Reduced-Intensity Conditioning Followed by Allogeneic Stem Cell Transplantation (allo-SCT) Is an Effective Salvage Treatment for Peripheral T-Cell Non-Hodgkin’s Lymphoma (PTCL).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1128-1128 ◽  
Author(s):  
Paolo Corradini ◽  
Anna Dodero ◽  
Marco Bregni ◽  
Francesco Zallio ◽  
Lucia Farina ◽  
...  
Keyword(s):  
De Novo ◽  
Present Report ◽  
Chronic Gvhd ◽  
High Dose Chemotherapy ◽  
High Dose ◽  
Unrelated Donor ◽  
Not Otherwise Specified ◽  
Short Course ◽  
Gvhd Prophylaxis

Abstract Patients with relapsed PTCL have a poor prognosis. We had previously shown the existence of a graft-versus-lymphoma effect against PTCL (J Clin Oncol, 2004). In the present report, we extended our previous observations to 26 patients (pts) receving allo-SCT. All patients received several courses of debulkying chemotherapy (usually 3 DHAP and/or high-dose chemotherapy) followed by the same RIC regimen containing thiotepa (10 mg/kg), fludarabine (60 mg/ms) and cyclophosphamide (60 mg/kg). GVHD prophylaxis consisted of cyclosporine A and short-course methotrexate. Patients’ median age was 45 years (range, 15–64). Histologic PTCL subtypes included: PTCL not otherwise specified (n=12), ALCL (n=7), angioimmunoblastic (n=3), others subtypes (n=4). Twenty-two pts (84%) received transplant from HLA-identical sibling, 3 from haploidentical sibling and one from unrelated donor. The median time from diagnosis to transplantation was 17 months. Thirteen patients (50%) had failed a previous auto and the majority received at least 2 lines of chemotherapy before allo-SCT. Seven (27%) and 13 pts (50%) were in CR and PR at the time of allo-SCT, respectively. At median follow-up of 27 months (range, 8–73), 17 (65%) were alive (n=14 in CR) and 9 died (n=6 disease, n=3 toxicity). The estimated 3-year TRM was 13%. The estimated 5 year OS and PFS projections were 61% (95% CI, 41–81%) and 51% (95% CI, 30–72%), respectively. Relapses occurred in the first 6 months after allo-SCT and we did not observe differences in PFS between specified and unspecified variants. De-novo acute GVHD (II/IV) and chronic GVHD incidence were 28% and 24%, respectively. Eight patients received DLI, 6 for relapse, 1 pre-emptive, 1 for infection: 3 responded (n=1 CR, n=2 PR). Following DLIs, 4 patients developed GVHD with associated a clinical response. In conclusion, our data indicate: 1) long-term disease control was achieved in patients with an aggressive subtype of NHL; 2) although optimal therapeutic strategies for relapsed PTCL are yet to be defined, further prospective evaluation of allo-SCT is required.

Long-Term Follow-up of a Randomized Trial Comparing Cyclosporine and Short Course Methotrexate with Cyclosporine and Mycophenolate Mofetil for Graft Versus Host Disease Prophylaxis in Myeloablative HLA-Identical Sibling Hematopoietic Cell Transplantation.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3073-3073
Author(s):  
Betty K. Hamilton ◽  
Brian J. Bolwell ◽  
Matt Kalaycio ◽  
Lisa Rybicki ◽  
Rabi Hanna ◽  
...  
Keyword(s):  
Randomized Trial ◽  
Conflicts Of Interest ◽  
Chronic Gvhd ◽  
Hematopoietic Cell ◽  
Short Course ◽  
Gvhd Prophylaxis ◽  
Significant Difference ◽  
Long Term Follow Up

Abstract Abstract 3073 The combination of a calcineurin inhibitor and methotrexate (MTX) is currently the gold standard for GVHD prophylaxis. MTX, however, is associated with toxicity including mucositis, delayed engraftment and other organ toxicity. We conducted a randomized trial comparing cyclosporine (CSA) and mycophenolate (MMF) with CSA and MTX for GVHD prophylaxis in recipients of myeloablative allogeneic hematopoietic cell transplants (HCT) with matched sibling donors (Bolwell et al, BMT 2004, 34:621). We showed reduced toxicity without an increased relapse rate in patients treated with MMF instead of MTX. Now, with a median follow up of almost 10 years, we report long-term outcomes of this study. From May 2001 until February 2003, 40 patients with hematologic malignancies were randomized to receive CSA (300mg/m2) and MMF (500mg three times daily) or CSA and short course MTX (5mg/m2 days 1, 3, 6, 11). Study endpoints included incidence of acute GVHD, severity of mucositis, time to engraftment of neutrophils and platelets and 100 day survival. Baseline variables were compared using the Wilcoxon rank sum tests or Chi square test. Outcomes were compared between MMF and MTX using the Pepe-Mori test. The two treatment arms were similar in patient characteristics such as age, disease, disease status, and CMV status. In total, 21 patients received MMF and 19 patients received MTX. The study was stopped early when an interim analysis demonstrated less mucositis, shorter length of stay and no difference in the incidence of GVHD or relapse with a median of 6 months of follow up. Currently, with a median follow up of 119 months (range 46–129 months) in survivors, there remains no difference in the incidence of or degree of acute (p≥0.35) or chronic GVHD (p≥0.53), overall survival (p=0.84) or relapse (p=0.41). There are 6 long term survivors in the MMF arm and 4 in the MTX arm. Of those that received MMF, 3 have mild chronic GVHD of the skin or upper GI tract and 1 has moderate chronic GVHD involving the skin, fascia, and vulva. Three of those who received MTX have mild chronic GVHD primarily of the skin. Only 3 patients (2 MMF and 1 MTX) remain off of all immunosuppression without evidence of GVHD. Eight patients (38%) died of relapse in the MMF arm versus 7 (37%) in the MTX arm which was also not statistically different (p=0.86). Death from GVHD was similar in both groups. Results from this updated analysis support our original conclusion that the combination of CSA and MMF results in decreased mucositis and more rapid engraftment compared with CSA and MTX, with no significant difference in GVHD, survival or relapse on long-term follow up. The primary limitation of this trial remains sample size and the ability to detect modest differences in survival. There remains limited data and virtually no long-term data comparing standard MTX based regimens with less toxic prophylaxis in myeloablative allogeneic HCT. Larger prospective studies with long-term follow up comparing GVHD prophylaxis regimens are warranted. Disclosures: No relevant conflicts of interest to declare.

