Allogeneic Hematopoietic Stem-Cell Transplantation with Reduced-Intensity Conditioning in Patients with High Risk Multiple Myeloma: Comparative Analysis of Outcomes Between Unrelated and Related Donor

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4513-4513
Author(s):  
Jean El-Cheikh ◽  
Sabine Furst ◽  
Anne Marie Stoppa ◽  
Roberto Crocchiolo ◽  
Catherine Faucher ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
High Risk ◽  
Unrelated Donor ◽  
Reduced Intensity Conditioning ◽  
Related Donor ◽  
Group 2 ◽  
Reduced Intensity ◽  
Group 1

Abstract Abstract 4513 Introduction: The purpose of this study was to assess the results of allogeneic stem cell transplantation (Allo-SCT) after reduced-intensity conditioning (RIC) from an unrelated donor in patients with high-risk multiple myeloma (MM) in a single centre. From January 2007 to January 2011 we consecutively transplanted 40 patients with MM. Patients and methods: Seventeen (43%) (Group 1) and 23 patients (57%) (Group 2) had unrelated and related donor respectively. The median age was 48 years (39–63) in the first group and 56 years (40–67) in the second group (P=0.0769). Thirty nine patients (98%) received one or more autologous transplantation. Ten patients (Group 1: N=5 (29%); Group 2: N=5 (22%)) were transplanted within whereas 30 patients were treated beyond (Group 1: N=12 (71%); Group 2: N=18 (78%) the first line treatment strategy. The disease status at transplantation was Complete Remission (CR) or VGPR in (35%) vs (43%), Partial remission (PR) in (59%) vs (52%) and Progression or Refractory Disease in (6%) vs (4%) (PD/RD) in the first and second group respectively (p=0.1770). Graft was peripheral blood stem cells (PBSC) in all patients in the related donor group and in 14 patients (82%) in the second group, the other 3 patients (18%) receiving marrow. Thirty-three patients (Group 1: N=14 (82%); Group 2: N=19 (83%) were treated with a RIC based on Fludarabine (30mg/m2/d × 5); Busulfan (4 mg/kg/d p.o. or 3.2 mg/kg/d IV over 2 to 3 days) and rabbit ATG (2.5 mg/kg/d × 2). Seven patients received Fludarabine (25mg/kg/d for 3 days) and 2 Gys total body irradiation (TBI). Post-graft immunosuppression consisted of cyclosporine (CSA) alone in 26 patients (65%), CSA and mycophenolate mofetil in 14 patients (35%). Result: The median follow-up was 22 months (1–49). None of our patient experienced a graft rejection. The cumulative incidence of grade II-III acute graft versus-host disease (GVHD) tended to be higher after unrelated donor graft (41% vs 17%) (p= 0.12). The cumulative incidence of chronic GVHD was no different between the first and second group (24% vs 30% respectively). At last follow up 24 patients (group 1: N=11 (65%); Group 2:N=14 (61%) were still alive of whom 17 are in CR (group 1: N=9 (53%); Group 2:N=8 (35%), 5 in PR (group 1: N=1 (6%); Group 2:N=4 (17%)and 2 in progressive disease (group 1: N=1; Group 2:N=1). The estimated probability of non relapse mortality (NRM) at day 100 was 0% in the two groups and not statically different at 2 years. (12% vs. 22% (P=0.4)) Also 2 year overall and progression-free survivals were not statiscally different after unrelated and related donor transplants (59% vs. 66% (P=0.110) and 42% vs. 44% (p=0.241)). The incidence of acute GVHD, OS, PFS and NRM were not significantly different between the two groups. Conclusion: Our experience, although limited, supports that high risk MM patients can benefit from a RIC Allo-SCT with unrelated donor when a HLA matched sibling donor is not available conducting to acceptable and comparable outcomes. This deserves further analysis in larger populations. Disclosures: No relevant conflicts of interest to declare.

Full Haplotype Mismatch Stem Cell Transplantation: Myeloablative with T-Cell Depletion Vs. Reduced Intensity Conditioning without T-Cell Depletion

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3533-3533 ◽  
Author(s):  
Heeje Kim ◽  
Woo-Sung Min ◽  
Ki-Seong Eom ◽  
Byung-Sik Cho ◽  
Seung-Ah Yahng ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
High Risk ◽  
Cell Depletion ◽  
Reduced Intensity Conditioning ◽  
T Cell Depletion ◽  
Group 2 ◽  
Reduced Intensity ◽  
Group 1

