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Veronica R Smith,
Uday Popat,
Stefan Ciurea,
Yago Nieto,
Paolo Anderlini,
Gabriela Rondon,
Amin Alousi,
Muzaffar Qazilbash, Partow Kebriaei,
Issa Khouri,
Marcos de Lima,
Richard Champlin,
Chitra Hosing
[show abstract]
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ABSTRACT: Plerixafor, a recently approved peripheral blood progenitor cell mobilizing agent, is often added to granulocyte-colony stimulating factor (G-CSF) to mobilize peripheral blood progenitor cells in patients with lymphoma or myeloma who cannot mobilize enough CD34+ cells with G-CSF alone to undergo autologous stem cell transplantation. However, data are lacking regarding the feasibility and efficacy of just-in-time plerixafor in combination with chemotherapy and G-CSF. We reviewed the peripheral blood stem cell collection data of 38 consecutive patients with lymphoma (Hodgkin's and non-Hodgkin's) and multiple myeloma who underwent chemomobilization and high-dose G-CSF and just-in-time plerixafor to evaluate the efficacy of this treatment combination. All patients with multiple myeloma and all but 1 patient with lymphoma collected the minimum required number of CD34+ cells to proceed with autologous stem cell transplantation (>2 × 10(6) /kilogram of body weight). The median CD34+ cell dose collected in patients with non-Hodgkin lymphoma was 4.93 × 10(6) /kilogram of body weight. The median CD34+ cell dose collected for patients with multiple myeloma was 8.81 × 10(6) /kilogram of body weight. Plerixafor was well tolerated; no grade 2 or higher non- hematologic toxic effects were observed.
American Journal of Hematology 06/2013; · 4.67 Impact Factor
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Hiroki Torikai,
Andreas Reik,
Frank Soldner,
Edus H Warren,
Carrie Yuen,
Yuanyue Zhou,
Denise L Crossland,
Helen Huls,
Nicholas Littman,
Ziying Zhang,
Scott S Tykodi, Partow Kebriaei,
Dean A Lee,
Jeffrey C Miller,
Edward J Rebar,
Michael C Holmes,
Rudolf Jaenisch,
Richard E Champlin,
Philip D Gregory,
Laurence J N Cooper
[show abstract]
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ABSTRACT: Long-term engraftment of allogeneic cells necessitates eluding immune-mediated rejection which is currently achieved by matching for human leukocyte antigen (HLA) expression, immunosuppression, and/or delivery of donor-derived cells to sanctuary sites. Genetic engineering provides an alternative approach to avoid clearance of cells that are recognized as "non-self" by the recipient. To this end, we developed designer zinc finger nucleases (ZFNs) and employed a "hit-and-run" approach to genetic editing for selective elimination of HLA expression. Electro-transfer of mRNA species coding for these engineered nucleases completely disrupted expression of HLA-A on human T-cells, including CD19-specific T-cells. The HLA-A(neg) T-cell pools can be enriched and evade lysis by HLA-restricted cytotoxic T-cell clones. Recognition by NK-cells of cells that had lost HLA expression was circumvented by enforced expression of non-classical HLA molecules. Furthermore, we demonstrate that ZFNs can eliminate HLA-A expression from embryonic stem cells which broadens the applicability of this strategy beyond infusing HLA-disparate immune cells. These findings establish that clinically-appealing cell types derived from donors with disparate HLA expression can be genetically edited to evade an immune response and provide a foundation whereby cells from one donor can be administered to multiple recipients.
Blood 06/2013; · 9.90 Impact Factor
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Koji Sasaki,
Gary Lu,
Rima M Saliba,
Qaiser Bashir,
Chitra Hosing,
Uday Popat,
Nina Shah,
Simrit Parmar,
Yvonne Dinh,
Sairah Ahmed,
Elizabeth J Shpall, Partow Kebriaei,
Jatin J Shah,
Robert Z Orlowski,
Richard Champlin,
Muzaffar H Qazilbash
[show abstract]
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ABSTRACT: The t(11;14)(q13;q32) is seen in 15-20% patients with multiple myeloma (MM). In general, it is not associated with worse outcome. We studied the impact of t(11;14)(q13;q32) on the outcome of patients with MM who received high-dose chemotherapy followed by an autologous hematopoietic stem cell transplantation (auto-HCT). Eligible patients underwent high-dose chemotherapy followed by auto-HCT at the M.D. Anderson Cancer Center between February 2000 and August 2010, and had conventional cytogenetic (CC) or fluorescent in situ hybridization (FISH) results available prior to auto-HCT (n=993). The cohort is divided into three groups of patients: (1) normal (diploid by CC, and negative by FISH; n=869); (2) t(11;14)(q13;q32) by CC or FISH (n=27); and (3) high-risk (HR) abnormalities by CC or FISH (n=97). Of the 27 patients with t(11;14)(q13;q32), 18 had isolated t(11;14)(q13;q32) while 9 patients had concurrent HR abnormalities. The primary objective was to compare the outcome of patients with t(11;14)(q13;q32) to patients with diploid or HR markers by CC or FISH studies. Median follow up in surviving patients was 37 months. 3-year PFS for normal, t(11;14)(q13;q32) and HR groups were 47%, 27% and 13%, respectively (p=<0.00001). 3-year OS for normal, t(11;14)(q13;q32) and HR groups were 83%, 63% and 34%, respectively (p=<0.00001). On multivariate analyses, t(11;14)(q13;q32) and HR abnormalities by CC or FISH, and relapsed disease at auto-HCT were associated with shorter PFS, while t(11;14)(q13;q32) and HR abnormalities by CC or FISH, β2 microglobulin of >3.5 and relapsed disease at auto-HCT were associated with shorter OS. In conclusion, patients with t(11;14)(q13;q32) had worse outcome than patients with normal CC or FISH, but better than patients with HR markers by CC or FISH studies.
Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 05/2013; · 3.15 Impact Factor
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Hagop Kantarjian,
Deborah Thomas,
Jeffrey Jorgensen, Partow Kebriaei,
Elias Jabbour,
Michael Rytting,
Sergernne York,
Farhad Ravandi,
Rebecca Garris,
Monica Kwari,
Stefan Faderl,
Jorge Cortes,
Richard Champlin,
Susan O'Brien
[show abstract]
[hide abstract]
ABSTRACT: BACKGROUND: CD22 expression occurs in >90% of patients with acute lymphocytic leukemia (ALL). Inotuzumab ozogamicin, a CD22 monoclonal antibody bound to calicheamicin, is active in ALL. METHODS: Patients with refractory-relapsed ALL received treatment with inotuzumab. The first 49 patients received single-dose, intravenous inotuzumab at doses of 1.3 to 1.8 mg/m2 every 3 to 4 weeks. In the next 41 patients, the schedule was modified to inotuzumab weekly at a dose of 0.8 mg/m2 on day 1 and at a dose of 0.5 mg/m2 on days 8 and 15, every 3 to 4 weeks, based on higher in vitro efficacy with more frequent exposure. RESULTS: Ninety patients were treated; 68% were in salvage 2 or beyond. Overall, 17 patients (19%) achieved a complete response (CR), 27 (30%) had a CR with no platelet recovery (CRp), and 8 (9%) had a bone marrow CR (no recovery of counts), for an overall response rate of 58%. Response rates were similar for single-dose and weekly dose inotuzumab (57% vs 59%, respectively). The median survival was 6.2 months overall, 5.0 months with the single-dose schedule, and 7.3 months with the weekly dose schedule. The median survival was 9.2 months for patients in salvage 1 (37% at 1 year), 4.3 months for patients in salvage 2, and 6.6 months for patients in salvage 3 or later. The median remission duration was 7 months. Reversible bilirubin elevation, fever, and hypotension were observed less frequently on the weekly dose. In total, 36 of 90 patients (40%) underwent allogeneic stem cell transplantation. Veno-occlusive disease was noted in 6 of 36 patients after stem cell transplantation (17%), was less frequent after the weekly schedule (7%), and with less alkylators in the preparative regimen. CONCLUSIONS: Inotuzumab single-agent therapy was highly active, safe, and convenient in patients with refractory-relapsed ALL. A weekly dose schedule appeared to be equally effective and less toxic than a single-dose schedule. Cancer 2013;. © 2013 American Cancer Society.
Cancer 04/2013; · 4.77 Impact Factor
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L M Poon,
Amir Hamdi,
Rima Saliba,
Gabriela Rondon,
Celina Ledesma,
Monique Kendrick,
Muzaffar Qazilbash,
Chitra Hosing,
Roy B Jones,
Uday R Popat,
Yago Nieto,
Amin Alousi,
Stefan Ciurea,
Elizabeth J Shpall,
Richard E Champlin, Partow Kebriaei
[show abstract]
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ABSTRACT: For patients with acute lymphoblastic leukemia (ALL) who relapse following allogeneic hematopoietic stem cell transplantation (HSCT), treatment options are limited, and the clinical course and prognostic factors affecting outcome have not been well characterized. We retrospectively analyzed outcomes of 123 adult patients with ALL who relapsed after a first HSCT performed at our center between 1993- 2011. First line salvage included: Second HSCT (n=19), donor lymphocyte infusion (DLI) with or without prior chemotherapy (n=11), radiation therapy (n=6), cytoreductive chemotherapy (n=30), mild chemotherapy (n=27) or palliative care (n=23), with median post relapse overall survival (OS) of 10 months, 6.5 months, 3 months, 4 months, 4 months, and 1 month, respectively. Despite a complete remission (CR) rate of 38% following first line salvage in the treated patients, the OS remained limited with 1- and 2- year OS rates of 17% (13-29) and 10 % (95% CI 6-20), respectively. On univariate analysis, adverse factors for OS included active disease at the time of first HSCT and short time to progression from first HSCT (<6 months). There was no difference in the 6-month survival post-relapse in patients with isolated extra-medullary (EM) relapse (44%) compared with combined EM and bone marrow (BM) relapse (29%), or those with isolated BM relapse (34%) (P =0.8). Our data provides more insight into the disease behavior and treatment outcomes of ALL at relapse following HSCT against which future trials may be compared.
Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 04/2013; · 3.15 Impact Factor
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Ann M Leen,
Catherine M Bollard,
Adam M Mendizabal,
Elizabeth J Shpall,
Paul Szabolcs,
Joseph H Antin,
Neena Kapoor,
Sung-Yun Pai,
Scott D Rowley, Partow Kebriaei,
Bimalangshu R Dey,
Bambi J Grilley,
Adrian P Gee,
Malcolm K Brenner,
Cliona M Rooney,
Helen E Heslop
[show abstract]
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ABSTRACT: Virus-specific T-cell lines could provide useful antiviral prophylaxis and treatment for immune-deficient patients if it were possible to avoid the necessity of generating a separate line for each patient, often on an emergency basis. We prepared a bank of 32 virus-specific lines from individuals with common HLA polymorphisms who were immune to Epstein-Barr virus, cytomegalovirus or adenovirus. Eighteen lines were administered to 50 patients with severe, refractory illness due to infection with one of these viruses after hematopoietic stem cell transplant. The cumulative rates of complete or partial responses at 6 weeks post-infusion were: 74.0% (95% CI: 58.5%-89.5%) for the entire group (n=50), 73.9% (51.2-96.6%) for cytomegalovirus (n=23), 77.8% for adenovirus (n=18), and 66.7% (36.9-96.5%) for Epstein-Barr virus (n=9). Only four responders had a recurrence or progression. There were no immediate infusion-related adverse events, and only two subjects developed de-novo graft-versus-host disease. Despite the disparity between the lines and their recipients, the mean frequency of virus-specific T-cells rose significantly post-infusion, coincident with striking decreases in viral DNA and resolution of clinical symptoms. The use of banked third-party virus-specific T-cells is a feasible and safe approach to rapidly treat severe or intractable viral infections after stem cell transplantation. (www.clinicaltrials.gov - NCT00711035).
Blood 04/2013; · 9.90 Impact Factor
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Meghan Karuturi,
Chitra Hosing,
Michelle Fanale,
L Jeffrey Medeiros,
Amin M Alousi,
Marcos J de Lima,
Muzaffar H Qazilbash, Partow Kebriaei,
Anas Younes,
Issa Khouri,
Borje S Andersson,
Richard Champlin,
Paolo Anderlini,
Uday Popat
[show abstract]
[hide abstract]
ABSTRACT: Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a distinct subtype of Hodgkin lymphoma characterized by unique clinical presentation, histological appearance, and indolent disease course. The recurrent nature of disease provides an opportunity to examine the role of stem cell transplant in its management. We report here a single center experience of 26 patients with relapsed NLPHL treated with high-dose chemotherapy and autologous stem cell transplantation between 1990 and 2008. With a median follow up of 50 months (range, 2-138 months), the 5-year overall (OS) and event-free survival (EFS) were 76% (SE 9%) and 69% (SE 10%), respectively. Our data suggests that the high-dose chemotherapy and autologous transplantation should be considered as an option for patients with relapsed NLPHL.
Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 03/2013; · 3.15 Impact Factor
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Sourindra N Maiti,
Helen Huls,
Harjeet Singh,
Margaret Dawson,
Matthew Figliola,
Simon Olivares,
Pullavathi Rao,
Yi Jue Zhao,
Asha Multani,
Ge Yang,
Ling Zhang,
Denise Crossland,
Sonny Ang,
Hiroki Torikai,
Brian Rabinovich,
Dean A Lee, Partow Kebriaei,
Perry Hackett,
Richard E Champlin,
Laurence J N Cooper
[show abstract]
[hide abstract]
ABSTRACT: The Sleeping Beauty (SB) transposon/transposase DNA plasmid system is used to genetically modify cells for long-term transgene expression. We adapted the SB system for human application and generated T cells expressing a chimeric antigen receptor (CAR) specific for CD19. Electrotransfer of CD19-specific SB DNA plasmids in peripheral blood mononuclear cells and propagation on CD19 artificial antigen presenting cells was used to numerically expand CD3 T cells expressing CAR. By day 28 of coculture, >90% of expanded CD3 T cells expressed CAR. CAR T cells specifically killed CD19 target cells and consisted of subsets expressing biomarkers consistent with central memory, effector memory, and effector phenotypes. CAR T cells contracted numerically in the absence of the CD19 antigen, did not express SB11 transposase, and maintained a polyclonal TCR Vα and TCR Vβ repertoire. Quantitative fluorescence in situ hybridization revealed that CAR T cells preserved the telomere length. Quantitative polymerase chain reaction and fluorescence in situ hybridization showed CAR transposon integrated on average once per T-cell genome. CAR T cells in peripheral blood can be detected by quantitative polymerase chain reaction at a sensitivity of 0.01%. These findings lay the groundwork as the basis of our first-in-human clinical trials of the nonviral SB system for the investigational treatment of CD19 B-cell malignancies (currently under 3 INDs: 14193, 14577, and 14739).
Journal of immunotherapy (Hagerstown, Md.: 1997) 01/2013; · 3.20 Impact Factor
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Fleur M Aung,
Benjamin Lichtiger,
Roland Bassett,
Ping Liu,
Amin Alousi,
Qaiser Bashier,
Stefan O Ciurea,
Marcos J de Lima,
Chitra Hosing, Partow Kebriaei,
Yago Nieto,
Betul Oran,
Simrit Parmar,
Muzaffar Qazilbash,
Nina Shah,
Issa Khouri,
Richard E Champlin,
Uday Popat
[show abstract]
[hide abstract]
ABSTRACT: Major ABO mismatching is not considered a contraindication to allogeneic haematopoietic stem cell transplantation (HSCT). Modern reduced-intensity conditioning and reduced-toxicity regimens cause much less myeloablation than conventional myeloablative regimens, such as cyclophosphamide with busulfan or total body irradiation, which may affect the incidence of pure red cell aplasia (PRCA). We estimated the incidence and described the natural history of PRCA in patients with major ABO-mismatched donor stem cells. Between 2007 and 2008, 161 (27% of all patients undergoing HSCT) underwent allogeneic HSCT with major ABO-mismatched stem cells and 12 (7·5%) of these patients developed PRCA. Thirty and ninety day T-cell and myeloid cell chimerism and neutrophil and platelet engraftment did not differ between patients who developed PRCA and those who did not. The only risk factor associated with PRCA was the use of a fludarabine/busulfan conditioning regimen. All patients with PRCA needed red cell transfusion for several months after HSCT resulting in significant iron overload. Pure red cell aplasia resolved spontaneously in the majority (seven patients) but only resolved after stopping tacrolimus in three patients. Hence, after major ABO-mismatched HSCT, the incidence of PRCA was 7·5% and it resolved spontaneously or after withdrawal of immunosuppression in the majority of patients.
British Journal of Haematology 01/2013; · 4.94 Impact Factor
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Partow Kebriaei,
Kaci Wilhelm,
Farhad Ravandi,
Mark Brandt,
Marcos de Lima,
Stefan Ciurea,
Laura Worth,
Susan O'Brien,
Deborah Thomas,
Richard E Champlin,
Hagop Kantarjian
[show abstract]
[hide abstract]
ABSTRACT: BACKGROUND: No highly effective salvage therapy exists for patients with relapsed acute lymphoblastic leukemia (ALL). Inotuzumab ozogamicin (IO) is a CD22 monoclonal antibody attached to calicheamycin that targets B lymphocytes in early stages of development, successfully inducing remission in patients with multiply relapsed ALL. METHODS: We describe our findings in 26 patients who received allogeneic hematopoietic stem cell transplantation (SCT) after treatment with IO between September 2010 and October 2011. RESULTS: Patients with a median age of 33 years (range, 5-70 years) received an allogeneic matched sibling donor (n = 9), matched- or 1-antigen mismatched unrelated donor (n = 16), or cord blood donor SCT (n = 1) while in complete remission (n = 23) or with active disease (n = 3). At the time of SCT, 15 patients were in complete remission without evidence of minimal residual disease (MRD) measured by multiparameter flow cytometry. Patients were heavily pretreated, including 5 patients who had received previous allogeneic SCT. Patients received a median of 3 courses of IO (range, 1-5 courses) before SCT. Seven patients are alive at a median follow-up of 13 months (range, 5-16 months), with 1-year event-free and overall survival (OS) of 22% and 20%, respectively. Patients without MRD at time of SCT had a markedly better 1-year OS of 42%. The cumulative incidence of nonrelapse mortality (NRM) at 6 months and 1 year were 40% and 60%, respectively, with 5 deaths attributed to venoocclusive disease (VOD). CONCLUSIONS: Treatment with IO allows more patients to undergo transplantation while in remission, with favorable overall survival in patients without MRD who undergo transplantation. Reduction in hepatic toxicity is needed to improve overall results.
