Patients with acute myelocytic leukemia carrying inversion 16 (inv16) or t(8;21) have a better initial response to high-dose cytarabine than patients without these chromosomal abnormalities. They ...presently do not undergo transplantation in first remission (CR1), but there is concern about late relapses.
From 1990 to 2004, 325 adult patients received transplantations in CR1 (159 patients with inv16 and 166 patients with t(8;21), including 35 and 60 patients, respectively, with additional chromosomal abnormalities). Genoidentical allografts were performed in 64 patients with inv16 and 81 patients with t(8;21), and autografts were performed in 95 patients with inv16 and 85 patients with t(8;21).
In patients with inv16, after allogeneic and autologous transplantation, the 5-year leukemia-free survival (LFS) rates were 59% and 66% (P = .5), the relapse incidence (RI) rates were 27% and 32% (P = .45), and the transplantation-related mortality (TRM) rates were 14% and 2% (P = .003), respectively. Female patients had a lower RI and a higher LFS. Additional chromosomal abnormalities, compared with no additional abnormalities, were associated with lower RI rate (12% v 34%, respectively; P = .01) and higher 5-year LFS rate (78% v 59%, respectively; P = .04). In patients with t(8;21), after allogeneic and autologous transplantation, the 5-year LFS rates were 60% and 66% (P = .69), the RI rates were 15% and 28% (P = .03), and the TRM rates were 24% and 6% (P = .003), respectively. Younger age and a lower WBC count at diagnosis were associated with a lower TRM and a better LFS. The TRM was lower and the RI was higher in patients with autologous transplantations versus allogeneic transplantations.
Both autologous and allogeneic transplantation resulted in similar outcomes.
Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN), an aggressive malignancy derived from plasmacytoid dendritic cells (PDCs), typically presents as cutaneous lesions, can also involve lymph nodes ...and spleen, and invariably terminates in an acute leukemic phase. Its diagnosis is based on this clinical presentation, as well as the unique pathological and immunophenotypic features of a cutaneous PDC neoplasm, with high expression of CD123 (interleukin-3 receptor IL-3R), CD304, and/or CD303 (Garnache-Ottou F et al., 2009); CD56 and CD4 are also commonly expressed. There is no accepted standard of care to treat BPDCN and therapeutic strategies have never been prospectively evaluated. Treatment approaches include: symptomatic therapy, intensive multi-agent chemotherapy, and allogenic hematopoietic cell transplantation. Although chemotherapy-naïve patients often respond to chemotherapy, most subjects experience recurrent disease shortly thereafter; median overall survival ranges from 9 to 13 months. Since BPDCN cells express high levels of IL-3R, the antitumor effects of SL-401, a novel targeted therapy directed to IL-3R, are being evaluated in preclinical and clinical studies. SL-401, which consists of IL-3 fused to a truncated diphtheria toxin payload, potently inhibits protein synthesis following IL-3R-mediated binding and internalization. Since normal hematopoietic cells express negligible levels of IL-3R, myelosuppression is negligible. To better understand the antitumor effects of SL-401 against BPDCN, the cytotoxicity of SL-401 was assessed in BPDCN patient-derived cell lines (CAL-1 and GEN2.2) and primary BPDCN cells isolated directly from patients (n = 12). Cytotoxicity was measured using flow cytometry (AV/7AAD staining) and an MTT assay after SL-401 treatment for 18 or 48 hours, respectively, as a single agent or compared with a range of cytotoxic agents. We confirmed the robust single agent activity of SL-401 against BPDCN cell lines (Angelot-Delettre F et al., ASH 2011) and found that treatment with SL-401 at concentrations substantially lower than peak concentrations achieved in patients induced a percent decrease in viability of BPDCN cell lines of 92% (62 ± 7% to 5 ± 2%) (n = 9 experiments) and primary BPDCN cells of 80% (50 ± 5% to 10 ± 1%) (n = 12 experiments) (Fig. A and B). Moreover, SL-401 was more effective than 7 out of 8 chemotherapeutic agents tested (Fig. C). SL-401 was also evaluated in a NOD-SCID IL2RγcKO (NSG) BPDCN mouse model. After 2 Gy irradiation, mice were injected with GEN 2.2 cells (1 x 106, IV) and then treated with SL-401 at clinically relevant doses or PBS (IP daily for 5 days) initiated on day 7 post-implantation. The median overall survival (OS) was significantly improved in mice receiving a single cycle of SL-401 compared to untreated controls (53 d vs. 15 d, respectively) (Figs. D and E). These findings provide strong in vitro and in vivo evidence that BPDCN cells are highly sensitive to SL-401. Since BPDCN patients express high levels of IL-3R (Garnache Ottou et al, 2009), these results also indicate that SL-401 may provide a clinical benefit for BPDCN patients. A Phase 2 multi-cycle trial in this orphan indication is currently being planned in North America and Europe. Display omitted
