A Disease and Stage Risk Grouping System for Patients Undergoing Allogeneic Stem Cell Transplantation

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 327-327
Author(s):  
Philippe Armand ◽  
Christopher J Gibson ◽  
Corey Cutler ◽  
Vincent T Ho ◽  
John Koreth ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Stem Cell Transplantation ◽  
Risk Groups ◽  
Low Risk ◽  
Disease Stage ◽  
Reduced Intensity Conditioning ◽  
T Cell Lymphomas ◽  
Risk Grouping ◽  
Reduced Intensity

Abstract Abstract 327 Background: The outcome of patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) varies significantly based on the patients' disease and stage at the time of HSCT. When analyzing outcomes of HSCT in heterogeneous patient populations, whether in retrospective or prospective studies, it is therefore necessary to stratify patients based on their disease/stage risk. At present, there is no robust method for doing so; the most commonly used breakdowns are based on older data that may not be applicable today, and do not incorporate cytogenetics for myeloid diseases, which are an important prognostic factor. Methods: We analyzed a cohort of 1539 patients transplanted between 2000 and 2009 at Dana-Farber/Brigham and Women's Hospital, and reviewed their disease type (including cytogenetics) and stage at HSCT. Based on proportional hazards modeling for overall survival (with a median follow-up of 35 months), we defined disease and stage risk groups, with independent analyses performed in the 812 patients who underwent myeloablative conditioning (MAC) and the 727 who underwent reduced intensity conditioning (RIC). We used the results to define overall disease/stage risk groups for both MAC and RIC HSCT. Results: Interestingly, the disease risk groups turned out to be identical for MAC and RIC; the stage risk groups were very similar, except for the assignment of CR>1 to low risk in MAC but high risk in RIC. The groups were as follows: Low-risk disease: AML with favorable cytogenetics, CLL, CML, Hodgkin lymphoma, and non-Hodgkin lymphoma (excluding extranodal T-cell lymphomas) Intermediate-risk disease: ALL, AML or MDS with intermediate cytogenetics, myeloproliferative neoplasms, and multiple myeloma High-risk disease: AML or MDS with adverse cytogenetics, extranodal T-cell lymphomas Low-risk stage: CR1, CR>1 (for MAC), PR1, untreated disease, CP CML High-risk stage: CR>1 (for RIC), PR>1, induction failure or active relapse, accelerated or blast phase CML Those groups could be combined to form 4 overall groups with highly significantly different OS and PFS (Table and Figure). Conclusion: We propose a disease/stage risk grouping scheme for patients undergoing HSCT, applicable to both myeloablative and reduced intensity conditioning transplantation, which separates patients into 4 groups with significantly different OS and PFS. This scheme could be used for prognostic purposes, and to stratify patients in retrospective studies or in clinical trials. In the future, it may be further validated and refined through registry studies. Disclosures: No relevant conflicts of interest to declare.

Cytomegalovirus Reactivation and Relapse Following Allogeneic Stem Cell Transplantation Using a Reduced Intensity Conditioning Regimen.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 5104-5104
Author(s):  
Revati Rao ◽  
Kevin Chin ◽  
Geoff Chan ◽  
Kellie Sprague ◽  
Andreas Klein ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Stem Cell Transplantation ◽  
Antiviral Therapy ◽  
Allogeneic Stem Cell Transplantation ◽  
Chronic Gvhd ◽  
Attributable Mortality ◽  
Reduced Intensity Conditioning ◽  
Cmv Reactivation ◽  
Reduced Intensity

Abstract Background: Recent studies have reported CMV reactivation rates of 42% to 65% in patients treated with allogeneic stem cell transplantation using reduced intensity conditioning regimens (RIT). However, published data on RIT patients who experience CMV reactivation, are treated successfully with antiviral therapy to eliminate detection, and who subsequently develop CMV relapse, is sparse. Methods: We performed a retrospective cohort analysis of 106 patients who underwent RIT at Tufts-New England Medical Center using a preparative regimen of pentostatin, extracorporeal photophoresis, and reduced total body irradiation, from 1997–2003. All patients received identical graft-versus-host disease (GVHD) prophylaxis, which consisted of IV cyclosporine and PO methotrexate. CMV serostatus was determined on all patients prior to transplant. All patients were screened weekly by CMV antigen capture assay after day +14. Patients did not receive CMV prophylaxis. CMV reactivation was defined as 2 consecutive positive (>2.1 pg/mL) CMV DNA measurements. CMV reactivation was treated with either Ganciclovir 5mg/kg IV daily or Valganciclovir 450mg PO BID until whole blood CMV DNA levels were no longer detectable. Patients were treated with antiviral therapy until a documented negative CMV DNA assay. Those found to have detectable CMV DNA after adequate therapy were then defined as having CMV relapse. Patients were also assessed for incidence of GVHD and mortality. Attributable mortality was defined as mortality in patients who had CMV relapse compared to those who had CMV reactivation without relapse. Fisher’s exact test was used to compare proportions, Kruskal-Wallis was used to compare means, and survival and time to reactivation and relapse were analyzed by Kaplan-Meier Results: Of 106 patients, 49 (46.2%) were CMV seropositive prior to transplant. Twenty -five (51%) of forty-nine CMV positive patients developed CMV reactivation at a median of 43 days (range 26 – 312 days) after receiving stem cells. Among patients with CMV reactivation, 36 were MRD and 13 were MUD. Nine (36%) of 25 patients with CMV reactivation developed CMV relapse. CMV relapse occurred at a median of 16 days (range 4 – 77 days) after CMV reactivation. CMV reactivation occurred earlier among those who relapsed (median 34 days, range 26 – 70 days) compared to those who did not relapse (median 55.5 days, 27 – 312 days, p=.03). Peak viral load was significantly higher in CMV relapsers (median 55.3 pg/mL, range 14.5 to 486.8) compared to non–relapse patients (median 4.4 pg/mL, range 2.1 – 58.2, p=. 0007). There was no difference in acute GVHD in the groups (100% vs. 75%, p=.26). However, those who did relapse had a higher incidence of chronic GVHD than those who did not (89% vs. 38%, p=.03). There was no difference in median survival between non-relapse and relapse patients (13 months vs. 16 months, p=. 99). The attributable mortality rate due to CMV relapse was 23%. Conclusions: Our results suggest there is a subgroup of patients who are at high risk for CMV relapse in the post RIT setting. Risks for CMV relapse include early reactivation and higher peak CMV viral loads. In addition, there was a higher risk of chronic GVHD in CMV relapse patients. We have identified a high- risk subset of patients who reactivate CMV for whom additional therapeutic strategies may be warranted.