Haploidentical Transplantation (HAPLO) with Post-Transplant High-Dose Cyclophosphamide for Graft Vs Host Disease (GVHD) Prevention in the Treatment of High Risk Hematological Neoplasms

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4545-4545
Author(s):  
Jorge Gayoso ◽  
Mi Kwon ◽  
David Serrano ◽  
Pascual Balsalobre ◽  
Javier Anguita ◽  
...  
Keyword(s):  
High Risk ◽  
Conflicts Of Interest ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Disease Status ◽  
Allogeneic Transplantation ◽  
High Dose ◽  
Unrelated Donor ◽  
Haploidentical Transplantation ◽  
Gvhd Prophylaxis

Abstract Abstract 4545 Introduction: Allogeneic transplantation is the only curative option in the treatment of multiple high risk hematologic neoplasms. Only 25–30% of patients have an HLA identical sibling donor and searching for a compatible unrelated donor or cord blood renders satisfactory results in around 60–70%. Haploidentical transplantation (HAPLO) offers a therapeutic alternative to more than 95% of such patients with the advantages of quick availability, easy programming and a committed donor. Patients and Methods: We evaluate the results of HAPLO with a reduced intensity conditioning regimen (Fludarabine 30 mg/m2 ×5 days (-6 to -2), Cyclophosphamide 14,5 mg/kg ×2 days (-6 and -5), IV Busulfan 3,2 mg/kg × 1–3 days (BUX, days -4 to -2) employing high doses of Cyclophosphamide post graft infussion (50 mg/kg days +3 and +4) as GVHD prophylaxis together with standard doses of cyclosporine and mycophenolate from day +5. Results: From Dec-2007, we have done 26 HAPLO in 4 spanish centers. Median age was 38 years (16–57), 20 were male and all were in advanced phases of their diseases (12 Hodgkin′s, 6 AML, 3 ALL, 2 MM, 1 MDS, 1 MF y 1 NHL). Previous autologous HSCT has been employed in 13 and allogeneic HSCT in 6 (2 MURD and 4 UCB). Disease status at HAPLO was CR in 8, PR in 14 and refractory in 4. Bone marrow was used in 16 and unmodified peripheral blood in 10. The haploidentical donor was patient′s mother (8), father (3), siblings (11) or other relatives (4). BUX was used in 1 dose (15), 2 doses (8) or 3 doses (2) and TBI 200 cGy in 1 case. Mean neutrophils engraftment was achieved on day +18 (13–26) and platelets >50K on day +27 (17–150) in all but 2 cases of graft failure (7.7%) due to progression (MF) or relapse (M7-AML). Main toxicities were grade 1–2 mucositis in 50%, febrile neutropenia in 75% and CMV reactivations in 58% with a 100 days NRM of 3.8% (1/26, VOD and MOF) and 10% NRM at 6 months (2/20). Grade II-IV acute GVHD appeared in 10/23 patients at risk (43%) and grade III-IV in 4/23 (17%). Chronic GVHD affected to 4/15 (27%), being extensive in 1/15 (6.7%). With a median follow-up of 9 months (1–38), 13/22 (59%) are alive in CR, progression or relapse has ocurred in 6/24 (25%). Immune reconstitution seems fast and complete in those evaluated. Conclusions: HAPLO with high-dose cyclophosphamide as GVHD prophylaxis is a useful alternative in the treatment of high risk hematologic tumours, with low toxicity, acceptable GVHD incidence and severity, long lasting remissions, and fast immunological reconstitution. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Unrelated Cord Blood Transplantation and Post-Transplant Cyclophosphamide (PT-CY)