(A) BPDCN cell lines CAL-1 and GEN 2.2 (n= 9) and (B) primary cells (12 patients) are sensitive to SL-401 (2.7 fM) treatment (18 h) in vitro. **p<0.001. (C) BPDCN cells were cultured alone or with SL-401 (2.7 fM) or ERW (erwinase, 10 UI/ml), KID (kidrolase, 10UI/ml), MTX (methotrexate, 4.5µg/ml), CYC (cyclophosphamide, 100 µmM), CYT (cytarabine, 80 µg/ml), DEX (dexamethasone, 250 µg/ml), VIN (vincristine, 20 ng/ml), or IDA (idarubicin, 0.078 µg/ml). The viability was evaluated by cytometry using AV/7AAD staining after 18 h of culture. Results (mean + SEM) of 4 experiments.*p<0.05. (D) Survival rate of 2 Gy irradiated NSG mice injected IV with 1 x 106 GEN 2.2 cells on day 0. SL-401 treatment IP (2 µg) daily for 5 days (pink area) was initiated on day 7. The solid and dotted lines show saline-treated controls (n = 3) and SL-401 treated animals (SL-401, n=4), respectively. Results from one representative experiment out of 3. (E) GEN 2.2 cells detected in a node 2 weeks post-injection. Cells were stained with standard MGG solution and show a blastic morphology.
Frankel:Stemline Therapeutics: Patents & Royalties, Research Funding. Brooks:Stemline Therapeutics: Employment, Equity Ownership. Rowinsky:Stemline Therapeutics: Employment, Equity Ownership.
Abstract
Abstract 2266
We conducted a national retrospective analysis on 63 patients (pts) with either myeloid or lymphoid BC CML who underwent a first allogeneic stem cell transplantation as ...consolidation therapy for BC, since 2000 in France and look at whether 1st and 2nd generation TKIs ±chemotherapy prior to transplant may impact on outcome. There were 46 males and 17 females, and the median age at transplant was 34 (range 3–63) years and the median delay between BC and transplant was 19.6 (2.3-113) months. Thirty six (57%) pts were in chronic phase (CP), 3 (5%) in accelerated and 24 (38%) in BC at CML diagnosis. Twenty three pts received 1 line of treatment, 26 pts 2 lines, and 14 pts 3 or more lines for CML treatment before BC. For BC treatment, 25/63 (39%) pts had chemotherapy without TKI and 29/63 (46%) had TKIs combined or not to chemotherapy (6 chemo+dasatinib, 4 chemo+imatinib, 8 dasatinib alone, 1 dasatinib and imatinib, 9 imatinib, 9 unknown). At transplant 35/63 (55%) were considered in 2nd CP and 28 (45%) still in BC. The majority of the pts had an identical sibling donor (42/63: 66%), 1 mismatched related, 7 matched unrelated, and 13 mismatched unrelated. Fifty-six (89%) pts had a standard conditioning regimen, 7 (11%) pts a RIC regimen and 39 (62%) had a TBI. The stem cell source was bone marrow in 33/63 (52%) pts, PBSC in 24/63 (38%) and cord blood for 6/63 (10%). Fourteen transplants were sex-mismatched (female donor for male recipient). The EBMT-Gratwohl score was low (1+2+3) for 35/63 (55%) pts, intermediate (4) for 14 pts and high (5) for 9 pts, (and 6) for 3 pts and undetermined for 2 pts. The median follow-up since transplant was 25 (range 0.43–109) months. The overall median time for neutrophil recovery (neutrophils > 0.5 109/l) was 20 days. Fourty-one (65%) pts had an aGVHD (29 grade i-II and 12 grade III-IV) with no statistical differences between stem cell sources (p=0.4 for cord vs BM and 0.58 for PBSC vs BM). The cumulative incidence of chronic GVHD (14 extensive, 10 limited) was 43% at latest follow-up, more frequent in RIC transplant. The cumulative incidence of CML relapse was 38% at 2 yrs and multivariate analysis demonstrated the significant impact on relapse of the status at transplant in favour of disease control prior to transplant HR 2.22 (1-4.93, p=0.05 and unexpectedly, no impact of BC treatment with or without TKIs prior to transplant and of other variables. The median overall survival (OS) was 22 months (see Figure 1).