A Phase II Trial of Sequential Treatment with Cytoreductive Therapy and Reduced Intensity Conditioning Allogeneic Stem Cell Transplantation for Relapsed/Refractory Acute Myeloid Leukaemia, High-Risk MDS and Other High Risk Myeoid Malignancies: An Interim Report.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3480-3480
Author(s):  
Dimitris A Tsitsikas ◽  
Dana Warcel-Sibony ◽  
Heather E. Oakervee ◽  
Samir G Agrawal ◽  
Matthew Smith ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Median Time ◽  
Sequential Treatment ◽  
Reduced Intensity Conditioning ◽  
Disease Free ◽  
Reduced Intensity ◽  
Acute Myeloid

Abstract Abstract 3480 Background: Outcomes for patients with refractory or relapsed acute myeloid leukaemia (AML) are extremely poor and allogeneic haemopoietic stem cell transplantation (HSCT) provides the best hope for prolonged disease free survival. Ablative HSCT combines high dose, anti-leukaemic chemoradiotherapy and the graft versus leukaemia (GVL) effect, but is associated with significant toxicity and mortality and these risks rise exponentially with advancing age. Several factors mitigate against an attempt to transplant patients after relapsed disease, including a low probability of achieving second remission, high re-induction mortality, prolonged cytopenias and opportunistic infections and prolonged hospitalization. Based on promising results [1], we undertook a phase II study of sequential chemotherapy immediately followed by reduced intensity conditioning (RIC)-Allo with the aim of increasing the safety and applicability of AlloHSCT, while maintaining its antileukaemic efficacy. Patients/Methods: All eligible patients received treatment with Daunorubicin 45mg/m2 OD IV D-15 to D-13 and AraC 1.5g/m2 BD IV D-15 to D-10, a three day rest period, and conditioning with Fludarabine 25mg/m2 D-6 to D-2 and Cyclophosphamide 1g/m2 D-3 and -2 before receiving HSCT. Graft versus Host Disease (GVHD) prophylaxis was with Cyclosporine and Methotrexate. To date 33 patients were enrolled (table 1), of whom 31 patients underwent transplant. Results: 28/31 (90.3%) patients engrafted (neutrophils ≥0.5 and platelets ≥ 20) at a median of 33.5 days (15-49), while 3 died between d21-51 due to sepsis. The median d30, d60 and d100 whole blood chimerism was 96% (range 4–100), 80% (range 5–100), and 76% (range 0–100) respectively. 6/31 (19.4%) developed acute GVHD; 5 grade 1–2, 1 grade 4. Chronic GVHD was documented in 8 patients, extensive GVHD in 4/8. 7 patients had CMV re-activation (no CMV disease) and 1 non-specified pneumonitis. Median time of hospitalization was 37 days (30-61). No patient has required DLI to date. 18 pts (56.25%) achieved complete remission (CR) as assessed by day 30 bone marrow (BM). 2 had <5% blasts BM, 4 refractory disease, 4 died before evaluation, and 3 did not have a BM examination. 7 (6 previously documented CR in BM) of the 33 patients (21.2%) relapsed. Median time to relapse was 162 days (59–408). 18 /33 (54.5%) have died; 6 (33.4%) of sepsis, 5 (27.8%) of relapsed leukaemia, 4 (22.2%) of GVHD, and 3 (16.7%) of refractory leukaemia. D100 treatment related mortality (TRM) was 18.2% (n=6) and overall TRM is 30.3% (n=10). Median time of TRM was 84 days (range 21–519). 15 of the 33 patients (45.5 %) are alive, 12 of whom (36.4%) are disease free with a median follow up of 13 months (range 2–31 months). For these patients, the underlying diagnosis was relapsed AML in 7 (50 %), refractory AML in 5 (28.6 %), high risk MDS in 2 (14.3%) and other in 1 (7.1 %). 2 patients with relapsed and 1 with refractory AML subsequently relapsed after having achieved remission. Overall survival for the 31 patients is 45.2% with disease-free survival of 38.7%. Conclusions: Sequential treatment with cytoreductive therapy and immediate RIC Allo is associated with good engraftment rates with a TRM acceptable for this high risk group. Our preliminary data indicate a favourable survival outcome for these patients with a particularly poor prognosis. 1. Schmid C, Scheuning M, Schwerdtfeger et al. Long-term survival in refractory acute myeloid leukemia afetr sequential treatment with chemotherapy and reduced-intensity conditioning for allogeneic stem cell transplantation. Blood. 2006;108:1092-1099. Disclosures: Gribben: Roche: Consultancy; Celgene: Consultancy; GSK: Honoraria; Napp: Honoraria.

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.

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