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3332-3332
Author(s):  
Patrizia Chiusolo ◽  
Andrea Bacigalupo ◽  
Simona Sica ◽  
Sabrina Giammarco ◽  
Elisabetta Metafuni ◽  
...  
Keyword(s):  
Cord Blood ◽  
Median Time ◽  
Cord Blood Transplantation ◽  
Chronic Gvhd ◽  
High Dose ◽  
Unrelated Donor ◽  
Immune Recovery ◽  
Post Transplant ◽  
Gvhd Prophylaxis ◽  
Unrelated Cord Blood

Background .There has been a decrease in the use of unrelated cord blood transplants (UCBT) in the past years: this is probably due to slow hematologic and immune recovery, resulting in a relatively high non relapse mortality (NRM). The addition of anti-thymocyte globulin (ATG) in the conditioning prevents graft versus host disease (GvHD) but makes immune recovery very slow. In addition there is a growing competition of unmanipulated haploidentical transplants. Aim of the study. We have opened a pilot study to test whether high dose post-transplant cyclophosphamide (PT-CY) would prevent GvHD but still allow for robust immune and hematologic recovery . Methods. We have grafted 10 patients with an unrelated CB unit and PT-CY. The conditioning regimen was thiotepa (10 mg/kg), busulfan 9.6 mg/kg and fludarabine 150 mg/m^2 (TBF). GvHD prophylaxis was cyclosporin (CSA) starting day 0 (3 mg/kg/day(i.v.), mycophenolate (MMF) 30 mg/kg starting day +1 (p.o) , and PT-CY 30 mg/kg days +3 and +5. The median patients' age was 58 (43-66), and the median weight was 75 kg (54-85) the diagnosis was AML in 8 patients, Ph'+ALL in one and RAEB in one patient; 6 patients were in remission and 4 had active disease. CB units. The HLA matching of the CB unit was 5/8 antigens/alleles (A,B,C,DRB1) in six patients, 4/8 in two and 2/8 in one. The median nucleated cell dose was 3.1x10^7/kg (range 1.8- 4.5). The ABO was mismatched in all 10 patients. Hematologic recovery: median time to neutrophils 0.5x10^9/l was day 23 days (range 17-27) and the median time to a platelet count of 20x10^9/L was 38 days (range 34-40). The median counts on day +50 were as follows: Hb 9,1 gr/dL (range 8.7-11.1), Neutrophils 2,3 x10e9/L (range 1-5), PLTs 56 x10e9/L (10-90). One patient failed to engraft and received a second transplant from an unrelated donor, which was successful. No patient developed pure red cell aplasia despite 9/10 being ABO major mismatched. CD4 recovery : the median CD4 count on day +50 was 74 /cmm (range 67-116) and on day +100 it was 111/cmm(range 100-136). CMV pre-emptive therapy occurred in 3/6 evaluable patients Outcome: two patients with advanced disease, died early of infections, within day +20. GvHD was seen in 1 patient as a transient rash. No patient was treated for GvHD. No patient developed chronic GvHD. No patient relapsed. Eight patients survive in remission, with a median follow up of 6 months, and a projected one year actuarial survival of 80%. Readmissions were extremely rare. Conclusions. These first 10 patients suggest that UCBT followed by PT-CY, CSA, MMF, as GvHD prophylaxis is feasible and leads to encouraging hematologic and immunologic recovery. We were particularly impressed with the lack of GvHD, the absence of relapses and the good quality of life. Figure Disclosures No relevant conflicts of interest to declare.

Higher CD 34 Cell Doses Reduce Non Relapse Mortality (NRM) and Do Not Increase the Incidence of Graft Versus Host Disease (GVHD) Following Unrelated Donor Blood Stem Cell Transplantation (SCT).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 5091-5091
Author(s):  
Sujaatha Narayanan ◽  
Michael J. Barnett ◽  
Yasser R. Abou Mourad ◽  
Donna L. Forrest ◽  
Donna E. Hogge ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Chronic Gvhd ◽  
Favourable Outcome ◽  
Unrelated Donor ◽  
Donor Blood ◽  
Cell Dose ◽  
Cd 34 ◽  
Short Course ◽  
Gvhd Prophylaxis ◽  
Neutrophil Engraftment

