scholarly journals Timed Sequential Busulfan and Post-Transplantation Cyclophosphamide in Matched and Haploidentical Transplantation: Results of a Phase II Study

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3373-3373
Author(s):  
Uday Popat ◽  
Rohtesh S. Mehta ◽  
Roland L. Bassett ◽  
Amanda L. Olson ◽  
Julianne Chen ◽  
...  
Keyword(s):  
Phase Ii ◽  
Research Funding ◽  
Phase Ii Study ◽  
Risk Index ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Fixed Dose ◽  
Pharmacokinetic Studies ◽  
Target Area ◽  
Haploidentical Transplantation

Abstract Background: Timed sequential busulfan (TSB) with fludarabine is a promising myeloablative conditioning regimen for patients undergoing matched donor transplantation. Whether this approach can be used for haploidentical transplantation using post-transplant cyclophosphamide (PTCy) GVH prophylaxis is not known. Furthermore, usefulness if any of PTCy GVH prophylaxis in matched donors receiving TSB is also not known. To address these issues, we conducted a prospective phase II study of TSB conditioning regimen with PTCy GvHD prophylxis. Methods: Patients with hematological malignancies and adequate organ function were eligible for this study if they had 8/8 matched related or matched unrelated or a haploidentical related donor. They received a fixed dose of busulfan 80mg/m2 on day -13 and -12. Fludarabine 40mg/m2 was given on day -6 to -2 followed by busulfan dosed to achieve target area under the curve (AUC) of 20,000 μmol-min for the whole course based on pharmacokinetic studies done on day -13 and -6. Thiotepa 5mg/kg was given on day -7 to recipients of haploidentical donor. Graft-versus-host disease (GVHD) prophylaxis included cyclophosphamide 50mg/kg given on day 3 and 4 and tacrolimus. Haploidentical donor recipients and later MUD recipients received mycophenolate mofetil, in addition. Results: Forty five patients with a median age of 48 (15-65) years were enrolled. Twenty four patients had AML or MDS, 9 CML or MPD, 5 Lymphoma, 4 Myeloma and 3 ALL. Donors were matched sibling 11, matched unrelated 18, and haploidentical 16. Disease risk index was high in 13, intermediate in 27, and low in 5 patients. Sixteen patients had comorbidity score of 3 or higher. With a median follow up of 12 months (1-22), 1 year OS, PFS, NRM and relapse rates were 73% (60-88%), 68% (54-84%), 17% (5-29%), and 17% (5-29%) (Table), respectively. There were no graft failures. The median time to neutrophil engraftment was 16 days (13-39), and that of platelets (≥ 20K/µL) was 26 days (11-167). Day 100 grade II-IV and III-IV acute GVHD rates were 42% (27-57%) and 7% (95% CI 0-15%), respectively; 1-year chronic GVHD and extensive chronic GVHD rates were 11% (1-21%) and 8% (0-17%), respectively. One year OS in recipients of matched sib, matched unrelated and haploidentical donor were 89% (71-100%), 66% (45-95%), and 69% (49-96%) respectively and were not significantly different (P=0.31). Conclusion: Timed sequential busulfan with PTCy results in lower incidence of severe acute and chronic gvhd and promising overall survival irrespective of donor source. Disclosures Oran: Celgene: Consultancy, Research Funding; ASTEX: Research Funding; AROG pharmaceuticals: Research Funding. Rezvani:Affirmed GmbH: Research Funding. Shpall:Affirmed GmbH: Research Funding. Champlin:Sanofi: Research Funding; Otsuka: Research Funding.

Post-transplant cyclophosphamide in matched and haploidentical transplant recipients receiving myeloablative timed sequential busulfan conditioning regimen: Results of a phase II study.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 7007-7007
Author(s):  
Uday R. Popat ◽  
Rohtesh S. Mehta ◽  
Roland Bassett ◽  
Amanda Leigh Olson ◽  
Amin Majid Alousi ◽  
...  
Keyword(s):  
Phase Ii ◽  
Disease Risk ◽  
Phase Ii Study ◽  
Risk Index ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Area Under The Curve ◽  
Pharmacokinetic Studies ◽  
Target Area ◽  
Post Transplant

