5.3 R-DHAP Immuno-Chemotherapy is an Effective Remission-Induction Treatment for Fludarabine-Refractory Patients or Those with del17p Before Allogeneic Stem Cell Transplantation; Results of the Planned Interim Analysis of the Dutch-Belgian Prospective Multicenter HOVON88 Trial

2011 ◽  
Vol 11 ◽  
pp. S244
Author(s):  
M. van Gelder ◽  
W. Ghidey ◽  
M. Chamuleau ◽  
J. Cornelissen ◽  
K. Wu ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Allogeneic Stem Cell Transplantation ◽  
Interim Analysis ◽  
Remission Induction ◽  
Induction Treatment

R-DHAP Immuno-Chemotherapy Is An Effective Remission-Induction Treatment for Fludarabine Refractory CLL Patients and Allows the Majority to Proceed to Allogeneic Stem Cell Transplantation. Results of the Planned Interim Analysis of the Dutch-Belgian Prospective Multicenter HOVON88 Trial,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3911-3911
Author(s):  
Michel Van Gelder ◽  
Wendim Ghidey ◽  
Martine ED Chamuleau ◽  
Jan J Cornelissen ◽  
Ka Lung Wu ◽  
...  
Keyword(s):  
Septic Shock ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Allogeneic Stem Cell Transplantation ◽  
Salvage Therapy ◽  
Interim Analysis ◽  
Remission Induction ◽  
Strict Adherence

Abstract Abstract 3911 Introduction Allogeneic stem cell transplantation (alloSCT) is the only potentially curative treatment for relapsed CLL patients with fludarabine refractory disease or a deletion 17p (del 17p). Retrospective analyses identified bulky disease and lack of response to last treatment as predictors for poor survival. The optimal salvage regimen for these patients is not clear, nor is it known what percentage of these patients does respond to salvage therapy before the transplantation. Here we report our results with R-DHAP studied in an international multicenter phase 2 study. The rationale for choosing R-DHAP is that in vitro treatment with platinum and a nucleoside analogue of fludarabine refractory CLL cells with or without dysfunctional p53 in vitro induces cell death independent of p53.1 Patients up to the age op 70 years with fludarabine refractory CLL (defined, according to the EBMT consensus, as relapse within 1 year after fludarabine monotherapy or within 2 years after fludarabine plus a monoclonal antibody) or with relapsed CLL with a del 17p (assessed by FISH), and in need of treatment were eligible for inclusion. Patients were treated with at least 3 cycles of R-DHAP salvage therapy (rituximab 375mg/m2 1st cycle, 500 mg/m2 later cycles, cisplatinum 100mg/m2, cytarabine 2×2000mg/m2 and dexamethasone 4×40mg) once per 4 weeks. A planned interim analysis as to toxicity and efficacy was performed following remisison-induction completion by the 20th patient. According to protocol, the study had to be reconsidered if less than eight out of the first 20 patients actually had received alloSCT, or in case of excessive toxicity. Results Twenty patients were included from Feb 16, 2009 till Jan 19, 2011. The median age was 59 years (range 43–68) and the median number of prior therapies was 3 (range 1–5). Fourteen were refractory to fludarabine monotherapy and 16 refractory to fludarabine containing immuno-chemotherapy. Ten of these 20 patients also had del 17p. Six had bulky lymph-adenopathy (>5 cm). Eleven patients completed all 3 R-DHAP cycles on protocol. Responses in these 11 patients were 1xCR, 6xPR and 4x stable disease (SD). Six of these 11 patients also had del 17p and their responses were 1xCR, 3xPR and 2x SD. All 11 patients subsequently proceeded to alloSCT. Three patients received only one or two cycles of R-DHAP as the treatment was considered to toxic and went off-protocol. All three had responsive disease. One patient responded to 1 cycle of R-DHAP but went of protocol due to infectious toxicity and did not proceed to alloSCT. Another patient had disease progression after the 1stR-DHAP and died. All eleven patients treated with 3-R-DHAP cycles and all three responding off-protocol patients received alloSCT immediately following R-DHAP. CTC grade 5 infectious toxicity was noted in 4 patients, including three with fatal septic shock and one with fatal encephalitis in 1. Nine other patients suffered from grade 4 infectious toxicity: febrile neutropenia (n=7), septic shock (n=1), pneumonia (n=3), urinary tract infection (n=1), or catheter-related infection. Despite infections, eight of these 13 patients could proceed to alloSCT. Optimized antibacterial and antifungal prophylaxis was amended to the protocol as from the 16th patient onwards. Since then 13 additional patients were entered in the study and until now none developed severe bacterial or fungal infection or died. Conclusions R-DHAP is an effective remission-induction regimen for fludarabine-refractory or early relapsed patients with or without del 17p, allowing a relatively high percentage of patients to proceed to alloSCT (14/20) Despite efficacious, significant infectious toxicity accompanied R-DHAP, necessitating strict adherence to antimicrobial prophylaxis. 1. Tonino SH, van Laar J, van Oers MH, Wang JY, Eldering E, Kater AP. ROS-mediated upregulation of Noxa overcomes chemoresistance in chronic lymphocytic leukemia. Oncogene. 2011;30:701–713. Disclosures: No relevant conflicts of interest to declare.

