Extracorporeal Photopheresis (ECP): Effective Therapy for Steroid Dependent and Refractory Acute Graft-Versus-Host Disease (GVHD)

Abstract Abstract 1973 Introduction: Outcome of patients with steroid refractory acute GVHD (aGVHD) remains poor and the optimal therapy remains ill-defined. ECP has been successfully used for treating steroid-resistant chronic GVHD. We studied the efficacy and outcome of ECP used as salvage therapy in patients with steroid refractory/dependent aGVHD at 2 centers: Vanderbilt University, USA and Nottingham, UK. Methods: Transplant and aGVHD characteristics of patients treated with ECP from 1/2006 to 8/2010 were reviewed. Steroid doses at onset and completion of ECP were available. Steroid refractory aGVHD was defined as progression after 3 days or no response after 7 days of systemic steroids. Steroid dependent aGVHD was defined as recurrence of aGVHD during steroid taper. Responses to ECP were abstracted from medical records and were determined at completion of ECP. Patients were transplanted for hematological malignancies on standard of care or IRB approved protocols. Results: Fifty two patients (Vanderbilt-29; Nottingham-23) were treated with ECP for steroid dependent (15, 29%) or steroid refractory (32, 63%) aGVHD at a median of 59 days (range, 12–99) after transplant. Indication for ECP was missing for 5 patients. aGVHD was seen after first transplant (44, 85%), second transplant (1, 2%) or after donor lymphocyte infusion (7, 13%), respectively. Grade 3–4 aGVHD was present at onset in 29 (57%) patients. Stage 3–4 skin, GI, and liver involvement occurred in 28 (37%), 15 (29%) and 9 (18%) patients, with three organ involvement at onset in 9 (17%) patients. All patients received systemic steroids prior to ECP for a median of 18 days (range, 10–91). Initial therapy consisted of 1 mg/kg or 2 mg/kg prednisone equivalent in 24 (46%) and 26 (50%) patients, respectively. Forty-one patients (79%) had either no or partial response after 7 days of steroid. ECP was administered as 2 treatments per week on a weekly to bi-weekly frequency and then stopped or tapered depending on response. Steroids were tapered at the discretion of the treating physician. Median number of ECP treatments was 12 (range, 2–45) given over a median duration of 55 days. Thirty-two (63%) patients responded to ECP (CR-26, 50%; PR-6, 12%). At the end of ECP treatment, grade 3–4 aGVHD was present in 17 patients (33%) with stage 3–4 involvement in skin (4, 8%), GI (10, 20%) and liver (10, 20%), respectively. The median steroid dose at termination of ECP in ECP-responders and non-responders was 0.15 mg/kg (range, 0–0.75) and 2 mg/kg (range, 0.15–2.3), respectively (P<0.001). ECP response: Donor type, stem cell source, aGVHD grade at onset, and organ –specific stage did not impact response. ECP response was superior for aGVHD developing after ablative regimen compared with reduced intensity/non-ablative regimens (76% vs. 48%, P=0.05). Patients with response at day 7 after initial steroid and subsequent steroid dependent aGVHD had a better response with ECP (80% vs. 50%, P=0.042). In logistic regression analyses, adjusted for regimen intensity, response at day 7 of initial steroid showed a trend for predicting ECP response (OR=4.22, 95% CI 0.95–18.7, P=0.058). Survival: Of the 52 patients, 28 (54%) are deceased (GVHD-19, relapse/progression-5, infections-4). The median follow up of the cohort after onset of ECP is 309 days (range, 12–1657). Median and 2-yr overall survival (measured from onset of ECP) is 442 days (95% CI, 0–993) and 42%. In univariate analyses, median survival after ECP onset was superior for patients who had an ablative transplant (not reached vs. 44 days, P=0.05), and had grade 2 or less aGVHD at onset (not reached vs. 79 days, P=0.028) (Fig. 1A). Indication of ECP (steroid dependent or refractory) did not impact survival. Patients with ECP response had a superior survival (measured from end of ECP) compared to non-responders (median survival, not reached vs. 14 days, P<0.001) (Fig. 1B) with a 65% 2-yr survival in ECP responders. In Cox proportional analyses, response to ECP was an independent predictor of survival (HR 0.091, 95% CI 0.034–0.263, P<0.001), after adjusting for regimen intensity and grade of aGVHD at onset. Conclusion: ECP is an effective steroid-sparing salvage therapy for patients with steroid dependent or refractory aGVHD with a response rate of 63% and 2-yr survival of 65% in responders. Based on this data, it is reasonable to undertake a prospective randomized study of ECP versus other agents, in patients with steroid dependent or refractory aGVHD. Disclosures: No relevant conflicts of interest to declare.

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Extracorporeal Photopheresis (ECP) for Acute Graft-Versus Host Disease (GvHD) after Allogeneic Hematopoietic Stem Cell Transplantation (allo-HSCT)

Blood ◽

10.1182/blood.v126.23.5466.5466 ◽

2015 ◽

Vol 126 (23) ◽

pp. 5466-5466

Author(s):

Sandra Eder ◽

Marie-Thérèse Rubio ◽

Ramdane Belhocine ◽

Myriam Labopin ◽

Eolia Brissot ◽

...