Abstract Abstract 3533 Some groups have continuously tried to reveal the possible role of full-haplotype mismatch stem cell transplantation (SCT) in patients who lack a compatible donor. However, the long-term event-free survival (EFS) rate after high-grade mismatch SCT using conventional myeloablative conditioning with T-cell depletion (TCD), even in complete remission (CR), is still only in the range of 10–30%. Most patients who were transplanted had heavily pretreated acute leukemia. The most important obstacle to overcome is the high rate of infection-related mortality associated with delayed immunological recovery in the setting of full-haplotype mismatch SCT, specifically by way of complete depletion of donor T cells in the graft. In contrast, by using unmanipulated donor cells and less aggressive conditioning regimens without TCD, most groups in Asia have reported EFS >40%. We investigated the role of reduced-intensity conditioning without TCD in HLA-mismatched related-donor SCT, specifically in patients with high-risk acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) who received unmanipulated granulocyte colony stimulating factor (G-CSF)-mobilized peripheral blood stem cells (PBSCs). SCT was performed in 32 consecutive patients. We compared two different protocols: one with more intensive conventional conditioning with TCD (group 1), and one with reduced intensity without TCD (group 2). The protocols differed between the two groups with respect to total body irradiation (1200 cGy in group 1 vs. 800 cGy in group 2) as well as busulfex, fludarabine, and anti-thymocyte globulin (ATG; thymoglobulin, Genzyme) treatments. No patient in group 1 received post-transplant graft versus host disease (GvHD) prophlyaxis or G-CSF. In contrast, all patients in group 2 received 1.25 mg/kg/day ATG for 4 consecutive days, together with our standard GvHD prophylaxis regimen of methotrexate (5 mg/m2 intravenous bolus on days 1, 3, 6, and 11) and tacrolimus starting at day –1. All patients received G-CSF-mobilized PBSCs. The median number of CD34+ cells infused was 14.2 (range, 4.3–20.6) × 106/kg for group 1 and 6.0 (range, 3.6–8.5) × 106/kg for group 2. The median numbers of CD3+ cells infused were 0.03 (range, 0.015–0.057) × 106/kg and 870 (range, 84–1260) × 106/kg, respectively. G-CSF was administered subcutaneously to all patients in group 2 at a dose of 5 mg/kg/day, from day 7 after transplantation until neutrophil recovery. GvHD, relapse, non-relapse mortality (NRM), overall survival, EFS, reconstitution of immunity, and natural killer (NK) cell alloreactivity were compared between the groups. The median patient age was 33 (range, 17–48) years for group 1 and 39 (range, 19–63) years for group 2. The median follow-up for surviving patients was 18 months (range, 8–100). The majority of patients had intermediate or unfavorable cytogenetic features. The transplanted patients were all successfully engrafted. The median times to neutrophil (>0.5 × 109/kg) and platelet (>20 × 109/kg) recovery were 12 and 13 days in group 1, and 11 and 10 days in group 2. The overall rates of acute and chronic GvHD were 50% and 33%, and 80% and 92% in groups 1 and 2, respectively. Of note, NRM differed significantly between the groups: 46.2% in group 1 vs. 9.5% in group 2 (P = 0.0014). The estimated probability of EFS at 2 years was 15.3% for group 1 vs. 59.2% for group 2 (P = 0.05). We did not find NK alloreactivity in any of the patients, based on the NK-killer cell immunoglobulin-like receptor (KIR) disparity between donor and recipient. However, we noted a significant difference in EFS between C1/C1 homozygotes and C1/C2 heterozygotes according to the donor NK-KIR ligands (P = 0.0175). Recovery of CD4+ cell numbers at 3 months after SCT showed a markedly different pattern between the groups, with a median of 4 cells/μl (range, 2–7) in group 1 vs. 311 cells/μl (range, 56–1226) in group 2. Our findings suggest that full-haplotype mismatch SCT using a Korean-adapted protocol is a feasible therapeutic strategy for patients with high-risk AML/MDS, specifically in CR, provided that there is a further defined plan for the investigation of NK/T-cell alloreactivity. Disclosures: No relevant conflicts of interest to declare.

Fludarabine Is Superior to Cladribine When Added to Busulfan and Low Dose TBI as Reduced Intensity Conditioning for Allogeneic Hematopoietic Cell Transplantation (HCT): A Prospective Randomized Trial.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1825-1825
Author(s):  
M. Markova ◽  
Juliet N. Barker ◽  
John E. Wagner ◽  
Jeffrey S. Miller ◽  
Mukta Arora ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Cell Transplantation ◽  
Cumulative Incidence ◽  
Unrelated Donor ◽  
Reduced Intensity Conditioning ◽  
Purine Analogues ◽  
Hematopoietic Stem ◽  
Platelet Recovery ◽  
Reduced Intensity