The TRM was 33% at latest follow-up, and it was significantly negatively influenced by the EBMT score (p=0.0077 for scores ≥ 4), BC status at diagnosis (p=0.04). The OS was not improved when using standard conditioning regimens (p=ns), but was improved by disease status at transplant (2nd CP better than persistent BC, p=0.01) and transplant with cord blood and BM stem cell sources over PBSC (p=0.011). Multivariate analysis on OS detected as significant adverse prognosis factors EBMT score ≥5 (HR=4.63 EBMT 5, and 4.77 EBMT 6). The types of treatment of BC CML had no significant impact (with or without stratification on chemotherapy). The median progression-free survival (PFS) was 5.8 months (see Figure 2).
The PFS was not significantly improved by standard conditioning regimens but again was improved by disease control prior to transplant (2nd CP better than persistent BC, p=0.001) and with cord blood and BM stem cell sources over PBSC (p=0.057). Multivariate analysis on PFS detected as significant adverse prognosis factors EBMT score ≥5 (HR=5.82 EBMT 5, and 3.82 EBMT 6), but again, the types of treatment of BC CML prior to transplant had no significant impact.
In conclusion, this analysis suggests that OS and PFS rates are significantly improved when compared to figures from the pre-TKI era. The use of 1st or 2nd generation TKIs alone or combined to chemotherapy does not seem to influence transplant results. CML status and the EBMT score are the major factors that can significantly influence transplant outcome.
Disclosures:
No relevant conflicts of interest to declare.
Abstract 2875
Radioimmunotherapy (RIT) is under study as a consolidation treatment after chemotherapy induction in follicular lymphoma patients. This approach also appears interesting in diffuse ...large B-cell lymphoma (DLBCL) patients >60 years, who are not candidates for bone marrow transplantation. 90Y-epratuzumab tetraxetan (Immunomedics, Inc.) is a radiolabeled humanized anti-CD22 antibody that has been used for a fractionated RIT, showing high rates of durable complete responses with manageable hematologic toxicity in previously-treated indolent and aggressive non-Hodgkin lymphoma (NHL) patients (Morschhauser et al., J Clin Oncol. 2010;28(23);3709-16). A French phase II trial sponsored by the GOELAMS group is ongoing, assessing fractionated RIT using 90Y-epratuzumab tetraxetan as a consolidation therapy after first-line chemotherapy in disseminated DLBCL patients >60 years. The protocol has been designed to include 75 patients; 64 patients have been already enrolled. We report the initial results, in particular safety data, on the first 29 available patients.
From October 2008 to November 2009, 29 untreated DLCBL patients >60 years were studied in several French institutions with an initial course of six cycles of R-CHOP14 followed 8 weeks later by two weekly infusions of 90Y-epratuzumab tetraxetan (15 mCi/m2 555 MBq/m2) 7 days apart. Hematologic and non-hematologic toxicities were evaluated using NCI-CTC v.3.0. Treatment responses were classified according to the 1999 International Workshop for Response Criteria for NHL.
