Evaluation of NIH Consensus Criteria for Classification of Late Acute and Chronic Gvhd in Reduce Intensity Conditioning (RIC) Stem Cell Transplantation (SCT).

Abstract Abstract 1139 Poster Board I-161 Background Chronic graft-versus-host disease (GVHD) occurs frequently after allogeneic stem cell transplantation (SCT) and has an impact on morbidity and survival. The National Institutes of Heath (NIH) consensus criteria for the diagnosis of GVHD, emphasized clinical manifestations of GVHD rather than the classical time of onset (day 100). Incidence and impact in term of relapse and no-relapse mortality (NRM) of this new classification is not well known after RIC. Methods We retrospectively reviewed 116 consecutive patients (pts) in Saint Louis' Hospital undergoing an SCT for hematologic malignancy and surviving at least day + 100 after RIC between August 2005 and December 2008. We evaluated non-relapse mortality (NRM) and recurrent malignancy. Cumulative incidence was computed using death as a competing event. Incidence of relapse and NRM was counted from 100 days post-transplant for patients without chronic GVHD or from chronic GVHD onset. Patients with relapse/progression before chronic GVHD onset were considered as not having chronic GVHD in these analyses. The association of occurrence of chronic GVHD with the risk of relapse and non-relapse death was analyzed using time-dependent covariates in cause-specific proportional hazards models. Results Among 116 pts ( M/F: 71/45), with a median age of 53 years old (19-68 years) 28 pts (24%) were transplanted for acute leukemia in, 11 pts (9%) for chronic leukemia, 27 pts (23%) for lymphoma, 30 pts (26%) for MPD/MDS and 20 pts (17%) for plasma cell disorder. Sixty-three pts (54%) received HLA-identical sibling transplantation, 53 pts (46%) received transplantation from unrelated donors. Source of stem cells was mobilized peripheral blood stem cell for 108 pts (93%), bone marrow for 4 pts (3%) and 4 cord blood (3%). After a median follow-up of 18 months (range 5-45 months), a total of 67 pts (58%) developed chronic GVHD according to the Seattle day 100 landmark criteria and when using NIH consensus criteria, 55 pts (47%) developed chronic GVHD, including 43 pts (53%) with classic chronic GVHD and 8 pts (10%) overlap syndrome. Patients reclassified included; 3 pts with late onset acute GvHD, 19 pts had recurrent and 8 had persistent acute GVHD (numbers do not to previous sentence because some of these patients latter developed chronic GvHD). The cumulative incidence of chronic GVHD at 36 months was 64% (95%CI; 53%-73%) when using Seattle criteria compared to 56% (95%CI; 45%-67%) with NIH chronic GVHD criteria. Two-year Cumulative incidences of relapse and NRM using both classifications are summarized in Table. In Cox model with GvHD as a time dependent covariate, the NRM was significantly higher in patients with late onset, persistent and recurrent acute GVHD compared to no GVHD (hazard ratio (HR) 31, 47 and 30; p = 0.005, p <0.0001, p <0.0001, respectively), whereas the NRM was statistically increased in case of chronic GVHD using Seattle day 100 criteria (HR: 2.8; P=0.034). Conclusion The cumulative incidence of chronic GVHD “decrease” about 10% when using NIH consensus criteria compared to Seattle criteria in our cohort of RIC. Most of the NRM occurred beyond 100 days after SCT was due to the increased risk of NRM in patients with late onset, recurrent or persistent acute GVHD. Disclosures No relevant conflicts of interest to declare.

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Impact of antithymocyte globulin (ATG)-containing conditioning regimens on patients undergoing allogeneic stem cell transplantation (allo-CST) for poor risk cytogenetic IPSS myelodysplastic syndrome (PRC-MDS): A report from the French Society of Stem Cell Transplantation and Cell Therapy (SFGM-TC).

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.6542 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. 6542-6542

Author(s):

Ibrahim Yakoub-Agha ◽

Gandhi Laurent Damaj ◽

Marie Robin ◽

Stephane Vigouroux ◽

Alice Garnier ◽

...