Abstract Purine analogues have been combined with alkylator/irradiation as immunosuppressive and anti-tumor conditioning prior to allogeneic hematopoietic stem cell transplantation (HCT) though differing purine analogues have not been compared. We prospectively tested Fludarabine (F) 40 mg/m2/d x 5d vs. Cladribine (C) 10 mg/m2/d x 5d plus Busulfan (Bu) (2mg/kg q12h x 2d) and total body irradiation (T) 200cGy followed by cyclosporine and mycophenylate mofetil in 19 recipients of matched sibling peripheral blood stem cell and 13 unrelated donor (URD) marrow HCT. Patients in each randomly assigned cohort [FBuT vs. CbuT] were similar in age (median 52 years in both groups), diagnosis (leukemia/MDS 38 vs. 31%; lymphoid malignancy 57 vs 69%), extensive pre-HCT therapy (56 vs. 63%), high risk disease status (81 vs. 93%) and Karnofsky (median 90 in each)[all p= NS] though fewer FBuT were URD recipients 25% vs. CBuT 56%, p=0.07. Engraftment was prompt in both groups (median 11 vs. 12 days), but the cumulative incidence of neutrophil engraftment was 75% (95% C.I. 54–96%) using CBuT vs. 100% with FBuT (p<0.01) and randomization was halted. Platelet recovery was prompt (median FBuT 18 vs CBuT 24 days) and after FBuT 75% (95% C.I. 49–100) vs. CBuT 69% (43–95) recovered platelets > 50,000/μL by day +180, p=0.19. The cumulative incidence of GVHD after FBuT vs. CbuT was similar (acute grade II/IV 56 vs. 69%, p=0.26) and (chronic 50 vs. 31%, p=0.27). Transplant related mortality at day +180 was also similar [FBuT 25% (4–46) vs. CbuT 38% (14–61), p=0.47]. Survival was equivalent: at 1 year 50% in each group; at 3 years FBuT 25% vs. CBuT 38%, p=0.55. Multivariate analyses adjusted for age, donor type, diagnosis and stage as well as conditioning regimen showed lower relative risk (RR) of engraftment with CBuT (RR 0.6 (95% C.I. 0.2–1.3) p=0.16) and with URD RR 0.4 (0.2–1.0) p=0.04). RR of Platelet recovery was equivalent with FBuT (RR 0.7 (0.3–1.7) p=0.45) but inferior with URD (RR .16 (.05–.5) p<0.01). RR of GHVD II/IV similar with FBuT RR 1.1, p=0.95, but more frequent with URD RR 2.0, p=.2 and high risk status patients (RR 4.5, 1.5–13.5, =<0.01). Prevalence of remission (CR or PR) at 18 months was high and was similar in both groups (FBuT 100% vs CBuT 86%, p=NS). These data suggest that older patients with advanced hematologic malignancies can achieve satisfactory post-transplant outcomes using either of these combination/reduced intensity conditioning regimens. Fludarabine may be superior to cladribine as a component of pre-HCT conditioning with Bu/TBI due to reduced risks of graft failure. Further modifications of the regimen may confirm universal engraftment with even lower peri-transplant morbidity.

Allogeneic Stem Cell Transplantation Using a Reduced Intensity Conditioning (RIC) Regimen Has the Capacity To Produce Durable Remissions and Long Term Disease-Free Survival in Patients with High Risk Acute Myeloid Leukemia (AML).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1141-1141
Author(s):  
S. Tauro ◽  
S. Mackinnon ◽  
K. Peggs ◽  
G. Begum ◽  
P. Mahendra ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Disease Free Survival ◽  
Allogeneic Transplantation ◽  
Disease Relapse ◽  
Reduced Intensity Conditioning ◽  
Free Survival ◽  
Disease Free ◽  
Reduced Intensity

Abstract The toxicity of allogeneic stem cell transplantation (SCT) can be substantially reduced by the use of a reduced intensity conditioning (RIC) regimen and this has increased the proportion of patients with myeloid malignancies eligible for allogeneic transplantation. However, the capacity of RIC allografts to produce durable remissions in patients with AML and MDS has not yet been defined and consequently their role in the management of these diseases remains conjectural. Seventy-six patients with high risk AML or MDS were allografted using a fludarabine/melphalan RIC regimen incorporating alemtuzumab. The median age of the cohort was 52 years (range 18–71 years). There were 46 males and 30 females; 41 patients received an allograft from an unrelated donor and 35 from a matched sibling donor. The 100 day transplant related mortality was 9% and no patient developed greater than Grade 2 graft-versus-host disease (GVHD). With a median follow-up of 36 months (range 13–70 months) 27 patients were alive and in remission with a 3y actuarial overall survival (OS) and disease-free survival (DFS) rate of 41% and 37% respectively. The 3y OS and DFS of patients with AML in complete remission (CR) at the time of transplantation was 48% and 42% respectively. In a multivariate setting, Cox regression analysis demonstrated prognostic significance of disease stage at the time of transplant with improved DFS in patients with AML in CR at the time of transplantation (HR=2.03, 95% CI=1.02–4.07). Disease relapse was the commonest cause of treatment failure occurring at a median time of 6 months post-transplant. Fourteen out of 27 (52%) patients relapsed within 6 months and 23/27 (85%) within twelve months defining a relatively narrow window for therapeutic intervention to prevent disease recurrence. The extended follow-up in this series identifies a high risk of early disease relapse but provides evidence that RIC allografts are capable of producing sustained disease free survival in a significant number of patients with AML who would be ineligible for allogeneic transplantation using a myeloablative conditioning regimen.