7007 Background: Myeloablative stem cell transplants have a lower rate of relapse than reduced intensity regimens. Timed sequential busulfan (TSB) with fludarabine (Flu) is a promising myeloablative regimen for patients undergoing matched sibling (MSD) or unrelated (MUD) donor transplantation (HCT) with low non-relapse mortality (NRM) (Popat et al Lancet Haematology 2018), but was not tested in haploidentical (haplo). Also, whether this approach can be used with post-transplant cyclophosphamide (PTCy) in MSD, MUD and haplo HCT is unknown. To address these issues, we conducted a prospective phase II study. Methods: Patients with hematological malignancies with MSD, MUD or haplo donor were eligible. They received fixed doses of Busulfan(BU) 80mg/m2 either on day -13 and -12 (n=45) or on -20 and -13 (n=10). Then, Flu 40mg/m2 was given on day -6 to -2 followed by Bu dosed to achieve target area under the curve (AUC) of 20,000 umol/min for the whole course based on pharmacokinetic studies. Thiotepa 5mg/kg was given on day -7 to haplo group. GVHD prophylaxis was PTCy 50mg/kg on day 3 and 4 and tacrolimus. Haplo and later MUD recipients also received mycophenolate mofetil. Results: 55 patients with a median age of 47 (15-65) years were enrolled. 30 patients had AML or MDS, 9 CML or MPD, 5 lymphoma, 5 myeloma and 6 ALL. About half had haplo 26 (47%); others had MUD 18 (33%) or MSD 11(20%). Disease risk index was high in 18 (32%), intermediate in 32 (58%), and low in 5 (9%) patients. Comorbidity score was ≥3 in 22 (40%) patients. With a median follow up of 17 months (5-28), 1-year OS, PFS, NRM and relapse rates were 71% (60-84%), 63% (51-77%), 20% (9-31%), and 17% (7-27%), respectively [Table]. There were no graft failures. Day 100 grade II-IV and III-IV acute GVHD rates were 38% (25-51%) and 9% (95% CI 1-17%), respectively; 1-year chronic GVHD and extensive chronic GVHD rates were 10% (2-28%) and 8% (0-15%), respectively. 1-year OS in MSD, MUD and haplo groups were 91% (75-100%), 72% (54-96%), and 62% (45-83%) respectively (P=0.11). Conclusions: Myeloablative TSB with PTCy is feasible in MSD, MUD and haplo HCT. It lowers the incidence of severe acute and chronic GVHD without apparent increase in relapse. Clinical trial information: NCT02861417. [Table: see text]

scholarly journals Transplantation for Congenital Sideroblastic Anaemia Is Feasible and Offers Outcomes Comparable to Other Transfusion Dependent Anaemias. a Joint Retrospective Study of the Paediatric Diseases and Severe Aplastic Anaemia Working Parties (PDWP/SAAWP) of EBMT

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 45-47
Author(s):  
Josu de la Fuente ◽  
Dirk-Jan Eikema ◽  
Paul Bosman ◽  
Robert F Wynn ◽  
Miguel Díaz ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Board Of Directors ◽  
Research Funding ◽  
Graft Failure ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Response To Treatment ◽  
Variable Response ◽  
Advisory Committees ◽  
Grade Ii