Keyword(s):

Immunosuppressive Therapy ◽

Calcineurin Inhibitor ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Median Number ◽

Low Grade ◽

Graft Versus Host ◽

Steroid Dependent ◽

Grade Iii ◽

Steroid Refractory

Abstract Background Graft-versus-host disease (GvHD) is a major limitation after allo-HSCT and remains a frequent cause of death. The 5-years survival is 25% and 5% for grade III and IV, respectively. Acute GvHD occurs in up to 45% of HLA-matched and up to 75% in case of unrelated donors. The standard-treatment consists of methylprednisolone (usually 2 mg/kg/day) and a calcineurin-inhibitor. No standardized second-line treatment for acute GvHD exists. Here, we report a pilot single-centre experience with extracorporeal photopheresis (ECP) for acute GvHD: the objective was to investigate the efficacy of ECP for patients with steroid-refractory/-dependent acute GvHD as well as an early intervention in patients with low-grade acute GvHD to avoid/taper steroids. Furthermore, we evaluated the reduction of immunosuppressive therapy. Patients' characteristics Between 2013 and 2014, 17 patients with acute GvHD (of whom two patients developed GvHD after donor lymphocyte infusion) were treated. Eight patients had a maximum grade of GvHD I/II (2/6 patients) and nine patients were graded as III/IV (6/3 patients). Organ involvement was as follows: skin only in 10, skin and liver in one, skin and gastrointestinal tract in two and all three organs were involved in four patients. Treatment before ECP consisted of topical steroids in one and 0.5 mg/kg methylprednisolone (due to side-effects of calcineurin-inhibitor) in the other patients with grade I. Six patients received 1 mg/kg and eight patients received 2 mg/kg methylprednisolone. One patient was treated with 2 mg/kg methylprednisolone and weekly methotrexate. Before start of ECP, one patient was steroid-free, six patients were steroid-refractory and nine patients were steroid-dependent. Thus, we treated patients with acute GvHD not only for steroid-refractory disease but also steroid-dependent disease and grade I GvHD to avoid a treatment with steroids. Results The median number of ECP sessions per patient was 12 (range, 5 - 36), seven patients received ECP twice a week. Best response to ECP was complete remission in 71%, partial response in 12% and no response in 17%, after a median number of 6 treatments (range, 2 - 9). Response was better for grade I/II: 87.5% received complete remission compared to 56% with grade III/IV, partial response was observed in 12.5% in patients with grade I/II versus 11% with grade III/IV. No responders comprised 33% with grade III/IV and 0% with grade I/II. Immunosuppressive therapy could be tapered successfully: mean reduction of steroids was 95% (range, 60 - 100) and mean reduction of calcineurin-inhibitor was 83% (range, 40 - 100). Six patients developed a rebound of GvHD during tapering (two patients) or after discontinuation (four patients) of ECP. Eleven patients (78%) developed chronic GvHD (two patients with severe grade), whereas it appeared in four patients during tapering of ECP and in seven patients after discontinuation of ECP after a median time of 116 days (range, 30 - 287). We could observe seven bacterial, 14 viral and one fungal infection in 14 patients, which are expected rates after allo-HSCT in patients with acute GvHD. After a median follow up of one year, two patients relapsed from their underlying disease and five patients died (one due to relapse and four due to infections). Conclusion In this single-centre pilot experience, we could show that ECP is an efficient and safe treatment in patients with steroid-refractory or steroid-dependent acute GvHD as well as an upfront-treatment in patients with low-grade GvHD. We were able to taper immunosuppressive therapy with a mean reduction of steroids of 95% and mean reduction of calcineurin-inhibitor of 83%. Best responses were seen in patients with I/II grade GvHD which concludes that ECP should be started as early as possible. Further studies are warranted to investigate a schedule to reduce the risk of rebound of acute GvHD (42% in our cohort) and development of chronic GvHD (78%). Disclosures Mohty: Janssen: Honoraria; Celgene: Honoraria.

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A Phase II Study of Decitabine In Advanced Chronic Myelomonocytic Leukemia (CMML)

Blood ◽

10.1182/blood.v116.21.1873.1873 ◽

2010 ◽

Vol 116 (21) ◽

pp. 1873-1873

Author(s):

Thorsten Braun ◽

Nathalie Droin ◽

Benoit de Renzis ◽

Francois Dreyfus ◽

Kamel Laribi ◽

...

Keyword(s):

