Is Conventional Allogeneic Haematopoietic Stem Cell Transplantation (HSCT) an Optimal Long-Term Strategy for Non Hodgkin Lymphomas: A Retrospective Study from 1987 to 2004.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3328-3328
Author(s):  
Anne-Sophie A.S. Michallet ◽  
Sophie S. Tartas ◽  
Quoc-Hung Q.H. Le ◽  
Franck F. Nicolini ◽  
Nicole N. Raus ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Overall Survival ◽  
Retrospective Study ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Haematopoietic Stem Cell ◽  
Allogeneic Hsct ◽  
Number Of Patients

Abstract Conventional chemotherapy in NHL does not substantially modify the natural course of disease especially for indolent lymphomas. A major advantage of allogeneic HSCT is the immunological recognition of lymphoma cells by the allogeneic donors cells and the low relapse risk in long-term survivors is highly suggestive of a graft-versus-lymphoma effect. However the still high mortality rate of this procedure mainly due to GVHD limits its indications. To determine the place of allogeneic HSCT in the NHL therapeutic strategies, we performed a retrospective study from 1987 to 2004. Twenty-six patients [17 males, 9 females, median age of 37 years (18–61)] underwent allogeneic HSCT: 18 conventional bone marrow transplantations and 8 allogeneic HSCT after reduced intensity conditioning (RICT) from HLA identical sibling donors. The diagnosis pre transplant were: 11 high grade lymphomas (9 phenotype B and 2 T), 8 patients with a transformation of an indolent form (2 CLL, 2 follicular and 3 marginal zone lymphomas, 1 mycosis fungoides) [73% aggressive forms of NHL] and 7 indolent forms (3 lymphocytic lymphomas, 3 follicular lymphomas and 1 mantle cell). All patients have received at least 3 courses of chemotherapy (3–7). Eighty-eight percent had a stage IV at diagnosis, 7% a stage III and 7% a stage II. At transplant, 10 (38.5%) were in complete remission, 2 in partial response, 9 in stable disease and 5 (19%) in relapse or progressive disease. Twenty-two patients received bone marrow as HSC source and 4 PBSC. Total body irradiation was used as part of the conditioning regimen in 78% of patients. With a median follow-up of 85 months (41–225) from diagnosis and 66 months (9–185) from transplantation, 13 (50%) are alive without evidence of lymphoma at last follow-up and 13 died [9 (35%) from transplant-related causes (1 acute GVHD grade IV, 3 pneumonitis, 1 septicemia, 1 veino-occlusive disease, 1 leucoencephalitis and 2 others causes) and 4 (15%) from relapse. Eight (30%) did not develop any acute GVHD, 9 a grade I, 4 a grade II, 3 a grade III and 2 a grade IV. Nineteen patients did not develop chronic GVHD, 6 a limited form and only one an extensive form. Overall survival at 5 years was 61.5% [95%CI (48%–83%)] from diagnosis and 57% [95% CI (40%–80%)] from transplantation. Transplant-related mortality was estimated at 35%. Multivariate analysis did not show any significant influence on overall survival (OS) of age, disease status, type of transplantation (conventional vs RICT), HSC source, TBI, acute or chronic GVHD but this lack of significance is probably in relation with the small number of patients. The long-term follow-up in this study demonstrated the effectiveness of allogeneic HSCT in achieving long-term disease control even in heavily pretreated aggressive NHL patients.

scholarly journals Bone marrow transplantation in 107 patients with severe aplastic anemia using cyclophosphamide and thoraco-abdominal irradiation for conditioning: long-term follow-up

Blood ◽  
1991 ◽  
Vol 78 (9) ◽  
pp. 2451-2455 ◽  
Author(s):  
E Gluckman ◽  
G Socie ◽  
A Devergie ◽  
H Bourdeau-Esperou ◽  
R Traineau ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Multivariate Analysis ◽  
Bone Marrow Transplantation ◽  
Marrow Transplantation ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Long Term Follow Up ◽  
Abdominal Irradiation