Congenital sideroblastic anaemias (CSA) are a rare group of disorders characterized by the presence of pathologic iron deposits within the mitochondria of erythroid precursors (ring sideroblasts) in the bone marrow due to heterogenous germline mutations leading to defects in mitochondrial heme synthesis, iron-sulfur (Fe-S) cluster biogenesis, or protein synthesis. Patients present with anaemia and relative reticulocytopenia, and systemic iron overload secondary to chronic ineffective erythropoiesis, leading to end-organ damage. The disease is heterogenous underlying the genetic variability and the variable response to treatment. Although a number of CSA patients have received a bone marrow transplant, the outcomes and toxicities are not known. This status makes it very difficult to understand the role of BMT in the management of CSA. A search in the EBMT database identified 28 patients receiving a HSCT for CSA between 1998 to 2018 by 24 participating centres. The median year of transplantation was 2014 (IQR 2004-2016). The distribution was equal between males (n=14) and females (n=14). The median age at transplantation was 7 years of age (3-10 years). Fifteen patients had a sibling HSCT (88%), one a family matched donor HSCT (6%) and one an unrelated matched (6%), the type of transplant being unknown in others (n=11). The source of stem cells was bone marrow in 20 cases (74%), peripheral blood in 4 cases (15%), cord blood in 2 (7%) and combined bone marrow and cord in one (4%). Five cases had a Bu/Cy based conditioning regimen, 4 had Bu/fludarabine based regimen and three fludarabine/treosulfan based conditioning with the rest having a variety of approaches. Eighty-six percent of cases had serotherapy with ATG or alemtuzumab. The median follow-up was 31.6 months (95% CI, 12.2-74.1%). The overall survival at 12 and 24 months was 88% (76-100) and 82% (66-99), respectively (figure 1). The median neutrophil engraftment was 18 (15-21) days and platelet engraftment >20 x 109/L was 29 (20-51) days, with a graft failure incidence of 7% (0-17) at 12 months. Two patients suffered from VOD. There were four deaths, three of which were related to transplant complications. The event free survival (survival without graft failure, relapse and second transplant) at 12 and 24 months was 85% (72-99) (figure 2). Six patients developed acute GvHD grade II and one case grade III; giving a grade II/III incidence of 28% (10-46). There was one case of limited and one of chronic GvHD, giving an incidence of 11% (0-26%) at 12 months and 24 months. In conclusion, whilst HSCT for CSA is a rare occurrence, these data demonstrate that HSCT for this condition is feasible and the outcomes are in keeping with those obtained for transplantation for transfusion dependent anaemias during the same time-period. Disclosures Handgretinger: Amgen: Honoraria. Moraleda:Gilead: Consultancy, Other: Travel Expenses; Jazz Pharmaceuticals: Consultancy, Research Funding; Novartis: Consultancy, Other: Travel Expenses; Sandoz: Consultancy, Other: Travel Expenses; Takeda: Consultancy, Other: Travel Expenses. Risitano:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Alnylam: Research Funding; Alexion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Jazz: Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees; Samsung: Membership on an entity's Board of Directors or advisory committees; Amyndas: Consultancy; RA pharma: Research Funding; Biocryst: Membership on an entity's Board of Directors or advisory committees; Apellis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Achillion: Membership on an entity's Board of Directors or advisory committees; Pfizer: Speakers Bureau. Peffault De Latour:Amgen: Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Apellis: Membership on an entity's Board of Directors or advisory committees; Alexion Pharmaceuticals Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

Allogeneic blood cell transplantation without posttransplant colony-stimulating factors in patients with hematopoietic neoplasm: a phase II study.

1996 ◽  
Vol 14 (4) ◽  
pp. 1314-1319 ◽  
Author(s):  
C Rosenfeld ◽  
R Collins ◽  
L Piñeiro ◽  
E Agura ◽  
J Nemunaitis
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Blood Cell ◽  
Cell Transplantation ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Chronic Gvhd ◽  
Allogeneic Blood ◽  
Platelet Recovery ◽  
Colony Stimulating Factors

PURPOSE There is limited experience with allogeneic blood cell transplantation (BCT). In an earlier pilot study, the combination of bone marrow and blood did not produce severe acute graft-versus-host disease (GVHD). We now report the results of a phase II study using blood stem cells alone in 19 patients. PATIENTS AND METHODS The median age was 40 years. All patients had hematopoietic malignancies and received transplants from HLA-identical sibling donors. GVHD prophylaxis consisted of cyclosporine plus prednisone. Posttransplant colony-stimulating factors were not administered. Donors were mobilized with subcutaneous granulocyte colony-stimulating factor (G-CSF; 16 microg/kg/d) for 5 days. Apheresis was performed on 2 consecutive days. RESULTS The median cell content of the two apheresis was 11.9 x 10(8) WBC/kg, 3.2 x 10(8) CD3/kg, and 8.3 x 10(6) CD34/kg. The median time to achieve an absolute neutrophil count (ANC) > or = 500/microL was 13 days, and 14 days to a platelet count > or = 50,000/microL. All patients engrafted. Platelet recovery was faster in marrow historic control groups. Blood cells in all tested cases contained more than 95% donor cells on day 30. The actuarial incidence of acute GVHD was 37%, and 13% for grade II-IV GVHD. Limited, corticosteroid responsive, chronic GVHD developed in 33% of assessable patients. At a median follow-up of 192 days, actuarial survival was 75%. CONCLUSION Transplantation of a high number of stem cells may lead to rapid engraftment without the use of posttransplant colony-stimulating factors. GVHD does not appear to be more severe than in similarly treated patients undergoing bone marrow transplantation. For allogeneic transplantation, mobilized blood cell collections are an alternative to bone marrow collections.

scholarly journals Treatment of chronic GvHD with mesenchymal stromal cells induces durable responses: A phase II study