Background: Higher CD34 cell doses have been shown to increase the incidence of acute (Przepiorka D et al, 1999) and extensive chronic GVHD (Zaucha et al, 2001) following HLA-matched sibling SCT. Less is known about the influence of CD 34 cell dose in the unrelated SCT setting. Methods: A retrospective review was performed involving 81 consecutive adult patients (pts) who underwent unrelated donor G-CSF mobilised blood SCT in Vancouver between June 2000 and October 2006. NRM, relapse risk (RR) and overall survival (OAS) estimates were determined using a Kaplan-Meier technique and univariate and multivariate analyses were done to identify factors predictive of GVHD and outcome, with particular focus on cell dose administered. Characteristics: There were 46 male and 35 female pts with a median age of 44 (range 17–58) years. Diagnoses included acute leukemia (39 pts), chronic leukemia (14 pts), lymphoma (15 pts) and other (13 pts). Conditioning was TBI-based in 80/81 pts and GVHD prophylaxis was with continuous infusion Cyclosporine and short-course Methotrexate (MTX) (15mg/m2 d +1 and 10mg/m2 d+3, d+6 and d+11). Fifty of 81 pts received >80% of the planned MTX dose. Forty three pts received SCT from a 10/10 high-resolution HLA-matched donor, 25 pts received a 1-antigen mismatched SCT, 12 pts received a 2-antigen mismatched SCT and 1 pt a 3-antigen mismatched SCT. The donor was male for 68 pts and female for 13 pts. Median CD 34 cell dose was 7.75x106 (range−9.46x104–33.6x106)/kg. Results: The estimated 3-year NRM, RR and OAS were 39% (95%CI 25%–50%), 30% (95%CI 17%–41%) and 43% (95%CI 31%–58%), respectively. In multivariate analysis, CD 34 cell dose >7.75x106/kg was associated with faster neutrophil engraftment, p<0.001 and reduced NRM (28% vs. 49%, p=.019), but did not influence the incidence of either acute or chronic GVHD or OAS. Multivariate analysis showed that the most important predictor of grade 3–4 acute GVHD (49% vs. 22%, p=.005), NRM (65 vs. 30%, p=.006), and OAS (24% vs. 50%) was administration of >80% of the planned MTX dose. Although having a female donor predicted for an increase in NRM (p=.03), it also was associated with a decrease in RR (0/13 pts) and did not affect OAS. Conclusion: A high CD34 cell dose in unrelated donor blood SCT is desirable in that it does not adversely influence the incidence of GVHD and is associated with faster neutrophil engraftment and a reduction in NRM. Delivery of at least 80% of the planned short-course MTX GVHD prophylaxis continues to be critical in producing a favourable outcome.

Dual Cord Blood Unit (dCBU) Transplantation Increases Short-Term Morbidity, but Has Similar Long-Term Outcome Compared to Matched Unrelated Donor (MUD) Transplantation After Myeloablative Conditioning.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3137-3137
Author(s):  
Matt Kalaycio ◽  
Brian J. Bolwell ◽  
Lisa Rybicki ◽  
Edward Copelan ◽  
Hien K. Duong ◽  
...  
Keyword(s):  
Chronic Gvhd ◽  
Hematopoietic Cell ◽  
Unrelated Donor ◽  
Term Survival ◽  
Long Term Outcome ◽  
Gvhd Prophylaxis ◽  
Significant Difference ◽  
Cell Source ◽  
Matched Sibling

Abstract Abstract 3137 In the absence of a matched sibling donor for allogeneic hematopoietic cell transplantation (HCT), a MUD is the most often used alternative hematopoietic cell source. Unfortunately, many patients do not have a well-matched MUD. For these patients, CBU transplant is a viable alternative donor source. To optimize hematopoietic engraftment in adult recipients two CBU are often required. We offer dCBU transplantation to patients lacking matched sibling and unrelated donors. This report compares outcomes between those treated with dCBU and MUD HCT at our institution. From 8/7/2009 through 12/2011, 22 hematologic malignancy patients received dCBU transplants using the conditioning regimen and GVHD prophylaxis described by the group at the University of Minnesota (Barker et al, Blood. 105: 1343, 2005). Thus, we treated patients with fludarabine 75mg/m2 D-8 to D-6, cyclophosphamide 120mg/kg D -7 to D -6, and total body irradiation (TBI) 1320 cGy D -4 to D -1. GVHD prophylaxis included cyclosporine and mycophenolate. We then selected 42 patients treated with MUD HCT (40 well-matched, 2 partially matched) for similar diagnoses from our database as a comparator group. Patients with MUD donors were treated with either etoposide 60mg/kg and TBI 1200cGy if they had acute lymphoblastic leukemia, or busulfan 16mg/kg orally (or the equivalent administered intravenously) D -8 to D -4 and cyclophosphamide 120mg/kg D -3 to D -2. GVHD prophylaxis for MUD patients included tacrolimus and methotrexate, except in one case where mycophenolate was substituted for methotrexate. The median age of the patients was 49 years (range 20–62 years) with no significant difference between treatment groups. Neither were there differences in diagnoses, HCT-comorbidity index, time from diagnosis to transplant, disease status, or CMV status. However, there was a significant difference with regard to race with 24% of dCBU HCT in African-American patients compared to none of the MUD HCT (P<0.001). Patients with MUD HCT recovered neutrophils and platelets faster (median 16 and 24 days respectively) compared to dCBU HCT (median 27 and 52 days respectively; P<0.001) resulting in shorter length of stay (median 29 versus 49 days; P<0.001) and contributing to a trend toward improved 100 day mortality (17% vs 38%; P=0.06). There was no significant difference in the incidence or severity for either acute or chronic GVHD between the groups. However, the incidence of infection was significantly greater with dCBU HCT (P<0.001). There was also a trend toward greater non-relapse mortality among patients treated with dCBU HCT(P=0.07) all of which occurred within the first 6 months of transplant. Cox proportional hazards analysis was used to identify univariable and multivariable prognostic factors for overall (OS) and relapse-free survival (RFS). Only age (OS: HR1.66; 95% CI 1.08–2.56; P=0.020. RFS: HR1.61; 95% CI 1.07–2.42; P=0.023) and CMV positivity in either donor or recipient (OS: HR 2.61; 95% CI 1.02–6.65; P=0.044. RFS: HR 2.71; 95%CI 1.07–6.86; P=0.035) were significant risk factors. Cell source did not significantly impact either RFS or OS (See figure). We conclude that although dCBU HCT results in increased early morbidity, there is no significant difference in risk for GVHD, and long-term survival outcomes are similar compared to MUD HCT. dCBU HCT is a useful alternative for patients lacking sibling and MUD donors. Disclosures: No relevant conflicts of interest to declare.