Phase Ii ◽

Conflicts Of Interest ◽

Cytogenetic Response ◽

Median Number ◽

Costal Margin ◽

Monocyte Count ◽

Blood Monocytes ◽

Grade 3 ◽

Wbc Count

Abstract Abstract 1873 Background: CMML, now classified among MDS/MPN, is prognostically heterogeneous. We (JCO 1988 6:1417, Blood 1996 88:2480) and others found prognosis in CMML to depend on both “MDS factors” (% marrow blasts, cytopenias, karyotype) and “MPN” factors, ie splenomegaly (SMG), WBC count, extramedullary disease (EMD). Treatment of advanced CMML is difficult. The hypomethylating agents Azacitidine and Decitabine (DAC) have shown efficacy in CMML, but in prognostically heterogeneous cohorts. We conducted a phase II trial of DAC in a well defined cohort of advanced CMML. Methods: To be included, CMML (according to WHO) should have: if WBC<13G/l an IPSS≥1.5; if WBC≥13G/l, two of the following criteria: marrow blasts≥5%, Hb<10g/dl, plts<100G/l, abnormal cytogenetics, SMG >5cm below costal margin, (SMG>5cm), EMD, based on our previous prognostic factors. Pts received DAC 20mg/m2/d IV for 5 days every 28 days for at least 3 cycles. Response criteria were based on IWG 2006 for pts with WBC <13G/L and for pts with WBC > 13 G/L also included evolution of WBC, SMG and EMD (Blood 1996 88:2480). Results: Between Nov 2008 and June 2009, 41 pts were included in 16 centers, of whom 39 completed at least one cycle and were considered evaluable for response (the 2 other pts died from septic shock before and during the first cycle respectively). Median number of cycles was 9 (range 1–17). Median age was 71 years (range 54–88), M/F:30/9. Seventeen pts had CMML 1 and 22 had CMML 2 (including pts with up to 29% marrow blasts). Median WBC count was 29.5G/l (range 4.1–147.3), median blood monocytes 3G/l (range 1.05–95.7), and median BM blasts 10% (1-29). Nine pts had WBC<13G/l and 30 WBC≥13G/l. Abnormal karyotype was found in 18 (46.2%) pts, including +8 and -7 in 7 and 1 case, respectively. 15 pts (38.6%) had SMG>5cm and 8 (20.5%) EMD involving skin (n=5) and lymph nodes (n=3). Overall Response Rate (ORR,) was 38.6% with 4 (10.3%) CR, 8 (20.5%) marrow CR and 3 (7.7%) Stable Disease (SD) with HI. 1 CR pt received allo SCT. 18 (46%) pts had SD without HI and 6 (15.4%) pts progressed to AML. 8 (36.4%) of the 22 RBC transfused pts became RBC transfusion independent. 3/10 (30%) pts with plt<50G/l reached plt>100G/l. Four pts had cytogenetic response (3 CR and 1 PR) exclusively among pts with +8. Median peripheral monocyte count decreased from 4.8G/l to 0.3G/l after 3 cycles of DAC among responders. SMG disappeared in 6/15 (40%) pts and EMD in 6/8 (75%) pts. 16 pts were receiving Hydroxyurea (HY) at inclusion which could be stopped in 12 of them. With a median follow up of 10 months (1-18), 7 pts had died from progression (n=3), sepsis (n=3) and unrelated cause (n=1). Overall Survival (OS) estimate was 60% at 2 years (median not reached). By comparison, in our previous trial of HY in CMML where inclusion criteria were the same, 2 year survival was 43% (median OS 20 months; Blood 1996 88:2480), for a median follow up of 11 months (range1-43). The only factor associated with response to DAC was WHO subtype, CMML 2 pts showing significantly better ORR (30.8% vs 7.7% in CMML 1; p=0.041).There was no difference in survival between CMML 1 and 2 pts. Treatment with DAC was generally well tolerated with, except for usual grade 3/4 cytopenias, and grade 3 fatigue (n=1). Conclusion: DAC is active in advanced CMML and safe in these elderly pts. A possibly better survival than with HY will have to be confirmed in randomized trials. Correlative genetic studies identifying markers potentially predicting response and survival for DAC are currently underway in our lab. Disclosures: No relevant conflicts of interest to declare.

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Mesenchymal Stem Cell (MSC) Based Cord Blood (CB) Expansion (Exp) Leads to Rapid Engraftment of Platelets and Neutrophils

Blood ◽

10.1182/blood.v116.21.362.362 ◽

2010 ◽

Vol 116 (21) ◽

pp. 362-362 ◽

Cited By ~ 8

Author(s):

Marcos De Lima ◽

Simon Robinson ◽

John McMannis ◽

Amin M Alousi ◽

Rima M Saliba ◽

...

Keyword(s):