2020 ◽  
Vol 9 (10) ◽  
pp. 1190-1202 ◽  
Author(s):  
Erik Boberg ◽  
Lena Bahr ◽  
Gabriel Afram ◽  
Carina Lindström ◽  
Per Ljungman ◽  
...  
Keyword(s):  
Phase Ii ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Phase Ii Study ◽  
Chronic Gvhd

The VcR-CVAD Regimen Produces a High Complete Response Rate in Untreated Mantle Cell Lymphoma (MCL): First Analysis of E1405 – A Phase II Study of VcR-CVAD with Maintenance Rituximab for MCL.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1661-1661 ◽  
Author(s):  
Brad S Kahl ◽  
Hailun Li ◽  
Mitchell R Smith ◽  
Randy D. Gascoyne ◽  
Elisabeth Paietta ◽  
...  
Keyword(s):  
Phase Ii ◽  
Research Funding ◽  
Response Rate ◽  
Complete Response Rate ◽  
Phase Ii Study ◽  
Cell Lymphoma ◽  
Complete Response ◽  
Mantle Cell ◽  
Grade 3

Abstract Abstract 1661 Poster Board I-687 Introduction One approach to improving outcomes in Mantle Cell Lymphoma (MCL) is to incorporate newer targeted agents into standard chemotherapy regimens. As the proteasome inhibitor bortezomib (Velcade‘) achieved a 33% response rate in relapsed MCL, we hypothesized that the incorporation of Velcade (Vc) into a modified R-hyperCVAD chemotherapy backbone would result in a high complete response rate (CR). The new regimen, VcR-CVAD, was tested for safety and efficacy in a phase II study within the Wisconsin Oncology Network (UW) and demonstrated a CR rate of 77% (Kahl, ASH 2008). To determine the safety and efficacy of this regimen in a cooperative group setting, we initiated E1405: a phase II study of VcR-CVAD with maintenance rituximab (MR) for untreated MCL. Methods Eligible patients had histologically confirmed, previously untreated MCL, PS 0-2, and adequate end organ function. The treatment plan included: Velcade 1.3 mg/m2 days 1 and 4, rituximab 375 mg/m2 IV day 1, cyclophosphamide 300 mg/m2 IV over 3 hrs q 12 hrs X 6 doses days 1-3, doxorubicin 50 mg/m2 continuous infusion over 48 hrs days 1-2, vincristine 1 mg IV day 3, dexamethasone 40 mg po days 1-4. Cycles were repeated every 21 days for 6 cycles and all patients received G-CSF support. Patients achieving SD, PR, or CR received MR administered as 4 weekly treatments every 6 months for 2 years (protocol therapy). Patients had an option to receive high dose chemotherapy and autologous stem cell transplantation (off protocol) rather than MR. The primary endpoint of the trial was the CR rate, incorporating PET imaging, to VcR-CVAD induction therapy. Results Seventy-six eligible patients were enrolled between 5/07 and 10/08. Baseline characteristics include median age 62 (40-76), 59M:17F, 91% stage III/IV, and 39% with elevated LDH. Sixty-four patients (84%) completed VcR-CVAD induction therapy. Reasons for treatment discontinuation included PD (1), toxicity (4), patient preference (2), and other/unknown (5). Response information is available on 74 patients while data is outstanding on 2 patients. The ORR was 96% (73/76; 95% CI, 89%-99%), CR rate 75% (57/76; 95% CI, 64%-84%) and the PR rate 21% (16/76; 95% CI, 13%-32%). Six of the PR patients were coded as such because of protocol violations in which a post-treatment bone marrow biopsy or PET scan was not obtained. The CR rate in the 68 completely restaged patients was 84%. Forty-four patients proceeded to planned MR while 21 patients went off protocol to SCT consolidation. Median follow up is currently too short (9 months) to assess PFS and OS. The major toxicity of the treatment regimen was expected myelosuppression. Grade 3-4 non hematologic toxicities were rare. No patients developed grade 3-4 neuropathy. There were no treatment related deaths. Conclusion The VcR-CVAD induction produced high overall response (96%) and CR rate (75%) in a representative MCL patient population treated on a cooperative group protocol. The CR rate was high and comparable to the UW pilot study (77%). No episodes of severe painful peripheral neuropathy were reported using the reduced vincristine dosage and the overall toxicity profile was very acceptable. Longer follow up is needed to determine if the high CR rate will translate into improved PFS and OS. Disclosures Kahl: Genentech: Consultancy, Research Funding; Millennium: Consultancy, Research Funding. Off Label Use: Bortezomib as front line treatment in MCL. Smith:Genentech: Research Funding; Millennium: Research Funding. Advani:Seattle Genetics, Inc.: Research Funding. Horning:Genentech: Honoraria, Research Funding.