R-DHAP Immunochemotherapy Is An Effective Remission-Induction Treatment For CLL Patients With Fludarabine Refractory Disease With Or Without Deletion 17p, Enabling The Majority To Proceed To Allogeneic Stem Cell Transplantation

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2883-2883
Author(s):  
Michel Van Gelder ◽  
Wendim Ghidey ◽  
Martine ED Chamuleau ◽  
Jan Cornelissen ◽  
Eefke J Petersen ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Allogeneic Stem Cell Transplantation ◽  
Fungal Infections ◽  
Remission Induction ◽  
Induction Treatment ◽  
Infection Prophylaxis ◽  
Refractory Disease ◽  
Bulky Disease

Abstract Introduction Allogeneic stem cell transplantation (alloSCT) is the only potentially curative treatment for relapsed CLL patients with fludarabine refractory disease and/or a deletion 17p del(17p). Retrospective analyses identified bulky disease and lack of response to last treatment as predictors for poor survival. There is an unmet need for active salvage regimens for these high-risk patients, but so far prospective data on salvage regimens prior to alloSCT are lacking. Here we report our results with R-DHAP remission-induction studied in a prospective international multicenter phase 2 study. The rationale for R-DHAP is formed by in vitro studies showing that platinum induces p53 independent cell death. Patients up to the age of 70 years with fludarabine refractory CLL (defined, according to the EBMT consensus, as relapse within 1 year after fludarabine monotherapy or within 2 years after fludarabine plus a monoclonal antibody) and/or with relapsed CLL with a del(17p) , and with an indication for treatment were eligible for inclusion. Patients received at least 3 cycles of R-DHAP salvage therapy (rituximab on day 1 (375mg/m2 1st cycle, 500 mg/m2 later cycles), cisplatinum 100mg/m2 (day 1), cytarabine 2x2000mg/m2 (day 2) and dexamethasone 40mg days 1-4) every 4 weeks. Response to R-DHAP was determined according to 2008 IWCLL guidelines. Results Forty patients have been included from February 2009 till April 2012. One patient was ineligible because of Richter’s syndrome at the time of inclusion. The median age was 59 years (range 43-69) and the median number of prior therapies was 2 (range 1-5). Twenty-four patients completed at least 3 cycles of R-DHAP. Due to long donor search. two of these received 4 cycles, two 5 and 1 six cycles. Nine patients received only one or two cycles of R-DHAP because of toxicity, and two patients never received R-DHAP due to poor performance. Overall response rate (ORR) for all 39 eligible patients was 56%: 6 CR (15%), 16 PR (41%). Five patients had SD (13%) and 2 PD (5%). ORR rates in patients with bulky lymphadenopathy (>5 cm, n=18) and in those having del(17p) (n=17) was 67% and 53% respectively. In the first 16 patients four infection related deaths occurred (3 septic shock and 1 encephalitis). After an amendment optimizing infection prophylaxis, no additional severe bacterial or fungal infections or infection related deaths were observed. Twenty-six patients proceeded to alloSCT (67%). With a median follow-up of 16 months (range 6-42 months) 2-years progression-free survival (PFS) and overall survival (OS) after transplantation is 63% and 72% respectively. Sixteen are free from progression and 3 progressed but are still alive. Seven patients died (3 from acute GVHD, 2 due to encephalopathy, 2 other reasons). Conclusion R-DHAP is an effective remission-induction regimen for fludarabine-refractory CLL patients even in those having bulky lymphadenopathy and/or del(17p), enabling a high percentage of patients to proceed to alloSCT resulting in a high PFS and OS at 2 years. Disclosures: No relevant conflicts of interest to declare.