Nonmyeloablative (NMA), HLA-Mismatched Unrelated Donor (mMUD) BMT with High-Dose Posttransplantation Cyclophosphamide (PTCy) Has Outcomes Similar to Matched BMT

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2002-2002 ◽  
Author(s):  
Yvette L. Kasamon ◽  
Ephraim J. Fuchs ◽  
Javier Bolaños-Meade ◽  
Mary S. Leffell ◽  
Marianna Zahurak ◽  
...  
Keyword(s):  
Risk Analysis ◽  
Chronic Gvhd ◽  
Competing Risk ◽  
High Dose ◽  
Unrelated Donor ◽  
Competing Risk Analysis ◽  
Hla Antigen ◽  
Platelet Recovery ◽  
Neutrophil Recovery ◽  
Gvhd Prophylaxis

Abstract Background: The results of NMA, related HLA-haploidentical (haplo) BMT with PTCy are comparable to matched BMT (Blood 2015;125;3024). However, patients (pts) may lack related donors, often because of familial disease susceptibility or cytotoxic antibodies against donor HLA molecules. Although partially HLA-mMUD BMT could be considered if a MUD is unavailable, mismatches > 1 HLA antigen have historically been associated with unacceptable rates of GVHD, graft failure, and nonrelapse mortality (NRM). We hypothesized that PTCy may overcome this HLA barrier. Methods: We developed a prospective, regimen-finding study of NMA BMT for hematologic malignancies pts without an acceptable matched or first-degree related haplo donor. The objective was to identify a regimen with ≤ 25% severe acute GVHD and ≤ 20% NRM by day 100, using mMUD's or non-first-degree relatives. Results of mMUD BMT with our standard conditioning are presented. Pt eligibility included age 0.5-75 years, no suitable family donor, ECOG PS ≤ 2, LVEF ≥ 35%, FEV1 and FVC ≥ 40% predicted, and adequate hepatic function. The mismatched donor shared ≥ 5/10 HLA alleles (based on molecular typing of HLA-A, -B, -Cw, -DRB1, and -DQB1) with ≥ 1 allele matched for a HLA class I gene and ≥ 1 allele matched for a class II gene. Donors matched at ≥ 1 allele at each locus were prioritized, followed by donors having the fewest number of mismatched loci. All pts received fludarabine (30 mg/m2 IV days -6 to -2), Cy (14.5 mg/kg IV days -6 and -5), TBI (200 cGy day -1) and T-cell replete bone marrow. GVHD prophylaxis consisted of high-dose PTCy (50 mg/kg IV days 3 and 4), mycophenolate mofetil on days 5-35, and either sirolimus (15 pts) or tacrolimus (1 pt) on days 5-180. GCSF was given from day 5 until neutrophil recovery. Safety was continuously monitored. Results: Sixteen pts (median age 57, range 37-66) received mMUD BMT on this study from 7/2011-6/2014 (9 AML cases, 4 MDS or MPN, 1 CML, 2 PTCL). Major reasons for utilizing a mMUD included the absence of an adult haplo first-degree relative and the presence of prohibitive donor-specific anti-HLA antibodies (DSA's). The unrelated grafts had a median of 2 HLA mismatches and included three 7/10 matches, one 6/10 match, and one 5/10 match. HLA-C mismatch was present in 10 grafts (63%) and complete DP mismatch in 6 (38%).By revised Disease Risk Index, 25% of pts were high risk, 69% intermediate risk, and 6% low risk; 69% were in CR at BMT. The median graft doses were 3.36 x 108 total nucleated cells/kg and 3.87 x 107 CD3+ cells/kg. All pts engrafted, and there were no non-relapse deaths or prohibitive toxicities. By competing-risk analysis, the estimated cumulative incidence (CuI) of neutrophil recovery was 100% by day 29, with a median of 20 (range 14-29) days. The CuI of platelet recovery ≥ 20,000/µL was 100% by day 46, with a median of 32 (range 12-46) days. By day 60, 14/15 (93%) evaluable pts achieved full donor chimerism in either CD3+ or unsorted cells. Notably, there were no cases of acute grade 3-4 GVHD. Acute grade ≥ 2 GVHD was limited to 2 cases of skin-only grade 2 GVHD and 1 case of grade 2 skin and ungradable visceral GVHD. By competing-risk analysis, the estimated CuI of acute grade 2 GVHD was 12% at day 100 (90% CI, 0-27%) and 19% at day 180 (90% CI, 2-37%)(Fig A). The CuI of any chronic GVHD at 1 and 2 years was 7% (90% CI, 0-18%)(Fig A). Critical illness prior to relapse was limited to 1 case of sepsis which resolved. With a 3-year median follow-up, the probability of PFS was 56% at 1 year and 50% at 3 years (Fig B). The estimated CuI of relapse was 44% at 1 year. Median OS has not been reached, with an estimated 1 year and 3 year OS of 68% (Fig B). Conclusion: These results suggest that virtually no pt should be denied allogeneic BMT because of lack of an HLA-matched or haplo donor. mMUD searches were successful in pts with DSA's that were too high for desensitization. Disclosures Off Label Use: posttransplantation cyclophosphamide for GVHD prophylaxis.