Treatment Outcome of Steroid-Refractory Chronic Graft-Versus-Host Disease with Weekly Rituximab Followed by Maintenance Rituximab: a KSBMT Multicenter Phase II Study.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1151-1151
Author(s):  
Seok Jin Kim ◽  
Chang Ki Min ◽  
Jong Wook Lee ◽  
Bin Cho ◽  
Chul Won Jung ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Oral Cavity ◽  
Phase Ii ◽  
Graft Versus Host Disease ◽  
Phase Ii Study ◽  
Chronic Gvhd ◽  
Graft Versus Host ◽  
Steroid Refractory

Abstract Abstract 1151 Poster Board I-173 Introduction The mainstay of treatment for chronic graft-versus-host disease (GVHD) is steroid. However, there is limited treatment option for steroid-refractory chronic GVHD. Although the pathogenesis of chronic GVHD is still uncertain, the possible relation of auto-antibodies with chronic GVHD (Patriarca F, et al. Exp Hematol 389-96, 2006) and the result from a previous pilot study (Cutler C, et al. Blood 756-762, 2006) suggested that a treatment strategy targeting against B cells might become another effective therapy for chronic GVHD. Thus, we performed a study to determine the efficacy of rituximab (Mabthera®, Roche), an anti-CD20 monoclonal chimeric antibody in patients with steroid-refractory chronic GVHD. Patients and methods This is a multicenter, open-labeled prospective phase II study performed by the Korean Society of Blood and Marrow Transplantation (NCT00472225). Patients should be diagnosed as chronic GVHD according to the criteria for clinical trials in chronic GVHD proposed by National Institutes of Health Consensus Development Project (Filipovich AH, et al. Biol Blood Marrow Transplant 945-56, 2005). The steroid-refractoriness was defined as the same severity during the last one month while patients received the equivalent of prednisone ≥0.5mg/kg per day or 1mg/kg every other day at least for 30 days or longer. The treatment schedule consists of induction (rituximab 375mg/m2 weekly IV for 4 consecutive weeks) and maintenance (rituximab 375mg/m2 monthly IV for 4 consecutive months). The response and the quality of life (SF36 questionnaire) were evaluated during the follow-up. Results 37 patients (20 male, 17 female) were evaluated, and their median age was 29 years (range 8-57 years, 7 patients from pediatrics and 30 from internal medicine). The time interval between transplantation and rituximab treatment was from 4.0 to 45.7 months. The most commonly involved organs were skin, oral cavity, eyes and lungs. The average number of involved organ per each patient was three and their average severity was grade 2-3. The median potential follow-up was 12.3 months (95% confidence interval: 12.06-12.54 months). The maximum response during follow-up was as follows: 8 complete response (21.6%), 22 partial response (59.5%), 6 no response (16.2%), and 1 disease progression (2.7%). Thus, the overall response rate was 81.1%. The dosage of steroid was reduced in all responders including complete withdrawal of steroid. The quality of life was improved in terms of physical health and mental/emotional health after treatment. However, 5 responders showed the progression of disease activity during follow-up, and infectious complications were life-threatening, thus, 8 patients died due to infections including pneumonia. The involvement of skin and oral cavity showed better response than the involvement of lungs and eyes. Conclusion The weekly administration of rituximab followed by monthly maintenance rituximab may be an effective treatment for steroid-refractory chronic GVHD, however, the active prophylaxis against infection should be considered. Disclosures No relevant conflicts of interest to declare.