Feasibililty of Azacitidine As Bridge to Allogeneic Stem Cell Transplantation in Patients with Higher-Risk MDS or Low-Blast Count AML: Results of the BMT-AZA Multicenter Prospective Study

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 66-66
Author(s):  
Maria Teresa Voso ◽  
Giuseppe Leone ◽  
Alfonso Piciocchi ◽  
Luana Fianchi ◽  
Paolo Di Bartolomeo ◽  
...  
Keyword(s):  
Overall Survival ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Allogeneic Stem Cell Transplantation ◽  
Causes Of Death ◽  
Disease Status ◽  
Response Assessment ◽  
Induction Treatment ◽  
N 93

Abstract Background Allogeneic SCT remains the only curative option in myelodysplastic syndromes (MDS). We prospectively evaluated in a multicenter phase 2 GITMO (Italian Bone Marrow Transplantation Group) trial, the feasibility of allogeneic stem cell transplantation (ASCT, primary protocol end-point) after induction treatment with azacitidine (Vidaza, Celgene). According to the protocol, patients had to perform at least 4 and up to 12 cycles of azacitidine as induction treatment before ASCT. Patients not eligible for ASCT could continue treatment until disease progression. Methods Between November 2010 and September 2014, 102 patients were enrolled by 20 Italian hematology centers. Nine patients never started treatment due to progressive disease (PD, n=2), refusal (n=3), or unknown causes (n=4). Of remaining 93 patients, 70 had with IPSS Int-2/High-risk MDS, 15 WHO-defined acute myeloid leukemia (AML) and 8 chronic myelomonocytic leukemia (CMML). There were 32 females and 61 males with median age 59 yrs (range 21-66.5 yrs). At treatment start, ECOG performance status was: 0 in 66 patients, 1 in 17 and 2 in 10 patients, while MDS HCT-index was: low (0) in 43 patients, intermediate (1-2) in 31 and high (>2) in 18 patients. All 93 patients started azacitidine s.c. at the standard dose of 75 mg/sqm/day, 7 days/month, at a median of 0.8 months (range 0-105 months) from initial MDS diagnosis. Results At response assessment after a median of 4.5 cycles (range 1-11), 25% of patients (n=19) achieved complete remission (CR), 3% marrow-CR (n=2), 14% partial remission (PR, n=11), 9% hematologic improvement (HI, n=7), 35% had stable disease (SD, n=27) and 14% PD (n=11). ASCT was performed in 48 patients (52%), after a median of 4.5 azacitidine cycles (range: 1-11). Data on ASCT are presently available for 45 patients, transplanted with bone marrow (n=10 pts) or peripheral blood stem cells (n=35 pts) from an HLA-identical donor (sibling in 11, and MUD in 34 cases). Forty-five patients did not receive ASCT due to: disease relapse or progression (n=16, 35%), adverse events (n=12, 27%), refusal (n=5, 11%), or other causes (n=12, 27%). At a median follow-up of 18.5 months (range 0.2-31.5), 43 patients are alive (25 received ASCT), and 50 patients died. Causes of death are reported in Table 1. Median overall survival (OS) for the whole patient cohort was 13.4 months (95% CI: 10.9-18.6, Figure 1). Disease status after azacitidine was predictive of significantly improved survival for patients in CR/PR/HI, compared to SD or PD (n=77 patients who completed at least 4 cycles, Figure 2). ASCT considered as time-dependent covariate was associated to a significantly longer survival (p=0.008, HR 0.4, 95% CI: 0.2-0.8). Stratification of MDS according to IPSS and karyotype was not associated to survival. Conclusions Our study shows that allogeneic transplantation following azacitidine is feasible in HR-MDS/CMML and AML, with about 50% of patients being able to undergo HSCT. These data favourably compare with previous studies in MDS on ASCT preceded by conventional chemotherapy. Disease status at the time of HSCT confirms its significant prognostic role for survival, also in the context of hypomethylating treatment, where stabilization of disease also represents a therapeutic target. Disease relapse or progression remain the major causes of death indicating the need for other strategies aimed at improving disease control in MDS. Figure 1. Overall survival (n=93 pts) Figure 1. Overall survival (n=93 pts) Figure 2. Survival according to disease status at response assessment after a median of 4.5 azacitidine cycles (n=77 evaluable pts) Figure 2. Survival according to disease status at response assessment after a median of 4.5 azacitidine cycles (n=77 evaluable pts) Disclosures Voso: Celgene: Honoraria, Research Funding. Off Label Use: Azacitidine used as induction treatment before allogeneic stem cell transplantation in MDS. Finelli:Janssen: Other: Speaker; Novartis: Other: Speaker; Celgene: Other: Speaker, Research Funding.