Since 1980, 107 consecutive patients (pts) underwent bone marrow transplantation (BMT) for nonconstitutional severe aplastic anemia (SAA) at our institution. All received conditioning with Cytoxan (150 mg/kg) and thoraco-abdominal irradiation (6 Gy) from an HLA-identical sibling donor. Mean age was 19 years (5 to 46 years). Forty-nine pts had less than 0.2 x 10(9)/L PMN and 53 failed to respond to previous immunosuppressive therapy before BMT. Graft-versus-host disease (GVHD) prophylaxis consisted of methotrexate (22 pts), cyclosporine (52 pts), or both (33 pts). With a median follow-up of 45 months (12 to 120 months), overall actuarial survival was 68% (confidence interval 95%:9.7). Of 16 factors tested, five were shown to adversely influence survival by multivariate analysis: grade greater than or equal to 2 acute GVHD (relative risk [RR]: 5.5), prior immunosuppressive therapy (RR: 3.5), female as donor (RR: 2.4), nonidiopathic SAA (RR: 2), and more than 0.2 x 10(9)/L PMN AA (RR: 2). Because acute GVHD was the most potent factor for survival, we analysed risk factors for acute GVHD. By multivariate analysis, 2 of 14 factors tested were independent: male as recipient (RR: 3) and previous alloimmunization of the donor (RR: 4.3). On long-term follow-up, chronic GVHD was observed in 49 pts of 89 surviving more than 100 days (55%). Multivariate analysis showed that infection before transplant (RR: 1.3) and previous history of acute GVHD (RR: 1.8) were associated with an increased risk of chronic GVHD.

scholarly journals Bone marrow transplantation in 107 patients with severe aplastic anemia using cyclophosphamide and thoraco-abdominal irradiation for conditioning: long-term follow-up

Blood ◽  
1991 ◽  
Vol 78 (9) ◽  
pp. 2451-2455 ◽  
Author(s):  
E Gluckman ◽  
G Socie ◽  
A Devergie ◽  
H Bourdeau-Esperou ◽  
R Traineau ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Multivariate Analysis ◽  
Bone Marrow Transplantation ◽  
Marrow Transplantation ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Long Term Follow Up ◽  
Abdominal Irradiation

Abstract Since 1980, 107 consecutive patients (pts) underwent bone marrow transplantation (BMT) for nonconstitutional severe aplastic anemia (SAA) at our institution. All received conditioning with Cytoxan (150 mg/kg) and thoraco-abdominal irradiation (6 Gy) from an HLA-identical sibling donor. Mean age was 19 years (5 to 46 years). Forty-nine pts had less than 0.2 x 10(9)/L PMN and 53 failed to respond to previous immunosuppressive therapy before BMT. Graft-versus-host disease (GVHD) prophylaxis consisted of methotrexate (22 pts), cyclosporine (52 pts), or both (33 pts). With a median follow-up of 45 months (12 to 120 months), overall actuarial survival was 68% (confidence interval 95%:9.7). Of 16 factors tested, five were shown to adversely influence survival by multivariate analysis: grade greater than or equal to 2 acute GVHD (relative risk [RR]: 5.5), prior immunosuppressive therapy (RR: 3.5), female as donor (RR: 2.4), nonidiopathic SAA (RR: 2), and more than 0.2 x 10(9)/L PMN AA (RR: 2). Because acute GVHD was the most potent factor for survival, we analysed risk factors for acute GVHD. By multivariate analysis, 2 of 14 factors tested were independent: male as recipient (RR: 3) and previous alloimmunization of the donor (RR: 4.3). On long-term follow-up, chronic GVHD was observed in 49 pts of 89 surviving more than 100 days (55%). Multivariate analysis showed that infection before transplant (RR: 1.3) and previous history of acute GVHD (RR: 1.8) were associated with an increased risk of chronic GVHD.

scholarly journals High Rate of Long Term Complete Remission for Patients with Chronic Lymphocytic Leukemia (CLL) Who Relapse after Allogeneic Stem Cell Transplantation and Receive Salvage with Donor Lymphocyte Infusions (DLI)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5860-5860
Author(s):  
Alan P Skarbnik ◽  
Mary E DiLorenzo ◽  
Tracy Andrews ◽  
Phyllis McKiernan ◽  
Scott D. Rowley ◽  
...  
Keyword(s):  
Overall Survival ◽  
Stem Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Disease Status ◽  
Advisory Committees