Allogeneic Hematopoietic Cell Transplantation From Combined Haploidentical Family Members and Unrelated Cord Blood (CB) Can Benefit High Risk Patients Lacking HLA-Identical Donors.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3378-3378 ◽  
Author(s):  
Elizabeth Shima Rich ◽  
Andrew Artz ◽  
Theodore Karrison ◽  
Lucy A Godley ◽  
Olatoyosi Odenike ◽  
...  
Keyword(s):  
High Risk ◽  
Cord Blood ◽  
Median Time ◽  
Research Funding ◽  
Hematopoietic Cell Transplantation ◽  
Bone Marrow Cells ◽  
Cord Blood Transplantation ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Blood Transplantation

Abstract Abstract 3378 Poster Board III-266 Introduction: Haploidentical-cord blood transplantation is a promising approach for patients (pts) who lack HLA donors and may improve rates of early engraftment while allowing long term cord blood reconstitution with low rates of GVHD. We enrolled 29 pts (17 AML/MDS, 4 ALL, 3 CML, 4 NHL/HL, 1 severe aplastic anemia) lacking HLA identical donors. The median age was 40 years (range, 4-67), and median weight was 75 kg (range, 14-125). Twenty-two (76%) pts had active disease at time of transplant; 6 had prior autologous transplants. 14 pts were Caucasian; 15 were other race or ethnicity. The haploidentical donor was the mother in 4; father in 3; child in 10; sibling in 10; and half-sibling in 2 cases. The median haploidentical CD34+ dose was 2.51 × 106/kg (range, 1.25-10.95); CD3+ cells were 1.0 × 104/kg (range, 0.3-3.7). Single unrelated CB units were matched by low resolution at HLA-A and B and high-resolution at DRB1, and matched 6/6 in 2 pts; 5/6 in 18 pts; 4/6 in 9 pts. Median cord total nucleated cells equaled 1.93 × 107/kg (range, 1.07-9.36); CD34+ cells were 0.08 × 106/kg (range, 0.03-0.75). The conditioning regimen for 18 pts was fludarabine (Flu) (30 mg/m2 on d-7 through -3), melphalan (Mel) (70 mg/m2 on d -3 and -2), and Thymoglobulin (rATG) (1.5 mg/kg on d-7, -5, -3, -1). Eleven pts received Flu, thiotepa (5 mg/kg on d -7 and -6), total-body irradiation (TBI) (12 Gy lateral opposed fields in 2 Gy fractions BID on d-3 through -1), and rATG. GVHD prophylaxis consisted of tacrolimus (Tac) + methylprednisolone or Tac + mycophenolate. Engraftment: Two pts died early (sepsis, CVA). Three other pts failed to engraft with either haploidentical or CB and died of infection on d36, 43, and 63. One of these had anti-donor HLA antibodies. 24 pts engrafted with a median time to ANC >500/mL of 10 days (range, 9-31) and median time to sustained platelets >20,000/mL of 20 days (range, 15-63). In the majority of pts, early haploidentical engraftment was replaced by durable engraftment of CB by 100 days. However, 3 pts had persistent hematopoiesis associated with only the haploidentical donor, while a fourth pt engrafted with only CB on day 31. Late graft failure and death from sepsis occurred in one of the patients with haploidentical engraftment. In unfractionated peripheral blood or bone marrow cells, median haploidentical chimerism was 95% (range, 0-100) on d14; 76% (range, 0-95) on d30; 6% (range, 0-87) on d100. Median unfractionated cord chimerism was <5% (range, 0-100) on d14; 20% (range, 0-100) on d30; 85% (range, 0-100) on d100. In the CD3+ compartment, median haploidentical chimerism was 95% (range, 0-100) on d14; 86% (range, 0-95) on d30; 6% (range, 0-79) on d100. Median CD3+ cord chimerism was 5% (range, 0-100) on d14; 26% (range, 0-100) on d30; 90% (range, 1-100) on d100. Toxicities and outcome: Other fatal toxicities included VOD (1), EBV-associated PTLD (1), ARDS (1), cardiac arrest (1), intractable seizures (1). Two patients developed TTP and later died of complications related to sepsis. Five pts relapsed of whom 4 have died. Acute GVHD (aGVHD) grade II occurred in 3 pts, one of whom developed the only case of chronic GVHD after failing to continue prograf. No aGVHD grade III-IV was seen. Twelve pts are currently alive; 11 are without disease. The median follow up for survivors is 186 days (range, 16-642). Estimated one year survival is 26% (95%CI, 6-46), and PFS is 19% (1-36). Conclusions: Combined haploidentical and CB transplantation results in early haploidentical engraftment followed by durable CB predominance in a majority of pts. The median times to neutrophil engraftment are considerably shorter - and the range narrower - than with other methods of cord blood transplantation. Early haploidentical engraftment failed in four patients; cord blood engraftment also failed in three of these pts and in three others. Rates of acute and particularly of chronic GVHD are low. Durable remissions can be achieved even in high risk pts regardless of age or remission status at the time of transplant. Disclosures: Rich: Genzyme: Research Funding. Odenike:Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees. van Besien:Genzyme: Research Funding.