Keyword(s):

Stem Cell ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Cumulative Incidence ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

French Society ◽

Poor Risk ◽

Increased Risk

6542 Background: Due to a risk of relapse of underlying disease in patients with PRC-MDS, the use of ATG, incorporated within the conditioning regimen prior to allo-SCT, is still controversial. Methods: Inclusion criteria included patients aged over 18 (n=101) who received allo-SCT transplanted between 1999 and 2009 from either a sibling (n=68) or HLA-allele-MUD (10/10) (n=33) for PRC-MDS. HLA matching was double-checked by the national Bone Marrow Donor Registry. Results: According to the FAB/WHO classification at diagnosis, 22 pts had RA/RARS/RCMD, 40 RAEB1, 30 REAB2 and 9 RAEB-t/AML. 34 pts had progressed to a more advanced disease before allo-SCT. At diagnosis, 89 patients had an IPSS int-2 or higher. At transplant, 36 pts were responders (CR, PR, CRm) and 62 with progressive disease (relapsed/refractory, untreated or stable disease without hematological improvement). Median age at transplantation was 54 years (range, 22-69). Pts received myeloablative conditioning (n=46) and nonmyeloablative (n=55). In this series, 48 patients received ATG as part of conditioning ('ATG' group), whereas 53 did not ('no-ATG’ group). As of April 1st 2011, 44 patients died of relapse and 22 of TRM. 3-year relapse, overall and event-free survival rates were not significantly different between the two groups. In contrast, the cumulative incidence of grade 2-4 acute GVHD was 48% in the no-ATG group and 30% ATG group (P <.005). Although the cumulative incidence of chronic GVHD was similar in the no-ATG and ATG groups, a trend for a lower TRM was observed in the ATG group (p=.06). In multivariate analysis, the absence of use of ATG was associated with an increased risk of acute grade 2-4 [HR = 1.92, p=.044]. Conclusions: The addition of ATG to the conditioning regimen resulted in a decreased incidence of acute GVHD without increasing relapse rates and compromising survival of patients undergoing allo-SCT for poor risk cytogenetic MDS.

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Sirolimus, Tacrolimus and Low-Dose Methotrexate Based Graft-Versus-Host Disease (GVHD) Prophylaxis After Non-Ablative or Reduced Intensity Conditioning in Related and Unrelated Donor Allogeneic Stem Cell Transplantation: Decreased Severe Early aGVHD but Persistence of Late Acute Gvhd

Blood ◽

10.1182/blood.v120.21.4194.4194 ◽

2012 ◽

Vol 120 (21) ◽

pp. 4194-4194

Author(s):

Ceberio Izaskun ◽

Sean Devlin ◽

Craig S. Sauter ◽

Juliet N Barker ◽

Hugo Castro-Malaspina ◽

...

Keyword(s):

Stem Cell ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Cumulative Incidence ◽