Phase II Prospective Multicenter Study of Treosulfan Based Reduced Intensity Conditioning In Allogeneic Hematopoietic Stem Cell Transplantation for Hematological Malignancies From 10/10 HLA Identical Unrelated Donor

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2353-2353 ◽  
Author(s):  
Mauricette Michallet ◽  
Mohamad Sobh ◽  
Stephane Morisset ◽  
Nathalie Tedone ◽  
Jacques-Olivier Bay ◽  
...  
Keyword(s):  
Stem Cell ◽  
Median Time ◽  
Cumulative Incidence ◽  
Unrelated Donor ◽  
Reduced Intensity Conditioning ◽  
Hematopoietic Stem ◽  
Cd34 Cells ◽  
Grade Ii ◽  
Reduced Intensity

Abstract Abstract 2353 Background: The key point in allogeneic hematopoietic stem cell transplantation (allo-HSCT) is to find the optimal balance between the graft-versus-host disease (GVHD) and the graft-versus-leukemia (GVL) effect particularly in the unrelated HSCT settings, without forgetting the important role of conditioning. Objective: To evaluate the toxicity and efficacy of a new reduced intensity conditioning regimen including Treosulfan, followed by allo-HSCT from a 10/10 HLA identical unrelated donor. Materials and Methods: This prospective study included adult patients presenting a hematological malignancy in need of allo-HSCT using a 10/10 HLA identical unrelated donor. Accepted diagnoses were: CML in 1st chronic phase (CP) resistant to imatinib, in 2nd CP or in complete remission (CR) after blast crisis. Multiple myeloma (MM) or chronic lymphocytic leukemia (CLL) in stage B or C in response after relapse post-auto-HSCT. Acute lymphocytic or myeloid leukemia (ALL, AML) patients in CR1 at high risk or <CR1. Myelodysplasic syndrome (MDS) with poor prognostic factors. The conditioning included: Treosulfan 12g/m2/day intra-venous (day-6 to day-4), fludarabine 30mg/m2/day intra-venous (day-6 to day -2) and ATG 2.5 mg/kg/day (day-2 to day-1). GVHD prophylaxis used cyclosporine A oral (5mg/kg/day) or iv. (3mg/kg/day) from day-1. Peripheral stem cells after mobilization by G-CSF were used as HSC source. Results: Between February 2005 and July 2009, 56 patients were included in 5 different French centers, 30 (54%) males and 26 females with a median age of 57 years (18-65.5). There were 38 (68%) myeloproliferative disorders [29 AML (14 in CR1, 14 CR2 & 1<CR), 8 MDS (1CR1 and 7<CR) and 1 CML in CR1] and 18 (32%) lymphoprolifative disorders [9 MM in PR, 6 CLL (2CR1 & 4PR) and 3 ALL(1CR1 & 2CR2)]. Among 45 explored for cytogenetics, 23 (51%) were normal and 22 with poor prognostic. Before transplantation, two patients did not receive any previous treatment, 21 received 1 line, 22 two lines and 11 > 2 lines. For sex-matching, 49% of patients were sex-mismatched (half of them were F>M). For CMV, 43% were -/-, 25% +/+, 28% +/&minus; and 1% -/+. For ABO matching, 52% were compatible, 24% major incomp. & 24% minor incopm. The median time between diagnosis and allograft was 15 months (4-168). The median number of infused CD34+ cells was 6.5 × 106/Kg(1-17.2) Fifty-four (96%) patients engrafted with a median time to neutrophils (>0.5G/l), and platelets (>50G/l) recovery of 16 days (4-86), 11 (4-82) respectively. Seventeen patients developed aGVHD grade ≥II (8 grade II, 2 grade III & 7 grade IV) with a cumulative incidence at 3 months of 31% (25-38). The cumulative incidence of cGVHD was, at 12 months: 32% (25-39) limited and 6% (2-10) extensive; at 18 months: 34% (27-47) limited and 8% (5-12) extensive. After a median follow-up of 13 months (1-57), the median overall survival (OS) was not reached with a 3 years probability of 52% (38-71). The median time of event free survival (EFS) was 15 months (8 - 57) with a 3-years probability of 47% (35-64). The cumulative incidence of relapse at 3 years was 25% (19-31) and the cumulative incidence of transplant-related mortality (TRM) at 12, 18 and 36 months was 20% (16-27), 23% (16-29) (same at 18 & 36 months) respectively. At the last follow-up, 22 patients died, 7 due to relapse and 15 due to TRM (5 pneumonia, 4 GVHD, 1 secondary malignancy and 6 other causes). We showed in a univariate analysis a higher 3-years OS of patients in CR1 (65%) compared to those <CR1 (44%) at transplantation with a significant better benefit for AML patients (76%). Patients with active cGVHD seem to benefit for the GVL effect on OS with a high significant difference (HR=0.2 (0.1-0.6) p=0.002). The multivariate analysis studying age, sex matching, ABO compatibility, CMV matching, type of disease, CD34+ cells number, cytogenetics, number of previous treatments, disease status and interval diagnosis-allo-HSCT showed: a negative significant impact of both minor ABO incompatibility (p<0.001) and CMV+/&minus; (p=0.01) on OS, a negative significant impact of patients <CR (p=0.03) on relapse. There was no impact of studied factors on TRM. Conclusion: We showed very promising results in terms of OS, relapse and TRM with an impressive GVL effect, in heavily pre-treated patients and transplanted using unrelated donors. Treosulfan appears to be a good choice for conditioning especially with a better outcome in AML patients in CR1. Disclosures: No relevant conflicts of interest to declare.