Significant Activity of the JAK2 Inhibitor, INCB018424 in Patients with Secondary, Post-Myeloproliferative Disorder (MPD) Acute Myeloid Leukemia (sAML): Results of An Exploratory Phase II Study.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 631-631 ◽  
Author(s):  
Farhad Ravandi ◽  
Srdan Verstovsek ◽  
Zeev Estrov ◽  
Jan A. Burger ◽  
Solly George ◽  
...  
Keyword(s):  
Phase Ii ◽  
Stable Disease ◽  
Research Funding ◽  
Phase Ii Study ◽  
Jak2 V617f ◽  
Jak2 V617f Mutation ◽  
Significant Activity ◽  
Stat Signaling ◽  
V617f Mutation ◽  
Grade 3

Abstract Abstract 631 Background: Mutations of JAK2 gene have been identified in a significant proportion of patients with MPDs with the selective JAK2 inhibitors demonstrating significant activity. Patients with AML following prior MPD (sAML) respond poorly to standard cytotoxic chemotherapy and have a poor outcome. Abnormalities of the Jak-Stat signaling pathway have also been identified in a number of other hematological malignancies; chromosomal translocations resulting in TEL-JAK2 constructs lead to the constitutive activation of STAT5, IL-3-independent cellular proliferation, and leukemogenesis. Similarly, infection with oncogenic viruses such as human T-cell lymphotrophic virus, type I, and Abelson murine leukemia viruses results in enhanced kinase activity of Jaks, possibly accounting for their leukemogenic potential. Furthermore, disrupted Jak-Stat signaling has been reported in a number of leukemias. Aim: To identify potential activity of INCB018424 in patients with advanced hematological cancers. Methods: We are conducting a phase II study of INCB018424 in patients with relapsed/refractory leukemias for which no standard therapies are anticipated to result in a durable remission. Patients with performance status 0,1,and 2 with adequate organ function and no active, uncontrolled intercurrent illness or infection receive INCB018424 orally at 25 mg BID daily for 4 weeks (cycle #1). Response is assessed after 2 cycles of treatment. Responding patients or patients with stable disease are allowed to continue until progression. Predetermined dose modifications to 15 mg or 10 mg BID are allowed for drug related toxicities. Results: Eighteen patients [median age, 68 years; (range, 53-88] with relapsed and refractory leukemias (9 de novo AML, 3 sAML, 2 ALL, 1 MDS, 2 CMML, 1 CML) have been treated. The median number of prior therapies is 2 (range,1 to 6). Five patients (1 with AML, 2 with sAML, and 3 with CMML) had the JAK2 V617F mutation. Cytogenetic abnormalities include diploid in 7, chromosome 5 and 7 in 5, t(2;9) in 1, and the Philadelphia chromosome in 2. Pts have received a median of 1 cycle of therapy (range, 1-5 cycles) with 8 pts having stable disease (3 for 2 cycles, 2 for 3 cycles, 1 for 4 cycles, and 2 for 5 cycles). Three patients (including 2 with sAML and 1 with CMML, all with JAK2 mutation) have had significant declines in their bone marrow blasts (to <5%) associated with significant decrease in the size of the spleen and clinical improvement. The regimen has been very well tolerated with only grade 3 side effects being elevation of liver enzymes in 2 patients (thought not to be related to the study drug) and grade 3 thrombocytopenia in 1 patient. Conclusion: INCB018424 has significant activity in sAML and CMML associated with JAK2 V617F mutation. Clinical studies combining it with chemotherapy in sAML are warranted. Disclosures: Ravandi: Incyte Corporation: Research Funding. Verstovsek:Incyte: Research Funding. Garrett:Incyte Corporation: Employment. Newton:Incyte Corporation: Employment.