Abstract Background: Allogeneic stem cell transplantation (SCT) remains the only curative option for CLL, in part due to allogeneic graft-vs-leukemia effect (GVL), which can lead to complete suppression of the CLL clone (Schetelig et al, JCO 2003). Management of post-SCT relapse remains challenging, and DLI has been successfully used as salvage, due to its potential to induce GVL (Delgado et al, Blood 2009). We evaluated outcomes of SCT for patients (pts) with a diagnosis of CLL transplanted at our center. Methods: 36 consecutive pts transplanted between 2004 and 2015 were reviewed. Kaplan Meier survival curves were produced to examine overall survival (OS), time to progression (TTP) and post-DLI survival. Univariate Cox Proportionate hazard models were also estimated to assess the impact of pt characteristics on the risk of survival and progression. Bivariate frequencies with Fisher exact tests, correlation analysis, and independent samples t-tests were performed to test associations across outcomes. Results: Sample was 72% male. Median age at time of SCT was 57 yo (range 42-74). Pts had a median time of 70 months (mos) between diagnosis (Dx) of CLL and SCT. Median follow-up post-SCT was 32 mos (range 1-118). Of the 30 pts with known disease status at the time of SCT, 16.7% were in complete remission (CR), 20% had stable disease (SD), 50% were in partial remission (PR) and 13.3% had progressive disease (PD). Median number of lines of therapy pre-SCT was 3 (range 1-8). Thirteen pts (36%) were refractory to their first line of therapy. 10 pts (27.8%) had del(17p), 11 pts (30.6%) had del(11q) and 8 pts (22.2%) had complex cytogenetics. Most patients (72%) received pre-SCT conditioning with FCR (Khouri et al, Exp Hematol 2004). 16 pts (44.4%) received rATG as part of their conditioning regimen. Graft-vs-host disease (GVHD) prophylaxis consisted of methotrexate and tacrolimus. 20 (55.6%) pts had acute GVHD and 19 (52.8%) had chronic GVHD. 5 (13.8%) pts had grade 3/4 acute GVHD and 1 (2.7%) had extensive chronic GVHD. When comparing pts who received SCT from unrelated donors (MUD, 24 pts) vs sibling donors (sib, 10 pts) there were no differences in rates of GVHD, disease progression or overall survival. Twenty-seven pts (75%) were in CR at first disease evaluation after SCT (CR conversion rate of 58.3%) and 2 pts (5.5%) had PD. On follow-up, another 15 pts (41.7%) presented PD. Median TTP was 14 months, with only 3 pts relapsing after 2 years from SCT. Eight pts who had PD and one patient who had a PR post-SCT received short-term anti-CLL therapy for disease debulking, followed by DLI. Six (66.6%) out of the 9 pts who received DLI achieved CR and are currently alive and in CR. Median follow-up post-DLI was 43 months and median duration of response to DLI was 47 mos (range 6-85 mos). Ultimately, 13 (36.1%) pts died, 8 (22.2%) were lost to follow-up, and 15 (41.7%) were alive at last contact. Disease progression was the most common cause of death (5 pts, 13.9%). Transplant-related mortality (TRM) was 13.9% (3 deaths due to infection, 2 deaths due to chronic GVHD). Only 2 deaths (5.5%) occurred during the first 100 days post-SCT, both due to infection. No deaths occurred due to acute GVHD. Median OS was 84 months. PFS (not accounting for pts who relapsed post-SCT but achieved CR with DLI) was 58% in the first year and 25% at five years. The median PFS was 19 months. Univariate and multivariate analysis of pre-SCT pt characteristics (age, time from Dx to SCT, number of therapies, stage, presence of adenopathy, MUD vs sib donor, cytogenetic abnormalities, ABO mismatch, disease status at SCT) did not show any statistically significant correlation with OS, PFS or GVHD rates. Conclusion: SCT remains the only curative option for CLL. Our experience shows that pts may achieve long-term survival with this approach. TRM was low (13.8%) and rates of acute and chronic GVHD were compatible with previous reports (Sorror et al, JCO 2005; Dreger et al, Blood 2010). Type of donor (MUD vs sib) did not impact outcomes, suggesting that patients without a matched sibling should not be denied transplantation if a MUD is available. Although 47% of the patients eventually progressed after transplantation, 66% of patients who received DLI for salvage were able to achieve CR and remain progression-free for a prolonged period of time, underlining the importance of the GVL effect. Most relapses occurred within the first 2 years post SCT and late relapses were rare. Figure 2 Figure 2. Figure 3 Figure 3. Disclosures Skarbnik: Gilead Sciences: Speakers Bureau; Seattle Genetics: Speakers Bureau; Genentech: Speakers Bureau; Abbvie: Consultancy; Pharmacyclics: Consultancy. Vesole:Celgene: Speakers Bureau; Takeda: Speakers Bureau; Janssen: Speakers Bureau; Amgen: Speakers Bureau; Novartis: Speakers Bureau. Goy:Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Writing support, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Research Funding; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Infinity: Consultancy, Membership on an entity's Board of Directors or advisory committees; Acerta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Feldman:Pharmacyclics: Speakers Bureau; Celgene: Speakers Bureau; Seattle Genetics: Consultancy, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau. Leslie:Seattle Genetics: Speakers Bureau; Celgene: Speakers Bureau. Leslie:Seattle Genetics: Speakers Bureau; Celgene: Speakers Bureau.