Cord Blood ◽

Platelet Transfusion ◽

Conflicts Of Interest ◽

Ex Vivo ◽

Chronic Gvhd ◽

Hla Antigens ◽

Median Number ◽

Transfusion Independence ◽

Cd34 Cells ◽

Grade Ii

Abstract Abstract 362 Delayed engraftment and low rates of platelet transfusion independence are frequently observed after CB transplantation (CBT). We conducted a study of ex-vivo co-culture of CB mononuclear cells with either third party haploidentical family member marrow derived MSCs (N=8) or off-the-shelf mesenchymal progenitor cells (MPCs) from Angioblast (N=24). Patients received a double cord blood transplant, with one of the 2 units undergoing ex vivo expansion using this system. MSCs create a microenvironment that promotes expansion and fosters the differentiation of hematopoietic cells. Patients must have had two CB units matched in at least 4/6 HLA antigens, with a minimum of 1×107 TNC/Kg per unit. Method: Diagnoses were AML/MDS (n=21), ALL (n=6), NHL (n=2), CLL (n=2), and HD (n=1). Fourteen patients (44%) were in CR (CR1, n=3, CR2 or more, n=11) and 18 (56%) had active disease at CBT. Preparative regimen: myeloablative fludarabine, melphalan, thiotepa and ATG (n=32), with rituximab in the 4 NHL/CLL cases. GVHD prophylaxis: tacrolimus and MMF. Median weight was 75.2 Kg (range, 15–118) and median age was 35.3 years (2.8-62 years). Donor-recipient HLA matching was 6 of 6 in 5%, 5 of 6 in 28% and 4 of 6 in 67% of the cases, respectively. Ex-vivo EXP: 100 ml of marrow was aspirated from the family donor and MSCs generated in ten T175 flasks, which took ∼21 days (n=8) or one vial of Angioblast MPCs was thawed and expanded to confluence in 10 flasks within 4 days (n=24). The CB unit with the lowest TNC dose was then thawed, divided into 10 fractions, and each placed into 1 flask containing the confluent layers of MSCs in expansion media with SCF, FLT3-ligand, G-CSF and TPO. After 7 days at 37°C, the non-adherent cells were removed from each flask, placed into each of ten one-liter Teflon-coated culture bags (American Fluoroseal) and cultured for an additional 7 days (14 days total), while 50 ml of media/growth factors was added to the flasks to culture the remaining adherent layer during that time period. On day 14 the cells from the bags and the flasks were combined, washed and infused along with a second unmanipulated CB unit. Result: The median number of total nucleated cell (TNC) and CD34+ cells infused/Kg in unmanipulated CB was 2.35 × 107 (range 0.2–8.2) and 0.95 × 105 (range 0–4). The median number of TNC and CD34+ cells infused/Kg after EXP was 5.8 × 107 (range, 0.3–14.4) and 8.7 × 105 (range, 0–93.4). This represented a median expansion of 14-fold (range 1–30) for TNC and 40-fold (range 4–140) for the CD34+ cells. Median time to neutrophil and platelet engraftment was 15 days (range 9–42) and 40 days (range 13–62). There were no toxicities attributable to the EXP cells. Thirty-one (97%) and 26 (81%) of all patients engrafted neutrophils and platelets, respectively. One patient died before engraftment. Thirty and one-hundred day non-relapse mortality is respectively 6% and 19%. Median donor(s) chimerism was 100% in the mononuclear, T lymphocyte and myeloid cell populations. On transplant day+21, EXP unit contributed with a mean of 19% of mononuclear cell, 16% of T cell, and 14% of myeloid chimerism. Subsequently, hematopoiesis was increasingly derived from the unexpanded unit with long-term engraftment provided by the unexpanded unit by six months posttransplant. Acute grade II-IV and III-IV GVHD rate was 50% and 16%; 25% of the grade II-IV GVHDs occurred beyond 100 days, and two patients developed chronic GVHD. With a median follow-up of 9 months, 11 patients are alive; actuarial one-year survival is 40%. Mortality was due to relapse in 26% and non-relapse causes in 74% of patients. Conclusion: MSC-CB Exp is feasible and leads to fast engraftment of neutrophils and platelets, and high-rates of platelet transfusion independence. Disclosures: No relevant conflicts of interest to declare.

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Erlotinib Is Not Effective In Patients (Pts) With JAK-2 V617F Positive Polycythemia Vera

Blood ◽

10.1182/blood.v122.21.1597.1597 ◽

2013 ◽

Vol 122 (21) ◽

pp. 1597-1597

Author(s):

Mohamad Cherry ◽

Mohamad Khawandanah ◽

Zhizhuang Joe Zhao ◽

Samer A Srour ◽

Howard Ozer ◽

...

Keyword(s):

Polycythemia Vera ◽

Conflicts Of Interest ◽

Growth Factor Receptor ◽

Median Number ◽

Preclinical Study ◽

Spleen Size ◽

University Of Oklahoma ◽

Grade 3

Abstract Introduction Erlotinib is an epidermal growth factor receptor small-molecule inhibitor and is FDA approved for the treatment of lung and pancreatic cancers. In preclinical study, in vitro colony culture assays revealed that erlotinib at micro-molar concentrations effectively suppressed the growth and expansion of Polycythemia Vera (PV) hematopoietic progenitor cells while having little effect on normal cells. Several JAK inhibitors are being studied for the management of PV, one of which has been approved for the treatment of myelofibrosis (ruxolitinib). Aim To study the clinical effect of erlotinib in pts diagnosed with JAK2V617F + PV. Methods We conducted a single arm, prospective phase II study at the University of Oklahoma and the Oklahoma City VA hospitals in pts with WHO defined JAK-2 V617F positive PV from June 2010 to August 2012. Appropriate IRB approval was obtained in accordance with Hilsinki declaration. Pts had to be requiring phlebotomy. Toxicity was assessed by treating physicians using NCI version 4. Dose modification for erlotinib was done using label recommendations. Results Five Caucasian pts were enrolled (3 (60%) males, with median age at enrollment of 63 years, range 26-79). Pts had pretreatment median hemoglobin14.4 g/dL (10.4 -19.2 g/dL), median platelet count 511 x109 (424-681 x109), median white blood cell (WBC) 14.4 x109(7.8- 18.3 x109). Three pts had splenomegaly prior to treatment. Median number of prior pharmacologic treatments (hydroxyurea, anagralide or interferon) was 1, range 0-2. Pts were given erlotinib 150 mg orally daily for 16 weeks: responders (phlebotomy free or decrease in spleen size) were allowed to continue a total of 1 year of treatment, while non-responders were taken off the study. Three (60%) patients received therapy for 16 weeks and did not achieve hematological response or improvement in spleen size. Two (40%) pts were taken off the study after 2 doses secondary to severe toxicities (grade 3 colitis in 1 case, and grade 3 facial rash in 1case). No therapy continued beyond 16 weeks (due to toxicity or lack of response). All pts in the study developed rash (grade 1 – 3) and diarrhea (grade 1 – 2). Three pts developed mucositis (see Table 1). No death was observed during the study and follow up period (median follow up was 23 months, range 12-37 months). Study was closed due to lack of efficacy. Conclusions Despite in vitro efficacy of erlotinib as potent inhibitor of JAK-2 activity, erlotinib is not effective in pts with JAK-2 V617F positive PV with poor toxicity profile. Poor accrual was related to potential toxicity of erlotinib compared to alternative treatments in view of lack of clinical efficacy. Disclosures: No relevant conflicts of interest to declare.