A Phase II Expansion Study Of Vorinostat In Combination With Idarubicin and Cytarabine For Patients With Acute Myelogenous Leukemia (AML) With FLT3 Molecular Alterations

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2684-2684 ◽  
Author(s):  
Koichi Takahashi ◽  
Elias Jabbour ◽  
Farhad Ravandi ◽  
Gautam Borthakur ◽  
Jorge E. Cortes ◽  
...  
Keyword(s):  
Phase Ii ◽  
Research Funding ◽  
Response Rate ◽  
De Novo ◽  
Phase Ii Study ◽  
High Response Rate ◽  
Myelogenous Leukemia ◽  
Abnormal Karyotype ◽  
Npm1 Mutation ◽  
Acute Myelogenous

Abstract Background The combination of vorinostat, idarubicin and cytarabine (IA+vorinostat) is associated with high response rate in patients with newly diagnosed acute myelogenous leukemia (AML) or higher-risk myelodysplastic syndromes (MDS) (JCO 2012;30:2204). In that study, presence of FLT3-ITD was associated with 100% overall response rate (ORR) in 11 patients. To confirm the efficacy of this combination, we extended the phase II study to treat 2 additional cohorts: one for patients with newly diagnosed (untreated cohort) and the other with relapsed and refractory (R/R cohort) AML or higher-risk MDS with FLT3 alteration (both ITD and D835 mutation). Methods Patients with the above diagnosis, ages 15 to 65 years, with appropriate organ function (measured cardiac ejection fraction ≥ 50%, serum creatinine ≤ 2 mg/dl, total bilirubin ≤ 2 mg/dl, and GPT/GOT ≤ 2.5 x upper limit of normal) whose eastern cooperative group (ECOG) defined performance status ≤ 2 were eligible for the study. Study treatment comprised of vorinostat 500 mg orally three times a day (days 1 to 3), idarubicin 12 mg/m2 intravenously (IV) daily x 3 days (days 4 to 6), and cytarabine 1.5 g/m2 IV as a continuous infusion daily x 3 - 4 days (days 4 to 7). Patients in remission could be treated with five cycles of consolidation therapy with lower dose combination and up to 12 months of maintenance therapy with single-agent vorinostat. Result Untreated cohort included 26 patients, whereas 13 patients were treated in R/R cohort (total 39 patients). Thirty six patients had de novo AML, 1 had de novo MDS and 2 had therapy-related AML. For the R/R patients, the median number of prior therapies was 3 (range: 1-6). The median age of the entire study group was 49 (range: 19-64) and 17 (44%) were male. Among the patients whose cytogenetic result were available, 20 (51%) patients had normal and 15 (39%) had abnormal karyotype. By Medical Research Council (MRC) criteria, 30 (77%) patients had intermediate risk and 9 (23%) had poor risk karyotype. Thirty three (85%) patients had FLT3-ITD only, 4 (10%) had both FLT3-ITD and D835 mutation, and 2 (5%) had D835 mutation only. Seventeen (44%) patients had NPM1 mutation. In untreated cohort (N = 26), CR and CRp were documented in 21 (80%) and 2 (8%) patients, respectively (ORR = 88%). In R/R cohort (N = 13), overall response (OR) was observed in 4 (30%) patients (CR in 2 [15%] and CRp in 2[15%]). Of those 4 patients who had OR in R/R cohort, 2 patients were refractory to other high-dose cytarabine-based regimen. The median duration of CR or CRp was 9.2 months (range: 0.1-48.4) in untreated cohort and was 2.9 months (range: 1.6-4.7) in R/R cohort. Twelve (46%) patients in the untreated cohort were bridged to stem cell transplant (SCT) while they were in 1st CR. None of the patients in R/R cohort were bridged to SCT. No difference in response was observed in 1) younger (Age < 60) vs. older patients, 2) normal vs. abnormal karyotype, 3) intermediate vs. poor risk cytogenetics by MRC criteria, 4) presence of RAS mutation, 5) presence of NPM1 mutation, or 6) de novo vs. therapy-related disease. The median overall survival (OS) was 21.7 months (95% CI: 8.1-35.3) in the untreated cohort and was 4.9 months (95% CI: 0.1-10.4) in the R/R cohort. Early treatment related mortality (defined by the death within 4 weeks of the induction) was documented in 1 (4%) patient in the untreated cohort and 2 (15%) patients in the R/R cohort. Toxicity profiles were similar to that reported in the original phase II study (JCO 2012;30:2204). Discussion Vorinostat in combination with IA provides high response rate and durable remission in previously untreateed AML or higher risk MDS patients with FLT3 alteration but is less effective in patients with R/R disease. Phase III randomized study of IA+/- vorinostat in previously untreated AML patients is ongoing (SWOG S1203). Disclosures: Off Label Use: vorinostat in MDS and AML. Cortes:Ambit: Research Funding; Astellas: Research Funding; Argo: Research Funding; Novartis: Research Funding.

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