scholarly journals Depletion of donor lymphocytes by counterflow centrifugation successfully prevents acute graft-versus-host disease in matched allogeneic marrow transplantation

Blood ◽  
1986 ◽  
Vol 67 (5) ◽  
pp. 1302-1308
Author(s):  
T de Witte ◽  
J Hoogenhout ◽  
B de Pauw ◽  
R Holdrinet ◽  
J Janssen ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Marrow Transplantation ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Allogeneic Marrow Transplantation ◽  
Primary Graft Failure ◽  
Acute Graft

Bone marrow from 22 histocompatible siblings was depleted of 98% of the lymphocytes using a combination of density flotation centrifugation followed by counterflow elutriation. Even with the marrow suppressive influence of methotrexate (MTX), the viability of the hematopoietic stem cells was not affected, as indicated by the normal repopulation after grafting in the evaluable patients. One patient (UPN 9) showed a primary graft failure, possibly resulting from persisting septicemia and long-term antibiotic therapy. Two patients have persistent host lymphocytes, one of whom was examined during relapse; the other remains in remission. Two patients did not receive immunosuppression after bone marrow transplantation (BMT), and acute graft-v-host disease (GVHD) developed in both. Nine patients received MTX as immunosuppression following BMT. GVHD did not develop in any of them, but fatal infections in the immediate posttransplant period developed in five patients. Eleven patients received cyclosporine (CsA) after transplantation. Beginning in week 5 after BMT, CsA was gradually replaced by MTX. Acute GVHD, substantial chronic GVHD, or fatal infections did not develop in any of these patients. Removal of 98% of the lymphocytes by counterflow centrifugation prevents development of acute GVHD, provided that immunosuppression is administered after BMT. Graft rejection was not observed, but the number of evaluable patients is limited at present.

Age Does Not Influence Long-Term Quality of Life (QOL) after Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) for AML/MDS.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2193-2193
Author(s):  
Munir Shahjahan ◽  
Jorge Alamo ◽  
Sergio Giralt ◽  
Michelle Detry ◽  
Mark Munsell ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Chronic Gvhd ◽  
Disease Status ◽  
Well Being ◽  
Marrow Transplant ◽  
Hematopoietic Stem ◽  
Younger Patients ◽  
Allogeneic Hsct