Low Dose ◽

Acute Gvhd ◽

Late Onset ◽

Chronic Gvhd ◽

Dose Methotrexate ◽

Gvhd Prophylaxis

Abstract Abstract 4194 Background: The morbidity and mortality associated with acute and chronic graft-versus-host disease (GVHD) remain significant after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Encouraging results have been reported with the combination of sirolimus, tacrolimus, and low-dose methotrexate after non-myeloablative allogeneic peripheral blood stem cell transplantation (PBSCT) (Alyea EP et al, Biol Blood Marrow Transplant 2008). We conducted a retrospective analysis of 74 patients with hematologic malignancies who underwent a non-myeloablative (NMA) or reduced intensity (RIC) allo-HSCT using sirolimus, tacrolimus, and low-dose methotrexate for GVHD prophylaxis. Methods: Between April 2008 and June 2011, 74 patients (M/F: 45/29), median age 51 years (range: 23–69) were transplanted for non-Hodgkin's lymphoma (63%), chronic lymphocytic leukemia/small lymphocytic lymphoma (20%), Hodgkin lymphoma (12%) and acute lymphoblastic leukemia or myelodysplasia (3%). At transplantation, 36 patients (49%) were in complete remission and 38 patients (51%) had chemotherapy sensitive active disease. Conditioning regimen was NMA in 59 patients and RIC in 15 patients. Donors were HLA-matched related (MRD, n = 30, 41%), matched unrelated (MUD, n = 37, 50%) or 9/10 HLA-mismatched unrelated (MMUD, n = 7). All patients received peripheral blood mobilized grafts. GVHD prophylaxis consisted of sirolimus and tacrolimus that were started on day -3 and doses were adjusted to maintain target serum trough levels of 3–12 ng/mL and 5–10 ng/mL, respectively, followed by methotrexate 5 mg/m2 on days +1, 3, 6. Tapering of sirolimus and tacrolimus began at day 60 in the absence of GVHD or relapse, with the goal of complete discontinuation of immunosuppressants by 6 months or earlier if patients were not in CR at transplant. Recipients of MUD (31 of 37) or MMUD (7 of 7) grafts were given 2 doses of anti-thymocyte globulin (ATG) on days −3, and −2. Forty-eight patients with CD20+ malignancies (65%) received rituximab at day -8 and +21, 28, 35, 42. Acute GVHD (aGVHD) was scored by IBMT Severity Index and chronic GVHD (cGVHD) based on NIH consensus criteria. Results: The cumulative incidence of Grade B-D and C-D classic aGVHD at day +100 were 14.9% and 2.7%, respectively. The cumulative incidence of aGVHD at 1-year was 31.1 % for grade B-D and 5.4 % for grade C-D, due to late-onset Grade B-D and Grade C-D aGVHD rates of 16.2% and 2.7%, respectively. The incidence of cGVHD at 1 and 2 years was 15% and 28%, respectively. The use of peri-transplant rituximab did not affect the incidence of Grade B-D aGVHD (p=0.55) or cGVHD (p=0.94). There was no difference in the incidence of Grade B-D aGVHD at day 100 between ATG (13.9%) and no ATG (15.8%) cohorts. There was a trend towards a modestly higher 2-year incidence of cGVHD in patients who did not receive ATG, despite the fact that these were predominantly recipients of MRD (37% vs. 21% in ATG cohort, p=0.12). Two patients (2.7%) developed thrombotic microangiopathy and 4 patients (5.4%) had renal toxicity, requiring modification of the immunosuppressant treatment. No sinusoidal obstructive sydrome was reported. To date, 15 patients have died; causes of death include disease recurrence (n=9) and GVHD (n=6). The cumulative incidence of non-relapse mortality and relapse at 1 year were 4% and 27%, respectively. The 1-year relapse rate in the ATG and no ATG cohorts was 11% and 28%, respectively (p=0.10). With a median follow up 2.6 (range: 0.8–3.9) years, progression-free and overall survival at 2 years were 64 % and 77 %, respectively. Conclusions: As previously reported this GVHD prophylaxis regimen is safe and effective, providing lower rates of acute GVHD compared to historical data. The incidence of chronic GVHD by NIH criteria was low due to an increase in late-onset acute GVHD. Rituximab therapy did not affect the incidence of acute and chronic GVHD. The addition of ATG in MUD and MMUD recipients resulted in a trend toward lower rates of chronic GVHD with no increase in the rate of relapse. Future strategies will need to focus on decreasing the incidence of late onset acute and chronic GVHD without increasing the risk of relapse. Disclosures: No relevant conflicts of interest to declare.

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Role of Donor Clonal Hematopoiesis in Allogeneic Hematopoietic Stem-Cell Transplantation

Journal of Clinical Oncology ◽

10.1200/jco.2018.79.2184 ◽

2019 ◽

Vol 37 (5) ◽

pp. 375-385 ◽

Cited By ~ 45

Author(s):

Mareike Frick ◽

Willy Chan ◽

Christopher Maximilian Arends ◽

Raphael Hablesreiter ◽

Adriane Halik ◽

...

Keyword(s):

Stem Cell ◽

Hematopoietic Stem Cell Transplantation ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Hematopoietic Stem Cell ◽