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Serum Asymmetric Dimethylarginine (ADMA) Levels Predict Steroid-Refractory Gvhd before Allogeneic Stem Cell Transplantion

Blood ◽

10.1182/blood.v124.21.3908.3908 ◽

2014 ◽

Vol 124 (21) ◽

pp. 3908-3908

Author(s):

Sascha Dietrich ◽

Aleks Radukjovic ◽

Michael Hess ◽

Ute Hegenbart ◽

Anthony D. Ho ◽

...

Keyword(s):

Stem Cell ◽

Endothelial Cell ◽

Risk Score ◽

Conflicts Of Interest ◽

Serum Markers ◽

Steroid Resistance ◽

Increased Risk ◽

Steroid Sensitive ◽

Grade 3 ◽

Steroid Refractory

Abstract Background: Graft-versus-host disease (GvHD) is the major complication of allogeneic stem cell transplantation (alloSCT) and its therapy-resistant form causes significant morbidity and mortality. The pathomechanism of steroid resistance is currently not completely understood, however, endothelial cell dysfunction seems to play an important role. Serum markers indicating endothelial cell distress such as angiopoetin-2 (Ang-2) and nitrates have been demonstrated to predict steroid-refractory GVHD already before alloSCT. In the current study we investigated ADMA, a strong indicator of endothelial dysfunction, as predictor of acute steroid-refractory GVHD. Methods: We performed a retrospective study of 521 patients who were treated by alloSCT between 3/2001-3/2013. Endothelial cell-associated serum markers were correlated with the course of GvHD, non relapse mortality and statin intake. Cut-offs were determined by maximally selected LogRank statistics. Results: During the post transplant period 114 patients developed a steroid-sensitive GvHD grade 1-2, 50 patients a steroid-sensitive GvHD grade 3-4, and 44 patients a steroid-refractory GvHD which had been always grade 3-4 maximum severity. 313 patients had no signs of GvHD. 266 patients were treated with pravastatin since 2010 when statin prophylaxis for cardiovascular long-term toxicity of calcineurin inhibitor immunosuppression was introduced as standard policy in our program. Median follow up of the whole cohort was 47 months. Median age was 53 years (range 17-75). High ADMA levels (>0.6 µM) significantly predicted steroid-refractory GVHD already before alloSCT (p=0.044, HR=3.5, 95% CI 1.1-11.8). In those patients who developed GVHD, high ADMA levels (>0.6 µM) were not only associated with an increased risk of steroid refractoriness, but also translated into increased non-relapse mortality (HR 2.2 CI 1.1-4.8, p=0.049). By multivariate analysis, the association of high ADMA levels with the risk of refractory GVHD remained significant in the whole cohort after adjusting for age, disease specific remission score, donor and conditioning (HR 6.4 CI 1.6-26.2, p=0.009). The ADMA cut-off was used to build a score along with the previously described predictors of GVHD refractoriness pretransplant Ang-2 (cut-off 1µg/ml) and nitrates (cut-off 26.5 µM). Serum levels of above the cut-off were counted as one point and 0-1 points were considered low risk, 2 points intermediate risk and 3 points high risk. The score was capable of separating risk groups of patients with a different likelihood to develop refractory GVHD (p=0.001, Figure 1) already before alloSCT. The highest risk group had also an increased NRM incidence (p= 0.02, Figure 1). Most interestingly, this endothelial risk score completely failed to predict outcome if patients were on statins (p=0.62). Conclusion: High serum ADMA predicts refractory GVHD already prior to alloSCT. Our results support the hypothesis that endothelial damage / vulnerability contribute to refractoriness of acute GVHD. Dept. Medicine V, University of Heidelberg, Germany Figure 1) Endothelial risk score predicts incidence of refractory GVHD before alloSCT. Figure 1). Endothelial risk score predicts incidence of refractory GVHD before alloSCT. Disclosures No relevant conflicts of interest to declare.

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Oral metronomic chemotherapy using cyclophosphamide in metastatic patients (pts) after standard treatment: Results of a randomized phase II trial

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.e13519 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. e13519-e13519

Author(s):

S. Clisant ◽

A. Adenis ◽

E. Dansin ◽

C. Desauw ◽

M. Degardin ◽

...