Abstract Allogeneic HSCT has the potential to cure patients with AML or MDS, but is associated with significant morbidity and complications that can affect the QOL of survivors. We examined QOL of AML/MDS patients surviving 2 years or more in remission after allo HSCT, including physical, psychosocial and functional well being. OBJECTIVES: We seek to describe QOL of long-term survivors (LTS) with AML/MDS and to compare QOL as a function of age at transplant. METHODS: Long-term survivorship was defined as survival in remission beyond 2 years from HSCT; 2 years was chosen given the stabilization of the failure rate on the 3rd year after HSCT. There were 544 adult AML/MDS patients treated with allogeneic HSCT between January 1976 and September 2001. Of these, 129 (24%) were in remission for at least 2 years and were eligible for the study. QOL was assessed using the standardized Functional Assessment of Cancer Therapy-BMT (FACT-BMT) questionnaire that measures multidimensional QOL concepts and consists of 5 subscales measuring physical (PWB), functional (FWB), social/family (SFWB), and emotional well being (EWB), including satisfaction with the doctor-patient relationship (RWD) (McQuellon et al., Bone Marrow Transplant, 1997). There was an additional concern (AC) subscale that asked questions related to job, appetite, body appearance, tiredness, interest in sexual activity etc. FACT-BMT allowed for responses to have values ranging from 0 (not at all) to 4 (very much). Specified QOL questions were recorded so that higher score reflected a higher QOL in the reported dimension. The questionnaire was mailed, and delivery could be confirmed for 121 patients out of whom 82 (68%) responded. Demographic and clinical characteristics were collected from patient charts and clinical database. RESULTS: Median age at transplant was 38.44 years (range 18.54–68.08). Median time from HSCT to receipt of questionnaire was 4.53 years. Gender: 47 males and 35 females. Diagnosis: AML (n=70) and MDS (n=12). Conditioning regimens were of reduced intensity in 29 cases and myeloablative in 53 cases. Stem cell source: bone marrow (n=52), and peripheral blood (n=30). GVHD prophylaxis: tacrolimus based in 61 cases and cyclosporine based in 18 cases; none in 2 cases. Disease status at HSCT: complete remission (n=40), relapsed (n= 37) and untreated disease (n=5). Median follow-up time was 4.53 years (range 2.0–21.1 yrs). There were no significant differences in QOL scores between the older and younger patients (above and below the median age at transplant) in the PWB, SFWB, EWB, FWB and RWD subscales. In the AC subscale, however, older patients had higher QOL scores than younger patients (mean score 37.97 vs. 33.25, p=0.005). When we compared non-myeloablative (NMA) vs. myeloablative (MA) regimens, there were no significant differences in mean QOL scores in all but the AC subscale where NMA group did better (39.00 vs. 33.34, p=0.001). Acute graft versus host disease (aGVHD) did not impact long-term QOL but lack of chronic GVHD was associated with better QOL score in the PWB, EWB, FWB and AC subscales (PWB: 25.04 vs. 20.62, p=0.005; EWB: 21.77 vs. 18.98, p=0.003; FWB: 22.91 vs. 18.00, p=0.008; and AC: 40.00 vs. 34.28, p=0.002). CONCLUSIONS: Among LTS with AML/MDS, older age did not affect QOL at a median of 4.5 yrs post HSCT.

Mutant TIRAP Gene Polymorphism Is Associated with Outcomes in HLA Genoidentical Bone Marrow Transplants Recipients with Leukemia.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 327-327 ◽  
Author(s):  
Vanderson Rocha ◽  
Raphael Porcher ◽  
Nabil Kabbara ◽  
Regis Peffault de Latour ◽  
Marie Robin ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Overall Survival ◽  
Fungal Infection ◽  
Lower Incidence ◽  
Cumulative Incidence ◽  
Gene Polymorphisms ◽  
Acute Gvhd ◽  
Fungal Infections ◽  
Chronic Gvhd ◽  
Adaptor Protein