Cumulative Incidence ◽

Chronic Gvhd ◽

Hematopoietic Stem ◽

Clonal Hematopoiesis ◽

Increased Risk

Purpose Clonal hematopoiesis of indeterminate potential (CHIP) occurs in the blood of approximately 20% of older persons. CHIP is linked to an increased risk of hematologic malignancies and of all-cause mortality; thus, the eligibility of stem-cell donors with CHIP is questionable. We comprehensively investigated how donor CHIP affects outcome of allogeneic hematopoietic stem-cell transplantation (HSCT). Methods We collected blood samples from 500 healthy, related HSCT donors (age ≥ 55 years) at the time of stem-cell donation for targeted sequencing with a 66-gene panel. The effect of donor CHIP was assessed on recipient outcomes, including graft-versus-host disease (GVHD), cumulative incidence of relapse/progression (CIR/P), and overall survival (OS). Results A total of 92 clonal mutations with a median variant allele frequency of 5.9% were identified in 80 (16.0%) of 500 donors. CHIP prevalence was higher in donors related to patients with myeloid compared with lymphoid malignancies (19.2% v 6.3%; P ≤ .001). In recipients allografted with donor CHIP, we found a high cumulative incidence of chronic GVHD (cGVHD; hazard ratio [HR], 1.73; 95% CI, 1.21 to 2.49; P = .003) and lower CIR/P (univariate: HR, 0.62; 95% CI, 0.40 to 0.97; P = .027; multivariate: HR, 0.63; 95% CI, 0.41 to 0.98; P = .042) but no effect on nonrelapse mortality. Serial quantification of 25 mutations showed engraftment of 24 of 25 clones and disproportionate expansion in half of them. Donor-cell leukemia was observed in two recipients. OS was not affected by donor CHIP status (HR, 0.88; 95% CI, 0.65 to 1.321; P = .434). Conclusion Allogeneic HSCT from donors with CHIP seems safe and results in similar survival in the setting of older, related donors. Future studies in younger and unrelated donors are warranted to extend these results. Confirmatory studies and mechanistic experiments are warranted to challenge the hypothesis that donor CHIP might foster cGVHD development and reduce relapse/progression risk.

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Genetic variations in the heparanase gene (HPSE) associate with increased risk of GVHD following allogeneic stem cell transplantation: effect of discrepancy between recipients and donors

Blood ◽

10.1182/blood-2009-08-236455 ◽

2010 ◽

Vol 115 (11) ◽

pp. 2319-2328 ◽

Cited By ~ 36

Author(s):

Olga Ostrovsky ◽

Avichai Shimoni ◽

Avital Rand ◽

Israel Vlodavsky ◽

Arnon Nagler

Keyword(s):

Stem Cell ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Human Leukocyte ◽

Nucleotide Polymorphisms ◽

Hematopoietic Stem ◽

Mortality And Morbidity ◽

Increased Risk

Abstract Graft-versus-host disease (GVHD) is the most common cause of nonrelapse mortality and morbidity after hematopoietic stem cell transplantation (HSCT). The well-documented involvement of heparanase in the process of inflammation and autoimmunity led us to investigate an association between HPSE gene single-nucleotide polymorphisms (SNPs) and the risk of GVHD. The present study indicates a highly significant correlation of HPSE gene SNPs rs4693608 and rs4364254 and their combination with the risk of developing acute GVHD. Moreover, the study revealed that discrepancy between recipient and donor in these SNPs may elevate significantly the risk of acute GVHD. This association was statistically significant when the recipients possessed genotype combinations dictating higher levels of heparanase compared with their human leukocyte antigen (HLA)–matched donors. In addition, HPSE gene SNPs disclosed a correlation with extensive chronic GVHD, nonrelapse mortality, and overall survival. Our study indicates involvement of heparanase in the development of acute and extensive chronic GVHD. Moreover, it suggests a possible mechanism for the aggressive behavior of T lymphocytes leading to GVHD when the recipients possess genotype combinations that dictate high levels of heparanase mRNA compared with their HLA-matched donors expressing low levels of heparanase.

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Long-Term Follow-up of Hematopoietic Stem Cell Transplantation with the Modified Peking Regimen for the Treatment of Acute Leukemia

Blood ◽

10.1182/blood-2019-124419 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2034-2034

Author(s):

Xi Yang ◽

Chenglong Li ◽

Rong Zhang ◽

Hong Zheng ◽

Qing Wei ◽

...