Twenty-six patients underwent the entire course of R-CHOP and 23 received the 2 weekly RIT injections. Following R-CHOP, grade 3–4 neutropenia was observed in 20 patients (68.9%) and grade 3–4 thrombocytopenia in 4 (13.7%). During RIT infusions, 4 patients showed transient change of pulse or blood pressure, with 2 attributed to vasovagal reactions. RIT toxicity included grade 3–4 hematologic toxicity in 18 of 23 patients (78.3%); the most common grade > 3 toxicities were neutropenia (N=18, 78.3%) and thrombocytopenia (N=17, 73.9%). Serious febrile neutropenia was observed in 4 cases (13.8%) after R-CHOP and in 2 patients (8.7%) following RIT. Compared to R-CHOP, RIT non-hematologic toxicity was uncommon; moderate or severe gastrointestinal toxicity was observed in 10 patients (34.5%) after R-CHOP and in 2 (8.7%) following RIT; moderate or severe infection in 9 patients (31.0%) after R-CHOP and in 1 (4.3%) after RIT; and moderate or severe mucositis in 10 (34.4%) patients following R-CHOP, while no patient had mucositis after RIT. Following RIT, red cells and/or platelets transfusions were given to 12 patients (52,2%). Following R-CHOP, 10 of the 25 patients (40.0%) achieved a complete response (CR) or unconfirmed CR (CRu), 13 patients (52.0%) had a partial response (PR) and 2 patients (8.0%) had a stable disease. Six weeks after RIT, 13 patients (56.5%) achieved a CR or CRu, 9 patients (39.1%) had PRs, and 1 patient (4.3%) had progressive disease. Four of 13 patients (30.7%) who achieved less than a CR or CRu with R-CHOP improved their remission status 6 weeks after RIT.
These preliminary results indicate the feasibility and safety of fractionated RIT with 90Y-epratuzumab as a consolidation therapy for elderly DLBCL patients. Additional data will be presented at the time of the communication.
Off Label Use: monoclonal antibody epratuzumab labeled with yttrium 90 in phase II clinical trial. Wegener:Immunomedics, Inc.: Employment, shareholders. Goldenberg:Immunomedics, Inc.: Employment, shareholders.
Abstract 2266
We conducted a national retrospective analysis on 63 patients (pts) with either myeloid or lymphoid BC CML who underwent a first allogeneic stem cell transplantation as consolidation ...therapy for BC, since 2000 in France and look at whether 1st and 2nd generation TKIs ±chemotherapy prior to transplant may impact on outcome. There were 46 males and 17 females, and the median age at transplant was 34 (range 3–63) years and the median delay between BC and transplant was 19.6 (2.3-113) months. Thirty six (57%) pts were in chronic phase (CP), 3 (5%) in accelerated and 24 (38%) in BC at CML diagnosis. Twenty three pts received 1 line of treatment, 26 pts 2 lines, and 14 pts 3 or more lines for CML treatment before BC. For BC treatment, 25/63 (39%) pts had chemotherapy without TKI and 29/63 (46%) had TKIs combined or not to chemotherapy (6 chemo+dasatinib, 4 chemo+imatinib, 8 dasatinib alone, 1 dasatinib and imatinib, 9 imatinib, 9 unknown). At transplant 35/63 (55%) were considered in 2nd CP and 28 (45%) still in BC. The majority of the pts had an identical sibling donor (42/63: 66%), 1 mismatched related, 7 matched unrelated, and 13 mismatched unrelated. Fifty-six (89%) pts had a standard conditioning regimen, 7 (11%) pts a RIC regimen and 39 (62%) had a TBI. The stem cell source was bone marrow in 33/63 (52%) pts, PBSC in 24/63 (38%) and cord blood for 6/63 (10%). Fourteen transplants were sex-mismatched (female donor for male recipient). The EBMT-Gratwohl score was low (1+2+3) for 35/63 (55%) pts, intermediate (4) for 14 pts and high (5) for 9 pts, (and 6) for 3 pts and undetermined for 2 pts. The median follow-up since transplant was 25 (range 0.43–109) months. The overall median time for neutrophil recovery (neutrophils > 0.5 109/l) was 20 days. Fourty-one (65%) pts had an aGVHD (29 grade i-II and 12 grade III-IV) with no statistical differences between stem cell sources (p=0.4 for cord vs BM and 0.58 for PBSC vs BM). The cumulative incidence of chronic GVHD (14 extensive, 10 limited) was 43% at latest follow-up, more frequent in RIC transplant. The cumulative incidence of CML relapse was 38% at 2 yrs and multivariate analysis demonstrated the significant impact on relapse of the status at transplant in favour of disease control prior to transplant HR 2.22 (1-4.93, p=0.05 and unexpectedly, no impact of BC treatment with or without TKIs prior to transplant and of other variables. The median overall survival (OS) was 22 months (see Figure 1).