Abstract Toll-like receptors (TLRs) and members of their signaling pathway are important in the initiation of the innate immune response to a wide variety of pathogens. The adaptor protein TIRAP, mediates downstream signaling of TLR2 and TLR4. A leucine (Leu) substitution at position 180 serine (Ser) of TIRAP was shown to protect from infections. We hypothesized that the incidence of infections and outcome after bone marrow transplantation (BMT) could be influenced by the TIRAP gene polymorphisms. Genotyping for TIRAP at Ser180 was performed in 107 donor/recipients pairs: 64% of recipients and 63% of donors were homozygote wild type (wt) Ser180/Ser180, 20% and 19% were Ser180/Leu180 and 17% and 18% Leu180/Leu180. Severe bacterial (pneumonia, septicemia and septic shock), viral or invasive fungal infections during 180 days after BMT, TRM (transplant related mortality), acute GVHD and survival were studied retrospectively. An allogeneic HLA-identical BMT was performed in 107 patients (median age was 35 years), with acute (n=39) or chronic Leukemia (n=68). Conditioning regimen consisted of Busulfan+Cyclophosphamide±others (BU-CY) in 73 (68%) patients and TBI+CY in 15 (14%) or TBI+Melphalan in 17 (16%). GVHD prophylaxis consisted of CsA+MTX in 94%. Median follow-up time was 77 months (18–147). Cumulative incidence of neutrophil recovery was 94%. Acute GVHD (II-IV) was observed in 42%, and chronic GVHD in 50 out of 98 at risk. Estimate 5-year survival was 54%. The cumulative incidence of any first infection by day 180 was 56%, being 28% for at least one bacterial infection, 39% for viral infection and 12% for invasive fungal infection (8 invasive aspergillosis, 4 disseminated candidiosis and 1 disseminated Malassezia furfur fungal infection). TRM cumulative incidence at 1 year was 35%. Recipient’s TIRAP gene polymorphisms were not associated with outcome. However, patients transplanted from a mutant TIRAP donor (Leu/Ser or Leu/Leu) had a trend to lower incidence of fungal infections (p=0.08); lower incidence of acute GVHD (p=0.03), decreased TRM (p=0.02) and improved overall survival (p=0.02). In a multivariate analysis, adjusting for other prognostic factors, TIRAP donor polymorphisms were associated with decreased TRM (HR=0.49, p=0.02): TRM at 1 year was 43% when donors were wt (Ser/Ser) as compared to 20% when donors were mutants. There was also a trend to decreased incidence of acute GVHD in patients with a mutant TIRAP donor as compared to the others (30% versus 49%; HR 1.88 p=0.06) and better overall survival (67% versus 44%, respectively HR 1.82; p=0.07). Recipients of bone marrow (BM) from wt TIRAP donors seemed to die more frequently from infection (1 yr cumulative incidence 21% vs 8%, p=0.07). In conclusion, the presence of a Leu substitution at position 180 in the TIRAP gene of BM donors decreases the incidence of TRM in HLA-identical BMT, probably reflecting better immune reconstitution and protection against infections. This finding can help defining better surveillance and prophylaxis of bacterial infections in BMT recipients from donors with the wt TIRAP (Ser/Ser) genotype.

Stable Long-Term Risk of Leukemia in Patients with Severe Congenital Neutropenia Maintained On G-CSF Therapy.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3206-3206 ◽  
Author(s):  
Philip S. Rosenberg ◽  
Cornelia Zeidler ◽  
Audrey Anna Bolyard ◽  
Blanche P. Alter ◽  
Mary Ann Bonilla ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cumulative Incidence ◽  
Bone Marrow Failure ◽  
Severe Congenital Neutropenia ◽  
Congenital Neutropenia ◽  
Hazard Curve ◽  
Number Of Patients ◽  
Increasing Trend