Upfront Allogeneic Stem Cell Transplantation for Remission Induction in High-Risk Acute Myeloid Leukemia Patients within the Randomized Multi- Center Trial AML2003.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 978-978 ◽  
Author(s):  
Markus Schaich ◽  
Thomas Illmer ◽  
Walter E. Aulitzky ◽  
Martin Bornhaeuser ◽  
Martin Griesshammer ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Induction Therapy ◽  
Allogeneic Stem Cell Transplantation ◽  
Allogeneic Transplantation ◽  
Remission Induction ◽  
High Risk Patients ◽  
Risk Patients

Abstract Introduction: Allogeneic hematopoietic stem cell transplantation (HSCT) remains the only curative treatment option for most high-risk patients with acute myeloid leukemia (AML). However, many high-risk patients regenerate with blasts or relapse early after induction therapy. Thus, consolidation with allogeneic HSCT in first CR is often not possible. Performing upfront allogeneic HSCT for remission induction as part of induction therapy has the potential to circumvent these problems and might furthermore reduce cumulative toxicity in high-risk patients. Therefore, in 2003 we started a prospective multicenter randomized trial that investigates both the feasibility and efficacy of upfront allogeneic stem cell transplantation for remission induction in high-risk AML patients. Methods: The AML2003 study compares in a randomized fashion an intensified treatment approach using upfront allogeneic transplantation in high risk patients as part of the induction therapy (IT) during marrow aplasia achieved by DA (daunorubicin 60 mg/ m2 – day 3–5; cytarabine 100 mg/m2 – day1–7) to a “conventional” treatment strategy, which allows for allogeneic transplantation only in patients achieving remission after two induction courses (DA). To do this, rapid analysis of cytogenetics, FLT3 status and HLA-DNA-typing of the patient and possible family donors is of utmost importance. This “fast search diagnostics” together with routine analyses of morphology and immunophenotyping is accomplished centrally in all enclosed patients. The dose-reduced preparative regimen for upfront allogeneic stem cell transplantation within induction therapy consisted of melphalan 150mg/m2 and fludarabine 150mg/m2. Results: Until the last update we recruited 679 patients <= 60 years with de novo (n=570) or secondary (n=109) AML. Out of 340 patients randomized for an intensified treatment approach we identified 139 patients (41%) with high-risk defined by cytogenetic criteria (n=87), FLT3 status (n=15) or day 15 blast count (n=37). Fast search strategy revealed HLA identical donors (related or unrelated) for 106 patients. Consequently, 78 high-risk AML patients assigned to the intensified treatment strategy received allogeneic transplantation. Upfront allogeneic stem cell transplantation for remission induction was feasible in 28 high-risk AML patients during marrow aplasia after IT1 (n=10) or IT2 (n=18), respectively. Fifteen of these patients received unrelated grafts. Conclusions: These preliminary results show that rapid risk profiling and fast donor-search is feasible in a large multi-center study. This leads to a significant proportion of upfront allogeneic stem cell transplants as part of the induction therapy within the group of high-risk AML patients, which may improve the disastrous prognosis of this group of patients in the future.