scholarly journals Unrelated donor marrow transplantation therapy for chronic myelogenous leukemia: initial experience of the National Marrow Donor Program

Blood ◽  
1993 ◽  
Vol 81 (2) ◽  
pp. 543-550 ◽  
Author(s):  
P McGlave ◽  
G Bartsch ◽  
C Anasetti ◽  
R Ash ◽  
P Beatty ◽  
...  
Keyword(s):  
Chronic Myelogenous Leukemia ◽  
Marrow Transplantation ◽  
Blast Crisis ◽  
Chronic Gvhd ◽  
Chronic Phase ◽  
Disease Free Survival ◽  
High Dose Chemotherapy ◽  
Myelogenous Leukemia ◽  
High Dose ◽  
Unrelated Donor

Abstract In the interval from December 1987 to November 1990, 196 consecutive patients with chronic myelogenous leukemia (CML) received unrelated donor marrow transplantation using marrow procured by the National Marrow Donor Program (NMDP) at 21 NMDP-affiliated marrow transplant centers. Baseline donor and recipient data as well as follow-up data were obtained systematically in all cases by the NMDP. The median interval from the initiation of a search for an unrelated donor to bone marrow transplantation was 8.4 months (range, 1.7 to 34.6 months). Median age of the recipients was 33.3 years (4.5 to 54.5 years). Seventy-five recipients were female and 121 were male. At time of transplant, 115 patients were in chronic phase, 51 in accelerated phase, 14 in blast crisis, and 16 in a second or subsequent chronic phase. In 133 cases, donors and recipients were identical at the HLA A, B, and DR loci using standard serologic typing, and in 63 cases, there was nonidentity at one HLA locus. Patients were prepared for transplantation with a combination of high-dose chemotherapy and total body irradiation (N = 169) or with high-dose chemotherapy only (N = 27). Thirty-five patients received marrow depleted ex vivo of T lymphocytes, whereas 161 patients received non-T-depleted marrow. One hundred seventy-four of 196 patients engrafted (absolute neutrophil count > or = 500/mm3 for 3 consecutive days). The median time to engraftment was 22 days (6 to 69 days). Twenty-two patients failed to engraft, and an additional 10 patients experienced late graft failure. The incidence of grades III or IV acute graft-versus-host disease (GVHD) was 0.54 +/- 0.10, and that of extensive chronic GVHD was 0.52 +/- 0.12. A lower incidence of both grades III and IV acute GVHD (P = .0003) and of extensive chronic GVHD (P = .01) were independently associated with use of T-depleted marrow. The actuarial incidence of hematologic relapse at 2 years is 0.11 +/- 0.06. The 2-year actuarial incidence of disease-free survival for patients transplanted in first chronic phase within 1 year of diagnosis is 0.45 +/- 0.21, in chronic phase more than 1 year from diagnosis is 0.36 +/- 0.11, in accelerated phase is 0.27 +/- 0.12, in second or subsequent chronic phase is 0.22 +/- 0.21, and in blast crisis is 0. Fifteen of 55 patients transplanted at 40 to 50 years of age survive.(ABSTRACT TRUNCATED AT 400 WORDS)

scholarly journals Unrelated donor marrow transplantation therapy for chronic myelogenous leukemia: initial experience of the National Marrow Donor Program

Blood ◽  
1993 ◽  
Vol 81 (2) ◽  
pp. 543-550 ◽  
Author(s):  
P McGlave ◽  
G Bartsch ◽  
C Anasetti ◽  
R Ash ◽  
P Beatty ◽  
...  
Keyword(s):  
Chronic Myelogenous Leukemia ◽  
Marrow Transplantation ◽  
Blast Crisis ◽  
Chronic Gvhd ◽  
Chronic Phase ◽  
Disease Free Survival ◽  
High Dose Chemotherapy ◽  
Myelogenous Leukemia ◽  
High Dose ◽  
Unrelated Donor