Abstract Abstract 3206 Poster Board III-143 BACKGROUND G-CSF therapy reduces sepsis mortality in patients with severe congenital neutropenia (SCN), but effective therapy has revealed a high syndromic predisposition to myelodysplastic syndrome and acute myeloid leukemia (MDS/AML), particularly in patients who require higher doses of G-CSF. Although the long-term risk of MDS/AML after 10 or more years on therapy remains uncertain, prior data on the limited number of patients with long-term follow-up suggested the hazard rate might be as high as 8%/year after 12 years on G-CSF. METHODS We updated prospective follow-up of 374 well-characterized patients with SCN on long-term G-CSF enrolled in the Severe Chronic Neutropenia International Registry (Blood. 2006 Jun 15; 107(12):4628-35). We ascertained event-free time, deaths from sepsis, and MDS/AML events that accrued since our previous report. Follow-up was censored for patients who received a bone marrow transplant. RESULTS The update yielded 3590 person-years of follow-up versus 2043 in the prior report; among patients treated for 10 or more years, there were 849 person-years versus just 67 previously. In all, there were 61 MDS/AML events and 29 deaths from sepsis, versus prior totals of 44 and 19, respectively. After including up-to-date follow-up, the estimated annual hazard of death from sepsis remained qualitatively stable, at 0.81%/year (95% Confidence Interval, CI: 0.56 – 1.16%/year). Similarly, during the first five years after the start of G-CSF therapy, the updated estimate of the hazard curve for MDS/AML showed the same increasing trend as the previous estimate. However, in contrast to the prior estimate that showed a subsequent increasing trend over time (with a large margin of error), the updated hazard curve attained a plateau: after 10 years on G-CSF, the estimated hazard of MDS/AML was 2.3%/year (95% CI: 1.7 – 2.9%/year). Although this aspect of the natural history appears less dire than first suggested, after 15 years on G-CSF, the cumulative incidence was 10% (95% CI: 6 – 14%) for death from sepsis and 22% (95% CI: 17 – 28%) for MDS/AML. Furthermore, for the subset of patients who failed to achieve at 6 months an absolute neutrophil count at or above the median value for the cohort (2188 cells/μL) despite doses of G-CSF at or above the median (8 μg/kg/day), the cumulative incidence after 15 years on G-CSF was 18% (95% CI: 7 – 28%) for death from sepsis and 34% (95% CI: 21 – 47%) for MDS/AML. With additional follow-up, the association of G-CSF dose at 6 months with the relative hazard of MDS/AML became more strongly statistically significant (P = 0.003 versus P = 0.024; the hazard of MDS/AML increased by 1.24-fold (95% CI: 1.08-1.43-fold) per doubling of the dose of G-CSF). CONCLUSIONS For SCN patients maintained on G-CSF therapy, the hazard of MDS/AML over the long-term falls significantly below the range suggested by preliminary data. The updated hazard estimate of 2.3%/year after 10 years on G-CSF (which includes both MDS and AML events) is similar to that for other inherited bone marrow failure syndromes with a high intrinsic risk of AML, notably Fanconi anemia and dyskeratosis congenita. Nonetheless, the cumulative incidence of both MDS/AML and sepsis death rises to very high levels, and the data continue to support the hypothesis that SCN patients with higher G-CSF requirements are also at higher risk of leukemia. Disclosures Boxer: Amgen Inc.: Equity Ownership. Dale:Amgen Inc.: Consultancy, Honoraria, Research Funding, Speaker.

Azacitidine (Vidaza®, Aza) and Donor Lymphocyte Infusions (DLI) In Patients with Acute Myeloid Leukemia (AML) or Myelodysplastic Syndromes (MDS) Relapsing After Allogeneic Hematopoietic Stem Cell Transplantation (HSCT): Interim-Analysis From the AZARELA-Trial (NCT-00795548).

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1294-1294
Author(s):  
Thomas Schroeder ◽  
Akos Gabor Czibere ◽  
Nicolaus Kröger ◽  
Uwe Platzbecker ◽  
Gesine Bug ◽  
...  
Keyword(s):  
Overall Survival ◽  
Missing Data ◽  
Salvage Therapy ◽  
Interim Analysis ◽  
Research Funding ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Significant Activity ◽  
Hematopoietic Stem ◽  
Allogeneic Hsct