Keyword(s):

Stem Cell ◽

Hematopoietic Stem Cell Transplantation ◽

Stem Cell Transplantation ◽

Acute Leukemia ◽

Cell Transplantation ◽

Cumulative Incidence ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Hematopoietic Stem ◽

Free Survival

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative treatment strategy for patients with acute leukemia. The ATG-based transplantation system initiated by Peking University people's hospital, known as the Peking regimen, has become a mainstream transplant system worldwide. Here, based on the Peking regimen, we report a modified protocol:(1)add Fludarabine and replace ATG with ATG-F in the conditioning regimen; (2)transfuse higher-dose cell collections from granulocyte-colony stimulating factor(G-CSF) primed bone marrow and peripheral blood samples; (3) add Basiliximab (a CD25-antibody) on day +3 for acute GVHD prophylaxis. In this study, 265 patients (158 patients with haplo-SCT and 107 patients with sibling-SCT) underwent allo-HSCT with our modified protocols. All patients achieved sustained full-donor chimerism. The incidence of grade II-IV and III-IV acute GVHD in haplo-SCT comparing with sibling-SCT was 36.1%(57/158) vs 17.8%(19/107)(P=0.001) and 13.3% (21/158) vs 9.3%(10/107)(P>0.05) respectively. The 2-year cumulative incidence of total chronic GVHD and extensive chronic GVHD in haplo-SCT was 41% (65/158) and 15% (24/158) respectively. The 3-year cumulative incidence of non-relapse mortality (NRM) in haplo-SCT and sibling-SCT was 6.3% (10/158) and 4.7%(5/107) respectively(P>0.05). The 100-day cumulative incidence of CMV viremia in haplo-SCT and sibling-SCT was 35.5% (56/158) and 23.4%(25/107) respectively(P=0.036). A total of 36 patients in haplo-SCT group and 24 patients in haplo-SCT group had recurrent disease, reaching a cumulative incidence of relapse of 20.8% in haplo-SCT and 23.4% in sibling-SCT at 3 years respectively(P>0.05). The relapse ratio of haplo-SCT and sibing-SCT in the 1st year, between the 1st and the 2nd year and after 2 years was 21.5% vs 14.1%(P>0.05), 1.3%(2/158) vs 0%(P>0.05) and 0% vs 6.5%(P=0.009) respectively. The 3-year overall survival(OS) and leukemia-free survival(LFS) rates in haplo-SCT and sibling-SCT was 78.8% vs 74.2% and 76.8% vs 75.04% respectively(P>0.05) by the Kaplan-Meier estimate. The 3-year GVHD-free and leukemia-free survival rates (GRFS) in haplo-SCT and sibling-SCT were 43.4% vs 69.5%(P=0.045) respectively. Lower OS in haplo-SCT was associated with III-IV aucte GVHD and lower MNC(<19×10^8/L) in grafts by Cox regression analysis. In a word, the results from our experience showed that the modified protocol based on the Peking Regimen is safe and reliable for acute leukemia patients and brings on a long-stage survival post transplantation. Disclosures Zheng: Pfizer: Research Funding.

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Multicenter, Prospective Study of Tacrolimus Plus Methotrexate As Graft-Versus-Host Disease Prophylaxis in HLA-Matched Sibling Peripheral Blood Stem Cell Transplantation: Comparison with Cyclosporine Group As Control

Blood ◽

10.1182/blood.v120.21.4177.4177 ◽

2012 ◽

Vol 120 (21) ◽

pp. 4177-4177

Author(s):

SeungHwan Shin ◽

JaeHo Yoon ◽

SeungAh Yahng ◽

SungEun Lee ◽

ByungSik Cho ◽

...

Keyword(s):

Stem Cell ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Cumulative Incidence ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Hazard Ratio ◽