In the interval from December 1987 to November 1990, 196 consecutive patients with chronic myelogenous leukemia (CML) received unrelated donor marrow transplantation using marrow procured by the National Marrow Donor Program (NMDP) at 21 NMDP-affiliated marrow transplant centers. Baseline donor and recipient data as well as follow-up data were obtained systematically in all cases by the NMDP. The median interval from the initiation of a search for an unrelated donor to bone marrow transplantation was 8.4 months (range, 1.7 to 34.6 months). Median age of the recipients was 33.3 years (4.5 to 54.5 years). Seventy-five recipients were female and 121 were male. At time of transplant, 115 patients were in chronic phase, 51 in accelerated phase, 14 in blast crisis, and 16 in a second or subsequent chronic phase. In 133 cases, donors and recipients were identical at the HLA A, B, and DR loci using standard serologic typing, and in 63 cases, there was nonidentity at one HLA locus. Patients were prepared for transplantation with a combination of high-dose chemotherapy and total body irradiation (N = 169) or with high-dose chemotherapy only (N = 27). Thirty-five patients received marrow depleted ex vivo of T lymphocytes, whereas 161 patients received non-T-depleted marrow. One hundred seventy-four of 196 patients engrafted (absolute neutrophil count > or = 500/mm3 for 3 consecutive days). The median time to engraftment was 22 days (6 to 69 days). Twenty-two patients failed to engraft, and an additional 10 patients experienced late graft failure. The incidence of grades III or IV acute graft-versus-host disease (GVHD) was 0.54 +/- 0.10, and that of extensive chronic GVHD was 0.52 +/- 0.12. A lower incidence of both grades III and IV acute GVHD (P = .0003) and of extensive chronic GVHD (P = .01) were independently associated with use of T-depleted marrow. The actuarial incidence of hematologic relapse at 2 years is 0.11 +/- 0.06. The 2-year actuarial incidence of disease-free survival for patients transplanted in first chronic phase within 1 year of diagnosis is 0.45 +/- 0.21, in chronic phase more than 1 year from diagnosis is 0.36 +/- 0.11, in accelerated phase is 0.27 +/- 0.12, in second or subsequent chronic phase is 0.22 +/- 0.21, and in blast crisis is 0. Fifteen of 55 patients transplanted at 40 to 50 years of age survive.(ABSTRACT TRUNCATED AT 400 WORDS)

Post-Transplantation High Dose Cyclophosphamide (Cy) Is Effective Single Agent for Prevention of Acute and Chronic Graft Versus Host Disease after Myeloablative HLA Matched Related and Unrelated Bone Marrow Transplantation (BMT)

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 56-56 ◽  
Author(s):  
Leo Luznik ◽  
Javier Bolanos-Meade ◽  
Robert Brodsky ◽  
B. Douglas Smith ◽  
Carol A. Huff ◽  
...  
Keyword(s):  
Acute Gvhd ◽  
De Novo ◽  
Chronic Gvhd ◽  
Immunosuppressive Treatment ◽  
High Dose ◽  
Post Transplantation ◽  
Gvhd Prophylaxis ◽  
History Of ◽  
Grade Ii ◽  
Low Incidence

Abstract Based on our results in animal models and promising results in HLA-haploidentical setting (L. Luznik, Blood 2002 and BBMT 2008), we studied whether high dose Cy alone is sufficient as GVHD prophylaxis after myeloablative HLA-matched related or unrelated BMT in patients with advanced, poor risk, hematologic malignancies. One hundred and seventeen consecutive patients (median age 48, range 23–65; 36 de novo AML, 23 2° AML (arising from previous MDS/MPD or therapy-related), 13 high-risk MDS, 9 ALL, 8 CML, 3 CLL, 5 MM, 9 NHL and 11 HL), of whom the majority (57%) were not in remission, received HLA-matched related (n=78) or unrelated (n=39) BMT. Conditioning consisted of oral or IV busulfan (pharmacokinetically adjusted) on days −7 to −3 and Cy (50 mg/kg/day) on days −2 and −1. Cy (50 mg/kg/day) was also given on days +3, and +4 as a sole agent for GVHD prophylaxis. All patients received bone marrow allografts without growth factor support. Three patients failed to engraft, but two were successfully rescued with a second allograft. The cumulative incidence of non-relapse mortality (NRM) at day 100 and 1 year after transplantation was 8.5% and 16%, respectively. Of the 18 patients dying of NRM, 2 were from VOD, 3 from non infectious pneumonia, 3 were from GVHD, 3 from sepsis/bacterial infections, 4 from MOF, and 3 of CNS/organ hemorrhage. The incidences of acute grade II–IV and grade III–IV GVHD were 43% and 11%, respectively. With a median follow-up of 19 months, 66 (56.4%) patients are alive, of whom 52 (44.4%) are in complete remission. Only 7/66 related and 4/32 unrelated patients developed chronic GVHD (classic limited in 7, overlap syndrome limited in 1, and classic extensive in 3 patients). Since in a competing risk model (relapse and death as competing risks) the cumulative incidence of chronic GVHD remained low, we analyzed the impact of the preceding history of acute GVHD and systemic immunosuppressive treatment given beyond the originally prescribed prophylaxis with high dose Cy on the incidence of chronic GVHD. Only one patient without a preceding history of acute GVHD developed de novo chronic GVHD. Overall, 3 patients with grade II–IV acute GVHD were untreated, 10 patients received steroids alone, 31 received steroids + a calcineurin inhibitor (CNI), and 7 received steroids + non CNI-based agents. The use of CNI for the treatment of acute GVHD did not appear to influence the development of chronic GVHD: 6/31 (19%) patients who received CNI-based immunosuppressive treatment developed chronic GVHD compared to 3/20 (15%) patients who did not. These results suggest that highdose of post-transplantation Cy is effective as the sole prophylaxis for acute and chronic GVHD after HLA-matched related or unrelated BMT. This approach is associated with rapid immunologic recovery as indicated by the low incidence of opportunistic infections, as well as a low incidence of acute and especially chronic GVHD. Further clinical and correlative studies are needed to elucidate the mechanisms behind the unique effectiveness of post-transplantation Cy on the prevention of acute and chronic GVHD.