A Novel Sequential Treatment Utilizing CPX-351 As Salvage Chemotherapy Followed by a Reduced Intensity Conditioning Allogeneic Stem-Cell Transplantation for Patients with Refractory Leukemia

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3030-3030
Author(s):  
Usama Gergis ◽  
Gail J. Roboz ◽  
Ellen Ritchie ◽  
Joseph M. Scandura ◽  
Karen-Sue B. Carlson ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Stem Cell Transplantation ◽  
Acute Leukemia ◽  
Reduced Intensity Conditioning ◽  
Co Morbidity ◽  
Phase 1B ◽  
Morbidity Index ◽  
Reduced Intensity

Abstract Abstract 3030 Introduction: Allogeneic Hematopoeitic Stem cell Transplantation (HSCT) using standard ablative or reduced intensity conditioning regimens is often ineffective in patients with primary refractory and relapsed acute leukemia. Sequential administration of cytoreductive chemotherapy followed by a Reduced Intensity Conditioning (RIC) regimen may lead to improved results (Schmid et al Blood 2006). CPX-351 is a novel liposomal formulation that encapsulates the combination of cytarabine and daunorubicin in a fixed 5: 1 ratio. In vitro, it selectively concentrates in the marrow compared to other organs. Clinically, CPX-351 is well tolerated, with a favorable extramedullary toxicity profile, making it an appropriate cytoreductive agent prior to conditioning for HSCT. Patients and Methods: In a 3+3 phase I trial, patients with relapsed or primary refractory acute leukemia were treated with escalating doses of CPX-351 starting at 60 mg/m2 on days - 28, -26 and -24 followed by RIC with IV busulfan 3.2 mg/kg/day on days -6 to -3 and fludarabine 30 mg /m2/day on days -6 to -3 (Bu/Flu). GVHD prophylaxis consisted of tacrolimus starting on day -3, at a starting dose of 0.03 mg/kg/24 hours as a continuous infusion and adjusted to achieve a trough level between 10 and 15 ng/ml. and methotrexate 10 mg/m2 IV on days 1, 3, 6 and 11 (Methotrexate dose was reduced to 5 mg/m2 after observing grade 3 mucositis in the first 3 patients). The protocol was amended to include a phase 1B in addition to the above mentioned phase 1A. In phase 1B, patients were treated with escalating doses of CPX-351 starting at 60 mg/m2 on days - 21, -19 and -17 followed by IV Bu/Flu conditioning. Thirty two patients (AML-27, ALL-2, CML in blast crisis-1, high risk MDS-2) have been enrolled to date. Nine patients are in-evaluable due to short follow up (2), sepsis resulting in aborted transplant plans (4), appendicitis (1), early death at day +12 due to sepsis prior to engraftment (1) and donor's unavailability after receiving one dose of CPX-351 (1). Twenty three patients who underwent HSCT are evaluable (AML-19, ALL-2, high risk MDS-2). We calculated the transplant co-morbidity index as well as the prognostic score identified by the CIBMTR in patients with refractory leukemia undergoing HSCT (Duval et al. JCO 2010). The twenty three evaluable patients have a median age of 58 (range 33–72), co- morbidity index 2 (range 0–6) and CIBMTR score 3 (range (2–5). All patients received HLA compatible grafts (MUD-15, MRD-8). Results: Nineteen patients achieved complete hematologic remission by day 30 post transplant. All nineteen patients had adequate donor's engraftment for neutrophils and platelets at a median time of 15 days (range 12–35) and 16.5 days (range 10–90) respectively. Four patients continued to have active disease by day 30. Five more patients had a disease relapse before or shortly after day 100 and one patient had a relapse 22 months post transplant for a total of 10 relapsed patients (43%). Three patients died of acute GI GVHD 2, 6 and 9 months after transplant (all were in remission). One patient died of a pre existing brain tumor progression and one patient died of liver cirrhosis due to iron overload one year after transplant for a total non relapse mortality of 21%. At a median follow up of 6 months, eight patients are alive without evidence of leukemia (35%). Acute GVHD grade II-IV occurred in 8 patients (35%) and was the cause of death in 3 patients. Chronic GVHD occurred in 3 patients (13%). Grade 2 mucosal injury as defined by Bearman toxicity criteria was the most common toxicity developing in 15 patients (65%). Conclusion: The maximum tolerated (MTD) dose of CPX-351 followed by RIC HSCT was not found after a series of 4 treatment cohorts on Arm A and 2 treatment cohorts on arm B. Further dose escalation to define MTD is ongoing in both arms. Remission status is not a prerequisite for a successful outcome in selected patients who otherwise are candidates for transplantation. Disclosures: Off Label Use: CPX is not FDA approved. Feldman:celator: Consultancy.