Gvhd Prophylaxis ◽

Matched Sibling ◽

Grade Ii

Abstract Abstract 4177 Background Graft-versus-host disease (GVHD) is an immunologic complication after allogeneic hematopoietic stem cell transplantation (HSCT) with significant mortality and morbidities. Allogeneic peripheral blood stem cell transplantation (PBSCT) has high risk of GVHD, especially chronic GVHD compared to bone marrow transplantation. Only limited data are available comparing the efficacy of FK506 with that of cyclosporine (CsA) in human leukocyte antigen (HLA)-matched sibling PBSCT. Methods Thirty-nine patients with various hematologic disease received PBSCT with FK506+methotrexate (MTX) as GVHD prophylaxis were compared to ninety-four historical control with CsA+MTX GVHD prophylaxis. Results The 1-year cumulative incidence of grade II-IV acute GVHD was significantly lower in patients who received FK506 than those in the CsA group (10.3% vs 28.2%, p=0.036). The female donor-male recipient pair (hazard ratio; 4.828, 95% CI; 17.84-13.06, p=0.002) and CsA prophylaxis (hazard ratio; 3.279, 95% CI; 1.14–9.43, p=0.027) were significant risk factor of acute GVHD in multivariate analysis. But, there was no difference in the 3-year cumulative incidence of chronic GVHD between the FK506 and the CsA group (77.6% vs 69.6%, p=0.793). The 3-year cumulative incidence of relapse (33.9% vs 23.1%, p=0.505) and 3-year treatment-related mortality (18.9% vs 28.4%, p=0.187) of the two groups were similar. The patients in the FK506 arm had a similar event-free survival (EFS) and overall survival (OS) with patients in the CsA arm (3-year EFS; 53.2% vs 55.1%, p=0.706, 3-year OS; 60.7 vs 61.5%, p=0.610). The age over 35 years (hazard ratio; 4.12, 95% CI; 1.95–8.70, p=0.001), female donor-male recipient pair (hazard ratio; 2.66, 95% CI; 1.52–4.65, p=0.001) and advanced pre-HSCT disease status (hazard ratio; 3.13, 95% CI; 1.72–5.71, p=0.001) were significant prognostic factors associated with OS in multivariate analysis. Conclusion These results demonstrated that the FK506+MTX can significantly reduce grade II-IV acute GVHD compared to CsA+MTX in sibling PBSCT with similar incidence of chronic GVHD, and comparable outcome in EFS, OS, relapse rate and TRM rate between two groups. Disclosures: No relevant conflicts of interest to declare.

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Allogeneic hematopoietic stem cell transplantation in thalassemia major: results of a reduced-toxicity conditioning regimen based on the use of treosulfan

Blood ◽

10.1182/blood-2012-04-423822 ◽

2012 ◽

Vol 120 (2) ◽

pp. 473-476 ◽

Cited By ~ 110

Author(s):

Maria Ester Bernardo ◽

Eugenia Piras ◽

Adriana Vacca ◽

Giovanna Giorgiani ◽

Marco Zecca ◽

...

Keyword(s):

Stem Cell ◽

Hematopoietic Stem Cell Transplantation ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Hematopoietic Stem Cell ◽

Cumulative Incidence ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Unrelated Donor ◽

Hematopoietic Stem

Abstract Sixty thalassemia patients (median age, 7 years; range, 1-37) underwent allogeneic hematopoietic stem cell transplantation (HSCT) after a preparation combining thiotepa, treosulfan, and fludarabine. Before HSCT, 27 children were assigned to risk class 1 of the Pesaro classification, 17 to class 2, and 4 to class 3; 12 patients were adults. Twenty patients were transplanted from an HLA-identical sibling and 40 from an unrelated donor. The cumulative incidence of graft failure and transplantation-related mortality was 9% and 7%, respectively. Eight patients experienced grade II-IV acute GVHD, the cumulative incidence being 14%. Among 56 patients at risk, 1 developed limited chronic GVHD. With a median follow-up of 36 months (range, 4-72), the 5-year probability of survival and thalassemia-free survival are 93% and 84%, respectively. Neither the class of risk nor the donor used influenced outcome. This treosulfan-based preparation proved to be safe and effective for thalassemia patients given allogeneic HSCT.

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Durable Remission after Prophylactic Donor Lymphocyte Transfusion Following Allogeneic Stem Cell Transplantation with Reduced Conditioning for High-Risk AML and MDS.

Blood ◽

10.1182/blood.v104.11.299.299 ◽

2004 ◽

Vol 104 (11) ◽

pp. 299-299

Author(s):

Michael Schleuning ◽

Christoph Schmid ◽

Georg Ledderose ◽

Johanna Tischer ◽

Meike Humann ◽

...