Clinical lymphoma, myeloma & leukemia 01/2013;
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ABSTRACT: The potency of clinical-grade T cells can be improved by combining gene therapy with immunotherapy to engineer a biologic product with the potential for superior (i) recognition of tumor-associated antigens (TAAs), (ii) persistence after infusion, (iii) potential for migration to tumor sites, and (iv) ability to recycle effector functions within the tumor microenvironment. Most approaches to genetic manipulation of T cells engineered for human application have used retrovirus and lentivirus for the stable expression of CAR(1-3). This approach, although compliant with current good manufacturing practice (GMP), can be expensive as it relies on the manufacture and release of clinical-grade recombinant virus from a limited number of production facilities. The electro-transfer of nonviral plasmids is an appealing alternative to transduction since DNA species can be produced to clinical grade at approximately 1/10(th) the cost of recombinant GMP-grade virus. To improve the efficiency of integration we adapted Sleeping Beauty (SB) transposon and transposase for human application(4-8). Our SB system uses two DNA plasmids that consist of a transposon coding for a gene of interest (e.g. 2(nd) generation CD19-specific CAR transgene, designated CD19RCD28) and a transposase (e.g. SB11) which inserts the transgene into TA dinucleotide repeats(9-11). To generate clinically-sufficient numbers of genetically modified T cells we use K562-derived artificial antigen presenting cells (aAPC) (clone #4) modified to express a TAA (e.g. CD19) as well as the T cell costimulatory molecules CD86, CD137L, a membrane-bound version of interleukin (IL)-15 (peptide fused to modified IgG4 Fc region) and CD64 (Fc-γ receptor 1) for the loading of monoclonal antibodies (mAb)(12). In this report, we demonstrate the procedures that can be undertaken in compliance with cGMP to generate CD19-specific CAR(+) T cells suitable for human application. This was achieved by the synchronous electro-transfer of two DNA plasmids, a SB transposon (CD19RCD28) and a SB transposase (SB11) followed by retrieval of stable integrants by the every-7-day additions (stimulation cycle) of γ-irradiated aAPC (clone #4) in the presence of soluble recombinant human IL-2 and IL-21(13). Typically 4 cycles (28 days of continuous culture) are undertaken to generate clinically-appealing numbers of T cells that stably express the CAR. This methodology to manufacturing clinical-grade CD19-specific T cells can be applied to T cells derived from peripheral blood (PB) or umbilical cord blood (UCB). Furthermore, this approach can be harnessed to generate T cells to diverse tumor types by pairing the specificity of the introduced CAR with expression of the TAA, recognized by the CAR, on the aAPC.
Journal of Visualized Experiments 01/2013;
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Harjeet Singh,
Matthew J Figliola,
Margaret J Dawson,
Simon Olivares,
Ling Zhang,
Ge Yang,
Sourindra Maiti,
Pallavi Manuri,
Vladimir Senyukov,
Bipulendu Jena, Partow Kebriaei,
Richard E Champlin,
Helen Huls,
Laurence J N Cooper
[show abstract]
[hide abstract]
ABSTRACT: Adoptive transfer of T cells expressing a CD19-specific chimeric antigen receptor (CAR) is being evaluated in multiple clinical trials. Our current approach to adoptive immunotherapy is based on a second generation CAR (designated CD19RCD28) that signals through a CD28 and CD3-ζ endodomain. T cells are electroporated with DNA plasmids from the Sleeping Beauty (SB) transposon/transposase system to express this CAR. Stable integrants of genetically modified T cells can then be retrieved when co-cultured with designer artificial antigen presenting cells (aAPC) in the presence of interleukin (IL)-2 and 21. Here, we reveal how the platform technologies of SB-mediated transposition and CAR-dependent propagation on aAPC were adapted for human application. Indeed, we have initiated clinical trials in patients with high-risk B-lineage malignancies undergoing autologous and allogeneic hematopoietic stem-cell transplantation (HSCT). We describe the process to manufacture clinical grade CD19-specific T cells derived from healthy donors. Three validation runs were completed in compliance with current good manufacturing practice for Phase I/II trials demonstrating that by 28 days of co-culture on γ-irradiated aAPC ∼10(10) T cells were produced of which >95% expressed CAR. These genetically modified and propagated T cells met all quality control testing and release criteria in support of infusion.