Impact of Peripheral Blood Stem Cell Recruitment on Outcome of Single or Double Autologous Hematopoietic stem Cell Transplantation for Multiple Myeloma.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 5221-5221
Author(s):  
Mauricette Michallet ◽  
Quoc-Hung Le ◽  
Anne-Sophie Michallet ◽  
Anne Thiebaut ◽  
Emmanuelle Tavernier ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Multivariate Analysis ◽  
Stem Cell ◽  
Light Chains ◽  
Hematopoietic Stem ◽  
Group 4 ◽  
Group 3 ◽  
Group 2 ◽  
Group 1

Abstract Multiple myeloma remains one of the best indication for intensive chemotherapy followed by autologous hematopoietic stem cell transplantation (autoT). Intensive therapy followed by autologous transplantation is superior to conventional chemotherapy and it was demonstrated that two autoT were superior to one except for patients in very good partial response or in complete response after the first autotransplant. Peripheral blood stem cells (PBSC) can be used as well as bone marrow as HSC source with the same efficacy but very few data have been reported regarding PBSC recruitment. The main goal of our work was to study the impact on overall and event-free survival (OS and EFS) of PBSC recruitment using either growth factors (GF) alone (steady state) or chemotherapy followed by GF. Secondly, we performed a multivariate analysis studying influence on OS and EFS of sex, age, lines of therapy, pretransplant status, TBI, PBSC recruitment and number of autoT. We have analyzed 193 PBSC autoT (1 autoT=160, 2 autoT=33) performed for 160 MM patients [81 males and 71 females, mean age: 55 years (39–71)]. At diagnosis, 88 patients presented a MM Ig G (70k and 18l), 28 Ig A (16k and 12l), 3 Ig D (1k and 2l), 21 light chains k and 13 light chains l, 3 non secreting and 4 with plasmocyte leukemias. According to Durie and Salmon classification 75% of patients were in stage III, 15% in stage II and 10% in progressive I. Before transplantation, patients have received 1 line of poly-chemotherapy (n=141), 2 lines (n=15) or 3 lines (n=4) and 154 were evaluated for the response with 11 complete remission, 113 partial remission and 30 stable or evolutive disease just before transplant. As HSC (n=189), patients received PBSC which were recruited by GF alone (n=105) or cyclophosphamide+GF (n= 84). Conditioning (n=189),consisted in melphalan and TBI (n=51), melphalan alone (n=132), melphalan associated to cyclophosphamide or busulfan (n=6). We divided the population into 4 groups : group 1 who received one autoT of PBSC recruited by GF (n=76), group 2 one autoT of PBSC recruited by chemotherapy+GF (n=50), group 3 two autoT of PBSC recruited by GF (n=16) and group 4 two autoT of PBSC recruited by chemotherapy+GF (n=17). The median follow-up (FU) of the 4 groups were different with shorter FU (group 3: 9.9 months, group 4: 13 months) for patients who received tandem autoT because of the recent character of this strategy as compared to a long term follow-up for patients who received only one transplant (group 1: 35months, group 2: 55.3 months). Probabilities of OS and EFS at 2 years were 76% (95%CI 67–87) and 60% (95%CI 49.5–73) for group 1, 77% (95%CI 65–90.5) and 70% (95%CI 57.5–85) for group 2, 87.5% (95%CI 73–100) and 72.9% (95%CI 49–100) for group 3, 100% and 66.7% (95%CI 36–100) for group 4. The difference was not significant because of follow-up differences between the 4 groups and small number of patients in groups 3 and 4. In addition, multivariate analysis did not show any significant influence of the different studied parameters on OS and EFS. Nevertheless, because of these interesting preliminary results, a longer follow-up is warranted for definitive conclusions.

Hematopoietic Stem Cell Transplantation following Reduced Intensity Conditioning for High Risk Patients with Paroxysmal Nocturnal Hemoglobinuria

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4407-4407
Author(s):  
Agata Mikolajewska ◽  
Haifa Kathrin Al-Ali ◽  
Nadezda Basara ◽  
Elliot Epner ◽  
Ernst Holler ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
High Risk ◽  
Stem Cell Transplantation ◽  
Paroxysmal Nocturnal Hemoglobinuria ◽  
Chronic Gvhd ◽  
Reduced Intensity Conditioning ◽  
Hematopoietic Stem ◽  
Reduced Intensity