Combination Treatment with Imatinib and Mitoxantrone/Etoposide Is a Suitable Preparative Regimen before Allogeneic Transplantation in Patients with Myeloid Blast Crisis of Chronic Myeloid Leukemia.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1105-1105
Author(s):  
Stefan Fruehauf ◽  
Julian Topaly ◽  
Eike C. Buss ◽  
Tanja Lahaye ◽  
Oliver G. Ottmann ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Allogeneic Stem Cell Transplantation ◽  
Conventional Treatment ◽  
Clonal Selection ◽  
Blast Crisis ◽  
Myelogenous Leukemia ◽  
Induction Treatment ◽  
Cytogenetic Remission

Abstract In advanced BCR-ABL-positive leukemia, combination of chemotherapy with imatinib is expected to result in better reduction of leukemia cell load and may delay or offset clonal selection of resistant leukemia cells, thus improving the survival. We carried out a prospective phase I/II combination trial for patients (pts) with myeloid blast crisis of chronic myelogenous leukemia (CML). Pts were treated with imatinib+mitoxantrone/etoposide in four cohorts starting from mitoxantrone 10mg/m2/d and etoposide 100 mg/m2/d for 2 or 3 consecutive days and start of imatinib 600mg/d from day 15 (coh. 1 and 2) or from day 1 (coh. 3 and 4, respectively). After hematologic reconstitution following the cytopenic phase, cytarabine was administered at a dose of 10mg/m2/d s.c. in addition to imatinib as maintenance treatment. A total of 16 pts (8 m, 8 f) are available for analysis, median age 59 years (range 37–74). All pts who received more intensive induction treatment (coh. 3 and 4, n=7) achieved a hematologic response (HR). In contrast, HR was achieved in 6 of 9 pts treated in coh. 1 and 2. The induction treatment was well tolerated with a treatment-related mortality rate of 12.5% (1 intracranial hemorrhage in coh. 1, and 1 pneumonia in coh. 4). A median of 8 (2–18) red blood cell concentrates and a median of 5 (1–8) platelet concentrates were required. Antibiotic treatment for febrile episodes was administered for a median of 10d (0–38). Of note, CTC grade 3 or grade 4 mucositis did not occur. Pts who received imatinib on day 1 (coh. 3–4) had a longer duration of severe leukopenia (WBC &lt;1/nl) with a median of 19 days (0–23) vs. 2 (0–14) but without increase of infection incidence. Six pts who achieved HR received an allogeneic stem cell transplantation with myeloablative conditioning. Three of 6 transplanted patients are alive and in complete cytogenetic remission at 735, 723, and 279 days after initiation of study treatment. Two patients died of transplant-related complications (GvHD and sepsis), 1 patient died from hematologic relapse. Of 10 pts who received only conventional treatment, 1 (coh. 1) is still alive and in a complete cytogenetic remission at day 1280 after initiation of study treatment. Median survival of transplanted pts was 486 days, and 142 days in the group with conventional treatment only (p=0.078). We conclude that the combination of mitoxantrone/etoposide and imatinib is a well tolerated induction protocol with mild non-hematological toxicity even in older patients. Eligible pts have an advantage from an allogeneic stem cell transplantation following response to the induction treatment.

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