The TRM was 33% at latest follow-up, and it was significantly negatively influenced by the EBMT score (p=0.0077 for scores ≥ 4), BC status at diagnosis (p=0.04). The OS was not improved when using standard conditioning regimens (p=ns), but was improved by disease status at transplant (2nd CP better than persistent BC, p=0.01) and transplant with cord blood and BM stem cell sources over PBSC (p=0.011). Multivariate analysis on OS detected as significant adverse prognosis factors EBMT score ≥5 (HR=4.63 EBMT 5, and 4.77 EBMT 6). The types of treatment of BC CML had no significant impact (with or without stratification on chemotherapy). The median progression-free survival (PFS) was 5.8 months (see Figure 2).
The PFS was not significantly improved by standard conditioning regimens but again was improved by disease control prior to transplant (2nd CP better than persistent BC, p=0.001) and with cord blood and BM stem cell sources over PBSC (p=0.057). Multivariate analysis on PFS detected as significant adverse prognosis factors EBMT score ≥5 (HR=5.82 EBMT 5, and 3.82 EBMT 6), but again, the types of treatment of BC CML prior to transplant had no significant impact.
In conclusion, this analysis suggests that OS and PFS rates are significantly improved when compared to figures from the pre-TKI era. The use of 1st or 2nd generation TKIs alone or combined to chemotherapy does not seem to influence transplant results. CML status and the EBMT score are the major factors that can significantly influence transplant outcome.
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No relevant conflicts of interest to declare.
This report updates a retrospective study from SFGM-TC registry concerning 1108 patients who underwent allogeneic hematopoeitic stem cell transplantation (HSCT) after reduced intensity conditioning ...(RIC) from HLA identical siblings (84%) and unrelated donors (16%) for hematological malignancies. At time of conditioning, 442 patients were in CR, 337 in PR, 107 in stable disease (SD) and 222 in progressive disease (PD). As conditioning, 255 patients received fludarabine and TBI (2 grays), 465 patients fludarabine, busulfan and ATG and 388 patients an other regimen. After transplant, 336 patients (30%) developed an acute GVHD ≥ grade II (grade II: 178, III: 80 and IV: 78). A chronic GVHD was present in 388 patients (35%) (185 limited and 203 extensive). With a median follow-up of 30 months, the 3 and 5-year probability of overall survival (OS) were 43.5% (40–47) and 32%(29–35) respectively and the 3 and 5-year probability of event-free survival (EFS) were 35%(31–39) and 28% (24.5–31) respectively. The TRM at 1 year, 2 years and 3 years was 15% (13–17), 18% (15.5–21) and 20% (17–23). A mixture model, gfcure with Splus statistical package determined the percentages of long-term survivors and its adequacy was verified graphically. The probability to be a long-survivor was 24% (17.5–32.5) (Fig.1) and to be a long event-free survivor was 23% (19–28) (Fig. 2). The multivariate analysis has tested recipient and donor age, disease status pre-transplant, number of transplants before RICT, HSC source, sex matching, HLA matching, CMV status and ABO compatibility. The only factor which had a significant impact on long-term survival after RICT was the disease status just prior conditioning: PR versus CR: HR: 3.63 1.14–9.18 p<0.001 and PD versus CR: HR: 4.35 2.22–8.51 p<0.0001. In conclusion, these updated data demonstrate that allogeneic HSCT after RIC was able to possibly cure 23% of patients with haematological malignancies and the most important factor to take into account remains to be in CR pre-transplant.
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Abstract
This report updates a retrospective study from SFGM-TC registry concerning 1108 patients who underwent allogeneic hematopoeitic stem cell transplantation (HSCT) after reduced intensity ...conditioning (RIC) from HLA identical siblings (84%) and unrelated donors (16%) for hematological malignancies. At time of conditioning, 442 patients were in CR, 337 in PR, 107 in stable disease (SD) and 222 in progressive disease (PD). As conditioning, 255 patients received fludarabine and TBI (2 grays), 465 patients fludarabine, busulfan and ATG and 388 patients an other regimen. After transplant, 336 patients (30%) developed an acute GVHD ≥ grade II (grade II: 178, III: 80 and IV: 78). A chronic GVHD was present in 388 patients (35%) (185 limited and 203 extensive). With a median follow-up of 30 months, the 3 and 5-year probability of overall survival (OS) were 43.5% (40–47) and 32%(29–35) respectively and the 3 and 5-year probability of event-free survival (EFS) were 35%(31–39) and 28% (24.5–31) respectively. The TRM at 1 year, 2 years and 3 years was 15% (13–17), 18% (15.5–21) and 20% (17–23). A mixture model, gfcure with Splus statistical package determined the percentages of long-term survivors and its adequacy was verified graphically. The probability to be a long-survivor was 24% (17.5–32.5) (Fig.1) and to be a long event-free survivor was 23% (19–28) (Fig. 2). The multivariate analysis has tested recipient and donor age, disease status pre-transplant, number of transplants before RICT, HSC source, sex matching, HLA matching, CMV status and ABO compatibility. The only factor which had a significant impact on long-term survival after RICT was the disease status just prior conditioning: PR versus CR: HR: 3.63 1.14–9.18 p<0.001 and PD versus CR: HR: 4.35 2.22–8.51 p<0.0001. In conclusion, these updated data demonstrate that allogeneic HSCT after RIC was able to possibly cure 23% of patients with haematological malignancies and the most important factor to take into account remains to be in CR pre-transplant.
