-one patients in group I and 15 in group II survive with a minimum of 2 years and a median of 3.7 years follow-up. At 4 years after transplant, actuarial survival is 51% (group I) and 67% (group II). Causes of death included interstitial pneumonia (six), relapse (five), GVHD without infection (five), infection (four), organ failure (three), and hemorrhage (two). Mortality increased with the progressive type onset of chronic GVHD and treatment failure. Toxicity included hypertension (13), nephrotoxicity (nine), nausea (seven), aseptic necrosis (five), neurologic abnormalities (four), and diabetes (three). Median cyclosporine levels at four and 36 hours were 296 and 64 ng/mL, respectively. Four patients required permanent discontinuation of cyclosporine, but none required renal dialysis. Karnofsky performance scores for 25 survivors are 90% to 100%, scores for six survivors are 70% to 89%, and scores for five survivors are less than 70%. Alternating-day cyclosporine and prednisone has acceptable toxicity and appears to improve survival in patients with high-risk chronic GVHD.

Full Donor T Cell Chimerism Predicts Transplant Outcomes In High Risk AML But Not In Intermediate Risk AML After a T-Deplete Alemtuzumab Conditioned Transplant

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5545-5545
Author(s):  
Amy Gudger ◽  
Vidhya Murthy ◽  
Duncan J Murray ◽  
Ben Bailiff ◽  
Maria Mushkbar ◽  
...  
Keyword(s):  
Overall Survival ◽  
Multivariate Analysis ◽  
T Cell ◽  
High Risk ◽  
Risk Group ◽  
Chronic Gvhd ◽  
Disease Free Survival ◽  
Intermediate Risk ◽  
Donor Chimerism ◽  
Number Of Patients

Abstract Reduced intensity conditioning (RIC) T-deplete regimens are now widely used as a platform to deliver a potentially curative T cell mediated graft-versus-leukaemia (GVL) effect in patients with haematological malignancies. T cell chimerism has been shown to correlate with the risk of both GVHD and disease relapse in T replete RIC AML allografts but it remains unclear whether such a correlation exists in patients undergoing an alemtuzumab based allograft for intermediate and high risk AML. We have therefore correlated T cell chimerism on D+60 and D+180 in 43 patients undergoing an alemtuzumab based RIC allograft for AML(high risk=20, intermediate risk=23) in CR1 with transplant outcomes. The conditioning used was Fludarabine 30mg/m2 for 5 days, Melphalan 140mg/m2 for 1 day and Alemtuzumab 30mg IV for 1 day for sibling transplants and 50mg IV over 2 days for unrelated donor transplants. The median age of the patients was 51 years (range 42-57 years) and median follow up was 45 months (range 6 – 108 months).18 patients received a graft from a sibling donor and 25 from an unrelated fully matched donor. The 3 year overall survival was 53% on the intermediate risk group and 40% on the high risk group. Overall 31% of patients relapsed in both groups. T cell full donor chimerism at D+60 and D+180 was significantly associated with better overall survival (52 months vs 18months p:0.04), 2 years disease free survival of (53% vs 32% p:0.03) and higher incidence (85%) of acute GvHD (p:0.01) and chronic GvHD(p:0.02) in the high risk AML group on both univariate and multivariate analysis. In the intermediate risk group though full donor chimerism was associated with improved disease survival on univariate analysis but this wasn’t confirmed on multivariate analysis and this was likely secondary to the small number of patients. In both univariate and multivariate analysis patients with full donor chimerism at 60 days were almost 80% more likely to have acute GVHD than patients with fully donor chimerism (p=0.04) and patients with full donor chimerism at D+180 were almost 85% more likely to achieve chronic GvHD(p:0.02). Preemptive DLI infusion for mixed chimerism post D+180 was given to patients without prior severe GvHD after stopping Ciclosporin and was associated with improved disease free survival and a trend for improved overall survival for both risk groups by potentially augmenting the GvL effect. The 2 year incidence of graft-versus-host disease post DLI was only 29%. Although conclusions of our study were limited by the small number of patients included, the high risk AML group of patients seems to benefit from acquisition of full donor T cell chimerism. In the intermediate risk group this effect was not demonstrated although probably a higher number of patients with molecular risk stratification is needed. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Intensive Multiagent Therapy, Including Dose-Compressed Cycles of Ifosfamide/Etoposide and Vincristine/Doxorubicin/Cyclophosphamide, Irinotecan, and Radiation, in Patients With High-Risk Rhabdomyosarcoma: A Report From the Children's Oncology Group

2016 ◽  
Vol 34 (2) ◽  
pp. 117-122 ◽  
Author(s):  
Brenda J. Weigel ◽  
Elizabeth Lyden ◽  
James R. Anderson ◽  
William H. Meyer ◽  
David M. Parham ◽  
...  
Keyword(s):  
Risk Factors ◽  
Risk Factor ◽  
High Risk ◽  
Bone Marrow Involvement ◽  
High Risk Group ◽  
Historical Cohort ◽  
Dismal Prognosis ◽  
Risk Patients ◽  
Metastatic Sites

Purpose Patients with metastatic rhabdomyosarcoma (RMS), except those younger than 10 years with embryonal RMS, have an estimated long-term event-free survival (EFS) of less than 20%. The main goal of this study was to improve outcome of patients with metastatic RMS by dose intensification with interval compression, use of the most active agents determined in phase II window studies, and use of irinotecan as a radiation sensitizer. Patients and Methods Patients with metastatic RMS received 54 weeks of therapy: blocks of therapy with vincristine/irinotecan (weeks 1 to 6, 20 to 25, and 47 to 52), interval compression with vincristine/doxorubicin/cyclophosphamide alternating with etoposide/ifosfamide (weeks 7 to 19 and 26 to 34), and vincristine/dactinomycin/cyclophosphamide (weeks 38 to 46). Radiation therapy occurred at weeks 20 to 25 (primary) but was also permitted at weeks 1 to 6 (for intracranial or paraspinal extension) and weeks 47 to 52 (for extensive metastatic sites). Results One hundred nine eligible patients were enrolled, with a median follow-up of surviving patients of 3.8 years (3-year EFS for all patients, 38% [95% CI, 29% to 48%]; survival, 56% [95% CI, 46% to 66%]). Patients with one or no Oberlin risk factor (age > 10 years or < 1 year, unfavorable primary site of disease, ≥ three metastatic sites, and bone or bone marrow involvement) had a 3-year EFS of 69% (95% CI, 52% to 82%); high-risk patients with two or more risk factors had a 3-year EFS of 20% (95% CI, 11% to 30%). Toxicity was similar to that on prior RMS studies. Conclusion Patients with metastatic RMS with one or no Oberlin risk factor had an improved 3-year EFS of 69% on ARST0431 compared with an historical cohort from pooled European and US studies; those with two or more risk factors have a dismal prognosis, and new approaches are needed for this very-high-risk group.

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