Abstract Abstract 1294 Background: Patients with AML or MDS who relapse after allogeneic HSCT have a poor prognosis and therapeutic options are limited. The DNA hypomethylating agent Aza has significant activity in patients (pts) with AML and MDS and retrospective analyses have recently shown encouraging results with the use of Aza +/− DLI in patients with AML and MDS, who relapsed after allogeneic HSCT (Czibere et al., 2010; Luebbert et al., 2010). In line with these clinical observations preclinical data suggest that Aza enhances a Graft-versus-Leukemia (GvL) effect while mitigating Graft-versus-Host Disease (GvHD). Design/Methods: To evaluate the activity and safety of Aza in combination with DLI as first salvage therapy in pts with AML or MDS relapsing after HSCT, we conducted a prospective, multicenter, single-arm phase-II trial. Pts were allowed to receive up to 8 cycles Aza (100 mg/m2/d d1-5, every 28 days) and 3 DLI with increasing dosages (1-5×106 – 1–5×108 cells/kg) after every 2nd Aza treatment cycle. Additional DLI were permitted. Results: Between January 2009 and May 2010, 30 pts from 6 German transplant centres were included into this trial. So far, 25 pts (15 female/10 male) were evaluable and are presented in this analysis: Of these, 23 (92%) suffered from AML (15 de novo/8 secondary following MDS), 1(4%) from a MDS (RAEB-1) and 1 (4%) from a myelodysplastic/myeloproliferative syndrome (MDS/MPS, CMML-1). Median age was 54 years (range 29–71). Conditioning was myeloablative in 24 pts (96%) and non-myeloablative in 1 patient (4%). Eight pts (35%) received a graft from a matched sibling donor, while 15 (65%) were transplanted with a matched unrelated donor (2 pts missing data). Peripheral blood stem cells (PBSC) were used in 24 pts (96%; 1 pt missing data). At the time of transplant 6 pts (24%) had primary induction failure, another 6 (24%) suffered from first or secondary relapse, 10 pts (40%) were in first or second complete remission (CR), while 3 pts (12%) were untreated. With regard to their molecular and genetic characteristics at diagnosis, 21 pts belonged to an adverse (9 pts) or intermediate (12 pts) group, whereas 2 pts were diagnosed with a favourable genetic phenotype (2 pts not performed). Prior to relapse 9 (36%) and 3 (12%) pts had episodes of acute GvHD and/or chronic GvHD, respectively. Relapse occurred in all pts after a median of 160 days (range 19–1199) following HSCT (median BM blasts: 34%, range 5–100%, median chimerism: 63% range-1-100%). At the time of relapse, karyotype was evaluable in 13 of 25 pts (52%). Of these 13 pts, 4 pts had a normal karyotype, while 9 had chromosomal aberrations including 6 pts with a complex karyotype. Patients received a median of 3 courses Aza (range 1–8) and 18 of 25 pts (72%) received DLI (median: 1, range: 1–4, median CD3 dose 5×106/kg/DLI, range: 1–207×106). Following treatment, overall response rate was 64% with 5 pts (20%) achieving a CR or CRi, 3 (12%) a partial remission (PR) and 8 (32%) a stable disease (SD). Median response duration was 266 days. Acute GvHD occurred in 6 pts (24%) (2 skin/6 liver/ 2 gut) after a median of 65 days (range 19–179) following the first DLI, while chronic GvHD was observed in 3 pts (12 %, all limited). Hematotoxicity (grade III-IV) was observed in 64% of all evaluated patients. Common adverse events were gastrointestinal side effects as well as infections. After a median follow-up of 100 days (range 25–485) 15 of 25 pts (60%) are currently alive. Median overall survival of all pts is 184 days (range 87–281). All pts, who achieved a CR/CRi, remained in ongoing remission for a median time of 229 days. Achieving a CR (CR: not reached vs. no CR: 117 days, p .008) or any type of response (CR/CRi, PR or SD) to the combination of Aza and DLI (any response: not reached vs. no response: 79 days, p .0001) were associated with a significantly longer overall survival. Conclusion: The combination of Aza and DLI as salvage treatment for patients with AML or MDS who relapse after allogeneic HSCT seems to be safe and shows significant anti-leukemic activity. Response, including CR rates, so far match those from retrospective analyses. Data presented in this interim-analysis suggest that salvage therapy with Aza and DLI is of substantial therapeutic benefit in these challenging patients. Disclosures: Platzbecker: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Bug:Celgene: Honoraria. Luft:Celgene: Research Funding. Fenk:Celgene: Research Funding. Kobbe:Celgene: Research Funding.

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