Keyword(s):

Primary Endpoint ◽

Randomized Study ◽

Sample Size Calculation ◽

Metronomic Chemotherapy ◽

Median Number ◽

Disease Rate ◽

Progression Rate ◽

Severe Toxicity ◽

Eligibility Criteria ◽

Grade 3

e13519 Background: Oral metronomic chemotherapy (OMC) has antiangiogenic properties and megestrol acetate (MA) is an orexigen used to maintain the general condition in critically ill pts. Anecdotal responses have been reported with each treatment. We hypothesized that each treatment offer disease control without significant severe toxicity. Methods: This multi-center-randomized study was aimed to assess the efficacy and tolerance of both treatments. Primary endpoint was stable disease rate at 2 months: 2mSD (RECIST). Main eligibility criteria were as follows: non-breast cancer, pts with progressive disease refractory to standard therapies or without established standard care, ECOG=0–1, neither hypercalcemia nor hypoalbuminemia. Pts were randomized to receive MA 160 mg b.i.d or OMC 50 mg b.i.d until severe toxicity or progression. The sample size calculation was based on Simon Minimax design (α=10%, β =90%, P0=5%, P1=20%). The second stage was allowed because at least 2mSD were seen among 12 first pts. Results: 88 pts were included from 9/2006 to 12/2008 (44 in each arm). Median age was 61 (22–84). Most common primaries were: colorectal cancer (30 pts), soft tissue sarcoma (17), lung cancer (13), head & neck (8) and unknown primaries (4). The median number of previous lines of treatment was 4 (0–10). As of 28 December 2008, 80 pts are assessable for primary endpoint: 6/40 pts (15%) experienced 2mSD in OMC arm whereas 2/40 pts (5%) in MA arm. Three long-lasting SD (6 months +) are currently being observed in 3 pts receiving OMC (2 sarcomas and 1 RCC). No Grade 3 or 4 toxicity was notified. Treatment was discontinued in 1 case because of MA- induced deep venous thrombosis. Conclusions: OMC and MA offer SD in patients with advanced, refractory and progressive tumors, without any significant toxicity. The non-progression rate with OMC (15%) is in a same range of efficacy that was recently reported with new targeted therapy or anti-angiogenic agents administered in such pts. The accrual is now completed, and a longer follow-up is necessary to better analyze the clinical benefit and the prognostic factors. [Table: see text]

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Clinical outcome of taxane-resistant (TR) hormone refractory prostate cancer (HRPC) patients (pts) treated with subsequent chemotherapy (ixabepilone (Ix) or mitoxantrone/prednisone (MP)

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.4558 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 4558-4558 ◽

Cited By ~ 6

Author(s):

A. M. Lin ◽

J. E. Rosenberg ◽

V. K. Weinberg ◽

W. K. Kelly ◽

M. D. Michaelson ◽

...

Keyword(s):

Prostate Cancer ◽

Median Survival ◽

Prospective Trial ◽

Median Number ◽

Epothilone B ◽

Common Grade ◽

Hormone Refractory ◽

Grade 3 ◽

Number Of Cycles ◽

Line Setting

4558 Background: The clinical course of TR HRPC pts has not previously been evaluated in a large, prospective study. No standard treatment exists for this pt population, although MP is frequently used. Ix is an epothilone B analogue with activity against TR cell lines. Methods: Metastatic HRPC pts with disease progression during or within 60 days of stopping T chemotherapy were eligible. In a 2-arm, non-comparative randomized phase II study, pts were assigned to receive either: 1) M 14 mg/m2 IV q3wks and P 5 mg PO BID or 2) I × 35 mg/m2 IV q3wks. Crossover was allowed for progression or toxicity. The study’s primary endpoint was to detect a ≥ 50% PSA decline by Consensus Criteria in at least 25% of 2nd-line pts (H0 = 10%, α = 0.04, β = 0.18 for each arm). Pts were followed for survival. Results: Forty-one evaluable pts each were accrued to Ix and to MP. The median follow-up is 5.0 months (range: 0.3–19.5). The median number of cycles administered to each 2nd-line arm is 3 (range: Ix: 1–8, MP: 1–12). Median survival from protocol entry is 13.0 months with Ix and 12.5 months with MP. Confirmed 2nd-line post-therapy (rx) ≥50% PSA declines were observed in 17% of Ix pts (95% CI = 7–32) and 20% of MP pts (95% CI = 9–35). Of pts with measurable disease, partial responses were observed in 1/18 pts on 2nd-line Ix (6%; 95% CI = 0.1–27.3) and in 1/15 pts on 2nd-line MP (7%; 95% CI = 0.2–31.9). Median duration on 2nd-line Ix and MP was 2.2 months and 2.3 months, respectively. Crossover to 3rd-line rx occurred in 39% of Ix pts and 68% of MP pts. Confirmed 3rd-line post-rx ≥50% PSA declines were observed in 3/24 Ix pts and in 4/13 MP pts. The most common grade 3/4 toxicity associated with 2nd-line rx was neutropenia as previously reported (41% of Ix pts, 54% of MP pts). Conclusions: This prospective trial has characterized TR HRPC pts as having an observed median survival of approximately 1 year. This may be a useful reference for the screening of effective agents in the 2nd-line setting for TR HRPC. Both Ix and MP appear to have only modest activity as 2nd- and 3rd-line rx in this highly selected TR HRPC population. This study was supported by Bristol-Myers Squibb and the Prostate Cancer Foundation. No significant financial relationships to disclose.