Keyword(s):

Stem Cell ◽

High Risk ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Allogeneic Stem Cell Transplantation ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Allogeneic Transplantation ◽

Chronic Infections ◽

Term Survival

Abstract Prophylactic transfusion of donor lymphocytes (pDLT) is an attractive form of maintenance therapy after allogeneic stem cell transplantation in patients with high risk of relapse. However, clinical experience is limited, and disease response is often achieved at the expense of severe graft-versus-host disease (GvHD). We here report our data on pDLT in high-risk AML and MDS. Cells were given within a prospective protocol that contained a sequence of chemotherapy, reduced intensity conditioning for allogeneic transplantation, and pDLT (FLAMSA-regimen). For pDLT, patients had to be in CR at least 120 days from transplantation, off immunosuppression for 30 days, and free of GvHD. 22/86 patients alive at day +120 fulfilled the criteria for pDLT. They had been transplanted for refractory or relapsed leukemia (n=9 each) or in CR1 because of unfavorable cytogenetics (n=4). 14 patients had an unfavorable karyotype, 8 with complex aberrations. Reasons for withholding pDLT in 64 patients included cGvHD or prolonged immunosuppression (n=38), refractory or relapsed leukemia (n=15), refusal of patient or donor (n=4 each), a history of grade IV acute GvHD (n=2), and chronic infections (n=3). The median time from transplant to first pDLT was 167 days (range 120–297). Median follow up of transfused patients is 696 days (range 209–1341). Ten patients received 1, 6 patients received 2, and 6 patients received 3 transfusions in escalating doses, containing a median of 1x106, 5x106 and 1x107 CD3+ cells/kg at pDLT 1, 2 and 3, respectively. Reasons for giving less than 3 transfusions were GvHD, relapse or refusal of the patient. Induction of GvHD was the main complication; grade III acute GvHD developed in 1, and chronic GvHD in 7 patients. So far, 5 patients have relapsed despite pDLT. One died of refractory leukemia, whereas 2 achieved secondary CR following adoptive immunotherapy. Two patients are currently under treatment. At present, 18/22 patients are alive and in CR at a median of 423 days post DLT. The current leukemia free survival at two years from first pDLT is 79%. Nineteen patients were complete chimeras at time of pDLT. pDLT converted mixed into complete bone marrow chimerism in 1, but failed in 2 cases. In our experience, pDLT is safe after allogeneic transplantation for high risk AML, when given at low doses and to a selected group of patients. Results are encouraging, and long term survival can be achieved. However, further studies need to define more precisely the contribution of pDLT to the therapeutic effect of the entire procedure.

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Donor Leukocyte Infusion after Stem Cell Transplantation in Patients with Juvenile Myelomonocytic Leukemia.

Blood ◽

10.1182/blood.v104.11.5001.5001 ◽

2004 ◽

Vol 104 (11) ◽

pp. 5001-5001

Author(s):

Ayami Yoshimi ◽

Peter Bader ◽

Susanne Matthes-Martin ◽

Jan Starý ◽

Thomas Klingebiel ◽

...

Keyword(s):

Stem Cell ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Juvenile Myelomonocytic Leukemia ◽

Donor Leukocyte Infusion ◽

Matched Sibling ◽

Myelomonocytic Leukemia ◽

Relapse Group

Abstract Juvenile myelomonocytic leukemia (JMML) is a rare clonal disorder of early childhood. Currently, only allogeneic stem cell transplantation (SCT) offers long-term cure. Relapse remains the major cause of treatment failure. Although graft-versus-leukemia (GVL) effect most likely plays an important role in controlling JMML, the benefit of donor leukocyte infusion (DLI) following SCT in JMML is currently unknown. Patients and methods: Twenty-one patients with JMML who received DLI after SCT, including 4 patients after given a second SCT, were studied (BMT 14, PBSCT 6, CB 1). The median age at SCT was 15 (8–99) months. A normal karyotype, monosomy 7 or other aberrations were observed in 15, 2, and 4 patients, respectively. Six patients were transplanted from a matched sibling and 15 from an alternative donor. Chimerism analyses were performed by microsatellite PCR system or FISH for sex mismatch in all the patients. Response was defined as the achievement of complete chimerism (CC) and no evidence of hematological relapse. DLI was given either for the development of mixed chimerism (MC) in 7 patients (MC group) or for cytogenetic/hematological relapse in 14 patients (relapse group). Prior to DLI, cyclosporin A had been stopped in all patients, and no child had received chemotherapy. Results of DLI: Five of the 21 patients received a single DLI, 16 patients 2–6 infusions (median 3). The total T cell dose given ranged from 9x104 to 2.4 x108/kg. Six of 21 patients responded: 3 of 7 patients in the MC group and 3 of 14 patients in the relapse group. The infusion of at least 1x107/kg T cells was needed for durable response. Response was observed in all karyotype subgroups. None of the 6 patients receiving DLI from a matched sibling responded. Five patients developed acute GVHD following DLI and 4 of them responded to DLI. On the contrary, only 2 of the 16 children who did not show acute GVHD after DLI responded. Chronic GVHD developed in 2 responders. The outcome of even the responders was unfavorable. Only one of the responders is alive in remission, with severe chronic GVHD, 72 months after DLI. Two patients relapsed 26 days and 54 months after DLI (one as gastric chloroma), and 3 died of complications of DLI (acute GVHD, bone marrow aplasia, and hyper-eosinophilic syndrome). Four non-responders and one responder with subsequent relapse were rescued by a second SCT. Conclusion: This study shows that DLI can induce a GVL effect in some of the JMML patients. However, the benefit of DLI in our series of patients was limited because of severe complications in responders and lack of a durable effect. Some modification of DLI, with previous cytoreduction by chemotherapy or a novel drug such as E21R and concomitant administration of cytokines such as interferon alpha, can possibly improve the result of DLI.