A Bortezomib-Based Regimen Offers Excellent Outcomes In Myeloablative HLA-Mismatched and Unrelated Donor Transplantation: Phase II Results

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3335-3335
Author(s):  
John Koreth ◽  
Haesook T. Kim ◽  
Paulina B. Lange ◽  
Bhavjot Bindra ◽  
Philippe Armand ◽  
...  
Keyword(s):  
Stem Cell ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Unrelated Donor ◽  
Myeloablative Conditioning ◽  
Upper Gi ◽  
Gvhd Prophylaxis ◽  
Grade Ii ◽  
Grade Iii

Abstract In a phase I/II trial of a novel bortezomib-based regimen for reduced-intensity conditioning (RIC) hematopoietic stem cell transplantation (HSCT) recipients of HLA-mismatched peripheral blood stem cell (PBSC) grafts, we documented low rates of graft-versus-host disease (GVHD) and non-relapse mortality (NRM), with promising survival. In registry analyses, myeloablative conditioning (MAC) HSCT recipients of both HLA-matched (MUD) and 1-locus mismatched donor (MMUD) grafts also have impaired outcomes, with day +100 grade III-IV acute GVHD rates of 28% and 37% respectively, 1-year NRM of 36% and 45% respectively, 1-year progression-free (PFS) of 47% and 38% respectively, and 1-year overall survival (OS) of 52% and 43% respectively. We therefore evaluated a similar bortezomib-based regimen in MAC HSCT recipients lacking 8/8 HLA-matched (-A, -B, -C, -DRB1) related donors. In a prospective single-arm phase II trial, we enrolled patients with hematologic malignancies, aged 18-60 years, receiving MUD, MMUD, or mismatched related donor (MMRD) grafts. Myeloablative conditioning was IV busulfan (130 mg/m2, without PK dose adjustment) and fludarabine (40 mg/m2) once daily for 4 doses (days -7 to -4). T-replete PBSC grafts with ≥ 2x106 CD34+ cells/kg were infused on day 0. GVHD prophylaxis comprised bortezomib (1.3 mg/m2 IV on days +1, +4, +7), methotrexate (15 mg/m2 IV on day +1, 10 mg/m2 on days +3, +6, +11) and tacrolimus from day -3, with a planned taper starting day +100 and complete by day +180. The primary endpoint was day +100 acute GVHD incidence. Secondary endpoints included NRM, relapse, PFS, OS and chronic GVHD at 1 year. The 34 patients (19 male, 15 female), accrued between March 2011 and November 2012, had a median age of 49 years (range, 21-60) and variable diagnoses (17 AML, 6 MDS, 4 NHL, 3 MPD, 2 ALL, 1 CML, 1 MM) and disease risk indices (Low 1, Intermediate 24, High 9). They received 8/8 MUD (n=14), 7/8 MMUD (n=18) or 7/8 MMRD (n=2) PBSC grafts. Mismatches (16 antigen-, 4 allele-level) involved HLA-A (9), -B (1), -C (6) and -DRB1 (4). The median follow up in survivors is 20 months (range, 7.2-25.5). The regimen was feasible and well tolerated. Mucositis was noted in the MAC recipients, but no doses were missed due to toxicity. Excluding 1 patient who died of sepsis prior to engraftment, neutrophil and platelet engraftment was prompt, at a median of 14 (range, 3-33) and 17 (range, 7-54) days respectively. Median day +30 donor chimerism was 99% (range, 90-100). Grade II-IV acute GVHD incidence by day +100 and +180 was 32% and 36% respectively, but only 18% and 21% respectively if upper GI GVHD (which had excellent long term outcomes) was excluded. Grade III-IV acute GVHD incidence by day +100 and +180 was 12%. 2-year cumulative incidence of NRM and relapse was 8.8% and 5.9% respectively. 2-year PFS and OS was 85% and 84% respectively (Figure). 2-year cumulative incidence of extensive chronic GVHD was 57%. For 8/8 MUD vs. 7/8 MMRD/MMUD, grade II-IV acute GVHD by day +180 was 30% vs. 40% (p=0.47) (excluding upper GI GVHD, 16% vs. 25%, p=0.42), and grade III-IV acute GVHD was 7% vs. 15% (p=0.48) respectively.FigureStudy SurvivalFigure. Study Survival In conclusion, bortezomib-based prophylaxis for MAC HSCT recipients of HLA-mismatched and unrelated donor grafts was safe and well-tolerated, with low rates of severe acute GVHD, NRM and relapse, and excellent long-term survival. On preliminary landmark analysis, upper GI GVHD did not appear to impair transplantation outcomes. Bortezomib-based prophylaxis is suitable for prospective randomized evaluation in myeloablative transplantation recipients lacking HLA-matched related donors. Disclosures: Koreth: Millennium pharmaceuticals: Research Funding; Takeda Pharmaceuticals: Consultancy. Off Label Use: Bortezomib for GVHD prophylaxis.

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