Abstract Objectives: Paroxysmal nocturnal hemoglobinuria (PNH) is a non malignant acquired hematopoietic stem cell disorder that can cause severe complications such as arterial or venous thrombosis or deficient haematopoiesis. These patients have a high mortality rate and should be evaluated for allogeneic stem cell transplantation (SCT). However, conventional conditioning has been associated with high treatment related toxicity. We report here the extended follow up of 7 previously published and 4 additional patients with high risk PNH after allogeneic HCT with reduced intensity conditioning (RIC). Patients: Eleven patients (3 males) with a median time from diagnosis to SCT of 16 (range 4 to 59) months were treated with red blood cell transfusions (n=9), anticoagulation (n=3), or immunosuppression (n=10): cyclosporine A (CSA, n=3), azathioprin (n=1), mycofenolate mofetil (MMF, n=1), antithymocyte globulin (n=1) or systemic steroids (n=9) until SCT. High risk PNH was characterized by venous thromboses: sinus veins (n=1), liver veins (n=3), vena portae (n=1), mesenterial veins (n=1) or thrombosis of lower extremity (n=1); bone marrow failure (n=6); recurrent life threatening haemolysis (n=8) or infections (n=5). Seven patients had more than one high risk feature. The median age at SCT was 34 (range 22 to 49) years. Conditioning regimen consisted of 2 Gy total body irradiation (TBI) at day 0 and fludarabine (30 mg/m2) at day-4 to -2 followed by treatment with MMF and CSA. The stem cell donors were related (n=2), allele matched unrelated (n=7) or mismatched (n=2). Results: The median follow up was 43 (range 2–101) months after SCT. The median time until neutrophil recovery was 17 (range 0–29) days and 4/11 patients (36%) did not develop ANC&lt;500/l. All but one patient (91%) showed primary donor engraftment with a median T-cell chimerism of 59 (range 38.3–99.3) % in the bone marrow at day 28 after SCT. The patient with primary graft failure received a second transplant from an alternative donor after RIC with 3 Gy TBI and showed stable engraftment. Six out of 11 (55%) patients developed grade II or III acute graft-versus-host disease (GvHD), which was treated with systemic steroids in 5 patients. Extensive chronic GvHD occurred in 3/11 (27%) of the patients. Three patients (27%) died of complications (pancreatitis with subsequent multiorgan failure, pseudomonas sepsis and haemorrhage) following steroid treatment for acute (n=1) and extensive (n=2) chronic GvHD 2, 12.5 and 14 months after SCT. The remaining 8 patients are alive and without clinical and laboratory evidence of PNH after a median follow up 61.5 (range 10–101) months after SCT. All surviving patients show an ECOG of 0–1 and 4/8 patients (50%) are off all immunsuppression. Conclusions: Allogeneic HCT with reduced intensity conditioning induces durable eradication of the PNH clone. The treatment related mortality even in high risk PNH with severe organ dysfunction was acceptable and due to complications after GVHD. All long term survivors have a good performance status and half of them are without any immunosuppression.

New Strategy for Allogeneic Peripheral Blood Stem Cell Transplantation After Reduced Intensity Conditioning in Multiple Myeloma: Interim Analysis of the IFM2005-03 Study.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4321-4321
Author(s):  
Mauricette Michallet ◽  
Mohamad Sobh ◽  
Mohamad Mohty ◽  
Anne Sirvent ◽  
Oumedaly Reman ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Interim Analysis ◽  
Peripheral Blood Stem Cell ◽  
Chronic Gvhd ◽  
Reduced Intensity Conditioning ◽  
First Line ◽  
Blood Stem Cell Transplantation ◽  
Reduced Intensity

Abstract Abstract 4321 Introduction The development of new agents with potent anti-tumor activity has considerably improved the survival of multiple Myeloma (MM) patients. However, there is still a high risk of relapse mainly due to the inability of these agents to cure and eliminate definitively the MM cells. Allografting remains the only available curative treatment particularly for patients with high risk factors. Material and methods This is an interim analysis of a prospective multicenter study for MM patients of age ≤ 65 years receiving reduced intensity conditioning (RIC) followed by allogeneic peripheral blood stem cell transplantation (allo-PBSCT) after achieving at least a partial response (PR) to auto-transplantation in first line. Patients previously received either VAD or VD as induction treatment followed by Melphalan 200 mg/m2. Patients must have an HLA identical donor either from siblings or unrelated 10/10 HLA donors, and at least one of the following poor prognostic factors (PPF) : β2 microglobulin >3mg/L, Del 13, t(4;14) and Del 17p. The conditioning regimen combined Fludarabine 30 mg/m2/d (d-5□d-1), Busilvex IV 3,2 mg/kg/d (d-4, d-3) and ATG 2,5 mg/kg/d (d-2, d-1). By day 90 post-allograft, a response assessment was done, patients not in CR received 4 cycles of Velcade 1.3 mg/kg, and after Velcade, if the CR was not achieved, increasing doses of donor lymphocyte infusions (DLI) were administered. This analysis included 11 patients, 9 males and 2 females, median age was 46 years [40-60], there were 8 IgG stageA (7κ & 1λ) and 3 IgA (1κ stage B & 2λ stage A). There were 3 patients with 1 PPF, 5 patients with 2 PPF and 3 patients with 3 PPF. Results Seven patients received 4 cycles of VAD (4 patients VAD+DCEP), 1 patient received 4 cycles of Velcade + dex. and 3 patients received other combinations (1PAD, 2VAD then Velcade). After induction, 7 patients were in PR and 4 in stable disease (SD). Patients received auto-HSCT after a median time of 6.6 months [4.5-8.7] from diagnosis. All patients were in PR after auto-HSCT and before allo-PBSCT. The median number of infused CD34+ cells was 6.5 ×106/kg [2.6-13.7] from 4 identical siblings and 7 matched unrelated donors. Sex matching was: F□M:4, F□F:1, M□F: 1 and MμM:5. At D90, 3 patients were in CR and 8 patients received Velcade after absence of CR (2 VGPR and 6 PR). After Velcade, the 2 VGPR evolved to CR and patients in PR became 1 CR, 1 VGPR and 4 remained in PR). One patient in VGPR and 3 in PR received DLI after Velcade, responses were: 1 VGPR and 3 patients progressed. There were 6 acute GVHD (5 grade II and 1 grade III) and 6 chronic GVHD (5 limited and 1 extensive), all GVHD were resolved at the last follow-up. After a median follow-up of 30 months, all patients are alive [100% overall survival (O.S.)], 3 patients are in CR, 3 in VGPR, 4 in PR and one in relapse without any active chronic GVHD even after DLI administration. Conclusion We showed completely different results from the IFM99-03 study in terms of O.S. and toxicity, this difference was due to the better conditioning with the introduction of Busilvex, also the impact of Velcade in eliminating the residual disease. According to these very promising results, we should reconsider the allo-HSCT as a first line treatment for MM especially for patients with PPF using either RIC or standard conditioning depending on age. Disclosures: No relevant conflicts of interest to declare.