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Myeloablative Treosulfan as Preparative Regimen for Allogeneic Haematopoietic Stem Cell Transplantation: A Single-Centre Experience.

Blood ◽

10.1182/blood.v104.11.3343.3343 ◽

2004 ◽

Vol 104 (11) ◽

pp. 3343-3343

Author(s):

Rudolf Trenschel ◽

Markus Ditschkowski ◽

Ahmet Elmaagacli ◽

Nina K. Steckel ◽

Michal Hlinka ◽

...

Keyword(s):

Stem Cell ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Advanced Disease ◽

Chronic Gvhd ◽

Water Soluble ◽

Haematopoietic Stem Cell ◽

High Dose ◽

Early Disease ◽

Increased Risk

Abstract Treosulfan (TREO), a water-soluble bifunctional alkylating agent, has demonstrated strong immunosuppressive and antileukemic activity as well as profound stem cell toxicity in animal studies. Due to the advantageous clinical toxicity profile lacking significant non-hematologic organ toxicities, high-dose TREO in combination with cyclophosphamide (CY) has recently been evaluated in patients (pts) with an increased risk for organ toxicities precluding standard myeloablative conditioning regimens before allogeneic stem cell transplantation (SCT). Between 8/00 and 10/03, we treated 52 patients (pts) not eligible for conventional therapy with TREO in order to reduce toxicity in a myeloablative setting. Diagnoses were AML (n=14), ALL (n=11), MM (n=8), NHL (n=7), MDS (n=5), CML (n=4) and aplastic syndromes (n=3). 18 patients were grafted in early disease (1st or 2nd complete remission, chronic phase, or incipient first relapse (BM blasts < 10%). The remaining pts were classified as having advanced disease. Donors were identical siblings (n=24), non-identical family members (n=l), matched unrelated (n=14) or mismatched unrelated (n=13) donors. Conditioning regimen consisted of TREO 36g/qm (n=19) or 42g/qm (n=28) and CY 120mg/kg BW, 5 pts received TREO 42g/qm and fludarabine 150mg/qm. GvHD prophylaxis consisted of CSA alone (n=l) or in combination with short course MTX (n=25), alemtuzumab (n=22) or ATG (n=4). ANC > 500/μl and platelets > 20000/μl were reached at day 15 and 16 respectively. Acute GvHD grade II - IV occurred in 31% of pts and chronic GvHD in 60% of pts. Overall (OS) and disease free survival (DFS) were closely related to disease status. OS and DFS was 93% and 82,9% after a median of 18 months (range 0,9–38,5 months) for pts with early disease. In advanced disease the OS was 57,4% and the DFS 47,9% after a median of 4,8 months (range 0,3 – 22,9 months), respectively. In early disease, a single patient died of invasive aspergillosis associated with grade IV aGvHD. Another patient developed a relapse of CML which was successfully treated with DLI. Clinical relevant adverse events occurred in patients with advanced disease: MOF (n=7), VOD (n=2), infectious problems associated to GvHD grades II – IV (n=4), and pulmonary embolism (n=l). TREO as part of a myeloablative regimen seems to be effective and safe even in pts not eligible for conventional myeloablative therapy.

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