Figure 1 Figure 1. Figure 2 Figure 2.
This retrospective study concerned 471 B-CLL patients registered in the SFGM-TC registry from Apr 1,984 to Feb 2,005, who underwent either autologous transplantation (n=313, 138 F and 175 M, median ...age = 54, 236 PBSC and 77 BM) or allogeneic transplantation (n=158, 78 F and 80 M, median age = 49, 76 PBSC, 81 BM and 1 cord blood cell transplant from 17 related and 141 unrelated donors). Among alloT patients, 50 were ABO incompatible and 70 sex-mismatched. The median interval diagnosis-transplantation was 32 months for autoT and 51 months for alloT. Just before conditioning 302 autoT and 143 alloT were evaluated for the disease status: 100 and 26 patients were in CR, 170 and 55 were in PR, 4 and 13 in stable disease (SD), 28 and 49 in progressive disease (PD) for autoT and alloT respectively. Among alloT patients, 73 received reduced intensity conditioning (RIC) and 85 standard conditioning (72 Cyt+TBI, 33 Fluda+TBI, 23 Fluda+Bu+ATG, 8 Cyt+Bu and 21 other). Before autoT the conditioning consisted of 224 Cyt+TBI, 45 BEAM and 44 other. After alloT, 71 patients developed an aGVHD ≥ grade II and 60 developed a cGVHD (25 limited and 35 extensive). The non-relapse mortality at 1 year was 29%. With a mean follow-up of 28 months for autoT and 40 months for alloT, the probabilities of 3-year, 5-year and 8-year overall survival were 80%, 66%, 45.5% after autoT and 52%, 48% and 35% after alloT respectively. An analysis aimed to determine the percentage of long-term survivors, or patients censored on the final plateau of survival curves was performed on alloT and autoT groups. A mixture model, gfcure with Splus statistical package determined the percentages of long-term survivors and its adequacy was verified graphically. The percentage of long-term survivors for the autoT group was 1.2%, with a mean survival length for uncured population of 160 months. Fig A shows that both curves were close and consequently shows good adequacy and the absence of a final plateau. The percentage of long-term survivors for alloT was 34.03% (figure1). Fig B shows rather good adequacy. The study of the impact of usual prognosis factors (age, time diagnosis-transplant, sex match, HLA match, CMV status, type of conditioning, BM or PBSC, ABO compatibility and disease status before transplantation) on the percentage of long-term survivors showed that only the status of disease at transplant had a significant impact: (CR vs SD or PD, HR: 0.11 0.02–0.5 p=0.01 and PR vs SD or PD, HR: 0.30 0.09–0.96 p=0.04). This study pointed out the possibility of curing B-CLL patients who responded to conventional chemotherapy with allogeneic transplantation rather than with autologous transplantation.