PLoS ONE 01/2013; 8(5):e64138. · 4.09 Impact Factor
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Marcos de Lima,
Ian McNiece,
Simon N Robinson,
Mark Munsell,
Mary Eapen,
Mary Horowitz,
Amin Alousi,
Rima Saliba,
John D McMannis,
Indreshpal Kaur, [......],
Laurence J N Cooper,
Laura Worth,
Muzaffar H Qazilbash,
Martin Korbling,
Gabriela Rondon,
Stefan Ciurea,
Doyle Bosque,
Ila Maewal,
Paul J Simmons,
Elizabeth J Shpall
[show abstract]
[hide abstract]
ABSTRACT: Background Poor engraftment due to low cell doses restricts the usefulness of umbilical-cord-blood transplantation. We hypothesized that engraftment would be improved by transplanting cord blood that was expanded ex vivo with mesenchymal stromal cells. Methods We studied engraftment results in 31 adults with hematologic cancers who received transplants of 2 cord-blood units, 1 of which contained cord blood that was expanded ex vivo in cocultures with allogeneic mesenchymal stromal cells. The results in these patients were compared with those in 80 historical controls who received 2 units of unmanipulated cord blood. Results Coculture with mesenchymal stromal cells led to an expansion of total nucleated cells by a median factor of 12.2 and of CD34+ cells by a median factor of 30.1. With transplantation of 1 unit each of expanded and unmanipulated cord blood, patients received a median of 8.34×10(7) total nucleated cells per kilogram of body weight and 1.81×10(6) CD34+ cells per kilogram - doses higher than in our previous transplantations of 2 units of unmanipulated cord blood. In patients in whom engraftment occurred, the median time to neutrophil engraftment was 15 days in the recipients of expanded cord blood, as compared with 24 days in controls who received unmanipulated cord blood only (P<0.001); the median time to platelet engraftment was 42 days and 49 days, respectively (P=0.03). On day 26, the cumulative incidence of neutrophil engraftment was 88% with expansion versus 53% without expansion (P<0.001); on day 60, the cumulative incidence of platelet engraftment was 71% and 31%, respectively (P<0.001). Conclusions Transplantation of cord-blood cells expanded with mesenchymal stromal cells appeared to be safe and effective. Expanded cord blood in combination with unmanipulated cord blood significantly improved engraftment, as compared with unmanipulated cord blood only. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT00498316 .).
New England Journal of Medicine 12/2012; 367(24):2305-2315. · 53.30 Impact Factor
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[show abstract]
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ABSTRACT: Adoptive transfer of antigen-specific T cells has been adapted by investigators for treatment of chronic lymphocytic leukemia (CLL). To overcome issues of immune tolerance which limits the endogenous adaptive immune response to tumor-associated antigens (TAAs), robust systems for the genetic modification and characterization of T cells expressing chimeric antigen receptors (CARs) to redirect specificity have been produced. Refinements with regards to persistence and trafficking of the genetically modified T cells are underway to help improve potency. Clinical trials utilizing this technology demonstrate feasibility, and increasingly, these early-phase trials are demonstrating impressive anti-tumor effects, particularly for CLL patients, paving the way for multi-center trials to establish the efficacy of CAR(+) T cell therapy.
Current Hematologic Malignancy Reports 12/2012;
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Yago Nieto,
Uday Popat,
Paolo Anderlini,
Ben Valdez,
Borje Andersson,
Ping Liu,
Chitra Hosing,
Elizabeth J Shpall,
Amin Alousi, Partow Kebriaei,
Muzaffar Qazilbash,
Simrit Parmar,
Qaiser Bashir,
Nina Shah,
Issa Khouri,
Gabriela Rondon,
Richard Champlin,
Roy B Jones
[show abstract]
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ABSTRACT: More active high-dose chemotherapy (HDC) regimens are needed for refractory Hodgkin's lymphoma (HL). We report a cohort analysis of 180 consecutive patients with primary refractory or poor-risk relapsed HL treated with busulfan/melphalan (N=39), gemcitabine/busulfan/melphalan (N=84) or BEAM (N=57) between 2005 and 2010. Their pre-HDC positron emission tomography (PET) scans were interpreted prospectively. Despite more prevalent poor-risk features in the gemcitabine/busulfan/melphalan cohort, such as PET-positive tumors at HDC, tumors growing at HDC, extranodal disease or bulky tumors at prior relapse, this cohort had improved outcomes compared to the busulfan/melphalan and BEAM cohorts, with EFS of 57%, 33% and 39%, respectively (P=0.01), at median follow-up of the whole population of 36 months (range, 3-72). Their respective OS rates were 82%, 52% and 59% (P=0.04). Secondary AML was seen in 5 patients after BEAM, versus none in the Gem/Bu/Mel and Bu/Mel cohorts (P=0.004). Multivariate analyses showed independent adverse effects of a HDC regimen different from gemcitabine/busulfan/melphalan (hazard ratio (HR) for EFS=2.3, P=0.0008; HR for OS=2.7, P=0.0005), positive PET at HDC (HR for EFS=2.2, P=0.004, HR for OS=3.1, P=0.0001) and >1 previous salvage line (HR for EFS=1.9, P=0.008, HR for OS =1.8, P=0.07). Gemcitabine/busulfan/melphalan improved outcomes in this cohort analysis of patients with refractory/poor-risk relapsed HL and merits evaluation in randomized phase III trials.
Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 11/2012; · 3.15 Impact Factor
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Betul Oran,
Uday Popat,
Gabriella Rondon,
Farhad Ravandi,
Guillermo Garcia-Manero,
Lynn Abruzzo,
Borje S Andersson,
Qaiser Bashir,
Julianne Chen, Partow Kebriaei,
Issa F Khouri,
Ebru Koca,
Muzaffar H Qazilbash,
Richard Champlin,
Marcos de Lima
[show abstract]
[hide abstract]
ABSTRACT: Risk stratification is important to identify patients with acute myelogenous leukemia (AML) who might benefit from allogeneic hematopoietic stem cell transplantation (allo-HSCT) in first complete remission. We retrospectively studied 150 patients with AML and diagnostic cytogenetic abnormalities who underwent myeloablative allo-HSCT while in first complete remission to evaluate the prognostic impact of persistent cytogenetic abnormalities at allo-HSCT. Three risk groups were identified. Patients with favorable/intermediate cytogenetics at diagnosis (n = 49) and patients with unfavorable cytogenetics at diagnosis but without a persistent abnormal clone at allo-HSCT (n = 83) had a similar 3-year leukemia-free survival of 58%-60% despite the higher 3-year relapse incidence (RI) in the latter group (32.3%, versus 16.8% in the former group). A third group of patients with unfavorable cytogenetics at diagnosis and a persistent abnormal clone at allo-HSCT (n = 15) had the worst prognosis, with a 3-year RI of 57.5% and 3-year leukemia-free survival of only 29.2%. These data suggest that patients with AML and unfavorable cytogenetics at diagnosis and a persistent abnormal clone at allo-HSCT are at high risk for relapse after allo-HSCT. These patients should be considered for clinical trials designed to optimize conditioning regimens and/or to use preemptive strategies in the posttransplantion setting aimed at decreasing RI.
Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 09/2012; · 3.15 Impact Factor
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Stefan O Ciurea,
Victor Mulanovich,
Rima M Saliba,
Ulas D Bayraktar,
Ying Jiang,
Roland Bassett,
Sa A Wang,
Marina Konopleva,
Marcelo Fernandez-Vina,
Nivia Montes, [......],
Muzaffar Qazilbash,
Simrit Parmar,
Elizabeth Shpall,
Yago Nieto,
Chitra Hosing, Partow Kebriaei,
Issa Khouri,
Uday Popat,
Marcos de Lima,
Richard E Champlin
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ABSTRACT: Haploidentical stem cell transplantation (SCT) has been generally performed using a T cell depleted (TCD) graft; however, a high rate of nonrelapse mortality (NRM) has been reported, particularly in adult patients. We hypothesized that using a T cell replete (TCR) graft followed by effective posttransplantation immunosuppressive therapy would reduce NRM and improve outcomes. We analyzed 65 consecutive adult patients with hematologic malignancies who received TCR (N = 32) or TCD (N = 33) haploidentical transplants. All patients received a preparative regimen consisting of melphalan, fludarabine, and thiotepa. The TCR group received posttransplantation treatment with cyclophosphamide (Cy), tacrolimus (Tac), and mycophenolate mofetil (MMF). Patients with TCD received antithymocyte globulin followed by infusion of CD34+ selected cells with no posttransplantation immunosuppression. The majority of patients in each group had active disease at the time of transplantation. Outcomes are reported for the TCR and TCD recipients, respectively. Engraftment was achieved in 94% versus 81% (P = NS). NRM at 1 year was 16% versus 42% (P = .02). Actuarial overall survival (OS) and progression-free survival (PFS) rates at 1 year posttransplantation were 64% versus 30% (P = .02) and 50% versus 21% (P = .02). The cumulative incidence of grade II-IV acute graft-versus-host disease (aGVHD) was 20% versus 11% (P = .20), and chronic GVHD (cGVHD) 7% versus 18% (P = .03). Improved reconstitution of T cell subsets and a lower rate of infection were observed in the TCR group. These results indicate that a TCR graft followed by effective control of GVHD posttransplantation may lower NRM and improve survival after haploidentical SCT.
Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 07/2012; · 3.15 Impact Factor
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Issa F Khouri,
Rima M Saliba,
William D Erwin,
Barry I Samuels,
Martin Korbling,
L Jeffrey Medeiros,
Rosamar Valverde,
Amin M Alousi,
Paolo Anderlini,
Qaiser Bashir, [......],
Alison M Gulbis,
Marcos de Lima,
Chitra Hosing, Partow Kebriaei,
Uday R Popat,
Nathan Fowler,
Sattva S Neelapu,
Felipe Samaniego,
Richard E Champlin,
Homer A Macapinlac
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ABSTRACT: In 2008, we reported favorable 5-year outcomes of nonmyeloablative allogeneic stem cell transplantation after fludarabine, cyclophosphamide, rituximab (FCR) conditioning for relapsed and chemosensitive follicular lymphoma. However, innovative strategies were still needed to treat patients with chemorefractory disease. We therefore subsequently performed a trial in which (90)Y-ibritumomab tiuxetan (0.4 mCi/kg) was added to the fludarabine, cyclophosphamide conditioning regimen ((90)YFC). Here, we report updated results of the FCR trial and outcomes after (90)YFC. For the FCR group (N = 47), since the last update, one patient developed recurrent disease. With a median follow-up of 107 months (range, 72-142 months), the 11-year overall survival and progression-free survival rates were 78%, and 72%, respectively. For the (90)YFC group (N = 26), more patients had chemorefractory disease than did those in the FCR group (38% and 0%, P < .001). With a median follow-up of 33 months (range,17-94 months), the 3-year progression-free survival rates for patients with chemorefractory and chemosensitive disease were 80% and 87%, respectively (P = .7). The low frequency of relapse observed after a long follow-up interval of 9 years in the FCR group suggests that these patients are cured of their disease. The addition of (90)Y to the conditioning regimen appears to be effective in patients with chemorefractory disease. This trial was registered at www.clinicaltrials.gov as NCT00048737.
Blood 05/2012; 119(26):6373-8. · 9.90 Impact Factor
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Hiroki Torikai,
Andreas Reik,
Pei-Qi Liu,
Yuanyue Zhou,
Ling Zhang,
Sourindra Maiti,
Helen Huls,
Jeffrey C Miller, Partow Kebriaei,
Brian Rabinovitch,
Dean A Lee,
Richard E Champlin,
Chiara Bonini,
Luigi Naldini,
Edward J Rebar,
Philip D Gregory,
Michael C Holmes,
Laurence J N Cooper
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ABSTRACT: Clinical-grade T cells are genetically modified ex vivo to express a chimeric antigen receptor (CAR) to redirect specificity to a tumor associated antigen (TAA) thereby conferring antitumor activity in vivo. T cells expressing a CD19-specific CAR recognize B-cell malignancies in multiple recipients independent of major histocompatibility complex (MHC) because the specificity domains are cloned from the variable chains of a CD19 monoclonal antibody. We now report a major step toward eliminating the need to generate patient-specific T cells by generating universal allogeneic TAA-specific T cells from one donor that might be administered to multiple recipients. This was achieved by genetically editing CD19-specific CAR(+) T cells to eliminate expression of the endogenous αβ T-cell receptor (TCR) to prevent a graft-versus-host response without compromising CAR-dependent effector functions. Genetically modified T cells were generated using the Sleeping Beauty system to stably introduce the CD19-specific CAR with subsequent permanent deletion of α or β TCR chains with designer zinc finger nucleases. We show that these engineered T cells display the expected property of having redirected specificity for CD19 without responding to TCR stimulation. CAR(+)TCR(neg) T cells of this type may potentially have efficacy as an off-the-shelf therapy for investigational treatment of B-lineage malignancies.
Blood 04/2012; 119(24):5697-705. · 9.90 Impact Factor
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ABSTRACT: Allogeneic hematopoietic stem cell transplantation (alloHSCT) is an effective post-remission therapy in patients with acute lymphoblastic leukemia (ALL), but is associated with significant toxicity, so the optimal timing and use of this modality remains an issue of debate. Increased advances in reduced-intensity transplant preparative regimens and alternative donors has increased the accessibility of allogeneic transplantation. A risk adapted paradigm, using minimal residual disease analysis, may help in the selection of patients at highest risk for relapse, who may benefit most from alloHSCT. In this review, we summarize the indications for allogeneic transplantation within the risk-oriented paradigm, and also explore the latest literature on reduced intensity transplant regimens, as well as alternative donor transplantation for patients with ALL.
Current Hematologic Malignancy Reports 03/2012; 7(2):144-52.