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Low-Dose Methotrexate as Salvage Therapy for Refractory Graft-Versus-Host Disease (GVHD) after Reduced-Intensity Conditioning (RIC) for Allogeneic Stem Cell Transplantation (allo-SCT).

Blood ◽

10.1182/blood.v106.11.1802.1802 ◽

2005 ◽

Vol 106 (11) ◽

pp. 1802-1802

Author(s):

Mohamad Mohty ◽

Hugues de Lavallade ◽

Catherine Faucher ◽

Sabine Furst ◽

Jean El-Cheikh ◽

...

Keyword(s):

Side Effects ◽

Salvage Therapy ◽

Low Dose ◽

Acute Gvhd ◽

Chronic Gvhd ◽

High Risk Population ◽

High Morbidity ◽

Dose Methotrexate ◽

Grade 3

Abstract Background. RIC regimens are increasingly used for allo-SCT. Although such regimens are associated with a relatively low early transplant-related mortality (TRM) in comparison to standard myeloablative allo-SCT, GVHD remains a matter of concern. Of note, corticosteroid-resistant GVHD is associated with high morbidity and mortality, and therapeutic options are limited for those patients. Furthermore, patients undergoing RIC allo-SCT are older than patients undergoing myeloablative allo-SCT, and are thus more exposed to the side effects and complications of long term corticosteroids (CS) administration. Low dose methotrexate (MTX) therapy is a well established modality for prophylaxis of GVHD after standard myeloablative allo-SCT. However, little is known about the role of this drug in the treatment of CS-resistant GVHD. Patients and Methods. The aim of this pilot single center study was to investigate the role and benefit of MTX in a curative setting after failure of CS treatment in 20 consecutive patients undergoing RIC allo-SCT. 20 patients experiencing severe GVHD received IV infusions of low dose MTX (5 mg/m2/infusion) at weekly intervals, for at least four weeks. Reasons for MTX administration were: refractory acute GVHD (after at least one week of 2 mg/Kg CS administration), CS-refractory chronic GVHD, chronic GVHD exacerbation after CS taper, or CS side effects and complications (CS-induced diabetes requiring insulin therapy, severe metabolic or psychiatric disorders). Responses to low dose MTX infusions were assessed one month after the last infusion in each involved organ. Results. 12 patients were treated for severe acute GVHD, while 8 patients received MTX for extensive chronic GVHD. Median age of patients was 51 (range, 22–60). Median time of administration of MTX was day +89 (range, 32–300) after allo-SCT. Of note, none of the patients received any other concomitant therapy for refractory GVHD. 13 patients responded to MTX administration (65 %) with 5 complete responses (25%). Among the 12 patients treated for acute GVHD, 7 responded (58%) of whom 5 CRs (42%). 3 patients did not respond and died from resistant GVHD. Interestingly, 5 patients from the group of grade 3–4 acute GVHD responded. Among the 8 patients treated for chronic GVHD, 6 were responders (75%). In addition, MTX allowed a significant reduction of CS daily dosage ranging from 25% to 80%, as assessed one month after the last administration of MTX. With a median follow-up of 287 days, no increase of CS therapy was necessary among these 6 MTX-responding patients. In the whole study population, toxicity of low dose MTX administration was low (transient and mild reversible cytopenia in 3 cases, 15%). Among the 20 patients, 14 are still alive (70%) with a median follow-up of 293 (range, 65–513) days. Overall, 2 patients died of progressive disease, while 4 patients died from refractory GVHD. Conclusions. In this study, the global response rate of severe GVHD to low dose MTX was impressively high (65%) if considered in terms of salvage therapy in this relatively elderly and high risk population. Low dose MTX appears to be a well-tolerated, inexpensive and likely steroid-sparing agent that is worthy of further investigation in prospective trials for treatment of refractory GVHD, but also as frontline therapy in combination with CS.

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Polychemotherapy in Combination with Thalidomide Followed by Autologous or Allogeneic Transplantation for Rescue after Autograft or Induction Therapy Failure in Patients with Multiple Myeloma.

Blood ◽

10.1182/blood.v108.11.3018.3018 ◽

2006 ◽

Vol 108 (11) ◽

pp. 3018-3018

Author(s):

Ute Hegenbart ◽

Stefan O. Schonland ◽

Thomas Moehler ◽

Axel Benner ◽

Sabine Gerull ◽

...

Keyword(s):