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Reduced-intensity conditioning regimens (RIC) had become a classical strategy of allogeneic hematopoietic stem cell transplantation (HSCT) and many patients are now transplanted with unrelated donor. ...The aim of this restrospective study was to evaluate the impact of HLA mismatches between donor (D) and recipient (R) at the allelic level on survival after RIC. We analyzed 103 patients registered in France from Jan 1999 to Dec 2003 with a median age of 46 years (18–67). All patients had hematologic malignancies: AL (n=35), MM (n=18), CLL (n=5), NHL (n=11), HD (n=9), CML (n=12), MDS (n=9), and MPS (n=4). 39% of the patients were in an advanced phase of the disease at time of HSCT. Anti-thymocytes globulins (ATG) were part of the conditioning regimen for 77% of patients. The main source of stem cells was PBSC (n=65). Seventy-one D/R pairs (69%) were 10/10 HLA match at the allelic level. Mismatches concerned 5, 6, 15, 2 and 7 D/R pairs for HLA-A, -B, -C, -DRB1 and -DQB1, respectively. The results showed that 96% of patients engrafted. Acute GVHD grade II to IV and grade III/IV occurred in 46% and 19% of patients, respectively. The risk of developing cGvHD was 45% at 2 years. Overall survival (OS) was 42% at five years. Among the 47 patients alive, the median disease free survival (DFS) was 28 months. Among non-HLA parameters studied, the only factor associated with a good OS was the diagnosis of lymphoid disease (HD or NHL or CLL) (p=0.003). Recipient age <46y was only associated with less acute GvHD grade II to IV (p=0.008). Among HLA mismatches, we found that HLA-A and/or -B allelic mismatches had a negative impact on OS (p=0.006), DFS (p=0.006), acute GvHD grade II to IV (p=0.05). On the other hand, HLA-C or -DQB1 mismatches did not impact on OS, DFS, acute or chronic GvHD. We could not analyze DRB1 mismatch since there was only 2 patients reported. In conclusion, HSCT following RIC, with match or mismatch unrelated donors, is a feasible approach with best results observed for patients with lymphoid malignancies (NHL, CLL or HD). Among allelic HLA mismatches, HLA-A and/or -B seemed to be deleterious as compared to HLA-C or DQB1. These results help to identify most suitable donors and patients who are likely to benefit from RIC with unrelated donors when there is not a fully HLA match donor available.
RIC regimens are mainly used for patients who cannot benefit from the myelo-ablative (MA) approach, due to age, previous SCT, or comorbidities, based on an expected early toxicity of MA regimen. Some ...centers may also choose the RIC strategy in young patients because they have no facilities for the management of prolonged neutropenia. The development of RIC has been so encouraging that programs now compare MA and RIC in patients who could tolerate both approaches. However, RIC may fail, and MA SCT be secondary considered.
Objective: The goal of this retrospective survey was to assess the toxicity and outcome of MA after RIC SCT.
Patients: 17 patients (14–63 y; 6 CML, 4 AML, 2 CLL, 2 myeloma, 1 NHL, 1 CMML, 1 myelodysplastic syndrome) received a MA SCT after RIC, for relapse (n=12), graft rejection (n=4), or in a planned program (n=1), from an HLA-id sibling (n=12), a familial mismatched donor (n=1), an unrelated donor (n=3) or a cord blood (n=1). The reason for initial RIC approach was age in 4, a research program in 6, comorbidities in 3, and previous autologous SCT in 4 patients. RIC included Fludarabin (Flu)-Busulfan (BU) in 8, Flu-2Gy irradiation in 4, Cyclophosphamide (CPM)-antithymocyte globulin (ATG) in 1, and various Flu- regimens in 4. One patient had 2 consecutive RIC SCTs before MA SCT. The median delay between RIC and MA SCT was 9 months (range: 2.5–36 months). The same donor was used for the 1st and 2nd SCT in 12/17 cases. The MA transplant was conditioned with BU-CY (±VP16) in 9, Cyclo-TBI in 4, and other regimens in 4 patients. The median follow-up after MA SCT was 9 months
Results: After the MA transplant, 1 patient developed veno-occlusive disease, 2 developed interstitial pneumonia. Five patients died from relapse between 8 and 21 mo after the MA SCT. Seven (41%) died from transplant-related causes at a median of 8 months (GVHD:3; infection:1; multi-organ failure:1; thrombotic microangiopathy:1; EBV proliferative disease:1). 5/17 (29.5%) patients are alive and well 4.5 to 26 months after MA transplant. Three of them have extensive chronic GVHD while they did not develop any GVHD after RIC. The delay between the 2 transplants did not influence the outcome.
Conclusion: This survey shows that MA after RIC SCT is feasible, and considering that most of these patients have been initially eligible for RIC because of their age or comorbidities, MA SCT had an acceptable toxicity. It may be considered for patients who relapsed or rejected after RIC transplant.