Allotransplantation with Reduced Intensity Conditioning Regimens Modified To Lessen Transplant-Related Mortality Is a Useful Treatment for High-Risk Myeloid Diseases.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 5328-5328
Author(s):  
Carolyn L. Bigelow ◽  
Stephanie L. Elkins ◽  
Cheryl L. Hardy ◽  
Joe C. Files
Keyword(s):  
High Risk ◽  
Cord Blood ◽  
Peripheral Blood ◽  
Conditioning Regimens ◽  
Group 3 ◽  
Group 2 ◽  
One Year ◽  
Reduced Intensity ◽  
Group 1

Abstract Our stem cell transplant program treats a spectrum of hematologic malignancies that includes a number of patients with high risk myeloid disease. These challenging patients have lead our adult allotransplant program to employ alternative approaches to standard conditioning over the last three years using reduced intensity conditioning. The regimens are amenable to modification, allowing a goal of maximizing length of remission or period of low tumor burden while minimizing transplant-related mortality. We have conducted a retrospective study of patients receiving modified reduced intensity regimens of fludarabine, melphalan and Campath. Incidence of relapse, survival, tempo of engraftment and incidence of grades I–II and III–IV acute GVHD were compared. Three modifications of the regimen were: fludarabine 30 mg/m2 x 5d, melphalan 140 mg/m2 x 1d, Campath 20 mg/d x 5 days (Group 1); fludarabine and melphalan the same and Campath 20 mg/d x 3d (Group 2); fludarabine and melphalan the same and Campath 20 mg/d x 1d (Group 3). Fifteen patients with a median age of 48, range 24 to 58 years, were in the study. Twelve patients had AML, two had CML and one had MDS. Six patients were in CR at time of transplant and nine had detectable tumor or disease. Patients were not randomized for a conditioning group but were transplanted in a consecutive fashion; seven patients were in Group 1, five patients in Group 2 and three patients in Group 3. Stem cell sources were related BM for four recipients, related peripheral blood for one, unrelated BM for four, unrelated peripheral blood for four, a combination of related BM and peripheral blood for one, and one cord blood. All patients received an adequate CD34+ cell dose and none of the products was manipulated. Match grade was 6/6 for 13 transplants, 5/6 for one and 4/6 for the cord blood transplant. GVHD prophylaxis was the same for all recipients (standard dose cyclosporine or tacrolimus and MMF) tapering after day 30. No failures to achieve a WBC graft, including the cord blood recipient, occurred. Neutrophils (ANC &gt;500/dl) engrafted at a median of day 13 (range 10 – 48 days). Median follow-up was seven months (range 1.5 – 30 months). Two patients in Group 1 had grade I aGVHD and one continued to chronic GVHD. One patient in Group 2 had grade II and one had grade III aGVHD. None in Group 3 had aGVHD. Relapse occurred in three patients in Group 1 and they received DLI immunotherapy; no relapse occurred in Group 2 or 3. Twelve patients survived to day 100; three from Groups 1 or 2 did not. Four were alive at one year and four others who are still alive have not reached the one year mark. Four of the seven patients who have died were from residual disease; the other three were from treatment-related toxicity within the first 100 days. Eight of 15 patients remain in follow-up. We conclude that the application of fludarabine, melphalan, Campath conditioning regimens has been successful in this high risk group of patients. The cell source from an unrelated or related donor does not impact outcomes. There was a very low incidence of toxicity related to aGVHD, no failure to engraft and no unexpected complications. Lastly, this regimen has allowed modification to enhance its tumoricidal properties to the extent that these patients with myeloid disease have experienced a low 20% incidence of relapse. We will continue to modify and expand the patient selection criteria to elderly (&lt; 70 years old) AML in remission.

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