Multiple Myeloma ◽

Salvage Therapy ◽

Chronic Gvhd ◽

Allogeneic Transplantation ◽

Disease Recurrence ◽

Median Number ◽

High Dose ◽

Hematopoietic Stem ◽

Total Body ◽

Number Of Cycles

Abstract BACKGROUND: Most patients (pts) undergoing high-dose therapy and autologous transplant for multiple myeloma (MM) develop disease recurrence. The optimal salvage treatment for these patients is not well defined. Autologous (auto-) and allogeneic (allo-) hematopoietic stem cell transplantation (SCT) have been used for salvage therapy. METHODS: We performed a retrospective analysis of pts with MM (n=118) treated in our institution who had failed after 1st-line therapy or relapsed after auto-SCT. Re-induction was performed with TCED (thalidomide, cyclophosphamide, etoposide and dexamethasone, median number of cycles 3). Seventy-four pts (median age, 59 yrs) received auto-SCT as salvage therapy, whereas 44 pts (median age, 53 yrs, p=0.43) underwent a reduced-intensity allo-SCT (related in 23 pts), using conditioning with 2 Gy total body irradiation and fludarabine in 40 pts or melphalan 140 mg/m2 / fludarabine in 4 pts. The majority of the pts (37 / 44) received allo- SCT a median of 59 (range 33–186) days after auto-SCT. Twenty pts in the auto-group and 9 pts in the allo-group were primary progressive, respectively (p=0.42). RESULTS: 89 pts (75%) responded to TCED chemotherapy (CR 4 pts, PR 65 pts, MR 22 pts, SD 13 pts). The number of pts progressing after TCED was equal in both groups (p=0.54). Remission status improved in 30 pts after auto-SCT (7 CR) and in 20 pts after allo-SCT (16 CR, p=0.001). After a median follow-up of 24 months for the auto-group and 21 months for the allo-group since the end of TCED therapy, the median event-free survival (EFS, figure 1) and overall survival (OS, figure 2) were 14 months in both groups (p=0.37) and 27 months versus 35 months (p=0.75), respectively. Incidence of chronic GvHD was 82% (62% extensive). TRM was 20% in the allo-group and differed significantly from the auto-group (1%, p=0.007). Three years after end of TCED 12/44 pts are alive (6 pts in CR) in the allo-group compared to 15/74 pts (1 pt in CR) in the auto-group. All but 1 pt with CR > 3 years after allo-SCT have extensive cGvHD. CONCLUSIONS: Both auto- and allo-SCT are feasible as salvage therapy for MM. Disease recurrence or progression remains the major cause of treatment failure. More CRs and more long term survivors in CR have been observed after allo-SCT confirming the contribution of the GvM-effect. Further concepts are necessary to maintain CR, to prevent relapse or progression and to reduce TRM after allo-SCT. Figure Figure Figure Figure

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Unrelated Umbilical Cord Blood Transplantation for Hematological Malignancies Using Fludarabine/BUCY2 Conditioning Regimen

Blood ◽

10.1182/blood.v118.21.4572.4572 ◽

2011 ◽

Vol 118 (21) ◽

pp. 4572-4572

Author(s):

Zimin Sun ◽

Huilan Liu ◽

Liangquan Geng ◽

Xingbing Wang ◽

Kaiyang Ding ◽

...

Keyword(s):

Cord Blood ◽

Graft Failure ◽

Conflicts Of Interest ◽

Cord Blood Transplantation ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Hematologic Malignancies ◽

Median Number ◽

Myelogenous Leukemia ◽

Blood Transplantation

Abstract Abstract 4572 Cord blood transplantation (CBT) is largely used to treat patients affected by hematological malignant disorders. Myeloablative TBI-based conditioning appears to provide reliable engraftment after CBT for malignancies. However, the toxicity of TBI limits their widespread use. So far, a standard non-TBI based regimen has not been firmly established. In order to overcome graft failure, we investigated a strategy using Fludarabine (FLU)/BUCY2 regimen in CBT for patients with hematologic malignancies. Seventeen patients(children 16, adult 1) with hematologic malignancies who underwent single-unit CBT used a conditioning regimen comprising FLU 120 ‡r/‡u, intravenous busulfan (BU) 12.8‡r/kg and cyclophosphamide (CY)120 mg/kg (FLU/BUCY2). All patients were given a combination of cyclosporine A and mycophenolate mofetil for graft-versus-host disease (GVHD) prophylaxis. Seventeen patients with acute leukemia (n=13), chronic myelogenous leukemia (n=4) were treated, thirteen of whom were high risk diseases and two were advanced-stage at CBT. Seventeen patients with a median age of 8 years (range,2.5–46 years) and a median weight of 32 kg (range, 12–55 kg)received the median number of nucleated cells and CD34+cells infused were 5.70× 107/kg (range: 3.15–9.60×107/kg) and 3.84× 105/kg (range:1.27–5.24 ×105/kg), respectively. The cumulative incidence of primary donor engraftment was 94% (16 patients); one patient had secondary graft failure. Median time to neutrophil≥0.5×109/L was 17 days (range 12–30) and platelet engraftment (≥20×109/L) was 35 days (range 14–56). Preengraftment syndrome (PES) developed in 71% of the patients at a median of 7days (range: 5–13).9 cases developed acute GVHD (56%), more than grade II in three cases. Two of fourteen patients who survived more than 100 days developed chronic GVHD. 12 cases are alive at a median follow-up of 7 months (range 3~ 11).The probability of overall survival at 100 days and 1 year are 88.2% and 67.9%, respectively. Two cases had extramedullary relapsed. Five cases died of severe GVHD (n=3), pulmonary toxicity (n=1) and secondary graft failure (n=1). Preliminary evidence of the small study suggests successful engraftment and decreasing relapse rate following FLU/BUCY2 regimen for CBT in patients with hematologic malignancies. But it had a tendency towards increasing the incidence of GVHD-related morbidity and mortality. Whether this regimen offers a survival benefit for patients with poor-risk leukemia has to be tested in larger prospective trials. Disclosures: No relevant conflicts of interest to declare.

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